Steroids and cytotoxic drugs in the treatment of membranous glomerulopathy.
Explore the source record for details and available documents.
Chlorambucil↗
Biomedical subjects
T Bertani
Publications and source records attributed to T Bertani.
Effect of platelet-activating factor and its specific receptor antagonist on glomerular permeability to proteins in isolated perfused rat kidney.
Platelet-activating factor (PAF) is a lipid mediator of inflammation believed to play a role in glomerulonephritis by favoring immune complex formation and modulating the subsequent inflammatory reaction. Some evidence indicates that PAF may also be one of the mediators of proteinuria. Previous work suggested that PAF can increase glomerular permeability to proteins, activating platelets and inflammatory cells to release cationic proteins. In the present study, we addressed the possibility that PAF might directly increase glomerular permeability to proteins independently of platelets and inflammatory cells. We used a preparation of isolated rat kidney perfused with an artificial cell-free medium. After stabilization and two 10-minute control clearance periods, kidneys perfused in a closed circuit were exposed to PAF (2 nM or 10 nM final concentration) or 2-lyso-PAF (10 nM final concentration) or vehicle for 40 minutes. Glomerular filtration rate, measured as creatinine clearance, and renal vascular resistance did not significantly change when either PAF (2 nM or 10 nM) or 2-lyso-PAF, or vehicle were added to the perfusion fluid. Unlike vehicle or 2-lyso-PAF, addition of PAF at the final concentration of 2 and 10 nM to the perfusate produced a dose-dependent progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by L-652,731, a specific PAF receptor antagonist, suggesting that PAF's effect on glomerular permeability to proteins is likely to be related to its biologic activity. Several pharmacologic manipulations addressed to the potential mediators of PAF effect on glomerular permeability to proteins would exclude that the effect of PAF on isolated perfused kidney is mediated by cyclooxygenase or lipoxygenase products, or is the result of oxygen-free radical generation. The possibility that PAF enhances glomerular permeability to proteins by changing the glomerular barrier electrostatic properties was explored using polyethylene-imine. Electron microscopy examination revealed no difference in the distribution of electron-dense deposits along the glomerular basement membrane in kidneys exposed to 10 nM PAF or vehicle.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Light chain nephropathy: histological and clinical aspects in 15 cases.
Fifteen patients aged 31-74 years (five male, ten female) on renal biopsy showed intense linear deposits of light chains along tubular basement membranes (TBM) by immunofluorescence, and/or granular dense deposits on electronmicroscopy. Multiple myeloma was diagnosed in ten patients. The onset of myeloma and nephropathy was simultaneous in six patients; nephropathy preceded or followed the diagnosis of myeloma in three and one patients respectively. The mode of onset of nephropathy was acute or rapidly progressive renal failure in five cases, chronic renal failure in seven, and heavy proteinuria in three. Only two patients had normal renal function at biopsy. Serum monoclonal component was kappa in five patients, IgG kappa in three, IgD kappa in one, IgG lambda in one, IgA lambda in one, absent in three, and not detected in one. On light microscopy eight cases had nodular glomerulosclerosis, three cast nephropathy and 14 TBM thickening. Immunofluorescence for monoclonal light chain(s) was positive in 11 of 13 cases. Electron microscopy showed finely granular deposits in the inner side of glomerular basement membranes (GBM) and the outer side of TBM in 11 of 11 tested cases. The evolution was towards chronic renal failure in 12 patients (six of whom required dialysis), death in two, unknown in one. Four patients died after a period of dialysis, from infections or cardiovascular complications.
Adult↗
Amiodarone induced phospholipidosis. Biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone.
Amiodarone, an antiarrhythmic drug, causes pulmonary fibrosis in some patients during chronic treatment but the mechanism is unknown. We studied the effects of amiodarone on pulmonary biochemistry, morphology and function at doses of 25 and 50 mg/kg/12 hr given to rats by gavage for four weeks. Plasma and pulmonary phospholipids were significantly augmented, 13% and 88% respectively, in the group given amiodarone 50 mg/kg/12 hr compared to pair-fed controls. Typical phospholipidosis-like light and electron microscopic alterations were seen in the lung, their severity related to the extent of biochemical changes induced by amiodarone. Pulmonary function tests revealed mild but not significant changes in O2 and CO2 alveolar exchange efficiency and lung compliance (P-V curve) of treated animals in comparison to pair fed controls. Plasma average concentrations of amiodarone and its main metabolite, desethylamiodarone, after four weeks were 2.46 +/- 0.18 and 0.73 +/- 0.13 micrograms/ml, respectively, in the 50 mg/kg/12 hr group. In the same group amiodarone and desethylamiodarone concentrations in lung were 163 +/- 26 and 569 +/- 153 times higher than those in plasma. A highly significant correlation was found between amiodarone concentrations in plasma and lung and phospholipid content in the lung. A subgroup of animals received amiodarone 50 mg/kg/12 hr for 8 weeks. The pulmonary phospholipidosis-like lesions were similar to those observed after one month of treatment, no fibrosis was evident on light microscopic examination.
