Abstract
Background
An underappreciated complication of laparoscopic nephrectomy in male living kidney donors is testicular pain, swelling, and hydrocele development. A recent cohort study in Ontario, Canada, found that male donors had a higher rate of hydrocelectomy (7.7 vs. 0.1 events/1000 person-years) and scrotal ultrasounds (25.6 vs. 6.9 events/1000 person-years) than nondonors, when followed for a median of 9 years.
Objective
To conduct a replication study in Alberta, Canada, examining the long-term risk of hydrocelectomy after laparoscopic living donor nephrectomy, comparing male donors to nondonors from the general population matched on baseline health indicators.
Design
Population-based matched cohort study using linked healthcare databases.
Setting
Alberta, Canada (April 1, 2002, to March 31, 2021).
Patients
We matched 115 male kidney donors who underwent a laparoscopic nephrectomy with 1150 nondonors. The matching characteristics were age at cohort entry, date of cohort entry, rural residence, income, prior vasectomy, and prior inguinal hernia repair.
Measure
ments: The primary outcome was a hydrocelectomy, and the secondary outcome was receipt of a scrotal ultrasound.
Methods
Males were followed for a median of eight years, with a maximum follow-up of 19 years.
Results
The rate of hydrocelectomy was higher in donors than in nondonors (3 of 115 [2.6%] vs. 1 of 1150 [0.1%]; 3.3 vs. 0.1 events/1000 person-years; P < 0.001). The rate of scrotal ultrasounds was also higher among donors than among nondonors (23.4 vs. 7.5 events/1000 person-years; P < 0.001).
Limitations
A low event rate impeded a precise estimation of the risk of hydrocelectomy attributable to donation.
Conclusions
In this population-based cohort study from Alberta, Canada, rates of hydrocelectomy and receipt of a scrotal ultrasound were significantly higher in males who underwent laparoscopic living donor nephrectomy than in male nondonors matched for age and other factors. Males considering living kidney donation should be informed of the risk of developing a symptomatic ipsilateral scrotal hydrocele in the years following laparoscopic nephrectomy.
Introduction
Knowledge of the risks of living kidney donation is essential for informed consent, donor follow-up, and guiding studies aimed at reducing these risks. An underappreciated complication of laparoscopic nephrectomy in male donors is testicular pain, swelling, and hydrocele development on the same side as their nephrectomy. While this complication was described in 13 studies from eight countries between 2003 and 2024, most were small (<150 donors), and only one study included a nondonor comparison group.1-13 Given the limited evidence, this complication has remained largely unknown and is not described in current international guidelines. 14
We recently sought to quantify the long-term risks for scrotal surgery, hydrocelectomy, and scrotal ultrasounds after laparoscopic living donor nephrectomy.
15
Our study used provincial administrative healthcare databases in Ontario, Canada, which contain encrypted patient-level data on health care use, procedures, and outcomes, and have been used extensively to study long-term outcomes in living kidney donors.16-19 While these databases lack information on patient symptoms, they accurately record surgical procedures and imaging with high sensitivity and near-perfect specificity.
20
Our population-based cohort study included 898 male living kidney donors and 8980 matched nondonors from the general population with baseline health indicators similar to those of donors. We found that laparoscopic nephrectomy was associated with a significantly higher risk of subsequent scrotal surgery, primarily for hydroceles (Box 1).
15
In donors vs nondonors, the rate of hydrocelectomy was 7.7 vs. 0.1 events per 1000 person-years, and the rate of receiving a scrotal ultrasound was 25.6 vs. 6.9 events per 1000 person-years. Our data also show that this complication is not limited to the perioperative period but may persist or worsen over time. • Population-based cohort study using linked administrative healthcare databases. • Male living kidney donors who had a laparoscopic nephrectomy and were matched (1:10) with nondonors from the general population on age, prior vasectomy, and other characteristics. Abbreviations: CI, confidence interval; HR, hazard ratio; No., number; NR, not reported. a For the analyses of hydrocelectomy, the P value was derived from a Cox proportional hazards regression while accounting for correlation within matched sets. For the analysis of scrotal ultrasound, the P value was obtained using a stratified log-rank test since the proportional hazards assumption was violated. b Results are reported as a range in donors to comply with Ontario privacy regulations to protect individual identities and reduce the risk of reidentification. c Not reported due to nonproportional hazards.Box 1. Long-term risk for hydrocelectomy and scrotal ultrasound after living donor laparoscopic nephrectomy: Results from a matched cohort study in Ontario, Canada.
