Polymorphisms in EGFR and IL28B are associated with spontaneous clearance in an HCV-infected Iranian population.

Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected--candidate--genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values<0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR)=2.06, 95% confidence interval (95% CI)=1.09-3.88, P=0.025; OR=2.09, 95% CI=1.23-3.60, P=0.007; and OR=1.95, 95% CI=1.15-3.35, P=0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance.

Status of the down-regulated canine testis using two different GNRH agonist implants in comparison with the juvenile testis.

Testicular function in the dog was down-regulated using two different GNRH agonist implants, with adult and juvenile testes serving as controls. Treatment resulted in an increased percentage of the interstitial area and decreased area of Leydig cell nuclei. Expression of StAR and the steroidogenic enzymes cytochrome P450 side-chain cleavage enzyme (P450scc, CYP11A1) and cytochrome P450 17α-hydroxylase-17,20-lyase (P450c17, CYP17A1) in Leydig cells was blocked at the mRNA and protein level, showing no differences between the two agonists. Staining for androgen receptor (AR) by immunohistochemistry was positive in Sertoli, Leydig and peritubular cells and some spermatogonia, with in situ hybridization confirming expression in Sertoli cells. At the mRNA level, expression of AR was not affected; however, translation was blocked (reduced percentage of AR-positive Sertoli cells), with the number of nuclei in basal position being decreased. In the juvenile testes, mRNA expression of StAR, CYP11A1 and CYP17A1 was higher compared with the other groups but distinctly lower for the AR. At the protein level, the expression was at the limit of detection for StAR; AR-positive Sertoli cells were not detected. Our observations show that the down-regulated testis is different from the juvenile one rather resembling the testicular status in seasonal breeders out of season.

Restart of steroidogenesis in dogs during recrudescence of testicular function following downregulation with a GnRH-agonist implant.

To date, no details are available concerning the restart of steroidogenesis following the downregulation of testicular endocrine and germinative function by gonadotrophin-releasing hormone (GnRH)-agonist implants. This restart was assessed by determining the expression of steroidogenic acute regulatory (StAR) protein, cytochrome P450 side-chain cleavage enzyme (P450scc) and cytochrome P450 17α-hydroxylase,17,20-lyase (P450c17). The re-establishment of steroidogenesis was initiated by the removal of the GnRH-agonist implant (18.5 mg azagly nafarelin, Gonazon) at 5 months after treatment. Testes were removed at 3-week intervals (weeks 0-24) and four groups were formed according to the stage of spermatogenesis as revealed by the most developed germ cells observed (developmental group [DG] spermatocytes to DG elongated spermatids). Five dogs served as untreated controls. Positive immunostaining for StAR, P450scc and P450c17 was restricted to Leydig cells. Western blot indicated the specifity of the respective antibodies with hints of a expression of canine-specific P450scc and P450c17 proteins. A significant effect of group was observed for a percentage of the immunopositive area (PIA) as an indicator of active Leydig cells for StAR (P<0.05), P450scc (P<0.001) and P450c17 (P<0.001), with PIA being lowest for the DG spermatocytes. With regard to the strength of the immunopositive signal, a significant effect of group was found for P450scc (P<0.01) and P450c17 (P<0.05), with the lowest intensity being observed in DG spermatocytes. At the mRNA level, the upregulation from DG spermatocytes to DG round spermatids was clearly evident but was only significant for P450scc (P<0.05). Thus, downregulation affects the whole cascade of steroidogenesis, whereas withdrawal of inhibition results in a rapid restart, in part indicating a rebound phenomenon.

Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients.

