KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors



# Introduction
Living kidney donation has become essential in increasing the donor pool as kidney transplant waiting lists continue to grow and organ shortage increases. [bib_ref] Shifting paradigms in eligibility criteria for live kidney donation: a systematic review, Ahmadi [/bib_ref] [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] The use of living kidney donors varies widely around the world. Among countries with active kidney transplant programs, the proportion of kidney transplants from living donors varies from less than 5 percent in countries such as Finland, Poland, Ireland, Spain, and Hungary to more than 70 percent in countries such as South Korea, Japan, Turkey, Saudi Arabia, Iran, Jordan, [bib_ref] Global trends in the rates of living kidney donation, Horvat [/bib_ref] and Mexico.Living kidney donation represents between one-third and one half of all kidney transplants in the United Kingdom, United States and Australia. [bib_ref] Screening and follow-up of living kidney donors: a systematic review of clinical..., Tong [/bib_ref] In most cases, transplantation with kidneys from living donors leads to better outcomes for transplant recipients compared to kidneys from deceased donors. Far less is understood about how donation affects the long-term health of donors.
Assessment of potential long term harms has primarily been studied by comparing donor data to data available on samples of non-donors collected for other purposes (i.e. NHANES). [bib_ref] Screening and follow-up of living kidney donors: a systematic review of clinical..., Tong [/bib_ref] These types of comparisons are subject to confounding from known and unknown factors and do not account for lifelong outcomes. These comparisons have been used to demonstrate the low risk associated with living kidney donation. While the comparisons are not ideal to draw this conclusion, they do suggest a low prevalence of major negative outcomes correlated with donation in the overall donor population. Far less is known about specific subgroups of living kidney donors, especially subgroups defined by sex and race.
Our need for improved understanding of long-term donor outcomes becomes more urgent as living kidney donation increases and eligibility criteria expand to accept kidneys from individuals with higher risk for negative health outcomes compared to traditional donors. These expanded donor criteria include accepting kidneys from older individuals and those with isolated medical abnormalities (overweight and obese, hypertension, reduced kidney function, etc.). [bib_ref] Recipient outcomes for expanded criteria living kidney donors: the disconnect between current..., Iordanous [/bib_ref] Guidelines are beginning to address the acceptance of kidneys from expanded criteria donors and the long-term care of donors. However, there is a great deal of variation among guidelines on how and if these issues are addressed. A recent systematic review of existing guidelines addressing living kidney donation concluded: "Multiple major guidelines for living kidney donation have been published, resulting in unnecessary duplicative efforts. Most do not meet standard processes for development, and important recommendations about thresholds for exclusion based on comorbidities are contradictory. There is an urgent need for international collaboration and coordination to ensure, where possible, that guidelines for living donation are consistent, evidence based, and comprehensive to promote best outcomes for a precious resource." [bib_ref] Screening and follow-up of living kidney donors: a systematic review of clinical..., Tong [/bib_ref] In an effort to address these shortcomings, the Kidney Diseases Improving Global Outcomes (KDIGO) assembled a Work Group to develop comprehensive guidelines addressing the evaluation and care of living kidney donors (LKD). We conducted this systematic review to synthesize and assess the currently available evidence on the topic. Full-text screening also identified trials and observational studies.

## Systematic reviews, randomized controlled trials, and observational studies
Full-text screening identified studies with total sample sizes (donor and comparator combined over 50; Data were extracted from studies with total sample sizes over 100. Duration of Follow-up Systematic reviews with outcomes measured at 0 to 90 days postnephrectomy were extracted.
Full-text screening identified studies with outcomes measured up to one year.
Full-text screening identified studies with outcomes measured one year or more post-donation; Data was extracted from studies with a mean duration of 5 years or more post donation. a -Healthy non-donor comparison groups must have matched or controlled for demographic and health characteristics to be considered 'healthy nondonor' comparisons.

## Literature searches and article selection
We searched Ovid Medline, Ovid Embase, and the Cochrane Library to identify previous systematic reviews, randomized controlled trials, and observational studies published and indexed in bibliographic databases through September of 2014. Our search strategy included relevant medical subject headings and natural language terms for the concept of living kidney donation (Appendix A). These terms were combined with filters to select RCTs, systematic reviews and observational studies. Bibliographic database searches were supplemented with backward and forward citation searches of highly relevant systematic reviews.
Two independent investigators reviewed titles and abstracts of search results published after 2003 to identify systematic reviews, trials and observational studies relevant to the topic. We relied on citation searching of relevant systematic reviews to identify relevant studies published prior to 2004. Citations deemed eligible by either investigator underwent full text screening. Two investigators independently screened full text to determine if PICODDs criteria were met. Discrepancies were resolved by a third investigator. We documented the inclusion and exclusion status of citations undergoing full-text screening. We often revisited the screening process as the Work Group identified new outcomes or subgroups not included in the original PICODDs. Screening criteria were liberal. We did not extract data from all eligible studies. In an effort to capture the highest quality and most relevant and meaningful data as efficiently as possible, we extracted data only from previous systematic reviews for peri/post-operative outcomes (KQ 1-3) and from systematic reviews and select observational studies for long-term outcomes (KQ 4-7). We extracted long-term outcomes data from observational studies with sample sizes over 100 and mean follow-up time of at least 5 years. Studies reporting long term outcomes had to have an adequate comparison group. For studies comparing living kidney donors to non-donors, we required that the non-donor comparison group have health characteristics suggesting eligibility for kidney donation. Studies comparing living kidney donors to the general population were not eligible.

## Data extraction
We extracted data from relevant comparisons in recent systematic reviews to replace the de novo extraction process for all peri/post nephrectomy outcomes. We extracted relevant narrative information from systematic reviews that did not provide meta-analyses. We extracted pooled results from previous meta-analyses. We extracted data from observational studies for long term outcomes.
One investigator extracted relevant study, population demographic, and outcomes data from studies eligible for extraction. In several cases, many comparisons were made within the same published study. In these cases, we extracted relevant comparisons but did not extract ineligible comparisons. Data fields extracted included author, year of publication, setting, donor and comparison inclusion and exclusion criteria, donor and comparison characteristics, followup duration, descriptions, and results of outcomes. Relevant data were extracted into tables for descriptive analysis.

## Assessment of previous systematic review quality and individual study risk of bias
We assessed the quality of eligible systematic reviews using modified AMSTAR criteria. We assessed risk of bias for observational studies using an instrument developed using the Research Triangle Institute Item Bank for assessing risk of bias and confounding in observational studies of interventions or exposures.Overall summary risk of bias is based upon the collective risk of bias inherent in each domain and confidence that results are believable given study limitations. We used overall summary risk of bias assessments when grading evidence quality as described below.

## Evidence profiles
A structured approach (GRADE) was used to grade the quality of the overall evidence [fig_ref] Table 2: Evidence Quality Assessment Criteria [/fig_ref]. ("Methods for Guideline Development," 2011) Evidence profiles were used to facilitate this process. The GRADE approach is prescriptive in how evidence quality is assessed. The study design suggests the initial quality of evidence; high for randomized controlled trials and low for observational studies. Evidence quality is then lowered by one level if the studies in the evidence base for a particular comparison have serious risk of bias and by two levels with very serious risk of bias. Evidence quality is also lowered when results across studies are inconsistent or very inconsistent, if the relationship between the intervention and the outcome is indirect or if the outcome does not directly influence patient well-being. Additionally, evidence quality is downgrade when estimates are imprecise and publication bias is likely. Evidence quality improves with a large effect size. A large effect size includes a relative risk confidence interval lower limit of at least 2; a very large effect size includes a relative risk confidence interval lower limit of 5. Evidence quality is also increased when an effect is demonstrated after all plausible confounding has been addressed.

# Results

# Search results
Our search identified 4,530 citations, of which 417 required full text review after title and abstract screening. We identified an additional 70 references via supplemental citation searching for a total of 484 references undergoing full text review . Studies excluded after full text review are listed in Appendix B along with exclusion reasons.

## Figure 2. literature flow diagram
We extracted study characteristics; conducted systematic review quality assessments and risk-of-bias assessments; and extracted relevant outcomes into evidence tables for all studies eligible for extraction (Appendix C for peri/post-operative studies; Appendix D for longterm outcomes studies).
We grouped results by Key Question:
 Key Question 1: Peri/Post Nephrectomy Outcomes: surgical approach  Key Question 2: Peri/Post Nephrectomy Outcomes: demographic subgroups  Key Question 3: Peri/Post Nephrectomy Outcomes: isolated medical abnormalities  Key Question 4: Long-term Living Kidney Donor Outcomes: comparison to healthy nondonors  Key Question 5: Long-term Living Kidney Donor Outcomes: demographic subgroups (i.e., comparison to healthy non-donors from the same demographic subgroup or donors of different demographic subgroups)  Key Question 6: Long-term Living Kidney Donor Outcomes: isolated medical abnormalities (i.e., comparison to non-donors with similar medical status or donors without IMA)  Key Question 7: Long-term Living Kidney Donor Outcomes: pregnancy-related

## -key question 1: peri/post-nephrectomy outcomes: surgical approach
Four recently published systematic reviews addressed peri and post-nephrectomy outcomes by surgical technique. (C. H. [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] C1. Three reviews compared open versus laparoscopic nephrectomy. [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] All RCTs included in were also included in [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Fonouni et al. report results from previous systematic reviews and RCTs searching PubMed through 2013 and included 11 reviews including the reviews by Wilson and Yuan and 4 RCTs (3 of which were included in .
One recent high quality systematic review compared right versus left laparoscopic donor nephrectomy. [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] The literature search through July 2013 identified 29 studies (one randomized controlled trial and 28 comparative studies) and analyzed 32,426 live kidney donors.

## 1a -open versus laparoscopic nephrectomy
Three reviews present evidence in the comparison of open living donor nephrectomy versus laparoscopic donor nephrectomy (Appendix [fig_ref] Table 3: Key Question 1 Evidence Profile 1a [/fig_ref]. [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] We assessed the quality of evidence on several outcomes including perioperative complications, operative time, blood loss, reoperation, length of hospital stay and time to return to work [fig_ref] Table 3: Key Question 1 Evidence Profile 1a [/fig_ref].

## Peri/post-operative complications
Four trials presented peri-/post-operative complications, variably defined. [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] 

## Operative time
Operative time was measured in 26 studies of 2188 donors in a systematic review by [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] The open group had significantly shorter operative time than the laparoscopic group [weighted mean difference (WMD): 50.5 minutes; 95% CI: 32.7 to 68.4]. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity across studies (I 2 =96%). Wilson et al. did not pool results, but showed that laparoscopic procedures took longer than open nephrectomy in five of six trials.(C. H. [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] Mean surgery times ranged from 101 to 164 minutes with open and 152 to 270 minutes with laparoscopic across six trials. Laparoscopic nephrectomy requires longer surgery time than open nephrectomy (low quality evidence).

## Intraoperative blood loss
Yuan et al. included 11 studies that reported blood loss in 917 donors. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Meta-analysis showed significantly greater blood loss with open compared with standard laparoscopic nephrectomy (WMD: -99.64 mL; 95% CI: -165.90 to -33.37) or hand-assisted laparoscopic group . [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] Rates of reoperation with either approach were low (0.7% with open and 2.2% with laparoscopic). Open and laparoscopic nephrectomy had similar rates of reoperation (moderate quality evidence).

## Length of hospital stay
Hospital stay (in days) was reported in 18 of the studies (1851 donors) included in the Meta-analysis showed significantly fewer hospital days with laparoscopic group than open group (WMD: -1.27; 95% CI: -1.72 to -.82). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity among trials (I 2 =93%). Wilson et al. reported data from five trials comparing open to laparoscopic nephrectomy and did not pool data. Three of five trials showed a statistically significantly shorter hospital stay with laparoscopic. Mean hospital stay was between 4 and 7 days with open and 2 and 6 days with laparoscopic. Length of hospital stay is longer with open nephrectomy than laparoscopic (low quality evidence).

