Impact of MELD-based allocation on end-stage renal disease after liver transplantation.

The proportion of patients undergoing liver transplantation (LT), with concomitant renal dysfunction, markedly increased after allocation by the model for end-stage liver disease (MELD) score was introduced. We examined the incidence of subsequent post-LT end-stage renal disease (ESRD) before and after the policy was implemented. Data on all adult deceased donor LT recipients between April 27, 1995 and December 31, 2008 (n = 59 242), from the Scientific Registry of Transplant Recipients, were linked with Centers for Medicare & Medicaid Services' ESRD data. Cox regression was used to (i) compare pre-MELD and MELD eras with respect to post-LT ESRD incidence, (ii) determine the risk factors for post-LT ESRD and (iii) quantify the association between ESRD incidence and mortality. Crude rates of post-LT ESRD were 12.8 and 14.5 per 1000 patient-years in the pre-MELD and MELD eras, respectively. Covariate-adjusted post-LT ESRD risk was higher in the MELD era (hazard ratio [HR]= 1.15; p = 0.0049). African American race, hepatitis C, pre-LT diabetes, higher creatinine, lower albumin, lower bilirubin and sodium >141 mmol/L at LT were also significant predictors of post-LT ESRD. Post-LT ESRD was associated with higher post-LT mortality (HR = 3.32; p < 0.0001). The risk of post-LT ESRD, a strong predictor of post-LT mortality, is 15% higher in the MELD era. This study identified potentially modifiable risk factors of post-LT ESRD. Early intervention and modification of these risk factors may reduce the burden of post-LT ESRD.

Sex-based disparities in liver transplant rates in the United States.

We sought to characterize sex-based differences in access to deceased donor liver transplantation. Scientific Registry of Transplant Recipients data were used to analyze n = 78 998 adult candidates listed before (8/1997-2/2002) or after (2/2002-2/2007) implementation of Model for End-Stage Liver Disease (MELD)-based liver allocation. The primary outcome was deceased donor liver transplantation. Cox regression was used to estimate covariate-adjusted differences in transplant rates by sex. Females represented 38% of listed patients in the pre-MELD era and 35% in the MELD era. Females had significantly lower covariate-adjusted transplant rates in the pre-MELD era (by 9%; p < 0.0001) and in the MELD era (by 14%; p < 0.0001). In the MELD era, the disparity in transplant rate for females increased as waiting list mortality risk increased, particularly for MELD scores ≥15. Substantial geographic variation in sex-based differences in transplant rates was observed. Some areas of the United States had more than a 30% lower covariate-adjusted transplant rate for females compared to males in the MELD era. In conclusion, the disparity in liver transplant rates between females and males has increased in the MELD era. It is especially troubling that the disparity is magnified among patients with high MELD scores and in certain regions of the United States.

The incidence of cancer in a population-based cohort of Canadian heart transplant recipients.

To assess the long-term risk of developing cancer among heart transplant recipients compared to the Canadian general population, we carried out a retrospective cohort study of 1703 patients who received a heart transplant between 1981 and 1998, identified from the Canadian Organ Replacement Register database. Vital status and cancer incidence were determined through record linkage to the Canadian Mortality Database and Canadian Cancer Registry. Cancer incidence rates among heart transplant patients were compared to those of the general population. The observed number of incident cancers was 160 with 58.9 expected in the general population (SIR = 2.7, 95% CI = 2.3, 3.2). The highest ratios were for non-Hodgkin's lymphoma (NHL) (SIR = 22.7, 95% CI = 17.3, 29.3), oral cancer (SIR = 4.3, 95% CI = 2.1, 8.0) and lung cancer (SIR = 2.0, 95% CI = 1.2, 3.0). Compared to the general population, SIRs for NHL were particularly elevated in the first year posttransplant during more recent calendar periods, and among younger patients. Within the heart transplant cohort, overall cancer risks increased with age, and the 15-year cumulative incidence of all cancers was estimated to be 17%. There is an excess of incident cases of cancer among heart transplant recipients. The relative excesses are most marked for NHL, oral and lung cancer.

Efficient utilization of the expanded criteria donor (ECD) deceased donor kidney pool: an analysis of the effect of labeling.

