Immunoglobulin A-dominant postinfectious glomerulonephritis: frequent occurrence in nondiabetic patients with Staphylococcus aureus infection

Immunoglobin A-dominant postinfectious glomerulonephritis is a distinct clinicopathologic entity that has been linked to staphylococcal infection, including methicillin-resistant Staphylococcus aureus. An association with diabetic nephropathy has been suggested. Although the morphologic features resemble other forms of postinfectious glomerulonephritis, immunofluorescence shows dominant or codominant immunoglobulin A immune-complex deposits. We encountered 7 patients with immunoglobulin A-dominant postinfectious glomerulonephritis over 2? years at a single center. All patients presented with renal failure and with varying degrees of hematuria, proteinuria, and hypertension. All patients had clinical infections at the time of presentation. Four patients had documented S aureus infections. Three patients had methicillin-resistant S aureus infection within 2 weeks before the renal biopsy; 2 of these had an infection with a community-associated methicillin-resistant S aureus-10 clone, equivalent to USA300. One patient had methicillin-sensitive S aureus infection. Diffuse proliferative endocapillary glomerulonephritis was found in all cases; 1 had a membranoproliferative glomerulonephritic pattern, and 1 patient had a crescentic glomerulonephritis. Immunofluorescence microscopy showed dominant immunoglobulin A subepithelial and mesangial immune complexes in 5 patients and codominant immunoglobulin A with immunoglobulin G in 2 patients. Electron microscopy revealed large subepithelial deposits ("humps") in all cases. Only 1 patient had clinical diabetes mellitus but without biopsy-proven diabetic nephropathy. Two patients died, including the patient with diabetes mellitus. Renal function improved after therapy in 5 nondiabetic patients, but full recovery was not seen during the follow-up. We confirm that immunoglobulin A-dominant postinfectious glomerulonephritis is often associated with S aureus and methicillin-resistant S aureus infections, and, for the first time, we document an association with community-associated methicillin-resistant S aureus.     

IgA dominant post-infectious glomerulonephritis update: pathology spectrum and disease mechanisms

IgA dominant postinfectious glomerulonephritis (PIGN) is a disease of adults, frequently diabetic. While idiopathic IgA commonly presents as a hematuric disease triggered by infection (synpharyngitic IgA for example, occurring 1–2 days after pharyngitis), IgA dominant PIGN typically occurs weeks or months after infection and presents with acute kidney injury, hematuria and proteinuria. Pathologically, the renal biopsy shows variable light microscopic findings ranging from diffuse proliferative glomerulonephritis to mesangial hypercellularity, dominant or co-dominant IgA deposits by immunofluorescence, and frequently but not always, subepithelial “hump”-shaped electron dense deposits. Some cases mimic vasculitis and have positive ANCA serology. The majority of cases are associated with Staphylococcal infections, often methicillin resistant (MRSA). In the last few years, infections other than Staphylococcus were identified as a cause of IgA PIGN leading some authors to use the term “infection related” IgA dominant PIGN. It is the aim of this review to discuss the salient clinical and pathologic features of IgA dominant PIGN and present the disease spectrum based on the recent literature and our own experience. Proposed pathophysiology and diagnostic criteria are discussed.     

血清HBsAg阳性IgA肾病肾组织HBV抗原蛋白及血清和肾组织HBV-DNA检测分析

目的探讨乙型肝炎病毒（HBV）感染与IgA肾病发病的关系。方法32例肾活检冰冻切片组织HBsAg和HBcAg蛋白和42例HBsAg阳性的肾活检石蜡切片组织及其部分血清HBV-DNA的检测。结果HBsAg和HBcAg在IgA肾病肾活检组织的总阳性率为59．1％，在非IgA肾病中的总阳性率为63．6％，二者差异无统计学意义。42例肾活检组织中，仅发现有5例（11．9％）在肾活检组织中有HBV-DNA的存在。且5例均为大三阳患者，其病理诊断为系膜增生性肾小球肾炎2例，轻微肾小球病变1例，基底膜病变1例，IgA肾病仅1例。血清HBsAg阳性的患者，同时进行了42例肾活检组织的血清HBV-DNA检测，其中大三阳患者为12例，其血清HBV-DNA均为阳性，而这12例血清阳性的肾活检组织中仅有5例HBV-DNA为阳性，其余30例血清及肾活检组织中HBV-DNA为阴性。结论HBsAg和HBcAg蛋白在IgA肾病肾活检组织和非IgA肾病肾活检组织表达差异无统计学意义，表明HBV感染与IgA肾病并无直接关系。     

