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Biomedical subjects

Giuseppe Remuzzi

Publications and source records attributed to Giuseppe Remuzzi.

At least 127 records · Page 7Linked to original sources
PubMed2004

Immunosuppressive treatment for idiopathic membranous nephropathy: a systematic review.

BACKGROUND: This study aims to assess whether immunosuppression is beneficial in the treatment of idiopathic membranous nephropathy (IMN). METHODS: We reviewed randomized controlled trials (RCTs) addressing the effect of immunosuppression on histologically proven IMN in adults with nephrotic syndrome followed up for at least 6 months. The literature was searched according to Cochrane Collaboration guidelines. Four therapeutic classes were considered: (1) steroids (alone), (2) alkylating agents (alone or in combination with steroids), (3) calcineurin inhibitors (alone or in combination with steroids), and (4) antiproliferative agents (alone). RESULTS: Eighteen RCTs were selected (1,025 patients). Overall, no differences were found between immunosuppressive treatment and placebo or no treatment. For oral glucocorticoid therapy, no beneficial effect was observed. For alkylating agents, a beneficial effect was observed on complete remission (relative risk [RR], 2.37; 95% confidence interval [CI], 1.32 to 4.25; P = 0.004). Excluding patients with particularly well-preserved renal function, there was no significant difference in complete remission. Cyclophosphamide therapy resulted in a lower rate of adverse-event discontinuations compared with chlorambucil (8 versus 21 discontinuations, respectively; RR, 2.34; 95% CI, 1.25 to 4.39; P = 0.008). For calcineurin inhibitors, no difference was observed. For antiproliferative agents, a paucity of data did not allow a conclusion. CONCLUSION: The meta-analysis failed to show a long-term effect of treatment on patient and/or renal survival. There is weak evidence that the immunosuppressive regimen increased the remission rate. The review of safety showed a higher number of discontinuations for adverse events in immunosuppressive-treatment groups and that cyclophosphamide had fewer side effects than chlorambucil.

Alkylating Agents↗
PubMed2003

Familial haemolytic uraemic syndrome and an MCP mutation.

BACKGROUND: Mutations in factor H (HF1) have been reported in a consistent number of diarrhoea-negative, non-Shiga toxin-associated cases of haemolytic uraemic syndrome (D-HUS). However, most patients with D-HUS have no HF1 mutations, despite decreased serum concentrations of C3. Our aim, therefore, was to assess whether genetic abnormalities in other complement regulatory proteins are involved. METHODS: We screened genes that encode the complement regulatory proteins-ie, factor H related 5, complement receptor 1, and membrane cofactor protein (MCP)-by PCR-single-strand conformation polymorphism (PCR-SSCP) and by direct sequencing, in 25 consecutive patients with D-HUS, an abnormal complement profile, and no HF1 mutation, from our International Registry of Recurrent and Familial HUS/TTP (HUS/thrombotic thrombocytopenic purpura). FINDINGS: We identified a heterozygous mutation in MCP, a surface-bound complement regulator, in two patients with a familial history of HUS. The mutation causes a change in three aminoacids at position 233-35 and insertion of a premature stop-codon, which results in loss of the transmembrane domain of the protein and severely reduced cell-surface expression of MCP. INTERPRETATION: Results of previous studies on HF1 indicate an association between HF1 deficiency and D-HUS. Our findings of an MCP mutation in two related patients suggest that impaired regulation of complement activation might be a factor in the pathogenesis of genetic forms of HUS. MCP could be a second putative candidate gene for D-HUS. The protein is highly expressed in the kidney and plays a major part in regulation of glomerular C3 activation. We propose, therefore, that reduced expression of MCP in response to complement-activating stimuli could prevent restriction of complement deposition on glomerular endothelial cells, leading to microvascular cell damage and tissue injury.

Adolescent↗
PubMed2003

Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease.

