Mesangial IgA Nephropathy Research Articles

Myofibroblasts, predictors of progression of mesangial IgA nephropathy?

The limited knowledge of the cellular mediators of renal scarring hampers progress in the management of progressive chronic renal failure (CRF). We have studied 38 patients with biopsy-proven mesangial IgA nephropathy with emphasis on attempting to define the role of myofibroblasts (alpha-smooth muscle actin/SMA-positive cells) in renal scarring. In 18 untreated patients, correlations were undertaken between known histological parameters of progression as well as the presence of myofibroblasts in tissues and the clinical outcome. alpha-SMA staining by an avidin-biotin-peroxidase method was confined to a large extent to the vascular smooth muscle cells of normal kidneys but extended to the tubulointerstitium and periglomerular space in scarred kidneys. Mild glomerular staining was also noted. The interstitial immunostain followed a similar distribution to that of interstitial type III collagen. Morphometric analysis showed the interstitial alpha-SMA staining to be a reliable histological predictor of outcome as it discriminated between progressors and non-progressors (chi 2 = 4.923, P = 0.026). The intensity of the interstitial alpha-SMA staining correlated with renal functional outcome; inversely with the reciprocal of serum creatinine slopes (r = -0.466, P < 0.025) and positively with the serum creatinine value at the end of the observation period (r = 0.704, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerulonephritis in rheumatoid arthritis.

We present data on 10 patients with RA who developed glomerulonephritis which was not related to gold or penicillamine therapy. Although two of these patients had received gold this had been discontinued 13 and 18 yr before the diagnosis of glomerulonephritis. Seven patients presented with nephrotic syndrome and three with proteinuria and microscopic haematuria. Renal histology showed a membranous nephropathy (five patients), mesangial IgA nephropathy (two patients), focal segmental necrotizing glomerulonephritis (two patients) and focal segmental glomerulosclerosis (one patient).

Deterioration of GFR in IgA nephropathy as measured by 51Cr-EDTA clearance

In 191 patients with mesangial IgA nephropathy, GFR was determined as clearance of 51Cr-EDTA. 86 (45%) of them had subnormal renal function 7.3 +/- 4.6 years after renal biopsy. The change in GFR was followed in 153 patients with repeated determinations of 51Cr-EDTA clearance. 50.3% of the patients had a loss of more than 1.1 ml/min/year, which we regard as pathological. The markers of progressive disease were: male sex, high output of urinary protein, severe histological lesions and presence of hypertension. Even patients lacking these markers had a significantly increased incidence of progressive disease. Of 93 patients, with initially normal GFR, 32% will have a subnormal GFR within five years and 25% will develop end-stage renal failure within 20 years. In 38 patients with six or more determinations of 51Cr-EDTA clearance, the predictive value of the first four determinations was calculated. Of 26 with a decrease of more than 1.1 ml/min/year, 13 (50%) developed subnormal GFR during follow-up, while 11 of 12 (91.7%) with a decrease of less than 1.1 ml/min/year (P less than 0.05) remained normal. This shows that repeated determinations of GFR with an accurate method will predict the final outcome early in the disease. We also confirmed that single or repeated determinations of clearance of creatinine are of little value in separating a normal GFR from a slightly decreased one, but more reliable in detecting a markedly reduced GFR.

Elevated urinary excretion of the C5b-9 complex in membranous nephropathy

In experimental membranous nephropathy, antibody binding to glomerular epithelial cell membrane antigens results in complement activation and formation of complement C5b-9 membrane attack complexes in glomeruli. During active disease, the C5b-9 complexes are shed into the urine. To test the hypothesis that a similar mechanism might be operative in human membranous nephropathy, we measured urinary excretion of C5b-9 and C5 in 146 proteinuric patients with biopsy-proven glomerular diseases or diabetes mellitus. Urinary excretion of C5b-9 relative to C5 excretion was higher in 40 patients with membranous nephropathy than in 106 patients with proteinuria due to non-membranous glomerulonephritis when analyzed by covariance analysis (P less than 0.0002). Urinary C5b-9 excretion was higher in membranous nephropathy than in membranoproliferative glomerulonephritis (N = 13, P less than 0.05), minimal change-focal sclerosis (N = 33, P less than 0.001), mesangial proliferative glomerulonephritis (N = 9, P less than 0.02) and IgA nephropathy (N = 7, P less than 0.025). Urinary C5b-9 excretion was also higher in patients with lupus nephritis (N = 18, P less than 0.02) compared to those with non-membranous glomerulonephritis. The lupus patients with the highest excretion had clinical or pathological features of membranous nephropathy. Nine patients with membranous nephropathy and elevated urinary C5b-9 excretion had a shorter duration of disease (P less than 0.05), lower serum creatinine levels (P less than 0.05) and more proteinuria (P less than 0.02) than the 31 membranous nephropathy patients with normal values.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined therapy for mesangial IgA nephropathy reduces proteinuria but does not improve renal function

