Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis

Background: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. ----- Methods: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. ----- Results: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. ----- Conclusions: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

L

First Characterization of ADAMTS-4 in Kidney Tissue and Plasma of Patients with Chronic Kidney Disease—A Potential Novel Diagnostic Indicator

Background: We have previously shown that metzincin protease ADAMTS-4 accompanies renal fibrogenesis, as it appears in the blood of hemodialysis patients. Methods: Native kidney (NKB) and kidney transplant (TXCI) biopsy samples as well as plasma from patients with various stages of CKD were compared to controls. In paired analysis, 15 TXCI samples were compared with their zero-time biopsies (TX0). Tissues were evaluated and scored (interstitial fibrosis and tubular atrophy (IFTA) for NKB and Banff ci for TXCI). Immunohistochemical (IHC) staining for ADAMTS-4 and BMP-1 was performed. Plasma ADAMTS-4 was detected using ELISA. Results: ADAMTS-4 IHC expression was significantly higher in interstitial compartment (INT) of NKB and TXCI group in peritubular capillaries (PTC) and interstitial stroma (INT). Patients with higher stages of interstitial fibrosis (ci > 1 and IFTA > 1) expressed ADAMTS-4 in INT more frequently in both groups (p = 0.005; p = 0.013; respectively). In paired comparison, TXCI samples expressed ADAMTS-4 in INT and PTC more often than TX0. ADAMTS-4 plasma concentration varied significantly across CKD stages, being highest in CKD 2 and 3 compared to other groups (p = 0.0064). Hemodialysis patients had higher concentrations of ADAMTS-4 compared to peritoneal dialysis (p < 0.00001). Conclusion: ADAMTS-4 might have a significant role in CKD as a potential novel diagnostic indicator

ISOLATED SYSTOLIC HYPERTENSION CHARACTERISTICS: DATA FROM THE BRISIGHELLA HEART STUDY (ITALY) AND THE ENAH STUDY (CROATIA)

Objective: Isolated systolic hypertension (ISH) in elderly is associated with increased global risk. It could be considered as a rough biomarker of increased arterial stiffness and advanced biological aging. In our study, we evaluate the association between ISH and other cardio-metabolic risk factors in two rural European populations from South Europe (Italy and Croatia). Design and method: In this international prospective long-term follow up study data on 5162 subjects from BrEnah cohort formed from original cohorts of Brisighella Heart Study (Italy) and ENAH Study (Croatia) were analized. Out of them 2253 subjects (694 from Croatia, 1559 from Italy; 980m, 1273f) were eligible for further analyses. BP was measured using Omron 6 device following the ESH guidelines. Fasting blood was analysed for glucose, lipids, uric acid, serum creatinine. Results: Results In general rural population from South Europe prevalence of ISH is high. Difference between Croatian and Italian subgroups was found (28.8% vs. 44.8%; p&lt;0.001; no gender differences) what is concordance with difference in age between two cohorts. Beside age, ISH was significantly associated with eGFR and various metabolic parameters including visceral obesity glucose intolerance and uric acid Conclusions: In this group of patients prevalence of ISH was high. Observed difference between Italian and Croatian subgroup is mostly due to difference in age. Metabolic disturbances are frequently associated with ISH additionally increasing global risk

METABOLIC SYNDROME IN EUROPEAN RURAL POPULATION-DATA FROM THE BRISGHELLA HEART STUDY (ITALY) AND ENAH STUDY (CROATIA)