Mutations in complement factor H (HF1) gene have been reported in non-Shiga toxin-associated and diarrhoea-negative haemolytic uraemic syndrome (D-HUS). We analysed the complete HF1 in 101 patients with HUS, in 32 with thrombotic thrombocytopenic purpura (TTP) and in 106 controls to evaluate the frequency of HF1 mutations, the clinical outcome in mutation and non-mutation carriers and the role of HF1 polymorphisms in the predisposition to HUS. We found 17 HF1 mutations (16 heterozygous, one homozygous) in 33 HUS patients. Thirteen mutations were located in exons XXII and XXIII. No TTP patient carried HF1 mutations. The disease manifested earlier and the mortality rate was higher in mutation carriers than in non-carriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in non-mutated patients half of the grafts were functioning after 1 year. Three HF1 polymorphic variants were strongly associated with D-HUS: -257T (promoter region), 2089G (exonXIV, silent) and 2881T (963Asp, SCR16). The association was stronger in patients without HF1 mutations. Two or three disease-associated variants led to a higher risk of HUS than a single one. Analysis of available relatives of mutated patients revealed a penetrance of 50%. In 5/9 families the proband inherited the mutation from one parent and two disease-associated variants from the other, while unaffected carriers inherited the protective variants. In conclusion HF1 mutations are frequent in patients with D-HUS (24%). Common polymorphisms of HF1 may contribute to D-HUS manifestation in subjects with and without HF1 mutations.

Amino Acid Sequence↗
PubMed2003

Doppler ultrasonography in posttransplant renal artery stenosis: a reliable tool for assessing effectiveness of revascularization?

BACKGROUND: Renal artery stenosis is usually treated by angioplasty and stenting, but the effectiveness of graft perfusion is difficult to establish on clinical grounds. METHODS: We compared changes in Doppler ultrasound parameters such as resistive index and peak systolic velocity with concomitant changes in renal vascular resistances, renal blood velocity, and wall shear stress measured before and 1 month after percutaneous transluminal angioplasty and stenting in 12 renal transplant patients with renal artery stenosis. RESULTS: After revascularization, peak systolic velocity and resistive index normalized in all patients. Changes in peak systolic velocity (-72%; P<0.001 vs. basal) were positively correlated (P<0.0001; r=0.87) with those in renal blood velocity (-88%; P<0.01 vs. basal) and with those (P<0.0005; r=0.80) in wall shear stress (-97%; P<0.005). Changes in resistive index (+21%; P<0.005) were negatively correlated (P=0.009; r=0.51) with those in renal vascular resistances (-40%; P<0.01). Changes in Doppler parameters (resistive index and peak systolic velocity) reflected those in renal vascular resistances and renal blood velocity with 100% sensitivity and specificity. CONCLUSIONS: Doppler ultrasound is a reliable, noninvasive, and easily available tool for identifying subjects who may benefit from kidney graft revascularization and to assess the effectiveness of the procedure.

Angioplasty, Balloon, Coronary↗
PubMed2003

Targeted downregulation of extracellular nephrin in human IgA nephropathy.

BACKGROUND: The identification of nephrin and CD2AP, podocyte proteins which modulate the properties of glomerular barrier selectivity, has made it possible to unravel the mechanisms undergoing foot process effacement and proteinuria. Here we explored the role of nephrin and CD2AP together with the integrity of the slit diaphragm in the pathogenesis of proteinuria in patients with acquired glomerular diseases. METHODS: Nephrin mRNA and protein expression were systematically evaluated in 28 renal biopsy samples from adult patients with primary glomerular disease and proteinuria by in situ hybridization and immunohistochemistry using antibodies directed against extra- and intracellular nephrin and compared with biopsy samples from normal controls. CD2AP protein expression by immunohistochemistry was also assessed. Morphometrical analysis of the filtration slit was performed by transmission electron microscopy. RESULTS: Nephrin mRNA and expression of the extracellular nephrin were markedly reduced in IgA nephropathy. No changes were found in patients with minimal change nephrosis and focal segmental glomerulosclerosis. The staining of intracellular nephrin and CD2AP did not change among patients. A comparable frequency of the filtration slits was observed in all patient groups, except in minimal change disease patients, due to extensive foot process effacement. The percentage of slit diaphragms with a filamentous image was markedly reduced in IgA nephropathy, but was comparable to controls in minimal change disease. Slit pore width showed a tendency to decrease both in patients with minimal change disease and IgA nephropathy. CONCLUSIONS: These results indicate that the ultrastructure of the filtration slit diaphragm is altered in patients with IgA nephropathy as a consequence of targeted downregulation of extracellular nephrin. Further studies are needed to evaluate the pathophysiological meaning of nephrin abnormality in IgA nephropathy and how these changes can be modulated by antiproteinuric therapy.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Tackling the shortage of donor kidneys: how to use the best that we have.

