Cinacalcet for hypercalcaemic secondary hyperparathyroidism after renal transplantation: a multicentre, retrospective, 3-year study.

AIMS: Our aim was to evaluate the long-term effect of cinacalcet in patients with hypercalcaemic secondary hyperparathyroidism (SHPT) after renal transplantation (RT) in order to expand real-world data in this population. METHODS: We performed a multicentre, observational, retrospective study in 17 renal transplant units from Spain. We collected data from renal recipients with hypercalcaemic (calcium >10.2 mg/dL) SHPT (intact parathyroid hormone (iPTH) > 120 pg/mL) who initiated cinacalcet in the clinical practice. RESULTS: We included 193 patients with a mean (standard deviation (SD)) age of 52 (12) years, 58% men. Cinacalcet treatment was initiated at a median of 20 months after RT (median dose 30 mg/day). Mean calcium levels decreased from a mean (SD) of 11.1 (0.6) at baseline to 10.1 (0.8) at 6 months (9.0% reduction, P < 0.0001). Median iPTH was reduced by 23.0% at 6 months (P = 0.0005) and mean phosphorus levels increased by 11.1% (P < 0.0001). The effects were maintained up to 3-years. No changes were observed in renal function or anticalcineurin drug levels. Only 4.1% of patients discontinued cinacalcet due to intolerance and 1.0% due to lack of efficacy. CONCLUSIONS: In renal transplant patients with hypercalcaemic SHPT, cinacalcet controlled serum calcium, iPTH and phosphorus levels up to 3 years. Tolerability was good.

Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study.

The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3(+) peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.

Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the Symphony Study.

BACKGROUND: The aim of this study was to determine the relationship between single-nucleotide polymorphisms (SNPs) in MRP2 genes and mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients of the Symphony Pharmacogenomic substudy. METHODS: Sixty-six renal transplant recipients of eight Spanish centres were randomized into four branches of immunosuppressive regimen: low dose of cyclosporine, standard dose of cyclosporine, tacrolimus and sirolimus, all in addition to mycophenolate mofetil and steroids. Fifty-five patients were genotyped for SNPs in MRP2, C24T and C3972T. Pharmacokinetic sampling was done before MPA administration and up to 12 h post-dose at Day 7, 1 month and 3 months post-transplant. Relationships of area under the curve (AUC) of MPA and MPAG plasma sampling with the presence of MRP2 SNPs and with the immunosuppressive regimens were studied. RESULTS: At steady-state conditions, MPA-reduced exposure was observed in C24T variant allele in MRP2 (CC: 68.73 ± 6.78; *T: 48.12 ± 4.90, P = 0.023); no significant differences linked to C3972T SNP were observed. Taking into account groups of treatment, lower MPA AUC in variant allele of C24T was only found under macrolides treatment with statistically significant differences at Month 3 (Tac and SRL, CC: 86.52 ± 10.98 versus *T: 41.99 ± 4.82, P = 0.001; CsA, CC: 52.31 ± 5.30 versus *T: 54.24 ± 8.30, P = 0.772); for C3972T, the same tendency was found but differences at steady state did not reach statistical significance. CONCLUSIONS: Renal transplant recipients T carriers of C24T MRP2 with macrolides treatment were associated with reduced MPA AUC in steady-state conditions. Patients treated with cyclosporine lost the effect of this polymorphism.

Prevention of cytomegalovirus disease using pre-emptive treatment after solid organ transplant in patients at high risk for cytomegalovirus infection.

BACKGROUND: The use of pre-emptive or prophylactic treatment to control cytomegalovirus (CMV) replication after solid organ transplant (SOT) remains controversial. The aim of this study was to evaluate whether administration of pre-emptive treatment to control viral replication guided by a highly sensitive diagnostic tool is an effective approach for preventing CMV disease, even in high-risk transplant recipients. METHODS: Plasma samples from eight SOT patients were tested using antigenaemia and real-time PCR (RT-PCR) assays. Pre-emptive treatment was administered guided by RT-PCR when viral load values were >1,000 copies/ml. RESULTS: All patients developed episodes of CMV infection, but none of them developed CMV disease or indirect effects. No patient in this study died or experienced graft rejection. Treatment was needed in 10 replication episodes. At the end of treatment, four had undetectable levels and the other six were cleared 3 weeks later. In 42.6% of tested samples RT-PCR was more sensitive for detecting viral infection. CONCLUSIONS: Pre-emptive monitoring of SOT patients at high risk for CMV infection protected patients from developing CMV disease during the first 6 months after transplant. The use of this sensitive method for guiding pre-emptive treatment diminished viral load early enough that it did not have consequences for patient health.

