Allison M. Brown

A COMPARISON OF THE EFFECTS OF DIALYSIS AND RENAL TRANSPLANTATION ON THE SURVIVAL OF OLDER UREMIC PATIENTS

BACKGROUND Patients over age 60 constitute half of all new patients accepted into the renal replacement therapy programs in Australia. However, the optimal treatment of their end-stage renal disease remains controversial. The aim of the present study was to compare survival for dialysis and renal transplantation in older patients who were rigorously screened and considered eligible for transplantation. METHODS The study cohort consisted of 174 consecutive patients over 60 who were accepted on to the Queensland cadaveric renal transplant waiting list between January 1, 1993 and December 31, 1997. Follow-up was terminated on October 1, 1998. Data were analyzed on an intention-to-transplant basis using a Cox regression model with time-varying explanatory variables. An alternative survival analysis was also performed, in which patients no longer considered suitable for transplantation were censored at the time of their removal from the waiting list. RESULTS There were 67 patients receiving a renal transplant, whereas the other 107 continued to undergo dialysis. These two groups were well matched at baseline with respect to age, gender, body mass index, renal disease etiology, comorbid illnesses, and dialysis duration and modality. The overall mortality rate was 0.096 per patient-year (0.131 for dialysis and 0.029 for transplant, P<0.001). Respective 1-, 3- and 5-year survivals were 92%, 62%, and 27% for the dialysis group and 98%, 95%, and 90% (P<0.01) for the transplant group. Patients in the transplant group had an adjusted hazard ratio 0.16 times that of the dialysis group (95% confidence interval 0.06-0.42). If patients were censored at the time of their withdrawal from the transplant waiting list, the adjusted hazard ratio was 0.24 (95% confidence interval 0.09-0.69). CONCLUSIONS Renal transplantation seems to confer a substantial survival advantage over dialysis in patients with end-stage renal failure who are rigorously screened and considered suitable for renal transplantation.

Frequency and severity of acute rejection in live-versus cadaveric-donor renal transplants

Background. Live donors are an increasingly important source of kidneys for transplantation in Australia. The aim of this study was to compare the rate and severity of rejection between patients receiving kidney transplants from live versus cadaveric donors. Methods. A retrospective analysis was undertaken of all patients receiving live-donor (n=109) and cadaveric-donor (n=389) renal transplants at our institution between April 1, 1994, and March 31, 2000. Follow-up was completed on all patients until graft loss, death, or May 31, 2001. Results. The baseline characteristics of the live-donor and cadaveric groups were similar, except for recipient age (mean±SD, 36.3±15.6 vs. 44.5±14.4 years, respectively; P <0.001); donor age (46.1±11.3 vs. 36.1±16.4 years, P <0.001); pretransplant dialysis duration (1.36±2.1 vs. 3.4±4.4 years, P <0.001); and the proportions of patients receiving first allografts (95% vs. 88%, respectively; P <0.05), antibody induction (8% vs. 20%, P <0.01), and mycophenolate mofetil (MMF) (60% vs. 37%, P <0.001). Acute rejection was observed in 48 (44%) live-donor and 108 (28%) cadaveric transplants (P =0.001). Cadaveric donor type was independently predictive of less acute rejection both on logistic regression (adjusted odds ratio [AOR], 0.47; 95% confidence interval [CI], 0.30–0.73; P =0.001) and multivariate Cox proportional hazards model analysis (hazard ratio, 0.49; 95% CI, 0.34–0.69; P <0.001). Patients receiving cadaveric-donor transplants were also significantly less likely to receive antibody therapy for rejection (univariate, 18% vs. 9%; P =0.006; multivariate AOR, 0.45; 95% CI, −0.25–0.82; P <0.01), independent of recipient age, gender, race, transplant number, human leukocyte antigen mismatch, sensitization, induction therapy, delayed graft function, MMF use, tacrolimus or cyclosporine A use, sirolimus-everolimus use, year of transplant, donor age, or dialysis duration. However, donor type did not independently influence graft survival, immunologic graft survival, or patient survival. Conclusions. Live-donor kidney transplant recipients had a higher rate and severity of rejection and a shorter rejection-free period than cadaveric renal transplant recipients. Further consideration of the reasons for this difference and the use of alternative immunosuppressive strategies for live-donor transplants are recommended.

