immunosuppressive therapy and kaposi's sarcoma after kidney transplantation

Ankara, Turkey, June 19–21, 2002

Tissue Typing and Immunosuppression SymposiumJune 19–21, 2002 Patalya Thermal Hotel Kizilcahamam, Ankara, Turkey

Turkish Transplantation Society Executive BoardPresident: Mehmet Haberal, MD FACSVice-president: Nevzat Bilgin, MDSecretary: Umit Saatci, MDMembers: Sedat Boyacioglu, MDHuseyin Gulay, MD

Abstract no.: 1THE RELATIONSHIP BETWEEN HLA TYPING AND HCV INFECTION AND OUTCOME OF RENAL TRANSPLANTATION IN HCV-POSITIVE PATIENTSA Hadhoud1, AM Abdulaziz1, L Al Menawi2, FA Shaheen3, A Abdulghaffar, F Al Abas5, MF Al Mobrak5

Department of 1Microbiology, 2Histopathology, 3Nephrology, 4Surgery, and 5Internal Medicine, 1Faculty of Medicine, Zagazig University, Egypt, 1–5King Abdulaziz Hospital & Oncology Center, Saudi Arabia

The role of HLA-antigens in susceptibility to hepatitis C virus (HCV) infection is still being debated. We analyzed HLA phenotype frequencies intwo major ethnic groups, namely Egyptian and Saudi nationals. The Egyptian group included 110 patients of whom 55 were HCV positive and theother 55 were HCV negative (control group). The Saudi group included 146 HCV-positive patients and 122 HCV-negative individuals (controlgroup). The results for the Egyptian population revealed increased frequencies of some HLA phenotypes and decreased frequencies of others butwithout any statistically significant difference. In contrast, in the Saudi population, the HLA-A19 phenotype was significantly increased in the HCV-positive patients when compared with the control group, while significantly decreased frequencies were found for HLA-B8, HLA-DRI and HLA-DR3. Our data suggest that there was no significant association between the HLA phenotypes and the susceptibility to HCV infection among theEgyptian population, while the overall data of the Saudi population seem to indicate that the expression of particular HLA-alleles could be associatedwith the susceptibility or resistance to the HCV infection. Further studies on larger numbers of patients are needed to support the role of the HLAsystem in HCV infection. A total of 108 HCV-positive patients underwent renal transplantation at the Jeddah Kidney Center, and the results werecompared with 100 age- and sex-matched controls. Graft survival at 36 months was 82% and 86% for the HCV positive and control subjects,respectively, while the patient survival rate was, respectively, 90% and 91%. Our data suggest that the outcome, at least in the short-term, of renaltransplantation in HCV-positive patients is very good.

Abstract no.: 2XENOTRANSPLANTATION: A VIEW TO THE PAST AND AN UNREALIZED PROMISE TO THE FUTURELH Toledo-Pereyra, F Lopez-Neblina*Borgess Research Institute, Michigan State University*, Vicksburg, MI, USA

Since the early 20th Century when Emerich Ullman transplanted a pig kidney into the arm of a woman (1902), Princeteau implanted portions of arabbit kidney into the kidney of a child who was dying of renal insufficiency (1905), Jaboulay transplanted two kidneys from a pig and a goat asdonor sources (1906), and Unger implanted a monkey kidney into a human (1910), xenotransplantation has made some strides, mostly related toadvanced surgical techniques, improved knowledge of immunological principles, and to steps associated with the development of the most effectiveimmunosuppressive therapy.Innovative surgical techniques were introduced by Alexis Carrel in the first decade of the 1900s, so that vascular anastomoses could be realizedwithout a considerable amount of thrombotic/embolic problems, long before heparin times. Inasmuch as these advances were soundly characterized,it became evident that the results were far from expected and that the time was not ripe for xenotransplantation.It took a further 50 years (1963) before Keith Reemtsma transplanted 13 kidneys from chimpanzees into patients with kidney failure. Remarkably,one patient survived for 9 months before dying from an electrolyte imbalance. In the ensuing years, Starzl (1964), Hardy (1964), Cooley (1968),Ross (1968), Barnard (1977), Bailey (1984) and a few others entered this new field with less than satisfactory accomplishments.The unsolvable barrier of hyperacute rejection required persistence and ingenuity. The recognition of xenoantibodies and their requirement for fulldepletion, through ex vivo porcine perfusion, plasmapheresis, immunoabsorption and complement inhibition, facilitated important advances in thisfield. The introduction of accommodation and molecular chimerism has further improved the knowledge of this newly conceived field. Advancedmolecular engineering techniques have recently permitted the creation of the clonal Gal-deficient pig by eliminating the a-1, 3 galactosyltransferasegene. These discoveries together with better immunosuppression raise hope for the yet unrealized promise of xenotransplantation.

Abstract no.: 3ANGIOTENSINOGEN AND PLASMINOGEN ACTIVATOR INHIBITOR-1 GENE POLYMORPHISM IN RELATION TO CHRONIC ALLOGRAFT DYSFUNCTIONK Reis1, T Arinsoy1, U Derici1, S Gonen2, Z Bicik1, O Soylemezoglu2 U Yasavul3, E Hasanoglu2, S Sindel1

Departments of 1Nephrology and 2Pediatric Nephrology, Gazi University, and 3Department of Nephrology, Hacettepe University, Ankara, Turkey

Chronic allograft dysfunction (CAD) is the most common cause of allograft failure in the long-term, and current immunologic strategies have littleeffect on this condition. The renin-angiotensin system (RAS) plays important roles in hypertension and progression of chronic renal disease. It isthought that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS, in addition to involvement in thrombotic risk and fibrosis. This studyinvestigated possible links between angiotensinogen (AGT) genotypes (M235T/MM, MT, TT) and PAI-1 genotypes (4G4G, 4G5G, 5G5G) and CADassessments of both types of polymorphism were performed in 82 renal allograft recipients (47 males and 35 females; mean age 34.87∫11.22 years).One hundred healthy subjects (54 males and 46 females; mean age 35.54∫10.26 years) were also investigated for AGT polymorphism, and 80 healthy

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subjects (45 males and 35 females; mean age 36.54∫12.41) for PAI-1 polymorphism. Genotypes were determined using polymerase chain reactionsequence-specific primers, and polymerase chain reaction followed by restriction fragment length polymorphism analysis.Kidney recipients with CAD had significantly lower frequencies of the MM genotype and the M allele than those without CAD. (P0.05 andP0.001, respectively) Presence of the MT genotype was significantly associated with CAD, and this genotype introduced a 3.5-fold risk of CADcompared with the MM genotype (P0.05; 95% confidence interval: 1.21–10.20). The transplant recipients with CAD also had significantly lowerfrequencies of the 5G/5G genotype and the 5G allele than those without CAD (P0.001 and P0.05, respectively). Presence of the 4G alleleintroduced a 1.94-fold risk of CAD compared with the 5G allele (95% confidence interval: 1.05–3.66). Determination of AGT M235T and PAI-1genotypes before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.

Abstract no.: 4EFFECT OF CHRONIC HEPATITIS C INFECTION ON LYMPHOCYTE SUBSETS IN RENAL TRANSPLANT PATIENTSB Akman, FN Özdemir, E Agca, R Emiroglu, M Turan, H MehmetBaskent University Faculty of Medicine, Ankara, Turkey

Chronic hepatitis C (HCV) infection is prevalent in renal allograft recipients. Consequently, this group is more likely to develop liver complicationsand have poorer graft outcome. The interaction between viral and host factors under immunosuppressive therapy is important in highlighting theresponse to HCV infection after renal transplantation. The aim of this study was to assess changes that occur in the lymphocyte subsets of HCV-infected kidney recipients, and to determine how these relate to allograft rejection. We investigated 50 patients (33 males and 17 females; mean age32.0∫9.9years; mean time since transplantation: 27.6∫26.5months) who were receiving standard immunosuppressive therapy. Data concerning acuteor chronic allograft rejection were retrieved from the patients’ records. Lymphocyte subsets (CD4, CD8, CD3, CD19, CD16–56), serum albuminlevels, and anti-HCV positivity were evaluated after renal transplantation, and findings in the HCV-positive and -negative groups were compared.Seven of the 50 patients had HCV infection. Anti-HCV positivity was detected before transplantation in three cases, and these patients receivedinterferon therapy before transplantation. Four patients were found to be HCV positive after transplantation. The anti-HCV (π) patients hadsignificantly lower serum albumin (P0.02), lower CD4/CD8 (P0.02) ratios, and a lower percentage of CD 19 (P0.001) and a higher percentageof CD8 (P0.01) cells. Chronic allograft rejection was observed in 71.4% of the HCV-positive patients (P0.04), whereas no acute rejection wasdetected in this group. The findings indicate that HCV infection may alter the immune response in renal transplant recipients, and that the immuno-genic potential of the virus may be higher in this patient group because of low serum albumin levels. It appears that this immunomodulatory actionand low albumin levels may increase the risk of chronic rejection for HCV-infected kidney recipients.

