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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 19 recordsLinked to original sources
PubMed2006

Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome.

Several mutations in the CFH gene have been described in non-Shiga-toxin-associated haemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by haemolytic anaemia, thrombocytopenia and acute renal failure. Mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (CD46) and complement factor I (CFI), were also involved in the pathogenesis of the disease. Anyway, mutations in the three genes account for no more than 50% of cases of non-Stx-HUS. Human complement factor H related 5 (CFHR5) is a recently characterised member of the human complement factor H (CFH) family that has been found as a component of immune deposits in human kidney with sclerotic lesions from different causes. CFHR5 possesses cofactor activity and has been proposed to play a role in complement regulation in the glomerulus. We screened CFHR5 gene for variations potentially involved in the aetiology of HUS. Forty-five patients with HUS and 80 controls were analysed. Altogether, 5 genetic variants in CFHR5 were found in overall 9/45 HUS patients and in 4/80 controls. Statistical analysis showed that allelic variants in CFHR5 were prefentially associated with HUS. Based on these data, we conclude that, though not causative, CFHR5 genetic alterations may play a secondary role in the pathogenesis of HUS.

Alleles↗
PubMed2006

Meeting report on the Bellagio Conference 'prevention of vascular diseases in the emerging world: An approach to global health equity'.

Representatives from five international organizations (International Society of Nephrology, World Heart Federation, International Diabetes Federation, International Atherosclerosis Federation, and International Society of Hypertension) participated in a strategic planning workshop in December 2005 in Bellagio, Italy sponsored by the Rockefeller Foundation. There were equal representatives from developed and developing countries. Global perspectives on diabetes and cardiovascular and renal diseases were presented, with special emphasis on China, India, Latin America, and Africa. The rationale and effectiveness of preventive measures were discussed. It was apparent that measures for primary prevention and early intervention for all the chronic vascular diseases are similar. The five organizations agreed that an integrated global approach to chronic vascular diseases is needed. They resolved to collaborate and work towards an integrated approach to chronic vascular diseases with the establishment of a 5-year plan for the prevention and treatment of chronic vascular diseases, including public advocacy, advising international and national agencies, and improving education and the practice of established approaches.

Chronic Disease↗
PubMed2006

Ways to boost kidney transplant viability: a real need for the best use of older donors.

Using kidneys from expanded criteria donors (ECD) increased transplant activity but resulted in a reduced graft survival. The relatively poor long-term outcome of ECD grafts may be the consequence of an imbalance between the number of viable nephrons supplied and the metabolic demand of the recipient. Providing more nephrons by dual transplants may improve outcomes but fails, per se, to confer the same benefit of single transplants from young donors. A biopsy-based score system has been presented by a panel of pathologists to assess whether kidneys from donors older than 60 years still contain enough viable nephrons to be made available for transplantation, and whether single or dual transplantation should be used. Allocating kidneys from older donors to a single or dual transplant on the basis of this scoring system allowed achieving a graft survival similar to that of single transplants from ideal donors and remarkably superior to that of single transplants from older donors not evaluated histologically before implantation. Thus, preimplantation histologic evaluation maximizes the success of ECD transplants and protects recipients from receiving organs at increased risk of premature failure. This may limit the number of patients who eventually must resume dialysis and need second transplants.

Adult↗
PubMed2006

Time to abandon microalbuminuria?

The term microalbuminuria--a urinary albumin excretion (UAE) between 20 and 200 microg/min--has been introduced to identify subjects at increased risk of renal and cardiovascular disease. However, the relationship between albuminuria and risk is not restricted to the microalbuminuric range and extends to as low as 2-5 microg/min. On the contrary, the increase of UAE above 200 microg/min (macroalbuminuria) heralds the onset of proteinuria (urinary protein excretion above 0.5 g/24 h) and progressive renal and cardiovascular disease. Albuminuria is a component of the metabolic syndrome and may represent a marker of the increased risk of renal and cardiovascular disease associated with insulin resistance and endothelial dysfunction. Proteinuria is a sign of established kidney damage and plays a direct pathogenic role in the progression of renal and cardiovascular disease. Albuminuria reflects functional and potentially reversible abnormalities initiated by glomerular hyperfiltration, proteinuria, a size-selective dysfunction of the glomerular barrier normally associated with glomerular filtration rate (GFR) decline that may result in end-stage renal disease. Thus, the limit of 200 microg/min segregates patients with albuminuria or proteinuria who are at quite different risk. Among subjects with albuminuria, however, there is a continuous relationship between albumin excretion and risk and no lower bound between normal albuminuria and microalbuminuria can be identified that segregates subjects at different risk. Thus, the terms microalbuminuria and macroalbuminuria could be replaced by the concepts of albuminuria- and proteinuria-associated diseases. Future studies are needed to identify levels of albuminuria below which therapy is no longer beneficial.

