Surg Today (2001) 31:695–700

Evaluation of the Acetaminophen Absorption Test for EarlyDetection of Orthotopic Small Bowel Transplant Rejection

Takayuki Miyauchi, Masashi Ishikawa, and Seiki Tashiro

First Department of Surgery, University of Tokushima, School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan

Introduction

Due to the unique immunogeneity of the small bowel,rejection remains the major obstacle to successful clini-cal transplantation despite the development of powerfulimmunosuppressive agents, such as tacrolimus.1 The de-velopment of improved methods for the early detectionof graft rejection is important for the success of clinicalsmall bowel transplantation. Moreover, the necessity forthese methods to be simple and safe has been stressed.We recently studied the advantages of the acetamino-phen (AC) absorption test for the early detection ofsmall bowel graft rejection in heterotopic small boweltransplantation, using randomly bred rats.2 In practicaloperative procedures for clinical small bowel trans-plantation, small bowel grafts are anastomosed to thealimentary tract of recipients treated with immunosup-pressants such as tacrolimus, steroids, and cyclophos-phamide.1 In the present study we tested the efficacyof this AC absorption test on orthotopic small boweltransplant models with tacrolimus treatment, using fullyallogenic rat combinations (Brown Norway-to-Lewis),with respect to practical small bowel transplantation.

Materials and Methods

Animals

Inbred male rat strains of Brown Norway (BN, RT1n)and Lewis (LEW, RT11) hybrids, each weighing be-tween 250 and 300 g, were used. They were commer-cially purchased from Seiwa, Tokyo, Japan.

Operative Procedures of Orthotopic SmallBowel Transplantation

All procedures were performed under light ether anes-thesia. The small intestine was transplanted orthoto-pically, as previously described by Kobayashi et al.3

Abstract We evaluated the efficiency of the acetami-nophen (AC) absorption test as a marker of graft rejec-tion in orthotopic small bowel transplantation (SBTX)in rats. Brown Norway (BN) rats were used as donorsand Lewis (LEW) rats as recipients. Orthotopic allo-genic SBTX was accomplished using a cuff techniquefor vessel anastomosis. Animals were divided into:group A (n � 9), untreated; group B (n � 15), extendedsmall bowel resection; group C (n � 12), syngeneicSBTX without immunosuppressants; group D (n � 15),allogenic SBTX with tacrolimus (0.1 mg/kg per day);group E (n � 15), allogenic SBTX with tacrolimus(0.5 mg/kg per day). Serum AC was measured 15 minfollowing the instillation of 0.15 g/kg AC into the stom-ach on postoperative days (POD) 1, 3, and 7. Graftswere examined histologically. The group D graftsshowed progressive acute rejection histologically, fromnormal on POD 1, to moderate on POD 3, and severeon POD 7. Serum AC in group D decreasedsignificantly from 53.1 � 3.9µg/ml on POD 1, to 35.0 �12.0 µg/ml on POD 3, and 10.9 � 5.6 µg/ml on POD 7.No remarkable change was observed in the othergroups. Serum AC correlated well with histologicalchanges in rats subjected to SBTX, resulting in acuterejection. The AC absorption test could be useful fordetection of progressive graft rejection in clinicalSBTX.

Key words Small bowel transplantation · Acetami-nophen · Rejection

Reprint requests to: T. Miyauchi, Department of Surgery,National Kochi Hospital, 1-2-25 Asakura-Nishi-machi, Kochi780-8503, JapanReceived: August 17, 2000 / Accepted: March 6, 2001

696 T. Miyauchi et al.: Acetaminophen Absorption Test

Briefly, after overnight fasting, a 20-cm segment ofproximal jejunum was harvested from the donor on avascular pedicle comprising the aorta and portal vein.The donor was then anticoagulated systemically with200 units of heparin administered intravenously imme-diately prior to graft removal. After excision of the graft,the intestinal lumen was flushed with 20ml of coldRinger’s lactate. The donor mesenteric artery, compris-ing the aortic orifice, and the portal vein were anasto-mosed to the recipient’s left renal artery and vein, usinga cuff technique. Extended resection of the recipient’ssmall intestine was performed, leaving 2cm of proximaljejunum and terminal ileum. Both ends of the graft wereanastomosed to the recipient’s remnant intestine in anend-to-end fashion.

