4. A 39-year-old CKD 5 patients secondary FSGS not yet on dialysis (eGFR is 16 mls/min) was referred to you to consider him for kidney transplantation. He has proteinuria 7 gm/day. His serum albumin is 16 gm/L (1.6 g/dL). He is currently on warfarin with INR 2.7. Native kidney biopsy is shown below (see below).
- How to prepare him for kidney transplantation?
- What is the indication of anticoagulation in this case?
- Does he need to be anticoagulated after transplantation?
- Discuss his long-term outcome with emphasis of his primary disease.
Thank you All
How would you treat his nephrotic range proteinuria and hypoalbuminaemia?
This is a key point in the management.
Renin Angiotensin Aldosteron System inhibitor RAASi is the main treatment of choice. If no improvement, then next step is medical nephrectomy with a combination of ACEi and or NSAIDs diclofenac or Indomethacin. If unsuccessful then surgical Nephrectomy.
Reference:
1-EefkeVos et al. preparing for kidney transplant:medical nephrectomy in children with nephrotic syndrom. Pediatric Transplantation.march 2020
Excellent
Yes, we can not operate on a patient with this low albumin. The patient will fall apart. Agree, medical nephrectomy first, if not successful, surgical nephrectomy.
I will recommend medical nephrectomy (using NSAIDS, ACEI or ARBS) rather than surgical nephrectomy because of concerns of surgical complications moreover it was found that native nephrectomy in patients with primary FSGS is associated with an increase in the frequency of recurrence of FSGS and this was explained by adsorption of circulating factors by the native kidney (1)
REFERANCES
Thank you, Dr Sherif
Yes, we can not operate on a patient with this low albumin. The patient will fall apart. Agree, medical nephrectomy first, if not successful, surgical nephrectomy.
Regarding the increased incidence of rec FSGS post-nephrectomy; how strong the evidence are?
FSGS postransplant recurrence rate is variable reported from 6-58% in
children(1) and 39% in adult (Tango project).(2).
However, not all patients with FSGS suffer from recurrence after kidney
transplantation, and genetic and secondary FSGS have a negligible risk
of recurrence.
References
1-Her Gyung et AL . Recurrence and Treatment after Renal
Transplantation in Children with FSGS.Biomedical Research
international.Volume 2016 |Article ID 6832971.
2- udrey Uffing, Maria José Pérez-Sáez et al.Recurrence of FSGS after
Kidney Transplantation in Adults.CJASN February 2020, 15 (2) 247-
256; DOI: https://doi.org/10.2215/CJN.08970719.
Patients with FSGS should have minimal proteinuria at the time of transplantation, and this will help in early detection of significant proteinuria post-transplantation (1). Therefore, the presented case which has significant proteinuria should have a trial of non-steroidal anti-inflammatory drugs (NSAIDs), with or without an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), as illustrated in the attached figure.
These drugs may induce medical nephrectomy associated with the shutdown of the remaining kidney nephrons. Nevertheless, if this strategy fails and significant proteinuria persists, nephrectomy may be considered (1).
References:
1) Vincenti F, Ghiggeri GM. New insights into the pathogenesis and the therapy of recurrent focal glomerulosclerosis. Am J Transplant. 2005; 5(6):1179.
Persistent proteinuria can be controlled either by:
Excellent
Yes, we can not operate on a patient with this low albumin. The patient will fall apart. Agree, medical nephrectomy first, if not successful, surgical nephrectomy.
Medical nephrectomy with ACEI&and /or NSAID is a safe non-invasive method to treat proteinuria before transplant.the other option is bilateral nephrectomy in case of not responding to medical nephrectomy.
Conservative Therapy ;
_ sure, we can not proceed to transplantation with such heavy protinuria and hypoalbuminemia, as this markedly increase risk of hypovolemia and hypo-perfusion of the graft which eventually leads to graft loss
_ increase thromboembolic complications after transplantation
_ so trial of medical nephrectomy with ACE I and or ARBS, must be started 1 st and follow up protinuria.
_ use of NSAIDs for medical nephrectomy can be added if protinuria not controlled with ACEi and ARBs
_ few cases can require bilateral nephrectomy prior to transplantation and to be kept on dialysis till transplantation.
Dear All
This is a tricky scenario that we see quite often. Looking forward to enjoy reading your answer
Surgical bilateral nephrectmy is the last to resort to in some case
This patient has severe hypoalbuminemia due to heavy proteinuria that should be corrected before TX because of risk of graft hypoperfusion and DGF. Medical nephrectomy by ACEi or ARBs is the first option and if fails, surgical nephrectomy is the second option. Recurrence rate of post- TX FSGS in secondary forms is negligible.
Low serum albumin is the indication of anticoagulation in this case
No. Because after medical or surgical nephrectomy, serum albumin will be normalized.
Because of the low rate of FSGS recurrence in secondary forms, a good long -term outcome could be predicted in this case.
the best pre-renal transplant in this case with Nephrotic range proteinuria+ hypoalbuminaemia+ CKD 5 + FSGS in kidney biopsy—–> bilateral nephrectomy
indication for anticoagulation in nephrotic syndrome: proteinuria>10 g/day, low serum albumin below 20 g/L.
Secondary FSGS usually result from adaptive response to various kidney insult and compensatory hypertrophy and hyper filtration of remaining nephrons. Secondary FSGS can be due to different etiologies such as reflux nephropathy, primary glomerular disease, hypertensive nephrosclerosis, viral or drug induced FSGs. so, identification of underlying disease is crucial in patients with secondary FSGS. These patients have low frequency of disease recurrence after kidney transplantation and it depends on underlying cause of secondary FSGS.
Distinguishing between primary and secondary FSGS is essential, because of different therapeutic approach. Therapy in secondary FSGS consists of conservative measures aimed at reducing intraglomerular pressure such as low sat diet, low protein diet, control of blood pressure with ACE inhibitors and ARBs, and utilization of anticoagulation if serum albumin is less than 2-2.5 gr/dl or proteinuria more than 10 gr/day based on KDIGO glomerular disease guidelines 2022. Corticosteroids and other immunosuppressive therapy are not indicated in secondary FSGS.
Treatment of heavy proteinuria pre transplantation by medical therapy with ACE inhibitors and ARBs and if there is no appropriate response to medical therapy, surgical nephrectomy prior transplantation is necessary for this patient. With appropriate treatment of proteinuria and improvement in serum albumin level, there is no need for prophylactic anticoagulation post transplantation.
– We need to correct his hypoalbuminemia either medically by combination of ACEI and NSAD or surgical nephrectomy
– Trial to know the cause of secondary FSGS and treat like viral infection, obesity as this will help to reduce the risk of recurrence.
– Trial to wean off anticoagulation before the surgery after successful correction of hypoalbuminemia
– Dietician advice regarding low salt diet and low fat
– Young age
– Albumen level less than 20 gm/dl
–
If average albumen level post-transplant so no need
– 2ry FSGS unlike primary type as the recurrence rate is less and the risk to progress to graft loss is less; however, he needs close monitoring of his urine level of proteinuria and arrange graft biopsy if level of proteinuria is increasing even with normal graft function.
How to prepare him for kidney transplantation?
For FSGS patients to be listed for kidney transplantation, it’s of great importance to identify the underlying cause whether primary or secondary. Idiopathic FSGS has high rate of recurrence in one third of patients and up to 55%, while primary FSGS with familial pattern of inheritence or having genetic cause for FSGS tend to have zero or low recurrence. Secondary causes have to be identified and uncovered so as to guard against recurrence of kidney insult.
This patient with heavy proteinuria needs antiproteinuric therapy as high doses of ACEi or NSAIDs to induce medical nephrectomy before proceeding to transplant process. If medical treatment fails to control this heavy proteinuria, then surgical nephrectomy has to be considered as a solution.Data is insufficient regarding the benefit of plasmapheresis and rituximab in reducing the risk of disease recurrence post Transplant.
What is the indication of anticoagulation in this case?
