Morphology of IgA nephritis (Berger disease). Immunohistologic, light- and electron microscopic findings

An IgA nephritis was diagnosed in 109 (24%) out of 445 renal biopsies with glomerular disease in the years from 1977 to 1985. The mean age of the patients in question was 29 years. The male:female sex ratio was 2.6:1. Immunohistologically, the characteristic branching mesangial IgA deposits were uniformly present. In addition 96% showed mesangial C3 and 54% mesangial IgG and/or IgM deposits. Besides, immunoglobulin and/or C3 deposits could be detected at glomerular basement membranes (20%). The histological types of IgA nephritis were minor glomerular abnormalities (10%), focal/segmental glomerulonephritis (29%), diffuse mesangioproliferative (58%), membranoproliferative (1 case), and sclerosing glomerulonephritis (2 cases). Additional tubulointerstitial lesions were found in 55%. Electron microscopically, in 53 cases under study, mesangial electron dense immunodeposits were seen. At the glomerular basement membranes, deposits could be found only in 23 examined cases (43%). The comparison of clinical data with morphological findings showed relationships between the degree of proteinuria and creatinine level increase with the histological type of IgA nephritis and with the degree of glomerular sclerosis, tubulointerstitial lesions, and electron microscopically proved glomerular basement membrane deposits. Hematuria seemed not to correlate with the morphological picture.     

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.     

Clinical, light, and electron microscopy findings in idiopathic haematuria

The electron microscopic findings are reported in detail in 20 patients submitted to renal biopsy with the major complaint or clinical finding of gross or microscopic haematuria. The lesions were classified histologically into four groups: group 1, minor glomerular alterations; group 2, focal mesangial thickening and/or cellular proliferation; group 3, diffuse mesangial proliferation; and group 4, other lesions. The major ultrastructural alterations included irregularity in thickness and density of the capillary basement membrane, with apparent discontinuity and bi- or multilaminar splitting of the lamina densa. There were varying degrees of foot process fusion, visceral epithelial polykaryocytosis, and granular deposits related to the capillary basement membrane. Densities were found in the mesangial basement membrane-like material, which was often markedly increased in quantity. A few microtubular aggregates were observed in endothelial cell cytoplasm. Changes consistent with acute diffuse proliferative and membrano-proliferative glomerulonephritis were also seen. The significant clinical findings, histological groups, and ultrastructural changes are correlated.     

Immunoglobulin and complement deposition in glomeruli of 756 subjects who had committed suicide or met with a violent death.

AIMS--To study immune deposits in renal glomeruli. METHODS--Tissue was obtained from 756 necropsy cases from people who had committed suicide or met with a violent death. Glomerular immune deposits were examined by immunofluorescence microscopy and a light microscopy. The clinical histories of all the decreased were studied to ascertain reasons for the deposits. RESULTS--Immune deposits were found in glomeruli in 91 (12%) cases. In 52 (6.8%) cases mesangial IgA was observed as a solitary finding in 34 (4.5%), and was accompanied by other immunoglobulins in 18 (2.4%). Mesangial IgM was present in 19 (2.5%) and IgG in 11 cases (1.5%). Two cases had capillary IgG (0.3%). Light microscopic examination showed mesangial enlargement in eight of the cases with mesangial IgA. These included one with IgA glomerulonephritis diagnosed before death. Two cases with normal glomerular morphology and mesangial IgA deposits had clinical laboratory evidence of renal disease. In two subjects with normal glomerular morphology, mesangial IgM and microscopic haematuria were present. In one case with capillary IgG membranous glomerulonephritis was detected. CONCLUSIONS--Ten cases had mesangial IgA together with morphological or clinical laboratory findings suggestive of renal disease. If all these are regarded as IgA glomerulonephritis, then its prevalence can be estimated at 1.3%. For IgM glomerulonephritis, a prevalence of 0.3% was deduced.     

Grading of acute and chronic renal lesions in Henoch-Sch?nlein purpura.

The renal outcome of 34 patients with Henoch-Sch?nlein purpura nephritis was assessed clinically and by grading acute and chronic renal lesions using a system we applied to primary IgA nephropathy. On a median follow-up period of 65 months, hypertension and the serum levels of creatinine and proteinuria at the time of renal biopsy were correlated with renal survival. Acute glomerular lesions including mesangial hypercellularity, endocapillary proliferation, necrosis, cellular crescents, and leukocytes infiltration were observed, respectively, in 41%, 12%, 50%, 29%, and 32% of the cases. Of these, only glomerular necrotizing lesion and cellular crescent were correlated with the renal survival. Chronic renal lesions based on a grading system applied to primary IgA nephropathy and assessing the extent of glomerular sclerosis (glomerular grading), of tubular loss and interstitial fibrosis (tubulointerstitial grading), and of hyaline arteriolosclerosis demonstrated correlation between these lesions, as well as with renal survival. On follow-up, these chronic renal lesions were predictors of subsequent clinical events associated with disease progression, such as impaired renal function, significant proteinuria, and development of hypertension. Despite some limitations related to the relatively small size, this series indicates that distinction of acute and chronic lesions of Henoch-Schonlein purpura nephritis is important for both the prognosis and management of patients.     

