PREDICTIVE BIOMARKERS OF LIVING DONOR LIVER TRANSPLANTATION

Öz

Objective: Liver transplantation using a living donor (LDLT) is currently the most popular method used in the worldwide. Appropriate biomarkers that predict graft status should be used to detect early post-transplant complications that may lead to a rejection reaction. Material and Method: The study involved a total of 44 liver recipients and 44 liver donors, from whom preoperative blood samples were taken and immunoassay and spectrophotometric studies were carried out. The levels of serum neopterin, interferon-gamma (IFN- y), indoleamine-2,3 dioxygenase (IDO), and -glutathione S transferase (a-GST) were assessed using an enzyme-linked immunosorbent test. The activity of glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) in erythrocytes was measured using spectrophotometry. Result and Discussion: “Neopterin, IDO, and G6PD levels were significantly higher in the recipient group than in the donor group. The differences in gender and blood groups were statistically insignificant. The rejection reaction developed in 25% of patients and none survived. These findings may facilitate the identification of novel predictive biomarkers for the diagnosis of acute rejection reactions after LDLT. The clinical use of novel non-invasive biomarkers may provide time and cost advantages.

Anahtar Kelimeler

• α-GST liver transplantation
• G6PD
• IFN-γ
• indoleamine-2,3-dioxygenase

Destekleyen Kurum

İNÖNÜ ÜNİVERSİTESİ BİLİMSEL ARAŞTIRMA PROJE BİRİMİ (İUBAP)

Proje Numarası

TDK-2019-1641

Teşekkür

The Department of Scientific Research Projects at İnönü University provided funding for the present study (Project number: TDK-2019-1641).

CANLI DONÖR KARACİĞER NAKLİNİN ÖNGÖRÜSEL BİYOBELİRTEÇLERİ

Öz

Amaç: Canlı donör karaciğer nakli (CDKN) şu anda dünya çapında en yaygın karaciğer nakli yaklaşımıdır. Rejeksiyon reaksiyonuna yol açabilecek erken nakil sonrası komplikasyonları tespit etmek için greft durumunu öngören uygun biyobelirteçler kullanılmalıdır. Gereç ve Yöntem: Çalışmaya toplam 44 karaciğer alıcısı ve 44 karaciğer donörü dahil edildi, bunlardan ameliyat öncesi kan örnekleri toplandı, immünoassay ve spektrofotometrik analizler yapıldı. Serum neopterin, interferon gama (IFN-y), indolamin-2,3-dioksijenaz (IDO) ve alfa- Glutatyon S- transferaz (a-GST) seviyeleri, enzime bağlı bir immünosorbent deneyi kullanılarak ölçüldü. Eritrositlerdeki glutatyon redüktaz (GR) ve glukoz-6-fosfat dehidrogenaz (G6PD) aktivitesi spektrofotometri ile ölçüldü. Sonuç ve Tartışma: Neopterin, IDO ve G6PD düzeyleri alıcı grupta donör grubuna göre anlamlı olarak yüksekti. Cinsiyet ve kan gruplarındaki farklılıklar istatistiksel olarak anlamsızdı. Hastaların %25’inde reddetme reaksiyonu gelişti ve hiçbiri hayatta kalmadı. Bu bulgular, CDKN sonrası akut rejeksiyon reaksiyonlarının teşhisi için yeni prediktif biyobelirteçlerin tanımlanmasını kolaylaştırabilir. Yeni invaziv olmayan biyobelirteçlerin klinik kullanımı, zaman ve maliyet avantajları sağlayabilir.

Anahtar Kelimeler

• α-GST karaciğer nakli
• G6PD
• IFN-γ
• indolamin-2,3-dioksijenaz

Proje Numarası

TDK-2019-1641

Kaynakça

1. 1. Rai, R. (2013). Liver transplantatation- an overview. The Indian Journal of Surgery, 75(3), 185-191. [CrossRef]
2. 2. Wertheim, J.A., Petrowsky, H., Saab, S., Kupiec-Weglinski, J.W., Busuttil, R.W. (2011). Major challenges limiting liver transplantation in the United States. American Journal of Transplantation, 11(9), 1773-1784. [CrossRef]
3. 3. National Library of Medicine Web site. (2023). Retrieved 2022 May 9, from https://www.ncbi.nlm.nih.gov/books/NBK553074/. Access date: 22.10.2022.
4. 4. Florman, S., Miller, C.M. (2006). Live donor liver transplantation. Liver Transplantation, 12(4), 499-510. [CrossRef]
5. 5. Appenzeller-Herzog, C., Hartleif, S., Vionnet, J. (2021). Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review. American Journal of Transplantation, 21(10), 3312-3323. [CrossRef]
6. 6. Ünüvar, S., Aslanhan, H., Tanrıverdi, Z., Karakuş, F. (2018). The relationship between neopterin and hepatitis B surface antigen positivity. Pteridines, 29(1),1-5. [CrossRef ]
7. 7. Ünüvar, S., Tanrıverdi, Z., Aslanhan, H. (2018). Potential prognostic role of ımmune system activation marker neopterin in patients with type 2 diabetes. Journal of Medical Biochemistry, 37(4), 465-469. [CrossRef]
8. 8. Tanrıverdi, Z., Meteroglu, F., Yüce, H., Şenyiğit, A., Işcan, M., Unüvar, S. (2021). The usefulness of biomarkers in diagnosis of asbestos-induced malignant pleural mesothelioma. Human and Experimental Toxicology, 40(11), 1817-1824. [CrossRef]

