HYPERSENSITIVITY ANGIITIS WITH GRANULOMATOUS GLOMERULITIS IN A PATIENT WITH PREEXISTING IgA NEPHROPATHY

Following a 6-year history of asymptomatic proteinuria and microhematuria, a 51-year-old man suffered from acute systemic eruption, liver dysfunction and acute renal failure immediately after developing a cold and taking drugs including piroxicam, aspirin and bristocycline. Renal biopsy revealed progressive IgA nephropathy associated with acute tubulointerstitial nephritis and granulomatous glomerulitis. Although the drug actually responsible for this condition was not defined, it is likely that drug-induced hypersensitivity angiitis with granulomatous glomerulitis was superimposed on preexisting IgA nephropathy in this patient. ACTA PATHOL JPN 38: 209–216, 1988.     

Decrease of IgA-specific suppressor T cell activity in patients with IgA nephropathy.

The activity of IgA-specific suppressor T cells was lower in eight patients with IgA nephropathy than in six patients with chronic proliferative glomerulonephritis without glomerular deposition of IgA, two patients with acute glomerulonephritis, or five healthy adult controls. It was determined by the quantitation of immunoglobulins produced from pokeweed mitogen-stimulated B cells cultured with the T cell supernatant (TCS) obtained from concanavalin A-stimulated T cells. Results from a study on an identical twin sister with IgA nephropathy suggested that the decreased activity of IgA-specific suppressor T cells might not be a cause but a result of increased IgA-bearing lymphocytes and serum IgA in patients with IgA nephropathy.     

IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy

Two pathological patterns of acute poststaphylococcal glomerulonephritis are well defined and include (1) an acute proliferative and exudative glomerulonephritis closely resembling classical acute poststreptococcal glomerulonephritis in patients with Staphylococcus aureus infection and (2) a membranoproliferative glomerulonephritis in patients with Staphylococcus epidermidis infection secondary to ventriculovascular shunts. In this study, we report a novel immunopathologic phenotype of immunoglobulin (Ig) A-dominant acute poststaphylococcal glomerulonephritis occurring in patients with underlying diabetic nephropathy. Five patients with type 2 diabetes presented with acute renal failure occurring after culture-positive staphylococcal infection. Renal biopsy disclosed an atypical pattern of acute endocapillary proliferative and exudative glomerulonephritis with intense deposits of IgA as the sole or dominant immunoglobulin, mimicking IgA nephropathy. The deposits were predominantly mesangial in distribution with few subepithelial humps. All five cases occurred superimposed on well-established diabetic nephropathy. Outcome was poor with irreversible renal failure in four of five (80%) cases. The possible pathophysiological basis of this atypical form of acute poststaphylococcal glomerulonephritis in diabetic patients is explored. Proper recognition of this entity is needed to avoid an erroneous diagnosis of IgA nephropathy, with corresponding therapeutic and prognostic implications.     

Immunoglobulin A nephropathy associated with Plasmodium falciparum malaria

Glomerulonephritis occurs as a rare form of renal manifestation in Plasmodium falciparum malaria. Herein, we report a case of falciparum malaria-associated IgA nephropathy for the first time. A 49-yr old male who had been to East Africa was diagnosed with Plasmodium falciparum malaria. Microhematuria and proteinuria along with acute kidney injury developed during the course of the disease. Kidney biopsy showed mesangial proliferation and IgA deposits with tubulointerstitial inflammation. Laboratory tests after recovery from malaria showed disappearance of urinary abnormalities and normalization of kidney function. Our findings suggest that malaria infection might be associated with IgA nephropathy.     

