Carmen Sivo

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis and the role of IL-6 in pathogenesis is becoming increasingly important. A recent whole genome DNA methylation screening in IgAN patients identified a hypermethylated region comprising the non-coding RNA Vault RNA 2-1 (VTRNA2-1) that could explain the high IL-6 levels. METHODS: The pathway leading to IL-6 secretion controlled by VTRNA2-1, PKR, and CREB was analyzed in peripheral blood mononuclear cells (PBMCs) isolated from healthy subjects (HS), IgAN patients, transplanted patients with or without IgAN. The role of double and single-strand RNA in controlling the pathway was investigated. RESULTS: VTRNA2-1 was downregulated in IgAN compared to HS and in transplanted IgAN patients (TP-IgAN) compared to non-IgAN transplanted (TP). The loss of the VTRNA2-1 natural restrain in IgAN patients caused PKR hyperphosphorylation, and consequently the activation of CREB by PKR, which, in turn, led to high IL-6 production, both in IgAN and in TP-IgAN patients. IL-6 levels could be decreased by the PKR inhibitor imoxin. In addition, PKR is normally activated by bacterial and viral RNA, and we found that both the RNA poly(I:C), and the COVID-19 RNA-vaccine stimulation significantly increased the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients. CONCLUSION: The discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a novel approach to treating the disease and may be useful for the development of precision nephrology and personalized therapy by checking the VTRNA2-1 methylation level in IgAN patients.

BACKGROUND: In Italy, nephrology residency is available in twenty-one nephrology schools, each with its own strengths and weaknesses. The present study is aimed at exploring the residents' satisfaction with their training programs. METHODS: Between April 20th and May 19th, 2021, a questionnaire on residency satisfaction consisting of 49 items was sent to 586 residents and 175 recently certified specialists (qualified to practice as nephrologists in 2019 and 2020), with a response rate of 81% and 51%, respectively. The teaching organization was contextualized with a survey involving 13 European nephrology schools. RESULTS: Most residency fellowship programs received a good rating with regard to "satisfaction", in particular for the following items: number of hospitalizations followed-up, chronic hemodialysis training, follow-up of transplanted patients, diagnosis and treatment of glomerulonephritis. The teachings that were identified as being of lower quality or insufficient intensity included vascular access management, ultrasound diagnostics and renal nutrition. The need for improvement in formal teaching programs was underlined. Young nephrologists were rather satisfied with their salary and with the quality of the work they were doing, but only few were interested in an academic career since it was generally held that it is "too difficult" to obtain a university position. Many young nephrologists who filled in the questionnaire felt that lack of experience in peritoneal dialysis and vascular access management was a barrier to finding an ideal job. Compared to other European training programs, the Italian program differs with regard to longer exposure to nephrology (as compared to internal medicine), and greater flexibility for internships in different settings, including abroad. CONCLUSIONS: This first nationwide survey on the satisfaction of residents in nephrology indicates that, despite rather good overall satisfaction, there is room for improvement to make nephrology a more appealing choice and to fulfill the needs of a growing number of renal disease patients.

ABSTRACT Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis characterized by the presence of IgA immune complexes in the glomeruli. Recently, a multihit model has been proposed to describe the pathogenesis of IgAN, but it is believed that further predisposing factors are present, including immunological, genetic and environmental factors. Newly, the role of IL-6 in pathogenesis is becoming increasingly important but reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA. Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non-IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain caused the activation of CREB by PKR, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, both in IgAN and in TP-IgAN patients. PKR is normally activated by bacterial and viral RNA and we found that both the RNA poly(I:C), the and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients. In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.

