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N Perico

Publications and source records attributed to N Perico.

At least 55 records · Page 3Linked to original sources
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

Measurement of glomerular filtration rate.

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the diagnosis and management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of an exogenous marker that is freely filtered by the kidney, and that does not undergo metabolism, tubular secretion or absorption, such as inulin. While its clearance provides the most accurate method of measuring GFR, it is not suitable for routine clinical practice. Labeled compounds as alternative filtration markers, including 125I-iothalamate and 99mTc-diethylenetriaminepenta-acetic acid (DTPA), provide accurate and precise GFR measurements, but their use may be limited for safety reasons. To avoid exposing patients to radiation, investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate (ionic) and iohexol (non-ionic). This approach provides similar accuracy to inulin clearance. The most important limitation of all renal clearance methods is that urine is collected by spontaneous voiding, stimulated by water loading, and thus subject to errors due to incomplete emptying of the bladder. Thus, plasma clearance of a suitable exogenous marker (51Cr-EDTA, 125I-iothalamate, iohexol) has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides more precise information, but repeated sampling makes this method cumbersome. To overcome this drawback, abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve (elimination phase). On analyzing the data with a simplified method that uses a one-compartment model (six blood samples only in the elimination phase), corrected with the Bröchner-Mortensen formula, an excellent correlation was found with inulin clearance. This method is currently employed for measuring GFR in multicenter clinical trials.

Animals↗
PubMed1996

Recovery of blood mononuclear cell calcineurin activity segregates two populations of renal transplant patients with different sensitivities to cyclosporine inhibition.

In vitro studies have shown that the immunosuppressive property of cyclosporine (CsA) depends on its ability to inhibit the phosphatase activity of calcineurin, a critical enzyme for T cell activation. Here we sought to investigate whether measurement of calcineurin activity in peripheral blood mononuclear cells (PBMC) from 30 renal transplant patients given CsA as a part of their immunosuppressive regimen would help in optimizing CsA therapy. We first documented that in PBMC from these patients complete inhibition of calcineurin phosphatase activity by in vitro addition of CsA occurs at concentrations that are easily achieved in vivo for a dose as low as 3 mg/kg/day orally, which corresponds to trough CsA blood levels of 100-150 ng/ml. However, ex vivo, at a blood CsA trough level of 250 ng/ml, calcineurin activity in PBMC was only inhibited from 40% to 70% as compared with controls. Patients on higher doses of CsA had a further inhibition of baseline calcineurin activity, although a complete suppression was never reached. A significant correlation was found between trough CsA concentration and the basal calcineurin activity (r=0.48; P=0.0085). To clarify the relationship between the daily exposure of patients to CsA and changes in the enzyme activity of calcineurin, we then correlated the pharmacokinetic profile of CsA in these patients with different CsA dosing (<4, 4-6, >6-8, >8 mg/kg/day) with the profile of calcineurin activity at different intervals from dosing. Each of the above CsA doses suddenly reduced calcineurin activity, with a nadir at 2 hr after maximum blood concentration. The degree of the inhibition was not a function of peak CsA blood levels. In all patients, CsA blood level returned to basal values 10 hr after dosing. By contrast, only in 50-70% of patients (depending on the dose) did calcineurin activity return to baseline at the same time point after dosing. In summary we have shown that (1) inhibition of calcineurin activity measured ex vivo in PBMC taken from CsA-treated transplanted recipients reflects the blood CsA trough level; (2) after CsA the time-course of inhibition of enzyme activity is relatively independent from CsA pharmacokinetics; (3) the rate of recovery of calcineurin activity 10 hr after CsA dosing segregates two populations of transplanted recipients -- one with complete recovery of the enzyme activity and another that never returns to the baseline calcineurin level.

Calcineurin↗
PubMed1996

Cyclosporine induces glomerulosclerosis: three-dimensional definition of the lesions in a rat model of renal transplant.

