David N. Churchill

Canadian Hemodialysis Morbidity Study

The objective of this study was to determine the probabilities of specific morbid events or death among patients with end-stage renal disease (ESRD) treated by hemodialysis. A prospective cohort study was performed between March 1988 and September 1989 in 18 hemodialysis centers in 13 Canadian cities, representing about one third of the hemodialysis population in Canada. The inception cohort consisted of 496 patients entering hemodialysis who had survived 1 month. The few new hemodialysis patients who received erythropoietin (EPO) in the last 3 months of the study were excluded. Survival curves were compared using the Cox proportional hazards regression model. Older age and history of cardiovascular disease were independently associated with a greater probability of death. Age and history of cardiovascular disease were also associated with a greater probability of nonfatal circulatory events (myocardial infarction, angina requiring hospitalization, or stroke), while a serum albumin level less than or equal to 30 g/L (3.0 g dL) was associated with an increased probability of pulmonary edema. The probability of surviving 12 months without receiving a blood transfusion was 47.2% for males and 27.5% for females. The incidence of non-A, non-B hepatitis, as estimated by unexplained elevations in serum aspartate aminotransferase (AST) values, was not different between patients receiving and not receiving blood transfusions. The probability of hospitalization for any cause was greater for patients with grafts for vascular access than for those with fistulae, for those with a history of cardiovascular disease, for those with a serum albumin level less than or equal to 30 g/L, and for those with renal disease due to diabetes or vascular disease. Hospitalization due to circulatory disease was more likely among those with a history of cardiovascular disease and among those with a lower serum albumin level. Hospitalization for infectious disease was more likely among those with a lower serum albumin level and less likely among those with a fistula for vascular access. Among all patients receiving hemodialysis treatment for more than 6 months, there were 14.8 hospital days per year.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

The quality of life in renal transplantation : a prospective study

Methodologically sound measures of quality of life are required to judge accurately the impact of successful renal transplantation on patient well-being. The time trade-off (TTO) method is a reproducible and valid measure which we used to prospectively assess changes in the quality of life of 27 patients on maintenance dialysis who subsequently underwent renal transplantation. TTO scores approaching 0 signify a very poor quality of life, while scores approaching 1 represent perfect health. Of 98 dialysis patients who completed baseline TTO interviews, 31 consecutive patients subsequently received 28 cadaveric and 3 living related kidney transplants. Four of 31 patients did not complete a second TTO assessment, because of death in 2 patients and graft loss in 2 others. The remaining 27 patients completed a second TTO interview an average of 30.9 months following transplantation (range 1.5-52, 95% confidence interval [CI] 24.4-37.5) and formed the study cohort. At the time of study the mean serum creatinine for the cohort was 173 mumol/L (range 90-290, 95% CI 152-195 mumol/L). The employment rate rose 27% following transplantation (P = 0.10); but when males alone were analyzed, a significant increase of 38% (P = 0.048) was noted. During the dialysis period, the mean baseline TTO score was 0.41 (95% CI 0.33-0.49), confirming the observations of others. Following transplantation, the mean TTO score rose to 0.74 (95% CI 0.67-0.81), a difference that is statistically significant (P < 0.001). The mean increase in TTO score observed as a result of successful transplantation was 0.33 (95% CI 0.26-0.40). This magnitude of improvement was found in 20 of 27 patients (74%), whose TTO scores lay within or above the 95% CI (0.26-0.40) for the mean change in score of 0.33. One patients score fell, while the remaining 6 patients had improvements in their TTO score which fell below the lower 95% CI value (0.26) for the mean change in score. We conclude that the 95% CI of 0.26-0.40 identifies a range in which clinically important improvements in quality of life will be found for the majority of patients receiving successful kidney transplants.

Quality of life of patients with ulcerative colitis preoperatively and postoperatively

Two instruments, the time trade-off technique and direct questioning of objectives, were used to assign the worth (utility) of the perceived quality of life of patients who had ulcerative colitis requiring surgery. Utilities ranged from 0 to 1 with 0 signifying death and 1 signifying full health. Two groups of patients were studied. Group 1 consisted of 20 patients (14 male and 6 female; mean age, 34.0 +/- 10.3 years) who were studied preoperatively and 1 year postoperatively. The mean preoperative utility was 0.58 +/- 0.34 using the time trade-off technique and 0.38 +/- 0.27 using the direct questioning of objectives. Mean utilities were significantly higher postoperatively, 0.98 +/- 0.07 using the time trade-off technique and 0.88 +/- 0.19 using the direct questioning of objectives (P less than 0.05). Group 2 included 93 patients who had had surgery at least 1 year previously. Twenty-eight had conventional ileostomies, 28 had Kock pouches, and 37 had ileal reservoirs. Mean utilities for these three subgroups ranged from 0.87 +/- 0.18 to 0.97 +/- 0.6. No significant differences were detected among the three subgroups. This study suggests that quality of life is improved after surgery for ulcerative colitis and is high irrespective of the surgical procedure.