The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy.

BACKGROUND: Exposure to mycophenolic acid (MPA), the primary active metabolite of mycophenolate mofetil (MMF), is correlated with therapeutic efficacy of MMF but varies depending on the concomitantly administered immunosuppressive drugs. METHODS: A 3-month pharmacokinetic substudy of the prospective, randomized, multicentre, open-label Symphony study was performed. Eighty-three adult renal transplant patients received standard-dose cyclosporine, MMF 2 g/day and corticosteroids, or daclizumab induction, MMF 2 g/day and corticosteroids plus low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The area under the concentration-time curve (AUC(0-12)) of MPA and its metabolites between treatment groups was compared. Pharmacokinetic sampling was performed before MMF administration and at 20, 40, 75 min; 2, 3, 6, 8, 10 and 12 h post-dose on Day 7 and Months 1 and 3. RESULTS: Compared with standard-dose cyclosporine, patients receiving low-dose tacrolimus or low-dose sirolimus had significantly higher AUC(0-12) values for MPA at Day 7 and Month 1 and for free MPA at Day 7, and significantly lower AUC(0-12) values for 7-O-MPA-glucuronide (MPAG) at Month 1 and for acyl-glucuronide at Months 1 and 3 (P < 0.05). AUC(0-12) of MPA and free MPA was significantly greater with low-dose tacrolimus and low-dose sirolimus than with low-dose cyclosporine in the first month (P < 0.05). The ratio of MPA to MPAG exposure was significantly higher in the three low-dose groups than in the standard-dose cyclosporine group (P < 0.05). CONCLUSIONS: Standard- and low-dose cyclosporine reduces the exposure of MPA and free MPA compared to low-dose tacrolimus or low-dose sirolimus in patients given the same dose of MMF.

Direct-acting Antivirals for the Treatment of Kidney Transplant Patients With Chronic Hepatitis C Virus Infection in Spain: A Long-term Prospective Observational Study.

BACKGROUND: Direct-acting antivirals (DAA) allow effective and safe eradication of hepatitis C virus (HCV) in most patients. There are limited data on the long-term effects of all-oral, interferon-free DAA combination therapies in kidney transplant (KT) patients infected with HCV. Here we evaluated the long-term tolerability, efficacy, and safety of DAA combination therapies in KT patients with chronic HCV infection. METHODS: Clinical data from KT patients treated with DAA were collected before, during, and after the treatment, including viral response, immunosuppression regimens, and kidney and liver function. RESULTS: Patients (N = 226) were mostly male (65.9%) aged 56.1 ± 10.9 years, with a median time from KT to initiation of DAA therapy of 12.7 years and HCV genotype 1b (64.6%). Most patients were treated with sofosbuvir-based therapies. Rapid virological response at 1 month was achieved by 89.4% of the patients and sustained virological response by week 12 by 98.1%. Liver function improved significantly after DAA treatment. Tacrolimus dosage increased 37% from the beginning of treatment (2.5 ± 1.7 mg/d) to 1 year after the start of DAA treatment (3.4 ± 1.9 mg/d, P < 0.001). Median follow-up was 37.0 months (interquartile range, 28.4-41.9) and death-censored graft survival was 91.1%. Adverse events resulting from DAA treatment, especially anemia, were reported for 31.0% of the patients. CONCLUSIONS: Chronic HCV infection can be treated efficiently and safely with DAA therapy in KT patients. Most patients retained stable kidney function and improved liver function. Tacrolimus dose had to be increased in most patients, potentially as a result of better liver function.

Anti-glutathione S-transferase T1 antibody-mediated rejection in C4d-positive renal allograft recipients.