Anti-coagulation is indicated in this case because of his low serum albumin( S.Albumin is 1.6 g/dl). According to KDIGO guidelines 2012 serum albumin <2.0 to 2.5 g/dl with additional risks for thrombosis is an indication for anticoagulation.
Does he need to be anticoagulated after transplantation?
No need for long lasting anticoagulation post transplantation once his serum albumin and protein excretion reverse to normal.
Discuss his long-term outcome with emphasis of his primary disease.
Recurrence is relatively common around one third of patients with risk of graft loss 5 times compared to those without disease recurrence and 5 years graft survival is 52% when disease recur.
1. Preparation of case of FSGS with heavy protinuria:
_ it is very crucial to detect secondary FSGS ( exclude infection as CMV, BK and HIV), also drug induced or small kidney mass
_ identify genetic causes with suggestive history of consanguinity, postive family history and early onset of the disease ( not consistent with our patient who is 39 years old now). Genetic study to confirm or exclude is essential.
_ Never to proceed in transplantation while the patient has heavy protinuria and hypoalbuminemia ) as this will endanger the graft perfusion at time of transplantation and perioperative.
_ control protinuria by ACE I and or ARBS and NSAIDs prior to transplantation.
_ even surgical nephrectomy can be required in some cases resistant to medical nephrectomy.
_ control of protinuria is essential to save the graft and improve the outcome, together with anticoagulation to prevent thromboembolic complications.
_perioperative plasmapheresis and immunoadsorption can be considered in 1ry FSGS in order to remove the circulating permeability factors and immune factors. So preemptive Plasmapheresis has been studied frequently to decrease the risk of recurrence but still not the standard.
2. Anticoagulation is indicated in such patient with hypoalbuminemia ( albumin less than 2 g/dl is an indication for anticoagulation).
3. Post transplantation:
_ if functioning graft and no FSGS recurrence, anticoagulation will not be needed once serum albumin > 2 gm /dl.
4. Identification of etiology of original kidney disease is crucial to determine the prognosis of the graft:
_ inherited or genetic causes has no or minimal risk of recurrence.
_ primary FSGS has high risk of recurrence in the graft which can occur on table, very early , which can be as high as 100% in case of retransplantation.
_secondary FSGS has very low Rika of recurrence, after treatment of the underlying cause
_ close follow up of the patient post transplant by urine analysis and A/C ratio is so important to early detect recurrence and follow up serum albumin ( hypoalbuminemia carries a high risk of graft vessel thrombosis and graft loss), that requires albumin replacement plus or minus antiplatlet or anticoagulant therapy.
_ graft biopsy is essential to confirm recurrence, E/M is mandatory to detect early changes as effacement of the podocyte foot processes.
_ L/M examination is of little value here.
_ monitoring of the graft function and tacrolimus trough level as usual
_ early Initiation of plasmapheresis plus or minus rituximab is essential to control protinuria. However, the additional cost and need for long term or even life long PEX make the condition very difficult and graft loss is expected.
1- FSGS caused by primary,secondary and genetic causes ,presence of FSGS in the renal biopsy does not established the diagnosis and even EM finding same in the primary and secondary FSGS so first exclude all causes of secndary suh as, reduced kidney mass, drugs or toxins (heroin and pamidronate) and viral infection(HIV).
usually secondary FSGS present by non nephrotic range protienurea and less renal impairement.
primary FSGS has high recuence rate in early postrenal transplantion;
prepare this pateint by medical nephroectomy ,by using ACE or ARBS inhibtors and NSAIDS first if failed go to surgical nephrotectmy.
2-indiction of anticoagulant is low serum albumin less than2gm/dl.
3- if the has no recurence and serum albumin above 2gm/dl even after recurence no indication to use warferin unless the patient has other indication than low Albumin.
4-Primary FSGS has high recurrence 80% posrenal transplantion and risk of graft loss 65% in 5 years postrenal transplantion ,so close monitring for protinurea and renal biopsy when indicated is crucial.and graft loss even with plasmopharsis and rituixmab.
but secondary FSGS rare to recure.
The kidney biopsy shows a light microscopy picture of a glomerulus with fibrous thickening of the Bowman’s capsule, a hyaline nodule and glomerulosclerosis involving more than 50% of the glomerulus, suggesting FSGS.
The patient with CKD-5 needs a kidney transplant. But he is having severe hypoalbuminemia, which is a risk factor for poor transplant outcomes.(1) Hence, it is important to build up his serum albumin prior to surgery.
For this, a medical nephrectomy should be tried first using ACE inhibitors, or NSAIDs. If it does not work, a surgical nephrectomy can be used as last resort.(2)
Other than the issue of hypoalbuminemia, the patient should be optimized by maintaining other parameters like managing anemia, fluid overload, electrolyte imbalances etc seen in CKD-5 patients prior to the kidney transplant.
The indications for anticoagulation in nephrotic syndrome have been laid down in KDIGO guidelines for glomerular disease management, especially for membranous nephropathy. (3)
Warfarin or low molecular weight heparin is used in patients with serum albumin less than 2-2.5 g/dl having high risk of venous thromboembolism. Aspirin is used as prophylaxis in patients with serum albumin 3-3.2 g/dl with high arterial thromboembolic risk. (3)
These can be extrapolated to any cause of nephrotic syndrome.
So, in the index case, anticoagulation is required.
Post-transplantation, the patient needs to be under surveillance. In the event of patient having hypoalbuminemia, he will be requiring anticoagulation as per the criteria. There is no indication to put him on routine anticoagulation post-operatively if serum albumin is above 2.5 g/dl.(4)
The patient is having CKD-5 with FSGS as his primary disease.
The patient and the family members should be counselled regarding the disease and its risks of recurrence post-transplant before the transplant.
The cause of FSGS has not been provided in the scenario. It could be primary or secondary.(5)
a) Primary FSGS: Almost one third of the patients will develop recurrence and the risk of graft loss is 65% at 5 year post-transplant, which is increased by 5 times. The risk factors for recurrence include a younger age, living donor, severe disease (low serum albumin and increased proteinuria), non-white race, rapidly progressive disease in the native kidneys or second transplant due to prior recurrence.
It is important to monitor proteinuria closely post-transplant and an early kidney biopsy in case of increasing or persisting proteinuria.
b) Secondary FSGS: The primary cause leading to the secondary FSGS will provide a clue towards the prognosis. These could be viral infections like HIV, CMV; or maladaptive changes due to obesity, relux nephropathy, renal agenesisi etc; or due to drugs like lithium, IFN etc.(6)
The patient and the family members should be counselled regarding the risk of recurrence. Secondary FSGS usually does not recur in absence of the primary cause leading to FSGS after the kidney transplant.
The risk of recurrence of secondary FSGS is lower, but proteinuria post-transplant should be closely monitored and a biopsy should be done if proteinuria recurs or increases.
References:
1) Yang SW, Choi JY, Kwon OJ. The impact of pretransplantation serum albumin levels on long-term renal graft outcomes. Transplant Proc. 2013 May;45(4):1379-82. doi: 10.1016/j.transproceed.2012.10.063. PMID: 23726577.
2) Vos E, Koster-Kamphuis L, van de Kar NCAJ, Bootsma-Robroeks CMHHT, Cornelissen EAM, Schreuder MF. Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome. Pediatr Transplant. 2020 Jun;24(4):e13703. doi: 10.1111/petr.13703. Epub 2020 Mar 25. PMID: 32212310.
3) Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DRW, Jha V, Liew A, Liu ZH, Mejía-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JF, Sethi S, Suzuki Y, Tang SCW, Tesar V, Vivarelli M, Wetzels JFM, Lytvyn L, Craig JC, Tunnicliffe DJ, Howell M, Tonelli MA, Cheung M, Earley A, Floege J. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4):753-779. doi: 10.1016/j.kint.2021.05.015. PMID: 34556300.
4) Gordon-Cappitelli J, Choi MJ. Prophylactic Anticoagulation in Adult Patients with Nephrotic Syndrome. Clin J Am Soc Nephrol. 2020 Jan 7;15(1):123-125. doi: 10.2215/CJN.05250419. Epub 2019 Oct 1. PMID: 31575616; PMCID: PMC6946067.
