Instituto de Nefrología y Urología, Servicio de Asistencia Renal Integral, Montevideo, Uruguay
Correspondence and offprint requests to: Dr Nelson Mazzuchi, Instituto de Nefrología y Urologia del Uruguay, Ramón y Cajal 2550, Montevideo 11600, CC. 16217, Uruguay.
Abstract
Background. Our aim was to compare survival among renal transplant recipients and haemodialysis patients treated in Uruguay.
Methods. All the patients transplanted in Uruguay (n=460) and all the patients who started haemodialysis (HD) in three centres in Uruguay (n=695) from 01 January 1981 to 31 December 1998 were included. Overall survival, adjusted survival and survival of the patients in the low-risk group were compared for HD patients and renal transplant recipients. Diabetic and non-diabetic patients were considered independently. The low-risk group was defined by the absence of any significant risk factor related to mortality on the Cox proportional hazard regression model (age more than 55 years at start of HD, previous history of diabetes, heart disease, cancer, and smoking habit). The significant variables were also used to adjust the survival curve.
Results. Overall survival was significantly greater in renal transplant recipients (P<0.0001). One-, five- and ten-year survival rates were 95.2, 88.0 and 78.8% for renal transplant recipients and 90.6, 62.7 and 39.8% for HD patients. In non-diabetic patients, adjusted survival rates (for age, heart disease, cancer, and smoking habit) were similar in renal transplant recipients and HD patients (P=0.8713). In the low-risk group as well, significant differences in survival between renal transplant recipients (n=289) and HD patients (n=134) were not observed (P=0.2312). Ten-year survival rates were 82.6 and 87.9% respectively. In diabetic patients 5-year survival rates adjusted for heart disease, smoking habit, and chronic pulmonary disease were 89.2% for renal transplant recipients and 40.9% for HD patients (P=0.0168) The relative risk of haemodialysis patients related to renal graft recipients was 2.85 (1.216.75).
Conclusions. We conclude that when the outcome is adjusted to co-morbid factors there is no difference between renal transplant recipients and haemodialysis patients survival in non-diabetic patients, while renal transplantation gives better survival rates than haemodialysis in diabetic patients.
Keywords: Cox proportional hazard model; diabetic; haemodialysis survival; low-risk patients; non-diabetic; renal transplant survival
Introduction
Patient survival after renal transplantation (RT) is markedly better than that seen with either haemodialysis (HD) or peritoneal dialysis [17]. Transplantation is also associated with a better quality of life and a higher degree of rehabilitation [5,6,811]. Some of the benefits associated with transplantation are related to patient selection, since dialysis patients with the most serious co-morbid conditions are not accepted for the transplant waiting list and hence remain in the dialysis group. Some previous comparative studies of dialysis vs renal transplant survival have considered that the transplant group is favoured by inclusion of these high-risk patients in the dialysis group [2,7,1214].
The present study uses the Cox proportional hazard regression model [15] to compare the relative risk of mortality for ESRD patients on dialysis vs after transplantation. Analysis was adjusted for the variables that were significantly and independently related with mortality.
Subjects and methods
Patient population
All the patients transplanted in Uruguay (n=460) and all the patients who started haemodialysis in three centres in Uruguay (n=695) from 1 January 1981 to 31 December 1998 were included. The mean age (range) of the 1155 patients was 50.9±19.2 (689) years, and 409 (35.4%) were women.
The follow-up of haemodialysis patients (HDP) showed that 220 patients died, 52 were transplanted, 14 were changed to CAPD, 12 recovered renal function, and 85 were transferred to other centres. In no case was the transfer due to medical complications. If any patient died during the 3 months after the transfer, they were considered as dead in this analysis. The median (minimummaximum) follow-up time was 2.10 (0.115.5) years and the follow-up of 42 patients was more than 10 years. The total risk exposure time was 2.245 patient years. The same nephrologists have been taking care of these patients during this follow-up time. The dialysis schedules, diet prescribed, vitamin supplementation, and other medical prescriptions have been described previously [16]. The aim of the treatment was to maintain the patients free of symptoms and rehabilitated. The dialysis characteristics have also been described previously [17].