15
To assess the validity and generalizability of these novel findings, we conducted a replication study in the province of Alberta, Canada. As before, we conducted a population-based cohort study using provincial administrative healthcare data. Our objective was to examine the long-term risk of hydrocelectomy after laparoscopic living donor nephrectomy, comparing male donors to nondonors from the general population matched on baseline health indicators. We also assessed whether donors were more likely to receive a scrotal ultrasound in follow-up than nondonors.
Methods
Design and Setting
We conducted a population-based matched cohort study using linked healthcare databases within the Alberta Kidney Disease Network (AKDN), which utilizes data from Alberta Health, the provincial health ministry. 21 Over 99% of Alberta residents are registered with Alberta Health and have universal access to hospital care and physician services. Alberta has two transplant centers located in Calgary and Edmonton, where all living kidney donor nephrectomies are performed. Before conducting the outcome analysis, we registered the protocol and analysis plan on clinicaltrials.gov (NCT07078123). 22 Differences between the registered protocol and this final report are presented in Table S1 in the supplement. We followed guidelines for reporting observational studies (Table S2). The protocol was approved by the research ethics boards at the University of Alberta and the University of Calgary, with a waiver of patient consent.
Data Sources
We ascertained baseline characteristics, including covariates and outcome data, from the AKDN database records (Table S3). The Alberta Health database contains information on demographic data, vital statistics, and diagnostic and procedure information for inpatient and outpatient physician services. These databases have been previously used for health services research, including studies of living kidney donors.23-26 Alberta adopted the Canadian Classification of Health Interventions (CCI) system for healthcare procedures on April 1, 2002, marking the start of accrual.
Population
Figure S1 shows the selection process.
Donors
We included all male residents of Alberta aged 18 years or older who underwent a donor nephrectomy between April 1, 2002, and March 31, 2020. Each donor’s nephrectomy date served as their cohort entry date. Living kidney donors were identified using an algorithm that required the presence of one diagnostic code for kidney donation (International Statistical Classification of Diseases, Tenth Revision, ICD-10: Z52.4) and one procedural code for kidney procurement or excision (CCI: 1.PC.58, 1.PC.89, or 1.PC.91) (Table S3). Similar codes have been used in prior studies to identify living kidney donors.23-27 There is no code to indicate the side of nephrectomy, although 90% were expected to be left-sided, which is preferred for donation due to the longer vein. 28
We excluded out-of-province donors, and a small proportion of donors (<5%) with missing data, such as sex or date of birth. We confirmed that no deceased donors were misclassified as living donors, as no living donor in the study died on or before the date of nephrectomy. We confirmed we did not misclassify kidney transplant recipients as donors, as no donor in the study had evidence of dialysis or an organ transplant before donation. We excluded males who, before cohort entry, received a scrotal ultrasound, scrotal diagnosis, or procedure (other than vasectomy or inguinal hernia repair). Lastly, we focused on males who had a laparoscopic donor nephrectomy and excluded those who underwent an open donor nephrectomy. This decision was made because in the Ontario study, complications requiring scrotal surgery were far more likely after laparoscopic nephrectomy compared to open nephrectomy, occurring at rates of 8.3 versus 1.5 scrotal surgeries per 1000 person-years, respectively. 15
Based on local surgical experience, the surgeon’s billing code for laparoscopic nephrectomy in Alberta identified fewer donors than expected during the accrual period. However, for the primary analysis, we excluded donors when it was uncertain whether they underwent a laparoscopic or open nephrectomy. In a post-hoc analysis, we included all donors during the accrual period, regardless of their nephrectomy coding (a laparoscopic, open, or uncertain procedure).
Nondonors
Living kidney donors are an inherently healthier subset of the population due to the rigorous evaluation and selection process used to determine suitability for donation. To identify a comparable healthy control group from the general population, we employed epidemiologic techniques of restriction and matching to select nondonors with similar indicators of baseline health as the donors. Briefly, a cohort entry date (simulated nephrectomy date) was randomly assigned to all males in Alberta based on the distribution of the donors’ nephrectomy dates (2002–2020). The 2,352,198 adult males were then restricted to those without medical conditions that would preclude donation (see Table S3 for restrictions). Only males who visited a family physician at least once in the prior two years were included to ensure primary healthcare access. As with donors, males with scrotal conditions recorded before cohort entry were excluded. These restrictions left 353,532 males (15% of 2,352,198) as eligible nondonor controls.
Matching
Each living kidney donor was matched to 10 eligible nondonors based on six baseline characteristics that might be associated with the risk of a hydrocelectomy, specifically age at cohort entry (±2 years and within age categories), since the risk of hydroceles increases with age29,30; the cohort entry date (±2 years), to account for any era effects; urban or rural residence (population ≥10,000 or <10,000) and income (categorized into fifths of average neighborhood income), as both a rural residence and lower income are associated with less healthcare access and worse outcomes31,32; and prior vasectomy and prior inguinal hernia repair, as both procedures, on occasion, lead to chronic scrotal pain, which can then result in hydrocele detection and repair.33,34 Each nondonor could only be selected once.
Baseline Characteristics
Baseline characteristics were assessed on the donation date or the simulated donation date for nondonors. This was designated the index date. The Alberta Health database provided demographic information, including age and sex. While race/ethnicity was not included in the database, approximately 75% of Alberta’s population is white. 35 Postal codes were linked to the Canadian Census using the Postal Code Conversion file to determine median neighbourhood household income quintile (level 5 being the highest) and rural versus urban location of residence. Demographic data were complete except for the income quintile (1.2%); patients missing this variable were assigned the middle (level 3) category. Medical comorbidities were identified based on validated algorithms, whenever possible, using hospital discharge records and physician claims at the index date (Table S3).
Outcomes
Males were followed from their index date until they died, emigrated from the province, lost their registration for provincially funded healthcare, or until the observation period ended on March 31, 2021. Emigration and loss of registration were the only reasons for losing follow-up. The latter occurred rarely and could happen for various reasons, including incarceration or joining the national armed forces.
The primary outcome was a hydrocelectomy involving excision of the tunica vaginalis. Physicians in Alberta submit billing codes for surgeries or ultrasound readings, resulting in well-coded procedures. To enhance confidence in the accuracy of the primary outcome measurement, we required evidence of both a surgeon’s fee-for-service code and a hospital-based procedural code. These codes were recorded in separate healthcare databases by different personnel at the time of the procedures, without any knowledge that this study would take place in the future. There is no code to indicate the side of hydrocelectomy. The secondary outcome was receipt of a scrotal ultrasound. Table S3 details the outcome codes.
Statistical Analysis
Before and after matching, baseline characteristics of donors and nondonors were compared using standardized mean differences, with values larger than 10% considered meaningful. 36 Descriptive variables were expressed as counts and percentages, medians and interquartile ranges (IQR), or means and standard deviations, as appropriate.
For the analyses of time-to-first-event outcomes with at least 20 events, hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression with robust variance estimation that accounted for the correlation within matched sets. The proportional hazards assumption was assessed using the Kolmogorov-type supremum test on 1000 simulated patterns and was not violated. Outcomes are reported as incidence rates per 1000 person-years and cumulative incidence with 95% CIs. The cumulative incidence was calculated using the Aalen-Johansen estimator, which counts the first event and treats death as a competing event, and was compared visually between donors and nondonors using graphical curves and at specific time points. For analyses of time-to-first-event outcomes with fewer than 20 events, only incidence rates are reported, and the p-value was derived from a log-rank test stratified on matched sets (to be conservative, hazard ratios and cumulative incidence estimates are not reported due to estimate instability).
The statistical test for the primary outcome was performed first, followed by the test for the secondary outcome, each at a two-sided significance level of 0.05 (hierarchical testing described in the clinicaltrials.gov record 22 ). Statistical analyses were performed using Stata/MP 19.0 (www.stata.com).
