The HDL mimetic CER-001 remodels plasma lipoproteins and reduces kidney lipid deposits in inherited lecithin:cholesterol acyltransferase deficiency.

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.

[Droghe d'abuso e rene].

Here we present a case of acute renal failure needing dialysis in a heroin addict patient chronically treated with Metadone. This give us the opportunity to review the renal effects of the main drugs of abuse, highlighting the shift occured from the four "old sisters" (Marijuana, Cocaine, Heroin and Amphetamine) to the news synthetic drugs (chiefly Synthetic Cathinones and Cannabinoids), that poses problems due to large diffusion, easy procurement, legal non-regulation and difficult analytical identification, raising medical and forensic questions. From a Nephrological point of view is essential to take great care over the need to diagnose this kind of pathology and to widen the search trying anyway to recognize the substances potentially involved.

Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial.

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.

Impaired hydration status in acutely admitted older patients: prevalence and impact on mortality.

BACKGROUND: impaired hydration is common in the older people, however studies of its effects on outcome in the acute setting are limited. OBJECTIVES: to assess (i) the prevalence of impaired hydration, (ii) its relationship with laboratory markers of altered hydration and with (iii) short- and long-term mortality. DESIGN: retrospective cohort study. SETTING: University Hospital-Internal Medicine Department. SUBJECTS: a total of 5,113 older patients consecutively acutely admitted from October 2015 to July 2016. METHODS: according to calculated serum osmolarity at admission hydration status was stratified in: low osmolarity (<275 mmol/L), euhydration (275-295 mmol/L), impending (296-300 mmol/L) and current dehydration (>300 mmol/L). Relationships with serum sodium, potassium, glucose, urea, estimated glomerular filtration rate (eGFR), haematocrit, urea/creatinine ratio (Urea/Cr) and urine specific gravity (USG) were determined. Charlson Comorbidity Index, Modified Early Warning Score, Glasgow Prognostic Score, Norton score and Nutritional Risk Screening-2002 were calculated. RESULTS: current and impending dehydration, euhydration and low-osmolarity were detected in 51.7, 17.1, 28.5 and 2.7% of the patients, respectively. Osmolarity correlated with urea (r = 0.846). Associations with serum sodium, creatinine, eGFR and urea/Cr were low but significant, being negligible that with USG and haematocrit. Serum sodium and urea increased in the transition from low- to high-osmolarity (P < 0.001 in all pairwise comparisons). In multivariate modelling current dehydration, functional dependence, clinical instability and high nutritional risk were associated (P < 0.001) with reduced short- and long-term survival. CONCLUSIONS: impaired hydration is common in older people acutely admitted to medical care and is associated with poor outcome. Early assessment of calculated serum osmolarity is mandatory to target dehydration and hypoosmolar disorders.

Hypothermic machine perfusion can safely prolong cold ischemia time in deceased donor kidney transplantation. A retrospective analysis on postoperative morbidity and graft function.

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.

Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort.

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.

Coupled Plasma Filtration Adsorption for Treatment of Capillary Leak Syndrome Superimposed to Acute Generalized Exanthematous Pustolosis: A Case Report.

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.

Prediction of early- and long-term mortality in adult patients acutely admitted to internal medicine: NRS-2002 and beyond.

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.

Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial.

INTRODUCTION: Primary 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 ANALYSIS: This 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 DISSEMINATION: The 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 NUMBERS: NCT03018535; 2011-006115-59.

[Vascular access survey in the Triveneto area: data analysis for the year 2017].

In 2017 the Italian Society of Nephrology operating in the Triveneto area investigated through a questionnaire, distributed to the various nephrological centers in the regions of Friuli Venezia Giulia, Trentino Alto Adige and Veneto, the differences concerning organizational models, choice of dialysis, creation and management of vascular access. The results emerging from the analysis of the collected data are presented.

Increased cancer risk in patients undergoing dialysis: a population-based cohort study in North-Eastern Italy.

