Publications by authors named "Glenn M Chertow"

563 Publications

National Estimates of CKD Prevalence and Potential Impact of Estimating Glomerular Filtration Rate Without Race.

J Am Soc Nephrol 2021 May 6. Epub 2021 May 6.

Veterans Affairs Palo Alto Health Care System, Palo Alto, California

Background: The implications of removing the adjustment for Black race in equations to eGFR on the prevalence of CKD and management strategies are incompletely understood.

Methods: We estimated changes in CKD prevalence and the potential effect on therapeutic drug prescriptions and prediction of kidney failure if race adjustment were removed from the CKD-EPI GFR estimating equation. We used cross-sectional and longitudinal data from adults aged ≥18 years in the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016, and the Veterans Affairs (VA) Health Care System in 2015. In the VA cohort, we assessed use of common medications that require dose adjustment on the basis of kidney function, and compared the prognostic accuracy of the Kidney Failure Risk Equation with versus without race adjustment of eGFR.

Results: The prevalence of CKD among Black adults increased from 5.2% to 10.6% in NHANES, and from 12.4% to 21.6% in the VA cohort after eliminating race adjustment. Among Black veterans, 41.0% of gabapentin users, 33.5% of ciprofloxacin users, 24.0% of metformin users, 6.9% of atenolol users, 6.6% of rosuvastatin users, and 5.8% of tramadol users were reclassified to a lower eGFR for which dose adjustment or discontinuation is recommended. Without race adjustment of eGFR, discrimination of the Kidney Failure Risk Equation among Black adults remained high and calibration was marginally improved overall, with better calibration at higher levels of predicted risk.

Conclusions: Removal of race adjustment from CKD-EPI eGFR would double the estimated prevalence of CKD among Black adults in the United States. Such a change is likely to affect a sizeable number of drug-dosing decisions. It may also improve the accuracy of kidney failure risk prediction among higher-risk Black adults.
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http://dx.doi.org/10.1681/ASN.2020121780DOI Listing
May 2021

Barriers to ACEI/ARB Use in Proteinuric Chronic Kidney Disease: An Observational Study.

Mayo Clin Proc 2021 May 2. Epub 2021 May 2.

Division of Nephrology, Stanford University School of Medicine, Palo Alto, CA.

Objective: To assess present angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use among patients with proteinuric chronic kidney disease (CKD) and examine barriers limiting this guideline-concordant care.

Patients And Methods: Using a nationwide database containing patient-level claims and integrated clinical information, we examined current ACEI/ARB prescriptions on the index date (April 15, 2017) and prior ACEI/ARB use in 41,743 insured adults with proteinuric CKD. Using multivariable logistic regression, we estimated adjusted associations between current ACEI/ARB use and putative barriers including past acute kidney injury (AKI), hyperkalemia, advanced CKD, and lack of nephrology care.

Results: Only 49% (n=20,641) of patients had an active ACEI/ARB prescription on the index date, but 87% (n=36,199) had been previously prescribed an ACEI/ARB. Use was lower in patients with past AKI, hyperkalemia, CKD stages 4 or 5, and a lack of nephrology care (adjusted odds ratios were 0.61 [95% CI, 0.58 to 0.64], 0.76 [95% CI, 0.72 to 0.80], 0.48 [95% CI, 0.45 to 0.51], and 0.85 [95% CI, 0.81 to 0.89], respectively).

Conclusion: Discontinuing, rather than never initiating, ACEI/ARB treatment limits guideline-concordant care in proteinuric CKD. Past AKI, hyperkalemia, advanced CKD, and lack of nephrology care were associated with lower use of ACEIs/ARBs, but these putative barriers may in many instances be inappropriate (AKI and advanced CKD) or modifiable (hyperkalemia and lack of nephrology care).
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http://dx.doi.org/10.1016/j.mayocp.2020.12.038DOI Listing
May 2021

SARS-CoV-2 Vaccine Acceptability in Patients on Hemodialysis: A Nationwide Survey.

J Am Soc Nephrol 2021 Apr 29. Epub 2021 Apr 29.

Department of Medicine (Nephrology), Stanford University, Stanford, California

Background: Patients on dialysis are at increased risk for COVID-19-related complications. However, a substantial fraction of patients on dialysis belong to groups more likely to be hesitant about vaccination.

Methods: With the goal of identifying strategies to increase COVID-19 vaccine uptake among patients on hemodialysis, we conducted a nationwide vaccine acceptability survey, partnering with a dialysis network to distribute an anonymized English and Spanish language online survey in 150 randomly selected facilities in the United States. We used logistic regression to evaluate characteristics of vaccine-hesitant persons.

