CKD in Other Organ Transplants

Transcription

1 CKD in Other Organ Transplants Alexander Wiseman, M.D. Associate Professor, Division of Renal Diseases and Hypertension Medical Director, Kidney and Pancreas Transplant Programs University of Colorado Health Sciences Center

2 Outline How common is CKD in non-renal organ transplant recipients? How do we define CKD in this population? What causes CKD in non-renal organ transplant recipients? What can be done to prevent CKD in non-renal organ transplant recipients? What is the impact of CKD and kidney transplant on survival in non-renal organ transplant recipients?

3 How common is CKD in nonrenal organ transplant recipients?

4 A 58 yo patient with a history of DM and Hepatitis C-related cirrhosis is referred to see you in clinic 3 months after successful liver transplant. Prior to transplant he had normal renal function with Cr of , and microalbuminuria. What are his chances of being a) alive, and b) with CKD IV/V, at 5 years? Alive A) 75% 15% B) 75% 5% C) 50% 15% D 50% 5% CKD IV/V

5 A 58 yo patient with a history of DM and Hepatitis C-related cirrhosis is referred to see you in clinic 3 months after successful liver transplant. Prior to transplant he had normal renal function with Cr of , and microalbuminuria. What are his chances of being a) alive, and b) with CKD IV/V, at 5 years? Alive A) 75% 15% B) 75% 5% C) 50% 15% D 50% 5% CKD IV/V Heart 75% 10% Lung 50% 15%

6 5-year Patient Survival , all organs LD Kidney DD Kidney LD Liver Heart DD Liver Lung Intestine Heart-Lung Successful transplantation creates a new population of patients with CKD SRTR 2010

7 Prevalence of CKD in non-renal transplants CKD (% with GFR<30) 50 Heart Lung Liver % Years after transplant Ojo AO et al, NEJM 2003;349: 931

8 How to measure GFR? Estimates of GFR in liver transplant candidates and recipients In 1447 patients at a single center from , I 125 iothalamate GFR was measured in patients at pre-transplant evaluation and at 3 months, 1 year, and yearly post-transplant GFR was compared to Cockcroft-Gault equation, the Nankivell equation, and the equations from the Modification of Diet in Renal Disease (MDRD) Study (6, 5, and 4 variables) Gonwa TA et al, Liver Transpl. 2004;10:301

9 Estimates of GFR in liver transplant candidates/recipients with GFR<40 Pre tx 1y post tx 5 y post tx n ml/min n ml/min n ml/min I 125 GFR CG Nank MDRD MDRD MDRD Following transplant, the MDRD Study equations had greater precision than other equations, but the precision was lower than reported for MDRD estimation of GFR in other populations Gonwa TA et al, Liver Transpl. 2004;10:301

10 CKD in liver transplant recipients: GFR at 3 months predicts future CKD 592 OLTx recipients from , 114 of whom had paired GFR data pretransplant through 15y: %pts No Renal Failure CKD </=IV at 5y CKD </=IV at 10 y > <60 GFR at 3 mo >2-fold increased risk (55% prevalence) of severe CKD at 5y if GFR < 60 ml/min at month 3 Sanchez EQ et al, Transplantation 2010; 89: 232

11 Predicting CKD in heart transplant recipients by GFR at 1-3, and 1-12 months In 233 patients who received a heart transplant and survived >1 month, the decline in (CrCl) was used to predict the outcomes of need for chronic dialysis or mortality >1-year posttransplant: HD incidence by CrCl between mo 1-12 HD incidence by CrCl between mo 1-3 Both a) a 30% drop in CrCl between mo 1-12 and b) a 30% decline in CrCl between mo 1-3 independently predicted the need for chronic dialysis Cantarovich M et al, Am J Transplant 2009;9:348

12 What causes CKD in non-renal organ transplant recipients?

13 Bloom R, Reese P JASN 2007;18:3031 The difference between AKI and AKI in solid. organ transplants: factors contributing to CKD