Abstract no.: 5INFLUENCE OF PARATHYROID HORMONE LEVEL ON RENAL ALLOGRAFT OUTCOME, AND CORRELATION WITH HISTOPATHOLOGICAL FINDINGSFN Özdemir, S Sezer, BH Özdemir, Z Arat, Ü Yakupoglu, M Turan, M HaberalBaskent University Faculty of Medicine, Ankara, Turkey

Elevated levels of intact parathyroid hormone (iPTH) are not uncommon after renal transplantation, and this disturbance may affect renal allograftfunction. This study investigated whether iPTH levels were related to histopathological findings of acute rejection in kidney graft biopsies. Thirty-eight renal transplant recipients (29 males, nine females; mean age 29.5∫10.3years) were studied. Renal allograft biopsy was performed in each caseto investigate increased creatinine levels. Lymphocyte and macrophage infiltration of the interstitium was evaluated immunohistochemically withmonoclonal antibodies to CD3 and CD68. Expression of HLA-DR and fibronectin were also studied. The proportion of interstitial cell stainingwas graded semiquantitatively. Serum calcium, phosphorus and iPTH levels before and after the renal transplantation were compared. Patients weregrouped according to their stabilized iPTH levels at 3 months post-transplantation. Group I (nΩ13) exhibited persistently elevated iPTH levels(levels elevated since surgery), and Group II (nΩ25) showed persistently low-normal iPTH levels. The mean age of the Group I patients wassignificantly lower, and their serum calcium levels post-transplantation were significantly higher than those in Group II (PΩ0.02 and PΩ0.03,respectively). Persistent elevation of iPTH was strongly associated with interstitial T-cell density, macrophage density, and glomerular fibronectinexpression in the renal allograft biopsies (P0.05). Also, the time to fibrosis was significantly shorter in Group I (PΩ0.02). The study revealed thatPTH has a potent immunomodulatory effect, and that persistent hyperparathyroidism has a significant impact on renal allograft outcome. The dataindicate that the serum iPTH level is a valuable indicator of immune response, and that regular monitoring of serum iPTH levels is essential afterrenal transplantation.

Abstract no.: 6NEW ADVANCES IN THE MOLECULAR BIOLOGY OF ISCHEMIA/REPERFUSION: MAPK PATHWAYSLH Toledo-Pereyra, F Lopez-Neblina*Borgess Research Institute, Michigan State University, MI, USA

Ischemia/reperfusion (I/R) is an important pathological condition frequently associated with the organ/cell transplantation response. The molecularmechanisms involved in the development and characterization of the I/R lesion are represented, in some way, by the changes occurring in theintracytoplasmic phosphorylated proteins (MAPK) which transmit the I/R signal downstream to the nucleus. The MAPKinases are at the center ofthese developments. As an example, one of the MAPK signaling pathways is represented by the activation of NF-kB. In this pathway, the MAPKphosphorilates the IkB fraction of the NF-kB complex, allowing this fraction to be degraded by ubiquitination and proteolytic degradation by theubiquitin-proteome system. Free NF-kB is translocated into the nucleus, with its subsequent effect on the activation and transcription of DNA withproduction of RNA, which would then copy the template of certain inflammatory cytokines (TNF-a, IL1-a, IL6), adhesion molecules (P-selectin,E-selectin, ICAM-1, VCAM-1) and chemokines (IL8) for future expression. At the same time, NF-kB can be activated by TNF-a and IL-1, whichwould then reach TNFR1, TRADD, TRAF2, MEK, JNK and c-Jun activation or return to the previous IkB route.MAPK pathways appear to be important in the regulation of the inflammatory response after I/R. p38, ERK and JNK are the best-known MAPKsystems, and their modification has direct implications for the I/R syndrome. Inhibition of p38 MAPK has been demonstrated to have a beneficialeffect after various types of ischemia. ERK inhibition might play a role in the increased production of TNF-a. The role of JNK is not as clear asthe other two proteins. A better understanding of the MAPK regulatory mechanisms intervening in I/R would allow us to develop an improved andeffective anti-inflammatory therapy for this pathological condition.

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Abstract no.: 7THE UNKNOWN MAN OF ALEXIS CARREL: THE FATHER OF TRANSPLANTATIONLH Toledo-PereyraBorgess Research Institute, Michigan State University, MI, USA

The contributions and great advances accomplished by the dedicated work and extraordinary genius of Alexis Carrel (1873–1944) made possiblethe establishment of a new discipline, now considered to be transplantation. His pioneering Nobel Prize winning vessel suturing work (1912) plowedthe way for an enhanced participation of surgical leaders in the demonstration of the feasibility of his newly introduced techniques. Even thoughmost of the scientific disciplines associated with transplantation were in their infancy, the possibility of offering a means to realize the surgical faceof transplantation presented an optimistic and new horizon for the developing field.Carrel remains an unknown man to the scientific and nonacademic readers of his life. In addition to his professional and well-advanced scientificworks, he was a mystical individual. He profoundly studied the human being, and through these studies he revealed himself. As one starts to unfoldhis complex personality through all his nonmedical writings, one begins to encounter the meticulous man, the impatient individual, the religiousbeliever, the truth seeker and, paradoxically, the acceptor of clairvoyance and the supernatural. His popular and the best-selling book of his times,Man The Unknown (1935), defined Carrel’s philosophical principles of life and confirmed his intense interest in discovering man and the mostimportant part of him, the unknown element. For Carrel, man was as complex as he believed himself to be: the unknown man.Scientists did not take Carrel’s philosophical incursions kindly. They did not accept his views and criticized him in all his nonscientific developments.Carrel nevertheless characteristically disregarded his critics and charged himself to search for new concepts and forthcoming ideas. He maintainedthis resilience through all his existence and his work defines the Carrel as the complex man he was, as the spiritual student he attempted to be, andas the philosopher of the human race he so desired to be in his writings.

Abstract no.: 8MOST PATIENTS WHO REJECT A KIDNEY TRANSPLANT HAVE ANTI-HLA-ANTIBODIESN El-Awar1, PI Terasaki1, V Lazda2, A Nikaein3, AN Arnold4

1One Lambda Inc., Canoga Park, CA, 2Regional Organ Bank of Illinois, Chicago, IL, 3University Hospital, Oklahoma City, OK, and 4Transplant Immu-nology, Sentara Norfolk General Hospital, Norfolk, VA, USA

To test the humoral theory of allograft rejection, we investigated whether all patients who reject a kidney have HLA-antibodies. Sera from 1363patients at four transplant centers who had rejected a kidney graft and transplant or who had rejected a graft and were waiting for a regraft werefirst tested by cytotoxicity AHG. Sera that were negative were tested by solid phase assays (ELISA or flow cytometry). Among the 1363 patientswho had rejected a kidney, 90% were found to have HLA-antibodies. Eighty-four per cent tested positive for the CDC-AHG assay and an additional6% of sera, when tested by solid-phase assays for IgG, IgM and IgA antibodies, was found to be positive for HLA. Among the four different centersthe range of positivity was 89–91%. We conclude that 90% of patients who reject a kidney transplant have detectable HLA-antibodies.

Abstract no.: 9NONCOMPLIANCE WITH IMMUNOSUPPRESSIVE MEDICATIONS AFTER RENAL TRANSPLANTATIONAJ Ghods, D NasrollahzadehTransplantation Unit, Hashemi Nejad Kidney Hospital, Iran University of Medical Sciences, Tehran, Iran

Noncompliance with immunosuppressive medications in renal transplant recipients results in a higher rate of acute-rejection episodes, allograftdysfunction, graft loss and patient death. We studied the incidence and risk factors of medications noncompliance in 286 renal transplant recipientswho were consecutively seen at our renal transplant clinic between February and April 2002. One hundred and seventy were male, 116 female. Theirage ranged from 12 to 70 years (mean 39.1∫11.6). The length of time since the date of transplantation ranged from 5 to 231 months (mean76.7∫53.5). The results of the study showed 70 patients (24.5%) to be noncompliant (7.7% noncompliant minor and 16.8% noncompliant major).The time since the date of transplantation was a significant risk factor in both the noncompliant minor and major groups (P0.001 and P0.001,respectively). The other risk factors associated with major noncompliance was young age (P0.001), lower level of education (P0.01), lowersocioeconomic class (P0.05), and addiction and psychiatric disorders (P0.05). Transplant recipients with major noncompliance also had moreacute-rejection episodes (P 0.001) and allograft dysfunction (P 0.01). We conclude that noncompliance with immunosuppressive medications isvery common in renal transplant recipients, resulting in significant acute-rejection episodes and allograft failure.