Albuminuria↗
PubMed2006

A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders.

The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.

Animals↗
PubMed2006

Imatinib ameliorates renal disease and survival in murine lupus autoimmune disease.

Platelet-derived growth factor (PDGF) has been proved to play an important role in progressive glomerular disease of systemic lupus. The present study investigated the tyrosine kinase inhibitor of PDGF receptor, imatinib, as a novel therapeutic approach for the cure of lupus nephritis in New Zealand Black/White (NZB/W)F1 hybrid mice with established disease. Two groups of NZB/W mice (N=30 each group), starting at 5 months of age, were given by gavage vehicle or imatinib (50 mg/kg b.i.d). Fifteen mice for each group were used for the survival study. The remaining were killed at 8 months. Imatinib significantly (P=0.0022) ameliorated animal survival with respect to vehicle. The drug significantly delayed the onset of proteinuria (% proteinuric mice, 7 and 8 months: 33 and 47 vs vehicle, 80 and 87, P<0.05) and limited the impairment of renal function. Imatinib protected the kidney against glomerular hypercellularity and deposits, tubulointerstitial damage, and accumulation of F4/80-positive mononuclear cells and alpha-smooth actin-positive myofibroblasts. The abnormal transforming growth factor-beta mRNA expression in kidneys of lupus mice was reduced by imatinib. In conclusion, findings of amelioration of animal survival and renal manifestations in NZB/W lupus mice with established disease by imatinib suggests the possibility to explore whether imatinib may function as steroid-sparing drug in human lupus nephritis.

Actins↗
PubMed2006

ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease.

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar Fromter (MWF) rats, an experimental model for progressive kidney disease, to quantify kidney structural lesions upon angiotensin-converting enzyme (ACE) inhibition therapy. Animals were studied at 50 weeks of age, when renal function and structure are severely altered, and after a 10-week observation period, without or with treatment with lisinopril (80 mg/l in drinking water). A group of untreated Wistar rats was used as controls. With age, proteinuria, and serum creatinine worsen, but lisinopril almost normalized proteinuria and stabilized serum creatinine. Serial section analysis of whole glomerular tufts showed that at baseline, glomerulosclerosis affected the entire glomerular population, and that these changes further increased with age. Lisinopril significantly reduced incidence and extent of glomerulosclerosis, with the presence of glomerular tufts not affected by sclerosis (23% of glomeruli). Glomerular volume was not significantly affected by treatment, and glomerular mass spared from sclerosis increased from 46.9 to 65.5% upon treatment, indicating consistent regeneration of glomerular tissue. Lisinopril normalized baseline glomerular transforming growth factor-beta and alpha-smooth muscle actin overexpression, and prevented worsening of interstitial changes. Hence, ACE inhibition, which is widely used in human kidney disease, may not only halt the progression of renal failure, but also actually induce the regeneration of new renal tissue.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Renal risk and renoprotection among ethnic groups with type 2 diabetic nephropathy: a post hoc analysis of RENAAL.

Type 2 diabetes is becoming the leading cause of end-stage renal disease (ESRD) worldwide. Prevalence of ESRD and the antihypertensive response to renin-angiotensin system intervention are suggested to vary among different ethnicities. The Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study, which included different ethnic groups, demonstrated a renoprotective effect of losartan. A post hoc analysis from RENAAL was performed where we examined in each ethnic group the ESRD risk, identified independent predictors for ESRD, effect of degree of baseline albuminuria, effect of 6-month antiproteinuric response to therapy on ESRD, and renoprotective effect of losartan assessed by albuminuria reduction and ESRD. Baseline albuminuria was the strongest predictor for ESRD in every ethnic group. Albuminuria reduction was associated with reduced risk of ESRD while losartan reduced albuminuria in every ethnic group. When accounting for independent predictors of ESRD, losartan exhibited renoprotection in all ethnic groups. In this type 2 diabetic population with nephropathy, baseline albuminuria is the predominant risk parameter for ESRD; early antiproteinuric effect of losartan predicts long-term renoprotection; and losartan appears to be renoprotective in all ethnic groups. Since the RENAAL study was not powered to determine ethnic responses, these results underline the need for prospective trials where the aim is renal protection among different ethnic groups.

Albuminuria↗
PubMed2006

Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective.

