Amit X. Garg

Chronic Kidney Disease and Mortality Risk: A Systematic Review

Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.

Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis.

BACKGROUND Acute kidney injury (AKI) is common in hospitalized patients. The impact of AKI on long-term outcomes is controversial. STUDY DESIGN Systematic review and meta-analysis. SETTING & PARTICIPANTS Persons with AKI. SELECTION CRITERIA FOR STUDIES MEDLINE and EMBASE databases were searched from 1985 through October 2007. Original studies describing outcomes of AKI for patients who survived hospital discharge were included. Studies were excluded from review when participants were followed up for less than 6 months. PREDICTOR AKI, defined as acute changes in serum creatinine level or acute need for renal replacement therapy. OUTCOMES Chronic kidney disease (CKD), cardiovascular disease, and mortality. RESULTS 48 studies that contained a total of 47,017 participants were reviewed; 15 studies reported long-term data for patients without AKI. The incidence rate of mortality was 8.9 deaths/100 person-years in survivors of AKI and 4.3 deaths/100 patient-years in survivors without AKI (rate ratio [RR], 2.59; 95% confidence interval, 1.97 to 3.42). AKI was associated independently with mortality risk in 6 of 6 studies that performed multivariate adjustment (adjusted RR, 1.6 to 3.9) and with myocardial infarction in 2 of 2 studies (RR, 2.05; 95% confidence interval, 1.61 to 2.61). The incidence rate of CKD after an episode of AKI was 7.8 events/100 patient-years, and the rate of end-stage renal disease was 4.9 events/100 patient-years. LIMITATIONS The relative risk for CKD and end-stage renal disease after AKI was unattainable because of lack of follow-up of appropriate controls without AKI. CONCLUSIONS The development of AKI, defined as acute changes in serum creatinine level, characterizes hospitalized patients at increased risk of long-term adverse outcomes.

Age Affects Outcomes in Chronic Kidney Disease

Chronic kidney disease (CKD) is common among the elderly. However, little is known about how the clinical implications of CKD vary with age. We examined the age-specific incidence of death, treated end-stage renal disease (ESRD), and change in estimated glomerular filtration rate (eGFR) among 209,622 US veterans with CKD stages 3 to 5 followed for a mean of 3.2 years. Patients aged 75 years or older at baseline comprised 47% of the overall cohort and accounted for 28% of the 9227 cases of ESRD that occurred during follow-up. Among patients of all ages, rates of both death and ESRD were inversely related to eGFR at baseline. However, among those with comparable levels of eGFR, older patients had higher rates of death and lower rates of ESRD than younger patients. Consequently, the level of eGFR below which the risk of ESRD exceeded the risk of death varied by age, ranging from 45 ml/min per 1.73 m(2) for 18 to 44 year old patients to 15 ml/min per 1.73 m(2) for 65 to 84 year old patients. Among those 85 years or older, the risk of death always exceeded the risk of ESRD in this cohort. Among patients with eGFR levels <45 ml/min per 1.73 m(2) at baseline, older patients were less likely than their younger counterparts to experience an annual decline in eGFR of >3 ml/min per 1.73 m(2). In conclusion, age is a major effect modifier among patients with an eGFR of <60 ml/min per 1.73 m(2), challenging us to move beyond a uniform stage-based approach to managing CKD.

Postoperative Biomarkers Predict Acute Kidney Injury and Poor Outcomes after Pediatric Cardiac Surgery

Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.

Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension.

