Treatment of IgA Nephropathy of Adults Presented by Nephrotic Syndrome
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The aim of this retrospective study was to evaluate the results of the immunosuppressive regiment in managing of IgA nephropathy associated with primary nephrotic syndrome at the Nephrology Clinic, University of Sarajevo Clinics Centre in period of 1997-2007. We studied 19 patients (4 women and 15 men) with idiopathic nephrotic syndrome, where pathomorphologic changes of IgA nephropathy were proved by kidney biopsy. The levels of diuresis, proteinuria, albuminemia, lipidemia and kidney function, as measure of efficiency of used therapy, were monitored. The IgA nephropathy present with the nephrotic syndrome was shown in 15.8% (19) patients underwent renal biopsy due to primary nephrotic syndrome in the period of observation. The average age of patients with IgA nephropathy was 34.9+/-14.1 years. Eight patients from this group were treated with corticosteroid therapy (1-1.5 mg/kg of body weight for 4 weeks, followed by 0.5 mg/ kg of body weight until therapeutic response was achieved, and finally gradual exclusion of therapy after eight weeks in responsive patients), 6 patients with corticosteroids and bolus cyclophosphamide (10-15 mg/kg BW), and in 5/19 patients cyclosporine therapy was used (3 mg/kg BW). Complete remission of nephrotic syndrome was achieved in 42.1% of the patients. In conclusion, in adults patients with primary nephrotic syndrome associated with IgA nephropathy, used immunosuppressive therapy resulted in a high percentage of achieved remissions.Keywords:
Immunoglobulin A
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.
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Discrimination between postinfectious IgA-dominant glomerulonephritis and idiopathic IgA nephropathy
A unique form of postinfectious glomerulonephritis (PIGN) with IgA-dominant deposition mimicking IgA nephropathy has been increasingly reported.We compared the clinical and histological features of 12 patients with postinfectious IgA-dominant glomerulonephritis to 134 patients with idiopathic IgA nephropathy.In addition to hypocomplementemia and subepithelial hump-shaped deposits characteristic of PIGN, patients with postinfectious IgA-dominant glomerulonephritis had older age (62.3 +/- 16.9 vs. 37.9 +/- 16.3 years; p < 0.001) and more frequently presented with acute renal failure (83.3% vs. 10.4%; p < 0.001) than patients with idiopathic IgA nephropathy. Moreover, glomerular changes including endocapillary proliferation, neutrophil infiltration, and capillary loops deposits by immunofluorescence were more commonly present in postinfectious IgA-dominant glomerulonephritis group (p < 0.001).PIGN could be characterized by glomerular IgA-dominant deposition resembling idiopathic IgA nephropathy. It is essential to differentiate postinfectious IgA-dominant glomerulonephritis from idiopathic IgA nephropathy because of the different treatments and prognosis of the two diseases.
Immunoglobulin A
Rapidly progressive glomerulonephritis
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The occurrence of nephrotic syndrome was studied in different types of glomerulonephritis. In 284 consecutive adult cases the diagnosis was confirmed by the histological evaluation of percutaneous renal biopsy. Nephrotic syndrome was more frequent in minimal change glomerulonephritis, in focal sclerosis and in membranous nephropathy. The incidence of glomerulonephritis decreases, while the relative incidence of nephrotic syndrome increases with age. Glomerulonephritis is more frequent in men whereas the relative incidence of nephrotic syndrome is higher in women.
