Factors Associated With an Electronic Health Record-Based Definition of Postacute Sequelae of COVID-19 in Patients With Systemic Autoimmune Rheumatic Disease.

OBJECTIVE: Many individuals with rheumatic disease are at higher risk for severe acute coronavirus disease 2019 (COVID-19). We aimed to evaluate risk factors for postacute sequelae of COVID-19 (PASC) using an electronic health record (EHR)-based definition. METHODS: We identified patients with prevalent rheumatic diseases and COVID-19 within the Mass General Brigham healthcare system. PASC was defined by the International Classification of Diseases, 10th revision (ICD-10) codes, relevant labs, vital signs, and medications at least 30 days following the first COVID-19 infection. Patients were followed until the earliest of incident PASC, repeat COVID-19 infection, 1 year of follow-up, death, or February 19, 2023. We used multivariable Cox regression to estimate the association of baseline characteristics with PASC risk. RESULTS: Among 2459 patients (76.37% female, mean age 57.4 years), the most common incident PASC manifestations were cough (14.56%), dyspnea (12.36%), constipation (11.39%), and fatigue (10.70%). Serious manifestations including acute coronary disease (4.43%), thromboembolism (3.09%), hypoxemia (3.09%), stroke (1.75%), and myocarditis (0.12%) were rare. The Delta wave (adjusted hazard ratio [aHR] 0.63, 95% CI 0.49-0.82) and Omicron era (aHR 0.50, 95% CI 0.41-0.62) were associated with lower risk of PASC than the early pandemic period (March 2020-June 2021). Age, obesity, comorbidity burden, race, and hospitalization for acute COVID-19 infection were associated with greater risk of PASC. Glucocorticoid (GC) use (aHR 1.19, 95% CI 1.05-1.34 compared to no use) was associated with greater risk of PASC. CONCLUSION: Among patients with rheumatic diseases, following their first COVID-19 infection, we found a decreased risk of PASC over calendar time using an EHR-based definition. Aside from GCs, no specific immunomodulatory medications were associated with increased risk, and risk factors were otherwise similar to those seen in the general population.

Effectiveness of a fourth dose of COVID-19 mRNA vaccine in patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs: an emulated target trial.

BACKGROUND: Patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs (DMARDs) might have blunted responses to COVID-19 vaccines. The initial mRNA vaccine series is defined as three doses for this population and a fourth booster dose is recommended. The effectiveness of the fourth dose in patients with systemic autoimmune rheumatic diseases using DMARDs is not well established. We aimed to assess the effectiveness of receiving versus not receiving a fourth dose of COVID-19 mRNA vaccine using a target trial framework, in a cohort of patients with systemic autoimmune rheumatic diseases receiving DMARD therapy. METHODS: We conducted an emulated target trial using observational data from the Mass General Brigham health-care system to compare receiving versus not receiving a fourth mRNA vaccine dose. Analysed patients had systemic autoimmune rheumatic diseases, were prescribed DMARDs, and were eligible for a fourth dose of BNT162b2 or mRNA-1273 vaccines between Jan 16 and June 11, 2022. To account for temporal changes, the study period was divided into 1-week intervals. Fourth-dose-exposed patients were included in a 1-week interval if they received a fourth mRNA dose in that interval; fourth-dose-unexposed patients were eligible for but had not received the fourth dose of the vaccine. The primary outcome was a SARS-CoV-2 infection; the secondary outcome was severe SARS-CoV-2 infection (ie, admission to hospital or death within -3 to +14 days of a positive test). We assessed the effectiveness of the fourth dose using time-stratified, overlap propensity score-weighted Cox regression models. FINDINGS: We included 4305 patients, 3126 of whom received a fourth dose of vaccine and 1179 who had not. The median follow-up time was 135 days (IQR 112-154) among patients who had received a fourth dose and 65 days (30-156) among patients who had not received a fourth dose. After overlap weighting in both groups, 1863 (72·7%) of 2563 participants were women, 700 (27·3%) were men, and 2242 (87·5%) were White. Rheumatoid arthritis was present in 1392 (54·3%) of 2563 participants; the most frequent treatments were conventional synthetic DMARDs (1489 [58·1%]) or biological DMARDs (1007 [39·3%]). SARS-CoV-2 infection risk was lower among patients receiving versus not receiving a fourth dose of vaccine (HR 0·59 [95% CI 0·47-0·74]). A fourth dose reduced the risk of admission to hospital or death within -3 to +14 days of SARS-CoV-2 infection (0·35 [0·14-0·85]). INTERPRETATION: In this emulated target trial, a fourth dose of COVID-19 mRNA vaccine reduced the risk of SARS-CoV-2 infection and severe COVID-19 among patients with systemic autoimmune rheumatic diseases using DMARDs during the Omicron era. Patients with systemic autoimmune rheumatic diseases should be encouraged to remain up-to-date with COVID-19 vaccinations. FUNDING: The National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Incidence, Microbiological Studies, and Factors Associated With Prosthetic Joint Infection After Total Knee Arthroplasty.