An evidence-based approach to earlier initiation of dialysis

The objective was to review evidence addressing the optimal time to initiate dialysis treatment. The database was derived from an evidence-based review of the medical literature and from the Canada-United States peritoneal dialysis study. The publications were divided into (1) those addressing the clinical impact of early versus late referral to a dialysis program; (2) those evaluating the association between residual renal function at initiation of dialysis and the concurrent nutritional status; (3) those evaluating the association between residual renal function at initiation of dialysis and subsequent clinical outcomes, including patient survival. There were five studies evaluating early versus late referral, three cohort design and two case-control design. Late referrals had worse outcomes than early referrals. The former had more serious comorbidity and many had been noncompliant with follow-up. The latter were more likely to have hereditary renal disease. Renal function was slightly worse at initiation among those referred late. Three studies addressed the association between renal function at initiation of dialysis and concurrent nutritional status. Two showed decreased protein intake with diminished glomerular filtration rate (GFR). Poor nutritional status is associated with decreased patient survival among both incident and prevalent dialysis patients. The third study reported excellent patient survival among patients with late initiation of dialysis. These patients had received a supplemented low-protein diet and were not malnourished at initiation of dialysis. Three groups have studied the association between GFR at initiation of dialysis and clinical outcomes. Decreased GFR at initiation of dialysis is associated with a increased probability of hospitalization and death. None of these studies has used the rigorous randomized clinical trial design, and they are therefore subject to bias. Referral time bias, comorbidity, patient compliance, and starting time bias are potential confounders. A randomized clinical trial is required to resolve this important issue. However, there is sufficient evidence to justify initiation of dialysis at a Ccr of 9 to 14 mL/min if there is any clinical or laboratory evidence of malnutrition.

The use of generic and specific quality-of-life measures in hemodialysis patients treated with erythropoietin

The effect of recombinant human erythropoietin (EPO) on the quality of life and exercise capacity of 118 hemodialysis patients was assessed in a randomized, double-masked placebo-controlled trial. Patients were randomized into three groups: 1) placebo, 2) EPO to achieve a hemoglobin of 95-110 g/L and 3) EPO to achieve a hemoglobin of 115-130 g/L. Patients were followed for six months. Quality of life was assessed using a disease-specific measure [the Kidney Disease Questionnaire (KDQ)] and two generic measures [Sickness Impact Profile (SIP) and the Time Trade OFF (TTO)]. The KDQ contains five dimensions. Functional capacity was assessed with a Six-Minute Walk test (SMW) and an Exercise Stress Test (EST). The mean hemoglobin at six months was 74, 102, and 117 gm/l in groups one, two and three, respectively. There was a marked improvement in quality of life with EPO therapy, but no difference between groups 2 and 3. The outcome measure that was the most responsive to change was the KDQ (P less than .001 for the fatigue and physical symptoms dimensions). The aggregate global (P less than .02) and physical (P = .005) scores of the SIP improved with EPO therapy, the psychosocial score did not. There was no improvement in the TTO. There was an improvement in the EST (P = .02) but not in the SMW. The reproducibility of the outcome measures in placebo-treated patients varied between 0.80 and 0.98 (intra-class correlation coefficient). The correlation among the outcome measures at six months was statistically significant in most cases, as was the correlation of change scores between baseline and six months.

Comparison of Subcutaneous and Intravenous Recombinant Human Erythropoietin for Anemia in Hemodialysis Patients with Significant Comorbid Disease

