Please provide a summary of these guidelines

• Acute kidney injury (AKI) is a common finding in kidney donors and recipients.
• AKI in kidney donor, which increases the risk of DGF, however, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction.
• Conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines.
• AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss.
• AKI that develops long after transplantation is often related to nephrotoxic drug reactions.
• In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality.
• Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.

====================================================================

1. Introduction

• Acute kidney injury a common problem in kidney transplantation, can take place both in the donor before organ harvesting, and in the recipient early after trans-plantation, as delayed graft function (DGF) acute deterioration of graft function.
• AKI in the graft could affect short- and long-term transplant outcomes.
• DGF, which is a heterogeneous condition resulting from factors related to procurement,organ quality, recipient medical condition, surgical insult, and graft injury-related to dialysis treatment itself, is most commonly defined as the requirement of dialysis sessions in the first week of post-transplantation in a patient who eventually becomes free of dialysis .

• According to recently published data, AKI affects 30% of kidneys coming from deceased donors and 50% of those coming from deceased donors after cardiac death (DCD) .
• Although DGF increases the risk of acute cellular rejection and reduces graft survival for DGF.

• AKI may develop post-transplantation after an initial recovery of kidney function or may occur late after transplantation.
• AKI can originate from severe and often unrecognized clinical conditions that may require a prompt intervention to prevent graft loss.

====================================================================

1.1. Acute Kidney Injury in the Donor DGF and Risk of Graft Failure

• Organs from expanded criteria donors (ECD), or donors after cardiac death, has augmented over the last two decades in order to expand the deceased-donor pool .
• The use of donors with AKI adds to these strategies for expanding the deceased-donor pool.
• AKI, which occurs in more than 25% of critically ill patients, depends on the un- derlying disease, the duration of kidney impairment, and the patient’s baseline kidney condition.
• Nonetheless, in many European national or international organ-sharing systems, it is current practice to decline about 50% of these kidneys with severe AKI (i.e., Kidney Disease Improving Global Outcomes (KDIGO) stage 2 and 3) due to a perceived higher risk of poor outcome after transplantation .
• The same scenario applies to the United States, where more than 18% of the kidneys recovered for transplant are discarded, and donor AKI more than doubles the discard rate .

• Kayler et al. , by analyzing registry US data from Scientific Registry of Transplant Recipients during the period 1995–2007, found that kidneys from donors with a terminal creatinine ≥ 2.0 mg/dL were associated with an increased risk of allograft failure only if they were procured from ECD, the relative increased risk of allograft failure in this setting being +17%.
• A subsequent retrospective study [13] analyzed the outcome of approximately 12,000 donors (72% of the offered donors) from the UK Transplant Registry (2003–2013).
• The study assessed graft function/primary nonfunction (PNF), estimated glomerular filtration rate (eGFR), and graft-survival at 90 days and 1 year were evaluated.
• Approximately 1900 donors (17%) were classified as AKI stage 1–3, according to AKI Network (AKIN) criteria.
• Graft failure at 1 year was greater for donors with AKI than for those without (graft survival 89% vs. 91%; DGF rates increased with donor AKI stage; p < 0.005), and PNF rates were significantly higher for AKIN stage 3 kidneys (9% vs. 4%, p = 0.04).
• In a US study from five organ procurement organizations in the period 2010–2013, Hall et al. reported a more reassuring scenario. this study DGF rate progressively increased from 28% for kidneys from donors without AKI to 34%, 52%, and 57% for donor AKI stage 1, 2, and 3 respectively, eGFR at six months post-transplantation was well-preserved irrespective of donor AKI stage.
• kidneys from donors with AKI stage 3 underwent machine perfusion, and approximately 90% underwent procurement biopsy to evaluate kidney quality histologically.
• A longer follow-up study including a total of 2430 transplants, of which 585 (24%) were from donors with AKI.
• None of the donors required dialysis.
• Although there was an early increase in graft loss among recipients of donors with AKI stage 3, the study confirmed that deceased-donor AKI was not associated with kidney allograft failure in the long term. In fact, after a median follow-up period of 4.0 years (interquartile range, 3.0–5.0 years), there were 623 (26%) all-cause graft failures, which included 402 deaths and 313 death-censored graft failures: all-cause graft failure was not statistically different across different AKI stages.
• By comparing donors with and without AKI, donors with AKI were older, had a higher mean kidney donor profile index (KDPI), had a longer mean cold ischemia time (CIT), and were more likely to undergo machine perfusion. Rather surprisingly, the presence of unfavorable donor-related risk factors such as high KDPI and long CIT (>14 h) did not affect the relationship between deceased-donor AKI and graft loss.

