Acute poststreptococcal glomerulonephritis superimposed on IgA nephropathy

Superimposition of poststreptococcal glomerulonephritis (PSGN) on the course of IgA nephropathy (IgAN) is uncommon. A case of PSGN during IgA nephropathy is presented. A 30-year-old man who had alternating gross and microscopic hematuria for 7 months underwent a renal biopsy. The first renal biopsy revealed IgAN with mesangial deposits of IgA and C3. Two months later, the patient suffered generalized edema, proteinuria, hematuria, an increased ASO titer and a decreased C3 level. A second renal biopsy revealed diffuse endocapillary proliferative glomerulonephritis with epimembranous hump-like electron-dense deposits of C3, but the original mesangial IgA deposits had disappeared. A diagnosis of acute PSGN was indicated. Two months after the onset of acute nephritic syndrome, the patient remained asymptomatic, except for microscopic hematuria and proteinuria. Some cases with persistent proteinuria or hematuria after PSGN are probably related to preexisting IgAN.     

Superimposition of poststreptococcal acute glomerulonephritis on the course of IgA nephropathy

A 17-year-old male with poststreptococcal acute glomerulonephritis (PSAGN) superimposed on the course of IgA nephropathy is presented. The histological findings of the first renal biopsy showed mild IgA nephropathy with a mesangial deposition of IgA and C3. Eighteen months later, acute nephritic syndrome with hypocomplementemia and rising antihyaluronidase titer occurred 10 days following the onset of an upper respiratory infection. The second renal biopsy revealed severe diffuse endocapillary proliferative and exudative glomerulonephritis with cellular crescents in 70% of the glomeruli. Immunofluorescence showed granular staining of C3 alone along the capillary walls. The pre-existing IgA deposits had disappeared. Typical 'humps' were observed by electron microscopy. The symptoms were gradually resolved by intensive steroid and anticoagulant therapy. Five months after the episode of acute nephritic syndrome, the patient was clear of symptoms except for mild proteinuria and hematuria. The third renal biopsy at that time showed morphologic changes similar to those of the first renal biopsy with mild mesangial IgA deposits.     

Histology and immunohistology of IgA nephropathy

IgA nephropathy is a histologically diverse glomerular disease characterized by mesangial or mesangial plus peripheral glomerular capillary immune complex deposits that contain IgA as the dominant or co-dominant immunoglobulin type. The most common histologic manifestation of IgA nephropathy is mesangial proliferative glomerulonephritis (GN), most often focal but not infrequently diffuse. However, the light microscopic appearance of IgA nephropathy spans the entire range from histologically normal to diffuse proliferative and crescentic glomerulonephritis, much as is the case with lupus nephritis. This review examines the histologic diversity as well as the immunohistologic features of IgA nephropathy.     

IgG, IgA and IgM rheumatoid factors in patients with glomerulonephritis

Rheumatoid factors (RF), autoantibodies to IgG, have been postulated to have some pathogenetic role in the development of some types of glomerulonephritis. A simple and sensitive solid-phase fluorescence immunoassay was employed to determine whether IgG, IgA and IgM RF were detectable in sera from patients with various types of glomerulonephritis, rheumatoid arthritis (RA) and those with various streptococcal infections. IgG, IgA and IgM RF were significantly increased in the majority of patients with RA, lupus nephritis (SLE), acute poststreptococcal glomerulonephritis (APSGN) and various streptococcal infections. The titers of IgG and IgA RF were significantly higher in patients with APSGN than in those with simple pharyngitis. IgM RF was increated in patients with IgA nephropathy (IgA-N) and in those with membranoproliferative glomerulonephritis type I (MPGN). No significantly high RF was observed in membranous nephropathy (MN) or chronic mesangial proliferative glomerulonephritis without IgA deposition (PGN). It is suggested that some autologous immune mechanisms may be involved in the pathogenesis of some types of glomerulonephritis.     

Mesangial IgA in IgA nephropathy arises from the mucosa

Numerous studies have attempted to elucidate the pathogenetic mechanisms of IgA nephropathy, analyzing kidney, serum, lymphocytes, and lymphoid tissue of patients with this glomerulonephritis. Based on studies of the molecular characteristics of the mesangial IgA, clinical features, and immunologic analysis of the mucosal tissue, a wide array of findings suggest that mesangial IgA indeed arises from the mucosa. These three areas of research are discussed, as well as the hypothesis of a systemic origin for the mesangial IgA.     

Detection and clinical usefulness of urinary interleukin-6 in the diseases of the kidney and the urinary tract.