A case of sarcoidosis revealed in the course of IgA nephropathy

A 36 year old man, who had been proteinuric for 14 years due to immunoglobulin A (IgA) nephropathy, was admitted because of an acute exacerbation in renal dysfunction with hypercalcemia. He had presented with aortic regurgitation and increased pulmonary marking by chest X-ray, but laboratory examinations had failed to make an exact diagnosis, On admission, noncaseating epithelioid granulomas were disclosed by muscle and skin biopsies. Ophthalmological evaluation revealed old uveitis and retinal changes conslstent with sarcoidosis. In this case, IgA nephropathy was thought to be the initial manifestation of sarcoidosis that developed latently. Sarcoidosis should be considered in a differential diagnosis of IgA nephropathy.     

Vogt-Koyanagi-Harada syndrome in two patients with immunoglobulin A nephropathy

We describe herein 2 patients who developed Vogt-Koyanagi-Harada syndrome in the course of renal biopsy-proven immunoglobulin A (IgA) nephropathy. A 61-year-old man with an 11-year history of IgA nephropathy and a 16-year history of thyroiditis, and a 56-year-old man with a 5-year history of IgA nephropathy developed Vogt-Koyanagi-Harada syndrome. At the time of the eye disease presentation, IgA nephropathy was stable without corticosteroids in both patients. Vogt-Koyanagi-Harada syndrome was successfully treated with intravenous administration of prednisolone tapered from 200 mg daily. Vogt-Koyanagi-Harada syndrome is associated with IgA nephropathy, suggesting a similar autoimmune mechanism for both diseases.     

Detection of polymeric IgA in glomeruli from patients with IgA nephropathy.

A study on the detection of polymeric IgA in glomeruli from renal biopsy specimens in patients with IgA nephropathy is described. Renal biopsy specimens were obtained from patients with IgA nephropathy. These specimens were stained with FITC-labelled anti-human J chain antisera and then examined with a fluorescent microscope. The J chain was observed in the glomerular mesangium by immunofluorescent staining. In parallel studies, renal biopsy specimens were treated with citrate buffer (pH 3.2) and the 'eluate' was neutralized by sodium hydroxide. The eluate was labelled with iodine-125, and the radiolabelled 'eluate' was fractionated by sucrose density-gradient ultracentrifugation. Polymerized IgA in the 'eluate' obtained from patients with IgA nephropathy was found to sediment predominantly as 9S to 11S using a sucrose density gradient analysis. Polymeric IgA in the fractions of the density gradient analysis was determined by anti-human IgA and anti-human J chain antisera. It was demonstrated that IgA and J chain were eluted from the glomeruli in some patients with IgA nephropathy. It is concluded that IgA deposited in the glomeruli is composed of dimers and/or larger polymers of circulating IgA in some patients with IgA nephropathy.     

Increase of IgA-specific switch T cells in patients with IgA nephropathy.

Enumeration and functional analysis of CD4+ T cells with receptors for the Fc portion of IgA (i.e. T alpha 4 cells) in the peripheral blood of patients with IgA nephropathy, their relatives and age-matched controls were performed to elucidate polyclonal activation of IgA production in this disease. Enumeration of T alpha 4 cells was performed by a fluorescence activated cell sorter, and functional analysis was carried out by separation of T alpha 4 cells, and IgM-, IgA- and IgG-bearing lymphocytes using panning methods followed by cultures of these cells for 7 days with pokeweed mitogen. There was a significant increase in the amount of peripheral blood T alpha 4 cells in patients with IgA nephropathy and their relatives. T alpha 4 cells specifically enhanced the switch of IgM-bearing cells to IgA-bearing cells, and this switch activity was inhibited by addition of human myeloma IgA. It is suggested that T alpha 4 cells may be responsible for polyclonal activation of IgA production in IgA nephropathy.     