Background:Intraoperative hypotension may contribute to postoperative acute kidney injury (AKI) and myocardial injury, but what blood pressures are unsafe is unclear. The authors evaluated the association between the intraoperative mean arterial pressure (MAP) and the risk of AKI and myocardial injury. Methods:The authors obtained perioperative data for 33,330 noncardiac surgeries at the Cleveland Clinic, Ohio. The authors evaluated the association between intraoperative MAP from less than 55 to 75 mmHg and postoperative AKI and myocardial injury to determine the threshold of MAP where risk is increased. The authors then evaluated the association between the duration below this threshold and their outcomes adjusting for potential confounding variables. Results:AKI and myocardial injury developed in 2,478 (7.4%) and 770 (2.3%) surgeries, respectively. The MAP threshold where the risk for both outcomes increased was less than 55 mmHg. Compared with never developing a MAP less than 55 mmHg, those with a MAP less than 55 mmHg for 1–5, 6–10, 11–20, and more than 20 min had graded increases in their risk of the two outcomes (AKI: 1.18 [95% CI, 1.06–1.31], 1.19 [1.03–1.39], 1.32 [1.11–1.56], and 1.51 [1.24–1.84], respectively; myocardial injury 1.30 [1.06–1.5], 1.47 [1.13–1.93], 1.79 [1.33–2.39], and 1.82 [1.31–2.55], respectively]. Conclusions:Even short durations of an intraoperative MAP less than 55 mmHg are associated with AKI and myocardial injury. Randomized trials are required to determine whether outcomes improve with interventions that maintain an intraoperative MAP of at least 55 mmHg.

Worldwide access to treatment for end-stage kidney disease: a systematic review

BACKGROUND End-stage kidney disease is a leading cause of morbidity and mortality worldwide. Prevalence of the disease and worldwide use of renal replacement therapy (RRT) are expected to rise sharply in the next decade. We aimed to quantify estimates of this burden. METHODS We systematically searched Medline for observational studies and renal registries, and contacted national experts to obtain RRT prevalence data. We used Poisson regression to estimate the prevalence of RRT for countries without reported data. We estimated the gap between needed and actual RRT, and projected needs to 2030. FINDINGS In 2010, 2·618 million people received RRT worldwide. We estimated the number of patients needing RRT to be between 4·902 million (95% CI 4·438-5·431 million) in our conservative model and 9·701 million (8·544-11·021 million) in our high-estimate model, suggesting that at least 2·284 million people might have died prematurely because RRT could not be accessed. We noted the largest treatment gaps in low-income countries, particularly Asia (1·907 million people needing but not receiving RRT; conservative model) and Africa (432,000 people; conservative model). Worldwide use of RRT is projected to more than double to 5·439 million (3·899-7·640 million) people by 2030, with the most growth in Asia (0·968 million to a projected 2·162 million [1·571-3·014 million]). INTERPRETATION The large number of people receiving RRT and the substantial number without access to it show the need to both develop low-cost treatments and implement effective population-based prevention strategies. FUNDING Australian National Health and Medical Research Council.

Shift work and vascular events: systematic review and meta-analysis

Objective To synthesise the association of shift work with major vascular events as reported in the literature. Data sources Systematic searches of major bibliographic databases, contact with experts in the field, and review of reference lists of primary articles, review papers, and guidelines. Study selection Observational studies that reported risk ratios for vascular morbidity, vascular mortality, or all cause mortality in relation to shift work were included; control groups could be non-shift (“day”) workers or the general population. Data extraction Study quality was assessed with the Downs and Black scale for observational studies. The three primary outcomes were myocardial infarction, ischaemic stroke, and any coronary event. Heterogeneity was measured with the I2 statistic and computed random effects models. Results 34 studies in 2 011 935 people were identified. Shift work was associated with myocardial infarction (risk ratio 1.23, 95% confidence interval 1.15 to 1.31; I2=0) and ischaemic stroke (1.05, 1.01 to 1.09; I2=0). Coronary events were also increased (risk ratio 1.24, 1.10 to 1.39), albeit with significant heterogeneity across studies (I2=85%). Pooled risk ratios were significant for both unadjusted analyses and analyses adjusted for risk factors. All shift work schedules with the exception of evening shifts were associated with a statistically higher risk of coronary events. Shift work was not associated with increased rates of mortality (whether vascular cause specific or overall). Presence or absence of adjustment for smoking and socioeconomic status was not a source of heterogeneity in the primary studies. 6598 myocardial infarctions, 17 359 coronary events, and 1854 ischaemic strokes occurred. On the basis of the Canadian prevalence of shift work of 32.8%, the population attributable risks related to shift work were 7.0% for myocardial infarction, 7.3% for all coronary events, and 1.6% for ischaemic stroke. Conclusions Shift work is associated with vascular events, which may have implications for public policy and occupational medicine.

