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Biomedical subjects

J M Grinyo

Publications and source records attributed to J M Grinyo.

At least 19 recordsLinked to original sources
PubMed2005

Sirolimus-based therapy with or without cyclosporine: long-term follow-up in renal transplant patients.

This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for > or =3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

Adult↗
PubMed2003

Histologic findings in protocol biopsies performed in stable renal allografts under different immunosuppressive schedules.

Protocol biopsies performed in stable renal allografts show different degrees of acute and chronic lesions. Histologic findings in protocol biopsies have been related to graft outcome. We evaluated histologic lesions observed in protocol biopsies performed in patients under different immunosuppression therapies. From June 1988 a protocol biopsy was performed at approximately 4 months in patients who fulfilled the following criteria: serum creatinine <300 micromol/L; stable renal function; and proteinuria <1 g/d. Histologic lesions were graded according to 1997 Banff criteria. For the present study we considered the following groups according to immunosuppressive schedule: (i) induction therapy with polyclonal or monoclonal antilymphocytic antibodies associated with cyclosporine and prednisone (n=201); (ii) cyclosporine, mycophenolate mofetil, and prednisone (n=127); and (iii) tacrolimus, mycophenolate mofetil, and prednisone (n=51). On protocol biopsy patients treated with tacrolimus displayed a lower acute score (0.61+/-1.01 vs 1.24+/-1.23 in group I, 1.28+/-1.41 in group II; P<.0001) and a higher proportion of normal biopsies (57.1% vs 41.9% in group I, 45.1% in group II; P=.016). A similar proportion of chronic lesions (chronic score of group I: 1.30+/-1.56; group II: 1.34+/-1.80; group III: 1.51+/-0.95; P=NS) was observed in the three groups. Protocol biopsies displayed fewer acute lesions in patients treated with tacrolimus. This result suggests that the efficacy of new immunosuppression schedules can be evaluated using the protocol biopsy as a surrogate marker of graft outcome.

Adult↗
PubMed2001

The enhancement of endogenous cAMP with pituitary adenylate cyclase-activating polypeptide protects rat kidney against ischemia through the modulation of inflammatory response.

BACKGROUND: Cyclic nucleotide analogue administration improves ischemia-reperfusion damage in several organs. The neuropeptide pituitary adenylate cyclase-activating polypeptide, PACAP-38, is a potent stimulus to enhance cellular cAMP levels. This study tested the protective effect of enhancing endogenous cAMP levels by PACAP-38 in a model of warm renal ischemia. METHODS: Sprague-Dawley rats underwent 40 min of bilateral warm renal ischemia. PACAP-38 continuous infusion began either before ischemia or at 6 hr or 18 hr after ischemia. A mini-osmotic pump infused PACAP-38 throughout 7 days of follow-up. Groups were constructed with sham, ischemic control, and dibutyryl cAMP treated animals, and four PACAP-38 treatment groups, using 16 pmol/hr or 160 pmol/hr of the compound, or delaying its administration by 6 hr or 18 hr after ischemia. Renal function was assessed by means of serum creatinine levels on days 1, 2, 3, and 7 after ischemia. Conventional histology was performed on day 7. Renal myeloperoxidase (MPO) activity, infiltrating CD45+ cells, plasma and tissue cAMP, and serum IL-6 were measured. RESULTS: Continuous administration of the high concentration of PACAP-38 ameliorated renal function and morphologic abnormalities induced by warm ischemia. Treatment with dibutyryl cAMP produced morphologic protection but only partial functional effect on the ischemic kidney. A 6-hour delay in the administration of the compound after ischemia offered similar protective effect, whereas an 18-hr delay did not. The neuropeptide clearly increased circulating cAMP after ischemia but not cAMP in renal tissue. PACAP-38 increased circulating IL-6, and minimized renal inflammatory cell infiltration induced by ischemia-reperfusion injury, as evidenced by a reduction of MPO activity and the number of CD45+ cells in ischemic renal tissue. CONCLUSIONS: Enhancement of endogenous circulating cAMP with PACAP-38 modulates postischemic inflammatory response and strongly protects from ischemic acute renal failure, even when administration is delayed for 6 hr after injury.

Acute Kidney Injury↗
PubMed2001

[Study of renal transplant by deconvoluted renogram with 99m Tc-mercaptoacetyltriglycine (Mag3)].

AIM: To evaluate the usefulness of the 99mTc-MAG3 renogram deconvolution and its derived parameters in kidney graft function monitoring. MATERIAL AND METHOD: 221 renograms were studied: 64 were diagnosed as functioning graft (FG), 37 as functioning graft with elevated serum creatinine (FG2), 59 as acute tubular necrosis (ATN), 30 as acute rejection (AR), 20 as urinary tract obstruction (OBS) and 11 as cyclosporine nephrotoxicity (TNX). The parameters evaluated were: maximal activity of conventional renogram and mean transit time (MTT), time to reach 20% (T20) and 80% (T80) of the height of the RRF and initial uptake (IU) from the deconvoluted renal retention function (RRF). RESULTS: MTT and T20 were significantly longer and IU significantly lower in non-functioning grafts. However, MTT and T20 became shorter than in FG when graft function is severely impaired. CONCLUSION: IU, MTT and T20 are more useful than maxim activity of renogram in monitoring kidney graft function and in evaluating renal dysfunction severity. IU is a very sensitive and early parameter.

