Risk of Scrotal Hydroceles After Nephrectomy For Kidney Cancer

Risk of Scrotal Hydroceles After Nephrectomy For Kidney Cancer

This population-based study will use provincial health administrative data to examine the risk of hospital admission for hydrocelectomy among males who underwent nephrectomy for kidney cancer, compared with males from the general population with similar baseline health characteristics, who did not undergo nephrectomy. We will use health administrative data from Ontario, Canada, to identify males who underwent nephrectomy for kidney cancer between 2002 and 2024. Four surgical cohorts will be constructed based on procedure type and surgical approach: laparoscopic total nephrectomy, open total nephrectomy, laparoscopic partial nephrectomy, and open partial nephrectomy. A propensity score will be calculated based on sociodemographic characteristics, comorbidities, and health care utilization. For each surgical cohort, patients will be matched to non-nephrectomy male controls (1:4) based on propensity score, age, index date, and modified Charlson Score (excluding cancer). The primary analysis will compare patients undergoing laparoscopic total nephrectomy and laparoscopic partial nephrectomy with matched non-nephrectomy controls from the general population. The primary outcome is hospital admission for hydrocelectomy. Secondary outcomes include diagnosis of hydrocele with receipt of a scrotal ultrasound, and receipt of a scrotal ultrasound. Additional analyses will compare surgical approaches.

*Background*

Previous reports among male living kidney donors have documented postoperative testicular pain and/or scrotal swelling on the side of nephrectomy. Many affected donors were subsequently diagnosed with hydroceles and required surgical intervention (hydrocelectomy). However, existing studies were generally small, had limited follow-up, and lacked appropriate comparison groups.

To address these limitations, a large population-based study of living kidney donors was conducted. Male donors who underwent laparoscopic donor nephrectomy had a substantially higher incidence of scrotal surgery than matched nondonors: 7.8% of donors (70/898) underwent scrotal surgery compared with 0.2% of nondonors (19/8,980), corresponding to 8.3 versus 0.2 events per 1,000 person-years. The hazard ratio was 38.8 (95% CI, 22.1-67.9; P < 0.001), and the 20-year cumulative incidence was 13.8% in donors versus 0.7% in nondonors.

In exploratory secondary analyses, additional surgical cohorts were examined to determine whether similar patterns were observed following other kidney or retroperitoneal procedures. Compared with the general nonsurgical population, patients undergoing nephrectomy for reasons other than donation also appeared to have higher rates of subsequent scrotal surgery. Among those undergoing partial nephrectomy, incidence rates were 1.1 events per 1,000 person-years after laparoscopic procedures and 0.8 events per 1,000 person-years after open procedures. Among those undergoing total nephrectomy, incidence rates were 2.9 and 1.5 events per 1,000 person-years following laparoscopic and open procedures, respectively.

Although these analyses were descriptive and unadjusted for confounding, the findings raise the possibility that aspects of nephrectomy surgery, particularly laparoscopic approaches, may contribute to hydrocele formation. The reasons for this potential difference between laparoscopic and open approaches remain unclear. One proposed mechanism is disruption of lymphatic drainage or venous outflow along the gonadal vessels during retroperitoneal surgery. Because nephrectomy involves mobilization of the kidney and surrounding structures, it may affect scrotal lymphatic or venous drainage. However, the long-term risk of hydrocele formation and repair after nephrectomy performed for kidney cancer has not been well characterized.

Primary Objective: To evaluate whether males who underwent laparoscopic nephrectomy (partial or complete) for kidney cancer have a higher risk of hospital admission for hydrocelectomy compared with males with similar indicators of baseline health selected from the general population.

*Study Setting and Data Sources*

This study will be conducted at ICES (ices.on.ca). ICES is an independent, non-profit research institute with legal authority under Ontario's health information privacy legislation to collect and analyze health care and demographic data without individual consent for the purposes of health system evaluation and improvement. Data use for this project is authorized under Section 45 of Ontario's Personal Health Information Protection Act (PHIPA), which does not require Research Ethics Board approval.

Data from multiple linked databases will be used to identify the cohort, establish baseline characteristics, and define outcomes. These databases include Ontario's Registered Persons Database (RPDB), the Ontario Health Insurance Plan (OHIP), and the Canadian Institute for Health Information's (CIHI) Discharge Abstract Database (DAD), National Ambulatory Care Reporting System (NACRS), and Same Day Surgery (SDS).

Given the nature of the data sources, minimal missingness is expected across study variables. This retrospective cohort study will rely entirely on existing administrative health data available at ICES. To promote research transparency and reproducibility, this study protocol will be registered on ClinicalTrials.gov prior to initiating outcome analyses.