Meta-Analysis: Risk for Hypertension in Living Kidney Donors

Context Does kidney donation increase a persons risk for hypertension? Contribution This review found 10 studies that compared blood pressure between kidney donors and healthy adults with similar age, sex, and ethnicity. Studies suggested that within 5 to 10 years of donation, kidney donors may have about a 5mm Hg increase in blood pressure over that anticipated with normal aging. Cautions Actual risks for hypertension were unclear because studies did not define hypertension uniformly and had incomplete follow-up information on many donors. Implications We need large, prospective, controlled studies with prolonged follow-up to better inform potential kidney donors of long-term risks associated with donation. The Editors Despite its advantages, living kidney donation remains a complex ethical, moral, and medical issue. Living kidney donation is practiced with the expectation that the risk for minimal short-term and long-term harm for the donor is outweighed by the psychological benefits of altruism and improved recipient health. The short-term complications of living donation are well established (1). However, the long-term risk for hypertension remains uncertain. A better understanding of this risk is central to donor selection and consent. This knowledge guides health policy on reimbursing costs of antihypertensive medication and the need for ongoing surveillance of the more than 80000 persons who have donated a kidney (2). The primary question of this review was whether normotensive adults who donate a kidney develop higher blood pressure and risk for hypertension compared with healthy nondonors acting as control participants. Reasons for considerably different estimates in the literature were also explored in meta-regression. Methods Study Selection We included studies in any language that examined 10 or more healthy normotensive adults who donated a kidney and had their blood pressure assessed at least 1 year later. We compiled citations from MEDLINE and EMBASE bibliographic databases from 1966 through November 2005. An experienced librarian developed the search strategies using sensitive terms for identifying clinical prognostic studies of living kidney donors (3, 4). We pilot-tested the search strategies and modified them to ensure that they identified known eligible articles. The final strategies included the terms living donors, cohort studies, course, longitudinal studies, hypertension, and blood pressure. We also compiled citations from information provided by primary study authors, the Science Citation Index, the Related Articles feature on PubMed, reference lists of previous reviews (5, 6), and reference lists of all studies included in our review. All citations were downloaded into Reference Manager, version 10.0 (Thomson ISI Research-Soft, Philadelphia, Pennsylvania). Pairs of reviewers independently evaluated the eligibility of each citation, and the full-text article was retrieved if either reviewer considered the citation potentially relevant. For all English-language publications, pairs of reviewers independently evaluated the eligibility of the full-text article; disagreements were resolved by a third reviewer. With the help of translators, a single reviewer evaluated the eligibility of all nonEnglish-language full-text articles. When data from the same group of donors were described in multiple publications, we reviewed all of the publications and cited the most representative one. Data Abstraction Pairs of reviewers independently abstracted the following data from all English-language studies meeting eligibility criteria: setting, methods, donor characteristics, control group characteristics, prognostic features, and hypertension outcomes. Disagreements were resolved by a third reviewer. For Czechoslovakian, Dutch, French, German, Italian, Japanese, Norwegian, Serbo-Croatian, and Spanish articles, data were abstracted by a single reviewer with the help of a translator. We attempted to contact primary authors of all included studies to confirm data and obtain missing data. Statistical Analysis Reviewer agreement on study eligibility was quantified by using the statistic. Variance estimates for changes in blood pressure before and after donation were not reported in most studies. If not reported, variance estimates were derived from t-statistics when available. Otherwise, variance estimates were calculated with where represents the correlation between the blood pressure measurements before and after donation (7). For the 2 studies that reported predonation, postdonation, and change variance estimates, we calculated average correlation coefficients of 0.92 and 0.84 for systolic blood pressure and diastolic pressure, respectively. To be conservative, we used a correlation of 0.5 to impute missing change variance estimates in the final meta-regression. We performed sensitivity analyses to this choice of correlation, and