9. 9. Mendoza, J.L., Escalante, N.K., Jude, K.M., Sotolongo Bellon, J., Su, L., Horton, T.M., Tsutsumi, N., Berardinelli, S.J., Haltiwanger, R.S., Piehler, J., Engleman, E.G., Garcia, K.C. (2019). Structure of the IFNγ receptor complex guides design of biased agonists. Nature, 567(7746), 56-60. [CrossRef]
10. 10. Czuczejko, J., Mila-Kierzenkowska, C., Szewczyk-Golec, K. (2019). Plasma α-Glutathione S-Transferase Evaluation in Patients with Acute and Chronic Liver Injury. Canadian Journal of Gastroenterology and Hepatology, 2019, 5850787. [CrossRef]
11. 11. Jochum, C., Beste, M., Sowa, J.P., Farahani, M.S., Penndorf, V., Nadalin, S., Saner, F., Canbay, A., Gerken, G. (2011). Glutathione-S-transferase subtypes α and π as a tool to predict and monitor graft failure or regeneration in a pilot study of living donor liver transplantation. European Journal of Medical Research, 16(1), 34-40. [CrossRef]
12. 12. Couto, N., Wood, J., Barber, J. (2016). The role of glutathione reductase and related enzymes on cellular redox homoeostasis network. Free Radical Biology Medicine, 95, 27-42. [CrossRef]
13. 13. Villegas, T., Olmedo, C., Muffak-Granero, K., Comino, A., Garrote, D., Bueno, P., Ferrón, J.A. (2012). Perioperative levels of glutathione reductase in liver transplant recipients with hepatitis C virus cirrhosis. Transplantation Proceedings, 44(6), 1542-1544. [CrossRef]
14. 14. Goralczyk, A.D., Moser, C., Scherer, M.N., Tsui, T.Y., Doenecke, A., Lorf, T., Schlitt, H.J., Obed, A. (2010). Glucose-6-phosphate dehydrogenase deficiency: a contraindication for living donor liver transplantation?. Transplant International, 23(11), e65-e66. [CrossRef]
15. 15. Hunaiti, A.A., Soud, M. (2000). Effect of lead concentration on the level of glutathione, glutathione S-transferase, reductase and peroxidase in human blood. The Science of The Total Environment, 248(1), 45-50. [CrossRef]
16. 16. Carlberg, I., Mannervik, B. (1981). Purification and characterization of glutathione reductase from calf liver. An improved procedure for affinity chromatography on 2',5'-ADP-Sepharose 4B. Analytical Biochemistry, 116(2), 531-536. [CrossRef]
17. 17. Han, S., Yang, J.D., Sinn, D.H., Ko, J.S., Kim, J.M., Shin, J.C., Son, H.J., Gwak, M.S., Joh, J.W., Kim, G.S. (2016). Higher bilirubin levels of healthy living liver donors are associated with lower posttransplant hepatocellular carcinoma recurrence. Transplantation, 100(9), 1933-1938. [CrossRef]
18. 18. Chiu, K.W., Chen, Y.S., de Villa, V.H., Wang, C.C., Eng, H.L., Wang, S.H., Liu, P.P., Jawan, B., Huang, T.L., Cheng, Y.F., Chen, C.L. (2005). Characterization of liver enzymes on living related liver transplantation patients with acute rejection. Hepato-Gastroenterology, 52(66), 1825-1827.
19. 19. Maheshwari, A., Mishra, R., Thuluvath, P.J. (2004). Post-liver-transplant anemia: Etiology and management. Liver Transplantation, 10(2), 165-173. [CrossRef]
20. 20. Pereboom, I.T., Lisman, T., Porte, R.J. (2008). Platelets in liver transplantation: friend or foe?. Liver Transplantation, 14(7), 923-931. [CrossRef]
21. 21. Artz, A.S., Wickrema, A., Dinner, S., Godley, L.A., Kocherginsky, M., Odenike, O., Rich, E.S., Stock, W., Ulaszek, J., Larson, R.A., van Besien, K. (2008). Pretreatment C-reactive protein is a predictor for outcomes after reduced-intensity allogeneic hematopoietic cell transplantation. Biology of blood and marrow transplantation: Journal of the American Society for Blood and Marrow Transplantation, 14(11), 1209-1216. [CrossRef]
