Childhood membranoproliferative glomerulonephritis: an approach to management.
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Aspirin↗
Biomedical subjects
C D West
Publications and source records attributed to C D West.
IgA synthesis by lymphocytes from patients with IgA nephropathy and their relatives.
To investigate the hypothesis that a predisposition to IgA nephropathy (IgAN) is linked to the major histocompatibility complex (MHC) and associated with poorly regulated IgA synthesis, we performed HLA typing and lymphocyte cultures on patients with IgAN and their relatives. Nineteen of 22 patients had elevated culture supernatant IgA concentrations (620 vs. 154 ng/2 X 10(6) cells, P = 0.007). Supernatant IgG and IgM were normal. No HLA antigen occurred with increased frequency in patients. There was an increased incidence of homozygous null C4 alleles in patients (P less than 0.01). In families, six of 11 mothers, six of 12 fathers, and seven of 15 siblings had elevated supernatant IgA concentrations. There was no segregation of abnormal IgA production with any HLA antigen or parental haplotype. The data confirm elevated in vitro IgA production by lymphocytes from patients with IgAN, but do not support a linkage with the MHC. The increased incidence of homozygous null C4 alleles may result from functional differences in C4 A and B gene products. The familial clustering of elevated IgA production without an obvious inheritance pattern suggest that shared environmental factors may be important in the development of IgAN.
Alleles↗
Minoxidil for control of acute blood pressure elevation in chronically hypertensive children.
Twenty-three episodes of acute elevation of BP related to renal disease in 13 chronically hypertensive children 2 to 18 years of age were treated with a single oral dose of minoxidil. All except one patient were receiving a diuretic and all but one a beta-blocking agent at the time of minoxidil treatment. The goal of lowering BP to or below the 95th percentile for age within four hours of minoxidil administration was achieved in 14 of 23 treatment episodes. The goal was achieved in nine of 11 (82%) when the dose of minoxidil was greater than or equal to 0.2 mg/kg and in five of 12 (42%) when the dose was less than 0.2 mg/kg (P less than .05). In patients treated with greater than or equal to 0.2 mg/kg of minoxidil, mean systolic and diastolic BP decreased significantly from pretreatment values within one hour. In patients receiving less than 0.2 mg/kg, mean systolic BP was never significantly reduced and mean diastolic BP did not change significantly for two hours. Adverse effects were minimal. The results indicate that minoxidil in a dose of 0.2 mg/kg in combination with a diuretic and beta-blocking agent will lower BP to safe levels in most patients with severe hypertension related to renal disease within four hours with minimal side effects.
Adolescent↗
The effect of null C4 alleles on complement function.
C4 is encoded at two polymorphic genetic loci (C4A and B), and "null" or unexpressed alleles are relatively common. An increased frequency of nulls has been reported in a variety of diseases. In the present study, C4 allotypes and C4 hemolytic efficiencies (the ratios of functional to antigenic levels) were determined for a population of 75 normal unrelated individuals. Of these, 28 had three gene products (single null at C4A or B) while three had no expressed C4A products and three had no C4B products (homozygous null). Mean antigenic C4 levels correlated with the number of expressed gene products but there was a wide spread of individual values. Those homozygous null for C4A had greater, and for C4B less, hemolytic efficiency than those with four gene products. However, there was no difference in the in vitro kinetics of C3 convertase formation between homozygous null C4A or C4B individuals. Therefore, the presence of null genes for C4 does not appear to compromise complement function sufficiently to account for the reported disease associations. Some of the associations may result from the fact that null genes for C4, as part of an extended HLA haplotype, may be genetically linked to disease susceptibility.
Adult↗
Atypical hypocomplementemic vasculitis syndrome in a child.
