Prevention of Acute Tubular Necrosis in Cadaveric Kidney Transplantation by the Combined Use of Mannitol and Moderate Hydration

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1 Prevention of Acute Tubular Necrosis in Cadaveric Kidney Transplantation by the Combined Use of Mannitol and Moderate Hydration ROLAND G. W. L. TIGGELER, M.D., JO H. M. BERDEN, M.D., ANDRIES J. HOITSMA, M.D., ROBERT A. P. KOENE, M.D. Recent studies have indicated that maximal hydration of the transplant recipient can substantially reduce the incidence of acute tubular necrosis (ATN). However, this policy requires invasive hemodynamic monitoring, prolonged mechanical ventilation, and bears the risk of overhydration. In a prospective trial we studied the incidence of ATN in recipients of cadaveric kidneys after restricted fluid infusion (Group 1, N = 21), after restricted fluid infusion along with 250 ml of mannitol 20% (Group 2, N = 19), and after a moderate hydration policy together with 250 ml mannitol 20% (Group 3; N = 21). Donorand preoperative recipient parameters were comparable in all three groups. The total amount of fluid administered and the incidence of ATN were as follows: Group ± 371 ml and 43%; Group ± 622 ml and 53%; and Group ± 675 ml and 4.8%. The moderate hydration policy in Group 3 resulted in a significantly higher peroperative systolic blood pressure compared to Groups 1 and 2. We did not observe any problems related to overhydration. The reduction of ATN incidence led to a substantial decrease in the number of hemodialysis treatments, radionuclide scans, ultrasound investigations, transplant biopsies, and rejection episodes in the first 3 months after transplantation. It is concluded that moderate fluid administration of 2.5 liters during the transplant procedure together with infusion of 250 ml of mannitol 20% immediately before vessel clamp release reduces the incidence of postoperative ATN below five per cent. The procedure is safe, simple, and does not require invasive hemodynamic monitoring. THE INCIDENCE OF postoperative acute tubular necrosis (ATN) after cadaveric kidney transplantation has been reported in the literature to vary from 30-60%. 1-4 There is controversy about the influence of ATN on the ultimate fate of the graft.47 In a recent analysis of 354 transplantations performed in our center, we found an incidence of ATN of 42% and a significant, negative influence on graft survival.8 Apart from its This study was supported by a grant from TNO Health Research ( ). Reprint requests: Roland G. Tiggeler, M.D., Division of Nephrology, St. Radboudziekenhuis, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Submitted for publication: June 28, From the Department of Nephrology, Sint Radboudziekenhuis, University of Nijmegen, Nijmegen, The Netherlands possible adverse effect on graft survival, it is important to prevent ATN because it hampers the diagnosis of early rejection, increases the necessity of diagnostic procedures (radionuclide scans, echography, and transplant biospies), and introduces dialysis-associated morbidity. Certain investigators claim that the use of the recently introduced immunosuppressive drug cyclosporine requires an immediate function of the graft.9 The hemodynamic condition of the donor prior to nephrectomy and the length of initial warm ischemia time have been considered major determinants in the development of ATN after surgery.' 01 However, a number of recent studies have indicated that the hemodynamic parameters of the recipient during the transplantation procedure are of even greater importance. Luciani et al.'2 and Carlier et al.'3 were able to reduce the incidence of ATN to 1 1% and six per cent, respectively, by maximal hydration of the recipient during the operation procedure. The fact that the hemodynamic condition of the recipient was much more important for the development of ATN than the hemodynamic parameters of the donor, the initial warm ischemia time, or the total ischemia time was further substantiated by an elegant study of Carlier et al.'4 They compared the incidence of ATN of paired kidneys from the same donor. One kidney was transplanted in their own center with maximal hydration, while the second kidney was transplanted with a conventional hydration policy in another center. The incidence of ATN after maximal hydration was 14.3% vs. 40.5% in the conventional treatment group (p < 0.01). However, maximal hydration has some major drawbacks. It requires invasive techniques to monitor pulmonary artery pressure, it makes intermittent positive pressure breathing during and after 246

