Cyclosporin A Administration during Pregnancy Induces a Permanent Nephron Deficit in Young Rabbits

Abstract

ABSTRACT. Cyclosporin A (CsA) is an immunosuppressive agent used to prevent graft rejection and to treat autoimmune disorders. Successful pregnancies can be achieved among CsA-treated women, although it is known that CsA is nephrotoxic and crosses the human placenta. The aim of this study was to evaluate the harmlessness of CsA toward the embryonic kidney. Twenty-one pregnant rabbits were divided into four groups. Groups of six and four female animals were subjected to daily injections of 10 mg/kg per d CsA (administered subcutaneously) for 5 d, from day 14 to day 18 of gestation or from day 20 to day 24 of gestation, respectively. In the third group, five female animals received the CsA diluent (Cremophor) from day 14 to day 18 of gestation. The fourth group consisted of six untreated female animals. Pregnancy outcomes among CsA-treated does demonstrated a reduced number of living pups, which were also growth-retarded, with exposure to CsA from day 20 to day 24 of gestation. However, pups exposed to CsA from day 14 to day 18 of gestation exhibited normal fetal growth, and blood concentrations of CsA matched human data. Examinations of kidneys at birth demonstrated vacuolation of proximal and collecting tubules and ureteric bud ends. Increased glomerular volumes and decreased nephron densities suggested nephron mass reduction, which was quantitatively evaluated in 1-mo-old animals. The nephron numbers were reduced by 25 and 33% in day 14 to 18 CsA-treated and day 20 to 24 CsA-treated animals, respectively, which displayed compensatory adaptation of the existing nephrons. However, foci of segmental glomerular sclerosis were already present, which would possibly jeopardize renal function later in life.

An emerging role for calcineurin Aα in the development and function of the kidney

“…Next, a more direct examination of the role of calcineurin specifically in kidney development was reported by Tendron et al (42). In their 2003 paper, the authors report that administration of cyclosporin A to pregnant rabbits at specific time periods during gestation resulted in significant changes in the kidneys of resulting pups (42). The authors examined the effects of cyclosporin A administration from embryonic days 13-17, which coincide with the onset of nephrogenesis, and days 18 -21, which coincide with early renal function in the developing offspring.…”

“…Next, a more direct examination of the role of calcineurin specifically in kidney development was reported by Tendron et al (42). In their 2003 paper, the authors report that administration of cyclosporin A to pregnant rabbits at specific time periods during gestation resulted in significant changes in the kidneys of resulting pups (42).…”

Molecular Diagnostics of Calcineurin-Related Pathologies

“…Cn is indispensable for renal growth, development, and maturation at its earliest stages (80,81 ) and functions in close association with COX-2 (cyclooxygenase 2) (82 ). Cn has been shown to relay Ca 2ϩ signals generated by such factors as Wnt, TGF-␤, insulin-like growth factor I, angiotensin II, and even polycystin 1, to activate NFAT (4,80,83 ).…”

Effect of Drugs on Renal Development

“…This is a lipophilic immunosuppressive drug and passes through the placenta to the fetus. After treatment of pregnant rabbits with cyclosporin A, the offspring were shown to have a reduced nephron number (22) with systemic hypertension and progressive chronic renal insufficiency in adulthood (23). In mice deficient in calcineurin in the developing urinary tract, a defective peristalsis of the pyelo-ureteral junction is described (24).…”