Renal failure after non-renal transplantation
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Presentation at the Belgian Transplant Society Meeting about kidney impairment after liver, lung, heart and intestinal transplantation
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Renal failure after non-renal transplantation
- 1. Renal failure after non-renal transplantation Maarten Naesens UZ - KU Leuven BTS meeting March 27th 2015 - Brussels
- 2. The number of patients with combined transplants in Leuven explodes Percentage of kidney transplants after or combined with a non-renal transplant 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 5% 10% 15% 20% 25% Percentageofallkidneytransplants Eurotransplant Percentage of kidney transplants after or combined with a non-renal transplant 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 5% 10% 15% 20% 25% Percentageofallkidneytransplants Eurotransplant Belgium Percentage of kidney transplants after or combined with a non-renal transplant 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 5% 10% 15% 20% 25% Percentageofallkidneytransplants Eurotransplant Belgium UZ Leuven
- 3. End-stage renal disease is frequent after non- renal transplantation Adapted from Ojo et al NEJM 2003 21% 18% 16% 11% 7%
- 4. CNIs are a major contributor to decreased renal function after nonrenal TX cyclosporine tacrolimus Acute CNI nephrotoxicity Chronic CNI nephrotoxicity
- 5. Kidney histology after non-renal transplantation: not always CNI nephrotoxicity Adapted from Kubal et al Transplantation 2012 Total=62 17.74% CNI nephrotoxicity 17.74% CNI nephrotoxicity + hypertensive nephropathy 43.55% Hypertensive nephropathy 8.06% Acute tubular necrosis 12.90% Other
- 6. CNI-avoidance in liver transplantation leads to improved renal function Klintmalm et al Am J Transplant 2014 N=260
- 7. CNI withdrawal after heart transplantation leads to improved renal function Andreassen et al Am J Transplant 2014 N=112 lowCsA+EvR+CS -> EvR + CS highCsA+MMF+CS
- 8. End-stage renal disease and non-renal transplantation: a matter of time Time Non-renal transplant Non-renal organ failure ESRD kidney transplant Scenario 1
- 9. End-stage renal disease and non-renal transplantation: a matter of time Time Non-renal transplant Non-renal organ failure Scenario 2 ESRD kidney transplant
- 10. End-stage renal disease and non-renal transplantation: a matter of time ESRD Time Non-renal transplant Non-renal organ failure Scenario 3 Kidney transplant ?Renal impairment
- 11. End-stage renal disease and non-renal transplantation: a matter of time ESRD Time Non-renal transplant Non-renal organ failure Scenario 3 Kidney transplant ?Renal impairment
- 12. The number of combined kidney + non-renal transplantations in UZ Leuven is higher *not including combined kidney+pancreas transplants * Percentage of the non-renal transplants combined with a kidney transplant 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 2% 4% 6% 8% 10% Percentageofallnon-renaltransplants Eurotransplant Percentage of the non-renal transplants combined with a kidney transplant 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 2% 4% 6% 8% 10% Percentageofallnon-renaltransplants Eurotransplant Belgium Percentage of the non-renal transplants combined with a kidney transplant 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 2% 4% 6% 8% 10% Percentageofallnon-renaltransplants Eurotransplant Belgium UZ Leuven
- 13. Combined kidney-pancreas and liver-kidney transplants are the most common Percentage of all combined kidney transplants in Belgium 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0% 20% 40% 60% 80% Kidney + pancreas Kidney + liver Kidney + heart Kidney + lung Kidney + other
- 15. Post-transplant dialysis is a risk factor for mortality after liver transplantation Nair et al Clin Transplant 2011 Single-center; N=653*
- 16. Heart transplant patients with dialysis have higher mortality compared to dialysis patients Alam et al Am J Transplant 2007 Years after initiation of dialysis
- 17. Patients wait-listed for a kidney after a previous non-renal transplant do badly Cassuto et al Am J Transplant 2010 First kidney Repeat kidney Kidney after heart Kidney after liver Kidney after lung
- 19. Hepatorenal syndrome: a reversible cause of renal failure? Wong F Nat Rev Gastroenterol Hepatol 2012
- 20. Cardiorenal syndrome: reversibility is very difficult to evaluate Partly based on Ronco et al JACC 2008 CRS type 1 CRS type 2 CRS type 3 CRS type 4 CRS type 5 Acute heart failure Chronic heart failure Acute renal failure Chronic renal failure RAAS activation, endothelial dysfunction, Na+ and H20 retention, uremic solute retention, Ca-P disturbance, hypertension, low cardiac output and hypoperfusion, subclinical inflammation, increased venous pressure, embolism, electrolyte disorders, anemia etc.
