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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 55 records · Page 3Linked to original sources
PubMed2001

Post-transplant renal artery stenosis: the hemodynamic response to revascularization.

BACKGROUND: Percutaneous transluminal angioplasty and stenting are relatively noninvasive approaches to treat post-transplant renal artery stenosis. However, the real impact of this procedure on renal function recovery has never been quantitated precisely to date. METHODS: In eight consecutive renal transplant patients with renal graft artery stenosis, blood pressure, body weight, and anatomical, functional, and Doppler ultrasound parameters were evaluated before and one month after renal artery transluminal angioplasty and stenting. On both occasions, glomerular filtration rate and renal plasma flow were evaluated by inulin and paraaminohippuric acid renal clearances, and glomerular size-selective function was evaluated by the fractional clearances of neutral dextran macromolecules. RESULTS: The correction of renal artery stenosis, by normalizing renal vascular resistances, fully restored kidney perfusion and decreased arterial blood pressure, relieved water and sodium retention, restored an almost laminar arterial blood flow, and normalized vascular shear stress without appreciable effects on glomerular barrier size-selective function and proteinuria. Preangioplasty and postangioplasty renal resistive indices and peak systolic blood velocity estimated by Doppler ultrasounds were significantly correlated with the effective renal plasma flow and the blood velocity calculated at the site of stenosis. All patients were discharged without sequelae one or two days after angioplasty. CONCLUSIONS: Percutaneous transluminal angioplasty and stenting are safe and effective procedures to normalize the functional changes sustained by hemodynamically significant artery stenosis after renal transplantation. Doppler ultrasound scanning is a reliable and reproducible technique to monitor the renal functional response to vascular reperfusion.

Adult↗
PubMed2001

Mycophenolate mofetil combined with a cyclooxygenase-2 inhibitor ameliorates murine lupus nephritis.

BACKGROUND: Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. Mycophenolate mofetil (MMF) has been described as being less toxic than conventional immunosuppressants, and it was effective in preventing progressive nephritis in lupus mice. Our study evaluated the therapeutic effect of MMF in NZB/W F1 hybrid mice with established disease. We also examined the combination of MMF with a selective cyclooxygenase-2 (COX-2) inhibitor, DFU, based on previous findings of excessive renal production of COX-2-derived thromboxane A2 (TXA2) in lupus nephritis. METHODS: Four groups of NZB/W mice (N = 30 each group), starting at five months of age, were given daily by gavage the following: vehicle, MMF 60 mg/kg, DFU 3 mg/kg, or MMF + DFU. Fifteen mice for each group were used for the survival studies, and the remaining mice were sacrificed at nine months. RESULTS: MMF or DFU alone partially delayed the onset of proteinuria compared with vehicle. Combined therapy was significantly (P < 0.05) more effective than single drugs. Animal survival was partially ameliorated by MMF and significantly improved by the drug combination in comparison with the vehicle (P = 0.005) and DFU alone (P < 0.03). At nine months, serum blood urea nitrogen (BUN) levels were lower in all of the treated groups than in the vehicle group. Renal damage was also limited, but to a greater extent in mice given the combined therapy. In untreated mice, renal COX-2 mRNA expression was up-regulated, and generation of TXB(2), the stable breakdown product of TXA(2), increased. DFU prevented the abnormal renal TXB(2) production, confirming the COX-2 origin of this eicosanoid, whereas renal 6-keto-PGF(1 alpha) and prostaglandin E(2) (PGE(2)) were not affected substantially. CONCLUSIONS: These results offer a strong case for exploring the possibility that in humans MMF combined with COX-2 inhibitors has a role in the treatment options for lupus nephritis. This combined drug therapy may be at least as effective as steroids but without the obvious nephrotoxicity of the latter.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. METHODS: Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. RESULTS: Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. CONCLUSIONS: The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.