22. 22. Amouzandeh, M., Nowak, G., Januszkiewicz, A., Wernerman, J., Rooyackers, O., Norberg, Å. (2018). Albumin mass balance and kinetics in liver transplantation. Critical Care, 22(1), 152. [CrossRef]
23. 23. Fuchs, D., Weiss, G., Reibnegger, G., Wachter, H. (1992). The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases. Critical Reviews in Clinical Laboratory Sciences, 29(3-4), 307-341. [CrossRef]
24. 24. Schäfer, A.J., Daniel, V., Dreikorn, K., Opelz, G. (1986). Assessment of plasma neopterin in clinical kidney transplantation. Transplantation, 41(4), 454-459. [CrossRef]
25. 25. Müller, T.F., Vogl, M., Neumann, M.C., Lange, H., Grimm, M., Müller, M.M. (1998). Noninvasive monitoring using serum amyloid A and serum neopterin in cardiac transplantation. Clinica Chimica Acta; İnternational Journal of Clinical Chemistry, 276(1), 63-74. [CrossRef]
26. 26. Oweira, H., Lahdou, I., Daniel, V., Hofer, S., Mieth, M., Schmidt, J., Schemmer, P., Opelz, G., Mehrabi, A., Sadeghi, M. (2016). Early post-transplant neopterin associated with one year survival and bacteremia in liver transplant recipients. Human Immunology, 77(1), 115-120. [CrossRef]
27. 27. Obara, H., Nagasaki, K., Hsieh, C.L., Ogura, Y., Esquivel, C.O., Martinez, O.M., Krams, S.M. (2005). IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. American Jjournal of Transplantation, 5(9), 2094-2103. [CrossRef]
28. 28. Karakhanova, S., Oweira, H., Steinmeyer, B., Sachsenmaier, M., Jung, G., Elhadedy, H., Schmidt, J., Hartwig, W., Bazhin, A.V., Werner, J. (2016). Interferon-γ, interleukin-10 and interferon-inducible protein 10 (CXCL10) as serum biomarkers for the early allograft dysfunction after liver transplantation. Transplant Immunology, 34, 14-24. [CrossRef]
29. 29. Yuasa, H.J., Takubo, M., Takahashi, A., Hasegawa, T., Noma, H., Suzuki, T. (2007). Evolution of vertebrate indoleamine 2,3-dioxygenases. Journal of Molecular Evolution, 65(6), 705-714. [CrossRef]
30. 30. Luan, X., Liao, W., Lai, X., He, Y., Liu, Y., Gong, J., Li, J. (2012). Dynamic changes of indoleamine 2,3-dioxygenase of Kupffer cells in rat liver transplant rejection and tolerance. Transplantation Proceedings, 44(4), 1045-1047. [CrossRef]
31. 31. Suarez-Fuentetaja, N., Domenech-Garcia, N., Paniagua-Martin, M.J., Marzoa-Rivas, R., Barge-Caballero, E., Grille-Cancela, Z., Pombo-Otero, J., Muñiz-García, J., Castro-Beiras, A., Crespo-Leiro, M.G. (2012). Indoleamine, 2-3 dioxygenase activity could be an early marker of graft rejection in heart transplantation. Transplantation Proceedings, 44(9), 2645-2648. [CrossRef]
32. 32. Yilmaz, N., Ustundag, Y., Kivrak, S., Kahvecioglu, S., Celik, H., Kivrak, I., Huysal, K. (2016). Serum indoleamine 2,3 dioxygenase and tryptophan and kynurenine ratio using the UPLC-MS/MS method, in patients undergoing peritoneal dialysis, hemodialysis, and kidney transplantation. Renal Failure, 38(8), 1300-1309. [CrossRef]
33. 33. Kaden, J., Abendroth, D., Völp, A., Marzinzig, M. (2015). Dynamics and diagnostic relevance of kynurenine serum level after kidney transplantation. Annals of Transplantation, 20, 327-337. [CrossRef]
34. 34. Ng, K.T., Yeung, O.W., Lam, Y.F., Liu, J., Liu, H., Pang, L., Yang, X.X., Zhu, J., Zhang, W., Lau, M.Y.H., Qiu, W.Q., Shiu, H.C., Lai, M. K., Lo, C.M., Man, K. (2021). Glutathione S-transferase A2 promotes hepatocellular carcinoma recurrence after liver transplantation through modulating reactive oxygen species metabolism. Cell Death Discovery, 7(1), 188. [CrossRef]