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Factors predicting duration of delayed graft function in non-heart-beating donor kidney transplantation
Factors Predicting Duration of Delayed Graft Function in Non-Heart-Beating Donor Kidney Transplantation J. Asher, C. Wilson, M. Gok, S. Balupuri, A.A. Bhatti, N. Soomro, D. Rix, B. Jaques, D. Manas, B. Shenton, and D. Talbot ABSTRACT Non-heart-beating donors (NHBDs) are an important potential source of donor organs, but kidneys from such donors are prone to delayed graft function (DGF) and primary nonfunction, which are multifactorial in origin but believed to be mainly due to warm ischemic injury. This retrospective study examined a series of 88 transplants from Maastricht category II and III NHBDs to examine the role of factors to predict the duration of DGF. The main factors affecting duration of DGF were total warm ischemic time, cold ischemic time, product of perfusate GST concentration and donor age, quality of postoperative graft perfusion, incidence of acute rejection, recipient cardiovascular risk score, maximum pressure on machine perfusion, and weight gain during machine perfusion. Primary nonfunction was not accurately predicted from these factors for kidneys that had passed the viability assessment.
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ON-HEART-BEATING DONOR (NHBD) kidney transplants offer the opportunity to compensate for the growing discrepancy between supply and demand for donor kidneys.1,2 They have been shown to have the same survival and long-term function as kidneys from traditional brain-stem dead donors3 but are associated with a higher incidence of primary nonfunction and a higher incidence and duration of delayed graft function (DGF).4 These are probably due to the inevitable primary warm ischemic injury associated with NHBD, although other factors may play a role. We aimed to evaluate the possible factors predicting the duration of DGF because prolonged DGF has the potential to cause morbidity due to additional dialysis requirements and prolonged hospital stay, as well as psychological morbidity in patients who see nonfunction of their graft. We also anticipate that the factors associated with prolonged DGF may increase the incidence of primary nonfunction, thereby with a deleterious effect on graft survival. MATERIALS AND METHODS We reviewed our series of 88 consecutive Maastricht category II and III NHBD kidney transplants from 1998 to 2004 to analyze the impact of possible predictors of DGF duration. The collective role of these predictors was further evaluated using a multiple regression analysis model. The cut-off values or methods of grouping of the factors are shown in Table 1. 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.11.036 348
RESULTS
Factors individually predicting significant differences in duration of DGF included ideal DTPA perfusion (mean duration 9 vs 22 days, P ⫽ .015, MWU); incidence of acute rejection (8.6 vs 14 days, P ⫽ .003, Kruskal-Wallis test); product of GST and donor age (9.2 vs 28.1 days, P ⫽ .001, MWU); kidney weight gain on machine perfusion (9.2 vs 18.9 days, P ⫽ .018, MWU); maximum systolic pressure on machine perfusion (8.2 vs 17.4 days, P ⫽ .021, t test); recipient cardiovascular risk score (10.3 vs 21.0 days, P ⫽ .017, t test) and total warm ischemic time (8.4 vs 16.8 days, P ⫽ .042, t test). The multiple regression model demonstrated the difficulty of predicting the duration of DGF as the best model only achieved r2 ⫽ 0.493 (r ⫽ 0.702, P ⫽ .014; DurbinWatson statistic 1.901). The factors, in order of importance, were: DTPA perfusion scan score; product of perfusate From the Liver and Renal Transplant Unit, Freeman Hospital (J.A., C.W., M.G., S.B., A.A.B., N.S., D.R., B.J., D.M., D.T.), and Department of Surgery, University of Newcastle upon Tyne (J.A., C.W., B.S.), Newcastle upon Tyne, UK. Funded by Northern Counties Kidney Research Fund and the Newcastle upon Tyne Hospitals NHS Trust. Address reprint requests to Dr John Asher, Liver and Renal Transplant Unit, Freeman Hospital, Newcastle upon Tyne, United Kingdom. E-mail: [email protected] © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 348 –349 (2005)
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Table 1. Potential Factors and Their Grouping Factor
Grouping or Cut Point
1°, 2°, and total warm ischaemic time Cold ischemic time Perfusate GST level Perfusate GST level multiplied by donor age Maximum systolic pressure on machine perfusion Weight gain on machine perfusion Quality of graft perfusion on postoperative DTPA scan Incidence and severity of acute rejection Recipient’s cardiovascular risk score Perioperative fall in recipient’s hemoglobin Initial dose of tacrolimus and dose divided by body mass
Cut points: 30 minutes for 1° or 2°, 60 minutes for total WIT Various cut points tried from 8 to 24 hours, but no differences found Cut point of 200 IU/L per 100g renal mass (Maastricht protocol) Cut point of 10,000 IU years/L per 100 g (approximate mean ⫹ 1 S.D.) Cut point of 63 mm Hg (point of inflection) Cut point of 25% weight gain on preperfusion weight Two groups: good perfusion vs moderate/poor/no perfusion No rejection; steroid-responsive; steroid-resistant or multiple episodes Two groups with cut point of 12 (corresponding to high risk score) Various cut points tried from 4 to 8 g/dL but no differences found Various cut points used, no significant differences found
Abbreviations: WIT, warm ischemia time; IU, international units; SD, standard deviation.
