Hypernatraemia and low eGFR at hospitalization in COVID-19 patients: a deadly combination.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on the general population and the burden of pre-existing comorbidities has heavily affected the outcome of the infection. Hyponatraemia has been frequently described. Conversely, hypernatraemia has rarely been described in COVID-19. METHODS: The studied cohort encompasses all COVID-19 patients consecutively admitted to the Messina Hospital, Italy, during the first wave of the epidemic. Since healthcare structures were not overwhelmed at that time, indications for hospitalization were homogeneous throughout the study period. Serum sodium levels, kidney function [estimated glomerular filtration rate (eGFR)], demographic and clinical characteristics were recorded at admission. Correlation between mortality, sodium and eGFR was evaluated by survival curves and univariate and multivariate regression models. RESULTS: Baseline biochemical and clinical data at the time of admission were available for 115 COVID-19-confirmed patients. The median age at admission was 73 years (48% men), with a median Charlson Comorbidity Index of 4. A total of 23.5% of patients presented with a sodium level ≥146 mmol/L, while 7.8% had sodium <135 mmol/L. Hypernatraemic patients were older, with higher comorbidity. Age, hypernatraemia and reduced eGFR were associated with increased mortality in both univariate and multivariate regression models (P < 0.001). The combination of hypernatraemia and reduced renal function at admission had an odds ratio of 47.67 (95% confidence interval 10.08-225.43) of dying compared with patients with an eGFR ≥60 mL/min and sodium <145 mmol/L. CONCLUSIONS: Our study suggests that the association between hypernatraemia and reduced eGFR at referral is a highly relevant prognostic marker for death during hospitalization. The role of this association should be further tested in larger, multicentre cohorts.

Left ventricular hypertrophy in chronic kidney disease: A diagnostic criteria comparison.

BACKGROUND AND AIMS: CKD patients have a high prevalence of LVH and this leads to an increase of cardiovascular risk. The aim of this study was to assess the prevalence of left ventricular hypertrophy (LVH) and left ventricular geometry in a group of 293 hypertensive patients with stage 2-5 chronic kidney disease (CKD), compared with 289 essential hypertensive patients with normal renal function. METHODS AND RESULTS: All patients underwent echocardiographic examination. Patients on stage 1 CKD, dialysis treatment, or with cardiovascular diseases were excluded. LVH was observed in 62.8% of patients with CKD and in 51.9% of essential hypertensive patients (P < 0.0001). We found increasingly higher left ventricular diameters, thicknesses, and mass from stage 2-5 CKD. Distribution of concentric and eccentric LVH was not very different between the two groups. However, after introducing mixed hypertrophy, the difference between the two groups group was disclosed (P = 0.027). Multiple regression analysis confirmed that the association between renal function and left ventricular mass (ß -0.287; P < 0.0001) was independent by potential confounders. Diastolic function was significantly worse in patients with CKD, especially in more advanced stages. CONCLUSION: Our study confirms that LVH is highly prevalent in patients with CKD, especially by using the most recent cut off; in this population, LVH is often characterized by the simultaneous increase of wall thicknesses and diameters with negative effects on diastolic function.

Is echocardiography mandatory for patients with chronic kidney disease?

This study aims at evaluating the prevalence of left ventricular diastolic dysfunction in a group of 319 hypertensive patients with stage 3b-4-5 chronic kidney disease (according to Kidney Disease Improving Global Outcomes classification), compared with 216 patients with essential hypertension and normal renal function. All patients underwent echocardiographic examination. Patients on stage 1-2-3a chronic kidney disease, dialysis treatment, or with previous manifestations of heart failure or other cardiovascular diseases were excluded. Patients with renal disease had significantly worse diastolic function (both considering trans-mitral flow and tissue Doppler imaging parameters). Diastolic dysfunction is found in 70.5% of the CKD group and in 41.6% of hypertensive patients (p < 0.0001). Multiple regression analysis shows an association between renal function and diastolic function (ß 0.223; p < 0.0001), independent of potential confounders. Our study shows that diastolic dysfunction is highly prevalent in patients with advanced chronic kidney disease; we posit that in this population, the risk of diastolic heart failure is very high. We think that patients with a marked decrease of glomerular filtration rate (GFR) must be considered at high risk for diastolic heart failure and should have an echocardiographic examination performed, even if asymptomatic and in the absence of evident cardiovascular disease.

Emerging therapeutic strategies for minimal change disease and focal and segmental glomerulosclerosis.

INTRODUCTION: Minimal change disease (MCD) and Focal and segmental glomerulosclerosis (FSGS) are two of the major causes of nephrotic syndrome (NS) in children and adults. According to KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, the treatment of adult primary MCD and FSGS should be based on immunosuppressants and antiproteinuric drugs. Recently, Rituximab, a humanized monoclonal antibody (mAb) has emerged as a potential treatment for steroid or calcineurin inhibitor-dependent patients; it has however demonstrated lower efficacy in those with nephrotic syndrome that is resistant to the above indicated drugs. AREAS COVERED: Analysis of ongoing and already completed clinical trials, retrieved from clinicaltrials.gov, clinicaltrialsregister.eu and PubMed involving new therapies for nephrotic syndrome secondary to MCD and FSGS. EXPERT OPINION: The most promising drugs under investigation for MCD and FSGS are mAbs. We are hopeful that new therapeutic options to treat multi-drug resistant MCD and FSGS will emerge from currently ongoing studies. What appears certain is the difficulty in enrolling patients affected by orphan renal diseases and the selection of valid endpoints in clinical trials, such as kidney failure.

