management of failing kidney graft.pptx

management of failing kidney transplantation

1. Management of Failing Graft Dr Murathan Uyar YYÜ Tıp Fakültesi İç hastalıkları ABD Nefroloji BD

2. Transplantation The best way to treat chronic renal failure by now D eceased donor transplant half-lives improved from 6.6 years in 1989 to 8.8 years in 2005 living donor transplantation half-lives did not improve (11.4 years in 1989 and 11.9 year in 2005) Returning to dialysis after a failed transplant comprised of 4-7 % depending on the type of transplantation USRDS data

3. Transplantation 5,588 in 2010 Transplant failure is the 4 th leading reason for starting dialysis after DM, HTN, GN

4. Transplantation USRDS

5. Mortality after allograft failure

6. Mortality after allograft failure

7. Mortality after allograft failure The USRDS database and The Canadian Organ Replacement Registry database revealed a > 3 fold ↑ in the annual adjusted death rates for patients returning to dialysis after graft loss with those with a functioning graft (9.4% vs. 2.8%, respectively) Suboptimal timing of dialysis , ongoing immunosuppresssion , chronic inflammation of graft , suboptimal control of risk factors like hypertension are all considered as risk factors for mortality

8. Mortality after allograft failure DOPPS study ( subgroup analysis ) 1856 (4.5%) returning to dialysis were compared with 2806 (6.8%) wait listed dialysis patients 32% greater all cause mortality 53% greater cardiac mortality 145% greater infection related mortality

9. General Management of CKD in KTR Besides the specific causes for late graft failure like : Chronic Antibody mediated rejection Calcineurin effect Hypertension Dyslipidemia Proeinuria Non immunologic risk factors for graft failure

10. General Management of CKD in KTR 9542 transplant patients compared with dialysis patients Transplant patients with eGFR < 30 ml/ min /1.73m 2 81% did not reach target blood pressure 52% did not reach target hemoglobin level 34% did not reach target cholesterol level

11. General Management of CKD in KTR Although an impaired response to erythropoietin is often observed, higher doses will improve anemia in the majority of patients That could prevent the need for blood transfusions, and consequently allosensitization . Additionally, correction of anemia could slow down the progression of chronic allograft dysfunction

12. CAPRIT study : a lower rate of decline in renal function and prolonged graft survival in kidney transplant recipients with moderate graft dysfunction when anemia is correctedwith a target hemoglobin level of 13-15 g/dl (complete correction) compared to a target hemoglobin level of 10.5-11.5 g/dl (partial correction). No difference in cardiovascular events and blood pressure DOI: 10.1681/ASN.2011060546

13. Timing of Initiaition of Dialysis Current guidelines for transplant naïve patients with progressive CKD advocate late-start dialysis (defined as dialysis initiation at an eGFR between 6-9mL/min) Studies on the optimal timing of dialysis reinitiation after a failed transplant are limited

14. Timing of Initiaition of Dialysis

15. Retrospective study Data source: USRDS Aim: To determine the effect of immunologic or transplant related factors and non-immunologic factors on mortality in patients who initiated dialysis after kidney transplant failure in the US between April 1995 and September 1998 N= 4741 patients who initiated dialysis after transplant failure Median follow-up: 15 + 11 months Retrospective study ‘Scientific Registry of Transplant Recipients’ to identify 747 failed kidney transplant patients with CKD Stage 5, who had restarted dialysis therapy. Early ( eGFR >10.5 mL / min /1.73m2) versus late reinitiation of dialysis mortality hazard ratio (HR) was calculated

