Family History of End-Stage Renal Disease: What does it mean for ESRD Risk?

In this post, Dr Tejas P. Desai, eAJKD web advisory board member and Dr. William Mc Clellan (WM) will share thoughts on a study published in the current issue of AJKD prospectively evaluating the risk factors for incident kidney failure among 19,409 participants of the Renal REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort study, focusing on the importance of family history in conjunction with baseline urine albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Incident cases of ESRD were identified through the United States Renal Data System.

eAJKD: Are there prior studies to support the role of family history as a risk factor for kidney disease?

WM: We knew that family history of ESRD was a significant risk factor for the occurrence of ESRD. This has been observed in a number of studies of incident and prevalent dialysis patients, but not in longitudinal cohorts. In previous work that we had done in REGARDS, we described an association between family history and the prevalence of impaired kidney function and albuminuria, but not with incident ESRD. We wanted to further explore the extent that a history of ESRD in a first-degree relative was associated with development of ESRD. To our knowledge, this longitudinal relationship has not been looked at before in prospective studies.

eAJKD: What was the most surprising aspect of the study results?

WM: Interestingly, the impact of family history on the incidence of ESRD was completely accounted for by the baseline reduction in eGFR, the presence of albuminuria at baseline, or both in the family members who had kidney disease. We had thought that perhaps there might be a small residual risk remaining from “pure” family history without the albuminuria and eGFR reduction, but this was not the case. The study doesn’t explain why family members are at increased risk for impaired kidney function, but, once you account for these patients kidney function and albuminuria, you have accounted for most of their excess risk of ESRD.

eAJKD: What comes next in studying this relationship?

WM: There are 2 issues. The first asks how clinicians can use this information. The second asks what sort of etiologic hypothesis do these observations engender. From my point of view, it’s the clinical relevance of the observation that seems to be the most important and actionable. We have nephrologists who have access to every family with an incident or prevalent patient on dialysis. Barry Freedman and his group in Wake Forrest, NC have been interested in how to leverage that information to at-risk families in order to provide educational or other healthcare interventions that lead to screening, detection and risk modification in family members who have impaired kidney function. I think that this targeted intervention is a very important potential step towards reducing the incidence of ESRD, especially in the African-American population. I would hope that our observations also would continue to support the efforts ofby the National Kidney Foundation, the KEEP family member screenings, and National Kidney Disease Education Program, all of which at least in part through their educational activities target their educational efforts at family members, and support individual clinicians who are caring for these families on a daily basis.

With respect to the etiologic issues, I think one of the things that these observations might do is focus the discussion on why there is a familial aggregation on some factors that are associated with the occurrence of albuminuria and impaired kidney function. We have noticed there are a number of genes associated with eGFR and some polymorphisms associated with susceptibility to proteinuria. Those, plus environmental factors that are associated with decreased eGFR or proteinuria, are worthy of investigation. One point that I would be very interested in seeing explored is the degree to which low birth weight, as described in the Brenner nephron number hypothesis, may explain this familial aggregation of impaired kidney function and subsequent of ESRD. Low birth weight is a surrogate for reduced nephron number, which is well established as a risk factor for impaired kidney function, and there is a possibility that these families are characterized by generations of low birth weight. It is important for nephrologists to be sure that every ESRD patient has information about familial risk. I think it is important for primary care providers to inquire about family history and incorporate that information into their health screening activities. For those of us who trying to sort out this familial aggregation, these results suggest that we should focus on the risk factors we already know about rather than searching for new risk factors.

In clinical practice, we ask patients about cardiovascular disease and stroke, and incorporate that into risk assessment. We’ve talked to clinicians about screening for proteinuria and albuminuria in diabetics. An extension of that would be to ask about family history of kidney disease and incorporate that information as well.

To view the entire article please visit AJKD.

1 Comment on Family History of End-Stage Renal Disease: What does it mean for ESRD Risk?

  1. I enjoyed reading the article and interview by McClellen et al. however I have to disagree with their conclusion that the increased risk of ESRD in relatives of patients with ESRD can be fully accounted for by eGFR reduction and albuminuria. The problem is the short 4 year median f/u. It is obvious that patients with a lower GFR and higher albumin excretion are more likely to progress to ESRD over a short period of time. It is possible that these same individuals would have had a higher GFR and normal albumin excretion if assessed a few years ago. Perhaps in 10 years many more of the patients with a family history of ESRD, despite normal eGFR and lack of albuminuria, will develop one or both risk factors and will eventually progress to ESRD. In addition it would have been interesting to know if any of the patients expressed the APOL1 gene and how that relates to low GFR, albumin excretion and incident ESRD in this cohort of patients. Only longer follow up will determine if the author’s conclusions are true.

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