Intensive plasma exchange in crescentic glomerulonephritis: help or no help?
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Antibodies↗
Biomedical subjects
R J Glassock
Publications and source records attributed to R J Glassock.
Early increased renal procollagen alpha 1(IV) mRNA levels in streptozotocin induced diabetes.
Changes in renal procollagen mRNA levels were measured shortly after the induction of streptozotocin induced diabetes in the rat. "Medullary" procollagen alpha 1(IV) levels seven days after diabetes induction was significantly higher in untreated diabetic rats (DM, N = 12; 244 +/- 57% of the mean control value), than in diabetic rats receiving small doses of insulin insufficient to achieve euglycemia (NPH, N = 10; 87 +/- 12%) and in diluent injected nondiabetic control rats (C, N = 15; 100 +/- 12%; P less than 0.01, DM vs. C and DM vs. NPH). "Medullary" procollagen alpha 1(I) mRNA levels were numerically increased in DM to a lesser degree (141 +/- 5%, ANOVA not significant) compared to C (100 +/- 13%), and this small increment was further normalized by insulin treatment (NPH, 120 +/- 11%). A trend for increased beta-actin mRNA levels in DM did not reach significance (P greater than 0.05). Increases in "medullary" procollagen mRNA levels did not correlate with kidney weight, glomerular tuft volume, creatinine clearance, food intake, or body weight gain, and occurred when renal morphology was normal by light microscopy. Statistically significant but weak correlations were noted between the serum glucose levels and "medullary" procollagen alpha 1(IV) mRNA levels (r = 0.43, P less than 0.05). In addition, weak correlations were noted between glycosuria and "medullary" procollagen alpha 1(I) levels (r = 0.38, P less than 0.05). In situ hybridization studies localized the increased procollagen alpha 1(IV) mRNA levels predominantly in the DM group primarily in the deep cortex and medullary outer stripe of proximal tubules. Glomerular procollagen alpha 1(IV), alpha 1(I), alpha 1(III) and beta-actin mRNA levels were not increased in untreated diabetic rats 7 or 28 days after diabetes induction. Thus, tubular procollagen alpha 1(IV) mRNA levels increased prior to any measurable change in glomerular levels and were ameliorated by insulin administration.
Animals↗
Secondary membranous glomerulonephritis.
Membranous glomerulonephritis of defined aetiology (secondary MG) is a common finding, particularly in children and older adults. Secondary MG can be readily detected by a combination of clinical, serological and morphological analysis in a majority of instances. Recognition of secondary MG has significant prognostic and therapeutic implications.
Drug-Related Side Effects and Adverse Reactions↗
Treatment of immunologically mediated glomerular disease.
Many immunologically mediated glomerular diseases can be successfully treated, but clinicians should be wary of unproven claims of efficacy, be cognizant of long-term deleterious effects of treatment, and should select patients with a careful eye on the natural history of the untreated disorder. It is hoped that as we gain a better understanding of the etiology and pathogenesis of the specific entities that a more rational form of therapy will emerge. The powerful tools of molecular biology and our better understanding of the inflammatory and scarring processes may provide new, highly effective and safe approaches to treatment. Like their predecessors, these approaches, however, will require very careful evaluation in human subjects by prospective controlled clinical trials. Even if we cannot favorably influence the immunological processes responsible for glomerular disease, attention to non-immunologic factors responsible for progression of disease, such as hypertension, may substantially slow the rate of progression of disease even in those patients whose fundamental disease process cannot be arrested or cured.
Glomerulonephritis↗
Laminin B1 is preferentially expressed in the cortex of rat kidney and is not affected by cyclosporine administration.
