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Clinical impact of delayed graft function for kidney transplantation
Clinical Impact of Delayed Graft Function for Kidney Transplantation j. Michael Cecka, Daniel A. Shoskes, and David W. Gjertson Approximately one quarter of cadaver kidneys transplanted in the US fails to function adequately to prevent the need for continued dialysis within the first week after transplantation. Patients who experience delayed graft function (DGF) spend more time in the hospital, are more difficult to manage medically, and often have poorer graft outcomes than those whose grafts function immediately. In the past, DGF has been regarded as a consequence of preservation and reperfusion injuries associated with the storage and transport of cadaver donor kidneys, which rarely are a factor in kidney transplants from living donors. However, it is now clear that DGF is affected by processes in the donor that occur during and after brain death, by immune injuries in the early posttransplant period, and by ischemia and reperfusion injuries. The health and age of the donor tissue also play important roles in the long-term survival of kidneys with DGF. As the transplant community focuses on understanding the limits of donor acceptability, DGF may serve as an important early marker for assessing the effectiveness of interventions to minimize damage to the donor tissue and for improving long-term success. In this report, we review some of the most important factors that are linked to DGF and relate their roles in either causing injury to the kidney or in affecting the degree of damage that results from the injury. Copyright © 2001 by W.B. Saunders Company
hen function of a transplanted kidney is de-
W layed or inadequate in the early period after transplantation, the consequences can be rather
grim. Based on analyses of data reported to the United Network for Organ Sharing (UNOS) Scientific Renal Transplant Registry for 34,647 cadaver kidney transplantations performed in the United States between 1994 and 1998, approximately 5% of the kidney grafts that do not function immediately will never function. Ten percent fail during the first month posttransplantation, and more than 20% are lost within 1 year. Even among those transplant recipients whose kidneys survive the first year, the
From the UnitedNelworkfor Organ Sharing ScientificRenal Transplant Regist9,, University of California at Los Angeles hnmunogeneties Center, Los Angeles, CA,"and the Department of Urologr, ClevelandClinic Florida, Fort Londerdale, FL. Supported in part through a subcontract with the United Netzwrk for Organ Sharing. Presented in part at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000. The opinions are thoseof the authorsand do not necessarib, reflectopinions or policies of the United Networkfor Organ Sharing. Address reprint requests to J. Michael Cecka, PkD, UNOS Scientific Renal Transplant Registry, UCLA Immunogenetics Center, Department of Pathology, 950 VeteranAve, Los Angeles, (24 90095. Copyright © 2001 by W.B.Saunders Company 0955-470X/01/1502-0006535.00/0 doi:l O.l O53/trre.2001.20807
rate of late graft loss is significantly greater when initial graft function was delayed. Half the kidneys that survive the first year subsequently fail within 7 years When graft function was delayed. That half-life can be compared with a half-life of nearly 12 years when the graft functioned immediately. Thus, delayed graft function (DGF) impacts on both early and long-term graft survival. Projected to 10 years, there is a 20% lower graft survival rate among transplant recipients with DGF (Fig 1). It has been estimated that as many as one third of the graft losses during the first 5 years among primary cadaver transplant recipients can be attributed to the influence of DGF. I DGF affects other clinical parameters after transplantation as well. The incidence of rejection episodes among patients with DGF is greater, 2 requiring additional immunosuppression, imaging studies, and biopsies. Hospital stays are longer, resulting in greater use of hospital resources: The cost of the transplantation increases when initial graft function is delayed.3,4 The incidence of DGF has changed very little during the past decade,5 even though improved immunosuppression has reduced the incidence of rejection episodes within the first 6 months from 55% to 22% during the same period. DGF affects approximately 1 of every 4 cadaver kidneys that are transplanted today.
Transplantation Reviews, Vol 15, No 2 (April), 2001: pp 57-67
57
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Years Posttransplant Figure 1. Effect of DGF on the long-term graft suta,ival rate ofcadaver donor renal transplants. The graft half-life (Tl/2) is the number of years until half the transplants that are still functioning at 1year ~dll fail. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.) In this review, we examine some of the factors associated with DGF and the clinical impact of DGF on the outcome of kidney transplants.