We report a patient who developed recurrent urticaria and angioedema at age 2 years, severe hypocomplementemic glomerulonephritis at 11 years, and end-stage renal disease at 14 years. His disease resembled the hypocomplementemic vasculitis syndrome but was atypical in its early age of presentation, severe hypocomplementemia, and progression to end-stage renal disease. Serum C1q levels were extremely low, and C4, C2, C3, and C5 levels were significantly reduced. Serum C1 inhibitor (C1INH) levels were slightly low, presumably from consumption. Circulating C1INH-C1r-C1s complexes were evidenced by reduced ratios of functional to antigenic C1INH and antigenic C1r to C1s. Family members had normal functional and antigenic levels of all complement components studied. The patient's serum, erythrocytes, platelets, and mononuclear cells did not activate complement when mixed with normal target serum. Absence of a circulating complement activator and the low serum C3 and C5 levels suggested the presence of a solid-phase complement activator, possibly related to renal or systemic vascular endothelium. As in patients with homozygous deficiencies of classical pathway components, a severe, prolonged, acquired C1q deficiency may have predisposed this patient to the development of glomerulonephritis.
Angioedema↗
The effect of prednisone in a high-dose, alternate-day regimen on the natural history of idiopathic membranoproliferative glomerulonephritis.
Experience in 45 children with diffuse proliferative MPGN of all three types has provided evidence that a high-dose, alternate-day regimen of prednisone alters the natural history of the disease. The experience has been gained over a 17-year period and the patients have been followed on the regimen for an average of 6.5 years. Evidence that the regimen has a salutary effect was provided by several observations: Survival was better than that in four other series in which the patients were not treated or treated sporadically. The difference was particularly marked when survival was compared with that in series in which the patients had diffuse proliferative lesions exclusively. Mesangial proliferation was less in biopsies obtained after 2 or more years of the alternate-day regimen. This was quantitated as a significant increase in the estimated percentage of open glomerular capillary lumens and a significant diminution in the prominence of PAS-positive mesangial matrix. In the second biopsy, as compared to the pre-regimen biopsy, no patient had a diminution in the estimated percent of open capillary lumens and 65% had a meaningful increase. Likewise, only 3% had an increase in prominence of PAS positive matrix and 68% had a diminution in matrix prominence. Of 32 patients who were hypoalbuminemic when the regimen started, the level rose into the normal range in 62%. The level became subnormal in none of the 13 who had a normal level at the start of the regimen. While receiving the regimen, renal function, as measured by serum creatinine levels, continued to be normal or improved in 73% and deteriorated in 27%. Hematuria disappeared in 80% of the 41 in whom it was present when the regimen started. Urinalysis became completely normal in 27% and none of these have relapsed while under observation. Comparison of data from 20 patients who did not receive the regimen for an average of 42 months after clinical onset with data for 25 patients who likewise were, on the average, 42 months from clinical onset but who had received the regimen for an average of 38 of those months provided the most convincing evidence that the regimen altered the natural history. In those receiving the regimen, the frequency of hematuria, proteinuria, and hypoalbuminemia was significantly less.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
The relationship of the spiral turns of the cochlea and the length of the basilar membrane to the range of audible frequencies in ground dwelling mammals.
The number of turns in the cochlear spiral and length of the basilar membrane in several mammalian species were compared with the octave range and the high-and low-frequency limits of hearing. Basilar membrane length and the number of spiral turns were not related. Among ground dwelling mammals, the number of turns in the cochlear spiral was more strongly related to octave range than was basilar membrane length. Basilar membrane length was inversely related to the high-and low-frequency limits of hearing. The best estimates of high-and low-frequency limits and octave range were derived from formulas which included both the number of turns in the cochlear spiral and the basilar membrane length as factors. The number of turns in the cochlear spiral was most highly correlated with the difference between the low-frequency limit of hearing and the lowest frequency mechanically analyzed by the traveling-wave envelope, peak-shift property of the basilar membrane [von Békésy, Experiments in Hearing (McGraw-Hill, New York, 1960)]. The coefficient of correlation for the number of spiral turns and the octave difference between the lowest audible frequency and the lowest frequency distributed as a unique point of maximum displacement along the basilar membrane was r = 0.997 (P less than .001) at 60 dB SPL. Mechanisms by which the spiral form of the cochlea may affect the motion of hair cells and the selective response of the tectorial membrane to differences among traveling-wave envelope slopes and peak locations were reviewed. It was proposed that in ground dwelling mammals, the spiral form of the cochlea extends the octave range of hearing and that through mechanisms such as these increases the sensitivity of the cochlea to frequencies below the low-frequency peak-shift limit of the basilar membrane.
Animals↗
A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.
