Greg Knoll

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

Mycophenolate Mofetil Dose Reduction and the Risk of Acute Rejection after Renal Transplantation

Mycophenolate mofetil (MMF) significantly decreases acute rejection rates after renal transplantation, but intolerance often occurs, leading to dose reduction. The clinical effect of MMF dose reduction has not been clearly established. This study determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close surveillance on such patients.

Tacrolimus versus cyclosporin for immunosuppression in renal transplantation : meta-analysis of randomised trials

Abstract Objective: To compare tacrolimus with cyclosporin for immunosuppression in renal transplantation. Design: Meta-analysis of randomised trials of two treatments after kidney transplantation. Identification: Four studies involving 1037 patients. Trials were included if they were randomised, the intervention group received tacrolimus, the control group received cyclosporin, the patients were followed for a minimum of 12 months, and patient survival, graft survival, incidence of acute rejection, need for antilymphocyte treatment, or the prevalence of diabetes mellitus after transplant was reported. Main outcome measures: Pooled estimates of patient mortality, allograft loss, and episodes of acute rejection 1 year after transplantation. Results: The odds ratio for loss of allograft with tacrolimus compared with cyclosporin was 0.95 (95% confidence interval 0.65 to 1.40). The odds ratio for mortality with tacrolimus was 1.07 (0.47 to 2.48). Treatment with tacrolimus was associated with a reduction in episodes of acute rejection (0.52; 0.36 to 0.75), a reduction in the use of antilymphocyte antibodies to treat rejection (0.37; 0.25 to 0.56), and an increased prevalence of diabetes mellitus after transplantation (5.03; 2.04 to 12.36) compared with treatment with cyclosporin. Conclusions: After renal transplantation, immunosuppression with tacrolimus results in a significant reduction in acute rejection compared with cyclosporin. Follow up studies of high methodological quality are needed to determine whether tacrolimus improves long term renal graft survival.

Estimating Glomerular Filtration Rate in Kidney Transplantation: A Comparison between Serum Creatinine and Cystatin C–Based Methods

Accurate measurement of GFR is critical for the evaluation of new therapies and the care of renal transplant recipients. Although not accurate in renal transplantation, GFR is often estimated using creatinine-based equations. Cystatin C is a marker of GFR that seems to be more accurate than creatinine. Equations to predict GFR based on the serum cystatin C concentration have been developed, but their accuracy in transplantation is unknown. GFR was estimated using four equations (Filler, Le Bricon, Larsson, and Hoek) that are based on serum cystatin C and seven equations that are based on serum creatinine in 117 adult renal transplant recipients. GFR was measured using radiolabeled diethylenetriaminepentaacetic acid (99mTc-DTPA), and the bias, precision, and accuracy of each equation were determined. The mean (99m)Tc-DTPA GFR was 58 +/- 23 ml/min per 1.73 m(2). The cystatin C-based equations of Filler and Le Bricon had the lowest bias (-1.7 and -3.8 ml/min per 1.73 m2), greatest precision (11.4 and 11.8 ml/min per 1.73 m2), and highest accuracy (87 and 89% within 30% of measured GFR, respectively). The cystatin C equations remained accurate even when the measured GFR was >60 ml/min per 1.73 m2. The creatinine-based equations were not as accurate, with only 53 to 80% of estimates within 30% of measured GFR. Cystatin C-based equations are more accurate at predicting GFR in renal transplant recipients than traditional creatinine-based equations. Further prospective studies with repetitive measurement of cystatin C are needed to determine whether cystatin C-based estimates of GFR will be sufficiently accurate to monitor long-term allograft function.

Treatment of polyomavirus infection in kidney transplant recipients: a systematic review.

