Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients.

Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.

Genotype and allele frequencies of drug-metabolizing enzymes and drug transporter genes affecting immunosuppressants in the Spanish white population.

Interpatient variability in drug response can be widely explained by genetically determined differences in metabolizing enzymes, drug transporters, and drug targets, leading to different pharmacokinetic and/or pharmacodynamic behaviors of drugs. Genetic variations affect or do not affect drug responses depending on their influence on protein activity and the relevance of such proteins in the pathway of the drug. Also, the frequency of such genetic variations differs among populations, so the clinical relevance of a specific variation is not the same in all of them. In this study, a panel of 33 single nucleotide polymorphisms in 14 different genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, MTHFR, NOD2/CARD15, SLCO1A2, SLCO1B1, TPMT, and UGT1A9), encoding for the most relevant metabolizing enzymes and drug transporters relating to immunosuppressant agents, was analyzed to determine the genotype profile and allele frequencies in comparison with HapMap data. A total of 570 Spanish white recipients and donors of solid organ transplants were included. In 24 single nucleotide polymorphisms, statistically significant differences in allele frequency were observed. The largest differences (>100%) occurred in ABCB1 rs2229109, ABCG2 rs2231137, CYP3A5 rs776746, NOD2/CARD15 rs2066844, TPMT rs1800462, and UGT1A9 rs72551330. In conclusion, differences were recorded between the Spanish and other white populations in terms of allele frequency and genotypic distribution. Such differences may have implications in relation to dose requirements and drug-induced toxicity. These data are important for further research to help explain interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

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.

Increased hospital stay and allograft dysfunction in renal transplant recipients with Cyp2c19 AA variant in SNP rs4244285.

Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventy-five renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23-39 days), compared with 12 days (95% CI, 10-15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (C(min)/[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to CYP3A5*1/*3 or CYP3A5*1/*1 genotype. Recipients with CYP2C19*2/*2 genotype also showed allograft delayed function (acute tubular necrosis in 3 patients). Genotyping of CYP3A5 and CYP2C19 in renal transplantation should be considered to be of interest when treating with tacrolimus and omeprazole, because CYP2C19*2/*2 variant indirectly elicits an increase of tacrolimus blood levels and, in our study population, the adverse effects described.

Clinical profile and post-transplant anaemia in renal transplant recipients restarting dialysis after a failed graft: changing trends between 2001 and 2009.

BACKGROUND: The aim of this study was to compare the clinical profile, outcome and the prevalence and management of anaemia between two cohorts of renal transplant patients with graft failure restarting dialysis in 2001 and 2009. METHODS: Cross-sectional, observational, retrospective and multicentre study of 397 patients in the 2001 cohort and 222 in the 2009 cohort. Data were recorded at 0, 3, 6, 9 and 12 months before the onset of dialysis resumption and during the first 90 days after restarting dialysis (mortality and hospital admission). RESULTS: Patients in the 2009 cohort were older at the time of inclusion in the study and transplantation, and restarted dialysis therapy with a significantly better glomerular filtration rate. In both cohorts, there was a rapid deterioration of renal function with statistically significant differences in serum creatinine and glomerular filtration rate between the monthly intervals -12 and 0. The mean haemoglobin value at -12 months was 11.6 g/dL [7.2 mmol/L] in the 2001 cohort when compared with 12.3 g/dL [7.6 mmol/L] in the 2009 cohort, and at the time of restarting dialysis 9.6 g/dL [6.0 mmol/L] versus 10.6 g/dL [6.6 mmol/L]. The percentage of patients treated with erythropoiesis-stimulating agents, at any time during the 12 months before readmission to dialysis, increased significantly from 61.5% in the 2001 cohort to 96% in the 2009 cohort. There were no significant differences between the 2001 and 2009 cohorts in mortality rate (8.8 versus 9.0%) or hospital admission (31.5 versus 31.1%) during the study time. CONCLUSIONS: At restarting dialysis, the proportion of patients with anaemia (and its severity) due to progressive graft nephropathy decreased over the past 8 years, increasing significantly the percentage of patients treated with erythropoietin. Differences in morbimortality after dialysis resumption were not observed, this is probably due to an increase in the age of donors and recipients.

