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Biomedical subjects

E Gotti

Publications and source records attributed to E Gotti.

At least 19 recordsLinked to original sources
PubMed2006

Scedosporium apiospermum soft-tissue infection: a case report and review of kidney transplant literature.

Scedosporium apiospermum is an environmental mould. Human infections caused by this organism have been observed; however, only a few case reports show its role as a telluric contaminant to kidney recipients. We have reported here a case of a dramatic soft tissue infection by S. apiospermum in a kidney-transplanted man. Surgical drainage together with voriconazole systemic therapy was successful.

Antifungal Agents↗
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↗
PubMed2001

Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients.

BACKGROUND: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is now routinely used as immunosuppressant in solid organ transplantation in a fixed daily dose regimen (2 g/d) in association with cyclosporine (CsA) and steroids. However, no correlation has been shown between fixed MMF dose and clinical outcome. METHODS: Here we examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring in 46 stable kidney transplant recipients. MPA plasma concentration profiles were measured by a reverse-phase high-performance liquid chromatography method 6-9 months after transplantation and related with routine laboratory analysis tests. Since MPA is extensively bound to serum albumin and only the free fraction is pharmacologically active, in a subgroup of 23 patients free plasma MPA was also determined. RESULTS: Despite a comparable MMF dose, a large interindividual variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.1-99.8 microg/mL. h) and in trough levels (range 0.24-7.04 microg/mL) was found. Patients with AUC >40 microg/mL. h showed a better (p<0.05) renal function than patients with lower AUC (creatinine clearance 85.7+/-23.2 versus 64.5+/-17.5 mL/min), despite no difference in CsA dose, CsA AUC and blood CsA trough level. The percentage of free plasma MPA but not total MPA correlated with the red blood cell and leukocyte count. CONCLUSIONS: Therapeutic MMF drug monitoring might contribute to a better management of kidney transplant recipient with the goal of optimizing drug dosing and limiting the risk of MMF-related toxicity.

Adult↗
PubMed2000

Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study.

BACKGROUND: Organ transplant recipients are at an increased risk of nonmelanoma skin cancer. Few data concern heart transplantation and populations from southern Europe. METHODS: A total of 1,329 patients who received their first kidney (1,062 subjects) or heart allograft (267 subjects) were included in a partly retrospective cohort study to evaluate the risk of skin cancer. The incidence rate per 1,000 person-years and the cumulative incidence were computed. Standardized morbidity ratio was estimated by comparison with Italian cancer registry data. To analyze the role of potential prognostic factors, Cox's regression method was used. RESULTS: The overall incidence rate of nonmelanoma skin cancer was 10.0 cases per 1,000 posttransplant person-years (95% confidence interval 8.2-11.7). This estimate was far higher than expected in the general population. The overall risk of developing skin cancer increased from a cumulative incidence of 5.8% after 5 posttransplant years to an incidence of 10.8% after 10 years of graft survival. In a Cox proportional hazard risk model, the most important factors that appeared to favor the development of skin cancer were age at transplantation and sex. After adjustment for age at transplantation and sex, no definite increased risk was documented among heart as compared with kindney transplant recipients. CONCLUSIONS: Our study confirms the increased risk of nonmelanoma skin cancer among organ transplant recipients in a southern European population.

Basal Cell Carcinoma↗
PubMed2000

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.

BACKGROUND: Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. METHODS: We studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. RESULTS: All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. CONCLUSIONS: Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Adolescent↗
PubMed2000

Recurrence after first cerebral infarction in young adults.

OBJECTIVE: We have investigated recurrence of stroke in a consecutive series of young adults, aged 16 to 45 years, after a first cerebral infarction. METHODS: From January 1, 1988 to December 31, 1996 we submitted those patients to a diagnostic protocol including angiographic, cardiological, and haematological investigations. The patients were followed at 6 month intervals up to December 31, 1998. RESULTS: We have evaluated and followed-up 135 patients, 71 men and 64 women, who were 3.99% of all the admitted stroke patients. At 12 months after stroke, 83 patients had returned to work, 40 patients were mildly to moderately handicapped, 4 were using a wheel-chair, and 8 had died. Follow-up was 26 to 123 months (mean 68.8). Recurrence of stroke, always of ischaemic nature, was seen in 15 patients (11.1%), 3 to 76 months after the first stroke (mean 27.4), for an annual incidence of 2.26%. Recurrence was significantly associated with Partial Anterior Circulation Syndrome and Haematological subtype of first stroke (respectively, P = 0.0209 and P = 0.0135, chi2 test), but not with age (< or = or > 35 years) or risk factors. Repetition of stroke was never fatal, but it caused heavy disability in 13 patients, 8 of whom had completely or nearly completely recovered after the first event. CONCLUSIONS: Our data suggest that recurrence of stroke is a major clinical problem also for the patients aged less than 45 years and that it might be more frequent with specific clinical syndromes and etiologic subtypes of first stroke.