Cyclosporine has proven beneficial as an immunosuppressive agent for organ rejection in kidney transplants as well as in heart and liver transplants. Cyclosporine administration, however, is associated with certain adverse effects, one of the most important being chronic nephrotoxicity characterized by focal cortical scarring. Recent experimental data show involvement of type I and possibly type IV collagens in this process. Because laminin represents another potential extracellular matrix target, we examined the effects of cyclosporine administration in rats on the expression of laminin at the messenger ribonucleic acid (mRNA) and protein levels. In untreated normal rats, laminin B1 mRNA is preferentially expressed in the renal cortices, as demonstrated by northern blots. Daily administration of cyclosporine leads to focal cortical interstitial fibrosis and tubular atrophy by 4 weeks with, as shown previously, elevated procollagen alpha-1 (type I) mRNA levels at 1 and 4 weeks. In contrast, the amounts of message for laminin B1 remain identical after 1 week and 4 weeks of cyclosporine administration, despite the development of fibrosis at 4 weeks. Similar results were obtained with antilaminin antibody. We conclude that laminin is abundant in renal cortical tissues as compared with its medullary contents and is not altered in the process of renal cortical fibrosis induced by cyclosporine.
Animals↗
Dimethyl sulfoxide enhances hexose monophosphate shunt activity in cultured glomerular mesangial cells, leukocytes and erythrocytes.
The effect of dimethyl sulfoxide (DMSO) on the rate of glucose oxidation by cultured rat glomerular mesangial cells, human erythrocytes and peritoneal exudate cells was studied. Mesangial cells, erythrocytes and peritoneal exudate cells incubated with DMSO showed enhancement of 14CO2 production from D-[1-14C] glucose but not from D-[6-14C] glucose. The concentration of DMSO required to stimulate respiratory burst activity was lowest for erythrocytes and highest for peritoneal exudate cells. Studies utilizing tritiated deoxyglucose revealed that the increased glucose oxidation associated with DMSO exposure was not due to increased transmembrane glucose movement at low concentrations of DMSO, and only partially responsible at high concentrations of DMSO. This study documents the ability of DMSO to specifically enhance the activity of the hexose monophosphate shunt pathway in all cells studied. The precise mechanism whereby DMSO stimulates shunt activity remains unknown.
Animals↗
Immune complex-induced glomerular injury in viral diseases: an overview.
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Animals↗
IgA antibasement membrane nephritis with pulmonary hemorrhage.
Goodpasture's syndrome has characteristically been described as being mediated by IgG antibodies. We have recently seen a 55-year-old man who developed renal failure and hemoptysis; a renal biopsy showed linear deposits of IgA and C3 involving glomerular and tubular basement membrane. Serologic tests for detecting (IgG) antiglomerular basement membrane antibodies were negative. Elution studies of kidney and lung showed the presence of an IgA antibasement membrane antibody only. The patient's serum contained IgA, but not IgG, antibodies reactive with glomerular and tubular basement membrane of normal human kidney and alveolar basement membrane of normal human lung. Attempts to transfer disease with the patient's IgA antibody to a monkey and to Lewis and Brown-Norway rats were unsuccessful. Immunoglobulin A antibasement membrane antibody must be considered in the design of immunoserologic procedures for the diagnosis of Goodpasture's syndrome.
Animals↗
Soluble oligovalent antigen-antibody complexes. I. The effect of antigen valence and combining ratio on the composition of fluorescein-carrier anti-fluorescein complexes.
Soluble oligovalent antigen--antibody complexes were prepared and analysed by ultracentrifugation in order to study the effect of the combining ratio, antigen valence and concentration upon the size and molecular composition of the composition of the complexes. Fluorescein (F) conjugates of rabbit serum albumin (RSA) and thyroglobulin (RTg) were combined with high affinity rabbit anti-F antibodies to form soluble complexes. The effect of the combining ratio paralleled findings in precipitating systems in that the largest soluble complexes were found at equimolarity and mild molar antibody excess. Tetravalent antigen formed precipitates at combining ratios near equimolarity, whereas trivalent antigens failed to precipitate at similar concentrations. Complexes prepared near equimolarity were most sensitive to changes in concentration, higher concentrations leading to larger complexes. The Ab/Ag ratios of different-size complexes in the same preparation were remarkably similar. This ratio was dependent on the antibody--antigen combining ratio, was limited by antigen valence and was not affected by concentration differences. The data support the hypothesis that soluble complexes are formed in two steps. First, antigen and antibody combine to form subunits whose Ab/Ag ratio is determined by the combining ratio and antigen valence. These subunits then combine to form larger complexes in a manner analogous to polymerization.