Previous description of chronic cyclosporine (CsA) renal toxicity commonly included vascular changes, tubular atrophy, and interstitial fibrosis. Glomerular injury was only occasionally documented and it is not clear whether glomerular changes may have an impact on the clinical syndrome of CsA toxicity observed in experimental animals and humans. At the moment the prevailing view is that when patients given CsA have glomerular lesions at a renal biopsy, these were due to concomitant chronic rejection or renal hypoperfusion rather than to CsA itself. As a follow-up of our previous work on the subject (abstract; J Am Soc Nephrol 2:1398, 1992) the present study was undertaken to clarify whether CsA is a direct cause of glomerular injury. We used a model of renal transplant among Lewis rats to better mimic the condition in which CsA is given to humans. Animals underwent kidney isografts and were given daily CsA or vehicle for as long as 12 months. At the end of the experiment specimens of renal tissue were analyzed by a serial section morphometric analysis technique, which allows precise evaluation at the individual glomerular level, glomerular volume and percentage of the capillary tuft affected by sclerosis. Among 85 glomeruli from CsA-treated rats, examined by three-dimensional morphometric analysis, only 12% were normal and 88% revealed segmental sclerosis. Data of single-section analysis compared with three-dimensional morphometric reconstruction showed that the former markedly underestimated the extent of glomerular injury. By three-dimensional analysis we showed that chronic CsA administration was associated with profound changes in glomerular capillary tuft volume distribution as compared to normal. Specifically, a subset of smaller than normal glomeruli emerged in CsA-treated animals in addition to a population of glomeruli which were larger than normal. No significant correlation was found between capillary tuft volume and sclerosis volume. These findings indicate that chronic administration of CsA induces in rats glomerular lesions comparable to the ones reported in human renal or heart transplant. Our present model may help investigating the mechanism(s) of chronic CsA renal toxicity, and will provide important clues for pharmacological manipulations aimed at reducing the long-term consequences of CsA on the kidney.

Animals↗
PubMed1996

The kidney triggers graft-versus-host disease in experimental combined transplantation of kidney and stem cell-enriched peripheral leukocytes.

As a preclinical step to human studies with combined stem cell-enriched peripheral leukocytes and organ transplantation from the same donor, a series of studies in rats was undertaken. These studies indicated that Lewis rats infused intravenously with major histocompatibility complex-incompatible (from Brown-Norway rats), stem cell-enriched peripheral leukocyte preparation alone never developed graft-versus-host disease (GHVD). However, GVHD invariably manifested in all animals a few days after the kidney was transplanted in rats that had been previously primed with stem cell-enriched peripheral leukocytes from the same kidney donor strain. GVHD was prevented by substituting the crude preparation of stem cell-enriched peripheral leukocytes with a purified preparation that was almost completely free of T lymphocytes. However, in these latter experiments all rats rejected their kidney graft within 10 days from the surgery. In rats previously given the crude stem cell-enriched peripheral leukocyte preparation, perioperative administration of the fusion protein CTLA4lg also prevented GVHD and prolonged kidney graft survival up to 106 to 175 days. By contrast, animals with kidney transplants, which were given CTLA4lg without stem cells, rejected their grafts within 35 days. All together, these findings may possibly contribute to the creation of rationally designed strategies of combining organ and bone marrow from the same donor to enhance mixed chimerism and prolong survival after organ transplantation.

Abatacept↗
PubMed1996

Glomerular filtration rate determined from a single plasma sample after intravenous iohexol injection: is it reliable?

The iohexol injection plasma clearance method is a good alternative to the inulin clearance method for determination of GFR, but requires multiple blood samples. To avoid this, methods have been developed which derive GFR from a formula that uses a single plasma concentration of the tracer and anthropometric data. The aim of this study was to evaluate whether a single plasma sample taken after iohexol injection allows reliable estimation of GFR. In this study, results of single-point determination were compared with those obtained by multiple-point plasma clearance. The GFR of 686 outpatients with different degrees of renal function were recalculated by use of the Jacobsson formula. The optimum time for sampling was found at 10 h after injection of the marker for clearances < 40 mL/min per 1.73 m2, 4 h for clearances between 40 and 99 mL/min per 1.73 m2, and 3 h for clearances > 100 mL/min per 1.73 m2. Results documented that for 75% of the patients, the simplified technique gave an error between -5% to +5% in the evaluation of GFR; for the remaining 25% of the patients, prediction error ranged from -22% to +40%. Furthermore, despite a highly significant correlation between multiple-point iohexol clearance (six plasma samples) and the single-point method (Y = 0.968X + 1.704, r2 = 0.988), the regression intercept was statistically different from 0 and the standard error of the slope estimate established that 95% confidence interval did not include 1.0 (the line of identity), thus indicating that the model can be rejected by the data at a significance level of 0.05. Thus the single-plasma-sample method to determine GFR after radiocontrast injection does not represent a real advantage over the multiple-point method and may lead to unacceptable errors in GFR calculation.