C3 nephritic factor (C3NeF) was used to assess the formation of the fluid-phase amplification convertase, C3b,Bb, in 37 serum specimens from 24 patients with systemic lupus erythematosus (SLE). C3b,Bb formation was measured by the concentration of Ba, released when C3b,B is activated. Incubation of normal human serum (NHS) with C3NeF accelerates C3b amplification loop turnover with the formation of large quantities of C3b,Bb. In contrast, sera from 22 of 24 patients with SLE formed little or no convertase when incubated with C3NeF. C3 conversion to C3b was commensurately reduced. The inhibition could not be attributed to depressed serum concentrations of C3, factor B, or classical pathway components. Inhibitor present in excess could be demonstrated in 23 of 34 specimens of SLE serum by mixing experiments. The spontaneous convertase formation that occurs when a portion of the serum H is inactivated with F(ab')2 anti-H was also shown to be inhibited in SLE serum. The inhibition was found, however, to be H dependent in that convertase formation was normal in SLE serum depleted of H. It is concluded that the C3b in most SLE sera is unusually susceptible to inactivation by H, but a functional abnormality was not demonstrable in either C3 or H isolated from SLE serum. The inhibition could be simulated in NHS by addition of heparin, 100 micrograms/ml. In vivo, inhibition of convertase formation could interfere with the solubilization and disposal of immune complexes by reducing the deposition of C3b on the immune complex lattice.
Complement Activating Enzymes↗
Adrenal corticoid hyperresponsiveness in hirsute women.
Data are limited on the existence of adrenal hyperplasia or cortisol oversecretion in women with hirsutism. Supranormal responses of cortisol (greater than 20 micrograms/dl) were observed at 15 and 30 minutes after the 8:00 A.M. adrenocorticotropin (0.5 U) injection (performed after 1 mg of dexamethasone taken orally at midnight) in 6 of the 12 hirsute women (hirsute I) and in all 4 women with Cushing's disease. Baseline plasma levels of corticoids, androgens, and gonadotropins, body weight, menstrual history, and degree of hirsutism were all indistinguishable between the two hirsute groups. The mean plasma levels of cortisol and 17-hydroxyprogesterone were both significantly greater in the hirsute I group and in those with adrenal hyperplasia caused by Cushing's disease than in normal subjects. Our data indicate that adrenal hyperplasia is a common abnormality in women with hirsutism. We speculate that this abnormality may contribute to the pathogenesis of hirsutism and ovarian dysfunction in many hirsute women.
Adolescent↗
Inherited complement component deficiencies in membranoproliferative glomerulonephritis.
Anecdotal reports of complement component deficiencies in patients with immune complex disease led to a systematic study of the levels of seven complement components in serum specimens from 178 patients with glomerulonephritis and 163 normal subjects. Deficiencies were found with significantly higher frequency (22.7%) among 44 patients with membranoproliferative glomerulonephritis (MPGN) types I and III, than among the normal subjects (6.7%, P less than 0.002) or among 134 patients with other glomerulonephritides (5.2%, P less than 0.001). The component deficiencies in MPGN were partial in nine patients and subtotal in one. They could not be ascribed to acquired hypocomplementemia or to a nephrotic syndrome. They were present over long periods, were found in family members, and involved C2, C3, factor B, C6, C7, and C8. Six were presumably the result of null structural genes, two were associated with a structurally abnormal component, and two were of unknown cause. The results give evidence that partial deficiency of one or more complement components is a factor predisposing to MPGN.
Adolescent↗
An inherited defect in the C3 convertase, C3b,Bb, associated with glomerulonephritis.
The control of the amplification C3 convertase, C3b,Bb, of the serum complement system has been found to be defective in five members of a family spanning three generations. One of the five has membranoproliferative glomerulonephritis (MPGN) type III and another has mild idiopathic rapidly progressive glomerulonephritis. The defect is manifested by low serum concentrations of C3 and usually factor B with normal levels of the proteins which control the convertase, H and I. C3 nephritic factor (C3NeF) was not demonstrable. Enhanced C3 conversion was produced by the incubation of their serum at 37 degrees C for 30 min. This conversion was further accelerated by incubation after increasing the serum magnesium concentration by increments ranging from 0.25 to 1.9 mM. Incremental additions of H to serum depleted of H indicated that the amplification convertase of affected family members required more H for its inhibition than did that of normal subjects. This requirement was reduced by the addition of purified normal C3 but not by the addition of purified C3 of the propositus. It is postulated that affected family members are heterozygous for a gene producing an abnormal C3 which, as a constituent of the amplification convertase, C3b,Bb, confers resistance to H. Investigation of this apparently nephritogenic defect may provide insight into the pathogenesis of these glomerulonephritides.
Adult↗
Reduced alternative complement pathway control protein levels in anorexia nervosa: response to parenteral alimentation.
Serum levels of 16 proteins, including 11 component and control proteins of the complement system were determined before and after nutritional repletion in five female patients with severe malnutrition secondary to anorexia nervosa. Before parenteral alimentation significantly decreased serum levels were found for IgG, IgM, transferrin, Clq, C2, C3, factor B, beta lH, C3b inactivator, properdin, and C4 binding protein. A significant increase in posttreatment serum levels compared with pretreatment levels were found for transferrin, C3, factor B, beta lH, and C3b inactivator. Of the proteins measured, the C3b amplification loop control and component proteins, beta lH, C3b inactivator, C3, and factor B rose to the normal range in response to therapy most rapidly. In the absence of an acute phase reaction, these proteins appear to be particularly good indices of malnutrition and its response to therapy.
Adolescent↗
Membranoproliferative glomerulonephritis characterized by focal, segmental proliferative lesions.
Of 61 children with membranoproliferative glomerulonephritis (MPGN), 6 (10%) were distinguished by segmental lesions in up to 1/3 of glomeruli. Light microscopy showed mild to moderate generalized mesangial proliferation in addition to segmental membranoproliferative lesions. Mesangial fluorescence with antiserum to C3 was present in all glomeruli while focal lesions were characterized by segmental granular fluorescence with antiserum to IgG. Segmental lesions, identified by electron microscopy in four biopsies, were produced by prominent mesangial proliferation. Subendothelial deposits were present in two. Contiguous subendothelial and subepithelial deposits were present in one, and in a fourth, capillary wall deposits could not be found although mesangial deposits were present. Circulating immune complexes were present in 2 of the 4 hypocomplementemic patients and 1 normocomplementemic patient. Clinically, all patients presented with hematuria (gross in 3) and five had proteinuria. Only one had hypoalbuminemia. All patients have improved (5 treated with alternate day prednisone) as judged by the return of complement levels to normal and by improvement in urinalysis and in glomerular morphology on subsequent biopsy. The results give evidence that focal, segmental MPGN is an early manifestation of Type 1 or, uncommonly, Type III MPGN and that the patients have an excellent prognosis.
Antigen-Antibody Complex↗
Circulating immune complexes in membranoproliferative glomerulonephritis.
Circulating immune complexes (CIC), measured by the solid-phase Clq method, were found to be in abnormal concentration in about half of 39 patients with membranoproliferative glomerulonephritis (MPGN). In contrast, they were present, usually in higher concentration, in nearly all patients with active lupus nephritis. Correlations between clinical course and CIC levels in patients with MPGN showed that complexes were always present when the disease was mild or "silent," but when renal impairment developed or was incipient, complexes were nearly always absent. In patients with disease of intermediate severity, characterized by definite proteinuria but without renal impairment, 50% had complexes. The presence of complexes when glomerular abnormality is relatively slight could be interpreted as indicating that the complexes measured were not nephritogenic, or that they program subsequent events that augment glomerular injury in the absence of complexes. The measurement of CIC in MPGN appears to have minimal value both in diagnosis and in determining prognosis.
Adolescent↗
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.
Chemical Precipitation↗
Membranoproliferative glomerulonephritis in two sibships.
In one sibship, a brother had membranoproliferative glomerulonephritis (MPGN) Type III and a sister, Type I. In both children, clinical and laboratory manifestations were typical. In another sibship, both boys had Type I MPGN by glomerular morphology but over a 4 year period of follow-up, neither had hematuria or hypocomplementemia, both common manifestations of this type. Several other reports give suggestive evidence of MPGN in siblings but details are scanty. The familial nature of the disease adds to the earlier observation of its predilection for the white race to strengthen the concept that genetic factors are involved in its origin.
Child↗
Dexamethasone in nonsuppressible Cushing's disease.
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Adrenocorticotropic Hormone↗