Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Individuals with rare kidney diseases account for 5–10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. Methods: People aged 0–96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan–Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1\ub773 m2 or more to first eGFR of less than 30 mL/min per 1\ub773 m2 (the therapeutic trial window). Findings: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9\ub76 years (IQR 5\ub79–16\ub77). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2\ub781 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0\ub70001), but better survival rates (standardised mortality ratio 0\ub742 [95% CI 0\ub732–0\ub752]; p<0\ub70001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. Interpretation: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3–5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. Funding: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity

The ambiguous role of the Na+–H+ exchanger isoform 1 (NHE1) in leptin-induced oxidative stress in human monocytes

Leptin, a 16-kDa cytokine produced mainly by the adipose tissue, is known to increase energy expenditure while at the same time lowering food intake by acting directly on the hypothalamus. ObRb, the leptin receptor mostly involved in intracellular signaling, is expressed in a wide range of tissues, thus allowing leptin to affect a much broader diversity of biological processes. High concentrations of leptin are encountered in patients with hyperleptinemia, a condition which very often accompanies obesity and which is a direct result of leptin resistance. In the present study, moderate and high concentrations of leptin (16 and 160 ng/ml) were mostly utilized in order to investigate the role of this cytokine in oxidative stress levels in human monocytes. Leptin was found to increase oxidative species production as measured with 2′,7′-dichlorodihydrofluorescein diacetate (general marker of oxidative species, but not O2−.) and dihydroethidium (marker of O2−.). Surprisingly, it also augmented superoxide dismutase activity. Inhibition of the Na+–H+ exchanger isoform 1 (NHE1) also inhibited leptin-induced superoxide anion production but at the same time amplified leptin-induced production of other oxidative species. Signaling proteins such as phosphoinositide 3 kinase and conventional isoforms of protein kinase C (α-, βi-, βii-), as well as NADPH oxidase, also participated in leptin signaling. Finally, leptin was found to increase glutathionylation levels of NHE1-bound heat shock protein 70 kDa (Hsp70) but not Hsp70 binding to NHE1

Peptide vaccines for hematological malignancies: a missed promise?

Despite the crucial aid that newly developed target therapies are providing to chemotherapy and stem cell transplant, the cure for many hematological malignancies is still an unmet need. Although available therapies are able to induce an effective debulking of the tumor, most of the time, an insidious minimal residual disease survives current treatments and it is responsible for an immediate or delayed relapse. Peptide-derived antitumor vaccines have been developed with the idea that an artificially "educated" immune system may exert an active specific antitumor response able to control and ultimately eradicate underlying post-treatment residual disease. This review will summarize current knowledge of peptide vaccines for hematological malignancies, trying to analyze promises and pitfalls of a safe and intelligent tool that after many years from its first appearance has not yet established its potential role as alternative immune mediated therapeutic approach for hematopoietic tumors