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Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency.

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

BACKGROUND Kidney failure is the major cause of morbidity and mortality in familial lecithin:cholesterol acyltransferase deficiency (FLD), a rare inherited lipid disorder with no cure. Lipoprotein X (LpX), an abnormal lipoprotein, is primarily accountable for nephrotoxicity. METHODS CER-001 was tested in an FLD patient with dramatic kidney disease for 12 weeks. RESULTS Infusions of CER-001 normalized the lipoprotein profile, with a disappearance of the abnormal LpX in favour of normal-sized LDL. The worsening of kidney function was slowed by the treatment, and kidney biopsy showed a slight reduction of lipid deposits and a stabilization of the disease. In vitro experiments demonstrate that CER-001 progressively reverts lipid accumulation in podocytes by a dual effect: remodelling plasma lipoproteins and removing LpX-induced lipid deposit. CONCLUSION This study demonstrates that CER-001 may represent a therapeutic option in FLD patients. It also has the potential to be beneficial in other renal diseases characterized by kidney lipid deposits.

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.

In deceased donor kidney transplantation (KT), a prolonged cold ischemia time (CIT) is a negative prognostic factor for KT outcome, and the efficacy of hypothermic machine perfusion (HMP) in prolonging CIT without any additional hazard is highly debated. We conducted a retrospective study on a cohort of 154 single graft deceased donor KTs, in which a delayed HMP, after a preliminary period of static cold storage (SCS), was used to prolong CIT for logistic reasons. Primary outcomes were postoperative complications as well as 1 year graft survival and function. 73 cases (47.4%) were managed with HMP and planned KT, while 81 (52.6%) with SCS and urgent KT. The median CIT in HMP group and SCS group was 29 hour:57 minutes [27-31 hour:45 minutes] and 11 hour:25 minutes [9-14 hour:30 minutes], respectively (P < .001). The period of SCS in the HMP group was significantly shorter than in the SCS group (10 vs. 11 hour:25 minutes, P = .02) as well as the prevalence of expanded criteria donors was significantly higher (43.8% vs. 18.5%, P < .01). After propensity score matching for these two baseline characteristics, the HMP and SCS groups showed comparable outcomes in terms of delayed graft function, vascular, and urologic complications, infections, and episodes of graft rejection. At 1 year follow-up, serum creatinine levels were comparable between the groups. Therefore, the use of HMP to prolong the CIT and convert KT into a planned procedure seemed to have an adequate safety profile, with outcomes comparable to KT managed as an urgent procedure and a CIT nearly three time shorter.

Background and Aims IgA-nephropathy (IgA-N) is a frequent cause of CKD and ESRD. The optimal therapeutic approach and the role of glucocorticoids and immunosuppression is still debated. Aim of this study was to perform a survey across several Italian centers focusing on the long-term outcome of patients with IgA-N at high risk of progression stratified according to the therapeutic approach employed. Method All the consecutive patients affected by biopsy proven IgA-N, proteinuria >1g/day and a follow-up longer than 24 months have been collected across 48 centers. The population has been divided in three groups according to the therapeutic approach: group-1 received ACEi or ARBs alone, group-2 a six months course of glucocorticoids while group-3 glucocorticoids and immunosuppressive drugs. Primary endpoints have been ESRD free-survival, halving of the eGFR free-survival and rate of non-responders (NR, proteinuria >1 g/day). Secondary endpoints have been assessment of the prognostic role of the time average proteinuria (TAP) as well as of the time average slope of proteinuria (TASP) and rate of severe adverse events (SAEs). Results 947 patients have been included and followed for a median time of 60 months (IQR 24-96). Baseline eGFR and proteinuria in the three groups have been respectively 68.1 (95%CI 63.9-72.4)-67.8 (95%CI 65.3-70.3)-63.3 (95%CI 58.5-68.1) ml/min/1.73m2 (p=0.191) and 2.38 (95%CI 2-2.77)-2.65 (95%CI 2.49-2.82)-3.26 (95%CI 2.89-3.64) g/day (p ESRD free-survival has been longer in the group-2 (p=0.004) (figure, panel A); at subgroup analysis this was restricted to the patients with a eGFR The proportion of NR has been significantly lower in group-2 compared to group-1 throughout the first 36 months of follow-up (figure, panel D); of note being NR during the first 36 months increased the risk of developing ESRD during the follow-up (OR 4 95%CI 2.2-7.3, p The rate of patients experiencing SAEs during the first 6 months of therapy in the three groups has been respectively 2%, 7% and 16%; of these withdrawn of the therapeutic approach employed has been necessary in 67%, 21% and 48%. During the whole follow-up the number of SAEs per 100 patients/years has been respectively 1.9-2.7 and 2.5 in the 3 groups. Conclusion In this large multicenter retrospective survey, the use of glucocorticoids in patients with IgA-N at high risk of progression has been associated to longer ESRD free-survival, longer time to the halving of the eGFR in the subgroup with eGFR