Importance: Despite the frequency of total knee arthroplasty (TKA) and clinical implications of prosthetic joint infections (PJIs), knowledge gaps remain concerning the incidence, microbiological study results, and factors associated with these infections. Objectives: To identify the incidence rates, organisms isolated from microbiological studies, and patient and surgical factors of PJI occurring early, delayed, and late after primary TKA. Design, Setting, and Participants: This cohort study obtained data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse on patients who underwent elective primary TKA in the VA system between October 1, 1999, and September 30, 2019, and had at least 1 year of care in the VA prior to TKA. Patients who met these criteria were included in the overall cohort, and patients with linked Veterans Affairs Surgical Quality Improvement Program (VASQIP) data composed the VASQIP cohort. Data were analyzed between December 9, 2021, and September 18, 2023. Exposures: Primary TKA as well as demographic, clinical, and perioperative factors. Main Outcomes and Measures: Incident hospitalization with early, delayed, or late PJI. Incidence rate (events per 10 000 person-months) was measured in 3 postoperative periods: early (≤3 months), delayed (between >3 and ≤12 months), and late (>12 months). Unadjusted Poisson regression was used to estimate incidence rate ratios (IRRs) with 95% CIs of early and delayed PJI compared with late PJI. The frequency of organisms isolated from synovial or operative tissue culture results of PJIs during each postoperative period was identified. A piecewise exponential parametric survival model was used to estimate IRRs with 95% CIs associated with demographic and clinical factors in each postoperative period. Results: The 79 367 patients (median (IQR) age of 65 (60-71) years) in the overall cohort who underwent primary TKA included 75 274 males (94.8%). A total of 1599 PJIs (2.0%) were identified. The incidence rate of PJI was higher in the early (26.8 [95% CI, 24.8-29.0] events per 10 000 person-months; IRR, 20.7 [95% CI, 18.5-23.1]) and delayed periods (5.4 [95% CI, 4.9-6.0] events per 10 000 person-months; IRR, 4.2 [95% CI, 3.7-4.8]) vs the late postoperative period (1.3 events per 10 000 person-months). Staphylococcus aureus was the most common organism isolated overall (489 [33.2%]); however, gram-negative infections were isolated in 15.4% (86) of early PJIs. In multivariable analyses, hepatitis C virus infection, peripheral artery disease, and autoimmune inflammatory arthritis were associated with PJI across all postoperative periods. Diabetes, chronic kidney disease, and obesity (body mass index of ≥30) were not associated factors. Other period-specific factors were identified. Conclusions and Relevance: This cohort study found that incidence rates of PJIs were higher in the early and delayed vs late post-TKA period; there were differences in microbiological cultures and factors associated with each postoperative period. These findings have implications for postoperative antibiotic use, stratification of PJI risk according to postoperative time, and PJI risk factor modification.