Background. Polyomavirus-associated nephropathy (PVAN) is an important cause of kidney graft loss but there is no consensus on its management. This study aimed to systematically document all published treatments for PVAN to determine the most effective therapy. Methods. A computerized search in MEDLINE, EMBASE, and Cochrane databases (1950–2008) was performed. References from review articles and published abstracts from the American Transplant Congress (2005–2008) were also included. Study selection criteria included (a) population: adult (>18 years) kidney-only, primary or repeat renal transplant recipients; (b) setting: polyoma viruria, viremia or biopsy-proven PVAN or both; and (c) treatment: immunosuppression reduction alone or with adjuvant agents. The primary outcome was graft failure rate, and secondary outcomes included acute rejection rate, elimination of viruria and viremia, graft function, patient survival, and adverse events. Results. Of 555 identified citations, 40 studies examining the effect of immunosuppression reduction alone or in combination with cidofovir, leflunomide, intravenous immunoglobulin, or ciprofloxacin were included for appraisal. Pooled results found a death-censored graft loss rate of 8/100 patient-years for immunosuppression reduction alone and 8 and 13/100 patient-years for the addition of cidofovir or leflunomide, respectively. Conclusions. There does not seem to be a graft survival benefit of adding cidofovir or leflunomide to immunosuppression reduction for the management of PVAN. However, the evidence base is poor and highlights the urgent need for adequately powered randomized trials to define the optimal treatment of this important condition.

The Burden of Chronic Kidney Disease in Renal Transplant Recipients

The National Kidney Foundation has developed guidelines for the diagnosis and classification of chronic kidney disease (CKD) but it is not known whether these are applicable to renal transplant recipients. This study determined the prevalence of CKD according to the stages defined in the guidelines, the complications related to CKD and whether the prevalence of complications was related to CKD stage in 459 renal transplant recipients. CKD was present in 412 patients (90%) and 60% were in CKD Stage 3 with a glomerular filtration rate (GFR) between 30 and 59 mL/min/1.73 m2. The prevalence of anemia increased from 0% in Stage 1 to 33% in Stage 5 (p < 0.001). Hypertension was present in 86% and increased from 60% in Stage 1 to 100% in Stage 5 (p = 0.02). The number of anti‐hypertensives per patient increased from 0.7 in Stage 1 to 2.3 in Stage 5 (p < 0.001). The number of CKD complications per patient increased from 1.1 in Stage 1 to 2.7 in Stage 5 (p < 0.001). We conclude that CKD and the complications of CKD are highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians identify patients at increased risk and target appropriate therapy to improve outcomes.

Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials.

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function, however, it also carries risk of acute rejection. We conducted a systematic review of randomized trials that involved CNI withdrawal from a sirolimus‐based immunosuppressive regimen. The search strategy yielded six trials (n = 1047 patients) reported in eight publications. CNI withdrawal from sirolimus‐based therapy, was associated with an increased risk of acute rejection (risk difference, 6%; 95% CI 2–10%, p = 0.002) but a higher creatinine clearance (mean difference, 7.49 mL/min; 95% CI 5.08–9.89 mL/min, p < 0.00001) at 1 year compared to continued CNI and sirolimus therapy. Graft loss (relative risk, 0.87; 95% CI 0.46–1.64, p = 0.66) and death (relative risk, 0.88; CI 0.40–1.96, p = 0.76) were similar in both groups at 1 year. Hypertension was significantly reduced in the CNI withdrawal group (relative risk, 0.56; 95% CI 0.40–0.78, p = 0.0006). CNI withdrawal from sirolimus‐based therapy is associated with an increased risk of acute rejection in the short term with a significant improvement in renal function and a reduction in hypertension. Longer follow‐up is needed to determine if these changes will result in a significant improvement in patient and graft survival.

Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence.

