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Transplant Nephrectomy Improves Survival following a Failed Renal Allograft (Journal Club)


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  • 1. Raj Kiran Medapalli, MD, MPH. Nephrology Fellow January 5 th 2011 Mount Sinai School of Medicine Division of Nephrology Journal Club
  • 2. Transplant Nephrectomy Improves Survival following a Failed Renal Allograft . JASN 21: 374–380, 2010. Journal Club January 5 th 2011 Raj Kiran Medapalli, MD, MPH.
  • 3. Failed renal allograft - Disease burden
    • Each year approximately 2000 patients enter dialysis in the US after allograft failure.
    • Approximately 20% of all patients on the renal transplant waiting list in the US (16,000 out of 80,000 listed) have had a previously failed allograft.
    • Source: Perl et al. Semin Dial 21:239–244, 2008
  • 4. Prognosis after failed primary renal allograft
    • 19208 pts with primary renal allograft failure between 1985 & 1995(USRDS). F/u until death, transplantation or 12/31/96. Mean f/u: 3.8 years.
    • Total mortality during f/u :
      • 34.5%
    • 5-yr patient survival before re-transplantation :
      • DM-Type1: 36%, DM-Type2: 49%, Non-diabetic ESRD: 65%
    • 5-yr repeat transplantation rates :
      • DM-Type1: 29%, DM-Type2: 15%, Non-diabetic ESRD: 19%
    • Repeat transplantation was associated with reduction in 5-yr mortality compared to waitlisted dialysis pts with prior allograft failure :
      • DM-Type1: 45% reduction
      • Non-diabetic ESRD: 23% reduction.
    • Most common causes of death :
      • Unknown (33%), heart disease (22.7%), cardiac arrest (18.4%), sepsis (15.5%), CVA (4.8%), GI/liver disease (3.8%), & malignancy (1.8%).
    • Source: Ojo et al. Transplantation. 1998: 66(12), 1651-59.
  • 5. Death after primary renal allograft loss 78564 pts who underwent primary renal transplant between 1988-1998; 10 yr follow-up. USRDS In comparison, annual death rate on renal transplant waiting list is 6.33% per 100-pt-years (9.27% for diabetics) Annual adjusted death rates per 100 pt-years Death with functioning transplant Death after graft loss N Annual rate % N Annual rate % Overall 10816 2.81 4712 9.42 Cardio-vasc 3402 0.69 2252 4.31 Infectious 1856 0.37 879 1.63 Malignancy 808 0.19 122 0.11
  • 6. Source: Kaplan and Meier-Kriesche. AJT 2002; 2: 970-74
  • 7. Potential explanations for high mortality in patients with allograft failure
    • Chronically rejected renal allograft serves as a nidus for immunoreactivity.
    • Analogous to clotted grafts with subclinical infection in patients on hemodialysis, the failed graft may contribute to a chronic inflammatory state characterized by hypoalbuminemia, elevated CRP & anemia.
    • Continued use of low-dosage immunosuppression increases risk of CV and infectious complications.
  • 8. Allograft nephrectomy after transplant failure
    • 19107 pts with allograft failure who initiated dialysis between 1995 and 2003 (USRDS). F/u until death, re-transplantation or 12/31/04 (mean f/u 2.4 yrs).
    • Patients categorized as having early graft failure (graft survival <12 months) & late graft failure (>= 12 months) based on initial exploratory analysis which suggested that the nephrectomy rates differed in these pts.
    • In 3707 patients with early transplant failaure:
      • Nephrectomy rate: 56%
      • Higher risk of death (HR: 1.13, 1.01-1.26)
    • In 15400 patients with late transplant failure :
      • Nephrectomy rate: 27%
      • Lower risk of death (HR: 0.88, 0.83-0.95)
    • Cumulative probability of nephrectomy at 1 week, 2 weeks, 3 months, 6 months and 1 year after transplant failure:
      • 5.3%, 7.9%, 17.6%, 25%, 30.9%.
      • 89% of the nephrectomies were performed within 1 yr of graft failure
      • Source: Johnston et al. AJT 2007. 7:1961-67.
  • 9.
    • Peri-operative mortality rate (within 90 days of nephrectomy): 5%
    • Median length of hospitalization: 6 days. (IQR: 4-12)
    • Sepsis was the most frequent non-fatal short term complication, followed by CHF.
    • Factors consistently associated with nephrectomy :
      • Age < 40 years at allograft failure
      • HLA mismatch > 3
      • Wait listing for repeat transplantation within 1 yr.
