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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 181 records · Page 10Linked to original sources
PubMed1996

Structural basis of diabetic nephropathy in microalbuminuric NIDDM patients: a light microscopy study.

The objective of the study was to evaluate early structural changes occurring in patients with non-insulin-dependent diabetes mellitus (NIDDM) and microalbuminuria by light microscopy. Basal renal biopsy was performed in patients who were subsequently randomized to different antihypertensive treatments. Fourteen NIDDM patients aged 36-65 years (duration of diabetes 9 +/- 7 years) with microalbuminuria (mean urinary albumin excretion 66 +/- 49 micrograms/min) underwent percutaneous renal biopsy. Control biopsies were obtained from five patients of similar age undergoing nephrectomy for renal neoplasia with normal renal function and no history of renal disease. Control and diabetic biopsies were processed by light microscopy and stained with haematoxylin and eosin, periodic acid Schiff, Masson's trichrome and silver methenamine. The percentage of globally sclerotic glomeruli was evaluated. Glomerular volume was determined using perimeter analysis. A semiquantitative assessment (range 0 to 3+) was made of mesangial sclerosis, interstitial fibrosis, tubular atrophy, arteriosclerosis and arteriolar hyalinosis. Glomerular volume was significantly increased in diabetic as compared to control glomeruli (3.2 +/- 8 vs 1.8 +/- 7, p < 0.01). Mesangial sclerosis (0.9 vs 0, p < 0.0001) and arteriolar hyalinosis (0.91 vs 0.2, p < 0.022) were significantly higher in diabetic compared to control subjects. No significant differences between diabetic and control subjects were found in the percentage of globally sclerotic glomeruli or in the extent of interstitial fibrosis, tubular atrophy and arteriosclerosis. Thus NIDDM patients with microalbuminuria show histological findings consistent with diabetic nephropathy characterized by glomerular hypertrophy, mesangial sclerosis and arteriolar hyalinosis. However, the renal histological changes are mild and appear less marked than in insulin-dependent diabetic patients.

Adult↗
PubMed1996

Abnormal permeability to proteins and glomerular lesions: a meta-analysis of experimental and human studies.

Whether abnormal protein traffic through the glomerular capillary is one of the possible causes of glomerular injury has been a matter of considerable controversy. Experimental and clinical evidence indicate an association between the two, and several explanations of potential pathophysiologic pathways are available that may explain protein-dependent forms of renal injury. However, none of the mechanisms suggested thus far have been definitely proven. A meta-analytic review was used to further explore the relationship between urinary protein excretion and glomerular injury in experimental and human proteinuric nephropathies. In experimental models a definite positive association (P < 0.0001) was found between urinary protein excretion and glomerulosclerosis. The overall effect size d for this relationship was 2.36 (95% confidence interval, 2.13 to 2.60), corresponding to a correlation coefficient of r = 0.76. Similarly, the correlation between albuminuria and glomerular sclerotic lesions was highly significant (overall d = 2.88; 95% confidence interval, 2.33 to 3.42; P < 0.0001; correlation coefficient, r = 0.82). In humans the meta-analytic correlation yielded analogous, although less striking, results (overall d = 0.58; 95% confidence interval, 0.43 to 0.73; P < 0.0001; correlation coefficient, r = 0.28). In conclusion, meta-analysis of data from studies examining urinary protein excretion revealed a significant positive correlation with glomerular sclerosis in both experimental models and human diseases. This study supports the role of abnormal protein traffic through the glomerular capillary as one of the possible causes of renal injury. However, the strong relationship found does not necessary establish a cause-and-effect relationship.

Animals↗
PubMed1996

Cyclosporine enhances leukocyte adhesion to vascular endothelium under physiologic flow conditions.