Glomerulonephritis in congenital cytomegalic inclusion disease

Except for renal transplant recipients, glomerulonephritis has only very rarely been associated with renal cytomegalovirus (CMV) infection. The kidneys of five infants with congenital cytomegalic inclusion disease, including renal infection, were examined at autopsy. Two of the infants had glomerulonephritis. The younger, a 4-month-old female, had diffuse proliferative and necrotizing glomerulonephritis; virus was present in nuclei and cytoplasm of glomerular endothelial cells and, possibly, in leukocytes as well. There were no electron-dense deposits. The other infant, a 5-month-old male, had diffuse mesangial and focal segmental proliferative and sclerosing glomerulonephritis; electron-dense mesangial deposits were seen ultrastructurally. Three additional infants (a newborn male, a 2-day-old male, a 6-week-old female), all with CMV in tubules and one with a single glomerular inclusion, had only rare glomerular abnormalities, i.e., mesangial proliferation in less than 10 per cent of glomeruli (one infant) and segmental sclerosis in less than 1 per cent of glomeruli (all three infants). Thus, congenital renal CMV infection was associated with proliferative glomerulonephritis in the two infants who survived the longest. The three with shorter survival times had only minor glomerular alterations.     

Transforming growth factor-beta receptors in self-limited vs. chronic progressive nephritis in rats

Increases in transforming growth factor-beta (TGF-beta) expression and extracellular matrix accumulation are transient in acute self-limited mesangial proliferative glomerulonephritis induced by a single injection of anti-thymocyte serum (ATS), while these increases persist following repeated injections that produce chronic progressive sclerosing glomerulonephritis with tubulointerstitial lesions. However, little is known about the expression of TGF-beta receptors (TbetaRs) in cells involved in the proliferative and sclerosing renal lesions. A study of protein and mRNA expression for type I (TbetaRI), type II (TbetaRII), and type III (TbetaRIII) TbetaR in both forms of nephritis was therefore carried out by immunohistochemistry and in situ hybridization. Inhibition of cell proliferation and stimulation of matrix production by TGF-beta1 were assessed in isolated glomeruli using [(3)H]thymidine incorporation and [(3)H]proline metabolic labelling, respectively. In acute self-limited nephritis, expression of TbetaRI, TbetaRII, and TbetaRIII increased in the glomerular and Bowman's capsular epithelial cells comprising the glomerular tuft adhesions to Bowman's capsules. However, TbetaRII expression was not prominent in proliferating mesangial cells. Glomeruli isolated from rats with acute self-limited nephritis at day 7, when mesangial cell proliferation was maximal, were partially resistant to the mitoinhibitory effects of TGF-beta1. In contrast, expression of all three TbetaRs was elevated in glomerular and tubulointerstitial lesions in chronic progressive nephritis, and glomeruli isolated from rats with chronic progressive nephritis 7 days after the second ATS injection were sensitive to TGF-beta1. These data suggest that distinct cellular responses to TGF-beta1 resulting from differential expression of TbetaR underlie the difference between acute self-limited mesangial proliferative and chronic progressive sclerosing ATS nephritis in the development of proliferative and sclerotic renal lesions.     

Heterogeneous IgA glomerulonephropathy in liver cirrhosis

Kidney and liver sections were obtained from 75 consecutive autopsy cases with liver cirrhosis discovered at post-mortem. Mesangial IgA as the predominant immunoglobulin was found in 36% (27) cases, with accompanying IgM in 10, and IgG in three subjects. IgA deposits occurred more frequently in micronodular cirrhosis than in macronodular and mixed types. There was no direct correlation with alcoholism or HBs antigen-orcein positivity in livers. The IgA antigen-antibody complexes formed against infectious and/or dietary antigens may bypass the liver phagocytic system via collateral shunts and cause the mesangial IgA deposits. IgA-bearing plasma cells in the liver (80%) may also contribute to the deposits. In cases of liver cirrhosis, there was a variable glomerular morphology including normal appearance by light microscopy (32%), minor changes (38.7%), diffuse mesangial sclerosis (12%), diffuse mesangial cell proliferation, and infrequently membranous and diffuse proliferative glomerulonephritis with a 'lobular pattern'. Five (6.7%) cases showed focal and segmental mesangiolysis with glomerular aneurysms, probably caused by toxic and/or infective agents bypassing the liver reticuloendothelial phagocytic system and acting on the mesangium to cause rupture of anchor points and formation of capillary aneurysms. The cirrhotic glomerulonephropathy was usually clinically latent, but two biopsy cases with mesangiocapillary glomerulonephritis had developed a nephrotic syndrome.     