Abstract no.: 10GASTRIC EMPTYING TIME IN RENAL TRANSPLANT RECIPIENTS TREATED WITH CYCLOSPORINE-AO Ozkaya1, U Derici2, N Buyan1, A Dalgic3, B Dalgic4, E Cingi5, M Kitapci5, S Sindel2, E Hasanoglu1

1Departments of Pediatric Nephrology, 2Adult Nephrology, 3General Surgery, and 4Pediatric Gastroenterology, Ankara, Turkey, Gazi University Hospital,5Nuclear Medicine

Gastric emptying time (GET) appears to be a rate-limiting factor in the absorption of cyclosporine-A (CsA), and may be responsible for intra- andinterpatient variabilities of CsA bioavailability. Few studies have assessed gastric motility after renal transplantation. The purpose of this study wasto evaluate gastric emptying of semisolid material in stable renal transplant patients, and to assess whether it is associated with blood CsA levels.Gastric emptying time of semisolids (GET1/2: half emptying time) was measured in 16 transplant recipients who were taking CsA (NeoralA),prednisolone and azathioprine (or mycophenolate mofetil). None of the subjects had a history of gastrointestinal, metabolic, or systemic disease orsurgery, and none was taking any drugs at the time of the study that affect gastrointestinal motility. Gastric emptying time (tΩ1/2) was measured byradionuclide methods. Data concerning the daily CsA dose, plasma levels of CsA (C0), and serum creatinine levels were also recorded. The meanGET (tΩ1/2) was 89.1∫26.4 min. Twelve of the patients exhibited delayed gastric emptying. The mean plasma CsA level for the group was 171.8∫56ng/ml, and the mean CsA dose was 4.1∫1.1 mg/kg/day. Gastric emptying time (tΩ1/2) was not significantly correlated with the serum creatininelevels, the time since transplantation, or the plasma levels of CsA. There was a weak-positive, but statistically insignificant, correlation between themean daily CsA dose and the GET (tΩ1/2; rΩ0.33, PΩ0.2). In conclusion, we cannot speculate whether a higher dose of CsA causes delayed gastricemptying or whether patients with delayed emptying require higher doses of CsA. However, we believe that determining GET after transplantationis important for adjusting the immunosuppressant dosage.

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Abstract no.: 11EFFECT OF BASILIXIMAB ON ACUTE REJECTION IN PEDIATRIC RENAL TRANSPLANTATION: RESULTS FROM TWO CENTERSA Duzova1, M Bakkaloglu2, A Dalgic3, N Buyan4, O Soylemezoglu4, A Bakkaloglu1

1Pediatric Nephrology Unit and 2Department of Urology, Pediatric Renal Transplantation Group, Hacettepe University Faculty of Medicine, Sihhiye,Ankara, 3Deparment of Surgery and Transplantation and 4Pediatric Nephrology Unit, Pediatric Renal Transplantation Group, Gazi University Facultyof Medicine, Besevler, Ankara, Turkey

Acute rejection is a major determinant of chronic allograft dysfunction and graft survival. This study evaluated the effect of basiliximab (SimulectA),a 156-kDa chimeric monoclonal antibody (human and murine) directed against the alpha chain of the interleukin (IL)-2 receptor of human lympho-cytes, on acute rejection in pediatric renal transplantation. Data were collected from two pediatric renal transplantation centers. Forty transplan-tations (22 males and 18 females; mean age 14.8∫3.6 years) were performed between 1996 and 2001. Twelve of the grafts came from cadavericdonors and 28 from living-related donors. Twenty-four of the patients were on hemodialysis, 15 were on peritoneal dialysis, and one case was a pre-emptive transplantation. All patients were placed on triple-drug immunosuppression [prednisolone π (azathioprine or mycophenolate mofetil)π(cyclosporine or tacrolimus)]. Basiliximab was also administered in 17 cases. The respective rates of biopsy-proven acute rejection in the basiliximabgroup and the standard-regimen group were 0% vs. 17.4% (P0.05) at 1 month post-transplantation; 0% vs. 26.1% (P0.05) at 3 months; and 0%vs. 26.1% (P0.05) at 6 months. Thirty and 16 patients had completed 1- and 3-year follow ups, respectively, at the time of writing; the 1- and 3-year graft survival rates were 96% (29/30) and 81% (13/16), respectively.Basiliximab significantly reduced the rates of acute rejection at 3- and 6 months post-pediatric renal transplantation. It was well tolerated by allpatients, and caused no significant adverse effects. The effect of basiliximab on long-term graft survival and chronic allograft dysfunction deservesfurther investigation.

Abstract no.: 12RELATIONSHIP BETWEEN ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM AND CHRONIC RENAL TRANSPLANT DYSFUNCTIONA Akcay1, S Sezer1, FN Özdemir1, FB Atac2, H Verdi2, M Terzioglu2, Z Arat1, T Colak1, M Haberal21Department of Nephrology, 2Molecular Biology and 3General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey

Chronic allograft dysfunction (CAD) is a complex phenomenon caused by underlying kidney disease and superimposed environmental and geneticfactors. We investigated the relationship between polymorphism in the gene encoding for angiotensin-converting enzyme (ACE) and CAD in renaltransplant recipients. The study included 125 patients who underwent transplantation over a 5-year period. The following information was collectedfor each case: date of transplantation, age and sex of donor and recipient, donor type, cold ischemia time, number of HLA mismatches, number ofacute-rejection episodes, and laboratory findings at discharge from hospital and annual rechecks. Blood pressure was measured at yearly intervalsthroughout the follow up. DNA isolated from mononuclear cells in peripheral blood was used as a template for amplification of insertion/deletion(I/D) polymorphism in the ACE gene by polymerase chain reaction. The proportions of patients with the different genotypes were DDΩ54.4%, IDΩ33.6%, and IIΩ12%. Chronic allograft dysfunction was detected in 36 (52.9%) of the recipients with DD genotype and 15 (26.3%) of those with IDor II genotypes (P0.003). Analysis of the major risk factors for CAD showed that the serum creatinine level at the time of hospital discharge, thecadaveric donor type, the ACE DD genotype, and the level of proteinuria at 1 year post-transplantation were associated with poorer renal function(P0.05). These findings suggest that the DD variant of ACE I/D gene polymorphism is associated with an increased risk of developing CAD.

Abstract no.: 13RELATIONSHIP BETWEEN PARKINSON’S DISEASE AND HLA-ANTIGENS IN TURKISH PATIENTSE Yilmaz1, H Apaydin, S Özekmekci, S Ertan, G ErkolIstanbul University Cerrahpasa Medical School, Department of Neurology, Movement Disorders Unit and Blood Bank Tissue Laboratory, 1, Istanbul,Turkey

This study focused on the immunogenetic aspect of Parkinson’s disease (PD). The frequencies of HLA-A, -B, -C, -DR and -DQ antigens weredetermined in 40 patients with idiopathic PD, and were compared with those in a representative sample of the Turkish population (nΩ160). Comparedwith values for the Turkish population, the frequencies of HLA-B22 and HLA-DR14 (6) antigens were higher in the PD group, with relative risks(RR) of 9.55 and 15.48, respectively. These frequency differences were statistically significant. The frequency of HLA-A24 (9) was also higher in thePD patients, but to a lesser extent than the antigens noted earlier (RRΩ2.38). The frequencies of HLA-DQ7 (3), HLA-DQ4, HLA-DR11 (5), HLA-DR1 and HLA-DR7 were lower in the PD group, with RR values of 0.177, 0.187, 0.69, 0.85 and 0.93, respectively. None of these frequencydifferences were statistically significant. The frequency of the HLA-DQ4 antigen in the PD group was significantly lower than that in the Turkishpopulation, and this difference was significant when the corrected P-value was used.

