Norman Muirhead

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

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)

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

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUND The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. METHODS Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. RESULTS The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). CONCLUSIONS MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

A disease-specific questionnaire for assessing quality of life in patients on hemodialysis.

A disease-specific questionnaire was developed for patients receiving chronic hemodialysis by interviewing patients to determine which aspects of their quality of life were adversely affected by their disease. The final questionnaire contained 26 questions in five dimensions (physical symptoms, fatigue, depression, relationships with others, frustration). The questionnaire demonstrated construct validity when compared with the Sickness Impact Profile, time trade-off technique and an exercise stress test. It was reproducible in stable, placebo-treated patients (correlation coefficient 0.85-0.98 for the 5 dimensions). It was more responsive than other measures in detecting an improvement with erythropoietin therapy in a randomized, placebo-controlled trial. This questionnaire should be useful for the assessment of the effect of various interventions upon the quality of life of hemodialysis patients.

Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation

Recent data suggest that optimal cyclosporine (CsA) exposure early post‐transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration‐controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral.

Supramaximal Dose of Candesartan in Proteinuric Renal Disease

High levels of proteinuria predict renal deterioration, suggesting that interventions to reduce proteinuria may postpone the development of severe renal impairment. This multicenter Canadian trial evaluated whether supramaximal dosages of candesartan would reduce proteinuria to a greater extent than the maximum approved antihypertensive dosage. The authors randomly assigned 269 patients who had persistent proteinuria (> or =1 g/d) despite 7 wk of treatment with the highest approved dosage of candesartan (16 mg/d) to 16, 64, or 128 mg/d candesartan for 30 wk. The median serum creatinine level was 130.0 micromol/L (1.47 mg/dl), and the median urinary protein excretion was 2.66 g/d; most (53.9%) patients had diabetic nephropathy. The mean difference of the percentage change in proteinuria for patients receiving 128 mg/d candesartan compared with those receiving 16 mg/d candesartan was -33.05% (95% confidence interval -45.70 to -17.44; P < 0.0001). Reductions in BP were not different across the three treatment groups. Elevated serum potassium levels (K+ > 5.5 mEq/L) led to the early withdrawal of 11 patients, but there were no dosage-related increases in adverse events. In conclusion, proteinuria that persists despite treatment with the maximum recommended dosage of candesartan can be reduced by increasing the dosage of candesartan further, but serum potassium levels should be monitored during treatment.

Prediction of early death in end-stage renal disease patients starting dialysis

Demand for dialysis for patients with end-stage renal disease is growing, as is the comorbidity of dialysis patients. Accurate prediction of those destined to die quickly despite dialysis could be useful to patients, providers, and society in making decisions about starting dialysis. To determine whether age and comorbidity accurately predict death within 6 months of first dialysis for end-stage renal disease, a prospective cohort study of 822 patients starting dialysis at one of 11 Canadian centers was performed. Patient characteristics were recorded at first dialysis. Follow-up continued until death or study end (at least 6 months after enrollment). One hundred thirteen of 822 (13.7%) patients died within 6 months. Although an existing scoring system predicted prognosis, adverse scores greater than 9 were found in only 9.7% of those who died; only 52% of those who scored higher than 9 died within 6 months. No score cutoff point combined high true-positive and low false-positive rates for predicting early death. Age, severity of heart failure or peripheral vascular disease, arrhythmias, malnutrition, malignancy, or myeloma were independent prognostic factors identified in multivariate models. However, the best fit discriminant and logistic models were also unable to accurately predict death within 6 months. Clinicians were very accurate in assigning patients to prognostic groups up to a 50% risk of death by 6 months, above which they tended to overestimate risk. However, clinicians were only marginally better than the predictive models in determining whether a given high-risk patient would die. The inability of a scoring system or clinical intuition to accurately predict death soon after starting dialysis for end-stage renal disease suggests that limiting access to dialysis on the basis of likely short survival may be inappropriate in Canada.

Evidence-Based Recommendations for the Clinical Use of Recombinant Human Erythropoietin

In an era of increasing scrutiny regarding use of health care resources, it is critical that physicians have rational, evidence-based guidelines for treatment decisions. This review of more than 200 published papers constitutes a comprehensive approach to evaluating the current evidence regarding the clinical use of recombinant human erythropoietin therapy in renal failure patients. After this review, specific recommendations are provided regarding who should receive r-HuEPO; what the target hemoglobin should be; the best route of administration of r-HuEPO; how iron status should be evaluated and managed; and monitoring and follow-up of patients taking r-HuEPO. Throughout the article, areas for important future research are also identified.

The Outcome Of Pregnancy Following Renal Transplantation—the Experience Of A Single Center

Many centers still recommend avoidance of pregnancy after renal transplantation because of fears for the safety of both mother and fetus. These fears are in part based on a lack of information concerning the effects of newer immunosuppressive drugs such as cyclosporine on the course and outcome of pregnancy. The present study examines the experience of first pregnancies following renal transplantation in a single center, with emphasis on the role of CsA. Data on the first pregnancies of 22 women transplanted between 1977 and 1988 were studied. The mean age of patients at the time of transplant was 23.4±3.1 years and interval from transplant to pregnancy was 34.5±24.5 months (range 1–75 months). Twelve patients received CsA alone or in combination with other immunosuppressives, while the remaining 10 patients received azathioprine and prednisone. Mean serum creatinine fell progressively during pregnancy in both CsA-and azathioprine-treated mothers. Mean CsA dose rose during pregnancy while mean CsA blood concentration fell during the 2nd trimester (P=0.042). The gestation period ranged from 27 to 40 weeks (35.5±3.3) with 14 pregnancies ending prematurely prior to 37 weeks. Thirteen deliveries occurred by Caesarian section. Hypertension complicated 10 pregnancies. Birth weight correlated directly with both maternal weight gain (r=0.57; P < 0.02) and gestational age (r=0.9; P < 0.01). Ten of 23 offspring were below the 10th percentile for weight. Mean birth weight ranged from 0.72 to 3.7 kg (2.3±0.84 kg). The mean birth weight and gestational age of children born to mothers taking CsA were lower than those in azathioprine treated mothers but these differences were not statistically significant. Successful pregnancy is possible following renal transplantation, although there is a high rate of prematurity, low birth weight, and intrauterine growth retardation. CsA dose requirements may be increased. Maternal risks including hypertension require that such pregnancies be handled by a multidisciplinary team approach.