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
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:
âWho Pleads for the Majority?â*
More
combined
transplants
Less single
kidney
transplants
âMay needâ
âCurrent needâ
*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.
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 318Âą17.7 Îźmol/L (meanÂąstandard 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 ONEâŚ
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 (42â48%) versus tacrolimus
groups (15â38%), 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 15â34 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 studiesâŚ
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 plusâŚ
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
(ââââ; red), both preand post-transplant (- - - -; red), and neither pre- nor post-transplant (None, ââââ; 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, reninâ angiotensinâaldosterone 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 â 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: 1048â1055, 2005
However, absolute risk of ESRD not to exaggerate: only 10% at 1 yearâŚ
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 DONâT 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.