5) Lim WH, Shingde M, Wong G. Recurrent and de novo Glomerulonephritis After Kidney Transplantation. Front Immunol. 2019 Aug 14;10:1944. doi: 10.3389/fimmu.2019.01944. PMID: 31475005; PMCID: PMC6702954.
6) De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC. Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach. J Am Soc Nephrol. 2018 Mar;29(3):759-774. doi: 10.1681/ASN.2017090958. Epub 2018 Jan 10. PMID: 29321142; PMCID: PMC5827609.
• How to prepare him for kidney transplantation?
Patients with significant proteinuria of the native kidney should undergo pretransplantation medical nephrectomy (with an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or nonsteroidal antiinflammatory drug), renal ablation, or surgical nephrectomy.
Nephrectomy is warranted for massive, refractory proteinuria resulting in clinically debilitating hypoalbuminemia.
• What is the indication of anticoagulation in this case?
Patient has severe hypoalbuminemia 1.6 g/dl which put the patient at high risk of thromboembolic events. Patient with albumin level less than 2.5 g in the setting of nephrotic syndrome indicates anticoagulation administration.
• Does he need to be anticoagulated after transplantation?
In the postoperative period, protein excretion from native kidneys decreases significantly within one month of transplantation; thus, proteinuria that is detected more than one month after transplantation is most likely derived from the allograft and should trigger further investigation. Serum albumin level also normalizes, so upon discharge no need for long term anticoagulation/
• Discuss his long-term outcome with emphasis of his primary disease.
Long term outcomes and risk of recurrence depends on the primary disease. So patients with primary FSGS has high risk of recurrence reaching 50% after first transplant, and up to 80% in the second transplant. Patients who developed ESRD due to secondary causes have to control their underlying comorbid conditions such as DM, hypertension, obesity or undergo treatment and cure of causative viral illness and recovery from substance addiction (eg. cocaine)
Ø Evaluation of secondary FSGS
-tests for parvovirus B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyomavirus (BKPyV), hepatitis C virus (HCV), (SARS-CoV-2) and if risk factors are present, HIV
-A review of the patient’s medications, looking for potentially causative agents, such as mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, bisphosphonates, interferon, heroin, and anabolic steroids
-Assessment of BMI
Ø Management include dietary salt restriction, strict blood pressure control, weight loss for those who are overweight or obese, and renin-angiotensin system blockade with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers , if protienuria is resistant nephrectomy can be needed
In FSGS induced by a drug or infection, treatment should be directed towards the cause, discontinuing the drug if possible or treating the infection.
Ø KDIGO adviced against routine usage of plasma exchange and Rituximab to prevent recurrence risk.
It is indicated due to severe nephrotic syndrome. He has proteinuria 7 gm/day. His serum albumin is 16 gm/L (1.6 g/dL) so he is liable to thromboembolic events
If the proteinuria resolves after transplantation and the graft is well functioning ,he won’t need anticoagulation
Secondary FSGS do not respond to immunosuppression and tend not to recur after kidney transplantation.
Having hypoalbuminemia less than 2.5g/dl and receiving a live donor graft render the patient more liable to recurrence post transplant
Reference
-Bennani H N etal . idney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence?J Clin Med. 2022 Jan; 11(1): 93.
-Shabaka A et al. Focal Segmental Glomerulosclerosis: State-of-the-Art and Clinical Perspective. Nephron 2020;144:413–427
-Uptodate 2021
How to prepare him for kidney transplantation?
1-Basically, we need to try to differentiate between primary and secondary cause of FSGS in the current scenario and it can be challenging either with electron microscopy or genetic testing. Indeed, the primary form of FSGS frequently recur in the graft with high rate of graft loss.
2-In view of severe form of proteinuria ,plan for medical nephrectomy with ACE inhibitors/ARBS or NSAIDS or with bilateral surgical nephrectomy if medical option failed.
3-Plasmapharesis and Rituximab:
Commencing perioperative plasmapheresis, the best results can be obtained when plasmapheresis is started early after transplantation, directly when there is evidence for FSGS recurrence. The recommended plasmapheresis prescription is 1–2 times plasma volume exchanges, 3–4 sessions per week for total 7–12 treatments until we will get clinical remission.
The use of rituximab to induces, the suggested dose is 2–6 doses of 375 mg/m2/dose given one time weekly or every 2 weeks.
What is the indication of anticoagulation in this case?
Anticoagulation indicated with serum albumin less than 20 mg/dl to avoid thrombotic complications either with LMWH or oral anticoagulation.
Does he need to be anticoagulated after transplantation?
If normalized serum albumin, No need for anticoagulation.
Discuss his long-term outcome with emphasis of his primary disease
Percentage of recurrence of FSGS is very high ranging from 30-50% in renal allografts and associated with poor graft survival.
The significant risk factors for recurrence are patients with young age at FSGS diagnosis, rapid deterioration of renal function and progression to ESRD that happened in aggressive forms of FSGS like collapsing variants, previous failed renal allograft due to recurrence.
–Further history ;
At the moment he needs to be manage properly before transplantation ;
Counseling ;
-Anti-coagulant is indicated in cases of severe hypo-albuminaemia(20- 25g/l), or thrombo-embolic phenomenon. This is well established in cases of membranous nephropathy where there is higher risk of venous or arterial thrombosis
-No need for anti-coagulation after transplantation ; Benefit versus risk balance but in any I don’t agree with him going to transplantation at the moment for previously stated reasons
-As mentioned before secondary FSGS have better prognosis than primary FSGS but the patient has to be prepared well and understood all the risks factors and the course of the disease after transplantation
In preparation for transplant the most important aspect is presence of proteinuria, for that medical nephrectomy would be first option and if it fails surgical nephrectomy should be considered.
He definitely needs anticoagulation at this stage as albumin is 1.6 g and general consensus is to anticoagulant such patients if albumin is less than 20-25.
If he stays hypoalbunemic he might be considered for anticoagulation for a brief period post transplant weighing the risk and benefit ratio.
The long term outcome of graft in secondary FSGS is variable depending upon the initial event like sec FSGS secondary to viral infection leads to ESKD where those due to hyperfilteration have more indolent course
In the multicenter TANGO cohort study of 176 transplant recipients with biopsy-proven primary FSGS as the cause of ESKD, graft loss occurred in 39 percent of patients with recurrent FSGS, compared with 15 percent of those without recurrence, over a median of five years
Ref: update
1- admission plasma infusion and dialysis, and plasmapharesis with rituximab, ACEI or ARBS
2-no transplantation except with normal serum albumin
3- surgical nephrectomy is possible option
4- anticoagulation due to nephrotic range proteinuria and edema
5- i think no need for anticoagulation post transplant
6- as regard recurrence and long term outcome :
30-70% of the primary cases can recur early or late post transplant, genetic type has low rate of recurrence, FSGS recur mostly late secondary to reduced renal mass.
Risk factors for recurrence of FSGS :
1- Young age
2- High BMI
3- White race
4- Rapid progression to ESRD in native kidney
5- Pre transplant severe proteinuria
6- Low serum albumin at the time of diagnosis
7- 80% risk of recurrence in second transplant
Prevention and treatment of recurrent FSGS:
1- Pre transplant plasmapheresis and rituximab is of benefit to prevent recurrence and also used in treatment of recurrence
2- Protocol biopsy is important in early detection.
1. This patient need several cessions of plasmapheresis and rituximab to reduce recurrence rate.
1 in every 3 patients with primary FSGS can develop recurrence post transplanr.
2. Because he has nephrotic syndrome and hypoalbunemia, anticoagulation to avoid thromboembolic complications.
3. Follow up of the serum albumin is imprtant posr transplant. Transplantation will not be done unless the patient improved from nephrotic syndrome.
4. Diet control with low salt diet
Fluid chart and balance
ACEi or ARB
Statins
Prophylacitic anticoagulant if serum albumin less than 2 gm/dl
Diuretic for releive of body odema
Immnosuppressive drugs
How to prepare him for kidney transplantation?