14 Your patient is continued on tacrolimus and has recurrent Hepatitis C, as well as DM following transplant. The patient continues to see you in clinic with a slow change in SCr until at 5 years the Cr is 2.0 mg/dl, and 24-hr urine protein is 1.2 g. If you perform biopsy, what is the most likely diagnosis? A) B) C) D) CNI nephrotoxicity Thrombotic Microangiopathy DM Other glomerular disease

15 Your patient is continued on tacrolimus and has recurrent Hepatitis C, as well as DM following transplant. The patient continues to see you in clinic with a slow change in SCr until at 5 years the Cr is 2.0 mg/dl, and 24-hr urine protein is 1.2 g. If you perform biopsy, what is the most likely diagnosis? A) B) C) D) CNI nephrotoxicity Thrombotic Microangiopathy DM Other glomerular disease In Heart Tx? In Lung Tx?

16 The role of calcineurin inhibitors in the CKD of nonrenal transplant recipients Acute Reversible vasoconstriction of afferent and efferent arterioles Dose-dependent Chronic Associations: Nodular hyalinosis, interstitial fibrosis Progressive arteriolopathy with ischemic glomerular collapse Mechanisms/existence still debated: Increased oxidative stress, upregulated fibrogenic cytokines (TGF-, MMP-9, PDGF), dysregulated RAAS all suggested Low level endothelial injury- TMA? English J et al, Transplantation 1987; 44: 135

17 The variable pathology of kidney disease after liver transplantation 81 OLT recipients who developed impaired kidney function (Cr>1.5 mg/dl or new proteinuria on dipstick UA) underwent kidney biopsy: Mean time post-tx 4.89 years DM in 44%, HTN in 65%, CNI use in 89% Mean SCr 2.0 mg/dl (MDRD GFR 38.7 ml/min) Mean 24-hr urine protein was 1.37 g. Underlying liver disease: HCV 51% HBV 11% ETOH 10% Cryptogenic 10% Kim JY et al, Transplantation. 2010; 89: 215

18 The pathology of kidney disease in 81 biopsies 5y after liver transplantation Glomerular abnormalities 100% FSGS 26% Membranous 11% MPGN 6% Glomerulosclerosis present in all bx Glom nodular expansion 28% Inc GBM thickness 48% Arterionephrosclerosis 100% Nodular hyalinosis 15% Glomerular abnormalities predominate, with features suggestive of diabetic nephropathy and hypertensive change, but also with specific glomerular disease processes CNI toxicity alone was a rare finding Kim JY et al, Transplantation. 2010; 89: 215

19 Renal biopsy after lung transplantation in patients with cystic fibrosis 15 patients with cystic fibrosis (CF) biopsied for an episode of accelerated renal function loss (RFL) after the perioperative period following lung transplant. Findings: Diabetic glomerulosclerosis 20% FSGS 26.7% Arteriosclerosis 53.3% CNI toxicity 93.3%, associated with TMA in 46.7%* Tubulopathy 66.7%, oxalate nephropathy in 33.3% Considering all biopsies, interstitial fibrosis was estimated at 38% and the percentage of sclerotic glomeruli 26%. * CNI nephrotoxicity was defined by hyaline deposits in the media c/w necrotic myocytes Lefaucheur C et al, Am J Transplant 2008; 8:1901

20 Biopsy-Diagnosed Renal Disease in Patients After Transplantation of Other Organs and Tissues 101 patients with 105 renal biopsies: Bone marrow Liver Lung Heart Biopsies n = 14 n = 41 n = 30 n = 20 Patients n = 14 n = 39 n = 28 n = 20 Age at biopsy (y) Hypertension 57% 62% 86% 90% Diabetes 7% 36% 39% 35% Time after tx (mos) egfr at biopsy (ml/min) Immunosuppression: CsA-based 43% 75% 33% 55% TAC-based 0 23% 33% 10% CNI plus mtor-i 0 5% 33% 35% No CNI at biopsy 57% Schwarz A et al, AJT 2010;10: 2017

21 Biopsy-Diagnosed Renal Disease in Patients After Transplantation of Other Organs and Tissues Bone marrow Liver Lung Heart Biopsies n = 14 n = 41 n = 30 n = 20 Acute tubular injury 79% 49% 75% 70% IF/TA >20% 50% 51% 64% 35% Arteriolar hyalinosis 21% 13% 64% 70% Benign nephrosclerosis 29% 41% 54% 40% Global glom. sclerosis 14% 18% 18% 30% Nephrocalcinosis 14% 13% 0 5% Primary glom. disease 29% 26% 0 15% IgA-nephropathy 6 2 Min. change 2 1 MPGN 3 1 Membranous GN 1 FSGS 1 Thrombotic microangiopathy 7% 13% 14% 0 Polyoma virus nephropathy 0 0 4% 0 Schwarz A et al, AJT 2010;10: 2017

22 CKD in non-renal transplant: Renal and patient outcomes by diagnosis Months Post-Transplant Patients with a diagnosis of primary glomerular disease, HTN, or CNI toxicity had similar kidney survival, and higher than those with TMA Utility of biopsy? Months Post-Biopsy TMA GN CNI GN CNI TMA Schwarz A et al, AJT 2010;10: 2017

23 What can be done to prevent CKD in non-renal organ transplant recipients?

24 The patient continues to see you in clinic 5 years following transplant; his egfr is 28 ml/min, and 24-hr urine protein is 1.2 g. No biopsy has been performed. He remains on Tacrolimus, has SBP in the 150s, and a HgbA1c of 7.9. What can be done at this point to preserve renal function? A) B) C) D) Perform biopsy and treat potential glomerular disease accordingly Reduce or eliminate CNI Treat HTN and DM aggressively Treat recurrent Hepatitis C

25 Recommendations to protect residual renal function in nonrenal solid-organ transplant recipients with CKD High suspicion for pretransplantation CKD Avoid hypotension Minimize nephrotoxic agents Optimize renal perfusion CNI-sparing regimens? Maintain euvolemia Optimize renal perfusion Aggressively treat hypertension per JNC VII ACE inhibitors and/or ARB Manage hyperglycemia and dyslipidemia per ADA and KDOQI guidelines Vigilance for adverse drug interactions Bloom R, Reese P JASN 2007;18:3031

26 Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal Function Il2ra/CsA/Steroids Everolimus (8-10 ng/ml) CsA discontinued at 4 weeks (n=52) Pred taper off by 5 weeks posttransplant CsA Maintenance CsA target over 12mo (If CNI complications, +MMF with CsA target 100 ng/ml) (n=26) Day 10 Randomization Masetti M et al, AJT 2010; 10: 2252

27 Early Withdrawal of CsA with Everolimus Monotherapy results in better GFR at 1y in de novo OLTx egfr at 1y: CsA 59.9 ml/min EVL 87.7 ml/min % CKD 3 at 1y: CsA 52.2% EVL 14.4% Masetti M et al, AJT 2010; 10: 2252

28 CNI withdrawal with SRL vs. CNI reduction in heart tx recipients with CKD 63 HTx pts with GFR<60 SRL (8-14 ng/ml) CNI tapered, discontinued when SRL therapeutic (mean 2.6 weeks) (n=30*) CNI/MMF/±Pred (CsA>100 or TAC>9) CNI reduction by 40% over 4 weeks (n=33) Randomization: mean 5.8y from transplant Groetzner J et al, Transplantation 2009; 87: 726

29 CNI withdrawal with SRL vs. CNI reduction in heart tx recipients with CKD Renal function significantly better with CNI withdrawal: n=6 initiated dialysis in CNI reduction arm 0 in CNI withdrawal No difference in rejection 4 in CNI reduction 2 in SRL In those not initiating dialysis: Higher rate of side effects in CNI withdrawal (SRL) primarily dermatologic >10 ml/min improvement in GFR with SRL transition/cni discontinuation Groetzner J et al, Transplantation 2009; 87: 726

