Plasma C-terminal agrin fragment and rapid kidney function decline in chronic kidney disease patients.
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ABSTRACT:
SUBMITTER: Lorenz G
PROVIDER: S-EPMC6531159 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Plasma C-terminal agrin fragment and rapid kidney function decline in chronic kidney disease patients.
Lorenz Georg G Hettwer Stefan S McCallum Wendy W Angermann Susanne S Wen Ming M Schmaderer Christoph C Heemann Uwe U Roos Marcel M Renders Lutz L Steubl Dominik D
Medicine 20190501 19
C-terminal agrin fragment (tCAF) is a promising biomarker for glomerular filtration. Data regarding biomarkers that have the ability to predict rapid progression of chronic kidney disease (CKD) are sparse but necessary in order to identify patients at high risk for rapid progression. This study addresses the value of tCAF as a predictor of rapid kidney function decline in CKD patients.We measured plasma tCAF in a retrospective observational cohort study of 277 prevalent CKD patients stage I-V. U ...[more]
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Project description:BackgroundDiabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics.MethodsSerum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF.ResultsWe found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2-14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule.ConclusionSerum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy.
| S-EPMC4668035 | biostudies-literature
Project description:Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether genes encoding agrin (AGRN) and neurotrypsin (PRSS12) were associated with sarcopenia phenotypes: muscle mass, strength and plasma C-terminal agrin fragment (CAF). PhenoScanner was used to determine if AGRN and/or PRSS12 variants had previously been implicated with sarcopenia phenotypes. For replication, we combined genotype from whole genome sequencing with phenotypic data from 6715 GenoFit participants aged 18-83 years. Dual energy X-ray absorptiometry assessed whole body lean mass (WBLM) and appendicular lean mass (ALM), hand dynamometry determined grip strength and ELISA measured plasma CAF in a subgroup (n = 260). Follow-up analyses included eQTL analyses, carrier analyses, single-variant and gene-burden tests. rs2710873 (AGRN) and rs71608359 (PRSS12) associate with muscle mass and strength phenotypes, respectively, in the UKBB (p = 8.9 × 10-6 and p = 8.4 × 10-6) and GenoFit cohort (p = 0.019 and p = 0.014). rs2710873 and rs71608359 are eQTLs for AGRN and PRSS12, respectively, in ≥ three tissues. Compared to non-carriers, carriers of rs2710873 had 4.0% higher WBLM and ALM (both p < 0.001), and 9.5% lower CAF concentrations (p < 0.001), while carriers of rs71608359 had 2.3% lower grip strength (p = 0.034). AGRN and PRSS12 are associated with muscle strength and mass in single-variant analyses, while PRSS12 has further associations with muscle strength in gene-burden tests. Our findings provide novel evidence of the relevance of AGRN and PRSS12 to sarcopenia phenotypes and support existing physiological data illustrating the importance of the NMJ in maintaining muscle health during ageing.
| S-EPMC10400504 | biostudies-literature
Project description:Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline (i.e., within 1 year) in chronic kidney disease (CKD) are rare but urgently needed to plan treatment. This study describes the association and predictive value of urinary uromodulin (uUMOD) for rapid progression of CKD.We assessed uUMOD, demographic/treatment parameters, estimated glomerular filtration rate (eGFR), and proteinuria in 230 CKD patients stage I-V. ESRD and 25% decline of eGFR was documented at the end of follow-up period and used as a composite endpoint. Association between logarithmic uUMOD and eGFR/proteinuria was calculated using linear regression analysis, adjusting for age, gender, and body mass index. We performed multivariable Cox proportional hazard regression analysis to evaluate the association of uUMOD with the composite endpoint. Therefore, patients were categorized into quartiles. The predictive value of uUMOD for the above outcomes was assessed using receiver-operating characteristic (ROC) curve analysis.Follow-up was 57.3?±?18.7 weeks, baseline age was 60 (18;92) years, and eGFR was 38 (6;156) mL/min/1.73?m. Forty-seven (20.4%) patients reached the composite endpoint. uUMOD concentrations were directly associated with eGFR and inversely associated with proteinuria (??=?0.554 and ??=?-0.429, P?<?.001). In multivariable Cox regression analysis, the first 2 quartiles of uUMOD concentrations had a hazard ratio (HR) of 3.589 [95% confidence interval (95% CI) 1.002-12.992] and 5.409 (95% CI 1.444-20.269), respectively, in comparison to patients of the highest quartile (?11.45??g/mL) for the composite endpoint. In ROC-analysis, uUMOD predicted the composite endpoint with good sensitivity (74.6%) and specificity (76.6%) at an optimal cut-off at 3.5??g/mL and area under the curve of 0.786 (95% CI 0.712-0.860, P?<?.001).uUMOD was independently associated with ESRD/rapid loss of eGFR. It might serve as a robust predictor of rapid kidney function decline and help to better schedule arrangements for future treatment.
