Renal normothermic perfusion is a near physiological perfusion of the kidneys under basal metabolic rate to preserve the metabolic function of the organ….It is considered better than static or cold hypothermic perfusion storage in terms of reducing the reactive oxygen species and preserving organ perfusion….At normal temperature, cellular metabolism is restored and ATP synthesis is restored…In addition to providing the cellular metabolism at room temperature, it also helps in providing nutrients and assessing the viability of kidneys by allowing biomarkers estimation
Organs from ECD or DCD donors are not being utilized for transplant because of the poor quality and there is still higher incidence of delayed graft function, primary non functioning of the graft which all contribute to poor prognosis of the transplant….
The components of Renal normothermic perfusion are
Perfusate – The composition of the perfusate is critical to provide oxygenation of tissues and it depends on the need i.e to assess viability or nutrient supplementation…. Most of the protocols use RBC to provide tissue oxygenation….Cambridge protocol uses Ringer lactate.. The Toronto group uses Ringer’s solution and STEEN solution for perfusion..MePEP protocol which uses human albumin and electrolytes….Buffers like sodium bicarbonate, dextran, gluconate are added….Antibiotics lie cefuroxime can be added…Heparin, dexamethasone are other additives…Till date no studies have investigated the value of individual perfusate or there is no ideal perfusate for renal normothermic perfusion…
Arterial pressure: Many debates are there about whether to do pulsatile or a non pulsatile flow and whether to use roller pumps or centrifugal pumps…Centrifugal pumps are used as there is a less chance of hemolysis during continuous perfusion…When there is continuous pressure MAP – 40-95 mm of Hg…There is a recommendation of 90/70 mm when there is pulsatile flow
Oxygen is provided though carbogen (95% o2 and 5% co2) ad Po2 is around 550 mm of Hg
Typically the temperature is set at 37 degree Celsius..It has been shown by studies that organ perfusion with temperature at 37, has better preservation of tubular function….Other studies also recommend gradual re warming instead of sudden warming…Controlled oxygenation re warming also enhances cortical micro circulation
Urine recirculation: The loss of fluid through the urine production from ex vivo perfusion of kidney needs to be replaced by colloids or RL…There have been studies to show that urine can be safely re circulated to maintain the volume during re circulation…
The urine/perfusate levels of many molecules have been tested in various pre clinical studies and they show that it their levels correlate with delayed graft function…However more evidence is needed till these translate into evidence….
The optimal time to start NMP is debatable and it depends on the aim of whether we need to perfuse or assess the viabilityA period of initial Cold storage and then NMP will negate all the microcirculatory damage associated with cold storage…There are many reports of using NMP initially and then later…
Theepa Mariamutu
2 years ago
Renal Normothermic Machine perfusion provides near physiological organ preservation technique as it perfuses warm solution through renal vasculature containing oxygen and nutrients.
can be used for organ preservation, viability assessment and for pretransplant repair of donor organ.
A significant number of organs from ECD are being discarded, this NMP technique can be used for pretransplant organ viability and quality assessment.
uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrients enriched perfusate through-out the NMP period.
The different fundamental facets of NMP :
Perfusate Composition
NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
recent preclinical research suggests that synthetic oxygen carriers can be used instead of RBCs with equal efficacy
Arterial Pressure Delivered By The Pump
There is no consensus about the optimal perfusion pressure use during NMP, whether it should be used in pulsatile or non-pulsatile fashion or whether centrifugal or roller pump should be used.
Preclinical studies are in favour of pulsatile perfusion with perfusion pressure should be maintained at MAP of 75 to 90 mmHg.
The centrifugal pump is better than roller pump as there is less damage to RBCs with centrifugal pump.
Oxygenation
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. However, hyperoxia can induce production of reactive oxygen species and increase the renal injury.
Temperature
The temperature during NMP is set at 37 ºC- can be different depending upon goal of NMP.
Urine Replacement
The loss of perfusate volume due to urine production by ex vivo perfused kidney, should be replaced to maintain perfusate volume.
Most of the preclinical studies showed that the urine produced by ex vivo perfusion of kidney can be reuse for perfusate replacement. It has been shown to maintain the perfusate flow rate.
Diagnostic Potential
Assessing Nephron Function and injury
Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Injured and dying cells shed or leak cytosolic and mitochondrial content, that could be used as injury markers in urine or perfusate.
Some of these are cell-specific; for example, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb, can be used for kidney injury marker in perfusate.
Assessing the Vascular Compartment
Endothelial damage is an important determinant of renal viability. As endothelium has limited regeneration capacity, damage to it can lead to poor long term graft survival.
Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood flow, and urine output during 1h of NMP performed at the end of SCS.
Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.
Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
When To Start
depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
can be used soon after the organ procurement and continued till anastomosed.
Using NMP as an assessment tool presumably has a wider range of options, where NMP can be used for short time at donor hospital or during transport or for short period of time at recipient hospital after arrival of organ before being implanted on recipient.
Protocols are of paramount importance.
Level of evidence
Level 5
Mohammed Sobair
2 years ago
Introduction:
The shift toward the utilization of older organ donors with more comorbidities has stressed the importance of robust Pretransplant organ viability assessment.
First:
Organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunctional (PNF), and graft failure.
Second:
many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their capacity to provide adequate short- and long-term function.2,4-6 These organs in particular would benefit from reliable Pretransplant organ viability and quality assessment because a Signiant number of kidneys that are currently discarded would presumably provide a favorable risk– benefit ratio to a proportion of waitlisted individuals.
Renal norm thermic machine perfusion (NMP) :
Provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrition.
NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
NMP might reduce DGF compared with static cold storage (SCS). RENAL NMP PROTOCOLS:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. Perfusate Composition:
Almost all NMP protocols described to date use red blood cell (RBC)-based perfusate to ensure adequate tissue oxygenation. Arterial Pressure Provided by the Pump: Pressure at 75 mm Hg.
Reported MAP during renal norm thermic perfusion range between 40 and 95 mm Hg. Oxygenation:
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Temperature:
The temperature during NMP is set at 37 ºC, but DIAGNOSTIC Potentials: Assessing Nephron Function and Injury
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function. Assessing the Immune (Cell) Compartment:
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release. Long-term Renal Function:
Almost all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival. WHEN TO START NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair.
Short period of NMP at the recipient center (strategy 3) has been most commonly reported.
Another possibility is to assess organs immediately after retrieval at the donor hospital (strategy 2). LOGISTICAL AND ECONOMIC IMPLICATIONS NMP:
Technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at norm thermic temperatures.
Level of evidence v.
Dalia Ali
2 years ago
First, organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.1-3 Second, many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their capacity to provide adequate short- and long-term function.
RENAL NMP PROTOCOLS NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement
Perfusate Composition
The composition of perfusate is not only of critical
importance to ensure optimal organ preservation but it is also likely to affect the interpretation of potential renal viability markers during NMP. Hence, the chosen perfusate composition might depend on the specific aim of the application of NMP (ie, preservation, viability assessment, or repair). Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
Arterial Pressure Provided by the Pump In the literature, there is no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
Oxygenation
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of carbon dioxide to create optimal acid-base homeostasis.
Temperature
Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the specific aim of ex vivo perfusion. Preclinical work has shown that, upon simulated organ reperfusion, tubular and renal function was better preserved when normothermic (37 ºC), instead of subnormothermic (32 ºC), perfusion preceded it. Nevertheless, the subnormothermic perfusion system used by Brasile et al did not seem to cause relevant renal injury and showed superior posttransplant urine production and serum creatinine levels compared with nonperfused kidneys.
Urine Replacement Loss of circulating volume by urine production of the ex
vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
DIAGNOSTIC POTENTIAL Although the potential of NMP as a diagnostic platform
has been recognized, the search for relevant and independently predictive viability markers has only just started and is likely to increase with wider clinical implementation of NMP.
Assessing Nephron Function and Injury Creatinine clearance and fractional sodium excretionare frequently reported as markers to assess nephron function. It is not known whether these parameters during NMP are predictive for posttransplant function. Importantly, because perfusate composition and perfusion pressures will change hydrostatic and oncotic pressures, they influence filtration and ultimately production and composition of “urine.”
Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile
inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.Additionally, the endothelium and epithelial cells play a key immunological role in this postreperfusion inflammatory response.
Long-term Renal Function
Currently, almost all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival. Because most acute injury restores after transplantation; chronic renal damage will determine longterm graft survival. Predicting long-term posttransplant renal graft survival during NMP would make this technique particularly valuable as a pretransplant diagnostic tool. The main reason for late graft loss is the progression of renal fibrosis, which is mainly the result of the continuous alloimmune response to the donor graft despite immunosuppression.
WHEN TO START NMP The optimal timing to start NMP largely depends on
the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy .The potential of NMP to ameliorate renal preservation and serve as a repair platform most likely demands prolonged NMP times
CONCLUSION An increasing number of centers are investigating renal
NMP, either as a preservation tool, a viability assessment tool, or a repair platform. Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance. Best practice guidelines and consensus on protocols would likely progress the field. Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
amiri elaf
2 years ago
Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool Please provide a summary of this article
*The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies.
*Organs from (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of (DGF), (PNF), and graft failure.
*Renal normothermic machine perfusion (NMP) provides
a near-physiological organ preservation technique
because it circulates a warm (35–37 ºC) perfusion solution
through the renal vasculature delivering oxygen and nutrients.
*NMP has the potential to increase the number of kidney transplants by evaluating and transplanting kidneys that had initially been discarded for transplantation
*NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
*Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
*NMP uses extracorporeal membrane oxygenation and
compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
*The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
*Almost all NMP protocols described to date use red
blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
*Recent preclinical research suggests that synthetic oxygen carriers feature equivalent oxygen-carrying capacities compared with RBCs.
*No consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
*Most experimental kidney NMP systems use a supra physiological perfusate oxygen concentration of approximately 550–650 mm Hg. However, hyperoxia can promote reactive oxygen species production, resulting in additional renal injury.
*Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the specific aim of ex vivo perfusion.
*Loss of circulating volume by urine production of the ex vivo per fused kidney should be replaced to maintain the circuit’s circulating volume.
DIAGNOSTIC POTENTIAL Assessing Nephron Function and Injury
*Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
*Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Assessing the Vascular Compartment
Endothelial damage is an important determinant of renal
viability.Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile
inflammation, triggering activation of innate and adaptive
immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release
*Predicting long-term posttransplant renal graft survival during NMP would make this technique particularly valuable as a pretransplant diagnostic tool.
*The optimal timing to start NMP largely depends on
the aim of its clinical application, that is, preservation,
viability assessment, or repair, all necessitating an individual tailored strategy.
*Best practice guidelines and consensus on protocols would likely progress the field.
* Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
What is the level of evidence provided by this article? Level (5)
Hinda Hassan
2 years ago
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement. An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform. Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance. Best practice guidelines and consensus on protocols would likely progress the field. Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP
level of evidence 5
Ahmed Omran
2 years ago
The optimal time to start NMP depends mainly on the aim of its application, which is, preservation, viability assessment, or repair, all need an individualized tailored approach,.
The potential of NMP to ameliorate renal preservation and work as a repair platform most likely require long NMP times .
Using NMP as an assessment tool has wider range of options (strategy 2, 3, and 4). A short period of NMP at the recipient center (strategy 3) has been most commonly practiced.
Another possibility is to assess organs promptly after retrieval at the donor hospital .
Application of NMP at the donor center avoids the complex logistics and safety problems associated with NMP during organ transport. Also, depending on geographical area of a country and experience of individual centers, the complexity of the various time-related strategies can be reduced by centralization of clinical renal NMP to larger hubs .
This could enhance the quality and allows better standardization of the procedure, as has been suggested for normothermic lung perfusion.
Summary
Increasing number of centers are studying renal NMP, either as a preservation tool, a viability evaluation tool, or repair platform. Great diversity exists among NMP protocols and interpretation of the readouts of NMP. In addition ,no validated (set of) ex vivo viability biomarkers have been identified so far To establish effective preservation by NMP, and use NMP as an objective pre-transplant organ evaluation tool and consequently interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of great importance. Best practice guidelines and consensus on protocols would likely make advances the field. Future scientific work should focus on identifying the ideal perfusate composition duration and pressures& the need for urine recirculation and specific additives, for each application point of renal NMP.
CARLOS TADEU LEONIDIO
2 years ago
markers, which are derived from our in vivo clinical frame of reference, are unlikely to be useful for the ex vivo assessment of viability of the organ.
– Assessment of vascular endothelial damage: Little is known about the significance of flow and resistance during PMN, although with increasing perfusion time, flow generally increases while resistance falls if perfusion pressures are kept constant. Flow – not resistance – is one of the parameters of the renal quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood flow and urine output during 1h of PMN.
– Immune compartment assessment: Removal of circulating leukocytes from the NMP perfusate is believed to minimize inflammation compared to whole blood perfusion.
PERSPECTIVES
It is expected the discovery of new biomarkers for pre-transplant evaluation and that would be collected during the NMP.
What is the level of evidence provided by this article?
This is level 5 – Narrative reviews, even if you review meta-analyses and systematic reviews.
MILIND DEKATE
2 years ago
Introduction Renal Normothermic Machine perfusion provides near physiological organ preservation technique as it perfuses warm solution through renal vasculature containing oxygen and nutrients. This NMP can be used for organ preservation, viability assessment and for pretransplant repair of donor organ. As significant number of organs from ECD are being discarded, this NMP technique can be used for pretransplant organ viability and quality assessment. To date there are multiple NMP protocol are being used in preclinical and clinical studies at different canters and there is no uniform standardized protocol. NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrients enriched perfusate through-out the NMP period. The different fundamental facets of NMP are 1) perfusate composition, 2) arterial pressure delivered by the pump 3) oxygenation 4) temperature and 5) urine replacement.
1) PERFUSATE COMPOSITION
Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
But recent preclinical research suggests that synthetic oxygen carriers can be used instate of RBCs with equal efficacy.
2) ARTERIAL PRESSURE DELIVERED BY THE PUMP
There is no consensus about the optimal perfusion pressure use during NMP, whether it should be used in pulsatile or non pulsatile fashion or whether centrifugal or roller pump should be used.
Preclinical studies are in favor of pulsatile perfusion with perfusion pressure should be maintained at MAP of 75 to 90 mmHg.
the centrifugal pump is better than roller pump as there is less damage to RBCs with centrifugal pump.
3) OXYGENATION
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. However hyperoxia can induce production of reactive oxygen species and increase the renal injury.
4) TEMPERATURE
Typically, the temperature during NMP is set at 37 ºC. But this can be different depending upon goal of NMP.
5)URINE REPLACEMENT
The loss of perfusate volume due to urine production by ex vivo perfused kidney, should be replace to maintain perfusate volume. Most of the preclinical studies showed that the urine produced by ex vivo perfusion of kidney can be reuse for perfusate replacement. It has been shown to maintain the perfusate flow rate.
DIAGNOSTIC POTENTIAL
Through the diagnostic potential of NMP has been recognized, the studies are ongoing to search for relevant and independently predictive viability marker.
1) Assessing Nephron Function and injury
Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Injured and dying cells shed or leak cytosolic and mitochondrial content, that could be used as injury markers in urine or perfusate.
Some of these are cell-specific; for example, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb, can be used for kidney injury marker in perfusate.
2) Assessing the Vascular Compartment
Endothelial damage is an important determinant of renal viability. As endothelium has limited regeneration capacity, damage to it can lead to poor long term graft survival.
Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood flow, and urine output during 1h of NMP performed at the end of SCS.
3) Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.
Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
WHEN TO START NMP
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
It can be used soon after the organ procurement and continued till anastomosed.
Using NMP as an assessment tool presumably has a wider rang of options, where NMP can be use for short time at donor hospital or during transport or for short period of time at recipient hospital after arrival of organ before being implanted on recipient.
An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform.
The great diversity exist among NMP protocol hence To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance.
Level of evidence
Level 5 , narrative review and animal studies.
rindhabibgmail-com
2 years ago
Renal normothermic perfusion machine till now has good result by providing near normal physiological organ preservation technique by giving warm solution containing nutrients and oxygen. it has a very good role in reducing the risk of DGF in ischemia time.
The solution is provided by different companies with different composition of nutrients, some centers uses red blood cell based perfusates to ensure adequate tissue oxygenation >95%.
Temperature at 37C by pulsatile/ gradual rewarming.
level of evidence V.
hussam juda
2 years ago
INTRODUCTION
· Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique via circulating a warm perfusion solution delivering oxygen and nutrients
· NMP may increase the number of kidney transplants by accepting kidneys that was discarded initially
· NMP reduces cold ischemia time and reduce DGF
RENAL NMP PROTOCOLS
Perfusate Composition
· Almost all NMP protocols use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation
· recent research suggests that synthetic oxygen carriers feature equivalent oxygen-carrying capacities compared with RBCs
· It should contains also: Impermeant (glucose, dextran, mannitol, lactate, gluconate) Na.Bicarbonate, Electrolytes, Antibiotics, Antioxidants, and some additives.
· The Cambridge group uses a perfusate based on Ringer’s solution which has a relatively low oncotic pressure
· The Toronto group uses a perfusate based on Ringer’s lactate and STEEN solution, which creates a physiological oncotic pressure and osmolarity
· MePEP consortium used a perfusate based on human albumin and electrolytes within physiological ranges
· The Oxford group used a perfusate contains 5% human albumin solution designed for prolonged renal perfusions that lasted up to 24h
Arterial Pressure Provided by the Pump
· Most groups use centrifugal pumps, which are considered to be less harmful to RBCs compared with roller pumps, especially during prolonged perfusions
· there is some evidence that pulsatile pressure during NMP results in enhanced renal blood #ow, creatinine clearance, sodium reabsorption, and lower tubular injury
· In continuous pressure, MAP range 40-90mmHg
· In Pulsatile 90/70 mmHg
Oxygenation
· Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg
· The Cambridge group used carbogen (95% O2 /5% CO2)
Temperature
· organ reperfusion, tubular and renal function was better preserved with normothermic (37 ºC), by abrupt or gradual rewarming.
Urine Replacement
· The Toronto and Cambridge groups replaced volume lost from urination, by adding Ringer’s solution or Ringer’s lactate to the perfusate
· Weissenbacher showed that recirculating the urine is feasible and that it results in a significantly higher perfusate flow rate
DIAGNOSTIC POTENTIAL
· Creatinine clearance and fractional sodium excretion are unlikely to be useful for ex vivo organ viability assessment
· Potential biomarkers during NMP, that may indicate renal injury: NGAL, LDH, AST, Lactate, KIM-1, L-FABP, FMN, π-GST, ET-1, VWF, VCAM-1/ ICAM-1, TBARS, Protein carbonyls, 8-isoprostane, ATP content/ ATP:ADP ratio
Long-term Renal Function
· long-term outcomes are affected by preexisting renal fibrosis in donor grafts, biological age of the donor, prolonged warm ischemia time and anastomosis time
· Recipient factors: increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications at the time of transplantation
WHEN TO START NMP? There are 4 Strategies:
1. NMP for the entire preservation interval;
2. a short period of NMP at the donor hospital followed by CP for transportation to the recipient center;
3. NMP at the recipient center only;
4. an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP
· Today, strategy 3 has been most commonly reported
LOGISTICAL AND ECONOMIC IMPLICATIONS
· As NMP will changes the current donation and transplantation logistics, this will necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for sterility
· The actual costs of NMP use still unknown, as it needs out-of-hours specialist expertise, disposables, perfusate components, equipment needed to obtain samples, analyses for viability assessment, facility fees, NMP training, and depreciation of the perfusion device
PROSPECTS
Near-infrared spectroscopy, MRI, PET, contrast-enhanced ultrasound, ultrafast ultrasound imaging, laser speckle imaging, and multiphoton microscopy imaging all are noninvasive diagnostic techniques
What is the level of evidence provided by this article?
Level 5 narrative review
AMAL Anan
2 years ago
Level of evidence is V
RENAL NMP PROTOCOL
Help in oxygenation and nutrition of kidney
Perfusate Composition
It preserve optimal organ
the pulsating blood pressure is about 90/70 with applying warm temp
with keeping o2 saturation 95%and using ringer for keeping urine recirculating
and using creatinine clearance and fraction sodium excretion as good biomarker
While the KIM1 and NGAL is bio marker for injury of tubules
mai shawky
2 years ago
club 5, renal normo-thermic machine perfusion Summary
· The urgent need to expand the donor pool to match the increased need for KT made us using cadaveric ECDs or graft after circulatory death which are highly susceptible to ischemia-reperfusion injury, increased risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
· Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation.
· it depends on the use of warm (35–37 ºC) perfusion carrying oxygen and nutrients to the allogarft.
· it acts through decreasing the ischemia time and hence minimizes the ischemia reperfusion injury.
· No standard protocol for NMP, but individualized and center based approach.
· Each protocol determines its own variables as perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
· Perfusate composition which is RBC-based perfusate or artificial oxygen carrying vehicle to enhance organ oxygenation, in addition Ringer’s solution to provide adequate nutritional supply. Perfusate with human albumin and electrolytes (Na, K, Ca, Cl) within physiological ranges was used. antibiotics, antioxidants, vasodilators as (verapamil or nitroglycerine), multivitamins, heparin, + or- additives like amino acids.
· No consensus about the ideal arterial pressure delivered by the pump, however, centrifugal (better for the RBC) or roller pump is best. The flow is either pulsatile or nonpulsatile, pulsatile is associated with better renal blood flow, creatinine clearance, sodium reabsorption, and less renal tubular injury. MAP of 75 mm Hg (40-95 mm Hg) seems to be associated with better graft outcome.
· Oxygenation using oxygen source supplying 550–650 mm Hg. balanced with a small percentage of CO2 to create optimal acid-base homeostasis.
· Temperature: gradual rewarming has typically been pursued up to 20 ºC over a period of 90 min.
· Urine replacement using ringer solution is still debatable.
· Biochemical parameters to assess graft viability and function;
o Creatinine clearance and fractional Na excretion are common markers of nephron function.
o Metabolic activity and oxygen consumption were useful markers of kidney metabolic activity in animal mode.
o KIM1, NFAL are markers of renal tubular injury.
NMP is still coasty and complicated technique.
Level of evidence: narrative review (level V)
Esraa Mohammed
2 years ago
INTRODUCTION
*organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
*many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their
capacity to provide adequate short- and long-term function.
RENAL NMP PROTOCOLS
NMP uses extracorporeal membrane oxygenation and
compound supplementation technology to provide the
kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period
2-Arterial Pressure Provided by the Pump
-contiuos presseure : MAP40-95 mmHg
-Pulsatile90/70 mmHg
3- Oxygenation
Carbo95%/ O2 /5% CO2
police 550-650 mmHg
4-Temperature
Abrupt rewarming
Gradual rewarming
5-Urine Replacement
Urine recirculation
Ringers
CONCLUSION
An increasing number of centers are investigating renal
NMP, either as a preservation tool, a viability assessment
tool, or a repair platform.
To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance.
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and speci! c additives, for each application area of renal NMP.
Hamdy Hegazy
2 years ago
1. Please provide a summary of this article 2. What is the level of evidence provided by this article? This is a narrative review article with level V evidence.
Renal Normothermic Machine Perfusion (NMP) is used to perfuse the donor kidneys after retrieval using a perfusion solution warmed at 35-37 C aiming to maintain cellular metabolism, provide oxygen and nutrition and shorten the duration of cold ischemia thus reducing the effects of ischemia reperfusion damage.
There different types of renal NMP Solutions. There is no ideal perfusate up till now, it needs more research. There are different protocols and NMP duration, timing to start and required pressures need more studies.
Perfusate composition and perfusion protocol: 1- Oxygen carrier (extra-corporeal membrane oxygenation) 2- Colloid 3- Impermeant: glucose, mannitol or lactate. 4- Buffers 5- Electrolytes: Na, K, Ca. 6- Antibiotics. 7- Anti-oxidants. 8- Additives: glucose, amino acids, vasodilators, heparin, steroids. 9- Arterial pressure can be provided by a pump via continuous/pulsatile pressures aiming for MAP 40-95 mmHg. Supra-physiological oxygenation is required PO2 555-650 mmHg. Urine replacement via either urine recirculation or Ringer’s Lactate.
NMP can be commenced in the Donor’s hospital after organ retrieval or in transit or in the recipient transplant center.
NMP implications: 1- Organ assessment (diagnostic) for nephron function and injury, and vascular and immune compartments assessment. 2- Preserving organs. 3- Active organ reconditioning (repair).
Limitations of NMP: 1- Complicated and Time consuming. 2- Technique failure. 3- Specialized perfusion room. 4- Needs well trained Staff. 5- High cost
Shereen Yousef
2 years ago
organs from ECDs or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
many kidneys offered for transplantation may be discarded due absence of tool to assess function and viability
Presence of reliable pretransplant organ viability and quality assessment would help to increase number of accepted organs.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients maintaining near normal cellular metabolism.
NMP has many advantages as it help evaluation of Viability of organs, advanced preservation strategy, platform for active organ reconditioning, reduces cold ischemia time and reduces,DGF ischemia-reperfusion injury.
Unfortunately there is no single unified NMP protocol exists to date.
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
▪︎NMP protocols can be divided into:
-perfusate composition
-arterial pressure delivered by the pump.
-oxygenation
– temperature.
– urine replacement.
*Perfusate Composition:Almost all NMP protocols uses RBC-based perfusates to ensure adequate tissue oxygenation.
*Arterial Pressure Provided by the Pump:no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
some evidence suggests that pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
Many centres Reported mean arterial pressure (MAP) during renal normothermic perfusion range between 40 and 95 mm Hg.
*Oxygenationexperimental kidney NMP systems use a supra physiological perfusate oxygen concentration of approximately 550–650 mm Hg.
*temperature
upon simulated organ reperfusion, tubular and renal function was better preserved when normother-mic (37 ºC), instead of subnormothermic (32 ºC), perfusion.
*Urine ReplacementVolume lost by urine production should be replaced ,adding Ringer’s solution or Ringer’s lactate to the perfusate is used to replace volume.
urine recirculation is used in some studies.
*Assessing Nephron Function and Injury
-kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb could be used as injury markers in urine or perfusate.
–Non–cell-specific injury markers aspartate aminotransferase and lactate correlated with posttransplant renal graft function .
-FMN correlate with posttransplant renal graft function.
*Assessing the Immune (Cell) Compartment
Removal of circulating leukocytes from the NMP perfusate minimize inflammation compared with whole blood perfusion.
-The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy
CONCLUSION
investigating renal NMP is ongoing in many centres, either as a preservation tool, a viability assessment tool, or a repair platform.
Great diversity exists among NMP protocols .
there is no validated (set of) ex vivo viability biomarkhave identified.
more uniformity in NMP protocols is of paramount importance.
Marius Badal
2 years ago
Summary:
The renal transplant pool over the years was limited and continues to be but with the introduction of ECD, DCD, and DBD, etc. there has been an improvement. So this article is about understanding renal normothermic machine perfusion (NMP). The introduction of this method in extended criteria is to improve graft outcome and survival. For the limited organ being donated, it is important that the organs are preserved properly and as such proper evaluation must be conducted before transplant. The principle behind NMP is to preserve the organs in a method close to organ physiology to provide warn solution that contains the proper nutrients or oxygen to the kidneys. This principle helps physicians to properly access the function of the allograft and the extent of the possible injury the graft may have. The importance of such is to increase the number of kidneys that can be used for kidney transplantation and as such to reduce organs from being lost. Its other function that is the NMP is to preserve the graft function and to reduce CIT and therefore limiting the ischaemic impact on the allograft. So NMP helps to reduce the risk of DGF when it is compared with static cold storage.
The NMP protocol composition contains:
1) Red blood cells based perfusate. That is important to ensure proper oxygenation to the organ
2) Lactate ringer solution is used due to its low oncotic pressures
3) Lactate ringer and STEEN
4) MsPEP consortium human albumin-based perfusate.
5) The temperature is set to about 37 degrees Celsius.
Other parameters that need to be monitored are:
1) The arterial pressure of the pump. The pressure must be one such that it must not cause endothelial injury of the allograft.
2) Oxygenation must be about 95% and the PaO2 about 550-650 mmHg
3) Temperature of about 37 degrees Celsius ensure proper renal circulation.
The problems with NMP are that it is expensive, complex, time-consuming, and also at risk of failure and it needs to be in a room that is specialized and operated by an experienced person.
