Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

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: 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) of 20-70mL/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 end point that comprised a sustained 50% decrease in eGFR, dialysis, kidney transplant, or eGFR<15mL/min/1.73m2. ANALYTICAL APPROACH: We divided Klotho into 6 groups to account for its nonnormal 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 demographic characteristics, kidney function, cardiovascular risk factors, sample age, and FGF23. RESULTS: Mean eGFR was 42mL/min/1.73m2, and median Klotho concentration was 0.31ng/mL (IQR, 0.10-3.27ng/mL). When compared with the lowest Klotho group, survival (HR, 0.77; 95% 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 the potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho concentration 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. PLAIN-LANGUAGE SUMMARY: Klotho is a protein that is vital to mineral metabolism and aging and may protect against cardiovascular disease. Klotho levels decrease in chronic kidney disease (CKD), but the association between Klotho and clinical outcomes in CKD remains uncertain. In a prospective cohort study of more than 1,000 people with CKD, circulating Klotho levels were not associated with kidney disease progression, cardiovascular outcomes, or mortality. These results suggest that the decrease in circulating Klotho levels in CKD does not play a prominent role in the development of poor clinical outcomes.

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.

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.

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.

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.

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.

Pulmonary Hypertension Subtypes and Mortality in CKD.

RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN: Observational retrospective cohort study. SETTING & PARTICIPANTS: We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES: Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES: All-cause mortality. ANALYTICAL APPROACH: Multivariable Cox proportional hazards analysis. RESULTS: In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS: The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS: In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.

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.

Association of post-discharge specialty outpatient visits with readmissions and mortality in high-risk heart failure patients.

Heart failure (HF) outcomes are especially poor in high-risk patients with certain comorbidities including diabetes mellitus (DM), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). Whether early specialty or primary care provider (PCP) follow-up after HF discharge affects outcomes in high-risk patients is unknown. METHODS: We analyzed patients discharged from a Get With The Guidelines HF-participating hospital from 2007-2012 with linked Medicare claims to investigate the association of medical specialist visit within 14 days of discharge stratified by comorbidity with the primary outcome of 90-day HF readmission. Secondary outcomes included 90-day and 1-year all-cause mortality. RESULTS: Out of 33,243 patients, 39.4% had DM, 19.8% had CKD, 30.0% had COPD, and 36.3% had no key comorbidity. Nephrologist visit in patients with CKD was associated with a 35% reduction in 90-day HF readmission (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.49-0.85). Pulmonologist visit in patients with COPD was associated with a 29% reduction in 90-day HF readmission (HR 0.71, 95% CI 0.55-0.91). In patients with no key comorbidity, PCP and Cardiologist visits were associated with decreased 90-day mortality (HR for PCP 0.79, 95% CI 0.66-0.94; HR for Cardiologist 0.78, 95% CI 0.63-0.96). In patients with DM, Endocrinologist visit was associated with a 42% reduction of 90-day mortality (HR 0.58, 95% CI 0.34-0.99). CONCLUSIONS: Specialist and PCP visit in the immediate post-discharge period may improve 90-day HF readmission and mortality in certain high-risk groups of patients with HF.

Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD.

RATIONALE & OBJECTIVE: An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789). EXPOSURE: Baseline carboxy-terminal FGF-23 (cFGF-23) level. OUTCOMES: All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years. ANALYTICAL APPROACH: We assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort. RESULTS: Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome. LIMITATIONS: Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds. CONCLUSIONS: Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.

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.

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

Placebo-controlled trials of sodium-glucose co-transporter-2 inhibitors demonstrate kidney and cardiovascular benefits for patients with type 2 diabetes and chronic kidney disease (CKD). We used real-world data to compare the kidney and cardiovascular effectiveness of empagliflozin to dipeptidyl peptidase-4 inhibitors (DPP4is), 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 the outcomes for empagliflozin and DPP4i initiators with type 2 diabetes between 2016 and 2020. The primary composite kidney outcome included 40% estimated glomerular filtration rate decrease, incident end-stage kidney disease, or all-cause mortality through 2 years or censoring. We also assessed cardiovascular and safety outcomes. Of 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 (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65 to 0.87) than DPP4is. The risks for mortality (HR 0.76, 95% CI 0.62 to 0.92) and a cardiovascular composite of stroke, myocardial infarction, or all-cause mortality (HR 0.81, 95% CI 0.70 to 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 to 1.88). Empagliflozin was associated with a lower risk of the primary outcome in patients with CKD (HR 0.68, 95% CI 0.53 to 0.88) and those without CKD (HR 0.79, 95% CI 0.67 to 0.94). In conclusion, the initiation of empagliflozin was associated with a significantly lower risk of kidney and cardiovascular outcomes than DPP4is over a median of just over 1 year. The association with a lower risk for clinical outcomes was apparent even for patients without known CKD at baseline.

Concordance With Screening and Treatment Guidelines for Chronic Kidney Disease in Type 2 Diabetes.

Importance: Chronic kidney disease (CKD) is an often-asymptomatic complication of type 2 diabetes (T2D) that requires annual screening to diagnose. Patient-level factors linked to inadequate screening and treatment can inform implementation strategies to facilitate guideline-recommended CKD care. Objective: To identify risk factors for nonconcordance with guideline-recommended CKD screening and treatment in patients with T2D. Design, Setting, and Participants: This retrospective cohort study was performed at 20 health care systems contributing data to the US National Patient-Centered Clinical Research Network. To evaluate concordance with CKD screening guidelines, adults with an outpatient clinician visit linked to T2D diagnosis between January 1, 2015, and December 31, 2020, and without known CKD were included. A separate analysis reviewed prescription of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in adults with CKD (estimated glomerular filtration rate [eGFR] of 30-90 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio [UACR] of 200-5000 mg/g) and an outpatient clinician visit for T2D between October 1, 2019, and December 31, 2020. Data were analyzed from July 8, 2022, through June 22, 2023. Exposures: Demographics, lifestyle factors, comorbidities, medications, and laboratory results. Main Outcomes and Measures: Screening required measurement of creatinine levels and UACR within 15 months of the index visit. Treatment reflected prescription of ACEIs or ARBs and SGLT2 inhibitors within 12 months before or 6 months following the index visit. Results: Concordance with CKD screening guidelines was assessed in 316 234 adults (median age, 59 [IQR, 50-67] years), of whom 51.5% were women; 21.7%, Black; 10.3%, Hispanic; and 67.6%, White. Only 24.9% received creatinine and UACR screening, 56.5% received 1 screening measurement, and 18.6% received neither. Hispanic ethnicity was associated with lack of screening (relative risk [RR], 1.16 [95% CI, 1.14-1.18]). In contrast, heart failure, peripheral arterial disease, and hypertension were associated with a lower risk of nonconcordance. In 4215 patients with CKD and albuminuria, 3288 (78.0%) received an ACEI or ARB; 194 (4.6%), an SGLT2 inhibitor; and 885 (21.0%), neither therapy. Peripheral arterial disease and lower eGFR were associated with lack of CKD treatment, while diuretic or statin prescription and hypertension were associated with treatment. Conclusions and Relevance: In this cohort study of patients with T2D, fewer than one-quarter received recommended CKD screening. In patients with CKD and albuminuria, 21.0% did not receive an SGLT2 inhibitor or an ACEI or an ARB, despite compelling indications. Patient-level factors may inform implementation strategies to improve CKD screening and treatment in people with T2D.

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.

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.