Good history to differentiate primary from secondary to infection and obesity
second treat hypoalbuminemia and anti proteinuric agent
Medical nephrectomy by combination of ACEi and NSAD; if not successful consider surgical nephrectomy
What is the indication of anticoagulation in this case?
Due to severe hypoalbuminemia loss of antithrombin iii and protein C and S in urine ; also due to increase synthesis of liver to protein which increase synthesis prothrombatic factors lead to prone of renal vein thrombosis and deep vein thrombosis
Does he need to be anticoagulated after transplantation?
stop worfarin 3 days before operation and start heparin as prophylactic
Discuss his long-term outcome with emphasis of his primary disease.
There’s risk of recurrence early post transplant especially if associated with increase of BMI and rate of recurrence around 9 to 32%, also rate of graft loss post transplant in recurrence cases around 39%
Prepare him for kidney transplantation:
Identification of cause of secondary FSGS is mandatory pretransplant as well as treatment of the cause and controlling the disease as much as possible.
This high grade proteinuria should be controlled, sign of improvement would be correction of the serum albumin level.
Treatment with ACE inhibitors, if failed nephrectomy would be the last resort for this case pretransplantation.
Anticoagulation is a must to avoid possible thromboembolic events.
Indication of anticoagulation in this case:
Low serum albumin levels denotes loss of anticoagulation factors as protein S , protein C and antithrombin III and deficiency leads to exposure of thrombotic events.
It is associated with increased hepatic synthesis of albumin and pro-thrombotic factors. There are higher levels of clotting factors V, VIII, and fibrinogen in patients.
Abnormalities are also found in platelet function. Albumin loss results in increased free arachidonic acid and formation of thromboxane A2, leading to platelet aggregation, which is further accentuated by hypertriglyceridemia.
Other contributing factors are the potential pro-coagulopathic role of corticosteroids, part of many glomerulonephritis treatment regimens, and volume contraction with concomitant diuretic use.
There is a need for anticoagulation post renal transplantation, preferably by heparin being suitable in the perioperative period.
Long-term outcome with emphasis of his primary disease:
There is association between FSGS recurrence and BMI at transplant as well as history of native kidney nephrectomies.
Proteinuria in patients with partial or no remission was higher than in patients with complete remission.
Plasmapheresis and rituximab were the most frequent treatment for recurrence.
Partial or complete remission occurred in 57% of patients and was associated with better graft survival.
Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes.
However secondary FSGS shows less recurrence unless the cause is untreated.
Reference:
CJASN February 2020, 15 (2) 247-256; DOI: https://doi.org/10.2215/CJN.08970719
How to prepare him for kidney transplantation?
Slide shows features of focal FSGS.
The patient has significant proteinuria at 7 gm /day. He will need medical Nephrectomy with ACE inhibitors or ARBi and NSAIDs. If this fails then surgical bilateral Nephrectomy after optimizing patient condition. Better look for causes of secondary FSGS, like infections, diabetes, sickle cell disease, obesity, reflux.
What is the indication of anticoagulation in this case?
He has low albumin at 1.6 g/dl. There is risk of thrombosis, so will need anticoagulation. This is due to the fact that there is urinary loss of antithrombotic factors and increased production of prothrombotic factors by liver.
Does he need to be anticoagulated after transplantation?
Warfarin to be stopped at least 3 days before surgery and INR check. Unfractioned heparin in peri operative period.
Discuss his long-term outcome with emphasis of his primary disease.
Since this is secondary FSGS, so the recurrence rate and risk of graft loss are low. So standard immunosuppression with CNI, MMF and steroid. Risk of recurrence and graft loss is high in primary FSGS
Hassan F Azawi et al. Nephrotic syndrome-induced thromboembolism in adults. Int J Crit Illn Inj Sci. 2016 Apr-Jun; 6(2): 85–88.
Heavy proteinuria during renal transplant associated with 2 risks:
Ponticelli et al shows that pre transplant heavy proteinuria associated with worse graft outcome & quantity of proteinuria can predict graft outcome.
So the best measure before transplantation is to do bilateral nephrectomy either by surgery, or less invasive bilateral renal artsy embolization ( associated with severe side effects) or medial by combining of ACE-I & NSAID.
This patient had clear indication for anticoagulation ( S. albumin <2.5) with target INR 2-3. After transplantation there will be no need of anticoagulation unless there will be a recurrence of nephrotic syndrome & low albumin.
Identification of FSGS type ( primary, secondary , or genetic) is very important for prediction of disease recurrence & graft outcome. The risk of recurrence & subsequent graft loss was high in primary FSGS , but it is very low in secondary or genetic types.
References:
1-Before transplantation
*Identify the underlying cause of 2nd FSGS
1-reduction in nephron mass (eg, history of reflux nephropathy, congenital absence or surgical removal of a kidney, low birth weight or premature birth)
2-Exposure to drugs and/or toxins associated with FSGS (eg, heroin, interferon, bisphosphonates [particularly pamidronate], anabolic steroids)
3-History of viral infections (eg, HIV, parvovirus B19, cytomegalovirus, Epstein-Barr virus, simian virus 40, hepatitis C)
4-Body mass index (BMI)Obesity
*Risk factors for FSGS recurrence
Young Age
Rapid progression to ESRD in the native kidney
Sever proteinuria pre transplantation.
Low serum albumin at diagnosis.
Risk of recurrence in the2nd allograft: 80%
*Before transplantation we need to do
medical nephrectomy by combination of ACEI and NSAID
If not effective do surgical nephrectomy
2-Anticoagulant
some centers, prophylactic warfarin therapy is given to high-risk patients including adolescents (>12 years of age), or those with a serum albumin concentration of less than 2 g/dL (20 g/L), a fibrinogen level of more than 6 g/L, or an antithrombin III level less than 70 percent of normal
3-After transplantation no need for further anticoagulant if the graft functioning and normalization of s.albumin
4-However, not all patients with FSGS suffer from recurrence after kidney transplantation, and genetic and secondary FSGS have a negligible risk of recurrence but need to control on underlying causes
For primary FSGS
Need cyclosporin ,high-dose methylprednisolone and rituximab in addition to immediate and intense plasmapheresis have worked well, achieving remission in more than 80% of recent recurrent cases
Reference
1-Up to date
2-Hee Gyung Kang, Il-Soo Ha, and Hae Il Cheong. Recurrence and Treatment after Renal Transplantation in Children with FSGS. BioMed Research International
Volume 2016, Article ID 6832971, 7 pages http://dx.doi.org/10.1155/2016/6832971.
Thank You, well done.
Slide shows focal segmental glomerulosclerosis or FSGS. An area of collagen ours sclerosis runs across the middle of this glomerulus.
This means that the patient has high risk of FSGS recurrence post kidney transplant.
Prepare pt for kidney transplant
Anticoagulation indication in this case
Anticoagulation after transplant :
Long term outcome
References :
Thank You, well done.
The patient is 39 yrs old with preemptive CKD ,due to secondary FSGS, with heavy proteinuria & low albumin, and on warfarin .
1-This patient needs to be admitted earlier to do full investigations as proteinuria is not the hallmark of secondary FSGS . The slide showed LM with glomerulosclerosis, we need EM to differentiate primary from secondary FSGS ( podocyte injury in primary one )
2-Treatment of heavy proteinuria with medical nephrectomy( ACEI & /or NSAID) ,if failed, surgical bilateral nephrectomy is needed.
3- Stop warfarin 3 days before surgery & he needs heparinization perioperatively to prevent allograft vascular thrombosis.
Hypoalbuminemia, & he is still preemptive.( high risk of thrombosis )
He usually needs anticoagulant perioperatively ( heparin infusion )& then can be discharged without anticoagulant.
Secondary FSGS has low rate of recurrence post-transplant, less aggressive & better prognosis, so no need for preoperative plasmapheresis & rituximab ( as this is used to decrease recurrence in primary FSCG ).
The patient needs to be on CNI & steroid post-transplant .
Thank You, well done.