Immunosuppressive Agents

Tacrolimus was supplied in powder form by FujisawaPharmaceutical, Osaka, Japan. The properties andimmunosuppressive activity of this drug have recentlybeen described.4,5 Tacrolimus was dissolved in patho-logical saline solution at a concentration of 1mg/ml andinjected into the recipient intramuscularly, followingthe experimental protocols.

Experimental Groups

The 66 experimental animals were divided into the fol-lowing five groups. Group A: left nephrotomy was car-ried out after laparotomy as the Sham operation of thecuff techniques. Group B: extended small bowel resec-tion was performed in Lewis rats, leaving 20cm ofproximal jejunum and 2 cm of terminal ileum. End-to-end anostomosis of the oral and anal ends of the rem-nant intestine was carried out using an interruptedone-layer suture. Group C: a 20-cm length of the LEWproximal jejunum was excised. Orthotopic small boweltransplantation (SBTX) was carried out in a syngeneiccombination (LEW-to-LEW). No immunosuppressiveagents were given to this group. Group D: a 20-cmlength of the BN proximal jejunum was obtained andortotopic SBTX was carried out in allogenic combina-tion (BN-to-LEW). Tacrolimus was injected intramus-cularly at a single dose of 0.1mg/kg per day from the dayof operation until postoperative day (POD) 6. Group E:orthotopic SBTX was carried out in a allogenic com-bination (BN-to-LEW). Tacrolimus was injected intra-muscularly immediately after surgery at a single dose of0.5mg/kg from the day of operation until POD 6.

Absorption Test

The AC absorption test was performed on PODs 1, 3,and 7 in three rats from group A, four from group C, and

five each from groups B, D, and E. AC at a dose of 0.15g/kg body weight (BW) was dissolved in 2ml of 0.45%saline. We previously evaluated the gastric emptying of apatient suffering from dumping syndrome after distalgastrectomy with the AC absorption test, and found thatthe serum AC level peaked 15min after oral instillation.6

Therefore, in this study, we collected 2-ml blood samplesfrom the femoral vein 15min following the oral instilla-tion of AC, using a stainless-steel gastric tube. Serum AClevels were measured by high-performance liquid chro-matography. Briefly, a liquid-chromatograph systemwas attached by a 3-cm length of stainless-steel capil-lary tubing to a 5-cm precolumn, connected to a 50-cmanalytical column. Both columns were 1/8-inch o.d.,0.055-inch i.d. stainless-steel tubing. The effluent wasmonitored with an ultraviolet-sensitive detector set at254nm and connected to a strip-chart recorder. Thegrafts were prepared for histological evaluation.

Histological Techniques and Evaluation

Immediately after completion of the AC absorption test,circumferential samples of the graft were processed forhistological examination by embedding into paraffinwax and staining with hematoxylin–eosin. The severityof graft rejection was classified into the following threephases, as previously described by Rosemurgy andSchraut.7 Phase I: minimal rejection: lymphocytes andplasma cell infiltrate are seen extending into the laminapropria without distortion of the villous architecture.Phase II: moderate rejection: the cellular infiltratesare seen extending from the mucosa and submucosa tothe muscularis propria, with shortening and blunting(edema) of villi and scattered epithelial sloughing. PhaseIII: severe rejection: complete mucosal destruction andheavy transmural cellular infiltration, predominantlyof lymphocytes and polymorphonuclear leukocytes, isseen. Intense serosal and submucosal infiltration is oftenidentified, being consistent with peritonitis.

Statistical Analysis

Statistical analysis was performed using Student’s t-test,or one-way analysis of variance, where appropriate. Sta-tistical significance was assigned at P � 0.05. Values areexpressed as the mean � SD (n � 3 for group A, n � 4for group C, and n � 5 for groups B, D, and E) in eachexperiment.

Results

Serum AC Levels

The findings in groups A and B are shown in Fig. 1. Ingroup A, being the control, the serum AC levels did not

697T. Miyauchi et al.: Acetaminophen Absorption Test

differ significantly on PODs 1 (26.0 � 4.0µg/ml), 3 (27.4� 6.0µg/ml), and 7 (26.9 � 3.7µg/ml). In group B, sub-jected to extended small bowel resection, the serum AClevels were significantly higher than those in group A (P� 0.01), but no significant difference was seen betweenPODs 1 (78.9 � 25.4 µg/ml), 3 (78.7 � 22.4 µg/ml), and 7(72.1 � 25.4 µg/ml). The findings in groups C, D, and Eare shown in Fig. 2. In group C, subjected to syngeneicsmall bowel transplant, the serum AC levels were high,and no significant difference was seen between PODs 1(57.3 � 7.8 µg/ml), 3 (59.7 � 9.8µg/ml), and 7 (66.8 �13.6 µg/ml). In group D, subjected to allograft transplantand given tacrolimus (0.1mg/kg BW per day), the serumAC levels decreased significantly from 53.1 � 3.9 µg/ml

on POD 1 to 35.0 � 12.0 µg/ml on POD 3, then to 10.9 �5.1 µg/ml on POD 7 (P � 0.05). In group E, subjected toallograft transplant and given tacrolimus (0.5mg/kg BWper day), the serum AC levels did not differ significantlybetween PODs 1 (52.8 � 6.8 µg/ml), 3 (55.4 � 9.7µg/ml),and 7 (63.3 � 14.1 µg/ml). On POD 1, the serum AClevels in group D did not significantly differ from thosein groups B, C, and E; however, they were significantlylower than those in groups B, C, or E on PODs 3 and 7.

Histological Evaluation

Table 1 shows the histological evaluation of the trans-plant grafts, following the classifications defined in Ma-terials and Methods. The histological findings of theremnant jejunums in group B did not differ significantlyfrom those of normal intestine during the experimen-tal period. The syngeneic LEW small bowel grafts didnot show signs of graft rejection either. In group D,subjected to allogenic small bowel grafts and giventacrolimus at a single dose of 0.1mg/kg BW per day, allof the five grafts appeared almost normal with no evi-dence of rejection on POD 1 (Fig. 3). On POD 3, PhaseII histology was seen in four grafts (Fig. 4) and Phase III

Fig. 1. Serum acetaminophen test after extended small bowelresection. Squares, control group: circles, extended smallbowel resection. *Significant differences by Student’s t-test(P � 0.01). POD, postoperative day

Fig. 2. Serum acetaminophen test after small bowel trans-plantation (SBTX). Circles, extended small bowel resection;squares, syngeneic (LEW-to-LEW) SBTX; closed triangles,allogenic (BN-to-LEW) SBTX with tacrolimus at a dose of0.1 mg/kg body weight; open triangles, allogenic (BN-to-LEW)SBTX with tacrolimus at a dose of 0.5 mg/kg body weight.

Significant differences by one-way analysis of variance (P �0.05). POD, postoperative day

Fig. 3. Histological findings of group D recipients on POD 1(H&E, �100). No evident cellular infiltration was identifiedand the villous architecture was preserved despite slightedema

698 T. Miyauchi et al.: Acetaminophen Absorption Test

histology was seen in one. By POD 7, phase III histol-ogy was seen in four grafts (Fig. 5) and Phase II histol-ogy was seen in one. Tacrolimus at a single dose of0.1mg/kg BW per day did not have a marked effect onadvances of allogenic small bowel graft rejection. How-ever, in group E, subjected to allogenic small bowelgrafts and given tacrolimus at a single dose of 0.5mg/kgBW per day, all of the grafts appeared normal fromPOD 1 to POD 3. On POD 7, three grafts appearednormal and the other two showed Phase I histology.Therefore, tacrolimus at a single dose of 0.5mg/kg BW

per day markedly reduced the rejection of allogenicsmall bowel grafts.

Discussion

In clinical small bowel transplantation, rejection oftenleads to lethal complications, such as sepsis, multipleorgan failure, and possibly host death.8 Grant et al. re-ported that the breakdown of the gut barrier function,even during the early stages of graft rejection, might

Table 1. Histological evaluation of the transplant graft

POD 1 POD 3 POD 7

Group Donor Tacrolimus Na Ib IIc IIId N I II III N I II III

C LEW None 5 0 0 0 5 0 0 0 5 0 0 0D BN 0.1 (mg/kg)e 5 0 0 0 0 0 4 1 0 0 1 4E BN 0.5 (mg/kg)f 5 0 0 0 5 0 0 0 3 2 0 0

a N represents normal state of the graft, with no evident sign of rejectionb I, c II, and d III represent the three histological phases, following the classification by Rosemurgy and Schraut,7 detailed in Materials and Methodse In group D, the recipients were given tacrolimus at a single dose of 0.1mg/kg body weight per day from the day of operation until postoperativeday (POD) 6f In group E, the recipients were given tacrolimus at a single dose of 0.5mg/kg body weight per day from the day of operation until POD 6

Fig. 4. Histological findings in group D recipients on POD 3(H&E, �100). Prominent cellular infiltration was identified inthe mucosa and submucosa, extending slightly into the muscu-laris propria. The villous architecture was still observed; how-ever, the height of the villi was markedly shortened and thevilli were distorted with edema

Fig. 5. Histological findings in group D recipients on POD 7(H&E, �100). Complete mucosal destruction developed rap-idly with heavy transmural cellular infiltration. The phase IIIhistology showed a patchy distribution (arrow). Phase III his-tology detected in Phase II histology

699T. Miyauchi et al.: Acetaminophen Absorption Test

lead to bacterial translocation, explaining the septiccomplications and graft death.9 Therefore, the earlydetection of graft rejection is important to ensure thesuccess of small bowel transplantation, and a number ofstudies have reported various methods for this. Mucosalbiopsy of the graft has been evaluated as the most pre-cise method of detecting graft rejection.10 However,some studies have suggested that this could contributeto misunderstanding a patchy distribution of smallbowel graft rejection.11 Furthermore, it might carry arisk of graft perforation. Safer methods for the detec-tion of rejection have used graft functional tests. Thefunctional tests of transplanted small bowel grafts havebeen divided into graft barrier functional tests and ab-sorptive functional tests. The barrier functional testswere evaluated by monitoring the increase in mucosalpermeability associated with graft rejection, using low-molecular-weight substances such as 51Cr-EDTA12 andpolyethylene glycol.13

In an experimental study using rat models, Grant etal. reported that permeability testing with 51Cr-EDTAclearly detected the mild histological changes in thegraft caused by rejection. Futhermore, they estimatedthe efficiency of this method in clinical small boweltransplantation.12 Polyethylene glycol has also beenevaluated to reflect well the destruction of the intestinalmucosal barrier function following graft rejection.13

These low-molecular-weight chemical substances crossover the destroyed mucosal barrier following graft re-jection and flow into the systemic circulation. They areexcreted in the urine by the glomerular clearance of thekidney. Therefore, these permeability function testsmight be affected by a host’s renal function and may notaccurately reflect the epithelial distortion of trans-planted grafts.

Absorption tests using physiological nutrients, suchas carbohydrates,14 have been reported to remain in thenormal ranges until a significant portion of the graftepithelium has been lost. Prior to intestinal transplanta-tion, a clinical examination is carried out to evaluate thefunction of the transplanted intestine, using the d-xylose absorption test. However, no mention has beenmade about whether this method can be used to detectgraft rejection.15 In experimental SBTX, Murase et al.have reported that maltose absorption was maintaineddespite gross anatomic distortion.16 Therefore, the ab-sorptive functional assays may not detect impending orearly rejection when minimal morphological changeshave occurred.

We recently reported that the AC absorption of atransplant graft suddenly decreased in relation to themild histological changes that occur with graft rejec-tion and demonstrated that this test would be a use-ful marker for the early detection of graft rejection,in a heterotopic small bowel transplant model using

randomly bred rat strains (Wistar-to-Wistar).2 p-Acetaminophen, which has a molecular weight of151.17, is available as an antipyretic and analgesic agent,and has few generalized side effects in its presenteddosage. This chemical substance is absorbed by passivetransport from the gastrointestinal tract, where the mostefficient uptake occurs in the intestine and the leastefficient, in the stomach.17 Based on these features, AChas been used as an effective method for evaluatinggastric emptying.6 In the present study, AC was ad-ministered into the stomach to assess the feasibility oforal administration. We also examined the influenceof tacrolimus as an immunosuppressive agent withconsideration of future clinical application.