Interleukin-6 (IL-6) plays a key role in inflammatory and immune responses in the host. In the present study, the IL-6 activity in urine from patients with various renal diseases was examined to elucidate the pathological and clinical significance of urinary IL-6. In patients with mesangial proliferative glomerulonephritis (mes-PGN) including, IgA nephropathy, the urinary IL-6 activity tended to increase with the progression of mesangial hypercellularity. In four patients with IgA nephropathy, urinary IL-6 activity increased markedly but transiently during episodes of acute exacerbation associated with upper respiratory tract infection. In addition, it was demonstrated that urine from patients with other types of PGN such as poststreptococcal acute glomerulonephritis and membrano-proliferative glomerulonephritis contained large quantities of IL-6. However, the levels of urinary IL-6 activity were almost within the normal range in non-proliferative glomerular diseases such as membranous nephropathy, minimal change nephrotic syndrome and lupus nephritis (WHO class I and V), non-glomerular bleeding and orthostatic proteinuria. It should be noted that a marked increase in urinary IL-6 was often observed in the patients with urinary tract infection. These results indicated that IL-6 in urine might be derived from various types of cells participating in inflammatory reactions not only in the renal parenchyma but also in the urinary tract.     

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.     

Spectrum of renal involvement in familial Mediterranean fever.

Kidney biopsies were performed on fifteen patients with a long-standing history of familial Mediterranean fever (FMF) and evidence of renal involvement. On light microscopy, seven patients were found to have amyloidosis, six mesangial proliferative glomerulonephritis (MsPGN) and two patients rapid progressive glomerulonephritis (RPGN). Immunofluorescent studies of the six biopsies with MsPGN were positive for mesangial IgA deposits (IgA nephropathy) in three patients and IgM mesangial deposits in three (IgM nephropathy). We conclude that in patients with FMF and renal involvement, non-amyloid renal lesions (IgA nephropathy, IgM nephropathy and RPGN) should be considered in the differential diagnosis in addition to amyloidosis.     

Strong association between IgA nephropathy and hepatitis B surface antigenemia in endemic areas

The frequency of hepatitis B surface antigen (HBsAg) was studied in the sera of 122 patients with primary IgA nephropathy. Hepatitis B surface (HBs) antigenemia was detected in 21 patients (17.2%) and this was significantly higher than the prevalence of HBsAg carrier in the general population (p less than 0.01). These patients had no clinical or laboratory findings to suggest acute or chronic liver diseases. Two glomerulopathic entities: mesangial proliferative glomerulonephritis with predominant mesangial IgA deposits and a mixed picture of membranous nephropathy with capillary IgG deposits and mesangial proliferative glomerulonephritis with mesangial IgA deposits, were observed in this group of patients. Glomerular deposits of HBsAg, hepatitis B core antigen (HBcAg), and both HBsAg and HBcAg were detected in three, five and four renal biopsy specimens respectively. Replication of hepatitis B virus (HBV) was suggested in two of the six renal biopsy specimens examined by HBV DNA gene probe. During the mean study period of 40 months (range 12-84), 19% of these patients with hepatitis B virus-associated IgA nephropathy developed progressive renal deterioration and one required maintenance dialysis therapy. Our study suggests that hepatitis B virus antigenemia may play a significant pathogenetic role in the development of IgA nephropathy in areas of high HBV endemicity and these HBV-associated IgA nephropathies can run an indolent but relentless slowly progressive clinical course.     

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.     

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。     

Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Schönlein nephritis: association between CD71 expression and IgA deposits

ABSTRACT. IgA nephropathy (IgA-N) that comprises Berger disease and Henoch-Sch?nlein Purpura (HSP) nephritis is defined by mesangial IgA deposits. Recently, this group has characterized a new receptor for IgA, the transferrin receptor (CD71), expressed on mesangial cells. To assess whether CD71 was involved in the pathogenesis of IgA-N, its expression was analyzed together with IgA deposits on 16 kidney biopsies from 16 patients with Berger disease (n = 4) or HSP (n = 12). These biopsies were compared with 17 kidney biopsies of a group of 15 patients (control group) with other glomerulonephritis, including systemic lupus erythematosus, poststreptococcal acute glomerulonephritis, membranoproliferative glomerulonephritis, steroid-sensitive minimal change nephrotic syndrome, steroid-resistant idiopathic nephrotic syndrome with focal and segmental glomerulosclerosis, and persistent and isolated proteinuria with minimal change on kidney biopsy. In this control group, IgA deposits could be observed in eight kidney biopsies of seven patients. These biopsies were also compared with normal kidney specimens (normal group). In normal kidney, it was found that CD71 was linearly expressed on tubular epithelium but was either not expressed or very dimly in glomeruli. In contrast, CD71 was strongly expressed in 105 of the 107 glomeruli of the kidney biopsies from the IgA-N group. For the control group, it was found that expression of CD71 in glomeruli was correlated to the presence of IgA deposits. Indeed, among the 87 glomeruli of nine kidney biopsies (eight patients) without IgA fixation, 78 exhibited no CD71 expression and nine exhibited a very dim one. On the other hand, all 49 glomeruli of the eight kidney biopsies (seven patients) in which IgA deposits were detected exhibited CD71 expression (P < 10(-4)). Performance of dual-labeling studies with confocal microscopy on kidney biopsies of IgA-N patients demonstrated that most of the IgA deposits co-localized with CD71. It was also demonstrated that the intensity of the expression of CD71 was not linked to the intensity of clinical or biologic findings but to the intensity of cellular proliferation in both IgA-N and control groups. These results show that mesangial CD71 expression is not specific to IgA-N. However, the association between IgA deposits and CD71 expression and their co-localization in the mesangium provide strong evidence that CD71 is a major IgA receptor on mesangial cells.     

