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G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 181 records · Page 10Linked to original sources
PubMed1997

Sequential monitoring of urine-soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction.

BACKGROUND: The significance of noninvasive techniques to the early diagnosis of acute rejection in kidney transplants remains elusive. In this study, we examined whether an early posttransplant increase in serum- and urine-soluble interleukin (IL) 2 receptor (sIL-2R) and IL-6 levels predicted acute rejection. METHODS: Sequential determinations of serum and urine sIL-2R and IL-6 were performed in the first 30 postoperative days in 40 renal transplant patients. Changes during the posttransplant period observed in 26 patients who had one or more episodes of acute rejection (group A) were compared with those recorded in 14 patients who did not experience acute rejection of their graft (group B). RESULTS: Serum sIL-2R was higher than normal in patients of groups A and B without statistical differences between the two groups. In the first 3 days after transplantation, urinary sIL-2R was higher than normal in group A but not in group B. Urinary sIL-2R at days 2 and 3 was significantly higher (P<0.05) in group A than in group B. In the first 5 days after transplantation, urinary IL-6 was persistently higher than normal in group A, whereas it progressively decreased to normal value on day 4 in group B. Sudden increases (doubling within 24 hr) in urine IL-6 preceded clinical diagnosis of acute rejection by a mean period of 2 days, with an 87% sensitivity and a 64% specificity, and also predicted recurrent rejection episodes. CONCLUSIONS: Sequential monitoring of urinary sIL-2R and IL-6 levels does allow very early diagnosis of rejection without invasive procedures. Specifically, high urinary sIL-2R in the first 5 posttransplant days identifies the subgroup of patients at risk. In the subsequent days, a sudden increase in urinary IL-6 occurs in those of the above patients who will indeed reject their graft.

Acute Disease↗
PubMed1997

Acquired transplant tolerance.

Increasing the acceptance rate of organs is the central goal of transplantation research. Long-term survival of vascularized organs without chronic immunosuppressive therapy has been achieved in experimental animals. In humans, the possibility of achieving immunological tolerance and a drug-free state has been reported occasionally in patients who after withdrawal of immunosuppressants because of major toxicity still carry a functioning graft. It has been proposed that organ transplant implies a migratory flux of donor 'passenger' leukocytes out of the graft into the recipient tissue or organs, to establish a persistent condition of 'microchimerism'. Although there is evidence that the same migratory mechanisms apply to all organ grafts, migration of 'passenger' leukocytes is less in kidney and heart than in liver. To enhance the acceptance of organs less tolerogenic than liver, perioperative infusion of donor bone marrow has been attempted to increase the donor 'passenger' leukocyte load. It has been suggested that the established microchimerism is not only associated with long-term acceptance of the graft, but it also plays an active role in induction and maintenance of donor-specific unresponsiveness. However, the intimate mechanism(s) responsible for prolonged graft survival in this setting remain speculative. Experimental evidence is also available that the thymus plays a major role in the development of self-tolerance and is critical in the induction of acquired tolerance to exogenous antigens. It has been reported that after intrathymic injection of donor cells clonal deletion of maturing thymocytes occurs and is the major mechanism in the induction of donor-specific tolerance, since peripheral T-cell component would be devoid of alloreactive population. Studies are warranted in the near future to explore whether the thymus technique can be employed to prolong survival or induce tolerance to allograft in humans. An interesting novel strategy for transplant tolerance is also the oral administration of alloantigens, which has been recently applied to the cardiac transplant model in rat. All these approaches will have a major impact in the near future on transplant medicine, opening new perspectives to obtain indefinite graft survival.

Animals↗
PubMed1997

The renoprotective properties of angiotensin-converting enzyme inhibitors in a chronic model of membranous nephropathy are solely due to the inhibition of angiotensin II: evidence based on comparative studies with a receptor antagonist.