Adult↗
PubMed1996

Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.

Colchicine, which inhibits cell microtubule assembly by preventing polymerization of tubulin monomers, inhibits cell-mediated immune responses and promotes long-term survival of major histocompatibility complex-incompatible renal allografts in rats. Here we evaluated the effect of blocking cell microtubule assembly by colchicine on T cell and endothelial cell adhesion receptors involved in transducing signals for T cell activation. By using immunofluorescence flow cytometry analysis, evidence is presented that colchicine, in a dose-dependent fashion, downregulated L-selectin and leukocyte function-associated antigen-1, but not CD2 and CD44 on the surface of naive human peripheral blood lymphocytes. This effect was confirmed in two subsets of T lymphocytes, namely, CD45RA- and CD45RO-positive cells. However, colchicine did not influence the rapid shedding of L-selectin from T lymphocytes exposed to activating stimuli. Colchicine inhibited expression of interleukin-2 receptor on activated T lymphocytes. This effect was observed when T lymphocytes were stimulated with both anti-CD3 and anti L-selectin monoclonal antibodies. Colchicine also inhibited lymphocyte function in vitro as documented by inhibition of the human mixed lymphocyte response in a dose-dependent fashion. Moreover, colchicine downregulated surface expression of intercellular adhesion molecule-1 and E-selectin on activated human umbilical vein endothelial cells. These results indicate that blocking cell microfubule assembly inhibits surface expression of adhesion molecules on T cells and endothelial cells, and provides insights into the complex mechanisms of the action of colchicine in vivo.

Antibodies, Monoclonal↗
PubMed1996

Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney.

Studies in experimental animals and humans have documented that inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors reduces urinary protein excretion rate and retards the development of renal injury. Here we sought to investigate whether angiotensin II (All) modified the size-selective properties to macromolecules of the glomerular capillary barrier in isolated perfused rat kidney preparation. Compared with basal values, continuous All infusion into the renal artery at the rate of 3 or 8 ng/min, but not at 0.6 ng/min, induced a progressive and significant increase in urinary protein excretion rate. Evaluation of the sieving properties of the glomerular barrier by fractional clearance of polydisperse Ficoll showed that All significantly enhanced the filtration of tracer molecules of radil > or = 34A. All-induced changes in urinary protein excretion rate and in Ficoll fractional clearance were completely prevented by pretreatment with the specific All Type 1 receptor antagonist SR 47436.

Angiotensin II↗
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↗
PubMed1995

Toward novel antirejection strategies: in vivo immunosuppressive properties of CTLA4Ig.

Allograft rejection is a process that depends on T cell receptor-ligand interaction and costimulatory signals generated when accessory molecules binds to their ligands, such as CD28 to the B7 molecules. We investigated the possibility that B7 blockade in vivo by the soluble CD28 receptor homolog CTLA4Ig modulates rejection process in a rat model of kidney allograft. Lewis rats orthotopically transplanted with MHC incompatible kidney from Brown-Norway rats were given an intraperitoneal injection of CTLA4Ig (0.2 or 0.5 mg/day) or a nonspecific immunoglobulin for seven days, starting the day of transplant. While control rats rejected the graft within 10 days, all animals given CTLA4Ig had a prolonged kidney allograft survival, independently from the dose of the fusion protein employed. Actually, at the dose of 0.2 mg/day kidney grafts survived 36 to 50 days (median 44 days), while with the highest dose graft survival was 40 to 60 days (median 50 days). In all CTLA4Ig-treated rats renal grafts were well functioning as documented by serum creatinine concentrations comparable to age- and sex-matched control rats 30 days after transplant. At this time in vitro mixed lymphocyte culture (MLR) experiments showed a significant reduction of proliferation of peripheral blood lymphocytes from CTLA4Ig-treated rats when challenged with BN but not third party Wistar Furth lymphocytes. We have also shown that combining a short course of CTLA4Ig (0.2 mg/day) with a dose of cyclosporine (CsA) low enough to fail to inhibit graft rejection allowed indefinite engraftment of kidney allograft without the need of continuous immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Abatacept↗
PubMed1995

Blocking cell microtubule assembly inhibits the alloimmune response in vitro and prolongs renal allograft survival by inhibition of Th1 and sparing of Th2 cell function in vivo.