Abstract no.: 14HLA PROFILE OF ETHNIC PAKISTANI POPULATION GROUPSMN Zafar, Y Zaidi, N Ahmed, K Abbas, SAA Naqvi, SAH RizviSindh Institute of Urology and Transplantation (SIUT), Dow Medical and Civil Hospital, Karachi, Pakistan

Class 1 HLA-A and -B and Class 2 HLA-DR allele frequencies were determined in Pakistani ethnic linguistic population groups. A total of 942potential kidney donors for living-related transplants were tested by Collaborative Transplant Study (CTS) 120 antisera trays for HLA-A and -B.All subjects homozygous for an allele, showing weak reactions or with crossreactions were retested by PCR-SSP using CTS primers, 24 for HLA-Aand 48 for HLA-B. Class 2 HLA-DR were determined only by PCR–SSP with 24 primers from the CTS. The common antigen frequencies forHLA-A were A1Ω0.312, A2Ω0.402, A11Ω0.312, A24Ω0.221, A26Ω0.178 and A19, and splitsΩ0.296. At HLA-B the common alleles were B8Ω0.234, B 35Ω0.213, B44Ω0.145, B51Ω0.197 and B60Ω0.177. Common HLA-DR alleles were DR 2Ω0.382, DR3(17)Ω0.424, DR5(11)Ω0.185, DR6(13)Ω0.180 and DR 7Ω0.240. These results provide baseline data for ethnic Pakistani population groups based on DNA methods. This will helpin studies relating to disease associations and cadaveric organ allocation programmes.

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Abstract no.: 15HLA-MATCHING BY DNA METHODS: IMPACT ON A LIVING-RELATED RENAL TRANSPLANTATION PROGRAMMEMN Zafar, N Ahmed, Y Abbas, K Abbas, SAA Naqvi, SAH RizviSindh Institute of Urology and Transplantation (SIUT), Dow Medical and Civil Hospital, Karachi, Pakistan

DNA methods have resulted in improved renal allograft survival rates in cadaveric renal transplantation. This paper describes the impact of DNAtyping by PCR-SSP on a living-related renal transplant (LRRT) programme. It evaluates error rates in serology, acute rejections, graft function andsurvival rates between the two typing methods. Serological typing was carried out on CTS 120 antisera Class 1, 60 antisera Class 2, 72 antiseraTerasaki Class 1 and 72 antisera Class 2 antigens. Low-resolution PCR-SSP typing was carried out by 24 primers for HLA-A, 48 for HLA-B and24 for HLA-DR. Of the 585 transplants: 159 (Group I) were serology based; 172 were serology and PCR-SSP based for HLA-DR (Group II); and254 were serology and PCR-SSP based for HLA-A and -B, and only PCR-SSP based for HLA-DR (Group III). Error rates in serology comparedwith PCR-SSP were 24% for HLA-A, 16% for HLA-B and 35% for HLA-DR. Acute rejections were 39%, 30% 26% in Groups I, II and III,respectively (PΩ0.02). Graft function of serum creatinine 1.5 mg/dl at 1 year was found in 26% of the Group I patients compared with 48% ofthose in Group III (P0.0001). One- and 3-year graft survival was 93% and 87% for Group II compared with 81% and 69% for Group I, respectively(PΩ0.0001). Matching by this combination of serology and PCR-SSP is not only economical for a developing country but also improves graftsurvival by 12% and 18% at 1 and 3 years, respectively.

Abstract no.: 16JOINT PAIN AND ARTHRITIS IN RENAL TRANSPLANT RECIPIENTS, AND CORRELATION WITH CYCLOSPORINE THERAPYH Kart-Köseoglu1, AE Yücel1, I Isyklar2, I Türker3, Z Akcaly4, M Haberal51Division of Rheumatology, 2Department of Radiology, 3Department of Internal Medicine, 4Division of Medical Oncology, and 5Department of GeneralSurgery, Baskent University Faculty of Medicine, Ankara, Turkey

To determine the prevalence of joint pain and arthritis in renal transplant recipients, and to investigate relationships with various laboratory andclinical parameters.Eighty-two patients who underwent renal transplantation (RT) and had a joint examination reported on their level of joint pain and arthritis byquestionnaire. The patients were then followed for a year, with repeated joint examinations and laboratory tests every 3 months. Thirty-one of 82patients (37.8%) complained of joint pain before the RT, and seven of these 31 individuals reported continued pain after the operation. Seventeenof the 82 (20.7%) began to suffer joint pain after the RT. Six (7.3%) and three (3.7%) of the 82 patients developed arthritis before and after thetransplantation, respectively. We found no statistical association between the joint pain and sex, age, cause of renal failure, dialysis duration, timesince transplantation, bone mineral density, human leukocyte antigen type, serum levels of urate, parathormone, calcium, alkaline phosphatase,phosphorus, C-reactive protein, erythrocyte sedimentation rate, donor source (living-related or cadaveric), or presence of HCV infection. However,levels of serum cyclosporine higher than 200 ng/ml were significantly correlated with the joint pain. This study shows that joint pain is commonbefore and after RT. In renal transplant recipients, joint pain is significantly correlated with serum cyclosporine levels.

Abstract no.: 17HISTOCHEMICAL DETECTION OF PANCREATIC TISSUE IN VITAMIN C-ADMINISTERED GUINEA PIGSB Kaplan1, B Gonul2, D Erdogan3, S Elbeg4, G Akyol51Department of Physiology, Faculty of Medicine, Baskent University, Ankara, and the Departments of 2Physiology, 3Histology-Embryology, 4NuclearMedicine and 5Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey

The aim of this study was to investigate the effects of fasting (F) periods and vitamin C supplementation on the serum C-peptide levels and endocrinepancreas of guinea pigs. Vitamin C supplementation (a single intraperitoneal dose of 500 mg/kgª1) was given at the beginning of the fasting period.The animals were divided into seven groups (nΩ6 each) as follows: Group I (untreated group) was given food and water ad libitum; Group II, IIIand IV were acute (24 h, 48 h) and chronic F (120 h) respectively; while Groups V, VI and VII were acute and chronic F with supplementary vitaminC (VitC π F24 h, VitC π F48 h and VitC π F120 h, respectively). Serum C-peptide levels were measured and pancreatic tissues were collected forimmunohistochemical evaluation. Serum C-peptide levels in the VitC π F24 and VitC π F48 groups were higher than in the F24 and F48 groups(P0.05). Immunohistochemical examination of the endocrine pancreas confirmed that vitamin C administration in fasting may indirectly increaseglucagon and insulin secretions.

Abstract no.: 18RELATIONSHIP OF HLA-DR EXPRESSION WITH REJECTION AND MONONUCLEAR CELL INFILTRATION IN RENAL ALLOGRAFT BIOPSIESB Handan Özdemir, P Kaynak Aksoy, A Nihan Haberal, B Demirhan, M HaberalBaskent University, Faculty of Medicine, Ankara, Turkey

Research on renal biopsies has shown that HLA class I antigens are distributed throughout the renal parenchyma, but that the distribution of HLA-DR varies greatly. We investigated HLA-DR expression in the biopsies of 90 renal transplants, and also semiquantitatively assessed the proportionsof CD68-, CD3-, and HLA-DR-positive infiltrating cells by immunohistochemistry. The relationships between tubular DR expression and interstitiallymphocyte and macrophage infiltration were examined.Forty of the biopsies showed acute rejection (AR), 33 showed chronic rejection (CR), 10 showed suspected rejection (SR), and seven showed noevidence of rejection (NR). HLA-DR expression was noted in 35/40 (87.5%) of the AR cases, 22/33 (66.6%) of the CR cases, and 6/10 (60%) of theSR cases. Only one (14.3%) of the NR cases exhibited HLA-DR antigen expression in the renal tubules. The proportions of lymphocyte andmacrophage infiltration observed in the interstitium were significantly correlated with the tubular DR expression in all cases (P0.01). Six monthsafter the biopsies were carried out, 24/35 (68.6%) of the AR patients with tubular DR expression showed second-episode rejection or deterioratedrenal function. The remaining 11 AR cases with tubular DR expression had stable renal function at this stage. The cases that had no significanttubular DR expression had no problems with rejection or functional deterioration.These findings are consistent with the theory that expression of HLA-DR antigens on renal tubular cells may be a marker of rejection and poorgraft outcome.

