Heparanase in glomerular diseases

Heparanase is an endo-beta(1-4)-D-glucuronidase that degrades heparan sulfate (HS) polysaccharide side chains. The role of heparanase in metastasis, angiogenesis, and inflammation has been established. Recent data suggest a role for heparanase in several proteinuric diseases and an increased glomerular heparanase expression is associated with loss of HS in the glomerular basement membrane (GBM). Furthermore, an increase in heparanase activity was detected in urine from proteinuric patients. Mice with transgenic heparanase overexpression developed mild proteinuria. Glomerular heparanase activity is proposed to lead to loss of HS in the GBM and proteinuria. Because the primary role of GBM HS for charge-selective permeability has been questioned recently, heparanase may induce or enhance proteinuria by (i) changes in the glomerular cell-GBM interactions, due to loss of HS; (ii) release of HS-bound factors and HS fragments in glomeruli; or (iii) intracellular signaling by binding of heparanase to glomerular cells. Which of these mechanisms is prevailing requires further research. The precise mechanisms leading to increased heparanase expression in the different glomerular cell types remain elusive, but may involve hyperglycemia, angiotensin II, aldosterone, and reactive oxygen species. This review focuses on the role of heparanase in HS degradation in proteinuric diseases and the possibility/feasibility of heparanase inhibitors, such as heparin(oids), as treatment options.     

Superimposed nephritis: a separate entity among glomerular diseases?

The concomitant occurrence of two glomerular diseases in the same patient was diagnosed in seven out of 105 patients undergoing renal biopsy for suspected glomerulopathy. The most frequently associated disease was a membranous type glomerulopathy. The follow-up was characterized by a rapid deterioration of renal function and two patients were required to start a chronic hemodialysis program soon after the diagnosis. It is suggested that the observed coexisting patterns of glomerular injury do not occur on the basis of chance alone and should be considered as a separate entity in glomerular pathology. In all cases, clinical and pathologic findings were strongly suggestive for two consecutive distinct pathologic processes, thus justifying the use of the term superimposed nephritis. It is reasonable to assume that the mechanisms responsible for glomerular damage and for the evolution of the disease in superimposed nephritis are different from those regulating the corresponding glomerulonephritis when occurring alone. The high prevalence of membranous pattern in superimposed nephritis indicates that pre-existing glomerular alterations might favor an immune reaction in the subepithelial space.     

Home dampness, current allergic diseases, and respiratory infections among young adults

BACKGROUND: The relation between home dampness and respiratory symptoms among adults is well confirmed, but data on specific allergic diseases and respiratory infections is more limited. Individual factors that may enhance susceptibility to the effects of home dampness are mainly unknown. METHODS: The association between home dampness and current physician diagnosed asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, common colds, and bacterial respiratory infections was studied in a questionnaire survey of 10 667 Finnish first year university students aged 18-25 years. The dampness categories analysed were visible mould and visible mould or damp stains or water damage during the last year. In multivariate analyses adjustment was made for parental education, active and passive smoking, type and place of residence, pets, and wall to wall carpets. The interaction effect of atopic heredity and dampness was investigated. RESULTS: Visible mould or damp stains or water damage was reported by 15.0% of the respondents. In multivariate models there was a positive association between home dampness and current asthma, allergic rhinitis, and atopic dermatitis, as well as common colds > or =4 times per year and other respiratory infections, but not between home dampness and allergic conjunctivitis. The strongest association was found between exposure to visible mould and asthma (OR 2.21, 95% CI 1.48 to 3.28) and common colds (OR 1.49, 95% CI 1.18 to 1.87). The risk of current asthma in damp homes was highest among subjects with atopic heredity. CONCLUSIONS: The risk of current asthma, allergic rhinitis, and atopic dermatitis was higher in damp homes. Of the respiratory infections, the risk of common colds was most clearly increased.     

Clinical aspects of glomerular diseases

This article discusses the current concepts of the pathophysiology of disturbed glomerular structure and/or function that lead to the cardinal clinical manifestations of glomerular disease, ie, alterations in glomerular filtration rate, disturbances in sodium homeostasis, proteinuria, and hematuria. The functional and anatomic bases of these alterations include changes in filtering surface area, filtration pressure and/or nephron mass, primary and secondary renal sodium and water retention, defects in size and/or charge-selective barriers to filtration of plasma proteins, and defects in capillary wall integrity. Longitudinal evaluation of albuminuria/gamma globulinuria and the investigation of dysmorphic hematuria may be helpful approaches to the study of glomerular disease.     