The follow-up of renal transplant recipients (RTR) showed that 54 patients died and 142 lost the transplanted kidney and returned to dialysis treatment. The median (minimummaximum) follow-up time was 2.86 (0.118.1) years, and the follow-up time of 56 patients was >10 years. The total risk exposure time was 1950 patient years. The renal transplants were carried out in two centres and most of them were cadaveric renal transplantation (374 patients, 81.3%).
The following data, collected at the start of HD or at the transplant date, were considered independent variables for the analysis: sex, age, and presence or absence of previous history (diabetes, chronic obstructive pulmonary disease, arteriosclerotic heart disease, cerebrovascular disease, cardiac failure, peripheral vascular disease, smoking habit, and alcoholism). The variable heart disease was defined by the presence of arteriosclerotic heart disease or cardiac failure. The definitions of the other variables were previously described [17]. Co-morbid conditions developing after the start of the observation period were not taken into account.
Statistical analysis
The survival analysis was carried out by the KaplanMeier method. Univariate and multivariate analysis of survival was performed to identify significant prognostic factors. The multivariate analysis was done using the Cox proportional hazard regression model [15]. BMDP statistical software was used. In HDP, survival time was measured as the time from the start of the first dialysis treatment until death from any cause, or the last date of follow-up alive. HDP receiving a transplant were censored at the date of the transplant. In RTR, survival time was measured as the time from the transplant date until death from any cause or the last date of follow-up alive. RTR who lost transplants were censored 3 months after restart of dialysis.
Overall survival, adjusted overall survival, and low-risk patient group (LRG) survival were compared for haemodialysed and transplanted patients. Diabetic (n=148) and non-diabetic (n=1007) patients were considered independently. Thirty-three transplanted patients and 115 patients treated with HD were diabetic.
The transplanted patient group included cadaveric and live donor transplantation. The survival of both categories were not significantly different (P=0.0846). The median (minimummaximum) time on dialysis before transplantation was 36 (3176) months. The survival analysis showed no association between time on dialysis before transplantation and survival after transplantation (P=0.4512).
The LRG was defined by the absence of any significant risk factor related to mortality on the Cox proportional hazard regression model. The significant variables were also used to adjust the survival curve.
Results
Overall survival was significantly higher in RTR (P<0.0001). One, five- and ten-year survival rates were 95.2, 88.0 and 78.8% for RTR and 90.6, 62.7 and 39.8% for HDP (Figure 1). RTR survival was better than HDP survival in both diabetic and non-diabetic patients. In diabetic patients, 5-year survival was 89.3% for RTR and 34.7% for HDP (P=0.0106). In non-diabetic patients, 5-year survival was 87.9% for RTR and 68.6% for HDP (P<0.0001).
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Non-diabetic patient adjusted survival for age, heart disease, cancer, and smoking habit, were similar in RTR and HDP (P=0.8713) (Figure 2). The adjusted relative risk of death for dialysis compared with transplantation was 1.03 (95% confidence interval, 0.661.64).
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The analysis of LRG survival agrees with adjusted survival analysis. There were no differences between HDP and RTR (P=0.23 12). Survival was high for both treatments. Ten-year survival rates were 87.9% for HDP and 82.6% for RTR (Figure 4).
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Several studies [2,3,1821] have examined survival rates for ESRD patients and compared results of patients treated by dialysis vs patients treated by transplantation. However, many of these studies did not consider patient selection bias or time-to-treatment bias [7].
In our study the patient selection bias was minimized by adjusting for all the variables significantly related with mortality in the Cox proportional hazard regression model. In several studies, the time-to-treatment bias has been eliminated by using a time-dependent Cox analysis [2,7,12,14]. The characteristics of our population do not allow us to use this analysis. Our population includes all the patients transplanted in Uruguay and only 15% of the patients on dialysis treatment in the country. Therefore, some but not all the patients included in the transplant group are also included in the analysed haemodialysis group. The dialysis treatment before transplantation of most of the transplant patients was carried out in other dialysis centres. On the other hand, most of the patients who lost their transplants restarted dialysis in other dialysis centres. Only 52 out of 460 patients transplanted and only 32 out of 142 patients who lost their transplants and restarted dialysis were treated in the three HD centres considered in our analysis. We could not compare survival from start of renal replacement therapy in both groups. Neither could we analyse the transplant group as an intent-to-treat design, leaving the patients in the transplant group even if the transplant failed. We compare survival from start of dialysis in the haemodialysis group and from transplantation in the transplant group. HDP were censored at the date of transplantation and RTR were censored 3 months after restarting dialysis. This design introduces some problems. By censoring HDP at the date of transplantation, mortality connected to complications during a long period on dialysis may influence the mortality after transplantation. On the other hand, by censoring RTR 3 months after restart of dialysis, will reduce the mortality connected to transplantation.