Inverse association between type 2 diabetes and aortic root dimension in hypertensive patients.

BACKGROUND: Some data support the concept that aortic root diameter (ARD) in hypertension may be regarded as a marker of subclinical organ damage. The impact of type 2 diabetes mellitus (DM) on cardiac structure and function is known, although the relationship between DM and ARD is not clear. The aim of our study was to evaluate the influence of DM on ARD in hypertensive patients. METHODS: We enrolled 1693 hypertensive patients (aged 63.7±9.6years). The population was divided into two groups: the first one with DM (n=747) and the second one without DM (n=946). ARD was measured by echocardiography at level of Valsalva's sinuses using echocardiography M-mode tracings. It was considered as absolute measure and normalized to height (ARD/H) and body surface area (ARD/BSA). Left ventricular mass index (LVMI) and some parameters of systolic and diastolic function have been valued by means of echocardiography and tissue Doppler imaging. RESULTS: The DM group was characterized by more elevated values of LVMI and a worst systolic and diastolic function. ARD value was significantly lower in DM group in comparison to patients without DM only when indexed for BSA (ARD/BSA=18.7±2.3mm/m2 vs 18.3±2.0mm/m2, p=0.01). This difference remained statistically significant, even after correction by age, sex and BMI (p=0.01). A multivariate linear regression analysis demonstrated an inverse relationship between DM and ARD/BSA after correction for potential confounders (ß=0.10, p<0.001). CONCLUSIONS: Our results confirm the hypothesis of a protective role of DM on aortic root dilatation.

Relationship between aortic root size and glomerular filtration rate in hypertensive patients.

OBJECTIVE: Recent studies suggest that enlarged aortic root diameter (ARD) may predict cardiovascular events in absence of aneurysmatic alterations. Little is known about the influence of renal function on ARD. Our study was aimed to assess the relationships between glomerular filtration rate (GFR) and ARD in hypertensive subjects. METHODS: We enrolled 611 hypertensive individuals (mean age: 52 ±â€Š15 years; men 63%). ARD was measured by echocardiography at the level of Valsalva's sinuses using M-mode tracings. It was considered as absolute measure, normalized to body surface area (ARD/BSA) and indexed to height (ARD/H). GFR was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. The study population was categorized into seven groups: subjects without chronic kidney disease (no CKD) and subjects with increasing severity of CKD (1, 2, 3a, 3b, 4, 5), as proposed by the 2012 Kidney Disease: Improving Global Outcomes guidelines. RESULTS: ARD/BSA and ARD/H showed a stepwise increase from the group with normal renal function to the groups with increasing severity of CKD. GFR correlated significantly with ARD (r = -0.17), ARD/BSA (r = -0.43) and ARD/H (r = -0.35; all P < 0.001). The associations of GFR with ARD/BSA (ß = -0.26; P < 0.001) and ARD/H (ß = -0.13; P = 0.01) held in linear multiple regression analyses, after adjustment for various confounding factors. CONCLUSION: Our study seems to suggest that a reduced renal function may adversely influence ARD. This may contribute to explain the enhanced cardiovascular risk associated with renal insufficiency.

High Affinity Binders to EphA2 Isolated from Abdurin Scaffold Libraries; Characterization, Binding and Tumor Targeting.

Abdurins are a novel antibody-like scaffold derived from the engineering of a single isolated CH2 domain of human IgG. Previous studies established the prolonged serum half-life of Abdurins, the result of a retained FcRn binding motif. Here we present data on the construction of large, diverse, phage-display and cell-free DNA display libraries and the isolation of high affinity binders to the cancer target, membrane-bound ephrin receptor tyrosine kinase class A2 (EphA2). Antigen binding regions were created by designing combinatorial libraries into the structural loops and Abdurins were selected using phage display methods. Initial binders were reformatted into new maturation libraries and low nanomolar binders were isolated using cell-free DNA display, CIS display. Further characterization confirmed binding of the Abdurins to both human and murine EphA2 proteins and exclusively to cell lines that expressed EphA2, followed by rapid internalization. Two different EphA2 binders were labeled with 64Cu, using a bifunctional MeCOSar chelator, and administered to mice bearing tumors from transplanted human prostate cancer cells, followed by PET/CT imaging. The anti-EphA2 Abdurins localized in the tumors as early as 4 hours after injection and continued to accumulate up to 48 hours when the imaging was completed. These data demonstrate the ability to isolate high affinity binders from the engineered Abdurin scaffold, which retain a long serum half-life, and specifically target tumors in a xenograft model.

Association between protein signals and type 2 diabetes incidence.

Understanding early determinants of type 2 diabetes is essential for refining disease prevention strategies. Proteomic technology may provide a useful approach to identify novel protein patterns potentially related to pathophysiological changes that lead up to diabetes. In this study, we sought to identify protein signals that are associated with diabetes incidence in a middle-aged population. Serum samples from 519 participants in a nested case-control selection (167 cases and 352 age-, sex- and BMI-matched normoglycemic control subjects, median follow-up 14.0 years) within the Whitehall-II cohort were analyzed by linear matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Nine protein peaks were found to be associated with incident diabetes. Rate ratios for high peak intensity ranged between 0.4 (95% CI, 0.2-0.8) and 4.0 (95% CI, 1.7-9.2) and were robust to adjustment for main potential confounders, including obesity, lipids and C-reactive protein. The proteins associated with these peaks may reflect diabetes pathogenesis. Our study exemplifies the utility of an approach that combines proteomic and epidemiological data.