IgA-dominant postinfectious glomerulonephritis: a report of 13 cases with common ultrastructural features

A unique form of postinfectious glomerulonephritis characterized by IgA-dominant immune complex deposits was recently described by Nasr et al (Hum Pathol. 2003;34:1235-1241), each case after a Staphylococcus infection in diabetic patients. Others have described glomerulonephritis with IgA-containing immune complex deposits in association with staphylococcal infections, although their histology was more varied and electron microscopy often did not to show large subepithelial deposits (“humps”) typical of postinfectious glomerulonephritis. In this report, we describe demographic, clinical, and renal biopsy findings in 13 cases of IgA-dominant postinfectious glomerulonephritis, each characterized by subepithelial humps at various stages of resolution. All patients presented with renal insufficiency (mean serum creatinine ± SD, 4.4 ± 2.7 mg/dL), hematuria (macroscopic in 3), and proteinuria (nephrotic range in 6). Based on histology and electron microscopy, postinfectious glomerulonephritis was classified as acute in 2 patients, subacute in 3, and resolving/persistent in 8. There were 6 patients who had recent Staphylococcus aureus infections (3 methicillin resistant), 5 who were diabetic, and 3 with nephropathy. A total of 4 patients (3 with serum creatinine >8.0 mg/dL at biopsy) developed end-stage renal disease, whereas 9 had a mean serum creatinine of 2.0 ± 1.1 mg/dL (range, 0.8-4.4) at 10 ± 13 months (range, 2-44) after biopsy. In summary, IgA-dominant postinfectious glomerulonephritis resembles poststreptococcal glomerulonephritis in its histologic spectrum and electron microscopy findings, is often associated with staphylococcal infections, occurs in diabetics and nondiabetics, and may resolve if renal failure at presentation is not severe.     

GLOMERULONEPHRITIS ASSOCIATED WITH LIVER CIRRHOSIS

The glomerular changes of 50 autopsy cases of liver cirrhosis of different etiologies, such as alcohol abuse, HB virus infection, and nonA–nonB virus infection, were studied by light, immunofluorescence and electron microscopy. The glomerular changes observed were as follows; membranoproliferative glomerulonephritis (MPGN) type 1 (7 cases), mild form or early stage of MPGN type 1 (7 cases), mesangial proliferative glomerulonephritis with sub–endothelial deposits (13 cases), and mesangial proliferative glomerulonephritis without subendothelial deposits (12 cases). These glomerular changes were frequently accompanied by predominant IgA deposition (78% of the immunofluorescence positive cases). Minimal glomerular changes without electron dense deposits were 11 cases, in which IgA was not present in the glomeruli. Thus, glomerulonephritis associated with liver cirrhosis has revealed a]spectrum'of glomerular changes from MPGN type 1 to mesangial proliferative glomerulonephritis with a common feature of predominant IgA deposition, despite various etiological factors of liver cirrhosis, such as alcohol abuse, hepatitis B virus infection, and nonA–nonB virus infection. A pathophysiological condition of liver cirrhosis, e.g. reduced phagocytic activity of the reticuloendothelial system of the cirrhotic liver, Is thought to be a major factor for development of these glomerular changes. The pathogenesis of IgA predominant glomerulonephritis associated with liver cirrhosis may be concerned in the pathogenesis of IgA nephropathy, which still remains to be clarified. ACTA PATHOL. JPN. 33: 333–346, 1983.     

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.     

Urinary tract and renal findings in acute Yersinia infections

We studied 71 patients with acute Yersinia infection for the occurrence of pathologic urinary and renal findings. Transient proteinuria and/or microhematuria was found in 17 patients (24%) and slightly elevated serum creatinine in seven patients (10%). Renal biopsy was done in two patients and revealed mild mesangial glomerulonephritis in both cases. One of these patients had IgA glomerulonephritis and Reiter's syndrome. Pyuria occurred in 16 patients (23%) and was frequently associated with Reiter's syndrome. Seventy-three patients with acute intrinsic renal failure were studied for the occurrence of acute Yersinia infection by determining Yersinia antibodies by ELISA. One out of 13 patients with acute glomerulonephritis but none of 60 patients with acute tubulointerstitial renal disease had acute Yersinia infection. Acute Yersinia infection seems to be rarely an etiologic factor in acute intrinsic renal failure. Our results indicate that transient proteinuria, microhematuria, pyuria or impaired renal function are frequent findings in patients with acute Yersinia infections. However, glomerulonephritis seems to be a rather infrequent and mild complication of acute Yersinia infection.     

