Selonsertib in Patients with Diabetic Kidney Disease: A Phase 2b Randomized Active Run-In Clinical Trial.

BACKGROUND: Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease. METHODS: We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min/1.73 m2 with UACR 150 to 5000 mg/g on maximum tolerated dose of ACE inhibitor or ARB. To account for an acute selonsertib-related decrease in eGFRcr, patients entered a 4-week selonsertib run-in period to establish treatment-specific baseline eGFRcr. Patients were randomized 1:1 to selonsertib 18 mg or matching placebo once daily. We followed all participants up until the last randomized participant completed 48 weeks follow-up. The primary efficacy outcome was the difference in eGFRcr slopes from treatment-specific baselines to week 84, evaluated at a prespecified two-sided P = 0.30. We also evaluated kidney clinical events (eGFRcr ≥40% decline from pre-run-in baseline, kidney failure, or death due to kidney disease) and adverse events. RESULTS: In total, 310 patients were randomized (selonsertib n=154, placebo n=156; 68% male, mean age 65 years, mean baseline eGFRcr 35 ml/min/1.73 m2). Mean difference between selonsertib and placebo eGFRcr slopes at week 84 was 1.20 ml/min/1.73 m2/year (95% CI, -0.41 to 2.81; P = 0.14). Kidney clinical events occurred in 17% (26/154) of patients randomized to selonsertib and 12% (19/156) of those randomized to placebo (difference 4.7%; 95% CI, -6.3% to 15.9%). The most common investigator-reported adverse event was acute kidney injury (selonsertib 11.0/100 and placebo 5.9/100 patient-years). CONCLUSIONS: Selonsertib attenuated the decline in eGFRcr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported acute kidney injury.

Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria.

BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes. METHODS: A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome. RESULTS: Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP. CONCLUSION: In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.

The Medical Costs of Determining Eligibility and Waiting for a Kidney Transplantation.

BACKGROUND: Recent efforts to increase access to kidney transplant (KTx) in the United States include increasing referrals to transplant programs, leading to more pretransplant services. Transplant programs reconcile the costs of these services through the Organ Acquisition Cost Center (OACC). OBJECTIVE: The aim of this study was to determine the costs associated with pretransplant services by applying microeconomic methods to OACC costs reported by transplant hospitals. RESEARCH DESIGN, SUBJECTS, AND MEASURES: For all US adult kidney transplant hospitals from 2013 through 2018 (n=193), we crosslinked the total OACC costs (at the hospital-fiscal year level) to proxy measures of volumes of pretransplant services. We used a multiple-output cost function, regressing total OACC costs against proxy measures for volumes of pretransplant services and adjusting for patient characteristics, to calculate the marginal cost of each pretransplant service. RESULTS: Over 1015 adult hospital-years, median OACC costs attributable to the pretransplant services were $5 million. Marginal costs for the pretransplant services were: initial transplant evaluation, $9k per waitlist addition; waitlist management, $2k per patient-year on the waitlist; deceased donor offer management, $1k per offer; living donor evaluation, procurement and follow-up: $26k per living donor. Longer time on dialysis among patients added to the waitlist was associated with higher OACC costs at the transplant hospital. CONCLUSIONS: To achieve the policy goals of more access to KTx, sufficient funding is needed to support the increase in volume of pretransplant services. Future studies should assess the relative value of each service and explore ways to enhance efficiency.

Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex.

BACKGROUND: The sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown. OBJECTIVE: We performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex. DESIGN: Prospective randomized placebo-controlled trial. PARTICIPANTS: A total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200-5000 mg/g) with and without type 2 diabetes. INTERVENTION: Dapagliflozin 10 mg versus placebo once daily. MAIN MEASURES: Primary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality. KEY RESULTS: Median follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope. CONCLUSIONS: Dapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit. TRIAL REGISTRY: clinicaltrials.gov NIH TRIAL REGISTRY NUMBER: NCT03036150.

Association of Diabetes with Changes in Blood Pressure during Hemodialysis: A Secondary Analysis of the Frequent Hemodialysis Network Daily Trial.

INTRODUCTION: Diabetes mellitus is a common cause of kidney failure and is often complicated by autonomic neuropathy, which may have implications for blood pressure (BP) homeostasis during hemodialysis (HD). METHODS: In this post hoc analysis of the Frequent Hemodialysis Network (FHN) Daily Trial, we used random effects Poisson and linear regression models to estimate the association of diabetes (vs. not) with intra-dialytic hypotension (IDH) and peri-dialytic BP parameters, respectively. We tested for differential associations according to the randomized treatment (6/week vs. 3/week HD) and pre-HD systolic BP. RESULTS: Of the 244 patients with intra-dialytic BP data, 100 (41%) had diabetes at baseline. The mean age was 51 ± 14 years; overall, 39% were female. In adjusted models, diabetes (vs. not) was associated with a 93% higher risk of developing IDH (IRR: 1.93; 95% CI: 1.26, 2.95). There was no evidence that the randomized treatment assignment modified the association between diabetes and IDH (pinteraction = 0.32), but more potent associations were noted among those with higher pre-HD systolic BP (pinteraction < 0.001). Diabetes (vs. not) was associated with a lower adjusted nadir intra-HD BP (-4.2; 95% CI: -8.3, -0.2 mm Hg) but not with the pre- or post-HD systolic BP. CONCLUSIONS: Among participants of the FHN Daily Trial, patients with diabetes had a higher risk of IDH and lower nadir intra-HD systolic BP than patients without diabetes, even when undergoing HD up to 6 times per week.

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes and mild/moderate chronic kidney disease.

AIM: To determine the comparative effectiveness regarding major cardiovascular events of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). MATERIALS AND METHODS: We assembled a cohort of commercially insured adult patients with T2DM in the United States (derived from Optum Clinformatics DataMart 2003-2021) who were new users of GLP-1 receptor agonists or SGLT-2 inhibitors. We compared risks of non-fatal myocardial infarction or stroke in patients with and without CKD, and further categorized by CKD stage: stages G1 or G2 [estimated glomerular filtration rate (eGFR) ≥60 ml/min] and A2 (urine albumin to creatinine ratio 30 to <300 mg/g) or A3 (urine albumin to creatinine ratio ≥300 mg/g), stage G3a (eGFR 45 to <60 ml/min/1.73 m2 ) and stage G3b (eGFR 30 to <45 ml/min/1.73 m2 ). We used proportional hazards regression after inverse probability of treatment weighting to compute hazard ratios and 95% confidence intervals. RESULTS: After accounting for the probability of treatment, patients with T2DM and CKD treated with SGLT-2 inhibitors experienced a 14% lower risk of non-fatal myocardial infarction or stroke (hazard ratio 0.86, 95% confidence interval 0.78-0.94) relative to those treated with GLP-1 receptor agonists. CONCLUSIONS: Recognizing the potential for residual confounding, selection bias and immortal time bias, commercially insured patients in the United States with T2DM and CKD treated with SGLT-2 inhibitors experienced significantly lower risks of non-fatal myocardial infarction or stroke relative to those treated with GLP-1 receptor agonists.

MyPlate Awareness and Engagement and Perceived and Objective Diet Quality in US Adults With Chronic Kidney Disease.

OBJECTIVE: Awareness of federal dietary guidelines has been associated with better perceived and objective diet quality. Little is known about the awareness of federal dietary recommendations among persons with chronic kidney disease (CKD) and the associations between recognition of guidelines, perception of diet quality, and objective quality of the diet in this population. DESIGN AND METHODS: We compared awareness of, and engagement with, MyPlate (a representation of 5 food groups from the US Department of Agriculture) along with perceived and objective diet quality, the latter assessed via Dietary Approaches to Stop Hypertension index scores, among US adults with and without CKD during 2017-2020. RESULTS: Among noninstitutionalized adults in the United States, 8.3% had albuminuria with normal or near-normal kidney function, 4.0% had estimated glomerular filtration rate 45-59 mL/minute/1.73 m2 (CKD stage G3a) and 1.6% had estimated glomerular filtration rate <45 mL/minute/1.73 m2 (CKD stages G3b/G4/G5). MyPlate awareness was lower among persons with CKD compared with those without CKD (19.6% vs. 26.4%, P < .001) and was lower among persons with more advanced CKD stages: 20.8%, 18.2%, and 16.3% in persons with CKD stages G1/G2, G3a, and G3b/G4/G5, respectively (trend P < .001). Among persons aware of MyPlate, a numerically higher proportion with CKD attempted to follow MyPlate recommendations (43.9% vs. 32.3%, P = .10); the proportion was highest among persons with moderate-to-advanced CKD (41.9%, 42.9%, and 56.9% among persons with CKD stages G1/G2, G3a, and G3b/G4/G5, respectively (trend P < .001)). Perceived and objective dietary quality (the latter based on concordance with the Dietary Approaches to Stop Hypertension diet) were slightly higher among persons with CKD relative to those without CKD. CONCLUSIONS: Adults with CKD have lower MyPlate awareness than adults without CKD. Enhancing diet education to persons with CKD could improve diet quality and potentially ameliorate CKD-associated complications.

Tenapanor: A Phosphate Absorption Inhibitor for the Management of Hyperphosphatemia in Patients With Kidney Failure.

Because of increased risks of cardiovascular disease and death, patients with hyperphosphatemia receiving maintenance dialysis are advised to limit phosphorus consumption and are prescribed phosphate binders in an effort to better control serum phosphate concentrations. Because of large pill size, pill burden, and tolerability issues, phosphate binder adherence is relatively poor. On ingestion, phosphate is absorbed from the intestine via transcellular or paracellular transport. Data show that inhibiting sodium-hydrogen exchanger 3 modulates paracellular phosphate absorption (the predominant pathway in humans). Tenapanor is a first-in-class, minimally absorbed, phosphate absorption inhibitor that selectively inhibits sodium-hydrogen exchanger 3, with a mechanism distinct from, and complementary to, that of phosphate binders. In phase 3 and postregistrational studies, tenapanor conferred statistically significant and clinically meaningful reductions in serum phosphate in patients receiving maintenance dialysis with hyperphosphatemia. Here, we review the available preclinical and clinical data on the effects of tenapanor on controlling intestinal phosphate absorption.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Active Kidney Involvement in the United States: 2016-2020.

Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and its subtypes, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA), frequently present with acute kidney injury and can often lead to kidney failure, even with successful induction therapy. Few contemporary, nationally representative studies have described hospital complications of AAV. Methods: Using data from the 2016-2020 National Inpatient Sample, a nationally representative database, we identified hospitalizations from adults with a new diagnosis of AAV (subtype or unspecified) and an inpatient kidney biopsy during the index hospitalization. We described baseline characteristics, associated inpatient procedures and complications, and compared lengths of stay and costs by geographic region, hospital characteristics, and AAV subtype. Results: We identified an average of 1,329 cases of hospitalized AAV with a concurrent kidney biopsy per year over the 5-year period. More than 50% were not designated as having a specific subtype, likely owing to delays in documentation of histopathology. Kidney involvement was severe as the majority of patients developed acute kidney injury, and the proportion of patients who required inpatient dialysis was approximately 24%. Approximately 20% of patients developed hypoxia. Inpatient plasmapheresis was delivered to 20.4% and 20.6% of patients with GPA and MPA, respectively. There were no clinically meaningful or statistically significant differences in adjusted length of stay or inpatient costs among AAV subtypes. Admission in the Midwest region was associated with shorter hospital stays and lower costs than that in the Northeast, South, or West regions of the USA (adjusted p = 0.007 and <0.001, respectively). Conclusion: AAV with acute kidney involvement remains a challenging, high-risk condition. Maintaining a high index of suspicion and a low threshold for kidney biopsy should help ameliorate short- and long-term complications.

Bias and Accuracy of Glomerular Filtration Rate Estimating Equations in the US: A Systematic Review and Meta-Analysis.

Importance: There is increasing concern that continued use of a glomerular filtration rate (GFR) estimating equation adjusted for a single racial group could exacerbate chronic kidney disease-related disparities and inequalities. Objective: To assess the performance of GFR estimating equations across varied patient populations. Data Sources: PubMed, Embase, Web of Science, ClinicalTrials.gov, and Scopus databases were systematically searched from January 2012 to February 2023. Study Selection: Inclusion criteria were studies that compared measured GFR with estimated GFR in adults using established reference standards and methods. A total of 6663 studies were initially identified for screening and review. Data Extraction and Synthesis: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 2 authors independently extracted data on studies that examined the bias and accuracy of GFR estimating equations. For each outcome, a random-effects model was used to calculate pooled estimates. Data analysis was conducted from March to December 2023. Main Outcomes and Measures: The primary outcomes were bias and accuracy of estimated GFRs in Black vs non-Black patients, as well as in individuals with chronic conditions. Bias was defined as the median difference between the measured GFR and the estimated GFR. Accuracy was assessed with P30 (the proportion of persons in a data set whose estimated GFR values were within 30% of measured GFR values) and measures of heterogeneity. Results: A total of 12 studies with a combined 44 721 patients were included. Significant heterogeneity was found in the bias of various GFR estimation equations. Race-corrected equations and creatinine-based equations tended to overestimate GFR in Black populations and showed mixed results in non-Black populations. For creatinine-based equations, the mean bias in subgroup analysis was 2.1 mL/min/1.73 m2 (95% CI, -0.2 mL/min/1.73 m2 to 4.4 mL/min/1.73 m2) in Black persons and 1.3 mL/min/1.73 m2 (95% CI, 0.0 mL/min/1.73 m2 to 2.5 mL/min/1.73 m2) in non-Black persons. Equations using only cystatin C had small biases. Regarding accuracy, heterogeneity was high in both groups. The overall P30 was 84.5% in Black persons and 87.8% in non-Black persons. Creatinine-based equations were more accurate in non-Black persons than in Black persons. For creatinine-cystatin C equations, the P30 was higher in non-Black persons. There was no significant P30 difference in cystatin C-only equations between the 2 groups. In patients with chronic conditions, P30 values were generally less than 85%, and the biases varied widely. Conclusions and Relevance: This systematic review and meta-analysis of GFR estimating equations suggests that there is bias in race-based GFR estimating equations, which exacerbates kidney disease disparities. Development of a GFR equation independent of race is a crucial starting point, but not the sole solution. Addressing the disproportionate burden of kidney failure on Black individuals in the US requires an enduring, multifaceted approach that should include improving diagnostics, tackling social determinants of health, confronting systemic racism, and using effective disease prevention and management strategies.

Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, following Single- and Multiple-Ascending Doses in Healthy Adults.

Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

Patient Perspectives on Using Telemedicine During In-Center Hemodialysis: A Qualitative Study.

Rationale & Objective: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, the United States federal government expanded originating telemedicine sites to include outpatient dialysis units. For the first time, nephrology practitioners across the United States could replace face-to-face visits with telemedicine for patients receiving in-center hemodialysis. This study describes patients' perspectives on the use of telemedicine during in-center hemodialysis. Study Design: A qualitative study. Setting & Participants: Thirty-two patients from underserved populations (older, less educated, unemployed, persons of color) receiving in-center hemodialysis who used telemedicine with their nephrologist during the COVID-19 pandemic. Analytical Approach: Telephone semistructured interviews were conducted in English or Spanish. Transcripts were thematically analyzed. Results: We identified 6 themes with subthemes: adapting to telemedicine (gaining familiarity and confidence, overcoming and resolving technical difficulties, and relying on staff for communication); ensuring availability of the physician (enabling an immediate response to urgent medical needs, providing peace of mind, addressing patient needs adequately, and enhanced attention and contact from physicians); safeguarding against infection (limiting COVID-19 exposures and decreasing use); straining communication and physical interactions (loss of personalized touch, limited physical examination, and unable to reapproach physicians about forgotten issues); maintaining privacy (enhancing privacy and projecting voice enables others to hear); and supporting confidence in telemedicine (requiring established rapport with physicians, clinical stabilty of health, and ability to have in-person visits when necessary). Limitations: Interviews were conducted later in the pandemic when some nephrology care providers were using telemedicine infrequently. Conclusions: Patients receiving in-center hemodialysis adapted to telemedicine visits by their nephrologists in the context of the COVID-19 pandemic and observed its benefits. However, further considerations regarding communication, privacy, and physical assessments are necessary. Integrating telemedicine into future in-center hemodialysis care using a hybrid approach could potentially build trust, optimize communication, and augment care.

This study describes patients' perspectives on the use of telemedicine while receiving in-center hemodialysis during the coronavirus disease 2019 (COVID-19) pandemic. Data are derived from semistructured interviews with thirty-two patients from underserved populations (older, less educated, unemployed, persons of color). We identified 6 major themes including adapting to telemedicine, ensuring availability of the physicians, safeguarding against infection, straining communication and physical interactions, maintaining privacy, and supporting confidence in telemedicine. These findings suggest that patients receiving in-center hemodialysis adapted to telemedicine visits by their nephrologists in the context of the COVID-19 pandemic and observed its benefits. However, further considerations regarding communication, privacy, and physical assessments are necessary. Integrating telemedicine into future in-center hemodialysis care using a hybrid approach could potentially build trust, optimize communication, and augment care.

The Use of Telemedicine by US Nephrologists for In-Center Hemodialysis Care During the Pandemic: An Analysis of National Medicare Claims.

Rationale & Objective: Because of coronavirus disease 2019 (COVID-19), the US government issued emergency waivers in March 2020 that removed regulatory barriers around the use of telemedicine. For the first time, nephrologists were reimbursed for telemedicine care delivered during in-center hemodialysis. We examined the use of telemedicine for in-center hemodialysis during the first 16 months of the pandemic. Study Design: We ascertained telemedicine modifiers on nephrologist claims. We used multivariable regression to examine time trends and patient, dialysis facility, and geographic correlates of telemedicine use. We also examined whether the estimated effects of predictors of telemedicine use changed over time. Setting & Participants: US Medicare beneficiaries receiving in-center hemodialysis between March 1, 2020, and June 30, 2021. Exposures: Patient, geographic, and dialysis facility characteristics. Outcomes: The use of telehealth for in-center hemodialysis care. Analytic Approach: Retrospective cohort analysis. Results: Among 267,434 Medicare beneficiaries identified, the reported use of telemedicine peaked at 9% of patient-months in April 2020 and declined to 2% of patient-months by June 2021. Telemedicine use varied geographically and was more common in areas that were remote and socioeconomically disadvantaged. Patients were more likely to receive care by telemedicine in areas with higher incidence of COVID-19, although the predictive value of COVID-19 diminished later in the pandemic. Patients were more likely to receive care using telemedicine if they were at facilities with more staff, and the use of telemedicine varied by facility ownership type. Limitations: Limited reporting of telemedicine on claims could lead to underestimation of its use. Reported telemedicine use was higher in an analysis designed to address this limitation by focusing on patients whose physicians used telemedicine at least once during the pandemic. Conclusions: Some US nephrologists continued to use telemedicine for in-center hemodialysis throughout the pandemic, even as the association between COVID-19 incidence and telemedicine use diminished over time. These findings highlight unique challenges and opportunities to the future use of telemedicine in dialysis care.

Emergency waivers issued during the coronavirus disease 2019 pandemic enabled reimbursement to US nephrologists for telemedicine care delivered during in-center hemodialysis. Using modifiers from Medicare claims, we examined telemedicine use in the first 16 months of the pandemic. Reported telemedicine use peaked early in the pandemic and declined subsequently. Telemedicine use was more common in areas that were remote and socioeconomically disadvantaged and at facilities with more staff. Telemedicine use also varied by facility ownership type. Some nephrologists continued to use telemedicine for in-center hemodialysis throughout the pandemic, even as the association between coronavirus disease 2019 incidence and telemedicine use diminished over time. These findings highlight unique challenges and opportunities to the future use of telemedicine in dialysis care.

Plasmapheresis in ANCA-Associated Vasculitis with Active Kidney Involvement in the United States (2016-2020): A Cross-Sectional Study.

INTRODUCTION: Plasmapheresis is currently recommended when antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presents with severe kidney and/or lung involvement. This cross-sectional study aimed at describing characteristics of hospitalized patients diagnosed with AAV with severe kidney involvement undergoing plasmapheresis in the US. METHODS: We defined the study population as adults hospitalized for active kidney involvement with a new diagnosis of AAV (by subtype or unspecified). We established the cohort from the 2016-2020 National Inpatient Sample by ICD-10-CM codes. In this cross-sectional study, we described demographic and clinical characteristics, associated inpatient procedures, lengths of stay, hospital costs, and disposition at discharge comparing patients treated and not treated with plasmapheresis. RESULTS: We identified a total of 975 cases of hospitalized AAV with acute kidney involvement in the US treated by plasmapheresis over the 5-year period. Demographic characteristics of patients who received plasmapheresis were similar to those in patients who did not (n=5670). There were no regional differences in the proportion of patients who received plasmapheresis; however, plasmapheresis was deployed more frequently among patients admitted to urban teaching hospitals relative to rural and non-teaching hospitals. Cases treated with plasmapheresis were more likely to have had acute kidney injury (AKI) (96% vs. 90%, p=0.0007), AKI requiring dialysis (52% vs 16%, p<0.001), hypoxia (40% vs. 16%, p<0.0001), and respiratory failure requiring mechanical ventilation (13% vs. 3%, p=0.0003). CONCLUSION: During 2016-2020, plasmapheresis was deployed in approximately 20% of patients being admitted for AAV and acute kidney involvement in the US. As standards of care and practice evolve, the role of plasmapheresis in the management of AAV with acute kidney involvement will require further study.

Practical Considerations and Implementation of Sodium-Glucose Co-Transporter-2 Inhibitors in Chronic Kidney Disease: Who, When, and How? A Position Statement by Nephrologists.

INTRODUCTION: There remains an unmet need to reduce kidney and cardiovascular risk in patients with chronic kidney disease (CKD). This report is therefore intended to provide real-world clinical guidance to primary care providers on sodium-glucose co-transporter-2 (SGLT2) inhibitor use in patients with CKD, focusing on practical considerations. Initially developed as glucose-lowering drugs, SGLT2 inhibitors preserve kidney function and reduce risks of cardiovascular events and mortality. Clinical benefits of SGLT2 inhibitors in CKD have been demonstrated in multiple clinical trials, yet utilization in practice remains relatively low, likely due to the complexity of labeled indications (past and present) and misconceptions about SGLT2 inhibitors as a class. METHODS: A panel of 8 US-based nephrologists convened in August 2022 to develop consensus guidance for the primary care community surrounding risk assessment as well as initiation and implementation of SGLT2 inhibitors in patients with CKD. Here, we provide an adapted version of the Kidney Disease: Improving Global Outcomes (KDIGO) heatmap and a treatment-decision algorithm. CONCLUSIONS: We advocate SGLT2 inhibitors as co-first-line therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors, where RAAS inhibitor dose titration need not be completed before initiation of an SGLT2 inhibitor. In fact, SGLT2 inhibitor therapy may facilitate up-titration or maintenance of optimal RAAS inhibitor dosing. We describe potential strategies to aid implementation of an SGLT2 inhibitor in clinical practice, including improving education and awareness among care providers and patients and dispelling misconceptions about the safety of SGLT2 inhibitors. In summary, we support the use of SGLT2 inhibitors with RAAS inhibitors as co-first-line therapy in most patients with CKD.

Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52 weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO. Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax and absolute and percent changes in CAC score from baseline to week 52. Results: Among evaluable patients receiving placebo (n = 15), 300 mg (n = 20), or 600 mg (n = 20), average Cmax across visits was not quantifiable (<0.76 µM), 15 µM, and 46 µM, respectively. These results suggest a more-than-proportional increase, without accumulation, with a Cmax ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple Emax models described 80% maximal effect at exposures >21.9 µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32 µM). Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier NCT02966028.

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

BACKGROUND: In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics. We also conducted mediation analysis to formally assess the role of diuretics in the effects of intensive systolic BP lowering. RESULTS: At baseline, diuretics were prescribed in 46% and 48% of participants in standard and intensive systolic BP-lowering groups, respectively, and in 46% and 74% in the corresponding groups during the trial. The lower risk of cardiovascular end points in the intensive group (HR, 0.75; 95% confidence interval [CI], 0.64 to 0.89) persisted after adjustment for postrandomization time-varying diuretics use (HR, 0.74; 95% CI, 0.62 to 0.89). Across the entire study population, time-varying diuretics use was not associated with cardiovascular end points (compared with no diuretics, HR for thiazide type, 0.89; 95% CI, 0.73 to 1.10, and loop/K sparing, 1.29; 95% CI, 0.97 to 1.73). However, thiazide-type diuretics were associated with lower risk of cardiovascular end points in the intensive (HR, 0.62; 95% CI, 0.46 to 0.85) but not in the standard (HR, 1.07; 95% CI, 0.82 to 1.39) group. In mediation analysis, HRs for total effect, direct effect (not mediated through diuretics use), and indirect effect (mediated through diuretics) of the intervention on cardiovascular end points were 0.66 (95% CI, 0.54 to 0.79), 0.67 (95% CI, 0.54 to 0.81), and 0.98 (95% CI, 0.88 to 1.10), respectively. The results were largely similar for all-cause mortality. CONCLUSIONS: The favorable effects of intensive systolic BP lowering on cardiovascular end points and all-cause mortality in SPRINT were independent of and not mediated by time-varying diuretics use. However, thiazide-type diuretics use associated with benefit if intensive systolic BP lowering was targeted.