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G Remuzzi

Publications and source records attributed to G Remuzzi.

521 records · Page 29Linked to original sources
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The role of the endothelium in hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in children, is caused by Shiga toxin-producing Escherichia coli infection. This infection leads to renal and other organ microvascular thrombosis. Endothelial injury has been recognized as the trigger event in the development of microangiopathic process. Evidence suggests that leukocyte as well as platelet activation participate in endothelial damage. Intrinsic abnormalities of the complement system may also play a role in HUS.

Complement System Proteins↗
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[Functional loss of the transplanted kidney: immunological and non-immunological factors].

During the past few years, the short-term graft survival after kidney transplantation has improved dramatically, a phenomenon not paralleled by an increase in the long-term graft survival. This is due to the progressive renal injury and dysfunction known as chronic transplant nephropathy or 'chronic rejection', a process that involves both immune and non-immune factors. Immunological factors include T- and B-cell recognition of alloantigens, cytomegalovirus infection, and endothelial cell activation followed by vascular smooth cells proliferation. Among nonimmune mechanisms, proteinuria and hypertension play a relevant role. Moreover, the reduced number of functioning nephrons may trigger an inflammatory process that, eventually, contributes to the loss of the graft. Several studies have documented the efficacy of blocking the renin-angiotensin system (RAS) in reducing proteinuria and preventing renal function deterioration in experimental models of chronic rejection. Early results are promising. However, available clinical trials are rather limited in terms of number of patients enrolled, consequently they cannot be considered definitive. Since several pathogenetic factors are involved in the progression of chronic transplant nephropathy, a multidrug approach with specific immunosuppressants and RAS-blocking drugs has been proposed to control/prevent chronic injury and progressive renal deterioration. Preliminary results in experimental models are promising. Data from prospective clinical trials are, however, mandatory to confirm the efficacy of a polypharmacological strategy in preventing chronic rejection.

B-Lymphocytes↗
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[Transplants].

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Humans↗
PubMedDate not supplied

[Hemolytic uremic syndrome].

Hemolytic uremic syndrome (HUS) is a disease characterized by non immune hemolytic anemia, low platelet count and renal impairment. In children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli (Stx-E. Coli): however, renal function recovers in up to 70% of patients. Plasma infusion or exchange reduces mortality and the risk of end-stage renal disease (ESRD) in adult patients. Non-Shiga toxin-associated HUS (non-Stx-HUS), accounting for only 5-10% of all disease cases, can be sporadic or familial. Collectively, non-Stx-HUS forms have a poor outcome. Up to 50% of cases progress to ESRD or have irreversible brain damage, and 25% can die during the acute phase of the disease. Genetic studies have recently documented that the familial form is associated with genetic abnormalities of complement regulatory proteins, and evidence is now emerging that similar genetic alterations can predispose to sporadic cases of non-Stx-HUS as well. Mutations of genes encoding for factor H, a glycoprotein that plays an important role in the regulation of the alternative pathway of complement and for MCP, a widely expressed transmembrane glycoprotein with an inhibitory role of activated C3, are reported in familial HUS. These mutations are more likely to predispose rather than to cause the disease directly.

Hemolytic-Uremic Syndrome↗
PubMedDate not supplied

[Nephrology].

Advances in biomedical technology have contributed effectively to the resolution of basic and clinical problems in Nephrology. Most of our insights on glomerular diseases come from animal models. Antibodies against components of the extracellular matrix have been shown to induce glomerular changes in vivo and the non-collagenous NC1 domain of type IV collagen has been demonstrated to contain the Goodpasture antigen. New pathogenetic mechanisms of glomerular injury are suggested by studies on the interaction of antibodies with glomerular cell surface antigens. Gp330, a glycoprotein expressed at the surface of glomerular visceral epithelial cells, has been recognized to be the most relevant antigen of Heymann nephritis. Antibodies able to crosslink gp330 bind to the antigen at the base of foot processes and the resulting immune complexes are shed into the subepithelial space where they form electron dense deposits. The complement membrane attack complex (C5b-9) is likely to be directly responsible for epithelial cell injury and proteinuria in this model. Other cell surface antigens of the glomerular capillary wall, such as dipeptidyl dipeptidase IV, podocalyxin, podoendin, have been characterized. A novel model of glomerular injury comes from the demonstration that a non-complement fixing monoclonal antibody to a surface sialo-glycoprotein (SGP-115/107) binds to glomerular visceral epithelial cells and causes morphological changes which appear epitope-specific and complement and leukocyte-independent. The mechanisms responsible for the progression of renal disease to glomerular sclerosis have been extensively explored in the last years. Among the hemodynamic factors intraglomerular hypertension has been established to play an important part, at least in some models.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Angiotensin-converting enzyme inhibition and calcium channel blockade both normalize early hyperfiltration in experimental diabetes, but only the former prevents late renal structural damage.

