IgM nephropathy in adults: incidence and correlation with electron microscopic features

IgM nephropathy is characterised on light microscopy (LM) by variable features of normal glomeruli to mesangial hypercellularity; and immunofluorescence (IF) deposits of LgM. Our aim was to study the incidence of IgM nephropathy in adults with primary glomerular disease, with correlation to electron microscopy (EM) features. All adults presenting with proteinuria glomerular hematuria underwent renal biopsy. We excluded patients with systemic diseases and post-infectious glomerulonephritis. All the specimens were evaluated by LM, IF and EM. Our series had 146 cases. Of the 42 cases diagnosed on LM as minimal change disease, mesangial deposition of IgM was present in 11 cases. In addition there were seven cases of mesangioproliferative glomerulonephritis with mesangial IgM deposition. Thus, there were a total of 18 cases of IgM nephropathy (12.3%). Only six of these 18 cases showed typical electron dense deposits in the mesangium on EM. We feel that IgM nephropathy is probably a separate pathological entity, comprising 12.3% of all adults with primary chronic glomerulopathy. Electron dense deposits are seen in only about a third of these cases.     

IgA nephropathy. Correlation of clinical and histologic features

The clinical and histologic features of 81 patients with IgA nephropathy were analyzed. Azotemia was present in 32 per cent of the patients, proteinuria was present in 88 per cent, and gross or microscopic hematuria was present in all of the patients tested. The median age of histologic diagnosis was 27 years. The median age at onset of clinical signs was 20 years. There was no increased incidence in any HLA-A or -B antigen within the patient population over our control population. All patients had glomerular mesangial IgA deposition (by definition) greater than or equal to IgG or IgM. Histologic changes were quantitated and ranged from normal to necrotizing and/or crescentic glomerulonephritis. Many patients (48 per cent) had mild or moderate generalized glomerlular hypercellularity. Nonparametric statistical analysis showed strong correlations among patient age at histologic diagnosis, creatinine, proteinuria, global glomerular sclerosis, and interstital fibrosis. Our analysis suggests that IgA nephropathy is an indolent disease generally beginning in childhood. It is a cause of renal insufficiency in a significant number of patients. Interpretation of this series and other reported studies suggests that most cases of IgA nephropathy in the United States are best considered idiopathic but that hereditary and secondary forms may exist.     

Intraglomerular tubular epithelial cells. A marker of glomerular hematuria

The occurrence of intraglomerular tubular epithelial cells (ITEC) was investigated in 202 consecutive renal biopsy specimens and were present in 111 (55%). Minimal, focal, or diffuse glomerular diseases were all represented. Of the patients with ITEC 110 (99%) had gross or microscopic hematuria, either alone or associated with proteinuria; however, ITEC were found only in one of 79 proteinuric patients with no documented hematuria. Intraglomerular tubular epithelial cells did not occur in four patients with drug-induced interstitial nephritis and microscopic hematuria, or in 11 normal controls. The pathogenesis of ITEC is not known, but our data indicate that the phenomenon is almost constantly found in association with glomerular hematuria. Identification of ITEC, therefore, should help to confirm the glomerular origin of hematuria when histologic alterations are minimal.     

Thin glomerular basement membrane disease: light microscopic and electron microscopic studies.

Benign recurrent hematuria usually indicates a good prognosis. This condition is associated with abnormally thin glomerular basement membranes. Of 680 renal biopsy cases in which lower urinary tract disease had been excluded by careful study, 25 cases from seven children and eighteen adults met the criteria for thin glomerular basement membrane disease, placing the incidence of the disease at 3.7%. The mean patient age was 32.4 years and the male to female ratio was 1 to 5.3. The primary finding was microscopic hematuria in eighteen patients and gross hematuria in five patients. Among eighteen patients who had microscopic hematuria, one patient also exhibited proteinuria and one patient suffered from acute renal failure due to acute drug-induced interstitial nephritis. Proteinuria was only found in one patient. All of the patients had normal renal function, with the exception of one who suffered from acute renal failure. The duration of hematuria from the time of detection to the date of biopsy ranged from 3 months to 30 years with a mean interval of 56.6 months. No apparent evidence of familial hematuria in any patient was noted. Under light microscopy most glomeruli were normal. However, five cases showed focal global sclerosis. Under immunofluorescence microscopy seventeen cases were negative for all immunoglobulins, for complement, and for fibrinogen. Eight cases showed nonspecific mesangial deposition of fibrinogen and/or IgM. Ultrastructurally, extensive diffuse thinning of the GBM was a constant finding. The mean thickness of the GBM was 203.2 +/- 28.3 nm (n = 25); the thickness in adult (201.4 +/- 27.5 nm; n = 18) did not differ from that in children (208.1 +/- 32.0 nm; n = 7).     

