Search PubMed⌕ Search

Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 127 records · Page 7Linked to original sources
PubMed1999

Antiproteinuric therapy while preventing the abnormal protein traffic in proximal tubule abrogates protein- and complement-dependent interstitial inflammation in experimental renal disease.

In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: (1) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; (2) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that (1) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; (2) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis.

Analysis of Variance↗
PubMed1999

In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano Studi Epidemiologici in Nefrologia.

The Ramipril Efficacy in Nephropathy Core and Follow-Up Study found that > or =36 mo of continued ramipril therapy decreased substantially the risk of end-stage renal failure (ESRF) in patients with chronic nephropathies and a urinary protein excretion rate > or =3 g/24 h. This study investigates the time-dependent changes in GFR in these patients and in control subjects who were randomized to conventional therapy during the Core period and switched to ramipril during the Follow-Up study. Analyses included 150 patients (continued ramipril: n = 74; switched to ramipril: n = 76) who had at least three GFR measurements (including baseline) during the whole observation period and a subgroup of 43 patients (continued ramipril: n = 26; switched to ramipril: n = 17) who had at least six GFR measurements, including at least three on the Core and at least three on the Follow-Up study. Ramipril (1.25 to 5 mg/d) and conventional therapy were targeted at achieving a diastolic BP below 90 mm Hg. The main efficacy variables were GFR and ESRF (need for dialysis). Analysis was by intention to treat. Throughout the study, the mean +/- SEM rate of GFR decline (deltaGFR) was significantly lower in patients continued on ramipril compared to those switched to ramipril (0.51+/-0.09 versus 0.76+/-0.10 ml/min per 1.73 m2 per mo, P<0.03). In patients on continued ramipril who had at least six GFR measured--but not in control subjects--deltaGFR progressively improved with time and, in the cohort with the longest follow-up, decreased from (in ml/min per 1.73 m2 per mo): 0.16+/-0.12 (at 18 mo) to 0.10+/-0.05 (at 60 mo). This rate was about 10-fold slower compared to patients on conventional therapy during the REIN Core study. Analyses of the individual slopes found that at the end of the follow-up, 10 of 26 patients on continued ramipril therapy had a positive deltaGFR and another 10 patients had an improvement of deltaGFR while on ramipril therapy. DeltaGFR significantly improved in parallel with a significant reduction in proteinuria. Changes in deltaGFR (P = 0.0001) and proteinuria (P = 0.04) were significantly different in the two groups. Baseline characteristics and changes in systolic and diastolic BP and 24-h urine urea and sodium excretion were comparable. The present results offer evidence that in chronic nephropathies, the tendency of GFR to decline with time can be effectively halted, even in patients with remarkably severe disease.

Adult↗
PubMed1999

Unrecognized pattern of von Willebrand factor abnormalities in hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.

Heterogeneous abnormalities in multimeric structure and fragmentation of endothelial-derived von Willebrand factor (vWF) have been reported in hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study was conducted to establish whether different patterns of vWF abnormalities were associated with different clinical syndromes. Plasmatic levels of vWF antigen (vWF:Ag), vWF release from endothelial cells (EC) exposed to patient sera, and vWF multimeric pattern were studied during episodes and again in remission in three groups of patients with severe forms of HUS and TTP paradigmatic of the most common clinical patterns of disease presentation: (1) plasma-responsive; (2) plasma-resistant; and (3) frequently relapsing. Plasma vWF:Ag and serum-induced vWF release from EC were increased in the acute phase of either plasma-responsive and plasma-resistant HUS and TTP, but normalized at remission only in plasma-responsive cases. Both indices were persistently normal in the relapsing forms. Enhanced vWF fragmentation as defined by disappearance of high molecular weight and increase in low molecular weight forms was a consistent finding of the acute phases, and always normalized in remission in all three groups. Unusually large vWF multimers were found exclusively in plasma of relapsing forms of HUS and TTP both during and between relapses. Enhanced levels of vWF:Ag and serum capability to induce vWF release in vitro are markers of disease activity and may reflect systemic endothelial injury and consequent activation. Their presence discriminates acute single-episode cases from relapsing forms and, when failing to normalize with plasma therapy, predicts plasma resistance. Enhanced low molecular weight multimers that closely paralleled disease activity suggest a permissive role of fragmented vWF in the formation of microvascular thrombi. Finally, finding of unusually large multimers exclusively in relapsing forms of HUS and TTP even between relapses, when no other clinical signs of disease activity could be detected, suggests that they cannot be the only factor in microvascular thrombosis.