Background. Conversion from a calcineurin inhibitor to sirolimus has been used as a strategy to improve deteriorating renal allograft function but the efficacy and safety of this intervention is unknown. Methods. We performed a systematic review of studies that involved conversion from a calcineurin inhibitor to sirolimus in kidney transplantation. The search yielded five randomized trials (n=1,040 patients) and 25 nonrandomized studies (n=977 patients). Results. In the randomized trials, conversion to sirolimus improved short-term creatinine clearance (weighted mean difference 6.4 mL/min; 95% CI 1.9 to 11.0) compared to controls. In the nonrandomized studies, renal function improved or stabilized in 66% (95% CI 61% to 72%), creatinine clearance improved (weighted mean change 5.7 mL/min; 95% CI 1.4 to 10.1), cholesterol increased (weighted mean change 20.8 mg/dL; 95% CI 11.2 to 30.4) and triglycerides increased (weighted mean change 40.1 mg/dL; 95% CI 18.6 to 61.7). Sirolimus was discontinued by 28% of patients (95% CI 0 to 59%) in the randomized trials and 17% (95% CI 12 to 22%) in the nonrandomized trials. Conclusion. Conversion to sirolimus is associated with an improvement in short-term renal function. However, given the discontinuation rate and potential side effects, adequately powered randomized trials with longer follow-up of hard outcomes are needed to determine whether this strategy leads to a lasting benefit in the clinical care of transplant recipients.

Kidney Transplantation in the Older Adult

The end-stage renal disease population is aging. Nearly half of all new patients are older than 65 years and one third are older than 70 years. Assessing the possibility of transplantation for older patients with end-stage renal disease often involves contemplating more complex issues, including cognitive impairment, decreased functional status, and frailty, which makes selecting appropriate candidates more difficult. Older transplant recipients have decreased patient and transplant survival compared with younger recipients. For example, 75% of deceased donor transplant recipients aged 30-49 years are alive after 5 years compared to only 61% for those older than 65 years. Despite poorer outcomes compared with younger recipients, older transplant recipients have a significant improvement in survival compared with similar patients who remain on the wait list, with decreases in mortality of 41%-61% depending on the study. Use of living donors, even older living donors, provides significantly better outcomes for elderly recipients compared with the use of deceased donors. However, in the absence of a living donor, survival is improved significantly by accepting an expanded criteria donor organ rather than waiting for a standard criteria deceased donor. Older transplant recipients experience more infectious complications and less acute rejection, but the risk of transplant loss from rejection is increased compared with younger patients. These immunologic issues, along with the fact that older patients often are excluded from transplant trials, have made selecting an ideal immunosuppressive regimen challenging. Prospective comparative trials of different agents in the elderly population are warranted to better define the risk-benefit profile. This review discusses transplantation outcomes, including patient and transplant survival, different donor types, quality of life, and immunosuppression for older dialysis patients.

Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients

BACKGROUND Blockade of the renin-angiotensin system by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers can cause hyperkalemia in patients with chronic renal insufficiency who are not on dialysis, but the risk of hyperkalemia in hemodialysis patients is unknown. SUBJECTS AND METHODS We conducted a prospective study of 251 adult hemodialysis patients to determine if renin-angiotensin system blockade was associated with hyperkalemia, defined as a predialysis serum potassium concentration of 5.5 mmol/L or higher. Medication use was determined by chart review and patient interview. Predialysis serum potassium concentration was measured monthly. RESULTS There were 367 episodes of hyperkalemia during 1877 person-months of follow-up. After adjustment for potential confounding variables and for clustering of episodes by patient, use of an ACE inhibitor or an angiotensin receptor blocker was associated with a significantly higher risk of hyperkalemia (odds ratio [OR] = 2.2; 95% confidence interval [CI]: 1.4 to 3.4). The increased risk of hyperkalemia with renin-angiotensin system blockade was seen in anuric dialysis patients (OR = 2.3; 95% CI: 1.3 to 4.2), as well as those with residual renal function (OR = 2.1; 95% CI: 1.0 to 4.1). CONCLUSION The use of ACE inhibitors or angiotensin receptor blockers is independently associated with an increased risk of developing hyperkalemia in chronic hemodialysis patients. The serum potassium concentration should be closely monitored when these medications are prescribed for hemodialysis patients.