PROTO-ONCOGENE EXPRESSION IN HUMAN GLOMERULAR DISEASES

The expression of the protein products and mRNA of c- fos , c- myc , p53, and c- raf was examined in normal renal tissues and biopsy specimens from 73 patients with various glomerular diseases. Immunofluorescent staining showed that there were cell nuclei stained for c-Fos, c-Myc, and p53, and cytoplasm positive for c-Raf, in the glomeruli of patients with proliferative types of glomerulonephritis, including IgA nephritis and lupus nephritis, and in patients with focal glomerular sclerosis. Glomerular expression of c- fos and c- myc mRNA was detected by in situ hybridization. The number of proto-oncogene-positive glomerular cells was significantly higher in lupus nephritis, IgA nephritis, and focal segmental sclerosis, as compared with minimal change nephrotic syndrome and normal specimens. In IgA nephritis, the population of glomerular cells positive for c-Fos and c-Myc and the grade of c-Raf immunoreactivity were significantly correlated with the proportion of proliferating cell nuclear antigen (PCNA)-positive glomerular cells, with histological grading of mesangial hypercellularity and matrix increase, and with the magnitude of proteinuria. These data indicate that proto-oncogene expression is associated with mesangial proliferation and matrix expansion in proliferative types of glomerulonephritis and in focal glomerular sclerosis.     

Treponemal antigen in immunopathogenesis of syphilitic glomerulonephritis.

A patient with syphilitic glomerulonephritis had a renal biopsy and was treated for secondary syphilis. Light, electron, and immunofluorescence microscopic studies revealed an acute proliferative glomerulonephritis with subepithelial, intramembranous, and subendothelial immune complex deposits containing IgG, IgA, IgM, C4, and C3. Similar local deposits containing predominantly IgM were noted in areas of mesangial proliferation. Indirect fluorescent antibody studies employing rabbit treponemal antibody and sheep antirabbit globulin conjugate revealed the presence of treponemal antigen in the glomerular deposits. This finding provides strong evidence for the immunopathogenesis of the glomerular lesion as well as a causal link with Treponema pallidum.     

Renal lesions in AIDS: a biopsy and autopsy study.

We studied renal lesions at biopsy (20 cases) and at autopsy (21 cases) among patients with the acquired immune deficiency syndrome (AIDS). Nephrotic syndrome with concomitant renal insufficiency was most common indication for biopsy. 85 percent of biopsies showed features of HIV associated nephropathy (HIVAN) which include: Focal segmental glomerulosclerosis (FSGS), glomerular collapse and mesangial hyperplasia. These glomerular changes were always accompanied by tubular microcysts and ultrastructurally, tubuloreticular inclusions (TRI) within the glomerular endothelium were often noted. Changes of HIVAN were also seen in two cases who were HIV negative at the time of biopsy but were positive on repeat testing. Minimal change disease, mesangiocapillary glomerulonephritis and diffuse proliferative lupus nephritis were other biopsy lesions. Autopsy findings were HIVAN (33 percent), tubular necrosis and opportunistic infections. We conclude that HIVAN is a distinct clinicopathologic entity that may sometimes be the first manifestation of the underlying disease state.     

Morphometric studies on numerical area density of glomerular cells (nuclear section) in the pathogenetic evaluation of minimal glomerular abnormalities

