Glomerular T cell and monocyte populations in patients with IgA nephropathy

Renal tissues from 19 patients with the minimal or slight stage of IgA nephropathy were examined for evidence of glomerular T cell or monocyte infiltration using monoclonal antibodies to identify T cells (OKT3, OKT11), T cell subsets (OKT4, OKT8), and monocytes and null cells (OKM1) by indirect immunofluorescence. Renal tissues from 12 patients at the same stage of mesangial proliferative glomerulonephritis without IgA deposition were also investigated by these procedures. Light microscopic examination of the same renal tissues was also performed. Reactive glomerular mononuclear cells were found to be numerous in patients with IgA nephropathy. The most prominent type of glomerular cells was OKT8 positive. T cell subsets and OKM1 positive cells in glomeruli from patients with IgA nephropathy were significantly increased as compared to those from patients with mesangial proliferative glomerulonephritis. Focal segmental proliferation of mesangial cells was observed in glomeruli which showed an accumulation of OKT8 positive cells. It is concluded that the immuno-regulatory mechanism involving T cells and/or monocytes might be one of the exacerbating factors in patients with IgA nephropathy.     

Extrarenal cytokines modulate the glomerular response to IgA immune complexes.

Clinical episodes of IgA nephropathy coincide recurrently with microbial infections. Cytokines produced during such infections may play a role in the pathogenesis of IgA-associated glomerulonephritis. To test this hypothesis, we examined the influence of passively administered proinflammatory cytokines (IL-1, IFN-gamma and IL-6) on the development of glomerulonephritis in an experimental model of IgA nephropathy. Glomerular IgA immune deposits were induced in mice by administration of IgA anti-phosphorylcholine (PC) with either a PC-containing carbohydrate antigen of Pneumococcal C polysaccharide (PnC) or a protein antigen of PC-conjugated bovine serum albumin (PC-BSA). The effect of IL-1 on the IgA-PC-BSA induced glomerular changes resulted in an increase of mesangial hypercellularity that was associated with mild proteinuria and hematuria. Mice treated with IL-1 and IgA-PnC developed diffuse proliferative glomerulonephritis with proteinuria and hematuria. In contrast, IL-6 treatment with IgA-PC-BSA of IgA-PnC failed to exert any significant renal effect. The combination of IL-6 and IL-1, however, intensified the mesangial hypercellularity of the IgA-PC-BSA, and induced severe proliferative glomerulonephritis with inflammatory monocytes and neutrophils infiltrates in the IgA-PnC treated mice. These glomerular changes were also accompanied by increased proteinuria and hematuria. Similarly, the combination of IFN with IL-1 produced histologic changes and compromised renal function more than IFN or IL-1 exerted independently. These results suggest that extrarenal cytokines influence the renal response to IgA immune deposits. We also conclude that a synergy of multiple cytokines and nephritogenic antigens immobilized in glomerular IgA immune deposits may lead to rapid progression of IgA-associated glomerulonephritis.     

Suppressive effects of fish oil on mesangial cell proliferation in vitro and in vivo

BACKGROUND: Mesangial cell proliferation is a characteristic feature of IgA nephropathy and many other forms of glomerulonephritis. Recent clinical studies have shown that dietary fish oil supplementation retards renal disease progression in patients with IgA nephropathy. The mechanism by which this effect occurs is unknown. METHODS: The anti-Thy 1.1 (ATS) model of mesangial proliferative glomerulonephritis was employed to test the hypothesis that dietary fish oil supplementation reduces mesangial cell proliferation following acute injury. Subcultured rat mesangial cells were used to determine the in vitro effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the primary components of fish oil, on proliferation. RESULTS: Following antithymocyte serum (ATS) administration, proteinuria was significantly decreased in animals treated with fish oil compared with sesame oil-treated controls. In ATS rats given fish oil, there was less mesangial cell and matrix expansion, mesangiolysis, or basement membrane disruption (delta% = -40%). ATS rats receiving fish oil had less glomerular cell proliferation (PCNA-delta% = -50%) and a reduction of alpha-smooth muscle actin expression (delta% = -27%) by mesangial cells. In subcultured rat mesangial cells, DHA, but not EPA, significantly inhibited proliferation. CONCLUSIONS: Fish oil inhibits mesangial cell activation and proliferation in ATS glomerulonephritis, reduces proteinuria, and decreases histologic evidence of glomerular damage. In vitro, the antiproliferative effects of fish oil are more likely related to the action of DHA. We suggest that orally administered fish oil, or purified DHA, may have a suppressive effect in acute phases or relapses of glomerulopathies by inhibiting activation and proliferation of mesangial cells.     