Adolescent↗
PubMed2000

The kidney transplant program at the Bergamo Center.

The kidney transplant program at the Ospedali Riuniti of Bergamo, Italy was established in 1989. Since its inception, 367 patients have been transplanted, including 357 kidney transplants from cadaveric donors and 10 from living-related donors. Overall 8-year patient and graft survival rates were 94% and 77%, respectively. By 1995 our unit co-ordinated the activity of the Department of Immunology and Clinics of Organ Transplantation, Ospedali Riuniti--Mario Negri Institute for Pharmacological Research, Bergamo. The dual "marginal" kidney transplant program in the same recipient was launched in August 1997, as a part of an international cooperative network which established the "Double Kidney Transplant Group" (DKG). To date, 19 dual kidney transplants have been successfully performed in our center. Four combined heart-kidney transplants and 2 combined liver-kidney transplants have also been performed. During the past 4 years several studies involving conventional antirejection drugs were carried out, particularly focussing our attention on cyclosporine (CsA) through pharmacokinetic and pharmacodynamic approaches: 1) a simplified method to evaluate daily exposure to CsA has been set up; 2) the monitoring of calcineurin activity in whole blood samples was evaluated as a way to optimize CsA dosing. As for the new immunosuppressants, studies are ongoing with mycophenolate mofetil (MMF). We are co-ordinating a prospective multicenter randomized trial of steroid sparing in kidney transplant recipients given MMF or azathioprine as a part of their immunosuppression therapy (MY.S.S. study). This involves 9 Italian transplant centers and 2 European centers. Up to now 325 patients have been randomized. Moreover we have set up an HPLC method for measuring plasma mycophenolic acid (MPA), and examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring. Further studies have been addressed to chronic allograft nephropathy. The nature and mediators of renal lesions in kidney transplant patients given CsA have been explored taking into account the gene expression of endothelin-1, RANTES and MCP-1 in graft specimens from patients who had evidence of CsA nephrotoxicity, chronic rejection, or no lesions at histological examination. The impact of percutaneous transluminal angioplasty and stenting of posttransplant renal artery stenosis on renal function recovery was also recently examined. From this study we conclude that the procedure is safe and effective to normalize the functional changes sustained by hemodynamically significant artery stenosis. Moreover, Doppler ultrasound scanning is an useful, reliable, non-invasive tool to monitor the renal function response to artery revascularization. Thanks to the long-lasting co-operation with the Negri Bergamo Laboratories, we had in the past and still have an active program in experimental animals to investigate strategies for transplant tolerance and transplant gene therapy, besides addressing some issues related to the immunological barrier of xenotransplantation.

Academic Medical Centers↗
PubMed1999

Nature and mediators of renal lesions in kidney transplant patients given cyclosporine for more than one year.

BACKGROUND: Cyclosporine (CSA) has improved patients and organ-graft survival rates, but its chronic nephrotoxicity is still an issue. Although prolonged vasoconstriction could contribute to chronic CsA tubulointerstitial changes by producing chronic ischemia, this relationship has been difficult to demonstrate thus far, and cellular origin and mediators of these structural alterations remain ill-defined. METHODS: As a part of a clinical trial in kidney transplant recipients on triple immunosuppressive therapy (CsA, azathioprine and steroid), which includes renal biopsy as "per protocol," 22 patients enrolled between 12 and 24 months posttransplantation underwent renal hemodynamic evaluation by measuring glomerular filtration rate and renal plasma flow by the plasma clearance of unlabeled iohexol and the renal clearance of para-aminohippuric acid, respectively. In parallel, the CsA pharmacokinetic profile was also determined. A week later, a protocol biopsy of kidney graft was performed. Light microscopy examination and localization of endothelin-1, RANTES, monocyte chemoattractant protein-1 gene expression by in situ hybridization in the graft specimens were evaluated and related to the pattern of histologic lesions. RESULTS: Ten out of 22 kidney transplant recipients who underwent the protocol biopsy had CsA nephrotoxicity, eight had chronic rejection, and four had no lesions at histological examination. The total daily exposure to CsA was higher in patients with CsA nephrotoxicity than in those with chronic rejection or no lesions at biopsy. Renal function was preserved in the CsA toxicity group as compared with the chronic rejection group, despite some degree of renal hypoperfusion. Tubular atrophy and striped interstitial fibrosis were found in all patients with light microscopical evidence of CsA nephrotoxicity, whereas glomerular and arteriolar lesions were less frequent. Intense staining for endothelin-1, RANTES, and monocyte chemoattractant protein-1 mRNAs selectively localized at tubular epithelial cells was found in biopsies taken from patients with CsA nephrotoxicity, but not in the chronic graft rejection group, whose tubuli had only minimal staining for RANTES mRNA on a few occasions. CONCLUSION: Long-term CsA administration to kidney allograft recipients leads to tubulointerstitial injury independently of its vascular effect. The possible contribution to the development of interstitial fibrosis of inflammatory and growth factors released by tubular cells in which CsA accumulates is proposed.