Amiodarone↗
Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis.
Release of acetyl glyceryl ether phosphorylcholine, platelet-activating factor (PAF), has been demonstrated to be associated with glomerular inflammatory damage in acute serum sickness. Moreover, PAF can increase glomerular permeability to proteins and induce mesangial contraction. Thus PAF might be a good candidate as a mediator of glomerular damage. However the in vivo evidence that PAF might cause glomerular injury is lacking. To evaluate if PAF has a major role in promoting glomerular inflammatory reaction and fibrin deposition, we studied the effect of a molecule, L-652,731, which blocks the PAF receptor, on the evolution of an experimental model of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN). GN was initiated by sheep-anti-rabbit nephrotoxic serum. A proliferative GN regularly occurred in which heavy proteinuria, intra and extracapillary proliferation of resident and inflammatory cells and fibrin deposition in Bowman's capsule were the prominent findings. Our results showed that the PAF receptor antagonist reduces the glomerular damage in anti-GBM GN, supporting the hypothesis that PAF is indeed a mediator of glomerular inflammatory reaction. PAF receptor blocking prevented renal function deterioration in the early phase of the disease, probably preserving glomerular hemodynamics. In the delayed phase of the disease the PAF receptor antagonist reduced proteinuria and prevented renal function deterioration and fibrin deposition. These effects appear to be mediated by an inhibitory action of PAF receptor blocking on macrophage accumulation and activation.
Animals↗
Indomethacin reduces proteinuria in passive Heymann nephritis in rats.
Indomethacin has been used to lower proteinuria in human glomerular diseases with controversial results. The mechanism of indomethacin beneficial effects has not been established. A possible explanation is that indomethacin reduces proteinuria by inhibiting the synthesis of renal prostaglandins (PGs); however, appropriate studies to address this issue have never been done. The objectives of the present study were: to investigate whether indomethacin influences protein excretion in an experimental model of immunologically-mediated glomerular disease; to establish if the possible favorable effect of indomethacin on proteinuria is related to a reduction in glomerular filtration rate (GFR); to establish the possible association between the antiproteinuric effect of indomethacin and its inhibitory effect on arachidonic acid (AA) metabolites of renal or extrarenal origin; and to further investigate the relationship between proteinuria and renal thromboxane (Tx) synthesis previously demonstrated in experimental models of nephrotoxic nephritis and adriamycin (ADR) nephrosis. To this purpose we used an experimental immune-complex disease, passive Heymann nephritis (PHN) which was induced in the rat by a single intravenous (i.v.) injection of heterologous serum directed against a brush border component (gp 330 antigen). Indomethacin at a dose of 6 mg/kg intraperitoneally (i.p.) administered for four consecutive days to PHN animals during the period of heavy proteinuria, effectively reduced urinary protein excretion. The reduction in proteinuria does not appear to be a consequence of a reduction in GFR as documented by inulin clearance. Glomerular synthesis and urinary excretion of vasodilatory prostacyclin (PGI2) and PGE2 were decreased or unchanged in PHN animals in respect to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
What is the basis for the use of steroids in the treatment of idiopathic membranous nephropathy?
In the past 30 years steroids have been widely employed in the management of primary glomerulopathies. At variance with 'minimal-change nephropathy', in which glucocorticoids are of well-known value, in other forms of immune-mediated glomerulopathies and particularly in idiopathic 'membranous glomerulopathy' results of controlled trials are inadequate or controversial. Retrospective analysis of the data reported in the literature indicates a beneficial effect in some series but appears disappointing in others. Certainly the use of high-dose steroids for a prolonged period of time can expose the patients to serious side effects. The aim of the present review is to critically evaluate the results obtained with the use of steroids in the treatment of 'membranous glomerulopathy' and reexamine the rationale of their use in the light of the new information on the glucocorticoids mechanism of action on the immune system.