Risk Factors for Delayed Function DGF is the manifestation of what may be an extremely complex set of processes. In most cases, DGF reflects injury or damage to the kidney, but a host of factors may contribute to the injury or influence the extent of damage and the long-term consequences. Some factors associated with an increased incidence of DGF reflect the health of the donor kidney, such as advancing donor age, donor death by cerebrovascular accident, and prolonged cold ischemia time; others suggest immune damage in the early posttransplantation period, such as the presence of broadly reacting anti-HIA antibody or previous graft loss in the recipient. 1,2,c~-~ In multivariate analyses, these factors appear to contribute independently to the incidence of DGF. Other recipient risk factors have been identified as well, in-
cluding positive cytomegalovirus serologic test resuits I in the transplant recipient (or in the donor when the recipient's test result was negative), obesity or large size disparities between the donor and recipient,l° and type of pretransplantation dialysis. Jl Black transplant recipients are more likely than others to experience DGF. 1 D o n o r Factors As pressures mount to expand the limits of donor acceptability, the health of the donor kidney has become an important issue for transplant surgeons and physicians. Older and sicker potential cadaver donors are being considered, and this trend is reflected in an increasing discard rate for kidneys from 5% in 1992 to nearly 8% in 1997 (UNOS data cited inl2). Health of the donor kidney and functional renal mass, influenced by donor age, cause of donor death, and underlying disease, are among the most important factors that determine functional reserve after injury and, ultimately, the long-term success of the transplant. Moreover, renal injury can occur be-
Clinical Impact of DGF
fore transplantation, during or shortly after brain death, and on reperfusion at the time of transplantation and may be exacerbated by a variety of immune and nonimmune assaults throughout the life of the graft. Brain death. We used to believe that differences in long-term graft survival between recipients of HLA-identical sibling grafts, those who received kidneys from living donors who shared 1 HLA-haplotype with the patient, and cadaver kidney recipients with no genetic relationship to the donor were caused by the obvious differences in tissue compatibility. However, the success of a growing number of poorly HLAmatched living unrelated donor transplants, ~3.v~ which have greater survival rates than cadaver kidney transplants, has shown that brain death itself is an important factor in cadaver donor transplants. It has been estimated that approximately 10% of cadaver kidneys show evidence of long-term damage from preretrieval injury based on a comparison of success rates between living unrelated and cadaver donor transplants? 3 Elegant animal models '-~-l'jhave shown that brain death is accompanied by important changes in physiologic characteristics, hemodynamics, endocrine function, and tissue morphologic characteristics, and initiates inflammatory processes that can damage the peripheral organs (reviewed inlS). The circumstances surrounding the tempo (and perhaps the cause) of brain death can also affect the profile of activation that occurs.~9 We are beginning to appreciate that beneath the calm appearance of brain death, cytokine storms are raging that influence the immunogenicity of the graft. HLA antigen expression is upregulated, making the brain-dead donor kidney a better target for preformed anti-HLA antibodies and a stronger immunogen than a kidney that has not been subjected to the inflammatory processes accompanying brain death. Using a rat model of brain death, kidneys transplanted from brain-dead animals were rejected significantly faster than those from anesthetized controls.2° The harmful effects of DGF in human transplantation are more pronounced when more HLA antigens are mismatched between the donor and recipient. '-'~The changes and renal injuries that occur during and after brain death have consequences well into the posttransplantation period. DGF is rare among recipients of living donor grafts compared with kidneys from cadaver donors,'~2 suggesting a causative association between brain death and DGF. The small percentage of living do-
59
nor graft recipients who experience DGF most often also experienced technical problems with surgery or, in the case of pediatric recipients of adult kidneys, hemodynamic problemsY s The early experience with laparoscopic donor nephrectomies from living donors was associated with a 7% DGF rate, 24,25 probably caused by the longer ischemic exposure during surgery. However, a more recent analysis of 75 laparoscopic procedures in which warm ischemia time was kept at an average of less than 5 minutes produced no cases of DGF after tr~.nsplantation36 Living donor transplant recipients with grafts that do not function immediately include the proportion with technical complications, as well as those in whom DGF results from immune causes in the recipient after transplantation. The incidence of DGF (defined as a need for dialysis in the first posttransplantation week) reported to UNOS between 1994 and 1998 was 5%. If we assume that all DGF among recipients of living donor kidneys is the result of recipient factors, the difference in the proportions of recipients who experience DGF after transplantation from a living (5%) or cadaver donor (25%) suggests that only approximately 20% of the cases of DGF in recipients of cadaver kidneys result from recipient immune factors. Thus, 80% of DGF can be attributed to damage to the kidney before transplantation. Donor age. Advanced donor age has been identified as a major risk factor for DGF ',6,9 and reduces long-term graft survival rates. 6,24UNOS data show a striking increase in DGF with advancing donor age 22 (Fig 2). In these analyses, 15% of those who received kidneys from 20-year-old donors experienced DGF, and the percentage increased to 40% when the donor was aged older than 65 years. The number of functional nephrons declines with advancing age in healthy individuals,27 and we have postulated that older kidneys may be more stressed after transplantation to accommodate the load,2~ predisposing the kidney to hyperfiltration damage. However, advanced age does not correlate with a greater incidence of DGF when considering living donor kidneys (Fig 2). Time for more careful evaluation and selection of living donors in general, and older donors in particular, may result in simply choosing healthier kidneys. Conversely, the damaging effects of brain death may take a larger toll on the aging kidney. Damage to the more limited number of functional nephrons could further reduce the aging kidney's reserves,28 or the aging kidney might be slower or limited in its ability to repair damage39
Cecka, Shoskes,and Gjertson