Colchicine inhibits cell microtubule assembly by binding to and preventing the polymerization of tubulin monomers. Although there are data to indicate that colchicine inhibits a variety of cell-mediated immune responses, the effects and mechanisms of inhibiting cell microtubule assembly on the alloimmune response have not been thoroughly investigated. It has recently been shown that colchicine prevents acute rejection and promotes the long-term survival of rat renal allografts. In this study, the effects and mechanisms of inhibiting cell microtubule assembly by colchicine on the alloimmune response in vitro and in vivo were examined. First, the effects of colchicine on T lymphocyte response to alloantigen in vitro were tested. In the standard one-way mixed lymphocyte response (MLR), responder Lewis rat lymph node cells were cultured with irradiated Brown-Norway stimulators. Colchicine inhibited the MLR in a dose-dependent manner, with 100% inhibition at a concentration of 25 ng/mL (6.25 x 10(-8) M) and 50% inhibition at a concentration of approximately 5 to 10 ng/mL. Colchicine also inhibited the generation of cytotoxic T lymphocytes as well as cytotoxic T cell effector function in vitro in a dose-dependent fashion. Second, detailed immunohistologic studies of renal allografts harvested from unmodified control (acutely rejecting) and colchicine-treated rats (Day 15 or 30) were performed. These studies showed that grafts from colchicine-treated animals had significantly fewer mononuclear cell infiltrates and less edema, and moderately decreased deposition of immunoglobulin M, C3, and fibrin, as compared with acutely rejecting control grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Immunosuppressive therapy abrogates unresponsiveness to renal allograft induced by thymic recognition of donor antigens.

This laboratory and others have previously shown that the intrathymic injection of donor cells or major histocompatibility complex allopeptides induced indefinite survival of a subsequent graft without immunosuppression. This approach may open interesting new perspectives for transplant medicine. Studies to explore the feasibility of the technique in humans can only be designed with some form of concomitant immunosuppression to avoid the risk of irreversible rejection in the case that the thymus approach fails. Thus, one of the first issue to address is whether conventional immunosuppression interfered with the process of thymus tolerance. This study was designed to investigate the above issue. In transplanted Lewis control rats, cyclosporin A (CsA) (10 mg/kg per day) and methylprednisolone (MP) (10 mg/kg twice daily) for 3 days were invariably followed by kidney graft rejection within 10 days. In subsequent experiments, five groups of Lewis rats were injected with medium alone or Brown-Norway (BN) leukocytes into the thymus, and 24 h later, they were orthotopically transplanted with major histocompatibility complex-incompatible kidneys from BN rats. At the time of transplantation, Lewis rats received MP (10 mg/kg twice daily) CsA (10 mg/kg per day), or the combination of the two (MP+CsA at the same dose) for 3 days. Lewis rats injected intrathymically with BN leukocytes but not receiving immunosuppressants had indefinite survival of their kidney graft. The effect of the intrathymic injection of donor cells of inducing unresponsiveness to a subsequent kidney graft was abolished by concomitant immunosuppression. All animals given immunosuppressants rejected their graft within 12 days after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The thymic way to transplantation tolerance.

Within the past three decades, extensive research has been carried out with the aim to prevent graft rejection by minimizing the side effects related to the use of immunosuppressants. The major goal in transplantation research remains the development of strategies that would allow one to achieve a state of donor-specific unresponsiveness in order to promote a condition of true tolerance without the need of immunosuppressants. Recent evidence has been provided that this is a pursuing goal, at least in experimental animals. The thymus plays the major role in the development of self-tolerance, and initial work in the late 1960s indicated that the thymus also plays a critical role in the induction of acquired tolerance to exogenous antigens. Recently, the interest in acquired thymic tolerance has been renewed by the observation that, in the rat, the thymus is an immunologically privileged site in which isolated pancreatic islets can be engrafted and survive indefinitely. Moreover, intrathymic injection of the islets induced donor-specific unresponsiveness, which allowed survival of a second donor-strain islet cell allograft transplanted into an extrathymic site. These findings on cellular allografts have been extended to vascularized organ allografts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate.