Clinical Trials as Topic↗
Renal histological lesions and clinical syndromes in multiple myeloma. Renal Immunopathology Group.
This retrospective multicenter study, based on 42 patients affected by renal damage due to multiple myeloma, analyzes the renal biopsy results, the clinical data at the time of biopsy and the subsequent renal outcome in order to clarify the correlations existing between clinical and histological changes. Plasmocytoma components were Bence Jones alone in 55% of the patients and light-chain excretion was present in over 90%. Rapidly progressive renal failure was the most frequent clinical presentation (27 cases). The histological lesions directly attributable to multiple myeloma were subdivided into 3 basic categories: related to light-chains, direct tumor involvement of renal parenchyma and attributable to systemic effects of neoplastic disease. Light-chains seemed to cause renal lesions in 59.4% of the cases. Myeloma cast nephropathy was the prominent bioptic diagnosis established (20 cases). Among the clinical, laboratory and histological parameters studied, only the degree of tubular-interstitial damage was significantly correlated to the renal outcome in the 32 patients who had an adequately documented follow-up period.
Acute Kidney Injury↗
Renal injury induced by long-term administration of cyclosporin A to rats.
Chronic administration of cyclosporin A (CyA) to animals and humans results in renal damage characterized by tubulointerstitial lesions and renal insufficiency. This nephrotoxicity limits the use of CyA in the management of graft rejection. Despite recent investigations in this area, relatively few studies correlate structural and functional abnormalities in animals undergoing long-term CyA treatment. The authors therefore treated 30 rats with CyA at the dose of 40 mg/kg/48 hr for up to 5 months. An additional group of 30 rats was given the vehicle alone and was considered as a control group. Renal morphology and function were studied. For evaluation of the effect of drug withdrawal, a third group of 25 animals received CyA for 3 months and was followed for another 2 additional months after drug withdrawal. The results show that the chronic administration of CyA to rats induced complex renal morphologic changes, associated with renal insufficiency, polyuria, and enhanced sodium excretion. Withdrawal of the drug resulted in almost complete normalization of morphologic and functional parameters. The early morphologic expression of CyA nephrotoxicity was isometric vacuolization and loss of brush border involving the proximal tubular cells, followed by a peculiar lesion in distal tubular cells due to glycogen accumulation. Glomerular and interstitial damage was mild and appeared only after 3 months of CyA administration. No vascular abnormalities were found in rats treated with CyA for 5 months. A CyA-induced decrease in the glomerular filtration rate (GFR) correlates with brush border loss but not with isometric vacuolization. The distal tubular glycogen accumulation was associated with the development of polyuria and enhanced sodium excretion. Given the high blood sugar level and severe glycosuria in animals treated chronically with CyA, it is also concluded that CyA possesses a diabetogenic effect which is likely to be responsible for glycogen accumulation at the tubular level.
Animals↗
Superimposed nephritis: a separate entity among glomerular diseases?
The concomitant occurrence of two glomerular diseases in the same patient was diagnosed in seven out of 105 patients undergoing renal biopsy for suspected glomerulopathy. The most frequently associated disease was a membranous type glomerulopathy. The follow-up was characterized by a rapid deterioration of renal function and two patients were required to start a chronic hemodialysis program soon after the diagnosis. It is suggested that the observed coexisting patterns of glomerular injury do not occur on the basis of chance alone and should be considered as a separate entity in glomerular pathology. In all cases, clinical and pathologic findings were strongly suggestive for two consecutive distinct pathologic processes, thus justifying the use of the term superimposed nephritis. It is reasonable to assume that the mechanisms responsible for glomerular damage and for the evolution of the disease in superimposed nephritis are different from those regulating the corresponding glomerulonephritis when occurring alone. The high prevalence of membranous pattern in superimposed nephritis indicates that pre-existing glomerular alterations might favor an immune reaction in the subepithelial space.
Adult↗
Adriamycin-induced glomerulosclerosis in the rat.
To evaluate long-term effect of sustained proteinuria induced by a single injection of adriamycin (ADR) on occurrence of focal segmental glomerulosclerosis (FSG), we treated 50 Sprague-Dawley (SD) rats, weighing 250 g with 5 mg/kg body weight of ADR. After six months of heavy proteinuria, 40% of ADR-treated rats did not develop FSG. In the remaining 60% of animals, a mild FSG was observed associated with the presence of large tubular casts and interstitial inflammation. Glomerulosclerosis was never observed in absence of tubulointerstitial lesions. Nine months after ADR, all rats exhibited FSG with renal insufficiency but the severest changes were restricted to the tubulointerstitial level. Our results indicate that chronic proteinuria induced by ADR is a relatively good model of glomerular sclerosis, however, the cause of glomerular sclerosis is probably different from that operating in other experimental models of FSG. Both sclerotic changes and progression of disease seem to be dependent on formation of tubular casts with consequent interstitial changes. This study raises the question of the relative role of tubulointerstitial changes in the subsequent development of FSG.