We investigated the effect of the expanded criteria donor (ECD) label on (i) recovery of kidneys and (ii) acceptance for transplantation given recovery. An ECD is age > or = 60, or age 50-59 with > or = 2 of 3 specified comorbidities. Using data from the Scientific Registry of Transplant Recipients from 1999 to 2005, we modeled recovery rates through linear regression and transplantation probabilities via logistic regression, focusing on organs from donors just-younger versus just-older than the ECD age thresholds. We split the sample at July 1, 2002 to determine how decisions changed at the approximate time of implementation of the ECD definition. Before July 2002, the number of recovered kidneys with 0-1 comorbidities dropped at age 60, but transplantation probabilities given recovery did not. After July 2002, the number of recovered kidneys with 0-1 comorbidities rose at age 60, but transplantation probabilities contingent on recovery declined. No similar trends were observed at donor age 50 among donors with > or = 2 comorbidities. Overall, implementation of the ECD definition coincided with a reversal of an apparent reluctance to recover kidneys from donors over age 59, but increased selectiveness on the part of surgeons/centers with respect to these kidneys.

Survival benefit-based deceased-donor liver allocation.

Currently, patients awaiting deceased-donor liver transplantation are prioritized by medical urgency. Specifically, wait-listed chronic liver failure patients are sequenced in decreasing order of Model for End-stage Liver Disease (MELD) score. To maximize lifetime gained through liver transplantation, posttransplant survival should be considered in prioritizing liver waiting list candidates. We evaluate a survival benefit based system for allocating deceased-donor livers to chronic liver failure patients. Under the proposed system, at the time of offer, the transplant survival benefit score would be computed for each patient active on the waiting list. The proposed score is based on the difference in 5-year mean lifetime (with vs. without a liver transplant) and accounts for patient and donor characteristics. The rank correlation between benefit score and MELD score is 0.67. There is great overlap in the distribution of benefit scores across MELD categories, since waiting list mortality is significantly affected by several factors. Simulation results indicate that over 2000 life-years would be saved per year if benefit-based allocation was implemented. The shortage of donor livers increases the need to maximize the life-saving capacity of procured livers. Allocation of deceased-donor livers to chronic liver failure patients would be improved by prioritizing patients by transplant survival benefit.

Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period.

New onset diabetes after transplantation (NODAT) and impaired fasting glucose (IFG) are common in kidney transplant recipients (KTRs). Calcinuerin inhibitor (CNI) therapy is a causal risk factor. NODAT is associated with increased mortality and diminished graft survival. We studied the incidence of NODAT and IFG in KTRs before and after a medically indicated switch of CNI therapy from cyclosporine (CsA) to tacrolimus (Tac). The study population consisted of 704 nondiabetic KTRs. Of them, 171 underwent conversion from CsA to Tac (group I) and 533 remained on the CsA since transplantation (Group II). Time-dependent Cox regression and generalized estimating equations were used to account for sequential CNI exposure. NODAT and IFG occurred in 15.2% and 22.1% of group I subjects and 15.6% and 25.8% of group II subjects, respectively (p = 0.90 for NODAT and p = 0.38 for IFG). Accounting for equal follow-up time since conversion from CsA to Tac, the adjusted 5-year NODAT-free survival was 87.4% and 91.4% in group I and group II, respectively (p = 0.90). In conclusion, conversion to Tac, compared to continuous exposure to CsA, carries quantitatively similar risk of impaired glucose metabolism in KTRs in the late posttransplant period.

Calculating life years from transplant (LYFT): methods for kidney and kidney-pancreas candidates.

The Organ Procurement and Transplantation Network (OPTN) Kidney Committee is considering a proposal for a new deceased donor kidney allocation system. Among the components under consideration is a strategy to rank candidates in part by the estimated incremental years of life that are expected to be achieved with a transplant from a specific available deceased donor, computed as the difference in expected median lifespan with that transplant compared with remaining on dialysis. This concept has been termed life years from transplant or LYFT. Median lifespans could be calculated, based on objective medical criteria, for each candidate when a deceased donor kidney becomes available, based on Cox regression models using current candidate and donor medical information. The distribution of the calculated LYFT scores for an average nonexpanded criteria donor kidney is similar across candidate sex, race/ethnicity, insurance status and, with the exception of diabetes, diagnosis. LYFT scores tend to be higher for younger candidates and lower for diabetics receiving a kidney-alone rather than a simultaneous kidney-pancreas transplant. Prioritizing candidates with higher LYFT scores for each available kidney could substantially increase total years of life among both transplant candidates and recipients. LYFT is also a powerful metric for assessing trends in allocation outcomes and for comparing alternative allocation systems.