| S-EPMC6571211 | biostudies-literature
Project description:Barriers associated with direct muscle quantification have prevented a consistent implementation of therapeutic measures for sarcopenia. Recently, the relevance of circulating C-terminal agrin fragment (CAF) as an accessible screening method alternative for sarcopenia has gained credence. Accordingly, this study aimed to verify the pertinence of plasma CAF as a biomarker for sarcopenia. Three hundred healthy adults aged between 50 and 83 years took part in this study. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older People criteria. Body composition was assessed using dual-energy x-ray absorptiometry, while muscle strength was examined using hand dynamometry. Plasma CAF concentrations were determined using a commercially available ELISA kit. CAF concentrations were significantly associated with appendicular lean mass (ALM), but not grip strength (p = .028, p = .575, respectively). Plasma CAF concentrations were significantly elevated in sarcopenic individuals compared to nonsarcopenic (p < .001). Overall, individuals with low grip strength or low ALM displayed significantly higher CAF levels compared to healthy controls, after adjusting for age and body mass index (p = .027, p = .003, respectively). In males, those with low grip strength or low ALM had significantly elevated CAF levels (p = .039, p = .027, respectively), while in females, only those with low ALM had significantly raised CAF concentrations, compared to healthy controls (p = .035). Our findings illuminate the potential relevance of CAF as an accessible biomarker for skeletal muscle health. CAF determination may enhance clinical practice by facilitating more widespread treatment strategies for sarcopenia. Nevertheless, future research is needed to confirm the diagnostic pertinence of CAF concentrations in screening for sarcopenia.
| S-EPMC8599080 | biostudies-literature
Project description:BackgroundIncreasing interest surrounds the utility of blood-based biomarkers for diagnosing sarcopenia. C-terminal agrin fragment (CAF), a marker of neuromuscular junction stability, is amongst the most promising candidates; however, a dearth of reference data impedes the incorporation of its use in public health settings. This study aimed to establish reference values for plasma CAF concentrations across adulthood in a large, well-characterized cohort of healthy adults; and comprehensively examine the association between plasma CAF levels and skeletal muscle health.MethodsOne thousand people aged between 18 and 87 years took part in this study (mean age = 50.4 years; 51% females). Body composition and muscle strength were examined using DXA and hand dynamometry. Plasma CAF concentrations were measured, in duplicate, using commercially available ELISA kits. Sarcopenia and individual sarcopenia signatures [low skeletal muscle index (SMI) only/low grip strength only] were classified using the EWGSOP2 algorithm.ResultsDetailed reference CAF values, according to sex and age, are presented. A significant but modest age-related increase in plasma CAF concentration was observed (P = 0.018). Across adulthood, CAF concentrations were negatively associated with grip strength and SMI (both P < 0.001). In people ≥50 years old, CAF concentrations were 22.6% higher in those with sarcopenia (P < 0.001), 11.3% higher in those with low SMI (P = 0.006) and 9.6% higher in those with low grip strength (P = 0.0034), compared with controls. People in the highest CAF concentration quartile, had 3.25 greater odds for sarcopenia (95% CI = 1.41-7.49, P = 0.005), 2.76 greater odds for low SMI (95% CI = 1.24-5.22, P = 0.012), and 2.56 greater odds for low grip strength (95% CI = 1.07-5.57, P = 0.037), compared with those in the lowest quartile. People with a CAF Z-score ≥2 had 9.52 greater odds for sarcopenia (95% CI = 3.01-30.05, P < 0.001) compared with a Z-score <1. Plasma CAF concentration had an acceptable level of diagnostic accuracy for sarcopenia (AUC = 0.772, 95% CI = 0.733-0.807, P < 0.001).ConclusionsThe reference values presented herein may guide the clinical interpretation of circulating CAF and help identify people at risk of poor skeletal muscle outcomes for inclusion in therapeutic interventions. Our findings add clarity to existing data, demonstrating a robust relationship between circulating CAF and skeletal muscle integrity in the largest adult cohort to date, and support the use of CAF as an accessible, cost-effective screening tool for sarcopenia. However, further research into the prognostic utility of plasma CAF, and the establishment of normative data from other populations, are urgently needed if routine CAF screening is to be embedded into public healthcare settings.