The kidney donors must be evaluated by:
1) Assessing the viability and vasculature using vascular resistance. The flow markers for endothelial damage.
2) Biomarkers like KIM-1, NGAL, and FMN to help to evaluate kidney injury.
3) The use of AST and LDH gives details on graft function.
So, NMP is a method for renal or allograft preservation to ensure it prolongs or try to prolong the graft function. There are biomarkers that can be used to help to understand what is going on with the graft as it relates to its functions. With better research hopefully, the perfusate composition must be one that may be physiologically to ensure proper functions.
The article level of evidence is 5
Huda Saadeddin
2 years ago
WHEN TO START NMP
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy .
The potential of NMP to ameliorate renal preservation and serve as a repair platform most likely demands prolonged NMP times .
Using NMP as an assessment tool presumably has a wider range of options (strategy 2, 3, and 4). Today, a short period of NMP at the recipient center (strategy 3) has been most commonly reported.
Another possibility is to assess organs immediately after retrieval at the donor hospital .
Applying NMP at the donor center avoids the complex logistics and safety issues associated with NMP during organ transport. Moreover, depending on geographical area of a country and expertise and experience of individual centers, the complexity of the various time-related strategies can be reduced by centralizing clinical renal NMP to larger hubs .
This could also enhance the quality and allows better standardization of the procedure, as has been proposed for normothermic lung perfusion.
CONCLUSION
An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform. Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance. Best practice guidelines and consensus on protocols would likely progress the field. Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
Mohamed Saad
2 years ago
Renal Norm thermic Machine Perfusion: The Road toward Clinical Implementation of a Promising pre-transplant Organ Assessment Tool. Introduction.
Kidney donation from ECD or DCD associated with ischemia -reperfusion injury , DGF and graft failure.
Renal normo-thermic machine perfusion (NMP) has a role in providing the kidney with oxygen and nutrients by circulating circulates a warm (35–37 ºC) perfusion solution through the renal vasculature, so it has a role in preserving organs for donation , assessment, or repair platform. Renal NMP Protocols.
NMP protocols can be divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement 1-Perfusate Composition.
blood cell (RBC)-based perfusates to ensure adequate tissue
oxygenation, with based material for nutrients supplementation as ringer based solution which used for 1-2 hrs before transplantation after long static cold time, The Oxford
group has published a discarded human kidney NMP study
in which a somewhat similar perfusate based on 5% human
albumin solution was used, till now no standard protocol and no randomized studies to prefer one to another. Arterial Pressure Provided by the Pump.
Reported mean arterial pressure(MAP) during renal norm thermic perfusion range between 40 and 95 mm Hg but still no consensus about the optimal one , using centrifugal pump in pulsatile manner is better than roller pump. some studies increase MAP to 70-95 mm Hg . Oxygenation.
Supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg is considered the standard in most centers but still tubular injuries from reactive oxygen species production, resulting in additional renal injury should be kept in mind. Temperature.
organ reperfusion, tubular and renal function was better preserved when norm thermic (37 ºC), instead of subnormothermic (32 ºC), perfusion preceded it. Urine Replacement.
Replacement by ringer lactate mainly and some studies acting on urine re-circulation . Diagnostic potential . Assessing Nephron Function and Injury.
Some markers are used to detect nephron function and injury but still not clinically implicated as oxygen consumption which affected by metabolic activity of tubular cells and oxygen supplementation, Also kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb which is contents of injured cells. In a pilot study, significantly higher levels of FMN during NMP were found in kidneys with DGF and PNF after transplantation. Assessing the Vascular Compartment.
To assess endothelial vasculature is important as it affect long term graft survival, Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group which combines macroscopic appearance, renal blood flow, and urine output during 1 h of NMP performed at the end of SCS. Assessing the Immune (Cell) Compartment.
Inflammatory cytokines are released during kidney perfusion, although it is currently unclear which cytokines could be predictive of outcome all these due to IRI and usage of cytokines filters still need more studies to be clear. Long-term Renal Function.
The severity of existing fibrosis correlates with the duration of graft survival, donor organ quality has impact on long term graft survival which is affected by many factors as ischemia time and anastomosis time, also recipient factors such as increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications at the time of transplantation are associated with adverse long-term outcome, still we need integrative approach to cover all these factors to detect long term graft survival . WHEN TO START NMP.
1-NMP for the entire preservation interval which is mainly long period from procurement till transplantation .
2- A short period of NMP at the donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for transportation to the recipient center to assess quality before retrieval.
3-NMP at the recipient center only to assess kidney quality just before transplantation.
4-an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP. CONCLUSION.
Still using NMP is local center based protocol, either as a preservation tool, a viability assessment tool, or a repair platform, Future researches needed to focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP, and to signify the effect of NMP on short and long term graft survival.
Level of evidence V (article review).
Dr. Tufayel Chowdhury
2 years ago
Introduction:
Organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution
through the renal vasculature delivering oxygen and nutrients.
Perfusate Composition:
Use red blood cell (RBC)-based perfusates to ensure adequate tis-
sue oxygenation.
The Cambridge group uses a perfusate based on Ringer’s solution, which has a relatively low oncotic pressure.
Arterial Pressure Provided by the Pump:
Pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
Oxygenation:
Most NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced
with a small percentage of carbon dioxide to create optimaL acid-base homeostasis.
Temperature:
Typically, the temperature during NMP is set at 37ºC.
Urine Replacement:
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge
groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
Assessing Nephron Function and Injury:
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
WHEN TO START NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application.
Today, a short period of NMP at the recipient center has been most commonly reported. This strategy provides the advantage to assess organ quality just before transplantation.
CONCLUSION:
NMP used either as a preservation tool, a viability assessment
tool, or a repair platform.
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
Huda Al-Taee
2 years ago
Summary:
The increased utilization of high-risk renal grafts for transplantation requires the optimization of pre-transplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury. Early clinical experience suggests that NMP might reduce DGF compared with static cold storage.
In recent years, considerable effort has been directed at the development of NMP as either organ preservation, assessment, or repair platform.
RENAL NMP PROTOCOLS:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
Perfusate Composition:
The composition of perfusate is not only of critical importance to ensure optimal organ preservation but it is also likely to affect the interpretation of potential renal viability markers during NMP. Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation. Recent preclinical research suggests that synthetic oxygen carriers feature equivalent oxygen-carrying capacities compared with RBCs.
To date, no study has convincingly investigated the roles of individual perfusate components or even compared existing #uids side-by-side to establish which components could lead to an optimal NMP, as well as the best posttransplant outcome.
Arterial Pressure Provided by the Pump:
There is no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or non-pulsatile fashion, and whether a centrifugal or roller pump is best. Although most groups apply a continuous pressure during normothermic perfusion, there is some evidence that pulsatile pressure during NMP results in enhanced renal blood #ow, creatinine clearance, sodium reabsorption, and lower tubular injury. Reported mean arterial pressure (MAP) during renal normothermic perfusion range between 40 and 95 mm Hg.
Oxygenation:
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of carbon dioxide to create optimal acid-base homeostasis.
Oxygen consumption during NMP is often reported. The most commonly used equation was introduced by Stubenitsky et al53 [(arterial Po2 –venous Po2 )×perfusate #ow rate/weight].
Temperature:
Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the speci!c aim of ex vivo perfusion.
It has been suggested that controlled oxygenated rewarming improves cellular homeostasis and mitigates rewarming injury in a porcine NMP model, g also enhances early post-transplant cortical microcirculation, thereby preventing the renal cells from being jeopardized by pumping against high cortical resistance.
Urine Replacement:
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. Ringer solution or recirculating the urine had been used.
DIAGNOSTIC POTENTIAL:
Although the potential of NMP as a diagnostic platform has been recognized, the search for relevant and independently predictive viability markers has only just started and is likely to increase with wider clinical implementation of NMP.
Assessing Nephron Function and Injury:
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.33,42,55,64,65 It is not known whether these parameters during NMP are predictive for post-transplant function.
Metabolic activity and oxygen consumption are high in tubular cells, and therefore, oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Injured and dying cells shed or leak cytosolic and mitochondrial content that could be used as injury markers in urine or perfusate and some of these are cell-specific; for example, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb. 2 Non–cell-specific injury markers aspartate aminotransferase and lactate correlated with post-transplant renal graft function, measured by peak serum creatinine. Flavin mononucleotide (FMN), a lesser-known biomarker, has also been shown to correlate with posttransplant renal graft function.
Assessing the Vascular Compartment:
Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
In vivo, endothelial damage and viability are reflected by an increase in vascular resistance related to a combination of disruption of the endothelial cell lining favoring thrombosis and the “no-reflow” phenomenon, which is the suboptimal restoration of perfusion after a period of ischemia.
Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood #ow, and urine output during 1h of NMP performed at the end of SCS.107 The use of this score has provided some proof that NMP kidney viability assessment can lead to transplantation of initially discarded kidneys.
Assessing the Immune (Cell) Compartment:
1 Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
despite the absence of circulating leukocytes during NMP, resident leukocytes are released. It is unclear what the implications of the presence and release of resident leukocytes are and whether the phenotype and behaviour of these cells could be predictive of post-transplant outcomes.
The use of a cytokine filter during 6h of pig kidney NMP reduced levels of interleukin-8 (neutrophil-attractant) and interleukin-6 (a proinflammatory cytokine) when compared with control. Nevertheless, no difference in kidney function during NMP could be noted, and these kidneys were not actually transplanted.
Long-term Renal Function:
The main reason for late graft loss is the progression of renal fibrosis.
preexisting renal fibrosis in donor grafts is associated with diminished long-term graft survival.
long-term outcomes are also affected by the quality of the donor organ, which is mainly determined by the biological age of the donor.
prolonged warm ischemia time and anastomosis time are associated with adverse long-term outcomes.
recipient factors, increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications at the time of transplantation are associated with adverse long-term outcomes.
WHEN TO START NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual-tailored strategy.
A short period of NMP at the recipient center (strategy 3) has been most commonly reported.
LOGISTICAL AND ECONOMIC IMPLICATIONS:
NMP is technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at normothermic temperatures.
Clinical implementation of NMP will result in structural changes to the current donation and transplantation logistics. This will most likely necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for the sterile conduct of NMP. In addition, dedicated staff, trained in organ perfusion, will need to join the surgical teams. Depending on when NMP is initiated in the donation and transplantation cascade, dedicated personnel may have to travel to the donor center or run organ perfusion hubs.
Level of evidence:
level 5 ( review article).
Mahmud Islam
2 years ago
This is a review article with level evidence of 5.
In this review, the NMP (normothermic machine) new technology to preserve organ perfusion at near physiological temperature (35-37). This can replenish the ATP synthesis and provide time for evaluating kidney functionality.
Different protocols are used, but most use RBCs as oxygen carriers. In addition, nutrition is vital. some centres use ringer lactate(Cambridge group). Toronto group use RL & STEEN solution.
Arterial pressure is also important, but there is no consensus regarding that. Most centres use centrifugal methods not to harm erythrocytes. MAP provided ranges between 45 and 95. 95 and 75 was found superior to 55 (Hsogood et al.).
The oxygenation pressure used is 550-650 mmHg. Cambridge group investigated altered oxygenation kinetics but found no effect on tubular function despite alteration.
Urine excreted by kidneys should be taken into consideration and replaced. There are many potential biomarkers are investigated in terms of renal injury evaluation. Clinical validation ist still in progress.
NMP can be used alone or in combination with cold perfusion according to the aim of preservation. This gives us an opportunity to evaluate kidney function before transplantation and predict the risk of DGF.
KAMAL YOUSIF ELGORASHI ADAM
2 years ago
Introduction. Organs from ECD, and those from DCD, are brone to ischemic reperfusion injury, which lead to DGF, PNF, and graft failure.
Many kidneys are reluctant from donation, because of doubt about the quality, and short-long term outcome. So those kidneys a valuable measure to assess viability and the degree of poor quality, in order to increase their performance and secure better function, and future survival.
NMP, provide a semi-physiological environment, (temp.35-37), with delivered O2 and nutrients. With normothermia, cellular viability, and biochemical mechanism take place as in living body. NMP, with many clinical experiences show a potential to increase the number of transplanted kidneys, that was initially possibly discarded. NMP also provide a preservative technique, and platform of active organ reconditioning. NMP, reduces CIT, which lead to reduce of ischemia-reperfusion injury, and by the end of the day reduces DGF. Renal NMP protocol; devided into;
Perfusate composition.
arterial pressure delivered by the pump.
Oxygenation.
Temperature.
Urine replacement.
Perfusate composition;
Work as organ preservation.
Affect the organ viability markers and reduce progression of the acute insults.
Perfusate composed of RBC- based perfusate, to ensure oxygenation.
Cambridge group use a perfusate based on ringer solution, (low oncotic pressure).
Toronto group use a perfusate based on ringer and STEEN solution, (physiological oncotic pressure and osmolarity).
MePEP group use a perfusate based on human albumin and electrolytes, used in porcine study to repair the kidney, (used for 24 Hrs).
Perfusated also supplied with, vasodilator, glucose and insulin.
Other; heparin, mannitol, antibiotics.
Arterial pressure provided by the pump;
Most group use a centrifugal pump, (less harm to RBCs compared to roller pump).
Pulsatile pressure results in enhanced RBF, CrCL, Na reabsorption, and lower tubular injury).
Hosgood and colleagues, found that higher MAPs (75 and 95 mmHg) associated with better outcome, compared to 55 mmHg in term of renal function and endovascular injury.
The Toronto group, use a MAP of 75 mmHg fixed rate.
Oxygenation;
Experimental kidney NMP used a supraphysiological perfusate O2, (550-650 mmHg), balanced with PCO2 to create optimum acid-base hemostasia, (hyperoxia result in additional renal injury).
Cambridge group; showed that reduction of O2 lead to decrease O2 kinetics, but didnot affect tubular function, CrCL, or biomarker of renal injury.
Temperature;
Typically set at 37C,
Urine replacement;
urine production replaced to maintain circuite circulatory volume.
Replacement fluid, (Ringer, urine recirculate).
Assessing Nephron function;
Report CrCL and FENa, as a marker of nephron function.
O2 consumption also used as biomarker as it used by tubular cells, (but it depend on O2 supplied.
KIM-1 and neutrophil gelatinase-associated lipocalin, used as biomarker in locating te site of injury.
Flavin mononucleotide (FMN), associated with DGF.
Assessing vascular compartment:
Endothelial damage is an important determinant of tissue viability, so if happen, it associated with adverse effect long term survival, because of slower regenerative derive.
Endothelial damage reflected by an increase in vascular resistance, a comopsite of factors,(distruption of endothelial lining, thrombosis, and n0-reflow phenomenon).
Flow considered a parameter of kidney quality.
Quality assessment score derived by Cambridge group,( composite of macroscopic appearance, RBF, and UOP), during 1 Hr, of NMP, this score provide some proof that lead to use of some discarded kidneys, based on fixed provided machine parameters.
Assessing immune cell compartment;
Ischemic re-perfusion injury result in sterile inflammation, immune system triggering, as well as leukocyte recruitment, with subsequent cyto-kemokines release.
Removal of this inflammatory celle by NMP perfusate help minimize such reaction and damage.
Ex-vivo filter use by NMP during 3 Hrs, help in reducing T-Cell infilterates post Tx, compared with controls.
Long term kidney function;
Most AKI restores shortly post Tx, CKD will determine the long-term survival.
NMP help in prediction long term graft survival (by pre-transplantation diagnostic tool).
Ongoing fibrosis is the main determinant factor of chronic graft loss, due to continious immunogenic process although use of Immunosuppressant.
Prolonged WIT, and anastomoses time as well as age donor and quality of donated kidney were associated with reduction of long-term survival.
When to start pump;
depends on the aim of clinical applications.
Strategy 1; prolong NMP time; need for preservation and repair.
Category 2; assess organ immedietly after retrieval.
Category 3; Assess organ quality just before Tx.
Category 4 applying NMP at donor center, through transportation to recipient center.
Conclusion; Increasing use of NMP by various centers, neither as a preservative tool, a viability assessment tool, or a repair platform. Developing field of using NMP and its important of improving quality of graft, and hence helping in expanding donor pool and reduce the number of waitlisting HD patient by reducing discarded rate of kidney of poor quality, necessiate more effort to be done in prooving types of biomarkers which can be used in assessing kidney injury, located side of injury, progression and restoration of insult, and finally gain a hoping kidney with short and long term survival.
Level of evidence ((V)) clinical review.
Sahar elkharraz
2 years ago
This article focus on pre transplant optimization of organ donation from older donor or donor with co- morbidity or from deceased donor with circulatory death which are exposed to ischemic perfusion injury lead to delay graft function.
it’s large randomized pre clinical trials on animal to compare NMP with SCS ( static cold storage), by Cambridge groups.
Renal normothermic machine ( NMP), provide organ preservation technique at temperature 35 to 37c by oxygenated perfusion solutions through renal vessels.
It’s help to resume and replenish ATP synthesis.
It’s lead to reduce cold ischemic time.
Renal NMP protocol: It’s extracorpeal membrane oxygenated and rich with nutrient perfusion solutions through the renal vessels.
It’s help for preservation/ viability assessment and repair by replenish the ATP. This perfused solutions consist of ringer lactate and Steen solutions to keep oncotic and osmolarity of kidney.
Some perfused solutions contain human albumin and electrolytes near to physiological range and other compositions contain glucose and insulin and albumin to maintain glucose absorption.
Arterial pressure provided by centrifuge pump because less harm on red blood cell. The mean arterial pressure by NMP is between 95 to 45 mmHg and systolic blood pressure 95 to 55 mmhg to maintain renal blood flow and creatinine clearance and sodium reabsorption and less tubular injury.
Oxygenated blood is high at 550 to 650 mmhg with minimal carbon dioxide to maintain acid base imbalance and no formation of free radical oxygen which may harm tubules.
Temperature// 32 to 37c and they showed gradually rewarming from 20 c to 32 c during 90 min no add protection.
Assess nephron function by creatinine clearance and fractional sodium excretion so NMP will not give idea on function of kidney post transplant .
Endothelial damage is important factor in viability of kidney and it reflects increased vascular resistance and means presence of plugged RBC in cortex and medulla which lead to thrombosis and no blood flow in kidney so by NMP lead to discard kidney from donation.
Kidney donor from DCD are exposed to activate innate and adaptive immune system lead to release leukocytes and by NMP lead to remove resident and activated leukocytes and reduce immunological risk.
All NMP assess and investigate bio markers of acute kidney injury and short term graft survival because the most acute kidney injury reversed post transplant but chronic damage lead to reduce graft survival so NMP give opportunity to diagnosis of kidney damage and fibrosis pre transplant and post transplant because graft fibrosis is the main reason for graft loss due to continue activation of immune response despite immunosuppressive agents.
Q2: level 5
Mohamad Habli
2 years ago
Introduction
DGF is a recognized risk factor associated with decreased graft and patient survival over the long term. To get the best possible outcome from each donor kidney and maximize the survival benefit relative to the dialysis population, effective organ preservation continues to be one of the greatest obstacles to reducing current DGF rates and their resultant negative long-term impact.
Numerous kidneys given for transplantation are ultimately not implanted due to doubts regarding their short- and long-term functionality. These organs would especially benefit from a reliable pretransplant organ viability and quality evaluation.
-Renal normothermic machine perfusion (NMP) is a near-physiological organ preservation approach since it pumps a warm (35–37 C) perfusion solution through the renal capillaries carrying oxygen and nutrients. NMP shortens the duration of cold ischemia and may ameliorate the ill effects of ischemia-reperfusion damage. Preclinical and early clinical data suggest that NMP may lower DGF compared to static cold storage (SCS).Substantial effort has been devoted to the development of NMP as an organ preservation, assessment, or repair platform.
Methods
This is a single center, retrospective cohort study evaluated the effect of HMP on the kidney preservation in comparison to static cold storage.
A total of 66 transplanted kidney outcomes were assessed for a duration of 6 years.
Case controls were matched according to graft type (DBD or DCD), donor age, cold ischemic time, and number of HLA mismatches.
Patients received a steroid sparing immunosuppressive regimen with alemtuzumab induction and long-term Tacrolimus monotherapy.
-NMP uses extracorporeal membrane oxygenation and compound supplementation technology to give the kidney with an oxygenated and nutrient-enriched perfusate during the NMP phase. NMP treatments can be loosely categorized according to perfusate composition, arterial pressure provided by the pump, oxygenation, temperature, and urine replacement.To provide appropriate tissue oxygenation, red blood cell (RBC)-based perfusates are used in virtually all NMP protocols documented to date.
-The Cambridge group uses Ringer’s solution-based perfusate, which has a comparatively low oncotic pressure.The Toronto team employs a perfusate composed of Ringer’s lactate and steensolution, which generates a physiological oncotic pressure and osmolarity. The MePEP consortium employs an additional perfusate composed of human albumin and electrolytes within physiological values. Various chemicals are routinely administered during perfusion to maintain a stable environment that is close to physiological.
– No study has conclusively examined the roles of specific perfusate components or compared existing #uids side-by-side to determine which components could lead to an ideal NMP and the best posttransplant result.
-There is no consensus regarding the appropriate perfusion pressure during NMP, whether it should be applied pulsatile or nonpulsatile, or whether a centrifugal or roller pump is superior.
– Some research suggests that pulsatile pressure during NMP increases renal blood flow, creatinine clearance, sodium reabsorption, and decreases tubular damage. Reported mean arterial pressure (MAP) during renal normothermic perfusion is between 40 and 95 mm Hg.
-The majority of experimental kidney NMP systems employ a supraphysiological perfusate oxygen content between 550 and 650 mm Hg. To create appropriate acid-base equilibrium, oxygen is often administered in conjunction with a little amount of carbon dioxide. It has been hypothesized that regulated oxygenation rewarming enhances cellular homeostasis and reduces rewarming harm in a porcine NMP model. Controlled oxygenation rewarming improves early posttransplant cortical microcirculation as well.
– Loss of circulating volume caused by urine output of the ex vivo perfused kidney should be replenished to preserve the circuit’s circulating volume. The Toronto and Cambridge teams replaced this volume by incorporating Ringer’s solution or Ringer’s lactate into the perfusate. Creatine clearance and fractional sodium excretion are widely cited as indicators of nephron function.
-Endothelial injury is a crucial predictor of renal viability. Due to the limited regenerating potential of endothelial cells, microvascular injury in the kidney has a detrimental influence on the long-term survival of grafts.
Future studies are needed to concentrate on determining the optimal perfusate composition, perfusion duration and pressures, as well as the necessity for urine recirculation and specialized additives, for each application area of renal NMP.
In conclusion, A growing number of centers are examining renal NMP as a preservation tool, a viability evaluation tool, or a platform for repair. There is considerable variation among NMP procedures and the interpretation of NMP readouts. There are no proven ex vivo viability biomarkers identified. Guidelines for best practices and unanimity on processes would certainly improve preservation approaches.
The provided article is a review article with level of evidence 5
Last edited 2 years ago by Mohamad Habli
Hussein Bagha baghahussein@yahoo.com
2 years ago
Summary Introduction
Due to the shortage of organs, more organs from marginal and ECDs are being utilized. Older donors and donors with comorbids are being utilized. Organs from DCD donors are also increasingly being utilized. These marginal donors have an increased risk of developing DGF, PNF and reduced graft survival. Many organs from marginal donors are discarded due to doubt of their viability. These organs would benefit from pre-transplant organ viability and quality assessment. A plethora of non perfusion-based pre transplant quality assessment tools exist that incorporate clinical and donor recipient variables. However, none of these models demonstrate adequate predictive power to guide clinical decision making for individual kidney donors.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35-37 degrees celsius) perfusion solution through the renal vasculature delivering oxygen and nutrients. At normothermia, cellular metabolism can resume and replenish ATP synthesis, which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury might be performed during NMP.
The potential of NMP goes beyond its diagnostic applicability, also encompassing the possibilities to serve as a promising superior preservation strategy and a platform for active organ reconditioning. Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
Renal NMP Protocols
The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, temperature and urine replacement. Perfusate Composition:
The composition of perfusate is not only of critical importance to ensure optimal organ preservation but it is also likely to affect the interpretation of of potential renal viability markers during NMP. Almost all NMP protocols use RBC-based perfusates to ensure adequate tissue oxygenation. NMP perfusates are typically supplemented with different compounds to provide nutrients that aim to preserve nutrient viability. the main component is either Ringers Lactate or RL with STEEN solution or normal saline with albumin.The perfusate also contains antibiotics, mannitol and Ca gluconate. It also has additives like glucose and vasodilators like verapamil. Arterial Pressure Provided By The Pump
There is no consensus in literature about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or non-pulsatile fashion and whether a centrifugal or roller pump is best. Most groups use centrifugal pumps, which are considered to be less harmful to RBCs. The MAPs during renal NMP range between 40 – 95 mmHg. Preclinical studies by Hosgood and colleagues found superior outcomes for higher MAPs (75-95 mmHg). Oxygenation
most experimental kidney NMP systems use supra-physiological perfusate oxygen concentration of approximately 550-650 mmHg. Administered oxygen is typically balanced with a small percentage of CO2 to create optimal acid base homeostasis. However, hyperoxia can promote reactive oxygen species, resulting in additional kidney injury. Temperature
Typically, the temperature during NMP is set at 37 degrees celsius but this may be different depending on on the specific aim of the ex vivo perfusion. Preclinical work has shown that, upon simulated organ perfusion, tubular and renal function was better preserved when normothermic instead of subnormothermic perfusion preceded it. An important question is whether normothermia should be induced abruptly or gradually.It has been suggested that controlled oxygenated re-warming improves cellular homeostasis and mitigates re-warming injury Urine Replacement
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuits circulating volume. Ringers lactate has been used to replace the lost volume. Weissenbacher at al showed that recirculating the urine is feasible and that it results in a significantly higher perfusion flow rate as well as a revitalized metabolism determined by unregulated levels of ATP synthase, NADH dehydrogenase and oligosaccharyltransferase.
Diagnostic Potential Assessing nephron function and injury
Creatinine clearance and FeNa are frequently reported as markers to assess nephron function. It is not known whether these parameters during NMP are predictive for post transplant function.
Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models. It is currently unclear how and if oxygen consumption indeed reflects viability as there is evidence that oxygen consumption in the kidney during NMP is dependent on the oxygen concentrations offered. Newer molecules have been investigated but none have been validated in large cohort of kidney transplants. Assessing Vascular Compartment
Endothelial damage is an important determinant of renal viability. In vivo endothelial damage and viability are reflected by an increase in vascular resistance relates to a combination of disruption of the endothelial cell lining favoring thrombosis and the no reflow phenomenon. Assessing the Immune (cell) Compartment
ischemia reperfusion injury causes sterile inflammation which triggers activation of innate and adaptive immune systems as weak as leucocyte recruitment that is reinforced by cytokine and chemokine release. Removal of circulating leucocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion Long Term Renal Function
Currently, almost all NMP studies investigate biomarkers correlated with acute kidney injury and short term graft survival. Because most acute injury restores after transplantation, chronic renal damage will determine long term graft survival. Predicting long-term post-transplant renal graft survival during NMP would make this technique particularly useful as a pre-transplant diagnostic tool
When To Start NMP
The optimal timing to start NMP is dependent on the aim of its clinical application, that is preservation, viability assessment or repair all necessitating an individual tailored strategy.
Prospects:
Finding novel biomarkers and elucidating pathophysiological processes can eventually pave the way for meaningful pre transplant kidney assessment followed by active initiation of regeneration by targeting the associated pathways ex vivo
Conclusion
An increasing number of centers are investigating renal NMP either as a preservation tool, a viability assessment tool or a repair platform. There is great diversity among NMP protocols and interpretation of readouts during NMP. No validated ex vivo viability biomarkers have been identifies. Best practice guidelines and consensus on protocols would likely progress the files
The level of evidence is level V as this is a review article
Abdulrahman Ishag
2 years ago
Normothermic machine perfusion (NMP);
Uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period
.
RENAL NMP PROTOCOLS;
The different fundamental facets of NMP protocols can be roughly divided into;
A-The perfusate composition.
B- Arterial pressure delivered by the pump.
C-Oxygenation .
D-Temperature.
E-Urine replacement .
1-The perfusate composition;
NMP perfusates are typically supplemented with different compounds to provide nutrients that aim to preserve renal cell viability.
a-Red blood cell (RBC)-based perfusates.
b-Perfusate based on Ringer’s lactate and STEEN solution, which creates a physiological oncotic pressure and osmolarity.
c-Perfusate based on human albumin and electrolytes within physiological ranges.