Late evolution of kidney transplants in elderly donors and recipients receiving initial immunosuppressant treatment with daclizumab, mycophenolate mofetil, and delayed introduction of tacrolimus.

BACKGROUND: Organ transplants in elderly recipients have increased over the past few years. This situation poses specific problems both in terms of organs and recipients; therefore, immunosuppressant regimens must be adapted accordingly. A previous study demonstrated good initial results in kidney transplant cases in which older donors and recipients (average ages of 64.4 years and 61.3 years) had received initial immunosuppressant therapy with daclizumab and mycophenolate mofetil as well as delayed introduction of reduced-dose tacrolimus. In this study we reviewed the long-term results in the same group of patients. METHODS: An observational, retrospective multi-centre study carried out at a national level to determine survival rates and renal function in 126 patients included in the initial study (127 patients who survived the first year with a functioning graft, 123 treated according to protocol). We gathered data from the 2nd to the 6th year for 120, 118, 113, 102 and 62 patients, respectively. The evolution of renal function, relevant clinical data, and safety profiles were also analysed. RESULTS: After five years, most patients continued with the initial immunosuppressant regimen: 92% tacrolimus and 80% mycophenolate mofetil; 48% had abandoned steroids and proliferation signal inhibitors had been introduced in 3%. Patient and graft survival (adjusted for patient death) after five years was 93.1% and 93.8%, respectively. The main cause of death was neoplasia (in 7 out of 10 cases) whilst graft loss was mainly due to death with a functioning graft. The other causes of death were 2 acute myocardial infarctions and a gastrointestinal haemorrhage. Renal function was moderately but significantly reduced with the passing of time (P<.001): average creatinine levels in the overall group of patients rose from 1.60 ± 0.50mg/dl after the 1st year to 1.63 ± 0.70 mg/dl at the end of study. MDRD dropped from 46.28 ± 15.64 ml/min after the 1st year to 45.69 ± 15.44 ml/min at the end of study (P<.01). Only two acute rejections were observed after the 1st year. There were 19 cardiovascular events registered in 12 patients. CONCLUSIONS: The regimen used in our study was useful and appropriate for elderly donor-recipient pairs as demonstrated by the good long-term survival results, continued optimum renal function, and acceptable safety profile.

Análisis de infección por citomegalovirus y sus consecuencias en el trasplante renal: revisión de una década / Analysis of cytomegalovirus infection and its consequences in renal transplantation: a decade analysis

Fundamento y objetivo: El citomegalovirus (CMV) es uno de los agentes patógenos más importantes en el paciente trasplantado renal. Puede ocasionar infección y enfermedad, de graves consecuencias, directas e indirectas. Pacientes y método: Estudio observacional descriptivo retrospectivo de todos los trasplantes renales realizados en el Hospital La Fe entre 1994 y 2005 (n=996). El diagnóstico de infección o enfermedad por CMV se realizó mediante serología, cultivo, determinación de antigenemia pp65 o cuantificación de CMV por reacción en cadena de la polimerasa (PCR) en sangre periférica. La profilaxis recibida fue aciclovir en 20 pacientes (2,4%), ganciclovir en 478 (56,8%), valganciclovir en 166 (19,7%,) y ninguna en 178 (21%). Resultados: La serología para CMV era positiva en 802 donantes (83%) y en 860 receptores (89%). Entre los receptores que padecieron enfermedad por CMV (N=60), perdieron el injerto cuatro y fallecieron seis. La infección precoz y la enfermedad precoz fueron significativamente más frecuentes (p<0,05) en los casos donante positivo-receptor negativo (D+/R-). Padecer infección precoz o tardía se asociaba a muerte por cualquier causa (odds ratio [OR] 2,03, intervalo de confianza del 95% [IC 95%] 1,24-3,31, p<0,05). La enfermedad precoz o tardía por CMV se asociaba a mayor pérdida del injerto por cualquier causa (OR 1,97, IC 95% 1,14-3,43, p<0,05). Tras regresión logística permanecía significativa la asociación entre infección por CMV y muerte por cualquier causa. Conclusiones: En pacientes con trasplante renal, presentar infección por CMV se asocia a muerte por cualquier causa (AU)

Background and objective: Cytomegalovirus (CMV) is one of the most important pathogens in renal transplant patients. It can cause infection and illness, as well as serious direct and indirect consequences. Patients and method: Descriptive retrospective observational study of all kidney transplants performed in the Hospital La Fe of Valencia between 1994 and 2005 (n=996). The diagnosis of CMV disease and disease was performed by serology, culture, pp65 antigenemia determination or quantification of CMV-PCR (polymerase chain reaction) in peripheral blood. Prophylaxis included acyclovir in 20 patients (2.4%), ganciclovir in 478 (56.8%), valganciclovir in 166 (19.7%) and none in 178 (21%). Results: CMV serology was positive in 802 donors (83%) and in 860 recipients (89%). Among the recipients who suffered from CMV disease (N=60), four lost the graft and six died. Early infection and early disease were significantly more frequent (p<0.05) in positive donor-negative recipient cases (D+/R-). Having early or late infection was associated with death from any cause (OR 2.03, CI 95% 1.24 to 3.31, p<0.05). Early or late CMV infection was associated with increased graft loss from any cause (OR 1.97, CI 95% 1.14 to 3.43, p<0.05). After logistic regression, the association between CMV infection and death from all causes remained significant. Conclusions: In renal transplant patients, having CMV infection was associated with death from any cause (AU)

[Analysis of cytomegalovirus infection and its consequences in renal transplantation: a decade analysis]. / Análisis de infección por citomegalovirus y sus consecuencias en el trasplante renal: revisión de una década.

BACKGROUND AND OBJECTIVE: Cytomegalovirus (CMV) is one of the most important pathogens in renal transplant patients. It can cause infection and illness, as well as serious direct and indirect consequences. PATIENTS AND METHOD: Descriptive retrospective observational study of all kidney transplants performed in the Hospital La Fe of Valencia between 1994 and 2005 (n=996). The diagnosis of CMV disease and disease was performed by serology, culture, pp65 antigenemia determination or quantification of CMV-PCR (polymerase chain reaction) in peripheral blood. Prophylaxis included acyclovir in 20 patients (2.4%), ganciclovir in 478 (56.8%), valganciclovir in 166 (19.7%) and none in 178 (21%). RESULTS: CMV serology was positive in 802 donors (83%) and in 860 recipients (89%). Among the recipients who suffered from CMV disease (N=60), four lost the graft and six died. Early infection and early disease were significantly more frequent (p<0.05) in positive donor-negative recipient cases (D+/R-). Having early or late infection was associated with death from any cause (OR 2.03, CI 95% 1.24 to 3.31, p<0.05). Early or late CMV infection was associated with increased graft loss from any cause (OR 1.97, CI 95% 1.14 to 3.43, p<0.05). After logistic regression, the association between CMV infection and death from all causes remained significant. CONCLUSIONS: In renal transplant patients, having CMV infection was associated with death from any cause.

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.

Early statin use is an independent predictor of long-term graft survival.