*Study Population*

Male patients undergoing nephrectomy will be identified using hospitalization records in CIHI-DAD and SDS between 2002 and 2024. Only the first nephrectomy occurring during the study period will be examined. Four nephrectomy cohorts will be constructed based on procedure type and surgical approach:

1. Laparoscopic total nephrectomy
2. Open total nephrectomy
3. Laparoscopic partial nephrectomy
4. Open partial nephrectomy

A fifth cohort of non-nephrectomy controls will be selected from the general male population.

*Baseline Characteristics and Matching*

Baseline variables will be assessed at the index date, defined as the date of nephrectomy surgery for exposed patients. For general population comparators who did not undergo nephrectomy, an index date will be randomly assigned based on the distribution of nephrectomy index dates (drawn from the surgical cohort being compared).

Baseline characteristics will be summarized using descriptive statistics and standardized differences. To reduce confounding, 1:4 propensity score matching will be performed, pairing each nephrectomy patient with up to four controls using greedy nearest-neighbour matching without replacement. Matches will be restricted using a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score. Matching variables will include the propensity score, age, index date, and modified Charlson Comorbidity Score (excluding cancer). Post-matching balance between groups will be assessed using standardized mean differences.

*Outcomes*

The primary outcome is hospital admission and receipt of surgery for hydrocele excision (hydrocelectomy). To ensure accurate outcome ascertainment, evidence of both a hospital-based procedural code (CCI codes: 1QH87LA, 1QH87LB, 1QH52HA, 1QH52LA, 1QH80LA, 1QG52HA, 1QG52LA) and a surgeon fee-for-service code (OHIP fee codes: S611, S630) is required, with each recorded in separate healthcare databases within 30 days of one another. The date of hospital admission will be recorded as the outcome date.

Observation time will be censored at death, emigration, or the maximum follow-up date (March 31, 2025). Secondary outcomes include receipt of a scrotal ultrasound and diagnosis of hydrocele with a scrotal ultrasound in administrative health records.

*Statistical Analysis*

Five cohorts will be defined: laparoscopic total nephrectomy, open total nephrectomy, laparoscopic partial nephrectomy, open partial nephrectomy, and non-nephrectomy controls. For all nephrectomy patients, the index date will be the date of surgery. For controls, index dates will be assigned by bootstrapping from the distribution of nephrectomy index dates (from the surgical cohort being compared).

The primary analysis will compare each laparoscopic nephrectomy cohort with matched non-nephrectomy controls.

1. Laparoscopic total nephrectomy vs. matched non-nephrectomy controls
2. Laparoscopic partial nephrectomy vs. matched non-nephrectomy controls

Incidence rates (per 1,000 person-years), rate differences, and hazard ratios (HRs) will be calculated using Cox proportional hazards models with robust variance estimation to account for matching. If the proportional hazards assumption is violated, stratified log-rank tests will be used, and restricted mean survival times will be estimated at 20 years. Cumulative incidence will be estimated using Aalen-Johansen methods to account for the competing risk of death and will be reported at 1, 5, 10, 15, 20, and 25 years. Subgroup analyses will stratify results by age (<39, 40 to 59, 60 to 79, 80+), cohort entry year (2002 to 2009, 2010 to 2017, 2018 to 2024), and modified Charlson score (0, 1 to 2, 3+) (cancer removed from score).

*Additional Analyses*

In additional analyses, the primary analysis will be repeated, comparing different surgical cohorts. These comparisons include:

Total nephrectomy:

i) laparoscopic total nephrectomy vs. open total nephrectomy, ii) open total nephrectomy vs. matched non-nephrectomy controls, and iii) laparoscopic total nephrectomy only vs laparoscopic total nephrectomy with ureterectomy.

Partial nephrectomy:

i) laparoscopic partial nephrectomy vs. open partial nephrectomy and ii) open partial nephrectomy vs. matched non-nephrectomy controls.

For comparisons of surgical approaches (open vs. laparoscopic) or the effect of ureterectomy, inverse probability of treatment weighting (IPTW) using propensity scores will be applied to balance baseline characteristics between groups. Weighted analyses will estimate the effect of the exposure (surgical approach or ureterectomy) on outcomes, targeting the average treatment effect in the treated (ATT). All estimates will be reported with 95% confidence intervals. Hierarchical testing will be applied, with significance testing stopping after the first non-significant result (α = 0.05 per test); all remaining estimates will be presented without p-values.

*Laparoscopic total nephrectomy*

Inclusion criteria

Male individuals who underwent laparoscopic complete/total nephrectomy between April 1, 2002, and March 31, 2024, with a most responsible diagnosis of malignant kidney, renal pelvis, or ureter cancer at the time of nephrectomy. The index date is defined as the date of the first laparoscopic total nephrectomy during the study period.

