Intravenous pulse methylprednisolone therapy of acute crescentic rapidly progressive glomerulonephritis.
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Acute Disease↗
Biomedical subjects
W G Couser
Publications and source records attributed to W G Couser.
Crescentic glomerulonephritis without immune deposits: clinicopathologic features.
Of 46 patients with acute crescentic glomerulonephritis involving 20 to 90% of glomeruli, 16 had no definable systemic disease and no significant glomerular immune deposits by immunofluorescent or electron microscopy. Anti-GBM antibody and circulating immune complexes were further excluded by radioimmunoassay and Raji cell assay in all patients tested. Clinical features included a 10:6 male:female ratio, mean age of 58 years (range, 13-77), disease duration of less than 3 months, rapidly deteriorating renal function, and frequent pulmonary manifestations. Nine patients had oliguria, serum creatinine concentrations over 6 mg/100 ml, and required dialysis, but three of these patients subsequently recovered renal function. These three patients and seven patients with creatinine concentrations of less than 6 mg/100 ml have not progressed to chronic renal failure. In this series, idiopathic acute crescentic glomerulonephritis without immune deposits was more common than was immune complex or anti-GBM nephritis. The clinical, laboratory, and pathologic characteristics of these patients were similar to those reported in anti-GBM and immune-complex-induced glomerulonephritis. These observations expand the spectrum of rapidly progressive crescentic glomerulonephritis. They suggest that glomerular immune deposits may be less important than other factors in determining the extent of renal injury and subsequent clinical course in crescentic glomerulonephritis.
Adolescent↗
Membranous nephropathy: a radioimmunologic search for anti-renal tubular epithelial antibodies and circulating immune complexes.
In an effort to elucidate immunopathogenic of membranous nephropathy (MN), freshly collected sera from patients with biopsy proven MN were assayed of circulating immune complexes (ICs) by the Raji cell method and for anti-renal tubular epithelial (RTE) antibodies by a newly established radioimmunoassay (RIA) and by indirect immunofluorescence. 6 of 26 MN patients tested by the Raji cell assay had detectable circulating ICs. However, 5 of these 6 patients had other medical conditions which might also explain the IC reactivity. 29 MN patients and 11 patients with other glomerular diseases had no demonstrable circulating anti-RTE antibodies. This study suggests that if RTE antigens possess a nephritogenic potential for man it is probably only rarely expressed. The inconstant detection of circulating immune complexes in idiopathic MN raises an speculation as to their immunopathogenic significance.
Adult↗
Determinants of glomerular localization of subepithelial immune deposits: effects of altered antigen to antibody ratio, steroids, vasoactive amine antagonists, and aminonucleoside of puromycin on passive Heymann nephritis in rats.
The role of circulating immune complex deposition versus in situ complex formation in membranous nephropathy is controversial. Passive Heymann nephritis in rats resembles membranous nephropathy in man and was induced by injection of sheep antibody to rat proximal tubular epithelial cell brush border antigen (anti-Fx1A). Minutes after injection of 1 ml. of anti-Fx1A, subepithelial immune deposits were seen by immunofluorescence and electron microscopy, and proteinuria appeared within 5 days. The effects of alterations in the dose of administered antibody, corticosteroid therapy, and vasoactive amine blockade on the development of subepithelial deposits and consequent proteinura were studied. Variation of the dose of anti-Fx1A from 0.25 ml. to 1 ml. resulted in a progressive increase in the size and number of glomerular capillary wall deposits, but no alterations in their distribution. Only those rats which received 1 ml. became proteinuric within 5 days. Corticosteroid therapy and vasoactive amine blockade, begun 24 hours prior to the induction of passive Heymann nephritis and continued until termination of the study 5 days later, had no effect on the amount or site of immune complex formation, nor on the extent of proteinuria as compared to untreated controls. In contrast, in rats with unilateral proteinuria produced by the selective perfusion of one kidney with aminonucleoside of puromycin 7 days prior to the induction of passive Heymann nephritis, there was a marked reduction of subepithelial deposits in the perfused kidney as compared to the nonperfused contralateral kidney. In this model of membranous nephropathy, systemic factors play little role in the development of subepithelial deposits, whereas local factors are critical. These findings are consistent with the hypothesis that subepithelial immune deposits form locally.
Adrenal Cortex Hormones↗
Rapid recurrence of membranous nephropathy in a related allograft.
A patient with membranous nephropathy (MN) received a renal allograft from his brother. The allograft functioned immediately but nephrotic range proteinuria developed seven days after transplantation in the absence of any signs of rejection. Renal function deteriorated five weeks after transplantation due to ureteric obstruction. Nephrostomy drainage resulted in the return of renal function to normal and demonstrated that the allograft was the source of the nephrotic range proteinuria. An open renal biopsy of the allograft performed at the same time revealed the presence of recurrent MN. The recipient was investigated in an attempt to identify possible humoral immune mechanisms that may explain this very rapid recurrence of MN.
