Biomedical subjects
R Habib
Publications and source records attributed to R Habib.
Infantile cystinosis: a reappraisal of early and late symptoms.
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[Hemolytic-uremic syndrome in children and arterial hypertension].
Seventy patients (55 infants and 15 children) with the hemolytic uremic syndrome (HUS) were reviewed to evaluate the incidence of hypertension in HUS. Refractory hypertension was only observed in 5 infants (3 at onset and 2 after several months), whereas it was present in 9 children (4 at onset and 5 in the course of the disease). Controllable hypertension was present in 10 patients (8 infants and 2 children). Histopathological examination of renal specimens in 52 patients showed 3 patterns: cortical necrosis in 10, Thrombotic microangiopathy (TMA) with predominant glomerular involvement in 29 and TMA with predominant arterial involvement in 13. Clinicopathologic correlations showed that severe hypertension was almost exclusively observed in the patients with "vascular TMA". Bilateral nephrectomy performed in 8 patients led to the rapid disappearance of hypertension, thus demonstrating the role of hyperreninaemia in the development of hypertension in the HUS.
A serum C3-activating factor: its characterization and its presence in glomerular deposits.
A non-IgG C3 activating factor (C3AF) isolated from the serum and plasma of a patient with membranoproliferative glomerulonephritis with subendothelial and subepithelial deposits (type III) was studied to define its molecular structure, functional characteristics, and presence in renal biopsies. Alternative complement pathway (ACP) activation of C3 was comparable to that of zymosan, but significantly less than that of IgG C3 nephritic factor (C3NeF). Functionally active isolate contained beta 1H globulin (beta 1H) and the C3AF protein, which had a gamma-electrophoretic migration. beta 1H present in the isolate exhibited an altered gamma-beta electrophoretic mobility. The function of this complex is heat labile. Time/temperature studies demonstrated that inactivated preparations of this isolate show a return to the normal beta migration of beta 1H followed by the development of an alpha 2 electrophoretic migration of the previously gamma-migrating material of functionally active isolate. Normal human serums contain an alpha 2 protein that shows complete antigenic identity with the gamma protein of C3AF, but this alpha 2 protein lacks C3 activating function. On polyacrylamide gel electrophoresis, the C3AF isolate contains a high m.w. protein of 500,000 to 590,000 that is composed of 2 major subunits. Carbohydrate is not demonstrable, and the protein is antigenically distinct from plasma fibronectin. Immunofluorescence studies of renal biopsies of patients with types I and III MPGN revealed the presence of C3AF antigen in granular deposits in 10 of 16 cases. The presence of this antigen in glomerular deposits was associated with C3 and beta 1H, but was independent of Ig. These studies suggest that the mechanism of ACP activation by C3AF results from interference with beta 1H function. The presence of this material in renal biopsies from some MPGN patients further suggests a pathogenetic role in mediating glomerular pathology.
Complement activation in nonsystemic glomerular diseases in children.
All forms of glomerulonephritis (GN) in man seem to be immunologically mediated and the complement system appears as one of the most important mediators of renal injury. The study of complement activation is therefore of great help in the identification of the immunopathogenic process involved in the various types of glomerular diseases. After a review of the molecular events of complement activation and the methods used to study the complement system in man, we will attempt to summarize current knowledge concerning complement in nonsystemic glomerular diseases frequently encountered in children. The terms used are those descriptive of glomerular morphology as defined either by light microscopy and electron microscopy (endocapillary-proliferative GN with humps, extramembranous GN, membranoproliferative GN) or by immunofluorescent microscopy (mesangial IgA GN).
Glomerular basement membrane changes in nonhereditary glomerular diseases.
Some examples of glomerular lesions developing in different types of nonhereditary glomerular diseases have been described. In most of them, secondary glomerular basement membrane changes are important factors in the development and progression of the glomerular lesions. When severe, they initiate irreversible glomerular scar formation.
