Mycophenolate Acid and Balancing the Risk for Male Allograft Recipients
Notice bibliographique
Résumé
We want to thank Kuypers and coauthors1,2 for addressing and commenting the updated manufacturer and European Medicines Agency (EMA) recommendations on the use of mycophenolate acid in renal transplant recipients. It is common practice in the transplant society to change immunosuppression in female recipients who wish to become pregnant by either withdrawal of mycophenolate mofetil (MMF) or switch to azathioprine if this is deemed more appropriate for rejection prevention. It has not been common practice to switch/withdraw fertile males from MMF if they want to become fathers or if they are sexually active—as recommended by EMA. Kuypers et al could only find 1 observational study in male recipients that specifically compared the incidence of congenital abnormalities in children fathered while taking MMF to the general population.3 The results did not support the EMA recommendations. Data were updated at the 26th International Congress of The Transplant Society in Hong Kong, August 2016, now with 268 pregnancies/278 outcomes, and the results remained the same, that is, comparable to and not higher than the general population (Abstract 698). Another previously published observational study focusing on pregnancies fathered by males on immunosuppression compared 4614 deliveries before with 474 deliveries after transplantation.4 The risk of preeclampsia was increased (adjusted odds ratio, 7.4; 95% confidence interval, 1.1-51.4) after transplantation. Importantly, no increased risk was found for congenital malformations or other outcomes when compared with pregnancies before transplantation or with the general population (2511506 births), that is, results not supporting the EMA recommendations. The article does not specify number of pregnancies with fathers on MMF but the authors estimate approximately 140 to 180 (personal communication). The EMA recommendations actually state that all “sexually active (including vasectomized) men taking MMF are recommended to use condoms”…..This must indicate that a female or male sexual partner may be subject to a severe risk associated with post conception exposure to semen and/or seminal fluid from men on MMF regardless of whether pregnancy or not is a warranted outcome. This puzzles us. MMF is a small molecule. Recommended dose in organ transplant recipients is up to 1000 mg twice daily with a therapeutic mycophenolic acid (MPA) trough concentration window of 1 to 4 mg/L. MPA maximal concentration (Cmax) is between 10 and 20 mg/L when used in the recommended dose. Normal semen volume during 1 ejaculation is 2 to 5 mL. Our unpublished data indicate dose linearity of MPA pharmacokinetics in the range of 100 to 1000 mg although others have shown an increased relative oral bioavailability of 250 mg as compared with 1000 mg (almost doubling).5 Taking the above into consideration, the maximal amount of MPA in seminal fluid from 1 ejaculation would be 0.1 mg (MPA Cmax × maximal semen volume = 0.02 mg/mL × 5 mL). We are not aware of any data suggesting that exposure of 0.1 mg MPA is toxic or teratogen even if assuming 100% bioavailability via the vaginal route (which is unlikely) the corresponding Cmax would be 0.0014 mg/L.5 There is a considerable risk of recipients developing rejection with withdrawal of MMF. Rejection can lead to decreased graft and patient survival and in worst case graft loss which in heart/lung/liver recipients is equal to death. In our opinion, public recommendations should be based on solid knowledge—not assumptions. We agree that more information is needed, but with the current knowledge, we strongly urge the EMA recommendations to be rewritten and modified.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,011 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».