Steroid sparing in vasculitis: Myth or reality?

Glucocorticoids are the cornerstone of therapy for all forms of vasculitis. However, glucocorticoid treatment carries with it the risk of glucocorticoid toxicity. Recent research efforts in vasculitis have emphasized investigation into strategies that reduce glucocorticoid exposure. These strategies include the adoption of rapid-acting steroid-sparing agents, reduced-dose glucocorticoid induction regimens, the early introduction of steroid-sparing agents for maintenance therapy, and the extension of maintenance therapy to minimize glucocorticoid exposure associated with disease relapse. These are critical advances to move us toward the goal of glucocorticoid-free treatment of vasculitis. The evidence supporting each of these strategies and directions for future research are explored.

Comparative Effectiveness of Rituximab- Versus Cyclophosphamide-Based Remission Induction Strategies in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis for the Risk of Kidney Failure and Mortality.

OBJECTIVE: To compare rituximab- versus cyclophosphamide-based remission induction strategies for the long-term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a real-world cohort. METHODS: We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3-ANCA+ and myeloperoxidase (MPO)-ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score-matched analyses to assess the association of rituximab- versus cyclophosphamide-based treatment strategies with the composite outcome of kidney failure or death. RESULTS: Of 595 included patients, 352 patients (~60%) received rituximab-based and 243 patients (~40%) received cyclophosphamide-based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO-ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2 ). There were 133 events at 5 years, and the incidence rates in rituximab- and cyclophosphamide-based regimens were 6.8 and 6.1 per 100 person-years, respectively. The risk of kidney failure or death was similar in both groups in multivariable-adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55-1.93]) and in propensity score-matched analyses (HR 1.05 [95% CI 0.55-1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. CONCLUSION: Rituximab- and cyclophosphamide-based remission induction strategies for AAV are associated with similar risks of kidney failure and death.

Longitudinal Patterns of Renal Function in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: A spectrum of chronic kidney disease (CKD) and end-stage renal disease (ESRD) may occur in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The longitudinal trajectory of renal function in AAV is poorly understood. METHODS: Patients with ≥2 creatinine measurements, including at baseline (±30 days of treatment initiation), were included from the Mass General Brigham AAV Cohort. We calculated estimated glomerular filtration rate (eGFR). We incorporated longitudinal changes in eGFR into a group-based trajectory model to identify patients with similar patterns of change in renal function. The chi-square test and the Kruskal-Wallis test were used to evaluate differences between groups in categorical variables and non-normally distributed continuous variables, respectively. RESULTS: In 255 AAV patients, we identified 4 renal trajectory groups: rapid decline (n = 20), impaired (n = 82), preserved (n = 129), and recovery (n = 24). The rapid decline and impaired groups had greater baseline comorbidity (P = 0.01) and lower prevasculitis eGFR (P = 0.02). Clinically significant CKD (eGFR <60 ml/minute/1.73 m2 ) persisted over 5 years in >75% of the impaired group, compared to <40% of patients in the preserved group (P < 0.001). ESRD occurred most frequently in the rapid decline (100%), followed by the impaired and preserved groups (7% each). Baseline AAV renal involvement was present prior to 95% of ESRD. However, ESRD etiology varied, with 90% of rapid-onset ESRD attributed to vasculitis, versus 17-44% in impaired or preserved groups (P = 0.001). CONCLUSION: We identified 4 longitudinal patterns of renal function after AAV diagnosis. Our findings highlight the burden of CKD in AAV and provide a framework for future research into personalized care in this vulnerable population.

Development and validation of case-finding algorithms to identify prosthetic joint infections after total knee arthroplasty in Veterans Health Administration data.

