Eliott Arroyo

Resumo Introdução: Lesão renal aguda (LRA) é um importante fator prognóstico negativo para a sobrevida em pacientes hospitalizados com COVID-19, porém existem poucos biomarcadores confiáveis para LRA e mortalidade. Estudo teve como objetivo avaliar se níveis elevados de fator de crescimento de fibroblastos 23 (FGF23) estão associados à ocorrência de LRA e à mortalidade em pacientes com COVID-19. Métodos: Nesta coorte prospectiva de 111 pacientes com COVID-19 hospitalizados no Indiana University Academic Health Center (abril–outubro de 2020), os níveis circulantes de FGF23 e de seu correceptor Klotho foram avaliados quanto à sua associação com LRA e com a sobrevida em 28 meses. Resultados: Dos 111 pacientes, 77 não apresentaram LRA (91,0 [69,2–101,3] mL/min/1,73 m2), 17 apresentaram LRA (39,7 [28,7–57,8] mL/min/1,73 m2) e 17 apresentavam doença renal crônica terminal (DRT; 11,9 [8,6–17,5] mL/min/1,73 m2). O tempo mediano de seguimento foi de 22,6 meses. Os níveis medianos de FGF23 foram mais elevados em pacientes com LRA (305,6 [134,6–350,8] RU/mL) e em pacientes com DRT (3.607,6 [440,5–7.452,7] RU/mL), em comparação com aqueles sem LRA (120,7 [64,3–249,7] RU/mL; P < 0,001). Pacientes (excluindo aqueles com DRT) com níveis elevados de FGF23 apresentaram maior probabilidade de LRA (OR: 2,30; IC 95%: [1,31–4,03]; P = 0,004). Além disso, cada aumento de uma unidade no log(FGF23) esteve associado a um risco 45% maior de mortalidade na coorte (HR: 1,45; IC 95%: [1,02–2,07]; P = 0,04), após ajuste para idade, doença cardiovascular e IMC. Os níveis de Klotho diferiram entre os grupos (sem LRA: 576,1 [455, 730] pg/mL; com LRA: 594,6 [416,774] pg/mL; DRT: 421,5 [330, 562] pg/mL; P = 0,04), mas não estiveram associados à presença de LRA. Conclusão: Níveis elevados de FGF23 estão associados à presença de LRA e à mortalidade em pacientes com COVID-19.

Introduction: Acute kidney injury (AKI) is a key negative prognostic factor for survival in patients hospitalized with COVID-19, but few reliable biomarkers for AKI and mortality exist. This study aimed to evaluate whether elevated fibroblast growth factor 23 (FGF23) levels are associated with AKI status and mortality in COVID-19 patients. Methods: In this prospective cohort of 111 COVID-19 patients hospitalized at the Indiana University Academic Health Center (April–October 2020), circulating FGF23 and its co-receptor Klotho levels were assessed for association with AKI and 28-month survival. Results: Of the 111 patients, 77 had no AKI (91.0 [69.2, 101.3] mL/min/1.73 m2), 17 had AKI (39.7 [28.7, 57.8] mL/min/1.73 m2), and 17 had end-stage kidney disease (ESKD; 11.9 [8.6, 17.5] mL/min/1.73 m2). Median follow-up was 22.6 months. Median FGF23 levels were higher in patients with AKI (305.6 [134.6, 350.8] RU/mL) and ESKD (3,607.6 [440.5, 7,452.7] RU/mL) compared to those without AKI (120.7 [64.3, 249.7] RU/mL; P < 0.001). Patients (excluding those with ESKD) with elevated FGF23 levels had increased odds of having AKI (OR: 2.30, 95% CI: [1.31, 4.03]; P = 0.004). Moreover, each unit increase in log(FGF23) was associated with a 45% higher risk of mortality in the cohort (HR: 1.45, 95% CI: [1.02, 2.07]; P = 0.04) after controlling for age, cardiovascular disease, and BMI. Klotho levels differed by group (without AKI: 576.1 [455, 730] pg/mL; with AKI: 594.6 [416, 774] pg/mL; ESKD: 421.5 [330, 562] pg/mL; P = 0.04), but were not associated with AKI status. Conclusion: Elevated FGF23 is associated with AKI status and mortality in patients with COVID-19.

