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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 37 records · Page 2Linked to original sources
PubMed1992

Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rats with renal isograft.

The question of whether pharmacological inhibition of the thromboxane A2 activity prevents cyclosporine-induced chronic renal dysfunction in a Lewis rat model of renal isograft was addressed. Transplanted animals were given a daily oral dose of cyclosporine (20 mg/kg; N = 15), cyclosporine (20 mg/kg) and the thromboxane A2 receptor antagonist GR32191 (3 mg/kg twice daily, by gavage; N = 15), or the vehicle alone (N = 12). Treatments were started the day of kidney transplant, and animals were monitored for 1 year. Cyclosporine-treated animals developed renal insufficiency, as documented by serum creatinine levels of 0.49 +/- 0.09, 0.95 +/- 0.12, and 1.38 +/- 0.15 mg/dL before and after 6 and 12 months of observation, respectively. Cyclosporine and GR32191 used in combination partially but significantly prevented the deterioration of renal function (serum creatinine, basal, 0.52 +/- 0.06; month 6, 0.68 +/- 0.04; month 12, 0.93 +/- 0.10 mg/dL). At the end of the study, GFR, as insulin clearance, was significantly lower in rats given cyclosporine (0.28 +/- 0.09 mL/min/100 g) than in rats given cyclosporine plus GR32191 (0.45 +/- 0.05 mL/min/100 g) or than in vehicle-treated animals (0.56 +/- 0.07 mL/min/100 g). Similar results were obtained for the effective RPF, measured as p-aminohippurate clearance. At the same time points, comparable to whole-blood cyclosporine levels were found in rats receiving cyclosporine alone and in those given cyclosporine plus GR32191. More than 50% of the animals on cyclosporine alone died from uremia before the end of the observation period. By contrast, rats receiving cyclosporine in combination with GR32191 had a prolonged survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Atrial natriuretic peptide and prostacyclin synergistically mediate hyperfiltration and hyperperfusion of diabetic rats.

The relative contribution of atrial natriuretic peptide (ANP) and vasodilatory prostaglandins to hyperfiltration in Wistar rats with experimental diabetes was studied 6-8 wk after streptozocin injection. Plasma levels of immunoreactive ANP were significantly higher (P less than 0.01) in hyperglycemic diabetic (72.9 +/- 11.7 pg/ml) than in normoglycemic diabetic (44.8 +/- 8.6 pg/ml) or nondiabetic (40.0 +/- 6.8 pg/ml) rats. Blocking endogenous ANP by specific ANP-antiserum infusion reduced significantly (P less than 0.01) glomerular filtration rate (GFR) and renal plasma flow (RPF) of hyperglycemic rats compared with preinfusion values (1.23 +/- 0.06-1.02 +/- 0.04; 2.87 +/- 0.25-2.40 +/- 0.10 ml.min-1.100 g-1, respectively). However, correction of hyperfiltration and hyperperfusion was only partial (nondiabetic rats GFR 0.85 +/- 0.07; RPF 2.27 +/- 0.13 ml.min-1.100 g-1). Because diabetic rats with hyperglycemia also had an increased urinary excretion of prostacyclin metabolite 6-keto-prostaglandin F1 alpha (220.6 +/- 62.8 ng/24 h) compared with nondiabetic rats (51.2 +/- 2.7 ng/24 h), we wondered whether excessive prostacyclin formation contributed to hyperfiltration and hyperperfusion in this setting. Indomethacin infusion partially reduced GFR (1.25 +/- 0.07 to 1.06 +/- 0.07 ml.min-1.100 g-1, P less than 0.05) and RPF (2.85 +/- 0.11 to 2.46 +/- 0.12 ml.min-1.100 g-1, P less than 0.01) in diabetic rats. The combined infusion of ANP antiserum and indomethacin normalized GFR and RPF in diabetic rats with hyperglycemia (1.27 +/- 0.05 to 0.88 +/- 0.05 and 2.84 +/- 0.10 to 2.22 +/- 0.06 ml.min-1.100 g-1, respectively; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Plasma manipulation in hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.

The hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are syndromes of microangiopathic hemolytic anemia dominated by renal failure in children and by neurological signs in adults. Microvascular thrombosis is the typical lesion and endothelial injury is likely the initial event. Over the last 40 years, the prognosis has significantly improved, probably as the result of better supportive management of anemia, renal failure, hypertension, and electrolyte and water imbalances, but still remains poor in adults with renal arteriolar thrombosis and neurological involvement. Many specific therapies have been used and, based on reports of a few cases, a consensus has been reached empirically that recognizes antiplatelet agents and plasma manipulation as the most appropriate therapy for adult HUS and TTP. Their effectiveness, however, still remains to be formally tested in prospective controlled trials. Recently, we saw a 23-year-old man with a history of recurrent episodes of HUS in childhood and of TTP since the age of 21. HUS always disappeared following blood transfusions, whereas prompt remissions of the episodes of TTP were obtained with plasma exchange. In order to avoid the use of plasma, alternate forms of therapy were tried. However, aspirin (50 mg/day), prednisone (1 mg/kg bw/d), and human immunoglobulins (0.5 mg/kg/d) were ineffective, and plasma exchange was needed to obtain remission. During two more recent relapses, fresh-frozen plasma was infused as the initial therapy and produced a complete remission within few days, thus preventing the need for plasma exchange. During the last relapse, plasma exchange with albumin and saline failed to induce remission and plasma infusion was required.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Verotoxin glycolipid receptors determine the localization of microangiopathic process in rabbits given verotoxin-1.

Infection with verotoxin-producing Escherichia coli has been implicated in the cause of hemolytic-uremic syndrome. Cases of thrombotic thrombocytopenic purpura and verotoxin infections have been also described. In this study we sought to determine the following: (1) whether verotoxin induces microvascular lesions in the rabbit, (2) the organ distribution of such lesions, and (3) the distribution of verotoxin glycolipid receptors in the various organs. Rabbits challenged with verotoxin-1 purified from E. coli O157:H7 had anorexia, lethargia, and limb paralysis; renal function, however, was normal. Central nervous system lesions found included pericellular and perivascular edema, focal hemorrhage, vascular lesions, and severe alterations of Purkinje cells. Histologic changes were also seen in the colon, with mucosal and submucosal edema and hemorrhage, and in the lung, with interstitial fibrosis and focal lymphohistiocitic infiltration. No lesions were detected in kidney, heart, liver, and spleen. Screening of various tissues for the presence of the verotoxin receptors revealed galabiosyl ceramide in the central nervous system and globotriosyl ceramide in the gastrointestinal tract, lung, and spleen. No receptors for verotoxin were found in the heart, liver, and kidney. These results indicate that organ localization of the disease in rabbits is dependent on the distribution of verotoxin receptors.

Administration, Oral↗
PubMed1992

Thrombospondin induces glomerular mesangial cell adhesion and migration.

BACKGROUND: Extracellular matrix components are known to modulate mesangial cell functions as adhesion, motility and proliferation. Among other extracellular matrix components, mesangial cells have been recently described to secrete thrombospondin (TSP), a high molecular weight glycoprotein, produced by several cell types, and known to play a role in embryogenesis, wound healing, angiogenesis, and tumorigenesis. The aim of this work was the functional and molecular characterization of TSP interactions with mesangial cells. EXPERIMENTAL DESIGN: Adhesion of mesangial cells to TSP-coated plastic, and chemotaxis in the Boyden chamber assay were tested. In order to identify TSP active domains, heparin, known to bind to the amino-terminal region of TSP, four monoclonal antibodies directed against specific domains of the molecule, and TSP fragments obtained by enzymatic digestion were used. RESULTS: We found that TSP induces mesangial cell adhesion and chemotaxis, in a dose dependent manner. Adhesion was inhibited by antiserum against TSP, and by an anti-CD36 monoclonal antibody tested in the presence of heparin, but not by the peptide Gly-Arg-Gly-Asp-Ser. We have also found that only the carboxy-terminal end of TSP retains the adhesive properties of the molecule, while all the fragments tested showed some degree of chemotactic activity. CONCLUSIONS: We conclude that TSP modulates mesangial cell adhesion and motility, thus acting as a potential autocrine and paracrine regulator of mesangial cell functions in normal and pathologic conditions.

Animals↗
PubMed1992

Pathophysiologic implications of proteinuria in a rat model of progressive glomerular injury.

