Association of suPAR, ST2, and galectin-3 with eGFR decline and mortality in patients with advanced heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m2, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (ß coefficient = -0.36 √(ml/min/1.73 m2), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m2) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m2) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.

A Phenomapping Tool and Clinical Score to Identify Low Diuretic Efficiency in Acute Decompensated Heart Failure.

BACKGROUND: Individuals with acute decompensated heart failure (ADHF) have a varying response to diuretic therapy. Strategies for the early identification of low diuretic efficiency to inform decongestion therapies are lacking. OBJECTIVES: The authors sought to develop and externally validate a machine learning-based phenomapping approach and integer-based diuresis score to identify patients with low diuretic efficiency. METHODS: Participants with ADHF from ROSE-AHF, CARRESS-HF, and ATHENA-HF were pooled in the derivation cohort (n = 794). Multivariable finite-mixture model-based phenomapping was performed to identify phenogroups based on diuretic efficiency (urine output over the first 72 hours per total intravenous furosemide equivalent loop diuretic dose). Phenogroups were externally validated in other pooled ADHF trials (DOSE/ESCAPE). An integer-based diuresis score (BAN-ADHF score: blood urea nitrogen, creatinine, natriuretic peptide levels, atrial fibrillation, diastolic blood pressure, hypertension and home diuretic, and heart failure hospitalization) was developed and validated based on predictors of the diuretic efficiency phenogroups to estimate the probability of low diuretic efficiency using the pooled ADHF trials described earlier. The associations of the BAN-ADHF score with markers and symptoms of congestion, length of stay, in-hospital mortality, and global well-being were assessed using adjusted regression models. RESULTS: Clustering identified 3 phenogroups based on diuretic efficiency: phenogroup 1 (n = 370; 47%) had lower diuretic efficiency (median: 13.1 mL/mg; Q1-Q3: 7.7-19.4 mL/mg) than phenogroups 2 (n = 290; 37%) and 3 (n = 134; 17%) (median: 17.8 mL/mg; Q1-Q3: 10.8-26.1 mL/mg and median: 35.3 mL/mg; Q1-Q3: 17.5-49.0 mL/mg, respectively) (P < 0.001). The median urine output difference in response to 80 mg intravenous twice-daily furosemide between the lowest and highest diuretic efficiency group (phenogroup 1 vs 3) was 3,520 mL/d. The BAN-ADHF score demonstrated good model performance for predicting the lowest diuretic efficiency phenogroup membership (C-index: 0.92 in DOSE/ESCAPE validation cohort) that was superior to measures of kidney function (creatinine or blood urea nitrogen), natriuretic peptide levels, or home diuretic dose (DeLong P < 0.001 for all). Net urine output in response to 80 mg intravenous twice-daily furosemide among patients with a low vs high (5 vs 20) BAN-ADHF score was 2,650 vs 660 mL per 24 hours, respectively. Participants with higher BAN-ADHF scores had significantly lower global well-being, higher natriuretic peptide levels on discharge, a longer in-hospital stay, and a higher risk of in-hospital mortality in both derivation and validation cohorts. CONCLUSIONS: The authors developed and validated a phenomapping strategy and diuresis score for individuals with ADHF and differential response to diuretic therapy, which was associated with length of stay and mortality.

Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.

BACKGROUND: No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD). METHODS: We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm. RESULTS: Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1ß in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups. CONCLUSIONS: We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711).

Age Modifies Intracranial and Gastrointestinal Bleeding Risk from P2Y12 Inhibitors in Patients Receiving Dialysis.

Background: Individuals aged ≥75 years are the fastest-growing population starting dialysis for end-stage kidney disease (ESKD) due to living longer with coronary artery disease. ESKD alone can increase bleeding risk, but P2Y12 inhibitor (P2Y12-I) antiplatelet medications prescribed for cardiovascular treatment can exacerbate this risk in patients with ESKD. The age-specific rates of bleeding complications in dialysis patients with ESKD on P2Y12-I remain unclear, as does how age modifies the bleeding risk from P2Y12-I use in these patients. Methods: In a retrospective cohort study, we collected data on 40,972 patients receiving maintenance hemo- or peritoneal dialysis who were newly prescribed P2Y12-I therapy between 2011 and 2015 from the USRDS registry. We analyzed the effect of age on the time to first bleed and the interactions between age and P2Y12-I type on modifying the effects of a bleed. Results: Twenty percent of the cohort were aged ≥75 years. There were 3096 (8%) gastrointestinal (GI) and 1298 (3%) intracranial (IC) bleeding events during a median follow-up of 1 year. Annual incidence rates for IC bleeds were 2% in those aged <55 years and 3% in those aged ≥75 years. Rates for GI bleeds were 4% in those aged <55 years and 9% in those aged ≥75 years. On clopidogrel, prasugrel, and ticagrelor, for every decade increase in age of the cohort members, the risk of IC bleed increased by 9%, 55%, and 59%, and the risk of GI bleed increased by 21%, 28%, and 39%, respectively. At age ≥75 years, prasugrel was associated with a greater risk of IC bleed than clopidogrel. At age ≥60 years, ticagrelor was associated with a greater risk of GI bleed than clopidogrel. Conclusions: More potent P2Y12-Is (prasugrel and ticagrelor) were associated with a disproportionately higher risk of IC bleed with increasing age compared with that of clopidogrel-prasugrel was much worse than clopidogrel at age ≥75 years. All three drugs were associated with only modest increase in the risk of GI bleed with every decade increase in age-ticagrelor was much worse than clopidogrel at ≥60 years of age. These results highlight the need for head-to-head clinical trials for the use of P2Y12-Is in patients with ESKD to determine age cutoffs where the risk of bleeding outweighs the benefits of thrombosis prevention.