SRTR program-specific reports on outcomes: a guide for the new reader.

Differences in outcomes indeed exist among transplant programs and organ procurement organizations (OPO). A growing set of tools are available from the Scientific Registry of Transplant Recipients (SRTR) to measure and assess these outcomes in the different phases of the transplant process. These tools are not intended to compare two individual programs, rather to help identify programs whose practices may need further scrutiny, to be either avoided, corrected or emulated. To understand which differences in outcomes might be due to underlying differences in populations served and which might be due to differences in treatment, it is important to compare outcomes to 'risk-adjusted' expected values. Further, it is important to recognize and assess the role that random chance may play in these outcomes by considering the p-value or confidence interval of each estimate. We present the reader with a basic explanation of these tools and their interpretation in the context of reading the SRTR Program-Specific Reports. We describe the intended audience of these reports, including patients, monitoring and process improvement bodies, payers and others such as the media. Use of these statistics in a way that reflects a basic understanding of these concepts and their limitations is beneficial for all audiences.

The survival benefit of deceased donor liver transplantation as a function of candidate disease severity and donor quality.

The survival benefit of liver transplantation depends on candidate disease severity, as measured by MELD score. However, donor liver quality may also affect survival benefit. Using US data from the SRTR on 28 165 adult liver transplant candidates wait-listed between 2001 and 2005, we estimated survival benefit according to cross-classifications of candidate MELD score and deceased donor risk index (DRI) using sequential stratification. Covariate-adjusted hazard ratios (HR) were calculated for each liver transplant recipient at a given MELD with an organ of a given DRI, comparing posttransplant mortality to continued wait-listing with possible later transplantation using a lower-DRI organ. High-DRI organs were more often transplanted into lower-MELD recipients and vice versa. Compared to waiting for a lower-DRI organ, the lowest-MELD category recipients (MELD 6-8) who received high-DRI organs experienced significantly higher mortality (HR = 3.70; p < 0.0005). All recipients with MELD > or =20 had a significant survival benefit from transplantation, regardless of DRI. Transplantation of high-DRI organs is effective for high but not low-MELD candidates. Pairing of high-DRI livers with lower-MELD candidates fails to maximize survival benefit and may deny lifesaving organs to high-MELD candidates who are at high risk of death without transplantation.

Repeat organ transplantation in the United States, 1996-2005.

The prospect of graft loss is a problem faced by all transplant recipients, and retransplantation is often an option when loss occurs. To assess current trends in retransplantation, we analyzed data for retransplant candidates and recipients over the last 10 years, as well as current outcomes. During 2005, retransplant candidates represented 13.5%, 7.9%, 4.1% and 5.5% of all newly registered kidney, liver, heart and lung candidates, respectively. At the end of 2005, candidates for retransplantation accounted for 15.3% of kidney transplant candidates, and lower proportions of liver (5.1%), heart (5.3%) and lung (3.3%) candidates. Retransplants represented 12.4% of kidney, 9.0% of liver, 4.7% of heart and 5.3% of lung transplants performed in 2005. The absolute number of retransplants has grown most notably in kidney transplantation, increasing 40% over the last 10 years; the relative growth of retransplantation was most marked in heart and lung transplantation, increasing 66% and 217%, respectively. The growth of liver retransplantation was only 11%. Unadjusted graft survival remains significantly lower after retransplantation in the most recent cohorts analyzed. Even with careful case mix adjustments, the risk of graft failure following retransplantation is significantly higher than that observed for primary transplants.

Mortality experience in recipients undergoing repeat transplantation with expanded criteria donor and non-ECD deceased-donor kidneys.