2 Vol. 201 * No. 2 ANURIA AFTER KIDNEY TRANSPLANTATION 247 surgery necessary, and it puts the patient at risk for the artery pressure were not inserted; blood pressure was development of pulmonary edema. Therefore, this procedure introduces additional risks for the patient and device at intervals of 5 minutes. measured manually or with an automatic manometer makes patient management more complicated. After surgery, blood pressure was monitored every 15 Recently Weimar et al.'5 reported that reduction in minutes, urinary output and drain production every the incidence of ATN comparable to that with maximal hour. Because all patients received a ureteric catheter, hydration could be obtained by infusion of 250 ml urine produced by the graft could be distinguished from mannitol 20% immediately before vessel clamp release. residual diuresis of the patient. Vasopressive agents and We decided to conduct a prospective study in which we diuretics were not administered. Blood transfusions were compared the incidence of ATN in one group of transplant recipients treated with mannitol infusion and a than 500 ml. The numbers of patients who received given only if blood loss during the operation was greater second group in which moderate hydration was applied blood transfusions were comparable in the three groups: in addition to mannitol, without the necessity of pulmonary artery pressure monitoring and forced ventilation Group 2-14 patients (19 units); and Group 3-10 Group 1-10 patients ( 16 units of packed erythrocytes); after surgery. The results show that mannitol infusion patients (19 units). alone did not alter the incidence of ATN, while the combined treatment of mannitol and moderate hydration Hydration Policy reduced ATN to five per cent, a result that is comparable to those obtained with maximal hydration. Group 1 (21 patients) received a restricted fluid infusion regimen consisting of 500 ml glucose 5% and 500 Patients and Methods ml saline 0.9% during the operation and 1000 ml/24 Two consecutive groups of patients receiving a cadaveric transplant in our center were studied prospectively. Twenty-one consecutive patients who received a graft in the period immediately preceding the start of this study served as controls. The total number of 61 transplantations were done between June 1, 1982 and June 1, All grafts were flushed and preserved in icecold Euro-Collins solution. Recipients were selected with the help of the Eurotransplant Organization, Leiden, The Netherlands, according to their HLA-DR, -B, and -A compatibility. A negative T cell crossmatch was a prerequisite to transplantation. The preoperative management was the same in all patients. Immunosuppression was started before surgery with 50 mg prednisolone I.V. and azathioprine 3.0 mg/ kg body weight I.V. and continued as described previously.'6 Cyclosporine was not used. The patients received cimetidine prophylactically to prevent peptic complications.'" Antibiotics were given once before surgery: gentamycine 1.5 mg/kg I.M. and lincomycine 600 mg I.M.8 Hemodialysis was performed before surgery if the serum potassium level exceeded 5.0 mmol/l; postoperative hemodialysis was performed if serum potassium level was above 5.8 mmol/l or urea level exceeded 45 mmol/l. Premedication consisted of diazepam (10 mg) and droperidol (5 mg). Anesthesia was induced with thiopental (3-5 mg/kg) and suxamethonium (1-9 mg/kg) and maintained with a mixture of nitrous-oxide and oxygen with fractional doses of fentanyl, droperidol, and suxamethodium if needed. Catheters for monitoring blood pressure, central venous pressure, and pulmonary hours plus the amount of urinary output and drain production thereafter. This group served as the control and the applied fluid administration as indicative for our infusion policy before we started this study. Group 2 (19 patients) received a restricted fluid regimen similar to Group l's, but in addition 250 ml mannitol 20% was infused within 10 minutes immediately before vessel clamp removal. Group 3 (21 patients) received from the start of the operation a fluid load of 1000 ml saline and 500 ml glucose 5% followed by 250 ml mannitol 20% in the last 10 minutes before the opening of the vascular anastomosis. Thereafter 500 ml saline and 500 ml glucose were given until the end of the operation. If the systolic blood pressure dropped below 120 mmhg, either