| S-EPMC11294022 | biostudies-literature
Project description:BackgroundC-terminal agrin fragment (CAF) is a biomarker for neuromuscular junction degradation. This study aimed to investigate whether 110-kDa CAF (CAF110) was associated with the presence and incidence of low muscle mass and strength.MethodsThis cross-sectional retrospective cohort study comprised women aged ≥65 years. We measured muscle mass using a dual-energy X-ray absorptiometry scanner, hand-grip strength, and blood sampling between 2011 and 2012. A follow-up study with the same measurements was conducted between 2015 and 2017. Low muscle mass and strength were defined as an appendicular skeletal muscle mass index <5.4 kg/m2 and hand-grip strength <18 kg, respectively. The CAF110 level was measured using enzyme-linked immunosorbent assay kits.ResultsIn total, 515 women (74.3 ± 6.3 years) were included in this cross-sectional analysis. Of these, 101 (19.6%) and 128 (24.9%) women presented with low muscle mass and strength, respectively. For low muscle mass, the odds ratios (ORs) of the middle and highest CAF110 tertile groups, compared with the lowest group, were 1.93 (95% confidence interval: 1.09-3.43; P = 0.024) and 2.15 (1.22-3.80; P = 0.008), respectively. After adjusting for age, the ORs remained significant: 1.98 (1.11-3.52; P = 0.020) and 2.27 (1.28-4.03; P = 0.005), respectively. Low muscle strength ORs of all the CAF110 tertile groups were not significant. In the longitudinal analysis, 292 and 289 women were assessed for incidents of low muscle mass and strength, respectively. Of those, 34 (11.6%) and 20 (6.9%) women exhibited low muscle mass and strength, respectively. For incident low muscle mass, the crude OR of the CAF110 ≥ the median value group was marginally higher than that of the CAF110 < median value group (median [interquartile range]: 1.98 [0.94-4.17] (P = 0.072). After adjusting for age and baseline muscle mass, the OR was 2.22 [0.97-5.06] (P = 0.058). All low muscle strength ORs of the median categories of CAF110 were not significant.ConclusionsCAF110 was not associated with low muscle strength. However, CAF110 may be a potential marker for the incidence of low muscle mass.
| S-EPMC10570065 | biostudies-literature
Project description:Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.
| S-EPMC5576932 | biostudies-literature
Project description:ObjectiveInvestigate the association of dispositional optimism with chronic kidney disease (CKD) and rapid kidney function decline (RKFD) and determine if there is modification by age, sex, and educational attainment among African Americans.MethodsOptimism was measured using the 6-item Life Orientation Test-Revised scale (categorized into tertiles and log transformed) among participants from the Jackson Heart Study (n = 1960). CKD was defined as the presence of albuminuria or reduced glomerular filtration rate of <60 mL/min/1.73m2, or report of dialysis at baseline examination (2000-2004). RKFD was defined as a decline >3 mL/min/1.73m2/year between baseline and exam 3 (2009-2013). The cross-sectional and prospective associations between optimism and kidney outcomes were tested using multivariable logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI), adjusting for demographics, education, risk factors, behaviors, and depressive symptoms. We tested effect modification by age, sex, and education.Results569 participants had CKD and 326 were classified as having RKFD by exam 3. After full adjustment, the OR for CKD was 0.73 for those who reported high (vs. low) optimism (95% CI 0.55-0.99) and 0.56 (95% CI 0.27-1.15) for the optimism score. After 7.21 median years of follow up, the OR for RKFD was 0.51 for those who reported high (vs. low) optimism (95% CI 0.34-0.76), and 0.26 (95% CI 0.10-0.56) for the optimism score, after full adjustment. There was no evidence of effect modification by demographics or educational attainment.ConclusionsHigher optimism was associated with a lower odds of CKD and a lower odds of RKFD.