Prolonged-release tacrolimus was developed to provide a more convenient once-daily dosing that could improve patient adherence. We conducted a multicenter, prospective, observational, 12-month study to describe the efficacy, safety and patient preference of conversion from tacrolimus twice-daily to once-daily formulation in stable kidney transplant recipients in routine clinical practice. Conversion was made on a 1 mg: 1 mg basis (1 mg: 1.1 mg in patients with trough levels <6 ng/mL). The study included 1832 patients (mean age (± SD): 50.0 ± 13.4 years; 62.7% male). After conversion, a modest reduction in tacrolimus trough levels, necessitating an increase in daily dose, was observed (mean changes at 12 months of -9.1% and +1.24%, respectively; p < 0.0001). Mean glomerular filtration rate did not change significantly (56.5 ± 19.7 mL/min at conversion vs. 55.7 ± 20.6 mL/min at 12 months). Proteinuria, blood pressure, lipid, hepatic and glucose parameters remained stable. Eight patients (0.4%) had acute rejection and 34 patients (1.85%) discontinued treatment. Almost all patients (99.4%) preferred the once-daily formulation, because of less frequent dosing (66%) and improved adherence (34%). In conclusion, at similar doses to twice-daily tacrolimus, once-daily formulation provided stable renal function, a low acute rejection rate, and good tolerability in stable kidney transplant recipients in the routine clinical practice setting.

Efficacy of low doses of pamidronate in osteopenic patients administered in the early post-renal transplant.

UNLABELLED: This study evaluates the efficacy of low doses of pamidronate after renal transplantation to prevent bone loss in osteopenic patients. Results show that pamidronate is safe and significantly reduced spinal bone loss when administered immediately after renal transplantation. INTRODUCTION: The purpose of this work is to evaluate the efficacy of two intravenous infusions of pamidronate in the immediate post-transplant period in a renal transplant (RT) population. METHODS: In this 12-month, randomized, double-blind, multicenter trial, 39 kidney recipients with diagnosed osteopenia received two doses of 30 mg of disodium pamidronate (n = 24) or placebo (n = 15), at surgery and 3 months post-RT. All patients received calcium and vitamin D. Bone density of the lumbar spine and total femur was measured by dual-energy X-ray absorptiometry (DXA) and X-rays were performed at RT, 6 and 12 months post-RT. Biochemical and hormonal determinations were performed before and after treatment. RESULTS: Pamidronate significantly reduced spinal bone loss, but no significant benefit was found for the incidence of fractures. Elevated baseline intact parathyroid hormone (iPTH) and bone remodeling markers returned to normal levels 3 months post-RT. However, normal procollagen type I N propeptide (PINP) concentrations were only maintained in the pamidronate group. After RT, a comparable graft function was observed in both groups according to creatinine values, 25-hydroxyvitamin-D (25-OH-D) levels were improved, and serum calcium levels normalized after a transient fall during the first 3 months. CONCLUSION: A low dose of pamidronate prevents bone loss in osteopenic patients when administered immediately after RT.

Treatment of BK virus-associated nephropathy with Cidofovir in renal transplantation.

BK virus-associated nephropathy (BKVN) has become recognized as an important cause of allograft dysfunction among transplant recipients. Despite reduction in immunosuppression, 30%-40% of recipients progress to allograft loss. Cidofovir is an antiviral agent that has been proposed for treatment of BKVN. We describe the clinical course, renal function, and blood viral measurement in 6 renal transplant recipients with BKVN who were treated with low doses of cidofovir. Administration of cidofovir was associated with clearance of BK virus DNA from blood and stabilization of renal function in 5 cases. These data suggest that cidofovir may be useful as adjuvant therapy for BKVN.

Treatment of anemia in renal transplantation: impact of a stricter application of hemoglobin targets.

OBJECTIVE: The CREATE and CHOIR studies showed a higher risk for cardiovascular events associated with hemoglobin (Hb) values >13 g/dL in patients with stage 3-4 chronic kidney disease. In 2007, a stricter policy on the use of erythropoietin (EPO) was adopted at our center, with an Hb target of 11 to 12 g/dL and withdrawal or reduction of EPO when Hb was >12.5 to 13 g/dL. This study was designed to evaluate this new approach. MATERIALS AND METHODS: The study included patients under follow-up at the transplant outpatient clinic on December 31, 2006 (n = 725), and December 31, 2007 (n = 768). Data were compared between the study populations concerning renal function, Hb, use of EPO, and associated costs. RESULTS: No significant differences in creatinine or Hb values were observed between the 2 groups (1.47 +/- 0.6 vs 1.42 +/- 0.9 mg/dL and 13.7 +/- 1.5 vs 13.7 +/- 1.6 g/dL, respectively). After implementation of the new protocol, the frequency of severe anemia (Hb <11 g/dL) increased (2% vs 4%; P = .10), the use of EPO decreased (22.1% vs 17.2%; P = .017), and the mean Hb of EPO-treated patients decreased (12.5 +/- 1.4 vs 11.9 +/- 1.0; P < .001). The Hb target (11-12 g/dL) was met in fewer than one third of patients, with no significant differences between the 2 study times. CONCLUSIONS: A strict policy on EPO application reduces its use and the rate of patients with "excessive" Hb values (which are associated with increased cardiovascular risks), with an acceptable slight increase in severe anemia cases.

