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Abstract: TH-PO361

Fosfomycin Trometamol Administration Enhances Cyclosporine Nephrotoxicity

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Ortega-Trejo, Juan Antonio, Molecular Physology Unit UNAM,, Mexico City, Mexico
  • Pérez-villalva, Rosalba, Molecular Physology Unit UNAM,, Mexico City, Mexico
  • Arreola, José M., INCMNSZ, Mexico City, Mexico
  • Ramírez, Victoria, INCMNSZ, Mexico City, Mexico
  • Sifuentes-Osornio, José, INCMNSZ, Mexico City, Mexico
  • Bobadilla, Norma, Molecular Physology Unit UNAM,, Mexico City, Mexico
Background

Urinary tract infection (UTI) is very frequent in renal transplant immunosuppressed patients and the clinicians face the growing increase in antibiotic resistance. Fosfomycin trometamol (Fos) has emerged as a potential UTI treatment, however its influence on calcineurin inhibitors nephrotoxicity (CIN) has not been explored. This study was designed to evaluate the effect of Fos in combination with cyclosporine (CsA) on CIN in the rat.

Methods

Twenty-four male Wistar rats were included and divided into four groups: 1) Control, 2) CsA 15 mg/kg s.c., 3) CsA+Fos 62.5 mg/kg and 4) CsA+Fos 500 mg/kg. Cyclosporinr was daily administered for 14 days, whereas, fosfomycin was starting on day 9 with three doses every 48 h. At the end of the study, functional studies were performed, and tissue samples were obtained.

Results

Table 1

Conclusion

CsA nephrotoxicity was characterized by a significant decrease in RBF and GFR, as well as with a reduction in eNOS, AGT, and AT1R mRNA levels. In CsA+Fos group, greater hypoperfusion, oxidative stress, and increased mRNA levels of pro-inflammatory cytokines were observed. This study shows that Fos increases CsA nephrotoxicity through increasing renal inflammation and alerts us to the combined use of these drugs in the clinical scenario.

GroupControlCsA 15 mgCsA+Fos 62.5 mgCsA+Fos 500 mg
RBF (mL/min)6.6 ± 0.23.2 ± 0.4*3.6 ± 0.4*2.5 ± 0.2*
GFR (mL/min)2.3 ± 0.51.0 ± 0.1*1.1 ± 0.1*0.9 ± 0.1*
Urinary H2O2(μM)219.2 ± 10.6304.9 ± 70.5234.1 ± 27.4401.7 ± 46.5*
Endothelin1.0 ± 0.13.1 ± 0.82.5 ± 0.53.4 ± 0.7
ETA1.0 ± 0.11.3 ± 0.31.6 ± 0.21.6 ± 0.2
ETB1.0 ± 0.10.8 ± 0.11.1 ± 0.21.3 ± 0.2
eNOS1.0 ± 0.10.5 ± 0.2*0.5 ± 0.10.6 ± 0.1
Nrf21.0 ± 0.12.0 ± 0.3*1.7 ± 0.21.9 ± 0.2
Catalase1.0 ± 0.10.9 ± 0.10.7 ± 0.10.8 ± 0.1
SOD11.0 ± 0.10.7 ± 0.10.5 ± 0.1*0.7 ± 0.1
Gpx11.0 ± 0.11.0 ± 0.31.1 ± 0.20.9 ± 0.2
AGT1.0 ± 0.10.3 ± 0.1*0.5 ± 0.1*0.6 ± 0.1*
AT1R1.0 ± 0.10.2 ± 0.1*0.3 ± 0.1*0.4 ± 0.1
AT2R1.0 ± 0.13.8 ± 1.06.2 ± 0.8*5.0 ± 1.4
MCP-11.0 ± 0.13.4 ± 0.43.4 ± 0.7*4.3 ± 0.7*
TNF-α1.0 ± 0.11.4 ± 0.32.3 ± 0.42.6 ± 0.8
IL-61.0 ± 0.11.8 ± 0.33.7 ± 0.6*3.2 ± 0.8*
IL-101.0 ± 0.17.4 ± 1.9*12.1 ± 2.4*9.6 ± 1.8*

Funding

  • Government Support - Non-U.S.