Results
Follow-Up Time
A total of 1265 males (115 kidney donors and 1150 nondonors) were followed for a median of 8.0 years (7.5 years for donors and 8.0 years for nondonors), with a maximum follow-up of 19.0 years. Observation periods were censored for 56 males (4.4%) due to death (two donors and seven nondonors) or provincial emigration or loss of registration (six donors and 41 nondonors) (of note, in competing-risk analyses, death was treated as a competing event rather than being censored). There were 10,240 total person-years of follow-up (917 for donors and 9323 for nondonors).
Baseline Characteristics
Baseline Characteristics of Living Kidney Donors and Nondonors in Alberta at the Time of Cohort entry a Before and After Matching
Abbreviations: No., number; IQR, interquartile range.
aFor living kidney donors, the date of cohort entry was the date of nephrectomy. For nondonors, the date of cohort entry was randomly assigned (simulated nephrectomy date) to establish the date that follow-up began. Percentages may not total 100 because of rounding.
bStandardized differences describe differences between group means relative to their pooled standard deviation. A value larger than 10% is considered meaningfully different. The standardized difference presented for median values is based on ranks.
Outcomes
Outcome Events Among Living Kidney Donors and Matched Nondonors in Alberta, Canada
Abbreviations: CI, confidence interval; No., number; NR, not reported.
aFor the analysis of hydrocelectomy (which had 4 outcome events), the hazard ratio was not reported because the interval of plausible estimates was wide, indicating substantial uncertainty about the true value of the parameter being estimated; the P value for the difference between groups was derived from a log-rank test stratified on matched sets. For the analysis of scrotal ultrasound, the hazard ratio, 95% CI, and p-value were derived from Cox proportional hazards regression, which accounted for the correlation within matched sets.
In total, 87 males (19 donors and 68 nondonors) had a scrotal ultrasound (the secondary outcome) (Table 2). The rate of this outcome was higher in donors than nondonors (16.5% vs. 5.9%; 23.4 vs. 7.5 events per 1000 person-years; hazard ratio for donors, 3.1; 95% confidence interval [CI], 1.9 to 5.2; P < 0.001) (Table 2, Figure 1). Cumulative incidence estimates at 1, 5, 10, and 15 years of follow-up are shown in Table S4. Cumulative incidence estimates of receipt of a scrotal ultrasound. Donors were matched to 10 eligible nondonors on age at cohort entry (±2 years), cohort entry date (±2 years), urban or rural residence (population ≥10,000 or <10,000), income (categorized into fifths of average neighborhood income), and prior vasectomy and prior inguinal hernia repair. The cumulative incidence was obtained using the Aalen–Johansen estimator, counting the first event, and treating death as a competing event. Shaded areas indicate the 95% CIs.
Post hoc analysis of all living donor nephrectomies (not restricted to surgeries coded as laparoscopic).
The primary analysis included 115 donors who had a laparoscopic nephrectomy as indicated by their surgeon’s billing code. In a post hoc analysis, we included all 286 living donors who underwent nephrectomy during the accrual period, recognizing that, with available billing codes, we often could not reliably distinguish between laparoscopic and open nephrectomies. Alberta transplant surgeons confirm that most surgeries during the accrual period were performed laparoscopically. We employed the same analytical methods as in the primary analysis, redoing the matching process with the same algorithm. Six donors with fewer than 10 nondonor matches were excluded. In total, 3091 males (281 kidney donors and 2810 nondonors) were followed for a median of 9.0 years (9.3 years for donors and 9.0 years for nondonors), with a maximum follow-up of 19.0 years. Baseline characteristics are presented in Table S5, and outcomes, including cumulative incidence rates, are presented in Tables S6 to S8.
In total, 15 males (12 donors and three nondonors) had a hydrocelectomy (Table S6). The rate of this outcome was higher in donors than nondonors (4.3% vs. 0.1%; 4.5 vs. 0.1 events per 1000 person-years, P < 0.001 [hazard ratio not reported due to the low event rate]).