Factor deficiency in the anemia of renal transplant patients with grade III-IV chronic kidney disease: baseline results of the ARES Study.

ARES is a multicenter, prospective study of the prevalence, management, and repercussions on the quality of life of anemia in renal transplant patients with a reduced renal function (creatinine clearance according to Cockcroft-Gault: 15 mL/min). The frequency of factor deficiency and its relationship with anemia were analyzed at the baseline time of the study. Of the 500 patients included in the main study, valid data were available for iron metabolism in n = 419 microg/dL; folic acid, n = 205 ng/mL; and vitamin B12, n = 210 pg/mL. Anemia was defined as hemoglobin

[Daclizumab in combination with mycophenolate mofetil and a late introduction of Tacrolimus at low doses, as a therapeutic approach in the elderly renal transplant donor-recipients pairs in kidney transplant]. / Daclizumab en combinación con Micofenolato Mofetil e introducción tardía de Tacrolimus a dosis bajas, como opción terapéutica en la pareja donante-receptor añoso en trasplante renal.

BACKGROUND: Nowadays, it is more frequent the use of kidneys from older donors in the renal transplantation. Moreover, it is also increasing the age of the recipients due to the ageing of the population treated with hemodialysis. This makes that recipients become older more commonly. This situation raises specific problems in the renal graft and in the recipient as well. In this manuscript we present the results of a multicenter study that analyzed an immunosuppressive strategy specifically designed to elderly renal transplant donor-recipients. METHODS: Patients > or =50 years were transplanted from donors > or =55 years. Immunosuppressive strategy consisted of daclizumab (2 doses of 1mg/Kg) in combination with steroids, mycophenolate mofetil (2g/daily during the first 45 days and then adjusted according to local practice) and Tacrolimus. Tacrolimus was introduced between 5 and 7 day post-transplantation, adjusting the predose levels between 4-8 ng/mL. Mean follow-up was 12 months. RESULTS: A total of 133 patients were included in the study. Mean age of recipients and donors was 61.3+/-6.2 years and 64.4+/-5.3, respectively. 42.9% of patients needed dialysis during the first week (median 4 days). Between first month and first year, serum creatinine improved from 2.0+/-1.0 mg/dl to 1.5+/-0.4 mg/dl. Similar improvements were observed when creatinine clearance (Cockroft-Gault) was calculated. The survival of patient and renal graft at 12 months was 97.7% and 96.1%, respectively. The acute rejection rate was 13.5%. Security profile was good, as expected. CONCLUSIONS: The Daclizumab and mycophenolate mofetil regimen with a late introduction of Tacrolimus at low doses is a good alternative in the elderly renal transplant recipients with a low immunologic risk.

Prevalence and management of potential candidates for simultaneous pancreas-kidney transplantation in a provincial setting.