Minor glomerular abnormalities (MGA) with hypercellularity (according to the WHO-nomenclature) are one of the most frequent glomerular lesions. Minimal proliferative changes in the glomerular structure can be proven only with the aid of morphometric methods. Morphometric glomerular studies were carried out in MGA with hypercellularity and with rare or minor deposits of immunoglobulins and/or complement (C3) or without deposits. Clinical symptomatology was variable (minimal to mild proteinuria, massive proteinuria, haematuria or haematuria with proteinuria). The groups examined were divided as follows: MGA without deposits and with minimal (mild) proteinuria. MGA with minor deposits and with minimal (mild) proteinuria. These two groups were statistically compared with: normal glomerular structure (after Wehner 1974); MGA with massive proteinuria or nephrotic syndrome (includes the minimal changes with nephrotic syndrome), which showed minor deposits of complement; diffuse mesangial proliferative glomerulonephritis (IgA-nephritis). The glomerular cell density, i.e. the total number of glomerular cells, averaged 3.48 cells/1,000 micron 2 in the first group and 4.26 cells/1,000 micron 2 in the second group. In normal renal corpuscles the average was 2.30 cells/1,000 micron 2. The first group has an average of 51% and the second group has an average of 84% higher cell density than normal renal corpuscles. The cell density in diffuse mesangial proliferative glomerulonephritis (IgA-nephritis) is increased by 160% compared with the norm. The first group was not statistically different in cell density from MGA with high proteinuria. We conclude, that MGA with hypercellularity and minimal to mild proteinuria represents a minimal mesangial proliferative glomerulonephritis.     

IgA dominant post-infectious glomerulonephritis: pathology and insights into disease mechanisms

IgA dominant post-infectious glomerulonephritis is a relatively recently described entity that typically presents with acute kidney injury, haematuria and proteinuria. Pathologically, the renal biopsy shows variable light microscopic findings ranging from mesangial hypercellularity to diffuse proliferative glomerulonephritis, but characteristic dominant or co-dominant IgA deposits by immunofluorescence, and subepithelial “hump”-shaped electron dense deposits. The majority of cases are associated with Staphylococcal infections. It is the aim of this review to discuss the salient clinical and pathologic features of IgA dominant post-infectious glomerulonephritis based on our own experience and review of the literature. Diagnostic criteria and pathophysiologic disease mechanisms are discussed.     

Contribution on the correlation between morphometric parameters gained from the renal cortex and renal function in IgA nephritis

The following findings were obtained in a comparative morphometric and clinical study of 130 adult men and women with immunologically confirmed IgA nephritis: (a) IgA nephritis develops in varying frequency as minimal proliferating intercapillary glomerulonephritis, low-grade mesangioproliferative glomerulonephritis, moderate to severe mesangioproliferative glomerulonephritis, or variously severe mesangioproliferative glomerulonephritis with signs of focal accentuation. (b) Tubular epithelial surface area and interstitial width in 62 of 130 cases of IgA nephritis was the same as in normal kidneys. IgA nephritis was complicated in 33 cases by interstitial cortical fibrosis, in 23 cases by acute renal failure, and in 12 cases by acute renal failure and interstitial fibrosis. (c) In IgA nephritis with acute renal failure, the tubular epithelium (only proximal tubular epithelium was measured) was significantly swollen. In IgA nephritis with interstitial fibrosis, the epithelial surface area of the proximal tubules was significantly smaller than the normal surface area. In IgA nephritis with acute renal failure (ARF) and interstitial fibrosis, tubular swelling was less severe than in ARF. Proximal tubular epithelial surface area, however, was significantly larger than the normal surface area. (d) In IgA nephritis, like in other inflammatory and noninflammatory glomerular diseases, a significant positive correlation existed between width of the cortical interstitium and height of serum creatinine level. Moreover, in IgA nephritis, significantly negative correlation existed between width of the cortical interstitium and C creatinine. (e) In IgA nephritis, significant negative correlations existed between C creatinine and age. (f) In IgA nephritis, a significant correlation existed between proximal tubular epithelial surface area and serum creatinine level and a significant negative correlation, between C creatinine and proximal tubular epithelial surface area, when ARF cases were excluded from the total group of IgA nephritis. (All correlations are closer when the cases with accompanying ARF are eliminated.) The discrepancy between the findings of Bennett et al. (Bennett WM, Walker RG, Kincaid-Smith P: Lab Invest 47:330, 1982) and ours is clarified when it is presumed that the group of patients investigated by Bennett et al. (N = 85) included just as many ARF cases as our material. Consequently, there is no reason to correct our interpretation of the influence of tubulointerstitial changes on glomerular function.     

Occurrence of mesangial IgA and IgM deposits in a control necropsy population

Kidney sections were obtained from 200 consecutive control necropsies of patients who died of traumatic injuries, with no clinical history of renal disease or other organic disease discovered at necropsy. Mesangial IgA as the predominant immunoglobulin was found in 8/200 (4%) cases, with accompanying IgM in two of them; and IgM alone in two (1%) subjects. Deposits of C3 alone in blood vessels was observed in nine (4.5%) cases. The glomerular morphology was essentially normal or minor change only, with one case showing diffuse mesangial hypercellularity. The high incidence of mesangial IgA deposits in the local apparently healthy population may reflect some common feature of the antigen(s) or complex involved. They may be of environmental, dietary or infectious origin. It is possible that many of these "spontaneous" deposits in the glomerular mesangium may result from the clearance of circulating non-nephritogenic immune complexes.     

