Philip J. Held

Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting Transplantation, and Recipients of a First Cadaveric Transplant

BACKGROUND AND METHODS The extent to which renal allotransplantation - as compared with long-term dialysis - improves survival among patients with end-stage renal disease is controversial, because those selected for transplantation may have a lower base-line risk of death. In an attempt to distinguish the effects of patient selection from those of transplantation itself, we conducted a longitudinal study of mortality in 228,552 patients who were receiving long-term dialysis for end-stage renal disease. Of these patients, 46,164 were placed on a waiting list for transplantation, 23,275 of whom received a first cadaveric transplant between 1991 and 1997. The relative risk of death and survival were assessed with time-dependent nonproportional-hazards analysis, with adjustment for age, race, sex, cause of end-stage renal disease, geographic region, time from first treatment for end-stage renal disease to placement on the waiting list, and year of initial placement on the list. RESULTS Among the various subgroups, the standardized mortality ratio for the patients on dialysis who were awaiting transplantation (annual death rate, 6.3 per 100 patient-years) was 38 to 58 percent lower than that for all patients on dialysis (annual death rate, 16.1 per 100 patient-years). The relative risk of death during the first 2 weeks after transplantation was 2.8 times as high as that for patients on dialysis who had equal lengths of follow-up since placement on the waiting list, but at 18 months the risk was much lower (relative risk, 0.32; 95 percent confidence interval, 0.30 to 0.35; P<0.001). The likelihood of survival became equal in the two groups within 5 to 673 days after transplantation in all the subgroups of patients we examined. The long-term mortality rate was 48 to 82 percent lower among transplant recipients (annual death rate, 3.8 per 100 patient-years) than patients on the waiting list, with relatively larger benefits among patients who were 20 to 39 years old, white patients, and younger patients with diabetes. CONCLUSIONS Among patients with end-stage renal disease, healthier patients are placed on the waiting list for transplantation, and long-term survival is better among those on the waiting list who eventually undergo transplantation.

Delayed graft function : Risk factors and implications for renal allograft survival

Delayed graft function (DGF) may be associated with diminished kidney allograft survival. We studied the risk factors that lead to nonimmediate function of a renal allograft and the consequences of DGF on short- and long-term renal transplant survival. Data from the U.S. Renal Data System were used to measure the relationships among cold ischemia time, delayed graft function, acute rejection, and graft survival in 37,216 primary cadaveric renal transplants (1985-1992). These relationships were investigated using the unconditional logistic and Cox multivariate regression methods. Cold ischemia time was strongly associated with DGF, with a 23% increase in the risk of DGF for every 6 hr of cold ischemia (P<0.001). Acute transplant rejection occurred more frequently in grafts with delayed function (37% vs. 20%; odds ratio=2.25, P=0.001). DGF was independently predictive of 5-year graft loss (relative risk=1.53, P<0.001). The presence of both early acute rejection and DGF portended a dismal 5-year graft survival rate of 35%. Zero-HLA mismatch conferred a 10-15% improvement in 1- and 5-year graft survival regardless of early functional status of the allograft. However, the 5-year graft survival rate in HLA-mismatched kidneys without DGF was significantly higher than that of zero-mismatched kidneys with DGF (63% vs. 51%; P<0.001). DGF independently portends a significant reduction in short- and long-term graft survival. Delayed function and early rejection episodes exerted an additive adverse effect on allograft survival. The deleterious impact of delayed function is comparatively more severe than that of poor HLA matching.

Association of Comorbid Conditions and Mortality in Hemodialysis Patients in Europe, Japan, and the United States: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

Mortality rates among hemodialysis patients vary greatly across regions. Representative databases containing extensive profiles of patient characteristics and outcomes are lacking. The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a prospective, observational study of representative samples of hemodialysis patients in France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States (US) that captures extensive data relating to patient characteristics, prescriptions, laboratory values, practice patterns, and outcomes. This report describes the case-mix features and mortality among 16,720 patients followed up to 5 yr. The crude 1-yr mortality rates were 6.6% in Japan, 15.6% in Europe, and 21.7% in the US. After adjusting for age, gender, race, and 25 comorbid conditions, the relative risk (RR) of mortality was 2.84 (P < 0.0001) for Europe compared with Japan (reference group) and was 3.78 (P < 0.0001) for the US compared with Japan. The adjusted RR of mortality for the US versus Europe was 1.33 (P < 0.0001). For most comorbid diseases, prevalence was highest in the US, where the mean age (60.5 +/- 15.5 yr) was also highest. Older age and comorbidities were associated with increased risk of death (except for hypertension, which carried a multivariate RR of mortality of 0.74 [P < 0.0001]). Variability in demographic and comorbid conditions (as identified by dialysis facilities) explains only part of the differences in mortality between dialysis centers, both for comparisons made across continents and within the US. Adjustments for the observed variability will allow study of association between practice patterns and outcomes.

