The cystatin C/creatinine ratio, a marker of glomerular filtration quality: associated factors, reference intervals, and prediction of morbidity and mortality in healthy seniors

Abstract

The ratio of cystatin C (cysC) to creatinine (crea) is regarded as a marker of glomerular filtration quality associated with cardiovascular morbidities. We sought to determine reference intervals for serum cysC-crea ratio in seniors. Furthermore, we sought to determine whether other low-molecular weight molecules exhibit a similar behavior in individuals with altered glomerular filtration quality. Finally, we investigated associations with adverse outcomes. A total of 1382 subjectively healthy Swiss volunteers aged 60 years or older were enrolled in the study. Reference intervals were calculated according to Clinical & Laboratory Standards Institute (CLSI) guideline EP28-A3c. After a baseline exam, a 4-year follow-up survey recorded information about overall morbidity and mortality. The cysC-crea ratio (mean 0.0124 ± 0.0026 mg/μmol) was significantly higher in women and increased progressively with age. Other associated factors were hemoglobin A1c, mean arterial pressure, and C-reactive protein (P < 0.05 for all). Participants exhibiting shrunken pore syndrome had significantly higher ratios of 3.5-66.5 kDa molecules (brain natriuretic peptide, parathyroid hormone, β2-microglobulin, cystatin C, retinol-binding protein, thyroid-stimulating hormone, α1-acid glycoprotein, lipase, amylase, prealbumin, and albumin) and creatinine. There was no such difference in the ratios of very low-molecular weight molecules (urea, uric acid) to creatinine or in the ratios of molecules larger than 66.5 kDa (transferrin, haptoglobin) to creatinine. The cysC-crea ratio was significantly predictive of mortality and subjective overall morbidity at follow-up in logistic regression models adjusting for several factors. The cysC-crea ratio exhibits age- and sex-specific reference intervals in seniors. In conclusion, the cysC-crea ratio may indicate the relative retention of biologically active low-molecular weight compounds and can independently predict the risk for overall mortality and morbidity in the elderly.

The mortality increase in cardiac surgery patients associated with shrunken pore syndrome correlates with the eGFRcystatin C/eGFRcreatinine-ratio

“…Purde et al investigated the presence and outcome of SPS within the framework of the SENIORLAB study, whose aim was to establish laboratory reference intervals in subjectively healthy seniors. They found a marked increase in morbidity and mortality in seniors afflicted by SPS and, interestingly, a retention of low-molecular weight proteins but not in very low-molecular weight proteins, corroborating the findings of Dardashti et al [2] and Purde et al [3] that SPS impacts mortality.…”

“…Shrunken pore syndrome (SPS) is defined as a condition in which estimated glomerular filtration rate (eGFR) based upon cystatin C is considerably lower than eGFR based upon creatinine in the absence of non-renal influences on the levels of cystatin C or creatinine [1]. SPS has been shown to be a risk factor for early and midterm mortality (2-5 years) independent of eGFR [2][3][4]. The condition was originally presumed to be present in late pregnancy and particularly in pre-eclampsia [5][6][7], but was later found to be present in all patient populations studied [2][3][4]8].…”

“…SPS has been shown to be a risk factor for early and midterm mortality (2-5 years) independent of eGFR [2][3][4]. The condition was originally presumed to be present in late pregnancy and particularly in pre-eclampsia [5][6][7], but was later found to be present in all patient populations studied [2][3][4]8]. In the first study showing that SPS was a risk factor for mortality, the value of the eGFR cystatin C /eGFR creatinine -ratio used to identify SPS was set to 0.6 [1].…”

Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis

“…The discrepancy in filtration estimates based on reduced pore size is expressed as a low ratio between eGFR cystatin C and eGFR creatinine and has recently been labelled as the shrunken pore syndrome [5]. This syndrome has been linked to cardiovascular disease and mortality [6][7][8].…”

The shrunken pore syndrome is associated with declined right ventricular systolic function in a heart failure population – the HARVEST study

“…when eGFR cystatin C ≤ 60% of eGFR creatinine [4]. Most recent data have identified the prevalence of the "Shrunken pore syndrome" to be associated with a significant rise in mortality in patients undergoing elective coronary artery bypass grafting (CABG) [5,6] and heart catheterization [7]. The mechanism behind the increased mortality in this high-risk…”