Fabry disease (FD) is an X-linked systemic lysosomal storage disease caused by mutations in the galactosidase-α (GLA) gene, which encodes the α-galactosidase A (α-AGAL) enzyme. FD can lead to serious complications, including early death, if left untreated. For over 20 years, enzyme replacement therapy (ERT) based on the use of agalsidase-α and agalsidase-β has been the standard treatment for FD, alongside new molecules that have enriched the therapeutic armamentarium and others that are being tested to expand it further. Unfortunately, ERT can be associated with the formation of inhibiting antidrug antibodies (ADAs), which impact ERT clinical efficacy and have consequences affecting safety and therapeutic adherence. A group of FD specialists discussed the problem of immunogenicity in FD, analyzing the most recent literature and the strategies that are currently being used to address it. Once formed, fluctuating levels of ADAs persist and have an impact on the clinical picture and prognosis of the disease that is still the subject of lively scientific debate. The critical nature of ADAs is demonstrated by their ability to bind to the enzyme, increasing drug clearance while forming immune complexes that can build up in the tissues causing chronic inflammation that aggravates the progression of the disease and affects the onset of acute reactions after the infusion, impacting therapeutic adherence. Although similar in their therapeutic mechanism, agalsidase-α and agalsidase-β differ in their production process, with resulting differences from a pharmacokinetic and pharmacodynamic point of view and diverse immunological implications: despite showing rather overlapping efficacy outcomes, agalsidase-α demonstrates a better tolerability profile, with a lower frequency of ADAs, than agalsidase-β. Given the extreme variability of the clinical picture, it is crucial for optimal FD management that the most appropriate molecule is chosen by taking into account the unique immunological risk profile of each single patient, and particular attention should be paid to naïve subjects by periodic measurement of ADAs during therapy and cross-referencing data to correlate serological and clinical patterns.

Increasingly sophisticated genetic panels have disproportionately increased the identification rate of novel gene variants in Mendelian conditions. In Fabry disease (FD), this phenomenon is particularly relevant because the pathogenicity of individual gene variants has an impact on treatment proposal. In fact, FD is characterized by a phenotypical heterogeneity depending on patients' biological sex and the underlying GLA mutation. This represents the main reason why integrating genetic data with phenotypic expression is challenging, and defining the pathogenic role of novel variants remains complex. The early discrimination between pathogenic and non-pathogenic GLA variants is crucial to enable timely initiation of treatments such as Enzyme Replacement Therapy (ERT), which has been shown to significantly slow down the progression of the disease. In fact, the most severe cases of FD have a significantly compromised quality of life up to reduced life expectancy, especially with regard to cardiac and renal complications. In recent years, some GLA variants have been reclassified following investigation and clinical observations by multidisciplinary working groups that have made it possible to better define if they are pathogenic or not. Regardless of the clinical scenario leading to the identification of a novel GLA variant (i.e., family screening, neonatal screening, clinical profile suggestive of FD, incidental finding), any genetic finding becomes relevant when it is complemented by laboratory, clinical and instrumental investigations that require a concerted effort among the many health care professionals involved in the diagnostic process. The present work summarizes the outcomes of a series of expert meetings with the aim to provide some shared and practical indications for managing the genetic report of a novel GLA variant so to promptly start the most suitable diagnostic journey and assess corresponding phenotype and clinical characterization.

Objectives: This systematic literature review aimed to identify studies assessing the clinical efficacy and real-world effectiveness of current and emerging treatments for Fabry disease. Methods: Searches of the MEDLINE, EMBASE, and Cochrane library databases, as well as relevant congress proceedings, were conducted to identify publications reporting on studies in patients of any age, sex, race, or ethnicity who received any approved or experimental treatment for Fabry disease, published before 17 June 2024. Results: Of 1881 publications screened, 234 reported data on renal, cardiac, cerebrovascular, and disease severity outcomes from 225 studies. The majority of reported studies were observational in nature (n = 150; 67%) and involved only adults (n = 172; 74%). Study designs and patient populations were highly heterogeneous, and cross-study conclusions about the effectiveness of different therapies could not be made. Enzyme replacement therapy (ERT) with agalsidase alfa or agalsidase beta stabilized renal function and cardiac structure in patients with Fabry disease. Early initiation of ERT in childhood or young adulthood was associated with better renal and cardiac outcomes than treatment initiation at a later age. The small number of comparator studies of agalsidase alfa and agalsidase beta suggested similar efficacy. Patients treated with migalastat and pegunigalsidase alfa also maintained stable renal function and cardiac structure. Conclusions: Overall, current treatments slow the progression of renal and cardiac decline in patients with Fabry disease. Large cohort studies with long-term follow-up and baseline stratification based on clinical phenotype are needed to address evidence gaps and provide clinicians with robust data to inform treatment decisions.