A Systematic Review and Meta-Analysis of Depression and Protein-Energy Wasting in Kidney Disease.

INTRODUCTION: Depression comorbid with chronic disease may be mediated by inflammation. We sought to characterize relationships between inflammatory biomarkers and depressive symptoms in patients with chronic kidney disease and end-stage kidney disease. METHODS: A systematic literature search was conducted by 2 authors up to March 19, 2019, for studies of patients with chronic kidney disease or end-stage kidney disease evaluating circulating inflammatory biomarkers associated with depression of chronic disease: albumin, C-reactive protein (CRP), high-sensitivity CRP, interleukin-6 (IL-6), tumor necrosis factor-α, and interleukin-1. Standardized mean differences in biomarkers between individuals with and without depression were computed and analyzed using mixed effects models. Correlations between biomarkers and the severity of depressive symptoms were computed. RESULTS: Thirty-four studies (5652 participants) compared biomarkers between depressed and nondepressed individuals. Individuals with depression had lower albumin levels (standardized mean difference, -0.37; 95% confidence interval [CI], -0.61 to -0.13), higher CRP levels (standardized mean difference, 0.76; 95% CI, 0.16-1.37), and higher IL-6 levels (standardized mean difference, 0.42; 95% CI, 0.21-0.63). Studies were heterogeneous for albumin, CRP, high-sensitivity CRP, and tumor necrosis factor-α. Twenty-three studies (3047 participants) investigated correlations between biomarkers and depressive symptoms. The severity of depressive symptoms correlated with albumin (Z = -0.25; 95% CI, -0.36 to -0.14), high-sensitivity CRP (Z = 0.28; 95% CI, 0.13-0.43), and IL-6 (Z = 0.34; 95% CI, 0.18-0.49). There was heterogeneity across studies of IL-6. Only 6 studies (321 participants) investigated the effect of antidepressant treatment on inflammatory biomarkers, which was insufficient to combine in meta-analysis. CONCLUSION: Lower albumin and higher IL-6 were associated with both the presence and severity of depression, CRP with the presence of depression, and high-sensitivity CRP with the severity of depressive symptoms. The effect of interventions to lower inflammation in patients with kidney disease and depression deserves investigation.

Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data?

Patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) are 10 times more likely to die of cardiovascular (CV) diseases than the general population, and dialysis-dependent patients are at even higher risk. Although traditional CV risk factors are highly prevalent in individuals with CKD, these patients were often excluded from studies targeting modification of these risks. Although treatment of hypertension is beneficial in CKD, the best target blood pressure has not been established. Trial data showed that renin-angiotensin-aldosterone blockade may prevent CV events in patients with CKD. The risks of aspirin may equal the benefits in NDD-CKD samples, and there are no trials testing aspirin in dialysis-dependent patients. Lipid-lowering therapy improves CV outcomes in NDD-CKD, but not in dialysis-dependent patients. Strict glycemic control prevents CV events in nonalbuminuric individuals, but showed no benefit in those with baseline albuminuria with albumin excretion > 300mg/g, and there are no data in dialysis-dependent patients. Data for lifestyle modifications, such as weight loss, physical activity, and smoking cessation, are mostly observational and extrapolated from non-CKD samples. This comprehensive review summarizes the best existing evidence and current clinical guidelines for modification of traditional risk factors for the prevention of CV events in patients with CKD and identifies knowledge gaps.

Differences in Whole Blood Platelet Aggregation at Baseline and in Response to Aspirin and Aspirin Plus Clopidogrel in Patients With Versus Without Chronic Kidney Disease.

Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16 non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome was residual platelet aggregability (RPA; proportion with <50% IPA). Baseline platelet aggregability was similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Ω, p = 0.007. CKD versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p = 0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19 polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms.

Utility of traditional circulating and imaging-based cardiac biomarkers in patients with predialysis CKD.

