C3 Glomerulopathy

Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a new classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN. Immune complex-mediated MPGN results from the deposition of immunoglobulin deposits and complements component C3 driven by classical complement pathway activation, while complement-mediated disease may be associated with complement alternative pathway dysregulation and is a new entity, C3 glomerulopathy. C3 glomerulopathy is an umbrella term, encompassing dense deposit disease (DDD), former MPGN type II, and C3 glomerulonephritis. C3 glomerulonephritis comprises examples of MPGN types I and III, in which immunofluorescence reveals predominant C3 deposits. By light microscopy, distinctive histologic patterns can be observed in both entities, including membranoproliferative, mesangial proliferative, crescentic and acute proliferative and exudative patterns, of which the membranoproliferative pattern seems to be the most common. DDD is defined by the presence of dense osmiophilic transformation of the glomerular basement membrane (GBM) on electron microscopy (EM). Only EM enables definite distinction of DDD from C3 glomerulonephritis. C3 glomerulopathy is a heterogeneous disease; genetic or acquired complement alternative pathway abnormalities have been identified in up to 40% of patients, including mutations in complement factors or autoantibodies directed against them

Antibody Mediated Rejection in Kidney Transplant Recipients

Antibody mediated rejection (ABMR) presents a significant challenge for long term graft survival in kidney transplantation. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of ABMR. Unfortunately, this progress has not yet translated into better outcomes for patients, as in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This chapter reviews the current understanding of ABMR, and details its diagnosis, and treatments, both those established in current routine clinical practice and those on the horizon

Viral Infections after Kidney Transplantation: CMV and BK

Opportunistic infections commonly occur during the first 6 months after kidney transplant, including cytomegalovirus (CMV) and polyomaviruses. Viral pathogens such as CMV and polyomaviruses, JC or BK virus (BKV), are able to replicate in the kidney and/or cause systemic disease, and symptomatic infection with these agents can be associated with significant morbidity and mortality in immunocompromised host. While BK virus usually replicates in kidney transplant causing BK virus nephropathy (BKN) with characteristic decoy cells in the urine, CMV infection more often leads to systemic infection involving the gastrointestinal tract (GIT), lungs, or liver and can only sporadically be detected in renal transplant. In both cases, the disease is most often due to reactivation of a latent virus. Prevention and early treatment of posttransplant infection are therefore crucial with kidney transplant recipients. Since BKV viruria and viremia can be seen without renal injury and viral nephropathy, a diagnosis of BKN must be confirmed by renal biopsy. To date, preemptive treatment is the best strategy for CMV infection, while no available standard therapy, except for reduction of immunosuppression, is available for BKV infection

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

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Reparative perineural hyperplasia in the gastric wall

Reparative perineural hyperplasia is an incidental and probably underreported reactive histologic finding thus far only reported in the setting of healing wounds or adjacent to a dermatofibroma in cutaneous specimens. It is characterized by a focal concentric proliferation of cytologically bland spindled perineurial cells and is hence considered a benign histologic mimic of neoplastic perineural invasion. Thus, it may present a diagnostic pitfall and we therefore consider it as a valuable entity to be aware of. To the best of our knowledge, this brief case report is the first to convey that reparative perineural hyperplasia may also occur in the gastrointestinal tract. It may therefore be a ubiquitous reactive histological phenomenon relating to previous surgical or traumatic wounds in various sites, that is, outside the thus far established setting of skin reexcision specimens

Perspectives of microscopy methods for morphology characterisation of extracellular vesicles from human biofluids