## Return to work
Time to return to work (in days) was reported in one systematic review; data from nine studies including 1016 donors. Pooled results show significantly less time to return to work with laparoscopic than open (WMD: -16.35 days; 95% CI: -23.0 to -9.7). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity among trials (I 2 =78%). Mean time to return to work varied from 10 to 66 days with laparoscopic and 27 to 91 days with open. Return to work is sooner with laparoscopic than open nephrectomy (high quality evidence).

## 1b -standard laparoscopic versus hand-assisted laparoscopic nephrectomy
Yuan et al. compared standard living donor laparoscopic nephrectomy and handassisted laparoscopic nephrectomy. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Peri/post-Operative Complications There was no statistical difference in peri-/post-operative complications when comparing standard versus hand-assisted laparoscopic techniques (OR: 0.62; 95% CI:0.27 to1.39). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Complication rates were below 15% with both techniques (7.5% with hand-assisted and 12% with standard). Complication rates are similar with hand-assisted and standard laparoscopic nephrectomy (low quality evidence).

## Operative time
There was no difference in operating time between standard and hand-assisted laparoscopic nephrectomy (WMD: -24.55 minutes; 95% CI:-50.81 to1.71). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity among studies (I 2 =92%). Mean operative times varied across studies and ranged from 121 to 269 minutes with hand-assisted and 180 to 311 minutes with standard. Standard and hand-assisted laparoscopic techniques have similar operating times (very low quality evidence).

## Intraoperative blood loss
There was no difference in blood loss between standard and hand-assisted nephrectomy (WMD: -20.65 mL; 95% CI: -43.88 to 2.57). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was little heterogeneity among studies (I 2 =0.8%). Blood loss was similar with standard or hand-assisted laparoscopic nephrectomy (very low quality evidence).

## Length of hospital stay
Six studies comprising 320 donors compared standard laparoscopic versus handassisted laparoscopic with respect to length of hospital stay. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Donors undergoing standard laparoscopic nephrectomy had significantly shorter hospital stays than those undergoing hand-assisted laparoscopic nephrectomy (WMD: 0.33 days; 95% CI: 0.10-0.56). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Mean length of stay ranged from 2 to 7 days with both techniques; statistical difference may not be clinically important. Standard laparoscopic has statistically significantly longer hospital length of stay, but the difference is not clinically meaningful (low quality evidence).

## 1c -left versus right laparoscopic live donor nephrectomy
One systematic review comprising one trial and 28 observational studies including a total of 32,426 donors. [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] assessed the evidence comparing right-with leftlaparoscopic live donor nephrectomy. Evidence profile for left versus right laparoscopic nephrectomy shows very low quality evidence for several outcomes [fig_ref] Table 5: Key Question 1 Evidence Profile 1c [/fig_ref].

## Peri/post-operative complications
There was no difference in the rate of complications with left or right laparoscopic nephrectomy (perioperative complications: OR: 1.31; 95% CI: 0.89 to 1.94; postoperative complications OR: 1.27; 95% CI: 0.86 to 1.88). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Data necessary to calculate absolute rates was not provided in the systematic review. Complication rates are similar with right-or left-nephrectomy (very low quality evidence).

## Operative time
Operation time (in minutes) in the 14 studies (2656 donors) reporting, was no different with left and right laparoscopic nephrectomy (WMD: 1.35 minutes; 95% CI: -11.73 to 14.44). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Mean operative times for each included study was not provided. Left and right nephrectomy have similar operating times (very low quality evidence). showed no difference in blood loss (in mL) between donors undergoing left or right nephrectomy in 15 studies reporting (3033 donors) (WMD: 4.36mL; 95% CI: -19.83 to 28.55). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Mean blood loss for each included study was not provided. Left and right living donor nephrectomy have similar blood loss (very low quality evidence).

## Intraoperative blood loss

## Length of hospital stay
Mean length of hospital stay (in days) in 11 studies (1730 donors) was no different between those undergoing left and right nephrectomy (WMD: 0.05 days; 95% CI: -0.08 to .019). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Mean length of stay for each included study was not provided. Left and right living donor nephrectomy have similar lengths of hospital stay (very low quality evidence). Standard laparoscopic nephrectomy has longer length of stay than hand-assisted, but difference is not clinically meaningful.

## Low

## -key question 2. peri/post nephrectomy outcomes by demographic subgroups: age
One systematic review examined peri/postoperative outcomes by donor demographic groups. [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] We did not identify systematic reviews that analyzed peri/post-operative outcomes by race or sex.

## 2a -older versus younger donors
We identified one systematic review that examined peri-/post-surgical outcomes by age. [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Young et al. included twenty-two articles comprising 987 donors (mean age: 66 years old; range: 60-85 at donation). Older donors were most commonly defined as 60 years. However, other definitions were used including: 61, 65 and 66 years. Young et al. pooled operating time, blood loss, and length of hospital stay by age group (Appendix C, table C6). The evidence profile for peri/post nephrectomy outcomes for older versus younger donors shows very low quality evidence for several outcomes [fig_ref] Table 6: Key Question 2 Evidence Profile 2a [/fig_ref].

## Operative time
Operative time was reported by 3 studies comprising 339 donors. Most were retrospective observational studies. There was no significant difference in operative time (minutes) between older and younger donors (WMD: 11 minutes; 95% CI: -3.0 to 25). [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Mean operative time ranged from 134 to 238 minutes with older donors and 128 to 203 minutes with younger donors. Operative time is similar in older and younger donors (very low quality evidence).

## Intraoperative blood loss
Young et al. included two studies (146 donors) reporting blood loss (mL) by age. No statistical difference by age was found (WMD: 6.0 mL; 95% CI: -91.0 to 103.0). [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Reported mean blood loss was 157 and 192 mL for older donors and 112 and 248 in younger donors in the two included studies. Blood loss is similar in older and younger donors (very low quality evidence).

## Length of hospital stay
Young et al. included three studies (339 donors) reporting length of hospital stay (in days) by age. In meta-analysis, no statistical difference by age was found (WMD: 0.0; 95% CI: -1.0 to 1.0). [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Mean length of stay ranged from 3 to 10 days with older donors and 3 to 11 days with younger donors. Hospital length of stay is similar in older and younger donors (very low quality evidence).

## -key question 3: peri and post-nephrectomy outcomes in living kidney donors with isolated medical abnormalities
We identified two systematic reviews that examined peri/post nephrectomy outcomes in donors with IMAs. Both analyzed peri/postoperative outcomes by overweight and obesity status. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] We did not identify systematic reviews that provided meta-analysis of peri/post-operative outcomes by other IMA groups.

## 3a -overweight/obese donors versus donors with normal bmi
Young et al. [fig_ref] Table 7: Key Question 3 Evidence Profile [/fig_ref] included 10 studies examining 484 living donors with a mean BMI of 34.5 kg/m 2 at donation (range: 32-39 kg/m 2 ). Eight studies used an obesity cut-point of 30 kg/m 2 ; the other studies used definitions of BMI 31 and 35 kg/m 2 . 14 studies and differentiated between obese and non-obese by defining the former group as those with a body mass index of >30kg/m 2 . [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Lafranca et al. performed additional analysis to gain better insight into differences within the high BMI group. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Three studies of the original analysis could be used as they described multiple cohorts. Kidney donors with a BMI of 30-34.9 kg/m 2 were compared with those with a BMI of 35 kg/m 2 and higher. These two systematic reviews comprised 16 unique studies. Studies were primarily retrospective observational studies. The evidence profile for peri/post nephrectomy outcomes for overweight/obese versus normal BMI donors shows very low quality evidence for several outcomes [fig_ref] Table 7: Key Question 3 Evidence Profile [/fig_ref].

## Peri/post-operative complications
Lafranca et al. pooled results from 7 studies analyzing perioperative complications by BMI status and showed no difference based upon BMI status (RR: 1.01; 95% CI: 0.75 to 1.36). [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] The complication rate was 7% in those with high BMI and 6% in those with low BMI. Complication rates are similar in obese and non-obese donors (very low quality evidence).

## Operative time
Lafranca et al. pooled data from 8 studies (n=1105) on operation duration of laparoscopic nephrectomy. The weighted mean difference was 16.9 minutes longer (95% CI: 9.06 to 24.76) for donors with high BMI. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] 

## Length of hospital stay
Hospital length of stay was similar across BMI categories (WMD:0.18; 95% CI: -0.02 to 0.39). [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Length of stay ranged from 1.7 to 7.4 days with high BMI and 1.6 to 5.8 with low BMI. Young et al. pooled similar data and found similar results; however Lafranca et al. is more up to date. Length of stay is similar in obese and non-obese donors (very low quality evidence). [fig_ref] Table 5: Key Question 1 Evidence Profile 1c [/fig_ref] We identified two systematic reviews [bib_ref] Meta-analysis: risk for hypertension in living kidney donors (Structured abstract), Boudville [/bib_ref] and nine observational studies [bib_ref] The long-term quality of life of living kidney donors: A multicenter cohort..., Clemens [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Acute dialysis risk in living kidney donors, Lam [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] that assessed long-term health outcomes after living kidney donation compared to healthy non-donors. Systematic reviews did not include only studies with comparison groups and comparison groups were not always 'healthy' comparisons. Studies reported mortality, cardiovascular events, ESRD, renal function, proteinuria, hypertension, psychosocial outcomes, GI bleeds, fragility fractures, and acute kidney injury requiring dialysis (Appendix D, Tables D5). Studies from which data were extracted reported mean or median lengths of follow-up ranging from 5.5 to 15 years. Several studies used the same group of donors so the number of unique donors analyzed across all outcomes is unclear. The evidence profile for peri/post nephrectomy outcomes for donors versus healthy non-donors shows very low to moderate quality evidence for several outcomes [fig_ref] Table 8: Key Question 4 Evidence Profile [/fig_ref].

## 19

## 4a -living kidney donors versus healthy non-donors

## Mortality
Three retrospective observational studies compared mortality among living kidney donors to healthy non-donors.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjen [/bib_ref] One study [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] compared 1,901 donors to 32,621 healthy non-donor participants of the Nord-Trndelag Health Study (The HUNT Study). The HUNT study population was drawn from a single county in Norway and enrolled participants without diabetes. Individuals were normotensive and not on blood pressure medications and had a BMI<30. Results revealed increased risk of death in donors (11.7% vs 7.4%, HR: 1.30; 95% CI: 1.11 to1.52) [fig_ref] Table 5: Key Question 1 Evidence Profile 1c [/fig_ref]. Donors were followed for an average of 15 years, while healthy non-donors were followed for 25 years confounding the results. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] In contrast, two studies (one from the United States with a follow-up of up to 12 years and one from Canada with a median follow-up of 6.5 years) revealed lower risk of death in donors compared to healthy non-donors. (A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] The quality of evidence for the outcome was very low.

## Cardiovascular outcomes
Cardiovascular events were reported in two studies.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjen [/bib_ref] One study revealed greater cardiovascular mortality in donors compared to healthy non-donors (3.6% vs 2.1%, HR: 1.40; 95% CI: 1.03 to1.91), [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] while another study reported no difference in composite death censored cardiovascular outcomes between donors and non-donors (1.3% vs 1.4%, RR: 0.91; 95% CI: 0.61 to1.35).(A. X. Quality of evidence for the outcomes was very low.

