Minimum mycophenolic acid levels are associated with donor‐specific antibody formation

Abstract

Although de novo DSA are associated with inferior graft survival, there are no effective strategies to prevent their formation. Underexposure to MPA (prodrug: MMF) also contributes to rejection rates early after transplantation, but the effect of this phenomenon on the formation of DSA long-term post-transplantation is unknown. Data are expressed as mean (standard deviation). All available data from 32 renal transplant recipients (age at transplantation 7.5 [4.5] yr) on tacrolimus and MPA immunosuppression with an average follow-up of 9.4 (s.d. 4.6) yr were analyzed. DSA were measured using the Luminex assay (>500 MFI was considered DSA-positive). Tacrolimus and MPA levels were measured with the Abbot Tacro II and EMIT assay, respectively. Among 1964 MPA and 3462 tacrolimus trough levels, the average MPA trough level was 3.2 (1.5) mg/L and the average tacrolimus level was 6.7 (2.8) ng/mL. At last follow-up, only 5/32 patients had undetectable DSA, with 5/32 having no class I antibodies and 6/32 having no class II antibodies. DSA formation was associated with a lower minimum MPA trough level (0.27 [0.23] vs. 0.47 [0.18] mg) and cystatin C eGFR (48 [21] vs. 70 [23] mL/min/1.73 m(2)) for class I DSA formers. The average eGFR of patients without class I DSA was 70 (23) mL/min/1.73 m(2), whereas the average eGFR of patients with class I DSA was 48 (21) mL/min/1.73 m(2) (p = 0.0071). MPA trough levels <1.3 mg/L long-term post-transplantation are associated with the formation of DSA. The association between the formation of DSA and minimum MPA exposure may support a strategy for preventing the formation of DSA.

Donor‐specific antibodies in a pediatric kidney transplant population—Prevalence and association with antiproliferative drug dosing

“…However, intolerability due to myelosuppression and gastrointestinal distress limits the feasibility of this target dose in some patients. Our findings confirm and expand previous observations regarding the increased immunological risk that comes with MMF dose reduction or suboptimal MMF exposure . Strategies to avoid this increased immunological risk could include MMF dose adjustments guided by therapeutic drug monitoring, conversion to enteric‐coated mycophenolate mofetil, or even conversion to adequate doses of MMF's “predecessor” azathioprine, especially when these antiproliferative agents are used in conjunction with tacrolimus and at later time points after transplantation when the advantages of MMF over azathioprine are less clear …”

“…Our findings confirm and expand previous observations regarding the increased immunological risk that comes with MMF dose reduction or suboptimal MMF exposure. 10,14 Strategies to avoid this increased immunological risk could include MMF dose adjustments guided by therapeutic drug monitoring, 15 conversion to enteric-coated mycophenolate mofetil, or even conversion to adequate doses of MMF's "predecessor" azathioprine, especially when these antiproliferative agents are used in conjunction with tacrolimus and at later time points after transplantation when the advantages of MMF over azathioprine are less clear. 15,16 Class II DSA formation had a higher prevalence than class I formation, 19.4% vs 9%, respectively, with 17.9% of patients demonstrating what we deemed clinically significant (MFI > 2000) class II DSA titers, fully recognizing that MFI readings can be misleading as described by Sullivan et al 17 Class II DSAs are more notorious for being difficult to treat, and their presence is predictive of graft dysfunction even before other changes, such as diminished renal function, become apparent.…”

“…However, it has been shown that optimization of B‐cell antiproliferative IS based on CNIs is less likely to be associated with DSA development than IS based on inhibitors of the mTOR, especially if there is minimal variability in CNI trough levels . A recent pediatric study has shown that a reduction in MMF dosing below the recommended amounts, for example, for gastrointestinal or hematologic side effects, is associated with a significant increase in the risk for rejection, both cellular and humoral and also suggests that lower mycophenolic acid levels are associated with the formation of DSA …”

“…9 A recent pediatric study has shown that a reduction in MMF dosing below the recommended amounts, for example, for gastrointestinal or hematologic side effects, is associated with a significant increase in the risk for rejection, both cellular and humoral and also suggests that lower mycophenolic acid levels are associated with the formation of DSA. 10 DSA surveillance, as recommended by published consensus guidelines, 1 was implemented in our institution's pediatric kidney transplant program in mid-2015 after a leadership change. We hypothesized that reduced-dose antiproliferative IS agent dosing after kidney transplantation is associated with asymptomatic development of DSA.…”

Results of early treatment for de novo donor‐specific antibodies in pediatric kidney transplant recipients in a cross‐sectional and longitudinal cohort

“…MMF underexposure was recently shown to be associated with development of dnDSA . As we did not monitor MMF levels, it is impossible to determine whether this contributed to the development of dnDSA in our patients.…”