To date, no study has convincingly investigated the roles of individual perfusate components or even compared existing #uids side-by-side to establish which components could lead to an optimal NMP, as well as the best posttransplant outcome.
2- B- Arterial pressure delivered by the pump;
No consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
Reported mean arterial pressure (MAP) during renal normothermic perfusion range between 40 and 95 mm Hg and Pulsatile 90/70
3-Oxygenation ;
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg.
4-Temperature;
Typically, the temperature during NMP is set at 37ºC, but this might be different, depending on the speci!c aim of ex vivo perfusion.
5-Urine replacement ;
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume.
DIAGNOSTIC POTENTIAL;
Although the potential of NMP as a diagnostic platform has been recognized, the search for relevant and independently predictive viability markers has only just started and is likely to increase with wider clinical implementation of NMP.
1-Assessing Nephron Function and Injury
2-Assessing the Vascular Compartment
3-Assessing the Immune (Cell) Compartment.
4- Assessing Long-term Renal Function.
1-Assessing Nephron Function and Injury;
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
2-Assessing the Vascular Compartment;
In vivo, endothelial damage and viability are reflected by an increase in vascular resistance related to a combination of disruption of the endothelial cell lining favoring thrombosis and the “no-reflow” phenomenon, which is the sub optimal restoration of perfusion after a period of ischemia.
3-Assessing the Immune (Cell) Compartment;
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.
Despite the absence of circulating leukocytes during NMP, resident leukocytes are released. It is unclear what the implications of the presence and release of resident leukocytes are and whether the phenotype and behavior of these cells could be predictive of post transplant outcomes.
4-Long-term Renal Function;
Because long-term graft survival and function are determined by multidimensional factors, an integrative approach may be required for pretransplant outcome prediction that combines viability measurements during NMP with donor, organ, and recipient characteristics, which all come with their own multifaceted complexity.
WHEN TO START NMP;
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
LOGISTICAL AND ECONOMIC IMPLICATIONS;
The actual costs associated with the clinical implementation of NMP remain largely unknown.
Other major costs comprise the NMP disposables, perfusate components, equipment needed to obtain samples, analyses for viability assessment, facility fees, NMP training, and depreciation of the perfusion device.
PROSPECTS;
Finding novel biomarkers and elucidating pathophysiological processes can eventually pave the way for meaningful pretransplant kidney assessment, followed by active initiation of regeneration by targeting the associated
pathways ex vivo.
CONCLUSION;
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
What is the level of evidence provided by this article?
Level V
Isaac Abiola
2 years ago
SUMMARY
Introduction
The introduction of expanded donor criteria has increased the donor pool for kidney transplantation, but the attendant rate of DGF, primary nonfunction and acute rejection has also increased. One of the major causes of the above is the increased susceptibility of DCD due to ischemic reperfusion injury. Moreso, many of the marginal kidney are usually discarded because of uncertainty on the quality and viability of the organ in short and long term. The normothermic machine perfusion is a tool that provides a near physiological state for the retrieve organ to preserve it and to do pretransplant viability test on the organ.
Function of NMP
assessment of renal function of the graft
serves as a promising preservative machine
reduces cold ischemic time
potential ability to reduce DGF
ability to serve as a repair tool
Renal NMP protocol
a) Perfusion composition
this comprises of, oxygen carrier, albumin, buffer, electrolytes, antibiotics, antioxidants, impermeant, and addictive
b) Arterial pressure provided by the pump
oxygenation, temperature, urine replacement
Diagnostic potential of NMP
assessing nephron function and injury
assessing the vascular compartment
assessing the immune (cell) compartment
long time renal function
The timing to deployment of NMP as tool depend on the aim if it is for preservation, viability assessment or repair of the graft
Logistic and economic implication of use of NMP
technically complex tool to deploy
time consuming in operation
risk of technical failure that may ultimately affect the quality of the organ
additional training and deployment of dedicated perfusion staff
Conclusion
The idea role played by NMP has still been investigated by many transplants’ centers if for preservation, viability or as a repair tool. Moreso, different school of thought exist on the NMP protocols and interpretation of results couple with lack of ideal biomarkers for viability of the retrieved organs
The level is 5, because is a narrative review with expert opinions
Rihab Elidrisi
2 years ago
NMP is anew technology which will add on the transplant and potentate the effect of the transplanted organ by keeping the organ in environment similar to the body.
This technique allowed us now to accept the kidney which used to be discarded in the past.
this technique allow to provide the transplant organ with oxygen and nutrients which is essential to reduce the DGF.
we can assess this machine by assessment for the creation clearance and and Na fraction excretion .
we need to sasses his endothelial vascular viability as well
when to start is depends on what we are looking for viability or repair and so on
The increased utilization of high-risk renal grafts for transplantation requires optimizing pretransplant organ assessment strategies. Unfortunately, current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. Initial clinical experience shows that NMP can potentially increase the number of kidney transplants by evaluating and transplanting kidneys that had initially been discarded for transplantation.
Preclinical and early clinical experience suggest that NMP might reduce DGF compared with static cold storage (SCS).
This review overviews the fundamentals of sizeable preclinical animal and clinical NMP protocols used by several leading centers because no single united NMP protocol exists to date also provides a framework to consider when assessing kidney viability during NMP and discusses the logistical and economic impact that clinical implementation of NMP is likely to have on the renal transplant field.
RENAL NMP PROTOCOLS:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP per
Ø Perfusate Composition:
Ø Arterial Pressure Provided by the Pump
Ø Oxygenation
Ø Temperature
Ø Urine Replacement DIAGNOSTIC POTENTIAL:
The potential of NMP as a diagnostic platform has been recognized. However, the search for relevant and independently predictive viability markers has just started and is likely to increase with more comprehensive clinical implementation of NMP.
1-Assessing Nephron Function and Injury
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
2- Assessing the Vascular Compartment:
Endothelial damage is an essential determinant of renal viability.
3- Assessing the Immune (Cell) Compartment
Long-term Renal Function
Currently, almost all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival.
WHEN TO START NMP
The optimal timing to start NMP depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual-tailored strategy.
LOGISTICAL AND ECONOMIC IMPLICATIONS
NMP is technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at normothermic temperatures
Clinical implementation of NMP will result in structural changes to the current donation and transplantation logistics. It will most likely necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for the sterile conduct of NMP.
In addition, dedicated staff trained in organ perfusion will need to join the surgical teams. I depend on when NMP is initiated in the donation and transplantation cascade.
CONCLUSION
An increasing number of centers are investigating renal NMP as a preservation tool, viability assessment tool, or repair platform. Great diversity exists among
NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish
practical preservation by NMP, as well as the use of NMP as an objective pretransplant organ assessment tool and
eventually, interpret NMP data on a standardized global
basis, more uniformity in NMP protocols is of paramount
V. Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool 1. Please provide a summary of this article 2. What is the level of evidence provided by this article?
Summary of the article Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool
Renal normothermic machine perfusion (NMP):
1. provides a near-physiological organ preservation technique;
a) It circulates a warm (35–37 oC) perfusion solution through the renal vasculature.
b) It delivers oxygen and nutrients.
c) At normothermia, cellular metabolism can resume and replenish ATP synthesis.
2. NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
3. Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
4. NMP serve as a promising superior preservation strategy and a platform for active organ reconditioning.
5. NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
6. The different fundamental facets of NMP protocols can be divided into:
a) The perfusate composition:
1) Oxygen carrier – RBCs, artificial oxygen carrier.
2) Colloid – human albumin.
3) Impermeant – glucose, Dextran 40, mannitol, lactate, gluconate.
4) Buffers – sodium bicarbonate.
5) Electrolytes – Na+, K+, Ca++, Cl-.
6) Antibiotics cefuroxime, amoxicillin/clavulanate.
7) Additives -glucose, amino acids, vasodilator, heparin, dexamethasone.
b) Arterial pressure delivered by the pump;
1) Continuous pressure with MAP range 40 – 95 mmHg.
2) Pulsatile pressure with MAP range 90/70 mmHg.
c) Oxygenation;
1) Carbogen (95% O2/5% CO2)
2) pO2 550 -650 mmHg.
d) Temperature;
1) abrupt rewarming
2) gradual rewarming
e) Urine replacement;
1) Urine recirculation
2) Ringer’s lactate/solution.
NMP; Diagnostic potential
1. Assessing nephron function and injury
a) Creatinine clearance and fractional sodium excretion.
b) kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin.
c) Aspartate aminotransferase and lactate correlated with posttransplant renal graft function.
d) Higher levels of Flavin mononucleotide (FMN) during NMP were found in kidneys with DGF and PNF after transplantation. 2. Assessing the vascular compartment:
Cambridge group uses macroscopic appearance, renal blood flow, and urine output during 1h of NMP performed at the end of SCS.
3. Assessing the immune(cell) compartment
Inflammatory cytokines are released during kidney perfusion, although it is currently unclear which cytokines could be predictive of outcome. 4. Long term renal function is affected by:
a) Pre-existing renal fibrosis in donor grafts.
b) The quality of the donor organ.
c) Prolonged warm ischemia time and anastomosis time.
d) Recipient’s factors; increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardio- vascular complications at the time of transplantation are associated with adverse long-term outcomes.
When to start NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair.
a) Preservation and repair need prolonged time on NMP(strategy 1).
· strategy 1: NMP for the entire preservation interval.
b) NMP as assessment tool has a wider range of options (strategy 2, 3, and 4).
· Strategy 2: a short period of NMP at the donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for transportation to the recipient center
· Strategy 3: NMP at the recipient center only.
· Strategy 4: an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP.
What is the level of evidence provided by this article?
This is a review article
Level of evidence grade 5
This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. At normothermia, cellular metabolism can resume and replenish ATP synthesis, which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury, might be performed during NMP. in recent years, considerable effort has been directed at the development of NMP as either an organ preservation, assessment, or repair platform.
Although NMP as an ex vivo organ evaluation platform may seem intuitive and technologically within reach, the key question in this regard is what to assess while a kidney is on the pump.
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement (figure 1).
file:///C:/Users/abosa/AppData/Local/Temp/msohtmlclip1/01/clip_image001.png
Although the potential of NMP as a diagnostic platform has been recognized, Assessing Nephron Function and Injury, Assessing the Vascular Compartment & Assessing the Immune (Cell) Compartment.
WHEN TO START NMP?
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy (figure 2)
file:///C:/Users/abosa/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png
LOGISTICAL AND ECONOMIC IMPLICATIONS
– Clinical implementation of NMP will result in structural changes to the current donation and transplantation logistics. This will most likely necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for the sterile conduct of NMP. In addition, dedicated staff, trained in organ perfusion, will need to join the surgical teams.
The actual costs associated with the clinical implementation of NMP remain largely unknow
– innovative imaging techniques could be applied during renal NMP such as MRI, PET & MPM imaging may provide more information about regional differences in the functional properties of the ex vivo perfused kidney. These techniques could be a valuable add-on to renal viability assessment during NMP in the near future.
CONCLUSION :
– An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform.
– Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified.
– To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance.
– Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
This article seeks to develop an understanding about NMP or renal normothermic machine perfusion. This is because of the importance of perfusion when using extended criteria organs for transplantation and the ever continuing scarcity of donor organs. Organs need to be preserved properly and assessed for validity before being accepted for the recipient.
NMP allows for a near physiological organ preservation technique that circulates warm solution through the kidneys providing oxygen and nutrients to kidney cells. This replenishes ATP formation and allows the physician to assess functional capacity of the kidney as well as extent of injury. In doing so, we aim to increase the number of kidneys that can be used for transplantation and reduce organ wastage.
Other than diagnosis, NMP also serves as a valuable organ preservation technique. A very important function it plays is reducing CIT and thus reducing the impact of ischemic reperfusion injury. The means that NMP can also reduce the incidence and risk of DGF in comparison with static cold storage.
The perfusate used in the NMP protocols are usually RBC based to ensure adequate oxygenation. Some centers use ringer’s solution since it has low oncotic pressure. Insulin is added to the solution in some cases to facilitate glucose absorption.
Temperature is set at 37 degree Celsius. Loss of circulating volume by urine production of the ex vivo perfused kidney has to be replaced to maintain circulating volume. This was done with ringer’s lactate addition and higher flow rate.
Nephron function and extent of injury can be assessed. Markers for this include creatinine clearance and fractional sodium excretion. Non specific injury markers include AST and lactate, corresponding to post transplant renal graft function.
Endothelial damage is assessed for renal viability. Increase in vascular resistance can occur due to disruption of endothelial lining favoring no reflow phenomenon and suboptimal restoration of perfusion following ischemia. Presence of RBC plugs can be seen contributing to injury. Increased flow and decreased resistance with the use of NMO will increase perfusion and keep perfusion pressures constant and stable, reducing injury extent and risk.
Late graft loss is usually from renal fibrosis due to continuous alloimmune response to the donor graft despite immunosuppression. NMP can help to diagnose this pre transplant.
Innovative imaging methods for NMP help widely. These include near infrared spectroscopy MRI, PET scan, contrast enhanced ultrasound, ultrafast ultrasound imaging, laser speckle imaging, and multi photon microscopy imaging. These help to focus on renal physiology during NMP non-invasively.
in conclusion
Renal NMP can be used as a preservation tool or viability assessment tool
No standardization exists at present
No biomarkers have been identified
Uniform protocols need to be established
Great amount of research is needed to progress in this area
Best practice guidelines need to be developed
Ideal perfusate composition, duration of perfusion and pressure and need for urine recirculation are some of the areas which need to be focussed in research to make NMP more widely practical and effect.
Level of evidence
This is a narrative review. Hence level of evidence is 5.
Please provide a summary of this article Introduction:
Organs from extended criteria donor, or after circulatory death donors, prone to ischemia reperfusion injury resulting in DGF, PNF, graft failure.
Many of offered kidneys are discarded, due to doubt in their viability and capacity to provide adequate short and long time graft function.
Makes the discovery of an organ assessment tool, for decreasing the organ decline based on a clinical guided decision. Normothermic Machine Perfusion (NMP) is a promising tool, providing near physiological organ preservation method, and decreasing the ischemia reperfusion injury. RENAL NMP PROTOCOLS: Perfusate Composition:
– Red blood cell base perfusate.
– Ringer’s solution based perfustae
– Ringer lacate and STEEN perfusate.
– MePEP consortium human albumin based perfusate.
All used to maintain a stable near-physiological environment during perfusion, no studies demonstrate which perfusion is better for post transplant outcomes. Arterial Pressure Provided by the Pump:
Pulsatile pressure during NMP results in enhanced renal blood #ow, creatinine clearance, sodium reabsorption, and lower tubular injury.
Superior renal function and endovascular injury outcomes for higher MAPs (75 and 95 mm Hg). Oxygenation:
Perfusate oxygen concentration of 550–650 mm Hg with a small percentage of carbon dioxide to create optimal acid-base homeostasis, but did not infuence tubular function, creatinine clearance, urine output, or biomarkers of renal injury during simulated reperfusion after NMP.
Stubenitsky oxygen consumption formula [(arterial Po2 –venous Po2 )×perfusate flow rate/weight]. Temperature:
Better tubular and renal functions was found with normothermic (37 ºC).
Controlled oxygenated rewarming also enhances early post-transplant cortical microcirculation, preventing the renal cells from damage by pumping against high cortical resistance. Urine Replacement:
Urine recirculation applied in Toronto results in a signicantly higher perfusate flow rate, revitalized metabolism determined by upregulated levels of ATP synthase, NADH dehydrogenase, no data in graft function to recommend such replacement. DIAGNOSTIC POTENTIAL: Assessing Nephron Function and Injury:
Creatinine clearance and fractional excretion of sodium frequently used markers for nephron function.
Oxygen consumption has been proposed as a marker of kidney metabolic activity in animals.
Kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and NGAL originates from the thick ascending loop could be a marker for tubular function.
AST and lactate correlated with post-transplant renal graft function, measured by peak serum creatinine. Assessing the Vascular Compartment:
Flow—not resistance—is one of the parameters of the kidney quality assessment score, which combines macroscopic appearance, renal blood #ow, and urine output during 1h of NMP performed at the end of SCS.
A loss of vasoactive response indicates endothelial dysfunction and might be used for viability testing. Long-term Renal Function:
Long-term outcomes related to :
Donor factors: quality of the organ, age of the donor, long warm ischemia time and anastomosis time. Recipient factors: older age, kidney disease recurrence, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications. These factors, are required for pre-transplant outcome prediction. WHEN TO START NMP:
Start NMP depends on the aim of organ preservation, viability assessment, or repair, necessitate an individual tailored strategy.figure attached. LOGISTICAL AND ECONOMIC IMPLICATIONS:
Special perfusion room, personnel to handle and transfer the organ to recipient center, time consuming, risk of technical failure, high cost, are the limitations of its use. PROSPECTS:
The multidimensional biological complexity of assessing renal allograft function and predicting post-transplant outcome mandates an integrative approach with the implementation of multiomics data (eg, a combination of genomics, transcriptomics, proteomics, and metabolomics).Such a multilayered omics approach could be performed during NMP- multiple imaging tools can be used eg; MRI, PET, CEUS …etc. CONCLUSION:
NMP is an organ preservation, viability assessment tool, and a repair platform, investigated in many centers with different protocols, it has some logistic and economic issues limiting its wide use.
Further studies identifying the ideal perfusate, perfusion duration and pressures, and the need for urine recirculation and specific additives, for renal NMP.
What is the level of evidence provided by this article? Level of evidence V – review article.
Kidney donation from DCD and ECD are at high risk of DGF and primary non function. The discard rate is high as there is concern about quality. A number of quality assessment tools exist but non can demonstrate adequate power to guide clinical decisions. More objective quality assessment tool are required pre transplant.
Renal normothermic machine perfusion -NMP provides near physiological organ preservation technique and its circulation is at 35-37C.
The solution used has temperature between 35-37C and is pulsatile by using a pump. It provides oxygen by extracorporeal membrane oxygen . Vasodilators , insulin and glucose can be added to solution. The solution is usually rich in nutrients like electrolytes. human albumin, ringer lactate etc.
The NMP reduced cold ischemia time leading to less reperfusion injury and DGF. It provides adequate environment of ATP synthesis. Thus , it can be used for donor kidney quality.
Oxygenation- O2 %- 95% /CO2 5%
PaO2 – 550-650 mmHg
Urine Replacement- Loss of circulating volume can be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
The advantages includes, preservation, assessment of viability and repair
Types of NMP.
1- Entire preservation
2- At donor site
3- At recipient site.
The NMP has some disadvantages like , higher cost , time consuming, need for more resources and logistics
What is the level of evidence provided by this article?
Normothermic machine perfusion (NMP) is a method used for preservation of organs, the solution is characterized by the followings:
Pulsatile (using centrifugal or roller pump)
Oxygenated (using RBCS or synthetic oxygen carriers)
Nutrient-enriched (using Ringer’s lactate, STEEN or human albumin 5%, electrolytes based solution)
Additives occasionally added (vasodilator and glucose ± insulin)
Warm solution (35–37 ºC)
NMP may offer several advantages over the cold solution machine perfusion including:
First, it allows for better evaluation of donor kidney quality and viability
Second, it provides optimal condition for cellular metabolism and ATP synthesis, which may be used for assessment of functional capacity of the kidney
Third, it reduces cold ischemia time, so decrease the incidence of ischemia perfusion injury with subsequent reduction in the incidence of DGF
Arterial Pressure Provided by the Pump
Pulsatile pressure Is associated with improvement of renal blood flow GFR and lower the incidence of ATN over static pressure
The use of centrifugal is preferred over roller pump as it is less harmfull of the RBCS
Target MAPs of 75 and 95 mm Hg is recommended over lower targets (40-75) in case of continuous pressure perfusion pump as it is associated with better renal function and lower endovascular injury
In pulsatile pressure target of 90/70 is reasonable
Oxygenation
Recommended O2 percent : 95% O2/5% CO2 (a small percentage of CO2 should be added for acid-base homeostasis.)
Recommended O2 pressure : Po2 550 – 650 mm Hg
Temperature
Better tubular and renal functions was found with normothermic (37 ºC), rather than subnormothermia (32 ºC), solutions
Normothermia can be reached either abruptly or gradually (reach 20 over 1.5 hour then abruptly to 37)
Assessment of the quality of donor kidney
Assessment of viability and vasculature using vascular resistance and flow as markers for endothelial damage
Biomarkers may be used to assess the integrity of PCT (KIM-1) and thick assesnding limb (neutrophil gelatinase-associated lipocalin) which is the most susceptible portion for ischemia
AST and LDH are nonspecific cell injury markers which was found to be correlated with graft function
Benefit of Normothermic machine perfusion (NMP)
Preservation
Viability assessment
Repair through removal of microthrombi and reduction of inflammation which can be done when using leuck-reduced perfusion compared to whole blood perfusion
When and where to start NMP
At the entire preservation period (donor and recipient site)
At the donor site for a short period followed by CP
At recipient site which is done either for a short period not followed by CP (the commonest) or intermittent followed by CP
Problems with NMP
Complex
Expensive
Risk of failure with risk of ischemia to the graft
Time consuming
Needs a specialized perfusion room , personnel trained in organ perfusion
The gap between demand-supply of organs has led to increased use of extended criteria donors (ECD) and donation of cardiac death (DCD) which is associated with increased delayed graft function (DGF), primary nonfunction (PNF) and graft failure. So a reliable qualitative assessment of organ pre-transplant will help in better graft outcomes.
Renal normothermic machine perfusion (NMP) is a near-physiological way of preserving organs by providing oxygen and nutrients at 35-37 degree Celsius temperature replenish the ATP synthesis and resuming cellular metabolism. NMP decreases cold ischemia time and hence ischemia-reperfusion injury. So, NMP has 3 major functions: evaluating viability of the kidney, preservation of the kidney, and active organ repair.
Renal NMP protocols:
1) Perfusate composition: It involves an oxygen carrier (RBCs or synthetic oxygen carriers), different compounds like albumin, Ringer solution, amino acids, glucose, electrolytes (sodium, potassium, calcium, chloride), buffer like sodium bicarbonate, antioxidants and antibiotics.
2) Arterial pressure provided by the pump:Centrifugal pump is less harmful for RBCs than roller pump. Continuous pressure with mean arterial pressure of approximately 75 mm Hg (range 40-95 mmHg) is used mostly, although pulsatile pressure has been shown to increase renal blood flow, creatinine clearance and sodium reabsorption.
3) Oxygenation: Use of supraphysiological pO2 of 550-650 mmHg with a small percentage of carbon dioxide (95% O2, 5% CO2) is preferred, although hyperoxia is associated with renal injury due to reactive oxygen species production.
4) Temperature: The temperature is set at 37 degree Celsius, but rewarming may be gradual or abrupt. Gradual rewarming from cold (0-7 degrees) preservation till 20 degrees has been shown to increase early post-transplant microcirculation.
5) Urine replacement: Replacement of lost fluid can be either by recirculation of the urine formed, or by addition of Ringer solution.
Diagnostic potential: Nephron function and injury can be assessed by looking at creatinine clearance, fractional sodium excretion and other biomarkers like NGAL (signifies severe renal injury), flavin mononucleotide (correlates with DGF and PNF), KIM-1(predicts DGF), etc. Endothelial damage is characterized by increase vascular resistance, thrombosis and ‘no-reflow’ phenomenon. Kidney quality assessment score includes renal blood flow, macroscopic appearance and urine output during first hour of NMP.
When to start NMP: The optimal timing of NMP initiation is not known, but depends on the intended aim of its use. If the aim is preservation as well as repair, then NMP should be used from procurement to implantation. If it is to be used only as assessment tool, then it can be used either at time of procurement, or at the transplant centre, or at an intermediary hub after procuring the organ and before transplanting it. The most commonly used strategy is short period of NMP at transplant center, assessing the quality just prior to transplanting the kidney.
NMP is complex, time-consuming, costly, needs extra manpower, with increased risk of technical failure exposing the organ to ischemia at normothermic temperatures. Pre-transplant organ viability assessment can be complemented by novel approaches including multiomics analysis and imaging methods like MRI, PET, contrast enhanced ultrasound etc.
To conclude, NMP has three-pronged advantage: organ viability assessment, organ preservation, and organ repair.
2. What is the level of evidence provided by this article?
The level of evidence is level 5: Narrative review
1. Please provide a summary of this article
Introduction
ECDs or DCD transplants are more susceptible to IRI which in turn increases the risk of DGF, PNF, & graft failure.
Many kidneys offered for are being discarded due to concerns about their ability to give adequate short- & long-term function.
Good pre-transplant organ viability assessment tools would have provided a favorable risk–benefit ratio to a number of waitlisted patients.
The existing non-perfusion-based pre-TX quality assessment models didn’t show adequate predictive value power to guide the decision for individual donor kidneys.
So, there is a need for a more objective & accurate pre-TX organ quality assessment tools.
Renal normothermic machine perfusion (NMP) would, likely, fill this gap as an assessment tool & reduces the organ discard rates.
Renal normothermic machine perfusion (NMP)
1.Allows near-physiological organ preservation via circulating a warm (35–37 ºC) solution through the renal vessels & thus permits normal cellular metabolism & ATP synthesis, & provide a better assessment of kidney functional & transplant-ability of organs that would have otherwise been discarded.
2.NMP is a promising superior preservation tool for active organ reconditioning.
3.NMP reduces CIT & reduces the adverse effect of IRI. NMP reduces DGF compared with static cold storage (SCS). Renal NMP protocols
NMP provides the kidney with oxygenated & nutrients-rich perfusate throughout an extra-corporeal membrane technology. Perfusate Composition:
-RBC-based perfusates are used to give adequate tissue oxygenation.
-Recent data suggest that synthetic oxygen carriers are equivalent to RBCs.
-NMP perfusates are enriched with nutrients to preserve renal cell viability.
-The Cambridge group uses Ringer’s solution as it has a low oncotic pressure.
-The Toronto group uses a perfusate based on Ringer’s lactate & STEEN solution that makes a physiological oncotic pressure & osmolarity.
-MePEP consortium uses a perfusate based on human albumin & electrolytes within physiological ranges.
-All centers seem supplement their perfusate with a vasodilator & glucose. Insulin is also added by some centers.
-Which perfusate components are most optimal for NMP remains to be investigated. Arterial pressure provided by the pump
-Centrifugal pumps are mostly used; they are less harmful to RBCs (compared to roller pumps).
-Continuous pressure is mostly used; however, pulsatile pressure allows better renal blood flow, creatinine clearance, Na+ reabsorption, & lower tubular injury.
-MAP during NMP is 40 – 95 mm Hg.
-Hosgood et al. found better outcome for higher MAPs (75 & 95 mm Hg) vs 55 mm Hg regarding renal function & endovascular injury during NMP & subsequent simulated reperfusion. Oxygenation
-Supra-physiologicalperfusate O2 concentration (550–650 mm Hg) are used, often balancedwith a small 5% CO2 for optimalacid-base status.
-O2 consumption during NMP is reported. Temperature
-Typically set at 37ºC; might differ according to specific aim of ex vivo perfusion.
-Tubular & renal function are better preserved with normothermic (37 ºC) vs sub-normothermic (32 ºC) perfusion.
-However, Brasile et al used subnormothermic
perfusion; there was no relevant renal injury, rather there was showed superior post-tranplant urine production & serum creatinine compared with nonperfused kidneys.
53 An important
-Controlled oxygenated rewarming enhances early post-transplant cortical microcirculation, & thus potect the renal cells injury from pumping against high cortical resistance.
-Gradual rewarming is done up to 20 ºC over a period of 90 min. Urine replacement
-Urine made by the ex vivo perfused kidney is replaced to maintain the circulating volume.
-Replacement is Ringer’s solution or Ringer’s lactate to the perfusate.
-Recirculating the urine is an alternative & lead to higher perfusate flow rate & better cell metabolism. Diagnostic potential Assessing nephron function & injury
-CrCl & FeNa are the markers for nephron function; however, it is not clear whether they predict post-transplant function during NMP bcz the changes in perfusate composition & perfusion pressures will change hydrostatic & oncotic pressures, & thus affect filtration & produced urine.
-Oxygen consumption is proposed as a marker of kidney metabolic activity in animal models; however, it is unclear if this works in NMP.
-Non–cell-specific injury markers AST & lactate correlated with post-transplant renal graft function, measured by peak serum creatinine.
