William F. Clark

Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario

Background : Post‐infectious irritable bowel syndrome is a common clinical phenomenon of uncertain aetiology.

Plasma Exchange When Myeloma Presents as Acute Renal Failure: A Randomized, Controlled Trial

Context Does plasma exchange benefit patients with multiple myeloma and renal failure? Contribution This 6-month randomized trial involved 104 patients with acute renal failure at the onset of myeloma. A composite outcome of death, dialysis dependence, or severely reduced kidney function occurred in 57.9% of patients given 5 to 7 plasma exchanges and in 69.2% of patients given conventional therapy (difference, 11.3% [95% CI, 8.3% to 29.1%]). Cautions Although these findings suggest no substantial benefits of plasma exchange, the wide 95% CI around the difference between groups means that large benefit or some harm is possible. The Editors Of patients with newly diagnosed myeloma, 12% to 20% present with acute renal failure (1-3). After correction of hypovolemia and hypercalcemia, 77% to 100% of patients with renal insufficiency may have biopsy-proven cast nephropathy or interstitial inflammation (4-8). Renal inflammation results from excessive filtered monoclonal light chains, which are transported to the interstitium of the kidney via specific receptors in the proximal tubule. These receptors are overloaded by excess light chains, resulting in an overflow to the distal tubule where combination with TammHorsfall protein produces obstructive casts (9-13). Plasma exchange transiently removes light chains and, thus, may be beneficial in treating some patients with acute renal failure (14-19). Two small, randomized trials involving 29 and 21 participants, respectively, provide conflicting results (4, 19). Despite a lack of convincing evidence, recent reviews and management guidelines endorse plasma exchange as useful for preventing acute renal failure associated with myeloma kidney (15, 20-23). The uncertainty about the role of plasma exchange prompted us to conduct a multicenter randomized, controlled trial in patients with myeloma-associated acute kidney failure. The primary research question was whether 5 to 7 plasma exchanges, in addition to conventional therapy, at the onset of myeloma with acute renal failure reduced the composite outcome of death, dialysis dependence, or a glomerular filtration rate (GFR) less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) at 6 months. Methods Study Participants Study participants included patients with newly diagnosed multiple myeloma and progressive acute kidney failure. All had a bone marrow aspirate with more than 10% plasma cells and a monoclonal light chain in their urine, plasma, or renal tissue. We defined progressive acute kidney failure as a serum creatinine level greater than 200 mol/L (>2.3 mg/dL) with an increase greater than 50 mol/L (>0.6 mg/dL) in the preceding 2 weeks despite correction of hypercalcemia, hypovolemia, and metabolic acidosis in patients with normal-sized kidneys on renal ultrasonography. Exclusion criteria were age less than 18 years or greater than 81 years, obstruction on renal ultrasonography (required examination), use of intravenous contrast or nonsteroidal anti-inflammatory drugs during the previous 2 weeks, previous treatment for myeloma, pregnancy, or inability to provide informed consent. Research Design and Intervention Fourteen Canadian medical centers participated in the trial: 3 centers recruited more than 10 patients each, 5 centers recruited 5 to 9 patients each, and 6 centers recruited fewer than 5 patients each. Patients who fulfilled entry criteria were referred by their oncologist or nephrologist to the apheresis physician at their center. The apheresis physician explained the nature of the study by using a human ethicsapproved letter of information. We requested informed consent, and if we obtained it, we randomly assigned the participants centrally by telephone, by using a computer random-number generator (24, 25), to either receive or not to receive plasma exchange. We stratified randomization by 4 strata according to whether patients were receiving vincristineadriamycindexamethasone (VAD) and whether patients were receiving short-term hemodialysis. Recruiting physicians were unaware of the treatment allocation before study entry. Of note, randomization used 104 of the 1568 concealed random-numbergenerated allocations, and the imbalanced assignment of 61 patients to plasma exchange and 43 patients to control was solely due to random chance. After random blinded allocation, participants were treated in an unblinded manner. We enrolled participants from September 1998 to October 2003. The institutional ethics review boards of the 14 Canadian sites approved the protocol. Patients who were randomly assigned to receive plasma exchange underwent 5 to 7 plasma exchange procedures within the first 10 days of study entry, concurrent with the initiation of chemotherapy. They received a routine plasma exchange of 50 mL per kg of body weight with acid citrate dextrose