Results: A total of 1515 (14% of eligible) patients responded; 20% of all responders, 29% of patients aged 18-44 years, and 29% of Black responders reported being hesitant to seek the COVID-19 vaccine, even if the vaccine was considered safe for the general population. Odds of vaccine hesitancy were higher among patients aged 18-44 years versus those 45-64 years (odds ratio [OR], 1.5; 95% confidence interval [95% CI], 1.0 to 2.3), Black patients versus non-Hispanic White patients (OR, 1.9; 95% CI, 1.3 to 2.7), Native Americans or Pacific Islanders versus non-Hispanic White patients (OR, 2.0; 95% CI, 1.1 to 3.7), and women versus men (OR, 1.6; 95% CI, 1.2 to 2.0). About half (53%) of patients who were vaccine hesitant expressed concerns about side effects. Responders' main information sources about COVID-19 vaccines were television news and dialysis staff (68% and 38%, respectively).

Conclusions: A substantial proportion of patients receiving in-center hemodialysis in the United States are hesitant about seeking COVID-19 vaccination. Facilitating uptake requires outreach to younger patients, women, and Black, Native American, or Pacific Islander patients, and addressing concerns about side effects.
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http://dx.doi.org/10.1681/ASN.2021010104DOI Listing
April 2021

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

N Engl J Med 2021 04;384(17):1601-1612

From the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.); the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Gonzalez M.D. and Aswad M.D. Health Care Services, Miami (A. Aswad); Clinical Research Consultants, Kansas City, MO (A. Awad); U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), Renal Associates, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio (P.P.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Praxis Medical Research, and the Department of Medicine, Division of General Practice, Faculdade de Medicina do ABC, São Paulo (M.R.B.); Akebia Therapeutics, Cambridge (Y.M.K.F., Z.K., B.J.M., W.L., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Division of Nephrology, Department of Medicine, Hofstra Northwell School of Medicine, Great Neck (S.F.), and the Division of Nephrology, New York Presbyterian, Queens (B.S.) - both in New York; Nephrology Associates, Augusta (H.H.), and Emory University School of Medicine, Atlanta (J.T.) - both in Georgia; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.); Stanford University School of Medicine, Palo Alto, CA (E.F.L., G.M.C.); the Department of Medicine, Memorial University, St. John's, NL, Canada (P.S.P.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Kidney Transplantation-Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, Lodz, Poland (R.Z.).

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.

Methods: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).

Results: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.

Conclusions: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNOVATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
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http://dx.doi.org/10.1056/NEJMoa2025956DOI Listing
April 2021

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

N Engl J Med 2021 04;384(17):1589-1600

From Stanford University School of Medicine, Palo Alto, CA (G.M.C., E.F.L.); Renal Associates, San Antonio (P.E.P.), U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Akebia Therapeutics, Cambridge (Y.M.K.F., S.B., Z.K., W.L., B.J.M., A.S., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Excellentis Clinical Trial Consultants, George, South Africa (S.A.); Bihor County Hospital Oradea, Oradea, Romania (G.B.); Qway Research, Hialeah, FL (F.P.C.); the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.G.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); Firma Clinical Research, Hunt Valley (T.L.), and the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.) - both in Maryland; the Department of Medicine, Memorial University of Newfoundland, St. John's, Canada (P.S.P.); the Division of Nephrology and Hypertension, University of North Carolina Kidney Center, Chapel Hill, and the W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury - both in North Carolina (P.R.-C.); the Division of Nephrology, New York-Presbyterian Queens, Flushing (B.S.); Firma Clinical Research, Chicago (C.T.); Emory University School of Medicine, Atlanta (J.T.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.).

Background: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.

Methods: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.

Results: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.

Conclusions: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PROTECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
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http://dx.doi.org/10.1056/NEJMoa2035938DOI Listing
April 2021

Targeting Sedentary Behavior in CKD: A Pilot and Feasibility Randomized Controlled Trial.

Clin J Am Soc Nephrol 2021 May 22;16(5):717-726. Epub 2021 Apr 22.

Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah

Background And Objectives: We tested the feasibility of reducing sedentary behavior common in CKD.

Design, Setting, Participants, & Measurements: We carried out a Sit Less, Interact, Move More intervention in a 24-week parallel-group, randomized controlled trial in patients with stages 2-5 CKD. In the intervention group (=54), accelerometry performed at baseline and repeated every 4 weeks was used to develop and monitor adherence to individualized plans targeting sedentary and stepping durations. The control group (=52) was provided national physical activity recommendations; accelerometry was performed at baseline and every 8 weeks. Between-groups changes from baseline to the average follow-up values at weeks 8, 16, and 24 of the sedentary and stepping durations were the coprimary end points.

Results: The mean age was 69±13 years. Fourteen percent were on dialysis or received a kidney transplant. Eight percent of the control group and 17% of the intervention group were lost to follow-up. Sedentary and stepping durations did not change in the control group. Within the intervention group, the maximum decrease in sedentary duration (-43; 95% confidence interval, -69 to -17 min/d) and increase in stepping duration (16; 95% confidence interval, 7 to 24 min/d) and the number of steps per day (1265; 95% confidence interval, 518 to 2012) were seen at week 20. These attenuated at week 24. In mixed effects models, overall treatment effects between groups on sedentary (-17; 95% confidence interval, -43 to 8 min/d) and stepping (6; 95% confidence interval, -3 to 15 min/d) durations and the number of steps per day, a secondary end point (652; 95% confidence interval, -146 to 1449), were not significantly different. The intervention significantly reduced secondary end points of body mass index (-1.1; 95% confidence interval, -1.9 to -0.3 kg/m) and body fat percentage (-2.1%; 95% confidence interval, -4.4% to -0.2%).

Conclusions: It is feasible to reduce sedentary duration and increase stepping duration in patients with CKD, but these were not sustained.

Clinical Trial Registry Name And Registration Number: National Health and Nutrition Examination Survey (NHANES), NCT02970123.
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http://dx.doi.org/10.2215/CJN.12300720DOI Listing
May 2021

The organ procurement costs of expanding deceased donor organ acceptance criteria: Evidence from a cost function model.

Am J Transplant 2021 Apr 21. Epub 2021 Apr 21.

Department of Surgery, Division of Transplant Surgery, University of California San Francisco, San Francisco, California.

A potential solution to the deceased donor organ shortage is to expand donor acceptability criteria. The procurement cost implications of using nonstandard donors is unknown. Using 5 years of US organ procurement organization (OPO) data, we built a cost function model to make cost projections: the total cost was the dependent variable; production outputs, including the number of donors and organs procured, were the independent variables. In the model, procuring one kidney or procuring both kidneys from double/en bloc transplantation from a single-organ donor resulted in a marginal cost of $55 k (95% confidence interval [CI] $28 k, $99 k) per kidney, and procuring only the liver from a single-organ donor results in a marginal cost of $41 k (95% CI $12 k, $69 k) per liver. Procuring two kidneys for two candidates from a donor lowered the marginal cost to $36 k (95% CI $22 k, $66 k) per kidney, and procuring two kidneys and a liver lowers the marginal cost to $24 k (95% CI $17 k, $45 k) per organ. Economies of scale were observed, where high OPO volume was correlated with lower costs. Despite higher cost per organ than for standard donors, kidney transplantation from nonstandard donors remained cost-effective based on contemporary US data.
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http://dx.doi.org/10.1111/ajt.16617DOI Listing
April 2021

A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy.

Kidney Int 2021 Apr 18. Epub 2021 Apr 18.

Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.
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http://dx.doi.org/10.1016/j.kint.2021.03.033DOI Listing
April 2021

Laboratory correlates of SARS-CoV-2 seropositivity in a nationwide sample of patients on dialysis in the U.S.

PLoS One 2021 15;16(4):e0249466. Epub 2021 Apr 15.

Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, United States of America.

Patients on dialysis are at high risk for death due to COVID-19, yet a significant proportion do survive as evidenced by presence of SARS-CoV-2 antibodies in 8% of patients in the U.S. in July 2020. It is unclear whether patients with seropositivity represent the subgroup with robust health status, who would be more likely to mount a durable antibody response. Using data from a July 2020 sample of 28,503 patients receiving dialysis, we evaluated the cross-sectional association of SARS-CoV-2 seropositivity with laboratory surrogates of patient health. In separate logistic regression models, we assessed the association of SARS-CoV-2 seropositivity with seven laboratory-based covariates (albumin, creatinine, hemoglobin, sodium, potassium, phosphate, and parathyroid hormone), across the entire range of the laboratory and in comparison to a referent value. Models accounted for age, sex, region, race and ethnicity, and county-level COVID-19 deaths per 100,000. Odds of seropositivity for albumin 3 and 3.5 g/dL were 2.1 (95% CI 1.9-2.3) and 1.3 (1.2-1.4) respectively, compared with 4 g/dL. Odds of seropositivity for serum creatinine 5 and 8 mg/dL were 1.8 (1.6-2.0) and 1.3 (1.2-1.4) respectively, compared with 12.5 mg/dL. Lower values of hemoglobin, sodium, potassium, phosphate, and parathyroid hormone were associated with higher odds of seropositivity. Laboratory values associated with poorer health status and higher risk for mortality were also associated with higher likelihood of SARS-CoV-2 antibodies in patients receiving dialysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249466PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049224PMC
April 2021

Effects of Myo-inositol Hexaphosphate (SNF472) on Bone Mineral Density in Patients Receiving Hemodialysis: An Analysis of the Randomized, Placebo-Controlled CaLIPSO Study.

Clin J Am Soc Nephrol 2021 May 7;16(5):736-745. Epub 2021 Apr 7.

Department of Medicine, Stanford University, Palo Alto, California.

Background And Objectives: In the CaLIPSO study, intravenous administration of SNF472 (300 or 600 mg) during hemodialysis significantly attenuated progression of coronary artery and aortic valve calcification. SNF472 selectively inhibits formation of hydroxyapatite, the final step in cardiovascular calcification. Because bone mineral is predominantly hydroxyapatite, we assessed changes in bone mineral density in CaLIPSO.

Design, Setting, Participants, & Measurements: Patients with coronary artery calcification at screening (Agatston score of 100-3500 U) were randomized 1:1:1 to receive placebo, 300 mg SNF472, or 600 mg SNF472 as an intravenous infusion during hemodialysis three times weekly for 52 weeks. Dual-energy x-ray absorptiometry (DXA) scans were obtained at baseline (screening) and end of treatment, and between-group changes from baseline were compared using analysis of covariance.

Results: Among 274 randomized patients, 202 had evaluable DXA scans at baseline and postrandomization (the DXA-modified intention-to-treat population). Mean (95% confidence interval) changes in total-hip bone mineral density from baseline to week 52 were -1.5% (-2.7% to -0.3%), -1.5% (-2.7% to -0.4%), and -2.5% (-3.8% to -1.2%) in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Mean (95% confidence interval) changes in femoral-neck bone mineral density from baseline to week 52 were -0.3% (-1.6% to 1.0%), -1.0% (-2.3% to 0.2%), and -2.6% (-4.0% to -1.3%), respectively. Regression analyses showed no correlation between change in coronary artery calcium volume and change in bone mineral density at either location. Changes in serum alkaline phosphatase, calcium, magnesium, phosphate, and intact parathyroid hormone levels were similar across treatment groups. Clinical fracture events were reported for four of 90, three of 92, and six of 91 patients in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively.

Conclusions: Bone mineral density decreased modestly in all groups over 1 year. In the 600 mg SNF472 group, the reduction appeared more pronounced. Reported fractures were infrequent in all groups.

Clinical Trial Registry Name And Registration Number: Effect of SNF472 on Progression of Cardiovascular Calcification in End-Stage-Renal-Disease (ESRD) Patients on Hemodialysis (HD), NCT02966028.
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http://dx.doi.org/10.2215/CJN.16931020DOI Listing
May 2021

Removing Race from eGFR calculations: Implications for Urologic Care.

Urology 2021 Mar 30. Epub 2021 Mar 30.

Department of Urology, Stanford University School of Medicine, Stanford, CA; Department of Medicine, Division of Nephrology, Stanford University School of Medicine, Stanford, CA. Electronic address:

Equations estimating the glomerular filtration rate are important clinical tools in detecting and managing kidney disease. Urologists extensively use these equations in clinical decision making. For example, the estimated glomerular function rate is used when considering the type of urinary diversion following cystectomy, selecting systemic chemotherapy in managing urologic cancers, and deciding the type of cross-sectional imaging in diagnosing or staging urologic conditions. However, these equations, while widely accepted, are imprecise and adjust for race which is a social, not a biologic construct. The recent killings of unarmed Black Americans in the US have amplified the discussion of racism in healthcare and has prompted institutions to reconsider the role of race in eGFR equations and raced-based medicine. Urologist should be aware of the consequences of removing race from these equations, potential alternatives, and how these changes may affect Black patients receiving urologic care.
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http://dx.doi.org/10.1016/j.urology.2021.03.018DOI Listing
March 2021

Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial.

Eur Heart J 2021 Mar;42(13):1216-1227

The George Institute for Global Health, Level 5, 1 King Street, Newtown, Sydney, NSW 2042, Australia.

Aims : Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.

Methods And Results : DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.

Conclusion : In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
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http://dx.doi.org/10.1093/eurheartj/ehab094DOI Listing
March 2021

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome.

Am J Nephrol 2021 31;52(3):180-189. Epub 2021 Mar 31.

Renal Associates PA, San Antonio, Texas, USA.

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome.

Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR.

Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy.

Discussion/conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.
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http://dx.doi.org/10.1159/000513777DOI Listing
March 2021

Effect of a Home-Based Exercise Program on Indices of Physical Function and Quality of Life in Elderly Maintenance Hemodialysis Patients.

Kidney Blood Press Res 2021 26;46(2):196-206. Epub 2021 Mar 26.

Nephrology Section, Veterans Affairs Palo Alto Health Care System, Stanford, California, USA.

Background: Patients on maintenance hemodialysis (MHD) exhibit muscle wasting and impaired physical function which can be reversed with regular exercise, but accessibility to exercise programs for this unique population is lacking. We assessed the efficacy of a home-based exercise program on a broad range of indices of physical function, quality of life (QoL), and cognitive decline in patients with MHD.

Design And Methods: Twenty-eight MHD patients, mean age 66 ± 7 years, were randomized to a 12-week home-based, case-managed aerobic and resistance exercise program or to usual care (13 exercise and 15 usual care). Comparisons were made for peak VO2, ventilatory inefficiency, 6-min walk test (6MWT), 1-min sit-to-stand (1STS), muscle strength, body composition, QoL, and cognitive measures.

Results: Peak VO2 improved significantly in the exercise group (p = 0.01 between groups); exercise time improved by 41 and 36% at the ventilatory threshold and peak exercise, respectively (p < 0.01 between groups), but there were no differences in ventilatory efficiency. Trends for improvements in 6MWT and 1STS in the exercise group were observed, but no differences were observed in strength or body composition. Among measures of QoL, general health determined by the SF-36 improved in the exercise group, but there were no differences between groups in cognitive function.

Conclusions: MHD patients improved exercise capacity and some indices of QoL following a 12-week home-based exercise program. Home-based exercise is feasible for patients undergoing MHD and may help to obviate accessibility barriers to regular exercise.
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http://dx.doi.org/10.1159/000514269DOI Listing
March 2021

A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY).

J Am Soc Nephrol 2021 Mar 25. Epub 2021 Mar 25.

Division of Nephrology, Stanford University School of Medicine, Stanford, California.

Background: Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis.

Methods: This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4.

Results: Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, <0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively.

Conclusions: A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone.

Clinical Trial Registry Name And Registration Number: AMPLIFY, NCT03824587.
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http://dx.doi.org/10.1681/ASN.2020101398DOI Listing
March 2021

Association of 152 Biomarker Reference Intervals with All-Cause Mortality in Participants of a General United States Survey from 1999 to 2010.

Clin Chem 2021 Mar;67(3):500-507

Department of Biomedical Informatics, Harvard Medical School, Boston, MA.

Background: Physicians sometimes consider whether or not to perform diagnostic testing in healthy people, but it is unknown whether nonextreme values of diagnostic tests typically encountered in such populations have any predictive ability, in particular for risk of death. The goal of this study was to quantify the associations among population reference intervals of 152 common biomarkers with all-cause mortality in a representative, nondiseased sample of adults in the United States.

Methods: The study used an observational cohort derived from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the United States population consisting of 6 survey waves from 1999 to 2010 with linked mortality data (unweighted N = 30 651) and a median followup of 6.1 years. We deployed an X-wide association study (XWAS) approach to systematically perform association testing of 152 diagnostic tests with all-cause mortality.

Results: After controlling for multiple hypotheses, we found that the values within reference intervals (10-90th percentiles) of 20 common biomarkers used as diagnostic tests or clinical measures were associated with all-cause mortality, including serum albumin, red cell distribution width, serum alkaline phosphatase, and others after adjusting for age (linear and quadratic terms), sex, race, income, chronic illness, and prior-year healthcare utilization. All biomarkers combined, however, explained only an additional 0.8% of the variance of mortality risk. We found modest year-to-year changes, or changes in association from survey wave to survey wave from 1999 to 2010 in the association sizes of biomarkers.

Conclusions: Reference and nonoutlying variation in common biomarkers are consistently associated with mortality risk in the US population, but their additive contribution in explaining mortality risk is minor.
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http://dx.doi.org/10.1093/clinchem/hvaa271DOI Listing
March 2021

Osteoporosis, Fractures, and Bone Mineral Density Screening in Veterans With Kidney Stone Disease.

J Bone Miner Res 2021 Mar 3. Epub 2021 Mar 3.

Department of Medicine, Division of Nephrology, Stanford University, Stanford, CA, USA.

Whether a link exists between kidney stone disease and osteoporosis or fractures remains an open question. In this retrospective cohort study, we sought to determine the prevalence of osteoporosis and fractures and rate of bone mineral density screening by dual-energy X-ray absorptiometry (DXA) in patients with kidney stone disease. We examined nationwide data from the Veterans Health Administration and identified 531,431 patients with kidney stone disease between 2007 and 2015. Nearly 1 in 4 patients (23.6%, 95% confidence interval [CI] 23.5-23.7) with kidney stone disease had a prevalent diagnosis of osteoporosis or fracture. In patients with no prior history of osteoporosis or bone mineral density assessment before a kidney stone diagnosis, 9.1% were screened with DXA after their kidney stone diagnosis, of whom 20% were subsequently diagnosed with osteoporosis. Our findings provide support for wider use of bone mineral density screening in patients with kidney stone disease, including middle-aged and older men, a group less well recognized as at risk for osteoporosis or fractures. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4260DOI Listing
March 2021

Chronic kidney disease, atherosclerotic plaque characteristics on carotid magnetic resonance imaging, and cardiovascular outcomes.

BMC Nephrol 2021 Feb 24;22(1):69. Epub 2021 Feb 24.

Department of Radiology, Vascular Imaging Lab, University of Washington, Seattle, WA, USA.

Background: It is unclear whether faster progression of atherosclerosis explains the higher risk of cardiovascular events in CKD. The objectives of this study were to 1. Characterize the associations of CKD with presence and morphology of atherosclerotic plaques on carotid magnetic resonance imaging (MRI) and 2. Examine the associations of baseline CKD and carotid atherosclerotic plaques with subsequent cardiovascular events.

Methods: In a subgroup (N = 465) of Systolic Blood Pressure Intervention Trial. (SPRINT) participants, we measured carotid plaque presence and morphology at baseline and after 30-months with MRI. We examined the associations of CKD (baseline eGFR < 60 ml/min/1.73m) with progression of carotid plaques and the SPRINT cardiovascular endpoint.

Results: One hundred and ninety six (42%) participants had CKD. Baseline eGFR in the non-CKD and CKD subgroups were 77 ± 14 and 49 ± 8 ml/min/1.73 m, respectively. Lipid rich necrotic-core plaque was present in 137 (29.5%) participants. In 323 participants with both baseline and follow-up MRI measurements of maximum wall thickness, CKD was not associated with progression of maximum wall thickness (OR 0.62, 95% CI 0.36 to 1.07, p = 0.082). In 96 participants with necrotic core plaque at baseline and with a valid follow-up MRI, CKD was associated with lower odds of progression of necrotic core plaque (OR 0.41, 95% CI 0.17 to 0.95, p = 0.039). There were 28 cardiovascular events over 1764 person-years of follow-up. In separate Cox models, necrotic core plaque (HR 2.59, 95% CI 1.15 to 5.85) but not plaque defined by maximum wall thickness or presence of a plaque component (HR 1.79, 95% CI 0.73 to 4.43) was associated with cardiovascular events. Independent of necrotic core plaque, CKD (HR 3.35, 95% CI 1.40 to 7.99) was associated with cardiovascular events.

Conclusions: Presence of necrotic core in carotid plaque rather than the presence of plaque per se was associated with increased risk of cardiovascular events. We did not find CKD to be associated with faster progression of necrotic core plaques, although both were independently associated with cardiovascular events. Thus, CKD may contribute to cardiovascular disease principally via mechanisms other than atherosclerosis such as arterial media calcification or stiffening.

Trial Registration: NCT01475747 , registered on November 21, 2011.
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http://dx.doi.org/10.1186/s12882-021-02260-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905597PMC
February 2021

Race and Place in ESKD.

Kidney Int Rep 2021 Feb 3;6(2):252-253. Epub 2020 Dec 3.

Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879200PMC
February 2021

Urate Lowering With Combination Therapy in CKD: Reason for Optimism or Einstein's Definition of Insanity?

Am J Kidney Dis 2021 04 7;77(4):478-480. Epub 2021 Feb 7.

Division of Nephrology, Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1053/j.ajkd.2020.11.007DOI Listing
April 2021

Aldosterone sensitivity: an opportunity to explore the pathogenesis of hypertension.

Am J Physiol Renal Physiol 2021 03 25;320(3):F325-F335. Epub 2021 Jan 25.

Stanford Hypertension Center, Stanford University School of Medicine, Stanford, California.

Aldosterone sensitivity is defined as an outcome variable for a given circulating level of aldosterone. In basic and translational studies, aldosterone sensitivity has been measured in differential tissue responses, e.g., lower urine sodium and higher urine potassium, as an index of the renal response; in clinical studies, aldosterone sensitivity has been measured in differential blood pressure responses. The concept of aldosterone sensitivity disrupts the conventional wisdom of the renin-angiotensin-aldosterone system and has the potential to uncover novel mechanisms of hypertension. Here, we review basic and translational science studies that uncovered differential renal responses to aldosterone and connect this earlier work to more recent observational studies and randomized trials that have demonstrated differential blood pressure responses for a given level of aldosterone in healthy and hypertensive persons. Black race and older age are associated with higher aldosterone sensitivity and blood pressure. We also discuss gaps in the field and how future basic and clinical studies might inform mechanisms of differential sensitivity.
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http://dx.doi.org/10.1152/ajprenal.00415.2020DOI Listing
March 2021

And Then There Were Three: Effects of Pretransplant Dialysis on Multiorgan Transplantation.

Transplant Direct 2021 Feb 15;7(2):e657. Epub 2021 Jan 15.

Department of Medicine, Division of Nephrology, Stanford University School of Medicine, Palo Alto, CA.

Background: Simultaneous liver-kidney (SLK) and simultaneous heart-kidney (SHK) transplantation currently utilize 6% of deceased donor kidneys in the United States. To what extent residual kidney function accounts for apparent kidney allograft survival is unknown.

Methods: We examined all adult SLK and SHK transplants in the United States during 1995-2014. We considered the duration of dialysis preceding SLK or SHK (≥90 d, 1-89 d, or none) as a proxy of residual kidney function. We used multinomial logistic regression to estimate the difference in the adjusted likelihood of 6- and 12-month apparent kidney allograft failure between the no dialysis versus ≥90 days dialysis groups.

Results: Of 4875 SLK and 848 SHK recipients, 1775 (36%) SLK and 449 (53%) SHK recipients received no dialysis before transplant. The likelihood of apparent kidney allograft failure was 1%-3% lower at 12 months in SLK and SHK recipients who did not require pretransplant dialysis relative to recipients who required ≥90 days of pretransplant dialysis. Among 3978 SLK recipients who survived to 1 year, no pretransplant dialysis was associated with a lower risk of apparent kidney allograft failure over a median follow-up of 5.7 years (adjusted hazard ratio 0.73 [0.55-0.96]).

Conclusions: Patients with residual kidney function at the time of multiorgan transplantation are less likely to have apparent failure of the kidney allograft. Whether residual kidney function facilitates function of the allograft or whether some SLK and SHK recipients have 3 functional kidneys is unknown. Sustained kidney function after SLK and SHK transplants does not necessarily indicate successful MOT.
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http://dx.doi.org/10.1097/TXD.0000000000001112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817305PMC
February 2021

Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial.

Lancet Diabetes Endocrinol 2021 01;9(1):22-31

The George Institute for Global Health, Sydney, NSW, Australia; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Background: Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause.

Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1·73m were randomly assigned (1:1) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. Secondary efficacy outcomes were a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality. In this study, we conducted a prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by aetiology of chronic kidney disease. DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150.

Findings: The study took place between Feb 2, 2017, and June 12, 2020. 4304 participants were randomly assigned (2152 to dapagliflozin and 2152 to placebo) and were followed up for a median of 2·4 years (IQR 2·0-2·7). Overall, 2906 (68%) participants had a diagnosis of type 2 diabetes, of whom 396 (14%) had chronic kidney disease ascribed to causes other than diabetic nephropathy. The relative risk reduction for the primary composite outcome with dapagliflozin was consistent in participants with type 2 diabetes (hazard ratio [HR] 0·64, 95% CI 0·52-0·79) and those without diabetes (0·50, 0·35-0·72; p=0·24). Similar findings were seen for the secondary outcomes: kidney-specific composite outcome (0·57 [0·45-0·73] vs 0·51 [0·34-0·75]; P=0·57), cardiovascular death or hospital admission for heart failure (0·70 [0·53-0·92] vs 0·79 [0·40-1·55]; P=0·78), and all-cause mortality (0·74 [0·56-0·98] vs 0·52 [0·29-0·93]; P=0·25). The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51-0·78), glomerulonephritides (n=695; 0·43, 0·26-0·71), ischaemic or hypertensive chronic kidney disease (n=687; 0·75, 0·44-1·26), and chronic kidney disease of other or unknown cause (n=412; 0·58, 0·29-1·19; P=0·53), with similar consistency seen across the secondary outcomes. The proportions of participants in the dapagliflozin and placebo groups who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes.

Interpretation: Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S2213-8587(20)30369-7DOI Listing
January 2021

Prolonged Hospitalization Following Acute Respiratory Failure.

Chest 2021 May 15;159(5):1867-1874. Epub 2020 Dec 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.

Background: A better understanding of the clinical features associated with prolonged hospitalization in acute respiratory failure may allow for better-informed care planning.

Research Question: What are the incidence, mortality, cost, and clinical determinants of prolonged hospitalization among patients with acute respiratory failure (ARF)?

Study Design And Methods: Using the National Inpatient Sample data from 2004 to 2014, we identified adults 18 years and older with International Classification of Diseases, 9th edition (ICD-9) codes for ARF requiring mechanical ventilation for at least 2 days (ICD-9 518.81 or 518.82, 96.7 or 96.04, and 96.05). Outcomes studied included incidence, in-hospital mortality, cost of hospitalization, and associated patient-level and hospital-level characteristics. Trends were assessed by logistic regression, linear regression, and general linear modeling with Poisson distribution.

Results: Of the 5,539,567 patients with ARF, 77,665 (1.4%) had a prolonged length of stay (pLOS), defined as ≥ 60 days. Among those with pLOS, 52,776 (68%) survived to discharge. Over the study period, the incidence of pLOS decreased by 48%, in-patient mortality decreased by 18%, per-patient cost of care rose, but the percentage of the total cost of ARF care consumed by patients with pLOS did not significantly decrease (P = .06). Prolonged LOS was more likely to occur in urban teaching hospitals (OR, 6.8; 95% CI, 4.6-10.2; P < .001), hospitals located in the northeastern United States (OR, 3.6; 95% CI, 3.0-4.3; P < .001), and among patients with Medicaid insurance coverage (OR, 2.1; 95% CI, 1.9-2.4; P < .001).

Interpretation: From 2004 to 2014, incidence and mortality decreased among patients with ARF and pLOS, and although per-patient costs rose, the percentage of total cost of care remained stable. There is substantial variation in length of stay for patients with ARF by US region, hospital teaching status, and patient insurance coverage.
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http://dx.doi.org/10.1016/j.chest.2020.11.023DOI Listing
May 2021

Effects of SNF472, a Novel Inhibitor of Hydroxyapatite Crystallization in Patients Receiving Hemodialysis - Subgroup Analyses of the CALIPSO Trial.

Kidney Int Rep 2020 Dec 4;5(12):2178-2182. Epub 2020 Nov 4.

Department of Medicine, Stanford University, Palo Alto, California, USA.

Introduction: Coronary artery calcium (CAC) is highly prevalent and linked with poor outcomes in patients receiving maintenance hemodialysis, and its reduction may improve patient prognosis. SNF472, a selective inhibitor of hydroxyapatite crystallization, slows CAC progression in patients receiving maintenance hemodialysis. In this analysis, we assessed the efficacy of SNF472 in prespecified patient subgroups.

Methods: In a randomized clinical trial SNF472 300 mg, SNF472 600 mg, or placebo were infused thrice weekly in 91, 92, and 91 patients receiving maintenance hemodialysis and with CAC at baseline, respectively. In prespecified subanalyses, the percent change in CAC volume score (CACvs) from baseline to week 52 in modified intention-to-treat (mITT) and per-protocol (PP) populations was calculated in the following subgroups: age, sex, diabetes mellitus, dialysis vintage, prior atherosclerotic cardiovascular disease, baseline use of non-calcium and calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, and statins.

