Publications by authors named "Ian H de Boer"

292 Publications

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes.

Diabetes Care 2021 Jul 8. Epub 2021 Jul 8.

Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, MI

Objective: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D.

Research Design And Methods: In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform.

Results: At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 ( = 0.039). Observations were confirmed in the validation subset.

Conclusions: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc21-0737DOI Listing
July 2021

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis.

Am J Cardiol 2021 Aug 6;152:63-68. Epub 2021 Jun 6.

Kidney Research Institute, University of Washington, Seattle, Washington.

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2021.04.023DOI Listing
August 2021

Associations of Microvascular Complications With the Risk of Cardiovascular Disease in Type 1 Diabetes.

Diabetes Care 2021 May 12. Epub 2021 May 12.

Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Rockville, MD.

Objective: We examined whether the presence of microvascular complications was associated with increased subsequent risk of cardiovascular disease (CVD) among participants with type 1 diabetes in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study followed for >35 years.

Research Design And Methods: Standardized longitudinal data collection included: ) stereoscopic seven-field retinal fundus photography centrally graded for retinopathy stage and clinically significant macular edema; ) urinary albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR); ) cardiovascular autonomic neuropathy (CAN) reflex testing; and ) adjudicated CVD events, including death from CVD, nonfatal myocardial infarction, stroke, subclinical myocardial infarction on electrocardiogram, confirmed angina, or coronary artery revascularization. Cox proportional hazard models assessed the association of microvascular complications with subsequent risk of CVD.

Results: A total of 239 participants developed CVD, including 120 participants who suffered major adverse cardiovascular events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The presence of microvascular disease (diabetic retinopathy, kidney disease, or CAN) was associated with increased risk of subsequent CVD and MACE (hazard ratios 1.86 to 3.18 and 2.09 to 3.63, respectively); associations that remained significant after adjusting for age and HbA. After adjustment for traditional CVD risk factors, however, only sustained AER ≥30 mg/24 h occurring alone and/or with eGFR <60 mL/min/1.73 m and the presence of both retinal and kidney disease remained associated with CVD.

Conclusions: Advanced microvascular disease, especially moderate to severe albuminuria or eGFR <60 mL/min/1.73 m, conveyed an increased risk of subsequent cardiovascular disease in the DCCT/EDIC cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-3104DOI Listing
May 2021

Retinal Capillary Nonperfusion on OCT-Angiography and Its Relationship to Kidney Function in Patients with Diabetes.

J Ophthalmol 2020 30;2020:2473949. Epub 2020 Nov 30.

Department of Ophthalmology, University of Washington, Seattle, WA, USA.

Background: Diabetic retinopathy and kidney disease share underlying mechanisms of microvascular damage and are often comorbid in people with diabetes. We evaluated whether there is a relationship between retinal capillary perfusion as measured by swept-source optical coherence tomography angiography and estimated glomerular filtration rate (eGFR) and albuminuria in patients with diabetes and chronic kidney disease (CKD).

Method: A cross-sectional pilot study was conducted at the University of Washington among a subset of participants with diabetes and CKD participating in a larger cohort study. Participants were excluded if they were known to have kidney disease from conditions other than diabetes. Ten participants (11 eyes) were included. Retinal nonperfusion (RNP) and vessel density (VD) were measured by swept-source optical coherence tomography angiography in 30° and 60° field of view (FOV) regions centered at the fovea. Correlations of RNP and VD with eGFR and albuminuria were analyzed.

Results: Participants had a mean age of 72 years, hemoglobin A1c of 8.1%, eGFR of 45 mL/min/1.73 m, and urine albumin-to-creatinine ratio of 162 mg/g. Mean (SD) RNP was 6.6% (4.2%) and 16.9% (7.7%) in 30° and 60° FOV regions, respectively. eGFR was negatively correlated to RNP in both the 30° and 60° FOV regions ( = -0.69, =0.004, and  = -0.46, =0.057, respectively), and correlations were stronger among a subset of 7 participants with evidence of diabetic retinopathy on exam and fundus photos. The estimated GFR was not significantly correlated with vessel density. Urine albumin-to-creatinine ratio was not significantly correlated with RNP or VD.