Background. Statin use in renal transplantation has been associated with a lower risk of patient death but not with an improvement of graft functional survival. The aim of this study is to evaluate the effect of statin use in graft survival, death-censored graft survival and patient survival using the data recorded on the Spanish Late Allograft Dysfunction Study Group.Patients and methods. Patients receiving a renal allograft in Spain in 1990, 1994, 1998 and 2002 were considered. Since the mean follow-up in the 2002 cohort was 3 years, statin use was analysed considering its introduction during the first year or during the initial 2 years after transplantation. Univariate and multivariate Cox regression analyses with a propensity score for statin use were employed to analyse graft survival, death-censored graft survival and patient survival.Results. In the 4682 evaluated patients, the early statin use after transplantation significantly increased from 1990 to 2002 (12.7%, 27.9%, 47.7% and 53.0%, P < 0.001). Statin use during the first year was not associated with graft or patient survival. Statin use during the initial 2 years was associated with a lower risk of graft failure (relative risk [RR] = 0.741 and 95% confidence interval [CI] = 0.635-0.866, P < 0.001) and patient death (RR = 0.806 and 95% CI = 0.656-0.989, P = 0.039). Death-censored graft survival was not associated with statin use during the initial 2 years.Conclusion. The early introduction of statin treatment after transplantation is associated with a significant decrease in late graft failure due to a risk reduction in patient death.

[Progression factors in chronic kidney disease. Non-immunological mechanisms]. / Factores de progresión de la enfermedad renal crónica. Mecanismos no inmunológicos.

Non-immunological factors in the progression of kidney disease in transplant patients are the following: high blood pressure, proteinuria, dislypidemia, etc. 1. Arterial hypertension treatment: Blood pressure must be measured periodically in all transplant patients. Similarly to native kidneys, in renal transplant patients arterial hypertension is a risk factor in the progression of kidney disease. Arterial hypertension represent a clinical marker of chronic allograft nephropathy and contributes to graft loss and to the morbid- mortality of these patients (Evidence level C). Blood pressure control should be < 130/80 mm Hg for renal transplant patients without proteinuria and 125/75 mm Hg for proteinuric patients (> 1 g/24 hours). Hypertension and proteinuria are frequently associated in the same patients, a global treatment of both seems more rational (Evidence level C). General measures should be instigated first with pharmacological therapy. All antihypertensive drugs are useful in renal transplant patients and the majority of patients will need two or more drugs. In proteinuric patients an angiotensin receptor antagonist or an ACE-inhibitor should be initiated. It is advisable to monitor the serum potassium and creatinine after the start of this drugs or during the treatment periodically, especially in patients with chronic kidney disease stage IV-V. 2. Proteinuria treatment: Proteinuria has been strongly correlated with reduced function and graft survival. Lowering proteinuria to values as near to normal as possible (< 0.5 g/24 hours). To reduce proteinuria, an angiotensin receptor antagonist, an ACE-inhibitor or a combination of both are required, with serum potassium or creatinine monitoring, especially in patients with chronic kidney disease stage IV-V. 3. Dyslipidemia treatment: For kidney transplant recipients the assessment of dyslipidemias should include a complete fasting lipid profile with total cholesterol, LDL, HDL, and triglycerides. Evidence from the general population indicates that treatment of dyslipidemias reduces cardiovascular disease and evidence in kidney transplant patients suggests that judicious treatment can be safe and effective in improving dyslipidemia. Therapeutic goal must be LDL < 100 mg/dl. (Evidence level C). 4. Others: Cigarette smoking, glucose intolerance or diabetes control and obesity should be assessed.

[Changes in bone and mineral metabolism in kidney transplant patients with chronic kidney disease]. / Alteraciones del metabolismo óseo mineral en la enfermedad renal crónica del paciente trasplantado renal.

