FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

Newly Grown Wool Mineral Content Response to Dietary Supplementation in Sheep.

Determination of wool mineral content to assess the animal' mineral status has been extensively used, but the results are controversial. One of the possible contributing factors is that the sampling material in previous studies was collected from a long staple, a fact that could mask the response to recent differences in mineral intake. Therefore, the aim of the present study was to test the sensitiveness of newly grown wool to different dietary mineral intake. Twenty Tsigai ewes were allocated into five dietary treatments with similar hay and concentrate intake but different premix inclusion rates in the concentrate (3, 4, 5, 6, and 7%). Wool was sampled on the left side from a 5 × 5 cm area using bent scissors at the beginning of the trial and from the very same area 28 days later. Samples after cleaning and mineralization were analyzed with ICP-OES (Perkin-Elmer, Optima 3300 DV) for calcium, phosphorus, magnesium, sodium, selenium, zinc, copper, and sulfur content. Long fleeces had significantly lower Ca and Se content compared to the newly grown wool samples of the group at the premix manufacturer's suggested level of supplementation (5%). Macrominerals in fresh wool did not respond to increased dietary supplementation. Se and Zn content of wool had a strong relationship with the daily intake (R2 = 0.95 and R2 = 0.97, respectively.) In conclusion, the mineral content of long fleeces can be different compared to recently developed wool fiber. This indicates that, in some cases, analyzing long staples for mineral status can be misleading. Our results showed that wool could be a sensitive indicator of low selenium and high zinc intake. Mineral interactions can significantly affect the actual availability of trace minerals; therefore, a more careful design of premixes is needed. The described method seems to be applicable in livestock farming, but the mineral interactions that may alter the results need to be further explored.

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.

BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

Investigating the relationship between mortality from respiratory diseases and childhood acute lymphoblastic leukaemia in Hungary.

Our aim was to investigate the ecological association between death from infectious disease of the respiratory system and the risk of acute lymphoid leukaemia (ALL) in children aged less than 7 years. Poisson regression analyses were carried out using overall data and gender-specific models. The study included 176 cases (92(52.3 %) boys and 84 (47.7 %) girls) of ALL in those aged 0-6 years in South Hungary. Eight cases were diagnosed before the age of 1 year. A significant risk of ALL disease was observed with higher levels of mortality from the chronic respiratory diseases (p = 0.035) and pneumonia (p = 0.010) among children aged 2-5 years (Odds Ratio for trend was 1.001 and 95%CI [1.000-1.002] and Odds ratio for trend was 1.013 and 95%CI [1.003-1.023], respectively). Significantly increased risk of childhood ALL was detected among children under 1 year of age residing in areas around birth with higher levels of mortality from influenza (Odds Ratio (OR) for trend was 1.05; 95%CI [1.01-1.09]; p = 0.012). This risk was also detected in girls (p < 0.001), but not in boys (p = 0.43). Our findings provide new evidence that will help to understand the different pattern of female and male childhood ALL occurrence , but further studies are needed using detailed individual medical history to clarify the role of influenza and other infectious diseases in the etiology of childhood ALL and to explain gender-specific effects.