GST and donor age; weight gain on machine perfusion; rejection score; maximum systolic pressure on machine perfusion; recipient cardiovascular risk score; cold ischemic time; total warm ischemic time; perioperative hemoglobin drop; and initial weight-adjusted tacrolimus dose. Surprisingly, the Maastricht category of the donor did not predict a significant difference in the duration of delayed graft function (13.4 ⫾ 12.0 days for category II, 9.9 ⫾ 16.8 days for category III, P ⫽ .288, 95% CI of difference ⫺3.0 to 10.0, t test). It did predict a higher risk of primary nonfunction, with a relative risk of 5.476, but this was not quite statistically significant (P ⫽ .0992, Fisher’s exact test), probably due to the small number of cases of primary nonfunction in this series (n ⫽ 6). No other pretransplant factors were significantly associated with primary nonfunction. DISCUSSION
Although the duration of DGF in NHBD kidney transplants is difficult to predict, certain factors help to identify patients at risk for a longer duration of DGF, allowing them to be counselled with greater accuracy. However, as our best multiple regression model only accounted for 49% of the variability in the duration of DGF, the greatest impact may be due to unknown factors that characterise NHBD
transplants, especially the uncontrolled (category II) donors. Based on this series, it was not possible to predict primary nonfunction, probably because the viability assessment performed in our centre, using machine perfusion characteristics5 and perfusate glutathione-S-transferase levels,6 excluded most kidneys that would have experienced primary nonfunction if they had been transplanted.
REFERENCES 1. Sanchez-Fructuoso AI, Prats D, Perez-Contin MJ, et al: Increasing the donor pool using en bloc pediatric kidneys for transplant. Transplantation 76:1180, 2003 2. Kootstra G, Wijnen R, van Hooff JP, et al: Twenty percent more kidneys through a non-heart beating program. Transplant Proc 23:910, 1991 3. Gok M, Buckley P, Shenton B, et al: Long-term renal function in kidneys from non-heart-beating donors: a single-center experience. Transplantation 74:664, 2002 4. Balupuri S, Buckley P, Snowden C, et al: The trouble with kidneys derived from the non heart beating donor: a single centre 10 year experience. Transplantation 69:842, 2000 5. Balupuri S, Strong A, Hoernich N, et al: Machine perfusion for kidneys: how to do it at minimal cost. Transplant Int 14:103, 2001 6. Kootstra G, Kievit J, Nederstigt A: Organ donors: heartbeating and non-heartbeating. World J Surg 26:181, 2002
N
ON-HEART-BEATING DONOR (NHBD) kidney transplants offer the opportunity to compensate for the growing discrepancy between supply and demand for donor kidneys.1,2 They have been shown to have the same survival and long-term function as kidneys from traditional brain-stem dead donors3 but are associated with a higher incidence of primary nonfunction and a higher incidence and duration of delayed graft function (DGF).4 These are probably due to the inevitable primary warm ischemic injury associated with NHBD, although other factors may play a role. We aimed to evaluate the possible factors predicting the duration of DGF because prolonged DGF has the potential to cause morbidity due to additional dialysis requirements and prolonged hospital stay, as well as psychological morbidity in patients who see nonfunction of their graft. We also anticipate that the factors associated with prolonged DGF may increase the incidence of primary nonfunction, thereby with a deleterious effect on graft survival. MATERIALS AND METHODS We reviewed our series of 88 consecutive Maastricht category II and III NHBD kidney transplants from 1998 to 2004 to analyze the impact of possible predictors of DGF duration. The collective role of these predictors was further evaluated using a multiple regression analysis model. The cut-off values or methods of grouping of the factors are shown in Table 1. 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.11.036 348
RESULTS