Combined therapy for mesangial IgA nephropathy reduces proteinuria but does not improve renal function

The effect of sodium cromoglycate on the induction of experimental IgA nephropathy

Mesangial IgA nephropathy was experimentally induced in ddY mice by oral and parenteral administration of the poliomyelitis vaccine (POLIO), and we then tried to investigate if IgA deposition could be prevented by the concurrent use of sodium cromoglycate (SCG), which is known to inhibit the local mucosal immune reaction. Mucosal and systemic immunity could be induced by the administration of POLIO; proteinuria, increased serum IgA levels, mesangial cell proliferation, mesangial matrix widening, mesangial deposits of IgA, and large electron dense deposits in the mesangium were observed. Concurrent administration of SCG and POLIO resulted in a significant decrease in the serum IgA level and mesangial IgA deposits. The later addition or abstinence of SCG after the 70th day did not influence the glomerular mesangial IgA deposition. But the serum IgA level was still decreased by the continuous treatment of SCG even after the 70th day. Thus, mesangial IgA nephropathy simulating IgA nephropathy in humans could be induced in ddY mice using POLIO and its induction could largely be prevented by the concurrent use of SCG. However mesangial IgA deposits already present could not be cleared by the late administration of SCG.

Polymorphs infiltrate glomeruli in mesangial IgA glomerulonephritis

During episodes of macroscopic hematuria, patients with IgA nephropathy commonly have polymorphonuclear neutrophils (PMNs) as well as fibrin and mononuclear cells in glomerular capillaries. We quantitated PMN and macrophage infiltration in glomeruli of 54 patients with IgA nephropathy in whom renal biopsies were obtained within 30 days of macroscopic hematuria. Control biopsies (N = 22) were from patients with IgA nephropathy and urinary erythrocyte counts below 50,000/ml. PMN monocyte/macrophages were quantitated using the monoclonal antibodies FMC10 and HAM56, respectively. In patients with heavy hematuria, 45.9 +/- 3.4% (mean +/- SE) of glomeruli were positive for PMNs (control 10.5 +/- 2.8%, P = 0.001) with a mean PMN count/glomerulus of 1.10 +/- 0.20 (control 0.13 +/- 0.03, P = less than 0.001). 65.6 +/- 9.7%. Of the glomeruli were positive for monocytes in the heavy hematuria group (control 40.0 +/- 8.4, P less than 0.05) with the mean monocyte count per glomerulus being 1.6 +/- 0.2 (control 0.6 +/- 0.1, P less than 0.01). We conclude that, in the acute phase of mesangial IgA nephropathy, PMN and monocytes are present and presumably participate in glomerular injury.

IGA nephropathy: a retrospective evaluation of prognostic indices in 176 patients.

One hundred and seventy-six patients with mesangial IgA nephropathy have been studied retrospectively. Mean follow up from apparent onset of the disease was 9.3 years and with follow up from the diagnostic renal biopsy of 4.6 years. Our aim was to evaluate the prognostic significance of sex, age and type of symptoms at onset. The degree of proteinuria, presence of hypertension or decreased renal function, histological lesions and IFL pattern at the time of the diagnostic renal biopsy were recorded. 17 of the patients developed End Stage Renal Failure (ESRF) during the study. According to the Logrank test (renal survival) and Cox stepwise proportional hazard model, severity of glomerular mesangial lesions and degree of proteinuria are the most important indicators of a poor prognosis. The significance of all other parameters disappear after correction for histological lesions and degree of proteinuria. Our conclusion is that a semiquantitative light microscopical examination is an excellent prognostic index in IgA nephropathy, as is a simple determination of protein excretion in the urine.

Immunoelectron microscopic studies of immune complex deposits and basement membrane components in IgA nephropathy.

