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. 2004 Oct;45(10):831–837.

Evaluation of oxidative stress markers for the early diagnosis of allograft rejection in feline renal allotransplant recipients with normal renal function

Krista B Halling 1, Gary W Ellison 1, Don Armstrong 1, Kasumi Aoyagi 1, Carol J Detrisac 1, John P Graham 1, Susan P Newell 1, Frank G Martin 1, James M Van Gilder 1
PMCID: PMC545987  PMID: 15532882

Abstract

The purpose of this study was to identify oxidative damage to renal allografts during graft rejection by evaluating changes in oxidative markers and plasma lactate levels in feline renal allotransplant recipients. Heterotopic renal allotransplantations were performed between 8 adult feline cross-matched donors. Following 14 d of immunosuppression, the drugs were discontinued to allow allograft rejection. Baseline and serial postoperative evaluations of serum creatinine, plasma lactate, plasma thiobarbituate reactive substances (TBARS), plasma creatol, urine creatol, and renal sonographic cross-sectional area were performed. When sonographic evaluation revealed the absence of blood flow to the allograft, the rejected kidney was nephrectomized and evaluated histopathologically. Allograft rejection occurred in all cats by day 26. A significant elevation in body temperature occurred during the rejection period. No significant change was observed between any of the time periods for plasma TBARS, creatol, or urine creatol. There was a significant decrease in plasma lactate levels throughout the study. Markers of oxidative stress from venous blood did not reflect renal allograft rejection in cats with a normally functioning native kidney. Renal allograft rejection may be associated with significant increases in body temperature and warrants further investigation.

Introduction

Chronic renal failure (CRF) is a progressive and potentially fatal disease commonly affecting adult cats. Medical therapy for CRF includes parenteral fluid administration in combination with protein-restricted diets or, more recently, hemodialysis. However, fluid therapy per se does not serve to reverse the progression of renal failure and its associated morbidity. Hemodialysis is not currently a practical means of long-term management of feline CRF due to the paucity of veterinary centres offering this therapeutic modality. Feline renal allotransplantation has become an accepted means of treating cats with chronic renal failure that is unresponsive to medical therapy (1). When successful, a renal allograft may offer the recipient an improved quality of life and extended lifespan (1). Mean and median survival times of 12 and 15 mo in cats following renal transplantation are reported, with long-term survival times as long as 8 y (1–4).

The long-term prognosis of a kidney transplantation patient is highly dependent on recipient acceptance of the allograft. Rejection of the donor kidney is a common complication, with reported frequencies in cats ranging from 9% to 18% (2–4). Rejection is initiated by both cellular and humoral immunity against antigens in the allograft. The histologic changes associated with renal allograft rejection are characterized by lymphocytic and mononuclear infiltration and smooth muscle proliferation in the intima of arteries in the donor kidney (5). These cellular infiltrations result in gradual occlusion of the arteries, causing renal ischemia and failure of the graft. Similar histologic findings have been reported with chronic renal allograft rejection in rat, canine, and human recipients (5–10). Methods to prevent allograft rejection in dog, cat, and human renal transplantation recipients typically include combination immunosuppression regimens of cyclosporine and prednisone (11–13). However, despite these pharmaceutical attempts to inhibit the recipient’s immune response to the allograft, chronic graft rejection still poses a significant threat to graft survival in both veterinary and human patients.

Failure to identify early graft rejection may result in the irretrievable loss of the organ and damage to the graft may be substantial prior to the onset of clinical and biochemical abnormalities. There is currently no single clinical, biochemical, or diagnostic imaging test to diagnose renal allograft rejection or to differentiate rejection from other disease processes of the allograft, such as acute tubular necrosis, cyclosporine nephrotoxicity, pyelonephritis, or thrombosis. In humans, the status of renal allografts is determined by the collective results of 3 tests: scintigraphic, sonographic, and histopathologic evaluations (14–19). However, recent research on the exact mechanism of organ rejection in human renal transplant patients incriminates the production of free radicals and subsequent oxidative cellular injury to the allografted organ (20–26). This damage may be associated with both posttransplant graft ischemia and acute or chronic graft rejection (27–30). Therefore, early determination of oxidative damage to the donated kidney may serve to identify early organ rejection and, consequently, enable early therapeutic intervention with immuno-modulation and antioxidants (20–22,28,31–37).

