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Several novel antigens have recently been characterized in membranous nephropathy (MN), but those involved in the rare cases of MN associated with inflammatory neuropathies (IN) remain elusive. Although several antibody specificities were identified in the serum, there is no evidence so far for their deposition in glomeruli. We report the case of a 73 y/o woman who was referred because of subacute onset of proximal asymmetric lower limb weakness together with ataxic gait. She was diagnosed with IN. Blood tests showed an eGFR of 73 ml/min/1.73m2, hypoalbuminemia (2.89 g/dl) and proteinuria (3.6 g/24h). Autoantibodies (ANA, ENA, DNA, LAC, anti-cardiolipin, ANCA) were undetectable. Serum Ig and complement levels were normal. A kidney biopsy with electron microscopy examination showed a classical picture of MN. Anti-PLA2R antibody was negative in the serum and PLA2R and THSD7A antigens were not detected in kidney tissue. Anti-contactin1 (CNTN1) antibody was found by ELISA at 1:100 serum dilution and shown to be mostly of IgG4 subclass by Western blot. CNTN1 antigen was co-localized with IgG4 within immune deposits by confocal microscopy. This observation suggests a pathophysiological link between IN and MN. CNTN1 should be considered as a potential candidate antigen involved in MN and tested in PLA2R negative forms associated with IN.

Valeria Cernaro, Sebastiano Calimeri, Alfredo Laudani, Domenico Santoro Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, ItalyCorrespondence: Valeria CernaroUnit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria N. 1, Messina 98124, ItalyTel/Fax +39.090.2212317Email valecern82@virgilio.itAbstract: Patients with progressive chronic kidney disease (CKD) commonly develop mineral and bone abnormalities and extraskeletal calcifications with following increased cardiovascular risk. A key pathophysiological role is played by hyperphosphatemia. Since diet and dialysis are often insufficient to control serum phosphorus levels, many patients require treatment with phosphate binders. Among them is lanthanum carbonate, an aluminum-free non-calcium-based compound. The present review summarizes the most recent literature data concerning the safety, efficacy and tolerability of lanthanum carbonate in patients with end-stage renal disease and hyperphosphatemia. The drug is taken orally as chewable tablets or powder with only minimal gastrointestinal absorption and resulting reduced risk of tissue deposition and systemic drug interactions. The dissociation of the drug in the acid environment of the upper gastrointestinal tract induces the release of lanthanum ions, which bind to dietary phosphate forming insoluble complexes then excreted in the feces. Even though there is no clear evidence that lowering serum phosphorus levels can improve patient-centered outcomes, a mortality benefit with all phosphate binders, especially non-calcium containing ones, is not excluded. Lanthanum carbonate has been suggested to decrease all-cause mortality but not cardiovascular event rate compared to other phosphate binders. It induces a lower suppression of bone turnover than calcium carbonate and calcium acetate and may improve systolic function and cardiac dimension compared to calcium carbonate. Moreover, the use of lanthanum carbonate has been associated with better nutritional status compared to other phosphate binders, lower risk for hypercalcemia than calcium-containing binders, and amelioration of mild metabolic acidosis contrary to sevelamer hydrochloride. Main adverse effects include nausea, alkaline gastric reflux, gastric deposition of lanthanum, gastrointestinal obstruction, subileus, ileus, perforation, fecal impaction, and reduction of gastrointestinal absorption of some drugs including statins, angiotensin-converting enzyme inhibitors and some antibiotics such as fluoroquinolones or tetracyclines.Keywords: adverse effects, chronic kidney disease-mineral bone disorder, CKD-MBD, hyperphosphatemia, lanthanum carbonate, phosphate binders

Kynurenine pathway of tryptophan metabolism is involved in the pathophysiology of chronic kidney disease (CKD) and diabetes mellitus, mainly through the inflammation-induced activity of indoleamine 2,3-dioxygenase (IDO), and few studies have investigated its potential link with proteinuria. Renin-angiotensin system inhibitors (RASis) are recommended in these patients to decrease proteinuria, slow CKD progression and reduce cardiovascular risk, but whether these drugs influence kynurenine levels in humans is unknown. We evaluated serum tryptophan and kynurenine in patients suffering from CKD with or without type 2 diabetes mellitus, their correlations with markers of reduced kidney function, and their relationship with RAS-inhibiting therapy. Of 72 adult patients enrolled, 55 were receiving RASis, whereas 17 were not. Tryptophan was assessed by HPLC (high-performance liquid chromatography); kynurenine was measured using an enzyme-linked immunosorbent assay kit; IDO activity (%) was calculated with the formula (kynurenine/tryptophan) × 100. Kynurenine levels were significantly lower in the group under RASis compared to the untreated group (1.56 ± 0.79 vs 2.16 ± 1.51 µmol/l; P = 0.0378). In patients not receiving RASis, kynurenine was inversely related to estimated glomerular filtration rate (eGFR) (r = - 0.4862; P = 0.0478) and directly related to both proteinuria (ρ = 0.493; P = 0.0444) and albuminuria (ρ = 0.542; P = 0.0247). IDO activity was higher in patients with history of cardiovascular disease compared to patients with no such history, and it negatively correlated with eGFR (ρ = - 0.554; P = 0.0210) in the same group. These findings may contribute to explain the well-known beneficial effects of RAS inhibition in CKD population, especially considering that kynurenine is emerging as a potential new biomarker of CKD.

A 2-year-old male neutered domestic shorthair cat from Florida, USA, presented with a one-month history of multiple subcutaneous nodules affecting the entire body. Dermatohistopathology revealed nodular to diffuse, eosinophilic, histiocytic, and mastocytic dermatitis and panniculitis with collagen flame figures, and many nematode larvae and adults within nodules and migration tracts. The worms were morphologically consistent with Dirofilaria striata. The serum antibody test was positive for D. immitis with a negative antigen assay result (both with and without heat treatment), and microfilariae were not recovered by a modified Knott's test. PCR and sequencing of 18S rRNA and mitochondrial 12S rRNA and cytochrome oxidase subunit I genes confirmed the presence of a Dirofilaria spp. Unfortunately, there is no available reference sequence or material for D. striata for comparison. The cat was treated with monthly topical 10% imidacloprid/1% moxidectin. Lesions clinically resolved within one month, but new lesions appeared on different locations despite the monthly treatment. Resolution occurred without changing the treatment regimen, as no additional nodules were noted after 1 year. This Dirofilaria sp. may cause subcutaneous nodules in the domestic cat and should be included in the differential diagnosis for felines with nodular dermatitis, and is present in Florida.

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.

Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional pathophysiological aspects of CRS, the need to find precise and easy-to-use markers has also evolved. Based on the new pathophysiological standpoints and an overall vision of the CRS, the literature on renal, cardiac, metabolic, oxidative, and vascular circulating biomarkers was evaluated. Though the effectiveness of different extensively applied biomarkers remains controversial, evidence for several indicators, particularly when combined, has increased in recent years. From new aspects of classic biomarkers to microRNAs, this review aimed at a 360-degree analysis of the pathways that balance the kidney and the heart physiologies. In this delicate system, different markers and their combination can shed light on the diagnosis, risk, and prognosis of CRS.

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease with autosomal recessive transmission, characterized by periodic fever attacks with self-limited serositis. Secondary amyloidosis due to amyloid A renal deposition represents the most fearsome complication in up to 8.6% of patients. Amyloidosis A typically reveals a nephrotic syndrome with a rapid progression to end-stage kidney disease still. It may also involve the cardiovascular system, the gastrointestinal tract and the central nervous system. Other glomerulonephritis may equally affect FMF patients, including vasculitis such as IgA vasculitis and polyarteritis nodosa. A differential diagnosis among different primary and secondary causes of nephrotic syndrome is mandatory to determine the right therapeutic choice for the patients. Early detection of microalbuminuria is the first signal of kidney impairment in FMF, but new markers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) may radically change renal outcomes. Serum amyloid A protein (SAA) is currently considered a reliable indicator of subclinical inflammation and compliance to therapy. According to new evidence, SAA may also have an active pathogenic role in the regulation of NALP3 inflammasome activity as well as being a predictor of the clinical course of AA amyloidosis. Beyond colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and anti-IL-6 tocilizumab may represent a key in optimizing FMF treatment and prevention or control of AA amyloidosis.