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Donor Age Figure 2. Effect of donor age on the incidence of DGF among recipients of cadaver or IMng donor kidneys. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.) The relationship between donor age and DGF is complex, and unfortunately, rapid tests for accurately assessing the functional capacity of aging cadaver donor kidneys are not yet available. Cause of donor death. Kidneys from donors who died as a result of stroke yield poorer long-term survival rates than kidneys from younger donors who were victims of motor vehicle accidents. Stroke victims are generally older, and accident victims tend to be younger, but multivariate analyses also have identified the cause of donor death as a significant risk factor influencing graft survival6,3° when accounting for the disparate age distributions. The cause of donor death appears to be the dominant factor affecting graft losses within the first year, and advanced donor age has a much larger role in longterm graft outcome.30,3~ The relationship between cause of donor death and DGF from UNOS data is shown in Figure 3. Kidneys from donors who died in motor vehicle accidents had the lowest incidence of DGF (18%), whereas 30% of the kidneys from donors who died of stroke had DGF. Nearly half (45%) of the
400 non-heart-beating donor kidneys, with their attendant problems of longer warm ischemia times, had DGF. 32 The mechanism of death, clinical management of the donor before brain death, and underlying disease processes differ between donors for whom death resulted from a motor vehicle accident or stroke. Characterizing these differences ultimately may provide some insight into the interplay between brain death and cause of death. In the 1970s and 1980s, numerous groups studied the survival rates of kidneys from donors treated with transfusions, cytotoxic drugs, and steroids in an effort to determine whether the immunogenicity of the kidney could be modified before transplantation.33, 34 Although these early investigations did not yield compelling results that graft survival was improved by such interventions in the donor,35,36 it would probably be worthwhile to reexamine differential donor pretreatment in the modern immunosuppression era. Anti-inflammatory drugs, blood transfusions, or other treatments provided to the patient who later becomes a kidney
Clinical Impact of DGF
61
50 Figure 3. Effect of cause of donor death on the incidence of DGF among recipients of cadaver donor kidneys.Abbreviations: MVA, motor vehicle accident; NHBD, non-heartbeating donor. (Data from the UNOS ScientificRenal Transplant Registry for transplants performed between 1994 and 1998 as presented at Tramplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
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donor may affect the changes that occur during subsequent brain death and organ storage. For example, it was recently reported that pretreatment of donor Lewis rats with mycophenolate mofetil for 7 days before harvest prolonged cardiac graft survival after extended cold ischemiaP 7 The investigators proposed that donor pretreatment affects glycosylation or expression of adhesion molecules in the graft endothelium and prevents or reduces ischemia-reperfusion injury. Similarly, in a rodent renal ischemia model, mycophenolate mofetil and the bioflavonoids, quercetin and curcumin, were synergistic in reducing apoptosis and adhesion molecule expression and enhancing renal epithelial regeneration. 38
Ischemia-ReperfusionInjuries Cold ischemta time. Ischemia is the main cause of renal injury during and after donor surgery. Cessation of blood flow leads to anaerobic metabolism and loss of adenosine triphosphate-dependent ion transport. 39 Flushing with cold preservation solution slows the metabolic rate and enzyme activity, but prolonged storage offsets this measure to some degree. On reperfusion, vascular constriction restricts oxygen availability and obstructs capillary flow. Good success rates with kidneys transplanted up to approximately 36 hours after procurement has provided more flexibility in allocation, and very few cadaver kidney transplantations are performed under the stringent time constraints applied to heart and liver transplants. Although some have noted a significant impact of prolonged cold ischemia time
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Cause of Death on long-term kidney graft survival,4° others have not.4~,42However, the effect of cold ischemia on DGF is clear. A recent study of 31 sequentially transplanted kidney pairs noted a significantly greater incidence of DGF among recipients of the second kidney, even though the difference in cold ischemia time was only 5 hours. 43 Cold ischemia was the most important predictor of DGF identified in analyses of the US Renal Data System database. ~ Recent analyses of UNOS data show that the correlation between cold ischemia time and the incidence of DGF is almost linear, indicated by the broad bars in Figure 4. Overall DGF incidence ranged from 14% when the kidney was transplanted within 12 hours to more than 45% when kidneys were transplanted after more than 48 hours of cold ischemia time. The effects of cold ischemia time and donor age were approximately additive in this analysis. Less than 10% of those who received kidneys from donors aged 19 to 30 years (open bars) and underwent transplantation in less than 12 hours experienced DGF. When the donor was older (closed bars), more than 20% had DGF, even witli short cold ischemia times. When cold ischemia time was 36 to 48 hours, more than half the recipients of older kidneys experienced DGF compared with less than 30% of those who received younger donor kidneys. Ischemia apparently produces less damage in younger donor kidneys than in those from donors aged older than 50 years. Donor age and duration ofischemia have been shown to act synergistically in their effects on chronic allograft dysfunction in an animal model.~ Thus, the
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Figure 4. Effectof cold ischemia time on the incidence of DGF among recipients of cadaver donor kidneys. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
processes that lead to injury of the donor kidney, such as brain death, ischemia, and reperfusion, have more pronounced effects on older donor kidneys. Pu/sat//e perfits/on. Evaluating kidneys from expanded and nonheart-beating donors, pulsatile perfusion of kidneys before transplantation either in lieu of or subsequent to simple cold storage offers some advantages in reducing the incidence of DGF and improving long-term graft survival. 45,46 As the fraction of nonideal donors continues to grow, the costeffectiveness of pulsatile perfusion is likely to improve because the savings from a reduction in the incidence of DGF would offset the additional costs of perfusion. One study of 30 donors considered marginal because of advanced age, cessation of heartbeat, and other criteria compared the early function rates for kidneys preserved by pulsatile perfusion with those of the mate kidneys and more ideal kidneys maintained by simple cold storage. 46 The results showed a significant improvement in early graft function (10% DGF) in the perfused kidneys compared with nearly 30% DGF in those stored without perfusion. A survey of 44 centers showed that 11 of the 12 centers that reported using pulsatile perfu-
sion for some or all of their kidneys had a lower incidence of DGF than the centers using ice storage. 47 Marginal kidney viability, particularly when the donor is at the extremes of acceptability, can be assessed using perfusion parameters before transplantation. Pharmacologic agents can be delivered to the kidney more effectively using this approach, as well. 48 Because the fraction of nonideal donors continues to grow, the cost-effectiveness ofpulsatile perfusion is likely to improve. The savings from a reduction in the incidence of DGF would offset the additional costs of perfusion.
