Mid- and Long-Term Health Risks in Living Kidney Donors

Living kidney donation is the gold standard treatment of end-stage renal disease (ESRD); more than 8000 living-donor kidney transplantations were done in 2013 in the United States, Brazil, and Japan alone (1). Although living donation is highly beneficial to recipients, it remains a complex ethical, moral, and medical issue. It is practiced with the expectation that risk for minimal short- and long-term harm to the donor is outweighed by the psychological benefits of altruism and improved recipient health (2). A short-term reduction in glomerular filtration rate after nephrectomy is a known consequence of kidney donation (3). However, the mid- and long-term health risks remain uncertain, despite their critical role in informing clinical guidelines for follow-up and supporting the process of informed consent (4, 5). Although narrative reviews (1, 6, 7) and individual studies have reported on the longer-term health risks of living kidney donation, most have not been systematically assessed and quantified. For example, the 3 previously published meta-analyses (each involving up to 6 studies comparing donors vs. a nondonor control group) focused only on a limited number of outcomes (such as hypertension and renal function) and involved only about half of the currently available data (3, 8, 9). Interpretation of the evidence has also been complicated by diverse selection criteria for nondonor control groups (for example, general population vs. based on donation criteria), follow-up durations, and analytic approaches (for example, different matching criteria or adjustment for potential confounders) (4, 10). To help quantify the mid- and long-term risks of living kidney donation, we conducted a systematic review and meta-analysis of observational studies comparing living kidney donors with control participants (nondonors) for a broad range of health outcomes. Methods Data Sources and Searches This review was done using a predefined protocol published in PROSPERO (CRD42017072284) and in accordance with MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. Studies published from April 1964 to 20 July 2017 were identified, without language restriction, through electronic searches using PubMed, Embase, Scopus, and PsycINFO. We supplemented this search by scanning reference lists of relevant articles (including studies as well as reviews and meta-analyses) and by backward and forward citation searching of all included studies. The computer-based searches combined terms related to living organ donation, health related quality of life, and epidemiological studies without health outcomes restriction (Supplement). Supplement. Supplementary Online Content Study Selection Studies were eligible for inclusion if they reported associations between living kidney donation and any health outcomes, disease traits, or health-related quality of life (HRQoL) using a validated instrument; had a mean follow-up after donation of at least 1 year; and provided a comparison group of control participants who had not donated a kidney. Outcomes evaluated in only 1 study (gout and kidney stones) were not included. Data Extraction and Quality Assessment Two investigators independently extracted data on the following characteristics using standardized protocols: sample size; study design; sampling population; location; year of publication; years of baseline survey (year of kidney donation); follow-up duration; participant sex, age range, and ethnicity; number of donors and control participants; selection criteria for control participants; outcomes recorded; outcome definitions and methods of ascertainment (Supplement Table 1); reported risk estimates; and degree of statistical adjustment used or, where relevant, mean level of disease traits and HRQoL assessment scores in donors and control participants. Discrepancies were resolved by discussion and adjudication by a third reviewer. We used the most up-to-date or comprehensive information when more than 1 article reported on the same study. Study quality was evaluated with the Newcastle-Ottawa Scale (NOS) (11), which uses a star system (maximum of 9 stars) to assess quality in the following 3 domains: selection of participants, comparability of study groups, and ascertainment of outcomes of interest. Studies with 4 stars or more were rated as medium or higher quality. We classified selection of control participants as +++ if they were eligible for nephrectomy based on medical status and assessment of renal function; ++ if they were eligible for nephrectomy based on medical status but without assessment of renal function, or if renal function was assessed but limited information on medical history was available; and + if limited screening or information on controls selection was available. Furthermore, we classified matching of donors with control participants as +++ if it was done according to age, sex, sociodemographic factors, or other factors potentially influencing the outcome of interest (for example, body mass index, blood pressure, medical history, and smoking history); ++ if it was based on age, sex, and sociodemographic factors; + if it was based only on age or sex; and null if no matching was done. Data Synthesis and Analysis Primary analyses involved only within-study comparisons to limit potential biases. We restricted primary analyses to studies with an NOS score of at least 4 and baseline recruitment period ending in or after 2000 to provide more reliable and contemporary summary estimates. Supplementary analyses involved all available studies. We used reported relative risks (RRs) or unadjusted RRs or odds ratios calculated from study-specific data to quantify the association between living kidney donation and each of the binary outcomes of interest. Hazard ratios and odds ratios were assumed to approximate the same measure of RR. Incidence rates per 1000 person-years in donors were extracted from studies or calculated as the ratio of events in donors and control participants over the number of person-years at risk. This number in each group was extracted from each study or estimated by multiplying the mean (or median) years of follow-up by the number of donors and control participants. For pregnancy outcomes, incidence of adverse outcomes per 100 pregnancies was calculated by dividing the number of adverse events by the number of pregnancies. We assessed continuous outcomes (disease traits and HRQoL outcomes) by comparing mean differences in living kidney donors with those in control participants for each study. Standardized mean difference (SMD) was calculated within each study as the mean difference between cases and control participants divided by the pooled SD (12). This estimate allows comparison among disparate outcome measures reported with different units. Summary RRs, incidence rates, and SMDs comparing donors with control participants were calculated for each outcome by pooling the study-specific estimates using the random-effects profile likelihood meta-analysis method (13). Consistency of findings across individual studies for outcomes reported in 3 or more studies was assessed by the I 2 statistic. Evidence of publication bias across studies was assessed for outcomes with more than 10 studies using funnel plots and the Egger test. All analyses were 2-sided, used a significance level of P< 0.05, and were done with Stata, version 14.2 (StataCorp). Role of the Funding Source None of the funding organizations were involved in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Results Overall, 52 unique studies from 17 countries involving 118426 donors and 117656 control participants met the inclusion criteria (Figure 1 and Appendix Table). Twenty-three studies were based in North America, 10 in Europe, 2 in Australia, 5 in South America, and 12 in other or several regions. Donors were primarily recruited from hospital registries: 39 studies recruited donors from hospitals and 11 from national or regional donor registries (2 studies did not report this information). The average follow-up ranged from 1 to 24 years, and 14 studies reported a mean or median follow-up of 10 years or more. Selection of the control population differed between studies, with 8 studies selecting control participants from population-based studies, 11 from the general population, 14 from siblings and other volunteers, and 19 from other sources. Twenty-seven studies used several characteristics to match the control and donor populations, and 17 excluded control participants with 2 or more contraindications for nephrectomy. Of these, only 5 selected the control population on the basis of completion of living donor screening or eligibility for nephrectomy based on medical status and renal function tests (Supplement Table 2). Twenty-eight studies were judged to have an NOS score of at least 4 (Supplement Table 3) and had a baseline recruitment period ending in or after 2000. Figure 1. Evidence search and selection. Appendix Table. Summary of 52 Included Unique Prospective Studies on Outcomes of Living Kidney Donation* Association With Disease Traits Twenty-six studies reported associations with disease traits, of which 17 reported information on blood pressure, 6 on metabolic markers, and 17 on markers of renal function (Appendix Table). In the primary analysis (up to 8 studies, 1040 donors, and 1032 control participants), living kidney donors had higher mean diastolic blood pressure (SMD, 0.17 [95% CI, 0.03 to 0.34]) and lower levels of high-density lipoprotein cholesterol than control participants (SMD, 0.29 [CI, 0.52 to 0.11]). Donors also had poorer renal function than control participants, with a lower mean estimated glomerular filtration rate (SMD, 1.59 [CI, 1.86 to 0.33]) and higher mean level of serum creatinine (SMD, 1.0