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Abstract no.: 19RELATIONSHIPS BETWEEN HLA-A, -B, -DQ AND -DR ANTIGENS AND INTERSTITIAL FIBROSIS IN RENAL ALLOGRAFTSBH Özdemir, T Colak, M Turan, B Demirhan, M HaberalBaskent University Faculty of Medicine, Ankara, Turkey

Although renal transplant recipients tend to exhibit similar clinical and immunological changes over time, some allograft biopsies show earlyinterstitial fibrosis (IF). To evaluate the relationship between HLA-antigens and IF in renal allografts, we reviewed the HLA-A, -B, -DQ, and -DRantigens in 88 renal transplant recipients.For each antigen type, we determined the number of patients who did and did not possess the antigen. We then determined the mean time to onsetof IF for each of these two groups, and statistically compared the means. In the second part of the analysis, we divided the 88 patients into thosewho did and did not show IF at 6 months post-transplantation, and then calculated the prevalence of each antigen type in the IF(π) and IF(–)groups. This same procedure was repeated with the patients grouped according to the presence of IF at 12 months post-transplantation. The groupsof patients with HLA-B8, -B27, -DQ2, -DQ5, -DQ6, -DQ7, -DR4, -DR13, and -DR15, had significantly shorter times to IF onset after transplan-tation than the corresponding groups without these antigens (P0.05). The groups that were IF(π) at 6 and 12 months post-transplantation hadsignificantly higher frequencies of HLA-B8, -B27, -DQ2, and -DR4 than the corresponding IF(–) groups at these two timepoints (P0.05).The results indicate that any kidney recipient with these antigens is predisposed to developing diffuse IF in their graft relatively soon after transplan-tation. We conclude that although there is multiple etiological agents in the pathogenesis of IF one can not exclude a HLA association in such cases.

Abstract no.: 20RENAL TRANSPLANTATION IN AMYLOIDOSIS: EFFECTS OF HLA MATCHING AND DONOR TYPE ON RECURRENCE OF PRIMARY DISEASEBH Özdemir, B Demirhan, FN Özdemir, M Turan, M HaberalBaskent University, Faculty of Medicine, Ankara, Turkey

The aim of this study was to evaluate the effect of HLA-matching and donor type on recurrence of amyloidosis after renal transplantation. Thirtypatients with systemic amyloidosis who received kidney transplants between 1985 and 2001 were included. Donor source and HLA tissue typing ofthe donor and recipient were evaluated in each case. Twenty of the 30 patients developed biopsy-confirmed recurrence of amyloidosis in theirallografts. The time from transplantation to diagnosis of amyloidosis in the graft ranged from 18 months to 10 years. Eighteen of the 20 patientswith recurrence had received their grafts from living-related donors (LRDs), and two had received their grafts from cadaveric donors. There was astrong correlation between amyloidosis recurrence and degree of HLA-DR matching (P0.05). Further, in the recipients of the LRD grafts, therisk of amyloidosis recurrence was significantly higher when the donor-recipient pair were HLA-identical than when they were not perfectly matched(P0.01). The incidence of amyloidosis recurrence in our cases was significantly higher than the rates reported for other series. Most of the casesin previous reports involved cadaveric grafts. The higher rate of amyloidosis recurrence in our cases may be explained by the high proportion ofLRD grafts, and by genetic susceptibility.

Abstract no.: 21EFFECTS OF HLA MISMATCHING ON GRAFT SURVIVAL IN LIVING DONOR-KIDNEY TRANSPLANTATIONM Haberal, R Emiroglu, Ö Basaran, E Tezel, H Karakayaly, N BilginDepartment of General Surgery Division of Transplantation, Baskent University Faculty of Medicine, Ankara, Turkey

To investigate the influence of HLA match on graft survival, we evaluated 878 live-donor and 183 cadaver-donor kidney transplantations performedat our hospital between October 1985 and November 2001. In the 878 live-donor cases, 273 of the donors were mothers, 131 were fathers, 281 weresiblings, 28 were offspring, 89 were second-degree relatives, and 76 were unrelated (68 spouses and eight emotionally attached friends).The 1-, 3-, and 5-year graft survival rates in the first-degree living-related transplantation group were 90%, 76%, and 66%, respectively. The corre-sponding rates in the second-degree living-related group were 90%, 75%, and 70%, respectively; and in the living-unrelated group were 80%, 70%,and 60%, respectively. The 1-, 3-, and 5- year graft survival rates for the cadaveric kidney transplantations carried out at our center during this sametime period were 78%, 60%, and 48%, respectively. These rates were significantly lower than those for each of the live-donor transplantations. Weanalyzed graft survival in relation to HLA mismatch, and a comparison of the findings showed that 0-mismatched cases had a statistically significantgraft survival advantage over those with 1, 2, 3,4 and 5 mismatches; however, there were no significant differences between the groups with 1, 2, 3,4 and 5 mismatches. In conclusion, even kidneys from live donors in transplantations with suboptimal donor-recipient HLA matching show better5-year survival than cadaveric grafts in transplantations. These results from a single centre suggest that immunological as well as nonimmunologicalfactors are associated with the pathogenesis of late graft loss.

Abstract no.: 22EFFECT OF GRAFT NEPHRECTOMY AND HLA TYPING ON LONG-TERM GRAFT FUNCTION AND SURVIVAL IN KIDNEY RETRANSPLANTATIONH Karakayaly, MC Yagmurdur, G Moray, E Tezel, R Emiroglu, M HaberalDepartment of General Surgery Division of Transplantation, Baskent University Faculty of Medicine, Ankara,Turkey

In this study, we retrospectively evaluated our long-term results of the recipients who received a second allograft. Between 3 November 1975 and 31December 2001, our transplantation team performed 1365 kidney transplantations. Fifty (3.6%) of these patients underwent retransplantations.Forty-seven received their second transplantation and the remaining three received their third transplantation. The same low-dose triple drug im-munosuppression protocol with prednisolone, azathioprine and cyclosporine A was used in both groups. There were two study groups: the patientsin Group 1 (nΩ19) underwent allograft nephrectomy, while those in Group 2 (nΩ31) did not. Demographic properties, rejection rates throughoutthe follow up period, serum creatinine levels within 12 months, graft and patient survival rates, postoperative complications, time interval betweenthe transplantations, and HLA matchings were studied. For statistical analysis the Student’s t and Kaplan–Meier tests were used, and P-values0.05 were accepted as significant.Forty-one patients who underwent re-transplantation received kidney from living related donors and remaining 9 patients from cadaveric donors.Mean interval between first and second transplantations was 50 months (range, 1–192 months). Mean blood creatinine levels was 1.8 mg/dL (range,0.8–6.5 mg/dL). HLA-AB and HLA-DR mismatches were 1.92∫1.1 and 0.9∫0.7, respectively.

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Acute rejection rates were significantly different between Group 1(9/19,47%) and Group 2(12/31,38%) (PΩ0.03). Graft loss was found to be lowerin Group 1 (6/19, 32%) than that in Group 2 (11/31 35%), though these values were not statistically different (P0.05). The average interval betweenfirst and second transplantations was 32,1∫21 months in Group 2 and 61,5∫46 months in Group 1 (PΩ0.018). The duration of hemodialysis beforesecond transplantation were 17∫9 months in Group 2 and 27∫11 months in Group 1 (PΩ0.04). One, 3 and 5 years graft survival rates (Group 2vs. Group 1) were 89% vs. 83%, 79% vs. 64% and 68% vs. 45%, respectively (P0.05). Also, the interval between first and second transplantationsmay have a negative correlation with second graft survival In conclusion, there appears to be no advantage associated with graft nephrectomy beforere-transplantations and longer duration of hemodialysis may decrease graft survival rates.

