In utero exposure to immunosuppressive drugs: experimental and clinical studies

Tendron, Anaïs; Jb, Gouyon; Decramer, Stéphane

doi:10.1007/s00467-001-0776-z

Cited by 101 publications

(89 citation statements)

References 63 publications

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“…CsA is thus used in pregnant patients for its graft and life-saving immunosuppressive effects despite the fact that it induces intrauterine growth retardation in over half of the pregnancies after renal and liver transplants (30). Short-term studies did not reveal any adverse effect of in utero exposure to CsA on renal function of the children born to female transplant recipients (31).…”

Section: Figurementioning

confidence: 99%

Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

Chang¹,

McDill²,

Neilson³

et al. 2004

J. Clin. Invest.

127

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Congenital obstructive nephropathy is the principal cause of renal failure in infants and children. The underlying molecular and cellular mechanisms of this disease, however, remain largely undetermined. We generated a mouse model of congenital obstructive nephropathy that resembles ureteropelvic junction obstruction in humans. In these mice, calcineurin function is removed by the selective deletion of Cnb1 in the mesenchyme of the developing urinary tract using the Cre/lox system. This deletion results in reduced proliferation in the smooth muscle cells and other mesenchymal cells in the developing urinary tract. Compromised cell proliferation causes abnormal development of the renal pelvis and ureter, leading to defective pyeloureteral peristalsis, progressive renal obstruction, and, eventually, fatal renal failure. Our study demonstrates that calcineurin is an essential signaling molecule in urinary tract development and is required for normal proliferation of the urinary tract mesenchymal cells in a cell-autonomous manner. These studies also emphasize the importance of functional obstruction, resulting from developmental abnormality, in causing congenital obstructive nephropathy.Nonstandard abbreviations used: calcineurin A (CnA); calcineurin B (CnB); cyclosporin A (CsA); embryonic day (E); flanked by loxP sites (floxed); postnatal day (P); smooth muscle (SM); α-smooth muscle actin (αSMA); SM cell (SMC); ureteric bud (UB); ureteropelvic junction (UPJ). Conflict of interest:The authors have declared that no conflict of interest exists. Methods Immunostaining.Immunostaining with an anti-Cnb1 polyclonal antibody (1:20, rabbit; Upstate Group Inc., Charlottesville, Virginia, USA) was done on 7-µm paraffin sections. Briefly, paraffin sections were dewaxed and rehydrated to PBS. High-temperature antigen retrieval was done by two treatments of 0.1 mM EDTA in a conventional microwave oven. The slides were incubated with 100 mM glycine for 10 minutes and a blocking solution (2% inactivated normal goat serum and 10 mg/ml BSA) for 45 minutes at room temperature. The anti-Cnb1 antibody was used at 1:20 for 45 minutes. An Alexa Flour 566-conjugated goat anti-rabbit antibody (Molecular Probes Inc., Eugene, Oregon, USA) was used at 1:500 in 10 mg/ml BSA in PBS. Whole-mount staining was done as described previously (22). Other antibodies used were a monoclonal anti-neurofilament antibody (1:100, mouse; University of Iowa, Developmental Study Hybridoma Bank, Iowa City, Iowa, USA) and a monoclonal anti-α-smooth muscle actin (anti-αSMA) antibody (1:200, mouse; Sigma-Aldrich, St. Louis, Missouri, USA), and a polyclonal Ki67 antibody (1:300, rabbit; Novocastra Laboratories Ltd., Newcastle upon Tyne, United Kingdom). Midline sagittal cryostat sections at 7 µm were used for the Ki67 immunostaining and the subsequent quantification. Only the mesenchymal cells were counted.Results were presented as number of Ki67-positive cells per 100 µm along the developing renal pelvic wall. Histology and β−gal assays. For standard histological e...

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Section: Figurementioning

confidence: 99%

Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

Chang¹,

McDill²,

Neilson³

et al. 2004

J. Clin. Invest.

127

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“…Such agents have also been shown to have an effect on renal development, especially mycophenolate mofetil (45,46). The pathways involved have not been clarified thus far, but a recent study has identified two factors involved: PDGF-B, potently inducing proliferation, and early growth response gene-1, a transcription factor (47).…”

Section: Drugs Disturbing Renal Developmental Factorsmentioning

confidence: 99%

Effect of Drugs on Renal Development

Schreuder¹,

Bueters²,

Huigen³

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryMany nephrotoxic effects of drugs have been described, whereas the effect on renal development has received less attention. Nephrogenesis ceases at approximately 36 weeks of gestation, indicating that drugs administered to pregnant women and to preterm-born neonates may influence kidney development. Such an effect on renal development may lead to a wide spectrum of renal malformations (congenital anomalies of the kidney and urinary tract [CAKUT]), ranging from renal agenesis to a reduced nephron number. Any of these anomalies may have long-term sequelae, and CAKUT is the primary cause for renal replacement therapy in childhood. This review focuses on research into the effect of drug treatment during active nephrogenesis during pregnancy and in preterm-born infants. Because the effects of many widely used drugs have not been unraveled thus far, more research is needed to study the effect on renal development and long-term renal sequelae after drug treatment during nephrogenesis.

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“…However, the concentration in fetal blood is much lower, and is 1-5% of that in the maternal serum [14][15][16]. Cyclosporine A cross the placenta, reaching about 5% fetal blood concentration compared to the concentration in the maternal serum [14][15][16][17][18]. Systematic literature review published in 2016 by the European League Against Rheumatism shows compatibility with pregnancy and lactation for azathioprine, cyclosporine, tacrolimus and glucocorticosteroids [19].…”

Section: Discussionmentioning

confidence: 99%

Intrauterine growth restriction in pregnant women after kidney transplantation as a marker of preeclampsia

et al. 2016

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Objectives: Delayed motherhood is associated with an increasing number of comorbidities such as glomerulonephritis, systemic lupus erythematosus, and diabetic nephropathy. Women after renal transplant belong to the group of patients who require a highly individualized approach to treatment and diagnosis. The aim of the study was to validate the commonly used diagnostic criteria for preeclampsia which seem to be irrelevant in patients with chronic renal insufficiency. Material and methods:The course of pregnancy and delivery were retrospectively analyzed in 48 renal transplant patients. Two patients were excluded. Group I included 23 patients with eutrophic neonates, while Group II consisted of 23 patients with fetal hypotrophy (birth weight of < 10 th percentile). Results:The duration of pregnancy was 34.5 and 35 weeks in Groups I and II, respectively. Mean birth weight in Groups I and II was 2608.64 g and 2046.30 g, respectively (p = 0.002). Mean weight percentile in Groups I and II was 36.57 and 2.91, respectively (p < 0.000). Proteinuria in the first half of pregnancy occurred in 16 and 14 patients from Groups I and II, respectively, and increased in the second half of pregnancy in 6 and 6 patients from Groups I and II, respectively. Patients from Group II were more prone to urinary tract infections (0.43 vs. 0.79; p = 0.02). Conclusions:Current diagnostic criteria for preeclampsia are insufficient in case of pregnant women after kidney transplant. General criteria should be applied with special care in women with chronic kidney disease or in patients with systemic lupus erythematosus. As a predictive factor of neonatal morbidity, intrauterine growth restriction seems to be more valuable than typical markers of kidney function.

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In utero exposure to immunosuppressive drugs: experimental and clinical studies

Cited by 101 publications

References 63 publications

Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

Effect of Drugs on Renal Development

Intrauterine growth restriction in pregnant women after kidney transplantation as a marker of preeclampsia

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