Neil Boudville

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

Psychosocial health of living kidney donors: a systematic review

Knowledge of the psychosocial benefits and harms faced by living kidney donors is necessary for informed consent and follow‐up. We reviewed any English language study where psychosocial function was assessed using questionnaires in 10 or more donors after nephrectomy. We searched MEDLINE, EMBASE, Web of Science, Psych INFO, Sociological Abstracts and CINAHL databases and reviewed reference lists from 1969 through July 2006. Independently, two reviewers abstracted data on study, donor and control group characteristics, psychosocial measurements and their outcomes. Fifty‐one studies examined 5139 donors who were assessed an average of 4 years after nephrectomy. The majority experienced no depression (77–95%) or anxiety (86–94%), with questionnaire scores similar to controls. The majority reported no change or an improved relationship with their recipient (86–100%), spouse (82–98%), family members (83–100%) and nonrecipient children (95–100%). Some experienced an increase in self‐esteem. A majority (83–93%) expressed no change in their attractiveness. Although many scored high on quality of life measures, some prospective studies described a decrease after donation. A small proportion of donors had adverse psychosocial outcomes. Most kidney donors experience no change or an improvement in their psychosocial health after donation. Harms may be minimized through careful selection and follow‐up.

Cardiovascular disease in kidney donors: matched cohort study

Objective To determine whether people who donate a kidney have an increased risk of cardiovascular disease. Design Retrospective population based matched cohort study. Participants All people who were carefully selected to become a living kidney donor in the province of Ontario, Canada, between 1992 and 2009. The information in donor charts was manually reviewed and linked to provincial healthcare databases. Matched non-donors were selected from the healthiest segment of the general population. A total of 2028 donors and 20 280 matched non-donors were followed for a median of 6.5 years (maximum 17.7 years). Median age was 43 at the time of donation (interquartile range 34-50) and 50 at the time of follow-up (42-58). Main outcome measures The primary outcome was a composite of time to death or first major cardiovascular event. The secondary outcome was time to first major cardiovascular event censored for death. Results The risk of the primary outcome of death and major cardiovascular events was lower in donors than in non-donors (2.8 v 4.1 events per 1000 person years; hazard ratio 0.66, 95% confidence interval 0.48 to 0.90). The risk of major cardiovascular events censored for death was no different in donors than in non-donors (1.7 v 2.0 events per 1000 person years; 0.85, 0.57 to 1.27). Results were similar in all sensitivity analyses. Older age and lower income were associated with a higher risk of death and major cardiovascular events in both donors and non-donors when each group was analysed separately. Conclusions The risk of major cardiovascular events in donors is no higher in the first decade after kidney donation compared with a similarly healthy segment of the general population. While we will continue to follow people in this study, these interim results add to the evidence base supporting the safety of the practice among carefully selected donors.

Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.

BACKGROUND Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes. METHODS Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis. RESULTS Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events. CONCLUSIONS Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.

The Long-Term Quality of Life of Living Kidney Donors: A Multicenter Cohort Study

Previous studies that described the long‐term quality of life of living kidney donors were conducted in single centers, and lacked data on a healthy nondonor comparison group. We conducted a retrospective cohort study to compare the quality of life of 203 kidney donors with 104 healthy nondonor controls using validated scales (including the SF36, 15D and feeling thermometer) and author‐developed questions. Participants were recruited from nine transplant centers in Canada, Scotland and Australia. Outcomes were assessed a median of 5.5 years after the time of transplantation (lower and upper quartiles of 3.8 and 8.4 years, respectively). 15D scores (scale of 0 to 1) were high and similar between donors and nondonors (mean 0.93 (standard deviation (SD) 0.09) and 0.94 (SD 0.06), p = 0.55), and were not different when results were adjusted for several prognostic characteristics (p = 0.55). On other scales and author‐developed questions, groups performed similarly. Donors to recipients who had an adverse outcome (death, graft failure) had similar quality of life scores as those donors where the recipient did well. Our findings are reassuring for the practice of living transplantation. Those who donate a kidney in centers that use routine pretransplant donor evaluation have good long‐term quality of life.