BACKGROUND: In southern Europe, the risk of cancer in patients with end-stage kidney disease receiving dialysis has not been well quantified. The aim of this study was to assess the overall pattern of risk for de novo malignancies (DNMs) among dialysis patients in the Friuli Venezia Giulia region, north-eastern Italy. METHODS: A population-based cohort study among 3407 dialysis patients was conducted through a record linkage between local healthcare databases and the cancer registry (1998-2013). Person-years (PYs) were calculated from 30 days after the date of first dialysis to the date of DNM diagnosis, kidney transplant, death, last follow-up or December 31, 2013, whichever came first. The risk of DNM, as compared to the general population, was estimated using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: During 10,798 PYs, 357 DNMs were diagnosed in 330 dialysis patients. A higher than expected risk of 1.3-fold was found for all DNMs combined (95% CI: 1.15-1.43). The risk was particularly high in younger dialysis patients (SIR = 1.88, 95% CI: 1.42-2.45 for age 40-59 years), and it decreased with age. Moreover, significantly increased DNM risks emerged during the first 3 years since dialysis initiation, especially within the first year (SIR = 8.52, 95% CI: 6.89-10.41). Elevated excess risks were observed for kidney (SIR = 3.18; 95% CI: 2.06-4.69), skin non-melanoma (SIR = 1.81, 95% CI: 1.46-2.22), oral cavity (SIR = 2.42, 95% CI: 1.36-4.00), and Kaposi's sarcoma (SIR = 10.29, 95% CI: 1.25-37.16). CONCLUSIONS: The elevated risk for DNM herein documented suggest the need to implement a targeted approach to cancer prevention and control in dialysis patients.

Influence of Timing of Initiation and Volume of Processed Plasma on the Outcome of Septic Shock Patients Treated with Coupled Plasma Filtration and Adsorption.

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.

[EBV-ASSOCIATED PNEUMONIA IN PATIENT WITH GRANULOMATOSIS WITH POLYANGIITIS (GPA) IN IMMUNOSOPPRESSIVE THERAPY TREATED WITH ACICLOVIR].

Granulomatosis polyangiitis (GPA) is an ANCA-related vasculitis (AAV) whose clinical manifestations mainly concern the respiratory tract (upper and lower) and the kidney. The treatment of GPA (as well as other AAV) includes the use of immunosuppressive drugs with numerous side effects; the most frequent complications are infectious and neoplastic. GPA frequently relapses. Epstein Barr Virus (EBV) is a ubiquitous virus; it is estimated that about 90% of the world's population has BEEN EXPOSED TO with this pathogen and has subsequently developed a latent infection. Under certain conditions including immunosuppression EBV may reactivate. We report the clinical case of a 67-year-old woman who presented with GPA involving the upper respiratory tract and renal failure with the need for hemodialysis treatment. The fourth month of induction therapy with cyclophosphamide and methylprednisone she presented with dyspnea and respiratory failure. After excluding pulmonary embolism and heart failure, a series of investigations including high resolution tomography and fibroscopy with broncoalveolar lavage (BAL) were performed which excluded recurrence of pulmonary vasculitis including alveolar haemorrhage A BAL demonstrated EBV-DNA. On this basis EBV pneumonia was diagnosed, and antiviral therapy with acyclovir was begun, followed by clinical and radiological improvement. In patients with GPA treated with immunosuppressive drugs pulmonary involvement may not only be due to the underlying vasculitis, but also to opportunistic agents, which must always be considered.

Inception and utility of a renal replacement registry using administrative health data in North-East Italy.

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.

[Lecithin:Cholesterol Acyltransferase Deficiency, from genes to therapy]. / Deficit di lecitina:colesterolo aciltransferasi, dalla genetica alla terapia.

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 (FLD) and fish-eye disease (FED), both characterized by severe alterations in plasma lipoprotein profile. Renal disease is the major cause of morbidity and mortality in FLD 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 (rhLCAT) in correcting dyslipidemia, and rhLCAT is presently under development.

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.

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 new 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 geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and 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.