Background and Aims Indole-3-acetic acid (IAA, also called auxin) is a protein-bound indolic uremic toxin deriving from tryptophan metabolism by the intestinal bacteria. Previous studies have shown that increased IAA is associated with enhanced tissue factor synthesis in endothelial and peripheral blood mononuclear cells, oxidative stress and endothelial inflammation with resulting higher risk of thrombotic events and both cardiovascular and all-cause mortality. An emerging biomarker of cardiovascular disease is the monocyte to high-density lipoprotein (HDL) ratio (MHR). Its prognostic value is related to the ability of monocytes to release several cytokines involved in inflammation and atherogenesis and to the protective role of HDL through removal of cholesterol from peripheral tissues and suppression of both monocyte progenitor cell proliferation and differentiation and monocyte activation. In this single-centre cross-sectional observational study, we investigated the potential association of IAA with MHR and other markers of cardiovascular risk in a cohort of patients with CKD and evaluated the effect of a single midweek dialysis session with AFB (Acetate-free Biofiltration) technique on IAA serum concentrations. Method We enrolled 61 non-dialysis CKD adult patients and 6 dialysis patients treated with AFB technique. IAA levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (Cat. number abx150354; Abbexa Ltd, Cambridge, UK). Post-dialysis IAA levels were corrected for haemoconcentration. Results In the whole cohort of 67 patients, IAA was directly related to creatinine (ρ = 0.247; P = 0.0441), potassium (r = 0.2871; P = 0.0185), Ca x P product (ρ = 0.256; P = 0.0365) and MHR (ρ = 0.321; P = 0.0082). After adjustment for creatinine, the correlation between IAA and potassium became not significant (r = 0.1968; P = 0.1133). Stratifying patients according to the history of cardiovascular disease, in the 40 patients with previous cardiovascular events IAA levels correlated significantly with uric acid (r = 0.3952; P = 0.0116) and MHR (ρ = 0.380; P = 0.0157). In the remaining 27 patients without history of cardiovascular disease, IAA only correlated with potassium (r = 0.3912; P=0.0481) and, though borderline significantly, with creatinine (ρ = 0.349; P = 0.0805). To assess whether IAA would independently predict MHR values, we evaluated potential correlations of MHR with risk factors for cardiovascular disease. MHR was related with fibrinogen (ρ = 0.426; P = 0.0010), arterial hypertension (ρ = 0.274; P = 0.0251), C-reactive protein (ρ = 0.332; P = 0.0061), gender (ρ = -0.375; P = 0.0017; 0 = male, 1 = female), and CKD stage (ρ = 0.260; P = 0.0337). A multiple regression analysis identified IAA as an independent predictor of MHR. Lastly, IAA levels were higher in dialysis patients compared to non-dialysis CKD patients (97.44 ± 21.58 versus 65.08 ± 24.38 ng/ml respectively; P = 0.0026) and it was significantly removed by a single AFB session (97.44 ± 21.58 versus 54.59 ± 21.74 ng/ml; P = 0.0028) with a reduction ratio of 43.80 ± 17.47%. Conclusion This study shows a statistically significant association between IAA and MHR. Based on previous experimental studies, such relationship could be explained by the activation of the transcription factor aryl hydrocarbon receptor. Indeed, IAA is a potent ligand of aryl hydrocarbon receptor and the latter has proinflammatory and proatherogenic activities and can reduce HDL levels. Moreover, AFB efficiently removes IAA during a single dialysis session. Prospective studies with appropriate sample size and sufficiently long period of observation are required to evaluate if decreasing IAA levels, through targeted therapeutic strategies in non dialysis CKD patients or by optimization of dialysis techniques and prescriptions in patients receiving renal replacement therapy, may reduce MHR levels and cardiovascular events and improve clinical outcomes and survival.

Background and Aims Thrombotic Microangiopathies (TM) are three distinct clinical syndromes presenting the same histological renal pattern: typical and atypical Hemolytic Uremic Syndrome (SEU- aSEU) and Thrombotic Thrombocytopenic Purpura (TTP). So far, the first report of a TM has been generally attributed to Eli Moschowitz. In 1922 he described the case of a 16 years old girl who died after acute onset of fever with petechial lesions and autoptic findings of hyaline thrombosis of terminal arterioles and capillaries, thus profiling the first case of TTP. Only in the 1955, Conrad Gasser described the first medical record of HUS, describing the case of a patient with a manifestation of bilateral necrosis of the renal cortex. We describe the first reported case of a Thrombotic Microangiopathy, in particular an experimentally induced aHUS by Richard M. Pearce in 1909. In this case, the trigger leading to aHUS was represented by snake venom injection in an experimental rabbit model. Method Pearce described acute glomerular lesions produced in the rabbit using dried venom of rattlesnake Crotalus Adamanteus. It was dissolved in salt solution in the proportion of 0.25 of a milligram to one cubic centimeter, rising gradually to two milligrams, and then followed by doses of 0.5 of a milligram of fresh venom at various intervals. The intervals between injections depended on the general condition of the animal and the amount of albuminuria. Results Rabbit kidneys showed well marked hemorrhagic and exudative lesions in the glomeruli; hyaline, granular, blood, and hemoglobin casts in both convoluted and collecting tubules; and granular degeneration of the epithelium of the convoluted tubules and loops of Henle. Pearce also described a “penetration of the cells of the compressed glomerular tuft into the mass of hemorrhage lying either in the tuft itself or in the capsular space” (Figure 1). In animals surviving 20-30 days after the first injection of the venom, the acute lesions were demonstrated to subside at the microscopic examination and their earlier presence was marked by “occasional casts and compressed masses of red cells in the glomerular spaces and tufts”. At the same time other models also showed “extensive granular degeneration of the convoluted tubules and many casts”. The renal autoptic findings presented the features of a vascular nephritis with severe endothelial changes. Conclusion Glomerular and tubular lesions of rabbits’ kidneys induced by crotalus’s venom showed typical features of what is today defined as aHUS. In this first experiment, the author described a glomerular tuft as “more analogous to the organization of a red thrombus than it is to any form of glomerular lesion known in man”, so we can affirm that Pearce described, ante litteram TMA histological features many years before other scientists.

Vitamin D modulates bisphosphonate (BP) efficacy, but its contribution to bone mineral density (BMD) after BP discontinuation is not known. To address this topic, we performed a retrospective analysis of postmenopausal women exposed to alendronate (ALN) to treat osteoporosis who regularly continued the supplementation of cholecalciferol or calcifediol at recommended doses. In the ninety-six recruited women (age 61.1 ± 6.9 years), ALN was administered for 31.2 ± 20.6 months and then discontinued for 33.3 ± 18.9 months. The modification of 25(OH)D serum levels over time was associated with a change of alkaline phosphatase (r = −0.22, p = 0.018) and C-terminal collagen type 1 telopeptide (r = −0.3, p = 0.06). Women in the tertile of the highest increase in 25(OH)D level showed a 5.7% BMD gain at lumbar spine, that was twice as great in comparison with participants with a lower 25(OH)D variation. At a multiple regression analysis, BMD change was associated with time since menopause (ß = 2.28, SE 0.44, p &lt, 0.0001), FRAX score for major fracture (ß = −0.65, SE 0.29, p = 0.03), drug holiday duration (ß = −2.17, SE 0.27, p &lt, 0.0001) and change of 25(OH)D levels (ß = 0.15, SE 0.03, p = 0.0007). After ALN discontinuation, improving the vitamin D status boosts the ALN tail effect on BMD.

