The influence of exposure to immunosuppressive treatment during pregnancy on renal function and rate of apoptosis in native kidneys of female Wistar rats

Abstract

Pregnancy puts a significant additional strain on kidneys. The aim of our study was to investigate the impact of immunosuppressive drugs on changes in native kidneys in female Wistar rats after exposure during pregnancy. The study was conducted on 32 dams, subjected to immunosuppressive regimens commonly used in the therapy of human kidney transplant recipients (cyclosporine A, mycophenolate mofetil and prednisone; tacrolimus, mycophenolate mofetil and prednisone; cyclosporine A, everolimus and prednisone). The animals received drugs for 2 weeks before pregnancy and during 3 weeks of pregnancy. In all treated dams lower body weight (but not kidney mass) and alterations in serum sodium and chloride ions were found; serum creatinine concentration was increased in dams treated with cyclosporine A, everolimus and prednisone. All treatment groups of dams showed increased apoptosis in the distal tubules. In histological examination the changed intensity of acidophilic or basophilic cytoplasm of epithelial cells was found in kidneys of rats treated with calcineurin inhibitors, mycophenolate mofetil and prednisone. All immunosuppressive regimens caused abnormalities affecting nephron tubules. Regimens containing calcineurin inhibitors and mycophenolate mofetil caused higher rate of apoptosis and more pronounced histopathological changes. Regimen based on everolimus despite the lower rate of apoptosis in the proximal tubules and lower accumulation of kidney injury markers revealed higher serum creatinine concentration. Thus, interpretation which combination of drugs is better or worse for long-lasting functioning of kidneys in pregnant females requires further studies.

Immunosuppressive treatment affects morphology and apoptotic intensity of the liver in pregnant Wistar rats

“…In our study among all the dams from treatment groups, in comparison with control dams, decreased liver weight was found. It is worth mentioning that a decrease in the body weight in treated rats was observed in a previous study [14]. Our results are in contrast with those of Neiashabouri et al [18], where female mice, until the sixth week of life, were given sirolimus at a dose of 14 mg/kg for 13 days per os.…”

“…This is the first study to examine the impact of immunosuppressants on apoptosis in the liver. Previous studies have examined apoptosis in the kidneys [11,[14][15][16][17]. In our study among all the dams from treatment groups, in comparison with control dams, decreased liver weight was found.…”

“…The authors explained this phenomenon by the activation of mTORC1, combined with sirolimus treatment. In other studies in rats, the weight of other organs, such as kidneys, was not altered by immunosuppressive drugs [2,14]. It may be that the liver is more vulnerable than the kidney to the impact of immunosuppressive drugs.…”

“…The model of treatment studied here reflects the immunosuppressive therapy commonly used in clinical practice in humans after kidney transplantation. The used doses of drugs allowed a therapeutic concentration to be obtained in the blood of animals [14]. This is the first study to examine the impact of immunosuppressants on apoptosis in the liver.…”

Serum Selenium, Iron, Zinc, and Copper Concentrations in Renal Transplant Recipients Treated with Mycophenolate Mofetil

“…There is a number of type of drugs applied in immunosuppressive treatment: (i) inhibitors of the enzyme inosine monophosphate dehydrogenase (IMDH inhibitors), such as mycophenolate mofetil; (ii) calcineurin inhibitors, such as cyclosporine and tacrolimus; (iii) inhibitors the mammalian target of rapamycin (mTORs), such as everolimus and rapamycin; and (iv) corticosteroids, including prednisone [ 15 , 17 , 18 , 34 ]. Renal transplant recipients are mostly given multidrug regimens, with one drug from each group.…”