Department of Transplantology and General Surgery, Ludwik Rydygier Medical College of Nicolaus Copernicus University, Bydgoszcz, Poland

Transcription

1 Assessment of lasminogen activato inhibito-1 and von Willeband facto as a maes of endothelial function in atients with end-stage kidney disease afte allotanslantation duing a one-yea follow-u Witold Dooszewski 1, Zbigniew Włodaczyk 2, Paweł Stóżecki 1, Jacek Manitius 1, Ewa Gabaczyk 3, Danuta Rość 3, Gażyna Odowąż-Syniewska 4 1 Deatment and Chai of Nehology, Hyetension and Intenal Medicine, Ludwik Rydygie Medical College of Nicolaus Coenicus Univesity, Bydgoszcz, Poland 2 Deatment of Tanslantology and Geneal Sugey, Ludwik Rydygie Medical College of Nicolaus Coenicus Univesity, Bydgoszcz, Poland 3 Deatment and Chai of Pathohysiology, Ludwik Rydygie Medical College of Nicolaus Coenicus Univesity, Bydgoszcz, Poland 4 Deatment and Chai of Laboatoy Diagnostic, Ludwik Rydygie Medical College of Nicolaus Coenicus Univesity, Bydgoszcz, Poland Abstact: Objectives. The aim of ou study was to detemine the endothelial function in atients with chonic kidney disease (CKD), stage V (end-stage enal disease ESRD), befoe and duing a one-yea obsevation afte kidney allotanslantation. Patients and methods. We studied 40 atients with stabile gaft function afte thei fist kidney tanslantation, including 21 females ( age 41 ±12.5 ys) and 19 males ( age 43.6 ±13.3 ys), teated aleady with hemodialysis because of ESRD. Results. Afte tanslantation we obseved significant decease in seum ceatinine concentations (C) (7.32 ±2.07 mg/dl to 1.50 ±0.45 mg/dl at 6 months and 1.61 ±0.58 mg/dl afte 12 months afte tanslantation). Duing 12 months we found changes only in lasminogen activato inhibito-1 (PAI-1) levels. Von Willebandt facto (vwf) levels emained unalteed duing follow-u and total homocysteine (thcy) concentation deceased, but this change was not statistically significant. Thee was no coelation between vwf and PAI-1 concentations and othe clinical and laboatoy findings. Conclusions. In ou study we did not find any imovement of endothelial function duing the fist yea afte kidney allotanslantation. The C concentation at the end of study was 1.6 mg/dl, which indicates the chonic kidney gaft insufficiency. We conclude that desite kidney allotanslantation endothelial function is imaied like in CKD, but with moe advanced abnomalities in the cadiovascula system. Key wods: chonic kidney disease, endothelium, kidney allotanslantation INTRODUCTION Endothelial dysfunction occus in numeous mobidities inceasing the isk of develoment of cadiovascula system diseases, e.g. in hyetension o dislyidemia, and also in smokes o esons unde stess [1-3]. It is emhasized that endothelial dysfunction is one of the fist otentially evesible manifestations of cadiovascula system athologies [4,5]. Atheoscleosis and its thombotic comlications ae a quite seious oblem in chonic kidney disease (CKD) atients and in esons with enal tanslant. Accoding to some authos, death isk in CKD atients duing enal elacement theay is inceased 10 to Coesondence to: d med. Witold Dooszewski, Kateda i Klinika Nefologii, Nadciśnienia Tętniczego i Choób Wewnętznych, Collegium Medicum Uniwesytetu Mikołaja Koenika, ul. Maii Skłodowskiej-Cuie 9, Bydgoszcz, Poland, neka@neka.co.l Received: Ail 4, Acceted in final fom: June 14, Conflict of inteest: none declaed. Pol Ach Med Wewn. 2007; 117 (5-6): Coyight by Medycyna Paktyczna, Kaków times in comaison with geneal oulation. It is, howeve, lowe in atients with enal tanslant than in dialyzed atients [6]. Theefoe, cuently the eseaches attention focuses on assessment of endothelium and its involvement in athogenesis of numeous diseases, including chonic kidney disease. Endothelial dysfunction leads to disution of intecellula communication; it esults in inceased exession of adhesion molecules, inceased chemokine secetion and adhesion and activation of ganulocytes and thombocytes. Theefoe, in diagnostic ocedue behavio of individual makes of endothelial function, e.g. lasminogen activato inhibito tye 1 (PAI-1), von Willeband facto (vwf), tissue lasminogen activato (t PA) [7], endothelin 1, asymmetic dimethylaginine, and also total homocysteine (thcy) [8] is analyzed. The aim of this study was assessment of changes in PAI-1 and vwf levels as makes of endothelial function within the fist 12 months afte kidney allotanslantation and detemination of elation between the indices of endothelial function and the assessed clinical aametes and additional tests within a six-month o one-yea eiod afte enal tanslantation. Assessment of lasminogen activato inhibito-1 and von Willeband facto... 1

2 PATIENTS AND METHODS Assent to cay out the study has been obtained fom Local Committee of Ethics of Scientific Reseach (L.dz. KB/87/2001 of ) at Ludwik Rydygie Medical College in Bydgoszcz of Nicolaus Coenicus Univesity in Touń (CM UMK). The study involved 40 atients afte the fist enal tanslant, including 21 females ( age 41.1 ±12.5 yeas) and 19 males ( age 43.6 ±13.3 yeas), who have eviously undegone enal elacement theay with hemodialysis due to end-stage enal disease. The atients wee hositalized in the Deatment of Tanslantology and Geneal Sugey of CM UMK. The atients wee Polish citizens and all had kidneys tanslanted fom a deceased donos. The eciients wee egisteed in the National Registe of Reciients of Vascula Ogans. They undewent equied qualification tests and they wee selected accoding to human leukocyte antigen (HLA). The selection has been made by HLA Laboatoy of Immunology Unit of the Tanslantology Institute in Wasaw. Patient histoies wee taken and medical examinations wee efomed; systolic (SBP) and diastolic (DBP) blood essue wee ecoded and ateial essue (MAP) was calculated. Causes of chonic kidney disease in the ogan eciients wee: chonic glomeulonehitis 24 atients (60%), obstuctive nehoathy 4 (10%), hyetensive nehoathy 3 (7.5%), acute tubula necosis 3 (7.5%), olycystic kidney disease 3 (7.5%), diabetic nehoathy 1 (2.5%), luus nehoathy 1 (2.5%) and tubulointestitial nehoathy 1 (2.5%). Diectly afte oeation the atients wee staying in the Deatment of Tanslantology and Geneal Sugey of CM UMK. Duing the stay, thei clinical state was assessed, diuesis was measued and laboatoy tests wee caied out accoding to the detemined schedule. At the same time tile dug immunosuessive theay was imlemented, including cyclosoine (22 esons) o tacolimus (18 esons) combined with azathioine o mycohenolate mofetil and ednisone. In ode to obtain coect values of the laboatoy aametes and thei mutual elations, a contol gou consisting of 14 voluntees ( age 40.1 ±11.2), including 7 females and 7 males aged was selected. They undewent single detemination of the studied laboatoy and clinical aametes. Blood samles fo tests of fibinolytic and coagulation system and fo othe laboatoy tests wee taken on the day of tanslantation (day 0), uon witten consent of the atient, immediately uon thei aival to the Deatment of Tanslantology and Geneal Sugey of CM UMK. Pio to enal tanslantation each atient was subjected to hemodialysis without anticoagulant as a outine eaation fo enal