BACKGROUND: Males of a substrain of Munich-Wistar rats (MWF/Ztm), selected for their large number of superficial glomeruli, develop spontaneous proteinuria with age, whereas females of this strain have a normal urinary protein excretion rate. EXPERIMENTAL DESIGN: We investigated the relationship between functional and structural glomerular alterations in four groups of male and female MWF/Ztm rats, respectively at 20 and 35 weeks of age. Systolic blood pressure, urinary protein excretion and composition of urinary proteins were periodically measured during the study. At the end of the observation period, renal function was evaluated with solute clearance technique and kidney tissue processed for morphologic and morphometrical analysis using light and electron microscopy. RESULTS: Systolic blood pressure in males was significantly higher than in females, and progressed toward systemic hypertension with age. Urinary protein excretion became spontaneously abnormal in males. About 50% of urinary proteins consisted of albumin, whereas 35% was a sex-dependent low molecular weight protein. Albumin excretion increased with age in these animals, whereas excretion of the sex-dependent protein decreased. Urinary protein excretion in females was significantly lower than in males of the same age, remaining near normal levels. No decline in renal function with age was observed in all animal groups. Glomerular structural alterations developed progressively with age in males, leading to important glomerular and tubular alterations. Female rats maintained almost intact glomerular morphology until the end of the study. Morphometric analysis showed an important increase in glomerular volume with age in males but not in females. This glomerular tuft enlargement was the result of an increase in the number of glomerular cells and a concomitant increase in cell volume. CONCLUSIONS: Male MWF/Ztm rats develop spontaneously systemic hypertension, proteinuria of glomerular origin, and glomerulosclerosis. Female rats develop less severe hypertension and are protected from proteinuria and glomerulosclerosis.

Aging↗
PubMed1991

High-performance liquid chromatographic determination of iothalamic acid in human plasma and urine.

A simple, rapid and sensitive method for the determination of iothalamic acid (IA) in both plasma and urine is reported. After extraction with ethyl acetate, IA was determined by strong anion-exchange high-performance liquid chromatography with ultraviolet detection at 254 nm. The lower limit of detection was 0.5 micrograms/ml. The average recovery was 73 and 57% from plasma and urine, respectively. Linearity was found over the investigated concentration range (up to 500 micrograms/ml for plasma and up to 10.0 mg/ml for urine). The reproducibility of the technique was good (coefficient of variation less than 6%) as was the precision and accuracy (coefficient of variation less than 2.5%). No interference from endogenous substances or any of the common drugs tested was found.

Acetates↗
PubMed1991

Low levels of the anticoagulant activity of protein C in patients with chronic renal insufficiency: an inhibitor of protein C is present in uremic plasma.

Twenty-nine of 54 uremic patients had low levels of protein C measured as anticoagulant activity, contrasting with normal levels measured as amidolytic activity or antigenic concentration. We demonstrate that this discrepancy is due to the presence of a soluble plasma inhibitor that interferes specifically with the anticoagulant activity of activated protein C. The inhibitor does not interfere with other coagulation assays. It is resistant to diisopropylfluorophosphate, high temperatures and repeated freezing and thawing. It can be dissociated from protein C by anti-protein C antibodies or by dialysis in vitro and in vivo. It binds to positively charged resins and can be eluted with high salt concentrations without losing its inhibitory capacity. The inhibitory effect is correlated with plasma creatinine levels and fluctuates with time.

Adult↗
PubMed1991

Endothelial cells express the interleukin-1 receptor type I.

Interleukin-1 (IL-1) profoundly affects a number of functions of vascular cells. Two distinct IL-1 receptors (IL-1R) are expressed on different cell types: the 80 Kd IL-1RI on T cells and fibroblasts, and the 68 Kd IL-1RII on B cells and myelomonocytic cells. The presence and functionality of IL-1R on vascular cells has been investigated by using polyomatransformed mouse endothelial cell (EC) lines (sEnd.1 and tEnd.1). These cells expressed specific and saturable binding sites for IL-1 (1,273 sites per cell with kd 9.5 x 10(-11) mol/L for sEnd.1, and 771 sites per cell with kd 8.5 x 10(-11) mol/L for tEnd.1, with radioiodinated IL-1 alpha as ligand). Binding of IL-1 was also evident at single cell level by autoradiography. By cross-linking studies, the molecular weight of the IL-1 binding protein on EC was approximately 80 Kd. This was confirmed by the presence in EC of mRNA for the 80 Kd IL-1RI. The IL-1RI on EC was apparently functional, since EC responded to IL-1 with IL-6 mRNA expression and IL-6 bioactivity production. These results were extended to human EC and vascular smooth muscle cells, which were also found to express mRNA for IL-1RI.

Animals↗
PubMed1991

Kidney graft survival in rats without immunosuppressants after intrathymic glomerular transplantation.

Isolated glomeruli from Brown-Norway (RT1n) rat kidney were inoculated into the thymus of 6 incompatible Lewis (RT1(1] rats pretreated for 2 days with 40 mg/kg oral cyclosporin daily and given 2.5 mg/kg subcutaneous dexamethasone at inoculation. 10 days later the left kidney from the Brown-Norway donor used to prepare glomeruli was transplanted orthotopically to the Lewis (RT1(1] rat that had received intrathymic glomeruli. Donor-specific unresponsiveness allowed the renal allograft to survive indefinitely without further immunosuppression. 6 control Lewis rats treated as above except that medium alone was injected intrathymically rejected a renal allograft within 7-9 days.

