Efficacy and Safety of Remdesivir in People With Impaired Kidney Function Hospitalized for COVID-19 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Few antiviral therapies have been studied in patients with COVID-19 and kidney impairment. Herein, efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-beta-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. METHODS: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury (AKI), chronic kidney disease (CKD), or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on Day 1; 100 mg daily up to Day 5) or placebo (enrollment: March 2021-March 2022). The primary efficacy endpoint was the composite of all-cause mortality or invasive mechanical ventilation (IMV) through Day 29. Safety was evaluated through Day 60. RESULTS: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 (37.0%) participants had AKI (remdesivir, 60; placebo, 30), 64 (26.3%) had CKD (remdesivir, 44; placebo, 20), and 89 (36.6%) had kidney failure (remdesivir, 59; placebo, 30); 31 (12.8%) were COVID-19 vaccinated. Composite all-cause mortality or IMV through Day 29 was 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = 0.61). Treatment-emergent adverse events were reported in 80.4% versus 77.5% and serious adverse events in 50.3% versus 50.0% of participants who received remdesivir versus placebo, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. CONCLUSIONS: Although underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in those with COVID-19 and severe kidney impairment. (EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351). TRIAL REGISTRATION: EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351.

Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex. DESIGN: FIDELITY post hoc analysis; median follow-up of 3 years. SETTING: FIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials. PARTICIPANTS: Adults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026). INTERVENTIONS: Randomised 1:1; finerenone or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: Cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes. RESULTS: Mean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups. CONCLUSIONS: Finerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups. TRIAL REGISTRATION NUMBERS: NCT02540993, NCT02545049.

Insulin: Trigger and Target of Renal Functions.

Kidney function in metabolism is often underestimated. Although the word "clearance" is associated to "degradation", at nephron level, proper balance between what is truly degraded and what is redirected to de novo utilization is crucial for the maintenance of electrolytic and acid-basic balance and energy conservation. Insulin is probably one of the best examples of how diverse and heterogeneous kidney response can be. Kidney has a primary role in the degradation of insulin released in the bloodstream, but it is also incredibly susceptible to insulin action throughout the nephron. Fluctuations in insulin levels during fast and fed state add another layer of complexity in the understanding of kidney fine-tuning. This review aims at revisiting renal insulin actions and clearance and to address the association of kidney dysmetabolism with hyperinsulinemia and insulin resistance, both highly prevalent phenomena in modern society.

A plain X-ray vascular calcification score is associated with arterial stiffness and mortality in dialysis patients.

BACKGROUND: Vascular calcifications are highly prevalent in dialysis patients and are associated with arterial stiffness and mortality. The use of simple and inexpensive methods to evaluate arterial stiffness and vascular calcifications is desired. The objective of this study was to evaluate the relationship of a simple vascular calcification score (SVCS) with pulse wave velocity (PWV) and pulse pressure (PP) and to evaluate their association with all-cause mortality. METHODS: 101 haemodialysis patients (71 men; 19% diabetic) were evaluated. At baseline, arterial stiffness was measured by PP and by PWV with Complior. SVCS was evaluated in plain X-ray of pelvis and hands. RESULTS: During a 43-month observational period, 31 patients died. By Kaplan-Meier analysis, SVCS >3 (P = 0.001), PP > 70 mmHg (P = 0.001) and PWV > 10.5 m/s (P < 0.001) were found to be associated with lower cumulative survival. Adjusting for multiple variables, association with mortality was maintained for SVCS >3 (HR = 3.308, P = 0.032) and PP > 70 mmHg (HR = 3.227, P = 0.031) in all patients and for PWV > 10.5 m/s (HR = 2.981, P = 0.047) in non-diabetic patients. Age (P < 0.001), systolic pressure (P = 0.004) and SVCS > 3 (P = 0.032) were associated with PWV. Diabetes (P = 0.031), calcium carbonate dose (P = 0.009) and SVCS > 3 (P = 0.012) were associated with PP. CONCLUSION: Higher SVCS, PWV and PP were associated with higher mortality in this population. SVCS was associated with arterial stiffness. Simple and inexpensive methods such as PP or SVCS may be used to detect mortality risk and to provide important information that may be relevant for guiding therapeutic intervention in dialysis patients.

Effect of empagliflozin beyond glycemic control: Cardiovascular benefit in patients with type 2 diabetes and established cardiovascular disease. / Efeito da empagliflozina para além do controlo glicémico: benefício cardiovascular em doentes com DMT2 e doença cardiovascular estabelecida.

The prevalence of type 2 diabetes (T2D) continues to increase, and its association with cardiovascular (CV) disease has led to the inclusion of CV endpoints in clinical trials on the treatment of T2D. This article explores the various trials already performed and under development in this field, with particular focus on the EMPA-REG OUTCOME trial. In this trial, empagliflozin, a sodium-glucose co-transporter 2 inhibitor, demonstrated a reduction in CV risk in patients with T2D and established CV disease, in addition to CV safety and a decrease in glycated hemoglobin. This represents a paradigm shift that has led to changes in the international guidelines for the treatment of T2D. These results were maintained in subsequent subgroup analysis for heart failure, chronic kidney disease and peripheral arterial disease, although there are many questions concerning the mechanisms involved in these effects, including whether they are hemodynamic, metabolic or due to decreased myocardial cytoplasmic sodium concentrations. With this reduction in risk for major CV events in patients with T2D, the EMPA-REG OUTCOME trial demonstrated CV protection from a hypoglycemic drug for the first time, and opened a new era in the treatment and management of T2D. This study has led to the development of ongoing trials that will establish which patients will benefit most from this therapy, particularly with regard to comorbidities.

The impact of functioning hemodialysis arteriovenous accesses on renal graft perfusion: Results of a pilot study.