DESCRIPTION: Recently, the Foundation has proposed new definitions KDIGO to refer to the alterations of bone - mineral metabolism in patients with chronic renal disease (CRD), relegating the traditional term of renal osteodystrophy (ODR). RECOMMEND: The term ODR exclusively to define alterations in bone morphology and architecture characteristic of the ERC. - And the term of bone-mineral alteration associated with the CRD to describe biochemical changes, and skeletal calcifications that occur as a result of alterations in mineral metabolism in the CRD. PATHOPHYSIOLOGY: The different metabolic abnormalities are secondary to the progressive loss of renal mass and renal function that leads to retention of phosphorus and a decrease in the levels of calcitriol which are responsible for the skeletal resistance to the action of PTH. CLINICAL FEATURES: The main clinical manifestations of abnormal bone mineral metabolism are posttransplantation osteoporosis and osteopenia producing an increase in fractures, osteonecrosis, and bone pain. DIAGNOSTIC METHODS: Biochemical parameters (calcium, phosphorus, PTH, 25 hydroxyvitamin D), X-ray bone densitometry and bone biopsy. (Evidence B). THERAPEUTIC ALTERNATIVES: It is recommended for the treatment and prevention of osteopenia - osteoporosis in transplant patients based on data from clinical evidence available from other study populations, such as in patients with chronic kidney disease. In addition to specific treatment, we must take into account the preventive measures to reduce the risk of fractures. Treatment includes specific measures for the prevention of bone loss (active metabolite of vitamin D analogues and bisphosphonates) and the treatment of persistent hyperparathyroidism (calcimiméticos). (Evidence B).

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.

Health-related quality of life of patients receiving low-toxicity immunosuppressive regimens: a substudy of the Symphony Study.

OBJECTIVE: To evaluate health-related quality of life (HRQoL) in patients with different low-toxicity regimens posttransplantation. METHODS: One hundred fifty-six patients were randomized to standard-dose cyclosporine A (CsA), mycophenolate mofetil, and corticosteroids or daclizumab induction, mycophenolate mofetil, and corticosteroids with a low dose of CsA, tacrolimus (Low-Tac), or sirolimus. SF-36 Health survey was completed at baseline, 3, 6, and 12 months. RESULTS: There were no differences between groups in SF-36 at baseline or at month 12. Low-Tac showed higher scores at month 3 than standard-dose CsA and low dose of CsA. Patients with serum creatinine less than or equal to 1.5 mg/mL had better HRQoL at 6 and 12 months. Proportion of these patients was higher in Low-Tac at 6 months. Physical component summary of Patients increased during follow-up, but mental component summary did not. Patients with acute rejection showed lower mental component summary at 6 months. CONCLUSIONS: No HRQoL differences were identified among groups, but the low-dose Tac group showed the fastest improvement.

Alteraciones del metabolismo óseo mineral en la enfermedad renal crónica del paciente transplantando renal / Changes in bone and mineral metabolism in kidney transplant patient with chronic kidney disease

Definición: Recientemente, la Fundación KDIGO (Kidney Disease: Improving Global Outcomes) ha propuesto nuevas definiciones para referirse a las alteraciones del metabolismo óseo-mineral de los pacientes con enfermedad renal crónica (ERC), relegando el término tradicional de «osteodistrofia renal» (ODR). Recomiendan: - El término de ODR para definir exclusivamente las alteraciones de la morfología y la arquitectura ósea propias de la ERC. - Y el término de alteración óseo-mineral asociada a la ERC para describir las alteraciones bioquímicas, esqueléticas y calcificaciones extraesqueléticas que ocurren como consecuencia de las alteraciones del metabolismo mineral en la ERC. Fisiopatología: Las diferentes alteraciones metabólicas son secundarias a la pérdida progresiva de masa renal y función renal, que conlleva una retención de fósforo y descenso de los niveles de calcitriol que son responsables de la resistencia esquelética a la acción de la PTH Manifestaciones clínicas: Las manifestaciones clínicas principales de las alteraciones del metabolismo óseo mineral postrasplante son la osteoporosis y la osteopenia, que producen un incremento de las fracturas, osteonecrosis y dolor óseo. Métodos diagnósticos: Parámetros bioquímicos (calcio, fósforo, PTH y 25 hidroxivitamina D), radiología ósea, densitometría y biopsia ósea (evidencia B). Alternativas terapéuticas: Para el tratamiento y la prevención de la osteopenia-osteoporosis en pacientes trasplantados se recomienda basarse en los datos de evidencia clínica disponibles de otras poblaciones de estudio, como la de los pacientes con ERC. Además del tratamiento específico, hay que tener en cuenta las medidas preventivas para reducir el riesgo de fracturas. El tratamiento específico incluye medidas para la prevención de pérdida de masa ósea (metabolitos activos de la vitamina D, activadores selectivos de los receptores de la vitamida D y bifosfonatos) y el tratamiento del hiperparatiroidismo persistente (calcimiméticos) (evidencia B) (AU)