Creatol, a newly discovered precursor of the uremic toxin methylguanidine, is produced exclusively from creatinine in the presence of hydroxyl radicals (23,38–41). Current studies in humans and rats that evaluate the biochemical processes occurring within the kidney during oxidative stress have demonstrated a positive correlation between serum creatol levels and oxidative damage (38–44). This relationship, therefore, suggests a possible mechanism of oxidative injury and renal graft rejection in cats. Creatol has been shown in humans and in rats to be specific for oxidative injury in the kidney (23,38–40,43), but it has not yet been evaluated as such in the cat. While thiobarbituate reactive substances (TBARS) are an accepted and very sensitive measurement of oxidative stress, their specificity for a particular organ system is poor (32). The authors, therefore, decided to obtain TBARS measurements concurrently with creatol to document oxidative injury.

Plasma lactate levels have been measured in humans and dogs, as a means of evaluating tissue hypoxia (45–48). Conditions of hypoxia or subphysiologic tissue perfusion result in a conversion from aerobic to anaerobic metabolism and secondary lactic acid production. The accumulated lactic acid further dissociates into lactate and hydrogen ions, resulting in hyperlactemia. Therefore, plasma lactate levels, while not specific for oxidative damage, may reflect early changes in allograft perfusion during the rejection period.

The objectives of this prospective study were to 1) identify oxidative damage to renal allografts during graft rejection by evaluating changes in oxidative markers (plasma creatol and TBARS) and plasma lactate, and 2) assess the effectiveness of these oxidative markers as early indicators of renal allograft rejection in cats. Renal allograft rejection was determined by monitoring changes in serum biochemical values, renal cross-sectional area, renal blood flow, and renal histopathologic characteristics in feline renal transplant recipients.

Materials and methods

Eight specific pathogen-free, intact, adult male cats, weighing between 4 and 5 kg, were used in this study. The cats were evaluated for major and minor whole blood compatibility to identify 4 blood-compatible pairs of cats. The cats had no detectable abnormalities on preoperative physical examination, complete blood (cell) count (CBC), and serum biochemical and urine analysis. Baseline values for plasma creatol, TBARS, and lactate were obtained, and abdominal ultrasonographs and renal biopsies were performed, prior to the allotransplantation.

The left and right kidneys of all cats were sonographically evaluated preoperatively to identify any aberrant renal vessels and to enable the following measurements to be made: kidney depth, width, and circumference; width of the renal pelvis; and kidney cross sectional area at the level of the renal pelvis. The renal artery and vein were evaluated for abnormalities such as duplication or intraluminal filling defects (thrombus formation). Color flow Doppler imaging was used to assess the arcuate arteries for normalcy.

Ultrasonic-guided biopsy specimens for histologic examination were obtained from the left and right kidney preoperatively (day -7) and from the left kidney on day 14 for evaluation of rejection, using an 18-gauge biopsy instrument (Tru-Cut Biopsy Needle; Allegiance Healthcare, McGaw Park, Illinois, USA). Histopathological evaluation was also performed following surgical removal of the rejected allograft. The biopsy samples were fixed in 10% formalin prior to processing. Each biopsy specimen was evaluated for the presence of changes consistent with renal graft rejection; namely, interstitial inflammation, interstitial fibrosis, interstitial edema, hemorrhage, necrosis, vascular changes (thrombosis), or glomerular lesions (membranoproliferative changes or atrophy) (5–10).

