Impaired selective renal filtration captured by eGFRcysC/eGFRcrea ratio is associated with mortality in a population based cohort of older women

Abstract

Deranged renal filtration of mid-sized (5–30 kDa) compared to smaller molecules (< 0.9 kDa) results in increased plasma levels of cystatin C (cysC) compared to creatinine resulting in a low eGFRcysC/eGFRcrea ratio. A ratio below 0.6 or 0.7, is termed shrunken pore syndrome (SPS), which in patient based studies is associated with mortality. Reference values for eGFRcysC/eGFRcrea ratio, the prevalence of SPS and the consequence of low eGFRcysC/eGFRcrea ratio in the general, elderly population are unknown. 75-yr old women (n = 849) from the population-based OPRA cohort, followed for 10-years had eGFR calculated with CKD-EPI study equation, and eGFRcysC/eGFRcrea ratio calculated. Mortality risk (HR [95% CI]) was estimated. Women with sarcopenia or on glucocorticoids were excluded. Almost 1 in 10 women (9%) had eGFRcysC/eGFRcrea ratio < 0.6 at age 75 and this did not increase appreciably with age. Women with ratio < 0.6 had higher 10-yr mortality risk compared with ratios > 0.9 (HRadj 1.6 [95% CI 1.1–2.5]). In elderly women eGFRcysC/eGFRcrea ratio < 0.6 is common and associated with increased mortality. Our results confirm patient-based findings, suggesting that identifying individuals with SPS may be clinically relevant to assessing mortality risk in the elderly.

Discordance Between Creatinine-Based and Cystatin C–Based Estimated GFR: Interpretation According to Performance Compared to Measured GFR

“… 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 Studies in multiple cohorts demonstrate that lower levels of eGFRcys relative to those of eGFRcr are associated with increased risk of frailty, heart failure hospitalizations, cardiovascular disease events, kidney failure, and mortality. 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 Thus, a discordance between eGFRcr and eGFRcys provides valuable prognostic information about various health outcomes, which can inform care for an individual patient in a clinical encounter. Measured GFR (mGFR) was not available in those studies.…”

The complexity of kidney disease and diagnosing it – cystatin C, selective glomerular hypofiltration syndromes and proteome regulation

“…According to the pore model for glomerular filtration [72,73], these observations could be explained by a shrinking (or elongation) of the pores [71]. Almost immediately after this observation, the presence of shrunken pore syndrome and/or an eGFR cystatin C /eGFR creatinine -ratio significantly below 1 was found to be strongly correlated to mortality, morbidity, heart failure and end-stage renal disease [63,[74][75][76][77][78][79][80][81][82][83][84][85][86][87][88]. Similar observations between an abnormally low eGFR cystatin C /eGFR creatinine -ratio and morbidity have recently been described in an American study, although it used the difference between eGFR cystatin C and eGFR creatinine to identify a specific reduction in the excretion of 5-30 kDa molecules [89,90].…”

“…However, later investigations have shown that the mortality of patients with abnormally low eGFR cystatin C /eGFR creatinine ‐ratio will start to increase already at a ratio of 0.90 and further increase as the ratio decreases [ 63 , 74 , 79 ]. To date, however, most studies have used an eGFR cystatin C /eGFR creatinine ‐ratio of 0.70 or 0.60 to diagnose hypofiltration syndromes [ 63 , 71 , 74 , 75 , 77 , 87 ]. Possibly, no general cut‐off should be used, so that the clinical setting at hand can be used to identify a suitable cut‐off.…”

“…However, several studies in healthy individuals [ 74 , 76 ], or patients without kidney disorders according to the KDIGO criteria, showed an increase in mortality and/or morbidity when the eGFR cystatin C /eGFR creatinine ‐ratio is significantly below 1.0, indicating a selective decrease in the filtration of 5–30 kDa molecules in selective glomerular hypofiltration syndromes [ 63 , 74 – 76 , 78 ]. The prevalence of selective glomerular hypofiltration syndromes in different populations varies with the cut‐off of the eGFR cystatin C /eGFR creatinine ‐ratio used for diagnosing the syndrome, but if a ratio <0.70 is used, the prevalence varies from 0.3% to 36% [ 63 , 71 , 74 , 76 , 87 ]. In population‐based studies, there is a variation between 8% and 17% at an eGFRcystatin C/eGFRcreatinine‐ratio <0.7 [ 74 , 87 ].…”

“…The prevalence of selective glomerular hypofiltration syndromes in different populations varies with the cut‐off of the eGFR cystatin C /eGFR creatinine ‐ratio used for diagnosing the syndrome, but if a ratio <0.70 is used, the prevalence varies from 0.3% to 36% [ 63 , 71 , 74 , 76 , 87 ]. In population‐based studies, there is a variation between 8% and 17% at an eGFRcystatin C/eGFRcreatinine‐ratio <0.7 [ 74 , 87 ]. This means that if only creatinine‐based GFR‐estimating equations are used, a significant number of patients with severe kidney disorders will be missed, which may infer serious health implications.…”