BACKGROUND: Chronic humoral rejection is a progressive form of graft injury, with defined diagnostic criteria, the crucial one being the evidence of circulating anti-donor antibodies. These antibodies are mainly directed against human leucocyte antigens (HLA), but other targets have also been described. We previously reported that antibodies against the Glutathione S-transferase T1 (GSTT1) enzyme appear in recipients without the GSTT1 gene who receive a graft from a GSTT1-positive donor. The primary aim of this study was to analyse the role of GSTT1 in cases of antibody-mediated rejection (AMR) in the absence of anti-HLA antibodies. A second objective was to describe the distribution of the GSTT1 enzyme in the human kidney. METHODS: Four renal biopsies from four renal transplanted patients with declined renal function and circulating anti-donor GSTT1 antibodies were studied for C4d deposits in sections of paraffin-embedded tissue samples. Anti-donor-specific HLA and MICA antibody detection was done with the Luminex platform and anti-GSTT1 antibodies were tested by indirect immunofluorescence on rat tissues and ELISA assay. DNA of the patients was extracted for GSTT1 genotyping. RESULTS: Four patients with the GSTT1 donor/recipient mismatch developed anti-GSTT1 antibodies 32, 42, 48 and 60 months after the transplant. One patient also had donor-specific anti-HLA antibodies. Their biopsies showed pathologic lesions compatible with chronic antibody-mediated rejection (CAMR), along with positive C4d deposition in peritubular capillaries in three of them, being no valuable in the other case. CONCLUSION: This is the first study reporting an association between the appearance of chronic antibody-mediated renal allograft rejection and the occurrence of de novo production of anti-GSTT1 antibodies, in the absence of anti-HLA donor-specific antibodies. This fact suggests a potential role of the GSTT1 system in anti-graft immune response.

CMV-specific T-cell immunity in solid organ transplant recipients at low risk of CMV infection. Chronology and applicability in preemptive therapy.

OBJECTIVES: To characterize whether the CMV-specific cellular immune response can be used as a predictor of the control of CMV infection and disease and determine thresholds in solid organ transplant (SOT) recipients seropositive for CMV (R+). METHODS: The CMV-specific T-cell response was characterized using intracellular cytokine staining and the evolution of clinical and virological parameters were recorded during the first year after transplantation. RESULTS: Besides having positive CMV serology, only 28.4% patients had positive immunity (CD8+CD69+IFN-γ+ ≥0.25%) at 2 weeks after transplantation. These patients had less indication of preemptive treatment (p = 0.025) and developed less high grade (≥2000 IU/ml) CMV replication episodes (p = 0.006) than patients with no immunity. Of the 49 patients with a pretransplant sample, only 22.4% had positive immunity, and had a detectable immune response early after transplantation (median of 3.7 weeks). However, only 50% of patients with negative pretransplant immunity acquired a positive immune response and it was significantly later, at a median of 11 weeks (p < 0.001). Patients that developed CMV disease had no CMV-specific immunity. CONCLUSIONS: Having CMV-specific CD8+IFN-γ+ cells ≥0.25% before transplant; 0.15% at two weeks or 0.25% at four weeks after transplantation, identifies patients that may spontaneously control CMV infection and may require less monitoring.

Alloimmune response against donor glutathione S-transferase T1 antigen in renal transplant recipients.

BACKGROUND: The long-term outcome of kidney transplantation could be influenced by the appearance of antibodies against donor-specific antigens. Glutathione S-transferase T1 (GSTT1) is a protein preferentially expressed in liver and kidney cells. Deletion of the GSTT1 gene results in a complete lack of protein expression, which occurs in 20% of the white population. GSTT1 donor-recipient mismatch has been deleterious in liver transplantation. The purpose of this study is to examine immunologic and clinical consequences of a GSTT1 donor-recipient mismatch in kidney transplantation. METHODS: The presence of anti-GSTT1 antibodies was studied retrospectively in sera from 135 patients who underwent transplantation before 1995. Samples from 89 patients who received a GSTT1-positive kidney graft between December 1998 and May 2001 were collected prospectively. GSTT1 genotypes and anti-GSTT1 antibodies were studied by using standard methods. RESULTS: Seven patients, all with the null genotype, produced anti-GSTT1 antibodies. No transplant recipient with a positive genotype produced these antibodies. Six of 7 patients with antibodies also were positive for hepatitis C virus. Clinical outcomes of these patients did not differ from those of the entire group. CONCLUSION: After kidney transplantation, some patients with the null GSTT1 genotype who received a GSTT1-positive graft developed an immune response, with production of anti-GSTT1 antibodies. The presence of these antibodies did not seem to produce functional impairment in the graft. Hepatitis C virus seems to have a prominent role in this particular allograft immune response.