INTRODUCTION: Simultaneous pancreas-kidney (SPK) transplantation is the best therapeutic option for correctly selected diabetic patients with advanced chronic kidney disease (CKD). OBJECTIVES: The objectives of this study were to quantify in a Spanish province the prevalence and incidence of type 1 and 2 diabetics with stage IV-V CKD who are potential candidates for SPK, and to analyze the selection for SPK in clinical practice. MATERIALS AND METHODS: All patients with diabetic neuropathy (DN) in predialysis, hemodialysis, or peritoneal dialysis (PD) in our transplantation referral area (population, 1.8 million; data collection ended December 7, 2005) were examined for basic SPK criteria (NTO 2005 Consensus). A new assessment was performed 9 months later, including new possible recipients, and patients were classified as: follows in study, excluded after study, added to SPK waiting list, or SPK-transplanted. RESULTS: In 2005, there were 1371 patients in dialysis or predialysis, including 179 (13%) with DN (41 type 1 and 138 type 2 DM); only 16 of these patients (8.9% of DN patients), 8.9 per million population (PMP), met the basic criteria for SPK transplantation. There were 68 with DN in predialysis, including 8 (11.7%) possible SPK candidates; 7 with DN in PD, no candidates for SPK; and 104 patients with DN in hemodialysis, including 8 (7.2%) SPK candidates. After 9 months, 7 new potential candidates were identified (incidence of 5.1 PMP/y). Of 23 possible candidates, 3 refused SPK, 7 awaited completion of study, 8 were excluded after study, 1 was on the SPK waiting list, and 7 underwent SPK transplantation. CONCLUSIONS: In our setting, approximately 9% of DN patients with stage IV-V CKD were potential SPK candidates in 2005 and 2006. After completion of studies, less than half were eventually included on the waiting list, generating an effective demand for SPK of 2-4 new patients PMP/y.

Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPA, myfortic).

AIM: A 12-month multicenter, double-blind trial in which maintenance renal transplant patients were randomized to remain on mycophenolate mofetil (MMF) or convert to enteric-coated mycophenolate sodium (EC-MPS, myfortic) has demonstrated that conversion from MMF to EC-MPS is safe. Patients completing the study were invited to enter an open-label extension. Upon entry to the extension, patients who had received MMF during the randomized phase were converted to EC-MPS ("newly-exposed EC-MPS" group) and were monitored separately from those who had been randomized to EC-MPS ("long-term EC-MPS" group). The aim of the extension study was to collect long-term safety and efficacy data on EC-MPS, and to confirm the safety of conversion from MMF to EC-MPS in a larger patient population. METHODS: All patients received EC-MPS 720 mg b.i.d. with cyclosporine microemulsion and corticosteroids per local practice. Data derived from the analysis of the first 24 months of the extension phase are presented. RESULTS: Of the 297 patients who completed the core study, 260 (88%) entered the extension; 195 (75%) completed the 24-month extension visit. For on-treatment patients > 95% of the planned daily dose of EC-MPS was administered, and < 13% of patients in both groups had discontinued EC-MPS due to adverse events by 24 months. The overall incidence of adverse events during the extension phase, including infections and hematological abnormalities, was comparable to that seen in the core study, with a similar safety profile in the newly-exposed and long-term EC-MPS groups. There were 3 deaths during the first 24 months of the extension, and 2 graft failures in both the "newly-exposed" and "long-term" EC-MPS groups. CONCLUSIONS: These data demonstrate that long-term use of EC-MPS is effective and has an acceptable tolerability profile in renal transplant patients, and confirm that conversion of maintenance renal transplant patients from MMF to EC-MPS is a safe therapeutic option.

Epidemiology of urinary infections in renal transplant recipients.

Urinary tract infection (UTI) remains a significant cause of infectious complications in renal transplant recipients. We evaluated prospectively all the UTIs in 161 kidney recipients transplanted between July 2003 and July 2005. All patients received prophylaxis with sulfadoxine-pyrimethamine. We excluded asymptomatic bacteriuria. Forty-one patients (25%) suffered at least one UTI episode. Ninety-two episodes of infection were confirmed with an incidence rate of 97 UTI episodes per 100 patient-years. The most common clinical features were uncomplicated acute bacterial cystitis, 71 episodes (77%), and acute pyelonephritis, 21 episodes (23%). Microbiological isolation was confirmed in 58 episodes (63%). Bacterial infections were the most frequent etiologies: gram-negative bacilli in 52 (90%), gram-positive cocci in 4 (7%), fungal in 2 (3%), and one viral BK virus (2%) infection. The causative microorganisms were E. coli as the principal isolated agent in 41 cases (71%), including 10 (24%) that were extended-spectrum betalactamases (ESBLEC). All episodes showed a favorable course. The survival rate of the graft at the end of the study period was 90.7%, and the survival rate of the transplant recipients was 97.5%. The incidence of UTI in transplant patients who received antibiotic prophylaxis was high. E. coli (ESBLEC) was the main agent isolated. Uncomplicated UTI, the most frequent post transplantation infection, showed a good prognosis.