Membranous Nephropathy
Minimal change disease
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Differential diagnosis of primary IgA nephropathy (IgAN) and IgA-dominant infection-related glomerulonephritis, particularly Staphylococcus infection−associated glomerulonephritis (SAGN), on a kidney biopsy sample can be challenging because of similar morphologic findings by light microscopy, immunofluorescence, and electron microscopy.1Spector D.A. Millan J. Zauber N. et al.Glomerulonephritis and Staphylococcal aureus infections.Clin Nephrol. 1980; 14: 256-261PubMed Google Scholar, 2Yamashita Y. Tanase T. Terada Y. et al.Glomerulonephritis after methicillin-resistant Staphylococcus aureus infection resulting in end-stage renal failure.Intern Med. 2001; 40: 424-427Crossref PubMed Scopus (13) Google Scholar, 3Satoskar A.A. Nadasdy G. Plaza J.A. et al.Staphylococcus infection-associated glomerulonephritis mimicking IgA nephropathy.Clin J Am Soc Nephrol. 2006; 1: 1179-1186Crossref PubMed Scopus (111) Google Scholar, 4Nasr S.H. Markowitz G.S. Whelan J.D. et al.IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy.Hum Pathol. 2003; 34: 1235-1241Crossref PubMed Scopus (87) Google Scholar, 5Bu R. Li Q. Duan Z.Y. et al.Clinicopathologic features of IgA-dominant infection-associated glomerulonephritis: a pooled analysis of 78 cases.Am J Nephrol. 2015; 41: 98-106Crossref PubMed Scopus (25) Google Scholar, 6Julian B.A. Wittke S. Haubitz M. et al.Urinary biomarkers of IgA nephropathy and other IgA-associated renal diseases.World J Urol. 2007; 25: 467-476Crossref PubMed Scopus (38) Google Scholar The clinical management approach, however, is very different. Immunosuppressive therapy is contraindicated in SAGN because it can lead to sepsis and even death.7Satoskar A.A. Molenda M. Scipio P. et al.Henoch-Schonlein purpura-like presentation in IgA-dominant Staphylococcus infection-associated glomerulonephritis–a diagnostic pitfall.Clin Nephrol. 2013; 79: 302-312Crossref PubMed Scopus (19) Google Scholar Antibiotics constitute the first line of therapy. In contrast to that, primary IgAN is treated either with conservative management or with immunosuppression.8Coppo R. Treatment of IgA nephropathy: recent advances and prospects.Nephrol Ther. 2018; 14: S13−S21PubMed Google Scholar There are no specific biomarkers to distinguish between these 2 diseases. Sophisticated methods, such as mass spectrometry−based proteomics, have been attempted, but definitive conclusions are still lacking.6Julian B.A. Wittke S. Haubitz M. et al.Urinary biomarkers of IgA nephropathy and other IgA-associated renal diseases.World J Urol. 2007; 25: 467-476Crossref PubMed Scopus (38) Google Scholar In addition these methods are expensive, with longer turn-around time. Here we present our observations from direct immunofluorescence staining of optimal cutting temperature-embedded frozen tissue (part of the routine diagnostic workup of kidney biopsy samples), which may help to differentiate between SAGN and IgAN, if one includes in the equation IgA staining in globally sclerosed glomeruli. We have previously published case series on our cohort of patients with culture-proven SAGN.3Satoskar A.A. Nadasdy G. Plaza J.A. et al.Staphylococcus infection-associated glomerulonephritis mimicking IgA nephropathy.Clin J Am Soc Nephrol. 2006; 1: 1179-1186Crossref PubMed Scopus (111) Google Scholar,6Julian B.A. Wittke S. Haubitz M. et al.Urinary biomarkers of IgA nephropathy and other IgA-associated renal diseases.World J Urol. 2007; 25: 467-476Crossref PubMed Scopus (38) Google Scholar We expanded this database by adding recent cases of SAGN (30 biopsy samples, including 1 Streptococcus mutans case) and IgAN (45 biopsy samples) (see Supplementary Methods). All 75 biopsy samples showed distinct granular staining for IgA in the nonsclerotic glomeruli (Figure 1). Globally sclerosed glomeruli were identified in 47 biopsy samples (29 with IgAN and 18 with SAGN). Among the 29 biopsy samples of IgAN, 20 (69%) had positive granular staining for IgA in the globally sclerosed glomeruli and 9 (31%) cases did not. Among the 18 kidney biopsy samples with SAGN, only 1 case (5.6%) showed positive staining for IgA in globally sclerosed glomeruli, whereas the remaining 17 (94.4%) did not (Table 1, Figure 1).Table 1Distribution of positive and negative staining for IgA in sclerotic glomeruli between cases with primary IgA nephropathy and infection-associated glomerulonephritisIgA staining in sclerotic glomeruliPrimary IgA nephropathyInfection-associated glomerulonephritisTotalPositive20121Negative91726Total291847P = 0.000001; χ2 = 18.1. Open table in a new tab P = 0.000001; χ2 = 18.1. Based on