Each cat in each blood-cross-matched compatible pair served as both a kidney donor and a kidney recipient. While the donor (left) kidney was being harvested from 1 cat, the recipient site in the paired cat was being prepared, such that the allograft was subjected to less than 40 min of warm ischemia time between cats. Once one kidney was transplanted, the left kidney of the paired cat was similarly prepared to be transplanted into the first cat. In short, each pair of cats exchanged their left kidney with the other cat in the pair, as described. The cats were premedicated with acepromazine (generic), 0.02 mg/kg body weight (BM), IM, and ketamine hydrochloride (Ketaset; Fort Dodge, Overland Park, Kansas, USA), 5 mg/kg BW, IM, induced with thiopental sodium (Pentothal Sterile Powder; Abbott, Abbott Park, Illinois, USA), 5 mg/kg BW, IV, and maintained on halothane inhalant anaesthetic for a unilateral nephrectomy and heterotopic renal transplantation of the left kidney (day 0). All surgeries were performed by a board-certified surgeon (GWE) experienced in feline renal transplantation. A routine ventral midline laparotomy was performed to expose the left external iliac artery and vein, which were then prepared as the recipient sites, according to the previously described technique (3,4). With the use of an operating microscope, the arterial and venous anastomoses were performed by using 1.5-mm and 2.5-mm microanastomotic devices (Precise microvasular anastomotic system; Medical Companies Alliance, Park City, Utah, USA), respectively, according to a previously described end-to-end renal artery-toexternal iliac artery and renal vein-to-external iliac vein technique (3,4). The ureter was anastomosed to the bladder with 7-0 polydioxanone (PDS-II; Ethicon, Somerville, New Jersey, USA) by using a previously described spatulated mucosal apposition technique (49). Warm ischemia time was recorded from the time of renal arterial occlusion until renal arterial and venous perfusion was reestablished. For all surgeries, the ischemia time was limited to 40 min.

To maximize allograft perfusion, mannitol (Mannitol; The Butler Company, Dublin, Ohio, USA), 1 g/kg BW, IV, was administered once; and to prevent thrombus formation, sodium heparin (generic), 100 IU/kg BW, SC, loading dose, followed by 60 IU/kg BW, SC, q12h for 48 h, was administered perioperatively. For 24 h post operatively, cefazolin sodium (Kefzol; Lilly, Indianapolis, Indiana, USA), 22 mg/kg BW, IV, q6h, was administered as an antimicrobial and buprenorphine hydrochloride (Buprenex; Reckett and Colman Pharmaceuticals, Richmond, Virginia, USA), 0.02 mg/kg BW, SQ, q6h, was administered for analgesia.

To prevent rejection of the allografts, immunosuppressive doses of cyclosporine (Neoral Oral Solution; Novartis Pharmaceuticals, East Hanover, New Jersey, USA), 5.0 to 7.5 mg/kg BW, PO, q12h, and prednisolone (generic), 1 mg/kg BW, PO, q24h, were administered on the day of surgery and continued for 14 d (1–4,11–13). Trough blood levels of cyclosporine were maintained between 350 and 500 ng/mL (1), by measuring trough serum cyclosporine levels every 2 to 4 d and adjusting individual doses accordingly. On day 14, the cyclosporine and prednisolone were discontinued to allow allograft rejection.

Postoperatively, daily monitoring of rectal body temperature, heart rate, and respiratory rate was performed. Serum creatinine, plasma lactate, plasma TBARS, and plasma creatol were measured on days -7 and +3, 7, 10, 14, 16, 18, 20, 22, 24, and 26. After initiation of the study, the authors elected to obtain urine samples to compare the levels of creatol in serum with those in urine. The creatol levels were determined from frozen plasma or urine samples deproteinized by the addition of trichloroacetic acid, as previously described (38,39,42,44). Sonographic measurements of renal cross-sectional area were performed at days -7 and +3, 7, 10, 14, 16, 18, 20, 22, 24, and 26. When sonographic and Doppler evaluation revealed the absence of blood flow to the allograft or a 20% increase in renal cross-sectional area, the rejected kidney was nephrectomized and the allograft was submitted for histopathologic evaluation. The protocol for preanaesthesia, induction, maintenance, and postoperative analgesia for the nephrectomies was similar to that described for the transplantation procedure.

