The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy.

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient's electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

Dialysis Patients Respond Adequately to Influenza Vaccination Irrespective of Dialysis Modality and Chronic Inflammation.

(1) Background: Chronic inflammation and suboptimal immune responses to vaccinations are considered to be aspects of immune dysregulation in patients that are undergoing dialysis. The present study aimed to evaluate immune responses in hemodialysis (HD) and online hemodiafiltration (OL-HDF) patients to a seasonal inactivated quadrivalent influenza vaccine (IQIV). (2) Methods: We enrolled 172 chronic dialysis patients (87 on HD and 85 on OL-HDF) and 18 control subjects without chronic kidney disease in a prospective, cross-sectional cohort study. Participants were vaccinated with a seasonal IQIV, and antibody titers using the hemagglutination inhibition (HI) assay were determined before vaccination (month 0) and 1, 3, and 6 months thereafter. Demographics and inflammatory markers (CRP, IL-6, IL-1ß) were recorded at month 0. The primary endpoints were the rates of seroresponse (SR), defined as a four-fold increase in the HI titer, and seroprotection (SP), defined as HI titer ≥ 1/40 throughout the study period. Statistical analyses were conducted in R (version 3.6.3) statistical software. The differences between groups were analyzed using chi-square and t-test analyses for dichotomous and continuous variables, respectively. To identify independent determinants of SR and SP, generalized linear models were built with response or protection per virus strain as the dependent variable and group, age, sex, time (month 0, 1, 3, 6), diabetes, IL-6, dialysis vintage, HD access, and HDF volume as independent explanatory variables. (3) Results: SR and SP rates were similar between control subjects, and dialysis patients were not affected by dialysis modality. SP rates were high (> 70%) at the beginning of the study and practically reached 100% after vaccination in all study groups. These results applied to all four virus strains that were included in the IQIV. IL-6 levels significantly differed between study groups, with HD patients displaying the highest values, but this did not affect SP rates. (4) Conclusions: Dialysis patients respond to influenza immunization adequately and similarly to the general population. Thus, annual vaccination policies should be encouraged in dialysis units. OL-HDF reduces chronic inflammation; however, this has no impact on SR rates.

Cardiorenal Syndrome: Challenges in Everyday Clinical Practice and Key Points towards a Better Management.

Under the term cardiorenal syndrome (CRS) falls an increasing number of patients who present with combined heart and kidney dysfunction. Despite the increasing knowledge concerning CRS pathophysiology, diagnosis, and treatment, many of the aforementioned aspects remain obscure in everyday clinical practice. Some of the challenges that clinicians face when they treat CRS nowadays is the need for a patient-centered management with early diagnosis, early intervention, the distinction of true kidney injury from permissive renal function deterioration during decongestion therapy, and the development of therapeutic algorithms to guide therapy.

Adherence to the Mediterranean Diet Is Associated with a More Favorable Left Ventricular Geometry in Patients with End-Stage Kidney Disease.

