Liver transplantation and subsequent risk of cancer: findings from a Canadian cohort study.

Characterization of the long-term cancer risks among liver transplant patients has been hampered by the paucity of sufficiently large cohorts. The increase over time in the number of liver transplants coupled with improved survival underscores the need to better understand associated long-term health effects. This is a cohort study whose subjects were assembled with data from the population-based Canadian Organ Replacement Registry. Analyses are based on 2034 patients who received a liver transplant between June 1983 and October 1998. Incident cases of cancer were identified through record linkage to the Canadian Cancer Registry. We compared site-specific cancer incidence rates in the cohort and the general Canadian population by using the standardized incidence ratio (SIR). Stratified analyses were performed to examine variations in risk according to age at transplantation, sex, time since transplantation, and year of transplantation. Liver transplant recipients had cancer incidence rates that were 2.5 times higher than those of the general population [95% confidence interval (CI) = 2.1, 3.0]. The highest SIR was observed for non-Hodgkin's lymphoma (SIR = 20.8, 95% CI = 14.9, 28.3), whereas a statistically significant excess was observed for colorectal cancer (SIR = 2.6, 95% CI = 1.4, 4.4). Risks were more pronounced during the first year of follow-up and among younger transplant patients. In conclusion, our findings indicate that liver transplant patients face increased risks of developing cancer with respect to the general population. Increased surveillance in this patient population, particularly in the first year following transplantation, and screening for colorectal cancer with modalities for which benefits are already well recognized should be pursued.

A comparison of the effects of C2-cyclosporine and C0-tacrolimus on renal function and cardiovascular risk factors in kidney transplant recipients.

BACKGROUND: There are few data directly comparing the effects of two-hour postingestion monitored cyclosporine (C2-CsA) vs. trough-monitored tacrolimus (C0-Tac) on renal function and cardiovascular risk factors. METHODS: We studied 378 (202 C2-CsA vs. 176 C0-Tac) incident kidney transplant recipients in Toronto, Canada, from August 1, 2000 and December 31, 2003. Outcomes included changes in estimated glomerular filtration rate (eGFR at 1 and 6 months by modification of diet in renal disease four-variable equation), mean arterial pressure (MAP), total cholesterol (TC), and new-onset diabetes mellitus (NODM) at six months posttransplant. The independent effect of treatment/monitoring strategies on continuous outcomes and time-to-NODM was modeled using linear and Cox regression, respectively. RESULTS: Mean eGFR was 59.5 vs. 62.9 ml/min at one month and 50.6 vs. 61.2 ml/min at six months for C2-CsA vs. C0-Tac, respectively. Multiple linear regression revealed the slope of eGFR to be 0.93 ml/min/month lower in C2-CsA patients. This was equivalent to an adjusted average eGFR difference of 4.64 ml/min between months one and six posttransplant. There was no significant difference in average MAP and TC. In a stepwise multivariable Cox model and a propensity score analysis, there was no significant association between the type of treatment/monitoring strategy and time-to-NODM. CONCLUSIONS: There was a greater decline in eGFR for patients on C2-CsA (vs. C0-Tac) between one and six months posttransplant. However, MAP, TC, and the risk of NODM were comparable in both treatment/monitoring groups. The long-term impact of short-term reductions in eGFR as a function of the type of treatment/monitoring strategy requires further study.

Evaluating the survival benefit of kidney retransplantation.

BACKGROUND: The magnitude of the survival benefit associated with kidney retransplantation has not been well studied. METHODS: Using data from the Canadian Organ Replacement Register (CORR), we studied patients (n=3,067) initiating renal replacement therapy during 1981-1998 who had received a transplant and experienced graft failure (GF). Such patients were followed until death, loss to follow-up or the end of the observation period (December 31, 1998). Using Cox regression, we estimated the post-GF covariate-adjusted hazard ratio (HR) for retransplant versus dialysis, and determined whether the contrast differed across patient subgroups. Through nonproportional hazards models, we also examine patterns in the retransplant/dialysis HR with time following retransplant. RESULTS: Overall, retransplantation is associated with a covariate-adjusted 50% reduction in mortality, relative to remaining on dialysis (HR=0.50; P<0.0001). This benefit is most pronounced in the 18- to 59-year age group. Retransplanted patients were at significantly higher risk of death relative to patients on dialysis only during the first month posttransplant (HR=1.66; P=0.047), and experienced significantly reduced mortality thereafter. CONCLUSIONS: Following primary graft failure, retransplantation is associated with significantly reduced mortality rates among Canadian end-stage renal disease patients. Further study should be undertaken to assess the applicability of our findings to other patient populations.

Predicting mortality after kidney transplantation: a clinical tool.

