Bronsther, OL

Cowan, S

Kramer, D

Pinna, A

Rao, PN

Snyder, J

Starzl, TE

Takaya, S

English

PubMed

D-Scholarship@Pitt

\ 5 4~ Effluent Levels of Hyaluronic Acid Can Predict Ultimate Graft Outcome After Clinical Liver Transplantation: A Prospective Series O.L. Bronsther, P.N. Rao, A. Pinna, J. Snyder, S. Cowan, D. Kramer, S. Takaya, and T.E. Starzl PRIMARY nonfunction (PNF) of the liver is an inexact term and investigators continue to debate the site and origin of preservation injury. Some grafts with PNF fail in the operating room. while other grafts have to be replaced between I and 14 days postoperatively. The pathology of such grafts displays a spectrum of findings ranging from marked hepatocellular swelling and cholestasis to massive ischemic necrosis. Both recipient and donor etiological factors potentially contribute to PNF. Donor factors in-clude the physiological condition of the heart-beating ca-daver before organ procurement. the methods of preser-vation. period of cold ischemia. and various reperfusion phenomena. To date. there has been no proven method to discriminate in advance of transplantation between clini-cally acceptable and unacceptable liver allografts. Because the critical target of preservation injury has been increasingly perceived to be the hepatocyte mi-crovasculature (HMV). U we attempted in this study to correlate hyaluronic acid (HA), an HMV-specific mark-' erKg-~ with ultimate graft outcome. Hyaluronic acid is a glycosoaminoglycan weighing 4 to 8 million kd. It is synthesized in the cell plasma membrane. deposited in the extracellular matrix. transported by the lymphatics. and uniquely catabolized by the liver HMV. I-~ Serum HA has been used to monitor liver graft function/> and as a prognostic marker after Tylenol poisoning. 7 Because HA is concentrated in HMV cells. the rationale for the present study was that preservation injury to these cells will result in the leakage of this substance into the organ effi!1ent. where it can be collected and assayed on the backtable before liver transplantation. I n a preliminary retrospective study. the feasibility was demonstrated of correlating effluent HA levels with graft function and viability in an accurate and reproducible manner. Effluent HA values of s400 I-Lg/L were associated with unequivocal early graft function. and grafts with HA values of >400 I-Lg/L were at high risk of developing PNF. ~ Therefore, we undertook the following prospective study. MATERIALS AND METHODS Seventy consecutive primary. crossmatch-negative. adult onho-topic livers were transplanted into 70 adult recipients. Standard organ procurement techniques were used. All livers were pre-,erved In University of WisconSin (UW) solution at 4°C. After variable periods of cold storage. 150 mL of cold Ringers lactate was flushed through the ponal vein. The suprahepatic cava was clamped and the effluent was collected through the mfrahepatic cava. These livers were then reftushed with 500 mL of cold UW solution. These perfusions were performed on the backtable while the livers were being prepared for implantation. All patients received I g of methylprednisolone in the operating room and Table 1. Graft Survival UneqUIVOCal Failure Failure From Group Cases (n) Graft SUMVal From PNF Other Causes HA ";400.0 58 55 0 3 ILQiL (94.8%) HA >400.00 12 6 6 0 I'QIL (50%) (50%) OverBlI9O-day graft survIVal = 87.10;. (61 of 70): overall incidence of PNF = 8.6% (6 of 70). were then maintained on FK 506 and 20 mgld of methylprednis-olone. Recipients were monitored daily for liver function. Ultra-sounds. biopsies, and