The term thrombotic microangiopathy (TMA) defines a lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis, and partial or complete obstruction of the vessel lumina. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different entities have been described: the hemolytic uremic syndrome (HUS) and the thrombotic thrombocytopenic purpura (TTP). Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP. Plasma infusion or exchange is the only treatment of proven efficacy. Bilateral nephrectomy and splenectomy may serve as rescue therapies in very selected cases of plasma resistant HUS or recurrent TTP, respectively.

Adult↗
PubMed2001

How renal cytokines and growth factors contribute to renal disease progression.

Terminal renal failure is the final common fate of chronic nephropathies regardless of the type of original insult. After removal of a critical number of nephrons, adaptive hemodynamic changes in the remaining nephrons ensure enough filtration power to the kidney but are ultimately detrimental. Such changes are largely mediated by the local formation of angiotensin II (AII) and prevented by the use of angiotensin-converting enzyme inhibitors, which also limit the forced opening of large unselective pores in the glomerular barrier, restoring size selectivity. Recent studies suggested that proteins filtered through the glomerular capillary, previously considered a marker of the severity of renal lesions, might have intrinsic toxicity on the proximal tubular cells and a contributory role in the progression of renal damage. Protein overload of proximal tubular cells induced the secretion of endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T expressed and secreted (RANTES) that was mainly directed toward the basolateral compartment of the cell. Evidence available in rat models of proteinuric renal disease shows that expression of genes encoding such vasoactive and proinflammatory molecules as ET-1, MCP-1, and RANTES was consistently upregulated, and synthesis of the corresponding peptides was enhanced in renal tissue. Additional mechanisms of proximal tubular cell activation leading to interstitial inflammation and matrix deposition are the filtration of protein-bound metals and hormones and deposition and activation of filtered complement. Limiting protein traffic and the biological effect of excessive tubular protein reabsorption by drugs interfering with AII synthesis or biological activity prevents renal disease progression.

Angiotensin II↗
PubMed2001

Research on renal endothelin in proteinuric nephropathies dictates novel strategies to prevent progression.

Proteinuria is one of the major risk factors for renal disease progression in patients with chronic nephropathies. Studies in disease models have helped to delineate mechanisms leading to renal structural damage as a result of persistent dysfunction of the glomerular barrier to proteins, even when the primary immune or non-immune insult to the kidney has ceased. From these preclinical studies, a role for endothelin in proteinuric chronic renal diseases has been suggested, thus providing the rationale for novel therapeutic approaches with endothelin receptor antagonists to maximize renoprotection so far achieved with blockade of the renin-angiotensin system by angiotensin-converting enzyme inhibition or angiotensin II receptor antagonism. Trials are needed to explore this potential area of clinical interest.

Angiotensin II↗
PubMed2001

Computational fluid dynamics of a vascular access case for hemodialysis.

Vascular accesses (VA) for hemodialysis are usually created by native arteriovenous fistulas (AVF) or synthetic grafts. Maintaining patency of VA continues to be a major problem for patients with end-stage renal disease, since in these vessels thrombosis and intimal hyperplasia often occur. These lesions are frequently associated with disturbed flow that develops near bifurcations or sharp curvatures. We explored the possibility of investigating blood flow dynamics in a patient-specific model of end-to-end native AVF using computational fluid dynamics (CFD). Using digital subtraction angiographies of an AVF, we generated a three-dimensional meshwork for numerical analysis of blood flow. As input condition, a time-dependent blood waveform in the radial artery was derived from centerline velocity obtained during echo-color-Doppler ultrasound examination. The finite element solution was calculated using a fluid-dynamic software package. In the straight, afferent side of the radial artery wall shear stress ranged between 20 and 36 dynes/cm2, while on the inner surface of the bending zone it increased up to 350 dynes/cm2. On the venous side, proximal to the anastomosis, wall shear stress was oscillating between negative and positive values (from -12 dynes/cm2 to 112 dynes/cm2), while distal from the anastomosis, the wall shear stress returned within the physiologic range, ranging from 8 to 22 dynes/cm2. Areas of the vessel wall with very high shear stress gradient were identified on the bending zone of the radial artery and on the venous side, after the arteriovenous shunt. Secondary blood flows were also observed in these regions. CFD gave a detailed description of blood flow field and showed that this approach can be used for patient-specific analysis of blood vessels, to understand better the role of local hemodynamic conditions in the development of vascular lesions.

