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Pharmacologic Blockade of v1 Integrin Ameliorates Renal Failure and Fibrosis .
Chang Y, Lau WL, Jo H, Tsujino K, Gewin L, Reed NI, Atakilit A, Nunes ACF, DeGrado WF, Sheppard D
(2017) J Am Soc Nephrol 28: 1998-2005
MeSH Terms: Animals, Fibrosis, Guanidines, Kidney, Male, Mice, Receptors, Vitronectin, Renal Insufficiency, Sulfonamides
Show Abstract · Added September 27, 2017
Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells is poorly understood. PDGF receptor (PDGFR) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR promoter-driven Cre system to delete v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR-Cre line to isolate and study renal fibroblasts We found that renal fibroblasts express three v integrins, namely v1, v3, and v5. Blockade of v1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-1 and prevented activation of the latent TGF- complex. Continuous administration of a recently described potent small molecule inhibitor of v1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of v1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.
Copyright © 2017 by the American Society of Nephrology.
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9 MeSH Terms
Growth Differentiation Factor-15 and Risk of CKD Progression.
Nair V, Robinson-Cohen C, Smith MR, Bellovich KA, Bhat ZY, Bobadilla M, Brosius F, de Boer IH, Essioux L, Formentini I, Gadegbeku CA, Gipson D, Hawkins J, Himmelfarb J, Kestenbaum B, Kretzler M, Magnone MC, Perumal K, Steigerwalt S, Ju W, Bansal N
(2017) J Am Soc Nephrol 28: 2233-2240
MeSH Terms: Disease Progression, Female, Growth Differentiation Factor 15, Humans, Kidney Failure, Chronic, Male, Middle Aged, Renal Insufficiency, Chronic, Risk Assessment
Show Abstract · Added September 19, 2017
Growth differentiation factor-15 (GDF-15) is a member of the TGF- cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Elevations in GDF-15 may identify a novel pathway involved in loss of kidney function among patients with CKD. Among participants in the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS), we tested whether kidney tissue expression of mRNA correlates with circulating levels of GDF-15 and whether elevations in circulating GDF-15 are associated with decline in kidney function. In matching samples of 24 patients with CKD from the C-PROBE study, circulating GDF-15 levels significantly correlated with intrarenal transcript levels (=0.54, =0.01). Among the 224 C-PROBE and 297 SKS participants, 72 (32.1%) and 94 (32.0%) patients, respectively, reached a composite end point of 30% decline in eGFR or progression to ESRD over a median of 1.8 and 2.0 years of follow up, respectively. In multivariable models, after adjusting for potential confounders, every doubling of GDF-15 level associated with a 72% higher (95% confidence interval, 1.21 to 4.45; =0.003) and 65% higher (95% confidence interval, 1.08 to 2.50; =0.02) risk of progression of kidney disease in C-PROBE and SKS participants, respectively. These results show that circulating GDF-15 levels strongly correlated with intrarenal expression of and significantly associated with increased risk of CKD progression in two independent cohorts. Circulating GDF-15 may be a marker for intrarenal -related signaling pathways associated with CKD and CKD progression.
Copyright © 2017 by the American Society of Nephrology.
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9 MeSH Terms
Genetic Variants Associated with Circulating Parathyroid Hormone.
Robinson-Cohen C, Lutsey PL, Kleber ME, Nielson CM, Mitchell BD, Bis JC, Eny KM, Portas L, Eriksson J, Lorentzon M, Koller DL, Milaneschi Y, Teumer A, Pilz S, Nethander M, Selvin E, Tang W, Weng LC, Wong HS, Lai D, Peacock M, Hannemann A, Völker U, Homuth G, Nauk M, Murgia F, Pattee JW, Orwoll E, Zmuda JM, Riancho JA, Wolf M, Williams F, Penninx B, Econs MJ, Ryan KA, Ohlsson C, Paterson AD, Psaty BM, Siscovick DS, Rotter JI, Pirastu M, Streeten E, März W, Fox C, Coresh J, Wallaschofski H, Pankow JS, de Boer IH, Kestenbaum B
(2017) J Am Soc Nephrol 28: 1553-1565
MeSH Terms: Adult, Aged, Europe, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Parathyroid Hormone, Polymorphism, Single Nucleotide
Show Abstract · Added September 19, 2017
Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (=22,653 and =6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of (=4.2 × 10), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within (=6.6 × 10), rs219779 adjacent to (=3.5 × 10), rs4443100 near (=8.7 × 10), and rs73186030 near (=4.8 × 10). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
Copyright © 2017 by the American Society of Nephrology.
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11 MeSH Terms
and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.