Inherited diseases of the glomerular basement membrane

The glomerular basement membrane (GBM) is a specialized form of basement membrane that has a major role in the maintenance of the glomerular filtration barrier. Like all basement membranes, it contains four main components: type IV collagen, laminin, nidogen, and heparan sulfate proteoglycans. Different isoforms of these large molecules are produced. These isoforms have a tissue-specific distribution; in the mature GBM, the major type IV collagen molecule is the alpha 3 alpha 4 alpha 5(IV) isoform, associated with laminin-521 (alpha 5 beta2 gamma 1), nidogen and agrin heparan sulfate proteoglycans. The importance of the GBM has been demonstrated by identification of hereditary glomerular diseases linked to structural anomalies of its components; for example, type IV collagen in Alport syndrome and familial benign hematuria, and laminin in Pierson syndrome. Type III collagen, an interstitial collagen, accumulates within the GBM of patients with the nail-patella syndrome, and abnormal deposition of fibronectin, another extracellular matrix protein, is characteristic of so-called fibronectin nephropathy. Development of animal models of these diseases has facilitated precise analysis of pathogenic mechanisms, but no specific treatments are available. Therapeutic trials in Alport syndrome nephropathy are underway, following promising preliminary results obtained in rodent and canine models of the disorder.     

Role of platelets in progressive glomerular diseases

There is increasing evidence that platelets are involved in the pathogenesis of glomerulonephritis. Intraglomerular platelets or their degradation products are observed in biopsies from patients with lupus nephritis, mesangioproliferative, membranous or IgA nephropathy. Moreover shortened platelet survival in patients with various glomerular diseases has also been described. In models of experimental glomerulonephritis, platelets may participate in glomerular injury, together with other mediators, by complex mechanisms. As extensively documented, platelets release within the glomerulus vasoactive, chemotactic and mitogenic substances that interact with a number of soluble mediators generated by renal resident or inflammatory cells and contribute to amplify glomerular injury. Thus platelet-activating factor and other platelet secretory products, polycationic macromolecules, platelet factor 4 and -thromboglobulin, alter glomerular permeability to proteins and enhance immune-mediated glomerular injury. Platelet-derived factors, like platelet-derived growth factor (PDGF) and transforming growth factor (TGF) mediate renal disease progression in experimental and human glomerulonephritis via their chemotactic activity for infiltrating leucocytes and their effect of promoting extracellular matrix synthesis by resident renal cells. In these settings increased renal expression of PDGF and TGF has correlated with clinical features. Specific PDGF and TGF inhibitors ameliorated experimental glomerular disease. A wide variety of therapies to inhibit platelet function have been employed over the years, however the results of clinical studies are controversial and do not allow conclusions to be drawn about the efficacy of anti-platelet agents in progressive renal disease. Identification of specific platelet inhibitors or interventions specific for platelet secretory products and their target cells will be crucial for understanding the exact role of platelets and their products in glomerular disease.     

Mechanisms of mesangial injury in glomerular diseases

Immune-mediated mesangial cell injury can be triggered by various mechanisms including the trapping of immune complexes, binding of specific antibodies to mesangial cells or indirect binding of immune complexes to mesangial cells via specific receptors. These receptors include specific receptors for IgG or IgA and complement receptors. Interactions of immune complexes or antibodies with mesangial cells contribute to activation of these cells and release of cytokines and chemokines, influx of inflammatory cells and either further activation of intrinsic renal cells or injury of the glomerulus. In this review a number of aspects of renal cell injury are summarized.     

尿液蛋白质组学在肾小球疾病研究中的应用

近几年来,蛋白质组学研究越来越多地应用于各个医学领域,各种功能蛋白质不仅是发挥机体正常生理作用的重要活性物质,也是与机体病理状态最具直接关系的物质.     

West Nile Virus Surveillance in the Lombardy Region,Northern Italy

In 2013, the circulation of West Nile virus (WNV) was detected in the Lombardy region and the following year a surveillance programme was activated with the aim of early identification of the viral distribution in mosquitoes and wild birds. A total of 50 959 Culex spp. mosquitoes grouped in six hundred and forty‐seven pools as well as 1400 birds were screened by RT‐PCR for the presence of West Nile virus leading to the identification of the viral genome in 32 mosquito pools and 13 wild birds. The surveillance was able to detect the WNV circulation on an average of 42 days (CI 95% 29.98–53.86; Student's t‐distribution) before the occurrence of human West Nile disease (WND) cases in the same area. These results demonstrate the presence of WNV in the Lombardy region and confirm entomological and wild birds surveillance as an effective measure for the early identification of WNV circulation in infected areas, thus providing a useful and cost‐effective tool for the public health authorities in the application of measures to prevent human infection.     

Para-capillary electron-dense deposits reduce glomerular filtration in patients with primary glomerular diseases

Background Electron-dense deposits are often found around glomerular capillary lumens in patients with glomerulonephritis, forming a portion of the blood-urine barrier (BUB). Methods Four hundred and four patients with primary glomerular diseases or donors for living-related kidney transplantation who underwent both percutaneous renal biopsy and renal clearance tests were included in the study. Sodium thiosulfate and paraamino hippurate double-clearance studies were performed with catheterized urinary collection. The filtration fraction (FF) was determined as follows: FF = sodium thiosulfate clearance/paraamino hippurate clearance (Cpah). Histomorphometric analyses were performed in 53 patients with overt para-capillary electron-dense deposits (PCEDD) by electron microscopic observations. Results Patients with membranous nephropathy and membranoproliferative glomerulonephritis showed significantly lower levels of FF than the donors for living-rebated kidney transplantation (normal controls). FF levels were significantly lower in patients with PCEDD than in those without (P < 0.001), while the levels of mean blood pressure and Cpah were comparable in the two groups. The PCEDD/BUB ratio demonstrated a significant negative correlation with FF (P < 0.0001; r² = 0.331). Patients with a ratio of 0.5 or more showed significantly lower FF levels than those with a ratio of 0.25 or less. Conclusions PCEDD significantly affected FF levels in patients with primary glomerular diseases. FF may not be an accurate indicator of intraglomerular blood pressure in patients with overt PCEDD.     