We described the characteristics in a referred cohort of type II diabetic patients in the Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes study evaluating the global prevalence and determinants of microalbuminuria (MA). A cross-sectional study evaluating 32,208 type II diabetic patients without known albuminuria from 33 countries was performed. Overall, 8057 patients were excluded, either because of prior known proteinuria or non-diabetic nephropathy (3670), or because of invalid urine collections (4387). One single random urinary albumin/creatinine ratio was obtained in 24,151 patients (75%). The overall global prevalence of normo-, micro-, and macroalbuminuria was 51, 39, and 10%, respectively. The Asian and Hispanic patients had the highest prevalence of a raised urinary albumin/creatinine ratio (55%) and Caucasians the lowest (40.6), P<0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P<0.0001. Estimated glomerular filtration rate was below 60 ml/min/1.73 m(2) in 22% of the 11,573 patients with available data. Systolic BP below 130 mmHg was found in 33 and 43% had an HbA1c below 7%. The frequency of patients receiving aspirin was 32%, statins 29%, and BP-lowering therapy 63%. A high prevalence globally of MA and reduced kidney function, both conditions associated with enhanced renal and cardiovascular risk, was detected in type II diabetic patients without prior known nephropathy. Early detection, monitoring of vascular complications, and more aggressive multifactorial treatment aiming at renal and vascular protection are urgently needed.

Albuminuria↗
PubMed2006

Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF.

It is not known how different steroid-free immunosuppressive combinations affect renal graft survival and long-term kidney transplant function. Here we sought to compare the impact on graft survival and long-term graft function of two tacrolimus (Tac)-based, prednisone-free maintenance immunosuppressive protocols: Tac/Mycophenolate Mofetil (MMF) vs. Tac/Sirolimus (SRL). Renal transplant patients given induction therapy with IL2-RA and methylprednisolone on days 0, 1 and 2 post-transplant were prospectively randomized to two maintenance immunosuppressive regimens with Tac/MMF (n = 45) or Tac/SRL (n = 37). During the 3-year follow-up the following data were collected: patient survival, renal allograft survival, incidence of acute rejection and glomerular filtration rate (GFR) at different time-points post-transplant. Cumulative graft survival was significantly different in the two groups: one kidney loss in the Tac/MMF vs. six kidney losses in the Tac/SRL (log-rank test p = 0.04). GFR at different time-points post-transplant was consistently and statistically better in the Tac/MMF than in the Tac/SRL group. The slope of GFR decline per month was flatter in the Tac/MMF than in the Tac/SRL group. This study showed that renal graft survival and graft function were significantly lower in the combination of Tac/SRL than Tac/MMF.

Acute Disease↗
PubMed2006

Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation.

A male child initially presented with atypical hemolytic uremic syndrome (HUS) at the age of 4 months and progressed within weeks to end stage renal disease (ESRD). At the age of 2 years he received a live-related kidney transplant from his mother, which, despite initial good function, was lost to recurrent disease after 2 weeks. Complement factor H analysis showed low serum levels and the presence of two mutations on different alleles (c.2918G > A, Cys973Tyr and c.3590T > C, Val1197Ala). His survival on dialysis was at risk because of access failure and recurrent bacteremic episodes. Therefore, at the age of 5 years he received a combined liver-kidney transplant with pre-operative plasma exchange. Initial function of both grafts was excellent and this has been maintained for over 2 years. This report suggests that despite setbacks in previous experience, combined liver-kidney transplantation offers the prospect of a favorable long-term outcome for patients with HUS associated with complement factor H mutations.

Child, Preschool↗
PubMed2005

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

Adrenal Cortex Hormones↗
PubMed2005

Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation.

The pharmacokinetics of mycophenolic acid (MPA)--the active metabolite of mycophenolate mofetil (MMF)--is significantly influenced by co-medications. The impact of sirolimus on daily MPA exposure, however, has not been investigated so far. As a part of the study aimed at investigating the efficacy of Campath-1H induction therapy in a steroid-free regimen in kidney transplantation, MPA plasma levels were serially measured in 21 patients treated with low-dose sirolimus (SRL) or low-dose CsA both in addition to low-dose MMF over 12 months post-operatively. Full pharmacokinetic profiles were compared at month 6 and 12 post-surgery. Mean dose-adjusted MPA trough levels were 4.4-fold higher in patients on combined SRL and MMF than in those given CsA and MMF. Pharmacokinetic studies demonstrated that mean MPA C(max) and T(max) were comparable in the two groups, while mean MPA AUC(0-12) was higher in SRL than CsA treated patients. The pharmacokinetic profile of SRL- but not of CsA-group showed a second peak consistent with the enterohepatic recirculation of MPA. These findings suggest that SRL and CsA have different effects on MPA metabolism and/or excretion eventually affecting its immunosuppressive property and/or toxicity. CsA, but not SRL, inhibits MPA enterohepatic recirculation, reducing MPA daily exposure.