Adult↗
The effects of aminonucleoside of puromycin and nephrotoxic serum on subepithelial immune-deposit formation in passive Heymann nephritis.
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Animals↗
Chronic interstitial nephritis and mixed cryoglobulinemia associated with drug abuse.
Two cases of chronic interstitial nephritis with renal insufficiency were associated with mixed cryoglobulinemia and parenteral drug abuse. Previously recognized causes of interstitial nephritis were not present in either case. Despite extensive interstitial inflammatory infiltrates, no substantial glomerular abnormalities or immune deposits were present in either patient. One patient had a history of intravenous injection of suspended methadone tablets containing talc crystals, and there was evidence of talc embolization in biopsy specimens of liver, spleen, and kidney. Interstitial nephritis associated with drug abuse has not been previously described to our knowledge, but the association in these cases seems not to have been fortuitous and warrants consideration in the evaluation of both parenteral drug abusers and patients with unexplained interstitial nephritis.
Adult↗
Renal sodium retention during volume expansion in experimental nephrotic syndrome.
We have studied sodium retention during volume expansion in rats with autologous immune complex nephropathy (AICN), a model of nephrotic syndrome (NS) in which GFR after volume expansion was not different from that in adjuvant-injected controls (C). AICN rats developed heavy proteinuria (298 +/- 27 vs. less than 10 mg/day), hypoalbuminemia (2.14 +/- 0.15 vs. 3.08 +/- 0.12 g/100 ml) and hypercholesterolemia (181 +/- 22 vs. 58 +/- 4 mg/100 ml). After saline, there were no significant differences in blood pressure (119 +/- 2 vs. 114 +/- 2 mm Hg), renal plasma flow (4.9 +/- 0.41 vs. 4.1 +/- 0.28 ml/min), inulin clearance (1.37 +/- 0.06 vs. 1.55 +/- 0.10 ml/min), or SNGFR (47 +/- 2 vs. 53 +/- 4 nl/min). Sodium excretion, however, was significantly lower in NS rats (4.7 +/- 1.1 vs. 9.2 +/- 1.2 muEq/min). Proximal sodium reabsorption was decreased in NS rats (35 +/- 2 vs. 41 +/- 2%, 2.5 +/- 0.2 vs. 3.3 +/- 0.2 nEq/min). Sodium delivery into the loop, however, was equal in NS and C, since the slightly lower filtered load in NS rats offset the depression in proximal reabsorption. Sodium reabsorption by the loop and by the distal convoluted tubules were equal in NS and C. Thus, sodium delivered into the cortical collecting ducts was the same in both groups (0.33 +/- 0.17 vs. 0.34 +/- 0.07 nEq/min; 4.5 +/- 0.6% of filtered sodium vs. 4.4 +/- 0.3%). The percent of filtered sodium excreted in the urine, however, was significantly lower in the NS rats, 2.18 +/- 0.48% vs. 4.0 +/- 0.58%. We conclude that antinatriuresis in this model of NS is determined beyond the superficial late distal convoluted tubule. The inability to excrete the sodium load during volume expansion is due to either enhanced reabsorption by the collecting duct or to abnormal function in deep nephrons.
Animals↗
Effect of aminonucleoside nephrosis on immune complex localization in autologous immune complex nephropathy in rats.
The effect of increased capillary permeability on glomerular immune complex localization was studied in rats immunized with proximal tubular antigen (Fx1A) to induce autologous immune complex nephropathy (AICN). AICN rats were made proteinuric by injection or unilateral renal perfusion with aminonucleoside of puromycin (PA) before developing subepithelial complex deposits. Control AICN kidneys developed diffuse granular deposits of IgG and Fx1A on the subepithelial surface of the glomerular basement membrane (GBM) at 3 wk by immunofluorescence and electron microscopy, and deposits increased in subsequent weekly biopsies. In contrast, PA-nephrotic AICN kidneys developed few or no GBM deposits and a significant increase in mesangial localization of IgG and Fx1A during the period of PA-induced proteinuria. These alterations in complex localization were documented both in rats with PA nephrosis and in unilaterally PA-nephrotic kidneys compared with contralateral controls in the same animals, thus excluding any effect of PA on the immunopathogenetic mechanism in AICN as an explanation for these findings. The absence of GBM deposits closely correlated with reduced staining for polyanionic glomerular sialoprotein in proteinuric kidneys, since PA-perfused kidneys studied 2 wk after resolution of proteinuria demonstrated return of normal staining for sialoprotein and development of subepithelial complex deposits similar to those in contralateral control kidneys. These studies demonstrate that properties of the glomerulus itself play an important role in determining the site of complex deposition in experimental AICN and suggest that electrophysical characteristics of the glomerular capillary wall may influence complex localization on the GBM.
