Matthew J. Oliver

Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy: A Randomized Controlled Trial

CONTEXT Hyperhomocysteinemia is frequently observed in patients with diabetic nephropathy. B-vitamin therapy (folic acid, vitamin B(6), and vitamin B(12)) has been shown to lower the plasma concentration of homocysteine. OBJECTIVE To determine whether B-vitamin therapy can slow progression of diabetic nephropathy and prevent vascular complications. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled trial (Diabetic Intervention with Vitamins to Improve Nephropathy [DIVINe]) at 5 university medical centers in Canada conducted between May 2001 and July 2007 of 238 participants who had type 1 or 2 diabetes and a clinical diagnosis of diabetic nephropathy. INTERVENTION Single tablet of B vitamins containing folic acid (2.5 mg/d), vitamin B(6) (25 mg/d), and vitamin B(12) (1 mg/d), or matching placebo. MAIN OUTCOME MEASURES Change in radionuclide glomerular filtration rate (GFR) between baseline and 36 months. Secondary outcomes were dialysis and a composite of myocardial infarction, stroke, revascularization, and all-cause mortality. Plasma total homocysteine was also measured. RESULTS The mean (SD) follow-up during the trial was 31.9 (14.4) months. At 36 months, radionuclide GFR decreased by a mean (SE) of 16.5 (1.7) mL/min/1.73 m(2) in the B-vitamin group compared with 10.7 (1.7) mL/min/1.73 m(2) in the placebo group (mean difference, -5.8; 95% confidence interval [CI], -10.6 to -1.1; P = .02). There was no difference in requirement of dialysis (hazard ratio [HR], 1.1; 95% CI, 0.4-2.6; P = .88). The composite outcome occurred more often in the B-vitamin group (HR, 2.0; 95% CI, 1.0-4.0; P = .04). Plasma total homocysteine decreased by a mean (SE) of 2.2 (0.4) micromol/L at 36 months in the B-vitamin group compared with a mean (SE) increase of 2.6 (0.4) micromol/L in the placebo group (mean difference, -4.8; 95% CI, -6.1 to -3.7; P < .001, in favor of B vitamins). CONCLUSION Among patients with diabetic nephropathy, high doses of B vitamins compared with placebo resulted in a greater decrease in GFR and an increase in vascular events. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN41332305.

Selection Bias Explains Apparent Differential Mortality between Dialysis Modalities

The relative risk of death for patients treated with peritoneal dialysis compared with those treated with hemodialysis appears to change with duration of dialysis therapy. Patients who start dialysis urgently are at high risk for mortality and are treated almost exclusively with hemodialysis, introducing bias to such mortality comparisons. To better isolate the association between dialysis treatment modality and patient mortality, we examined the relative risk for mortality for peritoneal dialysis compared with hemodialysis among individuals who received ≥4 months of predialysis care and who started dialysis electively as outpatients. From a total of 32,285 individuals who received dialysis in Ontario, Canada during a nearly 8-year period, 6,573 patients met criteria for elective, outpatient initiation. We detected no difference in survival between peritoneal dialysis and hemodialysis after adjusting for relevant baseline characteristics. The relative risk of death did not change with duration of dialysis therapy in our primary analysis, but it did change with time when we defined our patient population using the more inclusive criteria typical of previous studies. These results suggest that peritoneal dialysis and hemodialysis associate with similar survival among incident dialysis patients who initiate dialysis electively, as outpatients, after at least 4 months of predialysis care. Selection bias, rather than an effect of the treatment itself, likely explains the previously described change in the relative risk of death over time between hemodialysis and peritoneal dialysis.

Peritoneal Dialysis and the Process of Modality Selection

The process of modality selection and how it works is a critical determinant of peritoneal dialysis (PD) utilization. This very complex process has not been well analyzed. Here, we break it down into 6 steps and point out how problems at each step can significantly reduce the proportion of endstage renal disease patients initiating PD. It is important that any program wising it to grow its use of PD understand the steps and the points at which problems may be arising. Examples are presented.

Predicting the risk of 1-year mortality in incident dialysis patients: accounting for case-mix severity in studies using administrative data.