Adult↗
PubMed1998

Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.

In lupus nephritis (LN), renal thromboxane A2 (TXA2) production is increased, and inhibition of TXA2 activity improves renal function. In patients with LN, renal function depends very much on vasodilatory prostaglandins, and indeed inhibiting the prostaglandin-forming enzyme cyclooxygenase (COX) with aspirin or related compounds was detrimental on renal hemodynamics in these patients. There are no data so far on whether the excessive TXA2 production in LN derives from upregulation of type I or type II isoforms of COX. It was found that TXB2 synthesis and COX-2 gene expression were higher in peripheral blood mononuclear cells from patients with active LN compared to patients in the inactive form of the disease and to healthy subjects. Unlike COX-2, levels of COX-1 mRNA were comparable in lupus patients and control subjects and were not influenced by the disease activity. Immunoperoxidase studies on kidney biopsies showed COX-1 staining in glomerular arterioles and other renal vessels, with no evident difference between lupus biopsies and control specimens taken from either individuals who were free of renal disease or patients with non-lupus nephropathies. In contrast, COX-2 staining was definitely stronger in specimens from patients with active LN than control specimens. In active LN, COX-2-specific staining was localized mainly in the glomeruli, with a weaker signal on tubuli and in the interstitium. Double-staining studies with an antibody against the macrophage marker CD68 and an anti-COX-2 antibody definitely showed that COX-2 and CD68 often colocalized on the same cell, with only occasional glomerular COX-2-stained mesangial areas. Patients with non-lupus nephropathies had no increase in renal COX-2 expression. These results indicate that COX-2 upregulation is a specific finding of active LN and that monocytes infiltrating the glomeruli contribute to the exaggerated local synthesis of TXA2. If this is correct, COX-2 may soon become a target for therapeutic intervention in this disease.

Adult↗
PubMed1998

How to convert from traditional cyclosporine to the microemulsion formulation in stable renal transplant patients?

How to convert from traditional cyclosporine (CsA) to the microemulsion formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of changeover from traditional Sandimmune to Neoral formulation at two dose-ratio conversions on CsA pharmacokinetics, safety and tolerability particularly in terms of renal function. Thirty outpatients regularly followed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a comparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR and RPF) before, at day 15, and at month 6 after conversion to Neoral formulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA concentration (Tmax), and a greater bioavailability, as shown by an increase in the peak CsA concentration (Cmax) and the 12-h exposure to drug defined by the area under the time-concentration curve (AUC0-->12 h) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formulation. All of patients defined as 'low' absorbers became 'high' absorbers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conversion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conversion but mostly in those with 1:1 conversion. A limited sampling strategy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral formulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulation results in increased drug exposure that may reduce GFR in some patients who undergo 1:1 dose-ratio conversion. The Neoral formulation that permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and possibly chronic rejections. Efforts have to be made to find optimal therapeutic range and dosing schedule for this new formulation, which may be facilitated by using the limited sampling approach to predict AUC after only three-point sampling.

Administration, Oral↗
PubMed1997

Preparation of Pd/C catalysts via ultrasound: a study of the metal distribution.

Palladium supported on active carbon catalysts was prepared using ultrasound during one of the preparation steps. An investigation of the metal distribution into the pores of the support was performed both by a deep characterization of the prepared samples and by a catalytic reaction involving some organic reactants to be reduced.

Journal Article↗
PubMed1996

A logistic-regression model provides novel guidelines to maximize the anti-acute rejection properties of cyclosporine with a minimum of toxicity.