While recombinant human erythropoietin (rHuEPO) is an effective therapy for anemia in renal failure, most published studies concern benefits in relatively healthy hemodialysis patients. The present study compares intravenous and subcutaneous administration of rHuEPO in an unselected group of 128 hemodialysis patients who were randomized to receive rHuEPO in an initial dose of 150 U/kg/week in three divided doses by subcutaneous or intravenous injection. Following a 4-week placebo run-in period, patients received rHuEPO until their hemoglobin was stable between 105 and 125 g/l for 4 weeks and then followed for a further 24 weeks. Eighty-three patients completed the study, 45 in the subcutaneous and 38 in the intravenous group. There was no difference in mean hemoglobin at any stage between subcutaneous and intravenous patients. Mean rHuEPO dose at the time of stabilization was significantly lower in the subcutaneous group compared to the intravenous (205.9 +/- 135.4 vs. 274.1 +/- 142.4 U/kg/week; p = 0.019), mean time to hemoglobin target was 9.9 +/- 4.5 weeks for the subcutaneous group and 11.9 +/- 4.9 weeks for the intravenous group (p = 0.037). Time to stabilization was 14.9 +/- 4.7 weeks for the subcutaneous compared to 17.3 +/- 3.9 weeks for the intravenous group (p = 0.006). Diabetic patients had higher dose requirements for rHuEPO at all time points and required a longer time to reach stabilization than nondiabetics (18.6 +/- 4.6 vs. 15.6 +/- 4.3 weeks; p = 0.016). Quality of life estimated by a disease-specific Kidney Disease Questionnaire improved significantly during rHuEPO therapy in both groups. There was no significant change in dialysis prescription throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of High-Flux Hemodialysis on Quality of Life and Neuropsychological Function in Chronic Hemodialysis Patients

The objective was to evaluate the effect of high-flux hemodialysis on quality of life, intra- and interdialytic symptoms and neuropsychological function. The study was double-blind single cross-over with random allocation to order of treatment. The patients were stable adult hospital hemodialysis patients. Both the conventional and high-flux membranes were cellulose acetate, the dialysate was bicarbonate, and dialysate sodium was held constant. The high-flux membrane had an ultrafiltration rate of 15 ml/h/mm Hg transmembrane pressure, a B12 clearance of 88 ml/min and a beta 2-microglobulin clearance of 11.4 ml/min. The values of the conventional membrane were 3.5-5.0, 34-45 and negligible. Each treatment period was 4 months. Twenty-two patients completed both phases of the cross-over. The KT/V value was higher during high-flux than conventional treatment; 1.42 versus 1.27(p < 0.05). There were no differences between high-flux and conventional treatment with respect to quality of life. Symptoms during dialysis were less severe during high-flux than conventional treatment for 12/14 items. Only 3 items reached statistical significance (0.05 > p > 0.01) and none were clinically significant. Symptoms between dialyses were less severe during high-flux than conventional treatment for 18/20 items. No single item had a statistically significant improvement but 3 had clinically important improvement. Among the 23 neuropsychological variables, none demonstrated statistically significant changes.

A comparison of evaluative indices of quality of life and cognitive function in hemodialysis patients

In the setting of end-stage renal disease, the reproducibility and responsiveness of three health-related quality-of-life instruments were evaluated. The Time Trade Off instrument (TTO) is a generic instrument used to evaluate the utility of a health state. The Hemodialysis Quality-of-Life questionnaire (HQL) is a disease-specific instrument. A series of function-specific tests evaluated neurocognitive function. The TTO and HQL instruments are patient centric in that patient values define the health status while the neurocognitive function tests reflect the values of healthcare professionals. Forty-seven chronic hemodialysis patients participated. Those with adequate dialysis, defined as a Kt/V (a measure of small solute removal during hemodialysis) above 1.0 were maintained at the level for two administrations of the three instruments separated by six to eight weeks. The test-retest intraclass correlation coefficient exceeded 0.90 for all five domains of the HQL questionnaire and exceeded 0.70 for nine neurocognitive function tests. Patients with inadequate dialysis (Kt/V less than 0.8) had Kt/V increased to above 1.0. The TTO was not responsive. For the HQL questionnaire, an item was considered responsive if a 1-point improvement, on a 7-point Likert type scale, occurred significantly more often among those with an improvement in hemodialysis treatment compared to those without improvement. Only one item had such a change and therefore the HQL cannot be considered responsive.(ABSTRACT TRUNCATED AT 250 WORDS)

Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine

Mesalamines are slow-release formulations of 5-aminosalicylic acid (5-ASA) and are effective as primary treatment and maintenance therapy in inflammatory bowel disease. Interstitial nephritis is a recognized side effect. We report two cases of biopsy-confirmed interstitial nephritis in patients being treated with 5-ASA. Both had a trial of steroid therapy. One patient had partial recovery of renal function but the other patient was in chronic renal failure and likely was approaching the need for dialysis. Interstitial nephritis is an under-recognized complication of 5-ASA therapy. Early identification and withdrawal of this drug can lead to a partial or complete reversal of renal dysfunction.