-FMN, a lesser-known biomarker, also correlates with post-transplant renal graft function. Assessing the vascular compartment
In vivo, endothelial damage & viability are reflected by an increase in vascular resistance that is due to disruption of the endothelial cell lining.
Tietjen et al found RBC thrombotic plugs in cortex & medulla during NMP of discarded kidneys; these likely contribute to injury & the no-reflow phenomenon.
Cambridge group used flow (not resistance) as one of the parameters of the kidney quality assessment; this scoring gave some evidence that NMP kidney viability assessment can lead to TX of initially discarded kidneys.
Bath et al (porcine model of NMP) reported that kidneys, exposed to 2 h of WIT, have no vasodilatory capacity on exposure to acetylcholine, indicating irreversible injury of endothelial cells; in contrast, exposure to 16 h of CIT only showed a reduced response to acetylcholine. Assessing the Immune (Cell) Compartment
In vivo, IRI leads to sterile inflammation, thus activates innate & adaptive immune systems, as well as leukocyte recruitment which is reinforced by cytokine & chemokine release.
Leuko-reduction of NMP perfusate may minimize inflammation compared with whole blood perfusion. Long-term Renal Function
Predicting long-term post-TX graft survival during NMP would be valuable as a pre-TX diagnostic tool.
Preexisting renal fibrosis in donor grafts is associated with reduced long-term graft survival (severity of fibrosis correlates with the duration of graft survival).
Long term outcomes are also affected by:
-Quality of the donor organ
-Biological age of the donor
-Prolonged WIT
-Anastomosis time
-Regarding recipient factors
-Recurrence of native kidney disease
-Anti-HLA immunization
-Ethnic background (African American)
-Longer time on dialysis
-CV complications at the time of TX
So, an integrated approach, combining the above factors with viability measurements during NMP, is required for pre-TX outcome prediction. When to start NMP
Different applications exist:
1. NMP for the entire preservation interval
2. A short period NMP at donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for TX to the recipient center
3. Short NMP at the recipient center only
4. An intermittent NMP in an organ hub or at the recipient center, after which kidneys are again preserved with CP. Logistical & economic implications of NMP: Technically complex
Time-consuming
Risk of technical failure (leaving theorgan exposed to ischemia at normothermic temp).
No“stand-alone” renal NMP devices are available. requiring any perfusion to be supervised at all
Clinical use of NMP will structurally change the current donation & TX logistics.
True cost associated with the clinical use of NMP is unknown. Costs include payments to out-of hours expertise, the NMP disposables, perfusate components, equipments needed, facility fees, NMP training, etc.
Cost effectiveness is seen when considering the organs that might be salvaged from discard when NMP is used. Prospects
Identification of novel biomarkers would simplify analyses to a rapid point-of-care measurement leading to a very short pre-TX assessment time window. ========================== 2. What is the level of evidence provided by this article? Level V
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
Continuous pressure – MAP maintained at 40-95 mmHg
Oxygenation
Carbogen (95% O2/ 5% CO2), pO2 : 550-650 mmHg
Temperature
Gradual / abrupt rewarming
Urine Replacement
Urine recirculation
RL solution
The various Perfusate constituents per research group are
Cambridge group
Toronto group
MePEP group
Oxford group
When to start NMP:
Different applications of renal normothermic machine perfusion:
NMP for the entire preservation interval
Short period of NMP at the donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for transportation to the recipient center;
NMP at the recipient center only
an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP.
Conclusion:
Great diversity exists among NMP protocols
No validated ex vivo viability biomarkers have been identified, to date.
Best practice guidelines and consensus on protocols would likely progress the field.
What is the level of evidence provided by this article? Level V
Please provide a summary of this article
-The shift toward the utilization of older organ donors with more comorbidities has stressed the importance of robust pretransplant organ viability assessment.
-Organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
-Many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their capacity to provide adequate short- and long-term function.These organs in particular would benefit from reliable pretransplant organ viability and quality assessment.
-Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
-NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
– Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
-Considerable effort has been directed at the development of NMP as either an organ preservation, assessment, or repair platform.
-NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
– NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
-Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
-The Cambridge group uses a perfusate based on Ringer’s solution, which has a relatively low oncotic pressure .
-The Toronto group uses a perfusate based on Ringer’s lactate and STEEN solution, which creates a physiological oncotic pressure and osmolarity.
– Another perfusate that is based on human albumin and electrolytes within physiological ranges is used by the MePEP consortium To maintain a stable near-physiological environment during perfusion, various compounds are typically infused.
– No study has convincingly investigated the roles of individual perfusate components or even compared existing #uids side-by-side to establish which components could lead to an optimal NMP, as well as the best posttransplant outcome.
-There is no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
– There is some evidence that pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
-Reported mean arterial pressure (MAP) during renal normothermic perfusion range between40 and 95 mm Hg.
– Preclinical studies conducted by Hosgood and colleagues found superior outcomes for higher MAPs (75 and 95 mm Hg) and now typically set their pressure at 75 mm Hg.
-Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of carbon dioxide to create optimal acid-base homeostasis.
-Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the specific aim of ex vivo perfusion.
– It has been suggested that controlled oxygenated rewarming improves cellular homeostasis and mitigates rewarming injury in a porcine NMP model. Controlled oxygenated rewarming also enhances early posttransplant cortical microcirculation .
– Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
-Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
-Endothelial damage is an important determinant of renal viability. Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
-The absolute values of renal blood flow and urine production will strongly depend on perfusion pressure settings as well as perfusate composition (additives and oncotic pressures).
-In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release. Additionally, the endothelium and epithelial cells play a key immunological role in this postreperfusion inflammatory response.
– Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
-Long-term outcomes are also affected by the quality of the donor organ, which is mainly determined by the biological age of the donor and by factors during donation and transplantation.
-Recipient factors, increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background
(African American), longer time on dialysis, and cardiovascular complications at the time of transplantation are associated with adverse long-term outcomes.
-The potential of NMP to ameliorate renal preservation and serve as a repair platform most likely demands prolonged NMP times .
-Today, a short period of NMP at the recipient center has been most commonly report.
-Future researchshould focus on identifying the ideal perfusate composition,perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP. What is the level of evidence provided by this article?
Level 5
· Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
· At normothermia, cellular metabolism can resume and replenish ATP synthesis, which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury, might be performed during NMP.
· Initial clinical experience shows that NMP has the potential to increase the number of kidney transplants by evaluating and transplanting kidneys that had initially been discarded for transplantation.
· NMP improves cold ischemia time.
· It may may lower DGF compared to cold storage.
· Use of extracorporeal membrane oxygenation and nutrient-enrich the kidney perfusate.
· Perfusate composition, pump-delivered arterial pressure, oxygenation, temperature and urine replenishment are essential NMP aspects.
· The potential of NMP reaches beyond its diagnostic applicability, also encompassing the possibilities to serve as a promising superior preservation strategy and a platform for active organ reconditioning.
· An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform.
This study aims to review is to address the basics of the renal-NMP protocols and suggest basic outlines for future development and progress also high light the associated logistical and economic impact.
Summary
Normothermic machine perfusion technology with near physiologic perfusion of the organs which benefits with more objective assessment of the organ’s viability and quality at the time of organ procurement from marginal older donor with multiple comorbidities compared to the use of subjective assessment that limited to clinical donors’ elements with low predictive values. Based on that many centers move and started their own local NMP protocol and renal viability criteria. however, till date no validation exists of on-pump viability markers and still there is no standardized NMP protocols. The concept of renal normothermic machine perfusion (NMP) delivers a near-physiological organ protection technique because it circulates a warm (35–37 ºC) perfusion solution via the renal vasculature carrying oxygen and nutrients, and maintain normothermia, so cellular metabolism can continue and replenish ATP synthesis and this allowed for more accurate organ quality calculation including the renal functional capacity and the degree of renal injury and this will help in increased the numbers of transplantation.
NMP not only have diagnostic predictive values but also considered the preferred innovative preservation techniques and platform for active organ repairing by its effect on reducing the cold ischemia time, and reduce the risk of Ischemic reperfusion injuries and DGF risk compared to static cold storage (SCS).
When to start NMP ‘
Timing of NMP based on its clinical indication (organ preservation, viability assessment , or repair ) and summarized in four strategies( fig 2).
Logistical and economic implications of NMP
Technically its complex, over-whelming, there is a risk of technical failure which can ended with organ damage and discarded, need specialized setting either in operating theater for sterile conducts or special perfusion room., man power with skilled team trained in organ perfusion and worked with surgical team , the overall cost effectiveness not yet unknown but we should consider the cost of the NMP disposables , , perfusate component , equipment, facility fees , NMP training, an clinical research costs . Prospects
Predictions by finding a new biomarkers(still need clinical validation ) and many advanced imaging techniques like multiphoton microscopic imaging for optical sectioning of renal tissues and dynamic studies could be applied during the NMP which give more precise view for the viability and function of the renal tissues( nephron ,microvascular function and apoptosis , tubular endocytosis.
What is the level of evidence provided by this article?
The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies.
Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation.
NMP is rapidly gaining popularity, with various transplant centers developing their own NMP protocols and renal viability criteria.
First, organs from expanded criteria donors (ECDs) or those donated after cir- culatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
At normothermia, cellular metabolism can resume and replenish ATP synthesis,12 which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury, might be performed during NMP.
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfu- sate throughout the NMP period.
Oxygen concentration of approximately 550–650 mm Hg.
The Cambridge group investigated the effect of altered oxygenation during NMP (95% O2 /5% CO2 , P$2 550 mm Hg; 25% O2/5% CO2 /70% N2 P$2 206 mm Hg; 12% O2 /5% CO2 /83% N2P$2 81 mm Hg).
Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the speci!c aim of ex vivo perfusion.
Preclinical work has shown that, upon simulated organ reperfusion, tubular and renal function was better preserved when normothermic (37 ºC), instead of subnormothermic (32 ºC), per fusion preceded it.
Should be gradually rewarmed, starting from cold (0–7 ºC) preservation, is suggested to be approximately 20 ºC.
Ischemia-free kidney transplantation is another promising strategy to mitigate ischemic and hypothermia-induced injury.
Loss of circulating volume by urine production of the exvivo perfused kidney should be replaced to maintain the circuit’s circulating volume.
Ringer solution or ringer lactate used .
Some have used urine recirculation .
==================================================================== DIAGNOSTIC POTENTIAL
1- .Assessing Nephron Function and Injury
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
Oxygen consumption
KIM 1 from PCT
NGAL from TAH
FMN
==================================================================== Assessing the Vascular Compartment
Endothelial damage is an important determinant of renalviability.
Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
Flow is one of the parameter of renal quality .
As healthy endothelial cells respond to vasoactive substances, the disappearance of such a vasoactive response could convey information about endothelial dysfunction and might be incorporated as a variable in viability testing.
==================================================================== Assessing the immune cell compartment
Furthermore, despite the absence of circulating leukocytes during NMP, resident leukocytes are released.
It is unclear what the implications of the presence and release of resident leukocytes are and whether the phenotype and behavior of these cells could be predictive of posttransplant outcomes.
The main reason for late graft loss is the progression of renal fibrosis, which is mainly the result of the continuous alloimmune response to the donor graft despite immunosuppression.
Thereby, preexisting renal !brosis in donor grafts is associated with diminished long-term graft survival, in which the severityof !brosis correlates with the duration of graft survival.
It has been suggested that prolonged warm ischemia time and anastomosis time are associated with adverse long-term outcomes.
Great diversity exists among NMP protocols and interpretation of the readouts during NMP.
Biomarkers have been identi!ed exvivo.
Best practice guidelines and consensus on protocols would likely progress the !eld
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and speci!c additives, for each application area of renal NMP.
==================================================================== What is the level of evidence provided by this article?
Summary of Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment ToolIntroduction
Pretransplant organ viability assessment is crucial for:-
1- Organ from ECDs.
2- Donation after circulatory death.
And donation from those donors can result in DGF, PNF and Graft failure.
Renal normothermic machine perfusion NMP provides a near- physiological organ preservation technique and added assessment of Renal function capacity as well as severity of Renal injury.
NMP cause reduced DGF by reducing cold Ischemia time .
In this review as an ex-vivo organ evaluation plate form other key questions in this regard is what to assess while a kidney is on the pump. Renal NMP protocols:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient- enriched perfusate through out NMP protocol. NMP protocol division:-
1- Perfusate composition:-
NMP protocols use red blood cell based perfusate to ensure issue oxygenation also NMP perfusate provides nutrients that aim preserve Renal cell viability, it could be ringer solution or 5%human Albumin solution.
2- Arterial pressure provided the pump
No consensus about the optional prefusion pressure doing NMP .
It could be:-
(i) Pulsatile or
(ii) Non pulsatile fashion.
Centrifugal pumps considered to be less harmful to RBCs compared to roller pumps.
Reported mean arterial pressure( MAP )during Renal normothermic refusion range between 45-95 mmHg.
3-Oxygenation
550-650 mmHg This a proximately perfused oxygen concentrated from NMP system with small % of CO2 create optimal acid base homeostasis.
4-Temperature
Typically the temperature during NMP is set 37C.
5-Urine replacement
Replacement of urine production of the ex-vivo perfused kidney is crucial as to maintain the current circulating volume- by adding ringer, solution or lactate . Assessing Nephron function and injury
Maker of nephron function:-
(i) Creative clearance.
(ii) Fractional sodium excretion but still is not known whether these parameter doing NMP are predictive for post transplant function.
Flavin mononucleotide(FMN) a lesser known biomarker and is correlate with post transplant renal graft function .
In pilot study found that higher level of FMN during NMP in kidneys with DGF and PNF after Transplantation. Assessing the vascular compartment
Endothall damage is an impact and determinant of renal viability .little known about the meaning of flow and resistance during NMP , although with increasing perfusion time, flow is usually seen to increase white resistance drops. Assessing the immune(cell) compartment
In vivo Ischemic prefusion injury cause sterile inflammation triggering activation of innate and adaptive immune system.
As well as leukocytes that reinforce by cytokines and chemokine release.
Renal of leucocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood.
Perfusion .
The use of a cytokine filter doing the 6hour of pig kidney NMP reduced level of interleukin8 and interleukin 6. Long term Renal Function
Almost all NMP studies investigate biomarker correlated with acute injury and short term graft survival.
Pre existing renal fibrosis in donor graft is associated with decreased long-term graft survival .
The severity of Fibrosis corelated with duration of graft survival. When to start NMP
The optional timing to start NMP depend of the aim of its clinical application that is preservation viability assessment or repair, all necessitating an individual tailored strategy. Logistical and economic implication
NMP most likely necessitate transplant centre to establish a specialized perfusion room or use existing operating theatre for the sterile conduct NMP.
Assessment of hours specialized expertize will be mandatory to ensure a proper course of action other major cost is the equipment and devices. Prospects
Pretransplant kidney assessment is quidded by novel biomarker.
2 diagnostic approach could help
1- Assessment renal allograft function.
2- Predicting post transplant outcome . Conclusion
Great diversity exists among NMP protocols and interpretation of the read outs during NMP .
No biomarker have been identify ex-vivo.
Best practice quid lines and Conesus on protocol and likely progress the field.
Future research should focus on:
Ideal perfusion composition.
Perfusion duration and pressure.
Needs for urine recirculation for each application area of NMP
the evidence of article review is 5
Introduction
Organs from ECD or DCD donors are liable to ischemia reperfusion injury increasing the risk of DGF ,PNF and graft failure.
Therefore quality assessment for those kidneys will be mandatory to evaluate the risk associated with it’s transplantation or the loss associated with discarding it .
Meanwhile there are no predictive models to guide clinical decision for individual donor kidneys.
Renal normothermic machine perfusion (NMP) offers nearly physiological organ preservation by delivering oxygen and nutrients as a warm circulation solution circulates through the renal vasculature.
This enables evaluation of the capacity of renal function
NMP decreases cold ischemia time and lessen the effect of ischemia-reperfusion injury and DGF compared to cold storage.
Standardized NMP viability criteria will be needed.
This review sheds light on the clinical NMP protocols
applied by multiple centres because there does not exist a single NMP protocol . Renal NMP Protocols
NMP uses extracorporeal membrane oxygenation and
compound supplementation technology.
It can be divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement. Perfusate Composition
It affects the assessment of potential renal viability markers during NMP.
Most protocols use (RBC)-based perfusates to ensure adequate tissue oxygenation.
The perfusate is supplied with different compounds to be more nutritive.
A relatively low oncotic pressure ringer based perfusate is used by the Cambridge group to reperfuse kidneys after a long period of static cold storage to reassess the kidney 1–2h before transplantation.
Ringer’s lactate based and STEEN solution was used by Toronto group making a physiological oncotic pressure and osmolarity to preserve organs for a longer period in prolonged normothermic kidney perfusions till 16 h.
MePEP consortium used a perfusate based on human albumin and electrolytes where NMP is combined with mesenchymal stem cells to fix kidneys during ex vivo perfusion.
Oxford group used the same perfusate made for prolonged renal perfusions that lasted up to 24h.
Most centres add to their perfusate a vasodilator and glucose. Cambridge, Toronto, and MePEP groups added Insulin to facilitate glucose absorption. The pump providing the arterial pressure
There is no data available about the best perfusion pressure during NMP.
Centrifugal pumps and a continuous pressure during normothermic perfusion are mostly used.
MAP during renal normothermic perfusion is
40 -95 mm Hg although higher MAP had better outcomes. Oxygenation
A supraphysiological perfusate oxygen concentration of 550–650 mm Hg is used ,it is balanced with CO2 to have acid base homeostasis.
Meanwhile hyperoxia need to be avoided.
Oxygen consumption during NMP is mentioned.
The popular equation is [(arterial Po2 –venous Po2)×perfusate flow rate/weight]. Temperature
It is mostly 37 degrees but can be variable according to the perfusion aim.
Tubular and renal function were better with normothermic than with subnormothermic.
A study revealed good urine production and serum creatinine levels after transplantation with subthermic compared with nonperfused kidneys.
Controlled oxygenated rewarming improves cellular homeostasis and prevents rewarming injury and
enhances early posttransplant cortical microcirculation.
Ischemia-free kidney transplantation is another policy that reduced ischemic and hypothermia-induced injury. Urine replacement
Urine production leading to loss of the circulating volume need to be replaced , Toronto and Cambridge group replaced it by adding Ringer solution or Ringer lactate solution to the perfusate.
Others recirculated the urine to increase the perfusate flow rate. Diagnostic potential
Potential biomarkers with predictive viability assessment during NMP are studied. Assessing Nephron Function and Injury
By creatinine clearance and fractional sodium excretion but their predictive value for post transplantation function is unknown because perfusate can change hydrostatic and oncotic pressures and they represent in vivo organ viability and not ex vivo.
Oxygen consumption was suggested to be indicative of organ viability.
Kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin can be injury markers ,with localising the injury site.
Proximal tubular cells are more liable to warm ischemic injury, whereas distal tubular cells are more liable to cold ischemic injury .
FMN correlated with posttransplant renal graft function. Vascular compartment assessment
One study published that RBC plugs in cortex and
medulla during 4h of NMP of discarded kidneys, can cause injury and the no-reflow phenomenon.
Cambridge group included the flow as a parameter of the kidney quality assessment score .
This score indicated that initially discarded kidneys can be transplanted.
Absence of vasoactive response can be an indicator of endothelial dysfunction. Immune compartment evaluation
Sterile inflammation is caused by ischemia reperfusion injury ,removing the leucocytes from NMP perfusate can decrease the inflammation.
Leukocyte filter applied during 3h of ex vivo porcine lung NMP , reduced T-cell infiltration posttransplant compared with controls. Long term renal function
Late graft loss is due to progression of renal fibrosis, occurring due to alloimmune response to the donor graft despite immunosuppression.
The degree of fibrosis can correlate with graft survival.
Long term outcome is affected by the quality of the donated organ and there are recipient factors as well involved ,therefore all these factors need to be collectively considered to have a score that can predict long term outcome. Time to start NMP
It differs depending on the aim of it’s use either for preservation or repair or viability assessment.
Short period of NMP at the recipient center (strategy 3)
is the most commonly used enabling assessment of organ quality just before transplantation or strategy 2 which is assessment immediately after retrieval.
Time related complications can be avoided by centralizing clinical renal NMP to larger hubs (strategy 4) Logistic and economic aspects
Both have to be considered as NMP is complex and time consuming , expensive and necessitate lots of regulations.
NMP was proved to save some liver grafts from being discarded and it is thought to have the same impact on renal graft and cost effectiveness have to be evaluated between NMP cost and salvaging the grafts. Prospects
Novel biomarkers can facilitate kidney assessment before transplantation.
The biological complexity of evaluating renal allograft function and predicting posttransplant outcome necessitates an integrative approach as combination of genomics, transcriptomics, proteomics, and metabolomics.
Also innovative imaging methods as near-infrared spectroscopy, (functional) MRI ([f]MRI), PET, contrast-enhanced ultrasound, ultrafast ultrasound imaging, laser speckle imaging, and multiphoton microscopy imaging to evaluate renal viability during NMP. Conclusion
NMP has multiple protocols and is used for different aims eith preservation , evaluation or repair of the grafts.
● Organs from (ECDs) or DCD are more susceptible to ischemia-reperfusion injury, and a higher risk of (DGF), (PNF), and graft failure.
● As many kidneys offered discareded a doubt about their capacity to provide adequate short- and long-term function.
● A significant number of kidneys that are currently discarded would presumably provide a favorable risk–benefit ratio to a proportion of waitlisted individuals.
● (NMP) circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and neutrients
● NMP has the potential to increase kidney
discarded for transplantation.
● NMP is technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at normothermic temperatures.
● NMP uses as a preservation tool, or a viability assessment tool, or a repair platform.
● NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury
● RENAL NMP PROTOCOLS
Extracorporeal membrane oxygenation and
compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
● Almost all NMP protocols use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
Arterial Pressure Provided by the Pump
* centrifugal pumps are considered to be less harmful to RBCs
* pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury
● Typically set pressure at 75 mm Hg.
● Temperature is set at 37 ºC
● Assessing Nephron Function and Injury
typical renal functional markers such as Creatinine clearance and fractional sodium excretion are unlikely to be useful for ex vivo organ viability assessment.
● Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
● Additionally, there seems to be an inherent sensitivity of proximal tubular cells to warm ischemic injury, whereas cold ischemia elicits distal tubular cell
● Flavin mononucleotide (FMN), higher levels of FMN during NMP were found in kidneys with DGF and PNF after transplantation.
● Assessing the Immune (Cell) Compartment
● Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
● all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival.
● Because most acute injury restores after transplantation; chronic renal damage will determine long-term graft survival
● WHEN TO START NMP
depends on the aim of its clinical application , that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy
● For liver transplantation NMP has the potential to salvage a substantial number of organs from discard
The utilization of marginal organs from ECD is increasing and stresses the need for more objective and accurate pre-transplant kidney quality assessment tools.
Renal normothermic machine perfusion (NMP)
It uses extracorporeal membrane oxygenation and provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
NMPimplications:
-Diagnostic applicability (organ assessment)
-Serve as a promising superior preservation strategy.
-Platform for active organ reconditioning.
RENAL NMP PROTOCOLS
Perfusate Composition:
– To ensure optimal organ preservation, also it affects the interpretation of potential renal viability markers during NMP.
– The chosen depends on the specific aim of the application of NMP (preservation, viability assessment, or repair).
– All NMP protocols described to date use (RBC)-based perfusates to ensure adequate tissue oxygenation.
– Others include Ringer lactate, STEEN solution, human albumin and electrolytes.
– No study has investigated the roles of individual perfusate components or even compared existing fluids side-by-side to establish an optimal NMP and the best posttransplant outcome.
Arterial Pressure Provided by the Pump:
-There is no consensus about the optimal perfusion pressure, whether it should be pulsatile or non-pulsatile, and whether a centrifugal or roller pump is best.
– Centrifugal pumps are considered less harmful to RBCs than roller pumps, especially during prolonged perfusions.
– Continuous pressure is mostly used; there is some evidence that pulsatile pressure during NMP results in enhanced renal
blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
– MAP; typically set at 75 mm Hg, superior outcomes for higher MAPs (75- 95 mm Hg) compared with 55 mm Hg in terms of renal function and endovascular injury and subsequent simulated reperfusion.
Oxygenation
– Most systems use a supra-physiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of Co2 to create optimal acid-base homeostasis.
– Oxygen consumption during NMP is often reported based on certain calculations.
Temperature
– Typically set at 37 ºC, but it might be different, depending on the specific aim of ex vivo perfusion.
– Tubular and renal function was better preserved when normothermic (37 ºC) instead of sub-normothermic (32 ºC).
– Controlled oxygenated rewarming improves cellular homeostasis and mitigates rewarming injury, enhancing early posttransplant cortical microcirculation, thereby preventing the renal cells from being jeopardized by pumping against high cortical resistance.
Urine Replacement
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume.
DIAGNOSTIC POTENTIAL Assessing Nephron Function and Injury;
– The scarce data investigating perfusate or urine biomarkers during NMP originate from animal studies or small case series, and none have been validated in large cohorts of kidney transplants.
Assessing the Vascular Compartment
– Endothelial damage and viability are reflected by an increase in vascular resistance related to a combination of disruption of the endothelial cell lining favouring thrombosis and the “no-reflow” phenomenon, which is the suboptimal restoration
of perfusion after a period of ischemia.
– Combines macroscopic appearance, renal blood flow, and urine output during 1 h of NMP provided viability assessment, can lead to transplantation of initially discarded kidneys.
Assessing the Immune (Cell) Compartment;
– IRI causes sterile inflammation.
– Circulating leukocyte removal from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion, despite that fact resident leukocytes are released.
– Cytokines are released during kidney perfusion, although it is currently unclear which cytokines could predict the outcome.
Long-term Renal Function
– Predicting long-term graft survival would make this technique particularly valuable as a pre-transplant diagnostic tool.
– Long-term graft survival and function are determined by multidimensional factors; an integrative approach may be required for pre-transplant outcome prediction that combines viability measurements during NMP with donor, organ, and recipient characteristics, which all come with their own multifaceted complexity.
WHEN TO START NMP
– Depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
– Short period of NMP at the recipient center has been most commonly reported.
LOGISTICAL AND ECONOMIC IMPLICATIONS
– NMP is technically complex, time-consuming.
– Specialized perfusion room is needed for the sterile conduct of NMP.
– Dedicated staff trained in organ perfusion will need to join the surgical teams.
– The actual costs associated with the clinical implementation of NMP remain largely unknown.
There is an increased need for thorough pre-transplant organ viability assessment due to using of ECD donors. NMP can provide near-physiological organ perfusion, because it circulate perfusion solution at temperature 35-37C with delivering of O2 & nutrients. NMP can be used as preservative, viability assessment, & for repair. It may reduce DGF rate by reducing CIT.
Renal NMP protocols:
The protocol stiffer between centers according the following para meters:
Perfusate composition: it depend on aim of the NMP whether used for viability assessment, preservation or repairs. Almost all NMP protocol use RBC used perfusate, or Ringer solution based( low oncotic pressure) with short time NMP(1hr) , or Ringer lactate based perfusate or STEEN solution ( near physiological oncotic pressure) used for longer time up to 16hr, or albumin based perfusate which used for NMP last up to 24hr.
Arterial pressure: there was no consensus about the optimal NMP pressure( pulsatile[enhance renal blood flow, creatinine clearance, NA reabsorption & lower tubular injury] vs non pulsatile or centrifugal[most common type with less harm to RBC] vs roller).
Oxygenation: Most experimental kidney NMP use O2 concentration at 550-650mmHg but hyperoxia associated with reactive O2 species production result in more renal injury. Cambridge group found that reduce O2 concentration lead to decrease in O2 kinetics without significant effect on tubular function, creatinine clearance, UOP & biomarkers of renal injury.
Temperature: Typical NMP temperature 37C, but it may differ according specific aim of NMP of ex-vivo perfusion. Controlled O2 rewarming improve cellular hemostasis & enhance early post-transplant cortical microcirculation.
Urine replacement: Lossing of circulating volume by UOP replaced by Ringer solution or lactate added to perfusate or by recirculation of urine.
Assessment of vascular compartment:
Flow: combine of macroscopic appearance, renal blood flow & UOP at 1 hr of NMP.
Disapperance of vasodilation response.
Assessment of immune compartment:
Removal of WBC from perfusate can reduce inflammation compared to whole blood perfusate.