Animals↗
PubMed1991

Human placenta expresses endothelin gene and corresponding protein is excreted in urine in increasing amounts during normal pregnancy.

Systemic and renal hemodyanmic changes in normal pregnancy have been attributed in part to altered vascular synthesis of vasodilatory prostaglandins. Besides vasodilatory substances, endothelium also generates vasoconstrictors, including endothelin. We evaluated the capacity of placental tissue from normal pregnant women to express endothelin gene and to generate endothelin. Placental tissue expressed a single 2.3 kb preproendothelin messenger ribonucleic acid and produced comparable amounts of endothelin 3, Big endothelin 1, and endothelin 1 and a minor quantity of endothelin 2. To investigate the possible influence of placental endothelin production on plasma levels of the peptide, plasma endothelin concentrations were measured in normal pregnant women at delivery and were found to be numerically higher than those measured in nonpregnant subjects. Urinary excretion of endothelin, taken as a marker of the renal synthesis of the peptide, tended to increase, although not significantly, in the first 14 weeks of pregnancy. This trend continued throughout pregnancy, resulting in a significant increase from the second trimester to delivery.

Adult↗
PubMed1991

Increased urinary excretion of platelet activating factor in mice with lupus nephritis.

Platelet activating factor (PAF) is present in urine from humans and experimental animals in normal conditions. Very little is known about changes in PAF urinary excretion under pathologic conditions and no data are available about the origin of PAF in the urine. In the present study we explored the possibility that immunologic renal disease is associated with an increase in PAF urinary excretion using gas chromatography-mass spectrometry technique. To clarify the renal or extrarenal origin of urinary PAF we evaluated whether exogenously administered PAF (1-[1', 2'-3H]alkyl) is filtered through the glomerulus and excreted in the urine. The results show that: 1) urine from mice with lupus nephritis in the early phase of the disease contained amounts of PAF comparable to those excreted in normal mouse urine, 2) PAF levels increased when animals started to develop high grade proteinuria, 3) after intravenous injection of [3H] PAF in nephritic mice, a negligible amount of [3H] ether lipid, corresponding to [3H]1-alkyl -2-acyl-3-phosphocholine (alkyl-2-acyl-GPC), was recovered from the 24 h urine extract.

Animals↗
PubMed1991

Prevention and treatment of pregnancy-associated hypertension: what have we learned in the last 10 years?

High blood pressure (BP) complicates approximately 10% of all pregnancies. Hypertension in pregnancy falls into four categories: (1) preeclampsia-eclampsia, (2) chronic hypertension of whatever cause, (3) preeclampsia-eclampsia superimposed to chronic hypertension or renal disease, and (4) transient or late hypertension (gestational hypertension). Preeclampsia, the association of hypertension, proteinuria, and edema, accounts for more than 50% of all the hypertensive disorders of pregnancy and is a major cause of fetal and maternal morbidity and mortality. Unfortunately, distinguishing between preeclampsia and other causes of hypertension on clinical grounds can be difficult because of the lack of specific tests for differential diagnosis. Increased vascular resistance has been claimed as the primary cause of preeclampsia; however, a variable hemodynamic profile with relatively high cardiac outputs, normal filling pressures, and inappropriately high systemic vascular resistances is now reported by most investigators. Imbalance between vasodilator and vasoconstrictor eicosanoids may account for platelet activation and increased responsiveness to pressor peptides. Altered prostacyclin (PGI2) to thromboxane A2 (TxA2) ratio in maternal uteroplacental vascular bed may favor local platelet activation and vasoconstriction contributing to placental insufficiency and fetal distress. Alternatively, recent evidence seems to suggest that fetal umbilical placental circulation may be the site of the primary vascular injury. Whether low-dose aspirin prevents preeclampsia because it inhibits the excessive maternal TxA2 or whether the partial inhibition of fetal TxA2 is also of therapeutic value remains to be established. Treatment of severe hypertension in pregnancy is probably important to prevent cardiac failure or cerebrovascular accidents in the mother. The need for pharmacological therapy of mild to moderate hypertension is still debated, since no formal studies are available to clarify whether pharmacological treatment in such instances effectively reduces maternal or fetal risk. For the treatment of preeclampsia, hydralazine and nifedipine may be used when delivery is not applicable. Labetalol and diazoxide are effective for hypertensive emergencies. Life-threatening hypertension that does not respond to more conventional therapy is an indication for the use of sodium nitroprusside. For chronic hypertension, alpha-methyldopa remains the treatment of choice; if ineffective, hydralazine or beta-blockers are suitable. Effectiveness and safety of other molecules remain elusive.

