Impact of graft failure on patient survival on dialysis: a comparison of transplant-naïve and post-graft failure mortality rates
Panduranga S. Rao1,
Douglas E. Schaubel2,3 and
Rajiv Saran1,3
1 Division of Nephrology, Department of Medicine, 2 Department of Biostatistics, School of Public Health and 3 Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, MI, USA
Correspondence and offprint requests to: Panduranga S. Rao, MD, 303 A, Simpson Memorial Building, 102 Observatory, Ann Arbor, MI 48109, USA. Email: spandu{at}umich.edu
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Abstract
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Background. While the number of patients returning to dialysis after graft failure (GF) is increasing steadily, the impact of a failed kidney transplant on mortality among dialysis patients has not been studied well.
Methods. Data from the Canadian Organ Replacement Register were utilized to examine the outcomes of an incident cohort of patients (n = 25 632) initiating renal replacement therapy (RRT) between 1990 and 1998. Cox regression was used to compare covariate-adjusted mortality among five RRT categories: transplant-naïve dialysis, cadaveric primary renal transplant, living-donor primary renal transplant, post-GF dialysis and retransplant. RRT category-specific hazard ratios (HR) were estimated using Cox regression and adjusting for age, sex, race, calendar period, primary renal diagnosis and comorbid conditions.
Results. Mortality among post-GF dialysis patients was approximately equal to that of transplant-naïve patients (HR = 0.90; P = 0.30) while the HR for retransplanted patients was significantly decreased, relative to the transplant-naïve group (HR = 0.35; P<0.01). Diabetes was found to be a significantly (P<0.01) stronger mortality risk factor among post-GF dialysis patients (HR = 3.71) compared with the transplant-naïve group (HR = 1.73). In the post-GF group, cardiovascular disease (HR = 1.66) and other serious illness (HR = 2.07) were found to be much stronger risk factors for mortality than in the transplant-naïve group (HR = 1.33 and 1.43, respectively), although the differences failed to reach statistical significance.
Conclusions. These results suggest that transplant-naïve and post-GF dialysis patients have equivalent mortality risk and that mortality is significantly reduced upon retransplantation. In addition, the results highlight the importance of diabetes and, possibly, comorbid conditions as potential modifiable risk factors in the management of post-GF dialysis patients.
Keywords: dialysis; graft failure; outcome
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Introduction
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Survival probability following kidney transplantation has improved steadily over the last several years in the United States and Canada [1,2]. However, chronic allograft nephropathy with subsequent graft loss remains a vexing problem [3]. With the ultimate loss of the graft, patients must return to dialysis and are frequently relisted for transplantation. Indeed, this group forms a substantial portion of patients on the waiting list for kidney transplantation [4]. A limited number of studies have evaluated patients returning to dialysis after graft failure (GF) [514]. The majority have been single-centre studies [5,6,9,11,14] with relatively small sample sizes and, therefore, limited generalizability. A few large-scale studies have evaluated risk factors for mortality among post-GF patients [7,8,10,12,13]. However, only one previous study made an internal comparison between post-GF patients and another patient subgroup (patients with a functioning transplant) [13]. Thus, to the best of our knowledge, no large-scale study has addressed the question of whether patients on dialysis subsequent to a failed kidney transplant are at increased risk of death relative to patients who have not yet received a transplant (i.e. transplant-naïve patients).
Using national registry data, the primary focus of this investigation was to compare mortality risk between post-GF and transplant-naïve patients on dialysis. A secondary aim was to quantify differences, if any, in the contrast between transplant-naïve and post-GF mortality by patient subgroup and to determine if particular patient characteristics conferred an additional increase in mortality risk for post-GF relative to transplant-naïve patients.
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Subjects and methods
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Data were obtained from the Canadian Organ Replacement Register (CORR), a nationwide and population-based organ failure registry administered by the Canadian Institute for Health Information (CIHI) [15]. Demographic and baseline clinical data are collected upon renal replacement therapy (RRT) initiation and submitted by the centres directly to CIHI. The centres also submit follow-up forms, which provide the dates of therapeutic modality switches, transplantation, GFs and death.
Included in this cohort study were patients aged
18 years who initiated RRT between 1990 and 1998 (n = 25 632). In total, there were 28 257 patients who initiated RRT in Canada during the 19901998 period. Of these, 607 paediatric (age: <18 years) cases were excluded, while an additional 2018 patients who did not have comorbidity information were also excluded, leaving the final sample size of 25 632. Patients began follow-up on the date of RRT initiation and were followed until the earliest of death or 31 December 1998, which was the conclusion of the observation period. Follow-up time was divided into five mutually exclusive and exhaustive RRT categories: transplant-naïve dialysis, living-donor primary transplant, cadaveric primary transplant, post-GF dialysis and retransplant. On a given day, patients contributed follow-up to the particular RRT category in which they were categorized on that particular day. It is possible that a patient's entire follow-up would be counted towards only one category. On the other hand, it is also possible that a patient could contribute to several different categories, depending on the nature of his or her treatment history and outcomes.