Shortage of kidney donor is still a major limitation for renal transplantation programs. This review focuses on the emerging practices, adopted to increase transplant activities, of expanding the criteria for donor and recipient selection without exposing the recipient to the drawbacks of a graft with inadequate nephron mass. Expanding the donor pool inevitably led to consideration for kidney transplantation of organs from older donors or from donors with hypertension, diabetes or other renal diseases. To fit the reduced performance of these suboptimal organs with the renal requirement of the recipient, selection of recipients with reduced metabolic requirements or increase of nephron mass by simultaneous transplantation of two suboptimal kidneys in the same recipient have been pursued. However, a critical aspect of both approaches is to quantify functioning nephron mass provided to the recipient by pre-transplant kidney biopsies. Morphological parameters assessed on kidney biopsies at the time of donor evaluation may serve to quantify the preserved tissue and to discriminate chronic irreversible lesions from acute changes that may account for a transiently impaired renal function in the donor, but that may recover after transplant.

Graft Survival↗
PubMed2003

Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies.

BACKGROUND: Dyslipidemia frequently complicates chronic nephropathies and increases the risk of renal and cardiovascular events. This might be ameliorated by drugs, such as angiotensin-converting enzyme inhibitors, which effectively reduce proteinuria. METHODS AND RESULTS: In this longitudinal study, we evaluated the extent to which uptitration of the ACE inhibitor lisinopril to maximum tolerated doses (median [range]: 30 [10 to 40] mg/d) ameliorated proteinuria and dyslipidemia in 28 patients with nondiabetic chronic nephropathies. Maximum lisinopril doses significantly and safely reduced proteinuria, serum total, LDL cholesterol, and triglycerides without substantially affecting serum HDL and renal hemodynamics. Proteinuria already decreased at 10 mg/d. Serum lipids progressively and dose-dependently decreased during uptitration to maximum doses. Reduction in total and LDL cholesterol correlated with increases in serum albumin/total protein concentration and oncotic pressure, peaked at lisinopril maximum doses, and persisted after treatment withdrawal. Despite less proteinuria reduction, hypercholesterolemia decreased more (and reflected the increase in serum albumin) in hypoalbuminemic than in normoalbuminemic patients who, despite more proteinuria reduction, had less decrease in cholesterol and no changes in serum albumin. Changes in serum triglycerides were independent of changes in serum proteins, were strongly correlated with lisinopril doses (r=-0.89, P=0.003) and recovered promptly after treatment withdrawal. Lisinopril was well tolerated, did not affect renal hemodynamics, and caused symptomatic, reversible hypotension in only two patients. CONCLUSIONS: In chronic nephropathies, angiotensin converting enzyme inhibitor uptitration to maximum tolerated doses safely ameliorated hypertriglyceridemia by a direct, dose-dependent effect, and hypercholesterolemia through amelioration of the nephrotic syndrome, particularly in patients with more severe hypoalbuminemia.

Adolescent↗
PubMed2003

Proteinuria in diabetic nephropathy: treatment and evolution.

Diabetic nephropathy is characterized by increased urinary albumin excretion and loss of renal function. Increased urinary albumin (proteinuria) is a key component of this disease. Previously, its development led to end-stage renal disease with increased mortality and morbidity for diabetic patients versus nondiabetic patients. Several treatment strategies currently exist that can prevent, slow, and even reverse diabetic nephropathy. New trials suggest that a multidisciplinary approach focused on optimizing metabolic and hypertensive control, in addition to the use of angiotensin-converting enzyme inhibitors or angiotensin 2 receptor antagonists, is effective in halting the progression of disease. Screening and implementation of these strategies is needed to reverse the epidemic of diabetic renal disease.

Albuminuria↗
PubMed2003

Angiotensin-converting enzyme inhibition or angiotensin receptor blockade in hypertensive diabetics?

Hypertension increases the renal and cardiovascular risks in diabetic patients. The beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal and cardiovascular outcomes are discussed in this paper, with a particular focus on their optimal use in the hypertensive diabetic patient, with or without evidence of renal or cardiovascular disease. Although the mechanism of action of the two drug classes is not entirely similar, there is no evidence of differences in their clinical effects. Importantly, the achieved risk reduction with either drug is not similar across subsets of diabetic patients. Overt nephropathy of type 2 diabetes appears poorly responsive even to maximized renin-angiotensin system inhibition. This urgently calls for new interventions that may decrease renal and cardiovascular risk through other mechanisms than blood pressure lowering alone. Improving the outcome of type 2 diabetics is the major clinical challenge for the beginning of the third millennium.