Coupled plasma filtration adsorption (CPFA) is an extracorporeal supportive therapy based on nonspecific adsorption of pro- and anti-inflammatory mediators combined with continuous renal replacement therapy. The main field of CPFA application is septic shock, and there are limited data about its efficacy in the treatment of other acute conditions characterized by a dysregulation in immune homeostasis. Capillary leak syndrome (CLS) defines a life-threatening condition sustained by hypercytokinemia and characterized by abrupt onset of increased capillary permeability leading to severe generalized edema and hypovolemic shock refractory to fluid administration. Therapy for CLS is not specific and, at present time, it consists in the use of steroids or intravenous immunoglobulins. We present the case of a 34-year-old woman who developed CLS superimposed to acute generalized exanthematous pustulosis after initiating therapy with hydroxychloroquine for undifferentiated connective tissue disease. CLS did not respond to steroids and intravenous immunoglobulins, while it was successfully treated with CPFA. This observation supports the possible role of CPFA in restoring a proper immunologic homeostasis not only in sepsis but also in other devastating conditions sustained by hypercytokinemia.

Background Disease registries are useful tools for public health planning, evaluating clinical practice and providing information on cohorts of patients. Methods The administrative databases of the regional health information system of Friuli Venezia Giulia, Italy were used to build a regional registry of the resident population in renal replacement therapy (including dialysis and renal transplantation), through an algorithm taking into account hospital discharge and outpatient ambulatory care data. The registry includes an anonymous univocal identifier, the start date for the replacement therapy and changes of status (haemodialysis, peritoneal dialysis, renal transplantation). Data from the registry were used to estimate incidence rate, prevalence and mortality of patients receiving renal replacement therapy in 2014. In addition, we described an example of how the registry can be used to assess the prevalence of selected comorbidities. Results In Friuli Venezia Giulia in 2014, we estimated an incidence rate of renal replacement therapy of 166 per million inhabitants and a prevalence of 1,400 per million inhabitants. A total of 10% of the patients died in the study year. Hypertension, heart disease and diabetes mellitus were common co-morbidities. Conclusion The registry allows us to estimate the incidence rate and prevalence of renal replacement therapy and also to investigate specific issues regarding these patients through record linkage with other administrative health databases.

BACKGROUND & AIMS: In hospitalized patients malnutrition is a risk factor for adverse clinical outcomes. The Nutritional Risk Screening 2002 (NRS-2002) represents a quick and simple tool to identify malnutrition risk in this population. No study tested the predictive power of NRS-2002 on mortality adjusting for confounders related to patient's complexity, thus considering conditions such as functional status, illness-related severity and inflammation. The aim of this study was to explore the independent prognostic power and the relative weight of NRS-2002 screening tool to predict inhospital and post-discharge (up to 1 year) mortality, adjusting for variables representing the non-disease specific multidimensional complexity of patients admitted to Internal Medicine wards. METHODS: Retrospective observational study including 5698 consecutive patients acutely admitted to an Internal Medicine Department. Logistic regression models were run to test the predictive power of the NRS-2002 on patient mortality at different time intervals, adjusted for age, sex, Charlson comorbidity index, Glasgow Prognostic Score (GPS), BUN/creatinine ratio, Modified Early Warning Score (MEWS), and Norton index. The performance of the logistic models in predicting mortality was measured through the c-statistic. The different time of death between patients scored upon admission as NRS-2002 < 3 or ≥3 was evaluated through crude Kaplan-Meier curves and multivariate Cox proportional hazard analysis. RESULTS: Patients classified at high malnutrition risk (NRS-2002 ≥ 3) showed a higher and earlier mortality (Log-rank test: p < 0.001) compared to subjects in the NRS-2002 "low-risk" group. NRS-2002 ≥ 3 was an independent significant (p < 0.01) predictor of mortality in logistic regression at every time interval. Among the considered covariates, Charlson index, GPS and Norton scale showed a steadily higher OR than NRS-2002 in predicting both early and late mortality. The multivariate models demonstrated a very good discrimination for hospital and mid-term (up to 90 days) mortality. Being classified at risk for malnutrition (NRS-2002 ≥ 3) on admission independently increased the risk of one-year death (HR = 1.431; 95% CI: 1.277-1.603; p < 0.001) compared to the patients who were scored at low malnutrition risk. CONCLUSIONS: Malnutrition risk identified upon hospital admission by NRS-2002 independently contributes to early and late mortality in a population including a majority of elderly. However, risk of malnutrition has to be considered according to other factors related to comorbidities, functional status, illness severity and inflammation which reciprocally interact, concurring at worsening patient's outcome.