Li M, Li Y, Weeks O, Mijatovic V, Teumer A, Huffman JE, Tromp G, Fuchsberger C, Gorski M, Lyytikäinen LP, Nutile T, Sedaghat S, Sorice R, Tin A, Yang Q, Ahluwalia TS, Arking DE, Bihlmeyer NA, Böger CA, Carroll RJ, Chasman DI, Cornelis MC, Dehghan A, Faul JD, Feitosa MF, Gambaro G, Gasparini P, Giulianini F, Heid I, Huang J, Imboden M, Jackson AU, Jeff J, Jhun MA, Katz R, Kifley A, Kilpeläinen TO, Kumar A, Laakso M, Li-Gao R, Lohman K, Lu Y, Mägi R, Malerba G, Mihailov E, Mohlke KL, Mook-Kanamori DO, Robino A, Ruderfer D, Salvi E, Schick UM, Schulz CA, Smith AV, Smith JA, Traglia M, Yerges-Armstrong LM, Zhao W, Goodarzi MO, Kraja AT, Liu C, Wessel J, CHARGE Glycemic-T2D Working Group,, CHARGE Blood Pressure Working Group,, Boerwinkle E, Borecki IB, Bork-Jensen J, Bottinger EP, Braga D, Brandslund I, Brody JA, Campbell A, Carey DJ, Christensen C, Coresh J, Crook E, Curhan GC, Cusi D, de Boer IH, de Vries AP, Denny JC, Devuyst O, Dreisbach AW, Endlich K, Esko T, Franco OH, Fulop T, Gerhard GS, Glümer C, Gottesman O, Grarup N, Gudnason V, Hansen T, Harris TB, Hayward C, Hocking L, Hofman A, Hu FB, Husemoen LL, Jackson RD, Jørgensen T, Jørgensen ME, Kähönen M, Kardia SL, König W, Kooperberg C, Kriebel J, Launer LJ, Lauritzen T, Lehtimäki T, Levy D, Linksted P, Linneberg A, Liu Y, Loos RJ, Lupo A, Meisinger C, Melander O, Metspalu A, Mitchell P, Nauck M, Nürnberg P, Orho-Melander M, Parsa A, Pedersen O, Peters A, Peters U, Polasek O, Porteous D, Probst-Hensch NM, Psaty BM, Qi L, Raitakari OT, Reiner AP, Rettig R, Ridker PM, Rivadeneira F, Rossouw JE, Schmidt F, Siscovick D, Soranzo N, Strauch K, Toniolo D, Turner ST, Uitterlinden AG, Ulivi S, Velayutham D, Völker U, Völzke H, Waldenberger M, Wang JJ, Weir DR, Witte D, Kuivaniemi H, Fox CS, Franceschini N, Goessling W, Köttgen A, Chu AY
(2017) J Am Soc Nephrol 28: 981-994
MeSH Terms: Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Son of Sevenless Proteins, Zebrafish
Show Abstract · Added March 14, 2018
Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
Copyright © 2017 by the American Society of Nephrology.
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11 MeSH Terms
Comparative Effectiveness of Second-Line Agents for the Treatment of Diabetes Type 2 in Preventing Kidney Function Decline.
Hung AM, Roumie CL, Greevy RA, Grijalva CG, Liu X, Murff HJ, Ikizler TA, Griffin MR
(2016) Clin J Am Soc Nephrol 11: 2177-2185
MeSH Terms: Aged, Comparative Effectiveness Research, Creatinine, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Female, Glomerular Filtration Rate, Glycated Hemoglobin A, Humans, Hypoglycemic Agents, Incidence, Insulin, Kidney Failure, Chronic, Male, Metformin, Middle Aged, Retrospective Studies, Sulfonylurea Compounds, Tennessee
Show Abstract · Added July 27, 2018
BACKGROUND AND OBJECTIVES - Diabetes is the leading cause of ESRD. Glucose control improves kidney outcomes. Most patients eventually require treatment intensification with second-line medications; however, the differential effects of those therapies on kidney function are unknown.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS - We studied a retrospective cohort of veterans on metformin monotherapy from 2001 to 2008 who added either insulin or sulfonylurea and were followed through September of 2011. We used propensity score matching 1:4 for those who intensified with insulin versus sulfonylurea, respectively. The primary composite outcome was persistent decline in eGFR≥35% from baseline (GFR event) or a diagnosis of ESRD. The secondary outcome was a GFR event, ESRD, or death. Outcome risks were compared using marginal structural models to account for time-varying covariates. The primary analysis required persistence with the intensified regimen. An effect modification of baseline eGFR and the intervention on both outcomes was evaluated.