We investigated the effect of cyclosporine (CyA) on leukocyte adhesion to endothelium under flow conditions. Confluent human umbilical vein endothelial cells (HUVECs) were incubated for 24 hours with CyA (1, 5, and 10 micromol/L) and then exposed to a total human leukocyte suspension in a parallel plate flow chamber under laminar flow (1.5 dynes/cm2. Human umbilical vein endothelial cells stimulated with interleukin-1beta (20 U/mL) were used as a positive control. Adherent cells were measured by digital image analysis. Results showed that CyA dose-dependently increased the number of leukocytes adhering to HUVECs compared with control cells. Leukocyte adhesion markedly increased on HUVECs incubated with interleukin-lbeta, one of the most potent inducers of endothelial cell adhesiveness. Exposure of endothelial cells to CyA did not affect the number of rolling leukocytes, which was similar to control values. To examine the role of adhesion molecules in CyA-induced leukocyte adhesion, HUVECs were incubated with monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin before adhesion assay. Functional blocking of ICAM-1, VCAM-1, and E-selectin on endothelial cells significantly inhibited CyA (10 micromol/L)-induced leukocyte adhesion. Confocal fluorescence microscopy studies showed that CyA induced an increase in the endothelial surface expression of ICAM-1, VCAM-1, and E-selectin. Pretreatment of leukocytes with the platelet activating factor receptor antagonist L659,989 significantly reduced the number of leukocytes adhering to CyA-treated HUVECs. We suggest that CyA enhances leukocyte adhesion to endothelium by upregulating adhesive proteins on endothelial surface membrane. Blocking leukocyte receptor for platelet-activating factor partially prevents adhesion, suggesting a role for endothelial cell-associated platelet-activating factor in the interaction between leukocytes and CyA-treated endothelium.

Cell Adhesion↗
PubMed1996

Malignant vascular disease of the kidney: nature of the lesions, mediators of disease progression, and the case for bilateral nephrectomy.

A case of thrombotic microangiopathy presenting as a hemolytic uremic syndrome complicated by untreatable hypertension and ultimately requiring bilateral nephrectomy is discussed. Severe hypertension and renal failure may complicate the course of vascular diseases of the kidney, including thrombotic microangiopathy, chronic hypertension, and scleroderma. Toxins, pressure stress, and immune material may trigger the initial injury to vascular endothelium. The malignant course of these renal vascular diseases seems linked to the severity of vascular injury. Endothelial injury manifests with swelling and detachment of endothelial cells from the basement membrane, expansion of the subendothelial space, and newly formed basement membrane-like material. In arterioles, endothelial injury precedes myointimal swelling and proliferation, leading to vascular lumina narrowing or obliteration and secondary glomerular ischemia, with glomerular tuft collapse and garland-like wrinkling and thickening of the capillary wall. Endothelial cell injury is very likely the common determinant of a cascade of events that lead to irreversible renal failure. When the initial insult (toxins, mechanical stress, antibodies) is promptly removed, lesions are self-limiting and the patient usually recovers. However, a severe insult persisting for some time can lead to chronic and irreversible vascular lesions that, through renal ischemia, trigger maximal activation of the renin angiotensin system with a brisk elevation in arterial blood pressure that may combine to further vascular injury and renal ischemia. Moreover, enhanced shear stress in the severely narrowed microcirculation, through abnormal von Willebrand factor processing, can also favor endothelial injury and platelet aggregation, which may further worsen the vascular lesions and sustain the microangiopathic process. Plasma manipulation, arteriolar vasodilators, and angiotensin-converting enzyme inhibitors normally control the vicious circle, but in few severe cases bilateral nephrectomy remains the last chance to save the patient's life.

Adult↗
PubMed1996

Blocking both type A and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney.