Background and Aims Chronic kidney disease (CKD) is one of the most prevalent complication of Diabetes Mellitus and patients with both diseases are more exposed to atherosclerosis injury and premature death from cardiovascular disease (CVD). CVD is worsened by inflammation, oxidative stress, lipid accumulation and high-density lipoprotein cholesterol (HDL) reduction: patients with altered lipid metabolism more often present monocyte profile changes, with an altered pro-inflammatory phenotype leading to a significant risk of plaque formation and atherosclerosis. The alteration of the balance between monocyte and HDL, represented by the Monocyte/HDL ratio (MHR), is an easy way to evaluate the inflammatory status and to study appropriate strategies to treat high-risk patients. Method We evaluated 150 consecutive diabetic patients with CKD hospitalized in the Unit of Nephrology and Dialysis of the Policlinic G. Martino of Messina, Italy, with a history of CVD. We used the SMART-REACH SCORE, a model created to estimate life expectancy without recurrent cardiovascular events for individuals with a history of CVD. We performed a retrospective analysis of the MHR status of our patients to study its correlations with the 10-year risk and lifetime risk for myocardial infarction, stroke or vascular death, recurrent CVD events and free life-expectancy if standard care is provided. Results In the entire cohort of patients, MHR appeared to be positively correlated with ten-year risk (ρ=0.469; P Conclusion MHR can represent a valid tool to predict the recurrence of CVD in CKD patients with diabetes. This easy-to-perform marker of oxidative stress and CVD risk can be used alone or in a multiple biomarker panel, improving the stratification and management of patients with comorbidities and risk of life- threatening conditions.

Roughly 3% of patients worldwide with a new diagnosis of type 2 diabetes mellitus (T2DM) already have an overt nephropathy at diagnosis and about 20–30% of the remaining ones develop a complication of this kind later in life. The early identification of kidney disease in diabetic patients is important as it slows its progression, which is important not only because this reduces the need for renal replacement therapy, but also because it decreases the high rate of mortality and morbidity associated with a reduction in kidney function. The increasing prevalence of type 2 diabetes and the consequent greater probability of finding different types of kidney diseases in diabetic patients frequently gives rise to overlapping diagnoses, a definition encompassing the differential diagnosis between diabetic and non-diabetic kidney disease. The issue is made more complex by the acknowledgement of the increasing frequency of presentations of what is termed “diabetic kidney disease” without relevant proteinuria, in particular in T2DM patients. Distinguishing between diabetes related and non-diabetes related forms of kidney disease in diabetic patients is not only a semantic question, as different diseases require different clinical management. However, while the urologic and macrovascular complications of diabetes, as well as overlapping parenchymal damage, can be diagnosed by means of imaging studies, often only a kidney biopsy will make a differential diagnosis possible. In fact, the coexistence of typical diabetic lesions, such as nodular glomerulopathy or glomerulosclerosis, with different glomerular, vascular and tubulo-interstitial alterations has been extensively described, and an analysis of the dominant histological pattern can contribute to determining what therapeutic approach should be adopted. However, due to the high frequency of kidney diseases, and to the fact that T2DM patients are often affected by multiple comorbidities, a kidney biopsy is not generally performed in T2DM patients. What follows is a review aiming to discuss the diagnostic work-up, on the base of clinical, laboratory and imaging criteria, and evaluate the present indications and alternatives to renal biopsy.

Rationale & Objective: Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerulopathy characterized by complement dysregulation. MPGN progresses rapidly to kidney failure when it is associated with nephrotic syndrome. We assessed the effects of C5 convertase blockade in patients with MPGN and terminal complement activation. Study Design: Prospective off-on-off-on open-label clinical trial. Setting & Participants: Consenting patients with immune complex–mediated MPGN (n = 6) or C3 glomerulonephritis (n = 4) with sC5b-9 (serum complement membrane attack complex) plasma levels > 1,000 ng/mL and 24-hour proteinuria with protein excretion > 3.5 g identified from the Italian Registry of MPGN and followed up at the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7, 2015. Intervention: Anti-C5 monoclonal antibody eculizumab administered during 2 sequential 48-week treatment periods separated by one 12-week washout period. Outcomes: Primary outcome was change in 24-hour proteinuria (median of 3 consecutive measurements) at 24 and 48 weeks. Results: Median proteinuria decreased from protein excretion of 6.03 (interquartile range [IQR], 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks (P = 0.01) and to 5.06 (IQR, 3.1-5.8) g/d (P = 0.006) at 48 weeks of treatment, recovered toward baseline during the washout period, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndrome and all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7 ± 35.2 versus 87.4 ± 55.1 and 75.8 ± 42.7 versus 76.6 ± 44.1 mL/min/1.73 m2 at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washout in all patients. Limitations: Single-arm design, small sample size. Conclusions: Eculizumab blunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in just a subgroup. Trial Registration: Registered in the EU Clinical Trials Register with study no. 2013-003826-10.

Background The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on the general population and the burden of pre-existing comorbidities has heavily affected the outcome of the infection. Hyponatraemia has been frequently described. Conversely, hypernatraemia has rarely been described in COVID-19. Methods The studied cohort encompasses all COVID-19 patients consecutively admitted to the Messina Hospital, Italy, during the first wave of the epidemic. Since healthcare structures were not overwhelmed at that time, indications for hospitalization were homogeneous throughout the study period. Serum sodium levels, kidney function [estimated glomerular filtration rate (eGFR)], demographic and clinical characteristics were recorded at admission. Correlation between mortality, sodium and eGFR was evaluated by survival curves and univariate and multivariate regression models. Results Baseline biochemical and clinical data at the time of admission were available for 115 COVID-19-confirmed patients. The median age at admission was 73 years (48% men), with a median Charlson Comorbidity Index of 4. A total of 23.5% of patients presented with a sodium level ≥146 mmol/L, while 7.8% had sodium Conclusions Our study suggests that the association between hypernatraemia and reduced eGFR at referral is a highly relevant prognostic marker for death during hospitalization. The role of this association should be further tested in larger, multicentre cohorts.

Introduction: We present the clinical case of a 71 years old man with chronic renal failure of unclear etiology After 16 years of hemodialysis, he underwent successful deceased donor kidney transplantation 3 years ago His immunosuppression included basiliximab, tacrolimus, mychophenolate and prednisone 3 years after transplant renal function was stable and in normal range, but there was evidence of anemia, thrombocytopenia and mild leukopenia;mycophenolate dose was reduced with no significant improvement He developed low grade fever with urinary retention, requiring bladder catheterization;because of rapid deterioration of clinical picture, with dehydration and worsening of neurological status, he underwent hospitalization Methods: Blood chemistry tests showed pancytopenia with high inflammatory indices, hyperkalemia, hyponatremia;PCR SARS-Cov2 in nasopharyngeal swab was negative Brain CT was negative for acute lesions, chest CT showed minimal pleural effusion without lymphadenopathy Empiric antibiotic therapy with piperacillin /tazobactam and ciprofloxacin was started and mycophenolate was discontinued He was transferred to our facility Hematological tests confirmed severe pancytopenia, worsening renal function, coagulopathy with increased INR and APTT, increased inflammatory indices, normal haptoglobin, slightly increased LDH, hypoalbuminemia and hypergammaglobulinemia (See Table) Urine culture was positive for an extended spectrum beta-lactamase E Coli infection, and antibiotic therapy was targeted based on antibiogram Abdomen CT showed splenomegaly (17 cm in diameter) Patient underwent hematological consult, and a diagnosis of disseminated intravascular coagulation (DIC) secondary to infection was made, excluding a primary hematological cause Tacrolimus was discontinued and prednisone 5 mg was replaced with dexamethasone 20 mg/day The search for bacteria and fungi on blood was negative, as well as viremia by PCR for CMV, EBV, Parvovirus B19, HHV8, VZV, HSV, BKV, JCV HIV serology was negative [Formula presented] Results: We considered the diagnosis of visceral leishmaniasis and bone marrow aspirate and Leishmania PCR research on peripheral blood and bone marrow were performed Therapy with intravenous liposomal amphotericin B 4 mg /kg/day was started Laboratory tests showed:Leishmania serology: positive (1: 2560 at indirect immunofluorescence titration IFAT)Leishmania PCR on blood: positive (1300 leish/ml)Leishmania PCR on bone marrow: positive 1,500,000,000 leish/ml)Bone marrow aspirate smear showed Leishmania amastigotes inside macrophages (Image) Patient was treated with Liposomal amphotericin for 12 consecutive days, with a total dose of 48 mg/kg Dexamethasone was decreased and then switched to prednisone Conclusions: Patient’s clinical condition significantly and rapidly improved, with resolution of fever, pancytopenia and coagulopathy, and dramatic decrease of Leishmania copies on blood Two further doses of Liposomal Amphotericin were given weekly Our case focuses on the importance of considering leishmaniasis in the differential diagnosis for fever with pancytopenia and coagulopathy, especially in countries where the disease is endemic [Formula presented] Magnification (40x) of the bone marrow aspirate smear: the arrows indicate the presence of amastigotes No conflict of interest

Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin–Angiotensin–Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin–megalin–amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN.