INTRODUCTION: After a kidney transplant, it is unknown whether the maintenance of a functioning hemodialysis arteriovenous access could have deleterious effects on renal grafts. We hypothesize that maintaining an arteriovenous access can deviate a significant proportion of the cardiac output from the renal graft. The aim of this study was to investigate whether a temporary closure of the arteriovenous access could lead to an increase in graft perfusion. METHODS: We conducted a study in 17 kidney-transplanted patients with a functioning arteriovenous access. We evaluated, at baseline and 30 s after compression of the arteriovenous access (access flow occlusion), the hemodynamic parameters and the renal resistive index of the graft by Doppler ultrasound. RESULTS: After arteriovenous access occlusion 82.4% (n = 14) of the patients had a decrease in resistive index. All patients had a decrease in heart rate (67 vs 58 bpm, p < 0.001) and 14 (82.4%) had an increase in mean blood pressure (98.3 vs 101.7 mm Hg, p = 0.044). There was a significant decrease in the resistive index (ΔRI) after the access occlusion (0.68 vs 0.64, p = 0.030). We found a negative correlation in Qa (r2 = -0.55, p = 0.022) with the ΔRI, and Qa was an independent predictor of ΔRI in a model adjusted to pre-occlusion resistive index. CONCLUSION: Our results showed that temporary occlusion of an arteriovenous access causes a significant decline in renal graft resistive index and this decline is higher with the occlusion of accesses with higher Qa. These results suggest that the maintenance of arteriovenous accesses, mainly those with higher Qa, can decrease renal graft perfusion.

Bone mineral density, vascular calcifications, and arterial stiffness in peritoneal dialysis patients.

The objective of this study was to evaluate the correlation of bone mineral density (BMD), evaluated by DXA, with vascular calcifications, arterial stiffness, and vascular disease in patients on peritoneal dialysis. Vascular calcifications were evaluated by vascular calcification score on plain x ray, and arterial stiffness was measured by pulse wave velocity using the Complior device (Artech Medical, Pantin, France). Adjusting for multiple factors, lower BMD at the femoral neck, but not at the lumbar spine, was associated with higher pulse wave velocity (p = 0.037), higher vascular calcification score (p = 0.013), and peripheral artery disease (p = 0.006). These data reinforce the hypothesis of the existence of a link between bone disease and cardiovascular disease in dialysis patients.

Gastrointestinal Bleeding and Diffuse Skin Thickening as Kaposi Sarcoma Clinical Presentation.

A 56-year-old African patient received a kidney from a deceased donor with 4 HLA mismatches in April 2013. He received immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil, and prednisone. Immediate diuresis and a good allograft function were soon observed. Six months later, the serum creatinine level increased to 2.6 mg/dL. A renal allograft biopsy revealed interstitial fibrosis and tubular atrophy grade II. Toxicity of calcineurin inhibitor was assumed and, after a switch for everolimus, renal function improved. However, since March 2014, renal function progressively deteriorated. A second allograft biopsy showed no new lesions. Two months later, the patient was admitted due to anuria, haematochezia with anaemia, requiring 5 units of packed red blood cells, and diffuse skin thickening. Colonoscopy showed haemorrhagic patches in the colon and the rectum; histology diagnosis was Kaposi sarcoma (KS). A skin biopsy revealed cutaneous involvement of KS. Rapid clinical deterioration culminated in death in June 2014. This case is unusual as less than 20 cases of KS with gross gastrointestinal bleeding have been reported and only 6 cases had the referred bleeding originating in the lower gastrointestinal tract. So, KS should be considered in differential diagnosis of gastrointestinal bleeding in some kidney transplant patients.

A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients.

BACKGROUND: Cardiovascular morbidity and mortality are highly prevalent in haemodialysis (HD) patients and have been recently associated with vascular calcifications. The objective of our study was to assess the value of a simple vascular calcification score for the prediction of cardiovascular death, cardiovascular hospitalizations and fatal and non-fatal cardiovascular events in HD patients, and to correlate this score with cardiovascular disease and with other known predictors of vascular disease. METHODS: In this observational, prospective study 123 chronic HD patients (75 males and 48 females; 20% diabetic) were included, who were on low-flux HD treatment for 46.6+/-52 months (mean+/-SD). We set up a simple vascular calcification score based on plain radiographic films of pelvis and hands. Brachial pulse pressure and mean arterial pressure (MAP) were measured and cardiovascular events and hospitalization episodes were assessed. RESULTS: During an observational period of 37 months there were 17 cardiovascular deaths; 28 patients needed cardiovascular hospitalizations and 32 patients suffered fatal and non-fatal cardiovascular events. Coronary artery disease was diagnosed in 43 patients (35%), peripheral arterial disease in 33 patients (26.8%), cerebrovascular disease in 16 patients (13%) and vascular disease (coronary artery disease or peripheral arterial disease or cerebral vascular disease) in 61 patients (49.6%). By binary logistic regression, diabetes (P = 0.01), male sex (P<0.001), age (P = 0.02), HD duration (P = 0.02) and MAP (P = 0.03) were independently associated with a vascular score > or =3. This score > or =3 was independently associated with coronary artery disease (P = 0.008), peripheral arterial disease (P<0.001) and vascular disease (P = 0.001). Patients with a vascular calcification score > or =3 had a 3.9-fold higher risk of cardiovascular mortality (P = 0.03), a 2.8-fold higher risk of cardiovascular hospitalizations (P = 0.02) and a 2.3-fold higher risk of fatal or non-fatal cardiovascular events (P = 0.04). CONCLUSIONS: The present vascular calcification scoring represents a simple tool for the assessment of cardiovascular risk related with vascular calcifications in chronic HD patients.