In several models of renal disease progression, angiotensin-converting enzyme (ACE) inhibitors reduced proteinuria and limited glomerulosclerosis, which suggested that reduction of renal angiotensin II (Ang II) activity is crucial for the preservation of glomerular structure and function. However, it cannot be ruled out that other hormonal systems, including inhibition of the bradykinin breakdown, also play a role. We compared the effects of chronic treatment with the ACE inhibitor lisinopril with those of a specific Ang II receptor antagonist, L-158,809, on proteinuria and renal injury in passive Heymann nephritis (PHN), a model of immune renal disease that closely resembles human membranous nephropathy, with long-lasting proteinuria followed by tubulointerstitial damage and glomerulosclerosis. Passive Heymann nephritis was induced with 0.5 mL/100 g of rabbit anti-Fx1A antibody in 24 male Sprague-Dawley rats. The animals were divided into three groups of eight rats each, and were given the following in the drinking water on a daily basis: lisinopril (40 mg/L), L-158,809 (50 mg/L), or no therapy. Treatment started at day 7 (proteinuria was already present) and lasted 12 months. Eight normal rats were used as controls. Untreated PHN rats developed hypertension, while rats with PHN given lisinopril or L-158,809 all had systolic blood pressure values even lower than those of normal rats. Urinary protein excretion progressively increased with time in untreated PHN rats, who developed tubulointerstitial damage and glomerulosclerosis. Both lisinopril and L-158,809 exhibited a potent antiproteinuric effect and preserved glomerular and tubular structural integrity at a similar extent. Renal gene expression of transforming growth factor-beta and extracellular matrix proteins was also effectively reduced by the two treatments. These results indicate that ACE inhibitors and Ang II receptor antagonists are equally effective in preventing renal injury in PHN and suggest that the renoprotective effects of ACE inhibitors in this model are solely due to inhibition of Ang II.

Angiotensin II↗
PubMed1997

Understanding the nature of renal disease progression.

Animal and human proteinuric glomerulopathies evolve to terminal renal failure by a process leading to progressive parenchymal damage, which appears to be relatively independent of the initial insult. Despite the fact that the mechanism(s) leading to renal disease progression has been only partially clarified, several studies have found that the amount of urinary proteins (taken to reflect the degree of protein trafficking through the glomerular capillary) correlated with the tendency of a given disease to progress more than the underlying renal pathology. On the other hand, dietary protein restriction and ACE inhibitors were capable of limiting the progressive decline in GFR to the extent that they could effectively lower the urinary protein excretion rate. A constant feature of proteinuric nephritis is also the concomitant presence of tubulointerstitial inflammation. So far it was not clear if this is a reaction to the ischemic obliteration of peritubular capillaries that follows glomerular obsolescence or whether albumin and other proteins that accumulated in the urinary space are indeed instrumental for the formation of the interstitial inflammatory reaction. In recent years several studies have convincingly documented that excessive and sustained protein trafficking could have an intrinsic renal toxicity. Here we have reviewed the abundant evidence in the literature that the process of reabsorption of filtered proteins activates the proximal tubular epithelium. Biochemical events associated with tubular cell activation in response to protein stress include up-regulation of inflammatory and vasoactive genes such as MCP-1 and endothelins. The corresponding molecules formed in an excessive amount by renal tubuli are secreted toward the basolateral compartment of the cell and give rise to an inflammatory reaction that in most forms of glomerulonephritis consistently precede renal scarring.

Disease Progression↗
PubMed1997

Mycophenolate mofetil limits renal damage and prolongs life in murine lupus autoimmune disease.

Classical immunosuppressants like cyclophosphamide give excellent results in human lupus nephritis. However, they augment malignancies and viral infections. Here we investigated the effect of the new immunosuppressant agent, mycophenolate mofetil (MMF), in New Zealand Black x New Zealand White (NZBxW) F1 hybrid mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans. MMF has a selective antiproliferative effect on T- and B-lymphocytes, inhibits antibody formation and blocks the glycosylation of lymphocyte glycoproteins involved in the adhesion of leukocytes to endothelial cells. Two groups of NZBxW mice were used: group 1 (N = 20) given daily MMF (60 mg/kg p.o.) and group 2 (N = 15) given daily vehicle alone. Treatment started at three months of age and lasted until the death of the animals. Results showed that percentage of proteinuric mice was significantly reduced by MMF treatment and serum BUN levels were also lower than vehicle. MMF had a suppressive effect on autoantibody production and protected animals from leukopenia and anemia. Life survival of MMF treated lupus mice was significantly improved in respect to untreated animals. Thus, MMF delayed renal function deterioration and prolonged life survival in murine lupus nephritis. MMF has been already recognized as reasonably well tolerated in renal transplant patients and despite its gastrointestinal toxicity its overall safety profile appears superior to azathioprine. Human studies are needed to establish whether MMF may function as a steroid-sparing drug in lupus nephritis.

Animals↗
PubMed1997

Renal and systemic nitric oxide synthesis in rats with renal mass reduction.

