Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infectious disease of immunocompromised patients. Its incidence has decreased worldwide in the past, but data concerning its recent epidemiology are lacking. We retrospectively analyzed all German inpatient cases from January 1, 2014 to December 31, 2019, to describe the recent epidemiology, incidence, clinical course, mortality and underlying diseases of PCP. Simultaneously, we conducted a retrospective multi-center study at two German university hospitals, and analyzed PCP cases treated there to gain deeper insights on the basis of primary patient data. The incidence of PCP significantly increased from 2·3 to 2·6 per 100,000 population from 2014 to 2019 (1,857 to 2,172 cases, +17·0%, p < 0·0001), as well as PCP-related deaths (516 to 615 cases, +19·2%, p = 0·011). The spectrum of underlying diseases changed: Risk groups with established chemoprophylaxis for PCP based on international guidelines (HIV, hematologic malignancies, and transplantation) showed a significant decrease in PCP cases and deaths. Others, especially those with solid malignancies, and autoimmune and pulmonary diseases showed a significant increase in case numbers and deaths. Data from the retrospective multi-center study added information regarding prophylaxis and diagnostics of PCP. The incidence of PCP has reversed its trend, showing a significant increase in mortality on population level. Patients who were not previously considered in prophylactic measures are increasingly affected by PCP. This development deserves further investigation, and additional comprehensive guidelines for the use of chemoprophylaxis in new risk groups are needed. Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Kiel.

The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.

The Banff classification for kidney transplant pathology dichotomizes the rejection continuum into distinct diagnostic categories, introducing artificial cutoff points and threshold effects. To better reflect the underlying disease spectrum, in this cohort study of 19,500 biopsies from 8873 patients across 10 centers worldwide, we developed two indices for quantifying antibody-mediated rejection/microvascular inflammation and T-cell-mediated rejection/tubulointerstitial inflammation from histological lesion scores and calculated indices for overall activity and chronicity. These indices demonstrate excellent discrimination for the main diagnostic categories of rejection (AUCs from 0.95 to 0.99), with consistent performance across derivation and validation datasets. These indices strictly confine intermediate phenotypes to low index values and are associated to graft failure even within the diagnostic categories, thus reflecting the underlying rejection continuum. In this work, we demonstrate that four continuous indices provide implementable and interpretable global evaluation of kidney transplant histology that align with the continuous nature of the rejection process regardless of the underlying disease cause.

Background: Outcome data regarding clinically relevant endpoints after starting dialysis for end-stage renal disease (ESRD) are sparse, and early events after starting dialysis are particularly underestimated. The aim of this study was to describe patient-focused outcomes in ESRD patients starting from first dialysis. Methods: The data basis for this retrospective observational study were anonymized healthcare data from Germany's largest statutory health insurer. We identified ESRD patients who initiated dialysis in 2017. Deaths, hospitalizations and occurrence of functional impairment within 4 years after starting dialysis were recorded starting from first treatment. Hazard ratios in dialysis patients compared with an age- and sex-matched reference population without dialysis were generated, stratified by age. Results: The dialysis cohort included 10 328 ESRD patients who started dialysis in 2017. First dialysis was performed in-hospital for 7324 patients (70.9%), and 865 of these died during the same hospitalization. One-year mortality for ESRD patients initiating dialysis was 33.8%. Functional impairment occurred in 27.1% of patients, while 82.8% of patients required hospitalization within 1 year. Hazard ratios of dialysis patients compared with the reference population for mortality, functional impairment and hospitalization at 1-year were 8.6, 4.3 and 6.2. Dialysis patients 40-fold increased risk of adverse events compared with their peers. Conclusions: The emergence of morbidity and mortality after starting dialysis for ESRD is significant, especially in younger patients. Patients have a right to be informed about the prognosis associated with their condition.

Ten years after its initial description, ferroptosis has emerged as the most intensely studied entity among the non-apoptotic forms of regulated cell death. The molecular features of ferroptotic cell death and its functional role have been characterized in vitro and in an ever-growing number of animal studies, demonstrating that it exerts either highly detrimental or, depending on the context, occasionally beneficial effects on the organism. Consequently, two contrary therapeutic approaches are being explored to exploit our detailed understanding of this cell death pathway: the inhibition of ferroptosis to limit organ damage in disorders such as drug-induced toxicity or ischemia-reperfusion injury, and the induction of ferroptosis in cancer cells to ameliorate anti-tumor strategies. However, the path from basic science to clinical utility is rocky. Emphasizing ferroptosis inhibition, we review the success and failures thus far in the translational process from basic research in the laboratory to the treatment of patients.

Chronic kidney disease (CKD) is one of the most significant drivers of the global burden of disease and an increasing public health issue. Adequate monitoring and referral of high-risk patients to nephrologists are associated with improved management of CKD. We aimed to assess nephrology referral rates, monitoring of kidney function, and factors associated with failure to refer in Germany. We retrospectively analyzed ambulatory claims data of 73,675,956 German patients who were covered by statutory health care in 2022, building a cohort of 1,301,122 patients who had at least two diagnoses of CKD stage 3–5 within the calendar year. In our analysis, we focused particularly on patients with CKD stage 4. We identified 207,043 patients with CKD stage 4, of which 134,143/207,043 (64.8%) received nephrologist treatment in 2022. The median age of the cohort was 82 years. Failure to quantify proteinuria occurred in 61,991/72,900 (85.0%) non-referred patients compared to 51,382/134,143 (38.3%) referred patients. In a mixed logistic regression model, referral was less likely for women (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.71–0.74), higher age (OR per year 0.97, CI 0.96–0.97), nursing home inhabitants (OR 0.63, CI 0.61–0.65), and those with certain comorbidities. Regional factors (deprivation, population density, nephrologist density) were not associated with referral. A substantial proportion of patients with late-stage CKD are not receiving guideline-recommended kidney care in the German health care system, with disparities driven primarily by individual patient factors rather than geographical barriers. This study was funded by the University Hospital Schleswig-Holstein and the Central Research Institute of Ambulatory Health Care in Germany.