Exclusion criteria

• Individuals with data record errors (e.g., missing or invalid age, sex, or date of birth), who are less than 0 years of age or greater than 105 years of age, with a death record on or before their cohort entry, or have a date of last contact <4 months after cohort entry (to restrict to permanent residents of the province).
• Prior partial nephrectomy at any time in the lookback.
• Prior total nephrectomy before the start of accrual.
• Individuals who underwent conversion from laparoscopic to open nephrectomy during the same surgical episode.
• Individuals with no recorded primary care visit in the year prior to the index date.
• History of scrotal or male genital conditions or procedures prior to the index date, including hydrocele, hydrocelectomy, scrotal ultrasound, scrotal or testicular malignancy, or other scrotal/genital procedures.

*Laparoscopic partial nephrectomy*

Inclusion criteria

Male individuals who underwent laparoscopic partial nephrectomy between April 1, 2002, and March 31, 2024, with a most responsible diagnosis of malignant kidney, renal pelvis, or ureter cancer at the time of nephrectomy. The index date is defined as the date of the first laparoscopic partial nephrectomy during the study period.

Exclusion criteria

• Individuals with data record errors (e.g., missing or invalid age, sex, or date of birth), who are less than 0 years of age or greater than 105 years of age, with a death record on or before their cohort entry, or have a date of last contact <4 months after cohort entry (to restrict to permanent residents of the province).
• Prior total nephrectomy at any time in the lookback.
• Any nephrectomy before the start of accrual.
• Individuals who underwent conversion from laparoscopic to open nephrectomy during the same surgical episode.
• Individuals with no recorded primary care visit in the year prior to the index date.
• History of scrotal or male genital conditions or procedures prior to the index date, including hydrocele, hydrocelectomy, scrotal ultrasound, scrotal or testicular malignancy, or other scrotal/genital procedures.

*Open total nephrectomy*

Inclusion criteria

Male individuals who underwent open complete/total nephrectomy between April 1, 2002, and March 31, 2024, with a most responsible diagnosis of malignant kidney, renal pelvis, or ureter cancer at the time of nephrectomy. The index date is defined as the date of the first open total nephrectomy during the study period.

Exclusion criteria

• Individuals with data record errors (e.g., missing or invalid age, sex, or date of birth), who are less than 0 years of age or greater than 105 years of age, with a death record on or before their cohort entry, or have a date of last contact <4 months after cohort entry (to restrict to permanent residents of the province).
• Prior partial nephrectomy at any time in the lookback.
• Prior total nephrectomy before the start of accrual.
• Individuals who underwent conversion from laparoscopic to open nephrectomy during the same surgical episode.
• Individuals with no recorded primary care visit in the year prior to the index date.
• History of scrotal or male genital conditions or procedures prior to the index date, including hydrocele, hydrocelectomy, scrotal ultrasound, scrotal or testicular malignancy, or other scrotal/genital procedures.

*Open partial nephrectomy*

Inclusion criteria

Male individuals who underwent open partial nephrectomy between April 1, 2002, and March 31, 2024, with a most responsible diagnosis of malignant kidney, renal pelvis, or ureter cancer at the time of nephrectomy. The index date is defined as the date of the first open partial nephrectomy during the study period.

Exclusion criteria

• Individuals with data record errors (e.g., missing or invalid age, sex, or date of birth), who are less than 0 years of age or greater than 105 years of age, with a death record on or before their cohort entry, or have a date of last contact <4 months after cohort entry (to restrict to permanent residents of the province).
• Prior total nephrectomy at any time in the lookback.
• Any nephrectomy before the start of accrual.
• Individuals who underwent conversion from laparoscopic to open nephrectomy during the same surgical episode.
• Individuals with no recorded primary care visit in the year prior to the index date.
• History of scrotal or male genital conditions or procedures prior to the index date, including hydrocele, hydrocelectomy, scrotal ultrasound, scrotal or testicular malignancy, or other scrotal/genital procedures.

*Non-Nephrectomy Control Cohort*

Inclusion criteria

The control cohort will consist of male individuals identified in RPDB. Index dates will be randomly assigned by bootstrapping dates from the appropriate nephrectomy group, such that each control is assigned an actual nephrectomy index date randomly sampled with replacement from that group. Controls will be carefully screened to ensure that none are included in the nephrectomy cohort being compared.

Exclusion criteria

• Individuals with data record errors (e.g., missing or invalid age, sex, or date of birth), who are less than 0 years of age or greater than 105 years of age, with a death record on or before their cohort entry, or have a date of last contact <4 months after cohort entry (to restrict to permanent residents of the province).
• Any nephrectomy (partial or total).
• Individuals with no recorded primary care visit in the year prior to the index date.
• History of scrotal or male genital conditions or procedures prior to the index date, including hydrocele, hydrocelectomy, scrotal ultrasound, scrotal or testicular malignancy, or other scrotal/genital procedures.