In total, 188 males (44 donors and 144 nondonors) received a scrotal ultrasound (Table S6). The rate of this outcome was higher in donors than nondonors (15.7% vs. 5.1%; 17.7 vs. 5.3 events per 1000 person-years; hazard ratio for donors, 3.3; 95% CI, 2.3 to 4.7; P < 0.001).
Discussion
In this population-based cohort study from Alberta, Canada, rates of hydrocelectomy and receipt of a scrotal ultrasound were significantly higher in males who underwent laparoscopic living donor nephrectomy than in male nondonors matched for age and other factors.
This novel result aligns with our recent study done in Ontario, Canada, which also reported similar findings. 15 Thirteen other studies have reported instances of testicular pain and/or swelling in living kidney donors following nephrectomy (summarized elsewhere in a Supplemental Table 15 ).1-13 The prior studies describe a range of symptoms that may reflect different causes related to the nephrectomy. Following the procedure, some men may experience scrotal swelling and pain, potentially due to general edema, venous congestion from a divided gonadal vein, or from the surgical pneumoperitoneum that obstructs blood flow. Another possible consequence of living donor nephrectomy is the development of a symptomatic scrotal hydrocele on the same side as the nephrectomy in the years following the procedure, which may require a hydrocelectomy. This outcome was the focus of the present study, conducted in Alberta, and our previous study, conducted in Ontario.
Our Ontario-based study with a larger sample size of almost 900 male donors who underwent laparoscopic nephrectomy provides a better understanding of this complication. 15 Hydrocelectomies were often performed years later, once the transplant surgeon was no longer involved in care, and the procedures were performed under general anesthesia. In Canada, primary care physicians typically provide long-term donor care, including ordering a scrotal ultrasound when necessary. Twenty years after the laparoscopic nephrectomy, about 14% of male donors had scrotal surgery, and 31% underwent scrotal ultrasounds. In contrast, only 0.7% of nondonors had scrotal surgery, and 12% received ultrasounds. The median time from donation to scrotal surgery was 5.2 years, and the cumulative incidence over 20 years was 1 in 8 for donors vs 1 in 143 for non-donors. Scrotal surgeries were more than five times more common following laparoscopic nephrectomy than open nephrectomy.
The precise mechanism behind the development of an ipsilateral hydrocele that appears to worsen in the years following nephrectomy remains unclear, including why they are more common after laparoscopic than open procedures. Hydroceles arise from an imbalance of secretion and reabsorption of fluid from the tunica vaginalis, the closed peritoneal sac that surrounds the testis. While division of the gonadal vein may impair drainage from the tunica vaginalis, similar rates of hydrocelectomies after a left-sided and right-sided nephrectomy suggest reasons beyond gonadal vein division, which is always performed in left-sided nephrectomies but only in about half of right-sided nephrectomies.5,15 In the Ontario study, the rate of scrotal surgery did not differ significantly between donors who had had a left-sided vs. right-sided laparoscopic nephrectomy (weighted incidence rate, 8.1 vs. 11.3 events per 1000 person-years, respectively; p=0.47). Although uncertain, the energy devices used during laparoscopic nephrectomy may disrupt lymphatic drainage or increase the risk of reflex sympathetic dystrophy due to potential nerve damage to the spermatic plexus and cord. 9
The strengths of this replication study, conducted in Alberta, include its population-based sample of male living kidney donors, the careful selection of male nondonors with similar baseline characteristics to donors, unbiased outcome ascertainment, and a median follow-up of 8 years (with a maximum of 19 years) and a loss-to-follow-up rate of less than 5%. Males had access to a universal healthcare system that recorded all procedures when they were performed. The consistency of results across two Canadian provinces and the sizable magnitude of the observed effects support the validity of the finding.
