Kidney and Cardiovascular Effectiveness of Empagliflozin Compared to Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes.

Placebo-controlled trials of sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrate kidney and cardiovascular benefits for people with type 2 diabetes (T2D) and chronic kidney disease (CKD). We used real-world data to compare the kidney and cardiovascular effectiveness of empagliflozin to dipeptidyl peptidase-4 inhibitors (DPP4i), a commonly prescribed antiglycemic medication, in a diverse population with and without CKD. Using electronic health record data from 20 large US health systems, we leveraged propensity overlap weighting to compare outcomes for empagliflozin and DPP4i initiators with T2D between 2016 and 2020. The primary composite kidney outcome included 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease (ESKD), or all-cause mortality through 2 years or censoring. We also assessed cardiovascular and safety outcomes. Among 62,197 new users, 20,279 initiated empagliflozin, and 41,918 initiated DPP4i. Over a median follow-up of 1.1 years, empagliflozin prescription was associated with a lower risk of the primary outcome (HR 0.75, 95% CI 0.65-0.87) compared with DPP4i. Risks for mortality (HR 0.76, 95% CI 0.62-0.92) and a cardiovascular composite of stroke, myocardial infarction, or all-cause mortality (HR 0.81, 95% CI 0.70-0.95) were also lower for empagliflozin initiators. No difference in heart failure hospitalization risk between groups was observed. Genital mycotic infections were more common in patients prescribed empagliflozin (HR 1.72, 95% CI 1.58 - 1.88). Empagliflozin was associated with a lower risk of the primary outcome in patients with CKD (HR 0.68, 95% CI 0.53-0.88) and those without CKD (HR 0.79, 95% CI 0.67 - 0.94). In conclusion, initiation of empagliflozin was associated with a significantly lower risk of kidney and cardiovascular outcomes compared with DPP4i over a median of just over 1 year. The association with a lower risk for clinical outcomes was apparent even for people without known CKD at baseline.

Klotho and Clinical Outcomes in CKD.

RATIONALE & OBJECTIVE: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1088 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rate (eGFR) 20-70 ml/min/1.73m2. EXPOSURE: Plasma Klotho level at the year-1 study visit. OUTCOMES: 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney endpoint comprised of a sustained 50% decline in eGFR, dialysis, kidney transplantation, or eGFR <15 ml/min/1.73 m2. ANALYTICAL APPROACH: We divided Klotho into six groups to account for its non-normal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups. We sequentially adjusted for demographics, kidney function, cardiovascular risk factors, sample age, and FGF23. RESULTS: Mean eGFR was 42 ml/min/1.73m2, and median Klotho was 0.31 ng/ml (interquartile range 0.10-3.27 ng/ml). When compared to the lowest Klotho group, survival (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.32-1.89), heart failure hospitalization (HR 1.10, 95% CI 0.38-3.17), atherosclerotic cardiovascular events (HR 1.19, 95% CI 0.57-2.52), and CKD progression (HR 1.05, 95% CI 0.58-1.91) did not differ in the high Klotho group. In contrast, FGF23 was significantly associated with mortality and heart failure hospitalization independent of Klotho levels. LIMITATIONS: Despite adjustments, we cannot exclude potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho may not capture Klotho patterns over time. CONCLUSIONS: In a large, diverse, well-characterized CKD cohort, Klotho was not associated with clinical outcomes, and Klotho deficiency did not confound the association of FGF23 with mortality or heart failure hospitalization.

FGF23 and klotho at the intersection of kidney and cardiovascular disease.