Medium-Term Renal Function in a Large Cohort of Stable Kidney Transplant Recipients Converted From Twice-Daily to Once-Daily Tacrolimus.

BACKGROUND: There is some evidence pointing toward better renal function in kidney transplant recipients (KTR) treated with once-daily tacrolimus (QD-TAC) vs. twice-daily tacrolimus (BID-TAC). METHODS: This is an extension study of a 1-year, single arm prospective study of stable KTR who were converted from BID-TAC to QD-TAC (4.9 ± 4.0 years after transplantation) in Spanish routine clinical practice. Patient and graft survival, renal function, acute rejection episodes, and other analytic parameters were assessed at 24 and 36 months after conversion. RESULTS: A total of 1798 KTR were included in the extension study. Tacrolimus doses at 36 months were significantly lower compared to those at time of conversion (-0.2 mg/day; P = 0.023). Blood levels were lower than baseline during all the study (P < 0.001). Graft and patient survival at 3 years after conversion were 93.9% and 95.1%, respectively. Compared with baseline, the mean estimated glomerular filtration rate (eGFR) remained very stable at all timepoints (56.7 ± 19.8 vs 58.1 ± 24.6 mL/min per 1.73 m(2) at month 36; P = 0.623). Even when patients reinitiating dialysis were counted as eGFR = 0, the mean eGFR was very stable. In fact, a small but significant increase was observed at 36 months versus baseline (+0.1 mL/min per 1.73 m(2); P = 0.025). An increase in proteinuria was observed at 36 months versus baseline (+0.11 g/24 h; P < 0.001). Acute rejection rates were low during the study. CONCLUSIONS: Conversion from BID-TAC to QD-TAC in a large cohort of stable KTR was safe and associated with a very stable renal function after 3 years. Comparative studies are warranted to assess the feasibility of such conversion.

Early-onset anemia after kidney transplantation is an independent factor for graft loss: a multicenter, observational cohort study.

BACKGROUND: The association of anemia with outcomes after renal transplantation (RT) is unclear. METHODS: We performed a retrospective study that included patients who received a RT in Spain in 2007. We collected data on anemia (hemoglobin [Hb] <11 g/dL and/or erythropoietic agents and/or transfusion in the previous month) as well as transplantation and clinical data during follow-up. We used multivariate Cox models to predict graft and patient survival. RESULTS: We included 639 patients; 7.2% lost their graft and 6.3% died. The prevalence of anemia was 84% at 7 days, 77% at 1 month, 41% at 2 months, 16% at 12 months, 14% at 24 months, and 18% at 36 months. After adjusting by glomerular filtration rate (hazard ratio [95% confidence interval], 0.96 [0.93-0.98]), low Hb levels at 1 month remained as an independent predictor of graft loss (hazard ratio for each 1 g/dL increase, 0.72 [0.54-0.96]) along with a maximum panel-reactive antibody of more than 10% (3.80 [1.73-8.36]), a donor with stroke (3.30 [1.31-8.28]), and one or more acute rejection episode (13.89 [4.78-40.37]). Tacrolimus use was a protective factor (0.24 [0.11-0.50]). CONCLUSIONS: Low Hb levels in the early posttransplantation period (1 month) seem to be an independent prognostic factor for graft loss, but not for mortality, in Spanish RT patients regardless of graft function, recipient and donor characteristics, unfavorable events within the first month, and immunosuppression.

Effect of long-term steroid withdrawal in renal transplant recipients: a retrospective cohort study.