Key Points: Body fluid volumes are significantly higher at the end of the 3-day interdialytic interval compared with the 2-day interdialytic interval. V_E/VCO₂ slope, a noninvasive index of exercise pulmonary vascular resistance, is elevated after the 3-day interdialytic interval. VO₂Peak is similar across interdialytic intervals but was limited following dialysis by postdialysis fatigue. Background: The long interdialytic interval in thrice-weekly hemodialysis is associated with volume accumulation and excess cardiovascular risk. Few studies have evaluated cardiovascular functional changes after interdialytic intervals. This study sought to evaluate cardiovascular functional response patterns, as assessed by cardiopulmonary exercise testing, after the short and long interdialytic intervals. Methods: We conducted an exploratory single-center, quasi-experimental 2-arm study involving crossover of treatment sequences in patients on conventional thrice-weekly maintenance hemodialysis. All patients underwent cardiopulmonary exercise testing, bioelectrical impedance spectroscopy, and physical function testing on three study visits: posthemodialysis and prehemodialysis at the end of a 2-day and the 3-day interdialytic intervals. Results: Thirty-one patients (n=19 men, mean [SD] age 55 [12] years, median [interquartile range] dialysis vintage 56 [24–96] months) completed all study visits. Interdialytic weight gain and total body fluid were greater after the 3-day compared with the 2-day interval (P < 0.001). Ventilation/carbon dioxide production (V_E/VCO₂) slope, a noninvasive index of exercise pulmonary vascular resistance and right ventricular (RV) dysfunction, was significantly elevated at the 3-day (31.2 [4.8] L V_E/L VCO₂; P = 0.002) compared with the 2-day interval (29.5 [3.9] L V_E/L VCO₂). No significant differences between interdialytic intervals were observed for peak oxygen uptake (VO₂Peak) or VO₂ at the anaerobic threshold. Change (Δ) in V_E/VCO₂ slope (ΔV_E/VCO₂) the 2-day to the 3-day interval was correlated with Δbody weight (r=0.36, P = 0.04) and left ventricular mass index (r=0.44, P = 0.02). Conclusions: The long interdialytic interval is associated with abnormal exercise-derived ventilatory and hemodynamic responses, including ventilation-perfusion mismatch and potentially RV dysfunction and RV-pulmonary artery uncoupling during exercise as suggested by elevated V_E/VCO₂ slope.

Key Points: Mild-to-moderate CKD is associated with impairment in cardiovascular functional capacity as assessed by oxygen uptake at peak exercise (VO ₂ Peak). Cardiac output is significantly reduced in patients with mild-to-moderate CKD and is associated with impaired VO ₂ Peak. Assessment of VO ₂ Peak by cardiopulmonary exercise testing can detect decrements in cardiovascular function during early stages of kidney function decline that may not be captured using resting left ventricular geometric indices alone. Background: Traditional diagnostic tools that assess resting cardiac function and structure fail to accurately reflect cardiovascular alterations in patients with CKD. This study sought to determine whether multidimensional exercise response patterns related to cardiovascular functional capacity can detect abnormalities in mild-to-moderate CKD. Methods: In a cross-sectional study, we examined 3075 participants from the Framingham Heart Study (FHS) and 451 participants from the Massachusetts General Hospital Exercise Study (MGH-ExS) who underwent cardiopulmonary exercise testing. Participants were stratified by eGFR: eGFR ≥90, eGFR 60–89, and eGFR 30–59. Our primary outcomes of interest were peak oxygen uptake (VO ₂ Peak), VO ₂ at anaerobic threshold (VO ₂ AT), and ratio of minute ventilation to carbon dioxide production (VE/VCO ₂ ). Multiple linear regression models were fitted to evaluate the associations between eGFR group and each outcome variable adjusted for covariates. Results: In the FHS cohort, 1712 participants (56%) had an eGFR ≥90 ml/min per 1.73 m ² , 1271 (41%) had an eGFR of 60–89 ml/min per 1.73 m ² , and 92 (3%) had an eGFR of 30–59 ml/min per 1.73 m ² . In the MGH-ExS cohort, 247 participants (55%) had an eGFR ≥90 ml/min per 1.73 m ² , 154 (34%) had an eGFR of 60–89 ml/min per 1.73 m ² , and 50 (11%) had an eGFR of 30–59 ml/min per 1.73 m ² . In FHS, VO ₂ Peak and VO ₂ AT were incrementally impaired with declining kidney function ( P < 0.001); however, this pattern was attenuated after adjustment for age. Percent-predicted VO ₂ Peak at AT was higher in the lower eGFR groups ( P < 0.001). In MGH-ExS, VO ₂ Peak and VO ₂ AT were incrementally impaired with declining kidney function in unadjusted and adjusted models ( P < 0.05). VO ₂ Peak was associated with eGFR ( P < 0.05) in all models even after adjusting for age. On further mechanistic analysis, we directly measured cardiac output (CO) at peak exercise by right heart catheterization and found impaired CO in the lower eGFR groups ( P ≤ 0.007). Conclusions: Cardiopulmonary exercise testing–derived indices may detect impairment in cardiovascular functional capacity and track CO declines in mild-to-moderate CKD.