Angiotensin Receptor Antagonists↗
PubMed2003

Nonimmunosuppressive therapy of membranous nephropathy.

Idiopathic membranous nephropathy (MN) has a variable rate of progression to end-stage renal failure, with a significant number of patients going into spontaneous remission without therapy. For those who have persistent nephrotic proteinuria or manifest deterioration of renal function, steroids and immunosuppressive drugs are used. However, their long-term efficacy is challenged by a meta-analysis presented here. A different approach to reduction of proteinuria, a recognized progression promoter, is based on the notion that angiotensin II inhibition controls proteinuria and slows progression. Further, a more complex approach is required than simple administration of an angiotensin-converting enzyme (ACE) inhibitor: a multidrug approach to remission of nephrotic syndrome therefore is described here.

Adult↗
PubMed2003

Retarding progression of chronic renal disease: the neglected issue of residual proteinuria.

BACKGROUND: Findings that early changes in proteinuria independently predict long-term glomular filtration rate (GFR) decline (Delta GFR) would highlight proteinuria as a major determinant of progression in chronic renal disease. METHODS: We investigated whether percent changes (3 months vs. baseline) in proteinuria (adjusted for concomitant changes in GFR) and residual proteinuria at 3 months, predicted Delta GFR [over a median (IQ range) follow up of 31.3 (24.5 to 50.3) months] in 273 patients with proteinuric chronic nephropathies enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. RESULTS: Short-term changes and residual proteinuria (r = -0.23, P = 0.0001 for both) significantly correlated with Delta GFR and, at multivariate analyses, independently predicted Delta GFR (beta = -0.23, P = 0.0002; beta = -0.21, P = 0.0004, respectively). For comparable levels of residual proteinuria, patients with greater short-term reduction had slower Delta GFR (-0.28 +/- 0.04 mL/min/1.73 m2/ vs. -0.53 +/- 0.07 mL/min/1.73 m2/month, P = 0.04). On ramipril and conventional treatment, specular short-term changes in proteinuria (-18.2 +/- 3.5% vs. 24.2 +/- 6.7%, P < 0.0001, respectively) were associated with significantly different Delta GFRs. However, similar changes in proteinuria resulted in a difference in Delta GFR (ramipril, 0.39 +/- 0.07 mL/min/1.73 m2/month; conventional therapy, 0.74 +/- 0.11 mL/min/1.73 m2/month; P < 0.01) that was sevenfold higher (0.35 vs. 0.05 mL/min/1.73 m2/month) in patients with basal proteinuria > or =3 g/24 hours as compared to those with basal proteinuria 1 to 3 g/24 hours (ramipril, 0.25 +/- 0.06 mL/min/1.73 m2/month; conventional therapy, 0.30 +/- 0.07 mL/min/1.73 m2/month; P = NS). CONCLUSION: Regardless of blood pressure control and treatment randomization, short-term changes in proteinuria and residual proteinuria reliably predict long-term disease progression. Reducing proteinuria is renoprotective, particularly in nephrotic patients. As for arterial hypertension, proteinuria should be a specific target for renoprotective treatment.

Adolescent↗
PubMed2003

Combining lisinopril and l-arginine slows disease progression and reduces endothelin-1 in passive Heymann nephritis.