IgA nephropathy--accumulated experience and current concepts

Primary IgA nephropathy is the most common form of glomerulonephritis in Australia. The condition presents in a variety of ways, but commonly with synpharyngitic hematuria, most often in young men in the third and fourth decades. The course of the disease is indolent but there is progression to renal failure in up to one quarter of cases. Renal biopsy morphology is variable but the essential immunofluorescence finding is diffuse mesangial IgA staining of greater intensity but often in association with other immunoglobulins. C3 is usually also present. Mesangial cellularity is increased in some two-thirds of cases, one third being of a minor focal or variable extent and one-third diffuse. Focal segmental lesions, hyaline nodules and vascular changes are frequent. Crescents are also often present. The etiology of the disease is uncertain but has been linked with HLA antigens, elevated serum IgA levels, IgA polymers, immune complexes and impaired T cell function. Secondary forms of mesangial IgA deposition occur with mucosal defects, hyperglobulinemia or impaired hepatobiliary clearance, and these may offer some insight into the immunopathogenesis of the primary disease.     

Histological grading and staging of IgA nephropathy

More than 25 years have passed since immunoglobulln A (IgA) nephropathy was introduced as a disease entity inde pendent of glomerulonephritis. it has been known that more than 30% of cases have gona into end-stage renal fallure within 20 years, indicating the presence of a chornic active group in this disease. Histologicaily this disesase is com posed of at least three types of tissue damage:(1) minimal inflammation including deposition of IgA-containing sub stances with minor matriclal increase; (II) acute lesions char acterized by matricial damsge of glomerular basement membrane (membranolysis) and/or mesangial matrix (mes anglolysis) with inflammstory cell accumulation and/or intrinsic cell proliferation; and (III) chronic lesions mainly composed of postinfiammstory sclerosis. The progression is actually accelerated by the frequency of acute lesions, resuiting in increased glomerular scierosis focl. In such a situation, the histologic grading and stagi (G-S)system is proposed, with the aim of having a more preclse understanding of the disease prosses. The histological grade (G) is estimated by the extent of acute giomerular and tubulointer stitial lesions, and the stage (S) is evaluated by the increase of extracellular matrices of the glomerull and inerstitial fibrosis. The evaluation of G and S is expressed semiquanti tativety for more helpful clinical use.     

Pattern of glomerulonephritis in Hong Kong

A retrospective analysis of all renal biopsies (961) performed in two regional hospitals in Hong Kong during 1977-1985 revealed that IgA nephropathy was the most frequently encountered glomerulopathy. Lipoid nephrosis (minimal change nephrotic syndrome) remained the commonest cause of nephrotic syndrome in children. The frequencies of mesangiocapillary glomerulonephritis, focal glomerulosclerosis, and idiopathic membranous nephropathy were lower than in other populations. Membranous nephropathy was frequently associated with hepatitis B virus antigenemia, especially in children. Other chronic infections did not have a significant pathogenetic role in glomerular diseases. Lupus nephritis was the commonest secondary glomerular disease in our study, and over seventy percent of the renal biopsies showed advanced pathologies with either diffuse proliferative glomerulonephritis or membranous nephropathy.     

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.     

A case of multicentric Castleman's disease with membranoproliferative glomerulonephritis type 3-like lesion

Renal involvement is a significant complication of multicentric Castleman's disease (MCD) and various glomerular involvements have been reported. A 45-year-old Japanese man presented with persistent proteinuria, with lymphadenopathy and hypergammaglobulinemia. He had been diagnosed 4 years previously with MCD. As his renal impairment had progressed to renal failure, he underwent a renal biopsy. Histology revealed diffuse and global membranous lesions with large and heterogeneous epimembranous deposits. In addition, mesangial cell proliferation and focal extracapillary lesions were found. Under immunofluorescence, granular staining for anti-IgG, IgG1, IgG2 and IgA was strongly positive in the capillary loop, and weakly positive in the mesangium. As such, there was a diversity of histological features. Our perspective with regard to pathogenesis is that the formation of the immune-complex contributed to the membranoproliferative glomerulonephritis type 3-like lesion. This histological multiform with MCD is valuable for increasing our understanding of the mechanism for onset of immune-complex glomerular deposition and cellular proliferation of glomerulonephritis.