不同性别IgA肾病患者相关临床指标及病理特点对比

目的 通过对不同性别IgA肾病患者临床指标及病理特点的对比,了解性别间相关指标的差异,为临床积极有效的治疗该病提供依据。方法 回顾性分析2017年1月1日~2018年8月30日我院经肾穿刺活检确诊的361例IgA肾病患者的临床资料,比较不同性别IgA肾病患者的临床资料、危险度分级、病理分级及免疫荧光分型。结果 不同性别IgA肾病患者年龄、病程、舒张压、水肿、血尿、蛋白尿、血尿+蛋白尿、白蛋白、IgA、IgG、IgM、IgE、C3、C4、IgA/C3、肾小球滤过率、血钾、血钙、血磷、APTT、PT、FIB、左肾及右肾大小比较,差异无统计学意义（P＞0.05）;男性收缩压、血压高、肾功异常占比、胱抑素、肌酐、尿素、尿酸、甘油三脂、胆固醇、血钠、尿蛋白定量高于女性,差异有统计学意义（P＜0.05）。不同性别IgA肾病患者在1~3级占比比较,差异无统计学意义（P＞0.05）;男性IgA肾病患者在4级占比多于女性,差异有统计学意义（P＜0.05）。不同性别IgA肾病患者病理分级比较,差异无统计学意义（P＞0.05）。不同性别IgA肾病患者在IgA+IgM+C3、IgA+IgM+IgG、IgA+IgM+IlgG+C3占比比较,差异无统计学意义（P＞0.05）;男性IgA肾病患者在IgA+IgG+C3、IgA+C3分型中占比多于女性,差异有统计学意义（P＜0.05）。结论 男性IgA肾病的发病人数多于女性,且在IgA肾病中,男性的肾功能较女性差,推测其预后可能较差,因此当男性确诊为IgA肾病后,应更加关注其临床指标及病理相关指标,及早干预、及早治疗,制定合理地个性化治疗方案,延缓其进展。     

Acquired glomerular lesions in patients with Down syndrome

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.     

Detection of immunoglobulins and other serum proteins in the dermal and glomerular capillary walls from patients with diabetes mellitus

Deposition of immunoglobulins or acute phase reactant (APR) proteins in the dermal and glomerular capillary walls from patients with diabetes mellitus was examined to determine whether development of microangiopathy in such patients was related to exudation and/or entrapment of these proteins. Skin and renal biopsy specimens were obtained from patients with diabetic nephropathy and diabetes mellitus without nephropathy. These biopsy samples were stained with FITC-labeled anti-human IgG, IgA, IgM, C3, APR proteins, and beta-lipoprotein antisera. Linear depositions of IgA, IgG, and/or APR proteins were observed in the dermal and/or glomerular capillary walls from some patients with diabetic nephropathy or diabetes mellitus without nephropathy. It is indicated that deposition of such immunoglobulins in the dermal and glomerular capillary walls might be due to exudation and/or entrapment of these substances in patients with diabetes mellitus.     

Increase of Peripheral Blood B Cells with Fc Receptor for IgA in Patients with IgA Nephropathy

A B-cell subset with Fc receptors for IgA (B alpha cells) has been observed in human peripheral blood. To investigate aberrations of B cells in a diseased state, the percentages of B alpha cells were enumerated in peripheral blood from patients with IgA nephropathy, which is characterized by preponderant deposition of IgA-dominant immune complexes in the glomerular mesangial area. The present study showed a significant increase in B alpha cells in peripheral blood from patients with IgA nephropathy but not in those with chronic proliferative glomerulonephritis without mesangial IgA deposition. Most Fc alpha R-bearing cells were observed in surface IgA bearing lymphocytes. No linear correlation was observed between the levels of serum IgA and the percentages of B alpha cells. The addition of aggregated IgA to cultures did not induce Fc alpha R-bearing B cells in vitro. It is postulated that B alpha cells might have some pathogenetic role in the development of IgA nephropathy and that some antigenic stimuli might play a role in the increase of peripheral blood B alpha cells in patients with IgA nephropathy.     