these data, the sensitivity of positive IgA staining in globally sclerosed glomeruli for kidney biopsy samples with IgAN was 68.97% (confidence interval [CI], 49.17%−84.72%), and the specificity was 94.44% (CI, 72.71%−99.86%). The positive predictive value was 95.24% (CI, 74.56%−99.27%) and the negative predictive value was 65.38% (CI, 52.05%−76.67%). The positive likelihood ratio (i.e., the ratio between the probability of a positive test result given the presence of IgA nephropathy and the probability of a positive test result in SAGN) was 12.41 (CI, 1.82−84.70). Positive staining in the sclerotic glomeruli strongly favors primary IgAN. Negative staining in the sclerotic glomeruli raises the possibility of SAGN; however, considering that 31% of cases with primary IgAN also had negative staining in the sclerosed glomeruli, such a conclusion should be made with a caution. To evaluate whether these findings are valid on formalin-fixed paraffin-embedded tissue as well, we repeated direct immunofluorescence with proteinase antigen retrieval on formalin-fixed paraffin-embedded tissue sections of the same biopsy samples (part submitted for light microscopy). Excluding the biopsy samples that did not have globally sclerosed glomeruli in the tissue and some older cases with background serum staining, the final cohort included 16 cases of IgAN and 8 cases of SAGN. Among these, 13 of 16 IgAN and 1 of 8 SAGN cases showed positive IgA staining in globally sclerotic glomeruli, the remaining were negative in each group, giving a sensitivity of 81.25% and specificity of 87.50%. We had reported a significant difference in the presence of segmentally sclerosed glomeruli in kidney biopsy samples between patients with IgAN and SAGN.9Satoskar A.A. Suleiman S. Ayoub I. Hemminger J. Brodsky S.V. Bott C. et al.Staphylococcus infection-associated glomerulonephritis-spectrum of IgA staining and prevalence of ANCA in a single-center.Clin J Am Soc Nephrol. 2017; 12: 39-49Crossref PubMed Scopus (30) Google Scholar Because the current study included an expanded cohort of the previously reported patients, we reviewed the presence of segmentally sclerosed glomeruli in these biopsy samples. In the IgA nephropathy group, there were 24 cases with segmentally sclerosed glomeruli (S1 based on the MEST-C Oxford classification, where mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) and crescents (C) are evaluated) and 5 cases with S0. Among patients with SAGN, there were 2 cases with segmentally sclerosed glomeruli and 16 cases without segmentally sclerosed glomeruli in the tissue submitted for light microscopy (specificity, 88.89%; sensitivity, 82.76%). Our data indicate that staining in the globally sclerosed glomeruli may be another useful marker in the differentiation between IgAN and SAGN, but results should be interpreted only in the correct clinical context. The pathogenetic mechanism behind this finding probably has to do with the temporal relationship between the onset of glomerulonephritis and glomerular sclerosis. IgAN is known to be a chronic disease with continuous or intermittent deposition of immune complexes in the glomeruli over a prolonged period of time. The incidence of IgAN peaks at a younger age1Spector D.A. Millan J. Zauber N. et al.Glomerulonephritis and Staphylococcal aureus infections.Clin Nephrol. 1980; 14: 256-261PubMed Google Scholar; therefore, we hypothesize that the disease started before the glomerulus became sclerosed, and the immune complex deposits persisted even after it underwent sclerosis. On the other hand, SAGN is an acute, nonrecurring disease with a predilection for older adults in whom there is already age-related pre-existing glomerular sclerosis.2Yamashita Y. Tanase T. Terada Y. et al.Glomerulonephritis after methicillin-resistant Staphylococcus aureus infection resulting in end-stage renal failure.Intern Med. 2001; 40: 424-427Crossref PubMed Scopus (13) Google Scholar, 3Satoskar A.A. Nadasdy G. Plaza J.A. et al.Staphylococcus infection-associated glomerulonephritis mimicking IgA nephropathy.Clin J Am Soc Nephrol. 2006; 1: 1179-1186Crossref PubMed Scopus (111) Google Scholar, 4Nasr S.H. Markowitz G.S. Whelan J.D. et al.IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy.Hum Pathol. 