An increasing number of patients referred for transplantation are older and have complex comorbidity affecting outcome. Patient counseling is often empiric and time consuming. For the physician there are few clinical tools available to help quantify survival chances after transplantation. We used registry data to develop a series of tables that could be used in the clinical setting to predict survival probability. Using data from the Canadian Organ Replacement Registry, we generated clinical survival tables using Cox's regression model. Model covariates included age, race, gender, treatment period, primary renal disease cause, donor source, months on dialysis and comorbidities. A total of 6324 patients were included, 22% had > or =1 comorbid condition at baseline. After adjustment for age, gender and cause of renal disease, increased comorbidity was strongly associated with reduced patient-survival (P < 0.05). Age and comorbidity specific clinical survival tables showing the expected 1-, 3- and 5-year patient survival probabilities were generated. Separate tables were created for diabetics, nondiabetics, living-donor organs and deceased-donor transplantation. Patient-specific survival data can be estimated from registry data. We suggest annual or biannual tables generated by national registries across Europe and N. America, may be useful to those physicians faced with counseling patients and families.

Quotidian nocturnal hemodialysis improves cytokine profile and enhances erythropoietin responsiveness.

Inflammation is implicated in the pathogenesis of erythropoietin (EPO) resistance in patients with end-stage renal disease. Interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha are suggested to suppress erythropoiesis in uremia. Insulin like growth factor (IGF)-1 has been proposed to stimulate erythropoiesis. Nocturnal hemodialysis (NHD) has been demonstrated to improve anemia management with enhanced EPO responsiveness without altering survival of red blood cells. We tested the hypothesis that augmentation of uremia clearance by NHD results in a reduction of proinflammatory cytokine levels, thereby enhancing EPO responsiveness. Using a cross-sectional study design, 14 prevalent patients on NHD and 14 patients on conventional hemodialysis (CHD) matched for age and comorbidities and controlled for hemoglobin concentrations and iron status were studied. Outcome variables included EPO requirement and plasma levels of EPO, parathyroid hormone, C reactive protein, IL-6, TNF-alpha, and IGF-1. The primary outcome was to determine the between group differences in (1) cytokine profile and (2) EPO requirement. The secondary outcome was to examine the potential correlation between cytokine levels and EPO requirement. There were no significant differences in patient characteristics, comorbidities, hemoglobin, iron indices, and parathyroid hormone levels between the two cohorts. EPO requirement was significantly lower in the NHD cohort [90.5 +/- 22.1 U/kg/ week (NHD) vs. 167.2 +/- 25.4 U/kg/week (CHD), p = 0.04]. Plasma IL-6 levels were lower in the NHD cohort [3.9 +/- 0.7 pg/ml (NHD) vs. 6.5 +/- 0.8 pg/ml (CHD), p = 0.04]. C reactive protein tended to decrease [4.59 +/- 1.34 (NHD) vs. 8.43 +/- 1.83 mg/L (CHD), p = 0.14]. TNF-alpha, and IGF-1 levels did not differ between the two groups. Direct associations were found between EPO requirement and C reactive protein levels (R = 0.62, p = 0.001), and IL-6 levels (R = 0.57, p = 0.002). Augmentation of uremic clearance by NHD improves EPO responsiveness in end-stage renal disease. A possible mechanism for this improvement is through better control of inflammation, as manifested by lowering of plasma IL-6 levels. Further studies are required to clarify the mechanisms by which NHD decreases inflammation.

Baseline comorbidity in kidney transplant recipients: a comparison of comorbidity indices.

BACKGROUND: An increasing number of patients starting renal replacement therapy are older and have complex comorbidity. In keeping with these demographics, an increased number of older patients undergo transplantation each year. To date, no study has reported baseline comorbidity characteristics of those who underwent transplantation, validated the use of comorbidity indices, or asked whether comorbidity predicts patient outcome after kidney transplantation. Our objective is to report baseline comorbidity and compare the use of different indices for recipients of kidneys from both deceased and living donors. METHODS: Using data from the Canadian Organ Replacement Registry, we tested the ability of 4 comorbidity indices to predict patient survival by using a Cox regression model. Model covariates included donor source, age, race, sex, treatment period, primary renal disease cause, months on dialysis therapy, and comorbidities. RESULTS: A total of 6,324 patients were included; 22% had > or =1 comorbid condition at baseline. After adjustment for age, sex, and cause of renal disease, increased comorbidity was associated strongly with reduced patient survival. Of all comorbidity indices examined, the model containing the Charlson Comorbidity Index (CCI) offered the best fit. The model containing log--CCI had an index of concordance of 74%. CONCLUSION: The CCI is a suitable tool for the measurement of comorbidity in renal transplant recipients.