Control of his albuminuria by Ace or Ace plus NSAiDS .
Surgical nephrectomy if medical failed.
Better deceased donor than live donation ,risk of genetic triggered by secondary
FSGS, patient failed to. Response to treatment.
Albumin. Less than 2-2.5g/dl.
No unless the routine postsurgical prophylaxes’ anticoagulation or there’s an indication
for it.
this patient his albumin should be corrected before surgery.
Discuss his long-term outcome with emphasis of his primary disease.
secondary FSGS has low risk of postransplant recurrence if primary disease is
treated ,so patient has good prognosis.
Patients. With primary FSGS has high risk of recurrence I.e 30%with 50 %risk if graft
loss but new treatment improve graft survival to 70%.
Thank You, well done.
◇How to prepare him for kidney transplantation?
▪︎I think the aim of preparation of this pt is to prevent recurrence of his primary disease (FSGS) post transplant.
▪︎In this case it is important to diffentiate between the forms of FSGS( idiopathic, secondary and genetic ), because the ideopathic form is recurrent with a rate that can reach up to 80 %.
▪︎There is still no effective prophylaxis that can prevent FSGS recurrence [1]
▪︎This patient can receive prophylactic and perioperative treatment with plasmapheresis and high-dose (intravenous) cyclosporine .
▪︎In recent years, therapy with rituximab has shown promising results [2].
▪︎Medical nephrectomy is indicated in this patient and if failed then surgical nephrectomy.
◇What is the indication of anticoagulation in this case?
Because his serum albumin is <2.0 to 2.5 g/dl which can increase the risk of arteial and venous thromboembolism [3].
◇Does he need to be anticoagulated after transplantation?
▪︎This depends on the sevirity of hypoalbuminemia and the risk of bleeding.
▪︎I think with nephrectomy serum albumin level will be corrected and there will be no need to continue on anticoagulation.
◇Discuss his long-term outcome with emphasis of his primary disease?
▪︎Patients with a diagnosis of FSGS had poorer graft survival compared with the general transplant population [4].
▪︎Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure 5-times the risk compared to those without disease recurrence.
{NOTE: Risk factors for disease recurrence in patient with primary FSGS includes: younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence}.
____________________________________.
Ref:
[1] Alasfar S., Matar D., Montgomery R.A., et al. Rituximab and Therapeutic Plasma Exchange in Recurrent Focal Segmental Glomerulosclerosis Postkidney Transplantation. Transplantation. 2018;102:e115–e120.
[2] Michael Rudnicki. FSGS Recurrence in Adults after Renal Transplantation
https://doi.org/10.1155/2016/3295618
[3] Judit Gordon-Cappitelli and Michael J. Choi.Prophylactic Anticoagulation in Adult Patients with Nephrotic Syndrome
CJASN January 2020, 15 (1) 123-125; DOI: https://doi.org/10.2215/CJN.05250419
[4] Anna Francis, Peter Trnka, and Steven J. McTaggart Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis
https://doi.org/10.2215/CJN.03060316
Thank You, well done.
** How to prepare him for kidney
transplantation?
# This is a photomicrograph of focal segmental glomerulosclerosis (FSGS). An area of collagenous sclerosis runs across the middle of this glomerulus
He may needs medical nephrectomy with ACE inhibitors and/or non-steroidal anti-inflammatory drugs is a safe and non-invasive therapy to minimize proteinuria in ESRD before kidney transplantation. Studies suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy (1)
** What is the indication of anticoagulation in this case?
#Because the risks for arterial and venous thromboembolic events are increased with severe hypoalbuminemia
(serum albumin levels <2 to 2.5 g/dl. )
** Does he need to be anticoagulated after transplantation?
# If the risk of bleeding is perceived to be low, it would be reasonable to initiate prophylactic anticoagulation early, serum albumin levels <2 to 2.5 g/dl. For those at high risk of bleeding, it may be prudent to avoid anticoagulation.
Aspirin may be an alternative in those who have higher albumin levels, and/or if there is a high perceived risk of arterial or venous thromboembolic events with high bleeding risk. On Further increased risk of venous thromboembolic events with immobility, obesity, malignancy, recent surgery, pregnancy, medications, central venous catheters, or genetic predisposition would decrease the threshold to start prophylaxis. Evaluation for continuing anticoagulation would depend on the ongoing severity of hypoalbuminemia as well as the presence of the factors above.(2)
** Discuss his long-term outcome with emphasis of his primary disease.
# patients transplanted for FSGS have poorer long–term graft survival compared with patients transplanted for other causes of ESRD.
* LD recipients had significantly better long–term graft survival.
*Recurrence of FSGS was more common in children than in adults, occurring in approximately one third of transplanted children.
* Disease recurrence occurred largely within the first 2 years after transplantation and remains a serious post transplant complication, with one half of affected transplants failing within 5 years.
* In adult population, recurrence rate is 7.5%.
* Many of studies do not differentiate between first and subsequent transplants, which may bias results given the significantly higher risk of recurrence after loss of a first transplant with recurrent disease.
* After exclusion of genetic abnormalities that may predispose to FSGS, LD grafts should not be avoided in transplant recipients with primary FSGS.(3)
References
(1) Pomeranz A, Wolach B, Bernheim J, Korzets Z, Bernheim J. etal. Successful treatment of Finnish congenital nephrotic syndrome with captopril and indomethacin. J Pediatr. 1995; 126(1): 140- 142.
CrossrefCASPubMedWeb of Science®Google Scholar
(2)Glassock RJ: etal. Prophylactic anticoagulation in nephrotic syndrome: A clinical conundrum. J Am Soc Nephrol 18: 2221–2225, 2007 Abstract/FREE Full TextGoogle Scholar
(3) Haas M, Meehan SM, Karrison TG, Spargo BH et: Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 30: 621–631, 1997 [PubMed] [Google Scholar]
Thank You, well done.
What should we do to get him ready for the kidney transplant?
After a transplant, there is a significant risk of developing FSGS again.
However, only primary FSGS symptoms will return after the transplant.
I will investigate the patient’s medical history, do a physical examination, and order laboratory testing to look for any potential secondary reasons which should be corrected before transplantation to avoid recurrence after transplantation.
The following are examples of secondary causes: Parvovirus, HIV infection; obesity.
For primary FSGS: Preemptive therapeutic plasma exchanges and rituximab are both examples of treatments that might be used before a transplant.
As long as the patient has significant proteinuria and serum albumin is low, better to proceed with nephrectomy(medical first, If failed surgical) to avoid the postoperative complications.
What are the reasons for administering anticoagulation in this particular scenario?
Anticoagulation is necessary for hypoalbuminemia with a level below 25 g/L or 20 g/L.
Is it necessary to give him anticoagulant medication after the transplant?
Proteinuria will stop being a problem when he has a bilateral nephrectomy, and his albumin level should return to normal after that.
With the exception of primary focal segmental glomerulosclerosis (FSGS), recurrent glomerular disease is usually a late complication after transplantation. The recurrence rate of primary FSGS IS 20-50% and the incidence of graft loss secondary to recurrence is 50%.
Risk factors for recurrence – Several risk factors for recurrence of FSGS posttransplantation have been reported, including younger age of disease onset, rapid progression of the initial disease, being White, prior native kidney nephrectomy, lower body mass index (BMI) at transplantation, and history of recurrence in a prior allograft. In the United States, White recipients of African-American kidneys may be at particularly high risk of recurrence. On the other hand, Black recipients appear to represent a lower risk group, in which recurrence is less frequent.
A family history of FSGS generally predicts a lower risk of recurrence. However, the risk of recurrence of familial FSGS may depend upon the specific mutation.
–Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol 2020; 15:247.
–Francis A, Trnka P, McTaggart SJ. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol 2016; 11:2041.
Thank You, well done.
How to prepare him for kidney transplantation?
First of all, cause of secondary FSGS i.e., drug induced ,virus induced or reduced renal mass should be identified and then treated as it will help in achieving remission. Other supportive measures like controlling blood pressure ,diuretics for edema and statins for hyperlipidemia should also be done. For proteinuria, medical nephrectomy can be done with the help of ARBs or NSAIDs. If this fails then surgical nephrectomy can be done for proteinuria.
What is the indication of anticoagulation in this case?
According to KDIGO guidelines 2021, prophylactic anticoagulation should be considered if serum albumin is <20-25g/l and any of following like proteinuria>10g/day, BMI>35kg/m2,genetic disposition for thromboembolism or recent surgery or prolonged immobilization. And also the bleeding risk should be calculated with the help of GN risk tool before starting any anticoagulation.
In this case, patient has albumin level 1.6 gm/dl,which place the patient as high risk for thromboembolism.
Does he need to be anticoagulated after transplantation?
Yes, Anticoagulation after transplantation will be continue till the nephrotic syndrome settles and albumin level improves to at least 3 g/dl .
Discuss his long-term outcome with emphasis of his primary disease
The risk of recurrence in the allograft due to idiopathic FSGS is 30-50% and associated with increased graft loss ,however, recurrence in secondary FSGS is less and prognosis depends on the cause i.e.,I hyperfiltration and obesity haveis indolent course while ESRD develops due to viral infection
Risk factors for recurrence include:
– Young age at onset (< 6 years)
– Severe proteinuria
Rapid progression of initial disease towards ESRD
lower BMI
Prior history of recurrence in allograft
Recurrent disease in the first transplant are at very high risk up to 75% for recurrence in subsequent allografts
REFERENCE:
1- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020;15(2):247-256
Thank You, a structured answer, well done.
Dear all
When answering this scenario try not to tackle the medical aspect of a glomerular disease BUT try to respond to the fears of the surgical team in transplanting such a patient. This is the trick of the question.
How to prepare him for kidney transplantation?
What is the indication of anticoagulation in this case?
Does he need to be anticoagulated after transplantation?
Discuss his long-term outcome with emphasis of his primary disease.
Thank You, a structured answer, well done.
How to prepare him for kidney transplantation?
What is the indication of anticoagulation in this case?
Hypoalbuminemia below 25 g/L or 20 g/L depending on bromocresol green, or purple requires anticoagulation
Does he need to be anticoagulated after transplantation?
After bilateral nephrectomy, the proteinuria will resolve, so his albumin level should back to normal. So, there is no indication for anticoagulation
Discuss his long-term outcome with emphasis of his primary disease.
Secondary FSGS has a lower recurrence rate and infrequent association with allograft lost.
References:
Naciri Bennani H, Elimby L, Terrec F, Malvezzi P, Noble J, Jouve T, Rostaing L. Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med. 2021 Dec 24;11(1):93. doi: 10.3390/jcm11010093. PMID: 35011834; PMCID: PMC8745094.
Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020;15(2):247-256.
Thank You
The LM with PAS stain shows one glomerulus looks ischemic with fibrous thickening of bowman’s capsule and ischemic wrinkling tuft the central part of the tuft looks scarred and there is pink nodular hyalinosis near the hilum also capillary walls looks thick, we need sliver staining looking to the GBM and IF staining , EM will help us to see the pattern of the foot process effacements, sometimes difficult to differentiate between primary FSGS vs Secondary by clinical presentation and need genetic analysis with EM histological changes in which diffuse foot process effacement in favor the diagnosis of the primary FSGS while patchy or focal effacement of GBM more in favor the secondary FSGS.
-Primary or idiopathic FSGS due to podocyte injury by specific circulating proteins called suPAR , more aggressive with high rate of recurrence post transplant and associated with graft loss.
-secondary FSGS tend to be less aggressive with lower rate of recurrence post transplant and better prognosis , its due to many causes including viral infections ,obesity ,small nephron mass( adaptive phenomena ), drugs
-hereditary , genetic causes again in < 5% more in children’s and lower rate of recurrence.
Back to the case he is young 39 years old with heavy proteinuria and low albumin of 16 and looks like aggressive course with fast progression his current GFR only 16ml/min this patient need to be counselled about the high chance of early relapse of his primary FSGS early post-transplant in the first 3 months may be up to 30% (2).,especially if the disease course was aggressive in native kidney and lead to ESRD in < 3 years with failure of previous treatment options even the donor type preferred to go for DD program or LURD with screen of the donor for APOL1 gene ( black ethnic background)as its associated with increase risk of post transplant collapsing FSGS (3). another medical problem is the current low albumin of 1.6gm which need to control his heavy proteinuria by either medical nephrectomy with ACEI , NSAID or surgical nephrectomy ,
anticoagulation needed as he is at risk of thrombosis with low albumin and should be continue post transplant if his s-albumin below 20
steroid and CNI ,should be part of the maintenance IS to avoid early relapse .
ACEI or ARBS should be part of the BP control class with its antiproteinuric effect
There are many predictive factors associated with increased risk of Primary FSGS early relapse post transplantation including aggressive course of the disease with fast progression to ESKD in native kidneys, heavy proteinuria, young age and surgical nephrectomy of the native kidneys. According to recent data from the TANGO trial(2), the median cumulative incidence of post-kidney-transplant primary FSGS relapse occurs in 32% of the cohort, with a rate of graft loss up to 39% and > 80% after second transplant ,also the use of combination of rituximab and plasmapheresis for treatment of relapsing primary FSGS in majority of cases with variable rate of response however those with partial and complete remission have favorable graft outcome use of plasmapheresis with or with out rituximab as prophylaxes before transplant or immediately post-transplant to avoid recurrence in high risk group its of doubtful benefits based on the divers results from small studies so we should always assess the risk and benefits as there is higher risk of complications including surgical wound infection hematoma , viral infections in addition to the cost and logistics.
References:
————————-
1-Naciri Bennani H, Elimby L, Terrec F, Malvezzi P, Noble J, Jouve T, Rostaing L. Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med. 2021 Dec 24;11(1):93. doi: 10.3390/jcm11010093. PMID: 35011834; PMCID: PMC8745094.
2- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020;15(2):247-256.
3-DonorAPLO1 high risk genotypes associated with increased risk of de novo collapsing glomerulopathy in renal allografts.SantorielloD,Husain SA, De Serres SA,Bomback AS,CrewRJ,VasilscuER,Kiryluk K,MohanS,HawkinsGA,HicksPJ,CohenDJ,RadhakrishnanJ,StokesMB,MarkowitzGS,FreedmanBI,DAgati VD,Batal I:Kidney Int.2018;94(6):1189.
4-Park HS, Hong Y, Sun IO, Chung BH, Kim HW, Choi BS, Park CW, Jin DC, Kim YS, Yang CW. Effects of pretransplant plasmapheresis and rituximab on recurrence of focal segmental glomerulosclerosis in adult renal transplant recipients. Korean J Intern Med. 2014 Jul;29(4):482-8.
Excellent, Dr. Saja
Thank you for mentioning the TANGO project with an excellent study protocol. Check this if interested.
Uffing A, Riella LV. A, et al. large, international study on post-transplant glomerular diseases: the TANGO project. BMC Nephrol. 2018 Sep 12;19(1):229. DOI: 10.1186/s12882-018-1025-z. PMID: 30208881; PMCID: PMC6136179.
Thank you
Patients with nephrotic syndrome and hypoalbuminemia have unfavorable circulatory status and prevent optimal hydration which is very important perioperatively to ensure graft function and leads to increased risk of thromboembolic events, also proteinuria from native kidneys may hinder early detection of proteinuria post transplant due to either recurrence of FSGS or due to rejection.
so treatment to stop native proteinuria by nephrectomy is important before transplantation:
medical nephrectomy using ACEI, have antiproteinuric effect and are the first choice
surgical nephrectomy (additional operation and associated with morbidity)
embolization, less invasive but require specific intervention and may not be available.
As hypoalbuminemia is associated with increased risk of thromboembolic events.
No need for anticoagulation after correction of hypoalbuminemia
Idiopathic FSGS frequently recurs post transplant and recurrence is associated with increased risk of graft loss.