Animals↗
Experimental glomerulonephritis in the isolated perfused rat kidney.
The development of immune deposits on the subepithelial surface of the glomerular capillary wall was studied in isolated rat kidneys perfused at controlled perfusion pressure, pH, temperature, and flow rates with recirculating oxygenated perfusate containing bovine serum albumin (BSA) in buffer and sheep antibody to rat proximal tubular epithelial cell brush border antigen (Fx1A). Control kidney were perfused with equal concentrations of non-antibody immunoglobulin (Ig)G. Renal function was monitored by measuring inulin clearance, sodium reabsorption, and urine flow as well as BSA excretion and fractional clearance. Perfused kidneys were studied by light, immunofluorescence, and electron microscopy. All kidneys perfused with anti-Fx1A developed diffuse, finely granular deposits of IgG along the glomerular capillary wall by immunofluorescence. Electron microscopy revealed these deposits to be localized exclusively in the subepithelial space and slit pores. Similar deposits were produced in a nonrecirculating perfusion system, thereby excluding the formation of immune complexes in the perfusate caused by renal release of tubular antigen. Control kidneys perfused with nonantibody IgG did not develop glomerular immune deposits. Renal function and BSA excretion were the same in experimental and control kidneys. Glomerular deposits in antibody perfused kidneys were indistinguishable from deposits in rats injected with anti-Fx1A or immunized with Fx1A to produce autologous immune complex nephropathy. These studies demonstrate that subepithelial immune deposits can be produced in the isolated rat kidney by perfusion with specific antibody to Fx1A in the absence of circulating immune complexes. In this model deposits result from in situ complex formation rather than circulating immune complex deposition.
Animals↗
De novo development of membranous nephropathy in cadaver renal allografts.
Glomerulonephritis in transplant recipients often reflects recurrence of the immunopathogenetic mechanism causing the original renal disease. Membranous nephropathy (MN), a progressive immune complex mediated glomerular disease and the commonest cause of idiopathic nephrotic syndrome in adults, has been virtually unreported in transplant recipients. Two cases are reported here of typical MN (by clinical, light, immunofluorescent and electron microscopic criteria) developing de novo in the transplants of patients whose original diseases were anti-GBM nephritis and focal glomerular sclerosis. NM developed following episodes of viral hepatitis and renal infarction respectively. Possible mechanisms by which this lesion might develop in these patients are investigated and discussed. Chronic immune complex nephropathy (MN) can develop de novo in immunosuppressed transplant recipients apparently initiated by events in the post-transplant period.
Adolescent↗
Complement-independent nephrotoxic nephritis in the guinea pig.
Immunologic mechanisms of proteinuria were investigated in guinea pigs (GP) injected with sheep antiserum (NTS) to GP glomerular basement membrane (GBM). Linear deposition of sheep gamma 1 and gamma 2 IgG led to a prompt but transient (36 hr) increase in albumin excretion from control values of 0.026 +/- 0.013 mg/hr to maximal values of 26+/-12.1 mg/rh at six hours without detectable histologic or electron microscopic changes except for decreased staining for glomerular polyanion and epithelial cell foot process fusion. GBM permeability to anionic ferritin was not increased during proteinuria. Anti-GBM antibody deposits did not fix GP C3 or C4 in vivo or in vitro. NTS-induced proteinuria was the same in guinea pigs that were normal, greater than 95% depleted of C3 through C9, genetically deficient in C4, and depleted of circulating polymorphonuclear leukocytes (PMN). Prior administration of antihistamines, steroids, azathioprine, colchicine, indomethacin, heparin, aprotinin (Trasylol), and niridazole also failed to reduced proteinuria. Initial proteinuria subsided by 36 hr, did not recur despite linear deposition of GP gemma 1 and gemma 2 after day seven, and antibody to GMB-bound sheep globlin. In the GP nephrotoxic nephritis model, anti-GBM antibody deposits apparently mediate increased permeability to albumin by a currently undefined mechanism which is independent of complement, PMN, and other know mediators of inflammation.
Animals↗
Anti-immunoglobulin as an adjunct in producing long-term antigen-specific allograft survival. Organ localization of immune complexes.