Background: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. Methods: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). Results: We studied 562 patients (age 66.2 ± 14.5 y, 61% males, eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was “absent” in 50.7%, “resolving” in 15.6%, “new onset” in 16.6%, and “persistent” in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p &lt, 0.0001), K-binders (from 2.0 to 7.7%, p &lt, 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p &lt, 0.001), these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR &lt, 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). Conclusions: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

Objectives Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. Methods A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques. Results The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low–medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0–12 months), and high levels at T0–1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. Conclusion Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients. Trial registration The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.

Objectives Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. Methods Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. Results LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months. Conclusions Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. Trial registration The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).

Clinical Trial registry name and registration number: Zeus study, NCT02403115

Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.

Inflammation, oxidative stress (OS), atherosclerosis and resistant hypertension (RH) are common features of chronic kidney disease (CKD) leading to a higher risk of death from cardiovascular disease. These effects seem to be modulated by impaired anti-oxidant, anti-inflammatory and reverse cholesterol transport actions of high-density lipoprotein cholesterol (HDL). HDL prevents and reverses monocyte recruitment and activation into the arterial wall and impairs endothelial adhesion molecule expression. Recently, monocyte count to HDL-cholesterol ratio (MHR) has emerged as a potential marker of inflammation and OS, demonstrating to be relevant in CKD. Our research was aimed to assess, for the first time, its reliability in RH. We performed a retrospective study on 214 patients with CKD and arterial hypertension who were admitted between January and June 2019 to our Department, 72 of whom were diagnosed with RH. MHR appeared inversely related to eGFR (ρ = − 0.163; P = 0.0172). MHR was significantly higher among RH patients compared to non-RH ones (12.39 [IQR 10.67–16.05] versus 7.30 [5.49–9.06]; P

Background A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. Methods We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. Results At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. Conclusions This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. Clinical trial registry name and registration number Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

Pregnancy is still a challenge in women with autoimmune diseases or kidney transplantation. In this context, management of the immunosuppressive therapy is critical, but, in spite of more than 60 years of experience, many issues remain open, also because of the difficulty in disentangling, in complex patients, the effect of the disease and of the frequent multiple treatments. For this purpose, we have tried to synthesize the existing knowledge and the unresolved issues, to support counseling and promote patient empowerment.

Diabetes mellitus represents a growing concern, both for public economy and global health. In fact, it can lead to insidious macrovascular and microvascular complications, impacting negatively on patients’ quality of life. Diabetic patients often present diabetic kidney disease (DKD), a burdensome complication that can be silent for years. The average time of onset of kidney impairment in diabetic patients is about 7–10 years. The clinical impact of DKD is dangerous not only for the risk of progression to end-stage renal disease and therefore to renal replacement therapies, but also because of the associated increase in cardiovascular events. An early recognition of risk factors for DKD progression can be decisive in decreasing morbidity and mortality. DKD presents patient-related, clinician-related, and system-related issues. All these problems are translated into therapeutic inertia, which is defined as the failure to initiate or intensify therapy on time according to evidence-based clinical guidelines. Therapeutic inertia can be resolved by a multidisciplinary pool of healthcare experts. The timing of intensification of treatment, the transition to the best therapy, and dietetic strategies must be provided by a multidisciplinary team, driving the patients to the glycemic target and delaying or overcoming DKD-related complications. A timely nephrological evaluation can also guarantee adequate information to choose the right renal replacement therapy at the right time in case of renal impairment progression.

Chronic kidney disease (CKD) affects 3% of pregnancies, impacting on maternal and fetal outcomes, and at the same time, a recurrent question in nephrology regards gestation impact on kidney function. Observational studies stated that CKD stage, pre-existent hypertension, and proteinuria are the main predictors of possible complications, such as maternal CKD progression, maternal or fetal death, prematurity, small for gestational age (SGA) newborn, or admission to the neonatal intensive care unit. In this regard, given the prominence of proteinuria among other risk factors, we focused on primary nephrotic syndrome in pregnancy, which accounts for 0.028% of cases, and its impact on materno-fetal outcomes and kidney survival. Data extracted from literature are scattered because of the small cohorts investigated in each trial. However, they showed different outcomes for each glomerular disease, with membranous nephropathy (MN) having a better maternal and fetal prognosis than focal and segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), or minimal change disease (MCD). Nephrotic syndrome does not have to discourage women to undertake a pregnancy, but the correct management may include a specific evaluation of risk factors and follow-up for adverse materno-fetal events and/or maternal kidney disease progression.

Vogt, Bruno/0000-0002-1548-6387; Dufek, Stephanie/0000-0002-6323-6673; Liu, Lili/0000-0002-2622-9669; Paczek, Leszek/0000-0003-0160-3009; Cui, Zhao/0000-0002-5837-1926; amoroso, antonio/0000-0002-9437-9407; Rosen, Raphael/0000-0003-1025-1965; Loos, Ruth/0000-0002-8532-5087; coenen, marieke/0000-0001-8796-2031; zanoni, francesca/0000-0001-9567-6713; CUCCA, Francesco/0000-0002-7414-1995; Ars, Elisabet/0000-0002-4118-4358; Hamilton, Patrick/0000-0001-6703-3745 WOS:000563559600001 PubMed ID: 32231244 Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) [RC2-DK116690, R01-DK105124, R01-DK097053, R01-DK108805]; National Institute on Minority Health and Health Disparities (NIMHD)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Minority Health & Health Disparities (NIMHD) [R01-MD009223]; Charles Woodson Clinical Research Fund; Nephrotic Syndrome Study Network Consortium (NEPTUNE) [U54-DK-083912]; Columbia University, Columbia Glomerular Center; Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of MichiganUniversity of Michigan System; NephCure Kidney International; Halpin Foundation; National Key Research and Development Program of China [2016YFC0904100]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81621092]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81870460, 81570598]; Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee [17441902200]; Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant [20152207]; Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project [DLY201510]; International Cooperation and Exchange Projects of Shanghai Science and Technology Committee [14430721000]; Outstanding Young Scholar Award [81622009]; Shanghai Health and Family Planning Committee Hundred Talents Program [2018BR37]; Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea - Ministry of Health and Welfare, Republic of Korea; MRCMedical Research Council UK (MRC) [MR/J010847/1]; Manchester Academic Health Science Centre [MAHSC 186/200]; Greater Manchester Local Clinical Research Network; Kidneys for Life Charity; David and Elaine Potter Charitable Foundation; St Peter's Trust for Kidney, Bladder and Prostate Research; Kids Kidney Research UKKidney Research UK (KRUK); Kidney Research UKKidney Research UK (KRUK); Italian Ministry of Health grantMinistry of Health, Italy [GR-2011-02350438]; Department of Excellence Grant 2018-2022 - Italian Ministry of Education for the Department of Medical Sciences of the University of Turin; Columbia University; Poznan University of Medical Sciences, Poland; German Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01ER0804]; KfH Foundation for Preventive Medicine; Bayer Pharma AG; German Research FoundationGerman Research Foundation (DFG) [CRC 1140, KO 3598/3-1, CRC 992]; European Research CouncilEuropean Research Council (ERC) [ERC-2012ADG_2012-0314, 322947]; 7th Framework Programme of the European Community contract [2012-305608]; National Research Agency grant MNaims [ANR-17-CE17-0012-01]; Dutch Kidney Foundation [OW08, KJPB11.021]; National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); NIMHD We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project "Autoimmunity in Membranous Nephropathy", grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter's Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.).; The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznan University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3-1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012ADG_2012-0314 grant 322947, 7th Framework Programme of the European Community contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication.