Abstract no.: 23EFFECT OF HLA MATCHING AND DONOR-RECIPIENT BODY WEIGHT RATIO WITH TRANSPLANTS FROM SPOUSESR Emiroglu1, MC Yagmurdur1, H Karakayalı1, G Moray1, G Arslan2, N Bilgin1, M Haberal1

Departments of 1General Surgery and Transplantation and 2Anesthesiology, Baskent University Faculty of Medicine, Ankara, Turkey

Our transplantation team performed 1061 kidney transplantations from October 1985 to November 2001. Sixty-nine of these were interspousaltransplantations. In 61 cases the wife donated her kidney to the husband, and in the remaining eight cases the husbands were the donors. Theaverage number of HLA-A, -B, and -DR mismatches were 3.5, despite the fact that the HLA matching was better for the transplants performedfrom the first-degree relatives (average number of HLA-A, -B, and -DR mismatches was 2.1). Ten-year graft survival rates were 55% for the formerand 60% for the latter. HLA -A, -B, and -DR typing showed one antigen mismatch in one patient, two mismatches in nine, three mismatches in 17,four mismatches in 33, and more than four mismatches in eight patients. The mean recipient follow-up period was 90 months (range: 5–170 months).Mean ratio of donor body weight (DBW) to recipient body weight (RBW) was 0.9∫0.1 (0.7–1.2). Median serum creatinin levels and creatininclearance values were 1.9 mg/dl (1.1–3.6 mg/dl), 58.1 ml/min (25–106 ml/min), respectively. Statistically significant relationship between the DBW/RBW ratio and both the creatinin levels and the creatinin clearance values was observed. Eighteen rejection episodes were observed in the wife-to-husband transplantations and two in the husband-to-wife group. Ten recipients died in the follow-up period; the DBW/RBW ratio may have animportant role for post-transplant graft functions. We conclude that although HLA matching is not ideal in these cases, graft spouses offer a goodalternative to cadaveric kidneys, which are in critically short supply in Turkey.

Abstract no.: 24ANALYSIS OF THE RESULTS OF PAIRED CADAVERIC KIDNEYS WITH SIMILAR DONOR-RECIPIENT HLA MATCHINGSMC Yagmurdur, R Emiroglu, O Basaran, H Karakayalı, E Tezel, M HaberalDepartment of General Surgery Division of Transplantation, Baskent University Faculty of Medicine, Ankara, Turkey

In this study, we aimed to clarify the factors that may effect long-term graft and patient survivals. We retrospectively evaluated the outcome of 112renal transplant recipients who shared paired cadaveric kidneys between 1985 and July 2001.There were two study groups, each with 56 patients, according to the timing of the operations. The operations were performed by the same transplantteam, so Group 1 represents the recipients of the first kidney and Group 2, the second. The same low-dose triple drug immunosuppression protocolwith prednisolone, azathioprine and cyclosporine A was used in both groups. Cyclosporine A was converted to tacrolimus in seven patients inGroup 1 and in five patients in Group 2. Demographic properties, number of acute-rejection episodes, serum creatinine levels, creatinine clearancevalues, graft and patient survival rates, postoperative complications, recipient body weights, cold ischemia times, and de novo malignancies werestudied. To analyze our results the Chi-square and Wilcoxon Signed Ranks tests were used, differences, with P0.05 were accepted as significant.Regarding the HLA matchings, the groups were similar. Mean cold ischemia times were 22.1∫8.7 and 23.3∫9.1 h in Groups 1 and 2, respectively(P0.05). Acute-rejection rates within the first month following the transplantation were also similar in both groups. Serum creatinine levels andcreatinine clearance values at 30 days post-transplantation showed no significant difference between the groups (P0.05). One, 2 and 5 years’ graftsurvival rates (Group 1 vs. Group 2) were 97% vs. 92%, 74% vs. 77% and 27% vs. 24%, respectively. No statistically significant difference wasobserved on returning to the hemodialysis rates (10/56 vs. 13/56). In Group 2, the rate of proteinuria (over 200 mg/day) throughout the follow-upperiod was significantly higher than that in Group 1 (Chi-square, PΩ0.03). Three patients underwent re-transplantation: one in Group 1 and two inGroup 2. Three post-transplant malignancies were detected: one in Group 1 and two in Group 2. An interesting observation was the post-transplan-tation T-cell lymphoma diagnosis in both recipients of the same donor. Also, when compared, the patients were not significantly statistically differentaccording to their body weights, rejection rates and graft survival rates.In conclusion, the short- and long-term outcomes of consecutive-paired cadaveric kidney transplantations are comparable with similar cold ischemiatimes, HLA matching and immunosuppressive protocols.

Abstract no.: 25KIDNEY TRANSPLANTATION AT ONE CENTER IN 2001O Basaran, R Emiroglu, E Tezel, G Moray, N Bilgin, M HaberalDepartment of General Surgery Division of Transplantation, Baskent University Faculty of Medicine, Ankara, Turkey

The number of patients with end-stage renal disease increases, with kidney transplantation remaining the treatment of choice for this dismal disease.From January 1 to December 31, 2001, 48 kidney transplantations were performed at Baskent University Faculty of Medicine. Thirty-nine of therecipients were male and nine were female, and the average age of the patients was 31.8. Thirty-seven of these transplantations were performed fromliving donors, and 11 were from cadaver organs. Of these 48 patients, one died during the post-operative period as a result of septicemia. Graftnephrectomy was performed in one patient because of massive bleeding. There were 16 acute-rejection episodes in 12 patients during follow up, andall patients recovered. At the end of the year, the overall patient and graft survival rates were 98% and 95.8%, respectively. Despite these goodresults, there is an increasing number of patients on the waiting list and we are not able to use the full capacity of our center because of continuedorgan shortages.

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Abstract no.: 26IMMUNOSUPPRESSIVE THERAPY AND KAPOSI’S SARCOMA AFTER KIDNEY TRANSPLANTATIONM Haberal, O Basaran, G Moray, T Colak, MC YagmurdurDepartment of General Surgery Division of Transplantation, Baskent University Faculty of Medicine, Ankara, Turkey

Immunosuppressive therapy for organ transplant recipients is complicated by high rates of malignant diseases, one of these being Kaposi’s sarcoma(KS). We reviewed the records of 1075 patients who underwent kidney transplantation at our center between October 1985 and May 2002. A totalof 52 malignant diseases were observed in 50 patients (4.7%), during the post-transplantation period. Kaposi’s sarcoma was identified in 16 of these50 individuals. Of the 16 recipients, six were male and 10 were female. The mean age in the group was 39∫9 years (range: 10–62 years). At the timeof the KS diagnosis, 14 of the recipients were taking triple-drug immunosuppressive therapy consisting of cyclosporine A, azathioprine, and pred-nisolone. The other two individuals were receiving azathioprine and prednisolone. The mean time from transplantation to diagnosis with KS was24∫15.2 months (range: 8–74 months). One recipient had concomitant lymphoma and KS. The lesions of seven patients were limited to the skin,five cases involved the skin and gastrointestinal tract, and four patients had disseminated disease. After KS was confirmed, the first-line of treatmentwas to withdraw cyclosporine A and azathioprine, and taper the prednisolone. The tumors were managed with appropriate surgical and/or medicaltherapy. At the time of writing, nine individuals were still alive: four had normal renal function and five had lost their grafts as a result of chronicrejection. We have found the combination of immunosuppressive drug withdrawal and chemotherapy to be very effective in patients with limiteddisease, but the results in cases of generalized disease have been poor.

Abstract no.: 27IMPORTANCE OF A3 ALLELE OF HLA CLASS I IN RESPONSE TO HEPATITIS B VACCINE IN END-STAGE RENAL DISEASE PATIENTSM Turan1, FN Özdemir2, H Micozkadıoglu2, Z Arat3, S Gülmüs1, M Haberal31Immunology Laboratory, 1Department of Nephrology, and 3Department of General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey

Vaccination against hepatitis B virus (HBV) infection is very important for hemodialysis (HD) patients, as these individuals are at high risk becauseof intravenous interventions and therapies. The aim of this study was to examine how genetic factors may be related to the response of HD patientsto the HBV vaccination. This was carried out by investigating the frequencies of HLA class I and II alleles in responders and nonresponders. Thestudy included 256 (171 male and 85 female) HD patients who tested negative for antibodies to the hepatitis B surface antigen in pretransplantationevaluations performed at our center between 1986 and 1999. Each patient received four doses of 40 mg DNA-recombinant hepatitis B vaccine at 0,1, 2 and 6 months. Group I consisted of the 166 patients who responded to the vaccination (anti-HBsAg 10 SI U/l) and Group II consisted of the90 nonresponders (anti-HBsAg 10 SI U/l). The frequency of the HLA-A3 allele was significantly higher in Group I than in Group II (PΩ0.02).One hundred and seven of the 256 patients underwent renal allograft transplantation, and 14 recipients lost their grafts at a mean of 1326∫1394days. There was no significant difference in graft outcome between the responders and the nonresponders (P0.05). In conclusion, this was apreliminary study showing that HLA alleles may have immunomodulatory effects in end-stage renal failure patients. The response to hepatitis Bvaccination is affected multifactorially and HLA-A3 may be a genetic predictor for responders, but further studies and larger series are required.