In our previous study, 10-cm BN allogenic smallbowel transplant grafts showed severe signs of acuterejection in LEW recipients and all the recipients notgiven immunosuppressants died from peritonitis within6 PODs. Furthermore, tacrolimus at a single dose of0.5 mg/kg per day given for 4 days from the day ofoperation until POD 3 could not protect against acuterejection of the allogenic small bowel graft on POD 7,although it did significantly prolong the recipient’s sur-vival.18 On the basis of these results, we administeredtacrolimus to orthotopic SBTX recipients at a singledose of either 0.1 mg/kg per day or 0.5mg/kg per dayfrom the day of operation until POD 6 to protect againstlethal rejection in the present study. In clinical smallbowel transplantation, tacrolimus has recently becomeavailable as an immunosuppressive agent to protectagainst the progression of graft rejection, and manystudies have reported its efficacy.1,5,14,15 In the presentstudy the syngeneic (LEW-to-LEW) transplant graftsshowed no sign of graft rejection. This study alsoshowed that tacrolimus given at a single dose of 0.5mg/kg BW per day had the beneficial effect of protectingagainst allogenic (BN-to-LEW) graft rejection. Con-versely, tacrolimus given at a single dose of 0.1 mg/kgcould not reduce the progression of allo BN small bowelgraft rejection in Lewis recipients. On POD 1, samplesof the graft showed no evident sign of acute rejection.However, by POD 3, four grafts showed Phase II histol-ogy (moderate) and one graft showed Phase III histol-ogy (severe); then by POD 7, four grafts showed PhaseIII histology and one graft showed Phase II histology(moderate). Interestingly, the Phase III rejection (se-vere) showed a patchy distribution. We previously ex-amined the relationship between an abrupt decrease inserum AC levels and the moderate histological changeson POD 3 following heterotopic SBTX, using randomlybred rats.2 Similarly, in the present study, serum AClevels decreased significantly in accordance with theprogression of graft rejection from normal to moderatechanges. The serum AC levels in the syngeneic SBTXgroup showed high levels and no significant change dur-

700 T. Miyauchi et al.: Acetaminophen Absorption Test

ing the experimental period. No significant difference inserum AC levels was seen on any experimental day inthe extended small bowel resection, syngeneic SBTX,and allo SBTX groups given tacrolimus at a dose of0.5mg/kg per day. We believe that allo SBTX graftswould have similar AC absorption to syngeneic SBTXgrafts. The serum AC levels in the rats subjected toextended small bowel resection were significantlyhigher than those in rats given a sham operation duringthe experimental period. This finding was not studiedfurther. Nylander previously reported that in cases ofmassive distal resection of the small intestine, gastricevacuation was more effective than that in intact con-trols, the course of gastric emptying being relativelyfaster.19 Furthermore, Tanaka et al. recently speculatedthat AC should be absorbed well from the intestinedistal to Treiz ligament, but poorly from the duode-num.20 This suggests that extended small bowel resec-tion would increase the absorption of AC from thebrush-border membrane of the remnant intestine withacceleration of gastric emptying. We also believe thatthis AC absorption test would reflect the function of theAC absorption in the transplant grafts, because in thisstudy the length of the remaining small bowel in therecipients was only 4 cm, comprised of 2cm proximaljejunum and 2 cm distal ileum.

In conclusion, the AC absorption test accurately re-flected the progression of graft rejection in orthotopicrat small bowel transplantation because the decrease inserum AC levels correlated well with the progression ofgraft rejection from normal to Phase II (moderate) his-tology, which partially involved the patchy distributionof phase III histology. In this study, the features of thegraft rejection also showed patchy distribution, as previ-ously described by other authors.2,11 The results of thisstudy suggest that this chemical marker would be usefulfor the early detection of progressive graft rejection,and could possibly protect against complete graft de-struction in practical SBTX when effective rescuetherapy is performed. However, it should be borne inmind that serum AC levels might be affected by gastricemptying or the mobility of transplant grafts. There-fore, further studies are urgently required to clarifythese points.

Acknowledgment. The subject matter of this paper waspresented at the 37th World Congress of the InternationalSociety of Surgery, in Acapulco, Mexico, August 24–30, 1997.

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