Use of antibodies neutralizing epithelial cell infection to diagnose patients at risk for CMV Disease after transplantation.

OBJECTIVES: Although a CMV-specific T-cell response is associated with reduced risk for infection after transplantation, some patients still develop CMV disease. Thus, the characterization of additional parameters of the CMV-specific immune response that correlate with the control of CMV infection and disease and their use in defining thresholds that can be applied to clinical practice is of interest. METHODS: In a cohort of high risk solid organ transplant recipients we characterized CMV-specific T-cell responses using intracellular cytokine staining upon stimulation with pp65 and IE-1 peptides, and levels of CMV-specific antibodies neutralizing infection in fibroblast (MRC-5) and epithelial (ARPE-19) cells using microneutralization assays. RESULTS: Although patients with a positive (≥0.25%CD8(+)CD69(+)IFN-γ+) T-cell response were 6.4 fold more protected (OR 6.4, 95% CI 1.6-25.3; p < 0.001) from CMV infection than patients without a response, 2 (4.2%) patients developed disease. We defined a cut-off titer for epithelial cell neutralizing antibodies of ≥480 that correlated with disease protection. Thus, patients with a CMV-specific T-cell response and titers ≥480 were 14.2 fold more protected from CMV infection (OR 14.2, 95% CI 5-40.2; p < 0.001) and had no episodes of CMV disease. CONCLUSIONS: Our results indicate that antibodies neutralizing epithelial cell infection may have an important role in long-term protection. Quantification of antibodies neutralizing epithelial cells, in addition to the T-cell response, may be useful for identifying patients with lower risk for CMV disease.

Kidney Transplantation Results in Very Highly Sensitized Patients Included in a Virtual Crossmatch Program: Analysis of Kidney Pairs.

BACKGROUND: Kidney transplantation in highly-sensitized (HS) patients can improve with organ-exchange strategies based on virtual crossmatch (V-XM). Experience in very-HS patients is limited. METHODS: In June 2012, Andalusia started a V-XM protocol for very-HS patients (calculated panel reactive antibodies ≥95%). After organ allocation a cytotoxic-XM performed immediately before transplantation had to be negative for surgery to proceed. We analyzed results up until December 2015. Whenever possible we also compared the course of the recipient (non-HS) of the other kidney from the same donor. RESULTS: Of the 57 grafts, 52 kidney transplantations were performed (the pretransplantation cytotoxic-XM was positive in 5; predictive value 91.3%). Five patients (9.6%) experienced acute rejection (4 antibody-mediated rejections [AMRs]; 7.6%). Donor-specific antibodies developed in 10 patients. No patient died. One-year graft survival was 98%. We compared the course of the non-HS recipient of the other kidney, excluding cases with no pair (n = 5), pairs who were children recipients (n = 3), pancreas-kidney recipients (n = 5), or pairs already included in the V-XM protocol (n = 4). Finally, 35 pairs were studied. More HS-patients developed donor-specific antibodies (P = .016). No significant differences were seen in acute rejection, but AMR was more common (P = .057). No deaths occurred in either group, and there were no differences in graft survival or renal function. CONCLUSIONS: Although a few patients still developed AMR, our V-XM based protocol with a final pretransplantation cytotoxic-XM achieved very satisfactory results. Although the number of patients was limited, the initial survival of these high-risk recipients was comparable to the controls.

Hepatitis C Treatment With Direct-Acting Antivirals in Kidney Transplant: Preliminary Results From a Multicenter Study.