Objective: Prevalence and characteristics of metabolic syndrome (MS) differ among various populations worldwide. This might explain the observed divergences in association of MS with cardiovascular (CV) and chronic kidney disease (CKD) outcomes. Our aim was to analyze differences in MS between two rural continental populations from South Europe (Italy and Croatia) and its association with CKD and hypertension (HT). Design and method: In this international prospective long-term follow up study data on 5162 subjects from BrEna cohort formed from original cohorts of Brisighella Heart Study (Italy) and ENAH study (Croatia) were analyzed. Out of them 1839 subjects (796 m, 1043 w) were eligible for further analyses, 848 from Croatian and 991 from Italian cohort. NCEP ATP III defi nition was used for MS diagnosis, CKD was defi ned as eGFR &lt; 60 ml/min, and HT as BP &gt; = 140/90 mmHg and/or taking antihypertensive drugs. Results: Overall prevalence of MS in the whole group was 32% without differences between Croatian and Italian subgroups (32.8% vs. 31.4%; p = 0.55). In Croatian group MS was more frequently present in women (35.7% vs. 27.2%; p = 0.01), while this was not found in Italian group (32.8% vs. 30.0%).Signifi cant differences were observed in prevalence of pathological values of fasting blood glucose, triglycerides, HDL-cholesterol, waist circumference and blood pressure (52.2 vs. 40.2; 71.9 vs. 64.3; 34.2 vs. 69.9; 93.2 vs. 72.0; 89.9 vs. 95.8, respectively, all p &lt; 0.05).We failed to observe difference in the number (3,4 or 5) of diagnostic elements for MS between the two groups (p &gt; 0.05). There was no difference in prevalence of HT (84.9 vs. 86.3%, p = 0.62). However, CKD was signifi cantly more prevalent in Italian cohort (23.5% vs. 20.5%;p = 0.001). HT was signifi cantly more prevalent in MS than in non-MS group, while we failed to fi nd difference in CKD. Conclusions: Although prevalence of MS was the same in two European rural region, significant differences in characteristics of MS were observed between Croatian and Italian subgroups. Observed differences could be explained more with lifestyle and tradition than genetic variations. Characteristics of MS should be separately analyzed in each population and results should be implemented in national programs and strategies for CKD prevention

Interferon Therapy for HCV-Associated Glomerulonephritis: Meta-Analysis of Controlled Trials

A relationship between hepatitis C virus (HCV) infection and chronic glomerulonephritis (GN) has been asserted on the grounds of epidemiological and experimental data. Although this suggests a role for an antiviral approach to HCV-associated GN instead of the more conventional immunosuppressive (or supportive) therapy, the optimal management of HCV related glomerulonephritis remains controversial. To compare antiviral with immunosuppressive therapy for HCV-associated GN. Meta-analysis of controlled clinical trials (CCTs) of the two treatments (antiviral versus immunosuppressive) of HCV-associated GN. We used the fixed or random effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses. The rate of proteinuria and serum creatinine decrease after therapy for HCV-associated GN were regarded as the most reliable outcome end-points. We identified six studies involving 145 unique patients with HCV-associated GN. Pooling of study results demonstrated that proteinuria decreased more commonly after IFN than corticosteroid therapy (OR 1.92 (95% CI, 0.39; 9.57), NS), P-test for heterogeneity, 0.06 (I2=52.9%). In a sensitivity analysis including only CCTs using standard IFN-doses, OR was 3.86 (95% CI, 1.44; 10.33, (P=0.007)), P-test for heterogeneity, 0.18 (I2=35.9%). No improvement of serum creatinine after IFN compared to immunosuppressive therapy was noted (OR, 0.59 (95% CI, 0.21; 1.65), NS), P-test for heterogeneity, 0.76 (I2=0%). Only three CCTs gave information on the rate of proteinuria decrease over follow-up (OR, 5.08 (95% CI, 0.69; 37.31), NS). A few major side effects were noted after IFN administration. Our meta-analysis indicates that standard IFN-doses were more effective than immunosuppressive therapy in lowering proteinuria of patients with HCV-related glomerulonephritis. However, no significant improvement in serum creatinine was seen by IFN or steroid therapy across the studies. Also, information on proteinuria recurrence after the completion of antiviral therapy was not sufficient. Prospective, randomized trials based on combined antiviral therapy (pegylated IFN plus ribavirin) with adequate dose and follow-up are required to assess the efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis