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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 433 records · Page 24Linked to original sources
PubMed1986

Moderate doses of aspirin and risk of bleeding in renal failure.

Uraemic patients have a bleeding tendency thought to be due to platelet functional abnormalities, but haemodialysis paradoxically exposes patients to the thrombotic complications of arteriovenous shunts. Possible treatments of the latter have been debated. The effect of 100 mg/m2 aspirin on haemostatic function was studied in 29 uraemic patients on chronic haemodialysis who had normal or only slightly prolonged bleeding times. Aspirin did not significantly affect bleeding time in healthy controls but prolonged it in uraemic patients. In 12 of the 29 uraemic patients, the bleeding time after aspirin was longer than 15 min. Aspirin completely abolished thromboxane A2 generation by both control and uraemic platelets, indicating that its effect in uraemic patients is not due to differential inhibition of platelet cyclo-oxygenase. Products of lipoxygenase enzyme and factor VIII von Willebrand factor did not seem to have a role. A careful risk-benefit evaluation is necessary before giving aspirin to uraemic patients on haemodialysis to prevent thrombosis of the arteriovenous shunt.

Adolescent↗
PubMed1986

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↗
PubMed1986

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↗
PubMed1986

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↗
PubMed1986

Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A.

Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.

Animals↗
PubMed1986

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↗
PubMed1986

Role of renal prostaglandins in normal and nephrotic rats with diet-induced hyperfiltration.

Changes in glomerular hemodynamics have been observed in animals and humans after a high-protein feeding. It has been postulated that these changes can induce progressive deterioration of renal function favoring loss of glomerular permselectivity properties and subsequent glomerulosclerosis, especially when the renal mass is already reduced surgically or by a disease process. We studied the consequence of long-term protein supplementation on renal function parameters in normal animals and in animals affected by adriamycin nephrosis, a model of renal damage that closely mimics human "minimal change". We also wanted to investigate whether vasodilatory prostaglandins (PGs) generated at the renal level are responsible for the adaptive hemodynamic changes that follow dietary manipulation in normal animals and in animals with experimental nephrosis. The model of glomerular damage we used is characterized by heavy and persistent proteinuria induced in the rat by adriamycin (ADR). Two isocaloric diets were selected containing 20% and 35% protein. High-protein feeding induced a significant increase in glomerular filtration rate in both normal and nephrotic animals. In normal animals the high-protein diet did not modify the urinary excretion of 6-keto-PGF1 alpha, the stable breakdown product of prostacyclin (PGI2), but significantly reduced urinary excretion of prostaglandin E2. In nephrotic rats, the high-protein diet increased urinary excretion of 6-keto-PGF1 alpha, without modifying urinary excretion of prostaglandin E2. Glomerular synthesis of vasodilatory prostaglandins paralleled the urinary excretion pattern. The cyclooxygenase inhibitor indomethacin effectively inhibited urinary excretion of vasodilatory PGs but did not prevent hyperfiltration in normal animals fed the high-protein diet. At variance, when given to nephrotic animals fed the high-protein diet, indomethacin at a dose that reduced 6-keto-PGF1 alpha and prostaglandin E2 urinary excretion by 84% and 93%, respectively, inhibited hyperfiltration. We conclude that the same hemodynamic changes that occur in normal animals given a high-protein diet also take place when glomeruli are uniformly damaged by a disease process as in ADR nephrosis. However, whereas hyperfiltration in normal animals appears to be independent of renal PGs, in nephrotic animals an enhanced renal synthesis of PGI2 appears to play a crucial role in the adaptive changes responsible for hyperfiltration.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins?

Cyclosporine A (CsA) is a recently introduced immunosuppressive agent that represents a significant advance in the clinical control of graft rejection. However despite the remarkable effectiveness, one of the limiting factors to a more extensive use of CsA appears to be its nephrotoxicity. CsA is reported to induce a tubular epithelial damage whereas histological examination of glomeruli does not reveal abnormalities unless particularly high doses of the drug are used. On the other hand a decrease in glomerular filtration rate (GFR) has been reported in association with acute administration of CsA. Relatively few studies are available to compare structural and functional abnormalities in the same animals after an acute administration of CsA. Here we evaluated morphological abnormalities and renal function in the same animals treated for 20 days with CsA. Moreover in the attempt to find a link between tubular damage and decrease in GFR we studied the effect of CsA on the renin-angiotensin system as well as on glomerular synthesis of prostacyclin (PGI2) and prostaglandin E2 (PGE2). Our results confirmed that CsA induces a focal damage of tubular epithelial cells with isometric vacuolization of cytoplasm. No glomerular or vascular changes have been detected at histological examination. Serum creatinine was significantly elevated after 20 days of treatment, whereas creatinine clearance showed a progressive tendency to decrease without reaching a statistical significance. Plasma renin activity was found to progressively increase during CsA administration, whereas the synthesis of PGI2 and PGE2 by isolated glomeruli was not modified in CsA-treated animals in respect to animals receiving the solvent alone.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effect of short-term cyclosporine administration in rats on renin-angiotensin and thromboxane A2: possible relevance to the reduction in glomerular filtration rate.

A short-term treatment with Cyclosporine A (CyA) induces a decrease in glomerular filtration rate (GFR), promptly reversible after withdrawal of the drug. Several lines of evidence are now available as to indicate that this phenomenon is dependent on a hemodynamic perturbation resulting in a renal vasoconstriction. With the present work we have examined the relationship between the reduction in GFR which follows a short-term administration of CyA in rats and the biochemical changes in renin-angiotensin system and renal arachidonic acid metabolism. Our results show that CyA administration (25 mg/kg/day) for 45 days stimulates renin-angiotensin system with an increase in plasma renin activity. These changes are not accompanied by a parallel increase in the renal synthesis of vasodilatory prostaglandin E2 and prostacyclin as it occurs in other conditions of renin-angiotensin stimulation. At variance glomerular synthesis and urinary excretion of thromboxane A2 (TxA2) are increased progressively during CyA treatment. These changes in renal Tx precede the increase in serum creatinine and the decrease in GFR thus indicating that TxA2 might be an additional factor potentiating the effect of angiotensin II on glomerular hemodynamics. In conclusion the early reduction in GFR which follows daily administration of CyA in rats might be the result of a synergic action of angiotensin II and TxA2 on vascular tone and mesangial contraction which is not modulated by an increase in glomerular vasodilatory prostaglandins. If this explanation may be applied to early reduction in GFR observed in humans treated with CyA before tubular toxicity develops needs to be investigated further.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Cyclosporin-induced endothelial cell injury.

The administration of Cyclosporin-A (CyA) to animals and humans may induce an arteriolar damage. It has also been reported that CyA in some instances may cause an hemolytic uremic-like syndrome. This is a syndrome of vascular damage with thrombotic occlusions of the microcirculation. Endothelial injury is considered the first event in the pathogenetic cascade leading to hemolytic-uremic syndrome. We have used bovine aortic endothelial cells in culture to address the issue of CyA-induced arteriolar damage. Exposure of endothelial cells to different concentrations of CyA induced a time- and dose-dependent cell injury in vitro. The damage induced by CyA was characterized by an early cell detachment from culture substrate followed by cell lysis as documented by the increase in lactate dehydrogenase (LDH) and 51Cr release. Both detachment and lysis were negligible after short-term incubation of 1 microM CyA with endothelial cells. One micromolar CyA only induced lysis if incubations were prolonged above 6 hours. Ten and 50 microM CyA both induced marked endothelial cell detachment and lysis; lysis started 3 hours after incubation of endothelial cells with CyA and was maximal at the end of 24 hours incubation. CyA-induced injury was associated with dose- and time-dependent increase in prostacyclin and thromboxane A2 release by endothelial cells exposed to CyA independently from the concentrations of CyA used. CyA-induced generation of prostacyclin and thromboxane A2 was inhibited when the incubations were performed in the presence of aspirin (500 microM). These studies indicate that CyA exerts a direct cytotoxic effect on endothelial cells and might help in understanding the pathogenesis of CyA-induced vascular damage.