Adolescent↗
PubMed1999

Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals.

Chronic renal diseases progress to organ insufficiency, which may require replacement therapy within one to three decades even independently of the type of initial insults. In the majority of cases, the degrees of proteinuria and interstitial leukocyte infiltration and scarring are strictly correlated with the rate of disease progression. This study tests the hypothesis that excess intrarenal protein traffic may cause lymphocyte-dependent interstitial injury that, while not fully controlled by antiproteinuric therapy, can be further inhibited by concomitant immunosuppression. A primarily nonimmune model was used to reproduce progressive renal disease due to a critical loss of nephron mass. Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial inflammation, MHC class II antigen expression, and severe lesions. Combined treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II overexpression, dendritic cells, and all manifestations of the disease. Evidence of lymphocyte-mediated renal injury in the setting of excess protein traffic provides the basis for combining ACE inhibition and immunosuppression to halt progression of proteinuric kidney disease and minimize the need for dialysis or transplantation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Angiotensin-converting enzyme inhibition prevents loss of glomerular hydraulic permeability in passive heymann nephritis.

We used morphometric techniques and theoretical analysis to investigate structural and functional changes of the glomerular membrane that develop in passive Heymann nephritis (PHN), an experimental model of human membranous glomerulopathy The effect of angiotensin-converting enzyme (ACE) inhibition on the above parameters was also investigated to explore the mechanisms by which this treatment exerts functional and structural protection at the renal tissue level. Morphometric analysis of glomerular capillary by light and electron microscopy was performed in normal control rats and in rats injected with rabbit anti-Fx 1A antibody, 12 months after induction of PHN. A group of PHN rats treated with lisinopril during the observation period was also investigated. Glomerular capillary architecture was not significantly altered in PHN rats, thus glomerular volume and capillary lumen volume were comparable with normal controls; only mesangial volume was significantly elevated in PHN rats. Glomerular membrane structure was significantly affected by PHN: the thickness of the glomerular basement membrane (GBM) increased, and the frequency of epithelial filtration slits decreased. Electron-dense deposits in the subepithelial space of the GBM were estimated to occupy more than 20% of the GBM area. Theoretical analysis of glomerular hydraulic permeability allowed us to predict that, after these structural changes, the permeability of the GBM and the epithelial layer significantly decreased, with an average reduction in the ultrafiltration coefficient (Kf) of approximately 43%. ACE inhibition limited mesangial expansion and prevented changes of glomerular epithelial cells (filtration slit frequency) but not GBM thickening. Immune deposits within the GBM were only partially prevented by lisinopril. A selective effect on epithelial permeability was calculated in lisinopril-treated rats, and a partial preservation of Kf reduction was observed. These results suggest that structural changes of the GBM and epithelial cells that develop in PHN are responsible for the reduced filtration capacity observed in this model. ACE inhibition only partially prevented immune-deposits in the GBM and favorably affected epithelial cell structure. These selective effects on glomerular podocytes may contribute to preserve water and macromolecule permeability of the glomerular capillary wall in this immunologic model of kidney disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.

BACKGROUND: Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. METHODS: Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. RESULTS: We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic-uremic syndrome, 11 had normal levels of activity of von Willebrand factor-cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. CONCLUSIONS: Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolyticuremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

ADAM Proteins↗
PubMed1998

Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy.

BACKGROUND: The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study. METHODS: 97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n=51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n=46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mm Hg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat. FINDINGS: During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p=0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p=0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n=26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p=0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p=0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy. INTERPRETATION: In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (> or =36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.