Reduced incidence of new-onset diabetes mellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins).

Statins have anti-inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new-onset diabetes mellitus in renal transplant recipients. The records of all previously non-diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow-up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New-onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose > or =7.0 mmol/L or 2-h postprandial glucose > or =11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time-dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New-onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109-0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127-0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003-1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003-1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023-1.480]) and age > or =45 years (p = 0.01, HR 2.226[1.162-4.261]) were associated with increased diabetes. Statin use is associated with reduced new-onset diabetes development after renal transplantation.

Centre-specific variation in renal transplant outcomes in Canada.

BACKGROUND: The 'centre effect' has accounted for significant variation in renal allograft outcomes in the United States and Europe. To determine whether similar variation exists in Canada, we analysed mortality and graft failure (GF) rates among Canadian end-stage renal disease patients who received a renal allograft from 1988 to 1997 (n = 5082) across 20 transplant centres. METHODS: Patients were followed from the date of transplantation to the time of GF and/or death. A Cox proportional hazards model was used to estimate mortality and GF hazard ratios (HRs) adjusted for relevant covariates, including centre volume. Centre-specific HRs were derived by comparing each centre's outcome rates against all others. RESULTS: Twenty centres were included in the analysis. There was significant centre-specific variation in recipient and transplant characteristics (e.g. age, diabetes mellitus, donor source and centre volume) as well as covariate-adjusted facility-specific outcome rates. Facility-specific HRs for GF (including death with a functioning graft) ranged from 0.51 to 1.77, while mortality HRs (including death beyond GF) showed a similar spread (0.44-1.84). These HRs represent a 3- to 4-fold difference in transplant outcomes among the 20 centres studied. Centres performing less than 200 transplants over the study period were associated with lower graft and patient survival. CONCLUSIONS: These findings demonstrate significant centre-specific variation in the success of renal transplantation in Canada. Further studies are needed to elucidate the causes of this variation, with the goal of developing strategies to minimize the centre effect and ensure the best possible outcomes for all renal transplant recipients.

Changes in peritoneal dialysis practices in Canada 1996-1999.

OBJECTIVE: Over the past decade, clinical studies and clinical practice guidelines have suggested the use of higher small solute clearance targets for patients on peritoneal dialysis (PD). This study asks whether these recommendations have translated into changes in clinical prescription of PD. STUDY DESIGN: Data were collected annually from 1996 to 1999 on all prevalent dialysis patients in 24 Canadian centers, accounting for approximately 40% of the Canadian chronic dialysis population. Approximately a third of these patients were on PD. Full details of each patient's prescription were recorded, with particular attention to dwell volumes and frequency of exchanges for continuous ambulatory PD (CAPD) and to total treatment volumes and day dwells for automated PD (APD). The most recent Kt/V and creatinine clearance values available were recorded for each patient and the overall results for each year were compared to present treatment recommendations. SETTING: 24 university- and community-based hospitals. RESULTS: From 1996 to 1999, the use of APD, relative to CAPD, grew from 14% to 28% of all PD patients. Among CAPD patients, the proportion using dwell volumes greater than 2 L rose from 14% to 32%, and the proportion doing more than 4 dwells per day rose from 16% to 28%. The mean daily volume of prescribed fluid for CAPD patients increased from 8.3 to 9.1 L. As a result, the proportion of patients achieving a weekly Kt/V above 2.0 rose from 54% to 72%, and those receiving a Kt/V less than 1.7 fell from 22% to 10%. For creatinine clearance, those exceeding 60 L per week rose from 63% to 73%. For APD, the mean treatment volume rose from 11.8 L in 1996 to plateau at about 13.4 L in 1998 and 1999. However, the proportion of patients receiving more than 1 day dwell grew from 31% in 1998 to 40% in 1999, and the proportion that were "day dry" fell from 25% to 17%. For APD, the proportion of patients with a Kt/V above 2.0 rose from 67% to 77%, and with a creatinine clearance above 60 L, from 62% to 70%. The proportion with no recent clearance value recorded fell during the course of the study, from 45% to 27%. CONCLUSION: There was a marked change in PD prescription practices in Canada during the second half of the 1990s. This occurred in response to clinical studies and publication of guidelines. There is room for further improvement, especially with respect to the proportion of patients that did not have regular clearance measurements made.

Transplantation in Canada: review of the last decade from the Canadian Organ Replacement Register.