The relationship between the immune complex deposits of mesangial IgA nephropathy and the basement membrane components, type IV collagen and fibronectin, has been investigated by an indirect immunogold technique in four cases of mesangial IgA disease. Using paraformaldehyde-fixed, Lowicryl K4M resin-embedded kidney, IgA, IgM and C3 were localized in the mesangial electron-dense deposits with 10 and 20 nm gold-labelled secondary antibodies. In the same glomeruli, type IV collagen and fibronectin were rarely present within the electron-dense deposits, although both were distributed throughout the remainder of the mesangial matrix with the exception of the subepithelial regions. These two components were also present within the glomerular basement membrane and localized mainly on the endothelial aspect. A similar distribution of the basement membrane components was seen in a control kidney processed in the same way. This technique gives reproducible results and has demonstrated for the first time the relationship between the mesangial immune complex deposits of mesangial IgA nephropathy and the basement membrane components of the matrix in which they are found.

Primary mesangial IgA nephropathy in São Paulo, Brazil.

Primary mesangial IgA nephropathy in São Paulo, Brazil.

Immunofluorescence characterization of light chains in human nephropathies

Renal tissue from 185 patients with various nephropathies were studied by immunofluorescence, in order to look for the frequency and potential predominance of kappa or lambda light chain glomerular deposits. Four normal renal biopsies were used as controls. An overall study shows that light chains were present in glomeruli in 136 out of 185 cases; kappa light chain deposits were more frequent than lambda light chain deposits (73.5% and 64.3% respectively). An analytical study shows that this was not observed in all nephropathies studied. In mesangial IgA nephropathy, lambda light chain deposits were seen in 81% of cases (29 out of 37) and kappa light chain deposits were observed in 78% (30 out of 37 cases). In lupus nephritis, lambda light chain deposits were present in 13 out of 14 cases (92.8%) whereas kappa light chain deposits were demonstrated in 12 cases (85.7%). In other nephropathies such as membranous, endocapillary proliferative and amyloid nephritis, kappa was the predominant light chain observed in glomeruli or was present in the same number of cases as lambda light chain (mesangiocapillary glomerulonephritis). These findings show that in certain nephritides, for example IgA nephropathy and lupus nephritis, IgA and IgG deposits are mainly composed of lambda light chain in contrast with the normal kappa: lambda ratio in human serum of 2:1.

Renal disease in pregnancy. Three controversial areas: mesangial IgA nephropathy, focal glomerular sclerosis (focal and segmental hyalinosis and sclerosis), and reflux nephropathy.

Whether gestation has adverse effects on the course of renal disease is controversial. Three diseases regarding which conflicting opinions are especially noteworthy are IgA nephropathy, focal and segmental hyalinosis and sclerosis, and reflux nephropathy. We analyzed 102 pregnancies in 65 women with IgA nephropathy, noting hypertension in 63% of the gestations (severe in 18%), decreases in renal function in 22%, and biopsy evidence demonstrating a significantly greater amount of glomerular proliferation and crescents as well as focal and segmental hyalinosis and sclerosis when the renal histology from women who were pregnant and those who had never conceived were compared. Our experience with glomerular sclerosis is limited to 28 gestations in 15 patients, but the clinical findings resemble those of women with IgA nephropathy who conceived. Finally, we analyzed 227 pregnancies in 95 women with normal renal function and reflux nephropathy comparing results to 118 gestations in 42 patients with evidence of dysfunction (serum creatinine SCr greater than 1.25 mg/dL). Women with preserved function had good outcomes in general, whereas hypertension (36%) and an accelerated decline in function (8%) were observed in the groups that had moderate renal insufficiency in the initial stage of pregnancy. Increased proteinuria was the best predictor of progression of reflux nephropathy in both groups.

Genetic Polymorphism of C3 and Bf in IgA Nephropathy

C3 and Bf alleles were examined in the general population, in 67 patients with biopsy-confirmed mesangial IgA nephropathy and 81 patients with other types of glomerulonephritis, from the Heidelberg and Leiden renal programmes respectively. In both populations, a significant excess of homozygous phenotype C3FF (3.4% in controls; 10.4% in IgA nephropathy) and a deficit of C3FS heterozygous phenotype (35.8% in controls; 19.4% in IgA nephropathy) were observed in patients with IgA nephropathy, but not in other types of glomerulonephritis. No difference of C3 gene frequencies was found. C3FF was associated with an adverse clinical outcome (a higher prevalence of renal failure and hypertension). A significant excess of Bf-F gene frequency was noted (0.20 in controls; 0.33 in IgA nephropathy). In addition, an excess of phenotype BfFF was found (none in controls; 10.4% in IgA nephropathy). BfFF homozygotes also carried a higher risk of an adverse outcome (renal failure and hypertension). The data suggest a role for genetically coded (presumably) immunological factors in the genesis and course of IgA nephropathy.