RESULTS - There were 1989 patients on metformin and insulin and 7956 patients on metformin and sulfonylurea. Median patient age was 60 years old (interquartile range, 54-67), median hemoglobin A1c was 8.1% (interquartile range, 7.1%-9.9%), and median creatinine was 1.0 mg/dl (interquartile range, 0.9-1.1). The rate of GFR event or ESRD (primary outcome) was 31 versus 26 per 1000 person-years for those who added insulin versus sulfonylureas, respectively (adjusted hazard ratio, 1.27; 95% confidence interval, 0.99 to 1.63). The rate of GFR event, ESRD, or death was 64 versus 49 per 1000 person-years, respectively (adjusted hazard ratio, 1.33; 95% confidence interval, 1.11 to 1.59). Tests for a therapy by baseline eGFR interaction for both the primary and secondary outcomes were not significant (P=0.39 and P=0.12, respectively).
CONCLUSIONS - Among patients who intensified metformin monotherapy, the addition of insulin compared with a sulfonylurea was not associated with a higher rate of kidney outcomes but was associated with a higher rate of the composite outcome that included death. These risks were not modified by baseline eGFR.
Copyright © 2016 by the American Society of Nephrology.
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MeSH Terms
High Dose Omega-3 Fatty Acid Administration and Skeletal Muscle Protein Turnover in Maintenance Hemodialysis Patients.
Deger SM, Hung AM, Ellis CD, Booker C, Bian A, Chen G, Abumrad NN, Ikizler TA
(2016) Clin J Am Soc Nephrol 11: 1227-35
MeSH Terms: Adult, Aged, Amino Acids, Blood Glucose, C-Reactive Protein, Dietary Supplements, Double-Blind Method, Fatty Acids, Omega-3, Female, Forearm, Humans, Inflammation, Insulin Resistance, Male, Middle Aged, Muscle Proteins, Muscle, Skeletal, Protein Biosynthesis, Renal Dialysis, Renal Insufficiency, Chronic
Show Abstract · Added July 1, 2016
BACKGROUND AND OBJECTIVES - Protein energy wasting and systemic inflammation are prevalent in maintenance hemodialysis (MHD) patients. Omega-3 (ω-3) fatty acids have anti-inflammatory properties and have been shown to improve protein homeostasis. We hypothesized that administration of high-dose (2.9 g/d) ω-3 would be associated with decreased muscle protein breakdown in MHD patients with systemic inflammation.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS - This is a substudy from a randomized, placebo-controlled study (NCT00655525). Patients were recruited between September 2008 and June 2011. Primary inclusion criteria included signs of chronic inflammation (average C-reactive protein of ≥5 mg/L over three consecutive measurements), lack of active infectious or inflammatory disease, no hospitalization within 1 month prior to the study, and not receiving steroids (>5 mg/d) and/or immunosuppressive agents. The primary outcomes were forearm muscle and whole body protein breakdown and synthesis before and after the intervention. The patients received ω-3 (n=11) versus placebo (n=9) for 12 weeks. Analysis of covariance was used to compare outcome variables at 12 weeks. Models were adjusted for a propensity score that was derived from age, sex, race, baseline high sensitivity C-reactive protein, diabetes mellitus, and fat mass because the groups were not balanced for several characteristics.
RESULTS - Compared with placebo, ω-3 supplementation was significantly associated with decreased muscle protein breakdown at 12 weeks (-31, [interquartile range, -98--13] versus 26 [interquartile range, 13-87] µg/100 ml per min; P=0.01), which remained significant after multivariate adjustment (-46, [95% confidence interval, -102 to -1] µg/100 ml per min). ω-3 Supplementation resulted in decreased forearm muscle protein synthesis while the rate in the placebo group increased; however, there is no longer a statistically significant difference in skeletal muscle protein synthesis or in net protein balance after multivariate adjustment. There was no statistically significant effect of ω-3 supplementation on whole body protein synthesis or breakdown.
CONCLUSIONS - High-dose ω-3 supplementation over 12 weeks in MHD patients with systemic inflammation was associated with attenuation of forearm muscle protein breakdown but did not influence skeletal muscle protein synthesis, skeletal muscle net protein balance or any component of the whole-body protein balance. These results should be interpreted cautiously given the imbalance in the two groups and the short duration of the intervention.
Copyright © 2016 by the American Society of Nephrology.
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20 MeSH Terms
Pharmacokinetics and Pharmacodynamics of Extended Infusion Versus Short Infusion Piperacillin-Tazobactam in Critically Ill Patients Undergoing CRRT.