the results were qualitatively similar. For this study-level meta-analysis, the Q statistic was used to determine whether between-study heterogeneity was present; a P value less than 0.1 was considered statistically significant. The I2 statistic was used to quantify the magnitude of heterogeneity, with values of 0% to 30%, 31% to 50%, and greater than 50% representing mild, moderate, and notable heterogeneity, respectively (8). When justified, results were mathematically pooled by using techniques that accounted for within-study and between-study heterogeneity (random-effects method) (911). Reasons for diversity in study results were explored by using univariate and multivariate meta-regressions of donor cohorts: mixed models for continuous outcomes (PROC MIXED procedure, SAS statistical software, SAS Institute, Inc., Cary, North Carolina) and logistic normal random-effects models for binary outcomes (PROC NLMIXED procedure, SAS statistical software, SAS Institute, Inc.). At the study level, the association between the following donor characteristics and outcomes of hypertension, postdonation blood pressure, and change in blood pressure were considered: average age, the proportion of donors who were female, and average predonation blood pressure. Although potential donors vary in race, sex, and age at the time of nephrectomy, all are healthy and are confirmed to have normal blood pressure and renal function through rigorous evaluation. Nonetheless, we hypothesized that similar to the general population, donors would be more likely to develop hypertension if they were older, were male, and had a higher predonation blood pressure. Similarly, features of study methods associated with blood pressure outcomes after donation were considered. In meta-regression, we tested whether the study was conducted prospectively, the proportion of donors lost to follow-up, the duration of follow-up after nephrectomy, and the method by which blood pressure was assessed. For each meta-regression, only studies for which the factor of interest was available were included in the analysis. The explanatory ability of each factor was quantified by the proportion of between-study variability on the logit scale for binary outcomes and the proportion of between-study variability for continuous outcomes (11). A 2-tailed P value of 0.05 or less was considered statistically significant for binary outcomes, whereas for continuous outcomes, statistical significance was inferred by the proportion of variability explained by the factor and from the size of residual variance (11). Best-fit lines in meta-regression graphs were generated by generalized estimating equations (SAS procedure, PROC GENMOD, SAS statistical software) (12, 13). The generalized estimating equation models used estimates from the meta-regression models as the input values and were weighted by the estimated variances. An exchangeable correlation matrix was assumed for all such models. For models of binary outcomes, a binomial distribution with the logit link was used; for models of continuous outcomes, a normal distribution with the identity link was used. The 95% CI for each best-fit meta-regression line was computed as where g is the link function, xj is the vector of covariates, z is the percentile of the normal distribution, and x is the estimated standard error of the linear predictor. The variance estimate of the linear predictor was calculated as where is the empirical covariance matrix. The number of studies comparing donors with control participants was small and precluded meta-regression of these results. All analyses were conducted using SAS, version 8.02 (SAS Institute Inc.), and RevMan, version 4.2 (Cochrane Collaboration, Oxford, United Kingdom). Results were graphed in R 2.0.1 (R Foundation for Statistical Computing, Vienna, Austria). Role of the Funding Sources This review was supported by the London Multi-Organ Transplant Program, the Canadian Institutes of Health Research, the Physicians Services Incorporated Foundation, and the Canadian Council for Donation and Transplantation. Dr. Garg was supported by a Canadian Institutes of Health Research Clinician Scientist Award. Dr. Yang was supported by a Biomedical Fellowship from the Kidney Foundation of Canada. The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Results We screened 2886 citations and retrieved and evaluated the eligibility of 262 full-text articles. In addition to excluding studies ineligible for our review, we excluded 1 study that only reported mean arterial pressure in the absence of systolic blood pressure, diastolic blood pressure, or hypertension results (14). Some study cohorts also contained a substantial number of extended-criteria donors with hypertension, proteinuria, or a glomerular filtration rate of less than 80 mL/min per 1.73 m2 before surgery and did not separate reported outcomes from healthy donors. Becau

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