Family History, Genetics May Help to Predict, Detect Early-Stage CKD

A strong association between family history of chronic kidney disease (CKD) and increased susceptibility of CKD was found among Dutch patients, suggesting that genetics play a key role in CKD risk, according to a recent study.

The authors of the study, published in the American Journal of Kidney Diseases, said that the results could make it easier for physicians to detect early-stage CKD and better identify which patients carry a greater risk of developing the disease. Researchers also said that they wanted to establish CKD heritability and detect potential disease biomarkers.

CKD is a recognized global public health problem affecting between 3.3% and 17.3% of adults in Europe, the authors noted. Established risk factors, such as hypertension and diabetes, can explain between 50% and 70% of cases. Familial clustering of CKD and kidney-related markers could suggest that genetic factors or shared environmental factors could aid CKD pathogenesis.

Researchers noted that previous research has left many knowledge gaps regarding CKD predictability and genetic influence, saying that most studies analyzing genetic factors focused on patients with late-stage kidney disease, leading to kidney failure, rather than on early-stage CKD. A focus on detecting CKD earlier could help health care providers stratify risks of CKD development and better predict the disease.

The cross-sectional study contained baseline data from the LifeLines Cohort Study and Biobank, a population-based research study that began in 2006 with plans to follow 3 generations for up to 30 years. The project, containing information on more than 167,500 subjects from the northern Netherlands, was established as a resource for research on complex interactions between environmental, phenotypic, and genomic factors in the development of chronic diseases and healthy aging.

Participants had an initial 2 visits at a research site, including a physical examination and blood and urine collection, and have been invited back for additional exams every 5 years.

For the current study, investigators included 155,911 patients aged 8 or older with creatinine data available in their analysis. There were 29,703 family clusters and 39,836 individual subjects included. Creatinine data was used to estimate the glomerular filtration rate (eGFR).

Overall, more than 95% of the subjects were white and 58.1% were women. The mean age of the subjects was 43.1 (14.7) years. Male participants had a slightly less favorable renal risk profile compared to female participants but had similar distributions in CKD risk and kidney markers.

Investigators observed that participants with a first-degree relative with the disease had a 3-fold greater risk for CKD compared to the general population, independent of body mass index, hypertension, diabetes, hypercholesterolemia, history of cardiovascular disease, and smoking status (recurrence risk ratio [RRR], 3.04; 95% CI, 2.26-4.09).

Across all participants, 1862 cases of CKD with an eGFR of greater than 60 mL/min/173 m2 (CKDSCr) were observed, which translated into a 1.19% crude prevalence rate. Among the family clusters, 1725 families (5.8%) had at least 1 case of CKD_SCr. Among individuals, 2111 (5.30%) participants had at least 1 first-degree relative with CKD_SCr, including 1680 with at least 1 parent affected, 56 with at least 1 affected offspring, and 499 with at least 1 affected sibling.

CKD defining traits that investigators reported heritability estimates were eGFR (44%), urinary albumin excretion (20%), and urinary albumin-creatinine ratio (19%). Investigators also identified heritability estimates for kidney biomarkers, serum urea (31%), serum creatinine (37%), and uric acid (48%) as well as serum electrolytes, potassium (28%), calcium (27%), and sodium (22%).

Additionally, the investigators found that participants with an affected spouse had a 1.56-fold higher risk for CKD (RRR 1.56; 95% CI, 1.20-1.96), suggesting that shared environmental factor and/or assortative mating could somewhat contribute to CKD risk.

“The data presented in this study inform future work on risk stratification based on family history, and provide a step forward in disentangling genetic and environmental risk factors in CKD,” wrote the investigators.

Some of the limitations identified by the researchers related to a lack of gold standard 24-hour albuminuria measurements available for all participants, specific eGFR measurements rather than estimates, and kidney biopsy data. Additionally, data may have been missing because some affected family members did not participate in the study. The high racial heterogenicity also means that the data cannot be generalized to areas outside of the Netherlands.

According to the authors, the results could aid other researchers in developing future studies that should address the added value of risk stratification and the potential impact of looking at family data of patients with CKD.

Reference

Zhang J, Thio CHL, Gansevoort RT, Snieder H. Familial aggregation of CKD and heritability of kidney biomarkers in the general population: the Lifelines cohort study. Am J Kidney Dis. Published online December 22, 2020. doi:10.1053/j.ajkd.2020.11.012