Nearly one-quarter of the kidney transplant waiting list is composed of repeat transplantation candidates. Survival following retransplantation using expanded criteria donor (ECD) kidneys has not been adequately studied. Using data from the Scientific Registry of Transplant Recipients, we analyzed mortality after retransplantation with ECD and non-ECD deceased-donor kidneys. Adult patients who experienced graft failure and were relisted for transplantation between 1995 and 2004 were studied (n=9641). Follow-up began at the date of relisting and continued until death or the end of the observation period (December 31, 2004), with censoring at living-donor transplantation. Sequential stratification (an extension of Cox regression) was used to compare mortality between patients receiving an ECD retransplant and those remaining on the waiting list or receiving a non-ECD retransplant (conventional therapy). Of 2908 retransplantations, 292 used ECD kidneys. Survival after ECD retransplantation was approximately equal to that of conventional therapy, with an adjusted hazard ratio of 0.98 (p=0.88). In contrast, non-ECD retransplant recipients experienced a significant reduction in mortality (HR=0.44; p<0.0001). Based on these national data, recipients of ECD retransplantation do not have a survival advantage relative to conventional therapy, whereas non-ECD retransplantation is associated with a significant survival advantage.

Cancer incidence among Canadian kidney transplant recipients.

A number of studies have observed increased cancer incidence rates among individuals who have received renal transplants. Generally, however, these studies have been limited by relatively small sample sizes, short follow-up intervals or focused on only one cancer site. We conducted a nationwide population-based study of 11,155 patients who underwent kidney transplantation between 1981 and 1998. Incident cancers were identified up to December 31, 1999, through record linkage to the Canadian Cancer Registry. Patterns of cancer incidence in the cohort were compared to the Canadian general population using standardized incidence ratios (SIRs). We examined variations in risk according time since transplantation, year of transplantation and age at transplantation. In our patient population, we observed a total of 778 incident cancers versus 313.2 expected (SIR = 2.5, 95% CI = 2.3-2.7). Site-specific SIRs were highest for cancer of the lip (SIR = 31.3, 95% CI = 23.5-40.8), non-Hodgkin's lymphoma (NHL) (SIR = 8.8, 95% CI = 7.4-10.5), and kidney cancer (SIR = 7.3, 95% CI = 5.7-9.2). SIRs for NHL and cancer of the lip and kidney were highest and among transplant patients. This study confirms previous findings of increased risks of posttransplant cancer. Our findings underscore the need for increased vigilance among kidney transplant recipients for cancers at sites where there are no population-based screening programs in place.

Liver and intestine transplantation in the United States, 1995-2004.

Three years of survival data are now available and the impact of the model for end-stage liver disease (MELD) allocation system is becoming clear. After a decline in new registrants to the waiting list in 2002, the number increased to 10 856 new patients in 2004. Since the implementation of MELD, the percentage of patients who have been on the list for 1-2 years has declined from 24% to 19%. There has been a shift upward in the percentage of patients with higher MELD scores on the waiting list. An increasing percentage of adult living donor liver recipients are over the age of 50 years; from 1% in 1997 to 51% in 2004. Parents donating to children (93% of living donors in 1995), represented only 14% in 2004. Long-term adjusted patient survival declined with increasing recipient age in adults following either DDLT or LDLT. Cirrhosis caused by chronic hepatitis C virus (HCV) is the leading indication for liver transplantation and is associated with reduced long-term survival in recipients with HCV compared to those without HCV, 68% at 5 years compared to 76%. Although the intestine waiting list has more than doubled over the last decade, an increasing number of centers now perform intestinal transplantation with greater success.

Analytical methods and database design: implications for transplant researchers, 2005.

Understanding how transplant data are collected is crucial to understanding how the data can be used. The collection and use of Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) data continues to evolve, leading to improvements in data quality, timeliness and scope while reducing the data collection burden. Additional ascertainment of outcomes completes and validates existing data, although caveats remain for researchers. We also consider analytical issues related to cohort choice, timing of data submission, and transplant center variations in follow-up data. All of these points should be carefully considered when choosing cohorts and data sources for analysis. The second part of the article describes some of the statistical methods for outcome analysis employed by the SRTR. Issues of cohort and follow-up period selection lead into a discussion of outcome definitions, event ascertainment, censoring and covariate adjustment. We describe methods for computing unadjusted mortality rates and survival probabilities, and estimating covariate effects through regression modeling. The article concludes with a description of simulated allocation modeling, developed by the SRTR for comparing outcomes of proposed changes to national organ allocation policies.