Introduction. The aim of the study was to examine the impact of adherence to a Mediterranean-style diet (MD) on left ventricular hypertrophy (LVH) and cardiac geometry in chronic kidney disease patients on dialysis (CKD-5D), given the high prevalence of cardiovascular morbidity in this population. Methods. n = 127 (77 men and 50 women) CKD-5D patients (69 on hemodialysis and 58 on peritoneal dialysis) with a mean age of 62 ± 15 years were studied. An MD adherence score (MDS) (range 0−55, 55 representing maximal adherence) was estimated with a validated method. Echocardiographic LVH was defined by LV mass index (LVMI) > 95 g/m2 in women and >115 g/m2 in men. Based on LVMI and relative wall thickness (RWT), four LV geometric patterns were defined: normal (normal LVMI and RWT), concentric remodeling (normal LVMI and increased RWT > 0.42), eccentric LVH (increased LVMI and normal RWT), and concentric LVH (increased LVMI and RWT). Results. Patients with LVH (n = 81) as compared to patients with no LVH (n = 46) were older in age (66 ± 13 vs. 55 ± 16 years; p < 0.001) had lower MDS (24 ± 2.7 vs. 25 ± 4.3; p < 0.05) and higher malnutrition-inflammation score (5.0 ± 2.7 vs. 3.9 ± 1.9; p < 0.05), body mass index (27.5 ± 4.9 vs. 24.1 ± 3.5 kg/m2; p < 0.001), prevalence of diabetes (79% vs. 20%; p < 0.05), coronary artery disease (78% vs. 20%; p < 0.05) and peripheral vascular disease (78% vs. 20%; p < 0.01). In a multivariate logistic regression analysis adjusted for all factors mentioned above, each 1-point greater MDS was associated with 18% lower odds of having LVH (OR = 0.82, 95% CI: 0.69−0.98; p < 0.05). MDS was inversely related to LVMI (r = −0.273; p = 0.02), and in a multiple linear regression model (where LVMI was analyzed as a continuous variable), MDS emerged as a significant (Β = −2.217; p < 0.01) independent predictor of LVH. Considering LV geometry, there was a progressive decrease in MDS from the normal group (25.0 ± 3.7) to concentric remodeling (25.8 ± 3.0), eccentric (24.0 ± 2.8), and then concentric (23.6 ± 2.7) group (p < 0.05 for the trend). Conclusions. The greater adherence to an MD is associated with lesser LVH, an important cardiovascular disease risk factor; MD preserves normal cardiac geometry and may confer protection against future cardiac dysfunction in dialysis patients.

The p.Pro482Ala Variant in the CNNM2 Gene Causes Severe Hypomagnesemia Amenable to Treatment with Spironolactone.

Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia. Here, we report a family with a novel CNNM2 p.Pro482Ala variant, presenting with overt hypomagnesemia and mild neurological involvement (autosomal dominant renal hypomagnesemia 6, HOMG6, MIM# 613882). Using a bioinformatics approach, we showed that the p.Pro482Ala amino acid substitution causes a 3D conformational change in CNNM2 structure in the cystathionin beta synthase (CBS) domain and the carboxy-terminal protein segment. A novel finding was that aldosterone inhibition with spironolactone helped to alleviate hypomagnesemia and symptoms in the proband.

Dent-2 disease with a Bartter-like phenotype caused by the Asp631Glu mutation in the OCRL gene.

BACKGROUND: Dent disease is an X-linked disorder characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and chronic kidney disease (CKD). It is caused by mutations in the chloride voltage-gated channel 5 (CLCN5) gene (Dent disease-1), or in the OCRL gene (Dent disease-2). It is associated with chronic metabolic acidosis; however metabolic alkalosis has rarely been reported. CASE PRESENTATION: We present a family with Dent-2 disease and a Bartter-like phenotype. The main clinical problems observed in the proband included a) primary phosphaturia leading to osteomalacia and stunted growth; b) elevated serum calcitriol levels, leading to hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis; c) severe salt wasting causing hypotension, hyperaldosteronism, hypokalemia and metabolic alkalosis; d) partial nephrogenic diabetes insipidus attributed to hypercalcemia, hypokalemia and nephrocalcinosis; e) albuminuria, LMWP. Phosphorous repletion resulted in abrupt cessation of hypercalciuria and significant improvement of hypophosphatemia, physical stamina and bone histology. Years later, he presented progressive CKD with nephrotic range proteinuria attributed to focal segmental glomerulosclerosis (FSGS). Targeted genetic analysis for several phosphaturic diseases was unsuccessful. Whole Exome Sequencing (WES) revealed a c.1893C > A variant (Asp631Glu) in the OCRL gene which was co-segregated with the disease in male family members. CONCLUSIONS: We present the clinical characteristics of the Asp631Glu mutation in the OCRL gene, presenting as Dent-2 disease with Bartter-like features. Phosphorous repletion resulted in significant improvement of all clinical features except for progressive CKD. Angiotensin blockade improved proteinuria and stabilized kidney function for several years.

The Pathophysiological Role of Heat Shock Response in Autoimmunity: A Literature Review.

Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects of heat-shock proteins 27, 40, 70, 65, 60, and 90 in experimental and clinical autoimmune settings.