Renal clearance of inulin is the best available indicator of GFR but cannot be used routinely for clinical purposes and is also difficult to perform for clinical investigation when repeated measurements are required. The aim of this study was to find a reliable alternative to inulin clearance that would allow one to avoid the use of radioactivity and problems related to the continuous infusion of the marker. The plasma clearance of unlabeled iohexol, a nonionic contrast agent, was used. Forty-one patients (creatinine clearance 6 to 160 mL/min per 1.73 m2) underwent simultaneous measurements of renal clearance of inulin and plasma clearance of iohexol. Iohexol was given as a single iv dose, and blood samples were drawn up to 600 min after the administration. Iohexol concentrations (by HPLC) were analyzed by a two-compartment, open-model system. A highly significant correlation between the plasma clearance of iohexol and the renal clearance of inulin over a wide range of GFR values was found. By analyzing the data with a simplified method that uses a one-compartment model corrected with the Bröchner-Mortensen formula, an excellent correlation with the inulin clearance was also observed. When only patients with moderate to severe renal failure were considered, a significant correlation between the two methods was found. A further comparison between GFR determined with iohexol and iopromide, a new low-osmolarity, low-viscosity contrast medium, was also performed in a subgroup of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Preliminary results of intrathymic injection of donor cells to prevent acute rejection in human heart transplantation.

In rodents, the intrathymic injection of donor cells or major histocompatibility complex peptides induces indefinite survival of a subsequent allograft with little or no immunosuppression. Here, experiments have been performed in two patients with cardiac transplantation to establish (1) the safety and tolerability of the intrathymic injection of donor leukocytes at the time of transplant surgery and (2) whether conventional immunosuppression interfered with the process of the thymic recognition of alloantigens. It was shown that the intrathymic inoculation of donor cells is safe and can be done without undesired effects. However, the procedure, as performed, did not protect from acute graft rejection. There are data enough to attribute the failure of the thymus technique in these two patients to the concomitant use of immunosuppressants. The results of this study are relevant for future trials aimed at finding the appropriate experimental conditions for the use of the thymic approach in human organ transplantation.

Acute Disease↗
PubMed1995

Cyclosporine-induced renal dysfunction in experimental animals and humans.

Cyclosporine (CsA) has improved one-year allograft survival in renal, liver, heart and pancreas transplantation, and has now also been advocated as a promising treatment for some autoimmune diseases. However, the use of CsA is associated with major nephrotoxicity, very likely a consequence of its toxic effect on vascular endothelium as consistently documented in experimental animals and humans. Evidence is now available that in kidney transplant recipients each oral dose of CsA is followed by a transient reduction in renal plasma flow and glomerular filtration rate that results from a form of acute reversible renal hypoperfusion. The repeated daily episodes of acute renal hypoperfusion might explain the structural alterations of pre-glomerular vessels and glomerular obsolescence well documented in transplant recipients on chronic CsA for more than two years. In heart transplant recipients CsA measurements of renovascular pressures and flows and analysis of transglomerular sieving of dextrans showed that renal vascular resistance was elevated more than twofold, due largely to an increase in pre-glomerular resistance. Three-dimensional reconstruction of individual glomeruli showed a distribution of capillary tuft volume shifted to both smaller and larger glomeruli in CsA-treated patients and 40% of glomeruli had global or segmental sclerotic changes. However, the potential for glomerulosclerosis lesions that may develop in humans given CsA has been a major source of concern, since it has not been considered a direct consequence of CsA toxicity but rather due to the concomitant chronic rejection (as for kidney transplant) or renal hypoperfusion (as for heart transplant). Recent findings in a rat model of renal isograft showed that daily administration of CsA for 12 months induced glomerulosclerosis, and that the lesions are quite comparable to the ones reported in humans with renal and heart transplants. Strategies for optimizing CsA treatment or associated drugs that may reduce pre-glomerular vascular resistance should be part of future approaches for preventing CsA nephrotoxicity.

Animals↗