Analysis of variance (ANOVA) and student’s t-test were used to evaluate significant changes in serum creatinine, plasma creatol, plasma TBARS, and plasma lactate, and urine creatol throughout the study period. Regression analysis was performed by using a commercial computer software program (SAS Statistical Software, Cary, North Carolina, USA) to identify significant differences in the parameters above during the rejection period. For all analyses, statistical significance was defined as P < 0.05.

This study was approved by the University of Florida Institutional Animal Care and Use Committee (IACUC #8682). All cats were cared for according to IACUC standards and guidelines and were adopted to private individuals upon conclusion of the study.

Results

For the purpose of statistical analysis, the study was divided into the following 3 time periods: preoperative (pre) (day -7), postoperative period during immunosuppressive drug administration (post) (day 1 to 14), and final rejection period (rejection) (day 16 until removal of rejected kidney).

Complete rejection and subsequent removal of the allografts occurred in all cats between day 21 and 26 (mean: day 23.3; median: day 23). One cat developed an acute thrombus of the renal artery at the anastomosis site on day 3, with subsequent loss of the allograft. A nephrectomy was performed and this cat’s data were excluded from the study. At the end of the immunosuppressive period (day 14), biopsy samples of the allografts ranged from no pathological changes to a mild interstitial inflammation. At the conclusion of the study, all kidneys had microscopic evidence of arteritis and interstitial inflammation. In addition, the interstitium in these kidneys was expanded by edema or, in regions of infarction, by acute hemorrhage. These changes are consistent with previously described lesions of graft rejection (5–10).

A significant (P < 0.001) increase in mean rectal body temperature was observed between the postoperative (38.9°C; sχ̄= 0.16) and rejection (39.7°C; sχ̄= 0.18) time periods (Figure 1). Six of the 7 cats (86%) had a body temperature exceeding 39.9°C during the rejection period. The observed pyrexia resolved in all affected cats within 2 d of the nephrectomy.

Figure 1.

Figure 1

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Bar graph demonstrating mean body temperatures in renal allotransplant cats during the preoperative, postoperative, and rejection time periods. Superscript letters indicate significant differences (P < 0.05) between values.

The results of serum creatinine, plasma creatol, TBARS, lactate, and urine creatol analyses are shown in Figures 2 to 6. For both urine creatol and plasma TBARS, only the postoperative and rejection periods were analyzed, since the urine sampling was initiated following the transplantation surgeries and the preoperative samples for TBARS were hemolyzed. As all samples were batched and analyzed simultaneously at the conclusion of the study, it was not possible to obtain additional samples from the preoperative period to repeat the TBARS assay. No significant changes in mean values for serum creatinine, plasma creatol (P = 0.24), plasma TBARS (P = 0.14), or urine creatol (P = 0.16) were identified between any of the time periods. A significant decrease (P < 0.001) was observed in the mean values for plasma lactate between both the preoperative (3.37 mmol/L; sχ̄= 0.36) and postoperative (1.90 mmol/L; sχ̄= 0.18) time periods and between the postoperative and rejection (1.27 mmol/L; sχ̄= 0.20) time periods (Figure 5).

Figure 2.

Figure 2

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Bar graph demonstrating mean levels for serum creatinine in renal allotransplant cats during the preoperative, postoperative, and rejection time periods. Superscript letters indicate significant differences (P < 0.05) between values.

Figure 6.

