Family History Of Hematuria Research Articles

Guidelines for Genetic Testing and Management of Alport Syndrome.

Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Persistent Isolated Hematuria in a Japanese Woman.

A 43-year-old Japanese woman, with a family history of hematuria, underwent a kidney biopsy because of persistent hematuria without proteinuria, with serum creatinine of 0.55 mg/dl. Light microscopy revealed minor glomerular abnormalities. Electron microscopy predominantly showed thinning of the glomerular basement membrane (GBM); thickening and lamination were observed in small portions of the GBM (Figure 1A). Atypical Alport syndrome (AS) was suspected. Type IV collagen staining revealed weak α5(IV) expression with enhanced expression of α2(IV) in segmental lesions, consistent with AS (Figure 1, B and C). This case was presumed to be autosomal dominant AS (ADAS), because of the family history and preserved α5(IV) expression in the Bowman’s capsule, which indicate the mutation of COL4A3 or COL4A4 (Figure 1C) (1). Diagnosis of typical AS, namely, X-linked AS in males and autosomal recessive AS, is straightforward, and often made in childhood. In contrast, ADAS is usually suspected in adults because …

Internal carotid artery dissection, cerebral aneurysms and thin basement membrane nephropathy

JO N 2871 A previously well, 52-year-old woman presented after one week of headache, nausea and difficulty speaking. She had a history of hypertension treated with metoprolol and painless microscopic hematuria. There was no family history of hematuria or renal disease. Renal ultrasound and cystoscopy were normal, and a renal biopsy one year before presentation showed thin glomerular basement membrane nephropathy (TBMN, Fig. 1C). Examination revealed an expressive dysphasia and a right homonymous hemianopia. Blood pressure was 140/76; there were no overt clinical features suggestive of a connective tissue disorder. MRI and MR angiography showed a Nicholas J. Cutfield John L. Wilson L. Jonathan Zwi Barry J. Snow

Hereditary nephritis mimicking immune complex–mediated glomerulonephritis

The defining ultrastructural features of hereditary nephritis are "basket weave" lamellation or thinning of glomerular basement membranes. Electron-dense deposits are not seen and immunofluorescence (IF) is generally negative. In this study, we report 5 cases of hereditary nephritis in which substantial amounts of glomerular electron-dense deposits were identified on electron microscopy, with corresponding positive IF staining in 4 cases, suggesting immune complex-mediated glomerulonephritis. However, no case had histological evidence of glomerular endocapillary or extracapillary proliferation or leukocyte infiltration typical of active glomerulonephritis. Four cases were diagnosed at outside institutions simply as forms of glomerulonephritis without considering the possibility of hereditary nephritis and were sent for consultation in contemplation of possible immunosuppressive therapy. All patients had negative serologies and no known underlying infectious or autoimmune disease; 4 patients had family history of hematuria or renal disease. The glomerular electron-dense deposits were predominantly mesangial (4 cases) and intramembranous (4 cases), as well as subepithelial (2 cases) or subendothelial (1 case). Corresponding IF positivity for immune reactants was identified in 4 cases, and IgG was the predominant immunoglobulin deposited. A characteristic feature was the tendency for deposits to form between the complex layers of glomerular basement membrane material, favoring a process of nonspecific entrapment of immune reactants within the thickened, lamellated basement membrane. In all cases, a diagnosis of hereditary nephritis was confirmed by demonstration of the characteristic loss of immunoreactivity for the alpha5 subunit of collagen IV (4 cases) or Goodpasture's antigen (1 case) in renal or epidermal basement membranes. These cases expand the spectrum of unusual pathological findings in hereditary nephritis and emphasize the potential for hereditary nephritis to mimic immune complex glomerulonephritis.