Proteinuria and progression of glomerular diseases

One of the major challenges of nephrology is to develop therapeutic strategies to halt the progression of kidney diseases. In clinical settings, nephrotic-range proteinuria correlates with the rate of progression, particularly in glomerular diseases. Hence, the degree of proteinuria has been utilized to monitor the response to treatment as well as to predict outcome. However, the pathophysiology of proteinuria-induced progression remains unknown. Albumin accounts for the majority of the protein in nephrotic urine and as a result of this clinical observation studies have focused on understanding the adverse effects of albumin overload in the kidney. Albumin is internalized by receptor-mediated endocytosis in proximal tubule cells via low density lipoprotein (LDL) type receptor, megalin. Albumin at high concentrations mimicking nephrotic milieu has resulted in the upregulation of pro-inflammatory/fibrogenic genes and apoptosis in proximal tubule cells in in vivo and in vitro models of albumin overload. These properties of albumin on proximal tubule cells may explain extensive tubulointerstitial fibrosis and tubular atrophy observed in end-stage kidney disease. In addition to tubular toxicity, podocytes respond to proteinuric states by cytoskeletal alterations and loss of the differentiation marker synaptopodin. Identifying the molecular network of proteins involved in albumin handling will enable us to manipulate the specific signaling pathways and prevent damage caused by proteinuria.     

Advances in apheresis therapy for glomerular diseases

This article is an overview of the immunomodulatory effects of apheresis in renal diseases, especially primary and secondary glomerulonephritis, and the clinical evidence for the efficacy of apheresis therapy. Permeability factor(s) derived from circulating T cells are speculated to have a crucial role in the proteinuria of nephrotic syndrome (NS). Plasma exchange (PE); immunoadsorption plasmapheresis (IAPP), using protein A sepharose cartridges; low-density lipoprotein apheresis; and lymphocytapheresis (LCAP) have been used to remove such factors or pathogenic T cells. Other glomerular diseases induced by specific antibodies such as anti-glomerular basement membrane antibodies, anti-neutrophil cytoplasmic antibodies, and immune-complexes have also been treated with PE, double-filtration plasmapheresis, IAPP, and LCAP. Recommendations, based on the evidence from recent randomized controlled studies, have been established in apheresis therapy for various glomerular diseases.     

Glomerular apolipoprotein B deposition in glomerular diseases

In an attempt to elucidate the relationship between the progress of glomerular injury and abnormalities of lipid metabolism, we investigated glomerular deposition of apolipoprotein B (apo B) in renal biopsy specimens from 60 patients with glomerular diseases by indirect immunofluorescence using antihuman apo B-100 monoclonal antibody in comparison with clinical and histopathological findings. The patients were divided into 2 groups according to the intensity in staining of apo B in glomerulus (group A: negative or weakly positive; and group B: definitely positive). Staining of apo B in glomerulus was found in 37 patients (62%). The levels of serum total cholesterol, phospholipids, low density lipoprotein cholesterol and apo B in group B were significantly higher than in group A. The urinary protein excretion in group B was greater than that in group A. Group B was also shown to have a significantly decrease in renal function. Light microscopy revealed severe mesangial proliferation in patients with IgA nephropathy of group B. These findings suggested that glomerular apo B containing-lipoprotein deposition may play an important role in the progression of glomerular injury.     

Hyperperfusion injury of the human kidney in different glomerular diseases

Investigations of biopsy material from human kidneys with different forms of glomerulonephritis (n = 1,240) and with diabetic glomerulosclerosis (n = 406) performed in order to find changes caused by hyperperfusion of the kidney tissue gave the following results: (1) Hyperperfusion injury occurs in the different forms of glomerulonephritis with varying frequency. It was rarely found in immunologically negative mesangioproliferative glomerulonephritis. The highest incidence was found in patients with membranoproliferative glomerulonephritis type I. (2) Hyperperfusion injury was also found in kidneys with diabetic glomerulosclerosis. The frequency of this finding increased with the degree of the diabetic changes. (3) The hyperperfusion injury was seen as a complication of glomerulonephritis or diabetic glomerulosclerosis only when the patient clinically had developed malignant hypertension and when the serum creatinine level was elevated, a sign of compensated retention. (4) In patients with glomerulonephritis, the hyperperfusion changes occurred more frequently in males than in females. Diabetic glomerulosclerosis was complicated by hyperperfusion injury with the same frequency in both sexes. (5) Patients with hyperperfusion changes of the kidneys always excrete large amounts of protein in the urine. (6) Hyperperfusion changes occur first in the juxtamedullary glomeruli. The intermediate glomeruli are affected later and the subcapsular glomeruli last.