30 What is the impact of CKD and kidney transplant on survival in non-renal organ transplant recipients?

31 The patient develops progressive CKD over the next 2 years; his egfr is 19 ml/min. You refer him to a kidney transplant program who places him on the waiting list. You wonder if he will do well with transplant compared to your other patients who are waiting for a kidney transplant Who would you predict to benefit the most (in terms of improved survival) from kidney transplant? A) Your patient with liver transplant and CKD B) Your patient with failing kidney transplant who is back on the kidney wait list? C) Your patient with CKD awaiting his first kidney transplant

32 Growth in KTX Candidates with previous liver, heart, and lung transplants 3.3% <1% WAIT LIST No Tx Prev KTx Prev Heart Prev Lung Prev Liver N 280,138 47, Srinivas T R et al. CJASN 2010;5:

33 Wait List Death and Survival Benefit of Kidney Transplantation Among Nonrenal Transplant Recipients KA#1 KA#2 KALu KAH KALi Number 264,558 47, Age at listing years (SD) Diabetes 40.1% 23.8% 25.7% 32.4% 36.3% Chronic dialysis treatment 77.5% 72.6% 56.4% 62.1% 63.4% PRA Cause of end-stage renal disease Diabetes 32.7% 11.3% 3.3% 7.6% 11.0% HTN 18.5% 11.0% 3.6% 5.3% 4.0% GN 5.7% 5.6% 1.4% 1.0% 3.4% Polycystic kidney 7.3% 5.9% 0.6% 1.0% 1.7% Reflux/congenital 1.3% 1.5% 0.0% 0.1% 0.0% CNI nephrotoxicity 0.0% 0.2% 50.8% 45.2% 23.6% Retransplantation/graft failure 0.0% 38.3% 0.0% 0.0% 0.0% Other 22.3% 17.4% 12.7% 9.5% 16.7% Other/unspecified by UNOS 12.2% 8.8% 27.6% 30.3% 39.6% 1st transplant to kidney WL - yrs Cassuto JR et al. AJT 2010; 10: 2502

34 Wait List Death and Survival Benefit of Kidney Transplantation Among Nonrenal Transplant Recipients Waiting list Waitlist group HR for death vs waitlisted KA1 KA <0.001 KAH 1.92 <0.001 KALi 2.69 <0.001 KALu 3.80 <0.001 p Tx Conclusion: Patients with nonrenal transplants have a much higher rate/risk of death while on the kidney transplant waiting list compared to kidney candidates Cassuto JR et al. AJT 2010; 10: 2502

35 Wait List Death and Survival Benefit of Kidney Transplantation Among Nonrenal Transplant Recipients Tx Transplant group HR for death vs transplanted KA1 KA <0.001 KAH KALi KALu 4.26 <0.001 p Conclusion: Once kidney tx occurs, nonrenal transplant recipients have similar survival as kidney re-transplants (with the exception of lung tx recipients) Cassuto JR et al. AJT 2010; 10: 2502

36 Wait List Death and Survival Benefit of Kidney Transplantation Among Nonrenal Transplant Recipients KA2 vs WL KAH vs WL KALu vs WL KALi vs WL HR of death compared to wait-listed counterparts: Conclusion: Prior solid organ recipients benefit from kidney transplant; in fact, prior nonrenal transplant recipients have greater benefit than prior kidney transplant recipients! Cassuto JR et al. AJT 2010; 10: 2502

37 Conclusions CKD in solid organ transplants recipient is becoming an increasingly common presentation, and accounts for 3.3% of the kidney transplant waiting list These patients benefit from kidney transplantation, but have a higher rate of death while waiting (encourage use of living donor and ECD for this population) The causes of CKD are different for different types of transplants, with significant heterogeneity particularly in liver transplant recipients (and are NOT predominantly due to CNI!) Prediction of risk of CKD may be performed by examining GFR status within the first year following transplant (often within the first 3 months) Future studies should focus on kidney function preservation in those identified at high risk for progression to end-stage kidney disease and death.