16. Predictors of all cause mortality after kidney transplant failure a (Cox multivariate regression)   Hazard ratio 95% CI P Age at graft failure per year higher 1.04 1.03–1.04 <0.01 Female gender 1.31 1.10–1.56 <0.01 Race reference other        White 1.94 1.32–2.84 <0.01  Black 1.45 0.96–2.17 0.08 Cause of ESRD reference glomerulonephritis        Diabetes 1.76 1.43–2.16 <0.01  Polycystic kidney disease 0.85 0.57–1.26 0.42  Other 1.01 0.82–1.25 0.93 Peripheral vascular disease 1.94 1.54–2.43 <0.01 Congestive heart failure 1.26 1.05–1.53 0.01 Drug use 2.23 1.08–4.60 0.03 Smoking 1.35 1.01–1.81 0.04 Number of transplants ref 2        One 1.32 1.02–1.69 0.03  Unknown 0.79 0.55–1.14 0.22 Insurance reference neither Medicare or private        Private only 0.67 0.49–0.93 0.02  Medicare only 1.06 0.83–1.35 0.64  Both Medicare and private 0.99 0.74–1.36 0.43 GFR at dialysis initiation per mL/min higher 1.04 1.02–1.06 <0.01 Serum albumin at dialysis initiation per g/dL higher 0.73 0.64–0.83 <0.01 16 Timing of Initiaition of Dialysis Each 1 ml/min/m 2 higher eGFR at dialysis re-initiation was associated with a 4% higher risk of death after reinitiating dialysis (p< 0.01) ( eGFR at dialysis initiation for Nonsurvivors vs. Survivors: 9.7 + 4.8 vs. 8.0 + 3.7 ml/min/1.73 m 2 , respectively ) It is speculated that the sickest patients tended to require initiation of dialysis at higher levels of renal function It is speculated that the sickest patients tended to require initiation of dialysis at higher levels of renal function i

17. Timing of Initiaition of Dialysis (early vs. late) eGFR > 10.5 ml/min vs. eGFR < 10.5 ml/min Unadjusted model Adjusted model b Fully adjusted model c HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value eGFR (each 1 mL/min/1.73m 2 higher) 1.06 (1.01–1.11) 0.02 1.03 (0.98–1.09) 0.22 1.02 (0.97–1.07) 0.54 Early versus late reinitiation of dialysis 1.27 (0.93–1.74) 0.14 1.03 (0.74–1.43) 0.86 0.95 (0.68–1.33) 0.77 HR of death for other covariates in the above model  Age (each 1 year increase) N/A N/A 1.03 (1.02–1.04) <0.001 1.03 (1.01–1.04) <0.001  Gender (male versus female) N/A N/A 1.11 (0.82–1.50) 0.50 1.24 (0.91–1.69) 0.18  Presence of diabetes N/A N/A 1.86 (1.36–2.55) <0.001 1.66 (1.20–2.29) 0.002  Serum albumin (each 1 g/dL increase) N/A N/A N/A N/A 0.44 (0.33–0.59) <0.001  BMI (each 1 kg/m 2 increase) N/A N/A N/A N/A 0.99 (0.96–1.02) 0.38  Presence atherosclerotic heart disease N/A N/A N/A N/A 2.23 (1.44–3.46) <0.001 17 a The early versus late dialysis reinitiation dichotomy is based on eGFR >10.5 versus ≤10.5 mL/min/1.73m 2 . N/A, not applicable. b Model adjusted for age, gender and diabetes. c Model adjusted for age, gender, diabetes, serum albumin, BMI and presence atherosclerotic heart disease.

18. Timing of Initiaition of Dialysis They are confounded by indication bias and retrospective Dialysis reinitiation in patients with a failed allograft may rely on eGFR as a rough guide that must be redefined by patients’ comorbidities, nutritional status, and overall wellness

19. Modality choice

20. Management of Immunosuppression One of the most important issue No consensus on how to discontinue The British transplant society guideline recommends discontinuation of immunosuppression with tapering of steroids, except for patients who have the prospect of a retransplantation within 1 year . Recommendations are based on low level evidences . 10.1097/TP.0000000000000426

21. Management of Immunosuppression Benefits Preservation of residual kidney function Minimization of allosensitization Prevention of graft intolerance syndrome Prevention of adrenal insufficiency syndrome & reactivation of systemic disease ( SLE,vasculitis ) Risks Metabolic complications (diabetes, HTN, dyslipidemia) Long-term effects of steroids ( osteoporosis , myopathy , avascular necrosis ) Cardiovascular complications Increased susceptibility to i nfection Malignancy

