Intrarenal resistive index after renal transplantation.

BACKGROUND: The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear. METHODS: In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation. RESULTS: Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 [95% confidence interval {CI}, 2.14 to 12.64; P<0.001]; 3.46 [95% CI, 1.39 to 8.56; P=0.007]; and 4.12 [95% CI, 1.26 to 13.45; P=0.02], respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 [95% CI, 0.39 to 9.82; P=0.42]; 0.44 [95% CI, 0.05 to 3.72; P=0.45]; and 1.34 [95% CI, 0.20 to 8.82; P=0.76], respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87 ± 0.12 vs. 0.78 ± 0.14 [P=0.05], and 0.86 ± 0.09 vs. 0.78 ± 0.14 [P=0.007], respectively). CONCLUSIONS: The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft. (ClinicalTrials.gov number, NCT01879124 .).

Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.

OBJECTIVES: Prolonged calcineurin inhibitor maintenance therapy in kidney allograft recipients is complicated by the development of chronic irreversible drug-induced nephrotoxicity (CNIT). METHODS: In 304 de novo renal graft recipients, the association among tacrolimus exposure indices (dose, C(0), AUC(0-12h)), CYP3A5, CYP3A4 and ABCB1 polymorphisms, clinical covariables and de novo arteriolar hyalinization as a histologic sign of CNIT was examined. RESULTS: Tacrolimus C(0) and AUC(0-12h) at 3 and 12 months posttransplantation did not differ between patients with and without CNIT. Patients who developed CNIT more often carried the CYP3A5*1 allele (32.4% versus 15.2%, P = 0.01). Twenty-five percent of recipients with tacrolimus dose requirements exceeding 0.2 mg/kg per day at 3 months posttransplantation developed CNIT, whereas 16.2% of patients with dose requirements between 0.10 and 0.20 mg/kg per day and 4.5% of patients who needed less than 0.10 mg/kg per day developed CNIT (P < 0.0001). These early differences in tacrolimus dose requirements between recipients with and without CNIT persisted during subsequent follow-up. In a Cox proportional hazards analysis, the CYP3A5*1 allele (hazard ratio: 2.38; 95% confidence interval: 1.15-4.92) or tacrolimus dose range (hazard ratio: 2.06; 95% confidence interval: 1.30-3.27) and continued corticosteroid therapy (hazard ratio: 4.75; 95% confidence interval: 1.13-19.98) were independently associated with CNIT. A Kaplan-Meier survival curve demonstrated a significant difference in CNIT-free survival (93.5% versus 81.8% versus 66.9%; log-rank test: P = 0.0006) between patients with, respectively, tacrolimus dose requirements less than 0.1, 0.1 or greater, less than 0.2, and 0.2 mg/kg per day or greater. More patients with CNIT sustained graft loss during follow-up (32.3% versus13.7%, P = 0.004). CONCLUSIONS: High early tacrolimus dose requirements, predominantly but not exclusively encountered in CYP3A5*1 expressers, are associated with the development of calcineurin inhibitor-related nephrotoxicity, especially in recipients who continue corticosteroid therapy.

Calcium metabolism in the early posttransplantation period.

BACKGROUND AND OBJECTIVES: Information on the time course of serum calcium levels after renal transplantation is scanty, especially in the early posttransplantation period. Both the abrupt cessation of calcium-containing phosphorus binders and vitamin D (analogs) at the time of surgery and the recovery of renal function may be hypothesized to affect serum calcium levels in this period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this prospective observational study, biointact parathyroid hormone, calcidiol, calcitriol, calcium, and phosphorus levels were monitored in 201 renal transplant recipients at the time of transplantation and 3 mo thereafter. In addition, the serum calcium nadir and peak in each individual patient within this time frame were identified and the urinary fractional calcium excretion was determined at month 3. RESULTS: Serum calcium levels followed a biphasic pattern with a significant decline during the first postoperative week, followed by a significant increase. High pretransplantation parathyroid hormone levels protect against hypocalcemia within the first postoperative week but put patients at risk for hypercalcemia later. These complications, occurring in 41 and 14% of the patients, respectively, most probably reflect inappropriate calcium release from the skeleton, rather than inappropriate renal calcium handling. CONCLUSIONS: Our data indicate that both hypo- and hypercalcemia are prevalent in the early posttransplantation period. Pretransplantation parathyroid function is an important predictor of posttransplantation calcium levels.

Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients.

BACKGROUND: Two recent randomized clinical trials--Fixed Dose Versus Concentration Controlled and the Apomygre--evaluating the benefit of therapeutic drug monitoring of mycophenolate mofetil (MMF) in renal allograft recipients reported conflicting results. In both studies, target mycophenolic acid (MPA) AUC(0-12 h) ranges (ie, values used to guide MMF dosing) were derived from a previous study establishing target MPA AUC(0-12 h) ranges in cyclosporine-treated patients between 30 and 60 mg/L x h(-1). Both studies found an association between MPA exposure and acute rejection. However, only one of the studies found concentration-controlled MMF dosing to be significantly associated with less biopsy-proven acute-rejection episodes compared with fixed dosing. No reduced incidence of MMF-related adverse events (AEs) was observed in either of the 2 trials when MMF concentration-controlled and fixed dosing were compared. OBJECTIVE: The aim of this study was to assess the clinical utility of target MPA AUC(0-12h) ranges between 30 and 60 mg/L x h(-1) in associating drug exposure with AEs within different time windows after transplantation, thereby identifying patients at increased risk for MMF-related AEs. The effects of single nucleotide polymorphisms (SNPs) of the uridine glucuronosyltransferase 1A9 (UGT1A9) and MRP2 genes (ie, coding for the UGT1A9 and the multidrug resistance protein transporter MRP2)-both involved in MPA metabolism-on stratified MPA exposure were assessed by applying the current advised target MPA AUC(0-12h) ranges. METHODS: We conducted a 5-year clinical follow-up study in renal allograft recipients in whom MPA exposure was measured at 7 days, 6 weeks, 3 months, 1, 3, and 5 years post transplantation using abbreviated AUC measurements. MMF dose adjustments were based on clinical indications (eg, persistent leukopenia, chronic afebrile diarrhea, BK-polyomavirus infection of the renal allograft). Clinicians were blinded to the results of the AUC measurements. RESULTS: One hundred white de novo renal allograft recipients (59 men, 41 women; mean [SD] age 51.4 [13.8] years) were included in this study. Ninety-eight patients received a renal allograft from a deceased donor. Significantly more episodes of leukopenia were associated with MPA AUC(0-12h) ranges >60 mg/L x h(-1) (P=0.03). Anemia was also significantly associated with higher MPA exposure ranges (incidence of anemia was 40.8%, 52.2%, and 64.3% for MPA AUC(0-12h) ranges <30, 30-60, and >60 mg/L x h(-1), respectively; P=0.004). Mean MPA AUC(0-12h) was significantly higher in the time window immediately preceding or following leukopenia (mean [SD] 59.7 [31.0] vs 46.5 [26.0] mg/L x h(-1); P=0.004) and anemia (mean [SD] hemoglobin <12 g/L x d(-1): 52.5 [30.0] vs 42.2 [21.2] mg/L x h(-1), P=0.002; hemoglobin <10 g/L x d(-1): 56.2 [32.5] vs 45.6 [24.7] mg/L x h(-1), P=0.005). No association was found between incident episodes. of diarrhea or infection and target MPA AUC(0-12 h) ranges. A significantly higher proportion of MPA AUC(0-12 h) measurements in recipients carrying the UGTIA9 T-275A and/or C-2152T SNP were in the low MPA exposure range (23.7%, 16.6%, and 12.6% for MPA AUC(0-12 h) ranges <30, 30-60, and >60 mg/L x h(-1), respectively; P=0.02). CONCLUSIONS: Renal allograft recipients suffering from leukopenia or anemia related to MMF could potentially benefit, at least in part, from MMFdose adjustments based on target therapeutic MPA AUC(0-12 h) ranges between 30 and 60 mg/L x h(-1). This study did not find these target MPA AUC(0-12 h) ranges to be of clinical utility in guiding MMF dosing in patients with gastrointestinal or infectious AEs. Larger prospective studies are necessary to examine the risk for MPA underexposure in patients carrying the UGTIA9 T-275A and/or C-2152T SNP.