Mortality after kidney transplantation: a comparison between the United States and Canada.

There is a paucity of comparative studies on country-specific outcomes in kidney transplantation. We compared post-transplant mortality among primary, adult, solitary kidney transplant recipients (KTR) from the United States (n = 70 708) and Canada (n = 5773), between January 1, 1991 and December 31, 1998, using data from the Scientific Registry of Transplant Recipients and the Canadian Organ Replacement Register. Multivariable Cox regression revealed higher adjusted post-transplant mortality among U.S. (vs. Canadian) KTR (HR = 1.35 [95% CI 1.24, 1.47; p < 0.005]). Mortality risk in the first post-transplant year was similar in both countries but higher in the United States beyond the first year (HR = 1.49-1.53; p < 0.005). There was no difference in mortality among patients transplanted within 1 year of starting dialysis, but mortality was increased in U.S. (vs. Canadian) patients after 1-2 and 4+ years on dialysis (HR = 1.36-1.66; p < 0.005). Greater mortality was also seen in U.S. patients with diabetes mellitus and/or graft failure. In conclusion, there are considerable differences in the survival of KTR in the United States and Canada. A detailed examination of factors contributing to this variation may yield important insights into improving outcomes for all KTR.

Trends in CAPD technique failure: Canada, 1981-1997.

OBJECTIVE: Although important enhancements to continuous ambulatory peritoneal dialysis (CAPD) have occurred since its inception, few studies have explicitly evaluated trends over time in CAPD technique failure rates. To assist in quantifying the net benefit of improvements to CAPD for patient outcomes, we examined trends in technique failure rates among Canadian CAPD patients. PATIENTS: Patients initiating renal replacement therapy on CAPD (n = 7110) between 1981 and 1997. MAIN OUTCOME MEASURES: Technique failure (i.e., switch to hemodialysis). RESULTS: Total follow-up was 12,831 patient-years (pt-yr). There were 1976 technique failures, for a crude CAPD failure rate of 154.0/1000 pt-yr. Technique failure rate ratios (RR) estimated using Poisson regression and adjusted for age, gender, race, province, primary renal diagnosis, and follow-up time, were significantly reduced for the 1990-93 [RR = 0.75, 95% confidence interval (CI) = (0.68, 0.83)], 1994-95 [RR = 0.83, CI (0.75, 0.93)], and 1996-97 [RR = 0.78, CI (0.70, 0.87)] calendar periods relative to 1981-89 (RR = 1, reference). Among cause-specific technique failure rates, the greatest improvement was observed for peritonitis-attributable technique failure, with RR = 0.46, CI (0.41, 0.50) for 1990-97 relative to 1981-89. However, rates of technique failure due to inadequate dialysis were significantly elevated for the 1990-97 period [RR = 1.68, CI (1.44, 1.96)]. CONCLUSIONS: The collection of more detailed data on practice patterns would enable future studies to elucidate the cause-and-effect relationship between CAPD descriptors and technique failure, and hence assist in clinical decision-making.

Effect of renal center characteristics on mortality and technique failure on peritoneal dialysis.

BACKGROUND: Recent studies report decreased mortality in patients on peritoneal dialysis (PD) over time, suggesting that advances in PD have resulted in improved patient outcomes. Our investigation sought to assess the effect of renal center characteristics on mortality and technique failure (TF) rates. METHODS: Covariates of interest included center-specific cumulative number of PD patients treated, percentage of patients who initiated dialysis on PD, and academic status. Using data obtained from the Canadian Organ Replacement Register, the 17,900 patients who received PD during the 1981 to 1997 period were studied. Mortality and TF rate ratios (RR) were estimated using Poisson regression, adjusting for age, gender, race, primary renal diagnosis, province, follow-up time, and type of PD. RESULTS: As the cumulative number of PD patients treated increased, covariate-adjusted mortality significantly decreased (P < 0.05); a weaker yet significant association was observed between number of PD patients treated and TF. As the percentage of patients initiating dialysis on PD increased, TF rates decreased significantly. No association was observed between center academic status and PD mortality or TF rates. CONCLUSIONS: These results imply that a center's experience with and degree of specialization toward PD impact strongly on PD outcomes. One hypothesis is that a center's propensity to exploit technical and non-technical advances in PD increases directly with these variables. It is also possible that, through experience, centers become more adept at identifying appropriate patients to receive PD. More detailed research is required to evaluate these hypotheses.