22. Management of Immunosuppression Continuation of low-dose immunosuppression Residual kidney function İmprove survival Liberal fluid intake , improved quality of life In a decision analysis model Prolong life expectancy from 5.3 yrs to 5.8 yrs A survival benefit in patients who had > 2.97 mL/min of additional residual renal function   A survival benefit was apparent even at marginal GFR (additional GFR of 1.48 ml/min) DOI: 10.1053/ajkd.2002.33927

23. Management of Immunosuppression Continuation of low-dose immunosuppression USRDS registry analysis demonstrated that c/w hemodialysis, PD was associated with greater survival within the 1st yr after initiation of dialysis after kidney transplant failure, but lower after 2 years It is tempted to speculate that the early survival benefit of PD over HD was due to greater preservation of residual kidney functio n DOI: 10.3747/pdi.2014.00162

24. Current evidence supporting a benefit of residual renal function with continued immunosuppression is solely based on a decision model in PD patients and cannot be routinely recommended Indeed , there is insufficient evidence that the continuation of immunosuppression preserves renal function and improves patient survival after graft loss .

25. Management of Immunosuppression Continuation of low-dose immunosuppression Risk of Sensitization Weaning of immunosuppression is associated with human leukocyte antigen (HLA) allosensitization . 119 patients 24 on IS Only 8% became highly sensitized compared to 68% who weaned of IS DOI: 10.1097/TP.0b013e3182612921

26. Management of Immunosuppression Continuation of low-dose immunosuppression Single-center study N=69 unsensitized patients at the time of graft loss Follow up (months to years after graft loss) 4/15 without nephrectomy or transfusion developed de novo class I and/or class II anti-HLA antibodies when immunosuppression was discontinued In contrast, none of the eleven patients who continued immunosuppressants developed antibodies although 7/11 had a nephrectomy or blood transfusion 10.1016/j.humimm.2011.02.018

27. Management of Immunosuppression Continuation of low-dose immunosuppression Single center 49 patients 20 patients early withdrawal (<3 months ), 29 patients late withdrawal (>3 months ).

28. Management of Immunosuppression Continuation of low-dose immunosuppression S mall-sized retrospective studies do not provide strong evidence. This highlights the need for a well-conducted randomized trial to rationalize the management of immunosuppression after graft loss .

29. Continuation of low-dose immunosuppression

30. Continuation of low-dose immunosuppression - infection Retrospective multi -center study 197 failed transplants Continuation of IS IS withdrawal P-value 95% CI Infectious complications 1.7% 0.51% P < 0.001 Mortality (infectious) OR 2.8 95% CI:1.1-7.0 Mortality (CV) OR 4.9 95% CI: 1.8-13.5 Acute rejection rates P= 0.3 10.1034/j.1399-0012.2001.150606.x

31. Continuation of low-dose immunosuppression - infection Single center 186 patients 10.1097/01.TP.0000437558.75574.9c

32. Continuation of low-dose immunosuppression - infection

33. Continuation of low-dose immunosuppression - cardiovascular Same study with 197 patients

34. Continuation of low-dose immunosuppression - malignancy Recipients of organ transplants are at increased risk for developing certain neoplasm s. The intensity and duration of immunosuppression , T he ability of these agents to promote replication of various oncogenic viruses are important risk factors for the development of certain cancers in kidney transplant recipients

35. ANZDATA Registry 8163 patient 859 cancer 36 Multivariate analysis: The incidence was significantly lower during dialysis after transplant failure for: Non-Hodgkin’s : IRR 0.2 Lip cancer : IRR 0.04 Melanoma : IRR 0.16 All cases of Kaposi’s sarcoma occurred during transplant function SIR: standardized incidence ratios IRR: incidence rate ratios

36. Continuation of low-dose immunosuppression - malignancy For leukemia, lung cancer, and cancers related to ESKD, the risk remained significantly elevated after transplant failure . The cancers related to immunosuppression rapidly reverse as immunosuppression weaned .