Hepatitis C (HC) is a very relevant negative prognosis factor for graft and transplant recipient survival. New direct-acting antivirals (DAAs) allow us to solve this problem in an effective way. It is crucial to understand their real impact in our daily practice. We analyzed treatment results with DAA, free of interferon, in kidney transplant recipients (KTRs) from 15 Spanish hospitals (Grupo Español de Actualización en Trasplante), regarding effectiveness, tolerance, and impact on immunosuppression, renal function-proteinuria, and diabetes. One hundred nineteen KTRs were included (9 combined liver-kidney transplants). The main DAA used was sofobusvir (91%) combined with ledipasvir (55%), simeprevir (14%), or daclatasvir (13%); in 9 cases (7%), a paritaprevir-ritonavir-ombitasvir-dasabuvir combination (3D) was used; Ribavirin was used as a coadjuvant in 18%. Side effects were limited (23.5%) and without relevance in general, except in 7 patients for whom we needed to interrupt the treatment due to neurotoxicity (1) caused by drug interaction (3D and tacrolimus) or anemia (3) by Ribavirin or others. Ninety-four patients had completed the treatment when data were analyzed: virological response was seen in 97.8% % of cases. Liver function analysis improved: 84% normal versus 21% before starting the treatment (P < .001). Renal function and proteinuria did not change. Tacrolimus level at the end of DAA-treatment was significantly lower with respect to the beginning (5.8 ± 2.1 ng/mL vs. 7.4 ± 1.8 ng/mL, P = .03), despite a slight increase in the dose (2.6 mg/d vs. 2.3 mg/d, P = .17). DAA are highly effective in the treatment of hepatitis C in KTRs with good tolerance in general, making it possible to solve the problem and have a good chance to improve the prognosis in our transplantation patients. The use of these therapies in KTRs requires special control and coordination with digestive professionals, especially if 3D or Ribavirin is used.

Non-Heart-Beating Donor Kidney Transplantation Survival Is Similar to Donation After Brain Death: Comparative Study With Controls in a Regional Program.

Non-heart-beating donors (NHBD) are an increasing source of organs for kidney transplantation (KT) compared with donation after brain death (DBD), but the results in each regional transplantation program require local analysis. We compared 164 KT from NHBD (83 Maastrich type II A-B [T2] and 81 type III [T3]) with 328 DBD controls. NHBD kidneys were implanted with less cold ischemia, mean time on renal replacement therapy for NHBD recipients before transplantation was less too, and a higher proportion of thymoglobulin was also used. Besides NHBD-T2 more frequently showing the A group and patients being younger (48.9 ± 11 vs DBD 55.2 ± 15 years old; P < .001), there was a lower proportion of retransplant recipients and HLA sensitization; HLA-DR compatibility was slightly worse. Proportion of nonfunctioning allograft and necessity of dialysis after transplantation for NHBD were 4.9 and 68.3% versus DBD 4.3 and 26.9% (P < .001); renal function after a year was significantly less in NHBD (serum creatinine 1.79 ± 0.9 mg/dL vs 1.46 ± 0.5 in DBD; P < .001). NHBD recipient survival rates were 96% and 96% for the 1st and 3rd years, respectively, versus 96% and 94% for DBD, respectively (not significant [NS]). Graft survival rates censored by death were 91% and 89% (1st and 3rd years, respectively) versus 95% and 94% for DBD, respectively (NS). We did not find significant differences about survival between NHBD-T2 and T3. In the multivariable survival study (Cox, covariables with statistical significance demonstrated previously in our region), NHBD is not a prognosis factor for recipient or graft survival. Regarding current criteria for choosing donors and the graft allocation applied in Andalusia, short-term survival for NHBD transplantation is similar to DBD. Renal function in the short term is slightly worse, which is why it is important to monitor results over a long term, especially those from NHBD-T2.

Effect of new immunosuppressive regimens on cost of renal transplant maintenance immunosuppression.

Although newer immunosuppressive drugs control acute rejection better and have short-term economic advantages, their long-term cost-effectiveness is unknown. We studied the frequency with which different maintenance immunosuppression regimens were used in 3 renal transplantation cohorts treated in 1990, 1994, and 1998 (total number, 3279). We calculated the mean annual immunosuppressive costs based on the true costs in a medium-sized hospital. Cyclosporine, with or without azathioprine, was used almost exclusively as the initial maintenance immunosuppressive therapy in 1990-1994. In 1998, 65% of patients received mycophenolate mofetil (MMF), and 20% received tacrolimus (Tac). A growing number of patients from 1990-1994 were converted to MMF (12%-17%) and Tac (4%-8%), while treatment of those from the 1998 cohort remained stable. According to year 2000 costs, the mean immunosuppressive cost at 1 year in 1998 (5380 euros) was almost twice that of 1994 (2902 euros) or 1990 (2855 euros). In these 2 groups the mean cost was stable until 1996, then increased faster in the 1994 cohort (24.8%) than in the 1990 cohort (17.3%), although it remained significantly lower than that in 1998. Correction of the evolution of drug prices and the purchasing value of the peseta greatly absorbed these changes. The MMF and Tac regimens showed greater mean graft life, but without reaching statistical significance in a multivariate study. The introduction of new immunosuppressive drugs has had an important economic effect since 1996; its cost-effectiveness is still pending confirmation in Spain.