Whole blood perfusate associated with low aspartate aminotransferase compared to RBC based perfusate.
Using of cytokinins filter during 6 hr of pig kidney NMP can reduce level of IL-8 & IL-6 compared to control.
When to start NMP:
NMP starting time depend on Aim of NMP as preservation, viability assessment or repair.
Strategy 1: used for repair need prolong time .
Strategy 2: used for organ viability assessment after retrieval at transplantation center.
Strategy 3: the most common strategy used , short time NMP at transplant center.
Strategy 4: centralizing clinical renal NMP to larger hubs.
Logistic & economic implication:
NMP complex, time consuming & need supervision all the time.
need specialized perfusate room.
need staff trained with organ perfusion.
need personnel travel to transplantation center or run organ perfusion hubs.
This is a narrative review study discussing the impact of the normothermic renal perfusion machine in providing an organ preservation technique close to physiological temperatures and capable of adequately nourishing the organ.
These changes decrease cold ischemia time and minimize the impact of the inflammatory cascade of reperfusion syndrome after warm organ ischemia.
Five points are crucial:
1. Infusion composition
There is no uniformity in the components, however, most services use red blood cell perfusates. Ringer solutions and other electrolytes can also be used. Colloids such as albumin, buffers such as bicarbonate, electrolytes, antibiotics, and antioxidants generate this physiological environment for the organ. The pattern followed by the additives is to use a vasodilator in addition to glucose.
2. Blood pressure from the pump
Centrifugal pumps are considered to be superior and safer than scroll pumps and can generate continuous or pulsatile pressure.
3. Oxygenation
It is important to maintain constant O2 blood pressure with a low CO2 ratio. However, hyperoxia can cause tissue damage with the destruction of functional parenchyma, so monitoring at adequate values is important.
4. Temperature
In this specific case, a gradual increase in temperature to physiological to maintain cellular homeostasis and minimize the risk of reperfusion syndrome.
5. Urine replacement
The liquid loss must be replaced by Ringer’s solutions to prevent the organ from suffering hypovolemia.
This environment makes the organ more viable and less prone to injury from ischemic disorders, whether by cold or hot ischemia, in addition to removing microthrombi, decreasing proinflammatory cytokines, decreasing leukocyte recruitment, and minimizing reperfusion syndrome.
This entire process causes less organ damage, reducing the risk of late graft response and, consequently, acute and chronic rejection.
ECD organs, cardiovascular disease donors, or marginally responsive kidneys may have important benefits from this technique, making them less prone to reperfusion syndrome.
The big challenge comes in team training, adequate material, fluid therapy and monitoring, immediate maintenance, high costs, and our inability to assess early biomarkers to establish early kidney injury and proceed with the necessary care.
Robust pretransplant organ viability assessment is important, as organs from ECDs or DCD are at higher risk of DGF, PNF, and graft failure
NMP provides a near-physiological organ preservation technique (a warm (35–37 ºC) perfusion solution delivering oxygen and nutrients)
Aim of the study: overview of the fundamentals of current renal NMP protocols and provides a framework to approach further development of ex vivo organ evaluation.
Renal NMP protocols
NMP protocols: perfusate composition, arterial pressure delivered by the pump, oxygenation (po2 of 550–650 mm Hg), temperature (37 ºC), and urine replacement
Perfusate solution is either Ringer’s solution or human albumin
Perfusate composition are oxygen carriers (RBCs, artificial oxygen carrier), colloid, impermeants, buffers, electrolytes, antibiotics, antioxidants and others
Diagnostic potential
Nephron function and injury may be assessed with oxygen consumption, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells, neutrophil gelatinase-associated lipocalin (originates from the thick ascending limb), and flavin mononucleotide (FMN)
Flow is an important parameter of the kidney quality assessment which combines macroscopic appearance, renal blood flow, and urine output during 1 h of NMP performed at the end of SCS
It is unclear how to assess the immune compartment
Donor factors affection long term outcome of graft are pre- existing renal fibrosis, biological age of the donor. Recipient factors are increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and CV complications at the time of transplantation. Other factors are prolonged warm ischemia time and anastomosis time
When to starts NMP
When to start NMP is depends on its clinical application (preservation, viability assessment, or repair). Applications for NMP is for the entire preservation period or short period in the donor hospital or recipient hospital
Logistical and economic implications
In addition to the high cost of NMP, it is technically complex, time-consuming with risk of technical failure
Conclusion
NMP is either an organ preservation, assessment, or repair platform
No unified NMP protocols and no validated ex vivo viability biomarkers
More uniformity NMP protocols is of paramount for effective preservation and organ assessment
What is the level of evidence provided by this article?
Review study (level 5)
Renal normothermic perfusion is a near physiological perfusion of the kidneys under basal metabolic rate to preserve the metabolic function of the organ….It is considered better than static or cold hypothermic perfusion storage in terms of reducing the reactive oxygen species and preserving organ perfusion….At normal temperature, cellular metabolism is restored and ATP synthesis is restored…In addition to providing the cellular metabolism at room temperature, it also helps in providing nutrients and assessing the viability of kidneys by allowing biomarkers estimation
Organs from ECD or DCD donors are not being utilized for transplant because of the poor quality and there is still higher incidence of delayed graft function, primary non functioning of the graft which all contribute to poor prognosis of the transplant….
The components of Renal normothermic perfusion are
The urine/perfusate levels of many molecules have been tested in various pre clinical studies and they show that it their levels correlate with delayed graft function…However more evidence is needed till these translate into evidence….
The optimal time to start NMP is debatable and it depends on the aim of whether we need to perfuse or assess the viabilityA period of initial Cold storage and then NMP will negate all the microcirculatory damage associated with cold storage…There are many reports of using NMP initially and then later…
Renal Normothermic Machine perfusion provides near physiological organ preservation technique as it perfuses warm solution through renal vasculature containing oxygen and nutrients.
The different fundamental facets of NMP :
Perfusate Composition
NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
recent preclinical research suggests that synthetic oxygen carriers can be used instead of RBCs with equal efficacy
Arterial Pressure Delivered By The Pump
There is no consensus about the optimal perfusion pressure use during NMP, whether it should be used in pulsatile or non-pulsatile fashion or whether centrifugal or roller pump should be used.
Preclinical studies are in favour of pulsatile perfusion with perfusion pressure should be maintained at MAP of 75 to 90 mmHg.
The centrifugal pump is better than roller pump as there is less damage to RBCs with centrifugal pump.
Oxygenation
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. However, hyperoxia can induce production of reactive oxygen species and increase the renal injury.
Temperature
The temperature during NMP is set at 37 ºC- can be different depending upon goal of NMP.
Urine Replacement
The loss of perfusate volume due to urine production by ex vivo perfused kidney, should be replaced to maintain perfusate volume.
Most of the preclinical studies showed that the urine produced by ex vivo perfusion of kidney can be reuse for perfusate replacement. It has been shown to maintain the perfusate flow rate.
Diagnostic Potential
Assessing Nephron Function and injury
Assessing the Vascular Compartment
Assessing the Immune (Cell) Compartment
When To Start
Protocols are of paramount importance.
Level of evidence
Level 5
Introduction:
The shift toward the utilization of older organ donors with more comorbidities has stressed the importance of robust Pretransplant organ viability assessment.
First:
Organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunctional (PNF), and graft failure.
Second:
many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their capacity to provide adequate short- and long-term function.2,4-6 These organs in particular would benefit from reliable Pretransplant organ viability and quality assessment because a Signiant number of kidneys that are currently discarded would presumably provide a favorable risk– benefit ratio to a proportion of waitlisted individuals.
Renal norm thermic machine perfusion (NMP) :
Provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrition.
NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
NMP might reduce DGF compared with static cold storage (SCS).
RENAL NMP PROTOCOLS:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
Perfusate Composition:
Almost all NMP protocols described to date use red blood cell (RBC)-based perfusate to ensure adequate tissue oxygenation.
Arterial Pressure Provided by the Pump:
Pressure at 75 mm Hg.
Reported MAP during renal norm thermic perfusion range between 40 and 95 mm Hg.
Oxygenation:
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg.
Temperature:
The temperature during NMP is set at 37 ºC, but
DIAGNOSTIC Potentials:
Assessing Nephron Function and Injury
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
Assessing the Immune (Cell) Compartment:
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.
Long-term Renal Function:
Almost all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival.
WHEN TO START NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair.
Short period of NMP at the recipient center (strategy 3) has been most commonly reported.
Another possibility is to assess organs immediately after retrieval at the donor hospital (strategy 2).
LOGISTICAL AND ECONOMIC IMPLICATIONS NMP:
Technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at norm thermic temperatures.
Level of evidence v.
First, organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.1-3 Second, many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their capacity to provide adequate short- and long-term function.
RENAL NMP PROTOCOLS NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement
Perfusate Composition
The composition of perfusate is not only of critical
importance to ensure optimal organ preservation but it is also likely to affect the interpretation of potential renal viability markers during NMP. Hence, the chosen perfusate composition might depend on the specific aim of the application of NMP (ie, preservation, viability assessment, or repair). Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
Arterial Pressure Provided by the Pump In the literature, there is no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
Oxygenation
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of carbon dioxide to create optimal acid-base homeostasis.
Temperature
Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the specific aim of ex vivo perfusion. Preclinical work has shown that, upon simulated organ reperfusion, tubular and renal function was better preserved when normothermic (37 ºC), instead of subnormothermic (32 ºC), perfusion preceded it. Nevertheless, the subnormothermic perfusion system used by Brasile et al did not seem to cause relevant renal injury and showed superior posttransplant urine production and serum creatinine levels compared with nonperfused kidneys.
Urine Replacement Loss of circulating volume by urine production of the ex
vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
DIAGNOSTIC POTENTIAL Although the potential of NMP as a diagnostic platform
has been recognized, the search for relevant and independently predictive viability markers has only just started and is likely to increase with wider clinical implementation of NMP.
Assessing Nephron Function and Injury Creatinine clearance and fractional sodium excretionare frequently reported as markers to assess nephron function. It is not known whether these parameters during NMP are predictive for posttransplant function. Importantly, because perfusate composition and perfusion pressures will change hydrostatic and oncotic pressures, they influence filtration and ultimately production and composition of “urine.”
Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile
inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.Additionally, the endothelium and epithelial cells play a key immunological role in this postreperfusion inflammatory response.
Long-term Renal Function
Currently, almost all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival. Because most acute injury restores after transplantation; chronic renal damage will determine longterm graft survival. Predicting long-term posttransplant renal graft survival during NMP would make this technique particularly valuable as a pretransplant diagnostic tool. The main reason for late graft loss is the progression of renal fibrosis, which is mainly the result of the continuous alloimmune response to the donor graft despite immunosuppression.
WHEN TO START NMP The optimal timing to start NMP largely depends on
the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy .The potential of NMP to ameliorate renal preservation and serve as a repair platform most likely demands prolonged NMP times
CONCLUSION An increasing number of centers are investigating renal
NMP, either as a preservation tool, a viability assessment tool, or a repair platform. Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance. Best practice guidelines and consensus on protocols would likely progress the field. Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool
Please provide a summary of this article
*The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies.
*Organs from (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of (DGF), (PNF), and graft failure.
*Renal normothermic machine perfusion (NMP) provides
a near-physiological organ preservation technique
because it circulates a warm (35–37 ºC) perfusion solution
through the renal vasculature delivering oxygen and nutrients.
*NMP has the potential to increase the number of kidney transplants by evaluating and transplanting kidneys that had initially been discarded for transplantation
*NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
*Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
*NMP uses extracorporeal membrane oxygenation and
compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
*The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
*Almost all NMP protocols described to date use red
blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
*Recent preclinical research suggests that synthetic oxygen carriers feature equivalent oxygen-carrying capacities compared with RBCs.
*No consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
*Most experimental kidney NMP systems use a supra physiological perfusate oxygen concentration of approximately 550–650 mm Hg. However, hyperoxia can promote reactive oxygen species production, resulting in additional renal injury.
*Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the specific aim of ex vivo perfusion.
*Loss of circulating volume by urine production of the ex vivo per fused kidney should be replaced to maintain the circuit’s circulating volume.
DIAGNOSTIC POTENTIAL
Assessing Nephron Function and Injury
*Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
*Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Assessing the Vascular Compartment
Endothelial damage is an important determinant of renal
viability.Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile
inflammation, triggering activation of innate and adaptive
immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release
*Predicting long-term posttransplant renal graft survival during NMP would make this technique particularly valuable as a pretransplant diagnostic tool.
*The optimal timing to start NMP largely depends on
the aim of its clinical application, that is, preservation,
viability assessment, or repair, all necessitating an individual tailored strategy.
*Best practice guidelines and consensus on protocols would likely progress the field.
* Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
What is the level of evidence provided by this article?
Level (5)
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement. An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform. Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance. Best practice guidelines and consensus on protocols would likely progress the field. Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP
level of evidence 5
The optimal time to start NMP depends mainly on the aim of its application, which is, preservation, viability assessment, or repair, all need an individualized tailored approach,.
The potential of NMP to ameliorate renal preservation and work as a repair platform most likely require long NMP times .
Using NMP as an assessment tool has wider range of options (strategy 2, 3, and 4). A short period of NMP at the recipient center (strategy 3) has been most commonly practiced.
Another possibility is to assess organs promptly after retrieval at the donor hospital .
Application of NMP at the donor center avoids the complex logistics and safety problems associated with NMP during organ transport. Also, depending on geographical area of a country and experience of individual centers, the complexity of the various time-related strategies can be reduced by centralization of clinical renal NMP to larger hubs .
This could enhance the quality and allows better standardization of the procedure, as has been suggested for normothermic lung perfusion.
Summary
Increasing number of centers are studying renal NMP, either as a preservation tool, a viability evaluation tool, or repair platform. Great diversity exists among NMP protocols and interpretation of the readouts of NMP. In addition ,no validated (set of) ex vivo viability biomarkers have been identified so far To establish effective preservation by NMP, and use NMP as an objective pre-transplant organ evaluation tool and consequently interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of great importance. Best practice guidelines and consensus on protocols would likely make advances the field. Future scientific work should focus on identifying the ideal perfusate composition duration and pressures& the need for urine recirculation and specific additives, for each application point of renal NMP.
markers, which are derived from our in vivo clinical frame of reference, are unlikely to be useful for the ex vivo assessment of viability of the organ.
– Assessment of vascular endothelial damage: Little is known about the significance of flow and resistance during PMN, although with increasing perfusion time, flow generally increases while resistance falls if perfusion pressures are kept constant. Flow – not resistance – is one of the parameters of the renal quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood flow and urine output during 1h of PMN.
– Immune compartment assessment: Removal of circulating leukocytes from the NMP perfusate is believed to minimize inflammation compared to whole blood perfusion.
PERSPECTIVES
It is expected the discovery of new biomarkers for pre-transplant evaluation and that would be collected during the NMP.
This is level 5 – Narrative reviews, even if you review meta-analyses and systematic reviews.
Introduction
Renal Normothermic Machine perfusion provides near physiological organ preservation technique as it perfuses warm solution through renal vasculature containing oxygen and nutrients.
This NMP can be used for organ preservation, viability assessment and for pretransplant repair of donor organ.
As significant number of organs from ECD are being discarded, this NMP technique can be used for pretransplant organ viability and quality assessment.
To date there are multiple NMP protocol are being used in preclinical and clinical studies at different canters and there is no uniform standardized protocol.
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrients enriched perfusate through-out the NMP period.
The different fundamental facets of NMP are 1) perfusate composition, 2) arterial pressure delivered by the pump 3) oxygenation 4) temperature and 5) urine replacement.
1) PERFUSATE COMPOSITION
Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
But recent preclinical research suggests that synthetic oxygen carriers can be used instate of RBCs with equal efficacy.
2) ARTERIAL PRESSURE DELIVERED BY THE PUMP
There is no consensus about the optimal perfusion pressure use during NMP, whether it should be used in pulsatile or non pulsatile fashion or whether centrifugal or roller pump should be used.
Preclinical studies are in favor of pulsatile perfusion with perfusion pressure should be maintained at MAP of 75 to 90 mmHg.
the centrifugal pump is better than roller pump as there is less damage to RBCs with centrifugal pump.
3) OXYGENATION
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. However hyperoxia can induce production of reactive oxygen species and increase the renal injury.
4) TEMPERATURE
Typically, the temperature during NMP is set at 37 ºC. But this can be different depending upon goal of NMP.
5)URINE REPLACEMENT
The loss of perfusate volume due to urine production by ex vivo perfused kidney, should be replace to maintain perfusate volume. Most of the preclinical studies showed that the urine produced by ex vivo perfusion of kidney can be reuse for perfusate replacement. It has been shown to maintain the perfusate flow rate.
DIAGNOSTIC POTENTIAL
Through the diagnostic potential of NMP has been recognized, the studies are ongoing to search for relevant and independently predictive viability marker.
1) Assessing Nephron Function and injury
Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Injured and dying cells shed or leak cytosolic and mitochondrial content, that could be used as injury markers in urine or perfusate.
Some of these are cell-specific; for example, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb, can be used for kidney injury marker in perfusate.
2) Assessing the Vascular Compartment
Endothelial damage is an important determinant of renal viability. As endothelium has limited regeneration capacity, damage to it can lead to poor long term graft survival.
Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood flow, and urine output during 1h of NMP performed at the end of SCS.
3) Assessing the Immune (Cell) Compartment
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.
Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
WHEN TO START NMP
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
It can be used soon after the organ procurement and continued till anastomosed.
Using NMP as an assessment tool presumably has a wider rang of options, where NMP can be use for short time at donor hospital or during transport or for short period of time at recipient hospital after arrival of organ before being implanted on recipient.
An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform.
The great diversity exist among NMP protocol hence To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance.
Level of evidence
Level 5 , narrative review and animal studies.
Renal normothermic perfusion machine till now has good result by providing near normal physiological organ preservation technique by giving warm solution containing nutrients and oxygen. it has a very good role in reducing the risk of DGF in ischemia time.
The solution is provided by different companies with different composition of nutrients, some centers uses red blood cell based perfusates to ensure adequate tissue oxygenation >95%.
Temperature at 37C by pulsatile/ gradual rewarming.
level of evidence V.
INTRODUCTION
· Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique via circulating a warm perfusion solution delivering oxygen and nutrients
· NMP may increase the number of kidney transplants by accepting kidneys that was discarded initially
· NMP reduces cold ischemia time and reduce DGF
RENAL NMP PROTOCOLS
Perfusate Composition
· Almost all NMP protocols use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation
· recent research suggests that synthetic oxygen carriers feature equivalent oxygen-carrying capacities compared with RBCs
· It should contains also: Impermeant (glucose, dextran, mannitol, lactate, gluconate) Na.Bicarbonate, Electrolytes, Antibiotics, Antioxidants, and some additives.
· The Cambridge group uses a perfusate based on Ringer’s solution which has a relatively low oncotic pressure
· The Toronto group uses a perfusate based on Ringer’s lactate and STEEN solution, which creates a physiological oncotic pressure and osmolarity
· MePEP consortium used a perfusate based on human albumin and electrolytes within physiological ranges
· The Oxford group used a perfusate contains 5% human albumin solution designed for prolonged renal perfusions that lasted up to 24h
Arterial Pressure Provided by the Pump
· Most groups use centrifugal pumps, which are considered to be less harmful to RBCs compared with roller pumps, especially during prolonged perfusions
· there is some evidence that pulsatile pressure during NMP results in enhanced renal blood #ow, creatinine clearance, sodium reabsorption, and lower tubular injury
· In continuous pressure, MAP range 40-90mmHg
· In Pulsatile 90/70 mmHg
Oxygenation
· Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg
· The Cambridge group used carbogen (95% O2 /5% CO2)
Temperature
· organ reperfusion, tubular and renal function was better preserved with normothermic (37 ºC), by abrupt or gradual rewarming.
Urine Replacement
· The Toronto and Cambridge groups replaced volume lost from urination, by adding Ringer’s solution or Ringer’s lactate to the perfusate
· Weissenbacher showed that recirculating the urine is feasible and that it results in a significantly higher perfusate flow rate
DIAGNOSTIC POTENTIAL
· Creatinine clearance and fractional sodium excretion are unlikely to be useful for ex vivo organ viability assessment
· Potential biomarkers during NMP, that may indicate renal injury: NGAL, LDH, AST, Lactate, KIM-1, L-FABP, FMN, π-GST, ET-1, VWF, VCAM-1/ ICAM-1, TBARS, Protein carbonyls, 8-isoprostane, ATP content/ ATP:ADP ratio
Long-term Renal Function
· long-term outcomes are affected by preexisting renal fibrosis in donor grafts, biological age of the donor, prolonged warm ischemia time and anastomosis time
· Recipient factors: increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications at the time of transplantation
WHEN TO START NMP? There are 4 Strategies:
1. NMP for the entire preservation interval;
2. a short period of NMP at the donor hospital followed by CP for transportation to the recipient center;
3. NMP at the recipient center only;
4. an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP
· Today, strategy 3 has been most commonly reported
LOGISTICAL AND ECONOMIC IMPLICATIONS
· As NMP will changes the current donation and transplantation logistics, this will necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for sterility
· The actual costs of NMP use still unknown, as it needs out-of-hours specialist expertise, disposables, perfusate components, equipment needed to obtain samples, analyses for viability assessment, facility fees, NMP training, and depreciation of the perfusion device
PROSPECTS
Near-infrared spectroscopy, MRI, PET, contrast-enhanced ultrasound, ultrafast ultrasound imaging, laser speckle imaging, and multiphoton microscopy imaging all are noninvasive diagnostic techniques
What is the level of evidence provided by this article?
Level 5 narrative review
Level of evidence is V
RENAL NMP PROTOCOL
Help in oxygenation and nutrition of kidney
Perfusate Composition
It preserve optimal organ
the pulsating blood pressure is about 90/70 with applying warm temp
with keeping o2 saturation 95%and using ringer for keeping urine recirculating
and using creatinine clearance and fraction sodium excretion as good biomarker
While the KIM1 and NGAL is bio marker for injury of tubules
club 5, renal normo-thermic machine perfusion
Summary
· The urgent need to expand the donor pool to match the increased need for KT made us using cadaveric ECDs or graft after circulatory death which are highly susceptible to ischemia-reperfusion injury, increased risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
· Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation.
· it depends on the use of warm (35–37 ºC) perfusion carrying oxygen and nutrients to the allogarft.
· it acts through decreasing the ischemia time and hence minimizes the ischemia reperfusion injury.
· No standard protocol for NMP, but individualized and center based approach.
· Each protocol determines its own variables as perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
· Perfusate composition which is RBC-based perfusate or artificial oxygen carrying vehicle to enhance organ oxygenation, in addition Ringer’s solution to provide adequate nutritional supply. Perfusate with human albumin and electrolytes (Na, K, Ca, Cl) within physiological ranges was used. antibiotics, antioxidants, vasodilators as (verapamil or nitroglycerine), multivitamins, heparin, + or- additives like amino acids.
· No consensus about the ideal arterial pressure delivered by the pump, however, centrifugal (better for the RBC) or roller pump is best. The flow is either pulsatile or nonpulsatile, pulsatile is associated with better renal blood flow, creatinine clearance, sodium reabsorption, and less renal tubular injury. MAP of 75 mm Hg (40-95 mm Hg) seems to be associated with better graft outcome.
· Oxygenation using oxygen source supplying 550–650 mm Hg. balanced with a small percentage of CO2 to create optimal acid-base homeostasis.
· Temperature: gradual rewarming has typically been pursued up to 20 ºC over a period of 90 min.
· Urine replacement using ringer solution is still debatable.
· Biochemical parameters to assess graft viability and function;
o Creatinine clearance and fractional Na excretion are common markers of nephron function.
o Metabolic activity and oxygen consumption were useful markers of kidney metabolic activity in animal mode.
o KIM1, NFAL are markers of renal tubular injury.
NMP is still coasty and complicated technique.
Level of evidence: narrative review (level V)
INTRODUCTION
*organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
*many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their
capacity to provide adequate short- and long-term function.
RENAL NMP PROTOCOLS
NMP uses extracorporeal membrane oxygenation and
compound supplementation technology to provide the
kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period
1- Perfusate Composition
– Oxygen carrier
-colloid human albumin
– impermeants glucose dextran40 , manitol, locate, gluconate
-buffers sodium bicarbonate
– electrolytes Na, K, Can, Cl
– ANTIBIOTICS
-ANITIOXIDENT
ADDITIVES: GLUCOSE, AMINOACIDS, HEPARIN
2-Arterial Pressure Provided by the Pump
-contiuos presseure : MAP40-95 mmHg
-Pulsatile90/70 mmHg
3- Oxygenation
Carbo95%/ O2 /5% CO2
police 550-650 mmHg
4-Temperature
Abrupt rewarming
Gradual rewarming
5-Urine Replacement
Urine recirculation
Ringers
CONCLUSION
An increasing number of centers are investigating renal
NMP, either as a preservation tool, a viability assessment
tool, or a repair platform.
To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance.
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and speci! c additives, for each application area of renal NMP.
1. Please provide a summary of this article
2. What is the level of evidence provided by this article?
This is a narrative review article with level V evidence.
Renal Normothermic Machine Perfusion (NMP) is used to perfuse the donor kidneys after retrieval using a perfusion solution warmed at 35-37 C aiming to maintain cellular metabolism, provide oxygen and nutrition and shorten the duration of cold ischemia thus reducing the effects of ischemia reperfusion damage.
There different types of renal NMP Solutions. There is no ideal perfusate up till now, it needs more research. There are different protocols and NMP duration, timing to start and required pressures need more studies.
Perfusate composition and perfusion protocol:
1- Oxygen carrier (extra-corporeal membrane oxygenation)
2- Colloid
3- Impermeant: glucose, mannitol or lactate.
4- Buffers
5- Electrolytes: Na, K, Ca.
6- Antibiotics.
7- Anti-oxidants.
8- Additives: glucose, amino acids, vasodilators, heparin, steroids.
9- Arterial pressure can be provided by a pump via continuous/pulsatile pressures aiming for MAP 40-95 mmHg.
Supra-physiological oxygenation is required PO2 555-650 mmHg.
Urine replacement via either urine recirculation or Ringer’s Lactate.
NMP can be commenced in the Donor’s hospital after organ retrieval or in transit or in the recipient transplant center.
NMP implications:
1- Organ assessment (diagnostic) for nephron function and injury, and vascular and immune compartments assessment.
2- Preserving organs.
3- Active organ reconditioning (repair).
Limitations of NMP:
1- Complicated and Time consuming.
2- Technique failure.
3- Specialized perfusion room.
4- Needs well trained Staff.
5- High cost
organs from ECDs or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
many kidneys offered for transplantation may be discarded due absence of tool to assess function and viability
Presence of reliable pretransplant organ viability and quality assessment would help to increase number of accepted organs.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients maintaining near normal cellular metabolism.
NMP has many advantages as it help evaluation of Viability of organs, advanced preservation strategy, platform for active organ reconditioning, reduces cold ischemia time and reduces,DGF ischemia-reperfusion injury.
Unfortunately there is no single unified NMP protocol exists to date.
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
▪︎NMP protocols can be divided into:
-perfusate composition
-arterial pressure delivered by the pump.
-oxygenation
– temperature.
– urine replacement.
*Perfusate Composition:Almost all NMP protocols uses RBC-based perfusates to ensure adequate tissue oxygenation.
*Arterial Pressure Provided by the Pump:no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
some evidence suggests that pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
Many centres Reported mean arterial pressure (MAP) during renal normothermic perfusion range between 40 and 95 mm Hg.
*Oxygenationexperimental kidney NMP systems use a supra physiological perfusate oxygen concentration of approximately 550–650 mm Hg.
*temperature
upon simulated organ reperfusion, tubular and renal function was better preserved when normother-mic (37 ºC), instead of subnormothermic (32 ºC), perfusion.
*Urine ReplacementVolume lost by urine production should be replaced ,adding Ringer’s solution or Ringer’s lactate to the perfusate is used to replace volume.
urine recirculation is used in some studies.
*Assessing Nephron Function and Injury
-kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb could be used as injury markers in urine or perfusate.
–Non–cell-specific injury markers aspartate aminotransferase and lactate correlated with posttransplant renal graft function .
-FMN correlate with posttransplant renal graft function.