    • Factors uniquely associated Nx in patients with early graft failure :
      • Delayed graft function
    • Factors uniquely associated Nx in patients with late graft failure :
      • Female gender, Black race, absence of diabetes
      • Decreased donor transplant, induction with non-depleting antibody.
      • HD after transplant failure between 1995-97 compared with 2001-03. Source: Johnston et al. AJT 2007. 7:1961-67
    Allograft nephrectomy after transplant failure (US)
  • 10. Allograft nephrectomy & repeat transplantation
    • Nephrectomy and sensitization prior to repeat transplantation
      • 18% (3496) patients received a second transplant
      • 37% percent of these patients had a allograft nephrectomy prior to the 2 nd Tx.
      • In patients who had PRA levels of 0-10% or 11-30% prior to the 1 st transplant, the PRA levels prior to repeat transplantation were significantly higher in patients who had a transplant nephrectomy (p<0.0001)
      • No difference in patients who had PRA levels of > 31%.
    • Nephrectomy and 2 nd allograft survival after repeat transplantation
      • In patients with early graft failure :
        • Decreased risk of allograft failure after adjusting for multiple covariates (HR: 0.72, 0.56 to 0.94)
      • In patients with delayed graft failure :
        • Increased risk of allograft failure (HR: 1.20, 1.02 – 1.41)
        • Source: Johnston et al. AJT 2007. 7:1961-67
  • 11. Usual indications for transplant nephrectomy
    • Hyperacute allograft rejection (ABO incomp, anti-HLA abs, anti-endothelial abs)
    • Graft thrombosis (with/without rejection) – accounts for 45% of graft loss before 90d
    • Onset of symptoms and/or complications related to rejection and necrosis after withdrawal of immunosuppression
      • Graft tenderness, fever, hematuria, localized edema, and occasionally infection
    • History of early graft failure (with or without symptoms and/or complications)
      • These patients are at much high risk of graft complications independent of whether immunosuppressive medications are withdrawn or not.
      • Abrupt withdrawal of immunosuppression increases risk.
    • Signs and symptoms of a chronic inflammatory state with no other cause
      • Anemia, hypoalbuminemia, elevated CRP
    • Usual arguments against nephrectomy
    • Reported peri-operative complication rate: 6 to 37%
    • Concern that increased recipient immunoreactivity due to exposure to foreign antigens during nephrectomy operation can lead to reduced rates of repeat transplantation and possibly increased risk of subsequent allograft failure.
  • 12. Withdrawal of immunosuppression after allograft failure
    • No data from controlled prospective studies to guide us.
    • Usual practice :
    • For patients with early graft failure (< 1 year) :
      • Immediate withdrawal combined with preemptive nephrectomy
    • For patients with late allograft failure (>=1 year) :
      • CNI and anti-metabolite are withdrawn immediately.
      • Prednisone tapered by 1mg/month until the drug is discontinued.
      • Monitor for symptoms of adrenal insufficiency.
    • For patients with residual renal function :
      • Anti-metabolite is withdrawn immediately.
      • Initially CNI reduced to once daily in the morning.
      • Initially prednisone reduced to 5mg/d.
      • CNI & prednisone tapered slowly over 3-6 months.
      • Slow taper may preserve residual renal function longer.
    • For patients who develop symptoms of allograft rejection with withdrawal :
      • Administer 5-7 day course of prednisone (0.3-1.0 mg/kg/d)
      • Refer to surgery for nephrectomy.
  • 13.  
  • 14. Study Design - 1
    • Source database : USRDS.
    • Inclusion Criteria :
    • Age > 18 years
    • Returned to dialysis after allograft failure between Jan 1 st 1994 & December 31, 2004.
    • Single kidney transplant or 2 non-sequential kidney transplants.
    • Exclusion Criteria :
    • Renal allograft failed within 90 d of transplantation (because many of them will be 2/2 hyperacute rejection or graft thrombosis which are classical and accepted indications for nephrectomy).
    • Death within < 1 day after allograft failure (allograft failure 2/2 to death? Potential for misclassification in a retrospective database).
    • Did not have Medicare within 90 days of returning to dialysis (used medicare claims data used to define many variables).
    • Those without confirmed sequential transplants.
  • 15.  
  • 16.  
  • 17. Study Design - 2
    • Follow-up period :
    • From return to dialysis to study end (12/31/04) or death or lost-to-f/u.
    • Patients were considered lost-to-f/u if no evidence of dialysis billing for 12 consecutive months in the absence of an identified death date.
    • Variable definitions :
    • Receipt of transplant nephrectomy was ascertained using Medicare claims data (CPT codes).