Is mycophenolate mofetil less safe than azathioprine in elderly renal transplant recipients

Background. Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that has been shown to be superior to azathioprine in preventing early acute rejection in the general renal transplant population. However, it is uncertain whether these benefits also apply to older renal transplant recipients, who are known to be more susceptible to infectious complications and have considerably lower rates of rejection and immunological graft loss. Methods. A retrospective analysis was undertaken of all elderly (≥55 years old) renal transplant recipients who underwent renal transplantation at the Princess Alexandra Hospital (1994–2000) and received either MMF (n=60) or azathioprine (n=55) in combination with prednisolone and cyclosporin. Data were analyzed on an intention-to-treat basis using a multivariate Cox proportional hazards model. Results. The azathioprine- and MMF-treated groups were well matched at baseline with respect to demographic characteristics, end-stage renal failure causes and transplant characteristics. Compared with the MMF cohort, azathioprine-treated patients experienced a shorter time to first rejection [hazard ratio (HR) 4.47, 95% CI 1.53–13.1, P <0.01]. However, azathioprine-treated patients were also less likely to develop opportunistic infections (HR 0.11, 95% CI 0.03–0.41, P =0.001). No differences were observed between the two groups with respect to hospitalization rates, intensive care admissions, hematological complications, or posttransplant malignancies. Actuarial 2-year survival rates for the azathioprine- and MMF-treated patients were 100 and 87%, respectively (P <0.001). The principal cause of death in the MMF cohort was infection. Using a multivariate Cox regression analysis of patient survival, an adjusted hazard ratio of 0.01 (95% CI 0.001–0.08, P =0.001) was calculated in favor of azathioprine. Overall graft survival also tended to be better in patients receiving azathioprine (HR 0.27, 95% CI 0.06–1.33, P =0.11), Conclusions. In elderly renal transplant recipients, the combination of MMF, cyclosporin, and prednisolone appears to result in a worse outcome compared with the less potent combination of azathioprine, cyclosporin, and prednisolone. Future prospective studies need to specifically evaluate the risk/benefit ratios of newer, more potent immunosuppressive protocols, such as MMF-based regimens, in this important and sizeable patient subgroup.

Use of mycophenolate mofetil in immunosuppressive protocols in elderly renal transplant recipients

We welcome Dr. Sureshkamur’s reported experience with azathioprineand mycophenolate mofetil (MMF)-based immunosuppression protocols in elderly renal transplant recipients at the Allegheny General Hospital. In contrast with the results of our study (1) and those of Meier-Kriesche et al. (2), azathioprine-treated patients at the Allegheny General Hospital demonstrated significantly worse graft and patient survival rates than MMF-treated patients. Infectious complications were not reported by Dr. Sureshkamur, but it is noteworthy that the 1-year graft survival rate for azathioprine-treated patients at the Allegheny General Hospital was particularly poor (1-year survival of 79% vs. 96% for our unit). This indicates the possibility of under-immunosuppression in this cohort, which is supported to some extent by the relatively low dose of azathioprine used (1.5 mg/kg/day). The generalizability of Dr. Sureshkamur’s data is therefore questionable. Dr. Sureshkamur’s report is also limited by the presentation of univariate outcome analyses, the possibility of cointervention bias, and the lack of information about important confounding variables (e.g., live renal donor transplants), which may have been more prevalent in the MMF era. In contrast, our study attempted to overcome these potential pitfalls by statistically adjusting outcome results for all known potentially confounding factors, including immunosuppressive drugs, age, gender, racial status, body mass index, donor status, initial graft function, total ischemic time, episodes of acute rejection, exposure to antilymphocyte antibody preparations, diabetes mellitus, smoking status, and previous ischemic heart disease. Dr. Sureshkamur’s contention (3) that the observed differences in outcomes between the two studies could be explained by our use of intravenous methylprednisolone for the treatment of acute rejection is unlikely, because this occurrence was less frequent in the MMF group in our study and was adjusted for in the multivariate Cox proportional hazards model analysis. Finally, we agree with Dr. Sureshkamur’s concluding remarks that although the overall benefits of MMF-based protocols seem to be significant, their risk and benefit ratios need further evaluation in elderly patients. Only a prospective controlled clinical trial comparing azathioprineand MMF-based immunosuppression protocols in elderly renal transplant recipients will be able to definitively resolve this important issue.