Renal disease progression in the rat is associated with a time-dependent upregulation of renal endothelin-1 (ET-1) gene expression and synthesis. We have previously demonstrated that endothelin A receptor subtype (ETA) blockade in rats with remnant kidney reduced signs of disease activity, suggesting that ET-1 exerts part of its deleterious effects on the kidney through ETA. No data are available so far on the role of ETB receptor in progressive renal injury. We first studied renal ETA and ETB receptor gene expression in rats with remnant kidney on days 7, 30, and 120 after the surgical procedure. While renal expression of ETA was unaffected, ETB receptor gene was significantly upregulated with time in rats with remnant kidney, being 3.5-fold and sixfold higher than shamoperated rats at days 30 and 120. We also evaluated whether bosentan, a nonpeptidic ETA and ETB receptor antagonist, offered better protection against renal disease progression than reported for ETA-selective blockers and whether it improved survival in animals with renal ablation. Two groups of rats with renal mass reduction (n = 11 each) were given bosentan 100 mg/kg/d orally or its vehicle (carboxymethyl cellulose) beginning day 7 after the surgical procedure and were followed until the death of the vehicle-treated animals. Sham-operated animals comprised the control group. Bosentan partially prevented increases in blood pressure and proteinuria, but had a remarkable protective effect on renal function and significantly prolonged animal survival. These data suggest that blocking both renal ETA and ETB receptors might have major implications in the treatment of human progressive nephropathies.

Analysis of Variance↗
PubMed1996

Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury.

The term thrombotic microangiopathy (TMA) has been used extensively to encompass hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, two syndromes of hemolytic anemia, and thrombocytopenia associated with renal or brain involvement or both. There is evidence that endothelial damage is a crucial feature in the sequence of events that precedes the development of microvascular lesions. More recent studies would suggest that endothelial dysfunction could be a consequence of neutrophil activation. Activated neutrophils generate superoxide anions (O2-) that, combining with endothelial-derived nitric oxide (NO), form the highly cytotoxic hydroxyl radical. Seven patients with recurrent forms of TMA and seven healthy volunteers were studied. Plasma concentrations of the NO metabolites, nitrites/nitrates, were elevated in the acute phase of TMA, indicating an increased NO synthesis in vivo. In addition, elevated serum concentrations of tumor necrosis factor, a potent inducer of endothelial NO synthase, were found in acute TMA. Serum from patients with acute TMA induced NO synthesis in cultured endothelial cells more than normal serum. Enhanced stimulatory activity was no longer found in the recovery phase. Release of O2- by neutrophils ex vivo was higher than normal in patients with acute TMA, but decreased in the recovery phase. Exactly the same trend was observed for plasma malondialdehyde and conjugated dienes, indicating that excessive oxygen radical formation in acute TMA is associated with increased lipid peroxidation. Thus, in recurrent forms of TMA, NO formation was increased as compared with controls. This was associated with signs of lipid peroxidation, likely the consequence of the interaction of NO with neutrophil-derived oxygen products.

3,4-Methylenedioxyamphetamine↗
PubMed1996

Cyclosporine induces glomerulosclerosis: three-dimensional definition of the lesions in a rat model of renal transplant.

Previous description of chronic cyclosporine (CsA) renal toxicity commonly included vascular changes, tubular atrophy, and interstitial fibrosis. Glomerular injury was only occasionally documented and it is not clear whether glomerular changes may have an impact on the clinical syndrome of CsA toxicity observed in experimental animals and humans. At the moment the prevailing view is that when patients given CsA have glomerular lesions at a renal biopsy, these were due to concomitant chronic rejection or renal hypoperfusion rather than to CsA itself. As a follow-up of our previous work on the subject (abstract; J Am Soc Nephrol 2:1398, 1992) the present study was undertaken to clarify whether CsA is a direct cause of glomerular injury. We used a model of renal transplant among Lewis rats to better mimic the condition in which CsA is given to humans. Animals underwent kidney isografts and were given daily CsA or vehicle for as long as 12 months. At the end of the experiment specimens of renal tissue were analyzed by a serial section morphometric analysis technique, which allows precise evaluation at the individual glomerular level, glomerular volume and percentage of the capillary tuft affected by sclerosis. Among 85 glomeruli from CsA-treated rats, examined by three-dimensional morphometric analysis, only 12% were normal and 88% revealed segmental sclerosis. Data of single-section analysis compared with three-dimensional morphometric reconstruction showed that the former markedly underestimated the extent of glomerular injury. By three-dimensional analysis we showed that chronic CsA administration was associated with profound changes in glomerular capillary tuft volume distribution as compared to normal. Specifically, a subset of smaller than normal glomeruli emerged in CsA-treated animals in addition to a population of glomeruli which were larger than normal. No significant correlation was found between capillary tuft volume and sclerosis volume. These findings indicate that chronic administration of CsA induces in rats glomerular lesions comparable to the ones reported in human renal or heart transplant. Our present model may help investigating the mechanism(s) of chronic CsA renal toxicity, and will provide important clues for pharmacological manipulations aimed at reducing the long-term consequences of CsA on the kidney.

Animals↗
PubMed1996

Bilateral nephrectomy stopped disease progression in plasma-resistant hemolytic uremic syndrome with neurological signs and coma.

Four women were admitted over three years because of anemia and renal failure. They had evidence of hemolytic uremic syndrome (HUS) with severe vascular involvement and glomerular collapse. Despite intensive plasma exchange, all patients developed neurologic signs (with seizures and coma in 2) and papilledema. Three developed refractory hypertension and three required dialysis. All patients had abnormal von Willebrand factor (vWF) fragmentation as reflected by decreased high molecular weight and increased low molecular weight vWF multimers in the circulation. Assuming that the disease was sustained by shear stress-induced abnormal vWF fragmentation in damaged renal microvasculature, bilateral nephrectomy was done. Surgery was followed within two weeks by complete hematologic and clinical remission consistently associated with the restoring of vWF fragmentation pathway to normal. We speculate that in HUS resistant to plasma exchange or infusion, removing the kidneys eliminates a major site of vWF fragmentation, which would limit platelet activation and protect patients from the further spreading of microvascular lesions.

Adult↗
PubMed1996

Role of endothelin in the development of glomerulosclerosis.

Enhanced filtered load of proteins in glomerular diseases (overload proteinuria) results in significant increase in the rate of proximal tubular uptake that is true for all proteins tested so far, including albumin. The excess concentration of absorbed proteins in lysosomes may itself lead to cellular damage by spillage of lysosomal enzymes to the cytosol. In vitro evidence is also available of functional alteration of these tubular cells, including upregulation of genes encoding for endothelin-1 (ET-1) and other inflammatory mediators, when they are overloaded in culture with proteins or lipoproteins. This could affect renal function and structure given the inflammatory, growth factor, and vasoactive properties of ET-1. Findings in several experimental models of proteinuric progressive nephropathies have indeed documented enhanced renal ET-1 gene expression and excretion of the peptide into the urine which correlated with proteinuria and the degree of glomerular and tubulointerstitial damage.

Animals↗
PubMed1996

The kidney triggers graft-versus-host disease in experimental combined transplantation of kidney and stem cell-enriched peripheral leukocytes.

As a preclinical step to human studies with combined stem cell-enriched peripheral leukocytes and organ transplantation from the same donor, a series of studies in rats was undertaken. These studies indicated that Lewis rats infused intravenously with major histocompatibility complex-incompatible (from Brown-Norway rats), stem cell-enriched peripheral leukocyte preparation alone never developed graft-versus-host disease (GHVD). However, GVHD invariably manifested in all animals a few days after the kidney was transplanted in rats that had been previously primed with stem cell-enriched peripheral leukocytes from the same kidney donor strain. GVHD was prevented by substituting the crude preparation of stem cell-enriched peripheral leukocytes with a purified preparation that was almost completely free of T lymphocytes. However, in these latter experiments all rats rejected their kidney graft within 10 days from the surgery. In rats previously given the crude stem cell-enriched peripheral leukocyte preparation, perioperative administration of the fusion protein CTLA4lg also prevented GVHD and prolonged kidney graft survival up to 106 to 175 days. By contrast, animals with kidney transplants, which were given CTLA4lg without stem cells, rejected their grafts within 35 days. All together, these findings may possibly contribute to the creation of rationally designed strategies of combining organ and bone marrow from the same donor to enhance mixed chimerism and prolong survival after organ transplantation.

Abatacept↗
PubMed1996

Glomerular filtration rate determined from a single plasma sample after intravenous iohexol injection: is it reliable?

The iohexol injection plasma clearance method is a good alternative to the inulin clearance method for determination of GFR, but requires multiple blood samples. To avoid this, methods have been developed which derive GFR from a formula that uses a single plasma concentration of the tracer and anthropometric data. The aim of this study was to evaluate whether a single plasma sample taken after iohexol injection allows reliable estimation of GFR. In this study, results of single-point determination were compared with those obtained by multiple-point plasma clearance. The GFR of 686 outpatients with different degrees of renal function were recalculated by use of the Jacobsson formula. The optimum time for sampling was found at 10 h after injection of the marker for clearances < 40 mL/min per 1.73 m2, 4 h for clearances between 40 and 99 mL/min per 1.73 m2, and 3 h for clearances > 100 mL/min per 1.73 m2. Results documented that for 75% of the patients, the simplified technique gave an error between -5% to +5% in the evaluation of GFR; for the remaining 25% of the patients, prediction error ranged from -22% to +40%. Furthermore, despite a highly significant correlation between multiple-point iohexol clearance (six plasma samples) and the single-point method (Y = 0.968X + 1.704, r2 = 0.988), the regression intercept was statistically different from 0 and the standard error of the slope estimate established that 95% confidence interval did not include 1.0 (the line of identity), thus indicating that the model can be rejected by the data at a significance level of 0.05. Thus the single-plasma-sample method to determine GFR after radiocontrast injection does not represent a real advantage over the multiple-point method and may lead to unacceptable errors in GFR calculation.

Adult↗
PubMed1996

Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.

Colchicine, which inhibits cell microtubule assembly by preventing polymerization of tubulin monomers, inhibits cell-mediated immune responses and promotes long-term survival of major histocompatibility complex-incompatible renal allografts in rats. Here we evaluated the effect of blocking cell microtubule assembly by colchicine on T cell and endothelial cell adhesion receptors involved in transducing signals for T cell activation. By using immunofluorescence flow cytometry analysis, evidence is presented that colchicine, in a dose-dependent fashion, downregulated L-selectin and leukocyte function-associated antigen-1, but not CD2 and CD44 on the surface of naive human peripheral blood lymphocytes. This effect was confirmed in two subsets of T lymphocytes, namely, CD45RA- and CD45RO-positive cells. However, colchicine did not influence the rapid shedding of L-selectin from T lymphocytes exposed to activating stimuli. Colchicine inhibited expression of interleukin-2 receptor on activated T lymphocytes. This effect was observed when T lymphocytes were stimulated with both anti-CD3 and anti L-selectin monoclonal antibodies. Colchicine also inhibited lymphocyte function in vitro as documented by inhibition of the human mixed lymphocyte response in a dose-dependent fashion. Moreover, colchicine downregulated surface expression of intercellular adhesion molecule-1 and E-selectin on activated human umbilical vein endothelial cells. These results indicate that blocking cell microfubule assembly inhibits surface expression of adhesion molecules on T cells and endothelial cells, and provides insights into the complex mechanisms of the action of colchicine in vivo.

Antibodies, Monoclonal↗
PubMed1996

Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney.

Studies in experimental animals and humans have documented that inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors reduces urinary protein excretion rate and retards the development of renal injury. Here we sought to investigate whether angiotensin II (All) modified the size-selective properties to macromolecules of the glomerular capillary barrier in isolated perfused rat kidney preparation. Compared with basal values, continuous All infusion into the renal artery at the rate of 3 or 8 ng/min, but not at 0.6 ng/min, induced a progressive and significant increase in urinary protein excretion rate. Evaluation of the sieving properties of the glomerular barrier by fractional clearance of polydisperse Ficoll showed that All significantly enhanced the filtration of tracer molecules of radil > or = 34A. All-induced changes in urinary protein excretion rate and in Ficoll fractional clearance were completely prevented by pretreatment with the specific All Type 1 receptor antagonist SR 47436.

Angiotensin II↗