Summary We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.
Background. Monitoring changes in glomerular filtration rate (GFR) is the recommended method for assessing the progression of kidney disease. The aim of this study was to assess the decline of graft function defined by the annualized change in GFR and the factors which affect it.Methods. Four thousand four hundred and eighty-eight patients, transplanted during the years 1990, 1994, 1998 and 2002 in 34 centres in Spain with allograft survival of at least 1 year, were included in the study. GFR was estimated using the four-variable equation of the Modification of Diet in Renal Diseases (MDRD) study. Linear mixed effects model was applied to determine the relation between the covariates and the annualized change in GFR after transplantation.Results. The average GFR at 12 months was 51.4 ± 18.9 mL/min/1.73 m2; most patients were in stage 3 of chronic kidney disease classification. The average patient slope, calculated in a linear model with varying-intercept and varying-slope without covariates, was −1.12 ± 0.05 mL/min/year (slope ± standard error). Some variables were related to both the 12-month GFR (intercept) and the slope: recipient gender, hepatitis C virus (HCV) status, estimated GFR (eGFR) at 3 months and proteinuria at 12 months. Some variables were only related to the slope of eGFR: time on dialysis, primary renal disease and immunosuppression. Others affected only the 12-month GFR: donor age, delayed graft function, acute rejection and systolic blood pressure at 12 months. Higher graft function at 3 months had a negative impact on the GFR slope. Cyclosporine-based immunosuppression had a less favourable effect on the rates of change in allograft function.Conclusions. There was a slow decline in GFR. Poor graft function was not associated with an increased rate of decline of allograft function. Immunosuppression with cyclosporine displayed the worst declining GFR rate.
A low dose of pamidronate prevents bone loss in osteopenic patients when administered immediately after RT.
We conducted a randomized unblinded parallel clinical trial to compare the effectiveness, side effects and tolerance between calcium acetate (CA) and calcium carbonate (CC) in 80 stable chronic hemodialysis patients selected on the basis of their acceptable control of serum phosphorus (P) levels with aluminum hydroxide (AH). All patients were dialyzed against the same calcium dialyzate (1.62 mmol/l). The serum analytical tests included: calcium corrected to total protein, P, PTH (intact molecule) and bicarbonate. The study was divided into the following periods: P0: baseline measurements; P1: washout (winthdrawal of AH for 15 days); P2: random allocation to CA and CC treatment at doses equivalent to 75 mEq of elemental calcium, stratified according to previous doses of AH (2 months); P3: adjustment of doses until control P (2 months). CA was poorly tolerated in 7 patients and CC in 2 (NS). The changes in serum P levels between P0 and P2 periods were lower in the CA group (1.73 ± 0.25 vs. 1.80 ± 0.50 mmol/l; p = 0.26) than in the CC group (1.77 ± 0.35 vs. 1.93 ± 0.48 mmol/l; p = 0.03, paired t test). Serum calcium was hardly modified by CA (2.42 ± 0.20 vs. 2.47 ± 0.17 mmol/l; NS) while in the CC group, it rose significantly (2.40 ± 0.12 vs. 2.55 ± 0.22 mmol/l; p = 0.0004). There were no differences in the control of PTH or bicarbonate. At the P3 period, patients on CC treatment needed higher doses of elemental calcium to control P than the CA group (99.4 ± 31 vs. 83 ± 27 mEq; p = 0.01), and at these doses, hypercalcemia ( > 2.86 mmol/l) was more frequent in the CC group (30.5 vs. 16%; NS). We conclude that CA is slightly more effective and safer than CC, albeit less well tolerated.
(a) Dynamic testing of parathyroid function provided insights into the pathophysiology of PTH secretion in hemodialysis patients. (b) The magnitude of hyperparathyroidism was the most important predictor of the response to CTR. (c) Before CTR treatment, PTH was sensitive to calcium in Rs, and serum calcium was PTH driven in NRs, and (d) after the CTR-induced increase in serum calcium, calcium suppressed basal PTH relative to maximal PTH in both groups.
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