tanslantation. The aim of hemodialysis was achieving an otimum state of dehydation, comaable to so-called dy mass, enabling a sugey. Blood samles wee taken by unctue of the bend of the elbow by using minimum stasis, to lastic syinges containing 3.2% sodium citate, maintaining citate to blood ate of 1:9. Syinges with blood wee immediately tansoted in a cold box to the Deatment and Chai of Laboatoy Diagnostic CM UMK, whee they wee sun 3000 m in 4 C fo 20 minutes. Poo-latelet lasma obtained in this way was otioned and fozen in 70 C until thcy was detemined in the Deatment and Chai of Laboatoy Diagnostic CM UMK, and PAI-1 and vwf in the Deatment and Chai of Pathohysiology. Comlete blood count, blood uea nitogen (BUN), ceatinine (C), electolytes, total cholesteol, tiglyceides, total calcium, hoshous, glucose, tansaminases, uic acid (UAC) levels wee detemined using the emaining blood. The following fasting blood samles wee taken fom atients duing outine contol examination in 6- and 12-month intevals counting fom the day of enal tanslantation in the Tanslant Outatient Clinic of the Secialist Clinic Comlex of the CM UMK Univesity Hosital. In all membes of the contol and test gou glomeula filtation ate (GFR) was assessed, calculated accoding to Cockoft Gault fomula and detemined fo 1.73 m 2. The values obtained wee then subjected to statistical analysis. Statistical analysis The esults wee esented as a ± standad deviation. Pesence of nomal distibution of the analyzed statistical data was assessed by s of Shaio-Wilk test and standad Peason χ 2 test. In ode to use Student s t-test to comae two s of small samles, an analysis of nomal distibution was caied out. Consideing that the analyzed gou has 40 samles, a hyothesis of equality of 2 s was oosed, veified by U test of standad nomal distibution. Relations between the aametes wee analyzed by s of Seaman ank coelation coefficient (fo abnomal distibution) o Peason coelation coefficient (fo nomal distibution). Moeove, multifacto elations between the selected aametes wee tested. Fo all analyzes, <0.05 value was assumed to be statistically significant. Detemination esults wee dawn u using Excel fo Windows 98 and Statistica 5.0 PL fo Windows 98 by StatSoft. RESULTS Pio to enal tanslantation the atients wee undegoing enal elacement theay fo aox. 40 months, including males 35.5 ±25.3 months, and females 44.2 ±40.1 months. The diffeence was not statistically significant. 72% atients in the study gou wee teated fo ateial hyetension, mostly with two dugs. Mean cold ischemia time in tanslanted kidney was 1588 minutes. Chaacteistic incease in PAI-1 levels both duing the fist 6 months, and 12 months afte enal tanslantation (Fig. 1) was obseved in the study gou. The obtained values wee not significantly diffeent fom the contol gou (Tab. 1). POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2007; 117 (5-6)

3 Table 1. Clinical aametes and laboatoy test esults in contol and study gous io to enal tanslantation, 6 and 12 months aftewads Paametes Study gou Contol gou io to tanslantation ( 0 ) 6 months afte tanslantation ( 6 ) 12 months afte tanslantation ( 12 ) GFR (ml/min/1,73m 2 ) 2.43 ±1.61 A ±21.48 B,D ±22.07 C,E ±48.48 C (mg/dl) 7.32 ±2.07 A 1.50 ±0.45 B,D 1.61 ±0.58 C,E 0.91 ±0.07 MAP (mmhg) ±12.55 A ±8.84 B ±9.23 C,F ±10.51 SBP (mmhg) ±19.83 A ±14.93 B ±17.0 C,F ±14.33 DBP (mmhg) ±10.4 A 4.5 ±7.9 B ±7.86 C ±9.02 PAI-1 (ng/ml) ±14.04 A ±14.93 D ±21.36 E,F ±16.84 thcy (μmol/l) ±8.57 A 7.86 ±6.15 B ±6.22 C 8.39 ±2.54 vwf (%) ±20.28 A ±20.95 B ±25.12 C ± cholesteol (mg/dl) ± ±52.44 B,D ± ±37.03 Tiglyceides (mg/dl) ±91.36 A ± B ±75.48 C ±43.95 UAC (mg/dl) 4.03 ± ±1.26 B, D 6.62 ±1.59 C, E 4.42 ±1.19 Glucose (mg/dl) 95.6 ± ± ± ±7.44 Hemoglobin (g/dl) ±1.71 A ±2.39 D ±2.37 E, F ±1.25 Statistically significant diffeences ( <0.05) wee maked with lettes, deending on follow-u eiod: A 0 vs contol gou, B 6 vs. contol gou, C 12 vs. contol gou, D 0 vs. 6, E 0 vs. 12, F 6 vs. 12. Abbeviations: C ceatinine, DBP diastolic blood essue, GFR glomeula filtation ate, MAP ateial essue, PAI-1 lasminogen activato inhibito tye 1, SBP systolic blood essue, thcy homocysteine, UAC uic acid, vwf von Willeband facto Concentation of von Willeband facto was not showing significant changes in the study gou (Fig. 2), and values obtained both io to and afte enal tanslantation, wee significantly lowe than in the contol gou (tab. 1). Coelations between the obtained values of PAI-1, vwf and thcy afte enal tanslantation and the esults of laboatoy and clinical tests oved elation between the thcy levels (as deendent vaiable) and C and BUN levels (as indeendent vaiables) within 0 6, 6 12 and 0 12 months afte tanslantation. Relation between SBP (as indeendent vaiable) and thcy (as deendent vaiable) within the second half yea afte tanslantation was also obseved. No significant elations wee obseved between vwf and PAI-1 and the analyzed clinical and laboatoy values. Within the eiod io to tanslantation, the atients with chonic kidney disease (stage V) wee demonstating highe MAP ( ±12.55 vs ±10.51 mmhg), highe C level and lowe GFR than in the contol gou (table 1). The assessed makes of endothelial function (PAI-1, vwf) in the study gou wee significantly lowe, wheeas thcy levels wee highe than in the contol gou. Pio to enal tanslantation, the study gou did not diffe fom the contol gou in esect of UAC levels, cholesteol levels and lasma glucose concentation (Tab. 1). Afte enal tanslantation and uon it stated functioning, thee was obseved statistically significant decease in lasma C levels: 7.32 ±2.07 mg/dl io to tanslantation, to 1.50 ±0.45 mg/dl in 6 months afte tanslantation and 1.61 ±0.58 mg/dl afte 12 months since enal tanslantation (table 1). A value of ceatinine levels was 1.61 mg/dl and coesonding value of GFR was ±22.07 ml/kg/1.73 m 2 (Fig. 3). A multile egession analysis fo ceatinine levels as deendent vaiable was caied out only with the vaiables demonstating significant linea coelations. A elation between the ceatinine levels and body weight in the individual followu eiods was only found. Multile egessions caied out fo vwf and PAI-1 (as deendent vaiables) showed no significant coelations with laboatoy aametes and clinical data (as indeendent vaiables). Due to oosed hyothesis of imact of changes in the assessed aametes within 0 6 months afte tanslantation on functions of endothelium and tanslanted kidney, multifacto coelations wee caied out fo the tested deendent vaiables (vwf, PAI-1, thcy, C, GFR) within the eiod of 6 12 months afte tanslantation. PAI-1 levels demonstated elation with incease in body weight (invese elation) and decease in C levels within 0 6 months, and this elation did not ecu within 6 12 months of follow-u. Multifacto coelations wee also caied out fo the aametes detemining function of the tanslanted kidney. Thee was found a eeating elation between changes in C levels (deendent vaiable) and Δ thcy levels (indeendent vaiable) within follow-u eiods of 0 6 and 6 12 months afte enal tanslantation. Othe eeating coelations wee not found (Tab. 2). Assessment of lasminogen activato inhibito-1 and von Willeband facto...