BACKGROUND: Despite angiotensin-converting enzyme (ACE) inhibition is a very powerful therapy, it may not be uniformly renoprotective in patients with proteinuric nephropathies who might refer late in the course of the disease. In accelerated passive Heymann nephritis (PHN), a severe rat model of human membranous nephropathy, with proteinuria and increased urinary excretion of endothelin-1 (ET-1), early treatment with an ACE inhibition limited proteinuria as well as the exuberant formation of renal ET-1, while late treatment reduced urinary proteins not to a significant extent. Since biologic effects and production of ET-1 within the kidney are counteracted by nitric oxide, we studied the effect of combining lisinopril and l-arginine, the natural precursor of nitric oxide, starting late in the disease. METHODS: Uninephrectomized PHN rats were divided in four groups (N = 10) and daily given orally: vehicle; 1.25 g/L l-arginine; 40 mg/L lisinopril; and l-arginine + lisinopril. Treatments started at 2 months, when rats had massive proteinuria, until 9 months. Six normal rats served as control. RESULTS: Increase in systolic blood pressure was significantly limited by l-arginine. Lisinopril alone and the combination were more effective. Renal function impairment was not affected by l-arginine, partially ameliorated by ACE inhibitor and normalized by the combined therapy. In rats given l-arginine, proteinuria levels were similar to vehicle. ACE inhibitor kept proteinuria at values comparable to pretreatment and numerically lower than vehicle. Addition of l-arginine to lisinopril was more effective, with values significantly lower than vehicle. Glomerular and tubular changes were limited by the ACE inhibitor and further ameliorated by the combined therapy. Exaggerated urinary ET-1 of PHN was reduced by 23% and 40% after l-arginine and lisinopril, respectively, and by 62% with the combination. Defective urinary excretion of cyclic guanosine monophosphate (cGMP) was partially restored by lisinopril, while normalized by the combined therapy. CONCLUSION: Combining l-arginine with ACE inhibitors would represent a novel strategy for patients with severe nephropathy not completely responsive to ACE inhibition. Restoring the nitric oxide/ET-1 balance could be of benefit in halting renal disease progression.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.

BACKGROUND: Inhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated. METHODS: To address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13. RESULTS: All animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens. CONCLUSION: These findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.

BACKGROUND: Proteinuria predicts renal disease progression, and its reduction by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor antagonists (ARA) is renoprotective. METHODS: In this prospective, randomized, cross-over study of 24 patients with nondiabetic, chronic nephropathies, we compared the effects on proteinuria, renal hemodynamics, and glomerular permselectivity of 8 weeks with comparable blood pressure control achieved by benazepril (10 mg/day) and valsartan (80 mg/day) combined therapy with those achieved by benazepril (20 mg/day) or valsartan (160 mg/day) alone. RESULTS: Despite comparable changes in blood pressure and glomerular filtration rate (GFR), combined therapy decreased proteinuria more than benazepril (-56% vs. -45.9%, P=0.02) and valsartan (-41.5%, P=0.002). Changes in urinary protein to creatinine ratio followed the same trend. Filtration fraction and renal vascular resistances (RVR) decreased more with combined (-14.7%,-23.7%) or benazepril (-12.4%, -20.5%) than with valsartan (-2.7%, -12.5%, P < 0.05 vs. both). RVR changes, adjusted for GFR changes, were associated with those in proteinuria (P < 0.05). Changes in glomerular permeability were comparable and did not predict different changes in proteinuria in the three groups. CONCLUSION: At comparable blood pressure, combined ACEi and ARA decreased proteinuria better than ACEi and ARA. The greater antiproteinuric effect most likely depended on an ACEi-related hemodynamic effect, in addition to glomerular size selectivity amelioration. Long-term combined ACEi and ARA therapy may be more renoprotective than treatment with each agent alone.

Adult↗
PubMed2003

Predicting end-stage renal disease: Bayesian perspective of information transfer in the clinical decision-making process at the individual level.

BACKGROUND: Predicting outcomes such as end-stage renal disease (ESRD) by integration and better utilization at individual level of epidemiologic data may facilitate clinical decision-making processes. METHODS: To predict individual ESRD risk in an average patient in the United States, ESRD prevalence and levels of uncertainty and conditional risk factors independence were considered by population data (1998) and pooled analysis of 11 randomized trials. Data integration and input were by decision-tree simulation approach (simple, parallel, and sequential scenarios) and Bayes' theorem. Sensitivity analysis and risk profiles were employed to address uncertainty and assess different risk factor combinations. A health state values, associated with ESRD outcome levels, were taken from the literature. RESULTS: In this theoretical study, we provided a scholarly example about the use of two known risk factors (urinary protein >/=3 g/day and systolic blood pressure >/=140 mm Hg) to predict individual ESRD risk in an average patient in the United States. The highest posterior (decisional) probability of ESRD occurrence (risk of 3.61% to 5.07%) in the individual patient was associated with the worst health state, as assessed by multidimensional scenarios when both risk factors were present. CONCLUSION: Decision tree models through an empirical Bayesian approach may serve to predict the individual ESRD risk on the basis of simple epidemiologic, demographic, and clinical information that is easily available already at the first patient evaluation.

Algorithms↗