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.
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.
Fujishiro
Jun
J
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Suzuki
Chihiro
C
Kudou
Shinji
S
Yasue
Tokutaro
T
Hakamata
Yoji
Y
Takahashi
Masafumi
M
Murakami
Takashi
T
Hashizume
Kohei
K
Kobayashi
Eiji
E
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001018:Aortic Diseases / Q000453:epidemiology / Q000517:prevention & control*; D001157:Arterial Occlusive Diseases / Q000453:epidemiology / Q000517:prevention & control; D001772:Blood Cell Count; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006965:Hyperplasia / Q000517:prevention & control; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D019233:Retreatment; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000473:pathology; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000473:pathology
D007166:Immunosuppressive Agents; C501899:KRP-203; D049349:Receptors, Lysosphingolipid; D013438:Sulfhydryl Compounds; D016572:Cyclosporine; D009173:Mycophenolic Acid