Fung, JJ

Griffith, BP

Iwaki, Y

Kita, Y

Noguchi, K

Starzl, TE

Todo, S

Tzakis, AG

PubMed

Name not available

Daily serum interleukin-6 monitoring in multiple organ transplantation with or without liver allografts

D-Scholarship@Pitt

------ ----_._._-.(1).]--E~ Daily Serum Interleukin-6 Monitoring in Multiple Organ Transplantation With or Without Liver Allografts Y. Kita, Y. Iwaki, K. Noguchi, B.P. Griffith, A.G. Tzakis, S. Todo, J.J. Fung, and T.E. Starzl W E PREVIOUSLY reported that daily monitored serum or plasma interleukin-6 (lL-6) levels maybe a good premonitor of liver allograft rejection and also a useful predictor of long-term graft prognosis. I Histopathologically. liver allograft rejection is character-ized by a cellular infiltration consisting mainly of mono-cytes/macrophages and activated T lymphocytes. IL-6 is an inflammatory cytokine mainly secreted by monocytes/mac-rophages and endothelial cells. Kupifer cells and vascular endothelial cells in the liver may also secrete IL-6. There-fore, both infiltrating host immune cells and allograft cells (activated Kupifer and endothelial cells) may playa role in producing IL-6. The liver is the largest organ in the human body and potentially produces IL-6. The liver is also the major target organ of IL-6. To clarify this phenomenon (ie. that the major source of IL-6 is the liver allograft), we evaluated sequential serum IL-6 levels in various organ transplants with and without liver allografts. SUBJECTS AND METHODS FK 506 or cyclosporine (CyA). to which various doses of methyl-prednisolone were added, were used for baseline suppression. OKT3 was given when indicated. Daily monitoring of serum IL-6 was performed in cases of 18 kidney. 27 liver. 5 lung (single lung: 2. double lung: 3). 1 small bowel, 4 liver + kidney. 5 liver + islet (abdominal organ cluster transplantation), and 3 liver T small 1 9 + Table 1. Number of Various Organ Transplants Undergoing Serum IL-6 Monitoring Transplants Cases Kidney 18 Liver 27 Lung 5' Small bowel 1 Liver + kidney 4 Liver + islets (cluster) 5 liver + small bowel 3 Total 63 'Single: 2; double: 3. bowel transplantation using ELISA (Table I). ELISA was per-formed using a TWo-step sandwich enzyme immunoassay method with Quantikine (Research and Diagnostic Systems Inc. Minneap-olis. Minn.) as described elsewhere. I Daily monitored IL-6 levels were evaluated and compared to clinical courses and histopatho-logical diagnosis of rejection in all cases. From the Department of Surgery (Y.K.. B.P.G., A.G.T .. S.T., J.J.F., T.E.S.) and Pathology (Y.I.. K.N.), University of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to Thomas E. Starzl, MD. PhD. Department of Surgery, University of Pittsburgh, 3601 Fifth Ave, Pittsburgh, PA 15213. © 1996 by Appleton & Lange 0041-1345/96/$3.00/ + 0 Liver 300 19l9 Methylprednisolone + + --0- IL-6 OKT3 10mg x 5 days OKT310mg x 5 days 30 100 o _____ m Rejection (relapsing) 10 - 5 days Azathioprine 50-100 mg/day CMV Infection Postoperative days Transplantation Proceedings, Vol 28, No 3 (June). 1996: pp 1229-1234 10 o 50 Fig 1. A 52-year-old woman with alcoholic cirrhOSis under-went liver transplantation. She had many relapsing rejection episodes. 1229 ~ ) 1230 -No complication 300 -IL .. 1200 ~ -100 0 0 10 400 Rejection Bronchoalveolar lavage ~ 300 -IL .. 1 200 'i' ::! 100 20 573pg/ml 400 Infection 300 - IL .. 100 10 POS10perative days Fig 2. Serum IL-6 monitoring in lung transplant recipients. Upper: Double-lung transplant recipient with no complications. Middle: Single-lung transplant recipient with one relection epI-sode. Rejection was confirmed by bronchoalveolar lavage (BAL). An IL-6 spike was observed 1 day before BAL. Lower: Double-lung transplant reCipient with bacterial infection In both lung allografts. IL-6 levels were consistently high. RESULTS The normal mean value of IL-6 from J() healthv volunteers was IX ::':: 3.