Immunosuppressive treatment during pregnancy as a potential factor changing magnesium, calcium and phosphorus levels in hard tissues of female rats and their offspring

Immunosuppressive therapy is necessary to prevent transplant rejection, also in the case of pregnant transplant recipients, which means that the medications may influence foetal development. An ideal immunosuppressive regimen should provide for excellent immunosuppression with minimal or no side effects. Yet, current immunosuppressive therapy regimens commonly used in clinical applications fail to meet this criterion. One of the complications caused by immunosuppressive drugs are mineralisation disorders in hard tissues. Therefore, in this study, we evaluated the impact of three regimens of immunosuppressive therapy used after renal transplantation, containing medications which are indicated (prednisone, cyclosporine A (CsA), tacrolimus (Tc)) and contraindicated (mycophenolate mofetil (MMF), everolimus) during pregnancy on the concentrations of essential minerals, calcium (Ca), phosphorus (P) and magnesium (Mg), affecting normal bone formation. The samples were analysed using inductively coupled plasma optical emission spectrometry (ICP-OES, ICAP 7400 Duo, Thermo Scientific) equipped with a concentric nebuliser and a cyclonic spray chamber. The immunosuppressive regimens under study had no effect on the levels of Mg and P, but they did contribute to increased bone Ca levels in the mothers in the group receiving Tc, MMF and prednisone and group receiving CsA, everolimus and prednisone. In the offspring of tested mother rats, immunosuppressive therapies may affect Mg levels in hard tissues. The immunosuppressive regimens administered at therapeutic doses are harmful to rat foetuses as evidenced by the small number or lack of offspring in the tested groups

The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats

Joanna Kabat-Koperska,1 Agnieszka Kolasa-Wołosiuk,2 Bartosz Wojciuk,3 Iwona Wojciechowska-Koszko,3 Paulina Roszkowska,3 Barbara Krasnodębska-Szponder,3 Edyta Paczkowska,4 Krzysztof Safranow,5 Edyta Gołembiewska,1 Bogusław Machaliński,4 Kazimierz Ciechanowski1 1Department of Nephrology, Transplantology and Internal Medicine, 2Department of Histology and Embryology, 3Department of Microbiology and Immunological Diagnostics, 4Department of General Pathology, 5Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland Background: In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system – the thymus and the spleen. Methods: The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. Results: There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Conclusion: Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen–dependent manner. Keywords: immune system, immunosuppressive drugs, kidney transplantation, pregnancy, Wistar rat

Medication-Induced Hyperlactatemia and Lactic Acidosis: A Systematic Review of the Literature

Hyperlactatemia and lactic acidosis are two syndromes that are associated with morbidity and mortality. Medication-induced hyperlactatemia and lactic acidosis are diagnoses of exclusion and have the potential to be overlooked. The purpose of this systematic review is to identify published reports of medication-induced lactate level elevations to aid clinicians in diagnosing and comprehending the underlying mechanism of this rare adverse drug effect, and to provide management strategies. The PubMed database was searched for case reports, case series, retrospective studies, and prospective studies describing cases of medication-induced lactate level elevation, including lactic acidosis and hyperlactatemia, published between January 1950 and June 2017. A standardized search strategy was used, and the articles identified underwent two rounds of independent evaluation by two reviewers to assess for inclusion. Articles were included if they described at least one patient older than 12 years of age with hyperlactatemia or lactic acidosis caused by a medication with United States Food and Drug Administration (FDA) approval and if alternative etiologies for an elevated lactate level were ruled out. Metformin and nucleoside/nucleotide reverse transcriptase inhibitors were excluded since the pathophysiology and incidence of lactic acidosis have been well established for these agents. Overall, 1918 articles were identified, and 101 met inclusion criteria. A total of 286 patients experienced medication-induced lactate level elevations, from which 59 unique medications were identified. The most commonly identified agents were epinephrine and albuterol. Medication-induced lactate level elevation was classified as lactic acidosis (64.0%), hyperlactatemia (31.1%), or not specified (4.9%). The doses ingested included FDA-labeled doses (86%), intentional overdoses (10.8%), or prescribed doses exceeding the FDA-labeled dose (3.1%). Medications were continued without a change (40.8%), were permanently discontinued (34.4%), were continued with a dosage reduction (11.6%), or were initially withheld then resumed after lactate level normalized (2.9%); medication management for the remaining 10.0% was not reported. Forty-six patients died (16%). Six deaths were attributed by treating clinicians to be secondary to medication-induced lactic acidosis. Management strategies were heterogeneous, and treatment included supportive care, exogenous bicarbonate therapy, medication specific antidotes, and decontamination strategies. Unexplained lactate level elevations should prompt clinicians to assess for medication-induced lactate level elevations. Pharmacists are members of the health care team that are well positioned to serve as experts in the diagnosis and management of medication-induced lactate level elevations. This article is protected by copyright. All rights reserved