This nationwide population-based study of 1.76 million people in South Korea showed a strong familial aggregation of CKD such that individuals with an affected family member with CKD had a higher risk of incident CKD. Furthermore, once CKD had been diagnosed, family history of ESRD was also associated with a significantly higher risk of disease progression to ESRD. Thus, these findings reveal that the family history of kidney disease may be useful to early identify individuals at high risk of CKD and accurately classify patients’ risk of ESRD among patients with CKD.
There has been accumulating evidence that CKD has a familial predisposition. Over 30 years ago, Ferguson et al. reported that a family history of CKD was associated with a substantially higher risk of ESRD 24. A year later, Seaquist et al. found that there is a striking concordance of diabetic nephropathy between siblings with type 1 diabetes 25. Additionally, Lei et al. showed that the risk of ESRD was significantly higher in individuals with any family history of renal disease, and these associations could not be completely explained by clustering of other known risk factors for ESRD within the family, such as diabetes and hypertension 26. Notably, these observations have inspired several studies to search for genes contributing to the risk of a wider range of kidney diseases in the 21st century. For example, genome-wide association studies have identified many genetic regions associated with renal traits, such as diabetic nephropathy, estimated glomerular filtration rate, and albuminuria 27–32. As another notable discovery, the polymorphisms in the APOL1 (apolipoprotein L1) gene were found in 2010, which conferred very high risks of hypertensive nephrosclerosis and focal global glomerulosclerosis in a recessive manner 33–35. Interestingly, the higher prevalence of such a pathogenic APOL1 allele in Black Americans has been recognized as one of the plausible explanations responsible for the higher burden of CKD in this population than in White Americans 36, 37. Recently, the familial risk of CKD and ESRD has also been confirmed in several large observational studies. A cross-sectional, population-based cohort study including 87,849 Taiwanese patients with ESRD found that there was an association between having an affected first-degree relative with ESRD and the development of ESRD with a relative risk of 2.46 (95% CI, 2.32–2.62) 19. Furthermore, Zhang et al. more recently reported similar findings in European patients with an earlier stage of CKD, including 1,862 CKD cases of 155,911 study participants, noting that the risk of CKD in individuals with an affected first-degree member was three times higher than that in the general population (recurrence risk ratio 3.04, 95% CI 2.26–4.09) 38. Their study is particularly noble given that most studies examining familial contributions to kidney diseases have largely focused on the advanced stages, ESRD. As an extension of these studies, our study additionally confirmed that individuals with an affected family member with CKD are not only far more likely to develop CKD but also exhibit faster disease progression to ESRD. To the best of our knowledge, this is the largest study conducted to date examining more than 1.7 million people in Korea, providing strong statistical power. While the underlying mechanisms responsible for these associations await further investigation, the study findings suggest that a family history of CKD or dialysis is associated with an increased incidence of CKD and disease progression to ESRD and can be used to identify individuals at high risk of both kidney diseases.
A higher risk of kidney disease with an affected family member indicates that CKD is a hereditable condition. However, it is more evident that shared environment and shared genes likely contribute to kidney disease. Assuming that spouses share the family environment but not close genetic similarity with other family members, they have been used to estimate the relative contribution of shared environmental factors to susceptibility to kidney disease 19, 38, 39. In this regard, we also found that individuals having affected spouses with CKD were associated with a 30% higher risk of CKD. Likewise, among patients with CKD, those with affected spouses with ESRD were also associated with a 14% increased risk of ESRD. These findings are further supported by the aforementioned studies, which consistently showed that individuals with an affected spouse with CKD or ESRD were associated with a higher burden of each kidney disease. Accordingly, it should be emphasized that both genetic and shared environmental factors might be considered to better understand the complex nature of the familial contribution to kidney disease 40.
The validity of this study is strengthened by the use of the Korean NHIS database linked to the nationwide family tree database, which contains information on the entire population of South Korea. Given that the awareness of CKD by both patients themselves and other family members is likely to be low (i.e., when compared to awareness of other catastrophic illnesses such as ischemic heart disease, stroke, or malignancy that are often included in family history questionnaires), it seems to be more valid to ascertain an affected family member based on the nationwide family tree database rather than on questionnaire 17. However, this study has several limitations. First, we ascertained CKD entirely relied on ICD-10 codes due to the lack of relevant laboratory data such as estimated glomerular filtration rate and albuminuria, which might not precisely capture the disease burden. Hence, the study results may underestimate the true prevalence of CKD in this population. Second, the Korean NHIS database contains information recorded since 2002, and some patients with kidney disease who died before 2002 were not included in this database, which possibly leads to information bias in the ascertainment of affected individuals within family in this study. Third, residual confounding might still be a limitation as we did not capture complete data on potential risk factors such as blood pressure, obesity, health behaviors (e.g., smoking status), or medications (e.g., use of angiotensin-converting enzyme inhibitors and/or angiotensin-receptor blockers), some of which have been associated with CKD outcomes 41. Therefore, we could not assume that all measured covariables were sufficient to adjust for all biases. Nonetheless, we tried to address this shortcoming, at least in part by vigorous adjustment for measured covariables such as sociodemographic data and various comorbidities. Fifth, given the observational nature of our study design, we could not infer the causality of the observed associations between familial aggregation of CKD and disease occurrence and progression. Finally, our findings may not be generalizable to populations outside of South Korea, given the genetic architecture, social factors, environmental exposures, national healthcare policies, and chronic disease burden, including kidney disease, which may be distinct from other countries.
In conclusion, this national family cohort study of the Korean population revealed that a family history of CKD was associated with a significantly higher risk of not only CKD but also ESRD. While more accurate and readily applicable genetic testing is not currently available in routine clinical practice, these intriguing findings provide useful information suggesting that ascertainment of affected family members with CKD or ESRD is useful to early identify individuals at high risk of CKD, which is also valid to predict disease progression in patients with CKD. Hence, it should be emphasized that a detailed family history of kidney diseases should be taken as a part of clinical care to screen and treat high risk individuals in a timely manner.