In rats undergoing renal mass reduction (RMR) oral supplementation with the nitric oxide (NO) precursor L-arginine increases glomerular filtration rate and ameliorates signs of glomerular injury, suggesting that chronic renal failure in the rats is a condition of low NO formation in the kidney. On the contrary, data are available that in the systemic circulation of uremics, both rats and human beings, NO is formed in excessive amounts and may contribute to platelet dysfunction and bleeding tendency, well-known complications of uremia. The present study was designed to clarify the pathophysiology of renal and systemic NO synthesis in uremia. We showed that renal ex vivo NO generation, measured as the conversion of [3H] L-arginine to [3H] L-citrulline, was lower than normal in RMR rats, seven days after surgery, and progressively worsened with time in close correlation with signs of renal injury. Consistent with these results, urinary excretion of the stable NO metabolites, NO2-/NO3-, significantly decreased in rats with RMR. To go deeper into the cellular origin and biochemical nature of this abnormality we used two histochemical approaches that could locate either NO synthase (NOS) catalytic activity (NADPH-diaphorase) or NOS isoenzyme expression (immunoperoxidase). NADPH-diaphorase documented a progressive loss of renal NOS activity in RMR rats that co-localized with a strong progressive decrease of inducible NOS isoenzyme (iNOS) immunostaining. At variance with iNOS, endothelial cell NOS (ecNOS) staining was rather comparable in RMR and control kidneys. At variance to the kidney, in the systemic circulation of RMR rats the synthesis of NO increased as reflected by higher than normal plasma NO2-/NO3- concentrations. High systemic NO likely derives from vessels as documented by the increased NOS activity and higher expression of both iNOS and ecNOS in the aorta of RMR rats. Up-regulation of systemic NO synthesis might be an early defense mechanism against hypertension of uremia. On the other hand, more NO available to circulating cells may sustain the bleeding tendency, a well-known complication of uremia.

Animals↗
PubMed1997

The diagnosis of renal involvement in non-insulin-dependent diabetes mellitus.

Efforts aimed at early detection and effective treatment and prevention of renal involvement in non-insulin-dependent diabetes mellitus are needed to limit the increasing social burdens of end-stage renal disease and related complications. Microalbuminuria seems to meet all the criteria required for screening of early renal disease (incipient nephropathy) and detection of patients at increased cardiovascular risk. Histologic examination is needed to ensure diagnosis of overt diabetic nephropathy in patients with macroalbuminuric non-insulin-dependent diabetes mellitus without retinopathy. Regular screening for micro- and macroalbuminuria ensures that renal and extrarenal complications may be identified early and that preventive intervention therapy is instituted, including good metabolic control and raised blood pressure correction. Preliminary evidence suggests that this is a very cost-effective use of health-care resources.

Albuminuria↗
PubMed1997

Angiotensin-converting enzyme inhibitor therapy for non-diabetic progressive renal disease.

Chronic renal disease evolves to end-stage renal failure through events, including enhanced intraglomerular pressure and plasma protein ultrafiltration, mediated at least in part by angiotensin II. Angiotensin-converting enzyme inhibitors reduce intracapillary pressure and ameliorate glomerular size-selective function, which may account for their antiproteinuric effect and renoprotective potential. Thus, the Ramipril Efficacy in Nephropathy study found a significant correlation between enhanced urinary protein excretion and faster disease progression in non-diabetic patients with proteinuric chronic renal disease. In proteinuric non-diabetic renal disease at comparable levels of blood pressure control, angiotensin-converting enzyme inhibitors reduce proteinuria and slow disease progression to end-stage renal failure safely and more effectively than non-angiotensin-converting enzyme therapy. On the contrary, most non-proteinuric chronic renal diseases progress slowly and do not benefit specifically from angiotensin-converting enzyme inhibition therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Recent developments in the management of membranous nephropathy.

Idiopathic membranous nephropathy is one of the most commonly encountered forms of nephrotic syndrome in adults. The natural history of the disease, observed in a small sample of untreated patients, reveals that a large proportion of patients experience spontaneous remission, whereas approximately one third of them progress towards renal insufficiency, and thus require dialysis. Hence, several attempts to treat this condition have been investigated and several protocols, based on different combinations of corticosteroids and/or immunosuppressive agents, have been proposed. However, none of these protocols has been uniformly adopted by renal physicians, either because of no or limited efficacy of most of them, or due to the potential of short- and long-term untoward effects. In this review, we examine the available data on the natural course of the disease and the possibility of identifying clinical and laboratory characteristics that could help to predict the course of membranous nephropathy. We also summarise the results of the most relevant clinical trials, and offer an updated meta-analysis of treatment studies, including the latest data on cyclosporin.

