Letter to the Editor Nephron 2002;91:356–357 A Protective Role for Protein C Inhibitor on Graft Function in Renal Transplant Recipients? Gültekin Gençtoy Ahmet A. Kıykım Bülent Altun Mustafa Arıcı Yunus Erdem S¸ erafetin Kirazlı Ünal Yasavul Çetin Turgan S¸ ali Çagˇ lar Departments of Nephrology and Hematology, Hacettepe University School of Medicine, Ankara, Turkey Mustafa Arıcı, MD Hacettepe Hastanesi, Nefroloji Bölümü 06100–Sihhiye, Ankara (Turkey) Tel. +90 312 324 3109, Fax +90 312 311 3958, E-Mail marici@hacettepe.edu.tr ABC Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com © 2002 S. Karger AG, Basel 0028–2766/02/0912–0356$18.50/0 Accessible online at: www.karger.com/journals/nef Dear Sir, Fibrinolytic disturbances are thought to play an important role in processes leading to allograft dysfunction. The local balance between concentration and activity of plas- minogen activators (tPA: tissue plasminogen activator; uPA: urine plasminogen activator) and their inhibitors (PAI-1: plasminogen ac- tivator inhibitor-1; PCI: protein C inhibitor) may affect renal fibrogenesis and allograft survival [1]. Protein C inhibitor (PCI) is a member of serine protease inhibitor (serpin) family [2]. It was first described by Marlar and Griffin [3] as an inhibitor of activated protein C. Urinary PCI, purified and charac- terized by Stump et al. [4], was initially described as a new urokinase (UPA) inhibi- tor and therefore named plasminogen acti- vator inhibitor-3 (PAI-3). PCI is synthesized and localized in kidney tissue where it may provide protease inhibitor activity. Com- plexes of PCI with urokinase found in hu- man urine may be produced locally in the kidney. PCI antigen and RNA were demon- strated in renal tubular cells of human kid- ney tissue by Radtke et al. [2] in 1994. In this study, we have evaluated the role of plasma levels of PCI, PAI-I and tPA on allograft function in renal transplant recipi- ents (RTR). TPA and PAI-1 Ag levels were quantified by ELISA Tintelize kits (Biopool, Sweden). Plasma concentration of protein C inhibitor was determined by electroimmu- nodiffusion using 1.5% antiserum against human protein C inhibitor (Nordic, Tilburg, The Netherlands) in a 1% agarose gel and expressed relative (%) to pooled normal plas- ma. Plasma protein C inhibitor, PAI-I and tissue plasminogen activator levels were de- termined in 28 renal transplant recipients (20 living, 8 cadaveric, mean age 38 B 9 years). They had been engrafted for a period of 6 months to 10 years (mean 54 B 32 months). Mean serum creatinine levels were 1.52 B 0.52 mg/dl. Age- and sex-matched healthy volunteers served as control group. Plasma PCI levels of the RTR were higher than controls (206.5 B 53.5 vs. 102.1 B 15.9%, p = 0.001). Plasma PCI levels were negatively correlated with serum creatinine levels (r = –0.52, p = 0.014) in renal allograft recipients. Plasma PAI-I levels of RTR were also significantly higher than control group (91.3 B 53.5 vs. 37.9 B 9.9 ng/ml, p = 0.001), but there was no correlation with serum creatinine levels. Plasma tPA levels were not different in RTR and control group (6.0 B 2.3 vs. 4.6 B 1.5 ng/ml). Although UPA is produced in the kidney in appreciable concentrations, its physiologi- cal role in the renal tract is yet to be clarified [5, 6]. It may be speculated that UPA has profibrinolytic and mitogenic activity which might be harmful if uncontrolled. The pres- ence of UPA inhibitor PCI in an environ- ment that is exposed to UPA suggests that PCI may play a protective role in normal kidney tissue by blocking the profibrinolytic and mitogenic activity of UPA [7]. Further- more, PCI activity in the renal parenchyme may direct UPA activity towards the lumen of filtration system where proteolysis is re- quired to maintain an unrestricted flow of glomerular filtrate. Kidney tissue PCI levels may be indirectly reflected by plasma PCI levels and higher PCI tissue levels may pro- vide higher urine UPA activity. Further studies are warranted to measure renal par- enchymal PCI and UPA levels concomitant- ly with urine UPA and PCI levels in RTR. In conclusion, plasma protein C inhibitor levels are elevated in RTR and this might play a protective role for allograft function. PAI-I and tPA probably play an important role in the hypercoagulable state observed in RTR. In a rat renal transplant model tPA was shown to be upregulated only in the acute phase of rejection whereas PAI-I was in- duced and persistently expressed during the progressive phase of chronic rejection [8]. However, in this cross-sectional study we could not find any correlation between allo- graft function and PAI-I levels in RTR. Downloaded by: Universitat de Barcelona 161.116.100.129 - 2/6/2019 8:39:59 PM