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Background The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. Methods The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. Results Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08–1.17], liver disease (OR 2.27, 95% CI 1.21–4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07–1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92–0.99) were protective. Conclusions This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Background and objectives Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. Design, setting, participants, & measurements In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25–10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. Results At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: −16.3 g/m2; 95% confidence interval, −29.4 to −3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. Conclusions Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. Clinical Trial registry name and registration number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008–003529–17.

Background and Aims According to local resources, different vascular access (VA) procedures are employed in every country. In Italy, high variability exists in VA management among different dialysis units. In 2018, the DOPPS 5 study showed a declining prevalence of lower arm arteriovenous fistulas (AVF) in Europe with an increasing tendency of making upper arm AVFs and placing central venous catheters (CVCs). Accordingly, an Italian Survey in 2013 confirmed an increasing trend in CVCs use among different Italian regions. Hence, we made an epidemiologic, multicenter study to evaluate a possible relation between this trend and the variability of local VA management policies. Method VA data from 236 patients of prevalent patients were collected from five dialysis centers in the South of Italy. The prevalence of the various types of VAs was analyzed in relation to the following different VA surgery policies adopted in the participant centers: Results Age of patients was comparable among all centers while dialysis vintage was higher in center A (P Conclusion The reduced tendency of lower arm fistulas and the increasing prevalence of CVCs showed by the DOPPS 5 study might not be applicable to all Italian regions. In our study of 5 dialysis units in the South of Italy, the stability of the nephrologist’s surgical activity probably played a crucial role in explaining the observed decreased use of CVCs with a steadily high prevalence (over 70%) of the lower arm fistulas, regardless of aging.

Membranous nephropathy represents the most frequent cause of nephrotic syndrome in the adult, leading to end-stage renal disease in one third of all the patients. In the last years, the discovery of circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 containing 7A domain (THSD7A), shed light on the pathogenesis of idiopathic forms, being responsible for 70% and 3% of all the cases, respectively. These identifications allowed the development of serological and histologic tests to detect autoantibodies and relative targets for diagnostic and prognostic purposes. Rising evidences suggest that serum titer correlates with disease activity and response to therapy. For these reasons, for patients with nephrotic syndrome, a serum-based approach has been proposed, reserving renal biopsy only in cases with doubtful/negative serology. However, the recent introduction of useful criteria for the interpretation of PLA2R/THSD7A immunohistochemistry could lead to high values of sensitivity and specificity for the in situ detection of target antigens. The present multicentric study on a series of membranous nephropathy cases with available serum/histologic correlation will show the importance of the crosstalk among the different techniques, recovering the possible role of electron microscopy in challenging situations.

Purpose Membranous nephropathy (MN) is the most frequent cause of nephrotic syndrome in adults and the disease course is characterized by the "rule of third", with one-third of patients experiencing complete remission and the remaining experiencing relapses or progression of the disease. Additionally, the therapeutic approach is not standardized, leading to further heterogeneity in terms of response and outcome. Experimental design In this pilot study, MALDI-MSI analysis is performed on renal biopsies (n = 13) obtained from two homogeneous groups of patients, which differentially responded to the immunosuppressive treatments (Ponticelli regimen). Results A signal at m/z 1303 displays the greatest discriminatory power when comparing the two groups and is observed to be of higher intensity in the glomeruli of the non-responding patients. The corresponding tryptic peptide is identified as macrophage migration inhibitory factor (MIF). Conclusions and clinical relevance Despite much effort being made in recent years to understand the pathogenesis of MN, a biomarker able to predict the outcome of these patients following therapeutic treatment is still lacking. Here, a protein (MIF), verified by immunohistochemistry, that can differentiate between these MN patients and could be a valuable starting point for a further study focused on verifying its predictive role in therapy response is highlighted.

Background. Chest ultrasound (US) is a non-invasive wellvalidated technique for estimating extravascular lung water (LW) in patients with heart diseases and in end-stage renal disease. We systematically applied this technique to the whole peritoneal dialysis (PD) population of five dialysis units. Methods. We studied the cross-sectional association between LW, echocardiographic parameters, clinical [pedal oedema, New York Heart Association (NYHA) class] and bioelectrical impedance analysis (BIA) markers of volume status in 88 PD patients. Results. Moderate to severe lung congestion was evident in 41 (46%) patients. Ejection fraction was the echocardiographic parameter with the strongest independent association with LW (r ¼� 0.40 P ¼ 0.002). Oedema did not associate with LW on univariate and multivariate analysis. NYHA class was slightly associated with LW (r ¼ 0.21 P ¼ 0.05). Among patients with severe lung congestion, only 27% had pedal oedema and the majority (57%) had no dyspnoea (NYHA Class I). Similarly, the prevalence of patients with BIA, evidence of volume excess was small (11%) and not significantly different (P ¼ 0.79) from that observed in patients with mild or no congestion (9%). Conclusions. In PD patients, LW by chest US reveals moderate to severe lung congestion in a significant proportion of asymptomatic patients. Intervention studies are necessary to prove the usefulness of chest US for optimizing the control of fluid excess in PD patients.