Heterologous anti-immunoglobulin is a potent immunosuppressive agent that prolongs H-2- and H-3-incompatible skin graft survival. In conjunction with antithymocyte serum, anti-immunoglobulin promotes greater graft life than either antiserum used alone, without evidence of toxicity to recipient animals. Combination treatment with anti-immunoglobulin, antithymocyte serum, and donor spleen cells produces long-term allograft survival to the lifetime of the host and can result in antigen-specific immune unresponsiveness of sufficient strength to permit acceptance of a second-set graft. Anti-immunoglobulin complexes formed in treated mice appear to be localized primarily in the lymphatic reticuloendothelial system.
Animals↗
Ultrastructural dense deposit disease in diabetes mellitus.
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Adult↗
Beneficial effects of methylprednisolone "pulse" therapy in diffuse proliferative lupus nephritis.
Seven patients with diffuse proliferative lupus nephritis were subjected to highdose intravenous methylprednisolone (pulse) therapy. Following the pulse, five patients with rapidly deteriorating ranal function improved within three days and their serum-creatinine levels returned to baseline by one month. All seven patients demonstrated reversal of severe immunological abnormalities including increased serum D.N.A binding, decreased serum C3 levels, and reduced number of T lymphocytes in the peripheral blood. This form of therapy may make it possible to maintain patients with lupus nephritis on lower doses of steroids than is normally feasible.
Adolescent↗
The immunopathology of the aging rat kidney.
Immunofluorescence studies of rat kidneys from 3-24 mo. of age demonstrated deposition of immunoglobulins, predominately IgM, within the glomerular mesangium by age 3 mo. Immunoglobulins eluted in acid buffer, did not fix complement, were not associated with inflammatory changes, and increased markedly with the onset of proteinuria at about 12 mo. Rats 24 mo. old also had mesangial deposits of IgG and fibrin. No basement membrane deposits were seen, and autoantibodies to antigens in normal kidney, liver, spleen, and skeletal muscle were not demonstrable in serum or eluates of kidneys from aged animals. The focal and segmental glomerular sclerosis which develops in aged rats does not appear to be mediated by glomerular deposition of auto-antibody or immune complexes. Mesangial accumulation of macro-molecular material, perhaps as a consequency of the age-associated increase in glomerular permeability, may contribute to the development of the glomerular sclerosis of aging in the rat by impairing mesangial phagocytic or clearing mechanisms rather than through immunologically mediated tissue injury.
Aging↗
Prolongation of allograft survival by combination therapy with anti-thymocyte serum and anti-immunoglobulin.
Heterologous anti-immunoglobulin (AI) is a potent immunosuppressive agent which compares favorably to anti-thymocyte serum (ATS) in inhibiting E and EAC-rosette formation and diminishing the secondary antibody response to sheep erythrocytes and E. coli lipopolysaccharide. AI prolongs H-2 incompatible skin allograft survival than either antiserum used alone, without evidence of toxicity to recipient mice. AI does not cause significant immune complex glomerular or renovascular deposition and may act by interference with antigen binding.
Animals↗
Autologous immune complex nephropathy. I. Sequential study of immune complex deposition, ultrastructural changes, proteinuria, and alterations in glomerular sialoprotein.
Experimental evidence suggests that barriers to glomerular filtration of macromolecules exist at the glomerular basement membrane itself and at the level of the epithelial cell and epithelial slit pores. The distribution of negatively charged glomerular sialoprotein (GSP) at the latter site and the reduction in histochemical staining for GSP reported in several clinical and experimental glomerular diseases suggest a role for this material in the regulation of glomerular permeability. Alternatively, reductions in GSP associated with proteinuria may reflect only epithelial cell swelling consequent to the proteinuria. The sequence of subepithelial immune complex deposition, epithelial cell swelling and foot process fusion, alterations in histochemical staining for GSP, and development of proteinuria was studied in 12 Lewis rats biopsied weekly during development of autologous immune complex (Heymann) nephropathy. Deposition of IgG was detectable 3 weeks after antigen injection by immunofluorescence. Electron-dense deposits were first seen by electron microscopy coincident with the appearance of complement at week 4. Proteinuria began at 6 to 8 weeks, 3 to 5 weeks after detectable immune complex deposition. Proteinuric animals had marked subepithelial immune complex deposition and extensive epithelial cell swelling and foot process fusion. Despite these changes, there was no detectable reduction in staining for GSP until week 14, 6 to 8 weeks after onset of proteinuria. Reductions in GSP apparently do not play a role in altering glomerular permeability early in autologous immune complex (Heymann) nephropathy, and proteinuria and epithelial cell swelling can be present in this model without detectable changes in GSP. These findings suggest that early alterations in GSP reported in some other proteinuric disorders may be of pathogenetic significance rather than simply a reflection of changes in epithelial cell morphology secondary to proteinuria. In this experimental model of membranous nephropathy, immunofluorescence was more sensitive than electron microscopy in the early detection of immune deposits.
Animals↗