*Assessing the Immune (Cell) Compartment
Removal of circulating leukocytes from the NMP perfusate minimize inflammation compared with whole blood perfusion.
-The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy
CONCLUSION
investigating renal NMP is ongoing in many centres, either as a preservation tool, a viability assessment tool, or a repair platform.
Great diversity exists among NMP protocols .
there is no validated (set of) ex vivo viability biomarkhave identified.
more uniformity in NMP protocols is of paramount importance.
Summary:
The renal transplant pool over the years was limited and continues to be but with the introduction of ECD, DCD, and DBD, etc. there has been an improvement. So this article is about understanding renal normothermic machine perfusion (NMP). The introduction of this method in extended criteria is to improve graft outcome and survival. For the limited organ being donated, it is important that the organs are preserved properly and as such proper evaluation must be conducted before transplant. The principle behind NMP is to preserve the organs in a method close to organ physiology to provide warn solution that contains the proper nutrients or oxygen to the kidneys. This principle helps physicians to properly access the function of the allograft and the extent of the possible injury the graft may have. The importance of such is to increase the number of kidneys that can be used for kidney transplantation and as such to reduce organs from being lost. Its other function that is the NMP is to preserve the graft function and to reduce CIT and therefore limiting the ischaemic impact on the allograft. So NMP helps to reduce the risk of DGF when it is compared with static cold storage.
The NMP protocol composition contains:
1) Red blood cells based perfusate. That is important to ensure proper oxygenation to the organ
2) Lactate ringer solution is used due to its low oncotic pressures
3) Lactate ringer and STEEN
4) MsPEP consortium human albumin-based perfusate.
5) The temperature is set to about 37 degrees Celsius.
Other parameters that need to be monitored are:
1) The arterial pressure of the pump. The pressure must be one such that it must not cause endothelial injury of the allograft.
2) Oxygenation must be about 95% and the PaO2 about 550-650 mmHg
3) Temperature of about 37 degrees Celsius ensure proper renal circulation.
The problems with NMP are that it is expensive, complex, time-consuming, and also at risk of failure and it needs to be in a room that is specialized and operated by an experienced person.
The kidney donors must be evaluated by:
1) Assessing the viability and vasculature using vascular resistance. The flow markers for endothelial damage.
2) Biomarkers like KIM-1, NGAL, and FMN to help to evaluate kidney injury.
3) The use of AST and LDH gives details on graft function.
So, NMP is a method for renal or allograft preservation to ensure it prolongs or try to prolong the graft function. There are biomarkers that can be used to help to understand what is going on with the graft as it relates to its functions. With better research hopefully, the perfusate composition must be one that may be physiologically to ensure proper functions.
The article level of evidence is 5
WHEN TO START NMP
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy .
The potential of NMP to ameliorate renal preservation and serve as a repair platform most likely demands prolonged NMP times .
Using NMP as an assessment tool presumably has a wider range of options (strategy 2, 3, and 4). Today, a short period of NMP at the recipient center (strategy 3) has been most commonly reported.
Another possibility is to assess organs immediately after retrieval at the donor hospital .
Applying NMP at the donor center avoids the complex logistics and safety issues associated with NMP during organ transport. Moreover, depending on geographical area of a country and expertise and experience of individual centers, the complexity of the various time-related strategies can be reduced by centralizing clinical renal NMP to larger hubs .
This could also enhance the quality and allows better standardization of the procedure, as has been proposed for normothermic lung perfusion.
CONCLUSION
An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform. Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance. Best practice guidelines and consensus on protocols would likely progress the field. Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
Renal Norm thermic Machine Perfusion: The Road toward Clinical Implementation of a Promising pre-transplant Organ Assessment Tool.
Introduction.
Kidney donation from ECD or DCD associated with ischemia -reperfusion injury , DGF and graft failure.
Renal normo-thermic machine perfusion (NMP) has a role in providing the kidney with oxygen and nutrients by circulating circulates a warm (35–37 ºC) perfusion solution through the renal vasculature, so it has a role in preserving organs for donation , assessment, or repair platform.
Renal NMP Protocols.
NMP protocols can be divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement
1-Perfusate Composition.
blood cell (RBC)-based perfusates to ensure adequate tissue
oxygenation, with based material for nutrients supplementation as ringer based solution which used for 1-2 hrs before transplantation after long static cold time, The Oxford
group has published a discarded human kidney NMP study
in which a somewhat similar perfusate based on 5% human
albumin solution was used, till now no standard protocol and no randomized studies to prefer one to another.
Arterial Pressure Provided by the Pump.
Reported mean arterial pressure(MAP) during renal norm thermic perfusion range between 40 and 95 mm Hg but still no consensus about the optimal one , using centrifugal pump in pulsatile manner is better than roller pump. some studies increase MAP to 70-95 mm Hg .
Oxygenation.
Supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg is considered the standard in most centers but still tubular injuries from reactive oxygen species production, resulting in additional renal injury should be kept in mind.
Temperature.
organ reperfusion, tubular and renal function was better preserved when norm thermic (37 ºC), instead of subnormothermic (32 ºC), perfusion preceded it.
Urine Replacement.
Replacement by ringer lactate mainly and some studies acting on urine re-circulation .
Diagnostic potential .
Assessing Nephron Function and Injury.
Some markers are used to detect nephron function and injury but still not clinically implicated as oxygen consumption which affected by metabolic activity of tubular cells and oxygen supplementation, Also kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb which is contents of injured cells. In a pilot study, significantly higher levels of FMN during NMP were found in kidneys with DGF and PNF after transplantation.
Assessing the Vascular Compartment.
To assess endothelial vasculature is important as it affect long term graft survival, Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group which combines macroscopic appearance, renal blood flow, and urine output during 1 h of NMP performed at the end of SCS.
Assessing the Immune (Cell) Compartment.
Inflammatory cytokines are released during kidney perfusion, although it is currently unclear which cytokines could be predictive of outcome all these due to IRI and usage of cytokines filters still need more studies to be clear.
Long-term Renal Function.
The severity of existing fibrosis correlates with the duration of graft survival, donor organ quality has impact on long term graft survival which is affected by many factors as ischemia time and anastomosis time, also recipient factors such as increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications at the time of transplantation are associated with adverse long-term outcome, still we need integrative approach to cover all these factors to detect long term graft survival .
WHEN TO START NMP.
1-NMP for the entire preservation interval which is mainly long period from procurement till transplantation .
2- A short period of NMP at the donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for transportation to the recipient center to assess quality before retrieval.
3-NMP at the recipient center only to assess kidney quality just before transplantation.
4-an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP.
CONCLUSION.
Still using NMP is local center based protocol, either as a preservation tool, a viability assessment tool, or a repair platform, Future researches needed to focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP, and to signify the effect of NMP on short and long term graft survival.
Level of evidence V (article review).
Introduction:
Organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution
through the renal vasculature delivering oxygen and nutrients.
RENAL NMP PROTOCOLS:
Uses extracorporeal membrane oxygenation.
Perfusate Composition:
Use red blood cell (RBC)-based perfusates to ensure adequate tis-
sue oxygenation.
The Cambridge group uses a perfusate based on Ringer’s solution, which has a relatively low oncotic pressure.
Arterial Pressure Provided by the Pump:
Pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
Oxygenation:
Most NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced
with a small percentage of carbon dioxide to create optimaL acid-base homeostasis.
Temperature:
Typically, the temperature during NMP is set at 37ºC.
Urine Replacement:
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge
groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
Assessing Nephron Function and Injury:
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
WHEN TO START NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application.
Today, a short period of NMP at the recipient center has been most commonly reported. This strategy provides the advantage to assess organ quality just before transplantation.
CONCLUSION:
NMP used either as a preservation tool, a viability assessment
tool, or a repair platform.
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
Summary:
The increased utilization of high-risk renal grafts for transplantation requires the optimization of pre-transplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury. Early clinical experience suggests that NMP might reduce DGF compared with static cold storage.
In recent years, considerable effort has been directed at the development of NMP as either organ preservation, assessment, or repair platform.
RENAL NMP PROTOCOLS:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
Perfusate Composition:
The composition of perfusate is not only of critical importance to ensure optimal organ preservation but it is also likely to affect the interpretation of potential renal viability markers during NMP. Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation. Recent preclinical research suggests that synthetic oxygen carriers feature equivalent oxygen-carrying capacities compared with RBCs.
To date, no study has convincingly investigated the roles of individual perfusate components or even compared existing #uids side-by-side to establish which components could lead to an optimal NMP, as well as the best posttransplant outcome.
Arterial Pressure Provided by the Pump:
There is no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or non-pulsatile fashion, and whether a centrifugal or roller pump is best. Although most groups apply a continuous pressure during normothermic perfusion, there is some evidence that pulsatile pressure during NMP results in enhanced renal blood #ow, creatinine clearance, sodium reabsorption, and lower tubular injury. Reported mean arterial pressure (MAP) during renal normothermic perfusion range between 40 and 95 mm Hg.
Oxygenation:
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of carbon dioxide to create optimal acid-base homeostasis.
Oxygen consumption during NMP is often reported. The most commonly used equation was introduced by Stubenitsky et al53 [(arterial Po2 –venous Po2 )×perfusate #ow rate/weight].
Temperature:
Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the speci!c aim of ex vivo perfusion.
It has been suggested that controlled oxygenated rewarming improves cellular homeostasis and mitigates rewarming injury in a porcine NMP model, g also enhances early post-transplant cortical microcirculation, thereby preventing the renal cells from being jeopardized by pumping against high cortical resistance.
Urine Replacement:
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. Ringer solution or recirculating the urine had been used.
DIAGNOSTIC POTENTIAL:
Although the potential of NMP as a diagnostic platform has been recognized, the search for relevant and independently predictive viability markers has only just started and is likely to increase with wider clinical implementation of NMP.
Assessing Nephron Function and Injury:
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.33,42,55,64,65 It is not known whether these parameters during NMP are predictive for post-transplant function.
Metabolic activity and oxygen consumption are high in tubular cells, and therefore, oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
Injured and dying cells shed or leak cytosolic and mitochondrial content that could be used as injury markers in urine or perfusate and some of these are cell-specific; for example, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and neutrophil gelatinase-associated lipocalin originates from the thick ascending limb. 2 Non–cell-specific injury markers aspartate aminotransferase and lactate correlated with post-transplant renal graft function, measured by peak serum creatinine. Flavin mononucleotide (FMN), a lesser-known biomarker, has also been shown to correlate with posttransplant renal graft function.
Assessing the Vascular Compartment:
Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
In vivo, endothelial damage and viability are reflected by an increase in vascular resistance related to a combination of disruption of the endothelial cell lining favoring thrombosis and the “no-reflow” phenomenon, which is the suboptimal restoration of perfusion after a period of ischemia.
Flow—not resistance—is one of the parameters of the kidney quality assessment score developed by the Cambridge group, which combines macroscopic appearance, renal blood #ow, and urine output during 1h of NMP performed at the end of SCS.107 The use of this score has provided some proof that NMP kidney viability assessment can lead to transplantation of initially discarded kidneys.
Assessing the Immune (Cell) Compartment:
1 Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
despite the absence of circulating leukocytes during NMP, resident leukocytes are released. It is unclear what the implications of the presence and release of resident leukocytes are and whether the phenotype and behaviour of these cells could be predictive of post-transplant outcomes.
The use of a cytokine filter during 6h of pig kidney NMP reduced levels of interleukin-8 (neutrophil-attractant) and interleukin-6 (a proinflammatory cytokine) when compared with control. Nevertheless, no difference in kidney function during NMP could be noted, and these kidneys were not actually transplanted.
Long-term Renal Function:
WHEN TO START NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual-tailored strategy.
A short period of NMP at the recipient center (strategy 3) has been most commonly reported.
LOGISTICAL AND ECONOMIC IMPLICATIONS:
NMP is technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at normothermic temperatures.
Clinical implementation of NMP will result in structural changes to the current donation and transplantation logistics. This will most likely necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for the sterile conduct of NMP. In addition, dedicated staff, trained in organ perfusion, will need to join the surgical teams. Depending on when NMP is initiated in the donation and transplantation cascade, dedicated personnel may have to travel to the donor center or run organ perfusion hubs.
Level of evidence:
level 5 ( review article).
This is a review article with level evidence of 5.
In this review, the NMP (normothermic machine) new technology to preserve organ perfusion at near physiological temperature (35-37). This can replenish the ATP synthesis and provide time for evaluating kidney functionality.
Different protocols are used, but most use RBCs as oxygen carriers. In addition, nutrition is vital. some centres use ringer lactate(Cambridge group). Toronto group use RL & STEEN solution.
Arterial pressure is also important, but there is no consensus regarding that. Most centres use centrifugal methods not to harm erythrocytes. MAP provided ranges between 45 and 95. 95 and 75 was found superior to 55 (Hsogood et al.).
The oxygenation pressure used is 550-650 mmHg. Cambridge group investigated altered oxygenation kinetics but found no effect on tubular function despite alteration.
Urine excreted by kidneys should be taken into consideration and replaced. There are many potential biomarkers are investigated in terms of renal injury evaluation. Clinical validation ist still in progress.
NMP can be used alone or in combination with cold perfusion according to the aim of preservation. This gives us an opportunity to evaluate kidney function before transplantation and predict the risk of DGF.
Introduction.
Organs from ECD, and those from DCD, are brone to ischemic reperfusion injury, which lead to DGF, PNF, and graft failure.
Many kidneys are reluctant from donation, because of doubt about the quality, and short-long term outcome.
So those kidneys a valuable measure to assess viability and the degree of poor quality, in order to increase their performance and secure better function, and future survival.
NMP, provide a semi-physiological environment, (temp.35-37), with delivered O2 and nutrients.
With normothermia, cellular viability, and biochemical mechanism take place as in living body.
NMP, with many clinical experiences show a potential to increase the number of transplanted kidneys, that was initially possibly discarded.
NMP also provide a preservative technique, and platform of active organ reconditioning.
NMP, reduces CIT, which lead to reduce of ischemia-reperfusion injury, and by the end of the day reduces DGF.
Renal NMP protocol; devided into;
Perfusate composition;
Arterial pressure provided by the pump;
Oxygenation;
Temperature;
Urine replacement;
Assessing Nephron function;
Assessing vascular compartment:
Assessing immune cell compartment;
Long term kidney function;
When to start pump;
Conclusion;
Increasing use of NMP by various centers, neither as a preservative tool, a viability assessment tool, or a repair platform.
Developing field of using NMP and its important of improving quality of graft, and hence helping in expanding donor pool and reduce the number of waitlisting HD patient by reducing discarded rate of kidney of poor quality, necessiate more effort to be done in prooving types of biomarkers which can be used in assessing kidney injury, located side of injury, progression and restoration of insult, and finally gain a hoping kidney with short and long term survival.
Level of evidence ((V)) clinical review.
This article focus on pre transplant optimization of organ donation from older donor or donor with co- morbidity or from deceased donor with circulatory death which are exposed to ischemic perfusion injury lead to delay graft function.
it’s large randomized pre clinical trials on animal to compare NMP with SCS ( static cold storage), by Cambridge groups.
Renal normothermic machine ( NMP), provide organ preservation technique at temperature 35 to 37c by oxygenated perfusion solutions through renal vessels.
It’s help to resume and replenish ATP synthesis.
It’s lead to reduce cold ischemic time.
Renal NMP protocol: It’s extracorpeal membrane oxygenated and rich with nutrient perfusion solutions through the renal vessels.
It’s help for preservation/ viability assessment and repair by replenish the ATP. This perfused solutions consist of ringer lactate and Steen solutions to keep oncotic and osmolarity of kidney.
Some perfused solutions contain human albumin and electrolytes near to physiological range and other compositions contain glucose and insulin and albumin to maintain glucose absorption.
Arterial pressure provided by centrifuge pump because less harm on red blood cell. The mean arterial pressure by NMP is between 95 to 45 mmHg and systolic blood pressure 95 to 55 mmhg to maintain renal blood flow and creatinine clearance and sodium reabsorption and less tubular injury.
Oxygenated blood is high at 550 to 650 mmhg with minimal carbon dioxide to maintain acid base imbalance and no formation of free radical oxygen which may harm tubules.
Temperature// 32 to 37c and they showed gradually rewarming from 20 c to 32 c during 90 min no add protection.
Assess nephron function by creatinine clearance and fractional sodium excretion so NMP will not give idea on function of kidney post transplant .
Endothelial damage is important factor in viability of kidney and it reflects increased vascular resistance and means presence of plugged RBC in cortex and medulla which lead to thrombosis and no blood flow in kidney so by NMP lead to discard kidney from donation.
Kidney donor from DCD are exposed to activate innate and adaptive immune system lead to release leukocytes and by NMP lead to remove resident and activated leukocytes and reduce immunological risk.
All NMP assess and investigate bio markers of acute kidney injury and short term graft survival because the most acute kidney injury reversed post transplant but chronic damage lead to reduce graft survival so NMP give opportunity to diagnosis of kidney damage and fibrosis pre transplant and post transplant because graft fibrosis is the main reason for graft loss due to continue activation of immune response despite immunosuppressive agents.
Q2: level 5
Introduction
DGF is a recognized risk factor associated with decreased graft and patient survival over the long term. To get the best possible outcome from each donor kidney and maximize the survival benefit relative to the dialysis population, effective organ preservation continues to be one of the greatest obstacles to reducing current DGF rates and their resultant negative long-term impact.
Numerous kidneys given for transplantation are ultimately not implanted due to doubts regarding their short- and long-term functionality. These organs would especially benefit from a reliable pretransplant organ viability and quality evaluation.
-Renal normothermic machine perfusion (NMP) is a near-physiological organ preservation approach since it pumps a warm (35–37 C) perfusion solution through the renal capillaries carrying oxygen and nutrients. NMP shortens the duration of cold ischemia and may ameliorate the ill effects of ischemia-reperfusion damage. Preclinical and early clinical data suggest that NMP may lower DGF compared to static cold storage (SCS).Substantial effort has been devoted to the development of NMP as an organ preservation, assessment, or repair platform.
Methods
This is a single center, retrospective cohort study evaluated the effect of HMP on the kidney preservation in comparison to static cold storage.
A total of 66 transplanted kidney outcomes were assessed for a duration of 6 years.
Case controls were matched according to graft type (DBD or DCD), donor age, cold ischemic time, and number of HLA mismatches.
Patients received a steroid sparing immunosuppressive regimen with alemtuzumab induction and long-term Tacrolimus monotherapy.
-NMP uses extracorporeal membrane oxygenation and compound supplementation technology to give the kidney with an oxygenated and nutrient-enriched perfusate during the NMP phase. NMP treatments can be loosely categorized according to perfusate composition, arterial pressure provided by the pump, oxygenation, temperature, and urine replacement.To provide appropriate tissue oxygenation, red blood cell (RBC)-based perfusates are used in virtually all NMP protocols documented to date.
-The Cambridge group uses Ringer’s solution-based perfusate, which has a comparatively low oncotic pressure.The Toronto team employs a perfusate composed of Ringer’s lactate and steensolution, which generates a physiological oncotic pressure and osmolarity. The MePEP consortium employs an additional perfusate composed of human albumin and electrolytes within physiological values. Various chemicals are routinely administered during perfusion to maintain a stable environment that is close to physiological.
– No study has conclusively examined the roles of specific perfusate components or compared existing #uids side-by-side to determine which components could lead to an ideal NMP and the best posttransplant result.
-There is no consensus regarding the appropriate perfusion pressure during NMP, whether it should be applied pulsatile or nonpulsatile, or whether a centrifugal or roller pump is superior.
– Some research suggests that pulsatile pressure during NMP increases renal blood flow, creatinine clearance, sodium reabsorption, and decreases tubular damage. Reported mean arterial pressure (MAP) during renal normothermic perfusion is between 40 and 95 mm Hg.
-The majority of experimental kidney NMP systems employ a supraphysiological perfusate oxygen content between 550 and 650 mm Hg. To create appropriate acid-base equilibrium, oxygen is often administered in conjunction with a little amount of carbon dioxide. It has been hypothesized that regulated oxygenation rewarming enhances cellular homeostasis and reduces rewarming harm in a porcine NMP model. Controlled oxygenation rewarming improves early posttransplant cortical microcirculation as well.
– Loss of circulating volume caused by urine output of the ex vivo perfused kidney should be replenished to preserve the circuit’s circulating volume. The Toronto and Cambridge teams replaced this volume by incorporating Ringer’s solution or Ringer’s lactate into the perfusate. Creatine clearance and fractional sodium excretion are widely cited as indicators of nephron function.
-Endothelial injury is a crucial predictor of renal viability. Due to the limited regenerating potential of endothelial cells, microvascular injury in the kidney has a detrimental influence on the long-term survival of grafts.
Future studies are needed to concentrate on determining the optimal perfusate composition, perfusion duration and pressures, as well as the necessity for urine recirculation and specialized additives, for each application area of renal NMP.
In conclusion, A growing number of centers are examining renal NMP as a preservation tool, a viability evaluation tool, or a platform for repair. There is considerable variation among NMP procedures and the interpretation of NMP readouts. There are no proven ex vivo viability biomarkers identified. Guidelines for best practices and unanimity on processes would certainly improve preservation approaches.
The provided article is a review article with level of evidence 5
Summary
Introduction
Due to the shortage of organs, more organs from marginal and ECDs are being utilized. Older donors and donors with comorbids are being utilized. Organs from DCD donors are also increasingly being utilized. These marginal donors have an increased risk of developing DGF, PNF and reduced graft survival. Many organs from marginal donors are discarded due to doubt of their viability. These organs would benefit from pre-transplant organ viability and quality assessment. A plethora of non perfusion-based pre transplant quality assessment tools exist that incorporate clinical and donor recipient variables. However, none of these models demonstrate adequate predictive power to guide clinical decision making for individual kidney donors.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35-37 degrees celsius) perfusion solution through the renal vasculature delivering oxygen and nutrients. At normothermia, cellular metabolism can resume and replenish ATP synthesis, which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury might be performed during NMP.
The potential of NMP goes beyond its diagnostic applicability, also encompassing the possibilities to serve as a promising superior preservation strategy and a platform for active organ reconditioning. Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
Renal NMP Protocols
The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, temperature and urine replacement.
Perfusate Composition:
The composition of perfusate is not only of critical importance to ensure optimal organ preservation but it is also likely to affect the interpretation of of potential renal viability markers during NMP. Almost all NMP protocols use RBC-based perfusates to ensure adequate tissue oxygenation. NMP perfusates are typically supplemented with different compounds to provide nutrients that aim to preserve nutrient viability. the main component is either Ringers Lactate or RL with STEEN solution or normal saline with albumin.The perfusate also contains antibiotics, mannitol and Ca gluconate. It also has additives like glucose and vasodilators like verapamil.
Arterial Pressure Provided By The Pump
There is no consensus in literature about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or non-pulsatile fashion and whether a centrifugal or roller pump is best. Most groups use centrifugal pumps, which are considered to be less harmful to RBCs. The MAPs during renal NMP range between 40 – 95 mmHg. Preclinical studies by Hosgood and colleagues found superior outcomes for higher MAPs (75-95 mmHg).
Oxygenation
most experimental kidney NMP systems use supra-physiological perfusate oxygen concentration of approximately 550-650 mmHg. Administered oxygen is typically balanced with a small percentage of CO2 to create optimal acid base homeostasis. However, hyperoxia can promote reactive oxygen species, resulting in additional kidney injury.
Temperature
Typically, the temperature during NMP is set at 37 degrees celsius but this may be different depending on on the specific aim of the ex vivo perfusion. Preclinical work has shown that, upon simulated organ perfusion, tubular and renal function was better preserved when normothermic instead of subnormothermic perfusion preceded it. An important question is whether normothermia should be induced abruptly or gradually.It has been suggested that controlled oxygenated re-warming improves cellular homeostasis and mitigates re-warming injury
Urine Replacement
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuits circulating volume. Ringers lactate has been used to replace the lost volume. Weissenbacher at al showed that recirculating the urine is feasible and that it results in a significantly higher perfusion flow rate as well as a revitalized metabolism determined by unregulated levels of ATP synthase, NADH dehydrogenase and oligosaccharyltransferase.
Diagnostic Potential
Assessing nephron function and injury
Creatinine clearance and FeNa are frequently reported as markers to assess nephron function. It is not known whether these parameters during NMP are predictive for post transplant function.
Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models. It is currently unclear how and if oxygen consumption indeed reflects viability as there is evidence that oxygen consumption in the kidney during NMP is dependent on the oxygen concentrations offered. Newer molecules have been investigated but none have been validated in large cohort of kidney transplants.
Assessing Vascular Compartment
Endothelial damage is an important determinant of renal viability. In vivo endothelial damage and viability are reflected by an increase in vascular resistance relates to a combination of disruption of the endothelial cell lining favoring thrombosis and the no reflow phenomenon.
Assessing the Immune (cell) Compartment
ischemia reperfusion injury causes sterile inflammation which triggers activation of innate and adaptive immune systems as weak as leucocyte recruitment that is reinforced by cytokine and chemokine release. Removal of circulating leucocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion
Long Term Renal Function
Currently, almost all NMP studies investigate biomarkers correlated with acute kidney injury and short term graft survival. Because most acute injury restores after transplantation, chronic renal damage will determine long term graft survival. Predicting long-term post-transplant renal graft survival during NMP would make this technique particularly useful as a pre-transplant diagnostic tool
When To Start NMP
The optimal timing to start NMP is dependent on the aim of its clinical application, that is preservation, viability assessment or repair all necessitating an individual tailored strategy.
Prospects:
Finding novel biomarkers and elucidating pathophysiological processes can eventually pave the way for meaningful pre transplant kidney assessment followed by active initiation of regeneration by targeting the associated pathways ex vivo
Conclusion
An increasing number of centers are investigating renal NMP either as a preservation tool, a viability assessment tool or a repair platform. There is great diversity among NMP protocols and interpretation of readouts during NMP. No validated ex vivo viability biomarkers have been identifies. Best practice guidelines and consensus on protocols would likely progress the files
The level of evidence is level V as this is a review article
Normothermic machine perfusion (NMP);
Uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period
.
RENAL NMP PROTOCOLS;
The different fundamental facets of NMP protocols can be roughly divided into;
A-The perfusate composition.
B- Arterial pressure delivered by the pump.
C-Oxygenation .
D-Temperature.
E-Urine replacement .
1-The perfusate composition;
NMP perfusates are typically supplemented with different compounds to provide nutrients that aim to preserve renal cell viability.
a-Red blood cell (RBC)-based perfusates.
b-Perfusate based on Ringer’s lactate and STEEN solution, which creates a physiological oncotic pressure and osmolarity.
c-Perfusate based on human albumin and electrolytes within physiological ranges.
To date, no study has convincingly investigated the roles of individual perfusate components or even compared existing #uids side-by-side to establish which components could lead to an optimal NMP, as well as the best posttransplant outcome.
2- B- Arterial pressure delivered by the pump;
No consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
Reported mean arterial pressure (MAP) during renal normothermic perfusion range between 40 and 95 mm Hg and Pulsatile 90/70
3-Oxygenation ;
Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg.
4-Temperature;
Typically, the temperature during NMP is set at 37ºC, but this might be different, depending on the speci!c aim of ex vivo perfusion.
5-Urine replacement ;
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume.
DIAGNOSTIC POTENTIAL;
Although the potential of NMP as a diagnostic platform has been recognized, the search for relevant and independently predictive viability markers has only just started and is likely to increase with wider clinical implementation of NMP.
1-Assessing Nephron Function and Injury
2-Assessing the Vascular Compartment
3-Assessing the Immune (Cell) Compartment.
4- Assessing Long-term Renal Function.
1-Assessing Nephron Function and Injury;
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
2-Assessing the Vascular Compartment;
In vivo, endothelial damage and viability are reflected by an increase in vascular resistance related to a combination of disruption of the endothelial cell lining favoring thrombosis and the “no-reflow” phenomenon, which is the sub optimal restoration of perfusion after a period of ischemia.
3-Assessing the Immune (Cell) Compartment;
In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release.
Despite the absence of circulating leukocytes during NMP, resident leukocytes are released. It is unclear what the implications of the presence and release of resident leukocytes are and whether the phenotype and behavior of these cells could be predictive of post transplant outcomes.
4-Long-term Renal Function;
Because long-term graft survival and function are determined by multidimensional factors, an integrative approach may be required for pretransplant outcome prediction that combines viability measurements during NMP with donor, organ, and recipient characteristics, which all come with their own multifaceted complexity.