Abstract no.: 28POLYMORPHISMS OF ANGIOTENSIN-CONVERTING ENZYME, ANGIOTENSINOGEN, ANGIOTENSIN II TYPE 1 AND TYPE 2 RECEPTORS AND ENDO-THELIAL NITRIC OXIDE SYNTHASE IN TURKISH RENAL TRANSPLANT RECIPIENTS: A PRELIMINARY STUDYFB Atac1, A Akcay2, Fn Özdemir2, H Verdi1, M Terzioglu1, T Colak2, R Emiroglu3, M Haberal3

Departments of 1Molecular Biology, 2Nephrology, and 3General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey

Many researchers are now focusing on ways in which the renin-angiotensin system (RAS) and RAS gene polymorphism affect progressive renaldamage, hypertension, cardiac complications, and renal allograft function. In this study, we investigated the frequency of polymorphism in the genesfor angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type 1 and 2 receptors (AT1 and AT2), and endothelial nitricoxide synthase (ec-NOS) in Turkish renal transplant recipients. Angiotensin-converting enzyme insertion/deletion (I/D) polymorphism was assessedin 125 patients. M235T polymorphism of the angiotensinogen gene, 1166 A/C polymorphism of the AT1 receptor gene, and 3123C/A polymorphismof the AT2 receptor gene, and intron 4 VNTR polymorphism in the ec-NOS gene were assessed in 40 of the patients. The latter list was alsoinvestigated in 50 healthy controls from the general Turkish population. DD/ID/II genotypes of the ACE gene were detected in 56%, 34%, and 10%of the kidney recipient group, respectively. In the 40 recipients who were tested for the other polymorphisms, the corresponding figures for the AGTTT/TM/MM genotypes were 0%, 82.5%, and 17.5%, respectively; for the AT1 CC/CA/AA genotypes were 0%, 2.5%, and 97.5%, respectively; for theAT2 AA/CA/CC genotypes were 0%, 0%, and 100%, respectively; and for the ec-NOS intron 4 aa/ab/bb genotypes were 0%, 12%, and 88%,respectively. The results revealed that Turkish renal transplant recipients exhibit a wide-range of RAS gene and ec-NOS polymorphisms.

Abstract no.: 29POST-TRANSPLANT C-REACTIVE PROTEIN MONITORING PREDICTS CHRONIC REJECTION AND RENAL ALLOGRAFT SURVIVALS Sezer, FN Özdemir, A Akcay, E Külah, Z Arat, R Erdal, M HaberalBaskent University Faculty of Medicine, Ankara, Turkey

Chronic allograft nephropathy (CAN) is a major problem after renal transplantation, and chronic inflammation is an important element of thiscondition. C-reactive protein (CRP) is an important marker of inflammation and atherosclerosis. This retrospective study analyzed the value of post-transplantation CRP monitoring in the prediction of CAN and graft failure in kidney transplantation.The study included 125 renal transplant patients whose CRP levels were in the normal range (10 mg/l) at the time of transplantation. Serum CRPlevels before transplantation, at 1 month and at 1 year post-transplantation, at the time of CAN diagnosis, and the mean level throughout followup in patients without CAN were recorded. The CRP findings were compared in patients grouped according to whether or not they developed CAN.Chronic rejection was diagnosed in 40.8% of the patients, and 82.4% of this group progressed to graft failure at a mean of 45.8∫30.4 months afterthe diagnosis of CAN. When the group CRP results were compared, the levels before transplantation were similar, but at 1 month post-transplan-tation the levels in the group with CAN were significantly higher (P0.04). The mean CRP level at 1 year was also higher in the CAN group, butthis difference was not significant. The mean level at the time of the CAN diagnosis was significantly higher than the mean level during follow up

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in the group without CAN (P0.01). Thus, the CRP levels were significantly higher in CAN group than in the group without CAN at two of thetimepoints tested: immediately after transplantation and at the time of CAN diagnosis. Regression analysis showed that the high CRP level at 1month post-transplantation and at the time of the CAN diagnosis significantly influenced the allograft failure (P0.005 and P0.01, respectively).In conclusion, post-transplantation CRP monitoring provides important information concerning the risks of CAN and graft failure. Testing of CRPlevels should be part of the follow-up assessment after renal transplantation.

Abstract no.: 30RENAL TRANSPLANTATION OFFERS BETTER SURVIVAL IN HCV-INFECTED END-STAGE RENAL DISEASE PATIENTSS Siren, ÖF Nurhan, T Münire, B Sedat, A Zübeyde, H MehmetBaskent University Faculty of Medicine, Ankara, Turkey

Hepatitis C virus (HCV) infection is known to increase morbidity and mortality in the dialysis population. Renal transplantation is an offeredtreatment option after a careful pretransplant evaluation. This study assessed the impact of HCV infection on patient and allograft survival rates ina selected group of dialysis patients and kidney transplant recipients.The study included 252 end-stage renal disease patients who were receiving hemodialysis (HD) treatment or who received renal transplantation atour centre in 1995–96. Of the total, 116 [94 HCV (–) and 22 HCV (π)] underwent transplantation and 134 [106 HCV (–) and 30 HCV (π)] remainedon HD. We retrospectively investigated 5 years of follow-up findings in the records of these patients. All 22 HCV (π) individuals underwent liverbiopsy to ensure there was no advanced liver disease before transplantation. None of the recipients or HD patients showed decompensation relatedto liver disease during follow up.The overall 5-year patient survival rates for the kidney recipient and HD groups were 85.2% and 74.5%, respectively. Comparison of outcomes forthe HCV (π) recipients had a significantly higher 5-year survival rate than the HCV (π) HD patients (P0.04). The 3-year graft survival rates forthe HCV (π) and HCV (–) transplant recipients were comparable, but the risks of chronic rejection and graft loss at 5 years were higher in the HCV(π) group (P0.02, P0.006, respectively). In conclusion, renal transplantation should be the preferred therapy in HCV-infected dialysis patientsbecause it improves the survival rates. HCV infection is associated with increased rates of chronic rejection and graft loss at 5 years post-transplan-tation.

Abstract no.: 31PANEL-REACTIVE ANTIBODY POSITIVITY AND ASSOCIATED HLA-ANTIBODIES IN TURKISH END-STAGE RENAL DISEASE PATIENTSFN Özdemir1, M Turan2, S Sezer1, Z Arat1, A Gülmüs3, E Külah1, M Haberal31Department of Nephrology, 2Immunology Laboratory, and3Department of General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey

Pre and postrenal transplantation panel reactive antibody (PRA) screening is associated with increased rates of hyperacute or acute-graft rejectionand graft loss. It has been suggested that phenotypic HLA-antigens are involved in PRA sensitization. This study investigated the relationshipsbetween HLA-specific antibody frequencies and PRA sensitization in Turkish patients with end-stage renal disease (ESRD). Three hundred andforty patients on the renal transplantation waiting list participated. We determined the level of PRA sensitization and the candidates’ class I and IIHLA-antibody profile. Panel reactive antibody levels greater than 30% were accepted as positive. The frequencies of the different antibodies in thesensitized group were calculated. Twenty-four (7%) of the 340 patients showed PRA-ABC positivity and 34 (10%) showed DR positivity. Thirty-nine(11.5%) of the candidates were PRA-positive. The most frequent class I HLA-antibodies in this group were A2, A34, and B56, and the most frequentclass II antibodies were DR1, DR7, DR10, DR11, DR14, DR52, DQ1, DQ4, DQ6, and DQ7. Analysis showed that the presence of each of theseHLA class II antibodies was significantly correlated with PRA positivity. Apart from the presence of HLA-A2, A24, and DR11 antibodies, theHLA profile for the PRA-positive candidates differed from that of the general Turkish population. In conclusion, identification of the associatedHLA-specific antibodies and correlation with the Turkish population HLA-antigen distribution will identify high-risk patients as candidates fortransplantation.