## Esrd
Two studies compared the rate of ESRD in living kidney donors versus healthy nondonor controls. [bib_ref] Long-term risks for kidney donors, Mjen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Both studies showed high relative but low absolute risk increases. The study from Norway reported greater risk of ESRD in donors compared to healthy non-donors (0.5% vs 0.06%, HR: 11.38; 95% CI 4.37 to 29.63). [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Similarly, the study from the US reported 15-year cumulative incidence rates of ESRD of 30.8 (95% CI: 24.3 to 38.5) per 10,000 patient-years of follow-up in kidney donors compared to 3.9 (95% CI: 0.8-8.9) per 10,000 in healthy non-donors. Quality of evidence for the outcome was moderate.

## Acute dialysis
One study reported similar rates of acute dialysis events, as defined by claims in an administrative database, in donors vs non-donors (6.5 versus 9.4/100,000 person-years of follow-up, RR: 0.58 (95% CI 0.08-4.47).(S. O. Lee) Quality of evidence for the outcome was moderate.

## Renal outcomes
A systematic review of six studies (189 controls and 239 donors) with a follow-up of 6-13 years, reported 10 (95% CI: 15 to 6) ml/min/1.73m2 lower eGFR in donors compared to nondonors.(A. X. Quality of evidence for the outcome was very low.

## Proteinuria and blood pressure
One systematic review of three controlled studies (59 controls and 129 donors) with mean follow-up ranging between 7 and 15 years, reported proteinuria in donors to be 66 (95% CI: 2-108) mg/day greater than non-donors.(A. X. Albuminuria was higher in donors in 2 of 4 studies that compared donors with non-donor controls with the greatest difference of 57 (95% CI 32, 78) mg/day.(A. X. [bib_ref] Proteinuria and reduced kidney function in living kidney donors: A systematic review,..., Garg [/bib_ref] In two studies (67 donors and 51 controls) with follow-up ranging between 2 and 13 years, risk of microalbuminuria was higher in donors compared to controls (20.9% vs 3.9%, RR: 3.9 (95% CI 1.2, 12.6).(A. X. [bib_ref] Proteinuria and reduced kidney function in living kidney donors: A systematic review,..., Garg [/bib_ref] Another systematic review of data from 6 studies with at least 5 years of follow-up after donation reported weighted mean for systolic blood pressure 6 (95% CI 1.6 to 10.5) mmHg ,and diastolic blood pressure 4 (95%CI 0.9-6.7) mmHg higher in donors compared to non-donors. Quality of evidence for the outcomes was very low.

## Psychosocial outcomes
One study reported psychosocial outcomes in donors and healthy non-donors: there was no difference in SF-36 components scores, 15D QOL scores, or feeling thermometer scores. Quality of evidence for the outcomes was very low.

## Other outcomes
We identified three studies that addressed other outcomes after living kidney donation. All studies were done in the same population in Ontario, Canada. gastrointestinal bleeds in living donors compared to matched non-donors and found similar event rates in donors and non-donor (18.5 versus 14.9 /10,000 person years, (HR: 1.24; 95% CI: 0.87 to 1.81). [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors in comparison to matched non-donors and found similar event rate/10,000 person years in non-donors vs non-donors (18.7 versus 16.4) (HR: 0.88; 95% CI: 0.58 to1.32).(A. X. One study compared rates of kidney stones with need for surgical interventions (8.3 versus 9.7 per 10,000 person-years, RR: 0.85(95% CI 0.47-1.53) as well as hospitalizations for kidney stones (12.1 versus 16.1 per 10,000 person years, RR: 0.75(95% CI 0.45-1.24)) among kidney donors and healthy non-donors without prior history of kidney stones, respectively, and reported no difference. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Quality of evidence for these outcomes was very low. One retrospective observational study shows no difference in the rate of GI bleeding after a median of 6.5 years follow-up.

## Very low

## -key question 5: long-term health outcomes in living kidney: demographic subgroups 5a -older donors versus older healthy non-donors (table d6)
We identified eight studies that compared outcomes in older donors compared to older healthy non-donors. [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] [bib_ref] The long-term quality of life of living kidney donors: A multicenter cohort..., Clemens [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Mean (median) follow-up ranged from 5 to 15.1 years. Evidence profile for long term nephrectomy outcomes for donors versus healthy non-donors shows very low to moderate quality evidence for several outcomes [fig_ref] Table 9: Key Question 5 Evidence Profile [/fig_ref].

## Mortality
Three studies from the OPTN registry, [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] compared mortality between older donors and older healthy non-donors. Berger et al. reported survival at 5 and 10 years in donors over age 70 compared to matched non-donors from the NHANES III study. [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] At 10 years of follow-up, 73% of non-donors and 90% of donors were alive (HR for death: 0.37 (95% CI 0.21-0.65) for donors compared to non-donors). donors to a matched cohort of NHANES III. Both studies found mortality higher in older healthy non-donors than in older donors. The most recent study by Reese et al. reported similar risk of death for donors > 55 years old compared to non-donors > 55 years old from the Health and Retirement Study 4.9 versus 5.6 deaths per 1000 person-years, and lower risk of death in donors 60 years or older compared to non-donors 60 years or older (HR: 0.68; 95% CI: 0.49 to 0.95). The quality of evidence for the outcome was very low.

## Cardiovascular outcomes
Reese reported similar risk of death or cardiovascular event in older (> 55 and > 60) donors compared to non-donors with Medicare coverage. Garg et al reported no interaction between age and donation for the outcome of death censored cardiovascular events (p=0.48) and similar risk of cardiovascular events for donors and non-donors aged 55 and older (4.4% vs 6.4%, HR: 0.70 (95% CI: (0.3-1.4)).(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] The quality of evidence for the outcome was low.

## Psychosocial
One study reported psychosocial outcomes in donors 43 years old and older and healthy non-donors of the same age, there was no difference in SF-36 Mental component summary scores. Quality of evidence for the outcome was very low. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors in comparison to matched non-donors 55 years and older and found similar event rate/10,000 person years in donors vs non-donors (43.2 versus 39.5) (HR: 1.14; 95% CI: 0.56 to 2.35).(A. X. One study compared rates of kidney stones with need for surgical interventions (9.4 versus 10.4 per 10,000 person-years) as well as hospitalizations for kidney stones (11.1 versus 17.0 per 10,000 person years) among kidney donors and healthy non-donors 40 years or older without prior history of kidney stones, respectively, and reported no difference. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Age did not influence the association between donation and GI bleeding (p for interaction 0.6) , fractures (p for interaction 0.5) , or kidney stones (p for interaction 0.8 .(A. X. [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Quality of evidence was rated as low or very low for all of the reported outcomes. [fig_ref] Table 7: Key Question 3 Evidence Profile [/fig_ref] Sixteen included studies analyzed donor outcomes by age at donation They reported the following long-term outcomes: mortality, cardiovascular events, ESRD, renal function, proteinuria, hypertension, GI bleeds, fragility fractures and psychosocial outcomes. Mean lengths of follow-up ranged from 5.5 to 31 years. Quality of evidence was rated low to very low for all of the outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref].

## Other outcomes

## 5b -older donors versus younger donors

## Mortality
Four studies reported long-term mortality outcomes stratified by pre-donation age. In the three studies comparing mortality in older donors to younger donors (55 years or older in one, 60 years or older in two) as would be expected older donors had greater all-cause mortality than younger donors over an average follow-up time 5.5 to 6.8 years. [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] One small study reported no difference in frequency of deaths in donors who were younger than 18 years of age at donation compared to donors who were 18-30 years at donation over 30 year follow-up (5.1% versus 6.2%, p=0.990).(MacDonald et al.) The quality of evidence for the outcome was low.

## Cardiovascular outcomes
One study reported cardiovascular events by donor age.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] In donors aged 55 and older, the rate for cardiovascular events per 10,000 person years was 4.4, compared to 1.4 in their younger counterparts. Another study reported 9% greater risk of cardiovascular event for each year increase in donor age.(K. L. The quality of evidence for the outcome was low.

## Esrd
End-Stage Renal Disease was reported in two studies. The first reported cumulative incidence rates of ESRD at 15 years in donors 18-39 years, 40-49 years, 50-59 years and 60 years and older. ESRD rates were 29.4, 17.4, 54.6 and 70.2 per 10,000 person-years respectively. [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] In one study, white donors who were younger than 35 years of age at the time of donation were more likely to be listed for kidney transplant compared to White donors who were 35 years or older at donation (0.2% vs 0.05%, RR:4.10(95% CI 2.35-7.16); African American donors who were younger than 35 years at the time of donation were also more likely to be listed for kidney transplant compared to African American donors who donated kidney at 35 years of age or later (0.6% vs 0.11%, RR: 7.68( 95% CI 3.25-17.89). The quality of evidence for the outcome was very low.

## Renal function
Ten studies reported renal function by age. In the three that looked at those withGFR <60 mL/min, all found older donors at greater risk. [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] Age at donation was significantly associated with greater odds of CKD (defined as eGFR <60 ml/min/1.73m2) in three studies and not associated in one study. Greater donor age was correlated with lower GFR at follow-up in two studies in Swedish living donors.(Fehrman-Ekholm et al.)-(von Zur-Muhlen, Berglund, Yamamoto, & Wadstrom) Frequency of eGFR < 60 ml/min was greater among donors who were 60 years or older at the time of donation compared to donors who were younger than 60 years of age (80% vs 31%). Older age at donation was associated with increased risk of CKD diagnoses as determined by administrative billing claims over an average 7.7 yrs followup (4% increase per year).(K. L. Mean eGFR was 71ml/min among donors older than 60 at the time of donation compared to 78.5ml/min in younger donors after 6.7 years of follow-up. One study did not find any difference in eGFR, frequency of eGFR <60 ml/min, as well as eGFR < 45 ml/min among donors who donated before they turned 18 compared to donors who donated between the ages of 18 and 30. The one study that looked at serum creatinine found no difference at follow-up for those 21-35 and 36-50, but found a difference in those 51-69 (mean creatinine of 1.0 versus 0.8 mg/dL). The quality of evidence for the outcome was very low.

## Proteinuria
Three studies reported proteinuria by age at donation. In one, risk of proteinuria at 5 and 10 years was similar between older and younger donors. [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] In another study mean proteinuria (mg/24h) was also similar. In a study that compared adolescent to adult donors, odds of proteinuria (defined as >1+ on a random dipstick) were not significantly different between adolescent and adult donors at about 30 years of followup. The quality of evidence for the outcome was very low.

## Hypertension
Hypertension was reported in six included studies, defined by either blood pressure or treatment by medication. Dols et al. reported risk of HTN in older donors (>60 years old) comparable to that in younger donors (10% versus 6%, p=0.56). [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] In one study older age at follow-up was associated with 5 mmHg higher systolic blood pressure. The quality of evidence for the outcome was very low.

## Psychosocial outcomes
Gross et al found that 10 year increase in age at donation was associated with decreased risk of Mental health HRQOL impairment (scoring > 5 points below average) at follow-up (OR (95% CI) 0.74(0.65-0.85). Two studies reported similar SF-36 Mental Component Summary scores in donors of different age at donation. [bib_ref] The long-term quality of life of living kidney donors: A multicenter cohort..., Clemens [/bib_ref] [bib_ref] Longterm follow-up of living kidney donors: quality of life after donation, Johnson [/bib_ref] One study found that older age at donation was associated with increased likelihood of post-donation depression diagnoses.(K. L. Mjoen et al. found that older age at donation was associated with decreased risk of doubt toward donation. [bib_ref] Quality of life in kidney donors, Mjoen [/bib_ref] The quality of evidence for the outcome was very low.

## Diabetes
Donors who were younger than 18 years of age at donation had risk of drug treated diabetes similar to that of donors who were 18-30 years of age at donation (RR: 0.61; 95% CI: 0.15 to 2.60).(MacDonald et al.) One study reported that older age at donation was associated with a 5% higher risk of drug-treated diabetes over an average 7.7 yrs of follow-up.(K. L. The quality of evidence for the outcome was low.