Clinicopathological correlation of young onset chronic glomerulonephritis

In a retrospective analytical study involving 98 children with primary glomerulonephritis who were seen by us at our hospital during a 2-year period from 1984 through 1985 and who had renal biopsy performed previously, attempts were made to correlate pathological findings with both clinical findings and prognosis. The results are summarized as follows: 1) Of 87 patients with asymptomatic chronic glomerulonephritis, glomerular findings were those of minimal change lesion, mesangial proliferative nephritis, MPGN, membranous nephropathy and FGS or sclerosing nephritis in 29.9%, 51.7%, 13.8%, 1.1% and 3.5%, respectively. Among the other 11 patients in whom the diagnosis was made after manifesting the nephritic symptoms, minimal change was noted less frequently and MPGN was detected more frequently than in the aforementioned asymptomatic group. IgA nephropathy was estimated to account for 44.2% of cases of asymptomatic chronic nephritis. 2) Mild mesangial proliferation was observed relatively frequently and severe mesangial proliferation or MPGN rather infrequently in hematuria cases without proteinuria while in those with severe proteinuria minimal change lesion was uncommon and severe mesangial proliferative changes, MPGN or FGS were relatively frequent. 3) In 22 patients with IgA nephropathy and 11 with non-IgA nephritis the severity of glomerular changes was related to the intensity of proteinuria at the time of renal biopsy. 4) A 3 to 5 years' follow-up study of patients with mesangial proliferative nephritis inclusive of IgA nephropathy disclosed that 26-28% of patients became free from urinary abnormalities, 27-37% had persistent hematuria without proteinuria and 24-32% still had proteinuria of 2 plus or above. Patients with milder glomerular changes had a definitely better prognosis than those with severe glomerular lesions.     

Pathogenetic and therapeutic approaches to IgA nephropathy using a spontaneous animal model,the ddY mouse

IgA nephropathy is the most common primary chronic glomerulonephritis in the world and was first described by Berger et al. (J Urol Nephrol 74:694–695;1968). Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation. Glomeruli typically contain generalized diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. In advanced patients, global glomerular sclerosis, crescent formation and tubulo-interstitial fibrosis are marked in light microscopy. IgA nephropathy is generally considered to be an immune-complex mediated glomerulonephritis. Although more than 40 years have passed since this disease was firstly described, the pathogenesis/initiation factors of IgA nephropathy are still obscure. The objective of this review is to explain the pathogenesis and treatment based on our previous data of ddY mouse, a spontaneous animal model for IgA nephropathy.     

Unexpected IgA nephropathy during the treatment of a young woman with idiopathic dermatomyositis: case report and review of the literature

This article reports the unexpected discovery of IgA nephropathy in a 26-year-old Chinese woman 1.5 years after the onset of idiopathic dermatomyositis. The patient was taking immunosuppressive agents, prednisolone 25 mg and azathioprine 75 mg daily. Glomerulonephritis associated with idiopathic polymyositis/dermatomyositis is rare. A review of the medical literature indicates that the most common pattern seen in idiopathic polymyositis is mesangial proliferative glomerulonephritis. However, both membranous and mesangial proliferative glomerulonephritis are often seen in idiopathic dermatomyositis. It is still not clear, however, whether the humorally- mediated immune process in dermatomyositis and the cell-mediated immune process in polymyositis can explain the different patterns of occurrence of glomerular lesions in these two closely related disease entities.     

Primary antiphospholipid antibody syndrome and mesangial IgA glomerulonephritis

The antiphospholipid antibody syndrome (APS) is characterized by recurrent thrombosis, fetal loss, multiorgan involvement, and the presence of lupus anticoagulant and/or anticardiolipin antibody. When not associated with systemic lupus erythematosus, other collagen diseases, or ingestion of medications, the condition is called primary APS. The kidney may be involved in the APS syndrome with acute nephritis and renal failure. The cases with renal biopsy studies have shown variable glomerular morphology, ranging from mild mesangial changes to a diffuse endocapillary proliferative glomerulonephritis. The most frequent lesion is thrombotic microangiopathy or features seen in the hemolytic uremic syndrome. Apart from fibrin thrombus deposition, only a few cases have shown focal and segmental deposits of IgG and/or IgM and/or C3. We describe a patient with primary APS who had thrombosis with lower limb amputation and acute renal failure. The renal biopsy specimen showed a focal proliferative glomerulonephritis with endothelial proliferation and damage, with diffuse heavy mesangial deposits of IgA and fibrinogen. This case with diabetes mellitus, but without diabetic nephropathy, represents the occurrence of primary APS and mesangial IgA nephropathy which potentiated the renal injury, leading to acute renal failure. The relationship to the Henoch-Sch?nlein syndrome is discussed.     