WHEN TO START NMP;
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
LOGISTICAL AND ECONOMIC IMPLICATIONS;
The actual costs associated with the clinical implementation of NMP remain largely unknown.
Other major costs comprise the NMP disposables, perfusate components, equipment needed to obtain samples, analyses for viability assessment, facility fees, NMP training, and depreciation of the perfusion device.
PROSPECTS;
Finding novel biomarkers and elucidating pathophysiological processes can eventually pave the way for meaningful pretransplant kidney assessment, followed by active initiation of regeneration by targeting the associated
pathways ex vivo.
CONCLUSION;
Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
What is the level of evidence provided by this article?
Level V
SUMMARY
Introduction
The introduction of expanded donor criteria has increased the donor pool for kidney transplantation, but the attendant rate of DGF, primary nonfunction and acute rejection has also increased. One of the major causes of the above is the increased susceptibility of DCD due to ischemic reperfusion injury. Moreso, many of the marginal kidney are usually discarded because of uncertainty on the quality and viability of the organ in short and long term. The normothermic machine perfusion is a tool that provides a near physiological state for the retrieve organ to preserve it and to do pretransplant viability test on the organ.
Function of NMP
Renal NMP protocol
a) Perfusion composition
b) Arterial pressure provided by the pump
Diagnostic potential of NMP
The timing to deployment of NMP as tool depend on the aim if it is for preservation, viability assessment or repair of the graft
Logistic and economic implication of use of NMP
Conclusion
The idea role played by NMP has still been investigated by many transplants’ centers if for preservation, viability or as a repair tool. Moreso, different school of thought exist on the NMP protocols and interpretation of results couple with lack of ideal biomarkers for viability of the retrieved organs
The level is 5, because is a narrative review with expert opinions
NMP is anew technology which will add on the transplant and potentate the effect of the transplanted organ by keeping the organ in environment similar to the body.
This technique allowed us now to accept the kidney which used to be discarded in the past.
this technique allow to provide the transplant organ with oxygen and nutrients which is essential to reduce the DGF.
we can assess this machine by assessment for the creation clearance and and Na fraction excretion .
we need to sasses his endothelial vascular viability as well
when to start is depends on what we are looking for viability or repair and so on
Thank You
The increased utilization of high-risk renal grafts for transplantation requires optimizing pretransplant organ assessment strategies. Unfortunately, current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity.
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. Initial clinical experience shows that NMP can potentially increase the number of kidney transplants by evaluating and transplanting kidneys that had initially been discarded for transplantation.
Preclinical and early clinical experience suggest that NMP might reduce DGF compared with static cold storage (SCS).
This review overviews the fundamentals of sizeable preclinical animal and clinical NMP protocols used by several leading centers because no single united NMP protocol exists to date also provides a framework to consider when assessing kidney viability during NMP and discusses the logistical and economic impact that clinical implementation of NMP is likely to have on the renal transplant field.
RENAL NMP PROTOCOLS:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP per
file:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.gif
Ø Perfusate Composition:
Ø Arterial Pressure Provided by the Pump
Ø Oxygenation
Ø Temperature
Ø Urine Replacement
DIAGNOSTIC POTENTIAL:
The potential of NMP as a diagnostic platform has been recognized. However, the search for relevant and independently predictive viability markers has just started and is likely to increase with more comprehensive clinical implementation of NMP.
1-Assessing Nephron Function and Injury
Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
2- Assessing the Vascular Compartment:
Endothelial damage is an essential determinant of renal viability.
3- Assessing the Immune (Cell) Compartment
Long-term Renal Function
Currently, almost all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival.
WHEN TO START NMP
The optimal timing to start NMP depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual-tailored strategy.
LOGISTICAL AND ECONOMIC IMPLICATIONS
NMP is technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at normothermic temperatures
Clinical implementation of NMP will result in structural changes to the current donation and transplantation logistics. It will most likely necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for the sterile conduct of NMP.
In addition, dedicated staff trained in organ perfusion will need to join the surgical teams. I depend on when NMP is initiated in the donation and transplantation cascade.
CONCLUSION
An increasing number of centers are investigating renal NMP as a preservation tool, viability assessment tool, or repair platform. Great diversity exists among
NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified. To establish
practical preservation by NMP, as well as the use of NMP as an objective pretransplant organ assessment tool and
eventually, interpret NMP data on a standardized global
basis, more uniformity in NMP protocols is of paramount
importance
level 5 article review
Thank You
V. Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool
1. Please provide a summary of this article
2. What is the level of evidence provided by this article?
Summary of the article
Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool
Renal normothermic machine perfusion (NMP):
1. provides a near-physiological organ preservation technique;
a) It circulates a warm (35–37 oC) perfusion solution through the renal vasculature.
b) It delivers oxygen and nutrients.
c) At normothermia, cellular metabolism can resume and replenish ATP synthesis.
2. NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
3. Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
4. NMP serve as a promising superior preservation strategy and a platform for active organ reconditioning.
5. NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
6. The different fundamental facets of NMP protocols can be divided into:
a) The perfusate composition:
1) Oxygen carrier – RBCs, artificial oxygen carrier.
2) Colloid – human albumin.
3) Impermeant – glucose, Dextran 40, mannitol, lactate, gluconate.
4) Buffers – sodium bicarbonate.
5) Electrolytes – Na+, K+, Ca++, Cl-.
6) Antibiotics cefuroxime, amoxicillin/clavulanate.
7) Additives -glucose, amino acids, vasodilator, heparin, dexamethasone.
b) Arterial pressure delivered by the pump;
1) Continuous pressure with MAP range 40 – 95 mmHg.
2) Pulsatile pressure with MAP range 90/70 mmHg.
c) Oxygenation;
1) Carbogen (95% O2/5% CO2)
2) pO2 550 -650 mmHg.
d) Temperature;
1) abrupt rewarming
2) gradual rewarming
e) Urine replacement;
1) Urine recirculation
2) Ringer’s lactate/solution.
NMP; Diagnostic potential
1. Assessing nephron function and injury
a) Creatinine clearance and fractional sodium excretion.
b) kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin.
c) Aspartate aminotransferase and lactate correlated with posttransplant renal graft function.
d) Higher levels of Flavin mononucleotide (FMN) during NMP were found in kidneys with DGF and PNF after transplantation.
2. Assessing the vascular compartment:
Cambridge group uses macroscopic appearance, renal blood flow, and urine output during 1h of NMP performed at the end of SCS.
3. Assessing the immune(cell) compartment
Inflammatory cytokines are released during kidney perfusion, although it is currently unclear which cytokines could be predictive of outcome.
4. Long term renal function is affected by:
a) Pre-existing renal fibrosis in donor grafts.
b) The quality of the donor organ.
c) Prolonged warm ischemia time and anastomosis time.
d) Recipient’s factors; increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardio- vascular complications at the time of transplantation are associated with adverse long-term outcomes.
When to start NMP:
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair.
a) Preservation and repair need prolonged time on NMP(strategy 1).
· strategy 1: NMP for the entire preservation interval.
b) NMP as assessment tool has a wider range of options (strategy 2, 3, and 4).
· Strategy 2: a short period of NMP at the donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for transportation to the recipient center
· Strategy 3: NMP at the recipient center only.
· Strategy 4: an intermittent period of NMP that could be executed in an organ hub or at the recipient center, after which kidneys are again preserved with CP.
What is the level of evidence provided by this article?
This is a review article
Level of evidence grade 5
Thank You
This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients. At normothermia, cellular metabolism can resume and replenish ATP synthesis, which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury, might be performed during NMP. in recent years, considerable effort has been directed at the development of NMP as either an organ preservation, assessment, or repair platform.
Although NMP as an ex vivo organ evaluation platform may seem intuitive and technologically within reach, the key question in this regard is what to assess while a kidney is on the pump.
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period. The different fundamental facets of NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement (figure 1).
file:///C:/Users/abosa/AppData/Local/Temp/msohtmlclip1/01/clip_image001.png
Although the potential of NMP as a diagnostic platform has been recognized, Assessing Nephron Function and Injury, Assessing the Vascular Compartment & Assessing the Immune (Cell) Compartment.
WHEN TO START NMP?
The optimal timing to start NMP largely depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy (figure 2)
file:///C:/Users/abosa/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png
LOGISTICAL AND ECONOMIC IMPLICATIONS
– Clinical implementation of NMP will result in structural changes to the current donation and transplantation logistics. This will most likely necessitate transplant centers to establish a specialized perfusion room or use existing operating theaters for the sterile conduct of NMP. In addition, dedicated staff, trained in organ perfusion, will need to join the surgical teams.
The actual costs associated with the clinical implementation of NMP remain largely unknow
– innovative imaging techniques could be applied during renal NMP such as MRI, PET & MPM imaging may provide more information about regional differences in the functional properties of the ex vivo perfused kidney. These techniques could be a valuable add-on to renal viability assessment during NMP in the near future.
CONCLUSION :
– An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform.
– Great diversity exists among NMP protocols and interpretation of the readouts during NMP. Moreover, to date, no validated (set of) ex vivo viability biomarkers have been identified.
– To establish effective preservation by NMP, as well as use NMP as an objective pretransplant organ assessment tool and eventually interpret NMP data on a standardized global basis, more uniformity in NMP protocols is of paramount importance.
– Future research should focus on identifying the ideal perfusate composition, perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
level of evidence :
a narrative review, level 5
figure 1
Thank You
Summary
This article seeks to develop an understanding about NMP or renal normothermic machine perfusion. This is because of the importance of perfusion when using extended criteria organs for transplantation and the ever continuing scarcity of donor organs. Organs need to be preserved properly and assessed for validity before being accepted for the recipient.
NMP allows for a near physiological organ preservation technique that circulates warm solution through the kidneys providing oxygen and nutrients to kidney cells. This replenishes ATP formation and allows the physician to assess functional capacity of the kidney as well as extent of injury. In doing so, we aim to increase the number of kidneys that can be used for transplantation and reduce organ wastage.
Other than diagnosis, NMP also serves as a valuable organ preservation technique. A very important function it plays is reducing CIT and thus reducing the impact of ischemic reperfusion injury. The means that NMP can also reduce the incidence and risk of DGF in comparison with static cold storage.
The perfusate used in the NMP protocols are usually RBC based to ensure adequate oxygenation. Some centers use ringer’s solution since it has low oncotic pressure. Insulin is added to the solution in some cases to facilitate glucose absorption.
Temperature is set at 37 degree Celsius. Loss of circulating volume by urine production of the ex vivo perfused kidney has to be replaced to maintain circulating volume. This was done with ringer’s lactate addition and higher flow rate.
Nephron function and extent of injury can be assessed. Markers for this include creatinine clearance and fractional sodium excretion. Non specific injury markers include AST and lactate, corresponding to post transplant renal graft function.
Endothelial damage is assessed for renal viability. Increase in vascular resistance can occur due to disruption of endothelial lining favoring no reflow phenomenon and suboptimal restoration of perfusion following ischemia. Presence of RBC plugs can be seen contributing to injury. Increased flow and decreased resistance with the use of NMO will increase perfusion and keep perfusion pressures constant and stable, reducing injury extent and risk.
Late graft loss is usually from renal fibrosis due to continuous alloimmune response to the donor graft despite immunosuppression. NMP can help to diagnose this pre transplant.
Innovative imaging methods for NMP help widely. These include near infrared spectroscopy MRI, PET scan, contrast enhanced ultrasound, ultrafast ultrasound imaging, laser speckle imaging, and multi photon microscopy imaging. These help to focus on renal physiology during NMP non-invasively.
in conclusion
Level of evidence
This is a narrative review. Hence level of evidence is 5.
Thank You
Please provide a summary of this article
Introduction:
Organs from extended criteria donor, or after circulatory death donors, prone to ischemia reperfusion injury resulting in DGF, PNF, graft failure.
Many of offered kidneys are discarded, due to doubt in their viability and capacity to provide adequate short and long time graft function.
Makes the discovery of an organ assessment tool, for decreasing the organ decline based on a clinical guided decision. Normothermic Machine Perfusion (NMP) is a promising tool, providing near physiological organ preservation method, and decreasing the ischemia reperfusion injury.
RENAL NMP PROTOCOLS:
Perfusate Composition:
– Red blood cell base perfusate.
– Ringer’s solution based perfustae
– Ringer lacate and STEEN perfusate.
– MePEP consortium human albumin based perfusate.
All used to maintain a stable near-physiological environment during perfusion, no studies demonstrate which perfusion is better for post transplant outcomes.
Arterial Pressure Provided by the Pump:
Pulsatile pressure during NMP results in enhanced renal blood #ow, creatinine clearance, sodium reabsorption, and lower tubular injury.
Superior renal function and endovascular injury outcomes for higher MAPs (75 and 95 mm Hg).
Oxygenation:
Perfusate oxygen concentration of 550–650 mm Hg with a small percentage of carbon dioxide to create optimal acid-base homeostasis, but did not infuence tubular function, creatinine clearance, urine output, or biomarkers of renal injury during simulated reperfusion after NMP.
Stubenitsky oxygen consumption formula [(arterial Po2 –venous Po2 )×perfusate flow rate/weight].
Temperature:
Better tubular and renal functions was found with normothermic (37 ºC).
Controlled oxygenated rewarming also enhances early post-transplant cortical microcirculation, preventing the renal cells from damage by pumping against high cortical resistance.
Urine Replacement:
Urine recirculation applied in Toronto results in a signicantly higher perfusate flow rate, revitalized metabolism determined by upregulated levels of ATP synthase, NADH dehydrogenase, no data in graft function to recommend such replacement.
DIAGNOSTIC POTENTIAL:
Assessing Nephron Function and Injury:
Creatinine clearance and fractional excretion of sodium frequently used markers for nephron function.
Oxygen consumption has been proposed as a marker of kidney metabolic activity in animals.
Kidney injury molecule-1 (KIM-1) originates from proximal tubular cells and NGAL originates from the thick ascending loop could be a marker for tubular function.
AST and lactate correlated with post-transplant renal graft function, measured by peak serum creatinine.
Assessing the Vascular Compartment:
Flow—not resistance—is one of the parameters of the kidney quality assessment score, which combines macroscopic appearance, renal blood #ow, and urine output during 1h of NMP performed at the end of SCS.
A loss of vasoactive response indicates endothelial dysfunction and might be used for viability testing.
Long-term Renal Function:
Long-term outcomes related to :
Donor factors: quality of the organ, age of the donor, long warm ischemia time and anastomosis time. Recipient factors: older age, kidney disease recurrence, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and cardiovascular complications. These factors, are required for pre-transplant outcome prediction.
WHEN TO START NMP:
Start NMP depends on the aim of organ preservation, viability assessment, or repair, necessitate an individual tailored strategy.figure attached.
LOGISTICAL AND ECONOMIC IMPLICATIONS:
Special perfusion room, personnel to handle and transfer the organ to recipient center, time consuming, risk of technical failure, high cost, are the limitations of its use.
PROSPECTS:
The multidimensional biological complexity of assessing renal allograft function and predicting post-transplant outcome mandates an integrative approach with the implementation of multiomics data (eg, a combination of genomics, transcriptomics, proteomics, and metabolomics).Such a multilayered omics approach could be performed during NMP- multiple imaging tools can be used eg; MRI, PET, CEUS …etc.
CONCLUSION:
NMP is an organ preservation, viability assessment tool, and a repair platform, investigated in many centers with different protocols, it has some logistic and economic issues limiting its wide use.
Further studies identifying the ideal perfusate, perfusion duration and pressures, and the need for urine recirculation and specific additives, for renal NMP.
What is the level of evidence provided by this article?
Level of evidence V – review article.
Thank You
Please provide a summary of this article
Kidney donation from DCD and ECD are at high risk of DGF and primary non function. The discard rate is high as there is concern about quality. A number of quality assessment tools exist but non can demonstrate adequate power to guide clinical decisions. More objective quality assessment tool are required pre transplant.
Renal normothermic machine perfusion -NMP provides near physiological organ preservation technique and its circulation is at 35-37C.
The solution used has temperature between 35-37C and is pulsatile by using a pump. It provides oxygen by extracorporeal membrane oxygen . Vasodilators , insulin and glucose can be added to solution. The solution is usually rich in nutrients like electrolytes. human albumin, ringer lactate etc.
The NMP reduced cold ischemia time leading to less reperfusion injury and DGF. It provides adequate environment of ATP synthesis. Thus , it can be used for donor kidney quality.
Oxygenation- O2 %- 95% /CO2 5%
PaO2 – 550-650 mmHg
Urine Replacement- Loss of circulating volume can be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
The advantages includes, preservation, assessment of viability and repair
Types of NMP.
1- Entire preservation
2- At donor site
3- At recipient site.
The NMP has some disadvantages like , higher cost , time consuming, need for more resources and logistics
What is the level of evidence provided by this article?
Level of Evidence- V
Thank You
Normothermic machine perfusion (NMP) is a method used for preservation of organs, the solution is characterized by the followings:
NMP may offer several advantages over the cold solution machine perfusion including:
Arterial Pressure Provided by the Pump
Oxygenation
Temperature
Assessment of the quality of donor kidney
Benefit of Normothermic machine perfusion (NMP)
When and where to start NMP
Problems with NMP
Level of evidence V
Thank You
1. Please provide a summary of this article
The gap between demand-supply of organs has led to increased use of extended criteria donors (ECD) and donation of cardiac death (DCD) which is associated with increased delayed graft function (DGF), primary nonfunction (PNF) and graft failure. So a reliable qualitative assessment of organ pre-transplant will help in better graft outcomes.
Renal normothermic machine perfusion (NMP) is a near-physiological way of preserving organs by providing oxygen and nutrients at 35-37 degree Celsius temperature replenish the ATP synthesis and resuming cellular metabolism. NMP decreases cold ischemia time and hence ischemia-reperfusion injury. So, NMP has 3 major functions: evaluating viability of the kidney, preservation of the kidney, and active organ repair.
Renal NMP protocols:
1) Perfusate composition: It involves an oxygen carrier (RBCs or synthetic oxygen carriers), different compounds like albumin, Ringer solution, amino acids, glucose, electrolytes (sodium, potassium, calcium, chloride), buffer like sodium bicarbonate, antioxidants and antibiotics.
2) Arterial pressure provided by the pump: Centrifugal pump is less harmful for RBCs than roller pump. Continuous pressure with mean arterial pressure of approximately 75 mm Hg (range 40-95 mmHg) is used mostly, although pulsatile pressure has been shown to increase renal blood flow, creatinine clearance and sodium reabsorption.
3) Oxygenation: Use of supraphysiological pO2 of 550-650 mmHg with a small percentage of carbon dioxide (95% O2, 5% CO2) is preferred, although hyperoxia is associated with renal injury due to reactive oxygen species production.
4) Temperature: The temperature is set at 37 degree Celsius, but rewarming may be gradual or abrupt. Gradual rewarming from cold (0-7 degrees) preservation till 20 degrees has been shown to increase early post-transplant microcirculation.
5) Urine replacement: Replacement of lost fluid can be either by recirculation of the urine formed, or by addition of Ringer solution.
Diagnostic potential: Nephron function and injury can be assessed by looking at creatinine clearance, fractional sodium excretion and other biomarkers like NGAL (signifies severe renal injury), flavin mononucleotide (correlates with DGF and PNF), KIM-1(predicts DGF), etc. Endothelial damage is characterized by increase vascular resistance, thrombosis and ‘no-reflow’ phenomenon. Kidney quality assessment score includes renal blood flow, macroscopic appearance and urine output during first hour of NMP.
When to start NMP: The optimal timing of NMP initiation is not known, but depends on the intended aim of its use. If the aim is preservation as well as repair, then NMP should be used from procurement to implantation. If it is to be used only as assessment tool, then it can be used either at time of procurement, or at the transplant centre, or at an intermediary hub after procuring the organ and before transplanting it. The most commonly used strategy is short period of NMP at transplant center, assessing the quality just prior to transplanting the kidney.
NMP is complex, time-consuming, costly, needs extra manpower, with increased risk of technical failure exposing the organ to ischemia at normothermic temperatures. Pre-transplant organ viability assessment can be complemented by novel approaches including multiomics analysis and imaging methods like MRI, PET, contrast enhanced ultrasound etc.
To conclude, NMP has three-pronged advantage: organ viability assessment, organ preservation, and organ repair.
2. What is the level of evidence provided by this article?
The level of evidence is level 5: Narrative review
Thank You
1. Please provide a summary of this article
Introduction
ECDs or DCD transplants are more susceptible to IRI which in turn increases the risk of DGF, PNF, & graft failure.
Many kidneys offered for are being discarded due to concerns about their ability to give adequate short- & long-term function.
Good pre-transplant organ viability assessment tools would have provided a favorable risk–benefit ratio to a number of waitlisted patients.
The existing non-perfusion-based pre-TX quality assessment models didn’t show adequate predictive value power to guide the decision for individual donor kidneys.
So, there is a need for a more objective & accurate pre-TX organ quality assessment tools.
Renal normothermic machine perfusion (NMP) would, likely, fill this gap as an assessment tool & reduces the organ discard rates.
Renal normothermic machine perfusion (NMP)
1.Allows near-physiological organ preservation via circulating a warm (35–37 ºC) solution through the renal vessels & thus permits normal cellular metabolism & ATP synthesis, & provide a better assessment of kidney functional & transplant-ability of organs that would have otherwise been discarded.
2.NMP is a promising superior preservation tool for active organ reconditioning.
3.NMP reduces CIT & reduces the adverse effect of IRI. NMP reduces DGF compared with static cold storage (SCS).
Renal NMP protocols
NMP provides the kidney with oxygenated & nutrients-rich perfusate throughout an extra-corporeal membrane technology.
Perfusate Composition:
-RBC-based perfusates are used to give adequate tissue oxygenation.
-Recent data suggest that synthetic oxygen carriers are equivalent to RBCs.
-NMP perfusates are enriched with nutrients to preserve renal cell viability.
-The Cambridge group uses Ringer’s solution as it has a low oncotic pressure.
-The Toronto group uses a perfusate based on Ringer’s lactate & STEEN solution that makes a physiological oncotic pressure & osmolarity.
-MePEP consortium uses a perfusate based on human albumin & electrolytes within physiological ranges.
-All centers seem supplement their perfusate with a vasodilator & glucose. Insulin is also added by some centers.
-Which perfusate components are most optimal for NMP remains to be investigated.
Arterial pressure provided by the pump
-Centrifugal pumps are mostly used; they are less harmful to RBCs (compared to roller pumps).
-Continuous pressure is mostly used; however, pulsatile pressure allows better renal blood flow, creatinine clearance, Na+ reabsorption, & lower tubular injury.
-MAP during NMP is 40 – 95 mm Hg.
-Hosgood et al. found better outcome for higher MAPs (75 & 95 mm Hg) vs 55 mm Hg regarding renal function & endovascular injury during NMP & subsequent simulated reperfusion.
Oxygenation
-Supra-physiological perfusate O2 concentration (550–650 mm Hg) are used, often balanced with a small 5% CO2 for optimal acid-base status.
-O2 consumption during NMP is reported.
Temperature
-Typically set at 37ºC; might differ according to specific aim of ex vivo perfusion.
-Tubular & renal function are better preserved with normothermic (37 ºC) vs sub-normothermic (32 ºC) perfusion.
-However, Brasile et al used subnormothermic
perfusion; there was no relevant renal injury, rather there was showed superior post-tranplant urine production & serum creatinine compared with nonperfused kidneys.
53 An important
-Controlled oxygenated rewarming enhances early post-transplant cortical microcirculation, & thus potect the renal cells injury from pumping against high cortical resistance.
-Gradual rewarming is done up to 20 ºC over a period of 90 min.
Urine replacement
-Urine made by the ex vivo perfused kidney is replaced to maintain the circulating volume.
-Replacement is Ringer’s solution or Ringer’s lactate to the perfusate.
-Recirculating the urine is an alternative & lead to higher perfusate flow rate & better cell metabolism.
Diagnostic potential
Assessing nephron function & injury
-CrCl & FeNa are the markers for nephron function; however, it is not clear whether they predict post-transplant function during NMP bcz the changes in perfusate composition & perfusion pressures will change hydrostatic & oncotic pressures, & thus affect filtration & produced urine.
-Oxygen consumption is proposed as a marker of kidney metabolic activity in animal models; however, it is unclear if this works in NMP.
-Non–cell-specific injury markers AST & lactate correlated with post-transplant renal graft function, measured by peak serum creatinine.
-FMN, a lesser-known biomarker, also correlates with post-transplant renal graft function.
Assessing the vascular compartment
In vivo, endothelial damage & viability are reflected by an increase in vascular resistance that is due to disruption of the endothelial cell lining.
Tietjen et al found RBC thrombotic plugs in cortex & medulla during NMP of discarded kidneys; these likely contribute to injury & the no-reflow phenomenon.
Cambridge group used flow (not resistance) as one of the parameters of the kidney quality assessment; this scoring gave some evidence that NMP kidney viability assessment can lead to TX of initially discarded kidneys.
Bath et al (porcine model of NMP) reported that kidneys, exposed to 2 h of WIT, have no vasodilatory capacity on exposure to acetylcholine, indicating irreversible injury of endothelial cells; in contrast, exposure to 16 h of CIT only showed a reduced response to acetylcholine.
Assessing the Immune (Cell) Compartment
In vivo, IRI leads to sterile inflammation, thus activates innate & adaptive immune systems, as well as leukocyte recruitment which is reinforced by cytokine & chemokine release.
Leuko-reduction of NMP perfusate may minimize inflammation compared with whole blood perfusion.
Long-term Renal Function
Predicting long-term post-TX graft survival during NMP would be valuable as a pre-TX diagnostic tool.
Preexisting renal fibrosis in donor grafts is associated with reduced long-term graft survival (severity of fibrosis correlates with the duration of graft survival).
Long term outcomes are also affected by:
-Quality of the donor organ
-Biological age of the donor
-Prolonged WIT
-Anastomosis time
-Regarding recipient factors
-Recurrence of native kidney disease
-Anti-HLA immunization
-Ethnic background (African American)
-Longer time on dialysis
-CV complications at the time of TX
So, an integrated approach, combining the above factors with viability measurements during NMP, is required for pre-TX outcome prediction.
When to start NMP
Different applications exist:
1. NMP for the entire preservation interval
2. A short period NMP at donor hospital followed by CP (either static cold storage or hypothermic machine perfusion) for TX to the recipient center
3. Short NMP at the recipient center only
4. An intermittent NMP in an organ hub or at the recipient center, after which kidneys are again preserved with CP.
Logistical & economic implications of NMP: Technically complex
Time-consuming
Risk of technical failure (leaving the organ exposed to ischemia at normothermic temp).
No“stand-alone” renal NMP devices are available. requiring any perfusion to be supervised at all
Clinical use of NMP will structurally change the current donation & TX logistics.
True cost associated with the clinical use of NMP is unknown. Costs include payments to out-of hours expertise, the NMP disposables, perfusate components, equipments needed, facility fees, NMP training, etc.
Cost effectiveness is seen when considering the organs that might be salvaged from discard when NMP is used.
Prospects
Identification of novel biomarkers would simplify analyses to a rapid point-of-care measurement leading to a very short pre-TX assessment time window.
==========================
2. What is the level of evidence provided by this article?
Level V
Thank You
Summary:
Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
Renal NMP protocols
Oxygen carrier – RBC, artificial oxygen carrier
Colloid- human albumin
Buffers – sodium bicarbonate
Electrolytes – Na/K/Ca/Cl
Antibiotics
Anti-oxidants – mannitol
Additive – glucose, vasodilator, heparin, dexamethasone
Continuous pressure – MAP maintained at 40-95 mmHg
Carbogen (95% O2/ 5% CO2), pO2 : 550-650 mmHg
Gradual / abrupt rewarming
Urine recirculation
RL solution
The various Perfusate constituents per research group are
When to start NMP:
Different applications of renal normothermic machine perfusion:
Conclusion:
What is the level of evidence provided by this article?
Level V
Thank You
Please provide a summary of this article
-The shift toward the utilization of older organ donors with more comorbidities has stressed the importance of robust pretransplant organ viability assessment.
-Organs from expanded criteria donors (ECDs) or those donated after circulatory death are more susceptible to ischemia-reperfusion injury, resulting in a higher risk of delayed graft function (DGF), primary nonfunction (PNF), and graft failure.