Journal Article↗
PubMed1997

Prediction of cyclosporine area under the curve using a three-point sampling strategy after Neoral administration.

Accurate monitoring of cyclosporine (CsA) dosage is still a problem, because measurement of the area under the curve (AUC)--the most appropriate indicator of exposure to CsA--requires a number of blood samples to be taken over 12 h, which makes monitoring difficult in day-to-day clinical practice. This study investigated whether a limited sampling strategy in human kidney transplantation reflected the actual AUC better in patients given Neoral than in those being treated with Sandimmune. Stepwise multiple regression analysis of CsA blood levels recorded after Neoral administration to 20 renal transplant patients showed the best results in AUC prediction with three sampling points (1.5, 8, 11 h after Neoral dosing; r = 0.992 with an associated error in AUC prediction ranging from -8.0 to 8.8%). Because blood sampling at 8 and 11 h is not feasible in routine clinical practice, sample points from 0 to 3 h after Neoral dosing, i.e., up to the time of maximum mean blood CsA concentration plus 2 SD, were considered. The best results were obtained with a three-point strategy (0, 1, and 3 h after Neoral dosing; error in prediction: -9.0 to 7.2%), which gave an excellent correlation between measured and predicted AUC (r = 0.989). A similar analysis after Sandimmune given to the same patients always resulted in poor AUC prediction with a wide associated error. These findings indicate that with Neoral, but not Sandimmune, a limited strategy of three-point sampling taken early after dosing allows an excellent and perfectly reliable prediction of the actual AUC.

Ambulatory Care↗
PubMed1997

Renal expression of monocyte chemoattractant protein-1 in lupus autoimmune mice.

Mononuclear cell infiltration in glomeruli and renal interstitium is a prominent feature of some types of glomerulonephritis, including lupus nephritis. The mechanism(s) underlying monocyte influx into the kidney is not fully understood. Recently, monocyte chemoattractant protein-1 (MCP-1) has been identified as a chemotactic factor involved in the recruitment of monocytes/macrophages in the glomeruli of rats with mesangioproliferative as well as anti-glomerular basement membrane glomerulonephritis. In the study presented here, renal MCP-1 mRNA expression in New Zealand Black x New Zealand White (NZB/W) F1 mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans, was investigated. Northern blot analysis revealed a single 0.7 kb MCP-1 transcript of very low intensity in kidneys from 2-month-old NZB/W mice that had not yet developed proteinuria nor renal damage. Message levels, which increased markedly with the progression of nephritis and in association with mononuclear cell infiltration, were 10- and 15- fold higher in 8-10-month-old mice than in 2-month-old mice. By in situ hybridization, increased expression of MCP-1 mRNA was demonstrated in glomeruli and, even more striking, in tubular epithelial cells. Western blot analysis demonstrated increased expression of MCP-1 protein in kidneys of 10-month-old NZB/W mice, consistent with MCP-1 mRNA data. When NZB/W mice were treated with cyclophosphamide up to 12 months of age, expression of MCP-1 in the renal tissue remained low, the influx of inflammatory cells did not appear, and glomerular and tubular structures remained well preserved. These data suggest that elevated MCP-1 might act as a signal for inflammatory cells to infiltrate the kidney in lupus nephritis.

Animals↗
PubMed1997

Platelet-activating factor mediates angiotensin II-induced proteinuria in isolated perfused rat kidney.