Recipient Factors DGF has been observed more frequently in sensitized patients or those who underwent retransplantation and is more common when the donor and recipient are poorly mismatched for H I A antigens. 2 DGF also complicates management of the patient during the period of nonfunction, particularly in regard to monitoring immunosuppression and recognizing rejection episodes. The increased risk for immune injury for sensitized patients coupled with the potential masking of rejection by DGF predisposes
ClinicalImpact ofDGF the sensitized patient to more severe rejection. The degree of immune injury is determined in part by the severity of rejection in the early posttransplantation period. However, when alloantigen-driven responses exacerbate preexisting injuries to the donor kidney associated with brain death and ischemia, the status of the transplanted kidney will affect the degree of injury that is sustained as well. Sens/t/zation. The presence of preformed anti/-ILA antibodies has been associated with DGF for many years despite donor-specific cross-match tests designed to avoid transplantation in the face of antibodies that react with the donor's ~ antigens. The development and use of more sensitive crossmatch tests to detect even very low levels of donorreactive antibodies (reviewed in49) can reduce this source of immune injury. However, even among recent cadaveric kidney recipients, the presence of broadly reacting antibodies was associated with an increased incidence of DGF, shown in Figure 5. Donor-reactive anti-HLA antibodies are still missed or are permitted in some broadly sensitized patients, leading to DGF. From the perspective of optimal use of the scarce resource, ie, cadaver kidneys, the clear potential for antibody-mediated injury to the kidney should be avoided when possible, particularly in the patient who underwent retranplantation. Early rejection. DGF significantly increases the risk for early rejection episodes. Most studies have noted a greater incidence of rejection when graft function is delayed, and DGF may also predispose to multiple rejections,s° We recently examined the influence of DGF on rejection using UNOS data. To minimize the influence of donor-related factors, we
63
selected 3,250 kidney pairs from the same donor when 1 kidney functioned immediately and the other had DGF. Less than 10% of the transplant recipients with early function had a reported rejection episode before their hospital discharge, compared with nearly a quarter of those who had DGF, shown in Figure 6. This strong association between early acute rejection and DGF frames the debate regarding the longterm influence of DGF. Most agree that DGF affects 1-year graft survival and that DGF and rejection together lead to a poor long-term outcome. But does DGF affect long-term survival in the absence of rejection? Large multicenter database studies, using the need for dialysis in the first posttransplantation week as a surrogate for delayed function, found that DGF in the absence of rejection had a significant detrimental effect on long-term graft survival. ~,5 When analyzed with many other factors, including rejection, in a Cox regression model, DGF alone still remained a significant risk factor for 5-year graft survival. ~ Others (using more precise definitions) found that DGF had a negative impact on long-term survival only in conjunction with acute rejection episodesg.5~-53or when DGF was prolonged.54 Interpreting these conflicting results is difficult; in part because the analyses include variables known pretransplantation (such as donor age) and early graft outcomes (such as DGF and rejection) as components in the mix when assessing their impact on another outcome (long-term survival). The ranking of factors depends heavily on the specific mix and types of variables included in each study. Slow graft function, defined as an elevated serum
50 Figure 5. Effect of recipient sensitization status on the incidence of DGF among recipients of cadaver donor kidney transplants. Abbreviation: PRA, percentage of panel-reactive antibodies.(Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
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Figure 6. Incidence of acute rejection episodes before hospital discharge for recipients of 3,250 paired kidneys in which 1 kidney functioned immediately and the contralatera] kidney had DGF. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17,
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creatinine level day 3 but without the need for dialysis) 5 resulted in an increased incidence of acute rejection that was less than that observed in patients with DGF. There was no effect of slow graft function on long-term survival in the absence of rejection.