Five-Year Survival for End-Stage Renal Disease Patients in the United States, Europe, and Japan, 1982 to 1987

We compared the 5-year survival for new end-stage renal disease (ESRD) patients accepted for renal replacement therapy (RRT) between 1982 and 1987 in the United States (n = 150,862), Europe (European Dialysis and Transplant Association [EDTA]) (n = 124,796), and Japan (n = 66,244). Given these large samples that approach a census in each of the three regions, all results are statistically significant. Our analysis showed that the US patients were older and more likely to be diabetic than the patients in either EDTA or Japan. After correction for patient differences in age composition and the percent diabetic, Japan had the highest survival, followed by EDTA, and then the US. Overall, the US 5-year survival was 40%. When comparison is done by age, only the youngest patients in the US (less than 15 years) have longer survival than their counterparts in Europe and Japan. For ages greater than 14 years, the survival differences between the US and EDTA and between the US and Japan grow larger with higher patient age. The comparisons of mortality by diagnosis showed that the differences between the US and EDTA and between the US and Japan were least for diabetes. For non-diabetic patients, the age adjusted relative risk (RR) of mortality for the US compared with EDTA was 1.22, ie, 22% higher in the US; for the US compared with Japan, the RR was 1.40. In contrast, the RR for diabetic patients in the US compared with EDTA was 1.07, and 1.23 for the US compared with Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunosuppression and the Risk of Post-Transplant Malignancy Among Cadaveric First Kidney Transplant Recipients

The success of renal transplantation may be counterbalanced by serious adverse medical events. The effect of immunosuppression on the incidence of de novo neoplasms among kidney recipients should be monitored continuously. Using data from the Scientific Registry of Transplant Recipients, we studied the association of induction therapy by immunosuppression with antilymphocyte antibodies, with the development of de novo neoplasms. The study population included more than 41 000 recipients who received a cadaveric first kidney transplant after December 31, 1995, and were followed through February 28, 2002.

Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: Multivariate analyses from the United States renal data system

BACKGROUND Survival of transplant recipients after primary renal allograft failure has not been well studied. METHODS A cohort of 19,208 renal transplant recipients with primary allograft failure between 1985 and 1995 were followed from the date of allograft loss until death, repeat transplantation, or December 31, 1996. The mortality, wait-listing, and repeat transplantation rates were assessed. The mortality risks associated with repeat transplantation were estimated with a time-dependent survival model. RESULTS In total, 34.5% (n=6,631) of patients died during follow-up. Of these deaths, 82.9% (n=5,498) occurred in patients not wait-listed for repeat transplantation, 11.9% (n=789) occurred in wait-listed patients, and 5.2% (n=344) occurred in second transplant recipients. Before repeat transplantation, the adjusted 5-year patient survival was 36%, 49%, and 65% for type I diabetes mellitus (DM), type II DM, and nondiabetic end-stage renal disease, respectively (P<0.001; DM vs. nondiabetics). The adjusted 5-year patient survival was lower in Caucasians (57%, P<0.001) compared with African-Americans (67%) and other races (64%). The 5-yr repeat transplantation rate was 29%, 15%, and 19%, whereas the median waiting time for a second transplant was 32, 90, and 81 months for Caucasians, African-Americans, and other races, respectively (P<0.0001 each). Repeat transplantation was associated with 45% and 23% reduction in 5-year mortality for type I DM and nondiabetic end-stage renal disease, respectively, when compared with their wait-listed dialysis counterparts with prior transplant failure. CONCLUSIONS The loss of a primary renal allograft was associated with significant mortality, especially in recipients with type I DM. Repeat transplantation was associated with a substantial improvement in 5-year patient survival. Recipients with type I DM achieved the greatest proportional benefit from repeat transplantation.

The Impact of HLA Mismatches on the Survival of First Cadaveric Kidney Transplants

BACKGROUND The benefits of HLA-A, B, and DR matching of cadaveric kidney grafts and recipients remain controversial when viewed from the perspective of social equity and graft survival. METHODS We estimated graft survival using proportional-hazards techniques, adjusting for patient and donor characteristics, for a series of 30,564 Medicare patients receiving a first cadaveric kidney transplant between 1984 and 1990. The effects of minimal achievable HLA mismatches and maximal matching on graft survival were estimated by simulated allocation of a sample of organs to a sample of 20,000 candidates for transplantation. RESULTS The adjusted one-year graft survival was 84.3 percent for grafts with no mismatches and 77.0 percent for grafts with four mismatches. National rationing of donor organs to achieve minimal mismatching and maximal matching could potentially decrease the average number of HLA mismatches from 3.6 to 1.2, with a corresponding increase in the number of matches. As a consequence, projected five-year graft survival could potentially increase from 58.5 percent to 62.9 percent. This would be associated with a decrease in the proportion of kidneys allocated to black recipients from 22.2 to 15.0 percent. CONCLUSIONS Under ideal circumstances, a policy of maximal matching of cadaveric renal transplants would increase five-year graft survival by a comparatively small 4.4 percentage points, but the actual benefit is likely to be smaller.

