As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.

Introduction: Magnesium (Mg²⁺) deficiency is a common finding in the early phase after kidney transplantation (KT) and has been linked to immune dysfunction and infections. Data on the association of hypomagnesemia and the rate of infections in kidney transplant recipients (KTRs) are sparse. Methods: We conducted a single-center retrospective cohort study of KTRs transplanted between 2005 and 2015. Laboratory data, including serum Mg²⁺ (median time of the Mg²⁺ measurement from KT: 29 days), rate of infections including mainly urinary tract infections (UTI), and common transplant-related viral infections (CMV, polyoma, EBV) in the early phase after KT were recorded. The primary outcome was the incidence of infections within one year after KT, while secondary outcomes were hospitalization due to infection, incidence rates of long-term (up to two years) infections, and all-cause mortality. Results: We enrolled 376 KTRs of whom 229 patients (60.9%) suffered from Mg²⁺ deficiency defined as a serum Mg²⁺ < 0.7 mmol/L. A significantly higher incidence rate of UTIs and viral infections was observed in patients with versus without Mg²⁺ deficiency during the first year after KT (58.5% vs. 47.6%, p = 0.039 and 69.9% vs. 51.7%, p < 0.001). After adjustment for potential confounders, serum Mg²⁺ deficiency remained an independent predictor of both UTIs and viral infections (odds ratio (OR): 1.73, 95% CI: 1.04–2.86, p = 0.035 and OR: 2.05, 95% CI: 1.23–3.41, p = 0.006). No group differences according to Mg²⁺ status in hospitalizations due to infections and infection incidence rates in the 12–24 months post-transplant were observed. In the Cox regression analysis, Mg²⁺ deficiency was not significantly associated with all-cause mortality (HR: 1.15, 95% CI: 0.70–1.89, p = 0.577). Conclusions: KTRs suffering from Mg²⁺ deficiency are at increased risk of UTIs and viral infections in the first year after KT. Interventional studies investigating the effect of Mg²⁺ supplementation on Mg²⁺ deficiency and viral infections in KTRs are needed.

Objective: To characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX).Methods: We conducted a multicenter retrospective cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between “nephrotic” and “nephritic” indications. The primary outcome was the incidence of SI within 12 months after the first RTX application.Results: A total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m²versus 26.9 kg/m², HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI.Conclusions: After RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI.

Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome.

Hemodialysis patients (HD) are expected to have excess mortality in coronavirus disease 2019 (COVID-19). This was challenged by a recent study reporting HD patients to have comparable mortality and less ICU admissions when hospitalized with COVID-19. An altered immune system due to chronic inflammation might protect HD-patients from severe COVID-19. Therefore, we aimed to describe the peripheral blood immune phenotype in HD-patients and respective controls with COVID-19.Methods: Sixty-four patients (31 HD, 33 non-HD) with PCR-confirmed COVID-19 and 16 control patients (10 HD, 6 non-HD) were prospectively included. According to symptoms, COVID-19 patients were categorized as asymptomatic/mild, moderate or severe COVID-19 phenotypes. Cytokine profiling and immune phenotyping was performed.Results: Th1 and Th17 plasma cytokine levels were highly increased in HD patients without COVID-19 and were not significantly regulated during COVID-19. In non-HD COVID-19 patients these cytokines increased significantly with disease severity. While all patients with moderate or severe COVID-19 showed hallmarks of COVID-19 such as decreased CD3⁺, CD4⁺ and CD8⁺ and CD4⁺CD25^hiFoxP3⁺ regulatory T cells, significantly increased CD38⁺CD8⁺ effector memory and CD38⁺CD8⁺ TEMRA T cells were detected in moderate/severe COVID-19 HD patients, which was not observed in non-HD patients with moderate or severe COVID-19. Furthermore, CD161⁺CD8⁺ T cells decreased significantly in non-HD COVID-19 patients dependent on disease severity, but not in HD patients. Dynamics of B cells and subtypes were comparable in HD and non-HD COVID-19 patients.Conclusions: HD patients might be protected from severe COVID-19 due to their chronic inflammatory state with increased CD38⁺CD8⁺ effector memory and TEMRA T cells as well as CD161⁺CD8⁺ T cells.

The use of plasma exchange (PLEX) as adjunct therapy in the initial management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis remains to be discussed controversially in light of present evidence. In our Viewpoint we highlight scenarios where we think that physicians might still consider the use of PLEX, such as the most severe presentation forms including diffuse alveolar haemorrhage (DAH) with hypoxaemia and acute glomerulonephritis with significantly impaired kidney function. Recent sub-analyses of the PEXIVAS trial have focused on these patient populations and have provided outcomes of these patients. It became obvious that the mortality rates of those presenting with DAH were non-significantly lower and patients with severe GN show a trend of more pronounced estimated glomerular filtration rate (eGFR) recovery in the first weeks after PLEX. Notably, more patients reach a kidney function recovery as defined as eGFR increase ≥15 ml/min/1.73 m2 from baseline to week 52 when randomised to PLEX. These beneficial outcomes need to be balanced against the increased risk of serious infections and we recommend an individualized decision-making when considering addition of PLEX in the induction therapy.