PURPOSE: To determine the positive predictive values (PPVs) of ICD-9, ICD-10, and current procedural terminology (CPT)-based diagnostic coding algorithms to identify prosthetic joint infection (PJI) following knee arthroplasty (TKA) within the United States Veterans Health Administration. METHODS: We identified patients with: (1) hospital discharge ICD-9 or ICD-10 diagnosis of PJI, (2) ICD-9, ICD-10, or CPT procedure code for TKA prior to PJI diagnosis, (3) CPT code for knee X-ray within ±90 days of the PJI diagnosis, and (4) at least 1 CPT code for arthrocentesis, arthrotomy, blood culture, or microbiologic procedure within ±90 days of the PJI diagnosis date. Separate samples of patients identified with the ICD-9 and ICD-10-based PJI diagnoses were obtained, stratified by TKA procedure volume at each medical center. Medical records of sampled patients were reviewed by infectious disease clinicians to adjudicate PJI events. The PPV (95% confidence interval [CI]) for the ICD-9 and ICD-10 PJI algorithms were calculated. RESULTS: Among a sample of 80 patients meeting the ICD-9 PJI algorithm, 60 (PPV 75.0%, [CI 64.1%-84.0%]) had confirmed PJI. Among 80 patients who met the ICD-10 PJI algorithm, 68 (PPV 85.0%, [CI 75.3%-92.0%]) had a confirmed diagnosis. CONCLUSIONS: An algorithm consisting of an ICD-9 or ICD-10 PJI diagnosis following a TKA code combined with CPT codes for a knee X-ray and either a relevant surgical procedure or microbiologic culture yielded a PPV of 75.0% (ICD-9) and 85.0% (ICD-10), for confirmed PJI events and could be considered for use in future pharmacoepidemiologic studies.

Incident Rheumatoid Arthritis in HIV Infection: Epidemiology and Treatment.

OBJECTIVE: To assess the incidence, presentation, and management of rheumatoid arthritis (RA) in patients with HIV, including the use of disease-modifying antirheumatic drugs (DMARDs) in this immunosuppressed population. METHODS: Patients included in this study were from the Veterans Aging Cohort Study, a longitudinal cohort of veterans with HIV and age-, race-, and site-matched uninfected veterans. We identified all patients who had ≥1 rheumatologist-generated International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) code for RA and whose serum samples were tested for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. To further confirm the diagnosis of RA, medical charts were reviewed to verify whether patients met the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria for RA. We recorded DMARD use and adverse effects during the first contiguous course of treatment (i.e., >6 months of no interruption in DMARD treatment). RESULTS: This study included 56,250 patients with HIV and 116,944 uninfected individuals over 2,384,541 person-years. Of the 2,748 individuals in this cohort who were reviewed for a diagnosis of RA based on ICD-9 or ICD-10 codes, incident RA was identified in 215 individuals, including 21 patients with HIV. The incidence rate ratio of RA for patients with HIV compared to uninfected individuals was 0.29 (95% confidence interval 0.19-0.48). Most of the patients diagnosed as having RA (88%) were seropositive for RA-associated autoantibodies (RF and/or anti-CCP). However, high autoantibody titers were less frequent in RA patients with HIV compared to RA patients without HIV. In total, 5% of RA patients with HIV (1 of 21) had both high titers of anti-CCP and high titers of RF, compared to 41% of uninfected individuals (81 of 194). DMARDs were prescribed in 71% of RA patients with HIV (15 of 21) compared to 94% of RA patients without HIV (183 of 194). There was no indication that the DMARD safety profile was worse among RA patients with HIV who were prescribed DMARDs (n = 10 assessed) compared to RA patients without HIV who were prescribed DMARDs (n = 158 assessed). CONCLUSION: In this cohort, incident RA was less common in patients with HIV compared to uninfected individuals. Moreover, compared to RA patients without HIV, the seropositivity rate and titers of RA-specific autoantibodies were lower among RA patients with HIV, and those with HIV were prescribed DMARDs less frequently than those without HIV.