Access to Kidney Transplantation: Has the United States Eliminated Income and Racial Differences?

We analyzed the effect of patient and dialysis unit characteristics on access to kidney transplantation using several different approaches, including an analysis of individual patient data from a systematic random sample of 2900 new dialysis patients from each year 1981 to 1985 (14721 patients total). Additional analyses focused on the composition of transplant waiting lists and aggregate data from a 1984 census of 1133 dialysis and transplant units. White, male, young, nondiabetic, high-income patients treated in smaller units are more likely to receive a cadaver transplant under Medicare than are other kidney patients. Profit status of the dialysis unit was not found to be correlated to access to transplantation, although size of the unit may be correlated to access. Future analysis should focus on whether patient access has been inappropriately compromised. Possible factors unexplored in this analysis include differential patient preferences and medical suitability, as well as differential medical access.

Factors associated with health-related quality of life among hemodialysis patients in the DOPPS

ObjectiveTo identify modifiable factors associated with health-related quality of life (HRQOL) among chronic hemodialysis patients.MethodsAnalysis of baseline data of 9,526 hemodialysis patients from seven countries enrolled in phase I of the Dialysis Outcomes and Practice Patterns Study (DOPPS). Using the Kidney Disease Quality of Life Short Form (KDQOL-SFTM), we determined scores for 8 generic scale summaries derived from these scales, i.e., the physical component summary [PCS] and mental component summary [MCS], and 11 kidney disease-targeted scales. Regression models were used to adjust for differences in comorbidities and sociodemographic and treatment factors. The Benjamin-Hochberg procedure was used to correct P-values for multiple comparisons.ResultsUnemployment and psychiatric disease were independently and significantly associated with lower scores for all generic and several kidney disease-targeted HRQOL measures. Several other comorbidities, lower educational level, lower income, and hypoalbuminemia were also independently and significantly associated with lower scores of PCS and/or MCS and several generic and kidney disease-targeted scales. Hemodialysis by catheter was associated with significantly lower PCS scores, partially explained by the correlation with covariates.ConclusionAssociations of poorer HRQOL with preventable or controllable factors support a greater focus on psychosocial and medical interventions to improve the well-being of hemodialysis patients.

Relationship of dialysis membrane and cause-specific mortality

A number of studies have suggested that type of dialysis membrane is associated with differences in long-term outcome of patients undergoing hemodialysis, both in terms of morbidity and mortality. The purpose of this study was to determine the relationship of membrane type and specific causes of death. Data from the United States Renal Data System Case Mix Adequacy Study, a national random sample of hemodialysis patients who were alive on December 31, 1990, were used. Our study was limited to patients in this data set who were undergoing dialysis for at least 1 year (n = 4,055). For the main analytic models, membrane type was classified into two categories: unmodified cellulose or MC/SYN (which combines modified cellulose [MC] and synthetic membranes [SYN]). The relationships of membrane type and major causes of mortality were analyzed using Cox proportional hazards models, which adjusted for multiple (21) covariates, including demographics, comorbidity, Kt/V, and other parameters. Patients were censored at transplantation or 60 days after a switch to peritoneal dialysis. Compared with patients dialyzed with unmodified cellulose membranes, the adjusted relative mortality risk (RR) from infection was 31% lower (RR = 0.69; P = 0.03) and from coronary artery disease was 26% lower (RR = 0.74; P = 0.07) for patients dialyzed with MC/SYN membranes. No statistically significant difference (all P > 0.1) was found in mortality risk from cerebrovascular disease (RR = 1.08), other cardiac causes (RR = 0.86), malignancy (RR = 0.90), or other known causes (RR = 0.82) between patients dialyzed with MC/SYN compared with unmodified cellulose membranes. These results offer support to reported experimental and observational clinical studies that have found that unmodified cellulose membranes may increase the risk for both infection and atherogenesis. Further studies are necessary to evaluate the possibility of confounding factors, compare more specific membrane types, and determine the pathophysiology linking membrane type to cause-specific mortality.