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.     

Immune complex glomerulonephritis mediated by thyroid antigens.

Hypothyroidism, microscopic hematuria, and proteinuria developed in an 11-year-old girl. A renal biopsy specimen showed increased mesangial cells and matrix with focal glomerular basement membrane thickening. Three years later, a pronounced increase in proteinuria was detected. Elevated levels of antibody to thyroid microsomal antigen and thyroglobulin were found in the serum. A renal biopsy specimen showed a pronounced increase in mesangial cells and matrix with generalized glomerular basement membrane thickening. Electron microscopic studies demonstrated granular deposits in the capillary walls and mesangium. Immunofluorescent studies revealed granular deposits of IgG, IgM, and C3, primarily on the glomerular basement membrane. By indirect immunofluorescence, granular glomerular basement membrane and mesangial staining were detected with antibody specific for thyroglobulin and thyroid microsomal antigen. These observations suggest development of immune complex glomerulonephritis mediated by thyroid antigens.     

Electron microscopic study of the cases of minimal change nephrotic syndrome with mesangial IgA deposition.

Twenty-five cases of minimal change nephrotic syndrome(minimal change disease, MCD) with mesangial IgA deposition were evaluated electron microscopically. The thickness of the glomerular basement membrane(GBM) was 3875 +/- 1271 A and 3056 +/- 1201 A in adults and children, respectively. Alteration of the GBM was noted in 3 adults and eight children: splitting in 4, focal thinning in one, widening of the lamina rara interna in 10, and widening of the lamina rara externa in 4 cases. Minimal mesangial electron dense deposits were found in all but one adult, and an increase of the mesangial matrix and minimal mesangial proliferation were observed in 8 and 6 cases, respectively. Electron microscopic findings show representative findings of MCD in our cases. A relationship between the GBM alterations in these cases and frequent association of hematuria is suggested and discussed.     

Experimental glomerulonephritis in the mouse associated with mesangial deposition ofautologous ferritin immune complexes.

Mice undergoing prolonged (5 to 8 weeks) immunization with cadium-free feeritin were studied 1 to 32 days following the last ferritin injection. Urine protein was measured and renal tissue examined by light, immunofluorescence, and electron microscopy. Immunized animals developed significant proteinuria and circulating antibody to ferritin.by light microscopy, proetinuric animals had a proliferative glomerular lesion with mesangial hypercellularity and martrix increase, focal and segmental necrosis, fibrin deposits, and occasional crescents. Iron stains revealed prominent mesangial iron deposition. In immunized animals, IgG and C3 deposits were localized mainly in the mesanglium. Electron microscopic studies revealed marked deposition of ferratin complexesexpanded mesangial matrix and mesangial interposition. Ferratin immune complexes were also visualized in epithelial spaces. In the latter location ferritin immune complexes occasionally formed characteristic electron-dense subepithelial deposits. In this model, mesangial and subepithelial localization of autologous ferritin immune complexes is associated with development of glomerulonephritis and characteristic mesangial lesions resembling those seen in some types of human glomerulonephritis.     

Significance of mesangial IgA deposition in minimal change nephrotic syndrome: a study of 60 cases

We studied 60 cases of minimal change nephrotic syndrome (MCNS) with mesangial IgA deposits occurring over a 6 year period. There were 43 adults and 17 children. Hematuria occurred in 69.0% of the adults and 88.2% of the children. Two adults and six children had gross hematuria during the course of the disease. Mesangial IgA deposits were noted in 100% of the cases, and concomitant IgG or IgM deposits were found in 78.6% of adults and 73.7% of children. The fluorescent intensity of mesangial IgA deposits was trace (+/-) to 1+ in 86.1% and 70.6% of the adults and children respectively. Most of the patients showed electron microscopic findings consistent with minimal change nephrotic syndrome. We speculate that most of our cases are variants of minimal change nephrotic syndrome but are neither IgA nephropathy nor an overlapping syndrome, and that environmental or genetic factors may be related to the deposition of IgA in these MCNS patients.     