before or after clamp release, more fluid was given. After surgery, we administered glucose 5% and saline (in alternating volumes of 500 ml) at a rate of 100 ml/hr plus an amount to compensate for urine and drain production. The amount and rate of fluid administration were guided by the blood pressure and again efforts were made to keep systolic blood pressure at least at 120 mmhg. Two patients were excluded from this study. A 5-year-old child was excluded from Group 1 because of his low body weight of 13.5 kg, which required a different hydration policy. A patient with immediate postoperative diuresis but complete anuria after 16 hours due to renal artery thrombosis was excluded from Group 3. Acute tubular necrosis was considered to be present if the diuresis from the graft was less than 400 ml/24 hours, provided that the vascular anastomosis was patent

3 248 TIGGELER AND OTHERS Ann. Surg. * February 1985 TABLE 1. Comparison of Donor Parameters in the Three Groups Group 2 Group 3 Group I Restricted Fluid Moderate Hydration Restricted Fluid + Mannitol + Mannitol (N =21) (N =19) (N =21) Age (years) 27.8 ± ± ± 12.8 Systolic blood pressure (mmhg) 114 ± ± ± 22 Diastolic blood pressure (mmhg) ± 12 Warm ischemia time (min) 1.4 ± ± ± 4.1* Anastomosis time (min) 32.5 ± ± ± 7.3 Total ischemia time (hr) 32.8 ± ± ± 9.3 Diuresis (ml/last hr) 408 ± ± ± 430 Serum creatinine (umol/l) ± ± ± 29.6 HLA-AB match gradet ± ± 0.8 Number of DR mismatches 0.4 ± ± ± 0.5 * Significantly different in Group 3 vs. Group 1 (p < 0.01). t According to Festenstein et al.'" as judged by radionucleid scans, and in the absence of times, diuresis in the last hour before nephrectomy, hyperacute rejection or postrenal obstruction. Duration serum creatinine, and HLA match with the recipient of ATN was defined as the number of consecutive (Table 1). Only the initial warm ischemia time was postoperative days with a diuresis of the graft of less slightly but significantly longer in Group 3 compared than 400 ml/24 hours. Hemodialysis was required in with Group 1 but not longer than in Group 2. The most cases. The diagnosis of acute rejection was made parameters of the recipients before transplantation were according to standard criteria, (increase of serum creat- not significantly different in the three groups with regard inine, sodium retention, weight gain, hypertension, oli- to sex distribution, percentage of patients with lymphoguria, proteinuria, fever, and tenderness of the graft) cytotoxic antibodies, mean number of pretransplant after exclusion of prerenal or postrenal causes for the blood transfusions, number of patients treated with deterioration of graft function. Graft biopsies were only antihypertensive drugs, and systolic blood pressure (Table done when second rejection episodes occurred or if we 2). The mean age of Group 1 was lower than in Group had difficulty in distinguishing acute rejection from 2 while diastolic blood pressure was slightly higher. ongoing ATN. All values are expressed as means ± stan- The incidence of ATN in Groups 1 and 2 was as high dard deviations; statistical analysis was done with the as 43% and 53%, respectively, (Table 3) and comparable two-tailed Student's t-test for the means and the chi to the incidence of ATN in an earlier analysis of our square test for the percentages. Probability values below transplantation results.8 The mean duration. of ATN 0.05 were considered significantly different. was equal in Groups 1 and 2 and lasted for 6 days. By contrast, the incidence in Group 3 was only 4.8% (only one Results patient with ATN during 1 day). This difference is highly significant when compared to the incidence of The data of the donors were comparable among the ATN in Groups 1 and 2. Patients in Group 3 received three groups with regard to age, blood pressure, ischemia twice as much fluid as those in Groups 1 and 2, TABLE 2. Recipient Parameters in the Three Groups Before Transplantation Group I Group 2 Group 3 (N =21) (N =19) (N =21) Age (years) * Sex ratio (M/F) 9/12 13/6 13/8 Percentage of patients with antilymphocyte antibodiest Mean number of blood transfusions 5.5 ± ± ± 3.2 Number of patients with antihypertensive treatment Systolic blood pressure (mmhg) 156 ± ± ± 23 Diastolic blood pressure (mmhg) 96 ± ± 13t 91 ± 11 * Significantly different in Group I vs. Group 2 (p < 0.05). t Scored as positive if at least in one test prior to transplantation the serum showed a positive reaction with 30% of the test panel lymphocytes.

4 Vol. 201 * No. 2 ANURIA AFTER KIDNEY TRANSPLANTATION 249 TABLE 3. Results of the Three Different Hydration Policies Group 2 Group 3 Group I Restricted Fluid Moderate Hydration Restricted Fluid + Mannitol + Mannitol (N = 21) (N = 19) (N = 21) Number and (percentage) of patients with ATN 9 (43%) 10 (53%) 1 (4.8%)* Duration of ATN (days) 6.6 ± ± 3.4 1* Fluid load during operation per kg body weight (ml/kg) 19.0 ± ± ± 15.2* Total amount of administered fluid during operation (ml) 1059 ± ± ± 675* Change in body weight before and after transplantation (A%) Systolic blood pressure during operation (mmhg)t 124 ± ± ± 20* Diastolic blood pressure during operation (mmhg)t 75 ± ± 9 79 ± 12 Systolic blood pressure after surgery (mmhg)t 144 ± ± ± 28 Diastolic blood pressure after surgery (mmhg)t 82 ± ± ± 12 Diuresis during first 24 hours after transplantation in patients without ATN (ml/hr) 60 ± ± ± 67 * Significantly different from Groups 1 and 2. t Mean value of eight measurements during the first 2 hours after t Mean value of all measurements during anesthesia (5-minute in- transplantation (15-minute intervals). tervals). Significantly different from group 1. although, due to the immediate postoperative diuresis, tended to have higher diuresis per hour than the patients this resulted in only a subtle change of body weight. with immediate function in Group 1 (Table 3). This illustrates that our hydration policy is not hazardous Aside from the beneficial influence on eventual graft to the patient, which is further substantiated by the fact outcome, reduction of ATN incidence considerably fathat we did not observe any problems related to over- cilitated patient management after the operation (as is hydration. The major hallmark of the moderate hydra- demonstrated in Table 4). It led to a substantial decrease tion policy in Group 3 was a significantly higher systolic in the number of hemodialysis treatments, radionucleid blood pressure at the moment of vessel clamp removal. scans, and ultrasound investigations. Also, the number Peroperative diastolic blood pressures and postoperative of potentially hazardous hyperkalemic episodes was systolic and diastolic blood pressures were not different drastically reduced in Group 3. In Groups 1 and 2 we among the three groups. However, if we compared the had to perform a transplant biopsy in approximately lowest measured systolic blood pressure between the 30% of the patients, while this was not necessary in any start of mannitol infusion and the end of the operation of the Group 3 patients. The fact that the percentage of we found in Group 2 a significantly lower systolic blood patients in Group 3 who did not experience a rejection pressure in patients with ATN (105 ± 14 mmhg) than episode in the first 3 months was significantly higher in patients without ATN (123 ± 19 mmhg, p = 0.03). than in Group 1 is somewhat puzzling, especially since Such differences were not observed in Groups 1 or 3. the difference between Groups 2 and 3 was not signifi- Although mannitol infusion without further hydration cant. The incidence of urinary, pulmonary, or cytomeg- (Group 2) did not decrease the incidence of ATN, the alovirus infections was the same among the patients of patients of this group who showed immediate function the three groups. TABLE 4. Effects ofa TN on Postoperative Management Group 2 Group 3 Group I Restricted Fluid Moderate Hydration Restricted Fluid + Mannitol + Mannitol (N = 2 1) (N = 19) (N = 2 1) Number of hemodialysis treatments after transplantation * Number of radionucleic scans * Number of ultrasound investigations 5 1 t Percentage of patients with hyperkalemiat * Percentage of patients without rejection in first 3 months t Percentage of patients with transplant biopsies in first 3 months * Mean serum creatinine at 3 months (Amol/l) 99.7 ± ± ± 25.1 * Significantly different from Groups I and 2. t Significantly different from Group 1. t Potassium level > 5.8 mmol/l; requiring hemodialysis.