Thin basement membrane nephropathy

Thin basement membrane nephropathy. Thin basement membrane nephropathy (TBMN) is the most common cause of persistent glomerular bleeding in children and adults, and occurs in at least 1% of the population. Most affected individuals have, in addition to the hematuria, minimal proteinuria, normal renal function, a uniformly thinned glomerular basement membrane (GBM) and a family history of hematuria. Their clinical course is usually benign. However, some adults with TBMN have proteinuria >500 mg/day or renal impairment. This is more likely in hospital-based series of biopsied patients than in the uninvestigated, but affected, family members. The cause of renal impairment in TBMN is usually not known, but may be due to secondary focal segmental glomerulosclerosis (FSGS) or immunoglobulin A (IgA) glomerulonephritis, to misdiagnosed IgA disease or X-linked Alport syndrome, or because of coincidental disease. About 40% families with TBMN have hematuria that segregates with the COL4A3/COL4A4 locus, and many COL4A3 and COL4A4 mutations have now been described. These genes are also affected in autosomal-recessive Alport syndrome, and at least some cases of TBMN represent the carrier state for this condition. Families with TBMN in whom hematuria does not segregate with the COL4A3/COL4A4 locus can be explained by de novo mutations, incomplete penetrance of hematuria, coincidental hematuria in family members without COL4A3 or COL4A4 mutations, and by a novel gene locus for TBMN. A renal biopsy is warranted in TBMN only if there are atypical features, or if IgA disease or X-linked Alport syndrome cannot be excluded clinically. In IgA disease, there is usually no family history of hematuria. X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen alpha3(IV), alpha4(IV), and alpha5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation. Technical difficulties in the demonstration and interpretation of COL4A3 and COL4A4 mutations mean that mutation detection is not used routinely in the diagnosis of TBMN.

Mutations in the COL4A4 gene in thin basement membrane disease

Patients with thin basement membrane disease (TBMD) are often from families where hematuria segregates with the COL4A3 and COL4A4 genes. These genes also are affected in autosomal recessive Alport syndrome. The aim of this study was to demonstrate COL4A4 mutations in TBMD. Forty-eight unrelated individuals with TBMD who had no family members with autosomal recessive Alport syndrome were examined for COL4A4 mutations. The diagnosis of TBMD had been confirmed by renal biopsy (43/48, 90%) or by a family history of hematuria but without a renal biopsy (5/48, 10%). The 47 coding exons of COL4A4 were screened for mutations with the methods of enzyme mismatch cleavage or single stranded conformational polymorphism (SSCP) analysis, and exons that demonstrated electrophoretic abnormalities were sequenced. Nine variants that altered the coding sequences were identified. These were nonsense and frameshift mutations that resulted in stop codons (N = 3), and glycine (N = 3) and non-glycine missense variants (N = 3). Four intronic variants and three neutral polymorphisms were also detected. In total, four variants were considered 'pathogenic' principally because they resulted in stop codons or were not present in non-hematuric normal subjects. Three variants were considered 'possibly pathogenic' but two of these were each present in one of 46 non-hematuric normal subjects. Pathogenic COL4A4 mutations were demonstrated in three of the nine (33%) families in whom hematuria segregated with the COL4A3/COL4A4 locus. Two stop codons (R1377X and 2788/91delG) and a glycine substitution (G960R) resulted in hematuria in all 16 members who were tested from these three families. The S969X mutation described here in TBMD for the first time, as well as the R1377X mutation, also occur in autosomal recessive Alport syndrome.

Histopathology, ultrastructure, and clinical phenotypes in thin glomerular basement membrane disease variants

Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms. We examined kidney pathology and collagen α 3 to α 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, α 3 to α 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen α 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen α 3 to α 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure. We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved α 3 to α 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded. HUM PATHOL 33:836-845. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Nonfamilial hematuria associated with glomerular basement membrane alterations characteristic of hereditary nephritis: Comparison with hereditary nephritis

Characteristic ultrastructural alterations of the glomerular basement membrane (GBM) have been reported in hereditary nephritis and in children without a family history of renal disease. The clinical features, renal biopsy findings, and subsequent course were studied retrospectively in 48 children with such GBM changes to compare findings in those with and without a family history of nephritis and to determine the significance of the GBM changes in patients with nonfamilial disease. All 48 patients had hematuria. For 30, there was hematuria in at least one other member of the family (familial hematuria group); for 18, there was no familial incidence. There were no differences between the two groups with regard to clinical and pathologic findings. At the latest follow-up six boys with familial hematuria and three boys with nonfamilial hematuria had reduced renal function, and nine boys with familial hematuria and four boys and one girl with nonfamilial hematuria had neurosensory deafness. Our study results show that children with these GBM changes, with or without a family history of hematuria, tend to have a progressive course, with frequent occurrence of neurosensory deafness, and that the prognosis is more severe in boys. These observations suggest that such GBM changes in patients with nonfamilial hematuria may represent new mutations for hereditary nephritis.