Immunoelectron microscopy of IgA nephropathy

The distribution of IgA, IgG, IgM, C3, and albumin in kidney biopsy specimens from 11 children and adults with recurrent gross and microscopic hematuria and IgA nephropathy and 7 control specimens were evaluated by the direct peroxidase-labeled antibody method and electron microscopy. Granular masses of reaction product (RP), representing IgA, IgG, IgM, and C3, were observed within the mesangial matrix of glomeruli from all patients with IgA nephropathy. Occasional smaller masses of IgA-RP and C3-RP were noted along the peripheral glomerular capillary loops, the tubular basement membranes, and within the interstitial matrix of some patients. Large amounts of IgA-RP and C3-RP were present within the walls of small renal arterioles of several patients. These observations support the concept that immune-complex deposits are involved in the pathogenesis of IgA nephropathy and suggest that vascular deposits may have a more important role in the progression of the disease in some patients.     

The pathology of mesangial IgA nephritis with clinical correlation

Of 710 patients in whom renal biopsies with immunofluorescence, light and electron microscopic and clinical data were available, 239 had idiopathic mesangial IgA nephritis. In these 239 cases IgA was found alone in 45.7%, accompanied by IgG in 50.1%, IgM in 21.4%, C3 in 82.4% and fibrin in 37.2%. Serum immunoglobulin levels including IgA were not significantly raised, and complement C3 activation was via the alternative pathway. There was a wide range of glomerular lesions with minor change, minor change with focal and segmental lesions including sclerosis and mesangial cell hypercellularity, diffuse mesangial cell proliferation and, infrequently, diffuse sclerosing glomerulonephritis. The glomerular lesions were related to the stage, duration and severity of the disease. There was also a wide variability of clinical presentations, with asymptomatic and symptomatic microscopic haematuria-proteinuria, macroscopic haematuria, recurrent proteinuria, nephrotic syndrome, acute nephritis, hypertension, and uncommonly as acute renal failure and potassium losing nephritis. No aetiological agent was found, and both the streptococcus and HBsAg could not be identified. The disease(s) was the commonest type of primary glomerulonephritis (33.7%) in Singapore, another geographic area in addition to Japan and France, where this lesion has an apparent high incidence.     

Pathological implications of linear immunoglobulin G staining on the glomerular capillary walls in a case of infection‐related glomerulonephritis

We report a 32‐year‐old man with nephrotic syndrome and preceding symptom of infection. He had renal insufficiency, hypocomplementemia, and elevated titer of anti‐streptolysin O. Renal biopsy showed mesangial hypercellularity and focal segmental endocapillary hypercellularity with double contour of the glomerular basement membrane (GBM). Immunofluorescence study showed granular C3 staining on the mesangial areas and glomerular capillary walls (GCWs) and linear immunoglobulin G (IgG) staining on GCWs. Electron microscopy revealed sporadic subepithelial humps, discontinuous small and thin deposits in the endothelial side of the GBM and mesangial deposits. He was diagnosed with infection‐related glomerulonephritis (IRGN) with the striking finding of linear IgG staining, which is unusual in IRGN. The patient did not have diabetes mellitus or anti‐GBM disease. The patient's serum seemed not to contain IgG, which can bind to GCW. He showed normalization of complement within two months after relief from infection symptoms and a trend toward improvement in proteinuria, hematuria and renal function over 14 months. We discuss the possible mechanisms of linear IgG staining in our case based on clinical and experimental studies on IRGN with cationic bacterial protein as antigen.     

IgA-IgM nephropathy. A subgroup of primary mesangial glomerulonephritis

The renal biopsy material of Tampere University Central Hospital comprises 1992 renal biopsy specimens, accessioned during the years 1978-1989. Among these, there were three cases of mesangial glomerulonephritis with a peculiar type of immunofluorescent reactivity. Striking mesangial deposits of both IgA and IgM were found in glomeruli, whereas C3 deposits were absent or present in slight amounts. The light microscopic findings ranged from mild mesangial glomerulonephritis to more advanced forms of sclerosing glomerulopathy. Electron microscopic examination disclosed an increase of mesangial matrix, together with mesangial and paramesangial electron-dense deposits. Two of the patients had microscopic hematuria associated with proteinuria, and one had isolated proteinuria. The authors propose that this group of cases may represent a new subgroup of primary mesangial glomerulonephritis that has not been described previously. They differ immunohistologically from both IgA nephropathy and IgM nephropathy, and therefore could be designated as IgA-IgM nephropathy.     