Background:Administrative databases are increasingly being used to study the incident dialysis population and have important advantages. However, traditional methods of risk adjustment have limitations in this patient population. Objective:Our objective was to develop a prognostic index for 1-year mortality in incident dialysis patients using administrative data that was applicable to ambulatory patients, used objective definitions of candidate predictor variables, and was easily replicated in other environments. Research Design:Anonymized, administrative health data housed at the Institute for Clinical Evaluative Sciences in Toronto, Canada were used to identify a population-based sample of 16,205 patients who initiated dialysis between July 1, 1998 and March 31, 2005. The cohort was divided into derivation, validation, and testing samples and 4 different strategies were used to derive candidate logistic regression models for 1-year mortality. The final risk prediction model was selected based on discriminatory ability (as measured by the c-statistic) and a risk prediction score was derived using methods adopted from the Framingham Heart Study. Calibration of the predictive model was assessed graphically. Results:The risk of death during the first year of dialysis therapy was 16.4% in the derivation sample. The final model had a c-statistic of 0.765, 0.763, and 0.756 in the derivation, validation, and testing samples, respectively. Plots of actual versus predicted risk of death at 1-year showed good calibration. Conclusion:The prognostic index and summary risk score accurately predict 1-year mortality in incident dialysis patients and can be used for the purposes of risk adjustment.

THE IMPACT OF TREATMENT MODALITY ON INFECTION-RELATED HOSPITALIZATION RATES IN PERITONEAL DIALYSIS AND HEMODIALYSIS PATIENTS

♦ Background and Objectives: Infection is a major cause of morbidity and mortality in the dialysis population. This study compares the rates of infection-related hospitalization (IRH) in incident chronic dialysis patients initiating outpatient peritoneal dialysis (PD) and hemodialysis (HD). ♦ Methods and Patients: This was a retrospective cohort study at the dialysis program of a tertiary-care center in Toronto, Canada. Incident chronic dialysis patients that were eligible for both PD and HD and started outpatient dialysis between 1 January 2004 and 31 August 2008 were included. Dialysis modality was assigned at the start of outpatient dialysis treatment. All hospital admissions were reviewed and incidence of IRH was compared between PD and HD using Poisson regression. ♦ Results: Of 264 incident chronic dialysis patients, 168 (64%) were eligible for both treatment modalities: 71 (42%) started outpatient PD and 97 (58%) started outpatient HD. The unadjusted and adjusted incidence rate ratios (IRR) of IRH did not differ significantly between PD and HD: 1.23 [95% confidence interval (CI) 0.65 – 2.32, p = 0.37] and 1.14 (95% CI 0.58 – 2.23, p = 0.71) respectively. There was no difference between PD and HD in the risk of access loss (28% vs 35%, p = 0.73), modality change (22% vs 0%, p = 0.10), or death (17% vs 6%, p = 0.60) following hospitalization for infection. Patients starting outpatient treatment on PD versus HD were more likely to be hospitalized for peritonitis (IRR 3.20, 95% CI 1.16 – 9.09; p = 0.029) and there was a trend for fewer hospitalizations for bacteremia (IRR 0.19, 95% CI 0.028 – 1.30; p = 0.091). The risk of IRH did not differ between PD and HD in the subgroup of patients that received adequate predialysis care (IRR 1.16, 95% CI 0.59 – 2.27; p = 0.67) or when patients starting outpatient HD with a central venous catheter were excluded (IRR 1.52, 95% CI 0.53 – 4.37; p = 0.44). ♦ Conclusions: Patients that initiate outpatient peritoneal dialysis do not have a significantly increased risk of infection-related hospitalization compared to those that initiate outpatient hemodialysis.

Impact of Modality Choice on Rates of Hospitalization in Patients Eligible for Both Peritoneal Dialysis and Hemodialysis

♦ Background: Hospitalization rates are a relevant consideration when choosing or recommending a dialysis modality. Previous comparisons of peritoneal dialysis (PD) and hemodialysis (HD) have not been restricted to individuals who were eligible for both therapies. ♦ Methods: We conducted a multicenter prospective cohort study of people 18 years of age and older who were eligible for both PD and HD, and who started outpatient dialysis between 2007 and 2010 in four Canadian dialysis programs. Zero-inflated negative binomial models, adjusted for baseline patient characteristics, were used to examine the association between modality choice and rates of hospitalization. ♦ Results: The study enrolled 314 patients. A trend in the HD group toward higher rates of hospitalization, observed in the primary analysis, became significant when modality was treated as a time-varying exposure or when the population was restricted to elective outpatient starts in patients with at least 4 months of pre-dialysis care. Cardiovascular disease, infectious complications, and elective surgery were the most common reasons for hospital admission; only 23% of hospital stays were directly related to complications of dialysis or kidney disease. ♦ Conclusions: Efforts to promote PD utilization are unlikely to result in increased rates of hospitalization, and efforts to reduce hospital admissions should focus on potentially avoidable causes of cardiovascular disease and infectious complications.