Isolated Hematuria in Children: Indications for a Renal Biopsy

Previous reviews of hematuria in children and adolescents have included patients with proteinuria and other renal functional abnormalities such as hypertension and reduced GFR. We report the clinico-pathological correlations in 76 pediatric patients, aged 3 to 19 years, who underwent a renal biopsy because of isolated hematuria during the 10-year period, 1972 to 1981. All specimens were examined by light and electron microscopy and immunofluorescence techniques. The overall prevalence of abnormal renal histology was 56%. The vast majority (41 of 43) of the abnormal biopsy specimens could be classified into four distinct histological categories: (1) Alport syndrome (N = 9); (2) IgA nephropathy (N = 8); (3) thinning of the glomerular basement membrane (N = 17); (4) vascular C3 staining (N = 7). The children were divided into three clinical subgroups (1) isolated microscopic hematuria ( IMH ), N = 42; (2) IMH plus a family history of hematuria in a first degree relative, N = 15; and (3) IMH plus at least one episode of gross hematuria, N = 19. A significant graded increase in the likelihood of obtaining an abnormal renal biopsy was demonstrated (X2 = 10, P less than 0.007) from groups one to three. Sex, age at onset, or duration of hematuria were not associated with an increased proportion of histopathologic abnormalities. These findings indicate that the yield of a renal biopsy in children with isolated hematuria can be predicted accurately from specific clinical characteristics.

Isolated hematuria in children: Indications for a renal biopsy

AbstractIsolated hematuria in children: Indications for a renal biopsy. Previous reviews of hematuria in children and adolescents have included patients with proteinuria and other renal functional abnormalities such as hypertension and reduced GFR. We report the clinico-pathological correlations in 76 pediatric patients, aged 3 to 19 years, who underwent a renal biopsy because of isolated hematuria during the 10-year period, 1972 to 1981. All specimens were examined by light and electron microscopy and immunofluorescence techniques. The overall prevalence of abnormal renal histology was 56%. The vast majority (41 of 43) of the abnormal biopsy specimens could be classified into four distinct histological categories: (1) Alport syndrome (N = 9); (2) IgA nephropathy (N = 8); (3) thinning of the glomerular basement membrane (N = 17); (4) vascular C3 staining (N = 7). The children were divided into three clinical subgroups (1) isolated microscopic hematuria (IMH), N = 42; (2) IMH plus a family history of hematuria in a first degree relative, N = 15; and (3) IMH plus at least one episode of gross hematuria, N = 19. A significant graded increase in the likelihood of obtaining an abnormal renal biopsy was demonstrated (X2 = 10, P < 0.007) from groups one to three. Sex, age at onset, or duration of hematuria were not associated with an increased proportion of histopathologic abnormalities. These findings indicate that the yield of a renal biopsy in children with isolated hematuria can be predicted accurately from specific clinical characteristics.Hematurie isolee de l'enfant: Indication de la biopsie renale. Desrevues antérieures sur les hématuries de les enfants et de les adolescents incluaient les malades ayant une protéinurie et d'autres anomalies fonctionnelles rénales comme une hypertension et une diminution de GFR. Nous rapportons des corrélations clinico-pathologiques chez 76 malades pédiatriques, âgés de 3 à 19 ans, qui ont subi une biopsie rénale en raison d'une hématurie pendant une période de 10 ans, 1972 à 1981. Tous les échantillons ont été examinés en microscopie optique et électronique, et avec des techniques d'immunofluorescence. La prévalence globale d'une histologie rénale anormale était de 56%. La grande majorité (41 du 43) des échantillons biopsies anormales pouvait être classée en quatre catégories histologiquement distinctes:(1) Syndrome d'Alport (N = 9);(2) néphropathie à IgA (N = 8);(3) amincissement de la membrane basale glomérulaire (N = 17); et(4) coloration vasculaire avec C3 (N = 7). Les enfants ont été divisés en trois sous-groupes cliniques:(1) hématurie microscopique isolée (IMH), N = 42;(2) IMH plus une histoire familiale d'hématurie chez un parent du premier degré, N = 15;(3) IMH plus au moins un épisode d'hématurie macroscopique, N = 19. Une augmentation progressive significative de la possibilité d'obtenir une biopsie rénale anormale a été démontrée (X2 = 10, P < 0,007) des groupes un à trois. Le sexe, l'âge lors de la découverte, ou la durée de l'hématurie n'étaient pas associés à une proportion augmentée d'anomalies histopathologiques. Ces données indiquent que le résultat d'une biopsie rénale chez des enfants avec une hématurie isolée peut être prédit de façon précise à partir de caractéristiques cliniques spécifiques.