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When UNOS Registry transplantations were stratified with regard to DGF and rejection before hospital discharge, DGF had a deleterious effect on graft survival except when the discharge serum creatinine level was less than 2.5 mg/dL. 3 These results support
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Years Posttransplant Figure 7. Comparison of graft survival rates stratified by donor type and DGF. (Based on data reported to the UNOS Scientific Renal Transplant Registry for transplants performed between 1994-1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
Clinical Impact of DGF
the idea that injury occurs by degree. Some injury is reversible and may not affect long-term survival when it is reversed. Patient smwival can also be affected by DGF. 56-59 Increased deaths noted in pediatric recipients 56 and in the U N O S data 57 occurred early in the posttransplantation period, and it was suggested that difficulties treating patients with delayed function and overimmunosuppression in an attempt to salvage the graft may have contributed to the increased mortality. These results should raise caution because we transplant more older donor kidneys with a greater likelihood of DGF, often to older recipients who may be more vulnerable to immunosuppressive drugs. 6° A cornucopia of powerful new immunosuppressants have provided the means to effectively control the immune response, and as a result, both longterm and short-term graft survival rates have improved significantly during the past decade. 6t,62 Although there remains much to accomplish on this front, attacking the many other processes that injure the donor kidney before transplantation and that can affect long-term graft function is also an important goal. If we could devise measures to eliminate DGF among cadaver kidneys, what could we expect? The result might be similar to the results obtained with living donor transplants, shown in Figure 7. Actuarial survival values are similar through the first 5 years after transplantation. The half-life for cadaveric transplants remains somewhat lower. In the longterm, success would not be as good as with living donor grafts, but recipients of cadaver grafts tend to be older, and most long-term differences are likely caused by deaths among older patients. Eliminating or reducing the incidence of D G F among recipients of cadaver kidneys would still be better than what we have today, because 25% of cadaver kidneys do not function right away.
Summary DGF is an early manifestation of the cumulative damage or injury to the transplanted kidney caused by brain death, ischemia, or preservation and reperfusion, as well as immune assaults in the immediate posttransplantation period. Type and degree of injury may determine the ultimate consequences in terms of the clinical course, ranging from primary nonfunction to an accelerated chronic rejection process and later graft dysfunction and loss, to no longterm effect when damage is sufficiently reversed.
65
The factors that contribute to DGF are often the same as those that influence chronic rejection, 6~ suggesting that D G F may be a harbinger of later graft dysfunction. The health and functional reserve of the donor kidney may be key components for gauging the impact of these injuries and their relationship to DGF. Our understanding of the types of injuries and damage that occur before transplantation is still rather primitive, but the potential for intervention in the brain-dead donor and during the pretransplantation interval offers an.exciting opportunity for new research to prevent or reverse the initial damage to the kidney graft, c'4 DGF can serve as an important early marker for the success of these endeavors.
References 1. Ojo AO, Wolfe RA, Held PJ, et at: Delayed graft function: Risk factors and implications for renal allograft survival. Transplantation 1997,63:968 2. Cecka JlVl, Cho YW, Terasaki PI: Analysis of the UNOS Scientific Renal Transplant Registr5, at three years~Early events affecting transplant success. Transplantation 1992, 53:59 3. Freedland SJ, Shoskes DA: "Economicimpact of delayed graft function and suboptimal kidneys. Transplant Rev 1999, 13:23 4. Johnson CP, Kuhn EM, Hariharan S, et ah Pre-transplant identification of risk factors that adverselyaffect length ofstay and charges for renal transplantation. Clin Transplant 1999, 13:168 5. Shoskes DA, CeckaJM: Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 1998,66:1697 6. Terasaki PI, Gjertson DW, CeckaJM, et at: Significanceofthe donor age effect on kidneytransplants. Clin Transplant 1997, 11:366 7. PfaffWW, Howard RJ, Patton PR, et al: Delayed graft function after renal transplantation. Transplantation 1998,65:219 8. Tejani AH, Sullivan EK, Alexander SR, et ah Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1999,3:293 9. McLaren AJ,Jassem w, Gray DW, et al: Delayed graft function: Risk factors and the relative effects ofearly function and acute rejectionon long-termsurvival in cadavericrenal Transplantation. Clin Transplant 1999, 13:266 I0. Drafts HH, Anjum MR, WynnjJ, et al: The impact of pretransplant obesityon renal transplant outcomes. Clin Transplant 1997, 11:493 II. BleyerAJ, BurkartJM, Russel GB, et al: Dialysis modalityand delayed graft function after cadaveric renal transplantation. J Am Soc Nephrol 1999, 10:154 12. Becker YT: Use of marginal donors in kidneytransplantation. Graft 2000, 3:216 13. Terasaki PI, CeckaJM, Gjertson DW, et ah High graft survival rates of spousal and living-unrelateddonor kidney transplants. N EnglJ Med 1995,333:333