The importance of the co-morbidity added during dialysis treatment in RTR survival has been evaluated by the relationship between RTR survival and the length of time on dialysis before transplantation. It has been reported that increased time on dialysis prior to renal transplantation is associated with decreased survival of RTR [22]. However, another study observed remarkably good survival in RTR who had had more than 15 years on dialysis before their renal transplant [23]. In our analysis, no associations between RTR survival and time on dialysis before transplantation were observed. Besides, HDP and RTR survival was adjusted for co-morbidity collected at the start of HD and the transplant date respectively.
Our analysis concluded that when the outcome is adjusted to co-morbid factors, there are no differences between RTR and HDP survival in non-diabetic patients, while RT offered better survival rates than HD in diabetics patients. These data suggest that the differences observed in non-diabetic patients' survival with either dialysis or renal transplantation is not due to the relative efficacy of the treatments. The pretreatment clinical status of the patients would be the major factor determining the different outcomes. On the contrary, in diabetic patients, the different outcomes might be attributed to a higher benefit of renal transplant.
Our data agree with several studies [2,7,1214] that examined the risk of dying among patients treated with dialysis vs cadaveric renal transplantation by using a Cox model with a time-dependent covariate to adjust to the time of transplantation. Vollmer et al. [2] and Hutchinson et al. [12] found a similar survival with dialysis and cadaveric transplantation, after controlling for pretreatment risk factors. Garcia-Garcia et al. [13] found a markedly lower mortality risk among diabetic transplant recipients than diabetic dialysis patients, although their finding did not reach statistical significance. Port et al. [7] observed a markedly lower long-term risk (RR 0.25) among diabetic RTR compared with diabetic wait-listed dialysis patients (P<0.001) and did not observe differences among patients with glomerulonephritis or hypertension as causes of ESRD (P>0.05). The analysis of Port et al. [7] used a time-dependent Cox analysis to eliminate the time-to-treatment bias. Their dialysis group was limited to those patients who had been accepted onto the transplant waiting list, in order to reduce the bias related to patient selection.
In agreement with Port et al. [7] we observed, in diabetic patients, better survival for HDP early in the first year, but long-term higher survival for the RTR group. In our study, both groups have equal survival probabilities at the end of the first year. Port et al. observed that equal survival was reached at 325±91 days.
We suggest that ESRD patients without co-morbid risk factors at the start of dialysis is an ideal population for survival comparisons among different centres or different treatments [17]. When only the low-risk group (LRG) is used to compare survival, the patient selection bias is minimized. This approach is technically less difficult than the standardized survival methodology. The survival comparison between haemodialysis and transplant also showed the importance of the LRG. The analysis of the LRG survival, in agreement with the adjusted survival, showed no differences between the groups.
In diabetic patients, the improved outcome with transplantation is seen even if the evaluation of dialysed patients is limited to relatively healthy subjects. It is possible that restoration of near normal renal function following transplantation slows progression of microvascular disease by reducing the circulating levels of advanced glycosylation end-products [24]. These compounds accumulate in diabetic patients with renal failure and may contribute to the development of vascular disease, in part by cross-linking with collagen.
The knowledge of the different outcomes in haemodialysis and after transplantation between diabetic and non-diabetic patients may be useful to health-care professionals when advising patients that they would be acceptable as transplant candidates.
Diabetic ESRD patients would have a high long-term benefit when they receive a successful transplant, after a period of higher risk. The benefits for non-diabetic patients are less evident: transplantation would offer little additional survival benefit on average [7]. Moreover, the relative scarcity of cadaveric organs for the high demand and the increasing frequency of diabetes in the new ESRD patients must be considered. Diabetes is now the most common cause of new patients requiring renal replacement therapy, accounting for as many as 37% of the cases in the United States [1] and about 15 or 20% in Europe, Latin America and Japan [2527].
These findings about survival need to be put into perspective, with the consideration of a better quality of life observed in transplant recipients compared with dialysis patients [8], although the quality-of-life results should also be adjusted to the significant risk factors for a better comparison.
References