Adult↗
PubMed2004

Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of patients, with a rate of spontaneous complete or partial remission of nephrotic syndrome as high as 30% or more. Despite this, 30-40% of patients progress toward end-stage renal failure (ESRF) within 5-15 years. OBJECTIVES: To assess the benefits and harms of immunosuppressive treatment for IMN in adults. SEARCH STRATEGY: We searched the Cochrane Renal Group Specialised Register (December 2003), The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4, 2003), MEDLINE and Pre-MEDLINE (1966 - December 2003), EMBASE (1980 - December 2003), reference lists of nephrology textbooks, review articles, prospective trial registers, relevant trials and abstracts from nephrology scientific meetings and the internet without language restriction. We also contacted principal investigators of controlled studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive interventions for the treatment of IMN in adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed and extracted information. Information was collected on method, participants, interventions and outcomes (death, ESRF, proteinuria, serum creatinine, GRF, remission, adverse events). MAIN RESULTS: A total of 18 trials with 1025 patients were included. No differences were found when we combined data of all treatment categories as a group and compared them with placebo or no treatment. Oral glucocorticoids. No beneficial effect on any of the end points chosen for efficacy was observed. Alkylating agents showed a significant beneficial effect on complete remission (RR 2.37, 95%CI 1.32 to 4.25, P = 0.004) but not on partial remission (RR 1.22, 95%CI 0.63 to 2.35, P = 0.56) or complete or partial remission (RR 1.55, 95%CI 0.72 to 3.34, P = 0.27). Cyclophosphamide treatment resulted in significantly lower rate of discontinuations due to adverse events as compared to chlorambucil (RR 2.34, 95%CI 1.25 to 4.39, P = 0.008). There was no evidence of clinically relevant differences in favour of cyclosporin and there was insufficient data on anti-proliferative agents. REVIEWERS' CONCLUSIONS: This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil.

Adult↗
PubMed2004

Nephrotoxic aspects of cyclosporine.

Over the last 20 years cyclosporine (CsA) has improved the survival of kidney, heart, and liver transplants. However, with increasing use, evidence has accumulated that CsA therapy carries a variety of side effects, the most important being renal toxicity. CsA can lead to a wide spectrum of renal function impairments, including a marked and rapidly reversible decrease in renal hemodynamics (acute CsA nephrotoxicity), and a chronic form of renal damage that potentially progress irreversibly to end-stage renal disease (chronic CsA nephrotoxicity). All these manifestations are the consequence of the drug toxic effects on renal vessels and the tubulointerstitium. A proper diagnosis of CsA toxicity at early stages, the combination of low CsA doses with non-nephrotoxic immunosuppressants, and the development of more feasible strategies to monitor daily CsA exposure may contribute to a better CsA management, improve quality of life of transplant recipients, and prolong graft survival.

Chronic Disease↗
PubMed2004

Methods of cardio-renal protection in non-diabetic chronic nephropathies.

Angiotensin II (AII), the main effector of the Renin Angiotensin System (RAS), plays a central role in the hemodynamic and non-hemodynamic mechanisms of chronic renal disease and is currently the main target of interventions aimed to prevent the onset and progression of chronic nephropathies to end stage renal disease (ESRD). In addition to ameliorate glomerular hyperfiltration and size-selectivity, reduce protein traffic and prevent glomerular and tubulo-interstitial toxicity of ultrafiltered proteins, RAS inhibitors also limit the direct nephrotoxic effects of AII. Thus, both ACE inhibitors (ACEi) and AII antagonists (ATA) exert a specific nephroprotective effect in both experimental and human chronic renal disease. This effect is time-dependent and is observed across degrees of renal insufficiency. Forced ACEi or ATA up-titration above doses recommended to control arterial hypertension and combined treatment with both agents allow to optimise A II inhibition and maximize renoprotection. Multifactorial interventions combining RAS inhibition to treatments targeted also to non-RAS mechanisms may even achieve regression of glomerulosclerosis and chronic tubulo-interstitial injury. Studies are needed to assess whether renal damage can be reverted to such a point that renal function may be fully prevented from worsen, and possibly improve. The economic impact of even a partial improvement would be enormous. Moreover, chronic renal insufficiency is an independent risk factor for cardiovascular disease and effective nephroprotection may also decrease the excess cardiovascular morbidity and mortality associated with chronic nephropathies. In patients with renal insufficiency ACEi are even more cardioprotective than in those without, and are well tolerated. Thus, RAS inhibitor therapy should be offered to all renal patients without specific contraindications, including those closer to renal replacement therapy.

Angiotensin II↗