Cardiac biomarkers, such as cardiac troponin T (cTnT), brain natriuretic peptide (BNP), and N-terminal-pro-BNP (NT-pro-BNP), are commonly used to diagnose acute coronary syndrome and congestive heart failure exacerbation in symptomatic patients. Levels of these biomarkers are frequently chronically elevated in asymptomatic patients with ESRD who are receiving maintenance dialysis. Other imaging biomarkers commonly encountered in nephrologists' clinical practice, such as coronary artery calcium measured by computed tomography, left ventricular hypertrophy, and carotid intima-media thickness, are also frequently abnormal in asymptomatic patients with ESRD. This article critically reviews the limited observational data on associations between cTnT, BNP, NT-pro-BNP, coronary artery calcium, left ventricular hypertrophy, and carotid intima-media thickness with cardiovascular events and death in non-dialysis-dependent patients with CKD. Although sufficient evidence suggests that these biomarkers may be used for prognostication, the diagnostic utility of cTnT, BNP, and NT-pro-BNP remain challenging in patients with CKD. Decreased renal clearance may affect the plasma levels of these biomarkers, and upper reference limits were originally derived in patients without CKD. Until better data are available, higher cutoffs, or a rise in level compared with previous values, have been proposed to help distinguish acute myocardial infarction from chronic elevations of cTnT in symptomatic patients with CKD. Additionally, it is not known whether these biomarkers are modifiable and amenable to interventions that could change hard clinical outcomes in patients with CKD not yet undergoing long-term dialysis.

Association of urinary sodium/potassium ratio with blood pressure: sex and racial differences.

BACKGROUND AND OBJECTIVES: Previous studies reporting an association between high BP and high sodium and low potassium intake or urinary sodium/potassium ratio (U[Na(+)]/[K(+)]) primarily included white men and did not control for cardiovascular risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional study investigated the association of U[Na(+)]/[K(+)] with BP in 3303 participants using robust linear regression. RESULTS: Mean age was 43±10 years, 56% of participants were women, and 52% were African American. BP was higher in African Americans than in non-African Americans, 131/81±20/11 versus 120/76±16/9 mmHg (P<0.001). Mean U[Na(+)]/[K(+)] was 4.4±3.0 in African Americans and 4.1±2.5 in non-African Americans (P=0.002), with medians (interquartile ranges) of 3.7 (3.2) and 3.6 (2.8). Systolic BP increased by 1.6 mmHg (95% confidence interval, 1.0, 2.2) and diastolic BP by 1.0 mmHg (95% confidence interval, 0.6, 1.4) for each 3-unit increase in U[Na(+)]/[K(+)] (P<0.001 for both). This association remained significant after adjusting for diabetes mellitus, smoking, body mass index, total cholesterol, GFR, and urine albumin/creatinine ratio. There was no interaction between African-American race and U[Na(+)]/[K(+)], but for any given value of U[Na(+)]/[K(+)], both systolic BP and diastolic BP were higher in African Americans than in non-African Americans. The diastolic BP increase was higher in men than in women per 3-unit increase in U[Na(+)]/[K(+)] (1.6 versus 0.9 mmHg, interaction P=0.03). CONCLUSIONS: Dietary Na(+) excess and K(+) deficiency may play an important role in the pathogenesis of hypertension independent of cardiovascular risk factors. This association may be more pronounced in men than in women.

ANCA-negative glomerulonephritis associated with nonasthmatic Churg-Strauss syndrome.

BACKGROUND: A 36-year-old white male with a history of allergic rhinitis and sinusitis presented to the emergency room with abdominal pain and diarrhea. Physical examination revealed fever, hypoxemia and a maculopapular rash. Laboratory tests showed proteinuria, hematuria, leukocytosis, eosinophilia and an elevated erythrocyte sedimentation rate. INVESTIGATIONS: Physical examination, urine and blood analysis and culture, chest radiography, chest and abdominal CT, esophagogastroduodenoscopy, skin and kidney biopsy, serology and renal ultrasound. DIAGNOSIS: Pauci-immune focal necrotizing glomerulonephritis with crescents and interstitial eosinophilia, consistent with Churg-Strauss syndrome. MANAGEMENT: The patient was treated with methylprednisolone 1 g/day intravenously for 3 days. He also received oral clotrimazole and combined oral sulfamethoxazole and trimethoprim for prophylaxis against candidiasis and pneumonia, respectively. He left the hospital against medical advice and was lost to follow-up.

Lactic acidosis in an HIV-infected patient receiving highly active antiretroviral therapy.

BACKGROUND: A 51-year-old man with HIV infection on highly active antiretroviral therapy presented with abdominal pain and exertional dyspnea. Physical examination revealed increased respiration and cachexia. Laboratory tests showed a lactic acid concentration elevated to 6.4 mM. INVESTIGATION: Physical examination, blood chemistry, arterial blood gas, urine analysis, chest X-ray, and ultrasound of liver. DIAGNOSIS: Nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis, hepatitis and chemical pancreatitis. Proximal renal tubular acidosis with Fanconi's syndrome, secondary to treatment with tenofovir. MANAGEMENT: The patient was supported on intravenous and oral bicarbonate, riboflavin and phosphorus supplementation. Highly active antiretroviral therapy was discontinued. The patient's lactate level decreased about 2 weeks after discharge.