Animals↗
PubMed1985

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↗
PubMed1985

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↗
PubMed1985

Inhibition of human platelet aggregation by parathyroid hormone. Is cyclic AMP implicated?

Parathyroid hormone (PTH) is a polypeptide which in different in vitro systems raises intracellular cyclic AMP (cAMP) levels via adenyl cyclase activation and stimulates Ca2+ transport across cell membranes. We tested whether, on the basis of this mechanism, PTH would inhibit human platelet aggregation. The latter was tested in vitro by a photometric technique. Platelet aggregation induced by the calcium ionophore A 23187 was inhibited by PTH at concentrations (0.5-3 USP U/ml) similar to those effective in other in vitro systems. Higher concentrations of PTH were required to prevent aggregation initiated by adenosine-5'-diphosphate, arachidonic acid, or platelet-aggregating factor. The terminal synthetic fragment 1-34 b PTH was ineffective against all aggregation stimuli. The antiaggregating effect of PTH was potentiated by verapamil and theophylline and was additive to that of PGI2. However, PTH did not appear to increase platelet cAMP levels and was not counteracted by an inhibitor of platelet adenyl cyclase. It is therefore unlikely that PTH inhibits platelet aggregation through an adenyl cyclase stimulated increase of cAMP. Since PTH levels are markedly increased in uremic plasma, it might contribute to the defective platelet function and the bleeding tendency frequently occurring in uremic patients.

Adenylyl Cyclases↗
PubMed1985

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↗
PubMed1985

Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus.

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGF1 alpha than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1 alpha excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGF1 alpha and higher urinary TXB2. Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (CCr). In contrast, the urinary excretion of 6-keto-PGF1 alpha showed a significant linear correlation with both CCr and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGF1 alpha and TXB2 and in both CCr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGF1 alpha or PGE2 excretion. We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are associated with changes in glomerular hemodynamics and may play a role in the progression of SLE nephropathy.

Adolescent↗
PubMed1985

Acetyl glycerylphosphorylcholine aggregates human platelets through two distinct pathways, both dependent on arachidonic acid metabolism.

Acetyl glyceryl ether phosphorylcholine (AGEPC) is a mediator of inflammation and anaphylaxis, released from IgE-sensitized basophils when exposed to antigens. Convincing evidence shows that AGEPC is synthesized by inflammatory cells, and its mechanism of action has been extensively studied with particular interest focusing on platelet stimulation, the key event initiating the inflammatory cascade. However, widely different results have been reported so that the mode of action of AGEPC in activating platelets is still largely obscure. The objective of this investigation was to elucidate whether AGEPC stimulates human platelets independently from arachidonate metabolism, as previously suggested, and to define the role of nonsteroidal antiinflammatory drugs in inhibiting AGEPC-mediated platelet activation. Irreversible platelet aggregation in vitro occurred at low AGEPC concentrations, was dose dependent, and was accompanied by thromboxane A2 formation. Aspirin inhibited irreversible aggregation induced by low AGEPC concentrations. A thromboxane inhibitor, UK-37, 248-01, failed to affect AGEPC aggregation, suggesting a crucial role for cyclic endoperoxides in AGEPC's mechanism of action. A thromboxane/endoperoxide receptor antagonist 13-azaprostanoic acid prevented irreversible platelet aggregation induced by low AGEPC concentrations. The inhibiting effect of aspirin on AGEPC aggregation could be overcome by increasing the concentration of the agonist by a factor of 10, unless a lipoxygenase inhibitor, nordihydroguaiaretic acid, or 5,8,11,14-eicosatetraynoic acid was previously added to platelet-rich plasmas. The phospholipase inhibitor, mepacrine, completely suppressed human platelet aggregation induced by AGEPC. These results indicate that AGEPC induces irreversible aggregation in human platelets by two distinct pathways, both dependent upon arachidonic acid metabolism: a cyclooxygenase-dependent one at low AGEPC concentrations and a cyclooxygenase-independent one, possibly mediated through the formation of lipoxygenase products, at high AGEPC concentrations.

5,8,11,14-Eicosatetraynoic Acid↗