Hypertension is a clinical condition associated with an increase in cardiovascular morbidity and mortality. In chronic kidney disease (CKD), hypertension is also a driver of faster disease progression. Correct and appropriate treatment with antihypertensive medication reduces the risk of cardiovascular events and slows kidney disease progression. However, not all hypertensive patients achieve the desired blood pressure goals despite multiple antihypertensive therapies, and these are defined as patients with uncontrolled or resistant hypertension. Renal denervation has been successfully proposed to mitigate the hyperactivity of the sympathetic nervous system in patients with uncontrolled/resistant hypertension. The guidelines of the European Society of Cardiology and the European Society of Hypertension include renal denervation as a therapeutic option for treating hypertension in patients with uncontrolled or resistant hypertension. However, in patients with CKD, diffusion of the procedure has been limited by concerns over possible adverse effects on kidney function. Over the last few years, the improvement of the device-based procedure and the growing experience accumulated in several Nephrology centers have increased the use of renal denervation in patients with CKD. In patients with uncontrolled/resistant hypertension with a significant reduction of glomerular filtration rate (< 40 ml/min/1.73 m2), on dialysis, or living with a kidney transplant, the procedure significantly reduces blood pressure values over time without negative effects on kidney function. Taking into account the effectiveness of renal denervation in patients with uncontrolled or resistant hypertension and CKD, and the lack of defined indications concerning renal denervation in CKD, the Italian Society of Nephrology has decided to publish a position paper reviewing the available evidence in the medical literature.

Vitamin D [25(OH)D3] deficiency is common in hemodialysis (HD) patients and is considered an often ignored component in the pathogenesis of anaemia. We evaluated the effect of cholecalciferol supplementation on haemoglobin (Hb) levels in HD patients with vitamin D deficiency and anemia. Retrospectively, 117/256 patients with Hb levels <11 g/dl and vitamin D levels <30 ng/ml treated with cholecalciferol at a weekly dose of 25,000 IU p.o. for at least 12 months were selected. At follow-up (F-U), only 74 patients had taken cholecalciferol (G1); the remaining 43 were considered the control group (G2). PTH, 25(OH)D3 and ferritin were determined every 6 months. At baseline, there were no significant differences between the two groups; Hb levels were significantly correlated with 25(OH)D3 (r = .367; P < 0.001) and PTH (r = −.110; P < 0.05). At F-U in the G1 group, there was an increase in Hb from 10.2 ± 0.7 to 11.8 ± 1.2 g/dl (P < 0.001) and in 25(OH)D3 from 13.4 ± 6.2 to 35.0 ± 8.4 ng/ml (P < 0.05), PTH levels decreased from 542 ± 427 to 338 ± 280 pg/ml (P < 0.01). At the same time, the average dosages of ESAs remained unchanged. In this group, the patients insufficient for vitamin D (10–29 ng/ml) went from 69% to 39%, those deficient (<10 ng/ml) from 31% to 0%, while those sufficient (≥30 ng/ml) from 0 to 61%. In the G2 to F-U, there were no significant changes in the main parameters examined. Vitamin deficiency seems to be associated with anemia, so its supplementation would be desirable to improve the parameters of CKD-MBD and anemia. Our results need to be confirmed from studies conducted on a larger population.