Sex inequality in kidney transplantation rates.

BACKGROUND: Men in the United States undergoing renal replacement therapy are more likely than women to receive a kidney transplant. However, the ability to pay may, in part, be responsible for this finding. OBJECTIVE: To compare adult male and female transplantation rates in a setting in which equal access to medical treatment is assumed. METHODS: Using data from the Canadian Organ Replacement Register, the rate of first transplantations was computed for the 20, 131 men and the 13,458 women aged 20 years or older who initiated renal replacement therapy between January 1, 1981, and December 31, 1996. Poisson regression analysis was used to estimate the male-female transplantation rate ratio, adjusting for age, race, province, calendar period, underlying disease leading to renal failure, and dialytic modality. Actuarial survival methods were used to compare transplantation probability for covariable-matched cohorts of men and women. RESULTS: Men experienced 20% greater covariable-adjusted kidney transplantation rates relative to women (rate ratio, 1.20; 95% confidence interval, 1.13-1.27). The sex disparity was stronger for cadaveric transplants (rate ratio, 1.23) compared with those from living donors (rate ratio, 1.10). The 5-year probability of receiving a transplant was 47% for men and 39% for women within covariable-matched cohorts (P<.001). The sex disparity in transplantation rates increased with increasing age. The sex effect was weaker among whites and Oriental persons (Chinese, Japanese, Vietnamese, Cambodian, Laotian, Filipino, Malaysian, Indonesian, and Korean) and stronger among blacks, Asian Indians (Indian, Pakistani, and Sri Lankan), and North American Indians (aboriginal). CONCLUSION: Since survival probability and quality of life are superior for patients who undergo transplantation relative to those who undergo dialysis, an increased effort should be made to distribute kidneys available for transplantation more equitably by sex among patients undergoing renal replacement therapy.

The effect of small solute clearances on survival of anuric peritoneal dialysis patients.

OBJECTIVE: Primarily, to determine whether peritoneal small solute clearance is related to patient and technique survival among anuric peritoneal dialysis [continuous ambulatory (CAPD) and automated peritoneal dialysis (APD)] patients. A secondary goal was to describe the ability to attain Dialysis Outcomes Quality Initiative (DOQI) targets among anuric patients on peritoneal dialysis. DESIGN: Retrospective cohort study via chart reviews. SETTING: Peritoneal Dialysis Unit of Toronto Hospital (Western Division). PATIENTS: The study included 122 CAPD and APD patients between January 1992 and September 1997, with 24-hour urine volume less than 100 mL, or renal creatinine clearance (CCr) less than 1 mL/minute. Adequacy data were available for 115 patients. OUTCOME MEASURES: Mortality and technique failure (TF). Regression analysis was used to estimate the mortality and TF rate ratios (RR) for peritoneal Kt/V urea (pKt/V) and pCCr, adjusting for age, gender, diabetes, months of follow-up prior to anuria, albumin, transport status, coronary artery disease, cardiovascular disease, and peripheral vascular disease. RESULTS: Fifty seven per cent (51/89) of patients on CAPD and 81% (21/26) on APD had a weekly pKt/V > or = 2 and > or = 2.2, respectively (DOQI targets); whereas only 35% on CAPD (31/89) and 35% (9/26) on APD had a weekly pCCr > or = 60 U1.73 m2 and 66 L/1.73 m2, respectively. Median follow-up times among patients were 16.5 and 19.5 months pre- and postanuria, respectively. Patients with pKt/V > or = 1.85 experienced a strong decrease in patient mortality (RR = 0.54, p= 0.10); the effect was less pronounced for pCCr > or = 50 L/1.73 m2 (RR = 0.63, p = 0.25). No relationship was observed between pKt/V or pCCr and TF. CONCLUSION: Mortality was noticeably less frequent among patients with a pKt/V > or = 1.85 compared with those with a Kt/W < 1.85 (p = 0.10). Given the magnitude of the association, the failure to observe statistical significance relates to the size of the patient cohort. Our results imply that it is, in fact, possible to achieve DOQI targets among anuric patients on peritoneal dialysis.