Interleukins (IL)-17, IL-22, and IL-31 play roles in human atopic dermatitis (AD), but scant information is available on canine AD. Histopathological assessment for interleukin expression is a challenge due to a lack of canine specific antibodies. To evaluate the mRNA and protein expression of IL-17 and IL-22, and mRNA expression of IL-31 and their receptors in the skin of healthy and atopic dogs, seventeen atopic (10 with and 7 without an active infection) and 13 healthy privately owned dogs were sampled. RNAscope® In situ hybridization (ISH) for IL-17, IL-22, IL-31, and their receptors was performed on archived canine skin samples. Simultaneously, indirect immunofluorescence (IIF) was performed for IL-17 and IL-22. RNAscope® ISH probes were validated by RT-PCR and RNAscope® ISH on cytospin preparations of peripheral blood mononuclear cells from atopic dogs. IL-17, IL-22, IL-31, and their receptors were successfully detected by RNAscope® ISH and by IIF (IL-17 and IL-22) in both atopic and healthy canine skin. There was no significant difference in the expression of interleukins and their receptors between healthy and atopic skin with or without active infection. Data from both methodologies were similar. The role and the relationship among those proteins in atopic skin is unclear from this study results. Data from IIF and ISH were overlapping and support each other. Fresh skin samples taken at different times during the development of atopic dermatitis might better assess the role that interleukins and their receptors play in AD.

Feline allergic diseases present as challenging problems for clinicians, not least because of the number of reaction patterns of the feline skin, none of which are specific for allergy. Furthermore, there is some controversy over the nomenclature that should be used in their description.To review the literature, assess the status of knowledge of the topic and the extent to which these diseases could be categorized as atopic in nature, and make recommendations concerning nomenclature.Atopic diseases in humans and cats were researched. A comparison then was made of the essential features in the two species.There were sufficient similarities between human atopic diseases and the manifestations of feline diseases of presumed allergic aetiology to justify the use of "atopic" to describe some of the feline conditions affecting the skin, respiratory and gastrointestinal tract. However, none of the allergic skin diseases showed features consistent with atopic dermatitis as described in man and the dog.The term "Feline Atopic Syndrome" (FAS) is proposed to encompass allergic diseases of the skin, gastrointestinal tract and respiratory tract, and "Feline atopic skin syndrome" (FASS) proposed to describe allergic skin disease associated with environmental allergies. We are not aware of any adverse food reactions in cats that are attributable to causes other than immunological reactions against the food itself. We therefore propose an aetiological definition of "Food Allergy" (FA) to describe such cases.Une nouvelle anomalie congénitale de la tige pilaire ressemblant au phénotype nu des rongeurs est décrite dans une portée de quatre chats européens (DSH). Les données relatives aux anomalies de la tige pilaire et des follicules pileux sont rares en médecine vétérinaire.Décrire et comparer les anomalies structurelles de ces chats avec d’autres dystrophies félines et d’autres mammifères.Une portée de chats DSH avec alopécie progressive non-inflammatoire. MÉTHODES: L’évaluation histopathologique, la microscopie électronique à transmission et l’analyse des éléments par rayons X définissaient les changements pilaires et cutanés des chats nés alopéciques. Les données ont été comparées aux archives de chats normaux et de souris mutantes Dsg4ANTECEDENTES: se describe una nueva anomalía congénita del pelo que se asemeja al fenotipo de pelo lanceolado de los roedores en una camada de cuatro gatos domésticos de pelo corto (DSH). Los datos relacionados con los trastornos del pelo y los folículos siguen siendo escasos en medicina veterinaria. OBJETIVOS: Describir y comparar anomalías estructurales en estos gatos con otras distrofias capilares en gatos y otros mamíferos. ANIMALES: una camada de gatos DSH con alopecia no inflamatoria progresiva. MÉTODOS: evaluación histopatológica, por microscopía electrónica de barrido y de transmisión y el análisis de elementos basados en rayos X definieron los cambios en el pelo y la piel de los gatos nacidos con alopecia. Los hallazgos se compararon con datos de archivo de gatos normales y ratones mutantes de pelo lanceolado (Dsg4Es wird eine neue angeborene Haarschaft Abnormalität bei einem Wurf von vier Hauskatzen (DSH) beschrieben, die dem lanzenförmigen Haar Phänotyp von Nagern gleicht. Daten über Haarschaft- und Follikelstörungen bleiben in der Veterinärmedizin rar.Eine Beschreibung der Strukturabnormalitäten bei diesen Katzen und ein Vergleich mit anderen Haardystrophien bei Katzen und anderen Säugern.Ein Wurf von Hauskatzen mit einer progressiven nichtentzündlichen Alopezie.Mittels histopathologischer Evaluierung, Raster- und Transmissionselektronenmikroskopie, und Röntgen-basierter Elementanalyse wurden die Haar- und Hautveränderungen bei Katzen, die mit einer Alopezie geboren worden waren, definiert. Die Befunde wurden mit archivierten Daten von normalen Katzen und lanzenförmigen Haaren (Dsg4Die Licht- und Rasterelektronenmikroskopie der Haare zeigte Lanzen- oder Speer-Kopf geformte Defekte der Haarspitzen. Die histologischen Befunde zeigten geschwollene Haarschäfte, ursprünglich oberhalb der Haarwurzelmatrix und später auch in den distalen Teilen der telogenen Haarfollikel, ähnlich denen bei Dsg4Eine seltene Form einer angeborenen Alopezie, resultierend aus einer follikulären Dystrophie wird bei Katzen in einer ähnlichen Form beschrieben, wie es bereits bei einigen mutanten Mausstämmen mit einer Einzelgenmutation in Adhäsionsmolekülen oder Keratingenen publiziert worden war.背景: げっ歯類の槍状の毛の表現型に似た新しい先天性毛幹異常が4頭のドメスティック・ショートヘア（DSH）の同腹子で記述されている。毛幹および毛包の障害に関連するデータは、獣医学ではまだ不足している。 目的: 本研究の目的は、これらの猫の構造異常を説明し、猫や他の哺乳類の他の毛髪ジストロフィーと比較することであった。 動物: 進行性の非炎症性脱毛症を伴うDSH猫の同腹子。 方法: 組織病理学的評価、走査型および透過型電子顕微鏡法、およびX線ベース元素解析により、脱毛症で生まれた猫の毛および皮膚の変化が定義された。調査結果は、健常猫と披針形の毛（Dsg4背景: 在4只同窝家养短毛(DSH)猫中，发现了类似啮齿动物披针形毛发表型，这是一种新的先天性毛干异常。与毛干和毛囊疾病相关的数据在兽医学中仍然很少。 目的: 描述这些猫的结构异常，并与猫和其他哺乳动物的其他毛发形成不良进行比较。 动物: 患有进行性非炎性脱毛症的一窝DSH猫。 方法: 组织病理学评价、扫描和透射电子显微镜以及基于X射线的元素分析，定义了新生脱毛猫的毛发和皮肤变化。将结果与正常猫、披针形毛发(Dsg4lahJ)和角质75(Krt75tm1Der)突变小鼠的存档数据进行比较。 结果: 毛发的光学和扫描电子显微镜检查显示，毛尖存在披针形或矛头形缺陷。组织学发现毛干肿胀，最初在毛球基质上方，后来在终止期毛囊的远端部分发现，与在Dsg4lahJ Krt75tm1Der突变小鼠中观察到的相似。毛干和毛囊的透射电镜显示脱毛猫护毛的正常结构缺失。毛干缺损正下方的硫含量在统计学上显著降低（毛发硫营养不良）。 结论和临床重要性: 发现了猫的罕见先天性脱发形式，由毛囊发育不良所导致，与粘附分子或角质基因中单基因突变的几种突变小鼠品系中报告的毛囊和毛干变化类似。.Uma nova anomalia congênita da haste pilosa semelhante ao fenótipo de pelo lanceolado dos roedores foi descrita em uma ninhada de quatro gatos domésticos de pelo curto (DSH). Dados relacionados a enfermidades da haste e folículo piloso permanecem escassos na medicina veterinária.Descrever e comparar as anomalias estruturais nestes gatos com outras distrofias pilosas em gatos e outros mamíferos.Um gato DSH apresentando alopecia não inflamatória progressiva. MÉTODOS: Avaliação histopatológica, microscopia eletrônica de varredura e transmissão e análise elementar baseada em raio-X foram utilizadas para caracterizar as alterações de pele e pelos em gatos nascidos com alopecia. Os achados foram comparados a dados arquivados de gatos normais e ratos com mutação de pelo lanceolado (Dsg4À microscopia de varredura e óptica, observou-se pelos com defeitos nas pontas, que se apresentavam em formato de lança ou ponta de lança. Os achados histológicos foram hastes pilosas dilatadas, inicialmente acima da matriz do bulbo piloso e posteriormente nas partes distais dos folículos pilosos telógenos, similar ao observado nos ratos mutantes Dsg4