## Other outcomes
One study looked at the risk for GI bleeds in living donors by age at donation and found a two-fold greater event rate/10,000 person years in donors older than 40 years of age compared to those younger than 40 (23.4 versus 11.9), the difference was not significant. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors by age at donation and found a greater than three times higher event rate/10,000 person years in donors aged 55 and older compared to those younger than 55 (43.2 versus 12.7 -RR: 2.85; 95% CI: 1.24-6.55).(A. X. One study compared risk of surgical interventions for kidney stones and kidney stones with hospital encounters in donors 40 years or older at the time of donation versus donors younger than 40 years of age and did not find any difference. The quality of evidence for the outcomes was low to very low. [fig_ref] Table 8: Key Question 4 Evidence Profile [/fig_ref] Seven studies compared outcomes between male kidney donors / female kidney donors with male / female healthy non-donors respectively. Follow-up ranged from 5 to 25 years. Two studies evaluated mortality, one study cardiovascular outcomes, one study ESRD, one study depression, and one study each, all from the same donor cohort, evaluated GI bleeding, kidney stones and fragility fractures. Quality of evidenced low to very low for all of the outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref].

## 5c -male and female donors vs male and female healthy non-donors

## Mortality
One study reported relative risk of death for male donors and non-donors compared to female donors and non-donors. Males (including donors and non-donors) had a greater risk of death (AHR: 1.52; 95% CI: 1.41 to1.65) compared to female donors and non-donors . One study compared mortality of donors and healthy non-donors stratified by sex. Mortality of healthy non-donors was higher than that of donors in males and females. The quality of evidence for the outcome was very low.

## Esrd
One study reported relative risk of ESRD for male donors and non-donors compared to female donors and non-donors. Male donors and non-donors had similar risk of ESRD compared to female donors and non-donors (AHR: 0.90; 95% CI: 0.43 to 1.88). The quality of evidence for the outcome was very low.

## Psychosocial outcomes
Rates of diagnoses of depression were lower in male donors compared to non-donors (3.1 versus 4.7 per 100 person years), as well as female donors compared to non-donors (6.6 versus 9.2 per 100 person years).(K. L. The quality of evidence for the outcome was very low.

## Other outcomes
Three studies addressed other outcomes after living kidney donation; all studies were done in the province of Ontario population.(A. X. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] gastrointestinal bleeds in male and female living donors to matched non-donor controls of the same sex and found similar event rates in donors and non-donors (event rates were 15.7 vs 17.9 /10,000 person years for male donors and nondonors respectively, and 20.1 vs 12.9/10,000 person years for female donors and non-donors respectively, p for interaction 0.2). [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looking at the risk for fragility fractures in male and female living donors in comparison to matched non-donors found similar event rates in donors vs non-donors ( 12.9 vs 13.1/10,000 person years for male donors vs nondonors, and 18.8 vs 22.4/10,000 person years for female donors vs non-donors, p for interaction 0.7).(A. X. One study compared rates of kidney stones with need for surgical interventions (9.1 versus 13.7/ 10,000 person-years for male donors and non-donors and 7.7 vs 7.0 /10,000 person years for female donors and non-donors, p for interaction 0.4) as well as hospitalizations for kidney stones (9.1 versus 14.2/ 10,000 person-years for male donors and non-donors and 7.7 vs 7.0 /10,000 person years for female donors and non-donors, p for interaction 0.03). [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Quality of evidence was low or very low for all of the reported outcomes. [fig_ref] Table 9: Key Question 5 Evidence Profile [/fig_ref] Seventeen studies analyzed donor outcomes by sex. The studies reported mean / median lengths of follow-up ranging from 5.4 to 12.2 years. Quality of evidenced was low to very low for all of the outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref].

## 5d -male donors versus female donors

## Mortality
Two studies reported mortality. One small study reported two deaths, one among male and one among female donors (2.2% versus 1.7% respectively). In another study, male donors were 70% more likely to die during the 12 year follow-up compared to female donors (2.7% vs 1.9%). The quality of evidence for the outcome was very low.

## Cardiovascular events
In one study, male donors were more likely to have cardiovascular events compared to female donors (AHR: 2.11; 95% CI: 1.43 to 3.10).(K. L. In the Ontario study, female donors were less likely to have a death censored cardiovascular event compared to male donors, but the association was not statistically significant (2.4% vs 3.3%, HR (95% CI) : 0.57(0.26-1.23)).(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] The quality of evidence for the outcome was low.

## Esrd
Six studies analyzing data from 3 data sources, [bib_ref] Ethnic and gender related differences in the risk of end-stage renal disease..., Cherikh [/bib_ref] [bib_ref] Age, gender, race, and associations with kidney failure following living kidney donation, Gibney [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] all analyzing OPTN data but with different inclusion criteria, reported ESRD events by donor gender. One study reported 1 case of ESRD among male donors (2.2%) and one among female donors (1.7%). In one study, male donors had greater risk of ESRD compared to female donors (RR: 2.24; 95% CI: 1.30 to 3.86). In a study by Muzaale et al., women had a 15 year cumulative incidence of ESRD of 21.1 (14.9 to 29.9) per 10,000 person years compared to 44.1 (32.9 to 59.1) in men. In another study, men had greater risk of ESRD but it was not statistically significant.(Wafa 2011) One study reported greater risk of being waitlisted for a kidney transplant among male donors compared to female donors (0.18% versus 0.04%, RR: 4.83; 95% CI: 2.54 to 9.18). This was true among White and African American donors. The quality of evidence for the outcome was low.

## Renal function
Six studies reported renal function by gender. Two studies reported no significant increase in risk of post-donation eGFR <60 ml/min by MDRD in women compared to men.(J. H. One study reported greater odds of iohexol GFR < 60 ml/min/1.73m2 in women compared with men (OR: 3.11; 95% CI:1.11 to 8.67), One study reported greater risk of claims for CKD in male donors compared to female donors (AHR: 1.64; 95% CI: 1.16 to 2.34).(K. L. One study reported similar GFR in male (81.6) and female (79.4) donors at 10 year of follow-up, p-value was not provided, [bib_ref] Long-term follow-up of 102 living kidney donors, Karakayali [/bib_ref] while another study reported higher MDRD eGFR in males (69+13 ml/min/1.73m2) than females (65+12 ml/min/m2), p<0.01.(von Zur-Muhlen et al.) The quality of evidence for the outcome was very low.

## Proteinuria
Two studies reported proteinuria by gender. [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] In one study incidence of proteinuria (defined as > 150 mg/day of protein or >1+ dipstick proteinuria on UA) was similar between female and male donors (RR: 1.87; 95% CI: 0.63-5.50). [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] In the second study, albuminuria was less common in women (OR: 0.31, 95% CI: 0.12-0.79). The quality of evidence for the outcome was very low.

## Hypertension
Three studies reported HTN by gender.(El-Agroudy et al.; K. L. [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] In one study incidence of HTN was not different between male and female donors at 5.5 years. In another study HTN (>140/90 mmHg) was more common among female donors (24.7 versus 17.8%, p=0.03). A third study revealed a greater risk of drug-treated HTN among male donors (AHR: 1.21; 95% CI: 1.03 to 1.43).(K. L. The quality of evidence for the outcome was very low.

## Psychosocial outcomes
Three studies reported psychosocial outcomes by donor gender. K. L. One study reported that women were more likely to find the experience of donation stressful, though the finding was not significant. Another study reported that male donors were not more likely to have doubt toward donation. A study by Lentine et al. revealed a lower rate of depression diagnoses among male (3.1 per 100 person-years) compared to female (6.6 per 100 person-years) donors.(K. L. The quality of evidence for the outcome was very low.

## Diabetes
One study reported diabetes diagnosis by gender.(K. L. There was no significant difference in risk of diabetes by claims diagnosis or drug-treated diabetes between male and female donors.(K. L. The quality of evidence for the outcome was very low.

## Other outcomes
One study looked at the risk for GI bleeding in living donors by sex and found a small increase in GI bleeding/10,000 person years in male donors compared to female donors (20.1 versus 15.7, not significantly different (RR: 0.78; 95% CI: 0.39 to 1.55)). [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors by sex and found small and non-significant absolute differences in fracture risk in male donors compared to female donors (12.9 versus 18.8 per 10,000 person years) (RR: 0.71; 95% CI: 0.31 to 1.63).(A. X. The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Three studies compared outcomes of African American and/ or Hispanic LKDs to African American and Hispanic healthy non-donors. Follow-up ranged from 6.3 to 7.6 years [fig_ref] Table 1: PICODD Criteria [/fig_ref]. Quality of evidence was rated moderate for ESRD and low to very low for all other outcomes. [fig_ref] Table 1: PICODD Criteria [/fig_ref].

## 5e -african american / hispanic donors vs african american / hispanic healthy nondonors

## Mortality
One study compared mortality between AA donors and AA healthy non-donors, and white donors with white healthy non-donors. Non-donor mortality was slightly higher than donor mortality for both races. The quality of evidence for the outcome was very low.

## Esrd
One study compared absolute risk of ESRD in donors and healthy non-donors by race and ethnicity. There was a large and significant increase in relative risk of ESRD for African American, Hispanic, and white donors (compared to non-donors). The 15-year increase in absolute risk was small (< 0.5%). African American donors had the greatest absolute increase in the 15 year incidence of ESRD compared to controls (absolute risk increase 50.8 per 10,000 person years for AA donors (74.7 per 10,000 (95% CI, 47.8-105.8) in AA donors vs 23.9 per 10,000 (95% CI, 1.6-62.4) in AA non-donors) , 29.5 per 10,000 person years for Hispanic donors (32.6 per 10,000 (95% CI, 17.9-59.1) in Hispanic donors vs 6.7 per 10,000 person years (95% CI, 0-15.5) in Hispanic non-donors), and 22 per 10,000 person years for white donors (22.7 per 10,000 (95% CI, 15.6-30.1) in white donors vs 0.0 per 10,000 person years (95% CI, 0.0-0.0) in white non-donors). The quality of evidence for the outcome was moderate for all three racial groups (upgraded for effect size).

## Renal function
One study compared eGFR in African American donors compared to African American non-donors. The average serum creatinine was 1.2 +0.3 mg/dL and the average eGFR 77 +19 mL/min/1.73 m 2 in donors and 0.9 +0.2 mg/dL and 109 +17 mL/min/1.73 m 2 , in non-donors, respectively at an average follow-up of 6.8 years. The number (proportion) of donors with an eGFR < 60 and < 45 mL/min/1.73 m 2 was 16 (15.5%) and 6 (6%), respectively, in donors while none of the non-donors had an eGFR<60 mL/min/1.73 m 2 . The quality of evidence for the outcome was low.

## Proteinuria
One study compared risk of proteinuria (microalbuminuria) among African American donors and African American healthy non-donors. After an average of 6.8 years from donation, African American donors had greater mean urinary albumin than non-donors, 15 microgram/mg vs 7 microgram/mg, but the difference was not statistically significant. Incidence of microalbuminuria did not differ between African American donors and non-donors (5.8% vs 3.8% [RR: 1.52; 95% CI: 0.55 to 4.16]). The quality of evidence for the outcome was very low.

## Hypertension
One study compared risk of hypertension defined as BP> 140/90 mmHg or use of blood pressure medications among African American donors and African American healthy nondonors. After a mean follow-up of 6.8 years, African American donors had greater risk of hypertension compared to African American non-donors (40.8%vs 17.9%, absolute difference of 22.9%, [RR: 2.3; 95% CI: 1.6 to 3.4]). The quality of evidence for the outcome was very low.

## Diabetes
One study compared risk of diabetes among African American donors and African American healthy non-donors. After a mean follow-up of 6.8 years, African American donors had a frequency of diabetes similar to that of African American non-donors (1.9% vs 1.7%, absolute risk difference of 0.2%, [RR: 1.14; 95% CI: 0.21 to 6.13]). The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Eight studies reported living donor outcomes by donor race or ethnicity. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Quality of evidenced was low to very low for all of the outcomes.