In conclusion, current evidence supports the notion that, for standard-risk donors,
donor AKI does not impair transplantation outcomes.
The evidence is less convincing for marginal donors, such as elderly donors or donors with elevated KDPI (e.g., above 85%).
For the latter type of donors, we would suggest that protocols for organ quality assessment, minimization of cold ischemia times, and/or use of machine perfusion be implemented at each transplant center.

===================================================================

1.2. Recipient with AKI Early Post-Transplantation

The most common causes of DGF.

1- Donor-Related Risk Factors

• AKI and hemodynamic instability in ICU
• Prolonged cold ischemia time
• Graft quality (old age, CKD risk factors)
• Donor type (DCD vs. DBD vs. living donor)

2- Recipient-Related Risk Factors

• Surgery
• Complex vascular surgery/vascular complications (prolonged warm ischemia time)
• Increased BMI, concomitant surgery (e.g., ADPKD nephrectomy)
• High immunological risk/rejection
• Pre-transplantation oliguria (HD vs. PD; long dialysis vintage vs. pre-emptive)
• Pre-transplantation HD/UF session

3- Perioperative Risk Factors

• Peri-operative hypotension/hypovolemia
• High CNI blood levels

-The mechanisms that link DGF to long term outcomes, evidence of benefit of newer strategies for diagnosis and management of AKI are still lacking.
====================================================================

1.3. Biomarkers of DGF

• Monitoring of DGF in transplanted kidneys has been traditionally based on a combination of clinical (e.g., serum creatinine, urinary output), immunological (e.g., donor-specific antibodies, DSA), instrumental (e.g., resistive index at Doppler ultrasound), and histological parameters.
• Because of the limits and the complexity of the “traditional biomarkers”, over the last decade, new biomarkers have been introduced that can be easily measured in biological fluids, such as perfusion solution, patient’s serum, plasma, or urine.
• Among the most promising predictive donor biomarkers are elevated donor plasma mitochondrial DNA levels , donor urinary C5a levels , matrix metalloproteinase-2 levels, periredoxin-2 and periredoxin-1 antitrypsin, and exosomal neutrophil gelatinase- associated lipocalin (NGAL) mRNA that independently predict DGF.
• Among the recipient biomarkers, cell-free microRNAs (miRNAs) and a short non-coding RNAs that play a pivotal role in regulation of gene expression through epigenetic, transcriptional, and post-transcriptional mechanisms, such as miR-505-3p, have been demonstrated to be an independent predictor of DGF in DCD grafts. Both serum and urine lactate dehydro- genase (LDH) and NGAL have been shown to predict DGF and 1-year graft function, with serum NGAL being more reliable compared to urine NGAL .
• MiRNAs, have been the focus of several studies also in kidney transplant recipients.
• Recently, a panel of six urine miRNA has been proposed as DGF biomarker as it was found elevated in the first urine voiding after surgery and in urine collected daily in the first days after surgery in patients who developed DGF.