Our study has limitations. First, some male donors were excluded from the primary analysis due to unclear records on whether they had undergone laparoscopic or open nephrectomy. This exclusion led to a smaller-than-expected sample size and imprecision in estimating the risk of hydrocelectomy attributable to donation. However, a post hoc analysis including all male donors who underwent nephrectomy further reinforced the robustness of our findings. Second, the true extent of morbidity from hydroceles after living donor nephrectomy may be underestimated. 9 Some males with symptoms may not seek medical attention, avoid discussing sensitive topics, or wish to spare their kidney recipient from concern. 3 We lacked information on other treatments, and we acknowledge that surgery is likely reserved for more severe cases.37,38 We do not know whether the hydrocelectomy resolved the donors’ symptoms. Third, this was an observational study that utilized routinely collected healthcare data. Donors and nondonors with similar symptoms might have different thresholds for seeking medical care or undergoing surgery. 39 Fourth, the donor candidate evaluation during the study period lacked a baseline scrotal ultrasound, so we do not know if a hydrocele developed de novo after donation or if a pre-existing hydrocele worsened. Based on our clinical experience, many older men have pre-existing asymptomatic hydroceles. Fifth, the study lacked detailed data on the nephrectomy procedure (e.g., whether the gonadal vein was preserved in a right-sided nephrectomy), the surgical technique for hydrocele repair, hydrocele symptoms and laterality, physical exam findings, and the indication and findings of the scrotal ultrasound. In prior studies, most donors who reported scrotal content pain or swelling did so on the same side as the nephrectomy.2,3,5-7,9-11
Encouraging living kidney donation remains important, as it benefits not only donors and recipients but also their families and society. 40 However, our findings warrant action from the transplant community. Past and future donors should be informed about potential risks and advised on symptoms to monitor post-donation.2-5,10-12 Donors should have access to necessary medical care for any donation-related complications and should not incur a financial burden.41,42 Transplant centres may consider including a scrotal ultrasound in the pre-donation evaluation of male candidates to document baseline findings and aid in assessing donors who develop new symptoms following laparoscopic nephrectomy. Finally, further research is needed to understand why ipsilateral hydroceles develop after living donor nephrectomy and whether alternative surgical techniques can reduce this risk.
Supplemental Material
Supplemental Material - Long-Term Risk for Scrotal Hydrocelectomy After Laparoscopic Living Donor Nephrectomy: A Population-Based Matched Cohort Study
Supplemental Material for Long-Term Risk for Scrotal Hydrocelectomy After Laparoscopic Living Donor Nephrectomy: A Population-Based Matched Cohort Study by Amit. X. Garg, Anita Lloyd, Liane S. Feldman, Rhiannon Lyons, Eric McArthur, Mauricio Monroy-Cuadros, Kyla L. Naylor, Chris Nguan, MD, PhD
Supplemental Material
Supplemental Material - Long-Term Risk for Scrotal Hydrocelectomy After Laparoscopic Living Donor Nephrectomy: A Population-Based Matched Cohort Study
Supplemental Material for Long-Term Risk for Scrotal Hydrocelectomy After Laparoscopic Living Donor Nephrectomy: A Population-Based Matched Cohort Study by Amit. X. Garg, Anita Lloyd, Liane S. Feldman, Rhiannon Lyons, Eric McArthur, Mauricio Monroy-Cuadros, Kyla L. Naylor, Chris Nguan, MD, PhD
Footnotes
ORCID iDs
Author Contributions
All authors contributed to the conception and design, acquisition of the data, or analysis and interpretation of the data. AXG, JMS, and NL drafted the manuscript, and all authors revised it critically for important intellectual content. AXG and NL are the guarantors. Through AL, they had access to the data and take responsibility for its integrity and accuracy. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding
Grant support was provided by the Innovation Fund of the Alternative Funding Plan of the Academic Health Sciences Centres of Ontario. AXG was supported by the Kay Family Chair in Transformational Kidney Care. KLN was supported by a Health System Impact Embedded Early Career Researcher Award from the Canadian Institutes of Health Research.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
This study is based in part on data provided by Alberta Health and Alberta Health Services. The interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta or Alberta Health Services. Neither the Government of Alberta nor, Alberta Health or Alberta Health Services express any opinion in relation to this study. We are not able to make our dataset available to other researchers due to our contractual arrangements with the provincial health ministry (Alberta Health), who is the data custodian. Researchers may make requests to obtain a similar dataset at 
Trial Registration
ClinicalTrials.gov (NCT07078123).
Disclosures
No disclosures are reported from other authors.
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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