Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype.

UNLABELLED: Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs. OBJECTIVE: To characterize clinical-pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes. DESIGN: Retrospective study. SUBJECTS AND MEASUREMENTS: Clinical and pathological characteristics of 90 APAs and seven diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing. RESULTS: Mutation frequencies were as follows: KCNJ5, 37·1%; CACNA1D, 10·3%; ATP1A1, 8·2%; ATP2B3, 3·1%; and CTNNB1, 2·1%. Previously unidentified mutations included I157K, F154C and two insertions (I150_G151insM and I144_E145insAI) in KCNJ5, all close to the selectivity filter, V426G_V427Q_A428_L433del in ATP2B3 and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female and other mutations with male gender (P = 0·007). On computed tomography, KCNJ5-mutant tumours displayed significantly greater diameter (P = 0·023), calculated area (P = 0·002) and lower precontrast Hounsfield units (P = 0·0002) vs tumours with mutations in other genes. Accordingly, KCNJ5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 × 10(-6) vs non-KCNJ5 mutant and P = 0·0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma. CONCLUSIONS: KCNJ5-mutant tumours appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations.

Impaired Immune Response to SARS-CoV-2 Vaccination in Dialysis Patients and in Kidney Transplant Recipients.

Background: Patients with kidney failure on dialysis or after renal transplantation have a high risk for severe COVID-19 infection, and vaccination against SARS-CoV-2 is the only expedient prophylaxis. Generally, immune responses are attenuated in patients with kidney failure, however, systematic analyses of immune responses to SARS-CoV-2 vaccination in patients on dialysis and in kidney transplant recipients (KTRs) are still needed. Methods: In this prospective, multicentric cohort study, antibody responses to COVID-19 mRNA vaccines (BNT162b2 [BioNTech/Pfizer] or mRNA-1273 [Moderna]) were measured in 32 patients on dialysis and in 28 KTRs. SARS-CoV-2-specific antibodies and neutralization capacity were evaluated and compared with controls (n=78) of a similar age range. Results: After the first vaccination, SARS-CoV-2-specific antibodies were nearly undetectable in patients with kidney failure. After the second vaccination, 93% of the controls and 88% of patients on dialysis but only 37% of KTRs developed SARS-CoV-2-specific IgG above cutoff. Moreover, mean IgG levels were significantly lower in KTRs (54±93 BAU/ml) compared with patients on dialysis (503±481 BAU/ml; P<0.01). Both KTRs and patients on dialysis had significantly lower IgG levels compared with controls (1992±2485 BAU/ml; P<0.001 and P<0.01, respectively). Importantly, compared with controls, neutralizing antibody titers were significantly lower in KTRs and patients on dialysis. After the second vaccination, 76% of KTRs did not show any neutralization capacity against SARS-CoV-2, suggesting impaired seroprotection. Conclusions: Patients with kidney failure show a significantly weaker antibody response compared with controls. Most strikingly, only one out of four KTRs developed neutralizing antibodies against SARS-CoV-2 after two doses of vaccine. These data suggest that vaccination strategies need modification in KTRs and patients on dialysis.Clinical Trial registry name and registration number: Vaccination Against COVID-19 in Chronic Kidney Disease, NCT04743947.

Psychomotor slowing in hepatitis C and HIV infection.

BACKGROUND: Both HIV and hepatitis C virus (HCV) may enter the central nervous system and cause cognitive and/or motor dysfunction. There are limited data on cognition and no data on motor performance in HIV/HCV-coinfected patients. OBJECTIVE: To provide data on cognition and motor performance in HIV/HCV infected patients. METHODS: We compared 43 HIV-seropositive but HCV-seronegative patients, 43 HIV/HCV-coinfected patients, and 44 HIV-negative but HCV-positive patients, all of whom went through neuropsychologic testing and electrophysiologic assessment of basal ganglia-mediated motor function. RESULTS: No significant differences could be found among the groups with regard to premorbid verbal and actual nonverbal intelligence, attention, and memory; the HIV dementia scale; and all somatic and most psychiatric complaints. Affective disorders were less frequent in HIV-negative but HCV-positive patients. This group also scored lower for depression. For all 3 groups, significant pathologic slowing of most rapid alternating movements (right hand) compared with those of HIV/HCV-negative controls as well as significantly prolonged contraction times (both hands) could be diagnosed. Simple reaction times were significantly prolonged only in HIV/HCV-coinfected patients. CONCLUSIONS: Although clinically asymptomatic, both HIV-positive and HCV-positive patients may show affective disturbances and significant psychomotor slowing. A potential predictive value for the further course of infection, which is well established in HIV-positive patients, remains to be investigated in HCV-positive or HIV/HCV-coinfected patients.