We studied the potential renoprotective properties of a calcium channel blocker in moderately hyperglycemic diabetic rats both in the early phase of the disease and in the very long term, and compared such an effect with that of an angiotensin-I-converting enzyme (ACE) inhibitor. Three groups of diabetic rats, one receiving no therapy except insulin and the remaining two receiving insulin and the ACE inhibitor enalapril or the calcium blocker lacidipine and one group of nondiabetic control rats were followed for 4-6 weeks. Both antihypertensive drugs lowered systolic blood pressure comparably. At the end of the observation period, untreated diabetic rats exhibited elevation of glomerular filtration rate and renal plasma flow. Both enalapril and lacidipine treatment completely prevented whole-kidney hyperfiltration and hyperperfusion. Four additional groups of rats, similarly treated, were followed for 1 year. A comparable control of systolic blood pressure and blood glucose level was achieved with the two antihypertensive regimens throughout the whole study period. At 12 months, the average kidney weight was elevated to similar values in all diabetic groups relative to control rats. Untreated diabetic rats had progressive proteinuria and developed glomerulosclerosis. Enalapril markedly limited the development of proteinuria. By contrast, urinary protein excretion in diabetic rats given lacidipine markedly increased with time, and values were as high as those in untreated diabetic animals. Similarly, only enalapril was effective in limiting glomerular injury. These results indicate that ACE inhibition but not calcium channel blockade has a favorable effect in preventing renal disease progression in diabetic rats and suggest that the various antihypertensive regimens are not equally beneficial in protecting against diabetic glomerulopathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Studies of privileged sites and organ transplantation.

Extensive research has been carried out in the last years to try to prevent graft rejection by minimizing the side effects related to the use of immunosuppressants. Ideally, one would hope to achieve a state of donor-specific unresponsiveness in order to promote a condition of true tolerance without the need of immunosuppressants. Recent evidence has been provided that this is a pursuing goal, at least in experimental animals, and even in humans increasing data are available that tolerance is achieved in some patients years after transplantation. The interest in donor-specific transplant tolerance has been renewed by the recent observations that in the rat the thymus is an immunologically privileged site into which isolated pancreatic islets can be engrafted and survive indefinitely. Moreover, intrathymic injection induced donor-specific unresponsiveness, which allowed survival of a second donor-strain islet cell allograft transplanted into an extrathymic site. Findings on cellular allograft have been extended to vascularized organ allografts. Recent experiments documented that in the rat intrathymic injection of donor cells allows subsequent renal graft to survive indefinitely. Unresponsiveness to rat kidney graft is donor but not tissue specific and evidence is presented here that the thymus has a central role in such a phenomenon. Hopefully, these studies will open new perspectives in transplantation promoting indefinite graft survival without the complications of long-term immunosuppressants.

Animals↗
PubMedDate not supplied

Intrathymic transplantation of donor cells allows a stabilized, incompatible renal transplant to survive indefinitely after cyclosporine withdrawal.

Recent experiments have shown that exposure of maturing rat thymocytes to donor cells induces a condition of donor-specific unresponsiveness in the recipient that allows indefinite survival of a subsequent kidney transplant without the need for long-term immunosuppressants. Here, studies were performed in Lewis (RT1(1)) rats to determine whether (a) the process of unresponsiveness to kidney allograft induced by intrathymic donor cell inoculation occurred also with a noninbred strain of donor animals, and (b) this technique could allow the elimination of the need for daily immunosuppressive therapy in animals already transplanted with an incompatible kidney. Kidneys from noninbred Sprague-Dawley rats transplanted in incompatible Lewis (RT1(1)) rats, previously injected intrathymically with cells from the same donor, survived indefinitely. Intrathymic inoculation of donor cells into Lewis rats allowed a stabilized, incompatible renal allograft from Brown-Norway (RT1n) rats to survive indefinitely after discontinuation of immunosuppressive treatment with cyclosporine. These findings provide an approach for renal transplantation without immunosuppressive therapy and a potential strategy to overcome side effects related to the use of immunosuppressants in animals already transplanted.

