Giuseppe A. Andres

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Glomerular arachidonate cyclooxygenation by isolated rat glomeruli was assessed in vitro in antiglomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis by radioimmunoassay for prostaglandins (PG) and thromboxane. After a single intravenous injection of rabbit anti-rat GBM serum, we observed enhancement of glomerular thromboxane B2 (TxB2) synthesis as early as 2 to 3 h with smaller increments in PGF2 alpha, PGE2 and 6-keto-PGF1 alpha synthetic rates. On day 2 of the disease, the glomerular synthesis of TxB2 and, to a lesser extent, PGF2 alpha and PGE2 remained enhanced, whereas on days 8, 11, and 14, TxB2 was the only prostanoid synthesized at increased rates. Glomerular TxB2 synthesis correlated with the presacrifice 24-h protein excretion. 60 min after intravenous infusion of anti-GMB serum, glomerular filtration rate (GFR) decreased (0.66 +/- 0.04 to 0.44 +/- 0.03 ml/min per 100 g, P less than 0.05), without a significant change in renal plasma flow (RPF): 1.97 +/- 0.23 to 1.80 +/- 0.23 ml/min per 100 g) and without a change in glomerular PG synthetic rates. At 2 h, GFR and RPF reached a nadir (0.25 +/- 0.04 and 1.3 +/- 0.1 ml/min per 100 g, respectively) coinciding with a fivefold increment in glomerular TxB2. By 3 h GFR and RPF partially recovered to 0.43 +/- 0.07 and 1.77 +/- 0.20 ml/min per 100 g, respectively, P less than 0.05, despite further increments in TxB2 synthesis. This recovery of GFR and RPF coincided with increments in vasodilatory PG, (PGE2 and PGI2). The thromboxane synthetase inhibitor OKY-1581 markedly inhibited platelet and glomerular TxB2 synthesis and preserved GFR at 1, 2, and 3 h. Another thromboxane synthetase inhibitor, UK-38485, also completely inhibited platelet and glomerular TxB2 synthesis and prevented decrements of GFR at 2 and 3 h. A cyclooxygenase inhibitor, ibuprofen, inhibited platelet TxB2 and PGE2 synthesis and significantly reduced glomerular PGE2 but not TxB2 synthesis. In the ibuprofen-treated rats, the partial recoveries of GFR and RPF at 3 h were attenuated. The in vitro glomerular TxB2 synthesis correlated inversely with the presacrifice GFR and filtration fraction. These observations indicate that in anti-GBM nephritis there is enhanced synthesis of TxA2 and PG in the glomerulus that mediate changes in renal hemodynamics.

Evolution of membranous nephropathy into anti-glomerular-basement-membrane glomerulonephritis.

Abstract In a patient with biopsy-proved membranous nephropathy (nephrotic syndrome) acute fatal renal failure suddenly developed. Autopsy revealed rapidly progressive glomerulonephritis superimposed on the previous membranous changes. IgG eluted from the kidney was shown by immunofluorescence technic to bind to the glomerular basement membrane of normal human and monkey kidneys, and was capable of producing an acute anti-glomerular-basement-membrane nephritis in two monkeys. The IgG antibody, by radioisotopic methods, was specifically directed against primate kidney. It is postulated that immune complexes responsible for the original membranous nephropathy induced release of antigenic glomerular-basement-membrane fragments into the circulation, stimulating formation of antibodies to the membrane and producing fatal acute glomerulonephritis. (N Engl J Med 290:1340–1344, 1974)

Heroin nephropathy: A clinicopathologic and epidemiologic study☆

The existence of a nephropathy secondary to intravenous narcotic use remains a matter of debate. To determine whether heroin use and renal disease are associated, a clinicopathologic and epidemiologic study was undertaken in the Buffalo Standard Metropolitan Statistical Area (Buffalo-SMSA). Over the past 10 years, 23 addicts presented with the nephrotic syndrome and/or renal insufficiency. All patients were black men 18 to 45 years of age. Kidney biopsies performed on 21 patients uniformly showed sclerosing glomerulonephritis. End stage renal disease (ESRD) developd in 15 of these patients. In the epidemiologic evaluation which spanned four and a half years, heroin use was highly correlated with both sclerosing glomerulonephritis and ESRD. A history of intravenous heroin use was found in 26 per cent of the new cases of sclerosing glomerulonephritis and in 13 per cent of the new cases of ESRD in patients aged 18 to 45 years (p less than 0.000001). This investigation confirms the existence of heroin-associated sclerosing glomerulonephritis in black men. Heroin use appears to be a major risk factor for ESRD in the Buffalo-SMSA.

Anti-basement membrane antibodies and antigen--antibody complexes in rabbits injected with mercuric chloride.