Statistical methods
After summing across all patients within each RRT category, mortality rates were computed as the ratio of the number of deaths to patient-years (PY) of follow-up and expressed as mortality rates per 1000 PY. Cox regression was used to compare death rates among the five RRT categories, adjusted for the following covariates: age, sex, race, primary renal diagnosis, calendar period and comorbidity. Data were available on the following comorbid conditions (in the form of present/absent): coronary artery disease, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, malignancy and other serious illness (i.e. a condition not falling into the any of the aforementioned categories, but expected to significantly reduce 5 year survival probability, e.g. AIDS).
A Cox model was fitted to estimate covariate-adjusted hazard ratios (HR) for living-donor primary transplant, cadaveric primary transplant, post-GF dialysis and retransplant, each relative to the transplant-naïve group. The transplant-naïve group was chosen arbitrarily as the reference category, since comparisons with this group were of primary interest and since it contained the greatest number of PY and deaths. Such models were also fitted by age group to determine if the contrast between post-GF dialysis and transplant-naïve patients was different for different ages. In addition, we fitted separate models to the post-GF dialysis and transplant-naïve patients, in order to compare the strength of the various mortality risk factors in each group of patients. A model was fitted in which all post-GF patients (retransplanted and post-GF dialysis) were combined. Selected covariate-adjusted mortality HR for two separate models (one for transplant-naïve patients and one for post-GF dialysis) were calculated.
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Results
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Table 1 describes the characteristics of the study population (n = 25 632) at RRT initiation. The majority of the patients were Caucasian. Table 2 lists the characteristics of the transplant recipients in the study population.
Unadjusted mortality rates for the five RRT categories are listed in Table 3.
Covariate-adjusted mortality HR, computed using Cox regression, are presented in Table 4. For a given RRT category, the HR can be interpreted as the ratio of the death rate for that particular category, divided by the death rate for the transplant-naïve group, adjusted for covariates. Patients on dialysis following GF experienced mortality rates that were not significantly different from those of transplant-naïve patients, the covariate-adjusted HR being 0.90 [95% confidence interval (CI): 0.751.09; P = 0.30]. Patients with GF who were retransplanted experienced highly significantly decreased mortality risk, relative to transplant-naïve patients (HR = 0.35; 95% CI: 0.190.66). Results were virtually identical when, as a subanalysis, we refitted the model from Table 4 using only the subcohort of patients with no comorbid conditions (data not shown). The subanalysis of combined post-GF patients (retransplanted and post-GF dialysis) relative to transplant-naïve patients failed to show a difference in mortality (P = 0.05; data not shown). This underscores the importance of subdividing post-GF follow-up time into post-GF retransplant (where a significant reduction in mortality does occur) and post-GF dialysis (where no difference appears to exist).
Table 5 shows the comparison by age group using the Cox regression model, between transplant-naïve dialysis patients and (i) post-GF dialysis and (ii) retransplant patients. First, in the 1839 years age group, compared with transplant-naïve patients, post-GF dialysis patients had a nearly significant decreased risk of death (HR = 0.71; P = 0.07); for no other age category did the difference approach significance. Second, 1839 years was the only age group with significantly decreased retransplant mortality risk (HR = 0.35; P = 0.02). Note that insufficient data were available to estimate a retransplant HR for patients of age
60 years. The increase in mortality following GF, relative to transplant-naïve dialysis, is greatest for this subgroup. Similar analyses by other covariates, such as gender, race or primary renal diagnosis, revealed no such associations (data not shown).
In Table 6 we display selected covariate-adjusted mortality HR for two separate models: one for transplant-naïve patients and one for post-GF dialysis subjects. Among primary renal diagnoses, diabetes stands out as being a much stronger mortality risk factor among post-GF dialysis (HR = 3.71) compared with transplant-naïve (HR = 1.73) patients (P<0.01). Presence vs absence of another serious illness was also a much stronger risk factor for mortality in the post-GF dialysis group (HR = 2.07) compared with the transplant-naïve group (HR = 1.43), although the difference failed to attain statistical significance. Similarly, the presence of chronic obstructive pulmonary disease also conferred a higher mortality risk in the post-GF dialysis group (HR = 1.47) compared with the transplant-naïve group (HR = 1.14).
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Discussion
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The results of this cohort study indicate that covariate-adjusted mortality rates for post-GF dialysis and transplant-naïve patients are equivalent. Our results also suggest that the mortality risk associated with diabetes is significantly stronger among post-GF patients compared with the transplant-naïve group. Mortality risk was significantly reduced upon retransplantation.
