Early postoperative calculation of the tacrolimus concentration‐to‐dose ratio does not predict outcomes after kidney transplantation

Abstract

There is an emerging interest in the tacrolimus metabolism rate as it is linked to outcomes after transplantation [1][2][3][4][5][6][7]. We and others propose the concentration-to-dose (C/D) ratio as a simple surrogate for the individual tacrolimus (Tac) metabolism rate [5,8,9]. Recently, Jouve et al. [3] showed in a large retrospective singlecenter study that the C/D ratio was in contrast to the CYP3A5 genotype strongly associated with outcomes after renal transplantation (RTx). They used a C/D ratio cutoff of 1.05 µg/l 9 1/mg, which we used to guide risk stratification of RTx patients, as a low C/D ratio (fast Tac metabolism) is associated with, for example, an increased calcineurin inhibitor nephrotoxicity rate, a lower estimated glomerular filtration rate (eGFR), and five-year patient and overall graft survival [5,9].Initially, we proposed a classification of patient's Tac metabolism rate based on the C/D ratio expressed as the Tac trough level concentration normalized by the dose (mean C/D ratios at one, three, and six months after RTx) [5]. Notably, even a single C/D ratio calculated in stable patients three months after RTx predicted outcomes, as it is relatively stable over time after the third postoperative months [3,9].Since the negative effect of fast Tac metabolism becomes apparent within a month after RTx and the C/ D ratio is a simple but valuable tool to identify patients who might profit from modification of the immunosuppressive regime, we and others asked whether it can be reliable calculated within the first days after RTx to identify high-risk patients very early [5]?To this end, we retrospectively analyzed the data of 882 patients who received a donor kidney at the University Hospital of M€ unster between January 2007 and December 2017. The C/D ratio was calculated for each of the first ten postoperative days in cases of available Tac trough and dosage data and used to categorize patients. C/D ratio cutoff values were calculated for each day based on the ROC curve analysis and the Youden index maximum. We found a C/D ratio of 0.87 on the third day after RTx to allow the best prediction (compared with all other postoperative days) of the 3month Tac metabolism type (AUC = 0.741; P < 0.001). However, using this cutoff, the outcomes of slow and fast metabolizers were comparable showing the absent discriminative power of early postoperative C/D ratios after RTx (Fig. 1). Nevertheless, we would like to emphasize that these results need to be validated in a different data set to avoid biased results that might be too sensitive to the random noise in the given dataset.Additionally, we performed the analogous analyses by using the calculated best predictive cut-point of day 7 post-transplantation (0.88) as a comparatively more conceptualizable time point and calculated the corresponding estimated survival probabilities at one, three, and six months post-transplantation ( Figure S1). Although we found a significant impact on patient survival when this cut-point at 7 days was applied, this finding was...

The Tacrolimus Metabolism Rate and Dyslipidemia after Kidney Transplantation

“…The choice of the 3 month time point for the calculation of the C/D ratio was a compromise. We already know from previous analyses that the calculation of the C/D ratio at very early time points (postoperative day 1-10) is not able to predict the metabolism type at all [32]. However, we found acceptable correlations between the 3 month time point and the calculation at 1 month or 6 months [7].…”

Development of De Novo Donor-specific HLA Antibodies and AMR in Renal Transplant Patients Depends on CYP3A5 Genotype

“…32 However, studies involving European cohorts of renal allograft recipients found no significant association between CYP3A5 gene variant and either allograft survival or the occurrence of biopsy-proven rejection. 9,24,[41][42][43] A significantly higher rate of acute rejection events was found in Asian cohorts and may be due to the higher frequency of the expresser allele among Asians. 24,42 Accordingly, the previously published results of a meta-analysis pooling 25 studies of the association between CYP3A5 genotype and the risk of acute rejection found no significant effect.…”

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation

“…Low CDR has been associated with CNI toxicity, BK viremia, decreased allograft function, and an independent risk factor for DCGL (11,13,31). In contrast, some studies have reported that low CDR is not a significant risk factor for adverse allograft outcomes, such as BPAR and DCGL (15,16). In the present study, a low CDR itself was not observed as an independent risk factor for DCGL when other confounding factors (TAC-C0-TWA, TAC-C0-TWCV, age, and induction regimen, Supplemental Table 4) were adjusted (HR 1.66, 95% confidence interval 0.73-3.76).…”

“…Several recent studies on CDR have reported that RM is a significant factor affecting the prognosis of KT recipients ( 11 , 13 ). However, some studies have also reported that CDR is not a significant factor influencing allograft outcomes; therefore, the importance of CDR in KT remains controversial ( 15 , 16 ). In patients showing high IPV in RM status, fluctuations of administered drug doses increase, which may cause not only increasing fluctuation of TAC-C0 but also TAC peak concentrations, which may have a greater impact on adverse allograft outcomes.…”