- 21. Short bowel syndrome and renal failure: reversibility is very difficult to evaluate Short bowel syndrome Acute renal failure Chronic renal failure Hypovolemia, hypoperfusion, hypotension, electrolyte disorders, oxalate deposition, etc.
- 23. Risk factors for ESRD after non-renal transplantation Adapted from Ojo et al NEJM 2003 >90 60-89 30-59 <30 0 2 4 6 Relativerisk Relative risk for ESRD after non-renal transplantation eGFR (mL/min/173m2) p<0.0001 No dialysis preTX Dialysis preTX 0 2 4 6 Relativerisk Relative risk for ESRD after non-renal transplantation p<0.0001 No ARF postTX ARF postTX 0 2 4 6 Relativerisk Relative risk for ESRD after non-renal transplantation p<0.0001 20-30 30-40 40-50 50-60 60-70 0 2 4 6 Relativerisk Relative risk for ESRD after non-renal transplantation Recipient age p<0.0001 eGFR Dialysis preTX ARF postTX Recipient age
- 24. Risk factors for ESRD after liverTX: MELD allocation increases early ESRD Sharma et al Am J Transplant 2011 SRTR data 1995-2008 (N=59.242)
- 25. Renal Risk Index (RRI): prediction of ESRD after liver transplantation RRI Sharma et al J Am Soc Nephrol 2013 SRTR 2002-2010 (N=43.514)
- 26. Renal Risk Index (RRI): prediction of ESRD after liver transplantation Sharma et al J Am Soc Nephrol 2013 SRTR 2002-2010 (N=43.514) 10% at 1 year ROC AUC=0.76
- 27. Risk factors for postoperative renal failure after heart transplantation: not only GFR! Kilic et al J Thorac Cardiovasc Surg 2014 UNOS data 2000-2010 (N=14.635) Recipient age Heart failure cause Creatinine clearance Serum bilirubin BMI Diabetes mellitus Mechanical ventilation ICU Recent infection Blood transfusion Donor age Biatrial anastomosis Cold ischemia time Risk score
- 29. Organ allocation in scarcity: “Who Pleads for the Majority?”* More combined transplants Less single kidney transplants “May need” “Current need” *Matas A. Am J Transplant 2014
- 30. Waiting time for non-renal transplant is shorter than for single renal transplantation Eurotransplant Statistics for all ET Waitingtime(months)
- 31. Donor characteristics of non-renal transplants are better than for single kidney transplants Eurotransplant Statistics for all Eurotransplant Donorage(years)
- 32. Combined transplantations have better donor characteristics compared to single kidney Tx OPTN data 2002-2013 (N=118.833)Reese P et al Am J Transplant 2014
- 33. End-stage renal disease after liver transplantation: shorter kidney TX waiting time ESRD Time Liver transplant Liver failure Kidney transplant +500 Renal impairment
- 34. End-stage renal disease after other solid organ Tx: long waiting times in dialysis ESRD Time Other organ transplant Other organ failure Kidney transplant +0 Renal impairment
- 35. Conclusions • End-stage renal disease is a common problem in non-renal transplantation o Before transplantation: combined transplants o Immediately after transplantation: better risk stratification + decisions on combined transplantation o Late after transplantation: need for targeted approaches • Co-allocation of kidneys for combined transplantation is not based on good literature data. Literature should be generated from centers not performing combined transplants. • The problems of equity and overall benefit (efficacy) of combined transplantation need to be discussed by the transplant community.