IgA Nephropathy

From a series of 470 specimens of renal tissue examined by immunofluorescence microscopy, 20 specimens were identified and studied in detail from patients without evidence of systemic disease in which IgA was the predominant localizing immunoglobulin. All patients presented with hematuria which was recurrent or persistent, often being exacerbated by upper respiratory infection. Most of the group pursued a benign clinical course with little evidence of decline in renal function. Histopathologic changes in renal biopsy specimens of most of the group consisted of a proliferative glomerulonephritis of variable intensity. Characteristic alterations were seen by electron microscopy which included the presence of electron-dense deposits within the mesangium, the hilar regions of the glomerulus and the basement membrane of Bowman's capsule. Evidence for activation of complement by the alternate pathway at C3 was found with properdin localization in 14 of 15 specimens and with the absence of detectable Clq and C4 in 15 specimens studied for these early acting components. It is concluded that the combined clinical, morphologic and immunologic findings warrant consideration of IgA nephropathy as a distinct clinicopathologic entity.     

Idiopathic linear glomerular IgA deposition

Linear deposition of IgA immunoglobulin was found along the glomerular basement membrane in two patients with normal renal function and no pulmonary abnormalities. One patient had recurrent gross hematuria and a mild focal proliferative glomerulonephritis without deposits on electron microscopy; the second patient had a renal cell carcinoma. This observation of linear IgA antibody deposition in the absence of Goodpasture's syndrome or diabetes mellitus extends the spectrum of diseases associated with glomerular basement membrane-IgA deposition.     

Therapy of IgA Nephropathy

IgA nephropathy is the commonest form of glomerulonephritis worldwide, and is one of the major causes of terminal renal failure in most industrialised countries. It is defined by the dominance of IgA mesangial deposits in immunofluorescence studies. Corticosteroid-sensitive nephrosis lipoides (minimal change disease) with IgA deposits and superimposed crescentic glomerulonephritis are to be differentiated from primary IgA nephropathy (Berger's disease). In the latter, clinical manifestations are dominated by synpharyngitic macroscopic haematuria and permanent proteinuria. Terminal renal failure occurs in about 25% of patients after 10 years or more. Heavy proteinuria, hypertension, altered renal function and severe histological lesions at diagnosis are markers of poor prognosis. Primary IgA nephropathy is thought to be related to mesangial deposition of polymeric IgA1-containing immune complexes, owing to altered B cell responses to exogenous and endogenous antigens, together with hyperactivity of T helper type 1 and type 2 cells, both favoured by a genetic background. The 2 compartments of the IgA system (medullary and mucosal) may participate in the pathogenesis of the disease. Modulation of gut-associated lymphoid tissue and immune tonsillectomy are current lines of research. Although impressive results were obtained with an oligoantigenic diet, it is somewhat impractical. Pharmacological modulation of the mucosal immune response seems more promising. There is no proof that phenytoin, a drug which reduces bone marrow IgA synthesis, is beneficial. Emerging data suggest the potential of immune intervention in severely proteinuric patients before sclerotic lesions have occurred, using azathioprine and intravenous immunoglobulins. The benefit of early corticosteroid therapy is still unknown in both adults and children, and the efficiency of alkylating agents is unproven. The search for bacterial foci in primary IgA nephropathy is mandatory, as appropriate treatment may have a protective effect on renal function and help to improve or stabilise some patients. Slowing the progression of renal failure by a combination of ACE inhibitors, fish oil and, possibly, antiplatelet drugs is a promising therapeutic approach.     

