Change from cyclosporine to combination therapy of mycophenolic acid with the new sphingosine-1-phosphate receptor agonist, KRP-203, prevents host nephrotoxicity and transplant vasculopathy in rats.

Abstract

BACKGROUND:

Replacement of calcineurin inhibitor (CI) with anti-metabolic agents in transplant patients with CI-induced nephrotoxicity is performed clinically and improves renal function, but increases the risk of rejection. We investigated whether the change from cyclosporine (CsA) to a limited dose of mycophenolic acid (MPA) together with a new sphingosine-1-phosphate (S1P) receptor agonist, KRP-203, is sufficient to prevent both transplant vasculopathy and CsA-induced nephrotoxicity.

METHODS:

Orthotopic aortic transplantation was conducted in a high-responder rat combination of Dark Agouti (DA; major histocompatibility complex [MHC] haplotype RT-1a) to Lewis (RT-1(l)). After CsA administration (15 mg/kg/day) for 2 weeks, the recipients were divided into the following treatment groups for 6 weeks: MPA (10 mg/kg); KRP-203 (KRP; 1 mg/kg); and MPA + KRP. Serum creatinine (Cr), arteriolar hyalinosis and expression of transforming growth factor (TGF)-beta1 in the recipient kidney were examined as parameters indicating nephrotoxicity. Intimal hyperplasia was assessed by vascular occlusion, and graft-infiltrated cells were semi-quantitatively evaluated histologically and then characterized immunohistochemically.

RESULTS:

Continuous CsA treatment attenuated intimal hyperplasia and cell infiltration (2.9 +/- 0.3% and 0.4 +/- 0.1; p < 0.01 vs vehicle), but increased Cr and hyalinosis (0.43 +/- 0.03 mg/dl and 57.2 +/- 0.4%; p < 0.01) with upregulated TGF-beta1. Replacement of CsA by MPA or KRP treatment alone improved nephrotoxicity, but worsened intimal hyperplasia and cell infiltration. Conversion to MPA + KRP treatment prevented nephrotoxicity (Cr, 0.32 +/- 0.02 mg/dl; hyalinosis, 5.6 +/- 1.3%; p < 0.01 vs CsA) and markedly suppressed intimal hyperplasia and cell infiltration (3.6 +/- 1.2% and 1.0 +/- 0.3; p = not significant vs CsA), with reduced T-cell infiltrates in the graft.

CONCLUSIONS:

Changing from CsA to a combined therapy of MMF with S1P agonist is a promising strategy in clinical transplantation to overcome CI-induced nephrotoxicity and chronic rejection.

• Authors: Jun Fujishiro, Chihiro Suzuki, Shinji Kudou, Tokutaro Yasue, Yoji Hakamata, Masafumi Takahashi, Takashi Murakami, Kohei Hashizume, Eiji Kobayashi
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 25 Issue 7 Pg. 825-33 (Jul 2006) ISSN: 1557-3117 [Electronic] United States
• PMID: 16818126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• KRP-203
• Receptors, Lysosphingolipid
• Sulfhydryl Compounds
• Cyclosporine
• Mycophenolic Acid

Topics

• Animals
• Aorta (metabolism, pathology, transplantation)
• Aortic Diseases (epidemiology, prevention & control)
• Arterial Occlusive Diseases (epidemiology, prevention & control)
• Blood Cell Count
• Cyclosporine (adverse effects, therapeutic use)
• Drug Therapy, Combination
• Hyperplasia (prevention & control)
• Immunohistochemistry
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Kidney Diseases (chemically induced, etiology, prevention & control)
• Macrophages (pathology)
• Male
• Mycophenolic Acid (therapeutic use)
• Rats
• Rats, Inbred Strains
• Receptors, Lysosphingolipid (agonists)
• Retreatment
• Sulfhydryl Compounds (therapeutic use)
• T-Lymphocytes (pathology)
• Transplantation, Homologous
• Tunica Intima (pathology)