Using a population-based, matched, retrospective cohort approach, this study will evaluate the long-term risk of kidney stones among living kidney donors compared with matched healthy nondonors. Linked administrative health care databases from Ontario, Alberta, and British Columbia will be used and living kidney donors who donated between 1992 and 2024 will be identified and matched 1:10 to a carefully selected population of healthy nondonors based on baseline characteristics. The primary outcome is a surgical intervention for kidney stones (including shockwave lithotripsy, ureteroscopy or percutaneous nephrolithotomy). The secondary outcome is a hospital encounter with a kidney stone diagnosis.

*Background*

The long-term risk of kidney stones following living kidney donation remains poorly understood. After donation, living donors have a solitary kidney, where kidney stones can cause more serious complications. These complications include ureteral obstruction and acute kidney injury, resulting in hospitalization and the need for surgical intervention to treat the kidney stone.

Previous studies have reported only a few stones at the time of nephrectomy for donors, and only one long-term study examined donation-attributable risks for kidney stones and kidney stone surgical intervention following donation, finding no increased risk. However, this study was limited by a small sample size and short follow-up (median 8.4 years).

In the general population, kidney stones affect 10-15% of individuals over a lifetime, and while most stones pass spontaneously, some require surgical intervention such as shockwave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy. This study will evaluate whether living kidney donors, compared with healthy nondonors, have an increased risk of (i) kidney stones requiring surgical intervention and (ii) hospital encounters for kidney stones.

*Study Setting and Data Sources*

This study will be conducted at ICES (ices.on.ca), an independent, non-profit research organization designated as a prescribed entity under Ontario's health privacy legislation. This designation permits ICES to collect, use, and analyze health and demographic information without individual consent for the purposes of health system evaluation and improvement. The use of data for this project is authorized under Section 45 of Personal Health Information Protection Act (PHIPA) and does not require approval from a Research Ethics Board.

In Ontario, the study will use linked administrative health databases, including Trillium Gift of Life Network (TGLN), the Registered Persons Database (RPDB), the Ontario Health Insurance Plan (OHIP) Claims Database, and datasets from the Canadian Institute for Health Information (CIHI), including the Discharge Abstract Database (CIHI-DAD), National Ambulatory Care Reporting System (NACRS), and Same Day Surgery (SDS) database. As most hospital discharge and physician billing data are available beginning in 1991, July 1, 1992 will mark the start of the accrual period. Living kidney donors will be identified primarily through TGLN data, with CIHI-DAD used to supplement donor identification during periods when TGLN data are incomplete.

Comparable administrative data sources will be used in Alberta and British Columbia to enable harmonized analyses across provinces. All ethics approvals have been obtained in these provinces. In Alberta, data will be accessed through the Alberta Kidney Disease Network (AKDN) and Alberta Health Services (AHS), contingent on analyst assignment and data availability. Living kidney donors will be identified using CIHI-DAD, with demographic and vital statistics obtained from the Alberta Provincial Registry and Vital Statistics databases. Information on hospitalizations, diagnoses, and healthcare encounters will be obtained from CIHI-DAD, NACRS, and the Alberta Practitioner Claims database.

In British Columbia, data will be accessed through Population Data BC (PopDataBC) and the Healthcare Data Platform BC (HDPBC). Living kidney donors will be identified using data from BC Transplant and the Patient Records and Outcome Management Information System (PROMIS), accessed through BC Renal; if unavailable, CIHI-DAD will be used. Demographic and vital statistics will be obtained from PopDataBC's Consolidation File/Central Demographics database, and healthcare utilization data will be sourced from CIHI-DAD, CIHI-NACRS, and PopDataBC's Medical Services Plan database.

This retrospective cohort study will use existing administrative healthcare data. Consistent with best practices for observational research, the study objectives, design, and statistical analysis plan will be publicly registered on ClinicalTrials.gov prior to the initiation of outcome analyses.

*Study Population*

Living kidney donors will be accrued between July 1, 1992, and March 31, 2024, subject to data availability. The date of the donation nephrectomy will serve as the cohort entry date. Before nephrectomy, living donors undergo rigorous health screening. A similarly healthy segment of the general population will be selected using epidemiological techniques of restriction and matching. A random cohort entry date (simulated nephrectomy date) will be assigned to all persons who were residents of the province, according to the distribution of cohort entry dates among donors (July 1, 1992, to March 31, 2024). After a simulated nephrectomy date is assigned, the sample of nondonors will then be restricted to nondonors without medical conditions that would preclude donation. Additionally, only those who have visited a family physician at least once in the prior 2 years will be included to ensure health care access. We will further restrict to those who have no history of kidney stones prior to donation (simulated nephrectomy date), to capture de novo kidney stones in follow-up. Historically, having a history of kidney stones (symptomatic or seen on imaging) prevented an individual from becoming a living kidney donor. However, more recently, centres now accept individuals with small unilateral stones as living kidney donors. Follow-up will commence at cohort entry and will be censored at the earliest of the first occurrence of the outcome of interest, death, emigration from the province, or the end of the observation period (March 31, 2025).

*Baseline Characteristics and Matching*

Donors and nondonors will be matched 1:10 on cohort entry date (date of donation/simulated donation), sex, age, residential status (rural vs. urban), and neighborhood income quintile (if an urban resident). Baseline characteristics will be summarized descriptively, using mean (standard deviation), counts (percentages), and median (interquartile range, as appropriate. Standardized mean differences >0.10 indicate meaningful imbalance. Donor-specific characteristics will also be described where data are available, including pre-nephrectomy kidney function and donor-recipient relationship.

*Outcomes*

The primary outcome is the first occurrence of a surgical intervention for a kidney stone (including shockwave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy). The secondary outcome is the first hospital encounter for a kidney stone, including either an emergency department visit or hospital admission.