IgA nephropathy with subendothelial deposits

Summary IgA nephropathy with subendothelial deposits in the capillary walls of the glomeruli (IgA type 2) was compared histometrically and clinically with IgA nephropathy without subendothelial deposits (IgA type 1) and membranoproliferative glomerulonephritis with subendothelial deposits (MPGN). Study cases consisted of 32 biopsies from 26 patients of IgA type 1, 25 biopsies from 20 patients of IgA type 2 and 31 biopsies from 27 patients of MPGN. Histological changes of the glomeruli consisted of an increase in the mesangial matrix and hypercellularity in the mesangium in both types of IgA nephropathy, and the degree of the changes was a little higher in IgA type 2 than in IgA type 1 (0.02<P<0.05). Mesangial changes of MPGN were marked as compared with IgA type 1 and IgA type 2 (P< 0.001). Histometry of the mesangium on the cases followed up showed that the degree of mesangial thickening increased with lapse of time in IgA type 2 and MPGN, whereas it remained unchanged up to 13 years in IgA type 1. Proteinuria tended to be mild in IgA type 1, moderate in IgA type 2, and marked in MPGN. The impairment of renal function was observed in 21.9% of IgA type 1, in 36.0% of IgA type 2 and in 58.1% of MPGN. IgA type 2 has been shown to be pathologically and clinically intermediate between IgA type 1 and MPGN. These results suggest that there is a clinicopathological overlap between IgA nephropathy and MPGN with IgA deposition.     

Cross-reactivity of IgA antibodies between renal mesangial areas and nuclei of tonsillar cells in patients with IgA nephropathy.

A study on autoradiographical analysis of antigenic sites in patients with IgA nephropathy is described. Renal biopsy specimens were obtained from patients with IgA nephropathy. These specimens were treated with citrate buffer (pH 3.2) and the 'eluate' was neutralized by sodium hydroxide. The 'eluate' was labelled with 125iodine by the chloramine-T method. 125I-labelled eluate was then applied to the tonsillar cells obtained from the same and other patients with IgA nephropathy as well as to those with other glomerular diseases. The tonsillar cells were dipped into the emulsion (NBT-2) and then examined with a light microscope. It was demonstrated that the antibodies eluted from renal tissues of patients with IgA nephropathy specificially bound with the nuclear regions of tonsillar cells. The binding of eluted antibodies and tonsillar cells was completely inhibited by the addition of anti-human IgA antisera, but not inhibited by human IgA myeloma proteins. The eluted antibodies bound with tonsillar cells from the same patients, but only 10% of them bound with the tonsillar cells obtained from other patients with IgA nephropathy. It is concluded that IgA antibodies deposited in glomeruli specifically bind with tonsillar cells obtained from patients with IgA nephropathy and these antibodies show some heterogeneity among those patients.     

Stimulation of neutrophil apoptosis by immobilized IgA

In the current study, we analyzed whether immunoglobulin A (IgA) is able to modulate neutrophil apoptosis. We found that culture of neutrophils on immobilized plasma IgA (iIgAp) or secretory IgA (iIgAs) induced a marked increase in apoptotic rates. By contrast, soluble IgAp, IgAs, or aggregated IgAp exerted no effect. Promotion of apoptosis by iIgA was almost completely prevented by blocking antibodies directed to CD18 or CD11b and was shown to be dependent on the activation of the respiratory burst as suggested by the ability of catalase to prevent apoptosis stimulation; the effect of azide, an heme enzyme inhibitor that significantly increased promotion of apoptosis by iIgA; and the inability of iIgA to stimulate apoptosis of neutrophils isolated from chronic granulomatous disease patients. Stimulation of neutrophil apoptosis by IgA might contribute to the control of inflammatory processes in certain autoimmune diseases such as IgA nephropathy in which tissue deposits of IgA or IgA containing immune complexes are found.     

Cold reacting anti-nuclear factor (ANF) in families of patients with IgA nephropathy.