Notas do Editor
- This is a very relevant topic for this meeting, as it not only concerns nephrologists, but all transplant programs
- This graph is shown at every meeting. One of the most highly cited papers in the field of transplantation. Patients transplanted 1990-2000: how representative is this? Striking in this graph: is the steep slope in the beginning after transplantation of increase: at 1 year 10% of intestinal and liver transplants with ESRD. In addition: this analysis EXCLUDES all patients with a combined transplantation: not representative for current clinical practice!! Does not tell the whole truth
- This graph is shown at every meeting. One of the most highly cited papers in the field of transplantation. Patients transplanted 1990-2000: how representative is this? Striking in this graph: is the steep slope in the beginning after transplantation of increase: at 1 year 10% of intestinal and liver transplants with ESRD. In addition: this analysis EXCLUDES all patients with a combined transplantation: not representative for current clinical practice!! Does not tell the whole truth
- In this study: histology diagnoses made on the basis of predominant lesions, but it should be clear that difference histologically between CNIT and hypertensive nephropathy is very difficult Renal biopsies of 62 NRSOT recipients were evaluated for histological diagnoses. Biopsies were graded for chronic allograft damage index parameters and for arteriolar hyalinosis. The sum of all chronic allograft damage index parameters and arteriolar hyalinosis scores was called chronic damage index. RESULTS: The biopsies were performed at a median of 4 (range: 0.3-15.9) years after NRSOT and at serum creatinine of 318±17.7 μmol/L (mean±standard deviation). Twenty-two (35.5%) biopsies showed predominant features of chronic CNI nephrotoxicity, 27 (43.5%) predominant features of hypertensive nephropathy, and 12 (19.3%) an alternative primary renal pathology. Twenty-four (38.7%) patients had progression to end-stage renal disease, at a median of 1.5 (0-10.1) years after biopsy and 6.9 (0.3-19.2) years after NRSOT. The risk of renal progression was associated with in situ damage measured by chronic damage index.
- NEGATIVE STUDY FOR OUTCOME, BUT ILLUSTRATES THAT CNI-FREE IS POSITIVE FOR eGFR MANY STUDIES LIKE THIS ONE… The proportion of patientswho met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus.MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab.belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.
- Will not talk about scenario 2: is straightforward Scenario 1: is OJO paper: well known: question is whether CNI minimization will improve outcome. Many studies… Not the topic of this presentation.
- Will not talk about scenario 2: is straightforward? Not very: ESRD in terminal heart failure or hepatorenal syndrome could be reversible Scenario 1: is OJO paper: well known: question is whether CNI minimization will improve outcome. Many studies…
- Try to predict which patient will develop rapid ESRD, in order to provide a combined transplantation.
- Try to predict which patient will develop rapid ESRD, in order to provide a combined transplantation.
- Kidney-pancreas is different: these patients would not get the pancreas without the kidney in most cases. The kidney is actually the prime need, and the pancreas is a welcome additional benefit; Other organs just the opposite: the indication is for heart/lung/liver transplantation, and the kidney comes as a plus…
- If we consider combining a non-renal transplant with a kidney transplant, we need to take 3 issues into account: Recipient mortality with vs; without the combined kidney transplant Reversibility of the renal impairment after non-renal transplantattion Predictability of the end-stage renal disease after non-renal transplantation
- ABOUT MORTALITY Striking: preTX HD not that much impact on survival. It is post-TX ESRD that matters! * 3 patients excluded because of combined liver-kidney transplantation. This is a very representative population: limited bias by combined TX!!! Only 15 pts in the pr-TxP group!! Fig. 1. Survival of first orthotopic liver transplant recipients stratified by the need for any hemodialysis treatment pre-transplant (- - - -; black), posttransplant (————; red), both preand post-transplant (- - - -; red), and neither pre- nor post-transplant (None, ————; black).
- This is a cohort of patients, matched with a cohort of dialysis patients.
- Non-renal transplants on the wait list for a subsequent renal transplant have a very significantly higher risk of dying on the kidney wait list. THIS IS THE REASON FOR TRANSPLANTING THESE PATIENTS WITH ESRD AFTER NON-RENAL TRANSPLANTATION = NEED AN URGENT KIDNEY NO DOUBT THAT THESE PATIENTS WITH ESRD AFTER NONRENAL TRANSPLANT ARE AT EXTREME RISK THE FEAR FOR ESRD AFTER NONRENAL TRANSPLANT IS VERY LEGITIMATE = DILEMMA with: Also after succesfull kidney-post-nonrenal-tx, these patients have significantly worse outcome (patient survival) compared to single kidney recipients. Death-censored renal allograft survival is not different (which illustrates that these kidneys in itself are as good as in single kidney TX). The significantly higher risk of dying with a functioning kidney after kidney-post-nonrenal transplantation, compared to single kidney transplantation, means futile kidney transplants, that should be avoided!!