BACKGROUND:Fabry disease (FD) is a monogenic disease with highly variable clinical features. This variability suggests that additional pathogenetic pathways may exist besides the intra-lysosomal deposition of globotriaosylceramide (Gb3) and its deacylated form globotriaosylsphingosine (LysoGb3) caused by an enzyme deficiency. SUMMARY:It has been demonstrated that intralysosomal accumulation of Gb3 and LysoGb3 triggers an inflammatory response. Monocytes, macrophages, and dendritic cells overexpress the adhesion molecules, and cytokines release occurs, including interleukin β, tumor necrosis factor-alpha (TNFα), and transforming growth factor beta. These processes determine the activation of inflammation processes associated with chronic inflammation and tissue fibrosis. The pathogenetic mechanisms stimulated by Gb3 and LysoGb3 deposition could break free from the original activation, causing an irreversible effect, in which Fabry disease-specific therapy can play a limited role. A new disease mechanism, "Agalopathy" would coexist with enzyme deficiency. Missense variants in the coding sequence of the GLA gene would generate the misfolding of the altered protein alpha-galactosidase A. Emergence of misfolded proteins may generate stress of the endoplasmic reticulum, leading to induction of the unfolded protein response (UPR). The UPR causes the release of pro-inflammatory cytokines and contributes to inflammatory status. This mechanism could be activated independently of glycolipid deposition, and its relationship with inflammatory pathways deserves more research. Strikingly, a zebrafish GLA knockout model that naturally lacks the enzyme that synthesizes Gb3 shows many alterations in lysosomal functions. KEY MESSAGES:These pieces of evidence suggest the involvement of alternative pathways independent of Gb3 in FD pathogenesis. This review aims to describe these processes' role in the pathogenesis of renal damage in FD or Agalopathy nephropathies.

Secondary hyperparathyroidism (SHP) is a clinically significant complication commonly present in chronic renal disease, especially in patients on haemodialysis. Pharmacological therapy aims to reduce the level of parathyroid hormone (PTH). Among specific treatments, the long-acting calcimimetic etelcalcetide was authorised in Italy a few years ago based on clinical trial results. However, real-world evidence of its efficacy remains limited. This study, founded by the Italian Medicines Agency (Pharmacovigilance call 2012–14), aims to perform a comparative evaluation of SHP control with the use of the two calcimimetics etelcalcetide and cinacalcet in patients on chronic haemodialysis in a real-world setting. A cohort of new users of cinacalcet and etelcalcetide from the Lazio Regional Dialysis and Transplantation Registry, covering the years 2018–2020, was enrolled. Study endpoints were retrieved through an ad hoc survey in regional dialysis centres. Indicators of SHP control were serum levels of PTH, phosphorus and calcium, which were evaluated by comparing the proportions of patients at target and mean blood levels at baseline, 12 and 24 months of observation. Overall, 652 haemodialytic patients were enrolled, 59% males and a mean age of 64 years. The majority of patients (500) began treatment with etelcalcetide. In both treatment groups, serum PTH improved over time, as evidenced by an increased proportions of patients achieving the therapeutic target (etelcalcetide from 37.8 at baseline to 59.3% at 24 months; cinacalcet from 39.5 to 63.3%) and a significant decrease of PTH blood levels (etelcalcetide from 605.2 to 372.9 pg/mL; cinacalcet from 577.9 to 285.1 pg/mL). Serum phosphorus levels also showed improvements over time, with more patients reaching target levels (etelcalcetide from 23.0 to 36.0%; cinacalcet from 19.1 to 26.7%). however mean blood levels decreased in cinacalcet users only. Results for serum calcium levels were less promising, with no change over time in the proportion of cinacalcet users reaching target levels, while etelcalcetide users saw a decrease. Mean calcium levels remained stable across both treatment groups. The present study shows improvements in SHP control in both treatment groups with negligible differences between the two. Along with previous findings of a mortality reduction in patients treated with etelcalcetide with respect to cinacalcet, with a borderline statistical significance, this study confirms the efficacy and safety of etelcalcetide in SHP treatment in patients in haemodialysis.

BACKGROUND:Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS:the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS:Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS:This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Fabry nephropathy is a consequence of the deposition of globotriaosylceramide, caused by deficient GLA enzyme activity in all types of kidney cells. These deposits are perceived as damage signals leading to activation of inflammation resulting in renal fibrosis. There are few studies related to immunophenotype characterization of the renal infiltrate in kidneys in patients with Fabry disease and its relationship to mechanisms of fibrosis. This work aims to quantify TGF-β1 and active caspase 3 expression and to analyze the profile of cells in inflammatory infiltration in kidney biopsies from Fabry naïve-patients, and to investigate correlations with clinical parameters. Renal biopsies from 15 treatment-naïve Fabry patients were included in this study. Immunostaining was performed to analyze active caspase 3, TGF-β1, TNF-α, CD3, CD20, CD68 and CD163. Clinical data were retrospectively gathered at time of kidney biopsy. Our results suggest the production of TNFα and TGFβ1 by tubular cells, in Fabry patients. Active caspase 3 staining revealed that tubular cells are in apoptosis, and apoptotic levels correlated with clinical signs of chronic kidney disease, proteinuria, and inversely with glomerular filtration rate. The cell infiltrates consisted of macrophages, T and B cells. CD163 macrophages were found in biopsy specimens and their number correlates with TGFβ1 and active caspase 3 tubular expression. These results suggest that CD163+ cells could be relevant mediators of fibrosis in Fabry nephropathy, playing a role in the induction of TGFβ1 and apoptotic cell death by tubular cells. These cells may represent a new player in the pathogenic mechanisms of Fabry nephropathy.