-Many kidneys offered for transplantation are ultimately not transplanted because there is doubt about their capacity to provide adequate short- and long-term function.These organs in particular would benefit from reliable pretransplant organ viability and quality assessment.
-Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
-NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury.
– Preclinical and early clinical experience suggests that NMP might reduce DGF compared with static cold storage (SCS).
-Considerable effort has been directed at the development of NMP as either an organ preservation, assessment, or repair platform.
-NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
– NMP protocols can be roughly divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
-Almost all NMP protocols described to date use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
-The Cambridge group uses a perfusate based on Ringer’s solution, which has a relatively low oncotic pressure .
-The Toronto group uses a perfusate based on Ringer’s lactate and STEEN solution, which creates a physiological oncotic pressure and osmolarity.
– Another perfusate that is based on human albumin and electrolytes within physiological ranges is used by the MePEP consortium To maintain a stable near-physiological environment during perfusion, various compounds are typically infused.
– No study has convincingly investigated the roles of individual perfusate components or even compared existing #uids side-by-side to establish which components could lead to an optimal NMP, as well as the best posttransplant outcome.
-There is no consensus about the optimal perfusion pressure during NMP, whether it should be applied in a pulsatile or nonpulsatile fashion, and whether a centrifugal or roller pump is best.
– There is some evidence that pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
-Reported mean arterial pressure (MAP) during renal normothermic perfusion range between40 and 95 mm Hg.
– Preclinical studies conducted by Hosgood and colleagues found superior outcomes for higher MAPs (75 and 95 mm Hg) and now typically set their pressure at 75 mm Hg.
-Most experimental kidney NMP systems use a supraphysiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of carbon dioxide to create optimal acid-base homeostasis.
-Typically, the temperature during NMP is set at 37 ºC, but this might be different, depending on the specific aim of ex vivo perfusion.
– It has been suggested that controlled oxygenated rewarming improves cellular homeostasis and mitigates rewarming injury in a porcine NMP model. Controlled oxygenated rewarming also enhances early posttransplant cortical microcirculation .
– Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume. The Toronto and Cambridge groups replaced this volume by adding Ringer’s solution or Ringer’s lactate to the perfusate.
-Creatinine clearance and fractional sodium excretion are frequently reported as markers to assess nephron function.
-Endothelial damage is an important determinant of renal viability. Because of the limited regenerative capacity of endothelial cells, microvascular damage in the kidney has an adverse effect on long-term graft survival.
-The absolute values of renal blood flow and urine production will strongly depend on perfusion pressure settings as well as perfusate composition (additives and oncotic pressures).
-In vivo, ischemia-reperfusion injury causes sterile inflammation, triggering activation of innate and adaptive immune systems, as well as leukocyte recruitment that is reinforced by cytokine and chemokine release. Additionally, the endothelium and epithelial cells play a key immunological role in this postreperfusion inflammatory response.
– Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
-Long-term outcomes are also affected by the quality of the donor organ, which is mainly determined by the biological age of the donor and by factors during donation and transplantation.
-Recipient factors, increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background
(African American), longer time on dialysis, and cardiovascular complications at the time of transplantation are associated with adverse long-term outcomes.
-The potential of NMP to ameliorate renal preservation and serve as a repair platform most likely demands prolonged NMP times .
-Today, a short period of NMP at the recipient center has been most commonly report.
-Future researchshould focus on identifying the ideal perfusate composition,perfusion duration and pressures, and the need for urine recirculation and specific additives, for each application area of renal NMP.
What is the level of evidence provided by this article?
Level 5
Thank You
· Renal normothermic machine perfusion (NMP) provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
· At normothermia, cellular metabolism can resume and replenish ATP synthesis, which makes it likely that assessment of renal functional capacities, as well as the severity of the renal injury, might be performed during NMP.
· Initial clinical experience shows that NMP has the potential to increase the number of kidney transplants by evaluating and transplanting kidneys that had initially been discarded for transplantation.
· NMP improves cold ischemia time.
· It may may lower DGF compared to cold storage.
· Use of extracorporeal membrane oxygenation and nutrient-enrich the kidney perfusate.
· Perfusate composition, pump-delivered arterial pressure, oxygenation, temperature and urine replenishment are essential NMP aspects.
· The potential of NMP reaches beyond its diagnostic applicability, also encompassing the possibilities to serve as a promising superior preservation strategy and a platform for active organ reconditioning.
· An increasing number of centers are investigating renal NMP, either as a preservation tool, a viability assessment tool, or a repair platform.
Level of evidence: level 5
Thank You
This study aims to review is to address the basics of the renal-NMP protocols and suggest basic outlines for future development and progress also high light the associated logistical and economic impact.
Summary
Normothermic machine perfusion technology with near physiologic perfusion of the organs which benefits with more objective assessment of the organ’s viability and quality at the time of organ procurement from marginal older donor with multiple comorbidities compared to the use of subjective assessment that limited to clinical donors’ elements with low predictive values. Based on that many centers move and started their own local NMP protocol and renal viability criteria. however, till date no validation exists of on-pump viability markers and still there is no standardized NMP protocols. The concept of renal normothermic machine perfusion (NMP) delivers a near-physiological organ protection technique because it circulates a warm (35–37 ºC) perfusion solution via the renal vasculature carrying oxygen and nutrients, and maintain normothermia, so cellular metabolism can continue and replenish ATP synthesis and this allowed for more accurate organ quality calculation including the renal functional capacity and the degree of renal injury and this will help in increased the numbers of transplantation.
NMP not only have diagnostic predictive values but also considered the preferred innovative preservation techniques and platform for active organ repairing by its effect on reducing the cold ischemia time, and reduce the risk of Ischemic reperfusion injuries and DGF risk compared to static cold storage (SCS).
When to start NMP ‘
Timing of NMP based on its clinical indication (organ preservation, viability assessment , or repair ) and summarized in four strategies( fig 2).
Logistical and economic implications of NMP
Technically its complex, over-whelming, there is a risk of technical failure which can ended with organ damage and discarded, need specialized setting either in operating theater for sterile conducts or special perfusion room., man power with skilled team trained in organ perfusion and worked with surgical team , the overall cost effectiveness not yet unknown but we should consider the cost of the NMP disposables , , perfusate component , equipment, facility fees , NMP training, an clinical research costs .
Prospects
Predictions by finding a new biomarkers(still need clinical validation ) and many advanced imaging techniques like multiphoton microscopic imaging for optical sectioning of renal tissues and dynamic studies could be applied during the NMP which give more precise view for the viability and function of the renal tissues( nephron ,microvascular function and apoptosis , tubular endocytosis.
What is the level of evidence provided by this article?
Level 5 narrative review
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V. Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool
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RENAL NMP PROTOCOLS
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Perfusate Composition
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Arterial Pressure Provided by the Pump
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Oxygenation
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Temperature
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Urine Replacement
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DIAGNOSTIC POTENTIAL
1- .Assessing Nephron Function and Injury
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Assessing the Vascular Compartment
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Assessing the immune cell compartment
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Long-term Renal Function
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WHEN TO START NMP
1- Donor hospital
2- Transport and recipeint center.
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CONCLUSION
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What is the level of evidence provided by this article?
The level of evidence is 5
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Summary of Renal Normothermic Machine Perfusion- The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment ToolIntroduction
Pretransplant organ viability assessment is crucial for:-
1- Organ from ECDs.
2- Donation after circulatory death.
And donation from those donors can result in DGF, PNF and Graft failure.
Renal normothermic machine perfusion NMP provides a near- physiological organ preservation technique and added assessment of Renal function capacity as well as severity of Renal injury.
NMP cause reduced DGF by reducing cold Ischemia time .
In this review as an ex-vivo organ evaluation plate form other key questions in this regard is what to assess while a kidney is on the pump.
Renal NMP protocols:
NMP uses extracorporeal membrane oxygenation and compound supplementation technology to provide the kidney with an oxygenated and nutrient- enriched perfusate through out NMP protocol.
NMP protocol division:-
1- Perfusate composition:-
NMP protocols use red blood cell based perfusate to ensure issue oxygenation also NMP perfusate provides nutrients that aim preserve Renal cell viability, it could be ringer solution or 5%human Albumin solution.
2- Arterial pressure provided the pump
No consensus about the optional prefusion pressure doing NMP .
It could be:-
(i) Pulsatile or
(ii) Non pulsatile fashion.
Centrifugal pumps considered to be less harmful to RBCs compared to roller pumps.
Reported mean arterial pressure( MAP )during Renal normothermic refusion range between 45-95 mmHg.
3-Oxygenation
550-650 mmHg This a proximately perfused oxygen concentrated from NMP system with small % of CO2 create optimal acid base homeostasis.
4-Temperature
Typically the temperature during NMP is set 37C.
5-Urine replacement
Replacement of urine production of the ex-vivo perfused kidney is crucial as to maintain the current circulating volume- by adding ringer, solution or lactate .
Assessing Nephron function and injury
Maker of nephron function:-
(i) Creative clearance.
(ii) Fractional sodium excretion but still is not known whether these parameter doing NMP are predictive for post transplant function.
Flavin mononucleotide(FMN) a lesser known biomarker and is correlate with post transplant renal graft function .
In pilot study found that higher level of FMN during NMP in kidneys with DGF and PNF after Transplantation.
Assessing the vascular compartment
Endothall damage is an impact and determinant of renal viability .little known about the meaning of flow and resistance during NMP , although with increasing perfusion time, flow is usually seen to increase white resistance drops.
Assessing the immune(cell) compartment
In vivo Ischemic prefusion injury cause sterile inflammation triggering activation of innate and adaptive immune system.
As well as leukocytes that reinforce by cytokines and chemokine release.
Renal of leucocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood.
Perfusion .
The use of a cytokine filter doing the 6hour of pig kidney NMP reduced level of interleukin8 and interleukin 6.
Long term Renal Function
Almost all NMP studies investigate biomarker correlated with acute injury and short term graft survival.
Pre existing renal fibrosis in donor graft is associated with decreased long-term graft survival .
The severity of Fibrosis corelated with duration of graft survival.
When to start NMP
The optional timing to start NMP depend of the aim of its clinical application that is preservation viability assessment or repair, all necessitating an individual tailored strategy.
Logistical and economic implication
NMP most likely necessitate transplant centre to establish a specialized perfusion room or use existing operating theatre for the sterile conduct NMP.
Assessment of hours specialized expertize will be mandatory to ensure a proper course of action other major cost is the equipment and devices.
Prospects
Pretransplant kidney assessment is quidded by novel biomarker.
2 diagnostic approach could help
1- Assessment renal allograft function.
2- Predicting post transplant outcome .
Conclusion
Great diversity exists among NMP protocols and interpretation of the read outs during NMP .
No biomarker have been identify ex-vivo.
Best practice quid lines and Conesus on protocol and likely progress the field.
Future research should focus on:
Ideal perfusion composition.
Perfusion duration and pressure.
Needs for urine recirculation for each application area of NMP
the evidence of article review is 5
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Introduction
Organs from ECD or DCD donors are liable to ischemia reperfusion injury increasing the risk of DGF ,PNF and graft failure.
Therefore quality assessment for those kidneys will be mandatory to evaluate the risk associated with it’s transplantation or the loss associated with discarding it .
Meanwhile there are no predictive models to guide clinical decision for individual donor kidneys.
Renal normothermic machine perfusion (NMP) offers nearly physiological organ preservation by delivering oxygen and nutrients as a warm circulation solution circulates through the renal vasculature.
This enables evaluation of the capacity of renal function
NMP decreases cold ischemia time and lessen the effect of ischemia-reperfusion injury and DGF compared to cold storage.
Standardized NMP viability criteria will be needed.
This review sheds light on the clinical NMP protocols
applied by multiple centres because there does not exist a single NMP protocol .
Renal NMP Protocols
NMP uses extracorporeal membrane oxygenation and
compound supplementation technology.
It can be divided into the perfusate composition, arterial pressure delivered by the pump, oxygenation, temperature, and urine replacement.
Perfusate Composition
It affects the assessment of potential renal viability markers during NMP.
Most protocols use (RBC)-based perfusates to ensure adequate tissue oxygenation.
The perfusate is supplied with different compounds to be more nutritive.
A relatively low oncotic pressure ringer based perfusate is used by the Cambridge group to reperfuse kidneys after a long period of static cold storage to reassess the kidney 1–2h before transplantation.
Ringer’s lactate based and STEEN solution was used by Toronto group making a physiological oncotic pressure and osmolarity to preserve organs for a longer period in prolonged normothermic kidney perfusions till 16 h.
MePEP consortium used a perfusate based on human albumin and electrolytes where NMP is combined with mesenchymal stem cells to fix kidneys during ex vivo perfusion.
Oxford group used the same perfusate made for prolonged renal perfusions that lasted up to 24h.
Most centres add to their perfusate a vasodilator and glucose. Cambridge, Toronto, and MePEP groups added Insulin to facilitate glucose absorption.
The pump providing the arterial pressure
There is no data available about the best perfusion pressure during NMP.
Centrifugal pumps and a continuous pressure during normothermic perfusion are mostly used.
MAP during renal normothermic perfusion is
40 -95 mm Hg although higher MAP had better outcomes.
Oxygenation
A supraphysiological perfusate oxygen concentration of 550–650 mm Hg is used ,it is balanced with CO2 to have acid base homeostasis.
Meanwhile hyperoxia need to be avoided.
Oxygen consumption during NMP is mentioned.
The popular equation is [(arterial Po2 –venous Po2)×perfusate flow rate/weight].
Temperature
It is mostly 37 degrees but can be variable according to the perfusion aim.
Tubular and renal function were better with normothermic than with subnormothermic.
A study revealed good urine production and serum creatinine levels after transplantation with subthermic compared with nonperfused kidneys.
Controlled oxygenated rewarming improves cellular homeostasis and prevents rewarming injury and
enhances early posttransplant cortical microcirculation.
Ischemia-free kidney transplantation is another policy that reduced ischemic and hypothermia-induced injury.
Urine replacement
Urine production leading to loss of the circulating volume need to be replaced , Toronto and Cambridge group replaced it by adding Ringer solution or Ringer lactate solution to the perfusate.
Others recirculated the urine to increase the perfusate flow rate.
Diagnostic potential
Potential biomarkers with predictive viability assessment during NMP are studied.
Assessing Nephron Function and Injury
By creatinine clearance and fractional sodium excretion but their predictive value for post transplantation function is unknown because perfusate can change hydrostatic and oncotic pressures and they represent in vivo organ viability and not ex vivo.
Oxygen consumption was suggested to be indicative of organ viability.
Kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin can be injury markers ,with localising the injury site.
Proximal tubular cells are more liable to warm ischemic injury, whereas distal tubular cells are more liable to cold ischemic injury .
FMN correlated with posttransplant renal graft function.
Vascular compartment assessment
One study published that RBC plugs in cortex and
medulla during 4h of NMP of discarded kidneys, can cause injury and the no-reflow phenomenon.
Cambridge group included the flow as a parameter of the kidney quality assessment score .
This score indicated that initially discarded kidneys can be transplanted.
Absence of vasoactive response can be an indicator of endothelial dysfunction.
Immune compartment evaluation
Sterile inflammation is caused by ischemia reperfusion injury ,removing the leucocytes from NMP perfusate can decrease the inflammation.
Leukocyte filter applied during 3h of ex vivo porcine lung NMP , reduced T-cell infiltration posttransplant compared with controls.
Long term renal function
Late graft loss is due to progression of renal fibrosis, occurring due to alloimmune response to the donor graft despite immunosuppression.
The degree of fibrosis can correlate with graft survival.
Long term outcome is affected by the quality of the donated organ and there are recipient factors as well involved ,therefore all these factors need to be collectively considered to have a score that can predict long term outcome.
Time to start NMP
It differs depending on the aim of it’s use either for preservation or repair or viability assessment.
Short period of NMP at the recipient center (strategy 3)
is the most commonly used enabling assessment of organ quality just before transplantation or strategy 2 which is assessment immediately after retrieval.
Time related complications can be avoided by centralizing clinical renal NMP to larger hubs (strategy 4)
Logistic and economic aspects
Both have to be considered as NMP is complex and time consuming , expensive and necessitate lots of regulations.
NMP was proved to save some liver grafts from being discarded and it is thought to have the same impact on renal graft and cost effectiveness have to be evaluated between NMP cost and salvaging the grafts.
Prospects
Novel biomarkers can facilitate kidney assessment before transplantation.
The biological complexity of evaluating renal allograft function and predicting posttransplant outcome necessitates an integrative approach as combination of genomics, transcriptomics, proteomics, and metabolomics.
Also innovative imaging methods as near-infrared spectroscopy, (functional) MRI ([f]MRI), PET, contrast-enhanced ultrasound, ultrafast ultrasound imaging, laser speckle imaging, and multiphoton microscopy imaging to evaluate renal viability during NMP.
Conclusion
NMP has multiple protocols and is used for different aims eith preservation , evaluation or repair of the grafts.
-level of evidence is 5
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● Organs from (ECDs) or DCD are more susceptible to ischemia-reperfusion injury, and a higher risk of (DGF), (PNF), and graft failure.
● As many kidneys offered discareded a doubt about their capacity to provide adequate short- and long-term function.
● A significant number of kidneys that are currently discarded would presumably provide a favorable risk–benefit ratio to a proportion of waitlisted individuals.
● (NMP) circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and neutrients
● NMP has the potential to increase kidney
discarded for transplantation.
● NMP is technically complex, time-consuming, and entails a risk of technical failure, which would leave the organ exposed to ischemia at normothermic temperatures.
● NMP uses as a preservation tool, or a viability assessment tool, or a repair platform.
● NMP reduces cold ischemia time and may mitigate the detrimental impact of ischemia-reperfusion injury
● RENAL NMP PROTOCOLS
Extracorporeal membrane oxygenation and
compound supplementation technology to provide the kidney with an oxygenated and nutrient-enriched perfusate throughout the NMP period.
● Almost all NMP protocols use red blood cell (RBC)-based perfusates to ensure adequate tissue oxygenation.
Arterial Pressure Provided by the Pump
* centrifugal pumps are considered to be less harmful to RBCs
* pulsatile pressure during NMP results in enhanced renal blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury
● Typically set pressure at 75 mm Hg.
● Temperature is set at 37 ºC
● Assessing Nephron Function and Injury
typical renal functional markers such as Creatinine clearance and fractional sodium excretion are unlikely to be useful for ex vivo organ viability assessment.
● Metabolic activity and oxygen consumption are high in tubular cells and therefore oxygen consumption has been proposed as a marker of kidney metabolic activity in animal models.
● Additionally, there seems to be an inherent sensitivity of proximal tubular cells to warm ischemic injury, whereas cold ischemia elicits distal tubular cell
● Flavin mononucleotide (FMN), higher levels of FMN during NMP were found in kidneys with DGF and PNF after transplantation.
● Assessing the Immune (Cell) Compartment
● Removal of circulating leukocytes from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion.
● all NMP studies investigate biomarkers correlated with acute injury and short-term graft survival.
● Because most acute injury restores after transplantation; chronic renal damage will determine long-term graft survival
● WHEN TO START NMP
depends on the aim of its clinical application , that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy
● For liver transplantation NMP has the potential to salvage a substantial number of organs from discard
● Level : 5 review article
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The utilization of marginal organs from ECD is increasing and stresses the need for more objective and accurate pre-transplant kidney quality assessment tools.
Renal normothermic machine perfusion (NMP)
It uses extracorporeal membrane oxygenation and provides a near-physiological organ preservation technique because it circulates a warm (35–37 ºC) perfusion solution through the renal vasculature delivering oxygen and nutrients.
NMP implications:
-Diagnostic applicability (organ assessment)
-Serve as a promising superior preservation strategy.
-Platform for active organ reconditioning.
RENAL NMP PROTOCOLS
Perfusate Composition:
– To ensure optimal organ preservation, also it affects the interpretation of potential renal viability markers during NMP.
– The chosen depends on the specific aim of the application of NMP (preservation, viability assessment, or repair).
– All NMP protocols described to date use (RBC)-based perfusates to ensure adequate tissue oxygenation.
– Others include Ringer lactate, STEEN solution, human albumin and electrolytes.
– No study has investigated the roles of individual perfusate components or even compared existing fluids side-by-side to establish an optimal NMP and the best posttransplant outcome.
Arterial Pressure Provided by the Pump:
-There is no consensus about the optimal perfusion pressure, whether it should be pulsatile or non-pulsatile, and whether a centrifugal or roller pump is best.
– Centrifugal pumps are considered less harmful to RBCs than roller pumps, especially during prolonged perfusions.
– Continuous pressure is mostly used; there is some evidence that pulsatile pressure during NMP results in enhanced renal
blood flow, creatinine clearance, sodium reabsorption, and lower tubular injury.
– MAP; typically set at 75 mm Hg, superior outcomes for higher MAPs (75- 95 mm Hg) compared with 55 mm Hg in terms of renal function and endovascular injury and subsequent simulated reperfusion.
Oxygenation
– Most systems use a supra-physiological perfusate oxygen concentration of approximately 550–650 mm Hg. Administered oxygen is typically balanced with a small percentage of Co2 to create optimal acid-base homeostasis.
– Oxygen consumption during NMP is often reported based on certain calculations.
Temperature
– Typically set at 37 ºC, but it might be different, depending on the specific aim of ex vivo perfusion.
– Tubular and renal function was better preserved when normothermic (37 ºC) instead of sub-normothermic (32 ºC).
– Controlled oxygenated rewarming improves cellular homeostasis and mitigates rewarming injury, enhancing early posttransplant cortical microcirculation, thereby preventing the renal cells from being jeopardized by pumping against high cortical resistance.
Urine Replacement
Loss of circulating volume by urine production of the ex vivo perfused kidney should be replaced to maintain the circuit’s circulating volume.
DIAGNOSTIC POTENTIAL
Assessing Nephron Function and Injury;
– The scarce data investigating perfusate or urine biomarkers during NMP originate from animal studies or small case series, and none have been validated in large cohorts of kidney transplants.
Assessing the Vascular Compartment
– Endothelial damage and viability are reflected by an increase in vascular resistance related to a combination of disruption of the endothelial cell lining favouring thrombosis and the “no-reflow” phenomenon, which is the suboptimal restoration
of perfusion after a period of ischemia.
– Combines macroscopic appearance, renal blood flow, and urine output during 1 h of NMP provided viability assessment, can lead to transplantation of initially discarded kidneys.
Assessing the Immune (Cell) Compartment;
– IRI causes sterile inflammation.
– Circulating leukocyte removal from the NMP perfusate is thought to minimize inflammation compared with whole blood perfusion, despite that fact resident leukocytes are released.
– Cytokines are released during kidney perfusion, although it is currently unclear which cytokines could predict the outcome.
Long-term Renal Function
– Predicting long-term graft survival would make this technique particularly valuable as a pre-transplant diagnostic tool.
– Long-term graft survival and function are determined by multidimensional factors; an integrative approach may be required for pre-transplant outcome prediction that combines viability measurements during NMP with donor, organ, and recipient characteristics, which all come with their own multifaceted complexity.
WHEN TO START NMP
– Depends on the aim of its clinical application, that is, preservation, viability assessment, or repair, all necessitating an individual tailored strategy.
– Short period of NMP at the recipient center has been most commonly reported.
LOGISTICAL AND ECONOMIC IMPLICATIONS
– NMP is technically complex, time-consuming.
– Specialized perfusion room is needed for the sterile conduct of NMP.
– Dedicated staff trained in organ perfusion will need to join the surgical teams.
– The actual costs associated with the clinical implementation of NMP remain largely unknown.
Level 5 narrative review.
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There is an increased need for thorough pre-transplant organ viability assessment due to using of ECD donors. NMP can provide near-physiological organ perfusion, because it circulate perfusion solution at temperature 35-37C with delivering of O2 & nutrients. NMP can be used as preservative, viability assessment, & for repair. It may reduce DGF rate by reducing CIT.
Renal NMP protocols:
The protocol stiffer between centers according the following para meters:
Assessment of vascular compartment:
Assessment of immune compartment:
Long term renal function depend on:
When to start NMP:
NMP starting time depend on Aim of NMP as preservation, viability assessment or repair.
Strategy 1: used for repair need prolong time .
Strategy 2: used for organ viability assessment after retrieval at transplantation center.
Strategy 3: the most common strategy used , short time NMP at transplant center.
Strategy 4: centralizing clinical renal NMP to larger hubs.
Logistic & economic implication:
Level 5 study
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This is a narrative review study discussing the impact of the normothermic renal perfusion machine in providing an organ preservation technique close to physiological temperatures and capable of adequately nourishing the organ.
These changes decrease cold ischemia time and minimize the impact of the inflammatory cascade of reperfusion syndrome after warm organ ischemia.
Five points are crucial:
1. Infusion composition
There is no uniformity in the components, however, most services use red blood cell perfusates. Ringer solutions and other electrolytes can also be used. Colloids such as albumin, buffers such as bicarbonate, electrolytes, antibiotics, and antioxidants generate this physiological environment for the organ. The pattern followed by the additives is to use a vasodilator in addition to glucose.
2. Blood pressure from the pump
Centrifugal pumps are considered to be superior and safer than scroll pumps and can generate continuous or pulsatile pressure.
3. Oxygenation
It is important to maintain constant O2 blood pressure with a low CO2 ratio. However, hyperoxia can cause tissue damage with the destruction of functional parenchyma, so monitoring at adequate values is important.
4. Temperature
In this specific case, a gradual increase in temperature to physiological to maintain cellular homeostasis and minimize the risk of reperfusion syndrome.
5. Urine replacement
The liquid loss must be replaced by Ringer’s solutions to prevent the organ from suffering hypovolemia.
This environment makes the organ more viable and less prone to injury from ischemic disorders, whether by cold or hot ischemia, in addition to removing microthrombi, decreasing proinflammatory cytokines, decreasing leukocyte recruitment, and minimizing reperfusion syndrome.
This entire process causes less organ damage, reducing the risk of late graft response and, consequently, acute and chronic rejection.
ECD organs, cardiovascular disease donors, or marginally responsive kidneys may have important benefits from this technique, making them less prone to reperfusion syndrome.
The big challenge comes in team training, adequate material, fluid therapy and monitoring, immediate maintenance, high costs, and our inability to assess early biomarkers to establish early kidney injury and proceed with the necessary care.
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Please provide a summary of this article
Introduction
Robust pretransplant organ viability assessment is important, as organs from ECDs or DCD are at higher risk of DGF, PNF, and graft failure
NMP provides a near-physiological organ preservation technique (a warm (35–37 ºC) perfusion solution delivering oxygen and nutrients)
Aim of the study: overview of the fundamentals of current renal NMP protocols and provides a framework to approach further development of ex vivo organ evaluation.
Renal NMP protocols
NMP protocols: perfusate composition, arterial pressure delivered by the pump, oxygenation (po2 of 550–650 mm Hg), temperature (37 ºC), and urine replacement
Perfusate solution is either Ringer’s solution or human albumin
Perfusate composition are oxygen carriers (RBCs, artificial oxygen carrier), colloid, impermeants, buffers, electrolytes, antibiotics, antioxidants and others
Diagnostic potential
Nephron function and injury may be assessed with oxygen consumption, kidney injury molecule-1 (KIM-1) originates from proximal tubular cells, neutrophil gelatinase-associated lipocalin (originates from the thick ascending limb), and flavin mononucleotide (FMN)
Flow is an important parameter of the kidney quality assessment which combines macroscopic appearance, renal blood flow, and urine output during 1 h of NMP performed at the end of SCS
It is unclear how to assess the immune compartment
Donor factors affection long term outcome of graft are pre- existing renal fibrosis, biological age of the donor. Recipient factors are increased (biological) age, recurrence of native kidney disease, anti-HLA immunization, ethnic background (African American), longer time on dialysis, and CV complications at the time of transplantation. Other factors are prolonged warm ischemia time and anastomosis time
When to starts NMP
When to start NMP is depends on its clinical application (preservation, viability assessment, or repair). Applications for NMP is for the entire preservation period or short period in the donor hospital or recipient hospital
Logistical and economic implications
In addition to the high cost of NMP, it is technically complex, time-consuming with risk of technical failure
Conclusion
NMP is either an organ preservation, assessment, or repair platform
No unified NMP protocols and no validated ex vivo viability biomarkers
More uniformity NMP protocols is of paramount for effective preservation and organ assessment
What is the level of evidence provided by this article?
Review study (level 5)
Thank You