+ pgtmL. of whom 21 (7Wr) had nondetecrable « 10 pgtml) levels. We defined the normal [L-Il cutotf levels as XIJ pg,'mL. which was the mcan ::: 2 SD va[ue of the 30 healthy volunteers. The O1e;1O number of IL-6 measurements a\era!,!ed [6.5 per patient. Ali patients with infection subsequentlv devel-nped continuouslv high I L-h levels. Rejection cplsodes < lecurred in five cases (proven histopatholo!,!ically by ei!,!ht hiopsies) in kidncv transplantation. However. no splke-\haped IL-Il elevations (>Xh pgtml) \\ere found in these cases. KITA, IWAKI, DEMETRIS ET AL In liver and liver + islet transplantation. serum or plasma levels of IL-6 were decreased after liver (or liver + islet) transplantation, regardless of pre transplant values. Patients with infection subsequently developed continuously high IL-6 levels. In patients without infection, significantly higher levels of IL-6 were usually found prior to the histopathological diagnosis of rejection. IL-6 elevation was spike-shaped, correlated poorly with the histological grade of rejection. and was highly responsive to augmented immunosuppression. One representative case with late-phase relapsing rejection episodes is shown in Fig 1. On the same day or one day before the biopsy showing acute cellular rejection (ACR), an IL-6 spike was observed. Similar to the case with liver transplants, histopatholog-ical rejection episodes involving lung allografts showed spike-shaped IL-6 elevations 0 to 2 days before histopatho-logical diagnosis of rejection. Representative cases of no complication, rejection, and infection are shown in Fig 2. In the case of small bowel transplantation, no IL-6 elevation was observed during mild ACR on postoperative day (POD) 6 and the prominent ACR on POD 14. Since prominent ACR was proved on POD 14. antirejection therapy was initiated soon and treated successfully (Fig 3). In contrast, in transplantations combined with liver allo-grafts (liver + small bowel and liver + kidney), if the rejection episodes were found in the liver allograft, IL-6 spikes were also found 0 to 4 days before histopathological rejection. Interestingly, even with rejection episodes in other allografts (small bowel or kidney), IL-6 spikes were also found in the same fashion. A 4-year-old boy with gastroschisis (Fig 4) underwent liver + small bowel transplantation. Neither the liver nor small bowel biopsy showed any histological rejection in this case. Although liver biopsy on POD 15 showed no signs of rejection. serum glutamate oxaloacetate transaminase (GOT) levels rose again on POD 111. indicating liver dysfunction possiblv due to rejection .. ·\n (L-6 elevation spike was observed on POD 13. A 26-year-old woman with superior mesenteric artery thrombosis (Fig':;) underwent liver i- small bowel trans-plantation. Biopsies showed no signs of liver rejection. but clinical rejection was dia!,!nosed by the rise in serum total hilirubin (TI3) lC\ cis. Methylprednisolone bolus (I g) was administered ;111([ liver rejection appeared successfullv treated on POD 25. Biopsies undertaken on POD 25 and 35. however. showed reJection or the small howel allograft. During this pertud (POD 25 to POD 35). IL-Il spikes were also observed. A D+~-year-uld man with primarv ,clerosing cholangitis and polycystic kidnev underwenl combined liver and kidnev transplantation. and the pu,ttransplant course was unevent-ful (Fi!,! (J). Serum I L-h le\'els were alwavs in the normal range. :\ '+O-vear-old man with