## 5f -african american / hispanic donors versus white donors

## Mortality
Two studies reported on donor mortality by race. Compared to White donors, African American donors had 30 percent greater risk of death after a mean follow-up of 6.3 years (12 year mortality 2.8% vs 1.7%, HR: 1.3; 95% CI: 1.0 to 1.6). Hispanic donors had 40 percent lower mortality compared to White donors (HR: 0.6; 95% CI: 0.4 to 0.9). Aboriginal donors' risk of death was similar to White donors (RR: 1.33; 95% CI: 0.40 to 4.44). The quality of evidence for the outcomes was very low for African American and Aboriginal donors and low for Hispanic donor comparisons.

## Cardiovascular events
One study reported cardiovascular event risk (from administrative claims data) by race; African American (RR: 1.15; 95% CI: 0.63 to 2.11) and Hispanic (RR: 0.91; 95% CI: 0.37 to 2.26) donors had similar risk to White donors [fig_ref] Table 1: PICODD Criteria [/fig_ref] 

## Renal function
Three donor pool studies evaluated renal function in kidney donors by race and insurance status at a median follow-up of 7-14 years. In one study of Medicare-insured donors, African American race and Hispanic ethnicity were associated with a higher risk of postdonation CKD diagnoses compared to White donors.(K. L. Another report by the same group revealed greater risk of claims for CKD diagnoses in African American and Hispanic donors with private insurance compared to White donors with private insurance.(K. [bib_ref] Consistency of racial variationin medical outcomes among publicly and privately insured living..., Lentine [/bib_ref] In this study Hispanic ethnicity was not associated with increased risk of CKD diagnosis among Medicare insured donors.(K. L. In another study, Aboriginal donors had higher eGFR compared to White donors after 14 years of follow-up (adjusted difference 5.9 ml/min). The quality of evidence for the outcome was very low.

## Proteinuria
Two studies reported proteinuria by race or ethnicity. Both Medicare insured and privately insured African American donors had a higher risk and Hispanic donors had a similar risk of proteinuria diagnosis compared to similarly insured White donors.(K. L. Aboriginal donors have greater proteinuria compared to White donors (21% vs 4% with > 0.3 gm per 24 hours, RR for (95% CI) 5.89 (1.27 to 27.41)). The quality of evidence for the outcome was very low.

## Hypertension
Three studies with two unique cohorts reported hypertension risk by race.

## Psychosocial outcomes
One study with a mean follow up of 17 years reported psychosocial functioning by race. Whites reported higher level of social functioning than African Americans (p=0.0007). White donors were more likely to report good health than African Americans (p=0.0034) and other races (p=0.0004). One study found that non-Hispanic white donors had twice the likelihood of depression diagnoses based on billing claims as non-white or Hispanic donors.(K. L. The quality of evidence for the outcome was very low.

## Diabetes

## -key question long term outcomes of donors with isolated medical abnormalities
We found no studies that fit our inclusion criteria and compared outcomes of kidney donors with isolated medical abnormities to outcomes of otherwise healthy non-donors matched by the isolated medical abnormality. Following literature compares outcomes of donors with IMA to outcomes of donors without IMA. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Five studies compared long-term outcomes among donors by pre-donation BMI status. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] Followup ranged from 6.7 to 15.1 years [fig_ref] Table 1: PICODD Criteria [/fig_ref]. The quality of evidence was rated as very low for all outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref].

## 6a -obese donors versus non-obese donors

## Mortality
One study presented adjusted risk of death per 1 BMI unit increase in a combined cohort of kidney donors and healthy non-donors. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] The study did not find a significant increase in risk of death associated with greater BMI (AHR: 1.01; 95% CI: 0.99 to 1.03 per BMI unit). The quality of evidence for the outcome was very low.

## Cardiovascular mortality
One study presented adjusted risk of death from cardiovascular causes per unit BMI increase in a combined cohort of kidney donors and healthy non-donors. Higher BMI was associated with greater risk of cardiovascular mortality (AHR: 1.03; 95% CI: 1.01 to 1.07 per BMI unit). The quality of evidence for the outcome was very low.

## Esrd
One study presented adjusted risk of ESRD per unit BMI increase in a combined cohort of kidney donors and healthy non-donors. The study did not find a significant increase in risk of ESRD associated with greater BMI (AHR: 1.13; 95% CI: 0.96 to 1.32 per BMI unit). The quality of evidence for the outcome was very low.

## Renal function
Three studies analyzed the association of BMI and renal function. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] One study at high risk of bias reported follow-up eGFR of 83.9 ml/min in donors with BMI > 30 kg/m2 at baseline compared to eGFR of 78.5 ml/min in donors with normal BMI. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] One study revealed greater odds of iohexol GFR < 60 ml/min/1.73m2 at follow-up per unit increase in BMI at baseline (OR (95% CI): 1.12(1.02-1.23)) . Similarly, another study reported that higher BMI at donation was correlated with lower eGFR at follow-up.(von Zur-Muhlen et al.) The quality of evidence for the outcome was very low.

## Hypertension
Two studies reported blood pressure or hypertension by BMI at donation. One study reported MAP of 91.2 in donors with BMI >30 compared to MAP of 88.2 in donors with BMI < 30 at donation. One study reported increased odds of hypertension requiring medication at follow-up associated with greater BMI at donation (OR: 1.12; 95% CI: 1.04 to 1.21 per BMI unit). The quality of evidence for the outcome was very low.

## Psychosocial outcomes
One study revealed greater odds of physical component of HRQoL impairment (defined as Physical Component Score >1 SD below sex-by-age norms in donors with higher BMI. Donors with BMI >=35 were more likely to be impaired (OR: 4.32; 95% CI: 2.37 to 7.87) than donors with normal BMI. The same was true with donors whose BMI was 30 -34.9 (OR: 2.85; 95% CI: 2.37 to 7.87) and in donors with BMI 25 -29.9 (OR: 1.84; 95% CI: 1.31 to 2.65). The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Three included studies from three countries analyzed donor outcomes by pre-donation GFR.(J. H. The studies reported mean lengths of follow-up of 5.4 to 11 years. The quality of evidence was very low.

## 6b -donors with lower renal function versus donors with higher renal function

## Renal function
Three studies reported kidney function at follow-up by baseline kidney function.(J. H. One study reported no significant association between baseline measured creatinine clearance and odds of MDRD estimated GFR < 60 ml/min/1.73m2: (OR: 1.00; 95% CI: 0.98 to 1.03) per unit change in the measured creatinine clearance.(J. H. Another study revealed an association between greater eGFR at baseline (per 1 ml/min/1.73m2) and lower risk of developing chronic kidney disease defined as eGFR < 60 ml/min/1.73m 2 (OR: 0.95; 95% CI: 0.92 to 0.99). The third study reported a significant correlation between lower eGFR at baseline and lower eGFR at follow-up.(von Zur-Muhlen et al.) Quality of evidence was very low.

## Proteinuria
One study reported lack of correlation between lower measured GFR at donation and urine albumin-creatinine ratio at follow-up.(von Zur-Muhlen et al., 2014) Quality of evidence was very low.

## Hypertension
One study reported that lower measured GFR at donation was correlated to higher mean arterial blood pressure at follow-up.(von Zur-Muhlen et al.) The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Two studies included 110 donors with impaired glucose metabolism and 775 donors with normal glucose metabolism and followed them for 7-10 years. The quality of evidence was low to very low for all outcomes. (54,55)

## 6c -donors with impaired fasting glucose versus donors with normal glucose tolerance

## Mortality
One study reported mortality: 3 of 65 (4.6%) donors with glucose intolerance and 14 of 330 (4.1%) donors with normal glucose tolerance died during an average follow-up of 7.3 years (RR: 1.09; 95% CI: 0.32 to 3.68). Quality of evidence was very low.

## Esrd
The same study as noted above for mortality reported no cases of ESRD among 65 donors with impaired glucose tolerance and 2 cases of ESRD among 330 donors with normal glucose tolerance. Quality of evidence was very low.

## Renal function
Two studies reported kidney function at follow-up by glucose tolerance or fasting glucose impairment at baseline. One study reported similar MDRD eGFRs at mean follow-up of 10.2 years: donors with impaired fasting glucose at baseline had a mean eGFR of 70.7(16.1) ml/min/1.73m 2 versus donors with normal fasting glucose who had a mean eGFR of 67.3(16.6) ml/min/1.73 m 2 . Another study reported self-reported renal dysfunction in 7.7% of donors with glucose intolerance at baseline and 6.7% of donors with normal glucose tolerance at 7.3 years of followup. [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] Quality of evidence was very low.

## Proteinuria
One study reported similar albumin/creatinine ratios after 7.3 years of follow-up in donors with and without impaired fasting glucose at baseline (9.8 [23.6] mg/g versus 5.9 [11.0] mg/g, p=0.29). Quality of evidence was very low.

## Hypertension
Two studies did not find a difference in incidence of hypertension during the follow-up period between donors with impaired fasting glucose or glucose intolerance and donors with normal glucose metabolism. In one study, 35.6% of donors with impaired fasting glucose and 22.2% of donors with normal fasting glucose developed hypertension after 10.2 years of follow-up. [bib_ref] Prediabetic living kidney donors have preserved kidney function at 10 years after..., Chandran [/bib_ref] In the second study, 29.2% of glucose intolerant donors and 22.1% of donors with normal glucose metabolism developed blood pressure > 140/90 after 7.3 years of follow-up (RR (95% CI): 1.32(0.86-2.03)). [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] In the same study, 13.8% of donors with glucose intolerance and 11.2% of donors without glucose intolerance developed drug treated hypertension (RR(95%CI): 1.23(0.63-2.43)). [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] Quality of evidence was very low.

## Diabetes
Two studies reported greater frequency of diabetes at follow-up between donors with impaired fasting glucose, diabetes, or glucose intolerance and donors with normal glucose metabolism at baseline. In one study, 15.6% of donors with impaired fasting glucose and 2.2% of donors with normal fasting glucose developed diabetes after 10.2 years. [bib_ref] Prediabetic living kidney donors have preserved kidney function at 10 years after..., Chandran [/bib_ref] In the other study, 21.4% of donors with glucose intolerance and 2.4% of donors with normal glucose tolerance developed diabetes by selfreport, and 26.2 and 0% required medications for diabetes respectively after a mean follow-up of 7.3 years. [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] Quality of evidence was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] One included study analyzed donor outcomes by pre-donation presence of metabolic syndrome. Metabolic syndrome was defined as meeting three or more of the criteria 1) waist circumference of >88 cm in women or >102 cm in men; 2) hypertriglyceridemia; 3) hyperlipidemia; 4) hyperglycemia; and 5) hypertension (>130/85). This study reported on renal function and proteinuria. The mean length of follow-up was 5 years and data on 140 participants were analyzed. The quality of evidence was very low for all outcomes.

## 6d -donors with metabolic syndrome versus donors without metabolic syndrome

## Renal function
One study reported 5-year post-donation MDRD eGFR (mean (SD)) of 66.3(12.7) ml/min/1.73m2 in donors with and 71.8(16.2) ml/min/1.73m2 in donors without metabolic syndrome at baseline. The quality of evidence was very low.

## Proteinuria
One study reported 5-year post-donation 24-hour albuminuria (mean (SD)) of 0.5(0.6) mg/day in donors with and 0.2(0.5) mg/day in donors without metabolic syndrome at baseline. The quality of evidence was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Three included studies analyzed donor outcomes by pre-donation hypertension status. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] One study reported blood pressure as a risk factor for mortality, cardiovascular mortality, and ESRD in a combined cohort of donors and healthy non-donors. Two other studies defined hypertension as BP>140/90 easily controlled with one medication and reported renal function by hypertension status. However, evidence quality was assessed using only was assessed as having a high risk of bias and the comparison groups used in the two studies were not comparable. Quality of evidence was very low for all outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref].