- ABOUT REVERSIBILITY The pathophysiology of hepatorenal syndrome. Includes a | the development of splanchnic vasodilatation and b | the development of renal dysfunction. The solid arrows indicate a baseline condition, whereas the dotted arrows indicate hepatorenal syndrome occurring in the event of a precipitating factor. Abbreviations: AVP, arginine vasopressin; CO, cardiac output; EABV, effective arterial blood volume; GFR, glomerular filtration rate; Na, sodium; RAAS, renin– angiotensin–aldosterone system; RBF, renal blood flow; SNS, sympathetic nervous system; TNF, tumour necrosis factor.
- ABOUT REVERSIBILITY
- ABOUT REVERSIBILITY How to dissect reversible from irreversible renal impairment in the cardiorenal, hepatorenal and short bowel syndrome, is very complicated, and needs a lot of experience.
- The question therefore is really: how can we predict ESRD after non-renal transplantion?
- Ojo vs Ruebner: same results adults and pediatrics. Age eGFR Dialysis need (weak in adults: due to most severe, predicted to not recover combined TX, and not in analysis = selection bias!!) ARF = GFR decline by 50%, or need for dialysis THIS OF COURSE VALIDATED IN MANY STUDIES THEREAFTER; AS EXPECTED: MAINLY PARAMETERS OF KIDNEY FUNCTION ASSOCIATE WITH ESRD AFTER NON-RENAL TX!!! DOES THIS MEAN THAT A GFR CUT-OFF COULD BE DEFINED TO PREDICT ESRD (and perhaps combined TX? ) Problem: this is study done 15-25 years ago!! No MELD score, very different populations than nowadays. How valid??? Question thus is: how to decide between combined TX or single non-renal TX???? -> prediction on short-term renal outcome after non-renal transplantation.
- Start by liver transplantation, with important impact of MELD score on risk of ESRD post-transplantation Post-MELD for liver TX: clear increase in ESRD hazard – significant but NOT THAT DRAMATIC!!
- Lower sodium = better renal outcome (low sodium = suggestive of HRS) = more reversibility expected Other: e.g. 17. Campbell MS, Kotlyar DS, Brensinger CM, Lewis JD, Shetty K, Bloom RD, Markmann JF, Olthoff KM, Shaked A, Reddy KR: Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation. Liver Transpl 11: 1048–1055, 2005
- However, absolute risk of ESRD not to exaggerate: only 10% at 1 year… In the highest risk group, 80% did not develop ESRD by 5 years post-transplantation ROC AUC: obtained by email from Sharma: is clinically revelant, but not sufficient for deciding combined liver-kidney vs. kidney alone! So: prediction is possible, but not very powerful… This illustrates that is is not very feasible to correctly predict who will need a combined liver+kidney transplant
- Renal function is not the only parameter!! Postoperative renal failure (requiring dialysis) Divided into test and validation cohort 13 risk factors identified This score is a predictor of acute renal failure and not necessarily the need for chronic dialysis, Timing of development of ESRD is not mentioned in this text New-onset postoperative renal failure occurred in 1128 patients (7.7% ) in the entire study population other variables that may affect rates of renal failure are not available in the UNOS database and therefore are unable to be included in our risk index. These variables include the use of nephrotoxic medications, perioperative fluid balance, intraoperative and postoperative bleeding, and episodes of perioperative hypotension,
- Quote from AJT paper by IS IT ETHICAL TO ALLOCATE KIDNEYS TO PATIENTS WHO MAY NEED IT IN THE FUTURE, WHILE PATIENTS ALREADY NEEDING THE KIDNEY DON’T RECEIVE THE KIDNEY?
- This paper (viewpoint paper) is extremely important and contains many thoughts on important aspects of equity, SO, PATIENTS WHO MAY END UP IN ESRD IN THE FUTURE RECEIVE A YOUNGER KIDNEY, MORE RAPIDLY, THAN PATIENTS WHO ALREADY HAVE ESRD CONCLUSION: ETHICALLY CUMBERSOME TO ALLOCATE COMBINED ORGANS IN PATIENTS NOT YET IN ESRD Kidney donor profile index
- Wise decision: disencourage combined kidney+liver in patients with an increased (but not very high) chance of ESRD after liver TX 1 year waiting time = 33.3 points 500 extra points = equal to 15 years of waiting time!! (= same as HU listing) THIS IS ONLY THE CASE FOR KIDNEY-AFTER-LIVER! NOT FOR OTHER ORGANS, and not >360 days post-transplant Enige nadelen: Zo nierTX in tweede tijd nodig, afkomstig van andere donor 2 keer ingreep ipv 1 keer
- Try to predict which patient will develop rapid ESRD, in order to provide a combined transplantation.