====================================================================
2. Therapeutic Approach to AKI in Kidney Transplant
2.1. Donor and Recipient-Targeted Therapies

• To prevent DGF use of low-dose dopamine for donor pre-treatment before procurement is the strategy that is best supported by evidence coming from clinical trial.
• To preventing graft ischemia by recipient volume expansion before reperfusion with the use of various isotonic saline solutions, as well by avoiding preoperative dialysis with subtraction of volume .
• However, most of the studies targeting the recipients have been based on strate gies that reduce the activation of inflammation triggered by adaptive immune response that cause complement activation and endothelial dysfunction .
• Because rabbit anti-thymocyte globulin targets, besides T cells, also endothelial adhesion molecules and may help minimizing CNI use, they have been the induction treatment of choice to prevent DGF.
• Treatment with c1-esterase inhibitor (time 0 and 24 h after transplant) did not reduce DGF incidence but reduced the number and duration of dialysis treatments, with significantly improved kidney function 1 year later .
• The cumulative incidence of graft faiular was lower over 3.5 years among C1 esterase inhibitor-treated recipients compared with placebo, although no difference in eGFR slopes was observed between groups .
• Anti-C5 antibody (eculizumab) has also been tested to prevent DGF , but randomized studies failed to demonstrate clinical efficacy and one study reported an increased incidence of serious adverse events and graft loss in eculizumab-treated patients .

2.2. Organ-Targeted Therapy

• Use of machine perfusion for organ storage and of the in situ perfusion of organs from DCD donors have revived interest in treatment strategies aimed at preventing DGF by treating the renal graft ex vivo.
• Hypothermic perfusion machines are currently the most widely used and keep low temperature (4–10 ◦C), deliver a pulsatile flow, and optionally provide oxygenation (oxygenated versus non-oxygenated machine perfusions).
• A meta-analysis has shown that hypothermic machine perfusion is superior to static cold storage in preventing DGF in deceased donor kidney transplantation .
• This is true for both DBD and DCD kidneys.
• As kidneys from DCD donors have a higher overall DGF rate, fewer perfusions are needed to prevent one episode of DGF (7 vs. 14 in DBD kidneys) .
• However, in the hypothermic state, cells from the graft have dampened metabolic activity. Interest has grown around normothermic machine perfusion, in which the perfusion temperature is between 35 and 37 ◦C.

• Pharmacological treatments that may be administered to the graft via machine perfusion to prevent DGF and fibrosis is cell therapy based on multipotent adult progenitor cells (MAPC) [60 ].
• Multipotent adult progenitor cells possess immunomodulatory properties which could prove beneficial in minimizing subsequent ischemia reperfusion injury. Thompson et al. investigated the potential reconditioning capability of ex vivo administration of MAPC in a pre-clinical normothermic machine per- fusion model in kidney .
• MAPC-treated kidneys showed improvement in urine output, decreased expression of the kidney injury biomarker NGAL, and improved microvascular perfusion .

====================================================================
3. Early AKI in the Transplant Recipient after Initial Recovery

• AKI might develop early after transplantation after an initial recovery of graft function.
• The most common causes are surgical or medical complication, including acute rejection, whose diagnosis requires biopsy. Acute tubular necrosis, in the absence of inflammatory injury, is reported as one of the possible phenotypes of antibody-mediated rejection .
• Surgical (either vascular or urological) complications can be easily identified by renal ultrasound and/or CT scan.
• At this stage, ischemic acute tubular necrosis may be secondary to correctable causes such as hypovolemic status, high blood level of calcineurin inhibitors, arterial hypotension, and infections complicating the post-surgical course.
• Rarely, however, AKI may be the result of occult systemic disease that remained unrecognized until trans plantation, and that manifest as disease recurrence in the graft. Among them, acute crystal nephropathy may be caused by recurrent 2,8-dihydroxyadenine nephropathy, which may lead to graft loss if left untreated .
• Primary or secondary hyperoxaluria (e.g., in obese patients undergoing malabsorptive surgery before transplantation) may be an additional cause of acute crystal nephropathy.

====================================================================

4- Long-Term AKI in the Transplant Recipient

• AKI after transplantation is a risk factor for graft failure .
• Most common causes of AKI in the long-term follow-up post-transplantation can be divided into two groups:-

1- Asymptomatic AKI
2- And AKI with systemic symptoms.