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14. Gjertson DW, Cecka JM: Living unrelated donor kidney transplantation. Kidney Int 2000, 58:491 15. Finkelstein I, Tnledo-Pereyra I.M, Castanellos J: Physiologic and hormonal changes in experimentally induced brain-dead dogs. Transplant Proc 1987, 19:4156 16. Mertes PM, EI-Abassi K, Jaboin Y, et at: Changes in hemodynamic and metabolic parameters following induced brain death in the pig. Transplantation 1994, 58:414 17. Takada M, Nadeau KC, Hancock WW, et at: Effects ofexplosive brain death on cytokine activation of peripheral organs in the rat. Transplantation 1998, 65:1533 18. PratschkeJ, Wilhelm wJ, Kusaka M, et at: Brain death and its influence on donor organ quality and outcome after transplantation. Transplantation 1999, 67:343 19. Pratschkej', Wilhelm WJ, Kusaka M, et at: A model of gradual onset brain death for transplant-associated studies in rats. Transplantation 2000, 69:427 20. PratschkeJ, Wilhelm WJ, Kusaka M, et at: Accelerated rejection of renal allografts from brain-dead donors. Ann Surg 2000, 232:263 21. Shoskes DA, Hodge EE, Goormastic M, et at: HLA matching determines the susceptibility to harmful effects of delayed graft function. Transplant Proc 1995, 27:1068 22. CeckaJM: The UNOS Scientific Renal Transplant Registry, in Cecka JM, Terasaki PI (eds): Clinical Transplants 1998. LOs Angeles, UCLA Tissue Typing Laboratory, 1999, pl 23. Salvatierra O Jr, Singh T, Shifrin R, et at: Successful transplantation of aduh-sized kidneys into infants requires maintenance of high aortic blood flow. Transplantation 1998, 66: 819 24. Ratner LE, Kavoussi LR, Sroka M, et at: Laparoscopic-assisted live donor nephrectomy: A comparison with the open approach. Transplantation 1997, 63:229 25. Nogueira JM, Cangro CB, Fink JC, et al: A comparison of recipient renal outcomes with laparoscopic versus open livedonor nephrectomy. Transplantation 1999, 67:722 26. Leventhal JR, Deeick RK, Joehl RJ, et at: Laparoscopic live donor nephrectomy--Is it safe? Transplantation 2000, 70:602 27. NyengaardJR, Bendtsen TF: Glomerular number and size in relation to age, kidney weight and body surface in normal man. Anat Rec 1992, 232:194 28. Terasaki PI, Koyama H, Cecka JM, et al: Hyperfihration hypothesis in human renal transplantation. Transplantation 1994, 57:1450 29. Halloran PF, Melk A, Barth C: Rethinking chronic allograft nephropathy: The concept of accelerated senescence. J Am Soc Nephrol 1999, 10:1 30. Gjertson DW: Determinants of long-term survival of adult kidney transplants: A 1999 UNOS update, in CeckaJM, Terasaki PI (eds): Clinical Transplants 1999. LOsAngeles, UCLA Tissue Typing Laboratory, 2000, p341 31. Prommool S, Jhangri GS, Cockfield SM, et al: Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 2000, 11:565 32. Cho YW, Terasaki PI, Cecka JM, et al: Transplantation of kidneys from donors whose hearts have stopped beating. N EnglJ Med 1998, 338:221 33. Zinke H, Woods JE, Khan AU, et at: Immunological donor pretreatment in combination with pulsatile preservation in cadaveric renal transplantation. Transplantation 1978, 26:207 34. Frisk B, Berglin E, Brynger H: Transfused cadaver kidney donors and graft survival. Transplantation 1983, 35:352
35. JefferyJR, Downs A, Grahame JW, et at: A randomized prospective study of cadaver donor pretreatment in renal transplantation. Transplantation 1978, 25:287 36. SoulillouJP, Baron D, Rouxel A, et ah Steroid-cyclophosphamide pretreatment of kidney allograft donors---A control study. Nephron 1979, 24:193 37. ValentinJF, BruljnJA, Paul LC: Donor treatment with mycophenolate mofetil Protection against ischemia-reperfusion injury in the rat. Transplantation 2000, 69:344 38. Jones EA, Sboskes DA: The effect of mycophenolate mofetil and polyphenolic bioflavonoids on renal ischemia reperfusion injury and repair.J Urol 2000, 163:999 39. Land W, Messmer K: The impact of ischemia/reperfusion injury on specific and non-specific early and late chronic events after organ transplantation. Transplant Rev 1996, 10: 108 40. Held PJ, Kahan BD, Hunsicker LG, et at: The impact of HLA mismatches on the survival of first cadaveric kidney transplants. N Engl J Med 1994, 331:765 41. Peters TG, Shaver TR, Ames JE, et ah Cold ischemia and outcome in 17,937 cadaveric kidney transplants. Transplantation 1995, 59:191 42. Kyll6nen LE, Salmela KT, Eklund BH, et al: Long-term results of 1047 cadaveric "kidney transplantations with special emphasis on initial graft function and rejection. Transpl Int 2000, 13:122 43. Tandon V, BothaJF, Banks J, et at: A tale of two kidneys--How long can a "kidneytransplant wait? Clin Transplant 2000, 14:189 44. Tullius SG, Reutzel-Selke A, Egermann F, et at: Contribution of prolonged ischemia and donor age to chronic renal allograft dysfunction.J Am Soc Nephrol 2000, 11:1317 45. Tesi RJ, Elkhammas EI, Davies EA, et al: Pulsatile kidney perfusion for evaluation of high risk kidney donors safely expands the donor pool. Clin Transplant 1994, 8:134 46. Light JA, Gage F, Kowalski AE, et at: Immediate function and cost comparison between static and pulsatile preservation in kidney recipients. Clin Transplant 1996, 10:233 47. Szust J, OIson L, Cravero L: A comparison of OPO pulsatile machine preservation practices and results.J Transplant Coord 1999, 9:97 48. Polyak MM, Arrington BO, Stubenbord WT, et at: The influence of pulsatile preservation on