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). As CKD progresses, CKD-specific risk factors, such as disordered mineral homeostasis, amplify traditional cardiovascular risk factors. Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis by activating complexes of FGF receptors and transmembrane klotho co-receptors. A soluble form of klotho also acts as a 'portable' FGF23 co-receptor in tissues that do not express klotho. In progressive CKD, rising circulating FGF23 levels in combination with decreasing kidney expression of klotho results in klotho-independent effects of FGF23 on the heart that promote left ventricular hypertrophy, heart failure, atrial fibrillation and death. Emerging data suggest that soluble klotho might mitigate some of these effects via several candidate mechanisms. More research is needed to investigate FGF23 excess and klotho deficiency in specific cardiovascular complications of CKD, but the pathophysiological primacy of FGF23 excess versus klotho deficiency might never be precisely resolved, given the entangled feedback loops that they share. Therefore, randomized trials should prioritize clinical practicality over scientific certainty by targeting disordered mineral homeostasis holistically in an effort to improve cardiovascular outcomes in patients with CKD.

Plasma Serotonin and Cardiovascular Outcomes in Chronic Kidney Disease.

Background Platelet-poor plasma serotonin levels are associated with adverse cardiovascular outcomes. Although plasma serotonin levels increase in chronic kidney disease, the cardiovascular implications remain unknown. Methods and Results In 1114 participants from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we evaluated the association between plasma serotonin, categorized as undetectable, intermediate, and high (≥20 ng/mL) levels, and cross-sectional findings on echocardiography, including left ventricular hypertrophy, left ventricular ejection fraction, and pulmonary hypertension. We also analyzed whether serotonin was associated with time-to-event cardiovascular outcomes, including heart failure hospitalization and atherosclerotic cardiovascular disease (ASCVD) events, in addition to mortality. Because selective serotonin reuptake inhibitors decrease plasma serotonin levels, we specifically evaluated the influence of selective serotonin reuptake inhibitor use in the relationship between serotonin and outcomes. Plasma serotonin level inversely correlated with estimated glomerular filtration rate and directly correlated with blood pressure. High plasma serotonin was associated with left ventricular hypertrophy (adjusted odds ratio, 2.74 [95% CI, 1.11-7.41]). In contrast, undetectable plasma serotonin level was associated with the highest risk of heart failure (adjusted hazard ratio [HR], 2.26 [95% CI, 1.40-3.66]) and ASCVD events (adjusted HR, 1.96 [95% CI, 1.15-3.32]). Conclusions In a large chronic kidney disease cohort, plasma serotonin levels correlated with blood pressure, and elevated serotonin levels were associated with left ventricular hypertrophy. In contrast, undetectable plasma serotonin was associated with the highest risk of heart failure and ASCVD events.

Association of Chronic Renal Insufficiency with Inhospital Outcomes in Primary Heart Failure Hospitalizations (Insights from the National Inpatient Sample 2004 to 2018).

Chronic kidney disease (CKD) is a major co-morbidity in patients with heart failure (HF). There are limited contemporary data characterizing the clinical profile, inhospital outcomes, and resource use in patients hospitalized for HF with co-morbid CKD. We utilized a nationally representative population to address the knowledge gap. We examined the National Inpatient Sample 2004 to 2018 database to study the co-morbid profile, in-hospital mortality, clinical resource utilization, healthcare cost, and length of stay (LOS) in primary adult HF hospitalizations stratified by presence versus absence of a diagnosis codes of CKD. There were a total of 16,050,301 adult hospitalizations with a primary HF diagnosis from January 1, 2004, to December 31, 2018. Of these, 428,175 (33.81%) had CKD; 1,110,778 (6.92%) had end-stage kidney disease (ESKD); and 9,511,348 (59.25%) had no diagnosis of CKD. Patients with hospitalizations for HF with ESKD were younger (mean age 65.4 years) compared with those without ESKD. In multivariable analysis, those with CKD had higher odds of inhospital mortality (2.82% vs 3.57%, adjusted odds ratio [aOR] 1.30, confidence interval [CI] 1.28 to 1.26, p <0.001), cardiogenic shock (1.01% vs 1.79% aOR 2.00, CI 1.95 to 2.05, p <0.001), and the need for mechanical circulatory support (0.4% vs 0.5%, aOR 1.51, 1.44 to 1.57, p <0.001) compared with those without CKD. In multivariable analysis, those with ESKD had higher odds of inhospital mortality (2.82% vs 3.84%, aOR 2.07, CI 2.01 to 2.12, p <0.001), need for invasive mechanical ventilation use (2.04% vs 3.94%, aOR 1.79, CI 1.75 to 1.84, p <0.001), cardiac arrest (0.72% vs 1.54%, aOR 2.09, CI 2.00 to 2.17, p <0.001), longer LOS (Adjusted mean difference 1.48, 1.44 to 1.53, p <0.001) and higher inflation-adjusted cost (Adjusted mean difference 3,411.63, CI 3,238.35 to 3,584.91, p <0.001) compared with those without CKD. CKD and ESKD affected about 40.7% of all primary HF hospitalizations from 2004 to 2018. The inhospital mortality, clinical complications, LOS, and inflation-adjusted cost were higher in hospitalized patients with ESKD compared with patients with and without CKD. In addition, compared with those without CKD, hospitalized patients with CKD had higher inhospital mortality, clinical complications, LOS, and inflation-adjusted cost compared with patients with no diagnosis of CKD.

Noninvasive Risk Score to Screen for Pulmonary Hypertension With Elevated Pulmonary Vascular Resistance in Diseases of Chronic Volume Overload.

Volume overload promotes pulmonary hypertension (PH) through pulmonary venous hypertension. However, PH with elevated pulmonary vascular resistance (hereafter PH-PVR) may develop in patients with diseases of volume overload, such as heart failure or chronic kidney disease (CKD). In such cases, volume management alone may be insufficient to slow PH progression. An accurate, noninvasive method to screen for PH-PVR in these diseases would facilitate early targeted therapy. We integrated invasive hemodynamic and echocardiography data collected from a single-center clinical cohort and identified patients with CKD or heart failure at the time of assessment. We applied penalized regression to derive a risk score of clinical parameters and echocardiography data associated with PH-PVR and categorized patients into low- (≤5 points), intermediate- (6-10 points), or high-risk (>10 points) groups. Using an internal validation strategy, we evaluated the ability of this risk score to predict PH-PVR and determined the association of this risk classification with 3-year all-cause mortality. Of 2422 patients, 42.4% had PH-PVR. In adjusted analyses, tricuspid regurgitant velocity, right ventricular function, BMI, heart rate, and hemoglobin most strongly associated with PH-PVR. The risk score significantly associated with PH-PVR (age-adjusted odds ratio 11.69 for the highest-risk group, 95% confidence interval [CI] 6.54-20.92). The high-risk group also associated with a significantly higher risk of 3-year all-cause mortality in adjusted analyses (hazard ratio 1.85, 95% CI 1.50-2.27). In conclusion, a noninvasive risk score derived from echocardiography and clinical parameters significantly associated with PH-PVR and all-cause mortality in a cohort of patients with CKD and heart failure.

Hypoxia signaling in renal pericytes-is it safe to activate?

While excitement has grown for the use of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors for treating renal anemia, multiple preclinical studies have shown the complex and cell-type-dependent roles of HIFs in kidney disease pathogenesis, including renal fibrosis. Pan et al. now clearly show that activating the HIF signaling in the Gli1-lineage myofibroblasts restores erythropoietin production while not adversely affecting matrix production, mitigating the concerns of exacerbated fibrosis by HIF prolyl hydroxylase inhibitors.

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Statins and atherosclerotic cardiovascular outcomes in patients on incident dialysis and with atherosclerotic heart disease.

Statins failed to reduce cardiovascular (CV) events in trials of patients on dialysis. However, trial populations used criteria that often excluded those with atherosclerotic heart disease (ASHD), in whom statins have the greatest benefit, and included outcome composites with high rates of nonatherosclerotic CV events that may not be modified by statins. Here, we study whether statin use associates with lower atherosclerotic CV risk among patients with known ASHD on dialysis, including in those likely to receive a kidney transplant, a group excluded within trials but with lower competing mortality risks. METHODS: Using data from the United States Renal Data System including Medicare claims, we identified adults initiating dialysis with ASHD. We matched statin users 1:1 to statin nonusers with propensity scores incorporating hard matches for age and kidney transplant listing status. Using Cox models, we evaluated associations of statin use with the primary composite of fatal/nonfatal myocardial infarction and stroke (including within prespecified subgroups of younger age [<50 years] and waitlisting status); secondary outcomes included all-cause mortality and the composite of all-cause mortality, nonfatal myocardial infarction, or stroke. RESULTS: Of 197,716 patients with ASHD, 47,562 (24%) were consistent statin users from which we created 46,186 matched pairs. Over a median 662 days, statin users had similar risk of fatal/nonfatal myocardial infarction or stroke overall (hazard ratio [HR] 1.00, 95% CI 0.97-1.02), or in subgroups (age< 50 years [HR = 1.05, 95% CI 0.95-1.17]; waitlisted for kidney transplant [HR 0.99, 95% CI 0.97-1.02]). Statin use was modestly associated with lower all-cause mortality (HR 0.96, 95% CI 0.94-0.98; E value = 1.21) and, similarly, a modest lower composite risk of all-cause mortality, nonfatal myocardial infarction, or stroke over the first 2 years (HR 0.90, 95% CI 0.88-0.91) but attenuated thereafter (HR 0.98, 95% CI 0.96-1.01). CONCLUSIONS: Our large observational analyses are consistent with trials in more selected populations and suggest that statins may not meaningfully reduce atherosclerotic CV events even among incident dialysis patients with established ASHD and those likely to receive kidney transplants.

Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States.

RATIONALE & OBJECTIVE: Underlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes. STUDY DESIGN: Retrospective cohort study. SETTINGS & PARTICIPANTS: 4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States. PREDICTOR(S): Presence (vs absence) of pre-existing kidney disease. OUTCOME(S): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary). ANALYTICAL APPROACH: We used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations. RESULTS: Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]). LIMITATIONS: Potential residual confounding. CONCLUSIONS: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population.

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis.

RATIONALE & OBJECTIVE: Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. STUDY DESIGN: Multicenter, pragmatic, cluster-randomized clinical trial. SETTING & PARTICIPANTS: HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis. INTERVENTION: Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL). OUTCOMES: Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. RESULTS: The trial is currently enrolling. LIMITATIONS: HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. CONCLUSIONS: HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04095039.

Echocardiography to Screen for Pulmonary Hypertension in CKD.

INTRODUCTION: Pulmonary hypertension (PH) is a common yet incompletely understood complication of chronic kidney disease (CKD). Although transthoracic echocardiogram is commonly used to noninvasively estimate PH, it has not been validated in a CKD population. We investigated the utility of this diagnostic tool for CKD-associated PH in a large right heart catheterization (RHC) cohort. METHODS: We reviewed RHC and echocardiography data in 4036 patients (1714 with CKD) obtained between 2011 and 2014 at a single center. We used multivariate regression to determine the associations of echocardiography measurements with PH, and evaluated whether estimated glomerular filtration rate (eGFR) modified these associations. Using internal validation, we sequentially added measurements to predictive models and analyzed the incremental predictive performance using the change in the area under the receiver operating characteristic curve (ΔAUC) and net reclassification improvement. RESULTS: The echocardiography measurements most strongly associated with the diagnosis of PH included tricuspid regurgitant velocity (TRV), tricuspid annular plane systolic excursion (TAPSE), right atrial pressure, diastolic dysfunction, and right ventricular function. Among these measurements, eGFR significantly modified the associations of TAPSE and diastolic dysfunction with the diagnosis of PH. The model consisting of a combination of TRV, right atrial pressure, and TAPSE most accurately predicted the diagnosis of PH in a CKD population (AUC 0.82). CONCLUSIONS: The optimal model to predict PH diagnosis included TRV, right atrial pressure, and TAPSE. Since TAPSE more strongly associated with PH in the CKD population, these findings support a CKD-specific approach to the development of noninvasive screening algorithms for PH.

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

Prescribing rates and characteristics of recipients of tenofovir-containing regimens before and after market entry of tenofovir alafenamide.

BACKGROUND: Tenofovir alafenamide (TAF) is a new formulation of tenofovir disoproxil fumarate (TDF) that was approved in 2015. While clinical trial evidence suggests that TAF has more favorable outcomes related to kidney injury and loss of bone mineral density, TAF also leads to higher lipid levels compared with TDF. OBJECTIVES: To (a) determine prescribing rates of TDF and TAF among new recipients from 2014 to 2018 in a large academic health system and (b) compare baseline patient characteristics of those newly prescribed TDF versus TAF before and after the approval of TAF in November 2015. METHODS: Electronic health record data were used to identify new recipients of TDF or TAF from 2014 to 2018 and describe their total monthly TDF and TAF prescriptions by indication. Patient characteristics were compared among new recipients of TDF before November 2015, new recipients of TDF after November 2015, and new recipients of TAF. RESULTS: Monthly TAF prescribing rates increased to match TDF prescribing rates by April 2018 (82 vs. 88 prescriptions per month). TAF recipients and new recipients of TDF before November 2015 had similar racial distributions; both of these groups were more likely to be Black compared with new recipients of TDF after November 2015 (55% and 53% vs. 37%; P < 0.0001). TAF recipients also tended to have more comorbidities, including chronic kidney disease (7% vs. 2% and 2%; P < 0.0001), hepatitis C virus (8% vs. 5% and 3%; P < 0.0001), diabetes (13% vs. 5% and 6%; P < 0.0001), hypertension (27% vs. 13% and 13%; P < 0.0001), coronary artery disease (5% vs. 3% and 2%; P < 0.0001), hyperlipidemia (21% vs. 6% and 7%; P < 0.0001), and congestive heart failure (3% vs. 1% and 1%; P < 0.0001), compared with both new recipients of TDF before and after November 2015. CONCLUSIONS: TAF prescribing rates grew substantially in the 2.5 years after FDA approval. TAF is being prescribed more often than TDF in patients with chronic kidney disease and in patients with cardiovascular disease, suggesting that prescribers may be prioritizing the kidney safety profile over the effect on lipids. DISCLOSURES: This work was supported by the Duke Clinical Research Institute Executive Director's Pathway for Supplemental Funding. The research team received additional support from the National Institute of Diabetes, Digestive, and Kidney Disease R01DK112258 and P01DK056492 (CW) and from the National Institute of Allergy and Infectious Diseases 5T32AI100851 (MHM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Hung reports past employment by Blue Cross Blue Shield Association and CVS Health and a grant from Pharmaceutical Research and Manufacturers of America (PhRMA), unrelated to this work. The other authors have nothing to disclose. This work was accepted as a poster presentation for the AMCP Nexus 2020 Virtual, October 19-23, 2020.

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.

Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.

Therapeutic options for chronic kidney disease-associated pulmonary hypertension.

PURPOSE OF REVIEW: Pulmonary hypertension is a common and devastating complication of chronic kidney disease (CKD). Traditionally considered a consequence of volume overload, recent findings now expand this paradigm. These novel mechanisms herald new treatment options. This review summarizes the current evidence to provide a theoretical model of the contributing factors for CKD-associated pulmonary hypertension. Along this framework, we highlight current and emerging therapeutic strategies for each putative factor. RECENT FINDINGS: A series of retrospective studies of right heart catheterization data provide insights into the potential hemodynamic profile of CKD-associated pulmonary hypertension. These studies suggest that elevated pulmonary vascular resistance may commonly contribute to pulmonary hypertension. In addition, preclinical models implicate an increasing array of CKD-associated factors which influence pulmonary vascular biology. Many of these factors also adversely affect kidney function and CKD progression. Clinical trial and other prospective data for treatments of CKD-associated pulmonary hypertension remain limited. SUMMARY: Volume overload and left-ventricular dysfunction are the predominant focus of CKD-associated pulmonary hypertension treatment for most patients. However, new findings suggest that treatments targeting pulmonary vascular vasoconstriction and remodeling may be promising treatment options for select patients. Clinical trials are needed for all therapeutic strategies for CKD-associated pulmonary hypertension.