## 6e -hypertensive donors versus normotensive donors

## Mortality
In one study, a 1 mmHg increase in SBP was not associated with significant increase in risk of death in a mixed cohort of donors and matched non-donors without hypertension (AHR: 1.00: 95% CI: 1.00 to 1.01). The quality of evidence was very low.

## Cardiovascular mortality
In one study, a 1 mmHg increase in SBP was associated with a small but significant increase in the risk of cardiovascular death in a mixed cohort of donors and matched nondonors (AHR: 1.01; 95% CI: 1.00 to 1.02). The quality of evidence was very low.

## Esrd
In one study, 1 mmHg increase in SBP was associated with a small but significant increase in the risk of ESRD in a mixed cohort of donors and matched non-donors without hypertension (AHR: 1.01; 95% CI: 1.00 to 1.06). The quality of evidence was very low.

## Renal function
In one small study more donors with hypertension developed CKD as defined by eGFR < 60 ml/min/1.73m2 compared to donors without hypertension (67% vs 22%, RR: 2.97; 95% CI: 1.51 to 5.83) after 5.4 years of follow-up.(J. H. One study reported similar eGFRs in donors with (78.1 ml/min/1.73m2) and without (78.5 ml/min/1.73m2) hypertension at donation at mean follow-up of 6.7 years. The quality of evidence was very low.

## 6f -donors with proteinuria or hematuria versus donors without
None of the included studies analyzed donor outcomes by pre-donation proteinuria or hematuria. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Nine studies evaluated long term donor outcomes by relationship to the recipient. Follow-up ranged from 5 to 17 years. Quality of evidence was rated as moderate to very low for the outcomes [fig_ref] Table 2: Evidence Quality Assessment Criteria [/fig_ref].

## 6g -long term donor outcomes by relationship to the recipient

## Mortality or cardiovascular outcome
Two studies reported cardiovascular outcomes in donors by relationship to the recipient. Both studies used the same cohort of Ontario donors.(A. X. One study reported outcomes of cardiovascular events and mortality by relationship to the recipient. Genetically related living donors had cardiovascular event rate of 1.2 percent while unrelated donors had event rate of 1.6 percent over 6.2 years of follow-up.(A. X. In another study, event rate was similar between donors (1.6 per 1000 person years) and healthy non-donors (1.9 per 1000 person years) and the association was not modified by relationship to the recipient (p for interaction 0.87).(A. X. The quality of evidence for the outcome was very low.

## Esrd
One study reported 15 year cumulative incidence of ESRD by relationship to the recipient, cumulative incidence was lower in unrelated donors compared to related donors15.1 (95% CI: 8.7 to 26.3) versus 34.1 (95% CI: 26.9 to 43.3) per 10,000). The quality of evidence for the outcome was moderate.

## Renal function
One study did not find an association between relationship to the recipient and CKD (eGFR< 60ml/min/1.73m2).(J. H. Among donors who were a first degree relative of the recipient, 18% had CKD versus 28% among donors who were not first degree relative of the recipient, after 7.4 years of follow-up.(J. H. [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] The quality of evidence for the outcome was very low.

## Hypertension
One study did not find an association between relationship to the recipient and hypertension (15.9% in related and 17.3% in unrelated, RR (95% CI): 1.0(0.7-1.3)).(A. X. The quality of evidence for the outcome was very low.

## Psychosocial outcomes
Four studies reported psychosocial outcomes by relationship to the recipient. Related donors had better psychosocial outcomes compared to unrelated donors. Being a first degree relative of a recipient was associated with lower odds of physical HRQOL impairment. Relative other than first degree were 3.5 times more likely to regret donating compared to first degree relatives. Being an unrelated donor was associated with greater risk of having doubts towards donation. Rates of depression diagnoses didn't differ between donors related to recipients, spouses or partners of recipients, and not biologically related or spouse donors (4.9%, 5.0%, and 5.9% respectively) in a privately insured US sample.(K. L. The quality of evidence for the outcome was low.

## 6h -donors with history of kidney stones
We identified no studies analyzing long-term donor outcomes by pre-donation kidney stones status. One retrospective study with a moderate risk of bias shows that in living kidney donors higher BMI is associated with a slightly greater risk of developing hypertension over a mean follow-up of 6.7 years. One retrospective observational study shows similar mean albuminuria in donors with metabolic syndrome and those without metabolic syndrome over a mean follow-up time of 5 years.
Very Low In one study, a 1 mmHg increase in SBP was associated with an increase in the risk of cardiovascular death in a mixed cohort of donors and matched non-donors without hypertension.
Very Low

## Esrd
(1 retrospective observational study)

## Moderate-high unknown no serious indirectness
Serious Imprecision

## Undetected
In one study, a 1 mmHg increase in SBP was associated with an increase in the risk of ESRD in a mixed cohort of donors and matched non-donors without hypertension.

## Very low
Renal Function (1 retrospective observational study)

## Moderate-high unknown serious indirectness
Serious Imprecision

## Undetected
One retrospective observational study with a moderate-high risk of bias shows that CKD was more prevalent among donors with hypertension than donors without hypertension (OR=7.88, 95% CI: 1.14 to 54.45) after median follow-up of 5.4 years.
Very Low [fig_ref] Table 1: PICODD Criteria [/fig_ref] We identified two studies addressing pregnancy outcomes by pre-donation or postdonation timings. Both studies compared post-donation pregnancy (n=596) outcomes to pre-donation pregnancy (n=3343) outcomes in 1428 living kidney donors. Outcomes in the Ibrahim et al. study were ascertained by questionnaires using historical recall of events during pregnancy. Outcomes in the Reisaeter study were ascertained from a database. They reported the following outcomes: fetal loss, prematurity, gestational hypertension, gestational diabetes, preeclampsia, proteinuria and low fetal birth weight. Quality of evidence was very low for all of the outcomes.

## Key question 7: female donors of child-bearing age

## Preeclampsia
Preeclampsia was reported in both studies. Ibrahim et al. reported greater risk of preeclampsia with post-donation pregnancies (6.6%) compared to pre-donation pregnancies (0.9%), the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy, but not significant in the analysis limited to donors with both pre-and post-donation pregnancies. Reisaeter et al. also reported greater frequency of preeclampsia in post-donation pregnancies (5.7%) compared to pre-donation (2.6%) pregnancies. The quality of evidence was very low.

## Fetal loss
Fetal loss defined as stillbirth or fetal death was reported in both studies. Both studies compared frequency of stillbirths or fetal deaths between post-donation pregnancies and predonation pregnancies and found they were similar. The quality of evidence was very low.

## Miscarriage
Miscarriages were reported in one study. In analysis that included donors with either pre or post-donation pregnancies, frequency of miscarriages was higher in post-donation pregnancies (13.2%) compared to pre-donation pregnancies (8.2%). The difference was not significant in analysis limited to women with both pre-and post-donation pregnancies. The quality of evidence was very low.

## Prematurity
Prematurity was reported in both studies. Ibrahim et al. reported greater risk of prematurity with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (6% vs 3.7%, RR(95% CI):1.67(1.05-2.67)), but not significant in the analysis limited to donors with both pre-and postdonation pregnancies (8.7% vs 7.4%, RR(95% CI:1.18(0.59-2.34)). Reisaeter et al. did not find a significant difference in prematurity defined as either < 22 weeks (1% vs0.3%) or < 37 weeks (9.8% vs 7.5%) between post and pre-donation pregnancies. The quality of evidence was very low.

## Gestational hypertension
Gestational hypertension was reported in both studies. Ibrahim et al. reported greater risk of gestational hypertension with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (6.9% vs 0.6% (RR(95% CI): 10.9(5.8-20.6))), but not significant in the analysis limited to donors with both pre-and post-donation pregnancies (3.5% vs 0.5%, RR (95% CI): 7.1(0.9-58.2)) . Reisaeter et al. found a similar frequency of gestational hypertension in post and pre-donation pregnancies (2.8% vs 1.8%, RR (95% CI):1.59(0.45-5.62)). The quality of evidence was very low.

## Gestational diabetes
Ibrahim et al. reported greater risk of gestational diabetes with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (93.8% vs 0.8%, RR (95% CI): 5.0(2.5-10.2)), but not significant in the analysis limited to donors with both pre-and post-donation pregnancies (0.6% vs 0.5%, RR (95% CI): 1.38(0.65-2.89)). The quality of evidence was very low.

## Proteinuria
Ibrahim et al. reported greater risk of proteinuria with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (4.1% vs 1.0%, RR (95% CI): 4.1(2.13-7.99)), but not significant in the analysis limited to donors with both pre-and post-donation pregnancies (4.6% vs 1.5%, RR (95% CI): 2.36(0.72-7.7)). The quality of evidence was very low.

## Low fetal birth weight
One study found similar frequency of extremely low birth weight (< 500 gm) (0.9% vs 0.5%) and low birth weight (500-2500gm) (7.5% vs 5.5%, RR (95% CI): 1.38(0.65-2.89)) in post and pre-donation pregnancies. The quality of evidence was very low. Donors with both a pre-and a post-donation pregnancy had similar development of low birth-weight babies after post-donation pregnancy as compared to pre-donation pregnancy.

## Very low

# Discussion
We conducted a systematic review of evidence related to peri-/post-operative and long term outcomes of living kidney donation and how donor characteristics modify these outcomes. Except for the association of donation with increased risk of ESRD (moderate grade), evidence quality for all other comparisons was low or very low due to limitations with the evidence base. Evidence quality was primarily low or very low when the studies in the evidence base were observational. Limitations such as retrospective designs, selection bias, and confounding were common among observational studies. Confounding or inadequate control of prognostic variables are likely to be the most serious flaws in observational studies. The screening that potential living kidney donors experience is much more comprehensive than the screening of records about individuals' health status collected for other purposes. Matching living kidney donors to records of individuals in these secondary databases on a few variables such as age, sex, race, and BMI status is likely insufficient. An appropriate comparison would involve matching based upon results of health screenings similar to what potential donors experience. However, this represents a less feasible and more expensive study.

## Peri-and post-operative outcomes of living kidney donation
Results from previous systematic reviews assessing living kidney donors peri/postoperative outcomes by surgical approach provide evidence about three different comparisons: open versus laparoscopic nephrectomy, standard laparoscopic versus hand-assisted laparoscopic nephrectomy, and left versus right nephrectomy. We identified two systematic reviews that examined peri/post nephrectomy outcomes in donors with isolated medical abnormalities, namely older age and obesity. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Mixed quality evidence shows laparoscopic living donor nephrectomy results in longer operative times, more reoperations, shorter hospital stays and fewer days to return to work than open donor nephrectomy. Standard laparoscopic nephrectomy had shorter hospital stays than hand-assisted laparoscopic nephrectomy. Very low quality evidence shows similar results with left and right living donor nephrectomy on all outcomes. Apart from operative time, there appears to be no differences in peri and post-operative outcomes for older versus younger donors and donors with higher versus lower BMI.