Conclusions: Our proof-of-concept study showed that lower eGFR was significantly correlated with retinal nonperfusion in participants with diabetes and CKD. Advanced retinal imaging may enhance the noninvasive evaluation of kidney function in diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/2473949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949871PMC
November 2020

Rationale and design of the Kidney Precision Medicine Project.

Kidney Int 2021 03;99(3):498-510

Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Renal Section, Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.08.039DOI Listing
March 2021

The Multi-Ethnic Study of Atherosclerosis individual response to vitamin D trial: Building a randomized clinical trial into an observational cohort study.

Contemp Clin Trials 2021 04 12;103:106318. Epub 2021 Feb 12.

Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA, United States of America.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2021.106318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089051PMC
April 2021

SGLT2 Inhibitors in Diabetic Kidney Disease.

Clin J Am Soc Nephrol 2021 04 3;16(4):631-633. Epub 2021 Feb 3.

Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.18881220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092054PMC
April 2021

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease: A Randomized Placebo-Controlled Clinical Trial.

Clin J Am Soc Nephrol 2020 12 16;16(1):59-69. Epub 2020 Dec 16.

Cyclerion Therapeutics, Inc., Cambridge, Massachusetts.

Background And Objectives: Impaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models.

Design, Setting, Participants, & Measurements: In a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30-75 ml/min per 1.73 m, and urine albumin-creatinine ratio 200-5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1:1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12 weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin-creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters.

Results: Of 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of -28% (90% confidence interval, -36 to -18) in the pooled praliciguat group and -15% (-28 to 0.4) in the placebo group (difference -15%; -31 to 4; =0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (-4 mm Hg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10 mg/dl; -19 to -1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups.

Conclusions: Praliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease.

Clinical Trial Registry Name And Registration Number: A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.08410520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792638PMC
December 2020

Integrating Patient Priorities with Science by Community Engagement in the Kidney Precision Medicine Project.

Clin J Am Soc Nephrol 2021 04 30;16(4):660-668. Epub 2020 Nov 30.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

The Kidney Precision Medicine Project (KPMP) is a multisite study designed to improve understanding of CKD attributed to diabetes or hypertension and AKI by performing protocol-driven kidney biopsies. Study participants and their kidney tissue samples undergo state-of-the-art deep phenotyping using advanced molecular, imaging, and data analytical methods. Few patients participate in research design or concepts for discovery science. A major goal of the KPMP is to include patients as equal partners to inform the research for clinically relevant benefit. The purpose of this report is to describe patient and community engagement and the value they bring to the KPMP. Patients with CKD and AKI and clinicians from the study sites are members of the Community Engagement Committee, with representation on other KPMP committees. They participate in KPMP deliberations to address scientific, clinical, logistic, analytic, ethical, and community engagement issues. The Community Engagement Committee guides KPMP research priorities from perspectives of patients and clinicians. Patients led development of essential study components, including the informed consent process, no-fault harm insurance coverage, the ethics statement, return of results plan, a "Patient Primer" for scientists and the public, and Community Advisory Boards. As members across other KPMP committees, the Community Engagement Committee assures that the science is developed and conducted in a manner relevant to study participants and the clinical community. Patients have guided the KPMP to produce research aligned with their priorities. The Community Engagement Committee partnership has set new benchmarks for patient leadership in precision medicine research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.10270620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092068PMC
April 2021

Vitamin D in human serum and adipose tissue after supplementation.

Am J Clin Nutr 2020 Nov 12. Epub 2020 Nov 12.

Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.

Background: Serum 25-hydroxyvitamin D [25(OH)D] concentration is an indicator of vitamin D exposure, but it is also influenced by clinical characteristics that affect 25(OH)D production and clearance. Vitamin D is the precursor to 25(OH)D but is analytically challenging to measure in biological specimens.

Objectives: We aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of vitamins D3 and D2 in serum and to explore the potential of circulating vitamin D as a biomarker of exposure in supplementation trials.

Methods: The method was validated using guideline C62-A from the Clinical and Laboratory Standards Institute and was applied in 2 pilot clinical trials of oral vitamin D3 supplementation. Pilot study 1 included 22 adults randomly assigned to placebo or 2000 IU/d. Blood was collected at baseline, 1, 3, 6, and 12 mo. Pilot study 2 included 15 adults randomly assigned to 2000 or 4000 IU/d. Blood and subcutaneous (SUBQ) adipose tissue were collected at baseline and 3 mo.

Results: In study 1, mean change (baseline to 3 mo) in serum vitamin D3 was -0.1 ng/mL in the placebo group and 6.8 ng/mL in the 2000 IU/d group (absolute difference: 6.9; 95% CI: 4.5, 9.3 ng/mL). In study 2, mean change (baseline to 3 mo) in serum vitamin D3 was 10.4 ng/mL in the 2000 IU/d group and 22.2 ng/mL in the 4000 IU/d group (fold difference: 2.15; 95% CI: 1.40, 3.37). Serum and adipose tissue vitamin D3 concentrations were correlated, and the dose-response of vitamin D3 in adipose mirrored that in serum.

Conclusions: We validated a sensitive, robust, and high-throughput LC-MS/MS method to quantify vitamins D3 and D2 in serum. Serum and SUBQ adipose tissue vitamin D3 concentrations increased proportionally to dose with 3 mo of daily supplementation.These trials were registered at clinicaltrials.gov as NCT00552409 (pilot study 1) and NCT01477034 (pilot study 2).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqaa295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779222PMC
November 2020

Diabetes Management in Chronic Kidney Disease: Synopsis of the 2020 KDIGO Clinical Practice Guideline.

Ann Intern Med 2021 03 10;174(3):385-394. Epub 2020 Nov 10.

Diabetes Research Centre, University of Leicester, and Leicester General Hospital, Leicester, United Kingdom (K.K.).

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed a clinical practice guideline in 2020 for the management of patients with diabetes and chronic kidney disease (CKD).

Methods: The KDIGO Work Group (WG) was tasked with developing the guideline for diabetes management in CKD. It defined the scope of the guideline, gathered evidence, determined systematic review topics, and graded evidence that had been summarized by an evidence review team. The English-language literature searches, which were initially done through October 2018, were updated in February 2020. The WG used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of the recommendations. Expert judgment was used to develop consensus practice points supplementary to the evidence-based graded recommendations. The guideline document underwent open public review. Comments from various stakeholders, subject matter experts, and industry and national organizations were considered before the document was finalized.

Recommendations: The guideline includes 12 recommendations and 48 practice points for clinicians caring for patients with diabetes and CKD. This synopsis focuses on the key recommendations pertinent to the following issues: comprehensive care needs, glycemic monitoring and targets, lifestyle interventions, antihyperglycemic therapies, and educational and integrated care approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M20-5938DOI Listing
March 2021

Fibroblast Growth Factor 23 and Long-Term Cardiac Function: The Multi-Ethnic Study of Atherosclerosis.

Circ Cardiovasc Imaging 2020 11 9;13(11):e011925. Epub 2020 Nov 9.

Division of Cardiology, Department of Medicine (R.B.P., S.J.S., D.L-J.), Northwestern University Feinberg School of Medicine, Chicago, IL.

Background: Although FGF23 (fibroblast growth factor 23) is associated with heart failure and atrial fibrillation, the mechanisms driving these associations are unclear. Sensitive measures of cardiovascular structure and function may provide mechanistic insight behind the associations of FGF23 with various cardiovascular diseases.

Methods: In MESA (the Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of baseline serum FGF23 (2000-2002) with measures of left ventricular (LV) and left atrial mechanical function on cardiac magnetic resonance at 10-year follow-up (2010-2012).

Results: Of 2276 participants with available FGF23 and cardiac magnetic resonance at 10-year follow-up, participants with higher FGF23 levels were more likely White race, taking antihypertensive medications, and had lower kidney function. After covariate adjustment, FGF23 was associated with higher LV mass (β coefficient per 1 SD higher, 1.14 [95% CI, 0.16-2.12], =0.02), worse LV global circumferential strain (β coefficient per 1 SD higher, 0.15 [95% CI, 0.05-0.25], =0.003), worse LV midwall circumferential strain (β coefficient per 1 SD higher, 0.20 [95% CI, 0.08-0.31], =0.001), and lower left atrial total emptying fraction (β coefficient per 1 SD higher, -0.52 [95% CI, -1.02 to -0.02], =0.04). These associations were consistent across racial/ethnic groups and the spectrum of glomerular filtration rates. FGF23 was not associated with the presence of myocardial scar (odds ratio per 1 SD higher, 1.12 [95% CI, 0.86-1.45], =0.42).

Conclusions: In a multiethnic, community-based cohort, baseline FGF23 levels were independently associated with higher LV mass, lower LV systolic function, and reduced left atrial function over long-term follow-up. These findings provide potential mechanistic insight into associations of FGF23 with incident heart failure and atrial fibrillation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.120.011925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665116PMC
November 2020

Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study.

J Am Soc Nephrol 2021 01 28;32(1):188-198. Epub 2020 Oct 28.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.

Background: Conversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods.

Methods: We administered intravenous, deuterated 25(OH)D (d-25[OH]D) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D and deuterated 24,25-dihydroxyvitamin D at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D supplementation.

Results: The mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (=-17 ml/d per 10 ml/min per 1.73 m lower eGFR; 95% CI, -21 to -12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure ( for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D supplementation did not differ.

Conclusions: Using direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race.

Clinical Trial Registry Name And Registration Number: Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), NCT03576716.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020050625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894669PMC
January 2021

Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial.

Diabetologia 2021 Feb 24;64(2):437-447. Epub 2020 Oct 24.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA.

Aims/hypothesis: Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes.

Methods: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years.

Results: A total of 333 participants were randomised to vitamin D and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D, 370 to vitamin D and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index.

Conclusions/interpretation: Among adults with type 2 diabetes, supplementation with vitamin D or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years.

Trial Registration: ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-020-05300-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855668PMC
February 2021

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes.

Am J Nephrol 2020 14;51(10):839-848. Epub 2020 Oct 14.

Division of Nephrology, UT Health Science Center San Antonio, San Antonio, Texas, USA.

Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict.

Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques.

Results: At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was -5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68-0.79; p < 0.001).

Conclusion: Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000510830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606554PMC
October 2020

Temporal Relationship of Glycemia With Cardiac Arrhythmias in Patients With Type 2 Diabetes and CKD.

Am J Kidney Dis 2021 06 1;77(6):988-990. Epub 2020 Oct 1.

Department of Medicine, University of Washington, Seattle, WA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.08.008DOI Listing
June 2021

Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease: A Scientific Statement From the American Heart Association.

Circulation 2020 Oct 28;142(17):e265-e286. Epub 2020 Sep 28.

Chronic kidney disease (CKD) with type 2 diabetes (T2D) is a major public health problem, resulting in significant cardiovascular and kidney adverse outcomes worldwide. Despite the widespread use of standard-of-care therapies for CKD with T2D over the past few decades, rates of progression to end-stage kidney disease remain high with no beneficial impact on its accompanying burden of cardiovascular disease. The advent of the newer classes of antihyperglycemic agents, including SGLT2 (sodium glucose cotransporter 2) inhibitors and GLP-1 (glucagon-like peptide-1) receptor agonists, has changed the landscape of therapeutic options for patients with CKD with T2D, with demonstration of significant reductions in cardiovascular adverse events and progression to end-stage kidney disease. Several potential mechanisms exist through which these beneficial effects are achieved in both drug classes, which may be independent of their antihyperglycemic effects. This scientific statement summarizes the current literature on the cardiorenal protective effects with SGLT2 inhibitors and GLP-1 receptor agonists in patients with CKD and T2D. It reviews potential mechanistic pathways that may drive these benefits and summarizes the literature on adverse effects in patients with CKD and T2D at risk for or with established cardiovascular disease. Last, it provides practical guidance on a proposed collaborative care model bridging cardiologists, nephrologists, endocrinologists, and primary care physicians to facilitate the prompt and appropriate integration of these therapeutic classes in the management of patients with T2D and CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIR.0000000000000920DOI Listing
October 2020

Modelling kidney disease using ontology: insights from the Kidney Precision Medicine Project.

Nat Rev Nephrol 2020 11 16;16(11):686-696. Epub 2020 Sep 16.

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.

An important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient's phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41581-020-00335-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012202PMC
November 2020

Race, Ancestry, and Vitamin D Metabolism: The Multi-Ethnic Study of Atherosclerosis.

J Clin Endocrinol Metab 2020 12;105(12)

Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Context: A comprehensive characterization of racial/ethnic variations in vitamin D metabolism markers may improve our understanding of differences in bone and mineral homeostasis and the risk of vitamin D-related diseases.

Objective: Describe racial/ethnic differences in vitamin D metabolism markers and their associations with genetic ancestry.

Design, Setting, Participants: In a cross-sectional study within the Multi-Ethnic Study of Atherosclerosis (MESA), we compared a comprehensive panel of vitamin D metabolism markers across self-reported racial/ethnic groups of Black (N = 1759), White (N = 2507), Chinese (N = 788), and Hispanic (N = 1411). We evaluated associations of proportion African and European ancestry with this panel of markers in Black and Hispanic participants using ancestry informative markers. Latent class analysis evaluated associations between patterns of vitamin D measurements with race/ethnicity.

Results: Compared with Black participants, White participants had significantly higher serum concentrations of 25-hydroxyvitamin D and fibroblast growth factor-23; lower concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D; circulating vitamin D metabolite ratios suggesting lower CYP27B1 and higher CYP24A1 activity; higher urinary concentrations of calcium and phosphorus with higher urinary fractional excretion of phosphorus; and differences in vitamin D binding globulin haplotypes. Higher percent European ancestry was associated with higher 25-hydroxyvitamin D and lower parathyroid hormone concentrations among Black and Hispanic participants. Latent classes defined by vitamin D measurements reflected these patterns and differed significantly by race/ethnicity and ancestry.

Conclusions: Markers of vitamin D metabolism vary significantly by race/ethnicity, may serve to maintain bone and mineral homeostasis across ranges of 25-hydroxyvitamin D production, and be attributable, at least partly, to genetic ancestry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526733PMC
December 2020

Continuous Glucose Monitoring and Use of Alternative Markers To Assess Glycemia in Chronic Kidney Disease.

Diabetes Care 2020 10 11;43(10):2379-2387. Epub 2020 Aug 11.

Kidney Research Institute, University of Washington, Seattle, WA.

Objective: In chronic kidney disease, glycated albumin and fructosamine have been postulated to be better biomarkers of glycemic control than HbA. We evaluated the accuracy, variability, and covariate bias of three biomarkers (HbA, glycated albumin, and fructosamine) compared with continuous glucose monitoring (CGM)-derived measurement of glycemia across estimated glomerular filtration rate (eGFR) in type 2 diabetes.

Research Design And Methods: A prospective cohort study was conducted of 104 participants with type 2 diabetes, 80 with eGFR <60 mL/min/1.73 m (not treated with dialysis) and 24 frequency-matched control subjects with eGFR ≥60 mL/min/1.73 m. Participants wore a blinded CGM for two 6-day periods separated by 2 weeks, with blood and urine collected at the end of each CGM period. HbA, glycated albumin, and fructosamine were measured by high-performance liquid chromatographic, enzymatic, and colorimetric nitroblue tetrazolium methods, respectively.

Results: Within-person biomarker values were strongly correlated between the two CGM periods ( = 0.92-0.95), although no marker fully captured the within-person variability of mean CGM glucose. All markers were similarly correlated with mean CGM glucose ( = 0.71-77). Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; HbA was underestimated in those with albuminuria.

Conclusions: Glycated albumin and fructosamine were not less variable than HbA at a given mean CGM glucose level, with several additional sources of bias. These results support measuring HbA to monitor trends in glycemia among patients with eGFR <60 mL/min/1.73 m. Direct measurements of glucose are necessary to capture short-term variability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-0915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510019PMC
October 2020

Tubular Secretory Clearance Is Associated With Whole-Body Insulin Clearance.

J Clin Endocrinol Metab 2020 11;105(11)

Kidney Research Institute, Seattle, Washington.

Context: The kidneys eliminate insulin via glomerular and peritubular mechanisms; consequently, the kidney contribution to insulin clearance may be underestimated by the glomerular filtration rate (GFR) alone.

Objective: To determine associations of tubular secretory clearance with whole-body insulin clearance and sensitivity in a dedicated study of glucose and insulin metabolism.

Design, Setting, And Participants: We performed an ancillary, cross-sectional study of tubular secretion in the Study of Glucose and Insulin in Renal Disease (SUGAR). Hyperinsulinemic-euglycemic clamps were performed in 57 nondiabetic persons with chronic kidney disease and 38 persons without kidney disease.

Intervention: We measured plasma and 24-hour urine concentrations of endogenous solutes primarily eliminated by tubular secretion. Kidney clearances of secretory solutes were calculated as the amount of blood fully cleared of that solute per minute.

Main Outcome Measures: Whole-body insulin clearance, insulin sensitivity.

Results: Mean whole-body insulin clearance was 924 ± 228 mL/min. After adjustment for age, sex, Black race, fat and fat-free mass, each 20% lower estimated GFR was associated with a 13 mL/min lower insulin clearance (95% confidence interval [CI], 2-24 mL/min lower). Each 20% lower clearance of isovalerylglycine and xanthosine were associated with a 16 mL/min lower (95% CI, 5-26 mL/min lower) and 19 mL/min lower (95% CI, 7-31 mL/min lower) insulin clearance, respectively. Neither estimated GFR nor secretory solute clearances were associated with insulin sensitivity after adjustment.

Conclusions: These results highlight the importance of tubular secretory pathways to insulin elimination but suggest that kidney functions in aggregate contribute only modestly to systemic insulin clearance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500476PMC
November 2020

Relationship Between Chronic Kidney Disease, Glucose Homeostasis, and Plasma Osteocalcin Carboxylation and Fragmentation.

J Ren Nutr 2021 05 18;31(3):248-256. Epub 2020 Jul 18.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington; VA Puget Sound Healthcare System, Division of Nephrology, Seattle, Washington.

Objective: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study.

Methods: We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization-based mass spectrometric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test).

Results: The total plasma osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses.

Conclusions: In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jrn.2020.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854928PMC
May 2021

Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.

Kidney Int 2020 10 10;98(4):839-848. Epub 2020 Jul 10.

Steno Diabetes Center Copenhagen and University of Copenhagen, Copenhagen, Denmark. Electronic address:

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease represents the first KDIGO guideline on this subject. The guideline comes at a time when advances in diabetes technology and therapeutics offer new options to manage the large population of patients with diabetes and chronic kidney disease (CKD) at high risk of poor health outcomes. An enlarging base of high-quality evidence from randomized clinical trials is available to evaluate important new treatments offering organ protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. The goal of the new guideline is to provide evidence-based recommendations to optimize the clinical care of people with diabetes and CKD by integrating new options with existing management strategies. In addition, the guideline contains practice points to facilitate implementation when insufficient data are available to make well-justified recommendations or when additional guidance may be useful for clinical application. The guideline covers comprehensive care of patients with diabetes and CKD, glycemic monitoring and targets, lifestyle interventions, antihyperglycemic therapies, and self-management and health systems approaches to management of patients with diabetes and CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.06.024DOI Listing
October 2020

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

N Engl J Med 2020 06;382(26):2493-2503

From the Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston (A.D., A.B.G., S.E.R.); the Division of Geriatrics, Institute of Gerontology (A.T.G., C.W.), the Department of Biostatistics, School of Public Health (A.T.G., C.S.), Statistical Analysis of Biomedical and Educational Research (SABER) (C.S.), and the Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes (R.P.-B.), University of Michigan, Ann Arbor; the Departments of Medicine, Physiology, and Pharmacology and Toxicology (D.Z.C.) and the Division of Endocrinology and Metabolism (B.A.P.), University of Toronto, the Division of Nephrology, University Health Network (D.Z.C.), LMC Diabetes and Endocrinology (R.A.), and Lunenfeld-Tanenbaum Research Institute, Sinai Health System (B.A.P.), Toronto, the Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, AB (R.J.S.), BCDiabetes, Vancouver (T.G.E.), and the Division of Endocrinology, University of Alberta, Edmonton (P.S.) - all in Canada; the Departments of Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (A.P.); Steno Diabetes Center, and the Department of Clinical Medicine, University Copenhagen, Copenhagen (P.R.); the Division of Nephrology, Department of Medicine, University of California, Davis (M.A.), and the Department of Pediatrics and Stanford Diabetes Research Center, Stanford University, Palo Alto (D.M.M.) - both in California; the Departments of Medicine and Pediatrics (M.L.C., W.N.R.. M.M.) and Laboratory Medicine and Pathology (A.B.K.), University of Minnesota, Minneapolis; the Division of Endocrinology and Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine (J.P.C.), and JDRF (Juvenile Diabetes Research Foundation) (M.P.), New York; the Department of Medicine (I.H.B., I.B.H.) and the Nephrology Division (K.R.T.), University of Washington, and the Institute of Translational Health Sciences, Kidney Research Institute (K.R.T.), Seattle, and Providence Health Care, Spokane (K.R.T.) - both in Washington; the Department of Medicine, Emory University, Atlanta (J.S.H., G.E.U.); the Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis (J.B.M.); the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago (M.E.M., A.W.); the Barbara Davis Center for Diabetes, University of Colorado, Aurora (S.P.); and the Department of Medicine, State University of New York Upstate Medical University, Syracuse (R.S.W.).

Background: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.

Methods: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.

Results: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m in the allopurinol group and 67.3 ml per minute per 1.73 m in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m per year with allopurinol and -2.5 ml per minute per 1.73 m per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.

Conclusions: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1916624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375708PMC
June 2020

Metabolomic Markers of Kidney Function Decline in Patients With Diabetes: Evidence From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2020 10 5;76(4):511-520. Epub 2020 May 5.

Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA; Moores Cancer Center, University of California, San Diego, La Jolla, CA. Electronic address:

Rationale & Objective: Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression.

Study Design: Prospective cohort.

Setting & Participants: 1,001 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m were followed up prospectively for a median of 8 (range, 2-10) years.

Predictors: 13 urine metabolites, age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index, hemoglobin A level, blood pressure, urinary albumin, and eGFR.

Outcomes: Annual eGFR slope and time to incident kidney failure with replacement therapy (KFRT; ie, initiation of dialysis or receipt of transplant).

Analytical Approach: Several clinical metabolite models were developed for eGFR slope as the outcome using stepwise selection and penalized regression, and further tested on the time-to-KFRT outcome. A best cross-validated (final) prognostic model was selected based on high prediction accuracy for eGFR slope and high concordance statistic for incident KFRT.

Results: During follow-up, mean eGFR slope was-1.83±1.92 (SD) mL/min/1.73m per year; 359 (36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the time of entry to the CRIC Study. In our final model, after adjusting for clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and 3-methylcrotonyglycine had a significant negative association with eGFR slope, whereas citric and aconitic acid were positively associated. Further, 3-HIBA and aconitic acid levels were associated with higher and lower risk for KFRT, respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]).

Limitations: Subgroups for whom metabolite signatures may not be optimal, nontargeted metabolomics by flow-injection analysis, and 2-stage modeling approaches.

Conclusions: Urine metabolites may offer insights into DKD progression. If replicated in future studies, aconitic acid and 3-HIBA could identify individuals with diabetes at high risk for GFR decline, potentially leading to improved clinical care and targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529642PMC
October 2020

Kidney Function in Patients With Type 2 Diabetes After Vitamin D Supplementation-Reply.

JAMA 2020 04;323(14):1411-1412

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.1400DOI Listing
April 2020

Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney disease.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Division of Nephrology, Department of Medicine, School of Medicine, UCD, Sacramento, California, USA.

The maintenance of functional independence is the top priority of patients with chronic kidney disease (CKD). Defects in mitochondrial energetics may compromise physical performance and independence. We investigated associations of the presence and severity of kidney disease with in vivo muscle energetics and the association of muscle energetics with physical performance. We performed measures of in vivo leg and hand muscle mitochondrial capacity (ATPmax) and resting ATP turnover (ATPflux) using 31phosphorus magnetic resonance spectroscopy and oxygen uptake (O2 uptake) by optical spectroscopy in 77 people (53 participants with CKD and 24 controls). We measured physical performance using the 6-minute walk test. Participants with CKD had a median estimated glomerular filtration rate (eGFR) of 33 ml/min per 1.73 m2. Participants with CKD had a -0.19 mM/s lower leg ATPmax compared with controls but no difference in hand ATPmax. Resting O2 uptake was higher in CKD compared with controls, despite no difference in ATPflux. ATPmax correlated with eGFR and serum bicarbonate among participants with GFR <60. ATPmax of the hand and leg correlated with 6-minute walking distance. The presence and severity of CKD associate with muscle mitochondrial capacity. Dysfunction of muscle mitochondrial energetics may contribute to reduced physical performance in CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.133289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141399PMC
March 2020

Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease.

Nephrol Dial Transplant 2020 04;35(4):616-623

Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, WA, USA.

Background: Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown.

Methods: We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D.

Results: Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites.

Conclusion: Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139206PMC
April 2020

Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.

J Clin Invest 2020 03;130(3):1513-1526

Nephrology Division and.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI131190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269595PMC
March 2020
-->