Background. Steroids are largely effective for the immunosuppressive treatment in renal transplant patients, but cause severe side effects. Whether steroid withdrawal confers long-term beneficial effects remains unclear.Methods. Data on 4481 cadaveric kidney transplant recipients were collected to estimate the impact of steroid withdrawal on kidney function and graft and patient survival using multivariate Cox regression models.Results. A total of 923 patients (20.6%) had steroid treatment withdrawn. This was more common in recipients from younger donors and in older recipients, and in recipients with a first transplant, those who had pre-transplant or de novo diabetes mellitus and those with fewer episodes of acute rejection (AR) (22.4% vs. 29.2%, P < 0.001). Cox multivariate analysis stratifying by propensity scores showed that long-term steroid therapy was associated with a 70% increase in the risk of patient death. The repeated measures linear model showed that, although the abbreviated Modification of Diet in Renal Disease (aMDRD) values changed over time (P = 0.002), this was independent of steroid withdrawal (P = 0.08). In addition, of the 772 (17.2%) recipients who developed de novo diabetes mellitus, 204 (26.4%) ceased antidiabetic therapy, with more of these among those who ceased steroids (23% vs. 33.3%, P = 0.003). Blood pressure, cholesterol and triglyceride values were all significantly lower in the patients who ceased steroids.Conclusions. Steroid withdrawal in selected patients had no negative effect over time on renal function and graft survival, and it was associated with reduced mortality.

Open-label trial: effect of weekly risedronate immediately after transplantation in kidney recipients.

BACKGROUND: Treatment with oral risedronate to prevent bone mineral density (BMD) loss in renal transplant recipients has been shown to be effective. There is no agreement on the optimum moment of introduction or how long it should be continued. The aim was to evaluate the effectiveness of risedronate at doses of 35 mg/week in renal transplant recipients who underwent treatment immediately after transplant. METHODS: A randomized clinical trial was performed on 101 renal transplant patients. The study group (52 patients) received 35 mg risedronate weekly, vitamin D, and calcium, whereas the control group (49 patients) received only vitamin D and calcium. At baseline, 3, 6, and 12 months, basic biochemistry and mineral bone metabolic parameters were determined. Vertebra and hip fracture assessment was performed by means of x-ray and DEXA; an intention-to-treat analysis was performed. RESULTS: Patients in control group showed a significant worsening of BMD (P<0.05) 12 months into the study. At all follow-up points, lumbar BMD of the study group was significantly greater (P<0.05), whereas femoral BMD of those treated with risedronate was only significant at 6-month follow-up (P<0.05). There was a trend of more vascular calcifications and fractures in the control group, but this was not statistically significant. CONCLUSION: Weekly oral administration of risedronate immediately after renal transplantation contributes to an improved BMD, particularly in the femoral neck at 6-month follow-up, without major side effects. Long-term follow-up is needed to establish whether oral risedronate has an influence on vascular calcifications and bone fractures.

Renal transplantation in patients with hepatitis C virus antibody. A long national experience.

Background. Renal transplantation is the best therapy for patients with hepatitis C virus (HCV) infection with end-stage renal disease. Patient and graft survival are lower in the long term compared with HCV-negative patients. The current study evaluated the results of renal transplantation in Spain in a long period (1990-2002), focusing on graft failure.Methods. Data on the Spanish Chronic Allograft Nephropathy Study Group including 4304 renal transplant recipients, 587 of them with HCV antibody, were used to estimate graft and patient survival at 4 years with multivariate Cox models.Results. Among recipients alive with graft function 1 year post-transplant, the 4-year graft survival was 92.8% in the whole group; this was significantly better in HCV-negative vs HCV-positive patients (94.4% vs 89.5%, P < 0.005). Notably, HCV patients showed more acute rejection, a higher degree of proteinuria accompanied by a diminution of renal function, more graft biopsies and lesions of de novo glomerulonephritis and transplant glomerulopathy. Serum creatinine and proteinuria at 1 year, acute rejection, HCV positivity and systolic blood pressure were independent risk factors for graft loss. Patient survival was 96.3% in the whole group, showing a significant difference between HCV-negative vs HCV-positive patients (96.6% vs 94.5%, P < 0.05). Serum creatinine and diastolic blood pressure at 1 year, HCV positivity and recipient age were independent risk factors for patient death.Conclusions. Renal transplantation is an effective therapy for HCV-positive patients with good survival but inferior than results obtained in HCV-negative patients in the short term. Notably, HCV-associated renal damage appears early with proteinuria, elevated serum creatinine showing chronic allograft nephropathy, transplant glomerulopathy and, less frequently, HCV-associated de novo glomerulonephritis. We suggest that HCV infection should be recognized as a true risk factor for graft failure, and preventive measures could include pre-transplant therapy with interferon.