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.     

Role of immunoglobulin class in mediation of experimental mesangial glomerulonephritis

The contribution of immunoglobulin class to the histology and ultrastructure of renal lesions were examined in an experimental model of glomerulonephritis in which the glomerular deposits were selected to be predominantly IgM or IgG. The selection was accomplished by immunizing and then injecting rabbits with a carrier preparation plus heat-denatured (HD) DNA (n = 11) or ultraviolet-irradiated (uv) DNA [n = 11). It has been shown previously that HD DNA gives rise to an IgM antibody response and uv DNA to an IgG response. Groups of rabbits immunized with each preparation produced largely IgM (HD DNA) or IgG (uv DNA) anti-DNA antibody. After 10 and 20 weeks of injections, animals receiving both antigens developed diffuse mesangial hypercellularity with either IgM or IgG deposits accompanied by C3; by ultrastructural analysis all deposits were confined to the mesangium. By 28 weeks, heavy mesangial IgM and IgG deposits were noted but no quantitative or qualitative differences in the renal histology was observed. Individual animals developed sporadic hematuria and azotemia but proteinuria was not found. These results show that both IgM and IgG can mediate experimental mesangial proliferative glomerulonephritis and that the immunoglobulin class of the glomerular deposits does not influence the appearance of the renal lesion.     

Antigen as mediator of glomerular injury in experimental IgA nephropathy

IgA immune complexes (IgA-IC) are considered the primary cause of IgA nephropathy. Despite the consistent findings of IgA and frequently C3 glomerular deposits in most patients, the renal histopathologic lesion may vary from mild mesangial involvement to severe sclerosis. In the IgA immune deposits, IgA and C3 are considered to be relatively constant, whereas the composition of the antigen is expected to vary according to its origin. This report explored th possibility that the histopathologic lesion is a function of the antigen in an IgA immune deposit. To test this hypothesis we developed a passive model of IgA nephropathy whereby glomerular IgA deposits can capture, in situ, circulating antigens. In this model, glomerular IgA deposits (IgA/IgA-IC) were induced by administration of a constant amount of IgA anti-dinitrophenyl (antibody) and dinitrophenyl-conjugated IgA anti-phosphorylcholine (PC) as an antigen. The latter also served as antibody to capture, in situ, circulating PC-containing antigens. Mice that received only IgA/IgA-IC developed glomerular IgA and C3 deposits and a focal increase in mesangial cells and matrix, but no evidence of renal damage. A diffuse increase in mesangial cells and matrix developed in mice treated with IgA/IgA-IC and either PC-Ficoll (carbohydrate antigen) or PC conjugate of bovine serum albumin (protein antigen). In contrast, mice that received IgA/IgA-IC and pneumococcal C polysaccharide, a PC-containing antigen, developed severe diffuse mesangial hypercellularity with segmental necrosis and thrombosis. These mice also developed proteinuria and hematuria. Our results demonstrate that the antigen plays a critical role in development of glomerulonephritis associated with IgA-IC.     

Presence of monocytes in systemic lupus erythematosus-associated glomerulonephritis: marker study and significance

The presence and significance of monocytes in the glomerular lesions of 13 renal specimens obtained from ten patients with systemic lupus erythematosus-associated nephritis were studied. The monocytes were identified by the presence of intracytoplasmic lysozyme, as demonstrated by immunoperoxidase staining on paraffin-embedded tissue. Eight specimens obtained from six patients displayed monocytes. These were found most often associated with mesangial hypercellularity, and their appearance fluctuated with it. There was a positive correlation between the number of lysozyme-positive cells and the amount of proteinuria. We conclude that monocytes contribute to the endocapillary hypercellularity and affect protein filtration in lupus nephritis.     

Glomerular mannose‐binding lectin deposition is a useful prognostic predictor in immunoglobulin A nephropathy

There is accumulating evidence to support a hypothesis of the activation of the lectin complement pathway in immunoglobulin A nephropathy (IgAN). The glomerular deposition of mannose‐binding lectin (MBL), an initiator of the lectin pathway, has been identified, but its clinical significance has not been defined consistently. The aim of the present study was to investigate the value of glomerular MBL deposition as a useful histological biomarker in evaluating the severity and predicting the prognosis of IgAN. We included all consecutive patients with biopsy‐proven primary IgAN from December 2008 to July 2010. Renal deposition of MBL was detected by immunofluorescence. The biopsy material from 131 patients (72 men) was thus used for MBL staining. The deposition of MBL was observed in a predominantly mesangial pattern in 45 patients (34·35%), which presented as global or segmental deposition. Compared with the patients without glomerular MBL deposition, those with glomerular MBL deposition had more severe proteinuria, decreased renal function, lower levels of serum albumin and a greater possibility of hypertension at the time of renal biopsy; they had more severe histological changes according to the Oxford classification (i.e. mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis), and their ratio presented an increase as the histopathological phenotypes segregated according to Lee's classification; furthermore, the follow‐up data demonstrated that they had a lower renal remission rate. In conclusion, glomerular MBL deposition may predict a poor prognosis, and thus can be a new prognostic factor in IgA nephropathy.     

Thin-basement-membrane nephropathy in adults with persistent hematuria

Thin-basement-membrane nephropathy, also called benign recurrent hematuria, is characterized by diffuse thinning of the glomerular basement membrane and by hematuria. To determine the incidence of thin-basement-membrane nephropathy among patients with idiopathic hematuria, we conducted a prospective study in the nephrology units of three large hospitals in the Netherlands. Eighty normotensive adults without azotemia underwent renal biopsy because of recurrent macroscopic hematuria (n = 26) or persistent microscopic hematuria (n = 54). Idiopathic IgA nephropathy was found in 27 of the 80 patients. Light microscopical examination showed that 42 patients had normal renal tissue. The remaining 11 patients had mesangioproliferative glomerulonephritis (n = 5), interstitial nephritis (n = 3), or focal global glomerulosclerosis (n = 3). Tissue from the 42 patients whose renal biopsy specimens were normal when examined with light microscopy was analyzed morphometrically with electron microscopy to determine the thickness of the glomerular basement membrane. Two subsets of patients were identified by this analysis. In 18, thin-basement-membrane nephropathy was found (mean basement-membrane thickness [+/- SE], 191 +/- 28 nm; normal, 350 +/- 43 nm); all but one of these 18 patients had microscopic hematuria, which persisted during follow-up (median duration, 50 months). (Of the 54 patients who presented with microscopic hematuria, 17 [31 percent] had thin-basement-membrane nephropathy.) The thickness of the glomerular basement membrane was normal in the other 24 patients (361 +/- 69 nm); during follow-up, hematuria disappeared in all 13 of these patients who had macroscopic hematuria, and hematuria resolved in 5 of the 11 patients who had microscopic hematuria. We conclude that in patients with persistent microscopic hematuria, the incidence of thin-basement-membrane nephropathy is similar to that of idiopathic IgA nephropathy. Morphometric analysis of the thickness of the glomerular basement membrane should be included in the workup of adults with persistent microscopic hematuria that is not of urologic origin.     

Glomerular lesions in congenital endocardial fibroelastosis: clinical manifestations and ultrastructural studies in two patients

Two children with congenital fibroelastosis and recurrent episodes of heart failure had overt proteinuria and hematuria; one also had a reversible nephrotic syndrome. Urinary manifestations persisted during periods of cardiac compensation. Renal biopsies revealed mesangial hyperplasia by light microscopy, identical ultrastructural lesions in the glomerular basement membrane, and deposits of fibrin in one of the biopsy specimens studied by immunofluorscence. These changes detected by electron microscopy may result in an increase in glomerular permeability independent of the renal hemodynamic disturbances associated with cardiac insufficiency. The progression of the lesions appears to be slow, although urinary manifestations may simulate an intercurrent glomerulonephritis. Pulmonary hypertension and renal venous stasis with glomerular intravascular coagulation were discussed as possible pathogenic mechanisms.