Risk factors for recurrence include younger age at onset of disease, rapid progression to ESKD and white race.
accurate differentiation between idiopathic and secondary FSGS is important, EM may help in the differentiation
Secondary FSGS may be due to:
maladaptive forms due to abnormal stress and glomerular hypertension as with decrease of renal mass and hyperfiltration of remaining nephrons, may occur with obesity, vesicoureteric reflux or renal mass reduction, treated with ACEI.
viral associated FSGS due to HIV, CMV, parvovirus B19 or EBV improve after resolution of infection
drug induced FSGS due to antiviral therapy, lithium, heroin or anabolic steroids resolve after stopping the drug.
Vos E, Koster‐Kamphuis L, van de Kar NC, Bootsma‐Robroeks CM, Cornelissen EA, Schreuder MF. Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome. Pediatric Transplantation. 2020 Jun;24(4):e13703.
De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC. Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach. Journal of the American Society of Nephrology. 2018 Mar 1;29(3):759-74.
Hommos MS, De Vriese AS, Alexander MP, Sethi S, Vaughan L, Zand L, Bharucha K, Lepori N, Rule AD, Fervenza FC. The incidence of primary vs secondary focal segmental glomerulosclerosis: a clinicopathologic study. InMayo Clinic Proceedings 2017 Dec 1 (Vol. 92, No. 12, pp. 1772-1781). Elsevier.
Rudnicki M. FSGS recurrence in adults after renal transplantation. BioMed Research International. 2016 Oct;2016.
Thank You, a structured answer, well done.
How to prepare him for kidney transplantation?
As mentioned he is a case of secondary FSGS which as per L/M showing per-hilar segmental sclerosis with larger glomeruli that indicative of the compensatory hyper filtration which takes place in these patients but to differentiate need E/M which reveled diffuse foot process effacement on primary , whereas secondary FSGS usually does not.(1).
Patient has nephrotic proteinuria and hypoalbuminemia < 1.6 so he is high risk for thrombosis .
Start the patient on HD and trying medical nephrectomy by (NSAID+ACEI) if resistant prepare for surgical nephrectomy(2)
What is the indication of anticoagulation in this case?
Indication of anti-coagulation here low serum albumin <16 with nephrotic range proteinuria specially if this case of FSGS secondary to obesity for example or has had a history of thrombo-embolic events.(3)
Does he need to be anticoagulated after transplantation?
If proteinuria and hypoalbuminea improved so no indication for anti-coagulation unless there are new events post-operative.
Discuss his long-term outcome with emphasis of his primary disease?
FSGS is relatively common in late post-transplantation period >> 2nd FSGS due to reduced renal mass therefore controlling of the primary cause of FSGS is important (viral , obesity,ect).(4).
30-70% of cases of primary FSGS will recur after transplantation, and recurrence can occur immediately or months to years.
REFERNCES:
1- De Vriese, Sanjeev Sethi, Karl A, Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach, An S, JASN March 2018, 29 (3) 759-774; DOI: https://doi.org/10.1681/ASN.2017090958.
2- Eefke Vos,Linda Koster-Kamphuis,et al, Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome, 25 March 2020,https://doi.org/10.1111/petr.13703
3-KDIGO 2021 CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF GLOMERULAR DISEASES.
4- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020;15(2):247-256. doi:10.2215/CJN.08970719.
Thank You, a structured answer, well done.
We anticoagulate when serum albumin is below 20g/L
First, I need to know the primary disease that caused the secondary form of FSGS, in order to control it, as controlling the primary disease will lead to the resolution of secondary FSGS symptoms.
Causes of secondary ( non-genetic ) FSGS are:
In addition to controlling the primary cause ( if possible), other supportive measures need to be installed as controlling BP by ACEi, or ARB, controlling oedema with diuretics and salt restriction and controlling hyperlipidemia with statins.
hypoalbuminemia ( serum albumin is < 2.5 g/dl).
In a systematic review that was done for evaluating the indication for prophylactic anticoagulation in NS, the authors found that:
Don’t think so, if the disease is controlled and serum albumin level is above 2.5 g/dl.
secondary FSGS has a lower recurrence rate than primary FSGS, but the primary cause needs to be controlled.
References:
Excellent
What is the incidence of recurrenace of FSGS if it was genetic?
Familial FSGS in adults
comprising of those with mutations of podocin or structural podocyte proteins
have low to no risk (<3%) of disease recurrence post-transplant
The risk of recurrence of genetic FSGS is rare and depends on the specific mutation:
Reference:
UpToDate 2022, FSGS in the transplanted kidney. cited on 25th May 2022.
Surgical bilateral nephrectmy is the last to resort to in some case
Patient has risk factors for recurrence of FSGS. He is young, we do not know the speed of disease progression, he already has high pre-transplant proteinuria, and low albumin levels at diagnosis. We do not have information about the genotype, as APOL1 is supposed to have a reduced risk of recurrence.
With the data we have, there would be a high risk of recurrence of the underlying disease after transplantation, and one should be aware of the risks. Plasmapheresis and rituximab should be used to decrease the risk of recurrence as well as for treatment. After transplantation, the patient must adhere to the biopsy protocol.
There is an indication of anticoagulation pre and post-transplantation (low levels of albumina and proteinuria in high levels).
The patient needs to be aware of the risk of recurrence of the underlying disease and of possible therapies that can considerably decrease their immunity and increase the risk of adverse events, mainly related to infections derived from the use of rituximab and the immunosuppression to be performed.
Thank You.
How to prepare him for kidney transplantation?
The recurrence rates of FSGS post-transplant is high.
However, only primary FSGS recurs post-transplantation.
Primary FSGS is usually a diagnosis of exclusion.
This index case has the collapsing variant of FSGS.
I will search (by history, physical examination, & laboratory tests) for possible secondary causes & treat accordingly.
Secondary causes include:
– Obesity
– HIV
Collapsing FSGS is characterized by heavy proteinuria & rapid progression to ESRD.
Possible pre-transplant treatment includes preemptive therapeutic plasma exchanges & rituximab.
====================================
What is the indication of anticoagulation in this case?
Severe hypoalbuminemia, reflecting severity of nephrotic
Syndrome.
The risk for thromboembolic events in NS increases with severe hypoalbuminemia & particularly in those with membranous nephropathy.
The 2012 KDIGO Clinical Practice Guideline for GN
suggested (level 2C) that anticoagulation should be considered in membranous nephropathy if serum albumin is less than 2.0 to 2.5 g/dl with additional risks for thrombosis (proteinuria, >10 g/d; BMI,>35 kg/m2; FH family of VTE with documented genetic predisposition; NYHA class III or IV CHF; recent abdominal or orthopedic surgery; or prolonged immobilization).
In other glomerular diseases, including FSGS, the risk of thromboembolism is less likely compared to MN.
====================================
Does he need to be anticoagulated after transplantation?
This would depend on the ongoing severity of hypo-albuminemia as well as the presence of other predisposing factors.
====================================
Discuss his long-term outcome with emphasis of his primary disease.
Kidney transplantation is the treatment of choice in patients with FSGS, however recurrence of the disease post-transplant reduces long-term graft survival.
The recurrence rates of FSGS is 20-50%.However, only primary FSGS recurs post-transplantation.
The risk of recurrence is increased by:
– Young age at onset (< 6 years)
– Severe proteinuria with rapid progression towards ESRD
– Prior history of allograft loss due to recurrence.
Compared to recurrence of other GN, patients with FSGS recurrence have 2-fold higher risk of graft loss in 10 years.
Also there is higher protein excretion early after transplantation leading to rapid deterioration of the graft.
Post-transplant management strategies include:
– Daily monitoring of urinary protein excretion in the early post-transplant
period & subsequent frequent monitoring in the 1stpost-transplant year;
the period of highest recurrences.
– Immediate biopsy in all patients developing proteinuria,
– Intensive TPE, followed by rituximab (despite no clear evidence).