Figure 6

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Bar graph demonstrating mean levels for urine creatol (precursor of methylguanidine) in renal allotransplant cats during the preoperative, postoperative, and rejection time periods. Superscript letters within a row indicate significant differences (P < 0.05) between values.

Figure 5.

Figure 5

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Bar graph demonstrating mean levels for plasma lactate in renal allotransplant cats during the preoperative, postoperative, and rejection time periods. Superscript letters indicate significant differences (P < 0.05) between values.

Discussion

For all allografts in this study, sonographic and histopathologic evidence of rejection occurred within 7 to 12 d after cessation of immunosuppressive drugs (day 21 to 26). This time period is consistent with previous descriptions of the onset of acute kidney allograft rejection in humans and dogs (50,51). Criteria used in this study to identify complete rejection of the allograft (sonographic cessation of blood flow to the kidney or a 20% or greater increase over baseline in renal cross-sectional area) was based on previous reports demonstrating that these criteria accurately reflect the function and rejection status of kidney allografts (17,19,52). The evaluation of renal sonographic changes in humans has been associated with an 81% sensitivity for diagnosing acute graft rejection and an 88% predictive value of a positive test (17). Likewise, in the kidneys in the present study, acute allograft rejection was associated with sonographic increases in renal cross-sectional area (53). Ultrasonograph-guided renal biopsies were used in this study to qualify and confirm the time-dependant histological changes associated with allograft rejection, since they have been shown to have minimal morbidity or detrimental effects on renal function (54,55). The final histopathologic changes in all the kidneys were consistent with acute allograft rejection.

The significant elevations in body temperature observed in the cats during the rejection period likely reflected the inflammatory response and release of tissue pyrogens and cytokines that is associated with graft rejection (5–7). Given the immuno-suppressed status of the cats in this study, infection would be another differential diagnosis for the observed pyrexia. However, neither microorganisms nor suppurative inflammation was observed in any of the histopathologic samples. While CBCs or urine cultures were not repeated in the cats during allograft rejection, in the 6 cats that developed pyrexia in this study, the temperature elevations spontaneously resolved within 2 d of removal of the allograft. Although unexpected, the observed increase in body temperature during the rejection appears to be a significant finding, which may deserve further attention as a clinical indicator of acute renal allograft rejection in feline renal transplant recipients.

Contrary to the authors’ expectations, plasma lactate levels actually decreased continuously between each consecutive time period. In the early posttransplantation period and again during graft rejection, the kidney may experience decreased perfusion due to ischemia-reperfusion and inflammatory cell infiltration, respectively (5–7,10,21). Therefore, it is plausible that the lactate produced within the allograft during these episodes was sequestered within the kidney as a consequence of reduced venous outflow. Measured plasma lactate levels reflect the balance between lactate production and clearance. The kidney possesses 3 mechanisms for the metabolism of lactate: gluconeogenesis, oxidation, and excretion (1,47), and during conditions of hyperlactemia, increased amounts of lactate may be excreted into the urine (48). Furthermore, in a previous study evaluating urine biomarkers of renal autograft ischemia, lactate release in the urine was a reliable indicator of acute tubular necrosis and damage to proximal tubular metabolism (56). This considered, measurements of peripheral venous samples may provide a less sensitive reflection of changes in lactate levels than measurements of urine lactate. As a further consideration, the kidney does possess an intrinsic mechanism for the production of lactic acid (37), but it requires functional tubules for this metabolic role. The observed decreases in plasma lactate levels may possibly reflect loss of renal tubular integrity, resulting in an overall net reduction in lactate production, despite the accumulation of lactate expected due to decreased perfusion in graft rejection.