renal transplantation in the 1990s. Transplantation 2000, 69:249 49. Martin S, Taylor CJ: The immunologically sensitized renal transplant recipient: The impact of advances in technology on organ allocation and transplant outcome. Transplant Rev 1999, 13:40 50. Humar A, Payne WD, Sutherland DER, et at: Clinical determinants of multiple acute rejection episodes in kidney transplant recipients. Transplantation 2000, 69:2357 5 I. Troppmann C, Gruessner AC, Gillingham KJ, et at: Impact of delayed graft function on long-term graft survival after solid organ transplantation. Transplant Proc 1999, 3 I: 1290 52. Lehtonen SRK, Isoniemi HM, Salmella KT, et at: Long-term graft outcome is not necessarily affected by delayed onset of graft function and early acute rejection. Transplantation 1997, 64:103 53. Boom H, Mallat MJK, deFijterJW, et al: Delayed graft function influences renal function but not survival. Kidney Int 2000, 58:859
ClinicalImpact ofDGF
54. Giralclasse M, Hourmant M, Cantarovitch D, et al: Delayed graft function of more than six days strongly decreases longterm graft survival of transplanted kidneys. Kidney Int 1998, 54:972 55. Humar A, Johnson EM, Payne WD, et al: Effect of initial slow graft function on renal allograft rejection and survival. Clin Transplant 1997, 11:623 56. Tejani A, Sullivan EK, Alexander S, et al: Posttransplant deaths and factors that influence the mortality rate in North American children. Transplantation 1994, 57:547 57. Hirata M, Cho YW, CeckaJM, et al: Patient death after renal transplantation An analysis of its role in graft outcome. Transplantation 1996, 61:1479 58. Shoskes DA, Avelino L, Barba L, et al: Patient death or renal graft loss within 3 yr of transplantation in a county hospital: Importance of poor initial graft function. Clin Transplant 1997, I 1:618
67
59. Ojo AO, HansonJA, Wolfe RA, et al: Long-term survival in renal transplant recipients with graft function. Kidney Int 2000, 57:307 60. Meier-Kriesche HU, Ojo A, Hanson J, et al: Increased immunosuppressive vulnerability in elderly renal transplant recipients. Transplantation 2000, 69:885 61. CeckaJM: The UNOS Scientific Renal Transplant Registry, in Cecka JM, Terasaki PI (eds): Clinical Transplants 1999. Los Angeles, UCLA Immunogenetics Center, 2000, p l 62. Harihan S,Johnson CP, Bresnahan BA, et al: Improved graft survival after renal transplantation in the United States, 1988 to 1996. N EnglJ Med 2000, 342:605 63. Waaga AM, Gasser M, Easkowski I, et al: Mechanisms of chronic rejection. Curr Opin Immunol 2000, 12:517 64. Shoskes DA: Nonimmunologic renal allograft injury and delayed graft function: Clinical strategies for prevention and treatment. Transplant Proc 2000, 32:766
hen function of a transplanted kidney is de-
W layed or inadequate in the early period after transplantation, the consequences can be rather
grim. Based on analyses of data reported to the United Network for Organ Sharing (UNOS) Scientific Renal Transplant Registry for 34,647 cadaver kidney transplantations performed in the United States between 1994 and 1998, approximately 5% of the kidney grafts that do not function immediately will never function. Ten percent fail during the first month posttransplantation, and more than 20% are lost within 1 year. Even among those transplant recipients whose kidneys survive the first year, the
From the UnitedNelworkfor Organ Sharing ScientificRenal Transplant Regist9,, University of California at Los Angeles hnmunogeneties Center, Los Angeles, CA,"and the Department of Urologr, ClevelandClinic Florida, Fort Londerdale, FL. Supported in part through a subcontract with the United Netzwrk for Organ Sharing. Presented in part at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000. The opinions are thoseof the authorsand do not necessarib, reflectopinions or policies of the United Networkfor Organ Sharing. Address reprint requests to J. Michael Cecka, PkD, UNOS Scientific Renal Transplant Registry, UCLA Immunogenetics Center, Department of Pathology, 950 VeteranAve, Los Angeles, (24 90095. Copyright © 2001 by W.B.Saunders Company 0955-470X/01/1502-0006535.00/0 doi:l O.l O53/trre.2001.20807
rate of late graft loss is significantly greater when initial graft function was delayed. Half the kidneys that survive the first year subsequently fail within 7 years When graft function was delayed. That half-life can be compared with a half-life of nearly 12 years when the graft functioned immediately. Thus, delayed graft function (DGF) impacts on both early and long-term graft survival. Projected to 10 years, there is a 20% lower graft survival rate among transplant recipients with DGF (Fig 1). It has been estimated that as many as one third of the graft losses during the first 5 years among primary cadaver transplant recipients can be attributed to the influence of DGF. I DGF affects other clinical parameters after transplantation as well. The incidence of rejection episodes among patients with DGF is greater, 2 requiring additional immunosuppression, imaging studies, and biopsies. Hospital stays are longer, resulting in greater use of hospital resources: The cost of the transplantation increases when initial graft function is delayed.3,4 The incidence of DGF has changed very little during the past decade,5 even though improved immunosuppression has reduced the incidence of rejection episodes within the first 6 months from 55% to 22% during the same period. DGF affects approximately 1 of every 4 cadaver kidneys that are transplanted today.