The pathophysiology of Fabry nephropathy (FN) is induced by galactosidase A deficiency with a chronic exposure of glycolipids to every lineage of renal cells. Tissue damage is attributed to the activation of molecular pathways, resulting in tissue fibrosis and chronic kidney disease. Podocytes have been the primary focus in clinical pathophysiological research because of the striking accumulation of large glycolipid deposits observable in histology. Yet, the tubular interstitium makes up a large portion of the whole organ, and therefore, its role must be further considered in pathogenic processes. In this review, we would like to propose Fabry tubulopathy and its ensuing functional effects as the first pathological signs and contributing factors to the development of FN. We will summarize and discuss the current literature regarding the role of tubular cells in Fabry kidney pathophysiology. Starting from clinical and histological evidence, we will highlight the data from animal models and cell cultures outlining the pathophysiological pathways associated with tubular interstitial injury causing renal fibrosis in Fabry nephropathy.

The high variability in clinical features and outcomes observed in monogenic diseases like Fabry disease suggests the presence of additional pathogenetic pathways beyond the lysosomal deposition of Gb3 and Lyso-GB3. Research indicates that the deposition of Gb3 and Lyso-Gb3 can stimulate the inflammatory processes. Mononuclear immune-competent cells exposed to Gb3 deposition exhibit surface adhesion molecules and release pro-inflammatory and fibrotic cytokines such as IL β, TNFα, and TGFβ, culminating in the activation of inflammatory cascades associated with oxidative stress, apoptotic mechanisms maintained by renal residents and infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, in another avenue of inquiry (termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alpha-galactosidase A enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response (UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of pro-inflammatory cytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstrated that the pathogenetic mechanisms activated by Gb3 and Lyso Gb3 deposition can become independent from the initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-therapy or gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifest in the absence of Gb3 in the Zebrafish experimental model. This review endeavors to describe the role of these processes in Fabry nephropathy and aims to synthesize the available evidence on the pathogenesis of renal damage.

BACKGROUND:Entering dialysis is a critical moment in patients' healthcare journey, and little is known about drug therapy around it. A study funded by the Italian Medicines Agency offered the opportunity to leverage data from the Lazio Regional Dialysis and Transplant Registry (RRDTL) and perform an observational study on drug use patterns before and after initiating chronic dialysis. METHODS:Individuals initiating dialysis in 2016-2020 were identified from RRDTL, excluding patients with prior renal transplantation, stopping dialysis early, or dying within 12 months. Use of study drugs, predefined by clinicians, in the two years around the index date was retrieved from the drug claims register and described by semester. For each drug group, proportions of users (min 2 claims in 6 months) by semester, and intensity of treatment in terms of Defined Daily Doses (DDDs) for cardiovascular and antidiabetic agents were compared across semesters, stratifying by sex and age. RESULTS:In our cohort of 3,882 patients we observed a general increase in drug use after initiating dialysis, with the mean number rising from 5.5 to 6.2. Cardiovascular agents accounted for the highest proportions, along with proton pump inhibitors and antithrombotics over all semesters. Dialysis-specific therapies showed the most evident increase, in particular anti-anaemics (iron 4-fold, erythropoietins almost 2-fold), anti-parathyroids (6-fold), and chelating agents (4-fold). Use of cardiovascular and antidiabetic drugs was characterised by significant variations in terms of patterns and intensity, with some differences between sexes and age groups. CONCLUSIONS:Entering dialysis is associated with increased use of specific drugs and goes along with adaptations of chronic therapies.

Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92 years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). A total of 119 (9.8

The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.