The role of matrix metalloproteinases in the activation of mesangial cells

Mesangial cells play a prominent role in renal inflammatory disorders, especially in IgA nephropathy. This disease represents the most common form of glomerulonephritis that eventually leads to progressive kidney failure requiring renal replacement therapy. In kidney transplants, IgA nephropathy displays a high recurrence rate in the order of 50%. Increased cell proliferation rates and extracellular matrix (ECM) accumulation are crucial targets in the therapy of glomerulonephritis, including IgA nephropathy. The active role of matrix metalloproteinases (MMP) in the regulation of these two features is rapidly emerging. We studied a model of a specific type of mesangial cell-mediated glomerular inflammation, such as experimental mesangial proliferative glomerulonephritis and cultured proliferating mesangial cells. In addition, these tools allowed us to evaluate a new therapeutic strategy based on MMP inhibition. Inhibition of MMP activity and synthesis by antisense technology and by a synthetic inhibitor in vitro, successfully reverted the inflammatory mesangial cell phenotype to the physiologically existing resting state. In vivo, a hydramate-based MMP inhibitor attenuated excess mesangial cell proliferation and ECM accumulation in anti-Thy1.1 nephritis. The anti-proliferative effect was achieved by the induction of cell cycle arrest followed by apoptosis, mediated by the induction of p53, p21 and bax, but not by the Fas/FasL pathway. In conclusion, MMP inhibitors provide a new approach to the therapy of inflammation probably even beyond the field of renal disorders.     

IgA nephritis in Beh?et's disease: case report and review of the literature

We describe a 13-year-old girl with the incomplete type of Beh?et's disease who had recurrent oral and genital ulcers, folliculitis, proteinuria and hematuria. Renal biopsy specimens revealed diffuse proliferative glomerulonephritis with strongly positive IgA deposits in the glomerular mesangial area, which is histologically indistinguishable from primary IgA nephritis. Further studies of the IgA subclasses showed that IgA1 deposits were predominant in the glomerular mesangium. Primary IgA nephritis is thought to be associated with polymeric IgA1. So it appears that there may be a common underlying disease or mechanism involved in both primary IgA nephritis and the IgA nephritis in Beh?et's disease.     

原发性肾病综合征并发急性肾损伤48例临床病理分析

目的探讨原发性肾病综合征合并急性肾损伤的临床及病理特点,提高此类并发症的防治水平。方法对我院原发性肾病综合征合并急性肾损伤患者的临床和病理改变进行回顾性分析。结果原发性肾病综合征合并急性肾损伤的临床特征表现为大量蛋白尿、高度水肿,常合并胸腹腔积液。肾脏病理类型：系膜增生性肾小球肾炎、肾小球微小病变及IgA肾病多见。其中系膜增生性肾小球肾炎22例,占46%;微小病变型10例,IgA肾病9例。所有患者均依据病理分型给予激素和（或）细胞毒药物,同时行利尿、控制感染、抗凝等综合治疗,其中5例进行血液透析治疗,肾损伤大多好转,但增生硬化型肾炎等预后较差。结论原发性肾病综合征并发急性肾损伤临床并不少见,多发生于系膜增生性肾小球肾炎、肾小球微小病变及IgA肾病,尽早明确病理诊断和去除诱因,并予相应治疗,大多患者预后良好,肾功能可恢复正常。     

Experimental mesangial proliferative glomerulonephritis (the anti-Thy-1.1 model)

The anti-Thy-1.1 model is a rat model of mesangial proliferative glomerulonephritis characterized by initial mesangiolysis followed by mesangial cell proliferation and accumulation of mesangial matrix with subsequent resolution and the return to almost normal histology. In this review we discuss the pathogenesis of the initial injury, the mechanisms governing mesangial cell proliferation and matrix expansion, and some of the processes involved in the resolution of glomerular injury. Understanding these processes of mesangial cell injury and recovery may provide insights into the pathogenesis of human mesangial cell diseases such as IgA nephropathy.     

