Jager, Kitty J.

The extent to which eGFR varies across populations, in the absence of risk factors and comorbidities associated with kidney disease, remains uncertain. We aimed to develop eGFR reference values in healthy American adults and to compare them with previously described European eGFR reference values. This cross-sectional study compared newly described age-specific and sex-specific creatinine-based eGFR reference values from over 9000 healthy Americans from National Health and Nutrition Examination Survey with previously described eGFR reference values from over 1.5 million healthy individuals in the European CKD Burden Consortium. Health status was based on 14 criteria related to comorbidities, lifestyle factors, and medication use. eGFR was calculated using the European Kidney Function Consortium equation and modeled over the age span and by sex using a generalized additive model. The median eGFR in both 20-year-old American and European men was 98 ml/min per 1.73 m 2 . In both 20-year-old American and European women, the median eGFR was 101 ml/min per 1.73 m 2 . eGFR started to decrease at age 40 years, a result of the structure of the European Kidney Function Consortium equation. By age 79 years, the median eGFR in American and European men was 68 and 67 ml/min per 1.73 m 2 , respectively. The median eGFR in 79-year-old American and European women was 63 and 64 ml/min per 1.73 m 2 , respectively. When removing the effect of comorbidities, lifestyle factors and medication use associated with kidney function, achieved by restricting the analyses to individuals who did not have a presence or history of certain criteria, the distribution of eGFR was similar between healthy Americans and Europeans. This supports the notion that eGFR reference values may be generalizable to populations they were not derived from.

Abstract In the vast majority of cases, glomerular filtration rate (GFR) is estimated using serum creatinine, which is highly influenced by age, sex, muscle mass, body composition, severe chronic illness and many other factors. This often leads to misclassification of patients or potentially puts patients at risk for inappropriate clinical decisions. Possible solutions are the use of cystatin C as an alternative endogenous marker or performing direct measurement of GFR using an exogenous marker such as iohexol. The purpose of this review is to highlight clinical scenarios and conditions such as extreme body composition, Black race, disagreement between creatinine- and cystatin C–based estimated GFR (eGFR), drug dosing, liver cirrhosis, advanced chronic kidney disease and the transition to kidney replacement therapy, non-kidney solid organ transplant recipients and living kidney donors where creatinine-based GFR estimation may be invalid. In contrast to the majority of literature on measured GFR (mGFR), this review does not include aspects of mGFR for research or public health settings but aims to reach practicing clinicians and raise their understanding of the substantial limitations of creatinine. While including cystatin C as a renal biomarker in GFR estimating equations has been shown to increase the accuracy of the GFR estimate, there are also limitations to eGFR based on cystatin C alone or the combination of creatinine and cystatin C in the clinical scenarios described above that can be overcome by measuring GFR with an exogenous marker. We acknowledge that mGFR is not readily available in many centres but hope that this review will highlight and promote the expansion of kidney function diagnostics using standardized mGFR procedures as an important milestone towards more accurate and personalized medicine.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 . This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 . Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.