Incidence and Presentation of Sarcoidosis With and Without HIV Infection.

BACKGROUND: Case reports describe incident sarcoidosis in persons with HIV (PWH). The association between HIV and risk of sarcoidosis, and differences in presentation in PWH, have not been systematically assessed. METHODS: Subjects were selected from the Veterans Aging Cohort Study (VACS), a longitudinal cohort study including veterans with HIV and matched uninfected veterans. This was a prospective observational analysis in which we evaluated both the incidence (via incidence rate ratio) and presentation and treatment (by comparison of rates of organ involvement and use of medications) of sarcoidosis in PWH compared with HIV-negative controls. We also assessed risk factors (via Cox regression) associated with the development of sarcoidosis including CD4 count and viral load trajectory. RESULTS: Of 1614 patients evaluated via chart review, 875 (54%) had prevalent sarcoidosis and 325 (20%) had confirmed incident sarcoidosis. Incident sarcoidosis occurred in 59 PWH and 266 uninfected. The incidence of sarcoidosis was lower in PWH than uninfected (incidence rate ratio [IRR], 0.61; 95% CI, 0.46-0.81) and especially low in patients with unsuppressed viremia (IRR, 0.04; 95% CI, 0.02-0.08) compared with uninfected). At diagnosis of sarcoidosis, the median CD4 count among PWH was 409 cells/mm3; 77% had HIV-1 RNA <500 copies/mL. No significant differences were observed between PWH and uninfected in terms of organ involvement, disease severity, or use of oral glucocorticoids. CONCLUSIONS: HIV, particularly with persistent viremia, was associated with decreased risk of incident sarcoidosis; severity and treatment were similar between PWH and uninfected.

A Woman With Dyspnea, Weight Loss, and Splenic Lesions.

CASE PRESENTATION: The patient is a 37-year-old hospital employee and current smoker with a 10 pack-year smoking history, who presented with dyspnea, chest pain, and weight loss. She was in her usual state of health until 4 months prior to admission when she developed intermittent left-sided chest pain, cough productive of scant yellow sputum, fevers, and anorexia. Initial chest radiograph was normal and her outpatient physician prescribed azithromycin, which she took without improvement. One month prior to admission, a follow-up chest radiograph revealed a left-sided upper lobe consolidation; she received a course of levofloxacin without improvement. At follow-up, given her occupation, 13.6-kg unintentional weight loss, and persistent pulmonary symptoms and infiltrate despite treatment for pneumonia, her provider referred her for admission with particular concern for exclusion of active TB. As a hospital employee with clinical exposure, she underwent annual TB screening, which was always negative. She had no known exposure to patients with TB. Her most recent travel was to the Midwestern United States, without significant outdoors exposure. Review of systems was positive for wheezing, anorexia, and arthralgias of both knees and the left ankle and wrist. There was no hemoptysis, leg swelling, visual changes, palpitations, or muscle weakness.

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Inflammatory Biomarkers in Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), and HIV/HCV Coinfection.

BACKGROUND: Inflammation in human immunodeficiency virus (HIV)-infected patients is associated with poorer health outcomes. Whether inflammation as measured by the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) adds information to existing prognostic indices is not known. METHODS: We analyzed data from 2000 to 2012 in the Veterans Aging Cohort Study (VACS), overall and stratified by HIV/hepatitis C virus status (n = 89 786). We randomly selected a visit date at which all laboratory values of interest were available within 180 days; participants with HIV received at least 1 year of antiretroviral therapy. We followed patients for (1) mortality and (2) hepatic decompensation (HD) and analyzed associations using Cox regression, adjusted for a validated mortality risk index (VACS Index 2.0). In VACS Biomarker Cohort, we considered correlation with biomarkers of inflammation: interleukin-6, D-dimer, and soluble CD-14. RESULTS: Neutrophil-to-lymphocyte ratio and PLR demonstrated strong unadjusted associations with mortality (P < .0001) and HD (P < .0001) and were weakly correlated with other inflammatory biomarkers. Although NLR remained statistically independent for mortality, as did PLR for HD, the addition of NLR and PLR to the VACS Index 2.0 did not result in significant improvement in discrimination compared with VACS Index 2.0 alone for mortality (C-statistic 0.767 vs 0.758) or for HD (C-statistic 0.805 vs 0.801). CONCLUSIONS: Neutrophil-to-lymphocyte ratio and PLR were strongly associated with mortality and HD and weakly correlated with inflammatory biomarkers. However, most of their association was explained by VACS Index 2.0. Addition of NLR and PLR to VACS 2.0 did not substantially improve discrimination for either outcome.

Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure.

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%±9.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (P<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial.

BACKGROUND: Effective decongestion of heart failure patients predicts improved outcomes, but high dose loop diuretics (HDLD) used to achieve diuresis predict adverse outcomes. In the DOSE trial, randomization to a HDLD intensification strategy (HDLD-strategy) improved diuresis but not outcomes. Our objective was to determine if potential beneficial effects of more aggressive decongestion may have been offset by adverse effects of the HDLD used to achieve diuresis. METHODS AND RESULTS: A post hoc analysis of the DOSE trial (n=308) was conducted to determine the influence of post-randomization diuretic dose and fluid output on the rate of death, rehospitalization or emergency department visitation associated with the HDLD-strategy. Net fluid output was used as a surrogate for beneficial decongestive effects and cumulative loop diuretic dose for the dose-related adverse effects of the HDLD-strategy. Randomization to the HDLD-strategy resulted in increased fluid output, even after adjusting for cumulative diuretic dose (p=0.006). Unadjusted, the HDLD-strategy did not improve outcomes (p=0.28). However, following adjustment for cumulative diuretic dose, significant benefit emerged (HR=0.64, 95% CI 0.43-0.95, p=0.028). Adjusting for net fluid balance eliminated the benefit (HR=0.95, 95% CI 0.67-1.4, p=0.79). CONCLUSIONS: A clinically meaningful benefit from a randomized aggressive decongestion strategy became apparent after accounting for the quantity of loop diuretic administered. Adjusting for the diuresis resulting from this strategy eliminated the benefit. These hypothesis-generating observations may suggest a role for aggressive decongestion in improved outcomes.

Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure.

BACKGROUND: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF. METHODS AND RESULTS: Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR. CONCLUSION: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.

Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure.

BACKGROUND: Chloride plays a role in renal salt sensing, neurohormonal activation, and regulation of diuretic targets, and hypochloremia predicts mortality in acute heart failure (AHF). AHF therapies, such as diuretics, alter chloride homeostasis. We studied the association between (changes in) chloride levels and diuretic responsiveness, decongestion, and mortality in patients with AHF. METHODS AND RESULTS: Patients hospitalized for AHF in the PROTECT trial (n=2033) with serum chloride levels within 24 hours of admission and 14 days later were studied (n=1960). Hypochloremia was defined as serum chloride <96 mEq/L. Mean baseline chloride was 100.8±5.0 mEq/L. Low baseline chloride was associated with high bicarbonate, poor diuretic response, less hemoconcentration, and worsening heart failure (all P<0.01). Newly developed hypochloremia at day 14 was common and associated with a decline in renal function and an increase in blood urea nitrogen (P<0.01). In multivariable analyses, chloride measured at day 14, but not baseline chloride, was strongly and independently associated with mortality through 180 days (hazard ratio per unit decrease: 1.07 [1.03-1.10]; P<0.001). In comparison, sodium was not significantly associated with mortality after multivariable adjustment at any time point. Hypochloremia at baseline that resolved was not associated with mortality (P=0.55), but new or persistent hypochloremia at day 14 was associated with increased mortality (hazard ratio: 3.11 [2.17-4.46]; P<0.001). CONCLUSIONS: Low serum chloride at AHF hospital admission was strongly associated with impaired decongestion. New or persistent hypochloremia 14 days later was independently associated with reduced survival, whereas hypochloremia that resolved by day 14 was not. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354458.

Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights.

BACKGROUND: Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature. METHODS AND RESULTS: Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio. CONCLUSIONS: Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial.

BACKGROUND: Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. METHODS AND RESULTS: We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001). CONCLUSION: The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies.

Reduced Cardiac Index Is Not the Dominant Driver of Renal Dysfunction in Heart Failure.

BACKGROUND: It is widely believed that a reduced cardiac index (CI) is a significant contributor to renal dysfunction in patients with heart failure (HF). However, recent data have challenged this paradigm. OBJECTIVES: This study sought to determine the relationship between CI and renal function in a multicenter population of HF patients undergoing pulmonary artery catheterization (PAC). METHODS: Patients undergoing PAC in either the randomized or registry portions of the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial were included (n = 575). We evaluated associations between CI and renal function across multiple subgroups and assessed for nonlinear, threshold, and longitudinal relationships. RESULTS: There was a weak but significant inverse correlation between CI and estimated glomerular filtration rate (eGFR), such that higher CI was paradoxically associated with worse eGFR (r = -0.12; p = 0.02). CI was not associated with blood urea nitrogen (BUN) or the BUN to creatinine ratio. Similarly, no associations were observed between CI and better renal function across multiple subgroups defined by indications for PAC or hemodynamic, laboratory, or demographic parameters. A nonlinear or threshold effect could not be identified. In patients with serial assessments of renal function and CI, we were unable to find within-subject associations between change in CI and eGFR using linear mixed modeling. Neither CI nor change in CI was lower in patients developing worsening renal function (p ≥ 0.28). CONCLUSIONS: These results reinforce evidence that reduced CI is not the primary driver for renal dysfunction in patients hospitalized for HF, irrespective of the degree of CI impairment or patient subgroup analyzed.

The risk of death associated with proteinuria in heart failure is restricted to patients with an elevated blood urea nitrogen to creatinine ratio.

BACKGROUND: Renal dysfunction (RD) is associated with reduced survival in HF; however, not all RD is mechanistically or prognostically equivalent. Notably, RD associated with "pre-renal" physiology, as identified by an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), identifies a particularly high risk RD phenotype. Proteinuria, another domain of renal dysfunction, has also been associated with adverse events. Given that several different mechanisms can cause proteinuria, we sought to investigate whether the mechanism underlying proteinuria also affects survival in HF. METHODS AND RESULTS: Subjects in the Studies of Left Ventricular Dysfunction (SOLVD) trial with proteinuria assessed at baseline were studied (n=6439). All survival models were adjusted for baseline characteristics and estimated glomerular filtration rate (eGFR). Proteinuria (trace or 1+) was present in 26% and associated with increased mortality (HR=1.2; 95% CI, 1.1-1.3, p=0.006). Proteinuria >1+ was less common (2.5%) but demonstrated a stronger relationship with mortality (HR=1.9; 95% CI, 1.5-2.5, p<0.001). In patients with BUN/Cr in the top tertile (≥17.3), any proteinuria (HR=1.3; 95% CI, 1.1-1.5, p=0.008) and >1+ proteinuria (HR=2.3; 95% CI, 1.7-3.3, p<0.001) both remained associated with mortality. However, in patients with BUN/Cr in the bottom tertile (≤13.3), any proteinuria (HR=0.95; 95% CI, 0.77-1.2, p=0.63, p interaction=0.015) and >1+ proteinuria (HR=1.3; 95% CI, 0.79-2.2, p=0.29, p interaction=0.036) were not associated with worsened survival. CONCLUSION: Analogous to a reduced eGFR, the mechanism underlying proteinuria in HF may be important in determining the associated survival disadvantage.