Results: In the main trial, SNF472 significantly reduced CACvs progression compared with placebo (11% versus 20% mITT analyses;  = 0.016; 8% vs. 24% PP analyses;  < 0.001). Treatment differences for CACvs progression were similar across all subgroups, and all interaction values were non-significant in mITT and PP analyses.

Conclusions: SNF472 treatment for 52 weeks reduced CACvs progression compared with placebo in a broad range of patients receiving maintenance hemodialysis. Future studies will determine the impact of SNF472 on cardiovascular events in this population.
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http://dx.doi.org/10.1016/j.ekir.2020.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710828PMC
December 2020

Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats.

Am J Physiol Renal Physiol 2021 01 7;320(1):F133-F144. Epub 2020 Dec 7.

Ardelyx, Incorporated, Fremont, California.

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0-3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% ( < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.
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http://dx.doi.org/10.1152/ajprenal.00137.2020DOI Listing
January 2021

Reducing the Shortage of Transplant Kidneys: A Lost Opportunity for the US Health Resources and Services Administration (HRSA).

Am J Kidney Dis 2020 Nov 30. Epub 2020 Nov 30.

Department of Surgery, University of California San Francisco, San Francisco, CA.

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http://dx.doi.org/10.1053/j.ajkd.2020.10.007DOI Listing
November 2020

Correlates and Consequences of High Serum Irisin Concentration in Patients on Hemodialysis: A Longitudinal Analysis.

J Ren Nutr 2020 Nov 28. Epub 2020 Nov 28.

Division of Nephrology, Hennepin Healthcare, Minneapolis, Minnesota.

Objective: Irisin is a hormone released by muscle in response to exercise that acts on white adipose cells to stimulate browning of adipose tissue. We aimed to examine irisin correlates and consequences of irisin in patients receiving hemodialysis.

Design And Methods: A prospective cohort study was conducted using data from 749 prevalent patients receiving hemodialysis. Multivariable linear regression and multivariable generalized estimating equations were used to determine correlates of baseline and change in serum irisin concentration. Proportional hazards (Cox) regression was used to assess the association between serum irisin concentration and time to death.

Results: Age and body mass index were inversely associated with baseline and change in serum irisin concentration. Lower muscle mass as estimated by serum creatinine concentration was associated with lower irisin concentration (-1.38% per mg/dL (95% confidence interval [CI]: -2.45, -0.21) and with a 0.72% decrease in irisin concentration (95% CI: -1.48, -0.04) from baseline to 12 months. Each 50% higher serum interleukin-6 (IL-6) concentration was associated with 1.52% higher serum irisin concentration (95% CI: 0.38, 2.66) at baseline and an increase of 1.04% in irisin concentration over 1 year (95% CI: 0.47, 1.61). Irisin concentration at baseline was associated with higher hazard of death (hazards ratio: 1.45, 95% CI: 1.05 2.00); an increase in irisin concentration over 1 year was associated with a higher hazard of death (hazards ratio: 1.34, 95% CI: 1.01, 1.79). In formal mediation analysis, serum IL-6 was a mediator in the association between serum irisin and mortality.

Conclusions: Lower serum creatinine (reflecting lower muscle mass) and higher serum IL-6 were associated with higher serum irisin concentrations. Higher serum irisin concentrations were associated with higher mortality, which may be mediated by inflammation.
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http://dx.doi.org/10.1053/j.jrn.2020.05.005DOI Listing
November 2020

Toward telemedicine-compatible physical functioning assessments in kidney transplant candidates.

Clin Transplant 2021 Feb 14;35(2):e14173. Epub 2020 Dec 14.

Division of Nephrology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA.

Frailty is associated with adverse kidney transplant outcomes and can be assessed by subjective and objective metrics. There is increasing recognition of the value of metrics obtainable remotely. We compared the self-reported SF-36 physical functioning subscale score (SF-36 PF) with in-person physical performance tests (6-min walk and sit-to-stand) in a prospective cohort of kidney transplant candidates. We assessed each metric's ability to predict time to the composite outcome of waitlist removal or death, censoring at transplant. We built time-dependent receiver operating characteristic curves and calculated the area under the curve [AUC(t)] at 1 year, using bootstrapping for internal validation. In 199 patients followed for a median of 346 days, 41 reached the composite endpoint. Lower SF-36 PF scores were associated with higher risk of waitlist removal/death, with every 10-point decrease corresponding to a 16% increase in risk. All models showed an AUC(t) of 0.83-0.84 that did not contract substantially after internal validation. Among kidney transplant candidates, SF-36 PF, obtainable remotely, can help to stratify the risk of waitlist removal or death, and may be used as a screening tool for poor physical functioning in ongoing candidate evaluation, particularly where travel, increasing patient volume, or other restrictions challenge in-person assessment.
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http://dx.doi.org/10.1111/ctr.14173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906942PMC
February 2021