Placental, lipid, and glucidic effects of mammalian target of rapamycin inhibitors: impact on fetal growth and metabolic disorders during pregnancy after solid organ transplantation.

BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi) are a promising new family of immunosuppressive drugs. No teratogenic effects have been reported to date. Their lipid and glucidic effects should not be underestimated, however, especially during pregnancy. Moreover, mTORi may affect fetal growth by mTOR placental activity. OBJECTIVE: Our purpose was to highlight mTORi placental impact and metabolic implications to detect possible maternal or fetal effects and define management guidelines in pregnant women after solid organ transplantation. METHODS: A literature search was performed for articles from the Medline and Pubmed databases with the use of the following keywords: mTOR inhibitors, pregnancy, placental transport, lipid metabolism, glucose metabolism. RESULTS: mTOR works as a positive regulator of system A, system L, and taurine placental amino acid transporter activity, which are critical for the transport of amino acids to the fetus. Exposing trophoblast cells to rapamycin reduces system L activity; therefore, treatment with rapamycin in human pregnancies could alter fetal growth with intrauterine growth restriction (IUGR). Regarding the metabolic effects mTORi increase lipolysis, impair insulin's antilipolytic effect and reduce lipid storage, which may potentially contribute to dyslipidemia. Chronic rapamycin treatment reduces adipose tissue size and ß-cell mass/function, causes hyperlipidemia, severe insulin resistance, and glucose intolerance, and promotes hepatic gluconeogenesis. CONCLUSIONS: The studies on mTORi treatment in transplanted pregnant women have not focused to date on the potential metabolic and placental effects. Selection of women at high risk for metabolic disorders could be needed and consideration of switching to another immunosuppressive drug required if diabetes and abnormal blood lipids have been diagnosed in prepregnancy counseling. It seems to be mandatory to encourage prompt reporting of any additional cases of pregnancy during mTORi exposure to provide a better understanding of the placental effects and safety profile of these immunosuppressive drugs.

Is HE4 serum level a valid screening test in women candidates for kidney transplant? A case report and a review of literature.

While studying a candidate for kidney transplant it is essential to exclude active malignant diseases. Serum biomarkers help to exclude specific cancers. Tumor markers are proteins secreted by neoplastic cells that can mark their activities. HE4 is a new tumor marker used in ovarian cancer. It is an epithelium protein that appears overexpressed in ovarian cancer, but it is also present in other normal human tissues. Often in patients with kidney failure serum biomarkers are increased compared to healthy people. We report a case of a Caucasian woman suffering from kidney failure examined by our team to be included on the kidney transplantation list. Patient had a known pelvic mass. Determination of serum biomarkers, CA125 and HE4, was performed to exclude pelvic tumor, and we found high levels of HE4 with normal levels of CA125. A new transvaginal ultrasound was performed on the patient and it showed a pelvic mass near the left ovary. This mass resulted bigger than in the previous ultrasound, performed about a month before. We decided to perform a pelvic CT for improved diagnostic accuracy. The reports of this exam showed that the mass was a hematoma correlated with a previous knee prosthetic surgery. Even tough many serum biomarkers are higher in patients with renal failure, there is no study to demonstrate that HE4 blood levels are modified in these patients. This case report shows how HE4 can be elevated in people in hemodialysis in a benign situation, also in a pelvic mass not from the genital tract. There is no similar case described in literature.