crvpto!,!enlc cirrhosis and chronic renal failure underwent combined I i\er and kidney trans-plantation (Fi!! ., I. Biopsies ni hoth kidnev and liver allo-grafts ,IHlwed Illl signs <)1 releellon: however. he sulfcred MULTIPLE ORGAN TRANSPLANTATION IL .. : 754 pg/mi (POD 1) 255 pg/mI (POD 2) Rejection Methylprednisolone 2 g 1 g (Small bowel) - IL-6 I 1 0KT310 me -- T8 t ~/davuTday 200 I ~ 100 o+-----~K_----~~~~~~~~~~=---~~+ o Small bowel biopsy MlidACR (+) Prominent ACR (++) Postoperative days None to minimal ACR (-) (-) 4 1231 Fig 3. A 31-year-old man with gunshot injury to the superior mesenteric artery underwent small bowel transplantation. The serum IL-6 level was high POD 1 to 2 but decreased after-ward, and stayed within the nor-mal range regardless of biopsy-proven acute cellular rejection (ACR) episodes. from bacterial and fungal infection after POD 10. IL-6 levels were very high after POD 10 except for a few days. In the case of a 29-year-old man with cryptogenic cirrho-sis and chronic renal failure (Fig 8), the direct crossmatch test showed strong positive. Kidney biopsy on POD 18 showed mild to moderate ACR and vascular rejection, and liver biopsy showed no ACR. IL-6 spikes were observed on the day of biopsy (POD 18) and POD 16. This patient suffered from overwhelming relapsing kidney rejection that necessitated nephrectomy after POD 50. The liver allograft Rejection (Liver) Methyprednisolone 500 mg (liver) 200 t --+- IL-6 4 100 ~ GOT 'ti ---tr-- T8 CI §. c: ~ :c ~ ... 0 :c (!l 2 50 'iii 0 I-O+-----______ ~------~----~----------~r_----~l 0 o Small bowel biopsy Liver biopsy t (-) t (-) 20 30 Postoperative days Fig 4. A 4-year-old boy With gastroschisis underwent com-bined liver and small bowel transplant. One gram of methyl-prednisolone was administered for clinically suspected liver allo-graft relectlOn. 1232 KITA, IWAKI, DEMETRIS ET AL ...... pg/mI lPOD 5) .... , m pg/mI lPOD II ..... '._IPOD1' .... '1032PO/mlCPOO.' Rejection (Liver, Small bowel) Fig 5. A 26-year-old woman with superior mesenteric artery IL.., 3711_ lPOD Z) 200 I -100 : 11 (liver) 1 Methylprednisolone (liver) 1 9 (small bowel) -IL" I ---.- TB t thrombosis underwent com- 0 +---~---r~~h---*KKK----~---r--~--+ bined liver and small bowel 0 transplant. The first and second administration of methylpred- Small bowel biopsy nisolone (1 g) were for liver al-lograft rejection. The third was Liver biopsy for small bowel allograft rejec-tion. OLTx KTx 10 t (-) t (-) 20 t 30 t (-) (+) t t (-) (-) Postoperative days t No complication -ILoS 300 --0-- TB ~ Cr E in 200 .s '9 :: 100 t 40 (+) t (-) 4 2 0 10 Postoperative days 20 Fig 6. A 44-year-Old man with primary scleroSing cholangitis and polycystic kidney under-went combined liver and kidney transplantation. The posttrans-plant course was uneventful. Biopsy findings Kidney Liver t Mlmlmal fatty change NoACR I c :a ~ :a ! {! 15 :g :::-in ~b m-10 E II -.E c:c: :c== .; ! ;:U ~b 5 ",:I - ... o II I-cn MULTIPLE ORGAN TRANSPLANTATION f$?$?S?S?S?S?S& Amphotericin B Infection 10: .: ,: .: i: I: ,: .:,:.:.:,: I: .: .: .: iTobramycln 300 =- 200 E J ~ 100 Biopsy findings Kidney liver Biopsy findings I Kidney Liver E c. S: U> ~ OLTx KTx o _______ .Plperacillln Vancomycin Methylprednisolone 19 x 2 =-~ • • iiiOM·UM·4M~ -IL-6 -0-- T1I --4-- Cr "1 pgIIIII 1l1li pglmI 10 Postoperative days + NoACR + + Mild Ischemic Inlury Ischemic Injury Focal duct damage Pericholangitis 30 1 20.5. c :a i :i!i S 10.!! 20 + NoACR cholestasls OlTx KTx ReOlTx Nephrectomy OKT3 10 mglday • 3 days OKT3 10 mgJday •• 2 days I jMethYIPrrn,solone 19 x f - , , flepgllN +.2031 JIOi'"I 300 15 IL-6 ~ TB 200 10 --b- Cr 100 10 20 30 40 50 15 I 10 ! c ~ C> E 5 ci o =t :!?E "'-e" -.5 c:c: :gi ~t .<:IE !l2 oe .... <Il Postoperative days (Open kidney and liver biopsy) t , Moderate I.chemic Change No ACR Bleeding Mild ACR Cholestasts Ischemic Inlury Glomeruli. tubuli and Interstttial edema t Seve .. cholesl8Sls Mild lymphocytic Infiltration Mild penpheral flbros'. 1233 Fig 7. A 40-year-old man with cryptogenic cirrhosis and chronic renal failure underwent combined liver and kidney transplantation. He experienced bacterial and fungal infection af-ter POD 10. Fig 8. A 29-year-old man With cryptogenic Cirrhosis and chroniC renal failure underwent combined kidney and liver transplantation. He experienced relapsing rejection of the kidney allograft and subsequently un-derwent nephrectomy and liver retransplantatlon. 1234 was also damaged due to ischemic injury and possible rejection proven by open liver biopsy on POD 52. Until this procedure, many IL-6 spikes were observed. DISCUSSION In this study, we have shown that daily monitoring of serum IL-6 levels are useful in the diagnosis of graft rejection in recipients with liver allografts. Liver and possibly lung allografts may produce much more IL-6 than kidney al-lografts during rejection episodes. Although Yoshimura et al2 reported the efficacy of IL-6 in diagnosing renal allograft rejection, we could not detect high levels of serum IL-6 in kidney transplants, even in biopsy-proven rejection episodes found in five cases (eight biopsies). This is mainly attributable to the sensitivity of assay because Yoshimura et al used a bioassay method more sensitive than ours. Putting the EUSA assay sensitivity aside, in kidney or small bowel transplantation with liver allografts, we found significantly higher IL-6 concentrations in serum even when kidney or small bowel allografts were rejected. These results suggest that allografts of the liver and lung, which are relatively large organs compared to the kidney, may be major sources of IL-6 production during allograft rejection because the liver and lung contain many mono-cytes/macrophages and large vascular endothelial beds, and also may have many infiltrating activated T cells at the time of rejection. KITA, IWAKI, DEMETRIS ET AL Hoffmann et all also suggested that the localization of tumor necrosis alpha (lNF-a)-producing cells correlated with the distribution of monocytes and macrophages in liver allografts and that concomitan~ plasma levels were elevated compared to those of controls without complications. Since it is well known that lNF-a induces IL-6 production, our findings also imply the intragraft production of inflamma-tory cytokines during rejection episodes. Recently, Matsumoto et al4 reported that IL-6 partici-pa~es in the regulation of human biliary epithelial cell growth in vitro. The ability of IL-6 to directly promote bile duct epithelium DNA synthesis provides a link between liver inflammation such as allograft rejection and the repair response. Thus, the control of inflammatory cytokines is important to obtain longer graft survival without biliary epithelial growth such as vanishing bile duct syndrome. REFERENCES 1. Kita Y, Iwaki y, Demetris AJ, et al: Transplantation 57:1037, 1994 2. Yoshimura N, Oka T, Kahan BD, et al: Transplantation 51:172, 1991 3. Hoffmann MW, Wonigeit K, Steinhoff G, et al: Transplanta-tion 55:329, 1993 4. Matsumoto K, Fujii H, Michalopoulos G, et al: Hepatology 20:376, 1994 

Daily serum interleukin-6 Monitoring in multiple organ transplantation with or without liver allografts

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Daily serum interleukin-6 Monitoring in multiple organ transplantation with or without liver allografts

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