25-hydroxyvitamin D can undergo C-3 epimerization to produce 3-epi-25(OH)D3. 3-epi-25(OH)D3 levels decline in chronic kidney disease (CKD), but its role in regulating the cardiovascular system is unknown. Herein, we examined the relationship between 3-epi-25(OH)D3 and cardiovascular functional and structural endpoints in patients with CKD. We examined n = 165 patients with advanced CKD from the Cardiopulmonary Exercise Testing in Renal Failure (CAPER) study cohort, including those who underwent kidney transplant (KTR, n = 76) and waitlisted patients who did not (NTWC, n = 89). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline, 2 months, and 12 months. Serum 3-epi-25(OH)D3 was analyzed by liquid chromatography-tandem mass spectrometry. Patients were stratified into quartiles of baseline 3-epi-25(OH)D3 (Q1: –1, n = 51; Q2: 0.4 ng·mL^–1, n = 26; Q3: 0.5–0.7 ng·mL^–1, n = 47; Q4: ≥0.8 ng·mL^–1, n = 41). Patients in Q1 exhibited lower peak oxygen uptake (VO₂Peak = 18.4 [16.2–20.8] mL·min^–1·kg^–1) compared to Q4 (20.8 [18.6–23.2] mL·min^–1·kg^–1; P = 0.009). Linear mixed regression model showed that 3-epi-25(OH)D3 levels increased in KTR (from 0.47 [0.30] ng·mL^–1 to 0.90 [0.45] ng·mL^–1) and declined in NTWC (from 0.61 [0.32] ng·mL^–1 to 0.45 [0.29] ng·mL^–1; P < 0.001). Serum 3-epi-25(OH)D3 was associated with VO₂Peak longitudinally in both groups (KTR: ß [SE] =2.53 [0.56], P < 0.001; NTWC: 2.73 [0.70], P < 0.001), but was not with left ventricular mass or arterial stiffness. Non-epimeric 25(OH)D3, 24,25(OH)₂D3, and 25(OH)D3:24,25(OH)₂D3 ratio were not associated with any cardiovascular outcome (p's > 0.05). Changes in 3-epi-25(OH)D3 levels may regulate cardiovascular functional capacity in patients with advanced CKD.

Background: The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results: We conducted a cross‐sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low‐frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min ⁻¹ ·1.73 m ⁻² ), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage >12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min ⁻¹ ·kg ⁻¹ ) compared with predialysis (22.7 [5.2] mL·min ⁻¹ ·kg ⁻¹ ; P P 12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min ⁻¹ ·kg ⁻¹ ) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min ⁻¹ ·kg ⁻¹ ; P =0.033). Conclusions: Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low‐risk New York Heart Association class I and higher‐risk New York Heart Association class II to IV heart failure.