IntroductionPrimary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease may have different long-term outcomes. After 10 years of follow-up, 35%–50% of the untreated patients with persistent nephrotic syndrome may die or progress to end stage renal disease. The 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend that initial therapy should consist of alternating steroids and an alkylating agent for 6 months. Recent observational studies showed that the anti-CD20 antibody rituximab may be effective in inducing remission. We designed a pilot multicentre randomised trial to inform the design of a larger trial testing the efficacy and safety of treatment with steroids and cyclophosphamide versus rituximab in patients with primary MN and heavy proteinuria (>3.5 g/24 hours).Methods and analysisThis pilot, open-label, two-parallel-arm, randomised clinical trial will enrol 70 patients with primary MN and heavy proteinuria. Patients will be randomised in a 1:1 ratio to either the intervention arm (rituximab) or the active comparator arm (corticosteroid/alkylating-agent therapy). The study will provide estimates of the probability of complete remission of proteinuria and risk of serious side effects at 12 months to inform the design of a larger trial. We will also assess the recruitment potential of each participating centre to address study feasibility.Ethics and disseminationThe trial received ethics approval from the local ethics boards. We will publish pilot data to inform the design of a larger clinical trial.Trial registration numbersNCT03018535; 2011-006115-59.

Background: The extracorporeal removal of mediators is a rescue strategy for septic shock patients, which is still under investigation. Several techniques are available: coupled plasma filtration and adsorption (CPFA) combines plasma processing with renal replacement therapy. Methods: The study aimed to elucidate the role of both timing of initiation and intensity of treatment on the outcome, for which we retrospectively studied 52 patients. We collected the overall pre-CPFA time interval, starting from the first episode of hypotension in the wards and the volume of processed plasma (Vp), which we used as a proxy for intensity of treatment. Results: Timing of initiation did not significantly differ between survivors and non-survivors (25 vs. 27 h), while the Vp did (0.25 vs. 0.17 L/kg/session, p < 0.05). The significance of Vp was confirmed by a multiple logistic regression model. Conclusion: Our study confirms that intensity of CPFA, but not its timing of initiation, correlates with survival of septic shock patients.

Lecithin:cholesterol acyltransferase (LCAT) synthesizes most of the plasma cholesteryl esters, and plays a major role in HDL metabolism. Mutations in the LCAT gene cause two syndromes, familial LCAT deficiency and fish-eye disease, both characterized by severe alterations in plasma lipoprotein profile. Renal disease is the major cause of morbidity and mortality in familial LCAT deficiency cases, but an established therapy is not currently available. The present therapy of LCAT deficiency is mainly aimed at correcting the dyslipidemia associated with the disease and at delaying evolution of chronic nephropathy. LCAT deficiency represents a candidate disease for enzyme replacement therapy. In vitro and in vivo studies proved the efficacy of recombinant human LCAT in correcting dyslipidemia, and recombinant human LCAT is presently under development.

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Background Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB. Objective This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease. Methods Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced. Results The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband's wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband's lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification. Conclusion LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10⁻²⁶ and 4.84 × 10⁻⁹ and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

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

We report a visceral leishmaniasis case in an immunocompetent immigrant with acute renal failure. Parasites were demonstrated in bone marrow, peripheral blood, and kidney samples. A collapsing focal segmental glomerulosclerosis was documented, which was successfully treated with a single infusion of 10 mg/kg liposomal amphotericin B.

A 68-year-old woman was admitted with fever and pancytopenia (white blood cell count 0AE9 · 10/l, haemoglobin 8 g/dl, platelet count 9 · 10/l). Bone marrow examination showed acute promyelocytic leukaemia; cytogenetic and molecular analysis showed t(15;17) and a PML-RARa fusion protein (BCR3 transcript). Laboratory findings at diagnosis were: blood urea nitrogen 12 mmol/l, creatinine 160 lmol/l, uric acid 0AE4 mmol/l, lactate dehydrogenase 2259 U/l, total bilirubin 42 lmol/l, unconjugated bilirubin 28 lmol/l and haptoglobin

Objective— To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene. Methods and Results— Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre-β high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL 3 particle size were reduced in a gene–dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former. Conclusion— In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene–dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.

Warfarin-related nephropathy (WRN) is a renal complication of warfarin treatment associated with over-anticoagulation. We describe a case of a 73-year-old man affected by chronic kidney disease, essential hypertension and atrial fibrillation treated with warfarin. The patient presented a rapid course of kidney failure after many episodes of over-anticoagulation, and renal biopsy demonstrated WRN. Interestingly, the patient's warfarin pharmacogenetic profile showed that he was warfarin sensitive. This is the first report describing the presence of gene polymorphisms affecting warfarin metabolism in a subject with a biopsy-proven WRN. The patient was treated with corticosteroids obtaining a partial clinical response.