| S-EPMC7722009 | biostudies-literature
Project description:Agrin, a multidomain proteoglycan and neurotrypsin, a neuronal serine protease, are important for forming (neuromuscular) synapses. Proteolytical activity of neurotrypsin produces a C-terminal fragment of agrin, termed CAF, of approximately 22 kDA molecular size which also circulates in blood. The presence of CAF in urine suggests either glomerular filtration or secretion into urine. Blood levels of CAF have been identified as a potential novel marker of kidney function. Here we describe that several nephron segments in the mouse kidney express agrin and neutrotrypsin in addition to the localization of both protein in the glomerulum. Agrin mRNA and protein was detected in almost all nephron segments and mRNA abundance was highest in the inner medullary collecting duct. Neurotrypsin mRNA was mostly detected in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the inner medullary collecting duct. Moreover, we show that the proximal tubule absorbs injected recombinant CAF by a process shared with receptor-mediated and fluid phase endocytosis. Co-injection of CAF with recombinant human transferrin, a substrate of the receptor-mediated endocytic pathway as well as with FITC-labelled dextran (10 kDa), a marker of fluid phase endocytosis, showed partial colocalization of CAF with both markers. Further colocalization of CAF with the lysosomal marker cathepsin B suggested degradation of CAF by the lysosome in the proximal tubule. Thus, the murine kidney expresses agrin and neurotrypsin in nephron segments beyond the glomerulum. CAF is filtered by the glomerulum and is reabsorbed by endocytosis by the proximal tubule. Thus, impaired kidney function could impair glomerular clearance of CAF and thereby increase circulating CAF levels.
| S-EPMC4933355 | biostudies-literature
Project description:BackgroundFew investigations have evaluated the incremental usefulness of multiple biomarkers representing varying physiological pathways for predicting risk of renal outcomes in African Americans.Design, setting, participants, and measurementsWe related a multi-marker panel to incident chronic kidney disease (CKD) and rapid kidney function decline (RKFD) in 2813 Jackson Heart Study participants without prevalent CKD at exam 1 (2000-2004) and with complete assays at exam 1 for 9 biomarkers: adiponectin, aldosterone, B-natriuretic peptide [BNP], cortisol, high sensitivity C-reactive protein (hsCRP), endothelin, homocysteine, plasma renin activity and mass. Incident CKD was defined as estimated glomerular filtration rate (eGFR)?<?60 mL/min/1.73 m2 at exam 3 while RKFD was defined as eGFR ?30% loss between exams 1 and 3 (8.2 median years). We employed multiple logistic regression model to describe association between the panel and incident CKD and RKFD and used backward elimination strategy to estimate the most parsimonious biomarker model while controlling for conventional risk factors.ResultsThe multi-marker panel predicted the risk for both incident CKD (odds ratios [OR], 2.72; 95% confidence intervals [CI], 1.63, 4.56; P?=?0.001) and RKFD (2.61; 95% CI, 1.67, 4.08; P?< 0.001). Per standard deviation increase in log biomarker concentrations were significantly (multivariable adjusted odds ratios, [95% confidence interval], p-value) associated with incident CKD: plasma adiponectin (1.24 [1.07, 1.44], p?=?0.005) and leptin (1.3 [1.06, 1.61], p?=?0.011), and with RKFD: plasma adiponectin (1.22 [1.06, 1.40], p?=?0.006); hsCRP (1.17 [1.01, 1.36], p?=?0.031) and aldosterone (0.85 [0.74, 0.96], p?=?0.012). Moderate levels (3rd quartile) of aldosterone were inversely associated with incident CKD (0.54 [0.35, 0.82], p?=?0.004) while leptin was associated with RKFD (1.64 [1.10, 2.44], p?=?0.015). Biomarkers improved CKD risk prediction (P?=?0.003) but not RKFD risk prediction (P?=?0.10).ConclusionIn this community-based sample of African Americans, a multi-marker panel added only moderate predictive improvement compared to conventional risk factors.
| S-EPMC6147037 | biostudies-literature