Chronic Kidney Disease & Cystatin C: Latest Data Allows Better Risk Selection with the Ability to Issue More Cases
The conclusions of the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference were recently published.1 This expert panel started with the recognition that early identification and treatment of chronic kidney disease (CKD) can reduce the burden of coronary disease, end-stage renal disease, and premature mortality. They conclude, among other things, that those individuals with hypertension, diabetes, coronary disease, or other genetic or environmental risk factors be screened for CKD, Recommendation #1. They also advise combining creatinine and Cystatin C with newer, equations for the estimated glomerular filtration rate to improve the precision of CKD identification.
An international group of kidney specialists examined the revised eGFR equations and published their conclusions in the New England Journal of Medicine2. This study was complex, but in short, researchers’ re-fit GFR prediction models using pooled data from subjects who had their GFR measured using exogenous agents like inulin. They then validated these models against large pools of patients and calculated the average under- or over-estimation of GFR. They found that the newer, race-blind Cystatin C and creatinine equation had the least bias in black and non-black populations.
In the life insurance industry, race information is not commonly collected. Hence, the eGFR equations that use race are imputed as non-black, likely yielding significant underestimates of renal function in black applicants. The life insurance industry considers renal function when there is good evidence of significant impairment, such as an eGFR below 50 ml/min/1.73m2.
We have evaluated our CRL data, including over 46,000 cases with Cystatin C values. We found significant improvements when using the creatinine and Cystatin C equation compared to the prior creatinine-only CKD-Epi equation. If the eGFR threshold is set at 50ml/min/1.73m2, the EGFR Epi equation identifies about 15% of applicants with significant CKD. The combined equation identifies only about 9%, and shows that about half of those with CKD identified by creatinine alone are normal by the more accurate equation.
We continue to study the mortality implications of eGFR. But prior studies have shown that creatinine-based eGFR has a non-linear, J- or U-shaped mortality curve, with high values carrying excess mortality, likely due to sarcopenia in older individuals or those with cachexia. Determinations of eGFR based on Cystatin C seemingly do not have this problem . Initial CRL mortality studies of calculated eGFR using the combination of Cystatin C plus creatinine show risk improvement compared to creatinine alone.
Key take-away for Insurance companies; the combination of Cystatin C and the new eGFR equation significantly reduces over-calling of CKD allowing better offers to applicants. A strategy of testing hypertensive, diabetic, and older applicants, along with those who have CAD or low eGFR based on creatinine alone, would be expected to improve underwriting accuracy and placement rates by reducing unnecessary debits.
1 Kidney International (2021) 99, 34–47; https://doi.org/10.1016/j.kint.2020.10.012
2 N Engl J Med 2021;385:1737-49.DOI: 10.1056/NEJMoa2102953
3 Rothenbacher et al. BMC Medicine. (2020):18;300. https://doi.org/10.1186/s12916-020-01776-7
About the Authors:
Dr. Robert Stout serves as Chief Scientific Officer and Laboratory Director for CRL’s General Laboratory. He provides scientific direction and research leadership for all of CRL with particular focus on research for CRL’s Insurer Services business. Dr. Stout, who has been with CRL since 1983, holds more than ten U.S. Patents in science, including one for immunoassay method and apparatus development (U.S. Patent #4,414,324) and one for methods of determining chronic Hepatitis C infection (U.S. Patent #10,051,253). He is the author of numerous research and review articles and is a regular presenter at scientific meetings and conferences. Dr. Stout holds a B.S. in Biochemistry from California State University and a Ph.D. in Biological Chemistry from U.C.L.A. School of Medicine.
Dr. Steven J. Rigatti is a consulting medical director with Clinical Reference Laboratory, with 12 years’ experience in the life insurance industry. He is the current chair of the Mortality Committee of the American Academy of Life Insurance Medicine.