Clinicopathological associations in mesangial IgA nephropathy.

On hundred and fifteen renal biopsies performed in 112 patients with mesangial IgA nephropathy were reviewed and the histological disease patterns correlated with the clinical features at the time of initial biopsy. To determine the significance of macroscopic haematuria in this disease, specific comparisons were made between patients with a history of episodes of macroscopic haematuria and those with only microscopic haematuria. The mean age at initial biopsy was 38.3 years (90 males, mean 40.3 years; 22 females, mean 30.2 years). Histological examination showed 9 patients (8%) with class I disease (mesangial matrix expansion alone); 43 patients (38%) with class II disease (diffuse mesangial proliferation); 60 patients (54%) with class III disease (focal and segmental proliferation), including subsets of 20 patients (16%) with segmental sclerosis and/or synechiae and 23 patients (21%) with crescent formation. Class III disease and crescent formation correlated with an increased frequency of capillary loop IgA and glomerular fibrin deposition and with the presence of subendothelial and subepithelial deposits. The degree of renal impairment and the incidence of hypertension were increased in class III disease. Macroscopic haematuria patients were younger (mean 31.1 vs. 43.0 years; p less than 0.001), had less severe renal impairment (mean creatinine 116.2 vs. 213.3 mumol/l; p less than 0.001) and less class III disease (48 vs. 58%; p less than 0.05). The incidence of crescentic disease was equal in macroscopic (17%) and microscopic (23%) haematuria. Eventual progression to end-stage renal failure occurred in 12 patients (11%) and correlated with crescentic disease, renal impairment, hypertension and heavy proteinuria at the time of diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Points: Mesangial IgA nephropathy

Points: Mesangial IgA nephropathy

“Malignant” IgA Nephropathy

Most patients with mesangial IgA nephropathy who run a progressive course usually do so over a period of 10 to 20 years. This paper describes the course of three young men with similar presenting features and biopsy findings who progressed to end-stage renal failure in less than 4 years from presentation, even though initially all had serum creatinine levels that were in the normal range. They presented with macroscopic hematuria, which has previously been regarded as an indicator of a favorable prognosis, and all three had loin pain, constantly elevated urinary erythrocyte counts, and crescents in renal biopsies. In two cases, treatment appeared to be associated with stabilization of renal function, but deterioration to end-stage renal failure occurred rapidly after treatment was ceased.

Idiopathic IgA Mesangial Nephropathy

Histological features and data on the natural history after 1 to 45 years (mean 6.56 +/- 8.55) of total apparent duration and 1 to 13 years (mean 3.48 +/- 5.04) of post-biopsy follow-up, are reported in 374 patients (mean age, 33.9 +/- 11.9 yrs) with idiopathic mesangial IgA nephropathy, who presented with a history of macroscopic hematuria (56%), recurrent in two-thirds of the patients, or with persistent microscopic hematuria and no previous episodes of gross hematuria (44%). Mesangial cell proliferation ranged from minimal to diffuse. Associated varying degrees of extracapillary proliferation, segmental and global glomerular sclerosis, tubulo-interstitial damage and arteriolar hyalinosis usually correlated with each other and with the extent of mesangial proliferation (P less than 0.05). The actuarial curve of progression to renal death showed a 75% survival after 20 years from apparent onset. Progression to renal failure was more rapid in patients with: an older age at onset (P = 0.0582); male sex (P = 0.0730); no history of recurrent gross hematuria (P = 0.0406); high blood pressure (P = 0.0011); more marked global (P = 0.0007) and segmental (P = 0.0026) glomerular sclerosis; more severe interstitial sclerosis (P = 0.0147); more diffuse and global mesangial proliferation (P = 0.0820); mesangio-parietal pattern at immunofluorescence (P = 0.0778). However, all these parameters showed a poor predictive value if applied to any single patient.

Therapeutic perspectives in mesangial IgA nephropathy.

Therapeutic perspectives in mesangial IgA nephropathy.

Recurrence of mesangial IgA nephropathy after renal transplantation.

Recurrence of mesangial IgA nephropathy after renal transplantation.

Mesangial IgA Nephropathy

Mesangial IgA Nephropathy