Reference
1. LEA KATALINIĆ, LANA GELLINEO, MARIJANA ĆORIĆ and NIKOLINA BAŠIĆ. KIDNEY TRANSPLANTATION IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULO-SCLEROSIS. Acta Med Croatica, 71 (2017) 279-284
2. Judit Gordon-Cappitelli and Michael J. Choi
Prophylactic Anticoagulation in Adult Patients with Nephrotic Syndrome CJASN 15: 123–125, 2020. doi: https://doi.org/10.2215/CJN.05250419
Bilateral nephrectomy is also indicated in this patient.
Another point, the type of FSGS is not collapsing, rather there is an area of sclerosis across the glomeruli.
Bilateral nephrectomy wiil eliminate proteinuria so as not to interfere with interpretation of proteinuria post transplant
Thanks You
It is collapsing FSGS
Excellent
Spot on
Thank You, a structured answer, well done.
He has full blown nephrotic syndrome in the context of FSGS which might indicate that its primary FSGS, as there is no evidence of other pathology detected in the shown biopsy.Furthermore,the persistence of nephrotic syndrome at this advanced chronic kidney disease stage 4-5 is in line with FSGS.
RAAS blocker is indicated here to treat the nephrotic syndrome.Improvement of nutritional status is mandatory pre transplant.
The differentiation of idiopathic from secondary and genetic FSGS is mandatory in this case.As Secondary and genetic FSGS is non recurring post transplant , but the ideopathic is recurrent with a rate of recurrence can reach up to 80 %.
Although genetic FSGS is commonly presenting in childhood , cases of late presentation due to genetic mutations results in adult onset genetic FSGS.Testing for genes encoding for certain proteins causing FSGS like Nephrin, Podocin and Apol1 is helpful in discriminating ideopathic from genetic or secondary FSGS .
Electron microscopy might be differentiating primary idiopathic vs secondary FSGS.
The indication for Warfarin is the hypoalbuminemia of 1.6 gm/dl, As its associated with higher risk of thromboembolic disease and warfarin as prophylactic medicine is indicated in this situation.
Anticoagulation after transplantation is still indicated if the patient is hypoalbuminemic with serum albumin below 2 gm/dl.
Risk of recurrence of FSGS is up to 80% in idiopathic FSGS.
If the proteinuria is increasing drastically after transplantation harbering recurrence of idiopathic FSGS then treatment with PP and Rituximab might be of help.
The pre transplant proteinuria usually resolve within few weeks post transplant with rare existence beyond 10 weeks.
Reference:
1- An s. de Vreise et al.Differentiating primary, genetic and secondary FSGS in adults:A clinicopathologic approach. JASN march 2018.
2-M Khalid shamseddin and Greg A Knoll.Posttransplantation proteinuria:An approach to diagnosis and manageme. CJASN.July 2012.
Excellent
FSGS is classified according to the etiology into:
a) Primary: due to toxic circulating factor that cause generalized podocyte dysfunction
b) Secondary: due to hyperfiltration (obesity, DM, sickle cell anemia, single kidney), toxins, viral infection (HIV) or previous injury from any form of glomerulonephritis
c) Genetic: due to gene mutation for nephrin (NPHS1) or podocin (NPHS2)
Recurrence rate in patients with primary FSGS is high (up to 57%) especially in the early post-transplant period (first 3 months) (1), while secondary FSGS and genetic FSGS recur less.
In practice, it may be difficult to determine the actual risk of recurrence since sometimes it is difficult to differentiate between types of FSGS.
Nephrotic syndrome is considered a hypercoagulable state which may be explained by urinary loss of anticoagulants such as protein C, S, antithrombin III and plasminogen, and protein C and S.
Prophylactic anticoagulation is indicated in all cases of nephrotic syndrome when serum albumin is < 2 mg/dl due to the high risk of DVT and thromboembolism except in patients with high bleeding risk. (2, 3, 4)
Patients with serum albumin between 2 -2.5 mg/dl should receive prophylactic anticoagulation only if there is a low to intermediate risk of bleeding plus the presence of one of the following
Patients with serum albumin between 2 .5-2.9 rarely need anticoagulation, some may recommend anticoagulation only if the bleeding risk is low and one of the previous risk factors mentioned above is present (2, 3, 4)
Patients with Serum albumin ≥ 3 should not receive anticoagulation(2, 3, 4)
So … back to our case
A- The cause of secondary FSGS should be known as some causes may constitute a contraindication to transplantation such as drug addiction, and other causes may need treatment before transplantation like HIV.
B- The indication of anticoagulation, in this case, is thromboembolism prophylaxis since serum albumin is < 2 mg/dl
C- I will stop warfarin first, once the INR reaches below 1.6 I will initiate prophylactic low molecular weight heparin
D- Once INR < 1.6 we can initiate medical nephrectomy using NSAIDS and/or ACEI, till the patient becomes oliguric, proteinuria decreased to non-nephrotic range, and serum albumin increase.
E- Initiate HD according to indication
F- Once serum albumin is above 3 we can stop prophylactic anticoagulation and proceed with transplantation
G- No need for anticoagulation after transplantation except if the recurrence occurs and serum albumin meets the criteria mentioned above.
H- The patient should be informed of the risk of recurrence which will differ according to the cause of FSGS.
REFERENCES
1. Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol 2020; 15:247.
2. Glassock RJ. Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum. J Am Soc Nephrol 2007; 18:2221.
3. Lee T, Biddle AK, Lionaki S, et al. Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy. Kidney Int 2014; 85:1412.
4. Lin R, McDonald G, Jolly T, et al. A Systematic Review of Prophylactic Anticoagulation in Nephrotic Syndrome. Kidney Int Rep 2020; 5:435.
In practice, it may be difficult to differentiate between types of FSGS. In this case, the patient has severe proteinuria which is usually associated with the primary and not secondary type of FSGS, so primary FSGS should be excluded in this case
So … EM may be needed in this case
Primary FSGS recurs in half of the patients and once recurs it can cause graft loss in nearly half of the patients 2 years after recurrence.
Excellent?
But we need to identify those with a high risk of recurrence to council them.
Risk factors for recurrence of primary FSGS
a) Age: Patients with disease onset at a younger age are more prone to recurrence (1)
b) Race: White are at increased risk of recurrence than black (2), but others found an increased risk in non-white
c) Weight: Lower BMI at transplantation is associated with higher recurrence rate, on the other hand some studies found an increased risk in obese renal transplant recipients
d) Living donor kidney is associated with higher risk of recurrence than deceased donor kidney transplantation
e) Recurrence of FSGS in the previous transplants increases the risk of recurrence in the subsequent graft (up to 75%) (3).
f) Aggressive FSGS leading to renal failure within a short time after onset is associated with a higher recurrence rate.
g) Family history of FSGS is considered a lower risk factor for recurrence (4)
h) The histologic type is not shown to alter the risk for recurrence, although collapsing variant may be associated with more recurrence rate than other variants (5)
i) HLA mismatch and immunosuppression medications used do not alter risk for recurrence (6)
j) Native nephrectomy may be associated with an increased incidence of recurrence (evidence is low) and is explained by adsorption of circulating factor by the native kidney
REFERANCES
medical nephrectomy can be attempted with enalapril 0.09 mg/kg/day to max 0.30 mg/kg/day provided there is no hypotension or hyperkalemia.
if pt still has significant urine output then indomethacin 1-2mg/kg/day can be added on or in place of enalapril.
diclofena 50 mg thrice/week to 100mg/thrice per week can be added to enalapril in place of indomethacin post hemodialysis .
if medical nephrectomy fails options are-
renal artery embolisation
surgical nephrectomy
with this albumin should increase and anticoagulation can be stopped pre transplant .
if warfarin is still ongoing to be stopped 5 days before transplant day and unfractionated heparin started from 2 days prior to transplant .
serum albumin <2.5 gm/dl is an indication to start anticoagulation in a patient with nephrotic syndrome.
as a protocol all patients are anti coagulated in our unit post transplantation from the evening of surgery once clear urine is being passed till patient is mobilised.
its secondary Fsgs so dealing with the cause like weight reduction for obesity, hep c and hep b treatment prior to transplant
Thank You, we do not prefer embolisation as the patient will be left with bilateral painful dead kidneys.
Excellent