2003; 34: 1235-1241Crossref PubMed Scopus (87) Google Scholar Therefore, immune complexes are much less likely to deposit in pre-existing globally sclerosed nonfunctioning glomeruli. The main limitation of our study is the small number of cases. However, it is a stringently selected population of individuals with primary IgAN and culture-proven SAGN in whom the diagnosis was confirmed by a thorough clinical history and serologic and urinalysis findings. The numbers were limited also because we could include only those biopsy samples that contained globally sclerosed glomeruli in the small fraction of the biopsy sample submitted for direct immunofluorescence. The finding, however, is valid on formalin-fixed paraffin-embedded tissue as well. We also confirmed our previous reported finding that presence of segmentally sclerosed glomeruli favors a diagnosis of primary IgAN over SAGN. We believe that evaluation of IgA staining in sclerosed glomeruli can help to differentiate between primary IgAN and SAGN in the right clinical context, and can aid in patient management in most cases. All the authors declared no competing interests. Download .pdf (.01 MB) Help with pdf files Supplementary File (PDF)
Immunoglobulin A
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Minimal change disease
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Sixty-one Sudanese patients with the nephrotic syndrome were studied. The relevant clinical and biochemical features are presented and discussed. Renal biopsy examinations showed that 12 patients (19·7%) suffered some systemic disease which was causing the nephrotic syndrome, while 49 (80·3%) had primary renal disease. Of the latter, 21 patients (34·4%) had proliferative glomerulonephritis, 13 (21·3%) had membranous glomerulonephritis, ten (16·4%) had minimal change and five (8·2%) had focal sclerosing glomerulonephritis. Amyloidosis was encountered in four patients, three of whom also had hepatosplenic schistosomiasis.
Minimal change disease
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Pathogenesis
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A quarter of a century ago, Jean Berger, using recently developed immunofluorescence methods, discovered diffuse mesangial deposits of IgA on light microscopy of kidneys with focal, glomerular lesions.1 IgA nephropathy is now the most common form of glomerulonephritis throughout the world, accounting for up to 10 percent of patients treated for end-stage renal disease.2 Patients with IgA nephropathy have better long-term outcomes than those with other forms of glomerulonephritis; their frequency of end-stage renal disease is 13 to 20 percent 10 years after diagnosis and 25 to 34 percent 20 years after diagnosis.3 As in most other forms of glomerulonephritis, . . .
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Objective To study the role of immunoglobulin A(IgA) deposition in the progress of IgA nephropathy by observing the co-expression of matrix metalloproteinase-9(MMP-9),its tissue inhibitor-1(TIMP-1) and IgA in IgA nephropathy patients with variant glomerular lesions.Methods Co-expression of MMP-9/IgA and TIMP-1/IgA in renal tissues from 56 patients with IgA nephropathy(Lee levels I-V) was detected with immunofluorescence double-staining.Results The TIMP-1/IgA was lowly expressed while the MMP-9/IgA was highly expressed in glomeruli of patients with IgA nephropathy(Lee levels I-II).The expression level of TIMP-1/IgA was higher while that of MMP-9/IgA was lower in glomeruli of patients with IgA neprhropathy(Lee level III).The expression level of TIMP-1/IgA was the highest while that of MMP-9/IgA was lower in glomeruli of patients with IgA nephropathy(Lee level IV-V) and the lowest in sclerotic glomeruli of patients with IgA nephropathy.Conclusion The IgA deposition and TIMP-1 expression are increased while the MMP-9 expression is decreased during the progress of IgA nephropathy,which suggests that IgA deposition-induced imbalance of MMP-9/TIMP-1 is involved in glomerular sclerosis in patients with IgA nephropathy.
Immunoglobulin A
Immunofluorescence
J chain
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IgA nephropathy is by far the most popular mesangial proliferative glomerulonephritis which can induce nephrotic syndrome. The etiology and pathogenesis of IgA nephropathy are still elusive, however. The enigma is that the IgA molecules deposited in glomeruli are mainly IgA1 subclass produced in central lymphoid organs and not the IgA2 subclass produced in peripheral mucous membrane, contrary to the notion that mucosal defense mechanism may be exacerbated in patients with IgA nephropathy. Recent investigations have elucidated that clearance of IgA might be deteriorated in these patients due to the abnormalities in the O-glycosylation of the hinge region of IgA molecules. The etiopathogenesis of IgA nephropathy elucidated in recent years is discussed.
Pathogenesis
Immunoglobulin A
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Mesangial proliferative glomerulonephritis
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