Glomerular basement membrane changes in hereditary glomerular diseases.
Ultrastructural glomerular basement membrane changes are present in most hereditary glomerular diseases: thick and thin basement membrane with splitting of the lamina densa in Alport's syndrome, thin basement membrane in familial benign essential hematuria, and thick basement membrane with the presence of collagen-like fibrils in the nail-patella syndrome. They are useful markers for diagnosis. Moreover, their knowledge has set the problem of the primary biochemical defect in basement membrane metabolism accounting for morphological abnormalities and clinical disturbances. Further biochemical and immunochemical investigations are still required for a better understanding of hereditary glomerular diseases.
Membranous glomerulonephritis with extra-renal disorders in children.
Thirty of 85 children with membranous glomerulonephritis (MGN) had associated extraglomerular disorders. The relation of these associations to membranous glomerulonephritis (MGN) is discussed. The causal relationship of acute hepatitis (5 cases), persistent hepatitis B antigenemia (6 cases), systemic lupus erythematosus (2 cases) and syphilis (1 case) may be ascertained; in similar conditions a definite antigen (Ag) has been found in MGN deposits. The association with SS or SA hemoglobinopathy (3 cases) ans with a preceding streptococcal infection (4 cases) raises the possible responsibility of renal tubular epithelium (RTE) Ag and of a streptococcal Ag. D-penicillamine therapy (1 case) is a well-known cause of MGN although the acting Ag remains unknown. Four children had serum sickness-like symptoms, two had hematologic disorders and two had proximal tubular dysfunction, one of them with proven anti-tubular and anti-alveolar basement membrane antibodies. A decrease in plasma C4, Clq, and factor B with normal C3 was frequently observed. The multiple Ag previously described as causative of MGN are recalled. The prevalent incidence of HBsAg is stressed, and the necessity for further investigations in patients with MGN in order to find an underlying disease is emphasized.
Immunologically mediated tubulo-interstitial nephritis in children.
14 children with proven or presumably immunologically mediated tubulo-interstitial nephritis are presented. In 2 patients anti-tubular basement membrane antibodies were detected. In 6 immunofluorescence microscopy showed granular deposits of immunoglobulin and/or complement likely representing interstitial location of immune complexes. The findings by immunofluorescence were not significant in the remaining 6 patients. However, the association of renal disease to extra-renal disorders, namely chronic active hepatitis and ulcerative colitis, or uveitis or the presence of an epithelioid granuloma with multinucleated giant cells suggests that in such patients an immunologic disorder might be responsible for the tubulo-interstitial nephritis.
Clinicopathologic correlations in the nephrotic syndrome.
The wide utilization of renal biopsy and the introduction of electron microscopic and immunohistologic methods has allowed better definition of the clinico-pathological conditions associated with the nephrotic syndrome (NS). Two major categories of facts can be differentiated. In the first one, diffuse lesions of glomeruli, either secondary to specific diseases, or apparently primary diseases such as membranous or membrano-proliferative glomerulonephropathy (GN) are responsible for the increased permeability of the glomerular capillaries. In most of these, there is evidence that immunological mechanisms play a role in the injury of the glomerular capillary. Any of the following clinical symptoms are suggestive of this category of NS: an acute nephritic onset, a moderate NS, macroscopic hematuria, marked hypertension and/or renal insufficiency, poorly selective proteinuria and decreased plasma C3 levels. Patients affected with any of these glomerulopathies usually do not respond to steroids. In the second one, usually referred to as the idiopathic nephrotic syndrome (INS) the mechanism of glomerular capillary alteration is unknown and the nephrotic syndrome is more marked. Minimal change NS (MCNS) accounts for the great majority of INS and is characterized in most cases by a selective proteinuria, the absence of hematuria, a good response to steroids and a good prognosis. However, in some instances, renal biopsy reveals either diffuse mesangial proliferation (DMP) or focal glomerular sclerosis (which may be superimposed on MCNS or on DMP). In both instances, hematuria may be present and 50--75% of patients do not respond to steroids and have a poor prognosis. There is still considerable controversy about the exact relationship between these 3 patterns. We believe that they are not distinct entities but represent variants of the same disease. In addition to these 2 major categories of NS, there are, in infancy, 2 conditions associated with a NS of poor prognosis: congenital NS of Finnish type and infantile mesangial sclerosis. Since steroid-sensitive nephrosis is by far the commonest cause of NS especially in young children up to 8 years, a renal biopsy should be performed only in 2 instances: (a) when the clinical symptoms suggest diffuse glomerular lesions, and (b) when steroid resistance has been demonstrated.
[Complement and nephritic activity in membranoproliferative glomerulonephritis].
A study of complement profiles and of "nephritic activity" (NeF activity) has been carried out in 33 children presenting with membranoproliferative glomerulonephritis (MPGN), in order to determine the pathway of complement activation. By morphological studies two varieties of MPGN have been distinguished. In MPGN with subendothelial deposits, immunofluorescent studies and complement profiles show an activation by the classical pathway. The demonstration of NeF activity in 7 of 20 patients suggests that there is recruitment of the amplification pathway. In MPGN with dense deposits, immunopathological studies indicate an activation of the complement system through the alternate pathway, NeF activity being present in 10 of 13 patients. With the functional tests used, it is not possible to ascertain that the factors responsible for the NeF activity in MPGN with subendothelial deposits are identical to the C3NeF identified in MPGN with dense deposits and/or partial lipodystrophy.
[The hemolytic and uremic syndrome of the child].
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Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN)
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Early renal changes in hemizygous and heterozygous patients with Fabry's disease.
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Membranous glomerulonephritis associated with anti-tubular and anti-alveolar basement membrane antibodies.
The renal biopsy of a 3-year old boy with complete Fanconi syndrome showed the association of a membranous glomerulonephritis with severe tubulointerstial changes. Immunofluorescence microscopy disclosed linear and granular deposits of Ig along tubular basement membranes. The presence of anti-tubular basement membrane antibodies in the patient's serum was demonstrated by indirect immunofluorescence and radioimmunoassay. The child also developed pulmonary involvement associated with episodes of acute anemia. Anti-alveolar basement membrane antibodies were detected by indirect immunofluorescence. The present case is the first reported example of auto-immune disease characterized by the presence of anti-tubular and alveolar basement membrane antibodies associated with an immune complex glomerulonephritis.
The significance of pure diffuse mesangial proliferation in idiopathic nephrotic syndrome.
The prognostic significance of the finding of diffuse mesangial proliferation (DMP) in patients presenting with idiopathic nephrotic syndrome (INS) has not been well established. The clinical course, therapeutic response and final outcome of 38 patients in whom renal biopsy showed DMP are reported. They have been subdivided into 2 groups according to the absence (18 patients: group I) or presence (20 patients: group II) of superimposed lesions of focal and segmental sclerosis and/or hyalinosis (FSS/H). Clinical presentation was similar in both groups although patients in group I were less severely affected. Non of the patients of group II responded to corticosteroids, whereas in group I 2/16 responded and 2 infants remitted without treatment. At the latest assessment, 5/18 patients in group I and 10/20 in group II had progressed to terminal renal failure or had impaired renal function. Five patients in group I and 3 in group II were in clinical remission. Eight of 11 repeat biopsies performed in patients of group I showed the development of FSS/H. Thus patients with DMP seem prone to develop lesions of FSS/H. Their course if often worse than that of minimal change with FSS/H since 7 of the 10 patients who developed renal failure did so within 3 years of onset. The finding of DMP in a patient with idiopathic nephrotic syndrome is usually but not invariably an ominous feature.
[Recurrent macroscopic hematuria in children].
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Anaphylactoid purpura nephritis in childhood: natural history and immunopathology.
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