Clinical and pathological features in Venezuelan children with IgA nephropathy

IgA nephropathy (IgAN) is the most common glomerulonephritis in humans worldwide; its prevalence and prognosis vary according with geographical areas. The incidence is higher in adults under 30 years of age and in children, it occurs more frequently in patients between 3 and 10 years. Hematuria is the predominant manifestation at presentation of the disease and 20-40% of the cases progress to terminal chronic renal disease. Renal biopsies were performed in 426 children during the period 1980-2002, of them, 12 cases corresponded to IgAN. The clinico-pathological characteristics and evolution of patients were evaluated during an average of 3.85 years. Mean age of patients was 6.2 years, and it was more frequent in males. Hematuria and proteinuria were found in 100% of cases and proteinuria of nephrotic range in 75%. Hypertriglyceridemia and hypercholesterolemia in 91%, arterial hypertension in 50% and acute renal failure at presentation in 25%. The predominant histopathological patterns (WHO) were II and III, deposits of mesangial IgA, IgG and C3 were observed in all cases and C4 deposits in 25%. 41.7% of cases had complete remission, 41.7% maintained normal renal function with persistent proteinuria and 16% progressed to terminal chronic renal failure. The actuarial survival of patients was 100% at 3 years, 87% at 4 years and 76% at 8 years. Two patients died during the period of study, at 3.5 and 8.5 years. The variability of presentation of IgA nephropathy was confirmed in this study, which could be attributable to geographical differences, racial influences and clinicopathological features related to sanitary conditions. Despite of the frequency of bad prognosis characteristics at presentation of IgAN in our series, the evolution was similar to reports of other groups.     

Rheumatoid factor and glomerulonephritis

It is presently unknown whether rheumatoid factors have a pathogenic role in the development of various types of glomerulonephritis with immune deposits. Three isotypes of rheumatoid factors (RFs), which are autoantibodies to IgG, were measured using the solid-phase fluorescence immunoassay in sera from patients with diffuse proliferative lupus nephritis (DPLN), membranous lupus nephritis (MLN), IgA nephropathy (IgAN) and idiopathic membranous nephropathy (MN). RF activity of immunoglobulins deposited in the glomeruli from these patients was also studied by examining the binding of the FITC-conjugated human IgG and Fc portion of IgG to the glomeruli of renal biopsy specimens. IgG, IgA and IgM RFs were significantly increased in sera from patients with DPLN, and the increase was significantly lower in patients with MLN, IgAN and MN. Human IgG bound to immunoglobulin on the glomeruli only in DPLN, but not in MLN, IgAN or MN. The Fc portion of IgG was demonstrated to be involved in this reaction. It was suggested that RFs and IgG may play a major role in immune deposits on the glomeruli in DPLN and may be involved in the development of DPLN; however, this is not likely in MLN, IgAN or MN.     

Single light chain subclass (kappa chain) immunoglobulin deposition in glomerulonephritis

Renal glomerular disease characterized by the deposition of immunoglobulin light chains or monoclonal immunoglobulins was demonstrated by immunofluorescence microscopy in 11 patients. The most common histopathologic findings were those of mesangiocapillary glomerulonephritis, but considerable variability was observed. Lesions resembling diabetic glomerulosclerosis and amyloidosis were seen in some patients. Immunofluorescence findings in seven patients showed concomitant, equally intense staining for kappa light chain and immunoglobulin heavy chain (IgG or IgA), indicative of monoclonal immunoglobulin deposition. Specimens in the remaining cases stained predominantly for kappa light chain alone. In six cases the histologic and ultrastructural pattern was similar to that of type I mesangiocapillary glomerulonephritis. In three cases linear deposits were present, predominantly in subendothelial and inner glomerular basement membranes and, to a lesser degree, in mesangial locations, as in type II mesangiocapillary glomerulonephritis. In one of the latter cases dense deposits were intermixed with aggregates of amorphous fibrillar material indistinguishable from amyloid. In two cases involving IgA kappa chain deposition the histologic and ultrastructural appearance was that of mesangial glomerulonephritis. Considerable heterogeneity was found in the clinical features of the patient population. Specific clinical or serologic parameters for this disease could not be identified. Only one patient had an associated lymphoplasmacytic disorder. After follow-up periods ranging from six months to 17 years, all of the patients were alive, including four who had progressed to end-stage renal disease and required dialysis. Two of the latter patients underwent successful renal transplantation; one had been alive for five years and the other for three months without evidence of recurrence of the renal disease at the last follow-up examination.     

The immunochemical characterization of the light chains in the mesangial IgA deposits in IgA nephropathy

The immunochemical characterization of the light chains of the mesangial immunoglobulin A (IgA) deposits were studied in 45 patients with IgA nephropathy. Kappa and lambda light chains were detected with direct immunofluorescence (IF) method, using monospecific rabbit anti-human anti-kappa and anti-lambda anti-sera. The glomeruli of 42 renal biopsies studied were strongly positive for lambda light chain, while only 25 specimens were positive for kappa light chain. Sixty-five percent of the biopsies showed a predominance of lambda light chain IF staining in the mesangial deposits. This IF pattern is unique as compared with similar studies on renal biopsies from patients with systemic lupus erythematosus, idiopathic membranous nephropathy, and normal postmortem renal tissue. The results indicate that mesangial IgA deposits in IgA nephropathy consist mainly of IgA with lambda light chains despite the fact that the normal ratio of kappa to lambda light-chain-containing immunoglobulin in human serum is two to one.     