4 [ng/ml] P AI-1 "0" P AI-1 "6" P AI-1 "12" ±standad deviation ±standad eo Fig. 1. Changes in concentation of lasminogen activato inhibito tye 1 (PAI-1) in kidney tanslant atient duing one-yea follow- u [%] vwf "0" vwf "6" vwf "12" ±standad deviation ±standad eo Fig. 2. Changes in concentation of von Willeband facto antigen (vwf) in kidney tanslant atient duing one-yea follow-u Table 2. Coelation coefficients calculated fo lasma ceatinine levels in kidney tanslant atients, elated to studied clinical and laboatoy aametes io to tanslantation ( 0 ) and 6 ( 6 ) and 12 ( 12 ) months aftewads Paametes Body weight SBP DBP MAP PAI-1 vwf thcy UAC Cholesteol Tiglyceides Glycemia and values given esectively. Abbeviations see table 1 [mg/dl] ceatinine concentation changes C "0" C "6" C "12" ±standad deviation ±standad eo Fig. 3. Plasma ceatinine concentation in study gou duing oneyea follow-u (C 0 = 7.32 ±2.07 mg/dl; C 6 = 1.50 ±0.45 mg/dl; C 12 = 1.61 ±0.58 mg/dl). C ceatinine DISCUSSION Endothelial function was assessed based on changes in vwf and PAI-1 levels. In comaison with the contol gou, the study gou demonstated inceased PAI-1 levels in 6. and 12. month of the follow-u since tanslantation, as well as statistically highe PAI-1 levels io to tanslantation. The detemined vwf levels in each follow-u eiod in the study gou wee also statistically lowe than in the contol gou. The esults obtained in atients afte enal tanslantation divege fom exectations, what may esult fom the size of samle and shot follow-u eiod coveing 12 months afte enal tanslantation. Mean lasma C levels deceased fom 7.32 mg/dl to 1.5 mg/dl afte 6 months, and afte 12 months C was stabilized at the level of 1.61 mg/dl. GFR inceased fom 2.43 ml/min/1.73 m 2 to ml/min/1.73 m 2 and finally eached a level of ml/min/1.73 m 2. Alying binding citeia of diagnosing chonic kidney disease, accoding to National Kidney Foundation of 2002 [9], in the study gou thee was found stage II of chonic kidney disease. Alied POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2007; 117 (5-6)

5 classification shows significant elations between the kidney function and the isk of develoment of cadiovascula system diseases [10]. It is consideed that GFR decease below 60 ml/ min/1.73 m 2 has consideable imact on incease in isk fo the develoment of atheoscleosis, ischemic heat disease and cadiac insufficiency [11-13]. The fist 6 months afte tanslantation ae consideed a eiod of aticula isk fo develoment of sugical, infection and metabolic comlications, e.g. liid and cabohydate disodes [14,15]. Some authos find no diffeences in concentation o activity of selected aametes of coagulation system afte enal tanslantation, which at the same time ae the makes of endothelial function. It may ove the esistent imaiment of fibinolytic oeties of lasma. It seems that endothelial dysfunction is a consequence of oduction of eoxide anions, which inactivate nitic oxide (NO), and oxidized molecules of low density liooteins, accumulated in sites of vascula injuy, hame NO elease fom endothelial cells o inactivate it diectly. Most souces ovide infomation on fibinolytic defect in atients afte enal tanslantation. Pedominant abnomality found duing a long tem follow-u is imaied fibinolysis, seconday to inceased PAI-1 levels. Inceased concentations of PAI-1 antigen exess the imaiment of endothelial function and inceased thombotic tendencies, and theeby an inceased isk of unfavoable cadiovascula events. Data fom liteatue ove the genealized hemostatic defect in atient afte tanslantation, which may demonstate a natue of inceased activity of fibinolytic system o edomination of coagulation system [6], and also the fact that aleady in ealy stage of chonic kidney disease thee aea significant changes in lasma fibinolytic activity [6]. In CKD cases we obseve fequent coexistence of hyeinsulinemia, dysliidemia and hyehomocysteinemia [1,6]. Patients in ealy stage of CKD demonstate, like the dialyzed atients, lowe activity of tissue lasminogen activato (t-pa). It may esult fom hameing imact of liids on t-pa elease o its synthesis in endothelial cells. The obseved inceased concentation of PAI-1 antigen oved some of the data fom liteatue [6,16,17]. Howeve, othe authos [18,19] eot deceased activity of PAI-1 and inceased activity of t-pa afte tanslantation. They did not obseve significant imact of use of cyclosoine (CsA) on t-pa and PAI-1. The authos judged that lowe antigen concentation and lowe PAI-1 activity wee elated to the imact of numeous othe factos, like hyeliidemia, obesity o steoid theay, wheeas incease in concentation of PAI-1 antigen was elated to inceased insulin concentation. It was also obseved that in kidney eciients with ooly contolled hyetension, PAI-1 concentation and activity wee highe than in atients afte tanslantation with well contolled hyetension. Pekowska et al. [19] found inceased concentation and activity of PAI-1 in atients with chonic nehoathia of tanslant in comaison with eciients with stable gaft function. It shall ove ogessing endothelial dysfunction and deceased lasma fibinolytic activity, which altogethe incease the isk fo thomboembolic comlications. In the analyzed mateial thee wee not found statistically significant diffeences between the atients with nomal enal function and the atients with insufficient tanslanted kidney. Unbiased assessment of PAI-1 action afte tanslantation equies consideing a method alied to detemine activity and concentation of PAI-1 antigen. Due to sontaneous convesion of PAI-1 to inactive fom and occuence of t-pa/pai-1 lasma comlex in a given samle of eiheal blood, active, inactive and bound to t-pa molecules of PAI-1 ae found simultaneously. Available PAI-1 antigen detemination sets eact with each of the afoementioned PAI-1 molecule [16,18,20]. Theefoe, it seems that the method based on activity assessment is moe eliable, howeve, moe comlicated and laboious as well. Numeous factos have imact on the ocess of sontaneous convesion of PAI-1 fom active to inactive fom. It is thought that obesity, hyeliidemia and used glycocoticosteoids lead to consideable fluctuations of the ocess. Hemodialysis efomed io to tanslantation may influence the tested aametes of coagulation and fibinolytic system (vwf, PAI-1), as well as on biochemical aametes. Duing hemodialysis, due to inteaction of extacooeal ciculation with vascula system of the atient and lack of entie biocomatibility, lasma fibinolytic activity is inceased [6, 21,22]. The consequence is an inceased t-pa elease fom the vessel wall. Using of anticoagulant (heain) duing hemodialysis does not influence the afoementioned ocess. Obsevations wee based on comaison between dialysis with heain and insing out the dain system with 0.9% NaCl. Hemostasis is also influenced by latelet activation, tumo necosis α (TNF-α) elease and hyoxemia [6,21,22]. Action of the assessed makes of endothelial function also deends of alication of immunosuessive theay. Cyclosoine ovokes extension of euglobulin lysis time, decease in t-pa activity and incease in activity and concentation of PAI-1 antigen [6,17,23,24]. It is suggested that a mechanism of toxic influence of CsA and tacolimus (Tac), a calcineuin inhibito, is elated to hameing of activity of nitic oxide synthase, which is calcium/calmodulin-deendent enzyme. The effect of those actions is decease in synthesis and availability of NO [25]. Ligtenbeg et al. [26] demonstated imaied endothelial function in vasomoto eaction in atients afte enal tanslantation teated with CsA. Hameing imact of CsA on endothelial function was atly eliminated by administation of L-aginine, what oves CsA imact on bioavailability of NO. Also van den Doel et al. [24] oved that PAI-1 levels was highe in atients afte tanslantation, teated with cyclosoine, than in atients fom the contol gou and in atients afte tanslantation, to whom that dug was not administeed. Cyclosoine was elaced with azathioine in atients with stable tanslant function [6] and decease in PAI-1 activity was found within aox. 12 weeks fom convesion. At the same time, incease in t-pa concentation and activity was obseved, what was cetainly seconday to decease in PAI-1 concentation. Incidents of cyclosoine ovedose, accomanied by incease in PAI-1 con- Assessment of lasminogen activato inhibito-1 and von Willeband facto... 5

6 centation, additionally had to ove imact of this dug on incease in PAI-1 levels [6]. Imaied endothelial function duing administation of calcineuin inhibitos was also obseved by Ovuwoie et al. [25]. They did eseach on changes in vascula flow, which wee a esonse to a stimulus diectly boadening the vessels o to imact of agents inceasing the elease of vasodilatatos fom vascula endothelium. Elhasade et al. [16] assessed action of t-pa and PAI-1 in atients afte kidney allotanslantation. They found that in atients afte enal tanslantation concentation of t-pa antigen and t-pa activity wee slightly highe than in healthy esons, wheeas PAI-1 activity was significantly lowe in eciients, and concentation of PAI-1 antigen highe. Additional analysis of immunosuessive theay did not show imact of cyclosoine on t-pa and PAI-1 activity and on concentation of t-pa antigen; howeve, it was found elation between concentation of PAI-1 antigen and cyclosoine. The authos wee of the oinion that cyclosoine might diectly damage vascula endothelium, inceasing lasma thombotic activity, intensifying latelet activity and intefeing in metabolism of aachidonic acid and synthesis of ostaglandins [18,27]. Simila esults ae esented by van den Doel et al. [24], who studied lasma fibinolytic activity uon theay convesion fom cyclosoine to azathioine. Theay convesion led to incease in lasma fibinolytic activity in comaison with decease of PAI-1 antigen. No changes in concentation of t-pa antigen wee found, howeve, t-pa activity inceased. Moeove, duing CsA theay thee was found a elation between concentations of t-pa and PAI-1 antigens and ostaglandin E 2 and thomboxane B 2 levels. No links between those aametes wee obseved duing azathioine theay. Based on these obsevations, a conclusion was dawn of multile influence of CsA on endothelium and coagulation and fibinolytic system. Patients afte tanslantation demonstate numeous abnomalities in esect of fibinolysis in comaison with healthy esons. They also demonstate extended euglobulin lysis time, significantly deceased t-pa activity level, wheeas PAI-1 activity and levels ae significantly highe [6,17]. On the othe hand, van den Doel et al. [24] showed that in atients teated with CsA, PAI-1 levels wee significantly highe than in healthy esons and atients afte tanslantation, to whom CsA was not administeed. Comaing atients teated with CsA and ednisone fo at least 6 months, with a gou of atients, to whom CsA was changed to Aza, significant decease in PAI-1 activity was obseved within aox. 12 weeks afte they stoed taking CsA. At the same time, inceased t-pa activity was found, which was obably seconday to decease in PAI-1. Mechanism of CsA action is not entiely clea. Some suggest hameing effect on ostanoid elease, intensification of oxidative stess and diect imact of CsA on endothelial cells, as well as on heatocytes [24]. CsA imact on PAI-1 is undeniable, due to the fact that PAI-1 concentation significantly inceases, e.g. uon CsA ovedose. Glycocoticosteoids also have significant imact on coagulation system. The fist infomation concening this issue was ovided by the data on atients with Cushing s syndome, whee educed lasma fibinolytic activity was descibed [6]. Comaing atients, who undewent enal tanslantation 12 months ealie and atients with Cushing s syndome with healthy oulation, significant incease in both activity and concentation of PAI-1 antigen, measued befoe and afte assive hyeemia was found in gous of studied atients [6]. Uon coming off steoids, in atients afte enal tanslantation no consideable imovement was obseved in esect of coagulation system, what highlights multifacto effect on hemostasis. It is thought that glycocoticosteoids may influence PAI 1 synthesis gene omote [16,18]. Obsevations in atients with Cushing s syndome showed incease in both concentation and activity of PAI-1 [26]. Małyszko et al. [17] oved imact of glycocoticosteoids on develoment of insulin esistance, liid disode and obesity, and secondaily on fibinolysis. Howeve, the esults obtained in those studies vaied in esect of t-pa level Małyszko et al. [17] found its eduction, wheeas Elhasade et al. [16] and Pekowska et al. [19] incease in t PA level. Inconsistencies seem to be the esult of diffeent C concentations (i.e. diffeent enal function) and elated othe glycocoticosteoid doses. Analogous data concening atients subjected to steoid theay fo othe easons, as well as atients afte tanslantation taking steoids is esented by Patasi et al. in thei study [23]. Coming off steoids in atients afte tanslantation did not esult in adical imovement of hemostasis aametes. It oves influence of numeous factos on coagulation and fibinolytic system [8,17,18]. Immune esonse in eciient against the gaft may also have imact on PAI-1 and vwf. Wang et al. [27] assessed exession of PAI-1-mRNA in endothelial cells of ateial and caillay vessels of tanslanted kidneys. In case of both acute and chonic ejection, inceased values of PAI-1-mRNA in the vessel endothelium wee oved. Toy et al. [28] assessed action of fibin deosits, t-pa, PAI-1 and antithombin in enal biotates, taken due to ejection in the eiods of: 1 month, fom 1 month to 1 yea and 1 yea afte tanslantation. They found definitely highe amount of fibin and t-pa deosits in smooth muscle cells of vessels of biotates in atients with ejection within 1 month afte tanslantation. Also t-pa deosits showed tendency to be accumulated in enal tissue in inceased amounts, but thee wee no diffeence between the studied gous in this esect. No elation with othe makes of endothelial function was found. Thee wee also attemts to elate changes in vwf concentation to homocysteine level and liid disodes. Blann et al. [20,29] and Witztum et al. [30] found in thei studies that a change of lifestyle combined with educed cholesteol level led to educed vwf levels. Additionally, in multile analysis vwf levels coelated with total cholesteol level with the amount of consumed olyunsatuated fatty acids and cabohydates. Those elations wee indeendent of age, body weight, ate- 6 POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2007; 117 (5-6)

7 ial essue, smoking and seveity of ischemic heat disease. The authos suggest that cytotoxic low-density liooteins ae esonsible fo damage of endothelial cells [20,30]. It was oved in exeimental studies that vwf levels incease influenced by administation of steoids and cytokines (Il-1, TNF-α) oduced by monocytes and macohages. It was also obseved that high thcy concentation hames oduction of vwf, mainly by hameing of intacellula tansot [31,32]. The studies caied out showed no consideable imovement of endothelial function, assessed based on detemination of PAI-1 and vwf within a yea fom tanslantation in kidney tanslant atients. Afte a yea, lasma C concentation shows a value of 1.6 mg/dl, what coesonds to chonic gaft insufficiency. Theefoe, it may suggest that, in site of enal tanslantation, endothelium acts, like in atients with chonic kidney disease, but with moe advanced lesions in cadiovascula system. efeences 1. Elisaf M, Mikhailidis DP. Statins and enal function. 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The effect of cyclosoine on egulatos of fibinolysis in lasma allogaft eciients. Ann Tanslant. 1998; 3: Małyszko J, Małyszko JS, Pawlak K, et al. The coagulolytic system and endothelial function in cyclosoine kidney allogaft eciients. Tanslantation. 1996; 62: Pekowska A, Elhasade A, Gaciong Z, et al. Regulation of fibinolysis in lasma of kidney tanslant eciients. Tanslant Poc. 2002; 34: Pekowska A, Elhasade AS, Gaciong Z, et al. An association between fibinolytic activity and gaft function in tanslantation eciients. Tanslant Poc. 2001; 33: Blann AD. Von Willeband facto and the endothelium in vascula disease. B J Biochem Sci. 1993; 50: Piątkowska M, Kotschy M, Natowicz E, et al. Tkankowy aktywato lazminogenu tpa Ag i inhibito aktywatoa lazminogenu PAI-1 w czasie hemodializy u choych z zewlekłą niewydolnością neek. Pol Mek Lek. 1997; 2: Rość D, Bonisz M, Zastawna E, et al. Układ fibynolizy kwi choych na zewlekłą niewydolność neek oddawanych hemodializie. 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