    • Info on demographics, co-morbidities and baseline labs was obtained from the USRDS 2728 form that was completed closest to the start of dialysis.
    • Info on transplant variables, donor characteristics, immunological risk, and immunosuppression and delayed graft fxn obtained from USRDS UNOS registration forms.
    • Hospitalization for conditions associated with transplant nephrectomy (fever, anemia, hematuria, abd pian, urinary obstruction, sepsis, UTI, cachexia, malnutrition and rejection) during the f/u period identified using primary or secondary ICD-9 codes
  • 18. Study outcomes & Statistical analysis
    • Groups being compared: Nephrectomy vs. Non-nephrectomy.
    • All cause mortality (primary outcome)
    • Unadjusted mortality rates (per 100 p-yrs)
    • Adjusted mortality rate using Cox-regression analysis (hazard ratio):
        • Quartile of propensity score for likelihood of receiving allograft nephrectomy during follow-up (c-statistic: 0.76).
        • Variables known to be associated with mortality after failed transplant.
        • Other variables that differed between those who died and those who did not die during f/u.
    • 6 Sensitivity analyses (to test the impact of including each sub-group of patients who were excluded because of the exclusion criteria & establish robustness of the findings)
    • Likelihood of receiving 2 nd transplant during follow-up period.
    • Unadjusted rate of death within 30 days of Tx nephrectomy.
  • 19. Propensity Scores
    • The propensity score is the conditional probability of receiving the treatment given measured covariates .
    • In the absence of random assignment, adjustment for an estimated propensity score tends to balance the measured covariates that were used to construct the score among the treatment groups.
    • However, unlike random assignment of treatments, the propensity score does not balance covariates that were not measured .
    • The propensity score complements model-based procedures and is not a substitute for them . It is often used in conjunction with further model-based adjustments using regression or log-linear models.
  • 20. Propensity Scores
    • For e.g. each subject has a set of measured covariates (X) and an indicator of treatment (Z = 1 if treated and Z = 0 if control).
    • The propensity score, e(X), is the chance that a person with covariates X will receive treatment, that is, e(X) =prob(Z = 1|X).
    • What it means in the context of current study
    • Current retrospective study compares nephrectomy (Z = 1) with no-nephrectomy (Z= 0).
    • A propensity score was formulated from more than 50 covariates that characterized patient health at return to dialysis.
    • The covariates included, age, sex, race, smoking status, CAD, living donor vs. deceased donor kidney among other characteristics.
    • At baseline (return to dialysis) the two groups differed significantly in terms of many of these covariates.
  • 21. Propensity Scores
    • The propensity score e(X) = prob(Z = 1|X) was estimated using logistic regression to predict the probability of nephrectomy (Z) based on the covariates (X).
    • Patients were then divided into four strata according to their propensity score ; each stratum contained 25 percent of the patients.
    • Within each strata , the patients who did and did not undergo nephrectomy will have similar distributions of the covariates .
    • Patient outcomes were then compared among the two groups using Cox-regression analysis relating all-cause mortality to nephrectomy, multiple covariates and the four propensity score strata.
    • Accounting for the propensity score strata hence is an attempt to address and reduce the effect of possible treatment selection bias .
  • 22. Results
    • Mean f/u time: 2.93 ± 2.26 years.
    • Only 124 pts out of 10,951 pts (1.1%) were lost to f/u.
    • 3785 pts out of 10,951 pts (34.56%) died by the end of follow-up.
    • 3451 pts out of 10,951 pts (31.5%) had a transplant nephrectomy.
    • 53 patients died within 30 days of transplant nephrectomy (i.e., rate of death at 30 days of transplant nephrectomy is 1.5%)
    • Median time between return to dialysis and nephrectomy: 1.66 yrs (IQR: 0.73 - 3.02).
  • 23.  
  • 24.  
  • 25. b Defined as need for dialysis before hospital discharge after transplantation.
  • 26.  
  • 27. d Coded during any hospitalization occurring after return to dialysis after failed kidney transplant.
  • 28.  
  • 29. Unadjusted Rates (1994-2004) All-cause mortality Total N=10,951 32 vs. 36 per 100 Person Years (p=0.0324) Repeat transplantation Total N=10,951 10% vs. 4.1% (p<0.001)
  • 30. Adjusted for :
    • Quartile of propensity score.
    • Subject age, race, gender, lack of insurance.
    • CAD, MI, cardiac arrest, CHF, CVA.
    • Diabetes, HTN, COPD, Cancer.
    • Inability to ambulate/transfer.
    • Obesity.
    • Serum creatinine, albumin, hemoglobin.
    • Year of transplantation.
    • Donor age, donor race, donor cause of death, cold-ischemia time and anoxia.
    • Interim hospitalizations for any of the following: anemia, abdominal pain, urinary obstruction, sepsis, UTI, malnutrition, or complication of transplanted kidney.
  • 31. Adjusted rates + Sensitivity Analysis
  • 32. Results summary
    • Allograft nephrectomy vs. no-nephrectomy
    • 26-37% reduction in mortality in patients who underwent allograft nephrectomy after adjustment for potential confounders and likelihood of receiving nephrectomy (HR: 0.68, 95%CI: 0.63-0.74).
    • Beneficial effect on mortality is present regardless of timing of allograft failure and more pronounced in patients who experienced late allograft failure (HR: 0.65 vs. 0.76).
    • Patients who underwent allograft nephrectomy were 2.4 times more likely to undergo repeat transplantation (10% vs 4%, p < 0.001, unadjusted estimate).
    • Low risk of death from nephrectomy itself: Rate of death within 30 days of transplant nephrectomy was 1.5% (53 out of 3451 pts).
  • 33. Study strengths
    • USRDS - nationally representative sample.
    • When compared to the previous study by Johnston et al:
      • Excluded patients whose graft failed within 90days of transplantation (N=13K). Graft failure in many of these pts is likely secondary to hyperacute rejection or graft thrombosis - which are classical and accepted indications for nephrectomy.
      • Excluded pts who died < 1 day after allograft failure (N=7K). Allograft failure 2/2 to death? Potential for misclassification in a retrospective database.
      • Included a larger set of potential confounders.
      • Accounted for clinical events (hospitalizations) during f/u.
    • Also attempted to control for potential biases using propensity score method and adjusting for all relevant measured confounders which was no done in earlier studies.
    • Performed several sensitivity analyses to demonstrate robustness of the findings and examined the effect of some of the inclusion and exclusion criteria used.
  • 34. Study weaknesses
    • Registry data: susceptible to effects of missing data, misclassification and residual confounding from unmeasured variables
    • Treatment selection bias: the two groups had major differences at baseline with respect to many important co-morbidities which will impact the decision to perform the nephrectomy as well as mortality.
    • Propensity scoring mitigates the treatment selection bias to some extent but does not account for unmeasured variables.
    • No information on cause of graft failure and cause of death.
    • No information on timing of withdrawal of immunosuppression and immunosuppression at the time of nephrectomy.
    • Did not look at non-fatal complications of nephrectomy (need for transfusions, sepsis, etc)
    • Did not report morality rates by primary dz (diabetic, non-diabetic)
    • Did not look at wait listing rates.
    • Did not look at graft and patient survival in pts who underwent re-transplantation .
  • 35. My Conclusions - 1
    • Considering the following:
      • high overall annual mortality in patients with a failed transplant (10% per 100-pt yrs)
      • low peri-operative mortality associated with allograft nephrectomy (1.5%)
      • potential mortality benefit associated with it (26-37%) and
      • improved chances of receiving a 2 nd transplant (10% vs. 4%),
    • elective allograft nephrectomy should be discussed as an option and offered to stable dialysis patients with a failed renal allograft, especially to those patients who are good surgical candidates in general and to all patients with symptoms suggestive of rejection after withdrawal of immunosuppression.
  • 36.
    • Black race, cadaveric donor, receipt of OKT3/Thymo, episodes of rejection, DGF, etc, are more commonly seen in patients who underwent allograft nephrectomy in this study.
    • However, because this is a retrospective study we cannot conclude that there is relationship between these variables and nephrectomy. For e.g. we cannot use them to predict who will need or benefit more from a nephrectomy in the future.
    • Utility of such results technically limited to hypothesis generation.
    My Conclusions - 2
  • 37. My conclusions - 3
    • Routine allograft nephrectomy in stable dialysis patients with a failed renal allograft should be evaluated against current management strategies in a prospective setting.
    • A RCT trial may be difficult to do as recruitment will be difficult and drop out rate may be high (especially in the nephrectomy arm).
    • A multi-center prospective cohort study would also allow for more robust evaluation of this hypothesis:
      • Offer nephrectomy to all stable dialysis pts (>=90 days after re-initiation of dialysis) who meet preset eligibility criteria (to exclude high surgical risk pts) and follow patients who did and did not undergo nephrectomy for 5 years .
      • Examine mortality and its causes/predictors, timing of immunosuppresion withdrawal, early vs. late graft failure, immunogenecity, re-transplantation rates & graft survival.
      • Also examine histology , especially in asymptomatic patients to see if there was any sub-clinical inflammation.
  • 38.
    • Thank you.