An emerging theme from several previous studies is the susceptibility of the post-GF group on dialysis to higher mortality compared with transplant-naïve patients. Ojo et al. [13] reported a higher 5 year mortality rate in the post-GF dialysis group, ranging from 35% for the non-diabetic group to 51% in the type 2 diabetics [13]. The report of Meier-Kriesche et al. [12] was particularly notable for its mortality rate of 50% at 5 years. Gill et al. [7] looked at patients drawn from the United States Renal Data System (similar to that used by Meier-Kriesche) and reported a 3 year mortality rate of 33%. In comparing prior studies to the present investigation, it is important to note that none of these previous studies made explicit and internal comparisons between the post-GF and transplant-naïve groups on dialysis.
The absence of an increase in mortality in our population of post-GF dialysis patients could be due to a variety of reasons. It is possible that the duration of relatively normal renal function, during the time interval between transplantation and GF, afforded protection against the deleterious effects of receiving dialysis. Since these patients are, presumably, followed closely by the nephrologist because of their transplant, dialysis might be initiated earlier in the course of the failing kidney. This might result in better residual renal function at the initiation of dialysis, providing a survival advantage. It was not possible to test this hypothesis in the current study, since residual renal function data are not available in the CORR database. Available evidence does not suggest that post-GF patients are likely to be started on dialysis any earlier than transplant-naïve patients [8]. Indeed, there was no difference between the estimated glomerular filtration rate at the start of dialysis in transplant-naïve and post-GF patients in the study by Gill et al. [7]. It is tempting to speculate that some of the post-GF patients may have been receiving a degree of immunosuppression that, by way of anti-inflammatory effect, could provide a survival benefit. While the association of inflammatory markers with cardiovascular mortality is documented in dialysis patients [16], there is no evidence thus far that anti-inflammatory treatment is beneficial in dialysis patients. In the study by Jassal et al. [17], using a decision analysis model, there was a suggestion of survival benefit in peritoneal dialysis patients who were maintained on immunosuppression after GF.
The relative risk of death in the post-GF dialysis group, compared with the transplant-naïve dialysis group, was found to be age-dependent, with the 1839 years age group experiencing the lowest relative risk.
In this investigation, 15% of patients receiving a renal transplant experienced GF; only 21% of these patients were retransplanted. With the ever-increasing shortage of organs and the inevitable and relentless loss of the renal allograft due to rejection, the pool of patients on dialysis following GF can only be expected to increase in the future. As such, it is necessary to carefully evaluate the factors contributing to mortality risk in this subgroup of patients. Although the study population was quite large (n = 25 632), statistical power was somewhat limited in that only a modicum (n = 4654) of the patients under observation received a transplant, with only a fraction of those transplanted experiencing GF (n = 675). While this did not restrict the overall comparative analysis between post-GF and transplant-naïve mortality (for dialysis patients), the subgroup analyses were limited by small sample sizes.
There are several limitations to the CORR database, although their effect on our results is unclear. Ideally, comparisons between dialysis and transplanted subgroups would be restricted to patients who were wait-listed, and reliable wait-list data are unavailable from CORR. As a result, it is possible that post-GF patients on dialysis are actually at greater risk of death than comparable transplant-naïve patients, but that the post-GF patients represent a select group (e.g. each received a transplant). The comorbidity data represent another limitation, in that they are only collected at RRT initiation. It would have been preferable for these data to be updated at the time of transplant and GF. Moreover, although coverage of CORR is complete due to outstanding compliance on the part of the Canadian centres, data are submitted voluntarily and are not validated. Notwithstanding, results were virtually identical when, in an attempt to address the impact of these limitations, we restricted analysis to only patients with no comorbidity. While it is likely that results based on this Canadian cohort are generalizable to other parts of the world, further study of the effects of GF are warranted in other populations. For example, Churchill et al. [18] reported great differences in clinical and demographic characteristics between Canadian and US peritoneal dialysis patients; for example, the percentage of African patients was much higher in the US. It is possible that, despite important differences in case mix, the impact of GF on survival is similar in the US and Canada.
With the increasing number of failed transplants returning to dialysis, the observations from this study need to be confirmed by a formal clinical trial. Risk factors peculiar to this group may then be defined more clearly and appropriate interventions applied to lower this risk.
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Acknowledgments
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The authors thank the Canadian Organ Replacement Register (CORR) of the Canadian Institute for Health Information for providing the dialysis and transplant data analysed in this investigation. The collection and maintenance of CORR data is made possible by the wholehearted collaboration of the 87 renal programmes across Canada. The Canadian Society of Nephrology, the Canadian Society of Transplantation and their constituent members, along with nurses and technicians, have also made an essential contribution to the register since its inception in 1981.
Conflict of interest statement. None declared.
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Received for publication: 31. 5.04
Accepted in revised form: 20.10.04