Although cyclosporine has become the mainstay of immunosuppression in organ transplantation, there is still no consensus on the criteria to optimize its anti-rejection activity with minimum toxicity. A clear and objective definition of target cyclosporine trough levels at different times from renal transplantation is still lacking, primarily because of the lack of a model correlating cyclosporine levels with probability of rejection or toxicity. In this study, logistic-regression model was developed that was applied to data collected retrospectively from two postoperative periods, i.e., Days 0 to 9 and 10 to 30, in 135 consecutive cadaveric renal transplant recipients, for a total of 1851 determinations. Only minimum and maximum trough levels were considered for each period. Concentration-response curves were estimated for Days 0 to 9 (P = 0.0001 for efficacy and P = 0.028 for toxicity) and for Days 10 to 30 (P = 0.015 for efficacy and P = 0.037 for toxicity). Therapeutic intervals of 330 to 430 ng/mL (parent compound in whole blood) for Days 0 to 9 and 260 to 390 ng/mL for Days 10 to 30 predicted an incidence of acute rejection of 22% and 12%, respectively, with a reasonably low toxicity that primarily consisted of elevation of serum aminotransferases.

Adult↗
PubMed1996

Early ganciclovir therapy effectively controls viremia and avoids the need for cytomegalovirus (CMV) prophylaxis in renal transplant patients with cytomegalovirus antigenemia.

Cytomegalovirus (CMV) infection is still a problem for organ transplant recipients despite studies that long-term prophylaxis with high dose of acyclovir or ganciclovir given to all organ recipients may limit the consequences of infection and disease. In the present report of 160 consecutive renal transplant patients, we used a diagnostic assay for CMV antigenemia (detection of CMV antigen in peripheral blood leukocytes) and treated with ganciclovir only those patients who had a positive test. No patient in this series had routine prophylaxis. Out of 160 patients, 71 had clinical and/or laboratory signs of infection, and were tested for early antigen in peripheral leukocytes. The test was positive in 35, all of whom received a course of 3 wk ganciclovir treatment which effectively cured CMV in 34 count of 35. One patient was ganciclovir-resistant, but responded to foscarnet. None of the 36 patients who had no early antigenemia and did not receive treatment developed the disease. The treatment was extremely well tolerated in all our patients with no adverse events. Thus, even though this was not a controlled study, our present results may be taken to indicate that long-term acyclovir or ganciclovir for all organ transplant recipients might be no longer totally justified. We conclude that detecting viral antigen in circulating leukocytes identifies patients who are indeed at risk of developing severe CMV disease. When these patients are treated early enough, CMV is eliminated with a relatively short course of ganciclovir, which has virtually no side effects.

Adolescent↗
PubMed1995

Monocyte chemoattractant protein-1 is excreted in excessive amounts in the urine of patients with lupus nephritis.

BACKGROUND: In patients with lupus nephritis, mononuclear inflammatory cells infiltrate the renal interstitium and glomeruli, and the degree of leukocyte infiltration correlates with the severity of the renal dysfunction. The precise mediator signaling inflammatory cells to migrate into the kidney is not known. Recent findings that monocyte chemoattractant protein-1 (MCP-1), a chemotactic cytokine with a high degree of specificity for lymphocytes and monocytes, is overexpressed in glomeruli from rats with immunecomplex glomerulonephritis prompted us to explore the possibility that MCP-1 could be implicated in the renal inflammatory response of lupus erythematosus. EXPERIMENTAL DESIGN: Serum and urine levels of MCP-1 were evaluated in 10 patients with active lupus nephritis. Patients were studied at admission, before therapy, and at various time points after the first administration of high dose methylprednisolone. There was an additional observation of the four patients who underwent remission of clinical signs of the disease after chronic steroid treatment. Three additional groups, one (n = 9) of patients with inactive lupus nephritis, one (n = 9) of patients with nonlupus glomerulonephritis and high degree proteinuria, and one (n = 10) of healthy subjects, were also studied. RESULTS: In patients with active lupus nephritis, urinary MCP-1 was significantly higher than in lupus patients studied in the inactive phase of the disease or in healthy volunteers. High doses of i.v. methylprednisolone significantly lowered urinary MCP-1 in patients with active lupus nephritis. In patients undergoing remission of lupus nephritis after chronic steroid treatment, urinary MCP-1 did not correlate with either serum MCP-1 levels or proteinuria. Unlike in lupus, in patients with nonlupus forms of glomerulonephritis, urinary MCP-1 was comparable to controls. CONCLUSIONS: Altogether, the present data suggest a role for MCP-1 in mononuclear cell migration into the kidney in lupus nephritis.

Adult↗