The descriptive analyses presented in this chapter provide a brief overview of transplant activity in Canada. While Canada's cadaveric organ donation rate has remained static, between 13-14 per million population, transplant rates increased from 1992-2001. This growth was due to more organs being retrieved per cadaveric donor and increased rates of living donor transplants for kidney, most notably, but also liver. The steady climb of the transplant waiting list continued to outstrip the number of patients transplanted on an annual basis. In 2002, 237 people died will waiting for an organ transplant. Canada is a net importer of organs from the US, particularly hearts and lungs. Heart transplantation activity has varied least of all organ transplant types from 1992-2001, reflecting in large part the stagnant cadaveric donation rate and the fact that fewer than 40% of hearts were retrieved and transplanted from the available cadaveric donors. Liver, lung, most notably double lung, and pancreas/kidney-pancreas transplant activity all grew significantly from 1992-2001. Accumulated expertise in the surgical realm combined with improved donor management and organ preservation techniques have facilitated this growth. Patient and graft survival continue to increase in Canada both for patients who are very ill at the time of their transplant, and those not as ill. Future growth areas for transplantation in Canada will likely be in the area of living kidney and liver donation, continued kidney-pancreas transplantation and islet cell transplantation. Without significant improvements in cadaveric organ donation rates in Canada, exploration of expanded donation criteria like non-heartbeating donors as well as continued improvements in donor management for the purposes of increased organ retrieval, the transplantation rates for hearts, livers, and lungs are not expected to increase, and the gap between the number of patients waiting for a transplant and the number of patients transplanted will widen.

Trends in mortality and graft failure for renal transplant patients.

BACKGROUND: Several important advances in general medical management both before and after renal transplantation have occurred over the last 5-15 years, however, few studies have formally examined trends in the outcomes of renal transplantation. We, therefore, aimed to determine the degree to which these advances have resulted in improved outcomes such as survival of patient and graft. METHODS: We analyzed the rates of death and graft failure among the 11,482 Canadians with end-stage renal disease who received a kidney transplant in 1981-98. Patients were followed from the date of transplantation to the date of graft failure, the date of death or the end of the observation period, namely, Dec. 31, 1998, depending on which was the earliest. Rate ratios for mortality and graft failure--ratios of the rate for each calendar period to the rate for the arbitrarily chosen reference period, 1981-85--were estimated with a piece-wise exponential model that adjusted for age, sex, ethnicity, primary renal diagnosis, follow-up time and donor-organ source. RESULTS: The rates and adjusted rate ratios for death and graft failure decreased significantly and steadily over time. Relative to 1981-85, the adjusted mortality rate ratios were 0.70 (95% confidence interval [CI] 0.54-0.89), 0.65 (95% CI 0.52-0.82) and 0.53 (95% CI 0.41-0.67) for 1986-89, 1990-94 and 1995-98 respectively, and the adjusted graft failure rate ratios were 0.68 (95% CI 0.60-0.78), 0.62 (95% CI 0.54-0.70) and 0.51 (95% CI 0.44-0.58) respectively. The decrease was mostly among the cadaveric-organ recipients. Calendar period was as important a predictor of outcome as well-known prognostic factors such as age and primary renal diagnosis. INTERPRETATION: Decreases in mortality rates are probably related to refinements in patient management. Decreases in graft failure rates are probably the result of a combination of improved immunotherapy and better management of nonimmunologic conditions such as hypertension and hyperlipidemia.

Trends in mortality on peritoneal dialysis: Canada, 1981-1997.

Several technical and nontechnical improvements in peritoneal dialysis (PD) have occurred during recent years. Since few previous studies have examined trends in PD mortality over time, and to determine whether enhancements in PD have translated into improved patient outcomes, mortality rates among the 17,900 patients receiving PD in Canada during the period 1981-1997 were analyzed. Mortality rate ratios (RR) were estimated using Poisson regression, adjusting for age, race, gender, primary renal diagnosis, follow-up time, and type of PD (continuous ambulatory/cyclic versus intermittent). Adjusted mortality rates decreased significantly by calendar period, the reduction being monotonic: RR = 0.81, 95% confidence interval [CI], 0.75 to 0.87 for 1986-1989; RR = 0.73, 95% CI, 0.67 to 0.78 for 1990-1993; RR = 0.63, 95% CI, 0.58 to 0.67 for 1994-1997, with 1981-1985 serving as the reference period (RR = 1, fixed). The improvement in mortality was fairly consistent across patient subpopulations. When analyzed separately by follow-up time window, the mortality decrease was strongest in the first 12 mo after renal replacement therapy initiation. Supplementary analysis revealed that the trend in mortality rates was not attributable to corresponding trends in transplantation or technique failure rates, or modality switching patterns. Results were quite similar whether based on an "as-treated" or "intent-to-treat" analysis. More extensive data on practice patterns would empower future studies to elucidate the cause/effect relationship between PD practice patterns and patient survival.