Isolated kidney preparations (IPK) from male Sprague Dawley rats perfused at constant pressure were used to evaluate the effect of angiotensin II (AII) and platelet-activating factor (PAF) on renal function and urinary protein excretion. Compared with basal, intrarenal infusion of AII at 8 ng/min caused a progressive increase in protein excretion (11 +/- 6 versus 73 +/- 21 micrograms/min) in parallel with a decline in renal perfusate flow (RPF) (29 +/- 3 versus 18 +/- 3 ml/min). Addition to the perfusate of PAF at 50 nM final concentration also induced proteinuria (9 +/- 4 versus 55 +/- 14 micrograms/min) but did not change RPF (29 +/- 3 versus 30 +/- 3 ml/min). Preexposure of isolated kidneys to the PAF receptor antagonist WEB 2086 prevented the increase in urinary protein excretion induced by AII infusion (basal: 13 +/- 6; post-AII: 12 +/- 7 micrograms/min) but failed to prevent the vasoactive effect of AII (RPF, basal: 30 +/- 2; post-AII: 21 +/- 3 ml/min). In additional experiments, dexamethasone reduced the proteinuric effect of PAF remarkably. These results indicate that in isolated kidney preparation: (1) AII infusion induced proteinuria and decreased RPF; and (2) the effect of AII in enhancing urinary protein excretion was completely prevented by a specific PAF receptor antagonist, which, however, did not influence the AII-induced fall in RPF. It is suggested that PAF plays a major role in AII-induced changes in the permselective function of the glomerular capillary barrier.

Angiotensin II↗
PubMed1997

Prevention of transplant rejection: current treatment guidelines and future developments.

In the past 2 decades, progressive improvements in the results of organ transplantation as a therapeutic strategy for patients with end-stage organ disease have been achieved due to greater insight into the immunobiology of graft rejection and better measures for surgical and medical management. It is now known that T cells play a central role in the specific immune response of acute allograft rejection. Strategies to prevent T cell activation or effector function are thus all potentially useful for immunosuppression. Standard immunosuppressive therapy in renal transplantation consists of baseline therapy to prevent rejection and short courses of high-dose corticosteroids or monoclonal or polyclonal antibodies as treatment of ongoing rejection episodes. Triple-drug therapy with the combination of cyclosporin, corticosteroids and azathioprine is now the most frequently used immunosuppressive drug regimen in cadaveric kidney recipients. The continuing search for more selective and specific agents has become, in the past decade, one of the priorities for transplant medicine. Some of these compounds are now entering routine clinical practice: among them are tacrolimus (which has a mechanism of action similar to that of cyclosporin), mycophenolate mofetil and mizoribine (which selectively inhibit the enzyme inosine monophosphate dehydrogenase, the rate-limiting enzyme for de novo purine synthesis during cell division), and sirolimus (rapamycin) [which acts on and inhibits kinase homologues required for cell-cycle progression in response to growth factors, like interleukin-2 (IL-2)]. Other new pharmacological strategies and innovative approaches to organ transplantation are also under development. Application of this technology will offer enormous potential not only for the investigation of mechanisms and mediators of graft rejection but also for therapeutic intervention.

Animals↗
PubMed1997

Pharmacokinetics of candesartan cilexetil in patients with renal or hepatic impairment.

Five clinical studies were conducted to investigate the pharmacokinetic profile and safety of candesartan cilexetil in patients with either normal or impaired renal or hepatic function. Participants in these open-label, single- or parallel-group prospective studies were administered candesartan cilexetil 8 or 12 mg as a single oral dose and then, in all but one study, as a repeated once-daily oral dose regimen. A total of 94 patients of either gender aged between 18 and 75 years with normal or mild to moderate hepatic dysfunction (Study 1) and normal or mild to moderate/severe renal dysfunction (Studies 2-5) were included. Subjects recruited to all studies evaluating the effect of renal impairment also had some degree of hypertension. Patients with mild to moderate hepatic impairment showed no significant differences in the key plasma pharmacokinetic parameters or plasma protein binding profile of candesartan compared with healthy volunteers. In patients with mild to moderate or severe renal impairment there were significant increases in the maximum plasma concentration, area under the plasma drug concentration-time curve and elimination half-life of candesartan and its inactive metabolite (CV-15959) when compared to volunteers with normal renal function following repeated administration of candesartan cilexetil 8 or 12 mg. However, there was no evidence of accumulation following treatment with the 8 mg dose apart from those with severe disease requiring dialysis. Nevertheless, dialysis itself did not appear to affect the pharmacokinetic profile of candesartan or that of CV-15959. Candesartan cilexetil was found to have a good safety profile and to be well tolerated by patients with hepatic or renal impairment. There were no clinically relevant changes detected in vital signs, laboratory safety parameters or in ECG readings. The most common adverse events were headache and dizziness. This series of studies show that candesartan cilexetil 8 mg once daily is suitable for administration to patients with mild to moderate renal or hepatic impairment with no need for additional dose adjustment. A lower starting dose may be appropriate in patients with severe renal impairment including those requiring dialysis.

Adolescent↗