Animals↗
PubMedDate not supplied

[The role of endothelin in the progression of the renal disease in an experimental model of chronic kidney failure].

Recent in vitro and in vivo data suggest that endothelin, a potent vasoconstrictor peptide originally isolated from cultured porcine aortic endothelial cells, may be one of the factors accounting for progressive glomerulosclerosis in experimental and human glomerulopathies. Endothelin is expressed and produced by glomerular endothelial and mesangial cells in culture, has a mitogenic effect on mesangial cells and stimulates mesangial synthesis of extracellular matrix components such as type I, III and IV collagen and laminin. In rats with renal mass ablation, a model of chronic renal disease characterized by systemic hypertension, proteinuria and progressive glomerulosclerosis, a significant increase in urinary excretion of endothelin was documented 45 days after surgery as compared with basal values. Experiments involving the infusion of labeled endothelin into renal arteries of rats with renal mass ablation have suggested that the enhanced urinary excretion rate of endothelin could reflect an increased renal production of the peptide. Recent experiments done with Northern blot analysis have evidenced a 2.5 fold increase in pre-proendothelin transcript in kidney homogenates from rats with remnant kidney at 30 days after surgery. The increase averaged 4-5 fold at 60 and 120 days. In the same animals a significant correlation was found between urinary endothelin excretion and the percent of glomeruli affected by glomerulosclerosis. We conclude that the progression of renal disease after surgical ablation of renal mass is associated with an increased renal endothelin gene expression together with excessive urinary excretion of the corresponding protein. It is speculated that endothelin may mediate glomerular structural abnormalities associated with the progression of renal disease.

Animals↗
PubMedDate not supplied

Comparison of the effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats.

The mechanism by which angiotensin-converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in experimental nephropathies is not yet clear. Experimental evidence is available that the effect of ACE inhibitors on the glomerular function depends on the inhibition of angiotensin II generation, but it is possible that inhibition of the bradykinin breakdown also plays a relevant role. To establish the mediators of the effects of ACE inhibitors in glomerular injury, we compared the effects of the ACE inhibitor lisinopril with those of a specific angiotensin receptor (AT1) antagonist (ZD7155) on the renal function in male MWF/Ztm rats. After 4 months (end of the study), the untreated animals developed hypertension and proteinuria (160 +/- 10 mm Hg and 214 +/- 92 mg/24 h, respectively). In the lisinopril- and in the ZD7155-treated rats, a comparable systolic pressure control was achieved (121 +/- 12 and 118 +/- 14 mm Hg, respectively), and proteinuria was significantly prevented (averaging only 38 +/- 23 and 30 +/- 8 mg/24h, respectively) at the end of the study. The glomerular filtration rate was comparable in control and lisinopril-treated rats and significantly increased in ZD7155-treated rats. Both treatments significantly reduced the glomerular capillary pressure and significantly increased the ultrafiltration coefficient (Kf) as compared with untreated animals. In ZD7155-treated rats the Kf was also significantly higher than in untreated animals glomerular sclerosis and tubulointerstitital damage developed. Structural changes were absent in lisinopril- and ZD7155-treated animals. These results show that the antihypertensive and renal protective effects of ACE inhibitors are shared by the angiotensin receptor antagonist. Thus, angiotensin II is the likely mediator of proteinuria and glomerulosclerosis which develop spontaneously with age in this model.

Angiotensin Receptor Antagonists↗
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Passive Heymann nephritis: evidence that angiotensin-converting enzyme inhibition reduces proteinuria and retards renal structural injury.

