Familial Aggregation of CKD and Heritability of Kidney Biomarkers in the General Population: The Lifelines Cohort Study

Abstract

Rationale & objective: Chronic kidney disease (CKD) has a heritable component. We aimed to quantify familial aggregation of CKD in the general population and assess the extent to which kidney traits could be explained by genetic and environmental factors.

Study design: Cross-sectional 3-generation family study.

Setting & participants: Data were collected at entry into the Lifelines Cohort Study from a sample of the general population of the northern Netherlands, composed predominantly of individuals of European ancestry.

Exposure: Family history of CKD.

Outcomes: The primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m², where GFR was estimated using the CKD Epidemiology Collaboration creatinine equation. Among a subsample for which urinary albumin concentration was available (n=59,943), urinary albumin excretion was expressed as the rate of urinary albumin excretion (UAE) per 24 hours or urinary albumin-creatinine ratio (UACR).

Analytical approach: Familial aggregation of CKD was assessed by calculating the recurrence risk ratio (RRR), using adapted Cox proportional hazards models. Heritability of continuous kidney-related traits was estimated using linear mixed models and defined as the ratio of the additive genetic variance to total phenotypic variance. All models were adjusted for age, sex, and known risk factors for kidney disease.

Results: Among 155,911 participants with available eGFR data, the prevalence of CKD was 1.19% (1,862 cases per 155,911). The risk of CKD in those with an affected first-degree relative was 3 timeshigher than the risk in the total sample (RRR, 3.04 [95% CI, 2.26-4.09). In those with an affected spouse, risk of CKD was also higher (RRR, 1.56 [95% CI, 1.20-1.96]), indicative of shared environmental factors and/or assortative mating. Heritability estimates of eGFR, UAE, and UACR were 44%, 20%, and 18%, respectively. For serum urea, creatinine, and uric acid, estimates were 31%, 37%, and 48%, respectively, whereas estimates for serum electrolytes ranged from 22% to 28%.

Limitations: Use of estimated rather than measured GFR. UAE data only available in a subsample.

Conclusions: In this large population-based family study, a positive family history was strongly associated with increased risk of CKD. We observed moderate to high heritability of kidney traits and related biomarkers. These results indicate an important role of genetic factors in CKD risk.

Keywords: albuminuria; chronic kidney disease (CKD); estimated glomerular filtration rate (eGFR); familial aggregation; family history; genetic risk factor; heritability; kidney function; renal risk.