Prevalence of vertebral fractures and their prognostic significance in the survival in patients with chronic kidney disease stages 3-5 not on dialysis

The prevalence of vertebral fractures (VF) and their association with clinical risk factors and outcomes are poorly documented in chronic kidney disease (CKD) cohorts. The aim of the study was to evaluate the prevalence of VF in patients with non-dialysis dependent CKD (NDD-CKD), their value in predicting mortality and its correlation with parameters of bone mineral metabolism and vascular calcification. 612 NDD 3-5 stage CKD patients participating in the OSERCE-2 study, a prospective, multicenter, cohort study, were prospectively evaluated and categorized into two groups according to presence or absence of VF at enrollment. VF were assessed with lateral radiographs and Genant semi-quantitative method was applied. Three radiologists specialized in musculoskeletal radiology performed consensual reading of individual images obtained using a Raim DICOM Viewer and a Canon EOS 350 camera to measure with Java Image software in those who had traditional acetate X-ray. Factors related to VF were assessed by logistic regression analysis. Association between VF and death over a 3-year follow-up was assessed by Kaplan-Meier survival curves and Cox-proportional hazard models. VF were detected in 110patients(18%). Serumphosphatelevels(OR0.719,95%CI0.532to0.972,p = 0.032),ankle-brachial index 3 and serum phosphate, the presence of VF (HR 1.983, 95% CI 1.009-3.898, p = 0.047) were an independent predictor of all-cause mortality. In our study 18% of patients with NDD-CKD have VF. Factors associated with VF were age, low serum phosphate levels and peripheral vascular disease. The presence of VF was an independent risk factor for mortality in stages 3-5 NDD-CKD patients. Clinical trials are needed to confirm whether this relationship is causal and reversible with treatment for osteoporosis

Pathogenic mechanisms of SARS-CoV-2 infection and kidney disease: a clinical and molecular perspective

La infección por SARS-CoV-2 se ha convertido en un problema mundial de salud pública. Su presentación clínica es variada, desde benigna hasta un síndrome de distrés respiratorio agudo, afectación sistémica y fallo multiorgánico. La severidad del cuadro clínico depende de factores biológicos del virus y del huésped y de comorbilidades como la enfermedad renal. Además, la interacción entre el virus, la enzima convertidora de angiotensina 2 y la respuesta inmunológica exacerbada podría conducir al desarrollo de lesión renal aguda. Sin embargo, las implicaciones de la infección por SARSCoV-2 sobre las células renales, las repercusiones pronósticas en los pacientes con enfermedad renal crónica y su efecto a largo plazo sobre la función renal no están del todo claras. El objetivo es revisar el papel del SARSCoV-2 en la enfermedad renal aguda y crónica, y sus posibles mecanismos patogénicos en la afectación renal.The SARS-CoV-2 infection has become as a worldwide public health emergency. It exhibits a variety of clinical presentations, ranging from benign to acute respiratory distress syndrome, systemic involvement, and multiorganic failure. The severity of the clinical picture depends on host and virus biological features and the presence of comorbidities such as chronic kidney disease. In addition, the interaction between the virus, angiotensin-converting enzyme 2, and the exacerbated immune response could lead to the development of acute kidney injury. However, the implications of SARSCoV-2 infection on renal cells, the prognosis of patients with chronic kidney disease, and the long-term behavior of renal function are not entirely understood. This review aims to explore the role of SARS-CoV-2 in acute and chronic kidney disease and the possible pathogenic mechanisms of renal involvement

Is S100B involved in attention-deficit/hyperactivity disorder (ADHD)? comparisons with controls and changes following a triple therapy containing methylphenidate, melatonin and ω-3 PUFAs

Background: Increasing evidence supports a neuroinflammatory basis in ADHD damaging glial function and thereby altering dopaminergic (DA) neurotransmission. Previous studies focusing on the S100B protein as a marker of glial function have shown contradictory results. We conducted a clinical trial to investigate differences in S100B levels between ADHD patients and controls, as well as observe gradual changes in S100B concentrations after a triple therapy (TT) containing methylphenidate (MPH), melatonin (aMT) and omega-3 fatty acids (ω-3 PUFAs). Methods: 62 medication-naïve children with ADHD (ADHD-G) and 65 healthy controls (C-G) were recruited. Serum S100B was measured at baseline (T0) in ADHD-G/C-G, and three (T3) and six months (T6) after starting TT in the ADHD-G, together with attention scores. Results: A significant increase in S100B was observed in the ADHD-G vs. C-G. In the ADHD-G, significantly higher S100B values were observed for comparisons between T0–T3 and between T0–T6, accompanied by a significant improvement in attention scores for the same timepoint comparisons. No significant differences were found for S100B between T3–T6. Conclusion: Our results agree with the hypothesis of glial damage in ADHD. Further studies on the link between DA and S100B are required to explain the transient increase in S100B following TT

Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and their Combination in Patients with Chronic Kidney Disease: A Randomized Cross-over Clinical Trial

Background: SGLT2 inhibitors and MRAs reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with chronic kidney disease (CKD). We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and mineralocorticoid receptor antagonists (MRA) eplerenone alone and in combination in patients with CKD. Methods: We conducted a randomized open-label cross-over trial in patients with urinary albumin excretion ≥100 mg/24-hour, eGFR 30-90 mL/min/1.73m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week wash-out periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. Results: Of 57 patients screened, 46 were randomly assigned (mean eGFR 58.1 mL/min/1.73m2, median UACR 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks treatment with dapagliflozin, eplerenone, and dapagliflozineplerenone was -19.6% (95%CI -34.3, -1.5), -33.7% (95%CI -46.1, -18.5), and -53.0% (95%CI - 61.7, -42.4; p<0.001 vs dapagliflozin; p=0.0127 vs eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozineplerenone (r=-0.13; p=0.473; r=-0.08; p=0.658 respectively). Hyperkalemia was more frequently reported with eplerenone (N=8, [17.4%]) compared to dapagliflozin (N=0, [0%]) or dapagliflozin-eplerenone (N=2, [4.3%]; Pbetween-groups=0.0033). Conclusion: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment

Glomerular and tubular effects of dapagliflozin, eplerenone and their combination in patients with chronic kidney disease:A post-hoc analysis of the ROTATE-3 study

AIM: Sodium-glucose co-transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function.METHODS: This post-hoc analysis utilized data of the ROTATE-3 study, a randomized cross-over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro-hormonal markers and tubular sodium handling were assessed with mixed repeated measures models.RESULTS: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin-eplerenone was -34.8% (95% CI -52.2, -10.9), -5.9% (95% CI -32.5, 31.3) and -28.1% (95% CI -48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin-eplerenone [32.2% (95% CI -1.5, 77.4)], compared with dapagliflozin [-12.5% (95% CI -35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin-eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI -10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI -879.2, -32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI -926.1, -120.0). Dapagliflozin-eplerenone decreased proximal absolute sodium reabsorption [-971.0 mmol/min (95% CI -1411.0, -531.0)], but did not affect distal absolute sodium reabsorption [-9.2 mmol/min (95% CI -402.0, 383.6)].CONCLUSIONS: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects.</p

Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and their Combination in Patients with Chronic Kidney Disease:A Randomized Cross-Over Clinical Trial

BACKGROUND: SGLT2 inhibitors and MRAs reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with chronic kidney disease (CKD). We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and mineralocorticoid receptor antagonists (MRA) eplerenone alone and in combination in patients with CKD. METHODS: We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hours, eGFR 30-90 ml/min per 1.73 m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. RESULTS: Of 57 patients screened, 46 were randomly assigned (mean eGFR 58.1 ml/min per 1.73 m2, median UACR 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% CI, -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; P<0.001 versus dapagliflozin; P=0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (r=-0.13; P=0.47; r=-0.08; P=0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (n=8; 17.4%) compared with dapagliflozin (n=0; 0%) or dapagliflozin-eplerenone (n=2; 4.3%; P between-groups=0.003). CONCLUSIONS: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: European Union Clinical Trials Register, EU 2017-004641-25

Clinical Approach to Vascular Calcification in Patients With Non-dialysis Dependent Chronic Kidney Disease : Mineral-Bone Disorder-Related Aspects

Chronic kidney disease (CKD) is associated with a very high morbimortality, mainly from cardiovascular origin, and CKD is currently considered in the high- or very high risk- cardiovascular risk category. CKD-mineral and bone disorders (CKD-MBDs), including vascular and/or valvular calcifications, are also associated with these poor outcomes. Vascular calcification (VC) is very prevalent (both intimal and medial), even in non-dialysis dependent patients, with a greater severity and more rapid progression. Simple X-ray based-scores such as Adragão's (AS) are useful prognostic tools and AS (even AS based on hand-X-ray only) may be superior to the classic Kauppila's score when evaluating non-dialysis CKD patients. Thus, in this mini-review, we briefly review CKD-MBD-related aspects of VC and its complex pathophysiology including the vast array of contributors and inhibitors. Furthermore, although VC is a surrogate marker and is not yet considered a treatment target, we consider that the presence of VC may be relevant in guiding therapeutic interventions, unless all patients are treated with the mindset of reducing the incidence or progression of VC with the currently available armamentarium. Avoiding phosphate loading, restricting calcium-based phosphate binders and high doses of vitamin D, and avoiding normalizing (within the normal limits for the assay) parathyroid hormone levels seem logical approaches. The availability of new drugs and future studies, including patients in early stages of CKD, may lead to significant improvements not only in patient risk stratification but also in attenuating the accelerated progression of VC in CKD