*Statistical Analysis*

The primary analysis will examine the association between living kidney donation and the risk of kidney stones. Only the first qualifying event will be considered. Hazard ratios (HRs) and 95% confidence intervals (CIs) will be estimated using Cox proportional hazards regression with robust variance estimation to account for correlation within matched sets.

Prespecified subgroup analyses will be performed to evaluate potential effect modification in the association between living kidney donation and kidney stones. Analyses will be stratified by age at cohort entry (<55 vs ≥55 years), sex (male vs female), and cohort entry period (1992-2001, 2002-2012, and 2013-2024). For each subgroup, hazard ratios and 95% confidence intervals will be estimated using Cox proportional hazards regression with robust variance estimation, consistent with the primary analysis. Risk factor analyses will evaluate the association between baseline characteristics and the primary outcome, including age (modelled per 5-year increase), sex (male vs female), rurality (urban vs rural residence), neighbourhood income quintile (modelled per quintile), and cohort entry year (modelled per 1-year increase).

To enhance statistical power and generalizability, outcome estimates for the primary outcome from Ontario, Alberta, and British Columbia will be combined using a privacy-preserving Cox regression approach for multisite studies in which individual-level data cannot be shared. The secondary outcome will be combined across provinces based on data availability. The privacy-preserving approach requires a single transfer of summary-level outputs from each province and produces estimates equivalent to those obtained from pooled individual-level data. Province-specific baseline hazards will be assumed, with confounding control (e.g., matching) performed independently within each province. Summary-level risk-set tables will be securely transferred to a coordinating site to estimate combined hazard or risk ratios with corresponding 95% confidence intervals. In accordance with privacy requirements, all cell sizes of five or fewer will be suppressed (reported as ≤5) in publications, and all study personnel will comply with applicable data confidentiality and data use agreements.

*Additional Analyses*

Our primary analyses will exclude individuals with documented kidney stones before cohort entry. For donors with kidney stones before donation, we will provide descriptive estimates of the cumulative outcome incidence of kidney stone interventions and subsequent kidney stone diagnoses during follow-up.

*Donors*

Inclusion Criteria: Living kidney donors who underwent donor nephrectomy in Ontario, Alberta, and British Columbia, Canada, between July 1, 1992, and March 31, 2024 are eligible to enter the study.

Exclusion Criteria:

• Any person with data errors in their database records (such as missing or invalid age; it is expected to exclude very few persons for these reasons). Data errors also include evidence of prior dialysis or a prior solid organ transplant, as such individuals are not eligible to become donors.
• Any person who was not a permanent resident of the province (i.e., the patient lives outside of the province, and only came to the province to donate a kidney to the intended recipient). This will include anyone who is not eligible for the province's health insurance plan, anyone whose last contact date in the databases is less than 1 year after the cohort entry date, and anyone without a physician visit in the year following the nephrectomy hospital discharge.
• Any person who is <18 years of age on the date of nephrectomy (as only under exceptional circumstances should a person less than 18 be approved for living donation).
• Any person with a history of kidney stones.

*Non-donors*

Inclusion criteria: Before nephrectomy, living donors undergo rigorous health screening. A similarly healthy segment of the general population will be selected using restriction and matching. A random cohort entry date (simulated nephrectomy date) will be assigned to all persons who were residents of the province, according to the distribution of cohort entry dates among donors (July 1, 1992, to March 31, 2024).

Exclusion Criteria:

• Any person with data errors in their database records (such as missing or invalid age).
• Any person who was not a permanent resident of the province. This will include anyone who is not eligible for the province's health insurance plan and anyone whose last contact date in the databases is less than 1 year after the cohort entry date.
• Any person who is <18 years of age on the cohort entry date.
• Anyone who is pregnant at the time of the cohort entry date.
• Baseline illnesses and measures of health care access from historic records preceding the cohort entry date will be identified. The sample of eligible nondonors will be restricted to persons without a recorded medical condition that could preclude donation. Such recorded medical conditions will include a hospitalization for mental illness in the prior year; an intensive care unit admission in the prior year; a hospitalization for palliative care services in the prior year; multiple hospital admissions in the prior year; high comorbidity (as assessed by the Charlson comorbidity index and adjusted clinical group scores, where data are available); receipt of home oxygen therapy; residence at a long-term care facility; dementia; any record of prior nephrology consultation or kidney disease (including receipt of dialysis, a kidney biopsy, or a kidney procedure such as a partial or complete nephrectomy); previous solid organ transplant; disorders of the kidneys, ureters, or bladder; any record of cardiovascular disease (congestive heart failure, cardiovascular procedures, myocardial infarction, peripheral vascular disease, abdominal aortic aneurysm repair, ischemic stroke); hypertension in individuals <50 years of age (persons with this condition are not accepted as donors in Canada); any record of obstructive sleep apnea; any cancer diagnosis; any liver disease or cirrhosis; diabetes; any serious infection (hepatitis, HIV, infective endocarditis); any record of autoimmune rheumatic conditions (such as rheumatoid arthritis or systemic lupus erythematosus); and any record of alcoholism.
• To ensure the nondonors have access to health care services from physicians, nondonors who had no evidence of a family physician visit in the 2 years prior to cohort entry will be excluded. Additionally, nondonors with more than 5 family physician visits in the 2 years prior to cohort entry will be excluded, as this could suggest an active health issue that needs attention before donation could occur.
• Any person with a history of kidney stones.

Living kidney donors matched to nondonors from the general population with similar indicators of baseline health.

The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). Similarly, the Alberta and British Columbia datasets are held securely by their respective data stewards, and access is governed by provincial privacy legislation and data sharing agreements. The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.