Living kidney donation: outcomes, ethics, and uncertainty

Since the first living-donor kidney transplantation in 1954, more than half a million living kidney donations have occurred and research has advanced knowledge about long-term donor outcomes. Donors in developed countries have a similar life expectancy and quality of life as healthy non-donors. Living kidney donation is associated with an increased risk of end-stage renal disease, although this outcome is uncommon (<0·5% increase in incidence at 15 years). Kidney donation seems to elevate the risks of gestational hypertension and pre-eclampsia. Many donors incur financial expenses due to factors such as lost wages, need for sick days, and travel expenses. Yet, most donors have no regrets about donation. Living kidney donation is practised ethically when informed consent incorporates information about risks, uncertainty about outcomes is acknowledged when it exists, and a donors risks are proportional to benefits for the donor and recipient. Future research should determine whether outcomes are similar for donors from developing countries and donors with pre-existing conditions such as obesity.

Recent Peritonitis Associates with Mortality among Patients Treated with Peritoneal Dialysis

Peritonitis is a major complication of peritoneal dialysis, but the relationship between peritonitis and mortality among these patients is not well understood. In this case-crossover study, we included the 1316 patients who received peritoneal dialysis in Australia and New Zealand from May 2004 through December 2009 and either died on peritoneal dialysis or within 30 days of transfer to hemodialysis. Each patient served as his or her own control. The mean age was 70 years, and the mean time receiving peritoneal dialysis was 3 years. In total, there were 1446 reported episodes of peritonitis with 27% of patients having ≥ 2 episodes. Compared with the rest of the year, there were significantly increased odds of peritonitis during the 120 days before death, although the magnitude of this association was much greater during the 30 days before death. Compared with a 30-day window 6 months before death, the odds for peritonitis was six-fold higher during the 30 days immediately before death (odds ratio, 6.2; 95% confidence interval, 4.4-8.7). In conclusion, peritonitis significantly associates with mortality in peritoneal dialysis patients. The increased odds extend up to 120 days after an episode of peritonitis but the magnitude is greater during the initial 30 days.

The effect of low glucose degradation product, neutral pH versus standard peritoneal dialysis solutions on peritoneal membrane function: the balANZ trial

Background The balANZ trial recently reported that neutral pH, low glucose degradation product (biocompatible) peritoneal dialysis (PD) solutions significantly delayed anuria and reduced peritonitis rates compared with conventional solutions. This article reports a secondary outcome analysis of the balANZ trial with respect to peritoneal membrane function. Methods Adult, incident PD patients with residual renal function were randomized to receive either biocompatible or conventional (control) PD solutions for 2 years. Peritoneal equilibration tests were performed at 1, 6, 12, 18 and 24 months. Peritoneal small solute clearances and ultra-filtration (UF) were measured at 3, 6, 9, 12, 18 and 24 months. Results Of the 185 patients recruited into the trial, 85 patients in the Balance group and 82 patients in the control group had peritoneal membrane function evaluated. Mean 4-h dialysate:plasma creatinine ratios (D:P Cr 4h) at 1 month were significantly higher in the Balance group compared with controls (0.67 ± 0.10 versus 0.62 ± 0.10, P = 0.002). Over the 2-year study period, mean D:P Cr 4 h measurements remained stable in the Balance group but increased significantly in controls [difference −0.004 per month, 95% confidence interval (95% CI) −0.005 to −0.002, P < 0.001]. Similar results were obtained for dialysate glucose ratios (D/D0 glucose). Peritoneal UF was significantly lower in the Balance group than in controls at 3 and 6 months. Over the 2-year study period, peritoneal UF increased significantly in the Balance group but remained stable in controls (difference 24 mL/day/month, 95% CI 9–39, P = 0.002). No differences in peritoneal small solute clearances, prescribed dialysate fill volumes or peritoneal glucose exposure were observed between the two groups. Conclusions Biocompatible and conventional PD solutions exert differential effects on peritoneal small solute transport rate and UF over time. Adequately powered trials assessing the impact of these differential membrane effects on PD technique and patient survival rates are warranted.

Reimbursing Live Organ Donors for Incurred Non-Medical Expenses: A Global Perspective on Policies and Programs

Methods to reimburse living organ donors for the non‐medical expenses they incur have been implemented in some jurisdictions and are being considered in others. A global understanding of existing legislation and programs would help decision makers implement and optimize policies and programs.

Economic consequences incurred by living kidney donors: A canadian multi-center prospective study

Some living kidney donors incur economic consequences as a result of donation; however, these costs are poorly quantified. We developed a framework to comprehensively assess economic consequences from the donor perspective including out‐of‐pocket cost, lost wages and home productivity loss. We prospectively enrolled 100 living kidney donors from seven Canadian centers between 2004 and 2008 and collected and valued economic consequences (