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

Purpose Decline in physical function is commonly observed in patients with kidney failure on dialysis. Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical functioning of these patients has not been investigated. Methods In 51 peritoneal dialysis (PD) patients, we investigated the cross-sectional association between the physical functioning scale of the Kidney Disease Quality of Life Short Form (KDQOL-SF: Rand Corporation, Santa Monica, CA, USA) and an ultrasonographic measure of lung water recently validated in dialysis patients. The relationship between physical functioning and lung water was also analyzed taking into account the severity of dyspnea measured using the New York Heart Association (NYHA) classification currently used to grade the severity of heart failure. Results Evidence of moderate-to-severe lung congestion was evident in 20 patients, and this alteration was asymptomatic (that is, NHYHA class I) in 11 patients (55%). On univariate analysis, physical functioning was inversely associated with lung water ( r = –0.48, p < 0.001), age ( r = –0.44, p = 0.001), previous cardiovascular events ( r = –0.46, p = 0.001), and fibrinogen ( r = –0.34, p = 0.02). Physical functioning was directly associated with blood pressure, the strongest association being with diastolic blood pressure ( r = 0.38, p = 0.006). The NYHA class correlated inversely with physical functioning ( r = –0.51, p < 0.001). In multiple regression analysis, only lung water and fibrinogen remained independent correlates of physical functioning. The NYHA class failed to maintain its independent association. Conclusions This cross-sectional study supports the hypothesis that symptomatic and asymptomatic lung congestion is a relevant factor in the poor physical functioning of patients on PD.

To evaluate the actual use of different treatments for idiopathic membranous glomerulonephritis in Italy, we selected all patients who were registered with a diagnosis of this disease at the Italian Renal Biopsy Registry between 2001 and 2005. It was surprising that single-steroid treatment without immunosuppressive drugs was preferred in 34.4% of patients to steroids associated with immunosuppressive drugs (the Ponticelli regimen), used only in 26.6%. Ace inhibitors and angiotensin II receptor blockers were given as the therapy of choice in 23.4% of cases, as an adjunct to steroids in 41%, and to steroids/ immunosuppressants in 52%. Ace inhibitors and angiotensin II receptor blockers were thus used most in the treatment of idiopathic membranous nephropathy and it would therefore be interesting to assess the role of antiproteinuric agents in greater depth in future studies.

Cardiovascular events are the main cause of death in hemodialysis patients. Nevertheless, acute myocardial infarction may be misdiagnosed in uremic patients, because typical markers have a high rate of false positivity. A recent two-year prospective study showed that predialytic high serum concentrations of troponin T and CK-MB mass were associated with high mortality, cardiac mortality, myocardial infarction and unstable angina (MACEs). We studied 16 uremic patients (13 M; 3 W) on standard HD and 6 patients (4 M; 2 W) on on-line HDF, who had been taking folic acid for at least three months. Patients who suffered from acute or chronic cardiac ischemic disease were excluded. Anthropometric parameters, pre and post-dialytic pH, HCO3 and electrolytes did not differ between the two groups. Kt/V and URR % were lower in conventional HD vs on-line HDF (p

It is still a matter of debate as to which parameters should be used for noninvasive diagnosis of renovascular disease by renal Doppler sonography (RDS). The accuracy of RDS in the detection of renal artery stenosis (RAS) was tested in 95 consecutive, moderate to severe hypertensive patients (I-II World Health Organization [WHO] stages). Reno-aortic ratio (RAR) for peak systolic velocity (PSV) was also calculated to assist in the diagnosis of significant (>50%) RAS. Paired receiver-operating characteristic (ROC) analysis was plotted for evaluating the relationship between sensitivity and specificity for each parameter. In a subset of 57 kidneys, the influence of blood pressure and age on intraparenchymal parameters was evaluated. Measurements of maximal peak systolic velocity (PSV) at the site of stenosis, RAR for PSV, and minimum acceleration index in the main renal artery showed high accuracy (areas under the ROC curve 0.97, 0.88, and 0.80, respectively). Among intraparenchymal parameters, early systolic accel eration showed the best area under the ROC curve (0.90), but provided a low positive predictive value (29%) and was significantly influenced by blood pressure (multiple r=0.56; p=0.001). Pulsatility and resistive indices were found to be less powerful as absolute values, and both significantly influenced by blood pressure and age (multiple r= 0.60 and 0.50; p=0.001, p=0.02, respectively). However, interindividual variance of intrarenal indices should be minimized by calculation of side difference, although this procedure would become misleading or impossible in patients with bilateral RAS or a single kidney, respectively. These results support the use of extraparenchymal parameters for noninvasive detection of RAS, and emphasize that intrarenal parameters cannot be considered as absolute values.