Adult↗
PubMed1998

Identification of a novel gene--SSK1--in human endothelial cells exposed to shear stress.

To identify transcriptionally regulated genes potentially involved in the effect of shear stress on endothelial gene expression, we performed a differential display analysis of mRNAs from human umbilical vein endothelial cell (HUVEC) exposed to laminar shear stress (12 dynes/cm2) in comparison to HUVEC maintained in static condition. We identified a cDNA fragment overexpressed by laminar shear stress. The full-length, SSK1, was 3653 long and encoded for a novel protein of 1050 amino acids. Northern blot demonstrates that SSK1 mRNA is expressed at high levels also in placenta, a weak transcript was present in heart, skeletal muscle, kidney and pancreas. Homology searches of the protein databases showed that SSK1 is related to numerous serine-threonine kinases. The highest homology was found with a very recently described gene, BUBR1, an analogue of BUB1, which is a kinase involved in the regulation of cell cycle. The most conserved residues in catalytic domains II, III, VIb, VII, VIII and IX of serine-threonine protein kinases were found in the C terminal region of SSK1 which further supports the kinase nature of the new protein. The putative serine-threonine kinase SSK1 may represent a tool by which mechanical forces regulates phosphorylation events within endothelial cells.

Amino Acid Sequence↗
PubMed1998

Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion.

We addressed the role of hyperglycemia in leukocyte-endothelium interaction under flow conditions by exposing human umbilical vein endothelial cells for 24 h to normal (5 mM), high concentration of glucose (30 mM), advanced glycosylation end product-albumin (100 microg/ml), or hyperglycemic (174-316 mg/dl) sera from patients with diabetes and abnormal hemoglobin A1c (8.1+/-1.4%). At the end of incubation endothelial cells were perfused with total leukocyte suspension in a parallel plate flow chamber under laminar flow (1.5 dyn/cm2). Rolling and adherent cells were evaluated by digital image processing. Results showed that 30 mM glucose significantly (P < 0. 01) increased the number of adherent leukocytes to endothelial cells in respect to control (5 mM glucose; 151+/-19 versus 33+/-8 cells/mm2). A similar response was induced by endothelial stimulation with IL-1beta, here used as positive control (195+/-20 cells/mm2). The number of rolling cells on endothelial surface was not affected by high glucose level. Stable adhesion of leukocytes to glucose-treated as well as to IL-1beta-stimulated endothelial cells was preceded by short interaction of leukocytes with the endothelial surface. The distance travelled by leukocytes before arrest on 30 mM glucose, or on IL-1beta-treated endothelial cells, was significantly (P < 0.01) higher than that observed for leukocytes adhering on control endothelium (30 mM glucose: 76.7+/-3.5; IL1beta: 69.7+/-4 versus 5 mM glucose: 21.5+/-5 microm). Functional blocking of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 on endothelial cells with the corresponding mouse mAb significantly inhibited glucose-induced increase in leukocyte adhesion (67+/-16, 83+/-12, 62+/-8 versus 144+/-21 cells/ mm2). Confocal fluorescence microscopy studies showed that 30 mM glucose induced an increase in endothelial surface expression of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1. Electrophoretic mobility shift assay of nuclear extracts of human umbilical vein endothelial cells (HUVEC) exposed for 1 h to 30 mM glucose revealed an intense NF-kB activation. Treatment of HUVEC exposed to high glucose with the NF-kB inhibitors pyrrolidinedithiocarbamate (100 microM) and tosyl-phe-chloromethylketone (25 microM) significantly reduced (P < 0.05) leukocyte adhesion in respect to HUVEC treated with glucose alone. A significant (P < 0.01) inhibitory effect on glucose-induced leukocyte adhesion was observed after blocking protein kinase C activity with staurosporine (5 nM). When HUVEC were treated with specific antisense oligodesoxynucleotides against PKCalpha and PKCepsilon isoforms before the addition of 30 mM glucose, a significant (P < 0.05) reduction in the adhesion was also seen. Advanced glycosylation end product-albumin significantly increased the number of adhering leukocytes in respect to native albumin used as control (110+/-16 versus 66+/-7, P < 0.01). Sera from diabetic patients significantly (P < 0.01) enhanced leukocyte adhesion as compared with controls, despite normal levels of IL-1beta and TNFalpha in these sera. These data indicate that high glucose concentration and hyperglycemia promote leukocyte adhesion to the endothelium through upregulation of cell surface expression of adhesive proteins, possibly depending on NF-kB activation.