Background Chronic kidney disease (CKD) has a significant impact on psychological well-being. Here, the psychological evaluation of patients with CKD undergoing replacement treatment (dialysis or kidney transplantation) and conservative therapy (preemptive patients, who are waiting list for kidney transplantation) was analyzed. In addition, serum irisin levels, a protein displaying anxiolytic and antidepressant effects in mice, were measured in dialysis patients. Methods Dialysis ( N = 57), non-dialysis (preemptive, N = 31) and kidney transplant patients ( N = 33) were enrolled. All participants underwent psychometric tests including State–Trait Anxiety Inventory (STAI-Y 1 and 2 form), Psychological General Well-Being Index (PGWBI), Symptom Checklist-90-R (SCL-90-R), etc. Serum irisin levels in dialyzed patients were measured by ELISA assay. Results Dialysis patient group scored worse on all tests performed than both preemptive and kidney transplant patients. Indeed, dialysis patients displayed the lowest PGWBI score, and higher scores of BDI, and STAY-1 and STAY-2, compared with preemptive and kidney transplant patients. We also found that about 40% of dialysis patients showed significant psychological distress with higher clinical attention values in the somatization, obsessive-compulsive, depression, and anxiety domains assessed by SCL-90. Furthermore, the stratification of all patients into groups younger and older than 50 years showed that the older group of transplanted patients displayed better outcomes than the younger ones. Finally, stratification of dialysis patients according to irisin levels revealed that only those with higher serum irisin levels had better psychological conditions in tests. Conclusions Kidney transplantation as well as conservative therapy were related to a lower prevalence of depressive symptoms and other psychological disorders than dialysis. Furthermore, all transplanted patients over 50 years of age showed better outcomes than the younger ones. However, dialyzed patients with high levels of circulating irisin displayed better psychological conditions. Overall, our findings supported the importance to provide timely access to transplantation and to improve psychological support for dialysis patients.

Abstract BACKGROUND AND AIMS The global burden of chronic kidney disease (CKD) is growing, impacting around 10% of the worldwide population becoming the 5th cause of mortality by 2023, with high cost for the health care system (Glassrock et al. 2017). CKD can be identified using two easy and inexpensive tests (eGFR and ACR). Early stages of CKD are generally asymptomatic, hence challenging clinical recommendations for early detection of CKD. Indeed, a high percentage of patients in primary care are undiagnosed (Zilich et al. 2005). As a result, high-risk individuals, such as those with hypertension, diabetes, a family history of renal disease and cardiovascular disease, require targeted and accessible screening. In a study promoted by the Italian Society of Nephrology (SIN) and the Italian Society of General Practitioners (SIMG), 300 general practitioners (GPs) recruited a cohort of ∼500 thousand patients in the general population, showing that creatinine dosage was requested for only 17% of patients (Minutolo et al. 2008). Of this subgroup, 16% were affected by CKD, but only one out of eight patients was actually identified by the GP as nephropathic, with potential harm to the patient due to possible missed diagnosis. Such study highlighted that, in Italy, a nephrological consultation is usually requested only in 5% of patients with overt nephropathy in the conservative phase (eGFR 30–60), whereas the nephrological referral did not exceed 50% in cases of pre-dialysis disease (eGFR 30–15). With a global lack of CKD specialists, enabling GPs and building successful multidisciplinary teams to play a larger role in early detection and management will assist hospitals and health systems to alleviate the burden. METHOD An observational pilot study was undertaken between 1 May 2021 and 31 October 2021 in the Apulia region, Italy, within a framework called `The Disease Awareness iNnovaTion nEtwork’ (DANTE). We aimed at evaluating the impact of GPs targeted training by specialized nephrologists towards CKD awareness. A first meeting was set up with GPs in which trained nephrologists illustrated to the GPs the KDIGO CKD guidelines. The differences in terms of proportions between the two groups [baseline time (T0) versus time at 6 months (T6)] were evaluated with Pearson's. RESULTS A total of n = 17 854 of patients were enrolled at T0 versus n = 18 661 at T6 from the databases of 17 Apulian GPs who satisfied the entry criterion (having Millewin software installed on their systems). All of the comparisons in terms of percentage patients tested for ACR and eGFR between T0 and T6 resulted in a statistically significant P-value (<.0001) also when stratifying/disease groups (diabetes, hypertension and heart failure, Fig. 1). Patients with eGFR <60 mL/min were found to be 3.8% at T6, hence providing for an increase of detection of + 72.73% after GP CKD training awareness. CONCLUSION The DANTE pilot study was the first of its kind ever planned in Apulia. All of the diagnostic tests undertaken did register an increase of at least + 42.59% at T6, with an overall median increase of + 72.73%. Therefore, we can argue that teaching devoted to GPs by nephrologist it is able to improve GPs CKD awareness and increase its early diagnosis, which can slow down the progression of CKD, plus providing for high savings given the large cost gap between the early and late stages of CKD (Jommi et al. 2018).