Antihypertensive Agents↗
PubMed1991

Recombinant human erythropoietin to correct uremic bleeding.

Recombinant human erythropoietin may improve hemostasis of uremic patients by correcting anemia. However, a complete correction of renal anemia carries the risk of hypertension, encephalopathy, thrombosis, and hyperkalemia. Our aim was to establish the minimum level of packed cell volume (PCV) achieved with recombinant human erythropoietin that corrects the prolonged bleeding time in uremia. Twenty patients with chronic renal failure, anemia, and very prolonged bleeding time (greater than or equal to 15 minutes) were randomly allocated to erythropoietin or no specific treatment. The initial dose of erythropoietin was 50 U/kg intravenously (IV) three times a week. Every 4 weeks, the dose was increased by 25 U/kg until a normalization of bleeding time was achieved. Erythropoietin at a dose ranging from 150 to 300 U/kg/wk induced an increase in PCV to a range of 27% to 32% in all patients but one, and normalized bleeding time in all patients. A significant negative correlation (r = 0.898, P less than 0.001) was found between PCV and bleeding time measurements. Erythropoietin also significantly (P less than 0.01) increased values for red blood cell (RBC) distribution width (basal, 11.3 +/- 0.6; 12 weeks, 13.1 +/- 1.3). Platelet count and platelet function parameters did not significantly change. In untreated patients, no changes were recorded in all the parameters considered. These results establish in a controlled fashion that erythropoietin shortens bleeding time of uremic patients and indicate that a partial correction of renal anemia is enough to normalize bleeding time.

Adult↗
PubMed1991

Low-protein diet and glomerular size-selective function in membranous glomerulopathy.

We studied the effect of dietary protein restriction on glomerular function and proteinuria in nine patients with membranous nephropathy. Patients were randomly assigned to a 3-month period of a normal protein diet (NPD, 1.3 mg/kg/d) or of a low-protein diet (LPD, 0.6 mg/kg/d), in a cross-over design. Dietary protein restriction did not affect glomerular filtration rate (47.8 +/- 10.7 and 49.0 +/- 13.5 mL/min/1.73 m2, LPD and NPD, respectively) and renal plasma flow (456 +/- 119 and 499 +/- 161 mL/min/1.73 m2, LPD and NPD, respectively), nor did it significantly improve glomerular permselective function, as shown by urinary protein excretion (3.1 +/- 2.2 and 3.5 +/- 2.8 g/d, LPD and NPD, respectively) and fractional clearance of albumin, IgG, and neutral dextran molecules of graded molecular size (radii ranging from 2.8 to 6.0 nm). These results indicate that reduction of protein intake to 0.6 g/kg/d does not improve glomerular size selectivity in membranous nephropathy. Thus, in current clinical practice, a protein-restricted diet does not appear to be effective in reducing proteinuria in this category of patients.

Adult↗
PubMed1991

Morphometrical analysis of glomerular changes induced by cyclosporine in the rat.

Functional and morphologic techniques were used to study the renal changes induced by a long-term exposure of normal rats to cyclosporine A (CsA), as well as their potential reversibility. CsA treatment for 3 months resulted in a significant (P less than 0.01) reduction of glomerular filtration rate (GFR) as compared with vehicle-treated animals. Histological examination of the kidneys showed mild glomerular damage characterized by ischemic lesions, increased mesangial matrix, and intracapillary hypercellularity in the CsA-treated group, but not in the vehicle-treated group. Proximal tubular abnormalities and limited areas of interstitial fibrosis were also present in the CsA group. A complete reconstruction of glomerular corpuscle was used to evaluate the consequence of CsA-induced renal ischemia on capillary tuft volume. The results showed that in rats administered CsA for 3 months glomerular volume distribution was shifted toward small glomeruli. Prolongation of CsA administration for 5 months did not result in a further decrease in GFR, and was associated with the appearance of a subset of glomeruli that became larger than normal. We have also investigated whether, once established, CsA-induced renal injury is reversible. In rats that were administered CsA for 3 months and then treatment discontinued for 2 months, GFR returned to pretreatment values and partial reversibility of morphologic changes was observed. Morphometric analysis showed that 2 months after withdrawal of CsA, glomerular volume distribution was almost comparable to that observed in vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