Adult↗
PubMed2000

Practice variations in the evaluation of adult candidates for cadaveric kidney transplantation: a survey of the European Transplant Centers.

BACKGROUND: This survey was conducted to investigate similarities and differences in the diagnostic evaluation of adult candidates for cadaveric renal transplantation and the criteria for acceptance to the cadaveric renal transplant waiting-list in the European transplant centers. METHODS: A questionnaire listing 45 diagnostic procedures (consultations of 9 specialties, 18 imaging techniques and 18 laboratory investigations), 45 medical conditions constituting possible reasons for exclusion from renal transplantation, and 10 properties characterizing the responding transplant center was sent to 214 European transplant centers. RESULTS: A completed questionnaire was returned by 154 of 214 centers (72%). Significant disagreement (P<0.001) exists about the necessity of 28 of the 45 surveyed diagnostic procedures and about the acceptability of transplant candidates for 15 of the 45 surveyed medical conditions. The influence of center characteristics on the observed practice variations was examined by multinomial logistic regression (factors: Center size, waiting-list pressure, responsibility for organizing the diagnostic work-up, status of transplant center, responsibility for decision about acceptance of candidates and geographic location of center): In 13 of 28 controversial diagnostic procedures, geographic location of the centers turned out to be the only significant determining factor (P<0.001), whereas the dissent about medical conditions is not influenced significantly by the analyzed factors. CONCLUSION: The detected significant practice variations in the evaluation of renal transplant candidates may either indicate where scientific evidence is missing and more clinical research is needed or where the existing evidence has not been adequately disseminated and convincing guidelines should be established.

Adult↗
PubMed2000

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients.

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.

Acute Disease↗
PubMed2000

Different diagnostic approaches to adult candidates for cadaveric kidney transplantation in Europe.

We investigated which diagnostic procedures are mandatory for all transplant candidates irrespective of their individual situation in European transplant centres, how homogeneously these are applied and what centre characteristics determine differences in the diagnostic approach. A questionnaire was sent to European renal transplant centres asking which of 45 listed diagnostic procedures are mandatory for every transplant candidate. The 154 participating centres require 15.6 +/- 5.6 (4-33) mandatory tests, with significantly less mandatory diagnostics in centres in the UK (8.5 +/- 3.9) and Scandinavia (9.8 +/- 2.3). Geographic location is the single significant factor in multifactorial analysis of possibly related factors. Detailed analysis revealed 16 tests that are required significantly less often in the north of Europe. There are significant differences in the evaluation of renal transplant candidates across Europe. In some parts of Europe transplant candidates are either investigated more discriminately or less comprehensively than in other regions.

Adult↗
PubMed1997

Steroid withdrawal in mycophenolate mofetil-treated renal allograft recipients.

BACKGROUND: Acute rejection is an inherent risk of the withdrawal of steroids in renal allograft recipients. Mycophenolate mofetil is a potent immunosuppressant that, when given with cyclosporine (CsA), reduces the incidence of acute rejection and may facilitate discontinuation of steroids without increasing the risk of rejection. METHODS: In an open pilot study, steroids were withdrawn from 26 adult cadaveric kidney transplant recipients. Corticosteroids were discontinued between 4 and 30 (mean 17) months after transplantation, and steroid-free follow-up ranged from 7 to 18 (mean 10) months. RESULTS: Mean CsA doses, CsA blood levels, and serum creatinine at the time of steroid withdrawal and at last patient visit after cessation of steroids were 4.2+/-1.2 mg/kg/day and 3+/-0.8 mg/kg/day (P<0.001), 170+/-53 ng/ml and 113+/-34 ng/ml (P<0.001), and 133+/-36 microM/L and 130+/-37 microM/L (NS), respectively. No rejection episodes occurred after steroid withdrawal. CONCLUSIONS: This open study shows that corticosteroids can be safely and successfully withdrawn from renal allograft recipients receiving CsA and mycophenolate mofetil.

Acute Disease↗
PubMed1997

Neutrophils accentuate renal cold ischemia-reperfusion injury. Dose-dependent protective effect of a platelet-activating factor receptor antagonist.

