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Equations for estimating GFR with serum creatinine overestimate measured GFR in Blacks. The authors report new equations, without race as an inflation factor, using cystatin C and creatinine that reduced errors in estimation between Black participants and non-Black participants.

Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

Hereditary cystatin C amyloid angiopathy (HCCAA) is an Icelandic disease that belongs to a disease class called cerebral amyloid angiopathy, a group of heterogenous diseases presenting with aggregation of amyloid complexes and deposition predominantly in the central nervous system. HCCAA is dominantly inherited, caused by L68Q mutation in the cystatin C gene, leading to aggregation of the cystatin C protein. HCCAA is a very progressive and severe disease, with widespread cerebral and parenchymal cystatin C and collagen IV deposition within the central nervous system (CNS) but also in other organs in the body, for example, in the skin. Most L68Q carriers have clinical symptoms characterized by recurrent hemorrhages and dementia, between the age of 20–30 years. If the carriers survive the first hemorrhage, the frequency and severity of the hemorrhages tend to increase, resulting in death at average of 30 years with mean number of major hemorrhages ranging from 3.2 to 3.9 over a 5‐year average life span. The pathogenesis of the disease in carriers is very similar in the CNS and in the skin based on autopsy studies, thus skin biopsies can be used to monitor the progression of the disease by quantifying the cystatin C immunoreactivity. The cystatin C deposition always colocalizes with collagen IV and fibroblasts in the skin are found to be the main cell type responsible for the deposition of both proteins. No therapy is available for this devastating disease. Pathological features in cerebral vessels in hereditary cystatin C amyloid angiopathy.

Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50–90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents. HCCAA is a dominantly inherited disease which causes brain hemorrhages as a result of mutant cystatin C aggregation in carriers. Here, the authors show that n- acetyl cysteine can prevent aggregation of mutant protein in a cell model system and reverse protein deposition in the skin of mutation-carrying subjects.

PurposeThe aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI).MethodsThe RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724).Results364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C–C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78–0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75.ConclusionElevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.

Acute pancreatitis (AP) is characterised by self-digestion of the pancreas by its own proteases. This pathophysiological initiating event in AP occurs inside pancreatic acinar cells where intrapancreatic trypsinogen becomes prematurely activated by cathepsin B (CTSB), and induces the digestive protease cascade, while cathepsin L (CTSL) degrades trypsin and trypsinogen and therefore prevents the development of AP. These proteases are located in the secretory compartment of acinar cells together with cystatin C (CST3), an endogenous inhibitor of CTSB and CTSL. The results are based on detailed biochemical analysis, site-directed mutagenesis and molecular dynamics simulations in combination with an experimental disease model of AP using CST3 deficient mice. This identifies that CST3 is a critical regulator of CTSB and CTSL activity during AP. CST3 deficient mice show a higher intracellular CTSB activity resulting in elevated trypsinogen activation accompanied by an increased disease severity. This reveals that CST3 can be cleaved by trypsin disabling the inhibition of CTSB, but not of CTSL. Furthermore, dimerised CST3 enhances the CTSB activity by binding to an allosteric pocket specific to the CTSB structure. CST3 shifts from an inhibitor to an activator of CTSB and therefore fuels the intrapancreatic protease cascade during the onset of AP. Here, the authors show that cystatin C (CST3) regulates the activity of cathepsin B during pancreatitis in a pH dependent manner. Moreover, cathepsin B activity is inhibited by monomeric CST3 but activated by dimeric CST3.

The use of race in equations that estimate the glomerular filtration rate is problematic. In this study, the use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification. Estimating GFR with cystatin C generated similar results but eliminated negative consequences of race-based approaches.

Estimating equations for the glomerular filtration rate — EKFC eGFRcr (creatinine) and EKFC eGFRcys (cystatin C) — were tested. EKFC eGFRcys was unbiased and accurate, irrespective of the inclusion of race or sex.

This study presents an equation for estimating the glomerular filtration rate that uses both creatinine and cystatin C. It performs better than equations with either marker alone and is potentially useful for confirming chronic kidney disease. Clinical assessment of kidney function is part of routine medical care for adults. 1 More than 80% of clinical laboratories now report an estimated glomerular filtration rate (GFR) when serum creatinine is measured. 2 Despite standardization of serum creatinine assays, GFR estimates remain relatively imprecise 3 owing to variation in non-GFR determinants of serum creatinine, which may be affected in both acute and chronic illness. 1 Such imprecision can potentially result in the misclassification of patients whose estimated GFR is less than 60 ml per minute per 1.73 m 2 of body-surface area as having chronic kidney disease, leading to unnecessary diagnostic and therapeutic interventions. . . .

To investigate the association of the sarcopenia index (SI, serum creatinine value/cystatin C value × 100) with 3-year mortality and readmission among older inpatients, we reanalyzed a prospective study in the geriatric ward of a teaching hospital in western China. Older inpatients aged ≥ 60 years with normal kidney function were included. Survival status and readmission information were assessed annually during the 3-year follow-up. We applied Cox regression models to calculate the hazard ratio (HR) and 95% confidence intervals (CIs) of sarcopenia for predicting mortality and readmission. We included 248 participants (mean age: 81.2 ± 6.6 years). During the follow-up, 57 participants (23.9%) died, whereas 179 participants (75.2%) were readmitted at least one time. The SI was positively correlated with body mass index (BMI) (r = 0.214, p = 0.001), calf circumference (CC) (r = 0.253, p < 0.001), handgrip strength (r = 0.244, p < 0.001), and gait speed (r = 0.221, p < 0.001). A higher SI was independently associated with a lower risk of 3-year all-cause mortality after adjusting for potential confounders (HR per 1-SD = 0.80, 95% CI: 0.63–0.97). The SI was not significantly associated with readmission (HR per 1-SD = 0.97, 95% CI: 0.77–1.25). In conclusion, the SI is associated with 3-year all-cause mortality but not readmission in a study population of hospitalized older patients.