During the renal allograft rejections in this study, no significant elevation was observed in the oxidative marker creatol in the time period from preoperative to rejection. This again is in contrast to the authors’ hypothesis, based on the previous support of oxidative stress as a primary pathophysiological mechanism of graft rejection (20–26). Also, there was no significant change in both the plasma TBARS and the urine creatol measurements between the postoperative and rejection time periods. Although samples were batched prior to analysis, sample stability was, or considered to be a problem, since creatol and TBARS have been shown to be preserved successfully at −70°C for later high performance liquid chromatography (HPLC) analysis (38–43). Furthermore, creatol was detected in samples similarly assayed from 4 healthy pilot cats prior to initiation of this study.

Creatol is an intermediate molecule produced from creatinine under conditions of oxidative stress to the kidney. Creatol is then further converted to methylguanidine (MG). This 2nd reaction may occur quite rapidly, resulting in a very transient period during which the elevations in creatol can be detected (40,41). Therefore, it must be considered that this reaction may occur rapidly in the cat and that MG might be a more stable molecule and thus a more appropriate, albeit indirect, marker of oxidative damage during feline renal allograft rejection.

Another consideration for the lack of elevation in oxidative stress markers is that many of the previous studies supporting oxidative damage during allograft rejection (20–26) or the protective role of antioxidants in rejection (20–22,31–37) have been in human renal transplant recipients. In these patients, a functional native kidney has typically not been present. Our study was not a terminal one and, as such, all the cats maintained a contralateral native kidney. The potential effect of this functional kidney on peripheral venous sampling of oxidative markers must be considered. The kidney possesses intrinsic antioxidant capabilities (37), and it is certainly reasonable to postulate that the native kidney was effective in excreting or scavenging some of the creatol, creatinine, or TBARS that were being produced by the rejected allograft. This effect could be further investigated by a similar study in which the model is a bilaterally nephrectomized feline allotransplant model or where blood sampling is obtained directly from the renal vein of the allograft. Our results show that, in cats, measuring for creatinine or oxidative injury (creatol and TBARS) in blood samples obtained peripherally appears to be unreliable for the detection of renal allograft rejection.

A trend (P = 0.16) was observed for an elevation in urine creatol during the period of renal allograft rejection. The elevation was not statistically significant, but had baseline values been available, it might have been significant. While detectable in plasma, creatol is generally present in higher concentration in urine (38,39,42) and, while urine markers of rejection were not the principle focus of this study, the authors felt that concurrent urine measurements of creatol might be of interest. The inability to demonstrate increased creatol levels from the peripheral blood of the cats in this study suggests that urine may offer a more concentrated sample of creatol and be less influenced by the function of the native kidney.

In conclusion, our findings indicate that 1) serial evaluations of body temperature may be a sensitive method for the early detection of renal allograft rejection and thus deserve further attention as a clinical indicator of acute graft rejection in feline renal transplant recipients, and 2) peripheral venous markers of oxidative stress (TBARS, creatol) appear to be unreliable for the early detection of renal allograft rejection in cats with a normally functioning native kidney. Future studies evaluating urine samples for oxidative stress markers, such as creatol or MG, may represent a noninvasive and sensitive method of diagnosing renal allograft rejection and warrant further investigation. CVJ

Figure 3.

Figure 3

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Bar graph demonstrating mean levels for plasma creatol in renal allotransplant cats during the preoperative, postoperative, and rejection time periods. Superscript letters indicate significant differences (P < 0.05) between values.

Figure 4.

Figure 4

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Bar graph demonstrating mean levels for plasma thiobarbituate reactive substances (TBARS) in renal allotransplant cats during the preoperative, postoperative, and rejection time periods. Superscript letters indicate significant differences (P < 0.05) between values.

Footnotes

Dr. Halling’s current address is Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1.

Reprints will not be available from the authors.

Supported in part by the Morris Animal Foundation, the Resident Research Grant Competition, and the Mark S. Bloomberg Memorial Small Animal Surgery Resident Research Award.

Presented at the 11th Annual Symposium of the American College of Veterinary Surgeons, Chicago, Illinois, October 11, 2001.

College of Veterinary Medicine Journal Series Number 611.

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