37. Graft Intolerance Syndrome Graft intolerance syndrome is a clinical syndrome : Fever L ocal pain S welling of the graft M alaise H ematuria It is often accompanied by a refractory anemia and elevated C-reactive protein levels. İ t occurs in approximately 40% of patients after graft failure, mostly within the first year of dialysis initiation, and reflects a chronic inflammatory state induced by the retained graft

38. It may be temporarily treated with high doses of corticosteroids, but will require allograft nephrectomy or embolization in most cases.

39. Graft nephrectomy Area of controversy General approach is perform nephrectomy when the graft fails in <12 months . >12 months , in case of graft intolerance Syndrome .

40. Graft nephrectomy Absolute indications (commonly accepted) Primary nonfunction Hyperacute rejection Arterial or venous graft thrombosis Early recalcitrant acute rejection PTLD of the graft Early graft failure (< 12 months) Late graft failure ( > 12 months) No consensus guidelines

41. Graft nephrectomy USRDS data 10951 patient 3451 (31.5%) nephrectomised Receipt of allograft nephrectomy was associated with a 32% reduction (95% confidence interval [CI] 26 to 37%) in the relative rate of death compared with not receiving nephrectomy . 10.1681/ASN.2009050480

42. Graft nephrectomy Patients with an in situ failed kidney transplant : chronic inflammatory state anemia, erythropoietin resistance malnutrition Worse cardiovascular prognosis 10.1097/01.ASN.0000137879.97445.6E

43. Graft nephrectomy Discontinuation of immunosuppression and allograft nephrectomy has been implicated in allosensitization Memory B cells continue to produce antibodies with specificity for donor antigens Sensitization may occur due to the persistence of antigen-presenting cell or residual donor tissues and vessels Maintaining the nonfunctioning graft in situ serves as a “tank” or “sponge” that absorbs these antibodies

44. Graft nephrectomy Del Bello et al studied the occurence of donor specific antibodies . Compared the levels who had undergone nephrectomy with those who had not. At the beginning , 12-14% of patients had DSA At the end of follow-up, DSAs were present in 81% of patients who had undergone nephrectomy compared with 52.4% of those who had not

45. Graft nephrectomy Even with the theories that favor or oppose nephrectomy, graft removal should be performed based on clinical indications. I t should be individualized and never regarded as a routine procedure.

46. Immunosuppression withdrawal protocols Quick taper in chronic progressive graft failure Slow taper in recent acute rejection episode CNI + antimetabolite a + prednisone   CNI + mTOR inh + prednisone mTOR inh + prednisone Discontinue antimetabolite at initiation of dialysis Taper CNI over 4-6 weeks b Maintain same steroid dose at initiation of dialysis x 2-4 weeks, then taper by 1 mg/month (starting from 5 mg daily) until off   Discontinue mTOR inh at initiation of dialysis Taper CNI over 4-6 weeks b Maintain same steroid dose at initiation of dialysis x 2-4 weeks, then taper by 1 mg/month (starting from 5 mg daily) until off   Taper mTOR inh over 4-6 weeks b Maintain same steroid dose at initiation of dialysis x 2-4 weeks, then taper by 1 mg/month (starting from 5 mg daily) until off   DOI:10.1111/j.1525-139X.2011.00864.x

47. 48 Suggested algorithm for the management of immunosuppression after allograft failure DOI:10.1111/j.1525-139X.2011.00864.x tapering 1mg/ month for 6 months

48. Conclusions Low dose immunosuppression should be given to : Predialysis patients Patients who has the chance to be transplanted in 1 year Patients with recent acute rejection Patients with > 500-1000 ml/ day urine It should be discontinued in high risk patients : DM Obesity Advanced age Urosepsis Malignancy Neurogenic bladder

49. Conclusions Reinitiation of dialysis should not be based only on eGFR It seems reasonable to start dialysis when eGFR <6-9 ml/ min In patients with higher level of residual kidney function, dialysis reinitiation should be based on clinical and/or laboratory parameters (e.g. symptomatic uremia, volume overload or hyperkalemia refractory to medical therapy) In patients with significant comorbid conditions such as long-standing DM, infectious or urological complications, weaning of IS and early return to dialysis seem justifiable