Abstract Background and Aims Onconephrology is a recently developed discipline aimed at diagnosing and managing renal disease in cancer patients. Few data are available regarding clinical and histological aspects concerning the whole population referred to an onconephrology clinic. Our study aimed to describe the clinical and histopathological characteristics of these patients and to evaluate indices of renal function recovery, renal damage progression, and mortality; a specific aim was to determine in our cohort the prevalence of acute kidney injury (AKI), chronic kidney disease (CKD) and acute kidney disease (AKD) which included all patients meeting KDIGO criteria for AKD but not for AKI. Secondary aims were the analysis of the immunotherapy subgroup and to determine the rate of immune-related adverse events (IRAEs). Method In this prospective observational study, we consecutively enrolled 84 patients for the clinical analysis and 10 patients in two centres for the histopathological study. Clinical assessment in the former group were performed at the first visit (T0), 1 month (T1), 3 months (T2) and 1 year (T3) and compared with a pre-determined baseline. Complete oncological and nephrological assessments were performed. For kidney biopsies, histopathological findings were expressed with quantitative and semi-quantitative parameters. Outcomes were: AKI or AKD complete or partial recovery of renal function (respectively defined as: return to baseline; sCr reduction ≥ 0.3 mg/dl or ≥ 25% or improvement to a lower stage of AKI); a composite of events (MAKE) based on CKD development or progression or death (only at T3). Results Our population was predominantly elderly, hypertensive, in metastatic phase (64.2%), M>F; other factors associated with increased cardiovascular risk were: previous AKI (18.8%), diagnosis of type 2 diabetes (25.9%), history of former/current smoker (55.4% and 19.6%), hyperuricemia (mean uric acid 7 mg/dl), previous/current cisplatin treatment (15.5% and 3.6%). The estimated prevalence in our cohort was: AKI 30.1%; CKD 27.7%; AKI on CKD 25.7%; AKD 9.6%. Regarding AKI, 68.4% were stage 1; for CKD, most patients were stage 3A and 3B (28.2% and 46.2%). More than 1/3 of the patients presented with suspended anticancer treatment; complete therapy resume rates were modest. Complete and partial AKI recovery rates at T2 were both ∼33%. Renal function was fully recovered in 50% of the AKD patients. During the follow-up, a new episode of AKI was observed in 15.5% of the patients, more frequently in the first 3 months. Patients receiving immunotherapy showed worse renal function (sCr 2.02 vs 1.51 mg/dl at T0, p<.001) and higher mortality (4 vs 0, p<.05); patients with IRAEs (25.8%) presented more frequently with discontinued therapy (Table 1). Of 36 patients with data available at 1 year, 21 (58.3%) presented the outcome MAKE; 11 patients died, 4 in the first three months. No nephrological conditions were found to predict MAKEs; presence of metastasis and female sex were the only predictors with Cox regression. Patients who underwent renal biopsy showed marked heterogeneity in the diagnoses (4 Membranous nephropathy, 1 drug-induced podocyte damage, 1 extracapillary GN after SARSCoV2 vaccination, 1 Light/Heavy Chain Deposition Disease, 1 Chronic Tubulointerstitial Nephritis, 1 sclerohyalinosis, 1 nonspecific); histopathological data was unremarkable. Conclusion AKI and CKD occur frequently in the onconephrological population. These patients are susceptible to new AKI episodes. The absence of AKI recovery and anticancer therapy withdrawal are common, potentially holding negative prognostic value. Particular attention should be paid to patients undergoing immunotherapy, especially when associated with IRAE. A larger number of patients is needed to estimate the impact of nephrological factors in the extended follow-up.

ABSTRACT 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.

Research on membranous nephropathy truly exploded in the last 15 years. This happened because of the application of new techniques (laser capture microdissection, mass spectrometry, protein G immunoprecipitation, arrays) to the study of its pathogenesis. After the discovery of PLA2R as the major target antigen, many other antigens were identified and others are probably ongoing. Clinical and pathophysiology rebounds of new discoveries are relevant in terms of diagnosis and prognosis and it is time to make a first assessment of the innovative issues. In terms of classification, target antigens can be divided into: 'membrane antigens' and 'second wave' antigens. The first group consists of antigens constitutionally expressed on the podocyte membrane (as PLA2R) that may become a target of an autoimmune process because of perturbation of immune-tolerance. 'Second wave' antigens are antigens neo-expressed by the podocyte or by infiltrating cells after a stressing event: this allows the immune system to produce antibodies against them that intensify and maintain glomerular damage. With this abundance of target antigens it is not possible, at the moment, to test all antibodies at the bedside. In the absence of this possibility, the role of histological evaluation is still irreplaceable.