Extracellular vesicles (EVs) are nanometric membranous structures secreted from almost every cell and present in biofluids. Because EV composition reflects the state of its parental tissue, EVs possess an enormous diagnostic/prognostic potential to reveal pathophysiological conditions. However, a prerequisite for such usage of EVs is their detailed characterisation, including visualisation which is mainly achieved by atomic force microscopy (AFM) and electron microscopy (EM). Here we summarise the EV preparation protocols for AFM and EM bringing out the main challenges in the imaging of EVs, both in their natural environment as biofluid constituents and in a saline solution after EV isolation. In addition, we discuss approaches for EV imaging and identify the potential benefits and disadvantages when different AFM and EM methods are applied, including numerous factors that influence the morphological characterisation, standardisation, or formation of artefacts. We also demonstrate the effects of some of these factors by using cerebrospinal fluid as an example of human biofluid with a simpler composition. Here presented comparison of approaches to EV imaging should help to estimate the current state in morphology research of EVs from human biofluids and to identify the most efficient pathways towards the standardisation of sample preparation and microscopy modes

DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF STROMAL MYOFIBROBLASTS IN LARYNGEAL CARCINOGENESIS

Background. Recent studies have shown that stromal reaction in cancer has a more important diagnostic and prognostic significance than previously thought. CD34-positive stromal cells and myofibroblasts may play an important role in host response to invasive cancer. The aim of our studies was therefore to analyze the distribution and immunohistochemical phenotype of stromal cells in epithelial hyperplastic lesions (EHL) and squamous carcinoma (SC) of the larynx, and to establish their diagnostic and prognostic significance.Methods. We investigated samples of 62 resected larynxes with SC, 50 laryngeal biopsies of EHL and SC, and 5 samples of normal laryngeal mucosa. Immunohistochemistry was performed using antibodies against vimentin, a-smooth muscle actin (SMA), desmin, CD34 and leucocyte common antigen (LCA).Results. The stroma of normal laryngeal mucosa and EHL contained scattered CD34-positive cells, but there were no SMApositive myofibroblasts. In contrast, the stroma of SC contained SMA-positive cells but there were no CD34-positive stromal cells. We observed two patterns of stromal reaction in SC: one was characterised by a marked proliferation of myofibroblasts and desmoplasia, with scarce lymphocytic infiltration; this pattern tended to be associated with well or moderately differentiated SC. The other was characterised by few myofibroblasts, weak desmoplasia, and dense lymphocytic infiltration; the latter pattern tended to be associated with moderately or poorly differentiated SC.Conclusions. Our studies show that disappearance of CD34positive cells and appearance of SMA-positive myofibroblasts in the stroma is associated with transformation of laryngeal EHL to SC. This pattern of stromal reaction should be regarded as an additional marker of invasion. Our results also suggest that characteristics of stromal reaction in SC could be of prognostic significance.</p

The role of immune-related miRNAs in the pathology of kidney transplantation

MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation

Expression of fibrosis-related genes in liver and kidney fibrosis in comparison to inflammatory bowel diseases

Fibrosis is an important feature of inflammatory bowel diseases (IBD), but its pathogenesis is incompletely understood. Our aim was to identify genes important for fibrosis in IBD by comparison with kidney and liver fibrosis. First, we performed bioinformatics analysis of Gene Expression Omnibus datasets of liver and kidney fibrosis and identified CXCL9, THBS2, MGP, PTPRC, CD52, GZMA, DPT and DCN as potentially important genes with altered expression in fibrosis. We then performed qPCR analysis of the selected genes’ expression on samples of fibrotic kidney, liver, Crohn’s disease (CD) with and without fibrosis and ulcerative colitis (UC), in comparison to corresponding normal tissue. We found significantly altered expression in fibrosis for all selected genes. A significant difference for some genes was observed in CD with fibrosis in comparison to CD without fibrosis and UC. We conclude that similar changes in the expression of selected genes in liver, kidney fibrosis and IBD provide further evidence that fibrosis in IBD might share common mechanisms with other organs, supporting the hypothesis that fibrosis is the common pathway in diseases of various organs. Some genes were already active in IBD with inflammation without fibrosis, suggesting the early activation of profibrotic pathways or overlapping function in fibrosis and inflammation