In nonimmunological models of renal damage, abnormal traffic of proteins through the glomerular capillary is one of the possible causes of renal disease progression. Here we investigated whether in a model of immune-mediated glomerulonephritis long-lasting proteinuria resulted in renal structural damage and whether chronic treatment with perindopril, an angiotensin-converting enzyme (ACE) inhibitor, lowered proteinuria and retarded disease progression. Passive Heymann nephritis (PHN), a model of human membranous nephropathy, was induced with 0.5 ml/100 g of rabbit anti-Fx1 A antibody in 26 male Sprague-Dawley rats. Animals were then divided into two groups of 13 rats each, given daily vehicle or perindopril (1 mg/kg p.o). Treatment started at day 7 when proteinuria was already present and lasted 12 months. An additional group of normal rats was used as control. Renal biopsies were taken at months 8 and 12. Untreated PHN rats showed a significant increase in systolic blood pressure starting from month 8, that was normalized by perindopril administration. Urinary protein excretion progressively increased with time in untreated PHN rats that developed focal and segmental glomerulosclerosis and tubulointerstitial damage. Perindopril significantly reduced proteinuria and limited glomerular and tubulointerstitial injury. Urinary excretion of endothelin-1 (ET-1) and transforming growth factor-beta 1 (TGF-beta 1), two major mediators of renal damage in other models of glomerulonephritis, increased with time in PHN but only the former correlated with the degree of glomerulosclerosis. The effect of perindopril on proteinuria and renal structural damage was associated with a significant reduction in urinary ET-1 but not TGF-beta 1, suggesting that ET-1 may be an important determinant of disease progression in experimental membranous nephropathy.

Angiotensin-Converting Enzyme Inhibitors↗
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Endothelin: a mediator of renal disease progression.

Glomerulosclerosis and tubulointerstitial damage are characteristics of progressive renal diseases associated with chronic proteinuria. Since numerous studies have demonstrated a correlation between proteinuria and the degree of renal damage, a causal role for proteinuria in the development of progressive renal failure has been postulated. Some in vitro data suggest that endothelins (ET), a family of endogenous peptides, could be involved in the genesis and progression of glomerular damage. Moreover, evidence that tubular cells exposed to high molecular weight proteins are induced to release ET toward the basolateral compartment, together with the capability of these peptides to influence events occurring in the interstitium, suggest that ET could also participate in interstitial inflammation. Data are now available that ET actually plays a role in the progression of chronic renal disease in different experimental models including renal mass reduction, lupus nephritis and streptozotocin-induced diabetes.

Animals↗
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Selective dietary restriction of protein and calorie intakes prevents spontaneous proteinuria in male MWF rats.

BACKGROUND/AIMS: Previous observations indicate that protein and calorie restrictions can affect the course of renal disease progression. We compared the effects of selective protein and calorie restriction on glomerular hemodynamics and proteinuria in a model of spontaneous glomerular injury in the rat. METHODS: Three groups of male MWF rats were assigned to three different diets: standard diet (ST, 19% protein, 3.4 kcal/g), low protein (LP) and low calorie (LC). Proteinuria and systolic blood pressure were periodically measured. Glomerular hemodynamics and tuft volume were determined after 2 months of dietary treatment. RESULTS: The effective mean protein intake was 3.4 +/- 0.4, 1.6 +/- 0.2, and 3.2 +/- 0.2 g/day/rat, respectively, for the ST, LP, and LC diets, while caloric intake averaged 60 +/- 7, 59 +/- 9, and 30 +/- 2 kcal/day/rat. Both LP and LC diets significantly prevented proteinuria (104 +/- 32, 36 +/- 9, and 18 +/- 8 mg/day, respectively, in the three groups). The systolic blood pressure was unaffected by the diets. The LC diet induced lower body and kidney weights than the ST diet. The glomerular filtration rate was slightly but significantly increased by the LP diet, but not by the LC diet (0.64 +/- 0.14, 0.81 +/- 0.08, and 0.67 +/- 0.12 ml/min, respectively, for ST, LP and LC diets). The glomerular hydraulic pressures were not affected by the diets. No differences were also observed in glomerular volume. The incidences of glomerulosclerosis and tubulointerstitial changes were comparable in ST and LP diets and completely absent in the LC diet group. CONCLUSION: These results indicate that restriction of both protein and calorie intakes prevents spontaneous proteinuria in male MWF rats by preventing deterioration of glomerular perm-selective functions.

Albuminuria↗
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Abdominal pain and acute nephritis in a man with a recent renal transplant.

We describe a patient with renal transplant who developed abdominal pain and acute nephritis in the course of the follow-up. A biopsy of colon lesions revealed CMV inclusions, renal biopsy revealed acute glomerulonephritis with positive CMV-DNA on polymerase chain reaction. The renal disease and bowel symptoms completely resolved after antiviral treatment.

Abdominal Pain↗