Background and Aims Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder that affects about 1-1,5 cases per million individuals, characterized by hemolysis, peripheral blood cytopenia, bone marrow dysfunction, thrombosis, renal impairment and arterial and pulmonary hypertension. The first case of PNH was probably described in 1793 by a surgeon, Dr Charles Stewart, in the medical commentaries “Account of a singular periodical discharge of blood from the urethra”. In the following decades several cases have been reported by the most eminent physicians and scientists of the time. Method In 1882 Paul Strübing was the first to identify PNH as a new disease entity. Hijmans in 1911 considered the possibility that the complement system mediated the hemolysis of PNH erythrocytes and in the same year, Italian scientists Ettore Marchiafava and Nazari scrupulously described the pathogenesis of the affection. In the 1925 Enneking introduced for the first time the name “paroxysmal nocturnal hemoglobinuria”, to define this pathology. Results Despite the increased knowledge of this syndrome, therapies for PNH were still only experimental and symptomatic, with the use of antimicrobial agents, corticosteroids and blood transfusions. The natural history of PNH changed remarkably only in the 2007, with the introduction of Eculizumab complement blockade agent. The Ravulizumab, a long-acting C5 complement inhibitor approved on December 2018 by the U.S. food and drug Administration (FDA), and on July 2019 by the European Commission, represent a new promising instrument for PNH treatment. Conclusion Second generation of anti-complement agents are currently under investigation, representing future promising instruments for the treatment of PNH.

Background and Aims Lupus nephritis (LN) develops in about 50% of patients affected by Systemic Lupus Erythematosus (SLE) and it is associated with higher morbidity and mortality risk. Approximately 10 % of LN patients is expected to reach end stage renal disease (ESRD). Proteinuria at 1 year has been demonstrated as the best predictor factor of long-term renal outcome. We compared the effects of two different induction therapies (Euro Lupus protocol [EL] vs Mycophenolate [MMF]) in terms of eGFR, proteinuria, serum albumin and complement activation in LN patients related to our centre. Method We retrospectively reviewed the records of 34 adult patients with LN from 2011 to 2019. Patients were divided in two groups according to therapeutic strategy chosen: EL (n=21 patients, group 1) and MMF (n=13, group 2). Data with normal distribution are expressed as average ± standard deviation, while data with non normal distribution are referred to as median and interquartile range [IQR]. Basal values of eGFR, proteinuria, albumin and complement were compared to 1 year values with Student t-test for normal variables or with Wilcoxon test for non normal variables. Results The mean age of the patients was 41.27±17.43 years, there was a predominance of female (85,3%) LN was diagnosed at 32±16 years old. According to LN classification, 88.2% of them was affected by III, IV, V and mixed LN class Basal values of eGFR (estimated with CKD-EPI method) were similar between groups 1 and 2 (86.12±52.86 vs 73.75±30.35, P=0.4890) as well as proteinuria (2.00 [0.48-4.57] vs 0.71 [0.28-1.39] g/24h, P=0.3284). After one year of follow up, eGFR did not show significant differences between two groups, while proteinuria was significantly lower in group 1 (2.)). 00 [0.48-4.57] vs 0.44 [0.19-0.91] g/24h, P=0.0034) than in group 2 (0.71 [0.28-1.39] vs 0.15 [0.08-0.77] g/24h, P=0.4687) (fig.1). Moreover, we recorded in group 1 higher values of albumin after one year of follow up (3.20 [2.52-3.94] vs 4.33 [3.99-4.57] g/dl, P=0.0195) (fig.2) and C3 consumption (35.00 [1.00-81.25] vs 89.00 [2.00-112.50] mg/dl, P=0.0067) (fig.3), while group 2 did not show any statistically significant differences. Conclusion In patients affected by LN, EL protocol demonstrated to be more effective than MMF in reducing one year after proteinuria, thus improving albumin and C3 serum titer.

Background and Aims Kynurenine pathway of tryptophan metabolism is involved in the pathophysiology of chronic kidney disease (CKD) and diabetes mellitus (DM), mainly through the inflammation-induced activity of indoleamine 2,3-dioxygenase (IDO). Renin-angiotensin-aldosterone system inhibitors (RAASis) [angiotensin converting enzyme inhibitors (ACEis) and angiotensin II receptor antagonists (ARBs)] are recommended in these conditions to decrease proteinuria, slow CKD progression and reduce cardiovascular risk. The interactions between RAAS and the kynurenine pathway and the potential effects of RAASis have been reported in few experimental models but whether these drugs influence kynurenine levels in humans is unknown. We performed a single-centre cross-sectional observational study to evaluate tryptophan and kynurenine serum levels and IDO activity in CKD patients with and without type 2 DM, their correlations with markers of renal dysfunction, and their relationship with RAAS-inhibiting therapy. Method We enrolled 72 consecutive adult patients with CKD, of which 38 had DM, who were admitted to the Unit of Nephrology and Dialysis of our Hospital. Of them, 55 were receiving RAASis whereas 17 were not. Tryptophan was assessed by HPLC (high-performance liquid chromatography) analysis with an UltiMateTM 3000 chromatograph (Thermo Fisher Scientific, 168 Third Avenue Waltham, MA, USA); kynurenine was measured using an enzyme-linked immunosorbent assay (ELISA) kit (Catalogue n. K 7728; Immundiagnostik AG, Bensheim, Germany); IDO activity was calculated with the formula (kynurenine/tryptophan) x 100. Results Patients receiving RAASis and patients not under therapy only differed for frequency of arterial hypertension (100% vs 76.47%; P=0.002) and kynurenine levels, the latter being significantly lower in the treated group compared to the untreated one (1.56 ± 0.79 vs 2.16 ± 1.51 µmol/l; P=0.0378). Kynurenine did not correlate with estimated glomerular filtration rate (eGFR), proteinuria or albuminuria in the whole study cohort. Conversely, in patients not receiving RAASis it was inversely related to eGFR (r=-0.4862; P=0.0478) and directly related to proteinuria (ρ=0.493; P=0.0444) and albuminuria (ρ=0.542; P=0.0247); moreover, it varied across classes of albuminuria, being lower in patients with normoalbuminuria (0.98 ± 0.55 µmol/l) and higher in those with micro- (2.63 ± 1.53 µmol/l) and macroalbuminuria (3.09 ± 1.61 µmol/l) at the ANOVA test (F=4.008; P=0.042). In the same group, the relationship between IDO activity and eGFR was significant (ρ=-0.554; P=0.0210) and IDO activity differed across classes of albuminuria (F=3.702; P=0.05). Moreover, IDO activity was higher in patients with history of cardiovascular disease compared to those with no such history [10.22 (8.39 to 22.92) vs 7.57 (4.76 to 8.09) %; P=0.0343] whereas tryptophan had an opposite behaviour (17.00 ± 2.06 vs 22.00 ± 3.78 µmol/l; P=0.0036). Conclusion We observed lower kynurenine levels in CKD patients treated with RAASis compared to untreated patients, independently of the presence of DM, and a significant association between kynurenine and markers of renal damage only in the group not receiving RAASis. We could hypothesize that kynurenine may play a role in the pathophysiology of renal damage, as already suggested, and that drugs interfering with RAAS activation may act also by reducing kynurenine levels, in addition to their already known effects at the renal level. Indeed, kynurenine synthesis results to be higher in states of inflammation and RAAS has pro-inflammatory and pro-fibrotic actions; accordingly, RAASis could reduce the enzymatic activity responsible for kynurenine increase and this could be one of the mechanisms mediating the beneficial effects of RAAS inhibition on CKD progression. This may be relevant because kynurenine has shown pro-thrombotic effects and is emerging as a potential new biomarker of CKD.

Background and Aims A real progress in treating patients more than diseases, would rest on tailored medicine and go beyond the hypothesis that “one size fits all”. Glomerular diseases are not an exception to this consideration, and deserve case-by-case evaluation for choosing both the most suitable therapeutic agent and its appropriate dose, because a standardized treatment may result in worse prognosis. We analyzed the role of body mass index (BMI) in modifying renal outcomes of patients with nephrotic syndrome due to membranous nephropathy (MN) treated with immunosuppressive drugs. Method We performed a retrospective analysis of 29 MN patients related to our center (M 19, F 10), checking their anti PLA2R status at kidney biopsy time and any change in proteinuria, serum creatinine (SCr) and body mass index (BMI) between diagnosis and at last follow-up visit, in search of a correlation with their response to immunosuppressive treatment. Data with non normal distribution are expressed as median and interquartile range [IQR]. Results The median follow-up of our patients lasted 49 months [IQR 14-80]. At biopsy time, almost half of them was anti-PLA2R positive (n=14 subjects) while the other resulted to be negative and were thus screened for secondary causes of MN (n=15). Irrespective either of anti-PLA2R status or the administration of Ponticelli regimen or Rituximab, complete remission was achieved in 31% of patients, while 34.5% experienced a partial remission and 34.5% resulted non responder to at least a therapeutic protocol. Median proteinuria reduction was of 3.732g/24h [IQR 7.636-1.77 g/24h]. Median rise in SCr was 0.140 mg/dl [IQR -0.11 – 0.4 mg/dl]. Direct association between the proteinuria/BMI ratio at diagnosis and remission of proteinuria at last follow up was statistically significant (r=-0.7506; P Conclusion Albeit remission is not directly correlated with basal BMI, our results appear to confirm that an appropriate drug posology, not only according to patients’ renal or hepatic function but also to their body mass, may result in more effective individualized therapies in MN; nevertheless, this recorded association must be confirmed by large scale randomized clinical trials.

Nephrotoxic drugs prescriptions are often prescribed inappropriately by general practitioners (GPs), increasing the risk of chronic kidney disease (CKD). The aim of this study was to detect inappropriate prescriptions in patients with CKD and to identify their predictive factors. A retrospective study on patients with creatinine values recorded in the period 2014&ndash, 2016 followed by 10 GPs was performed. The estimated glomerular filtration rate (eGFR) was used to identify CKD patients. The demographic and clinical characteristics and drugs prescriptions were collected. A descriptive analysis was conducted to compare the characteristics and logistic regression models to estimate the predictive factors of inappropriate prescriptions. Of 4098 patients with creatinine values recorded, 21.9% had an eGFR &lt, 60 mL/min/1.73m2. Further, 56.8% received inappropriate prescriptions, with a significantly lower probability in subjects with at least a nephrologist visit (Adj OR 0.54 (95% CI 0.36&ndash, 0.81)) and a greater probability in patients treated with more active substances (1.10 (1.08&ndash, 1.12)), affected by more comorbidities (1.14 (1.06&ndash, 1.230)), or with serious CKD (G4/G5 21.28 (7.36&ndash, 61.57)). Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most used contraindicated drugs (48.5%), while acetylsalicylic acid was the most inappropriately prescribed (39.5%). Our results highlight the inappropriate prescriptions for CKD authorized by GPs and underline the need of strategies to improve prescribing patterns.

Objective.Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis.Methods.Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls.Ex vivoNET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques.Results.Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3–C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant ofDNASE1L3.Ex vivoNET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases.Conclusion.Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rareDNase1L3mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered atClinicalTrials.gov, study numberNCT02403115).

The close relationship between kidney and heart is well known. Cardiovascular impairment contributes to the worsening of renal function and kidney failure worsens cardiovascular health. Atrial fibrillation (AF) is a frequent issue in patients with Chronic Kidney Disease (CKD) and several studies have demonstrated that AF impacts negatively on their quality of life and outcomes. Understanding the mechanisms leading to the progression of CKD, new-onset AF and acute myocardial infarction (AMI) is a key issue. The evaluation of Glomerular Filtration Rate (GFR) could make the difference in this equilibrium and suggests specific strategies in the treatment of the population at major risk of cardiovascular events. This intriguing connection paves the way for necessary further investigations.

Current knowledge on the role of exosomal microRNA (miRNA) in canine leishmaniasis (CL), with particular regards to the interaction between miR-122 and lipid alterations, is limited. The aim of this study was to isolate/characterize exosomes in canine serum and evaluate the expression of miR-122 in ten healthy and ten leishmaniotic dogs. Serum exosomes were isolated using a polymer-based kit, ExoQuick&reg, and characterized by flow cytometry and transmission electron microscopy, whereas miR-122-5p expression was evaluated by quantitative reverse-transcriptase polymerase chain reaction. A significant decreased expression of exosomal miR-122-5p, decreased serum levels of high-density lipoproteins, and increased serum levels of low-density lipoproteins were seen in leishmaniotic dogs when compared with healthy dogs. These results suggest that hepatic dysfunctions induced by the parasite interfere with lipoprotein status. The decreased expression of exosomal miR122 represents an additional effect of Leishmania infection in dogs as in people.

Background and Aims Idiopathic Focal Segmental Glomerulosclerosis (FSGS) is a rare glomerulonephritis often complicated by a chronic relapsing course frequently characterized by dependency or resistance to immunosuppressive treatment. Moreover, about half of the patients with active disease would develop end-stage renal disease within 10 years from the diagnosis, highlighting the need of novel therapeutic approaches. Rituximab (RTX), a chimeric monoclonal antibody against CD20, showed promising results in pediatric steroid-dependent/frequently relapsing FSGS and in post-transplantation recurrence. However, evidence about its role in the FSGS of the adult is still lacking with small case series suggesting conflicting results. In this study we assess the efficacy of RTX in the largest cohort of adults with FSGS currently available in literature. Methods Adults with biopsy proven idiopathic FSGS treated with RTX were retrospectively identified among several Italian nephrology units. Response to RTX was evaluated at 3, 6, 12 months and, when available, during the long-term follow-up. A positive response (POR) was defined as: (1) proteinuria 50% compared to baseline, (2) stable renal function (3) decreased or stable dose of glucocorticoids and other immunosuppressants. Severe Adverse Events (SAEs) have been recorded. Results 31 patients have been identified: 18 steroid-dependent, 11 steroid-resistant, and 2 patients with major contraindication to steroid therapy. RTX has been administered at a median of 87 months (IQR 54–96) from the diagnoses using heterogeneous schedules of administration. Overall, the POR rate at 6 months was 52% (steroid-dependent=69%; steroid-resistant=22%). At univariate analyses, POR to RTX at 6 months was associated to the steroid-dependent status (p=0.0347) and a proteinuria at RTX Conclusion RTX may be an option in the FSGS of the adult, especially in the steroid-dependent patients and the ones with less severe nephrotic syndrome. In the responders, a RTX based maintenance therapy may be required.

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.

Canine atopic dermatitis (AD) is a very common inflammatory skin disease, but limited data are available on the genetic characterization (somatic mutations, microarrays, and genome-wide association study (GWAS)) of skin lesions in affected dogs. microRNAs are good biomarkers in inflammatory and neoplastic diseases in people. The aim of this study was to evaluate microRNA expression in the skin of atopic beagles, before and after exposure to Dermatophagoides farinae. Four atopic and four unrelated age-matched healthy beagle dogs were enrolled. Total RNA was extracted from flash-frozen skin biopsies of healthy and atopic dogs. For the atopic dogs, skin biopsies were taken from non-lesional (day 0) and lesional skin (day 28 of weekly environmental challenge with Dermatophagoides farinae). Small RNA libraries were constructed and sequenced. The microRNA sequences were aligned to CanFam3.1 genome. Differential expressed microRNAs were selected on the basis of fold-change and statistical significance (fold-change ≥ 1.5 and p ≤ 0.05 as thresholds. A total of 277 microRNAs were sequenced. One hundred and twenty-one differentially regulated microRNAs were identified between non-lesional and healthy skin. Among these, two were increased amount and 119 were decreased amount. A total of 45 differentially regulated microRNAs between lesional and healthy skin were identified, 44 were decreased amount and one was increased amount. Finally, only two increased amount microRNAs were present in lesional skin when compared with that of non-lesional skin. This is the first study in which dysregulation of microRNAs has been associated with lesional and non-lesional canine AD. Larger studies are needed to understand the role of microRNA in canine AD.

Even though fertility is reduced, conception and delivery are possible in all stages of CKD. While successful planned pregnancies are increasing, an unwanted pregnancy may have long-lasting deleterious effects, hence the importance of birth control, an issue often disregarded in clinical practice. The evidence summarized in this position statement is mainly derived from the overall population, or other patient categories, in the lack of guidelines specifically addressed to CKD. Oestroprogestagents can be used in early, non-proteinuric CKD, excluding SLE and immunologic disorders, at high risk of thromboembolism and hypertension. Conversely, progestin only is generally safe and its main side effect is intramestrual spotting. Non-medicated intrauterine devices are a good alternative; their use needs to be carefully evaluated in patients at a high risk of pelvic infection, even though the degree of risk remains controversial. Barrier methods, relatively efficacious when correctly used, have few risks, and condoms are the only contraceptives that protect against sexually transmitted diseases. Surgical sterilization is rarely used also because of the risks surgery involves; it is not definitely contraindicated, and may be considered in selected cases. Emergency contraception with high-dose progestins or intrauterine devices is not contraindicated but should be avoided whenever possible, even if far preferable to abortion. Surgical abortion is invasive, but experience with medical abortion in CKD is still limited, especially in the late stages of the disease. In summary, personalized contraception is feasible, safe and should be offered to all CKD women of childbearing age who do not want to get pregnant.

No study has assessed whether the prognosis of coexisting diabetes mellitus and chronic kidney disease (DM-CKD) is dictated by DM per se or by the extent of proteinuria.In this pooled analysis of four prospective studies in CKD patients treated with drugs inhibiting the renin-angiotensin system, we compared the risk of all-cause mortality, fatal and non-fatal cardiovascular (CV) events and end-stage renal disease (ESRD) between patients with (n = 693) and without diabetes (n = 1481) stratified by proteinuria level (0.15, 0.15-0.49, 0.5-1 and 1 g/day).The group with DM-CKD was older (69 ± 11 versus 65 ± 15 years), had a higher body mass index (29.6 ± 5.4 versus 27.5 ± 4.8 kg/m2) and systolic blood pressure (143 ± 19 versus 136 ± 18 mmHg), prevalent CV disease (48% versus 29%) and lower estimated glomerular filtration rate (34.5 ± 17.9 versus 36.6 ± 19.0 mL/min/1.73 m2). During 4.07 years of follow-up, there were 466 patients with ESRD, 334 deaths and 401 CV events occurred. In the subgroup with urine protein0.15 g/day (N = 662), the risks of ESRD, CV events and mortality were similar in diabetic and non-diabetic patients. Conversely, in DM-CKD patients, the mortality risk was higher in proteinuric patients {hazard ratio 1.92 [95% confidence interval (CI) 1.25-2.95); 1.99 (1.26-3.15) and 1.98 (1.28-3.06) for proteinuria 0.15-0.49, 0.5-1 and1 g/day, respectively}, whereas in non-diabetics the mortality risk increased only for proteinuria 0.5-1 g/day [HR 1.60 (95% CI 1.07-2.40)] and1 g/day [HR 1.69 (95% CI1.20-2.55)]. In both groups, CV risk had a trend similar to that of mortality. ESRD risk increased progressively across strata0.5 g/day independent of diabetic status.We provide evidence that patients with non-proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, in the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and CV events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes.

Ciclosporin (CsA) is a common treatment for canine atopic dermatitis (cAD). cAD is a very common skin disease with a multifactorial pathogenesis due to complex interactions between the host and the environment. The purpose of this study was to describe the physical and immunological effects of CsA in cAD using a canine model of AD. Fourteen beagles were enrolled; seven received CsA orally every 24 h for 28 days, and seven received placebo. All dogs were exposed to relevant allergens, house dust mite solution, one day prior to treatment and once weekly thereafter for 28 consecutive days. Canine atopic dermatitis extent and severity index-03 (CADESI-03) and skin biopsies were performed on day 0, 14, and 28. Quantitative RT-PCR was used to determine levels of cutaneous cytokines and barrier function markers. Indirect immunofluorescence was used to determine protein expression and distribution of nuclear messengers, barrier function and inflammatory [thymic stromal lymphopoietin (TSLP)] markers. The data were tested for normality and then the upaired two samples Student's t-test and the repeated measurements ANOVA, followed by the Dunnett's Multiple Comparison Test as post-hoc analysis, were performed. A P value of0.05 was considered statistically significant. A significant decrease in CADESI-03 occurred for the treatment group compared to placebo (p = 0.023) on day 28. On day 14, a significant increase in TSLP protein expression [p = 0.019 (placebo); p = 0.02 (CsA)] and a significant decrease in Transforming Growth Factor (TGF)-β mRNA [p = 0.01 (placebo); p = 0.015 (CsA)] were noted in both groups compared to baseline. On day 28, a significant increase in canine beta defensin (cBD)103 [p = 0.012 (placebo)] and cBD3-like mRNAs [p = 0.044 (placebo)], and filaggrin [p = 0.035 (CsA)] and TSLP protein expressions [p = 0.0092 (CsA)] were seen compared to baseline. In contrast, a significant decrease in mRNA of Tumor Necrosis factor (TNF)-α [p = 0.013 (CsA)], Interleukin (IL)-10 [p = 0.038 (CsA)], TGF-β [p = 0.017 (CsA)], and caspase 14 [p = 0.014 (CsA)] was seen on day 28 compared to baseline. Comparison of the groups revealed no significant effect on skin immunologic milieu or barrier markers despite evident improvement of physical signs in the treatment group. Although this study confirmed the usefulness of CsA for the treatment of cAD, a clear involvement of CsA on some of the currently known immunological alterations present in cAD was not determined. However, it is important to note that there was no measurable exacerbation of skin barrier dysfunction secondary to CsA administration in this model.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell–integrin interaction are sufficient to initiate profibrotic processes. SSc fibroblasts express both αvβ3 and αvβ5 integrins and their activation induces myofibroblasts differentiation. The aim of the present study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis. SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: HOCl alone (n=8), HOCl + Cilengitide (n=8), or Vehicle alone (n=8). Treatment with cilengitide 20 (mg/kg/i.p./day) was started 4 weeks after the first administration of HOCl and maintained throughout the remaining experimental period (2 weeks). Lung, skin, and heart fibrosis were evaluated by histology while kidney morphology by PAS staining. Collagen type I, focal adhesion kinase (FAK), and a-SMA were evaluated by immunostaining and p-FAK and TGF-β1 by Western blot and gene expression. Both cutaneous and pulmonary fibrosis induced by HOCl were attenuated by cilengitide treatment. Cilengitide administration reduced a-SMA, TGF-β1, and p-FAK expression and the increased deposition of fibrillar collagen in the heart and prevented glomeruli collapse in the kidneys. The inhibition of aνβ3 and aνβ5 integrin signaling prevented systemic fibrosis and renal vascular abnormalities in the reactive oxygen species model of SSc. Integrins aνβ3 and aνβ5 could prove useful as a therapeutic target in SSc.

Ingestion of coffee (which is a mixture of over 1000 hydrosoluble substances) is known to protect from type-2 diabetes mellitus and its complications, and other chronic disorders associated with increased oxidative damage in blood and tissues. This protection is generally attributed to polyphenols and melanoidins. Very few studies were conducted on the amelioration of classic blood markers of oxidative stress induced after a few days of caffeine administration, but results vary.To assess whether caffeine per se could account for antioxidant properties of coffee in the short-term, we tested the ability of pure caffeine ingestion (5â¯mg/kg body weight/day in two daily doses for seven consecutive days) to improve plasma levels of six biochemical indices in healthy male volunteers (nâ¯=â¯15). These indices were total antioxidant capacity (TAC), glutathione (GSH), oxidized glutathione (GSSG), GSH to GSSG ratio, lipid hydroperoxides (LOOH) and malondialdehyde (MDA).We found that all indices changed significantly (Pâ¯