Arteriovenous Anastomosis↗
PubMed2001

Remission achieved in chronic nephropathy by a multidrug approach targeted at urinary protein excretion.

Regardless of the pattern of renal involvement, increased urinary protein excretion rate is the best independent predictor of progression of chronic nephropathies and short-term reduction in proteinuria has been reported to be renoprotective in the long term. Despite such evidence, however, the therapeutic target in renoprotection is almost exclusively on blood pressure control. We report the clinical course of a patient with chronic nephropathy after the institution of a multidrug treatment titrated against urinary protein excretion to achieve renoprotection. The present findings indicate that adjusting renoprotective therapy according to the decline in protein excretion in a multidrug strategy may stabilize or even reverse renal disease progression. This approach should be formally explored in prospective studies.

Adult↗
PubMed2001

Platelets: an update on diagnosis and management of thrombocytopenic disorders.

Thrombocytopenia in the pregnant patient may result from a number of causes, most of which involve either immune-mediated platelet destruction or platelet consumption. Many of these disorders share clinical and laboratory features, making accurate diagnosis difficult. Moreover, uterine evacuation is indicated in the therapy of some disorders, while in others alternative interventions may allow the pregnancy to be carried to term. These and other issues are discussed as part of a comprehensive review of the differential diagnosis and management of thrombocytopenia in pregnancy. The term "refractory ITP" is used with reference to two distinct groups of patients: 1) patients in whom the platelet count cannot be easily increased, including those who are poorly responsive to initial single agent treatment, and 2) those with persistent thrombocytopenia despite the use of conventional therapies. An approach to management of the former group will be presented, followed by a discussion of patients with chronic refractory ITP. The latter will include presentation of new data on the role of Helicobacter pylori in ITP and whether its treatment ameliorates thrombocytopenia, as well as the use of rituximab and other modalities. Thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) are rare, but life threatening causes of thrombocytopenia. Ultra-large multimers of von Willebrand factor (vWF) aggregate platelets intravascularly, and congenital or immune-mediated deficiencies of a metalloprotease that cleaves these ultra-large multimers may cause TTP. However, little information exists concerning the behavior of this protease in other physiological and pathological conditions. Levels of this protease have now been measured in healthy individuals of different ages, full-term newborns, pregnant women and a patients with variety of pathologic conditions, and these data will be reviewed herein. Heparin-induced thrombocytopenia/thrombosis (HIT/T) remains the most common antibody-mediated, drug-induced thrombocytopenic disorder, and a leading cause of morbidity and mortality. Based on clinical correlations and murine models, there is increasing evidence that antibodies to complexes between platelet factor 4 (PF4) and heparin cause HIT/T, and the molecular composition of the relevant antigen has also become better defined. However, the introduction of sensitive ELISAs to measure anti-PF4/heparin antibodies has complicated diagnosis in some settings in which the incidence of such antibodies in unaffected patients exceeds the incidence of the disease. In addition, the FDA approval of Lepirudin and Argatroban has expanded the repertoire of agents available for therapy of HIT/T and may change the approach to management of asymptomatic patients with thrombocytopenia. However, the optimal use of these drugs in commonly encountered settings remains in evolution, and a need for alternative approaches to prevention and treatment is evident.

ADAM Proteins↗
PubMed2001

Drug-induced thrombotic microangiopathy: incidence, prevention and management.