other invasive procedures were performed as clinically indicated. Assay \ The effluent was assayed for HA values using a radiometric assay marketed by Pharmacia Diagnostics.s All samples. including stan-dards. were run in duplicate. Variation of results never exceeded 2.2%. The assays can be performed in <3 hours. Statistical Analysis \ The Mann-Whitney U test. a nonparametric equivalent to the standard two-sample t test. was used to compare HA and liver function values between groups. Univariant logistic regression was used to predict PNF based on HA values. RESULTS Graft Survival Table I shows an overall90-day graft survival of87.1'/C (61 of 70). PNF was only noted in livers with effluent HA Table 2. Donor Age and Cold Ischemia Time Group Cases (n) Donor Age (rangel CIT (range) HA s 400.0 58 343 !: 14.4 y" 14.7 !: 4.3 h" I'QIL E1~F ERK~OPKRF HA > 400.0 12 40.6 !: 1 1 .0 y" 14.2 !: 3.B h" !J.9IL (17-55) (102-210) ·NS. From the Pittsburgh Transplant Institute, Department of Sur-gery, UniverSity of Pittsburgh Health Science Center (O.L.B., P.N.R., A.P., J.S., SC., S.T., IE.S.), and Department of Anesthl-ology and Critical Care. Presbytenan University Hospital (O.K.). Pittsburgh, Pennsylvania. Address reprint requests to Oscar L. Bronsther, MD, 3601 Fifth Ave, 5/C Falk Clinic. Pittsburgh. PA 15213. ~; 1993 by Appleton & Lange 0041-1345/931$3.001 + 0 1538 Transplantation Proceedings. Vol 25. No 1 (February). 1993: pp 1538-1540 EFFLUENT LEVELS OF HYALURONIC ACID 1MMMI---------------------------~ - 800-....J -E CO ... C) o ... (.) E 600 t:J SUCCESSFUL GRAFT • PNF • • I!I • 400 4--------4e~: ------~K--------~ tI « :c 200 I p=O.0002 I t:J llJ o 4-_--.. __ -IoF.ljL. ---D---r--""""q"-~ o 1 2 3 Graft outcome Fig 1. Individual HA values and graft outcome. levels >400 /-LgiL. None 0\58 livers with low etHuent HA levels developed PNF. while 6 of 12 livers with high effluent HA levels developed PNF (P < .(05). Graft survival beyond 90 days was achieved in 55 of 58 livers with low etHuent HA values compared with 6 of 12 livers with high etHuent HA values (e < .(01). Three livers with low etHuent HA levels failed belween the 7th and 10th days postoperatively. These livers were lost to hepatic artery thrombosis in two cases and death from pneumonia in the third. Study Parameters 1539 Table 4. Analysis of Fal .. PolltlYe Uverl Group Clinical Group AST(IU/L) AlT (lUlL) '5400.0 1287:t 1326 983 :!: 1041 (n ~ 58) 2 PNF 5137 :!: 4110 4046:!: 3545 (n = 6) 3 False-positive 4237:!: 2940 3502:!: 2230 (n = 6) AST: group 1 \IS group 3. P < .003: group 1 vs group 2, P < .05: group 2 vs group 3. p: NS. AlT: group 1 vs group 3. P < .002: group 1 vs group 2. P < .05; group 2 \IS group 3, p: NS. cantly elevated in the group with high etHuent HA levels (>400 J.Lg/L) vs the group with low etHuent HA levels (:s400 J.Lg/L) (P < .006 and P < .0005) !Table 3). Indil'idual Effluent HA Lel'els and Graft Outcome. Mean HA values of successful grafts were 218.6 :t 16.2 (mean:!: SE) J.LglL vs mean values for PNF grafts of 549.3 ::: 74.9 J.Lg/L (Fig I). All six grafts lost to -,PNF had significantly higher HA levels when compared with suc-cessful grafts (P = .00(2). All PNF grafts had effluent HA values >400 J.LglL. Analysis of False-Positive Livers False positives were defined as livers that were success-fully transplanted despite etHuent HA levels >400 J.LglL. However. these false-positive livers had a pattern of enzyme release similar to the six livers that experienced PNF (Table 4). 1.0 -pc---..... IIR&::-------------, 0.8 Donor Age and Cold Ischemia Time. No significant O.S differences are noted in either variable between the two groups !Table 2). Peak Asparate Aminotransferase (AST) and Alanine 0.4 Aminotransferase (AL TJ Levels After Orthotopic Lil'er Transpl(/ntation. Asparate aminotransferase and AL T values in the first 7 postoperative days were both signifi- 0.2 Table 3. AST and AL T Levell After OL T Group AST (IUL) HA ,; 400.0 1287:!: 1326 /-LgL (n ~ 57) HA :. 400.0 4687 :!: 3439 ~i (n = 12) P <.0006 'W,lcoxon SIgn rank lest. ALT (lUL) 983 :!: 1041 (n = 57) 3774 :!: 2438 (n = 12) ·0005 0.0 +--~-KK---KKKKKKIr__--K-__K-~-_r-:::=---_1 o 200 400 600 800 1000 HA VALUES Fig 2. HA values analyzed as predictors of graft outcome using stepwise logistic regression. Analysis showed that an Increase of effluent HA values IS Significantly associated With an increase in the probability of PNF (improved chi-square of22.135; P ~ .0001). 1540 Degree of Discrimination Logistic regression was used to test whether graft success and PNF was associated with effluent HA levels (Fig 2). Analysis showed that HA values were significantly asso-ciated with both events (improved chi-square of 22.135, P = .00(1). This implies that an increase in effluent HA levels is associated with an increase in the probability of PNF. DISCUSSION AND CONCLUSIONS Six percent to 8% of transplanted livers never adequately function, with consequent death or retransplantation.9 PNF is the leading cause of early graft loss and is respon-sible for enormous morbidity, mortality, and expense. We believe that systematic measurements of HA effluent lev-els will allow detection of livers that already have been seriously damaged and are at high risk of developing PNF. In this study. half the 12 livers failed from PNF in the high-risk group (HA >400 ~FK Conversely, livers with low HA values were uniformly suitable for transplantation, with no examples of PNF among 58 livers in the good risk group. Even though six livers with HA values >400 ~i BRONSTHEA. RAO, PINNA ET AL ultimately survived and were classified as false positives, these livers exhibited a severe injury pattern just short of catastrophic. The position of these livers on a risk scale can be seen with logistic regression analysis in Fig 2. If the HA value in future cases were known in advance. the use of these organs would be unwarranted. REFERENCES I. Otto G, Wolff H. Verlings I. et a1: Transplantation 42:122. 1986 :!. McKeown CMB. Edward V, Phillips MJ. et a1: Transplan-tation 46: 128. 1988 3. Fraser JR. Laurent TC, Engstrom-Laurent A. et al: Clin Exp Phannacol Physio1 II: 17. 1984 4. Erikson S, Fraser JRE. Laurent TC. et al: Exp Cell Res 144:223. 1983 5. Adams DH. Wang L, Hubscher SG. et aJ: Transplantation 42:429. 1989 6. Pollard SG, Forbes MA. Metcalfe SM, et al: Transplant Proc :!2:2301. 1990 7. Bramley PN. Rathbone BJ. Forbes MA. et aJ: J Hepatol 13:8. 1991 8. Rao PN, Bronsther OL. Snyder JT, et a1: Transplant Proc (in press) \ 9. Todo S. Nery J, Yanaga K. et aJ: JAMA 211:261. 1989 \ 

Effluent levels of hyaluronic acid can predict ultimate graft outcome after clinical liver transplantation: a prospective series.

Name not available

Effluent levels of hyaluronic acid can predict ultimate graft outcome after clinical liver transplantation: a prospective series

http://d-scholarship.pitt.edu/4928/1/31735062113299.pdf

Effluent levels of hyaluronic acid can predict ultimate graft outcome after clinical liver transplantation: a prospective series.

Abstract

Similar works

Full text

Available Versions

D-Scholarship@Pitt

Name not available

Name not available