Antibodies↗
Soluble oligovalent antigen--antibody complexes. II. The effect of various selective forces upon relative stability of isolated complexes.
Soluble oligovalent antigen--antibody complexes were isolated and analysed by ultracentrifugation to assess the effect of several forces upon the composition and stability of soluble complexes. Complexes were prepared with fluorescein (F) conjugates of rabbit serum albumin (RSA) or thyroglobulin (RTg) and high affinity rabbit anti-F antibodies. Isolated complexes containing two antigen molecules (Ag2 complexes) tended to dissociate and form an equilibrium with complexes containing one antigen molecule (Ag1 complexes). This equilibrium was thermolabile, concentration dependent and affected by the original combining ratio and the area in the gradient from which complexes were harvested. Small amounts of free antibody dissociated from soluble complexes also to form a dynamic equilibrium; this equilibrium was much less affected by the above parameters. The data support the concept that complexes grow in size by a process analogous to polymerization of simple subunits and that the driving forces for polymerization are of a lower order of magnitude and more affected by physical variables than the primary reaction between antibody and its antigen.
Antibody Affinity↗
Acute interstitial nephritis due to methicillin.
Fourteen patients are described with a syndrome of methicillin-induced interstitial nephritis. In all patients severe renal dysfunction developed with an average peak serum creatinine of 8 mg/100 ml. An increased total peripheral eosinophil count was found in all patients. All patients had sterile pyuria and each of nine patients studied by Wright's stain of urine sediment had marked eosinophiluria. These findings are suggestive of methicillin-induced interstitial nephritis, although proteinura was a variable finding in our patients. Eight of 14 patients in our study received prednisone therapy for their interstitial nephritis, and the time lapse between maximal and final base line serum creatinine levels was statistically less in the prednisone-treated compared to the nontreated groups. Clinical manifestations of this syndrome are discussed, and the light and electron microscopic and immunofluorescent findings on renal biospy are described.
Adult↗
Estimation of relative glomerular capillary surface area in normal and hypertrophic rat kidneys.
The quantity of antiglomerular baSEMent membrane antibodies (antiGBM) binding to the glomeruli of rats 4 hr after i.v. injection of 660 microgram of antiGBM was used as a measure of relative glomerular capillary surface area (Sr). Intact immature and adult rats (N = 27) weighing 46 to 440 g were studied to assess the effect of normal growth on Sr. Young adult rats (N = 36) were studied at 0, 8, 15, and 22 days following uninephrectomy or sham operation to assess the effect of hypertrophic kidney growth on Sr. Bound antiGBM increased from 95 microgram to approximately 350 microgram as rats grew from 46 to 200 g; further growth was associated with no further growth was associated with no further increases in bound antiGBM. In contrast, there was no progressive increase in Sr following uninephrectomy or sham operation despite as 45% increase in kidney weight at 22 days over the comparable kidney in the sham-operated rats (1.32 +/- SEM 0.06 g vs. 0.91 +/- SEM 0.01 g, P less than 0.0001). Thus, increases in GFR during early normal kidney growth parallel anatomic increases in Sr, but increases in GFR with later growth or with compensatory hypertrophy in young adult rats are not accompanied by changes in Sr.
Animals↗
A clinical and immunopathologic dissection of rapidly progressive glomerulonephritis.
This contribution seeks to illustrate the immunopathogenetic complexities of the syndrome of rapidly progressive glomerulonephritis. As with most of the clinical syndromes of glomerular disease, rapidly progressive glomerulonephritis may be dissected into a number of categories based upon combinations of clinical, morphologic and immunologic observations. It has been demonstrated that such observations have an important bearing on the natural history, prognosis and treatment of this syndrome. Much remains to be learned, particularly with respect to etiological factors, the genesis of extracapillary proliferation and the means of modifying or preventing these diseases.