Efficacy and safety of enteric-coated mycophenolate sodium in renal transplant patients with diabetes mellitus: post hoc analyses from three clinical trials.

To examine the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) in renal transplant patients with diabetes mellitus, six- and 12-month data from three clinical trials with EC-MPS (Studies B301, B302, and myPROMS) were analyzed post hoc. Studies B301 (de novo patients) and B302 (maintenance patients) followed a randomized double-blind design whereas myPROMS was an open-label study in de novo and maintenance renal transplant patients in which all patients received EC-MPS as part of their immunosuppressive regimen. In studies B301 and B302, diabetic patients were compared against mycophenolate mofetil (MMF, CellCept), the reference drug. For myPROMS, data from diabetic and non-diabetic patients were compared. In total, 246 diabetic patients receiving EC-MPS were analyzed. In study B301, the efficacy failure rate [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up] in diabetics at 12 months was 17.6% (EC-MPS) vs. 26.2% (MMF), and of BPAR alone 14.7% vs. 19.0% (both n.s.). In de novo patients from myPROMS, the treatment failure rate was similar in diabetic (20.3%) and non-diabetic patients (27.1%), as was the incidence of BPAR (17.7% vs. 23.1%, both n.s.). The overall incidence, severity and pattern of AEs were comparable between EC-MPS and MMF in de novo patients. This was supported by the safety results assessed in maintenance patients (B302) indicating no increased safety risk with the use of EC-MPS in the diabetic patient population, if compared with MMF. Likewise, apart from a higher incidence of severe/serious infections in diabetics, the safety profile of EC-MPS was not different to non-diabetics in myPROMS. In conclusion, preliminary data suggest that EC-MPS in combination with cyclosporine (+/- steroids) can be used efficiently and safely for the prophylaxis of organ rejection in diabetic renal transplant patients. Moreover, diabetic patients can apparently be safely converted from MMF to EC-MPS. More data from prospective studies are needed to fully judge the efficacy and safety profile of EC-MPS in the diabetic transplant population.

Impact of the new drugs in the cost of maintenance immunosuppression of renal transplantation. Is it justified?

BACKGROUND: The new immunosuppressive drugs control acute rejection better, and have potentially short-term economic advantages. However, their long-term cost-effectiveness must still be determined. The Spanish study of chronic transplant nephropathy provides data that facilitates the assessment of the economic importance of maintenance immunosuppression (MI). METHODS: We determined the frequency of use of the different MI drugs and their combinations in three renal transplantation cohorts performed in 1990, 1994 and 1998 (total: 3279), and their evolution over time. Based on the real costs found in a medium-sized service in our country at the end of 2000, the mean annual costs of MI drugs were calculated. We performed a multivariate analysis of graft survival in the 1998 cohort. RESULTS: In 1990 and 1994, cyclosporine (CsA) with or without azathioprine (AZA) was used almost exclusively as the initial MI drug. In 1998, 76% received mycophenolate mofetil (MMF) and 20% tacrolimus (TAC). During their follow-up, a growing number of patients from the 1990 and 1994 groups were converted to MMF (12 and 17%) and TAC (4 and 8%), while the treatment of those from 1998 remained stable. Using prices from the year 2000, the mean cost of the MI at the end of the first year in 1998 (5380) was almost double that of 1994 (2902) and 1990 (2855). In these two groups, the mean cost remained stable until 1996; afterwards, it increased in both, more rapidly in the 1994 (24.8%) than in the 1990 (17.3%) group, although it remained significantly inferior to that of 1998. Correction for the evolution of the drug prices and the peseta purchasing value lessened these changes in an important way. The new regimens allowed for the withdrawal of steroids in a greater proportion of cases; TAC was associated with a less frequent use of lipid-lowering drugs and antihypertensive drugs. In the whole patient group, the regimens with MMF and/or TAC showed a tendency to greater mean life of the organs, but without reaching statistical significance in the multivariate analysis of patients in 1998. CONCLUSIONS: The introduction of new drugs in the MI applied in Spain has had an important economic impact since 1996. Their cost-effectiveness is still pending confirmation in our country.