## Long term outcomes of living kidney donation
Moderate quality evidence shows a correlation between living kidney donation and ESRD. Very low quality evidence shows a correlation between kidney donation and mortality, cardiovascular events, low kidney function, proteinuria, hypertension, and psychosocial outcomes. Very low quality evidence shows that age does not modify the associations. In living kidney donors, older age is a risk factor for all cause and CV mortality, ESRD, CKD, HTN, fractures. There is very low grade evidence that female donors have lower reported death rates, CV events, and ESRD events but higher prevalence of lower eGFR compared to male donors. It is unknown whether gender modifies outcomes of living kidney donation. African American race appears to be a risk factor for ESRD, hypertension, CKD, proteinuria, and diabetes. Aboriginal ethnicity appears to be a risk factor for diabetes, HTN, and proteinuria. Association of Hispanic ethnicity with poor outcomes is inconsistent. We found moderate grade evidence that African American, Hispanic and White donors appear to have greater absolute risk of ESRD compared to non-donors, with African American donors sustaining the greatest increase in absolute risk. We found very low grade evidence from small retrospective observational studies with nonuniform exposure, outcome definitions and ascertainment and high attrition rate that some isolated medical abnormalities are associated with risk of worse kidney function, proteinuria, hypertension or diabetes but it remains unclear whether donation modifies association between isolated medical abnormalities and clinical outcomes. From evidence of very low grade from two studies with serious design limitations preeclampsia, gestational hypertension, and preterm delivery complicated post-donation pregnancies more frequently than pre-donation pregnancies. Interpretation of the evidence is limited by the retrospective observational nature of the studies, risk of bias introduced by unobserved differences between donors and controls, high attrition in some studies, small sample sizes to ascertain clinical outcomes, short duration follow-up to see rare events such as ESRD and non-uniform outcome definitions and ascertainment. As all evidence in the field is of an observational nature, no causality can be inferred. In addition, our report does not address the impact of these donor characteristics on recipient outcomes which are also an important component in donation decision making.

## Outcomes of living kidney donors compared to healthy non-donors
Living kidney donation is an intervention for which it may not be possible to conduct a randomized controlled trial to evaluate the short-term and long-term outcomes compared to not donating a kidney. Kidney donors are carefully selected for donation and are healthier than general population. In order to minimize bias, our review included only studies that compared long term outcomes in living kidney donors to outcomes of matched healthy controls. However, there is strong potential for findings to be biased by selection and/or residual confounding between donors and controls. Furthermore, some findings (such as increased mortality in older vs. younger donors or those with comorbidities) may be due to underlying demographics or comorbidities rather than kidney donation itself.
We included four studies that compared clinical outcomes such as mortality, cardiovascular events, and ESRD during long-term follow-up of on average 5 years to 15 years.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] The data were obtained from administrative donor registries of three countries: the United States, the Canadian province of Ontario, and Norway. Non-donor comparisons were obtained from an administrative database in one study(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] and from population based cohorts in the other studies. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Two studies showed lower mortality in living kidney donors(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] while another study [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] found higher all-cause mortality and cardiovascular mortality in kidney donors compared to controls. The discrepancy in the findings is puzzling. It is difficult to find biological plausibility of nephrectomy extending life span. It is likely that the lower mortality in donors can be explained by residual confounding. Mjoen et al. demonstrated greater mortality in living kidney donors compared with matched non-donor controls. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] However, these results might have been confounded by several issues -donors were almost 10 years older than non-donors (mean age of 46.0 versus 37.6), time of cohort entry differed between donors and non-donors, and donors were followed for up to 43.9 years compared to non-donors who were followed for a maximum of 24.9 years allowing for more events to occur. These differences could have biased the study towards finding greater mortality among donors compared to non-donors. Alternatively, it is possible that mortality differences were due to lower kidney function and greater incidence of ESRD in donors compared to non-donors. Therefore, it is difficult to draw conclusions on long-term mortality due to living kidney donation.
Two studies compared ESRD in living kidney donors compared with healthy non-donor controls. [bib_ref] Long-term risks for kidney donors, Mjen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Both showed rates of ESRD almost 10 times higher among donors compared to non-donors, though absolute risk increases were small. For example, in Norway, incidence of ESRD in donors was 302 per million person years compared to the overall incidence of ESRD of 100 per million person-years. In the US study, estimated lifetime risk of ESRD was 90 per 10,000 donors. Although higher than the rate of 14 per 10,000 in healthy non-donors it was still lower than the rate of 326 per 10,000 representatives of the general population [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] These estimates are limited by the relatively short follow-up duration making lifetime ESRD risk estimates imprecise. Additionally, neither data source had longitudinal measurements of kidney function among kidney donors and comparator population. Despite these limitations, the evidence raises concern about of the effect of kidney donation on ESRD risk, especially in those with very long life expectancy.
Two systematic reviews reported lower eGFR, slightly higher proteinuria, and greater incidence of hypertension among kidney donors compared with healthy non-donors Although quality of evidence for these outcomes is very low, it is possible that these early changes mediate the association between kidney donation and greater rate of ESRD in kidney donors. In addition, related donors have a family history of ESRD and therefore are inherently at increased risk. For example, in the Mjoen study all nine donors who developed ESRD were related to graft recipients and had immunologic causes of ESRD [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] However, family history of ESRD does not fully explain the increase in ESRD rates among kidney donors: in the Muzaale et al. study, donors with biological relationship to the recipient had only about twice the 15 year cumulative incidence of ESRD (34.1) compared to non-related donors (15.1 per 10,000). [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] As 15 year incidence of ESRD is 8 times higher in donors compared to healthy non-donors, some of the increased risk is likely attributable to donation itself rather than donor characteristics. However, because of study design limitations, we graded the evidence as moderate. Life time risk of ESRD associated with donation, especially for young donors remains unclear. Prospective cohort studies with contemporaneous recruitment of kidney donors and matched healthy non-donors with long term follow-up and longitudinal measurements of kidney function, urinary protein and blood pressure as well as ascertainment of clinical outcomes such as cardiovascular events, ESRD and death are needed to fill in the information gap. Meanwhile, current evidence provides important information for informed consent of potential donors. Evidence of greater risk of ESRD among kidney donors might impact criteria for donor selection, especially among young donors who have long projected life spans and are at risk for health event outcomes. Evidence of risk associated with kidney donation should also promote careful follow-up among kidney donors and promotion of good access to care for donors as well as healthy lifestyle choices in order to mitigate the risks associated with kidney donation.

## Long term outcomes in living kidney donors within demographic subgroups (age, sex, race) age
Eight studies compared long-term outcomes in older donors and older healthy nondonors. In all three studies that compared mortality in older donors to older healthy nondonors, [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] mortality was higher among older healthy non-donors than in older donors. This finding likely reflects residual selection bias, as older individuals who are approved for donation are likely healthier than their older non-donor counterparts selected from population cohort studies based on available data. Older age did not modify the association between donation and CV events,(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] clinically significant nephrolithiasis, [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] gastrointestinal bleeding, [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] or fractures.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] Over a limited follow-up duration, greater donor age increased risk for death, [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] cardiovascular events,(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] ESRD, [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] lower kidney function [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] hypertension [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] and diabetes.(K. L. However, this is not surprising as age is significant risk factor for all these outcomes regardless of kidney donation status. Thus the greater outcomes noted in older versus younger donors may not be due to kidney donation per se. Psychosocial outcomes were similar to younger donors. Older donors were less likely to regret donating. [bib_ref] Quality of life in kidney donors, Mjoen [/bib_ref] As few studies checked for interaction between age and donation for outcomes of interest, it remains unknown whether age modifies long term risks inherent in donation. year cumulative incidence of ESRD in donors 60 years or older, 50-59 years and 18-39 years with the lowest cumulative incidence among donors who were 40 to 49 years of age at donation. [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Greater cumulative incidence in very young donors is concerning. Life time risk of ESRD is higher for young donors compared to older donors.
A single center study evaluated long term outcomes among donors who donated their kidney before 18 years of age. [bib_ref] Medical outcomes of adolescent live kidney donors, Macdonald [/bib_ref] The study found that donating a kidney prior to the age of 18 did not increase the risk of hypertension, proteinuria, eGFR<60 ml/min/1.73m2 and diabetes over an average of 31 years of follow-up compared to donating between 18 and 30, though for those who developed these conditions time to diagnosis was similar between the age groups. [bib_ref] Medical outcomes of adolescent live kidney donors, Macdonald [/bib_ref] In conclusion, older donors had similar to better outcomes compared to older healthy non-donors though these findings are likely due, at least in part, to selection biases between groups. Age is a risk factor for poor outcomes after donation, though it is unknown whether donation modifies the risk associated with age. Most available studies have limited follow-up making estimation of life time risk of uncommon events difficult. Life-time risk of long term harms associated with donation (e.g. ESRD) is greater in young donors with long life expectancy. However, because the life-time risk of ESRD is greater in those with long-life expectancy regardless of kidney donation status it is not clear whether donation alters that risk. Long cohort studies that include donors and matched non-donors of all age groups are needed to better delineate the risks.

## Sex
Mortality of healthy non-donors was higher than that of donors in both sex strata. Male sex was a risk factor for death [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] and cardiovascular events.(K. L. Male donors had greater risk of ESRD compared to female donors in one study and a greater risk of being placed on a kidney transplant waiting list, but male sex was not a risk factor for ESRD in a mixed cohort of donors and healthy non-donors. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] Association between sex and lower GFR and hypertension in kidney donors was inconsistent. [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] ; K. L. Psychosocial outcomes were largely similar between genders [bib_ref] Longterm follow-up of living kidney donors: quality of life after donation, Johnson [/bib_ref] [bib_ref] Quality of life in kidney donors, Mjoen [/bib_ref] , though one study found that, among privately insured U.S. donors, women had twice the rate of post-donation depression diagnoses compared to men.(K. L. For all of these outcomes it is not clear if kidney donation alters the risk association with an individual's sex.

## Race
When compared with healthy African American non-donors, African American donors have slightly lower mortality but greater rate of ESRD. [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] While the evidence for mortality is likely explained by residual confounding, evidence for ESRD is concerning. Although overall rate of ESRD is low, there is a significant increase in the rate of ESRD in donors compared with healthy non-donors across all races, with African American donors acquiring the greatest risk (absolute risk increase 50.8 / 10,000 person years for African American donors, 29.5 for Hispanic donors, and 22 for White donors, compared to nondonors). [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] In addition, African American donors have higher risk of hypertension but not of albuminuria or diabetes compared with African American nondonors. [bib_ref] Medical outcomes in African American live kidney donors: a matched cohort study, Doshi [/bib_ref] When compared to White donors, African American donors had a greater risk of death, hypertension, diabetes mellitus, chronic kidney disease, proteinuria.. [bib_ref] Living kidney donors requiring transplantation: focus on African Americans, Gibney [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] However, White donors more commonly developed depression diagnoses compared with non-White donors.(K. L. While African American donors incur the highest ESRD risk attributable to donation on top of already higher risk of ESRD associated with African American race, there is greater organ shortage in African American population with ESRD. Incident rate of ESRD in African Americans is more than 3 times that of Caucasians and African American patients have decreased access to transplantation, that manifests in lower rates of placement on the waiting list and longer waiting times while waitlisted.(K. L. [bib_ref] Health outcomes among non-Caucasian living kidney donors: Knowns and unknowns, Lentine [/bib_ref] Despite the need for African American living kidney donors it is essential to select donor candidates who are less likely to incur harms of donation and to develop ESRD. Further research is needed to establish risks attributable to donation in African American donors compared to healthy African American non-donors and to determine how isolated medical abnormalities such as obesity, metabolic syndrome, glucose intolerance and mild hypertension modify the risk. Testing for apolipoprotein L1 (APOL1) alleles associated with poor renal prognosis might help risk stratification of African American living donors.
Aboriginal donors had higher eGFR, but had greater frequency of hypertension, diabetes, and proteinuria compared to White donors. [bib_ref] Long-term medical outcomes among Aboriginal living kidney donors, Storsley [/bib_ref] 

## Long term outcomes in living kidney donors with isolated medical abnormalities
We identified studies that provided long term follow-up of living kidney donors by kidney function at donation, presence of proteinuria, hematuria, history of nephrolithiasis, obesity, impaired glucose tolerance or fasting glucose, and presence of metabolic syndrome.