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.     

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.     

RENAL GLOMERULAR CHANGES ASSOCIATED WITH LIVER CIRRHOSIS

Renal glomerular changes associated with 79 liver cirrhosis cases were studied by light and electron microscopy, and immunofluorescent methods. The glomerular changes were classified as follows: 1) Mixed membranous and proliferative glomerulonephritis type having subepithelial, subendothelial, mesangial and paramesangial deposits (37 cases), 2) membranous glomerulonephropathy type (6 cases), 3) IgA nephropathy type (3 cases), and 4) glomerulosclerosis type (5 cases). Clinically, the patients with marked renal glomerular changes had proteinuria, hematuria, and retention by the PSP test. It was suggested that the essential renal glomerular changes in liver cirrhosis was immune-complex mediated glomerulonephritis and that glomerular sclerosis was merely a secondary change to glomerulonephritis.     

Mesangiopathic glomerulonephritis in Zuni (New Mexico) Indians

Zuni is a Pueblo Indian village having more than a sixfold greater incidence of nondiabetic end-stage renal disease than the rest of the United States. Renal biopsy specimens from 44 patients with nondiabetic renal disease were subdivided into two groups. In group 1, 21 patients with asymptomatic microscopic hematuria revealed a mild mesangiopathic glomerulonephritis in 18 cases. The predominantly staining immunoglobulin was IgM in ten specimens and IgA in eight specimens. In group 2, 23 patients with symptomatic renal disease presented with nephrotic range proteinuria (11), renal insufficiency (eight), and hypertension (four). A mesangiopathic glomerulonephritis was diagnosed in 16 cases, and in 11 was IgA predominant. Three cases of membranoproliferative glomerulonephritis occurred in group 2. Five cases revealed focal glomerulosclerosis without immune deposits (three in group 1 and two in group 2). More than half (57%) of the patients undergoing biopsy were related. Cases of symptomatic nondiabetic renal disease showed a significant tendency to cluster among the members of four families, suggesting a hereditary influence in the pathogenesis of immune-mediated glomerulonephritis in the Zuni.     

A case of severe IgA nephropthy assocaited with psoriatic arthritis an idopathic interstitial pneumonia

A patient is described with severe IgA nephropathy associated with psoriatic arthritis, idiopathic interstitial pneumonia and brain hemorrhage that developed serially over one and a half years. The histological findings of the renal biopsy showed severe endo-and extracapillary proliferative glomerulonephritis. Massive IgA deposits were observed by immunoflurorescence not only in the mesangium but also along the capillary walls. Electron microscopy revealed abundant electron-dense deposits in the mesangial and subendothelial areas. The overlapping or coexistence of these conditions has rarely been reported.     

显微镜型多血管炎肾活检病例的临床病理分析

目的探讨血清抗中性粒细胞胞质抗体（ANCA）及肾小球内有无免疫球蛋白（Ig）沉积在显微镜型多血管炎（MPA）肾活检病例中的病理诊断价值及其临床病理意义。方法34例MPA均为该系2000年1月至2007年3月7年间的就诊患者,其临床资料比较完整,后经肾穿刺活检而确诊者,分别对其血清ANCA阳性和阴性及肾小球内有无Ig沉积的临床病理特点进行比较。结果34例MPA患者,约1／5—1／2病例伴有各种肾外症状;经血清ANCA检测,阳性者26例（76．5％）;阴性者8例（23．5％）;其尿蛋白多呈轻一中度,呈肾病综合征者仅3例;肾功能减退者32例。经病理检查显示,24例为新月体性肾炎,8例为局灶节段性肾炎,其他类型者仅2例;伴肾血管坏死或内膜炎症7例,内膜增厚24例;伴间质炎性细胞浸润29例,其中21例伴有中性粒细胞浸润。经临床与病理比较分析,发现ANCA阳性组的新月体形成率显著高于ANCA阴性组（P〈0．05）;在26例ANCA阳性组病例中,肾小球Ig沉积者的尿蛋白定量显著高于无Ig沉积组（P〈0．05）,其中1例合并IgA肾病。结论对MPA的诊断有赖于对患者血清ANCA的检测和肾活检组织的病理学检查;ANCA是促进肾小球新月体形成的一个重要因素;Ig在肾小球内的沉积对患者蛋白尿的加重起促进作用。