Cell Adhesion↗
PubMed1998

Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes.

OBJECTIVE: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. DESIGN: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. SETTING: Research centre in Italy. SUBJECTS: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. MAIN OUTCOME MEASURES: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. RESULTS: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P = 0.0001 and P < 0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P = 0.0003, multivariate P = 0.004) and end stage renal failure (P = 0.002 and P = 0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P < 0.0005). In the lowest third of the protein:creatinine ratio (< 1.7) there was 3% renal failure compared with 21.2% in the highest third (> 2.7) (P < 0.05). CONCLUSIONS: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis.

Circadian Rhythm↗
PubMed1998

Prognosis of diabetic nephropathy: how to improve the outcome.

Chronic renal diseases, including diabetic nephropathy, evolve to terminal renal failure by a process leading to progressive parenchimal damage which appears relatively independent of the initial insult. When glomerular permselectivity is lost, proteins filtered through the glomerular capillary, through proximal tubular cell activation and up-regulation of genes of inflammatory and vasoactive mediators, may give rise to an inflammatory reaction that in the long-term can contribute to renal scarring. If this interpretation is correct, the best approach to try to retard the progression of several renal diseases would be to limit the excessive traffic of macromolecules throughout the glomerular capillary by molecules, as the angiotensin-converting-enzyme (ACE) inhibitors, that may help restore perm-selective properties to normal. Thus, the present review addresses the mechanism(s) of the renal protective effect of ACE inhibitors and analyzes the evidence so far available of their salutary effect in human nephropathies, with particular focus on diabetic nephropathy. The issue of whether ACE inhibitors alone or in combination with other antihypertensives (namely non-dihydropyridinic calcium channel blockers) may even prevent the onset of nephropathy at the stage of normoalbuminuria is discussed.

Albuminuria↗
PubMed1998

Renoprotective effect of contemporary blocking of angiotensin II and endothelin-1 in rats with membranous nephropathy.

BACKGROUND: We previously showed that chronic administration of an angiotensin converting enzyme (ACE) inhibitor to rats with passive Heymann nephritis (PHN), a model of membranous nephropathy with proteinuria and increased renal synthesis of endothelin-1 (ET-1), reduces urinary proteins and partially limits the exaggerated ET-1 renal synthesis. Here we compared the effect of an ETA receptor antagonist and an ACE-inhibitor given as single therapies with a combination of the two drugs in uninephrectomized PHN rats. METHODS: PHN was induced with a single i.v. injection of rabbit anti-Fx1A antibody in 40 male Sprague Dawley rats. To accelerate the onset of renal damage rats underwent uninephrectomy seven days later and were subsequently treated until eight months with the ETA receptor antagonist LU-135252 (50 mg/kg b.i.d. p.o.) or the ACE-inhibitor trandolapril (1 mg/kg in the drinking water) or the combination of the two drugs. RESULTS: Either LU-135252 or trandolapril given alone prevented the increase in systolic blood pressure (SBP). Combined therapy was even more effective than single drugs. While LU-135252 and trandolapril reduced proteinuria by 23 to 25%, the drug combination resulted in 45% lowering of urinary proteins. Serum creatinine was significantly decreased by the combination, but not by the single drugs. Glomerulosclerosis and tubulointerstitial damage were more reduced by combined therapy than by LU-135252 or trandolapril alone. CONCLUSIONS: These data suggest that contemporary blocking angiotensin II (Ang II) and ET-1 in an accelerated model of PHN had an additive renoprotective effect than single blocking Ang II or ET-1 and would represent a therapeutic advantage for renal disease patients who do not completely respond to ACE inhibitors.

Angiotensin II↗