Antibodies↗
Permselectivity of the glomerular capillary wall. Facilitated filtration of circulating polycations.
To examine the electrostatic effects of fixed negative charges on the glomerular capillary wall, polydisperse [(3)H]DEAE dextran, a polycationic form of dextran, was infused into 10 Munich-Wistar rats. Fractional clearances of DEAE ranging in radius from 18 to 44A were determined in these rats, together with direct measurements of the forces and flows governing the glomerular filtration rate of water. These results were compared with data previously obtained in Munich-Wistar rats receiving tritiated neutral dextran (D) and polyanionic dextran sulfate (DS). Measured values for the determinants of the glomerular filtration rate of water in rats given DEAE were found to be essentially identical to those in rats given either D or DS. In addition, DEAE was shown to be neither secreted nor reabsorbed. Fractional clearances of polycationic DEAE were increased relative to both D and DS, the increase relative to D being significant for effective molecular radii ranging from 24 to 44A. Fractional DEAE clearances were also measured in a separate group of six Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN). Fractional DEAE clearances in NSN rats were reduced significantly, relative to values measured in normal rats, for effective DEAE radii ranging from 18 to 42A. Moreover, in NSN rats, fixed negative charges on the glomerular capillary wall were greatly reduced, relative to non-NSN rats, as evidenced by a reduction in intensity of colloidal iron staining. Thus, in NSN rats, DEAE clearances were essentially indistinguishable from values obtained with both neutral D and polyanionic DS.
Animals↗
Nehprotic syndrome with glomerular mesangial IgM deposits.
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Adolescent↗
Detection of circulating immune complexes in patients with glomerulonephritis.
A panel of three immune complex (IC) assays was used in this study to test sera from patients with glomerulonephritis (GN): the Raji cell radioimmune assay (IRCA), the radio-labeled C1q binding assay (IC1qBA), and the microcomplement consumption test (MCT). The sensitivity and specificity of each assay was evaluated in preliminary studies, and the greater sensitivity (5 to 10microgram of aggreagated human gamma-globulin (AHG) per ml of serum) and IgG specificity of the IRCA was apparent. Problems related to the preliminary heat inactivation of test sera, the interaction of C1q with substances other than IC, and the effects of suboptimal storage of test sera were experienced with the MCT and, to a lesser extent the IC1qBA. The individual reactivities of the different assays were exploited by using them in combination. Thus ICs were detected by one or more of the assays in 87% of patients with systemic lupus erythematosus (SLE), 65% of patients with GN associated with other systemic diseases, and 39% of patients with primary GN. ICs were detected more frequently in patients with acute GN than chronic GN, and in patients with low serum C3, C4, and properdin factor B (C3PA) levels.
Acute Disease↗
Chronic nephritis induced by antibodies reacting with glomerular-bound immune complexes.
The pathogenesis of chronic membranous glomerulonephritis induced in rats by passive immunization with heterologous antibodies to rat renal tubular epithelial (RTE) antigens was investigated. This model is designated as "passive Heymann nephritis" (PHN) in order to contrast it with classical Heymann nephritis induced by active immunization with homologous RTE in adjuvant. A single i.v. injection of heterologous (rabbit) antibody to RTE evoked chronic proteinuria after a latent period of one to three days. The onset of proteinuria was accompanied by the granular deposition of rabbit IgG and rat beta1C globulin along the glomerular capillary wall. Renal isografts developed PHN only when transplanted within the first three days following injection of the heterologous anti-RTE antibodies. The data suggest that the heterologous antibodies form immune complexes with RTE antigens preexisting in the circulation, and these complexes subsequently deposit in the glomerular capillary walls. Chronic proteinuria is then perpetuated by a host reaction to the foreign protein in the deposits (i.e., rabbit IgG), in a fashion analogous to that seen in the autologus phase of nephrotoxic serum nephritis. These studies indicate that continued glomerular deposition of preformed circulating immune complexes may not always be a requisite for the perpetuation of glomerular injury in immune complex disease.
Absorption↗