Inosine 5′-Monophosphate Dehydrogenase Activity for the Longitudinal Monitoring of Mycophenolic Acid Treatment in Kidney Allograft Recipients

Abstract

Background. Mycophenolic acid (MPA) is a standard immunosuppressant in organ transplantation. A simple monitoring biomarker for MPA treatment has not been established so far. Here, we describe inosine 5′-monophosphate dehydrogenase (IMPDH) monitoring in erythrocytes and its application to kidney allograft recipients. Methods. IMPDH activity measurements were performed using a high-performance liquid chromatography assay. Based on 4203 IMPDH measurements from 1021 patients, we retrospectively explored the dynamics early after treatment start. In addition, we analyzed the influence of clinically relevant variables on IMPDH activity in a multivariate model using data from 711 stable patients. Associations between IMPDH activity and clinical events were evaluated in hospitalized patients. Results. We found that IMPDH activity reflects MPA exposure after 8 weeks of constant dosing. In addition to dosage, body mass index, renal function, and coimmunosuppression affected IMPDH activity. Significantly lower IMPDH activities were found in patients with biopsy-proven acute rejection as compared to patients without rejection (median [interquartile range]: 696 [358–1484] versus 1265 [867–1618] pmol xanthosine-5′-monophosphate/h/mg hemoglobin, P < 0.001). The highest IMPDH activities were observed in hospitalized patients with clinically evident MPA toxicity as compared to patients with hospitalization not related to MPA treatment (1548 [1021–2270] versus 1072 [707–1439] pmol xanthosine-5′-monophosphate/h/mg hemoglobin; P < 0.001). Receiver operating characteristic curve analyses underlined the usefulness of IMPDH to predict rejection episodes (area, 0.662; confidence interval, 0.584-0.740; P < 0.001) and MPA-associated adverse events (area, 0.632; confidence interval, 0.581-0.683; P < 0.001), respectively. Conclusions. IMPDH measurement in erythrocytes is a novel and useful strategy for the longitudinal monitoring of MPA treatment.

Temporary hold of mycophenolate boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients

“…25/29 received CNI based medication while 4 patients received Belatacept. All patients stopped MPA or Aza 4-7 days before the fourth vaccination, based on the assumption that pharmacodynamic drug effects wean after 3-4 days (17). Treatment was paused until day 28-35 (mean depicted as “day 32” in all figures; second time point for serological response analysis).…”

“…Erythrocyte IMPDH activity was measured as described recently (17) as a part of clinical routine. The last available IMPDH in a steady state condition before change in MPA dose is reported in Table 1.…”

“…The inosine monophosphate dehydrogenase (IMPDH) activity in erythrocytes has recently been described as a useful pharmacodynamic marker for MPA exposure that reflects the MPA exposure after 8 weeks of constant dosing (17). High IMPDH levels were found in patients with MPA toxicity and low levels in patients with biopsy-proven acute rejections (17).…”

“…The inosine monophosphate dehydrogenase (IMPDH) activity in erythrocytes has recently been described as a useful pharmacodynamic marker for MPA exposure that reflects the MPA exposure after 8 weeks of constant dosing (17). High IMPDH levels were found in patients with MPA toxicity and low levels in patients with biopsy-proven acute rejections (17). In the current cohort, the mean IMPDH activity before MPA hold at a time of steady state was 1192.73 pmol XMP/h/mg Hb (±474.24), and IMPDH activity did not negatively correlate with anti-S1 domain IgG on day 32 (Supplementary Figure 1C).…”

Predictors of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Patients: Baseline Characteristics, Immunosuppression, and the Role of IMPDH Monitoring

“…Because of the well-known dose-response variability of MPA, therapeutic drug monitoring (TDM) has been established, either as MPA blood level or inosine 5′-monophosphate dehydrogenase (IMPDH) monitoring [ 15 , 16 ]. We recently described that IMPDH activity measurement in erythrocytes is a useful strategy for longitudinal monitoring of MPA treatment [ 17 ]. The robustness and reproducibility of this method led to routine IMPDH monitoring of all MPA-treated patients in our clinic.…”