Long-Term Risk of Gout in Living Kidney Donors

*Background*

Elevated serum uric acid is a major risk factor for gout. Kidney function plays an important role in uric acid regulation, as reduced glomerular filtration rate (GFR) decreases uric acid excretion and increases serum uric acid levels. Living kidney donation results in a sustained 25% to 40% reduction in GFR following nephrectomy. Consistent with this physiological change, donors have higher serum uric acid levels than healthy nondonors, with differences observed as early as six months after donation and persisting years later.

Prior population-based research found that living kidney donors were more likely to be diagnosed with gout and receive gout-related medications compared with healthy nondonors. However, this study was limited by a shorter follow-up (median follow-up 8.4 years). Because the donation-attributable risk of gout remains uncertain, it is not usually discussed in donor counselling or follow-up care. With an additional decade of administrative health data now available, this study will evaluate the long-term risk of gout among living kidney donors compared with matched healthy nondonors.

*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, 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. 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 baseline characteristics that might be associated with risk for gout: cohort entry date (date of donation/simulated donation), sex, age, residential status (rural vs. urban), and income quintile (if urban). Baseline characteristics will be summarized using descriptive statistics. Continuous variables will be reported as mean (standard deviation) or median (interquartile range [IQR]), as appropriate, and categorical variables will be reported as counts (percentages). Given the anticipated large cohort size and the limitations of hypothesis testing in this context, differences between donors and nondonors at cohort entry will be assessed before and after matching using standardized mean differences (SMDs), with values greater than 0.10 indicating 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 health care encounter with gout recorded as a diagnosis (≥2 physician claims on separate days within 3 years [the second claim date will define the event date], emergency department visit for gout, or hospitalization for gout). Secondary outcomes include receipt of a dispensed prescription for the composite of allopurinol, colchicine, or febuxostat, and each medication separately.

*Statistical Analysis*

The primary analysis will examine the association between living kidney donation and the risk of gout. 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 gout (primary outcome only). 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 gout before cohort entry. For donors with gout before donation, we will provide descriptive estimates of cumulative outcome incidence 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 gout.

*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 gout.