Animals↗
Tubulo-interstitial lesions mediate renal damage in adriamycin glomerulopathy.
The present study was designed to investigate the relationship between proteinuria, focal sclerosis, and tubulo-interstitial changes in the evolution of renal damage in experimental nephrosis. We utilized an accelerated unilateral model of adriamycin (ADR) nephrosis characterized by morphological changes more severe than in the classical model. The first events in ADR-induced glomerulopathy were epithelial cell damage and proteinuria. Subsequently, tubular casts were formed at the distal level. The cast formation preceded the development of interstitial damage, which was determined by tubular obstruction and breaking of tubular basement membrane (TBM), which in turn promoted an interstitial inflammatory reaction. Despite the severity of tubulo-interstitial damage observed after a long period of heavy proteinuria, the incidence of focal segmental glomerulosclerosis (FSG) was very low. The results of the present study indicate that chronic proteinuria is not necessarily accompanied by the development of focal sclerosis. Tubulo-interstitial lesions appear to be the most important determinant for the progression of renal damage in this model.
Animals↗
Effect of aspirin and sulindac in rabbit nephrotoxic nephritis.
Glomerular damage in nephrotoxic nephritis is mediated by circulating cells (neutrophils, platelets, and macrophages) infiltrating the glomerular tuft and responsible for the inflammatory reactions. It has been suggested that inflammatory cells may participate in glomerular inflammation through the synthesis and release of eicosanoids derived from the metabolism of arachidonic acid. On the other hand, old data and recent evidence indicate that eicosanoids derived from renal arachidonic acid metabolism play an important role in maintaining hemodynamics, especially in disease conditions. We wanted to evaluate the differential role of arachidonic acid metabolites derived from circulating or renal cells on the evolution of nephrotoxic nephritis. We used a nonselective cyclooxygenase inhibitor, aspirin, which blocks eicosanoid synthesis both in circulating cells and in renal tissue, as compared with a selective cyclooxygenase inhibitor, sulindac, which inhibits arachidonic acid metabolism in circulating cells, partially sparing renal cyclooxygenase. Aspirin, at a dosage that almost completely inhibits both circulating cell and renal arachidonate metabolites, worsens the morphologic expression of rabbit nephrotoxic nephritis and negatively influences the clinical course of the disease. Sulindac, at a dose that suppresses circulating platelet cyclooxygenase activity by 90%, but only partially affects renal prostaglandin synthesis, prevents extracapillary proliferation and reduces proteinuria without negative influence on glomerular hemodynamics.
Animals↗
Renal biopsy in patients with acute renal failure and prolonged bleeding time: a preliminary report.
A significant percentage of acute renal failure patients may benefit from a diagnostic renal biopsy, but this procedure carries an unacceptable risk of hemorrhagic complications. We have previously shown that red cell transfusions and 1-deamino-8-D-arginine vasopressin (DDAVP) are effective in managing uremic bleeding. We now report the results of giving washed red cell transfusions or DDAVP to 9 patients with uremia due to acute renal failure to improve hemostasis and allow a diagnostic renal biopsy. All patients admitted to the study had prolonged bleeding time (BT), ie, more than 10 minutes, and our procedure shortened BT in all cases, though in two patients BT after the therapeutic procedure was still longer than normal. In these two, biopsy was not performed. The seven patients whose BT became normal underwent percutaneous biopsy. Only minor clinical complications were registered. Computerized tomography (CT) revealed an incidence of perirenal hematomas comparable to that usually reported in patients with normal or slightly depressed renal function who undergo renal biopsy. Our findings indicate that red cell transfusions or DDAVP can temporarily restore hemostasis, allowing a diagnostic percutaneous biopsy in patients with acute renal failure.
Acute Kidney Injury↗
Low-protein diet prevents glomerular damage in adriamycin-treated rats.