Antibodies against the donor antigen glutathione S-transferase T1 after renal transplantation.

The aim of the present study was to determine whether a kidney graft expressing the glutathione S-transferase T1 enzyme (GSTT1) could cause an alloimmune response in a recipient with the null GSTT1 genotype that was similar to that observed in liver transplant. We have found anti-GSTT1 antibodies in the sera of a number of patients and confirmed that only one of the four possible genetic combinations--positive donor/null receptor--could lead to the production of these antibodies. Nevertheless, the main finding of this study is that in kidney transplantation, this mismatch was not sufficient to trigger an immune reaction. Longer follow-up of the posttransplant evolution of the patients is required in order to clarify the contribution of the factors involved in this process.

Cost of renal transplant maintenance immunosuppression: effect of control of vascular risk factors.

In 3 renal transplant cohorts treated in Spain in 1990, 1994, and 1998 (total number, 3279), we studied the frequency of certain cardiovascular risk factors. Their effect on the cost of drugs was assessed from the data from 1 center; the mean cost of antihypertensive agents per patient-year was 349 euros, and of lipid-lowering drugs was 294 euros. Between 1990 and 1998 the frequency of use of antihypertensive agents at 2 years increased from 70% to 80%, and that of lipid-lowering agents from 12% to 46% (P < .001). Patients received various regimens of immunosuppression at the second year, as follows: (1) steroid-free: cyclosporine, 2.3%; tacrolimus, 9.9%; cyclosporine plus mycophenolate, 16.2%; and tacrolimus plus mycophenolate, 11.8% (P < .001); (2) antihypertensive agents: 74.9% of patients receiving tacrolimus, with or without mycophenolate, versus 80.7% of those receiving cyclosporine (P = .022); (3) lipid-lowering drugs: 28.4% of patients receiving tacrolimus, with or without mycophenolate, versus 51.1% of those receiving cyclosporine (P < .001). The increase in associated drug costs must be added to the recent large increase in the cost for immunosuppressive agents, which rose from 3854 euros per year, in 1990 to 5374 euros per year in 1998. A lower cost of associated drugs tends to lessen the overall cost of therapies with tacrolimus. Because cardiovascular disease is the main cause of death, these findings should be taken into account in the assessment of the long-term cost-benefit ratio.

Pharmacokinetics of mycophenolate mofetil in kidney transplant patients with renal insufficiency.

Mycophenolate mofetil (MMF) is an immunosuppressant that is widely used for prophylaxis of rejection in solid organ transplantation. In this study, we examined the effect of renal insufficiency on the pharmacokinetics of MMF, particularly on the free fraction of drug in renal transplant patients. Our study was performed on 10 patients with severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min), and 10 control patients with preserved renal function (CrCl >90 mL/min). All the patients had received a cadaveric donor graft at least 1 year prior and were clinically stable under treatment with MMF and cyclosporine. For each patient, we determined 12-hour areas under the curve (AUC(0-12 h)) for the metabolites: mycophenolic acid (MPA), 7-O-mycophenolic acid glucuronide (MPAG), and the free non-protein-bound fraction of MPA (f-MPA). The two groups were matched for age, sex, and MMF dose. Mean AUC(0-12 h) values for MPA were similar in both groups. The renal insufficiency group showed a significantly increased AUC(0-12 h) for MPAG (1550 +/- 392 vs 3527 +/- 1130 microg.h/mL, P < .001) and increased trough and AUC(0-12 h) values for f-MPA (0.023 +/- 0.02 vs 0.094 +/- 0.07 microg/mL, P = .003, and 0.87 +/- 0.3 vs 1.52 +/- 0.8 microg . h/mL, P = .016, respectively). We proposed that these differences should be taken into account when deciding upon the dose of this drug for the subset of patients with impaired transplant function.