Shotwell MS, Nesbitt R, Madonia PN, Gould ER, Connor MJ, Salem C, Aduroja OA, Amde M, Groszek JJ, Wei P, Taylor ME, Tolwani AJ, Fissell WH
(2016) Clin J Am Soc Nephrol 11: 1377-83
MeSH Terms: Acute Kidney Injury, Adult, Aged, Anti-Bacterial Agents, Bacterial Infections, Critical Illness, Dialysis Solutions, Female, Hemodiafiltration, Humans, Infusions, Intravenous, Male, Middle Aged, Penicillanic Acid, Piperacillin, Piperacillin, Tazobactam Drug Combination, Time Factors
Show Abstract · Added June 2, 2016
BACKGROUND AND OBJECTIVES - Infection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of β-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 μg/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate.
RESULTS - Sixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion.
CONCLUSIONS - Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.
Copyright © 2016 by the American Society of Nephrology.
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17 MeSH Terms
Celebrating the ASN at 50.
Harris RC, Ibrahim T, Nath KA
(2016) J Am Soc Nephrol 27: 1575-6
MeSH Terms: Nephrology, Societies, Medical, United States
Added April 26, 2017
1 Communities
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3 MeSH Terms
Provider Knowledge, Attitudes, and Practices Surrounding Conservative Management for Patients with Advanced CKD.
Parvez S, Abdel-Kader K, Pankratz VS, Song MK, Unruh M
(2016) Clin J Am Soc Nephrol 11: 812-20
MeSH Terms: Adult, Aged, Attitude of Health Personnel, Clinical Competence, Conservative Treatment, Female, Health Care Surveys, Health Knowledge, Attitudes, Practice, Humans, Kidney Failure, Chronic, Male, Middle Aged, Nephrology, Patient Participation, Practice Patterns, Physicians', Primary Health Care, United States, Young Adult
Show Abstract · Added November 29, 2018
BACKGROUND AND OBJECTIVES - Despite the potential benefits of conservative management, providers rarely discuss it as a viable treatment option for patients with advanced CKD. This survey was to describe the knowledge, attitudes, and practices of nephrologists and primary care providers regarding conservative management for patients with advanced CKD in the United States.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We developed a questionnaire on the basis of a literature review to include items assessing knowledge, attitudes, and self-reported practices of conservative management for patients with advanced CKD. Potential participants were identified using the American Medical Association Physician Masterfile. We then conducted a web-based survey between April and May of 2015.
RESULTS - In total, 431 (67.6% nephrologists and 32.4% primary care providers) providers completed the survey for a crude response rate of 2.7%. The respondents were generally white, men, and in their 30s and 40s. Most primary care provider (83.5%) and nephrology (78.2%) respondents reported that they were likely to discuss conservative management with their older patients with advanced CKD. Self-reported number of patients managed conservatively was >11 patients for 30.6% of nephrologists and 49.2% of primary care providers. Nephrologists were more likely to endorse difficulty determining whether a patient with CKD would benefit from conservative management (52.8% versus 36.2% of primary care providers), whereas primary care providers were more likely to endorse limited information on effectiveness (49.6% versus 24.5% of nephrologists) and difficulty determining eligibility for conservative management (42.5% versus 14.3% of nephrologists). There were also significant differences in knowledge between the groups, with primary care providers reporting more uncertainty about relative survival rates with conservative management compared with different patient groups.
CONCLUSIONS - Both nephrologists and primary care providers reported being comfortable with discussing conservative management with their patients. However, both provider groups identified lack of United States data on outcomes of conservative management and characteristics of patients who would benefit from conservative management as barriers to recommending conservative management in practice.
Copyright © 2016 by the American Society of Nephrology.
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MeSH Terms
Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD.
de Boer IH, Zelnick L, Afkarian M, Ayers E, Curtin L, Himmelfarb J, Ikizler TA, Kahn SE, Kestenbaum B, Utzschneider K
(2016) J Am Soc Nephrol 27: 2861-71
MeSH Terms: Cross-Sectional Studies, Female, Glucose, Homeostasis, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Renal Insufficiency, Chronic, Severity of Illness Index
Show Abstract · Added February 5, 2016
Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of 59 participants with nondiabetic CKD (mean eGFR =37.6 ml/min per 1.73 m(2)) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemic-euglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (mean[SD] 3.9[2.0] versus 5.0 [2.0] mg/min per µU/ml; P<0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P<0.001) and was also lower in participants with CKD than controls (876 [226] versus 998 [212] ml/min; P<0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, -0.7; 95% confidence interval, -1.4 to 0.0 mg/min per µU/ml) and insulin clearance (adjusted difference, -85; 95% confidence interval, -160 to -10 ml/min). Among participants with CKD, eGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65% of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.
Copyright © 2016 by the American Society of Nephrology.
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11 MeSH Terms