The term thrombotic microangiopathy (TMA) describes syndromes characterised by microangiopathic haemolytic anaemia, thrombocytopenia and variable signs of organ damage due to platelet thrombi in the microcirculation. In children, infections with Shigella dysenteriae type 1 or particular strains of Escherichia coli are the most common cause of TMA; in adults, a variety of underlying causes have been identified, such as bacterial and viral infections, bone marrow and organ transplantation, pregnancy, immune disorders and certain drugs. Although drug-induced TMA is a rare condition, it causes significant morbidity and mortality. Antineoplastic therapy may induce TMA. Most of the cases reported are associated with mitomycin. TMA has also been associated with cyclosporin, tacrolimus, muromonab-CD3 (OKT3) and other drugs such as interferon, anti-aggregating agents (ticlopidine, clopidogrel) and quinine. The early diagnosis of drug-induced TMA may be vital. Strict monitoring of renal function, urine and blood abnormalities, and arterial pressure has to be performed in patients undergoing therapy with potentially toxic drugs. The drug must be discontinued immediately in the case of suspected TMA. Treatment modalities sometimes effective in other forms of TMA have been used empirically. Although plasma exchange therapy seems to be of value, the effectiveness of this approach has yet to be proved in multicentre, randomised clinical studies.

Adult↗
PubMed2001

Renoprotective therapy in patients with nondiabetic nephropathies.

End-stage renal failure (ESRF) represents a major health problem. Early diagnosis and effective measures to slow or to stop renal damage are essential goals for nephrologists to prevent or delay progression to ESRF. Identifying mechanisms of progressive parenchymal injury is instrumental in developing renoprotective strategies. Protein traffic through the glomerular barrier is an important determinant of progression in chronic nephropathies and proteinuria is the best predictor of renal outcome. At the moment, ACE inhibition is the most effective treatment in patients with chronic nondiabetic proteinuric nephropathies, reducing protein traffic, urinary protein excretion rate and progression to ESRF more effectively than conventional treatment. Low sodium diet and/or diuretic treatment may help to increase the antiproteinuric effect of ACE inhibitors by maximally activating the renin-angiotensin system. Intensified blood pressure control, whatever treatment is employed, also enhances the antiproteinuric response to ACE inhibitors. However, since this is not always sufficient to normalise urinary proteins and fully prevent renal damage, additional treatments may be needed in patients poorly or not responding to ACE inhibitors. These may include angiotensin II receptor antagonists, non-dihydropyridine calcium antagonists and perhaps low doses of nonsteroidal anti-inflammatory drugs. Preliminary data on multidrug treatments including these additional antiproteinuric agents are encouraging, but additional studies in larger patient numbers are needed to better define the risk/benefit profile of this innovative approach.

Angiotensin Receptor Antagonists↗
PubMed2001

Pharmacokinetic study of the new cyclosporine-A formulation (Neoral) in adult allogeneic bone marrow transplant recipients.

BACKGROUND AND OBJECTIVES: A major problem encountered during oral cyclosporin-A (CsA) administration to prevent acute graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) is its irregular pharmacokinetics. The aim of this study was to evaluate the pharmacokinetics of Neoral, a new water-free microemulsion formulation of CsA. DESIGN AND METHODS: Eighteen patients aged over 18 were enrolled into the study. When able to eat normally after allo-BMT, patients received CsA orally and after 4 days a 12-hour CsA pharmacokinetic profile was constructed. Three patients received Sandimmune 10 mg/kg/day, 5 patients received Neoral 7.5 mg/kg/day and 10 patients Neoral 5 mg/kg/day. CsA concentration was analyzed on whole blood by high-performance liquid chromatography (HPLC). RESULTS: Neoral showed concentration-time profiles characterized by a smooth and faster rise to the Cmax value compared to that produced by Sandimmune. The comparison between pharmacokinetic parameters obtained in patients receiving Neoral 5 mg/kg/day or 7.5 mg/kg/day showed a proportional increase of the AUC (4776+/-1084 vs. 7746+/-2006 ng/mL h) and C(max) (1027+/-203 vs. 1514+/-231 ng/mL). In all patients to whom 7.5 mg/kg/day of Neoral were given, C(trough) levels were always above the threshold of 200 ng/mL. INTERPRETATION AND CONCLUSIONS: Our data suggest that oral administration of Neoral 7.5 mg/kg/day early after allo-BMT may represent an appropriate dose resulting in adequate CsA C(trough) levels without significant renal toxicity.

Adult↗