Abstract New Zealand rabbits were injected three times a week with 2 mg of mercuric chloride (HgCl2) (MC) to test the hypothesis that toxic agents release autologous antigens, generating antibody response and tissue injury. After 2 weeks of injections the rabbits developed anti-basement membrane antibodies binding to renal and extrarenal basement membranes and to the peri- and endo-mysium of skeletal muscles. Glomerular histology appeared normal. Membranous glomerulonephritis developed 1–2 months later with granular subepithelial deposits containing rabbit IgG and C3. Similar deposits were present in the basement membranes of other organs. Raji cell tests for immune complexes in the sera were negative in the initial stages and positive in the late stages of the disease. Radioactive MC was found in the cytoplasm of renal tubular, intestinal, and hepatic epithelial cells but not in glomerular deposits. Renal eluates and selected sera reacted with the basement membranes and the collagen matrix in normal or collagenase-digested sections of renal or extrarenal normal rabbit tissues. This reactivity was reduced or abolished by washing tissue sections in PBS or by absorption of renal eluates with whole kidney homogenates. The findings are consistent with the hypothesis that MC induces a biphasic disease characterized first by the production of antibodies to basement membranes and the extracellular collagen matrix and subsequently by antigen-antibody complexes formed in situ and in the circulation and presumably containing soluble polysaccharide components of the collagen matrix.

Glomerulonephritis induced in the rabbit by antiendothelial antibodies.

The effects of interaction between endothelial angiotensin converting enzyme (ACE) and goat anti-rabbit ACE (GtARbACE) antibodies were studied in rabbit glomeruli. By immunofluorescence ACE was not detectable in normal glomeruli. However, when kidneys were perfused with GtARbACE antibodies glomerular bound IgG was seven times higher than that of non-immune IgG and granular deposits of goat IgG were found on the endothelium of glomeruli and arteries. Rabbits injected intravenous for 4 d with GtARbACE antibodies showed on day 1 granular deposits of goat IgG on the glomerular endothelium; from day 3 to 24 there was gradual development of subepithelial deposits of goat IgG, rabbit IgG and C3. When GtARbACE antibodies were similarly injected into proteinuric rabbits there was formation of subepithelial granular deposits of goat IgG and ACE. The results document that a glomerular endothelial antigen is redistributed in vivo by a specific ligand, an event associated with formation of immune deposits. Furthermore, if the glomerular permeability is artificially increased, immune complexes shed from nonglomerular endothelia into the circulation can contribute to form subepithelial immune deposits.

Tubular Lesions Produced by Autoantibodies to Tubular Basement Membrane in Human Renal Allografts

In two patients with chronic glomerulonephritis who received renal allografts, transplant failure was associated with binding of transplantation antibodies to the graft and with glomerular and vascula

Studies on the formation of glomerular immune deposits in Brown Norway rats injected with mercuric chloride

Brown Norway rats injected with mercuric chloride (HgCl2) develop autoantibodies which immunolocalize along the glomerular basement membrane at first in a linear pattern and then in a granular pattern. The aim of this study was to characterize the specificity of these antibodies and to investigate the mechanisms responsible for the formation of granular immune deposits in the subepithelial zone of the glomerular basement membrane. The rats were found to develop circulating anti-laminin, anti-type IV collagen, anti-heparan sulfate proteoglycan, and anti-entactin antibodies. Antibodies against laminin and type IV collagen were found in relatively high titers in the sera and were specifically concentrated in the nephritic kidneys. Antibodies eluted from the nephritic kidneys with either linear or granular deposits reacted with basement membrane antigens synthesized and secreted by cultured rat glomerular visceral epithelial cells. Thus, in this model, the interaction of anti-laminin and type IV collagen antibodies with antigens secreted by glomerular visceral epithelial cells might, together with other mechanisms, contribute to the formation of granular immune deposits in the subepithelial part of the glomerular basement membrane.

Gametes contain angiotensin converting enzyme (kininase II)

The localization of angiotensin converting enzyme (ACE) in the gonads of the normal rabbit was studied by immunofluorescence and immunoelectron microscopy. The enzyme is present in the cytoplasm of testicular spermatids and of epididymal and ejaculated spermatozoa, and on the surface of follicular and tubal cocytes. These findings support the hypothesis that ACE has a role in gamete maturation and in fertilization.

An immunologic renal tubular lesion in man

Abstract A distinctive renal tubular lesion has been observed in seven patients, characterized by granular deposition of IgG and/or β1C along the basement membrane of proximal tubules and by corresponding electron-dense deposits. Associated histologic findings were tubular cell damage, interstitial fibrosis and irregular, generally scanty lymphocytic infiltrates. Three of the patients had lupus erythematosus, one lipoid nephrosis, one membranoproliferative glomerulonephritis, one unclassified tubular and interstitial disease and one rapidly progressive glomerulonephritis. Two patients with extensive deposits had suggestive evidence of tubular dysfunction. On the basis of their resemblance to experimental models, it is suggested that the tubular deposits represent immune complexes containing autoantibody and autologous antigens.

Experimental Chronic Serum Sickness in Rats

This article describes a method of immunization that produces chronic serum sickness in rats within a relatively short time. Fisher rats, which were immunized subcutaneously three times with bovine serum albumin (BSA) in adjuvant, responded with high titers of antibodies to BSA. 2 weeks after the third subcutaneous immunization, daily increasing amounts of BSA were injected either intraperitoneally or intravenously. When an intravenous dose of 2mg of BSA was reached, the rats were given daily intravenous injections of BSA for several weeks. This procedure, which avoided death from anaphylaxis, induced severe proliferative glomerulonephritis in all the rats and produced deposition of antigen-antibody complexes in many other organs besides the kidney. This highly reproducible model of experimental chronic serum sickness in inbred animals may have applications for the study of the mechanisms of immune complex disease.