## Body mass index
Our systematic review includes five studies that compared long-term outcomes of kidney donors by pre-donation BMI, [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Single-centre long-term followup of live kidney donors demonstrates preserved kidney function but..., Von Zur-Muhlen [/bib_ref] BMI was not associated with all-cause mortality or ESRD in a cohort of donors and matched healthy non-donors. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] Higher BMI was associated with lower GFR at follow-up, greater risk of hypertension [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Single-centre long-term followup of live kidney donors demonstrates preserved kidney function but..., Von Zur-Muhlen [/bib_ref] and greater odds of physical component of health related quality of life impairment. The quality of evidence was very low for all outcomes. High BMI is generally considered a contraindication for donation: four existing guidelines considered BMI > 35 a contraindication (ERBP, BTS, SEN ONT, AF). A study by no difference in short term (3 months and 12 months) mortality after kidney transplantation by donors' BMI. A systematic review that addressed a question of the relation between BMI and short-term outcomes of laparoscopic donor nephrectomy did not find any difference between high and low BMI for short term outcomes such as warm ischemia time, estimated blood loss, length of stay, perioperative complications, or decrease in GFR, but did find longer operation duration, greater risk for conversion to open nephrectomy, and greater rise in serum creatinine in donors with higher BMI. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Only one study had follow-up that exceeded one year; this did not find any difference in serum creatinine between donors with BMI >30 compared to donors with lower BMI, but found greater risk of developing hypertension in obese donors over 11 years of follow-up. [bib_ref] Long-term renal function and cardiovascular disease risk in obese kidney donors, Tavakol [/bib_ref] Two other systematic reviews found greater incidence of hypertension among overweight and obese donors compared to non-obese donors. [bib_ref] Shifting paradigms in eligibility criteria for live kidney donation: a systematic review, Ahmadi [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Our systematic review confirms their finding that obesity is a risk factor for hypertension and cardiovascular disease in kidney donors. These findings are consistent with obesity as a risk factor in a non-donor population.(P. [bib_ref] Overweight and obesity as determinants of cardiovascular risk: the Framingham experience, Wilson [/bib_ref] It remains unknown if donation modifies long term risk of obesity and how obesity interacts with other donor characteristics. From the current literature it is unclear if there is a threshold BMI above which donor prognosis worsens. Future large prospective cohort studies that compare donors from various BMI categories to healthy non-donors from the same BMI category are needed to determine whether overweight and obese donors can be safely accepted for live kidney donation.

## Impaired glucose metabolism, diabetes or metabolic syndrome
We identified two studies that reported long term outcomes of donors with impaired glucose metabolism and one study that reported long term outcomes of donors with metabolic syndrome compared to donors without these abnormalities. Non-surprisingly, donors with impaired glucose metabolism were more likely to be diagnosed with diabetes during the followup compared with donors with normal glucose metabolism. Other outcomes did not differ between the groups. Donors with metabolic syndrome had lower eGFR and higher proteinuria that was small in magnitude and of uncertain clinical significance, compared to donors without metabolic syndrome. This evidence is of very low quality.

## Baseline renal function
Three studies reported long term outcomes by baseline renal function with very low grade of evidence for all outcomes. These data are limited by variable definition of kidney function at baseline and follow-up, retrospective nature and high attrition. None reported clinical outcomes. Although, in one study donors with baseline eGFR > 90 ml/min took a longer time to develop CKD compared to donors with baseline eGFR< 90 ml/min (median time to CKD > 7 years compared to 3.55 years respectively), [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] evidence was insufficient to recommend a kidney function threshold for kidney donation. In addition, it is unknown whether other donor characteristics such as age, race, or presence of other medical abnormalities should modify the threshold GFR. Further studies are needed to inform clinical practice.

## Blood pressure
Only three studies reported long-term donor outcomes by baseline blood pressure. Quality of evidence was low to very low for all outcomes. Higher baseline blood pressure in a mixed cohort of donors and healthy non-donors was associated with cardiovascular mortality and ESRD [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] mirroring findings in the general population. Donors with baseline hypertension were more likely to develop CKD at follow-up.(J. H. [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] Again, it is unknown whether donation modifies the risk associated with hypertension or how other donor characteristics interact with hypertension influencing the risk of donation.

## Proteinuria, hematuria, nephrolithiasis
We found no studies with >100 participants with > 5 years of follow-up that reported outcomes of living kidney donors by proteinuria, hematuria, or history of nephrolithiasis. Donors without a history of nephrolithiasis have a risk of nephrolithiasis comparable to that of matched non-donors. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Male donors had lower rate of surgical procedures for nephrolithiasis compared to male non-donors over 8.4 years of follow-up. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Few studies of long term outcomes for donors with isolated medical abnormalities were available. Most were retrospective with incomplete follow-up and outcome ascertainment. Studies were too small to document clinical and patient centered health outcomes. Definitions of isolated medical abnormalities and outcomes differed between the studies. Further research should determine life-time risk of ESRD and cardiovascular events associated with the isolated medical abnormalities of interest in the general population and how kidney donation alters the risk associated with medical abnormalities. Pooled data from the currently available well characterized population based cohorts with measurement of proteinuria, kidney function, blood pressure, lipid and glucose metabolism, etc. as well as careful ascertainment of renal and cardiovascular outcomes can be used to define life time risk in the general population. Well-designed prospective cohort studies that include both kidney donors and matched healthy non-donors with standardized definitions and measures of participant characteristics and outcomes are needed to establish risks attributable to kidney donation. Knowledge of these baseline risks and more importantly the risks attributable to kidney donation would greatly facilitate the donor selection process and informed consent.

## Female donors of child-bearing age -pregnancy outcomes
Our report includes two studies of pregnancy outcomes in kidney donors. [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] Both studies compared outcomes of post-donation pregnancies to outcomes of pre-donation pregnancies and found a greater rate of preeclampsia in post-donation pregnancies (6.6% in post-and 0.9% in pre-donation pregnancies in the Ibrahim et al study and 5.7% in post-compared to 2.6% in pre-donation pregnancies in the Reisaeter study). [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] In addition, Ibrahim but not Reisaeter reported greater rates of prematurity and gestational hypertension in postdonation pregnancies. [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] Both studies had design features limiting validity and generalizability. One was done in a single center in Norway and pregnancy outcomes were obtained from a centralized birth registry. [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] Another study was done in Minnesota. Pregnancy outcomes were self-reported by women years after their pregnancies and had a substantial number of donors lost to follow-up. Neither study had matched healthy comparison groups. Neither study reported blood pressure values, kidney function or proteinuria during pregnancy. Bias due to recall in the Ibrahim study as well as bias due to ageing of women between pregnancies could have confounded the results.
After the conclusion of our literature search we became aware of an additional study that would have met eligibility criteria. [bib_ref] Gestational Hypertension and Preeclampsia in Living Kidney Donors, Garg [/bib_ref] used an administrative provincial healthcare database from Ontario to match 85 kidney donors without prior history of pregnancy complications in 1:6 ratio with 510 healthy non-donors and followed them prospectively for a median of 10.9 years for the primary outcome of gestational hypertension or preeclampsia. Donors had 131 pregnancy and non-donors had 788 pregnancies during the follow-up. Overall donors and non-donors were matched well with respect to their known characteristics. Outcomes were obtained from diagnostic claims codes. Similarly to the above studies, they found that the combined outcome of gestational hypertension or preeclampsia was more common in donors compared to non-donors (11% vs 5%). There were no differences between donor and non-donor pregnancies for outcomes of Cesarean section, preterm birth at < 37 weeks of gestation, or low birth weight.(A. [bib_ref] Gestational Hypertension and Preeclampsia in Living Kidney Donors, Garg [/bib_ref] Study limitations included that this was a retrospective cohort, used claims based outcome definitions, lacked biochemical parameter measures during pregnancy, controlled for a limited number of variables and thus had potential for unmeasured differences between donors and non-donors, was relatively small in sample size, was conducted in a predominately white population in a single province in Canada and may have had differential outcome ascertainment.(A. [bib_ref] Gestational Hypertension and Preeclampsia in Living Kidney Donors, Garg [/bib_ref] Despite these limitations, this study addressed some sources of bias that affected prior evidence. While supporting prior findings of greater rate of pre-eclampsia and gestational hypertension in kidney donors the overall grade of evidence for these outcomes would not change significantly with inclusion of this study to our report. Other maternal and fetal outcomes were similar in donors and matched non-donors, although the study was not powered to detect rare outcomes.

# Limitations
We focused our inclusion criteria to studies with at least 100 participants, adequate controls, and follow-up of at least 5 years. In the absence of randomized controlled trials, the best available evidence comes from observational studies. Unfortunately, few prospective cohort studies have been conducted and the bulk of the evidence on this topic comes from retrospective studies. These studies rarely have sufficient data to adequately match donors to non-donor comparison groups or statistically control for all potential confounders. The risk that selection bias between donor and non-donors results in differences in outcomes observed is large. Thus the quality of evidence for each outcome was rated as low to very low. Outcomes are often varied in how they are reported and may not be validated, or do not allow pooling or have small absolute differences of unknown clinical importance. Psychosocial outcomes are defined by a variety of instruments, rarely validated and quite heterogeneous with few clinical differences. This significantly limits our confidence in study results. It is unclear whether the differences in long-term outcomes are due to donation or to inherent differences between the groups. Data for long term outcomes are particularly scarce for donors with isolated medical abnormalities. While clinicians, policy makers, patients and donors must act the strength and quality of data currently available limits accurate information. Further research in the area is needed to inform clinicians, policy makers, donors and recipients alike.

# Future research needs
In theory, randomized trials could generate estimates of donor risk that are less prone to bias; however, randomized trials of donation are not ethically feasible. Large prospective cohort studies with contemporaneously identified kidney donors and matched healthy non-donors with careful cohort characterization, uniform variable definition and outcome ascertainment are needed. If included, donors with isolated medical abnormalities can be matched to non-donors with similar conditions and condition severity. In particular it would be helpful to know how healthy non-donors differ from healthy donors. Studies that conduct further "donor screening" of healthy non-donors may yield such information. Further research that determines lifetime risk associated with living kidney donation is necessary to fully understand the effect of living kidney donation on donors and their families. This is particularly important because much of the association of outcomes with demographics and comorbidities observed in donors is not unique and may not be due to donation (e.g. increase mortality, cardiovascular events etc. with age, hypertension, obesity etc.). In addition, the field would benefit from determining life-time risk of ESRD and cardiovascular events associated with the isolated medical abnormalities of interest in the general population and how this risk is modified by kidney donation. This information can be used to determine donor acceptance criteria, to provide informed consent of prospective living donors, and to structure long term donor follow-up and support programs.
[table] Table 1: PICODD Criteria [/table]
[table] Table 2: Evidence Quality Assessment Criteria [/table]
[table] Table 3: Key Question 1 Evidence Profile 1a: Peri/Post Nephrectomy Outcomes -Open versus Laparoscopic Nephrectomy [/table]
[table] Table 4: Key Question 1 Evidence Profile 1b: Peri/Post Nephrectomy Outcomes -Standard Laparoscopic versus Handassisted Laparoscopic Nephrectomy [/table]
[table] Table 5: Key Question 1 Evidence Profile 1c: Peri/Post Nephrectomy Outcomes -Left versus right laparoscopic live donor nephrectomy [/table]
[table] Table 6: Key Question 2 Evidence Profile 2a: Peri/Post Nephrectomy Outcomes -Older versus younger donors [/table]
[table] Table 7: Key Question 3 Evidence Profile: Peri/Post Nephrectomy Outcomes -Obese versus non-obese donors [/table]
[table] Table 8: Key Question 4 Evidence Profile: Long Term Living Kidney Donation Outcomes -Living Kidney Donors compared to Healthy Non-donors [/table]
[table] Table 9: Key Question 5 Evidence Profile: Long Term Living Kidney Donation Outcomes -Older donors versus Older Healthy Non-donor Controls [/table]