• Asymptomatic AKI may be caused by acute rejection in patients with poor drug adherence, or by polyomavirus BK infection nephropathy. However, it is most commonly secondary to drug toxicity and drug-to-drug interaction with calcineurin inhibitors (CNI) .
• Non-steroid anti inflammatory drugs (NSAID) are a common cause of AKI from nephrotoxic drugs.
• Recently one long-term longitudinal cohort study assessed risk of AKI with NSAID prescriptions in kidney transplant recipients .
• NSAID prescriptions were dispensed to 5% of kidney transplant recipients (2 per 100 patient-years), with 70% of them receiving high doses .
• The median time from transplant to NSAID prescription was 4 years (interquartile range:2–5 years).
• NSAID prescription was associated with a significantly increased risk of AKI, which was further augmented by higher NSAID dose and longer NSAID duration .

AKI with symptoms, bacterial infection and especially urinary tract infections are by far the most common cause .
The prevalence of urinary tract infection history among kidney transplant recipients varies widely from 23% to 75%, with associated bacteremia occurring in 40% of them .

• The highest incidence has been reported in the first 3–6 months .
• Infection with hypovolemia is an additional common cause, which occurs in the setting of acute gastroenteritis causing vomiting and diarrhea.
• Garg et al. recently analyzed trends in rates of hospitalizations in kidney transplant recipients with primary diagnosis of AKI, secondary diagnosis of AKI, and AKI-requiring dialysis over an 11-year study period .
• Incidence of hospitalization increased in most recent eras for all types of AKI, mostly driven by sepsis. Overall, risk of hospitalization for AKI was 5% (11% in the first 3 years).
• Primary AKI hospitalization rate showed an annual increase of +7.0%, and secondary AKI an annual increase rate of 21%.
• However,the increasing trend of hospitalization for AKI may reflect increasing diagnosis of milder forms of AKI in less sick patients occurred in most recent years.
• KDIGO) change in creatinine diagnostic criteria, was developed in England and Wales in order to identify AKI in the general population and facilitate a better outcome .
• A prospectivenational cohort study, which collected data on 1224 renal transplants recipients (2010–2014),showed that 35% patients had at least one episode of AKI .
• This incidence rate was higher than the 12% reported by Mehrotra et al. , probably because it involved also non-hospitalized patients.

Because the evidence that these alerts impact outcome is lacking, further developments
of those electronic alerts and clinical studies are needed before implementation can be
recommended for routine clinical care.

====================================================================

5. COVID-19-Associated AKI in Kidney Transplant Recipients

• Because of the ongoing immunosuppression and multiple co-morbidities.
• AKI is a common finding in patients with coronavirus disease 2019 (COVID-19), possibly due to direct and indirect viral injury, and has been associated with higher rates of death when compared to COVID-19 patients without AKI.
• Although graft biopsies have not been performed routinely, AKI in kidney transplant recipients with COVID-19 does not seem to be commonly due to acute rejection, despite the frequent reduction of antirejection therapy during infection.

===================================================================.
6. Conclusions

• AKI, a common event in kidney transplantation in both the donor and the recipient, may have consequences on both short- and long-term graft functions.
• Several studies have been performed trying to identify biomarkers for predicting which donor AKI carries the highest risk of graft failure, and to implement treatment strategies to minimize the impact of AKI on short- and long-term graft dysfunction.
• While the research on biomarkers has not translated into clinical applications, the use of hypothermic machine perfusion has become a consolidated practice to prevent DGF.
• AKI occurring after early post-transplantation after initial recovery of graft function is usually related to surgical or medical causes that may occasionally cause graft failure if left untreated.
• Development of AKI later after transplantation often has an unfavorable impact on allograft outcomes because it may reflect the chronic use of nephrotoxic drugs or serious underlying medical conditions.
• E-alert systems have been proposed to help in identifying outpatients developing AKI during long term follow-up, but evidence on the beneficial effect on patient outcomes is still lacking.
• Longer follow-up studies are needed to understand the impact of COVID-19-assoaicted AKI in kidney transplant recipients.

====================================================================