BACKGROUND: Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease. METHODS: LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study, n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed. RESULTS: In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33–5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23–4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E’ within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83–4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09–8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events. CONCLUSIONS: LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.

The long-term effect of protection by two doses of SARS-CoV-2 vaccination in patients receiving chronic intermittent hemodialysis (CIHD) is an urging question. We investigated the humoral and cellular immune response of 42 CIHD patients who had received two doses of SARS-CoV-2 vaccine, and again after a booster vaccine with mRNA-1273 six months later. We measured antibody levels and SARS-CoV-2-specific surrogate neutralizing antibodies (SNA). Functional T cell immune response to vaccination was assessed by quantifying interferon-γ (IFN-γ) and IL-2 secreting T cells specific for SARS-CoV-2 using an ELISpot assay. Our data reveal a moderate immune response after the second dose of vaccination, with significantly decreasing SARS-CoV-2-specific antibody levels and less than half of the study group showed neutralizing antibodies six months afterwards. Booster vaccines increased the humoral response dramatically and led to a response rate of 89.2% for antibody levels and a response rate of 94.6% for SNA. Measurement in a no response/low response (NR/LR) subgroup of our cohort, which differed from the whole group in age and rate of immunosuppressive drugs, indicated failure of a corresponding T cell response after the booster vaccine. We strongly argue in favor of a regular testing of surrogate neutralizing antibodies and consecutive booster vaccinations for CIHD patients to provide a stronger and persistent immunity.

S1P and its receptors have been reported to play important roles in the development of renal fibrosis. Although S1P₅ has barely been investigated so far, there are indications that it can influence inflammatory and fibrotic processes. Here, we report the role of S1P₅ in renal inflammation and fibrosis. Male S1P₅ knockout mice and wild-type mice on a C57BL/6J background were fed with an adenine-rich diet for 7 days or 14 days to induce tubulointerstitial fibrosis. The kidneys of untreated mice served as respective controls. Kidney damage, fibrosis, and inflammation in kidney tissues were analyzed by real-time PCR, Western blot, and histological staining. Renal function was assessed by plasma creatinine ELISA. The S1P₅ knockout mice had better renal function and showed less kidney damage, less proinflammatory cytokine release, and less fibrosis after 7 days and 14 days of an adenine-rich diet compared to wild-type mice. S1P₅ knockout ameliorates tubular damage and tubulointerstitial fibrosis in a model of adenine-induced nephropathy in mice. Thus, targeting S1P₅ might be a promising goal for the pharmacological treatment of kidney diseases.

Hemodialysis patients faced an excess morbidity and mortality during the COVID-19 pandemic. We evaluated the effect of second-generation mRNA vaccines against Omicron BA.4 and BA.5 variants of SARS-CoV-2 on humoral immunity. The study population comprised 66 adult hemodialysis patients who have encountered four SARS-CoV-2 antigen contacts through vaccination or infection. We assessed their humoral response using an anti-SARS-CoV-2 spike receptor binding domain IgG antibody assay (S-RBD-ab), measuring neutralizing antibodies against ancestral strain of SARS-CoV-2, Delta, and Omicron in a surrogate virus neutralization test (SVNT), and specifically against BA.5 in a plaque reduction neutralization test (PRNT) before and four weeks after vaccination with Comirnaty Original/Omicron BA.4-5. During the following six months, SARS-CoV-2 infections and symptom severity were documented. The bivalent mRNA vaccine led to a 7.6-fold increase in S-RBD-ab levels and an augmented inhibition of the Omicron variant in SVNT by 35% (median). Seroconversion in the Omicron BA.5-specific PRNT was attained by in 78.4% of previously negative patients (29/37). Levels of S-RBD-ab correlated with inhibition in the Omicron-specific SVNT and neutralization titers in the BA.5-PRNT. Eleven SARS-CoV-2 infections occurred in the six-month follow-up, none of which took a life-threatening course. The bivalent mRNA vaccine improved the SARS-CoV-2 virus variant-specific humoral immunity in chronic hemodialysis patients. Measurement of S-RBD-ab can be used in hemodialysis patients to estimate their humoral immunity status against Omicron BA.5.

Surgical aortic valve replacement (SAVR) in kidney transplant recipients (KTR) is associated with high morbidity and mortality, and an increased risk of postoperative graft failure potentially leading to graft loss. Transcatheter aortic valve implantation (TAVI) emerged as an alternative in high-risk patients. However, data on TAVI in kidney transplant recipients are limited. We performed a retrospective analysis of 40 KTR in which aortic valve replacement was performed at our center between 2005 and 2015. The outcomes and follow-up of TAVI (n=20; 2010-2015) and SAVR (n=20; 2005-2015) were analyzed with respect to patient and graft survival. Baseline characteristics in both groups were comparable. Hospital stay after TAVI was significantly shorter compared to SAVR (19 [11.5-21.75] days vs. 33 [21-62] days, p=0.001). Acute graft failure occurred more frequently after SAVR (45% vs. 89.5%; p=0.006). Thirty-day mortality was 10% in both groups. However, in-hospital mortality reached 25% in the SAVR group (TAVI 10%), indicating a more complicated course after surgery. Moreover, during a median follow-up time of 1928 days in TAVI patients and 2717 days in patients after SAVR, graft loss occurred only in the surgically treated group (n=7). While one-year survival after TAVR was 90% compared to 69% after SAVR, long-term follow-up showed comparable results (at 5 years: TAVI 58% vs. 52% SAVR; log-rank-test: p=0.86). In KTR, TAVI can be performed with good mid- to long-term results. Compared to SAVR, renal outcomes seem to be improved after TAVI, suggesting better graft survival.