The immunohistology of IgA nephropathy

The glomerular immunohistologic characteristics of 180 patients with IgA nephropathy (IgAN), defined by 2+ or greater (out of 0 to 4+) mesangial IgA-dominant or codominant immunostaining and no evidence for systemic lupus erythematosus, were compared with those of 84 patients with proliferative lupus glomerulonephritis and 254 patients with other forms of proliferative glomerulonephritis. The IgAN population increased in number by only 5% if the IgA immunostaining criterion was lowered to 1+, and it decreased by only 2% if IgA codominant staining was disallowed. A distinctive immunohistologic feature of IgAN in comparison with other immune complex-mediated glomerulopathies, in addition to the predominance of IgA immunostaining, was a high frequency (67%) of patients with greater lambda- than kappa-immunoglobulin light chain immunostaining. There was no correlation between the absolute or relative intensities or frequencies of IgA, IgG, or IgM immunostaining and the severity of glomerular disease; however, the presence of capillary wall immune deposits correlated with more severe disease. Terminal complement components were consistently present and were more conspicuous in more severely injured glomeruli. Immunostaining for the early classical complement activation pathway component C1q was absent or scanty in IgAN. This finding was particularly useful in the immunohistologic differentiation of IgAN from proliferative lupus glomerulonephritis, which was the form of glomerulonephritis with the greatest overlap with IgAN with respect to IgA immunostaining. When the diagnostic criteria for IgAN were 2+ or greater, dominant or codominant mesangial IgA immunostaining and less than 2+ C1q immunostaining, an immunohistologic diagnosis of IgAN was made with 98% accuracy.     

Paulista Registry of glomerulonephritis: 5-year data report.

BACKGROUND: The Paulista Registry of Glomerulopathies was created in May 1999 and comprises several centres of S?o Paulo, the most populous Brazilian State, that concentrates people from all regions of the country who look for health care. METHODS: This report includes data from 2086 patients from Brazil submitted to renal biopsy due to the presumed diagnosis of glomerular diseases, registered prospectively since May 1999 until January 2005. Data were collected by the integrants of the 11 centres involved, utilizing a standardized questionnaire. RESULTS: The mean age of the patients was 34.5+/-14.6 years. Primary glomerular diseases were more frequent in males (55.1%) than in females; on the other hand, secondary glomerular diseases were more frequent in females (71.8%). The most common clinical presentation was nephrotic syndrome and the frequency of hypertension, at this time, was 55.5%. There was a predominance of indication of biopsies in the third, fourth and fifth decades of life. The most common primary glomerular diseases were focal and segmental glomerulosclerosis (29.7%), followed by membranous nephropathy (20.7%), IgA nephropathy (17.8%), minimal change disease (9.1%), membranoproliferative glomerulonephritis (7%), crescentic glomerulonephritis (4.1%), advanced chronic glomerulopathy (4%), non-IgA mesangial glomerulonephritis (3.8%), diffuse proliferative glomerulonephritis (2.5%), focal segmental proliferative glomerulonephritis (1%) and others (0.3%). The most frequent secondary glomerular disease was lupus nephritis, corresponding to 66.2% of the cases, followed by post-infectious glomerulonephritis (12.5%), diabetic nephropathy (6.2%), diseases associated to paraproteinaemia (4.9%), hereditary diseases (4.6%), vasculitis (3.2%), malignancies (0.9.%), secondary focal segmental glomerulosclerosis (0.6%) and others (0.9%). CONCLUSION: Focal segmental glomerulosclerosis was the most frequent primary glomerular disease, followed by membranous nephropathy and IgA nephropathy. Lupus nephritis predominated over all the other secondary glomerular diseases.     

Sequential occurrence of IgA nephropathy and Henoch-Schönlein purpura: support for common pathogenesis

We report a patient who developed Henoch-Schönlein purpura (HSP) 13 years after he presented with IgA nephropathy (IgAN). In both HSP and IgAN renal biopsy most commonly reveals focal proliferative glomerulonephritis on light microscopy and immunofluorescence displays mesangial IgA deposits. In addition, patients with HSP or IgAN have elevated serum IgA levels, circulating IgA immune complexes, IgA-bearing lymphocytes, immunoglobulin-producing cells, and binding of IgG to glomerular components of similar molecular weight. The occurrence of both diseases in the same patient or the same families and the presence of immune abnormalities compatible with HSP or IgAN in relatives of patients with these diseases suggest a common pathogenesis.     

C1q肾病的诊断及治疗

C1q肾病是一种以系膜增生为主的肾小球疾病,其特点为免疫荧光染色可见系膜区高强度C1q沉积,电镜下可见系膜区电子致密物沉积,根据组织病理学特点主要分为3类,包括微小病变(MCD)、局灶节段性肾小球硬化(FSGS)和免疫介导的增生性肾小球肾炎。C1q肾病的临床表现具有多样性,可表现为肾炎或肾病范围内蛋白尿,伴有或不伴有血尿和肾功能损伤。虽然目前糖皮质激素是治疗C1q肾病的主要方法,但多数研究认为C1q肾病对糖皮质激素治疗反应较差。中西医结合治疗有望提高C1q肾病的疗效。     

Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), characterized by predominant or exclusive deposition of IgA1 in glomerular mesangium, is the most common primary glomerulonephritis worldwide. At present, the treatment is always limited due to the incomplete understanding of the pathogenesis of IgAN. Mesangial deposited IgA1 is the common final pathway leading to glomerulonephritis and renal injury. IgA1 protease, a proteolytic enzyme with strict substrate specificity for human IgA1, may be an effective therapeutic candidate for IgAN by removing the mesangial deposited IgA1.     

