Source: Ojo et al. Transplantation. 1998: 66(12), 1651-59.
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
Source: Kaplan and Meier-Kriesche. AJT 2002; 2: 970-74
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.
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.
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)
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)
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.
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.
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.
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
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.
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.
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.
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 .
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).
b Defined as need for dialysis before hospital discharge after transplantation.
d Coded during any hospitalization occurring after return to dialysis after failed kidney transplant.
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)
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.
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.
Adjusted rates + Sensitivity Analysis
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).
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.
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 .
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.
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
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.