Factors individually predicting significant differences in duration of DGF included ideal DTPA perfusion (mean duration 9 vs 22 days, P ⫽ .015, MWU); incidence of acute rejection (8.6 vs 14 days, P ⫽ .003, Kruskal-Wallis test); product of GST and donor age (9.2 vs 28.1 days, P ⫽ .001, MWU); kidney weight gain on machine perfusion (9.2 vs 18.9 days, P ⫽ .018, MWU); maximum systolic pressure on machine perfusion (8.2 vs 17.4 days, P ⫽ .021, t test); recipient cardiovascular risk score (10.3 vs 21.0 days, P ⫽ .017, t test) and total warm ischemic time (8.4 vs 16.8 days, P ⫽ .042, t test). The multiple regression model demonstrated the difficulty of predicting the duration of DGF as the best model only achieved r2 ⫽ 0.493 (r ⫽ 0.702, P ⫽ .014; DurbinWatson statistic 1.901). The factors, in order of importance, were: DTPA perfusion scan score; product of perfusate From the Liver and Renal Transplant Unit, Freeman Hospital (J.A., C.W., M.G., S.B., A.A.B., N.S., D.R., B.J., D.M., D.T.), and Department of Surgery, University of Newcastle upon Tyne (J.A., C.W., B.S.), Newcastle upon Tyne, UK. Funded by Northern Counties Kidney Research Fund and the Newcastle upon Tyne Hospitals NHS Trust. Address reprint requests to Dr John Asher, Liver and Renal Transplant Unit, Freeman Hospital, Newcastle upon Tyne, United Kingdom. E-mail: [email protected] © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 348 –349 (2005)
PREDICTING DURATION OF DGF GRAFT FUNCTION
349
Table 1. Potential Factors and Their Grouping Factor
Grouping or Cut Point
1°, 2°, and total warm ischaemic time Cold ischemic time Perfusate GST level Perfusate GST level multiplied by donor age Maximum systolic pressure on machine perfusion Weight gain on machine perfusion Quality of graft perfusion on postoperative DTPA scan Incidence and severity of acute rejection Recipient’s cardiovascular risk score Perioperative fall in recipient’s hemoglobin Initial dose of tacrolimus and dose divided by body mass
Cut points: 30 minutes for 1° or 2°, 60 minutes for total WIT Various cut points tried from 8 to 24 hours, but no differences found Cut point of 200 IU/L per 100g renal mass (Maastricht protocol) Cut point of 10,000 IU years/L per 100 g (approximate mean ⫹ 1 S.D.) Cut point of 63 mm Hg (point of inflection) Cut point of 25% weight gain on preperfusion weight Two groups: good perfusion vs moderate/poor/no perfusion No rejection; steroid-responsive; steroid-resistant or multiple episodes Two groups with cut point of 12 (corresponding to high risk score) Various cut points tried from 4 to 8 g/dL but no differences found Various cut points used, no significant differences found
Abbreviations: WIT, warm ischemia time; IU, international units; SD, standard deviation.
GST and donor age; weight gain on machine perfusion; rejection score; maximum systolic pressure on machine perfusion; recipient cardiovascular risk score; cold ischemic time; total warm ischemic time; perioperative hemoglobin drop; and initial weight-adjusted tacrolimus dose. Surprisingly, the Maastricht category of the donor did not predict a significant difference in the duration of delayed graft function (13.4 ⫾ 12.0 days for category II, 9.9 ⫾ 16.8 days for category III, P ⫽ .288, 95% CI of difference ⫺3.0 to 10.0, t test). It did predict a higher risk of primary nonfunction, with a relative risk of 5.476, but this was not quite statistically significant (P ⫽ .0992, Fisher’s exact test), probably due to the small number of cases of primary nonfunction in this series (n ⫽ 6). No other pretransplant factors were significantly associated with primary nonfunction. DISCUSSION
Although the duration of DGF in NHBD kidney transplants is difficult to predict, certain factors help to identify patients at risk for a longer duration of DGF, allowing them to be counselled with greater accuracy. However, as our best multiple regression model only accounted for 49% of the variability in the duration of DGF, the greatest impact may be due to unknown factors that characterise NHBD
transplants, especially the uncontrolled (category II) donors. Based on this series, it was not possible to predict primary nonfunction, probably because the viability assessment performed in our centre, using machine perfusion characteristics5 and perfusate glutathione-S-transferase levels,6 excluded most kidneys that would have experienced primary nonfunction if they had been transplanted.
REFERENCES 1. Sanchez-Fructuoso AI, Prats D, Perez-Contin MJ, et al: Increasing the donor pool using en bloc pediatric kidneys for transplant. Transplantation 76:1180, 2003 2. Kootstra G, Wijnen R, van Hooff JP, et al: Twenty percent more kidneys through a non-heart beating program. Transplant Proc 23:910, 1991 3. Gok M, Buckley P, Shenton B, et al: Long-term renal function in kidneys from non-heart-beating donors: a single-center experience. Transplantation 74:664, 2002 4. Balupuri S, Buckley P, Snowden C, et al: The trouble with kidneys derived from the non heart beating donor: a single centre 10 year experience. Transplantation 69:842, 2000 5. Balupuri S, Strong A, Hoernich N, et al: Machine perfusion for kidneys: how to do it at minimal cost. Transplant Int 14:103, 2001 6. Kootstra G, Kievit J, Nederstigt A: Organ donors: heartbeating and non-heartbeating. World J Surg 26:181, 2002