Adriamycin (ADR) induces glomerular damage in rats with persistent proteinuria which develops 13 to 15 days after a single intravenous (i.v.) injection (5 mg/kg). Electron microscopy (EM) shows alterations of glomerular visceral epithelial cells with foot process fusions. The disease resembles minimal change nephropathy in humans. We studied the effect of two isocaloric diets with different protein content on urinary protein excretion, renal function, and glomerular morphology in rats treated with ADR. Six groups of rats were used. Group 1 received a single i.v. injection of ADR and was fed a standard diet containing 20% protein. Group 2 was fed a low-protein diet containing 6% protein starting 7 days before ADR. Group 3 was fed a low-protein diet starting the day after ADR. Group 4 served as control. Two additional groups of rats (5 and 6) were used to study the kidney distribution of ADR. Unlike animals fed the standard diet, animals fed the low-protein diet did not develop proteinuria. The kidney distribution of ADR measured at different intervals after drug injection was not influenced by the diet. Renal function as determined by glomerular filtration rate (GFR) and renal plasma flow (RPF) was not significantly modified in nephrotic rats receiving the standard diet compared to control animals. The low-protein regimen induced a significant elevation in RPF compared to the standard diet, but had no influence on GFR. Light and transmission EM studies showed alterations of glomerular visceral epithelial cells with fusion of foot processes in rats fed the standard diet, whereas no significant abnormalities of glomerular epithelial cells were detectable in animals receiving the low-protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis.
Altered glomerular metabolism of arachidonic acid (AA) has already been demonstrated in experimental nephrotoxic nephritis. The enhanced synthesis of thromboxane A2 (TxA2) in isolated glomeruli that has been found may mediate changes in renal hemodynamics. The objectives of this investigation were: to check whether glomerular AA metabolism is also altered in a model of glomerulopathy in which no leukocyte infiltration or platelet deposition could be demonstrated; to establish a correlation between the altered AA metabolism and proteinuria; and to explore whether the alteration of the prostaglandin (PG) pathway found in isolated glomeruli is an in vitro artifact or reflects a modification in vivo. We used a model of glomerular damage characterized by heavy and persistent proteinuria, which was induced in the rat by a single intravenous injection of adriamycin. At light microscopy, minimal glomerular abnormalities were found in this model. Electron microscopy showed profound alterations of glomerular epithelial cells with extensive fusion of foot processes and signs of epithelial cell activation. Electron microscopy of numerous glomeruli showed no platelet deposition or macrophage and leukocyte infiltration in this model. Isolated glomeruli from nephrotic rats studied 14 or 30 d after a single intravenous injection of adriamycin (7.5 mg/kg) when animals were heavily proteinuric generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. No significant changes were found in the other major AA metabolites formed through cyclooxygenase. Urinary excretion of immunoreactive TxB2 was also significantly higher in nephrotic than in normal animals. Administration of a selective Tx synthetase inhibitor, UK-38,485, from day 14 to day 18 after adriamycin resulted in a significant reduction of proteinuria compared with pretreatment values. Glomerular synthesis and urinary excretion of TxB2 were normal during the UK-38,485 treatment. Additional experiments showed that elevated glomerular synthesis and urinary excretion of TxB2 were not a consequence of increased substrate availability. Maximal stimulation of the renin-angiotensin axis with furosemide increased glomerular TxB2 synthesis in normal rats, which was significantly lower than in nephrotic animals. Finally, experiments using a unilateral model of adriamycin nephrosis indicated that the enhancement of glomerular TxB2 synthesis is not simply a consequence of the nephrotic syndrome. We conclude that: there is an abnormality of glomerular AA metabolism in nephritic syndrome, which leads to increased TxA2 production; the increased Tx generation correlates with protein excretion and might be responsible for altering the glomerular basement membrane permeability to protein; and the alteration found in isolated glomeruli probably reflects a modification in vivo, in that urinary excretion of immunoreactive TxB2 is also consistently increased in adriamycin nephrosis.
Animals↗
Renal biopsy in patients with acute renal failure and prolonged bleeding time.
Explore the source record for details and available documents.
Acute Kidney Injury↗
Tubular microfibrils in the glomeruli of membranous nephropathy.
The presence of tubular microfibrils in the mesangium and capillary walls of the renal glomeruli is a rare occurrence that has been reported by others in different glomerular disease processes. The two cases presented in this report demonstrated such microfibrils in membranous glomerulonephropathy, an association previously described in only one other case. These microfibrils differed in size and structural characteristics from collagen fibers, amyloid fibrils, and cryoglobulin microtubules.
Adult↗