The emergence of cold reacting anti-nuclear factor (ANF) in families of patients with IgA nephropathy was examined to determine whether some immunological alterations among family members affect the development of this disease. The procedure for the detection of the cold reacting ANF was reported previously. Fifty-five per cent of sera from 66 relatives of IgA nephropathy 24 patients was found to have the IgM cold reacting antibody. The incidence of ANF in healthy adults was 3%. Both household and non-household consanguineous relatives showed antibody in their sera. Sixty-five per cent of consanguineous relatives who had close household contacts with IgA nephropathy patients showed cold reacting ANF, whereas only 10% of non-consanguineous relatives who had close household contact had this antibody. It is suggested that familial susceptibility or genetic factors, in addition to environmental factors, may be responsible in the development of IgA nephropathy.     

IgA-associated glomerulonephritides: a study with monoclonal antibodies

Thirty-six renal biopsies from patients with various glomerulonephritides which exhibited prominent IgA deposits were studied by indirect immunofluorescence technique utilizing monoclonal antibodies specific for alpha chain (IgA), IgA1 and IgA2 subclasses, secretory IgA, and secretory component. The ability of the IgA deposits to bind free secretory component in vitro was examined in five biopsies of IgA nephropathy of Berger and in five biopsies of lupus nephritis. All the biopsies revealed IgA1 deposits. Associated IgA2 was found in lupus nephritides and hepatic glomerulopathy. Secretory IgA and free secretory component were not detected in any biopsy. In situ free secretory component binding was demonstrated in IgA nephropathy of Berger but not in lupus nephritides. These results indicate that polymeric IgA1 molecules are the chief nephritogenic antibodies in IgA nephropathy of Berger, that there is a high frequency of association of IgA1 and IgA2 in lupus nephritides and, perhaps, hepatic glomerulopathy, and that secretory IgA does not appear to play a role in IgA-associated glomerulonephritis.     

Chronic granulomatous disease as a risk factor for autoimmune disease

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune disorders. In this report, we describe antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease have important treatment implications for patients with CGD.     

Lysis of the glomerular basement membrane in children with IgA nephropathy and Henoch-Shönlein nephritis

An electron-microscopic study of the glomerular basement membrane was made on 242 renal biopsies from 222 children with a variety of renal diseases. Lysis of the basement membrane was observed in 16 of the 25 children with Henoch-Sch?nlein nephritis, 36 of the 72 with IgA nephropathy and one with acute poststreptococcal glomerulonephritis. Lysis was frequently associated with subepithelial dense deposits and polymorphonuclear leukocytes, and these are thought to play a role in the lytic process. There was a significant correlation between the presence of lysis of the basement membrane, the degree of proteinuria and the severity of glomerular changes by light microscopy. These findings suggest that the degree of lysis is an indication of the severity of the disease and lysis is associated with progressive disease and a worse prognosis in Henoch-Sch?nlein nephritis and IgA nephropathy.     

IgA nephropathy associated with chronic hepatitis B virus infection in adults: the pathogenetic role of HBsAG

Five adult cases of IgA nephropathy associated with chronic hepatitis B virus infection were studied. Serum HBsAg and anti-HBc were present in five patients and HBeAg in four patients. Glomerular changes were typical of primary IgA nephropathy in four patients, and a mixed picture of IgA and membranous nephropathy was demonstrated in one patient. Immunofluorescence microscopy using polyclonal and monoclonal antibodies against HBsAg, HBcAg, and HBeAg revealed mesangial deposits of HBsAg in renal biopsies from four patients. One renal biopsy showed only mesangial and capillary HBcAg by polyclonal antiserum, and virus-like particles were demonstrated in the intramembranous electron-dense deposits on ultrastructural examination. Mesangial HBeAg was not detected in the renal biopsies from these patients with IgA nephropathy. As for the single patient with a mixed picture of IgA and membranous nephropathy, granular deposits of HBeAg with a distribution similar to IgG were detected in the glomerular capillary walls in addition to the mesangial deposition of HBsAg. These findings suggest that HBsAg rather than HBeAg may play a role of the pathogenesis in some of the adult patients with IgA nephropathy associated with chronic hepatitis B virus infection.