Abstract no.: 32PRURITUS AND HLA IN HEMODIALYSIS PATIENTSÜ Saatci, E Basın, FN Özdemir, M Turan, H Micozkadıoglu, M HaberalBaskent University Faculty of Medicine, Ankara, Turkey

Pruritus is a common problem among hemodialysis (HD) patients, and the etiopathogenesis of uremic pruritus is still unclear. This study evaluatedthe relationships between pruritus and human leukocyte antigen (HLA) types in individuals on HD. Seventy-nine HD patients (32 females and 47males; mean age: 38.76∫14.04 years; age range: 9–70 years) were studied. The HD duration in the group ranged from 9 to 142 months (mean:52.53∫32.48 months). Subjects were assigned to one of two groups, one with pruritus (nΩ45) and one without pruritus (nΩ34). Demographic andlaboratory parameters were compared in patients with and without pruritus. There were no significant differences between the groups with respectto age, sex, or HD duration. There were also no significant differences in the groups’ serum levels of Hb, ferritin, BUN, creatinine, Ca, P, PTH, uricacid, AST, ALT, GGT, total bilirubin and ALP (P0.05 for all). There were also no differences between the two groups according to the presenceof HbsAg and anti-HCV (P0.05). The frequency of the HLA-B35 allele was significantly higher in the pruritus group than in the group withoutpruritus (P0.05). The pruritus group also had higher frequencies of HLA-A3 and -DR4, but these differences were not significant (P0.05). Theresults of this preliminary study indicate that the HLA-B35 antigen may contribute to pruritus in HD patients. Further studies are needed to clarifythe role that the HLA system plays in pruritus in this patient group.

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Abstract no.: 33INFLUENCE OF SIMVASTATIN IN THE TREATMENT OF HIGHLY SENSITIZED DIALYSIS PATIENTS: LONG-TERM PRE- AND POST-RENAL TRANSPLAN-TATION OUTCOMESFN Özdemir1, A Akcay1, T Colak1, M Turan2, A Gülmüs3, M Haberal31Department of Nephrology, 2Immunology Laboratory, and 3Department of General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey

The graft survival rates of sensitized kidney recipients have been shown to be lower than those of nonsensitized patients. Therefore, panel reactiveantibody (PRA) and cross-match determination is accepted as mandatory screening for renal transplantation candidates. Our recent previous studyshowed that simvastatin has a significant immunosuppressive effect in PRA-positive and/or crossmatch-positive patients. We present the long-termpre and post-transplantation outcomes of simvastatin treatment in highly sensitized dialysis patients. Thirty patients were followed for a meanperiod of 22 months. The PRA and flow cytometric measurements were performed at monthly intervals. Ten patients underwent successful kidneytransplantation (eight living-related and two cadaveric). None of the patients developed hyperacute or acute rejection, and there was no graft lossduring the 16.1∫8.2 months of post-transplantation follow up. Of the 18 patients who stayed on dialysis throughout the study with PRA-positivity,six were lost to follow up and three spontaneously stopped taking the simvastatin. In the latter three cases, the PRA levels rose significantly afterthe drug was discontinued. Eight of the remaining nine PRA-positive patients showed significant drops in mean PRA level over the study period,and entered the range considered acceptable for transplantation. Only one patient showed persistently high PRA levels throughout the study. In onepatient, the drug had to be discontinued because of acute toxic hepatitis. In conclusion, the results indicate that long-term continuous simvastatintherapy is effective in immunized and highly sensitized dialysis patients. Meanwhile, it has a beneficial effect on 1-year graft survival rates insensitized renal transplantation patients.

Abstract no.: 34OUR EARLY EXPERIENCE OF TACROLIMUS CONVERSION IN THE KIDNEY TRANSPLANTSG Moray, MC Yagmurdur, R Emiroglu, Ö Basaran, M HaberalBaskent University Faculty of Medicine, Ankara, Turkey

Tacrolimus has been known as an effective immunosuppressive drug since 1987, and in our clinic we have used this agent since November 1999.Our transplantation team has performed 1359 kidney transplantations since 1975. Until November 1999, all of these recipients received a standardlow-dose triple-drug immunosuppressive regimen of prednisolone, azathioprine, and cyclosporine A. Since November 1999, cyclosporine A wasreplaced by tacrolimus in 95 kidney recipients. In this study, our early results are analyzed.The mean follow-up period after alteration of the immunosuppressive protocol was 12 (1–24) months. The mean time interval between the transplan-tation and the tacrolimus replacement was 34∫11.4 months (1–158 months). Chronic allograft nephropathy in 16 (17%) patients, nephrotoxicityrelated to cyclosporine A in 22 (23%) patients and steroid-resistant acute rejection in 57 (58%) were the indications of tacrolimus conversion. Oneacute-rejection episode in 30 patients, two in 17, and three in 10 patients were observed before starting the tacrolimus. After the drug conversion,one acute rejection in 17 and two acute rejections in four patients were observed. Graft loss was seen in 15 (15%) patients after the drug conversion.Tacrolimus was withdrawn because of diabetes mellitus in seven patients, epilepsy in four, and severe Nocardia sepsis, lymphoma and Kaposisarcoma in one patient each. Decreases of serum creatinin levels and also increases in blood glucose levels showed a statistically significant associationwith the tacrolimus doses (PΩ0.0004, PΩ0.04, respectively). The decrease in creatinin clearance values was closely related to the increase in tacrolimuslevels. The target range with maximum efficacy and minimum toxicity seems to be 10–15ng/ml.Tacrolimus conversion can be successful in cases of rejection and nephrotoxicity, but dose-dependent blood glucose elevations must be followedclosely in these patients.

Abstract no.: 35CHRONIC REJECTION: PROSPECTS FOR THERAPEUTIC INTERVENTION IN FIBROPROLIFERATIVE VASCULAR DISEASEP Häyry1,2,5, E Aavik1,2, M Sarwal3, D du Toit4, J Vamvakopoulos1,2

1Transplantation Laboratory, University of Helsinki & Helsinki University Central Hospital, Helsinki, Finland, 2Rational Drug Design Programme,Biomedicum Helsinki, Helsinki, Finland, 3Department of Pediatric Transplantation, Stanford University, Stanford, CA, USA, and 4Department of Surgery,Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa

Vascular disease, manifesting as either transplant arteriopathy or native atherosclerosis, is currently the main obstacle to successful transplantoutcome. In addition, vascular restenosis following balloon angioplasty or stenting continues to limit the long-term efficacy of these procedures.Neointimal hyperplasia is refractory to conventional immunosuppression although newer agents, such as rapamycin, have shown considerablepromise in its control. By allowing a large-scale study of gene expression during vascular remodelling, the emerging field of genomics is poised torevolutionise the drug-discovery process. Here we summarise our initial experience using genomic methods to identify new targets for therapeuticintervention in vascular disease.

Abstract no.: 36GENERICS IN TRANSPLANTATION, AND THE INTERNATIONAL RULES AND REGULATIONS ON THEIR USEMAMA MasriRizk Hospital, Beirut, Lebanon

By definition a product identified by its official chemical name rather than an advertised brand name is called a generic. If a drug exerts itspharmacological effects at the same site, and has the same potency, dosage form and bioavailability as a brand name reference-listed drug (RLD),it is consider as a generic. However, inactive ingredients can differ between a brand name and a generic. Generics gained ground in the drug marketthrough the regulations of the FDA; they currently account for more than 42% of the total prescription rate in the USA. These regulations includethe abbreviated new drug application (ANDA) for the registration process and drug substitution at the pharmacy level without patient or physicianconsent. This coupled with a keen interest of third-party payers and the health authorities to reduce the high transplant health budget (2 billionUS$) made it necessary to introduce generics into the field of transplantation. Using the above-mentioned definition we can theoretically say thatall antilymphocytes produced in the same animal species are generic of each other. Moreover monoclonal antibodies that are directed against the

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same target and have the same bioavailability are also considered generics of each other. Of all the immunosuppressive drugs that have beenintroduced into the field of transplantation, none has been as dominant as Cyclosporine. Cyclosporine became and remains the backbone for anyimmunosuppressive protocol. In 1992, Consupren, the first non-FDA approved generic to Sandimmun, was introduced. Although Consupren wasnot bioequivalent to Neoral, the long-term results in kidney transplantation have been similar for both drugs. The introduction of Consuprenresulted in a nearly 40% reduction in the total cost of immunosuppressive therapy. Interestingly, the cost of the brand name drug Neoral was alsoreduced by 20%. The cost reduction allowed the introduction of the new immunosuppressive agents MMF and Rapamycin. Currently there are fiveFDA-approved Cyclosporine generics with a 20% market share in the USA and 0% in Europe. Alternative formulations to both Rapa and MMFshould be available soon. These forms are not by definition generics and are considered by the FDA to be new brand names acting on the same siteas Cell Cept and Rapaimmune. Their introduction would be a great welcome and would definitely result in cost saving in transplantation.

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immunosuppressive therapy and kaposi's sarcoma after kidney transplantation

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