IgA nephropathy: lessons from an animal model, the ddY mouse

IgA nephropathy is the most common primary chronic glomerulonephritis, and was first described by J. Berger (Transplant Proc. 1969;1:939-944). Histopathologically, IgA nephropathy is characterized by expansion of glomerular mesangial matrix, with mesangial cell proliferation. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA, IgG and C3. Since pathogenesis of IgA nephropathy is still obscure, it is important to try to determine the initiation and progression of this disease using a suitable animal model. Several investigators, including Rifai's group (Rhode Island, USA) and Emancipator's group (Cleveland, Ohio, USA), reported various experimental animal models for this disease. In 1985, Imai et al first reported that the ddY strain of mouse can serve as a spontaneous animal model for IgA nephropathy. These mice show mild proteinuria without hematuria, and mesangioproliferative glomerulonephritis with severe glomerular IgA deposits in association with an increase of serum IgA level (Imai et al. Kidney Int. 1985;27:756-761). Electron-dense deposits are observed in the glomerular mesangial areas by electron microscopy. Furthermore, Muso's group succeeded in generating a mouse model of IgA nephropathy with a high incidence and early onset of glomerular IgA deposition (Miyawaki et al. Nephron. 1997;76:201-207). The selection procedure was successful in increasing the serum IgA level of the selected line. The selected ddY line (HIGA mice) showed only mild proteinuria (100-300 mg/dL) and did not show hematuria. These immunohistopathological findings in ddY mice resemble those in IgA nephropathy patients. The objectives of this review are to introduce the genetic background, Th1/Th2 polarization, expansion of extracellular matrices (ECMs) and treatment of IgA nephropathy of the ddY mouse. These findings from the ddY mouse appear to be useful in determining the pathogenesis and treatment of patients with IgA nephropathy.     

肾活检患者451例临床与病理构成对比分析

目的 分析珠海地区肾脏疾病的病理及临床特点.方法 回顾性分析我院451例肾活检患者的临床及病理资料,探讨其病因、临床特点及病理类型的关系.结果 451例肾活检患者中,男、女高峰发病年龄为19～37岁,分别占59%及65%.原发性肾小球疾病共369例（占81.81%）,临床类型排在前3位的依次为无症状血尿、蛋白尿149例（占40.38%）、慢性肾小球肾炎104例（占28.18%）、肾病综合征76例（占20.60%）,病理类型排在前3位的依次为IgA肾病251例（占68.02%）、系膜增生性肾小球肾炎（MsPGN）33例（占8.94%）、微小病变型肾病（MCD）24例（占6.50%）;继发性肾小球疾病69例（占15.30%）,临床类型排在前3位的依次为狼疮肾炎26例（占37.68%）、乙型肝炎相关性肾小球肾炎24例（占34.78%）、紫癜肾炎9例（占13.04%）.结论 原发性肾小球疾病是目前最主要的肾小球疾病,IgA肾病在原发性肾脏疾病中发病率最高,继发性肾小球疾病中狼疮肾炎排在首位.     

Pattern of glomerular diseases among adults in Rajshahi, the Northern Region of Bangladesh

To obtain a recent and comprehensive insight into the pattern of glomerular diseases in the Bangladeshi population, we studied 95 adequate renal biopsies done during July 2008 to June 2009, by light and direct immunofluorescence microscopy in the Department of Pathology, Rajshahi Medical College, Northern Region of Bangladesh. Of these, 38 (40%) were males and 57 (60%) were females, with a male to female ratio of 1:1.5. The most frequent clinical presentation was nephrotic syndrome (67.37%). Primary glomerular disease accounted for 91.25% of all glomerular disease and, of them, focal and segmental mesangial proliferative glomerulonephritis was the most common histological lesion in 29.47%. Diffuse mesangial proliferative glomerulonephritis (GN) was the second most common lesion (15.79%), followed by focal segmental GN (11.58%), minimal change disease (10.53%), membranous GN (7.37%), IgA nephropathy (6.85%), chronic sclerosing GN (2.11%) and crescentic GN (2.11%). Lupus nephritis was the most prevalent among secondary GN.