5 250 TIGGELER AND OTHERS Ann. Surg. February 1985 Discussion Conclusion This study shows that a moderate hydration policy of The advantages of a low incidence of post-transplant the recipient together with infusion of mannitol during ATN are obvious. The necessity for several diagnostic the transplantation procedure can substantially reduce the incidence of post-transplant ATN. Avoiding ATN has, at least in our experience, a beneficial effect on graft survival and facilitates patient management after surgery. The reduction of ATN incidence that could be achieved with this approch is comparable to the results of other investigators who used maximal hydration with administration of more than 5 liters of fluid, consisting of electrolyte solutions, plasma proteins, and packed red cells.'2"3 This latter regimen, however, required hemodynamic monitoring, intermittent positive pressure breathing during the operation, and mechanical ventilation after surgery. Our hydration regimen, while circumventing these techniques with their potential risks, is not associated with problems due to overhydration. The second conclusion that can be drawn from this study is that infusion with mannitol alone without additional hydration does not alter the incidence of ATN, and this is in obvious contrast with the experience of Weimar et al.' in their controlled study. The explanation for the fact that mannitol is only effective in moderately hydrated recipients may be found in the hemodynamic actions of mannitol. It induces an increase in intravascular volume due to an increased osmotic pressure gradient, as well as a systemic and renal afferent arteriolar vasodilation.'9-22 The vasodilatory effect probably outweighs the increase of intravascular volume. This is supported by our observation that those patients in Group 2 who developed ATN had a significantly lower systolic blood pressure after mannitol infusion. Therefore, it seems that the preventive effect of mannitol on post-transplant anuria can only be achieved when, along with mannitol, a fluid load is given to compensate for the mannitol-induced systemic vasodilation. Systolic blood pressure is a simple parameter for monitoring the fluid administration. In our experience, efforts should be directed to keep it at 140 mmhg at the moment of clamp release and during the first hours thereafter. Recently, it has been found that the administration of furosemide during the operation is not essential for the prevention of ATN.23 Our results confirm this observation, since none of our patients received this drug. Our study does not rule out the possibility that moderate hydration alone without infusion of mannitol is equally effective. Another controlled randomly allocated study would be necessary to elucidate this point, which is in our opinion mainly of academic interest since the infusion of mannitol immediately before clamp release is a simple maneuver with no risk to the patient. and therapeutic interventions decreased considerably, with a concomitant decrease in the risks and cost of the treatment. Furthermore, initial dietary restrictions are no longer needed and the immediate diuresis after transplantation has a beneficial effect on the mental condition of the patient. We found that a moderate hydration regimen during operation with 2 to 2.5 liters of fluid, along with infusion of 250 ml of mannitol 20% just before clamp release will reduce the incidence of post-transplant ATN to less than five per cent. Special attention should be given to keep the systolic blood pressure at 140 mmhg at the moment of revascularization of the graft. Acknowledgments The cooperation of the staff members of the Departments of Anesthesiology (head: Professor Dr. J. Crul), Vascular Surgery (head: Professor Dr. S. H. Skotnicki), and Urology (head: Professor Dr. F. M. J. Debruyne) is gratefully acknowledged. References 1. Kjellstrand CM, Casali RE, Simmons RL, et al. Etiology and prognosis in acute post-transplant renal failure. Am J Med 1976; 61: Flanigan WJ, Ardon LF, Brewer TE, Caldwell FT. Etiology and diagnosis of early post-transplant oliguria. Am J Surg 1976; 132: Anderson CB, Etheredge EE. Human renal allograft blood flow and early renal function. Ann Surg 1977; 186: Brophy D, Najarian JS, Kjellstrand CM. Acute tubular necrosis after renal transplantation. Transplantation 1980; 29: Cho SI, Bradley JW, Nabseth DC, et al. Significant factors in immediate outcome of cadaver kidney transplants. Surg Forum 1976; 37: Anderson CB, Sicard GA, Haid SD, Etheredge EE. Cadaver kidney characteristics and immediate renal allograft function. Proc Clin Dial Transplant Forum 1977; 7: Opelz G, Sasaki N, Terasaki PI. Prediction of long-term kidney transplant survival rates by monitoring early graft function and clinical grades. Transplantation 1978; 25: Berden JHM, Hoitsma AJ, Buys WCAM, et al. Results of kidney transplantations in Nijmegen ( ). Neth J Med 1982; 25: European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multi-centre trial. Lancet 1983; II: Grundman R, Kammerer B, Franke E, Pichlmaier H. Effect of hypotension on the results of kidney storage and the use of dopamine under these conditions. Transplantation 1981; 32: Grundmann R, Strumper R, Kursten K, et al. Nierenkonservierung nach Collins and Sacks: Der Einfluss von 0-30 min warmer ischamie auf die erreichbare konservierungszeit. Langenbecks Arch Chir 1978; 346: Luciani J, Frantz Ph, Thibault Ph, et al. Early anuria prevention in human kidney transplantation. Advantage of fluid load under pulmonary arterial pressure monitoring during surgical period. Transplantation 1979; 28:

6 Vol. 201 * No. 2 ANURIA AFTER KIDNEY TRANSPLANTATION Carlier M, Squifflet JP, Pirson Y, et al. Maximal hydration during anesthesia increases pulmonary arterial pressures and improves early function of human renal transplants. Transplantation 1982; 34: Carlier M, Squifflet JP, Pirson Y, et al. Confirmation of the crucial role of the recipients maximal hydration on early diuresis of the human cadaver renal allograft. Transplantation 1983; 36: Weimar W, Geerlings W, Bijnen AB, et al. A controlled study on the effect of mannitol on immediate renal function after cadaver donor kidney transplantation. Transplantation 1983; 35: Hoitsma AJ, Reekers P, Kreeftenberg JG, et al. Treatment of acute rejection of cadaveric renal allografts with rabbit antithymocyte globulin. Transplantation 1982; 33: Roermund HPC van, Tiggeler RGWL, Berden JHM, et al. Cimetidine prophylaxis after renal transplantation. Clin Nephrol 1982; 18: Festenstein H, Sachs JA, Paris ANI, et al. Influence of HLA matching and blood transfusion on outcome of 502 London Transplant Group renal graft recipients. Lancet 1976; 1: Jarberg PO. Acute effects of furosemide and mannitol on central hemodynamics in the early postoperative period. Acta Anesth Scand 1978; 22: Johnston PA, Bernard DP, Perrin NS, Levinsky NG. Prostaglandins mediate the vasodilatory effect of mannitol in the hypoperfused rat kidney. J Clin Invest 1981; 68: Powers SR, Shah D, Ryon D, et al. Hypertonic mannitol in the therapy of the acute respiratory distress syndrome. Ann Surg 1977; 185: Goldberg AH, Lelienfeld LS. Effects of hypertonic mannitol on renal vascular resistance. Proc Soc Exp Biol Med 1965; 199: Barry JM, Bennet WM. Failure of furosemide to reduce dialysis requirement after cadaver kidney transplantation. Dial Transplant 1980; 9: