Masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism.

Introduction: While it is well known that thyroid function may affect kidney function, the transition of the chronic kidney disease (CKD) status before and after treatment for thyroid disorders, as well as the factors affecting this change, remains to be explored. In the present study, we focused on the change in kidney function and their affecting factors during the treatment for both hyperthyroidism and hypothyroidism. Methods: Eighty-eight patients with hyperthyroidism and fifty-two patients with hypothyroidism were enrolled in a retrospective and longitudinal case series to analyze the changes in kidney function and their affecting factors after treatment for thyroid disorders. Results: Along with the improvement of thyroid function after treatment, there was a significant decrease in estimated glomerular filtration rate (eGFR) in hyperthyroidism (an average ΔeGFR of -41.1 mL/min/1.73 m2) and an increase in eGFR in hypothyroidism (an average ΔeGFR of 7.1 mL/min/1.73 m2). The multiple linear regression analysis revealed that sex, eGFR, free thyroxine (FT4) and free triiodothyronine (FT3) could be considered independent explanatory variables for ΔeGFR in hyperthyroidism, while age, eGFR, and FT3 were detected as independent explanatory variables in hypothyroidism. In addition, the stratification by kidney function at two points, pre- and post-treatment for thyroid disorders, revealed that 4.5% of the participants with hyperthyroidism were pre-defined as non-CKD and post-defined as CKD, indicating the presence of "masked" CKD in hyperthyroidism. On the other hand, 13.5% of the participants with hypothyroidism presented pre-defined CKD and post-defined non-CKD, indicating the presence of "reversible" CKD status in hypothyroidism. Conclusions: We uncovered the population of masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism, thereby re-emphasizing the importance of a follow-up to examine kidney function after treatment for hyperthyroidism and the routine evaluation of thyroid function in CKD patients as well as the appropriate hormone therapy if the patient has hypothyroidism.

Effects of Wnt-ß-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells.

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-ß-catenin signaling. However, the relation between Wnt-ß-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-ß-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.

Influence of cytochrome P450 (CYP) 3A5 polymorphisms on the pharmacokinetics of lansoprazole enantiomers in CYP2C19 extensive metaboliser renal transplant recipients.

BACKGROUND AND OBJECTIVE: Lansoprazole is extensively metabolised by cytochrome P450 (CYP) 2C19 and CYP3A4. The purpose of this study was to evaluate the effects of CYP3A5 polymorphism (A6986G) on the pharmacokinetics of lansoprazole enantiomers in renal transplant recipients who are CYP2C19 extensive metabolisers (EMs). METHODS: Among 40 Japanese CYP2C19 EMs, 20 had the CYP3A5*1 allele (*1/*1 in two subjects and *1/*3 in 18 subjects) and 20 had the CYP3A5*3/*3 genotype. After repeated oral doses of racemic lansoprazole 30mg once daily for 28 days, plasma concentrations of lansoprazole enantiomers were determined using high performance liquid chromatography. RESULTS: The mean area under the plasma concentration-time curves from 0 to infinity (AUC(infinity)) of (R)- and (S)-lansoprazole in recipients with the CYP3A5*1 allele were 3145 and 384 ng * h/mL, respectively, compared with 4218 and 587 ng * h/mL in recipients with the CYP3A5*3/*3 genotype. The AUC(infinity) and the maximum plasma concentration of (R)- and (S)-lansoprazole in subjects with the CYP3A5*3/*3 genotype were greater than subjects with CYP3A5*1/*1 + *1/*3 alleles. The mean R/S ratio for AUC of lansoprazole in each CYP3A5 genotype group was the same (12.6). CONCLUSION: Our findings show that CYP3A5 genotype is not an important determinant of enantioselective disposition of lansoprazole. Based on our results and those of previous studies, the enantioselective disposition of lansoprazole appears to be primarily influenced by enantioselective metabolism by CYP2C19 rather than by CYP3A.