IgA nephropathy in patients with familial Mediterranean fever

Two patients with a long-standing history of familial Mediterranean fever were found to have both microscopic hematuria and proteinuria during the acute attacks. Kidney biopsies from both patients revealed diffuse mesangial proliferative glomerulonephritis with intense mesangial IgA and C3 deposits and no evidence of amyloidosis. To our knowledge these are the first 2 cases documenting the presence of mesangial IgA nephropathy in patients with familial Mediterranean fever.     

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.     

Glomerulonephritis associated with hepatitis B surface antigenemia. Report of a case with features of both membranous and IgA nephropathy

A 40-year-old man with hepatitis B surface (HBs) antigenemia developed the nephrotic syndrome. Renal biopsy revealed a glomerulonephritis with features of both membranous glomerulonephropathy and IgA nephropathy. Histologically some glomeruli showed mesangial expansion and hypercellularity only, while others contained sclerotic segments. Direct immunofluorescence demonstrated granular IgG-bearing deposits along the peripheral glomerular capillaries and IgA-containing ones in the mesangium. HBs antigen was detected by indirect immunofluorescence both along the glomerular capillary walls and within the mesangium. Granular epimembranous and mesangial deposits were observed by electron microscopy. A few mesangial deposits consisted of spherical particles, 35-100 nm in diameter. Although 3 cases of mixed membranous and IgA nephropathy have been previously reported, this appears to be the first one to be associated with HBs antigenemia.     

Genetic Polymorphism of C3 and Bf in IgA Nephropathy

C3 and Bf alleles were examined in the general population, in67 patients with biopsy-confirmed mesangial IgA nephropathyand 81 patients with other types of glomerulonephritis, fromthe Heidelberg and Leiden renal programmes respectively. In both populations, a significant excess of homozygous phenotypeC3FF (3.4% in controls; 10.4% in IgA nephropathy) and a deficitof C3FS heterozygous phenotype (35.8% in controls; 19.4% inIgA nephropathy) were observed in patients with IgA nephropathy,but not in other types of glomerulonephritis. No differenceof C3 gene frequencies was found. C3FF was associated with anadverse clinical outcome (a higher prevalence of renal failureand hypertension). A significant excess of Bf-F gene frequency was noted (0.20in controls; 0.33 in IgA nephropathy). In addition, an excessof phenotype BfFF was found (none in controls; 10.4% in IgAnephropathy). BfFF homozygotes also carried a higher risk ofan adverse outcome (renal failure and hypertension). The data suggest a role for genetically coded (presumably) immunologicalfactors in the genesis and course of IgA nephropathy.     

Pathogenic IgA in IgA nephropathy: still the blind men and the elephant?

IgA nephropathy (IgAN), the most common glomerulonephritis worldwide, remains an important cause of end-stage renal failure. The pathology is characterized by mesangial deposition of IgA. The disease is now recognized as arising from anomalies of the IgA molecule and the kidneys are innocent bystanders. The immunochemical nature of the IgA molecule and its mesangial uptake command a pivotal role in the pathogenesis of IgAN.     

A pediatric occurrence of crescentic glomerulonephritis associated with antineutrophil cytoplasmic antibodies and mesangial IgA deposits

Antineutrophil cytoplasmic antibody-(ANCA) associated glomerulonephritis usually shows histopathologic features of pauciimmune crescentic glomerulonephritis and occurs late in life. We report a 14-year-old Japanese girl presenting with proteinuria, hematuria and mildly elevated serum creatinine. A renal biopsy specimen demonstrated crescentic glomerulonephritis, immunofluorescence showed mesangial IgA staining. Electron microscopic examination disclosed paramesangial deposits. Serum ANCA against myeloperoxidase (MPO) were detected at high titers. Myeloperoxidase-ANCA-related nephritis accompanied by IgA nephropathy is considered rare in childhood and teen years. Yet, if ANCA assays and detailed electron microscopic examination of renal specimens were performed routinely in patients with rapidly progressive glomerulonephritis, the diagnosis might be more frequent in young patients.