as the anticoagulant through a Spectra cell separator (Gambro BCT, Lakewood, Colorado), using 5% human serum albumin and normal saline as the replacement solutions. Chemotherapy was either melphalan and prednisone taken daily for 4 days every 28 days for up to 12 cycles or 4 days of slow intravenous infusion of VAD given on days 1 to 4, 9 to 12, and 17 to 20 for 28-day cycles up to 6 cycles. For participants allocated to plasma exchange, we stopped VAD treatment 1.5 hours before the plasma exchange and did not give VAD treatment during the plasma exchange. After the plasma exchange, patients received a bolus volume of VAD that would have been the amount infused during this time. Measurements We assessed the following blood and urine test results at study entry and at 1 and 6 months: serum creatinine, serum calcium, serum albumin, and 24-hour urine for protein levels. We used DurieSalmon staging to classify the severity of multiple myeloma at presentation, and we estimated GFR by using the Modified Diet in Renal Disease (MDRD) equation (26, 27). Our primary outcome, assessed at 6 months, was a composite measure that included death, dialysis dependence, and an estimated GFR less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) calculated from the 6-month serum creatinine level. We included this GFR as a component of the outcome because this degree of kidney impairment is associated with increased risk for death, cardiovascular events, and hospitalization (28). Statistical Analysis On the basis of historical data, which suggested a probable event rate greater than 50%, we calculated a sample size that would detect an effect of plasma exchange on dialysis dependence, without informative censoring from death, at 6 months (4, 17, 19). To detect a difference of 50% in that outcome with a type 1 error of 0.05 (2-sided) and a type 2 error probability of 0.20, we required a sample size of 46 participants per group. We used this historical-based power analysis to provide a conservative estimate of sample size to detect a statistically significant difference in the composite outcome of death, dialysis dependence, or a GFR less than 0.29 mLs2m2 (<30 mL/min per 1.73 m2) in our future study. The safety subcommittee conducted an interim analysis when the fiftieth participant had completed the 6-month follow-up to prevent some patients from unnecessarily receiving a less effective treatment. The committee evaluated differences between the plasma exchange and control groups, with respect to the primary composite and secondary outcomes at 6 months by using Pearson chi-square. The committee evaluated the time to death by treatment groups by using KaplanMeier survival analysis with a log-rank test for differences between groups. It conducted univariate and multivariate modeling of death and composite outcomes by using logistic regression to determine the unadjusted and adjusted odd ratios for the selected baseline determinants of chemotherapy, dialysis, age, urine protein level, serum albumin level, and DurieSalmon stage for plasma exchange (29). The committee performed these secondary analyses to determine which factors, if any, influenced outcomes. No variables were missing for analyses, except for age of 1 patient, which reduced our GFR determination to 57 of 58 patients in the plasma exchange group. We conducted all statistical analyses by using the Statistical Package for the Social Sciences (SPSS), version 12.0 for Windows (SPSS, Inc., Chicago, Illinois). All significance testing used 2-tailed tests, reflecting the open-ended research hypothesis. Role of the Funding Source The Canadian Institute of Health Research, Gambro BCT, and The Kidney Foundation of Canada funded the trial. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the paper for publication. Gambro BCT has a direct financial interest in the study outcome since they are the purveyor of the Gambro Spectra, which was the cell separator used in the trial. Results Of 104 patients who were initially enrolled in the study, 7 were withdrawn. Of these 7 patients, 3 were ineligible and 4 were lost to follow-up (Figure 1). Among the 4 patients lost to follow-up, 1 was a homeless person and the other 3 withdrew from all medical care and follow-up after diagnosis. Thus, intention-to-treat analyses included 58 patients in the plasma exchange group and 39 patients in the conventional therapy control group. No patient crossed over from his or her treatment assignment group during the trial, and all 58 patients randomly assigned to receive plasma exchange received 5 to 7 treatments. Figure 1. Flow of patients through the study to death or dialysis dependence. Baseline characteristics were similar between groups (Table 1). Forty-three participants had a monoclonal , 36 participants had a monoclonal , and the remainder had a monoclonal BenceJones protein in excess. The monoclonal protein occurred in both the plasma and urine in 59 participants, in the plasma in 76 participants, in the urine in 79 participants, and in the casts of the renal biopsy in 1 participant. Table 1. Baseline Charact