Description: Recently, the Foundation has proposed new definitions KDIGO to refer to the alterations of bone - mineral metabolism in patients with chronic renal disease (CRD), relegating the traditional term of renal osteodystrophy ODR). Recommend: - The term ODR exclusively to define alterations in bone morphology and architecture characteristic of the ERC. - And the term of bone-mineral alteration associated with the CRD to describe biochemical changes, and skeletal calcifications that occur as a result of alterations in mineral metabolism in the CRD. Pathophysiology: The different metabolic abnormalities are secondary to the progressive loss of renal mass and renal function that leads to retention of phosphorus and a decrease in the levels of calcitriol which are responsible for the skeletal resistance to the action of PTH. Clinical features: The main clinical manifestations of abnormal bone mineral metabolism are posttransplantation osteoporosis and osteopenia producing an increase in fractures, osteonecrosis, and bone pain. Diagnostic methods: Biochemical parameters (calcium, phosphorus, PTH, 25 hydroxyvitamin D), X-ray bone densitometry and bone biopsy. (Evidence B) Therapeutic alternatives: It is recommended for the treatment and prevention of osteopenia - osteoporosis in transplant patients based on data from clinical evidence available from other study populations, such as in patients with chronic kidney disease. In addition to specific treatment, we must take into account the preventive measures to reduce the risk of fractures. Treatment includes specific measures for the prevention of bone loss (active metabolite of vitamin D analogues and bisphosphonates) and the treatment of persistent hyperparathyroidism (calcimiméticos). (Evidence B) (AU)

Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. METHODS: The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (deltaVvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of deltaVvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. RESULTS: A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The deltaVvintima/artery was not different between treatment and placebo groups (6.9+/-8.2% vs. 6.9+/-7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (kappa 0.86 vs. 0.33). CONCLUSIONS: In summary, there were no differences in deltaVvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

PCR assays for the early detection of BKV infection in 125 Spanish kidney transplant patients.

BK virus (BKV) reactivation arises from immunocompromised conditions and can produce a tubulointerstitial nephropathy (BKVN) in kidney transplant recipients (KTR). Approximately 5% of KTR develop BKVN, and about 45% of these lose their graft. Therefore, using molecular tools to test for BKV may be helpful in early detection. A series of 125 Spanish KTR, originating from a single transplant center, were studied in relation to BKV infection in the first post-transplant year. First, we carried out a urinary cytological study, looking for decoy cells as a possible marker of virus replication. Secondly, in all positive cytological samples and in some negative cytological samples (selected at random), we performed qualitative polymerase chain reaction (PCR) assays in serum and urine amplifying two different genome regions (LT and VP1). A transcription control region (TCR)-BK polymorphism sequence analysis was also performed in those BK PCR positive cases. Twenty-three of 125 (18.4%) KTR presented decoy cells in at least one urinary cytological sample. Molecular studies revealed that 10 of 125 (8%) KTR were BK PCR-serum positive cases (seven LT+/VP1- and three LT+/VP1+); and 13 of 40 (32.5%) KTR were BK PCR-urine positive cases (five LT+/VP1- and eight LT+/VP1+). When we compared PCR-urine and cytological results in 40 KTR, only 15% (six cases) revealed simultaneous positivity in both studies. In the context of clinical graft dysfunction, three patients demonstrated BK DNA presence in the renal biopsy. Finally, sequence analysis of the TCR was performed in 13 BK-PCR positive cases determining the AS, JL, WW, and WW-like viral variants. TCR sequence analysis, allows us to demonstrate the possible implication of the donor in BK infection studying four BK-PCR positive patients paired by donor.

Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation.

BACKGROUND: Corticosteroid-free maintenance immunosuppression after organ transplantation eliminates the well-known corticosteroid-related side effects and may help to improve long-term outcome. We investigated whether a corticosteroid-free tacrolimus (Tac)/mycophenolate mofetil (MMF) regimen, in combination with daclizumab (Dac) induction therapy, provides adequate immunosuppression after renal transplantation. METHODS: This 6-month, open-label, multicenter, parallel-group study involved 538 renal patients randomized (1:1) to a Dac/Tac/MMF regimen (n = 260) or a Tac/MMF/corticosteroids regimen (n = 278) as a control group. RESULTS: Of the patients who completed the study, 88.8% in the Dac/Tac/MMF group were free from corticosteroid therapy at month 6. The incidence of biopsy-proven acute rejection was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5.0% with Tac/MMF/corticosteroids and Dac/Tac/MMF, respectively (P = NS for both comparisons). Renal function was also similar in both groups: median serum creatinine at month 6 was 125.0 micromol/L (Tac/MMF/corticosteroids) and 131.0 microml/L (Dac/Tac/MMF), P = 0.277. The overall safety profile was similar with both regimens. However, compared with the Tac/MMF/steroid regimen, a significantly reduced incidence of new-onset insulin-dependent diabetes mellitus (5.4% vs. 0.4%, P = 0.003) was found with steroid-free immunosuppression. Moreover, mean total cholesterol concentrations increased from baseline in the Tac/MMF/corticosteroids group by 0.19 mmol/L, whereas in the Dac/Tac/MMF group, levels decreased by 0.19 mmol/L, P = 0.005. CONCLUSIONS: Corticosteroid-free immunosuppression with a Dac/Tac/MMF regimen is as effective at preventing acute rejection after renal transplantation as a standard triple regimen of Tac/MMF/corticosteroids. Furthermore, the safety benefits reported with Dac/Tac/MMF treatment may help improve the long-term outcome for renal-transplant patients.

Proteinuria: a new marker of long-term graft and patient survival in kidney transplantation.

BACKGROUND: Proteinuria developing after renal transplantation is associated with increased renal failure. Moreover, proteinuria in the general population has been shown to be associated with morbidity and mortality due to cardiovascular disease, which is the main cause of death in renal transplant patients. The purpose of the present study was to investigate whether persistent proteinuria following renal transplantation was associated with a worse patient and graft survival. METHODS: We analysed kidney recipients included in the Spanish Chronic Allograft Nephropathy Study (n = 3365). Proteinuria at 1 year post-transplantation was analysed as a categorical variable (< 0.5, 0.5-1, > 1 g/day). RESULTS: Post-transplant proteinuria at 1 year was detected in 15.3% of patients. Graft survival in proteinuric patients was significantly lower as compared with patients without proteinuria and the survival was worse with increasing amounts of proteinuria. In the groups with proteinuria, renal graft function at the time of the analysis was worse than in the group without proteinuria. Patient survival was lower in patients with proteinuria although there was no difference between the two groups of proteinuric patients. The main cause of death was vascular disease in all groups of patients but especially in proteinuric patients. The relative risk of graft failure and patient death was higher in proteinuric patients: graft failure [0.5-1 g/day: 2.33 (1.79-3.01, P<0.0001); > 1 g/day: 3.46 (2.73-4.39, P<0.0001)], patient death [0.5-1 g/day: 2.05 (1.39-3.01, P = 0.0002); > 1 g/day: 2.3 (1.55-3.39, P<0.0001)]. CONCLUSIONS: Proteinuria, as in native kidney disease, is an excellent marker of poor long-term allograft prognosis and is an independent risk factor for total and cardiovascular mortality in the renal transplant population.