This study was undertaken to evaluate whether the renal damage induced by cold ischemia-reperfusion was worsened by neutrophils (PMN), and if blockade of platelet-activating factor (PAF) could effectively decrease this injury. After flushing with EuroCollins, 85 kidneys from Sprague-Dawley rats underwent either no cold ischemia or a 4-h cold ischemia, and then were reperfused for 75 min at 37 degrees C and 100 mm Hg in an isolated perfusion circuit. Reperfusion was performed with a Krebs-Henseleit solution containing 4.5% albumin, with and without human PMN (7.5 x 10(5) cells/ml) and with and without addition of a PAF receptor antagonist (BN 52021). Hemodynamic and functional parameters were continuously assessed during reperfusion. At end of the study, PAF production was evaluated. Presence of PMN during reperfusion of nonischemic kidneys produced no alteration of functional parameters or PAF production. After 4-h cold ischemia, the presence of PMN during reperfusion produced a significant worsening of plasma flow rate, glomerular filtration rate and sodium reabsorption in comparison with kidneys reperfused without PMN. Also, higher production of PAF was observed in the kidneys reperfused with PMN than in the kidneys reperfused without PMN. After 4-h cold ischemia, addition of BN 52021 during reperfusion in the presence of PMN significantly increased the plasma flow rate, glomerular filtration rate and sodium reabsorption in comparison with kidneys reperfused without this PAF antagonist. This effect was dose dependent. After 4-h cold ischemia, addition of BN 52021 during reperfusion in the absence of PMN produced no significant effect on functional parameters in comparison with kidneys reperfused without this PAF antagonist. These results indicate that PMN contribute to renal cold ischemia-reperfusion injury evaluated in the isolated perfused kidney. Treatment with a PAF receptor antagonist attenuated this injury in a dose-dependent manner, which suggests that it is mediated by PAF.

Animals↗
PubMed1996

Changes in renal hemodynamics and physiology after normothermic ischemia in animals supplemented with eicosapentaenoic acid.

In order to determine whether treatment of animals with an n-3 fatty acid, eicosapentaenoic acid (EPA), could modify renal hemodynamics and physiology after normothermic ischemia, we studied 42 Spraque Dawley rats orally supplemented with either olive oil or a purified lysine salt of EPA for 4 weeks. Four experimental groups were established. Three groups were treated with increasing doses of EPA: 20 mg/kg per day (EPA 20), 40 mg/kg per day (EPA 40) and 80 mg/kg per day (EPA 80), and one group was supplemented with isovolumetric olive oil (OLI). A control group that received neither EPA nor ischemia was also studied. On day 28, right nephrectomy was performed, followed by 30 min of left renal warm ischemia. Basal arterial pressure and renal blood flow (RBF) were monitored in two kidneys before arterial occlusion and continuously thereafter throughout the experiment in one kidney using an electronic transducer and a flowmeter. From 60 to 120 min after the end of ischemia, urine output (microliter/min), glomerular filtration rate (GFR, microliter/min), measured by inulin clearance, and fractional reabsortion of sodium (FRNa) were determined every 20 min. Renal plasma flow (RPF, ml/min) and renal vascular resistance (VR, mm Hg/ml per min) were calculated. RPF was estimated as RBF (1-hematocrit). Before ischemia, the mean RPF and RBF were higher in EPA-fed than in olive oil-fed animals and after ischemia showed a significantly greater increase in EPA-fed animals than in olive oil-fed animals. Mean VR was lower in EPA-fed animals than in olive oil-fed animals, both before arterial occlusion and after ischemia. Mean urine output was similar in the OLI and EPA 20 groups, and significantly higher in the EPA 40 and EPA 80 groups than in the control group. GFR was significantly lower in the OLI and EPA 20 groups than in the control group. Finally, the EPA 40 group showed a similar and the EPA 80 group a slightly higher GFR than the control group. We conclude that EPA supplementation provides protection from renal ischemic-reperfusion injury, and this effect is more evident at higher EPA doses.

Animals↗
PubMed1996

Longitudinal study of the frequency of cytotoxic T cell precursors in kidney allograft recipients.

Clonal deletion or inactivation of donor-specific alloreactive cells are important mechanisms that are believed to account for acquired immune tolerance in allograft recipients. Serial assessment of precursor cytotoxic T lymphocyte frequencies (CTLpf) by limiting dilution analysis (LDA) provides information at the clonal level on changes in the alloimmune response of graft recipients. We performed a longitudinal study of 15 cadaveric kidney recipients before and every 3 months throughout the first year after transplantation (Tx). Pre-Tx values of donor CTLpf showed high interindividual variability without a predictive value for the clinical outcome. All patients with well functioning kidneys had decreased CDLpf at 3 months post-Tx in comparison with pre-Tx values. This decrease was donor-specific in four patients and was permanent in two cases throughout the study. Most patients presented decreased anti-donor CTLpf values from 6 to 9 months, whereas a partial recovery of donor CTLpf was observed in three patients. Reversible acute rejection was diagnosed in three patients, and it was associated with a marked increase in anti-donor CTLpf, returning to pre-Tx values by 9 months post-Tx. In addition, one patient with chronic rejection displayed a transient increase in CDLpf 6 months after Tx. The results of this sequential study indicate the establishment of a state of either hyporesponsiveness or functional clonal inactivation, transient or permanent, which could facilitate allograft acceptance.

Adult↗