Acute Interstitial Nephritis Due to Drugs: Review of the Literature with a Report of Nine Cases

Acute interstitial nephritis due to drugs commonly presents as acute renal failure and may be commoner than is presently realized. Drugs implicated include not only methicillin and other penicillins but also diuretics and nonsteroidal anti-inflammatory agents. The mechanism of injury likely involves an immunologic disturbance, possibly a delayed hypersensitivity reaction. Differential diagnosis from other causes of acute renal failure may be difficult, but coincident evidence of an acute allergic reaction may help, as may the detection of eosinophils in the urine or avid uptake of 67Ga by the kidneys. Definitive diagnosis may require renal biopsy, which will reveal normal glomeruli and a patchy but usually heavy interstitial infiltrate with lymphocytes, plasma cells, and eosinophils. Diagnosis of acute interstitial nephritis is important, because withdrawal of the offending agent will usually result in rapid improvement in renal function, and steroid therapy may reduce residual chronic renal damage.

Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis

BACKGROUND & AIMS Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS. METHODS We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls). RESULTS Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r(2) < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. CONCLUSION This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS following acute gastroenteritis.

Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery

Background Although postinfectious irritable bowel syndrome (PI-IBS) is a well-recognised complication of acute gastroenteritis, its prognosis remains poorly defined. The natural history of PI-IBS was assessed among participants in the Walkerton Health Study (WHS), which has followed the long-term effects of a large outbreak of acute gastroenteritis related to municipal water contamination in May 2000. Methods WHS participants were invited to return for annual assessment at a research clinic. Adult residents of Walkerton at the time of the outbreak who enrolled in 2002/2003 and returned for assessment in 2008 were eligible for a PI-IBS study cohort if they had no prior history of IBS or inflammatory bowel disease. A modified Bowel Disease Questionnaire was used to diagnose IBS by Rome I criteria and to identify IBS subtypes. Results Of 4561 WHS participants, 2451 returned for their 8 year assessment and 1166 were eligible for the PI-IBS study cohort (688 females, mean age 46.2 years). The prevalence of IBS among 742 eligible subjects who suffered acute gastroenteritis during the outbreak declined from 28.3% after 2–3 years to 15.4% after 8 years, but remained significantly increased compared with controls who did not have acute gastroenteritis (OR 3.12; 95% CI 1.99 to 5.04). Independent risk factors for PI-IBS at 8 years included female gender, younger age, prior anxiety/depression, and fever or weight loss during the acute enteric illness. IBS subtypes were not stable over time. Conclusions Acute gastroenteritis can trigger IBS symptoms that persist for at least 8 years. Characteristics of the host and the acute enteric illness can predict the long-term risk of PI-IBS.

Elevated blood pressure in relation to overweight and obesity among children in a rural Canadian community.

OBJECTIVE. Childhood overweight and obesity may result in premature onset of cardiovascular risk factors such as hypertension. Rural populations in North America may be at increased risk for overweight. We evaluated whether overweight and obesity were associated with prehypertension and hypertension in a well-characterized population of children in rural Canada. METHODS. The study population for this cross-sectional study was composed of children (aged 4–17 years) who were participants of the Walkerton Health Study (Canada) in 2004. Prehypertension and hypertension were defined on the basis of percentiles from the average of 3 blood pressure measures taken on a single occasion. Percentiles for BMI and blood pressure were calculated by using the 2000 Centers for Disease Control and Prevention growth charts. Multinomial logistic regression was used to evaluate the odds for prehypertension and hypertension resulting from overweight and obesity. RESULTS. Of 675 children (98.7% white), 122 (18.1%) were overweight and 77 (11.4%) were obese. Prehypertension and hypertension were detected in 51 (7.6%) and 50 (7.4%), respectively. After adjustment for family history of hypertension and kidney disease, obesity was associated with both prehypertension and hypertension. Overweight was associated with hypertension but not prehypertension. These associations were observed across the genders and children aged <13 and ≥13 years, except that overweight was not associated with hypertension among girls. CONCLUSIONS. In this population of children who lived in a rural community in Canada, overweight and obesity were strongly associated with elevated blood pressure. Whether blood pressure normalizes with improvements in diet, physical activity, and environment is an area for additional study.

Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial

BackgroundGranulomatosis with polyangiitis (GPA, Wegener’s) and microscopic polyangiitis (MPA) are small vessel vasculitides collectively referred to as anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). AAV is associated with high rates of morbidity and mortality due to uncontrolled disease and treatment toxicity. Small randomized trials suggest adjunctive plasma exchange may improve disease control, while observational evidence suggests that current oral glucocorticoid doses are associated with severe infections in patients with AAV. A randomized study of both plasma exchange and glucocorticoids is required to evaluate plasma exchange and oral glucocorticoid dosing in patients with AAV.Methods/designPEXIVAS is a two-by-two factorial randomized trial evaluating adjunctive plasma exchange and two oral glucocorticoid regimens in severe AAV. Five hundred patients are being randomized at centers across Europe, North America, Asia, and Australasia to receive plasma exchange or no plasma exchange, and to receive standard or reduced oral glucocorticoid dosing. All patients receive immunosuppression with either cyclophosphamide or rituximab. The primary outcome is the time to the composite of all-cause mortality and end-stage renal disease.PEXIVAS is funded by the National Institute of Health Research (UK), the Food and Drug Administration (USA), the National Institutes of Health (USA), the Canadian Institute of Health Research (Canada), the National Health and Medical Research Council (Australia), and Assistance Publique (France). Additional in-kind supplies for plasma exchange are provided by industry partners (TerumoBCT, Gambro Australia, and Fresenius Australia).DiscussionThis is the largest trial in AAV undertaken to date. PEXIVAS will inform the future standard of care for patients with severe AAV. The cooperation between investigators, funding agencies, and industry provides a model for conducting studies in rare diseases.Trial registrationCurrent Controlled Trials:(ISRCTN07757494) and clinicaltrials.gov:(NCT00987389)

Urine Volume and Change in Estimated GFR in a Community-Based Cohort Study

BACKGROUND AND OBJECTIVES The effect of increased fluid intake on kidney function is unclear. This study evaluates the relationship between urine volume and renal decline over 6 years in a large community-based cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective cohort study was undertaken in Canada from 2002 to 2008. We obtained 24-hour urine samples from adult participants with an estimated GFR (eGFR) ≥60 ml/min per 1.73 m(2) at study entry. Percentage annual change in eGFR from baseline was categorized as average decline <1% per year, between 1% and 4.9% (mild-to-moderate decline) or ≥5% (rapid decline). RESULTS 2148 participants provided valid 24-hour urine samples, grouped as <1 L/d (14.5%); 1 to 1.9 L/d (51.5%); 2 to 2.9 L/d (26.3%); and ≥3 L/d (7.7%). Baseline eGFR for each category of urine volume was 90, 88, 84, and 87 ml/min per 1.73 m(2), respectively. Overall, eGFR declined by 1% per year, with 10% demonstrating rapid decline and 40% demonstrating mild-to-moderate decline. An inverse, graded relationship was evident between urine volume and eGFR decline: For each increasing category of 24-hour urine volume, percentage annual eGFR decline was progressively slower, from 1.3%, 1.0%, 0.8%, to 0.5%, respectively; P = 0.02. Compared with those with urine volume 1 to 1.9 L/d, those with urine volume ≥3 L/d were significantly less likely to demonstrate mild-to-moderate decline (adjusted odds ratio 0.66; 95% confidence interval 0.46 to 0.94) or rapid decline (adjusted odds ratio 0.46; 95% confidence interval 0.23 to 0.92); adjusted for age, gender, baseline eGFR, medication use for hypertension (including diuretics), proteinuria, diabetes, and cardiovascular disease. CONCLUSIONS In this community-based cohort, decline in kidney function was significantly slower in those with higher versus lower urine volume.

Association between estimated glomerular filtration rate at initiation of dialysis and mortality

Background Recent studies have reported a trend toward earlier initiation of dialysis (i.e., at higher levels of glomerular filtration rate) and an association between early initiation and increased risk of death. We examined trends in initiation of hemodialysis within Canada and compared the risk of death between patients with early and late initiation of dialysis. Methods The analytic cohort consisted of 25 910 patients at least 18 years of age who initiated hemodialysis, as identified from the Canadian Organ Replacement Register (2001–2007). We defined the initiation of dialysis as early if the estimated glomerular filtration rate was greater than 10.5 mL/min per 1.73 m2. We fitted time-dependent proportional-hazards Cox models to compare the risk of death between patients with early and late initiation of dialysis. Results Between 2001 and 2007, mean estimated glomerular filtration rate at initiation of dialysis increased from 9.3 (standard deviation [SD] 5.2) to 10.2 (SD 7.1) (p < 0.001), and the proportion of early starts rose from 28% (95% confidence interval [CI] 27%–30%) to 36% (95% CI 34%–37%). Mean glomerular filtration rate was 15.5 (SD 7.7) mL/min per 1.73 m2 among those with early initiation and 7.1 (SD 2.0) mL/min per 1.73 m2 among those with late initiation. The unadjusted hazard ratio (HR) for mortality with early relative to late initiation was 1.48 (95% CI 1.43–1.54). The HR decreased to 1.18 (95% CI 1.13–1.23) after adjustment for demographic characteristics, serum albumin, primary cause of end-stage renal disease, vascular access type, comorbidities, late referral and transplant status. The mortality differential between early and late initiation per 1000 patient-years narrowed after one year of follow-up, but never crossed and began widening again after 24 months of follow-up. The differences were significant at 6, 12, 30 and 36 months. Interpretation In Canada, dialysis is being initiated at increasingly higher levels of glomerular filtration rate. A higher glomerular filtration rate at initiation of dialysis is associated with an increased risk of death that is not fully explained by differences in baseline characteristics.

An Outbreak of Acute Bacterial Gastroenteritis Is Associated With an Increased Incidence of Irritable Bowel Syndrome in Children

OBJECTIVES:Acute bacterial gastroenteritis is associated with subsequent post-infectious irritable bowel syndrome (PI-IBS) in adults. Less is known about this relationship in children. In May 2000, contamination of municipal water by Escherichia coli 0157:H7 and Campylobacter species caused a large outbreak of acute gastroenteritis in Walkerton, Ontario. We assessed this association among a cohort of children enrolled in the Walkerton Health Study (WHS).METHODS:WHS participants who were under age 16 at the time of the outbreak but who reached age 16 during the 8-year study follow-up were eligible for the pediatric PI-IBS study cohort. Eligibility also required no diagnosis of IBS or inflammatory bowel disease before the outbreak and permanent residency in the Walkerton postal code at the time of the outbreak. Validated criteria were used to classify subjects as having had no gastroenteritis (unexposed controls), self-reported gastroenteritis, or clinically suspected gastroenteritis during the outbreak. From 2002 to 2008, standardized biennial interviews used a modified Bowel Disease Questionnaire to diagnose IBS by Rome I criteria. Risk factors for IBS were identified by logistic regression.RESULTS:In all, 467 subjects were eligible for the pediatric PI-IBS study cohort (47.1% female; mean age 11.6±2.44 years at the time of the outbreak). Of these, 305 were exposed to GE (130 clinically suspected and 175 self-reported) and 162 were unexposed controls. The cumulative incidence of IBS was significantly increased among exposed subjects vs. controls (10.5% vs. 2.5%; odds ratio 4.6, 95% confidence interval (1.6, 13.3)). In an unadjusted risk factor analysis, IBS was associated with a shorter time interval from exposure to assessment of IBS symptoms, female gender, diarrheal illness lasting more than 7 days, weight loss >10 lb, and antibiotic use during the outbreak. In adjusted analyses, both female gender and time interval to assessment of IBS symptoms remained independent predictors of PI-IBS.CONCLUSIONS:Acute bacterial gastroenteritis is associated with subsequent IBS in children as in adults. Risk factors for PI-IBS in children are similar to those identified among adults. Confirmation of these findings in similar cohorts is needed.