Transplantation Reviews, Vol 15, No 2 (April), 2001: pp 57-67
57
Cecka, Shoskes, and Gjertson
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Years Posttransplant Figure 1. Effect of DGF on the long-term graft suta,ival rate ofcadaver donor renal transplants. The graft half-life (Tl/2) is the number of years until half the transplants that are still functioning at 1year ~dll fail. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.) In this review, we examine some of the factors associated with DGF and the clinical impact of DGF on the outcome of kidney transplants.
Risk Factors for Delayed Function DGF is the manifestation of what may be an extremely complex set of processes. In most cases, DGF reflects injury or damage to the kidney, but a host of factors may contribute to the injury or influence the extent of damage and the long-term consequences. Some factors associated with an increased incidence of DGF reflect the health of the donor kidney, such as advancing donor age, donor death by cerebrovascular accident, and prolonged cold ischemia time; others suggest immune damage in the early posttransplantation period, such as the presence of broadly reacting anti-HIA antibody or previous graft loss in the recipient. 1,2,c~-~ In multivariate analyses, these factors appear to contribute independently to the incidence of DGF. Other recipient risk factors have been identified as well, in-
cluding positive cytomegalovirus serologic test resuits I in the transplant recipient (or in the donor when the recipient's test result was negative), obesity or large size disparities between the donor and recipient,l° and type of pretransplantation dialysis. Jl Black transplant recipients are more likely than others to experience DGF. 1 D o n o r Factors As pressures mount to expand the limits of donor acceptability, the health of the donor kidney has become an important issue for transplant surgeons and physicians. Older and sicker potential cadaver donors are being considered, and this trend is reflected in an increasing discard rate for kidneys from 5% in 1992 to nearly 8% in 1997 (UNOS data cited inl2). Health of the donor kidney and functional renal mass, influenced by donor age, cause of donor death, and underlying disease, are among the most important factors that determine functional reserve after injury and, ultimately, the long-term success of the transplant. Moreover, renal injury can occur be-
Clinical Impact of DGF
fore transplantation, during or shortly after brain death, and on reperfusion at the time of transplantation and may be exacerbated by a variety of immune and nonimmune assaults throughout the life of the graft. Brain death. We used to believe that differences in long-term graft survival between recipients of HLA-identical sibling grafts, those who received kidneys from living donors who shared 1 HLA-haplotype with the patient, and cadaver kidney recipients with no genetic relationship to the donor were caused by the obvious differences in tissue compatibility. However, the success of a growing number of poorly HLAmatched living unrelated donor transplants, ~3.v~ which have greater survival rates than cadaver kidney transplants, has shown that brain death itself is an important factor in cadaver donor transplants. It has been estimated that approximately 10% of cadaver kidneys show evidence of long-term damage from preretrieval injury based on a comparison of success rates between living unrelated and cadaver donor transplants? 3 Elegant animal models '-~-l'jhave shown that brain death is accompanied by important changes in physiologic characteristics, hemodynamics, endocrine function, and tissue morphologic characteristics, and initiates inflammatory processes that can damage the peripheral organs (reviewed inlS). The circumstances surrounding the tempo (and perhaps the cause) of brain death can also affect the profile of activation that occurs.~9 We are beginning to appreciate that beneath the calm appearance of brain death, cytokine storms are raging that influence the immunogenicity of the graft. HLA antigen expression is upregulated, making the brain-dead donor kidney a better target for preformed anti-HLA antibodies and a stronger immunogen than a kidney that has not been subjected to the inflammatory processes accompanying brain death. Using a rat model of brain death, kidneys transplanted from brain-dead animals were rejected significantly faster than those from anesthetized controls.2° The harmful effects of DGF in human transplantation are more pronounced when more HLA antigens are mismatched between the donor and recipient. '-'~The changes and renal injuries that occur during and after brain death have consequences well into the posttransplantation period. DGF is rare among recipients of living donor grafts compared with kidneys from cadaver donors,'~2 suggesting a causative association between brain death and DGF. The small percentage of living do-
59
nor graft recipients who experience DGF most often also experienced technical problems with surgery or, in the case of pediatric recipients of adult kidneys, hemodynamic problemsY s The early experience with laparoscopic donor nephrectomies from living donors was associated with a 7% DGF rate, 24,25 probably caused by the longer ischemic exposure during surgery. However, a more recent analysis of 75 laparoscopic procedures in which warm ischemia time was kept at an average of less than 5 minutes produced no cases of DGF after tr~.nsplantation36 Living donor transplant recipients with grafts that do not function immediately include the proportion with technical complications, as well as those in whom DGF results from immune causes in the recipient after transplantation. The incidence of DGF (defined as a need for dialysis in the first posttransplantation week) reported to UNOS between 1994 and 1998 was 5%. If we assume that all DGF among recipients of living donor kidneys is the result of recipient factors, the difference in the proportions of recipients who experience DGF after transplantation from a living (5%) or cadaver donor (25%) suggests that only approximately 20% of the cases of DGF in recipients of cadaver kidneys result from recipient immune factors. Thus, 80% of DGF can be attributed to damage to the kidney before transplantation. Donor age. Advanced donor age has been identified as a major risk factor for DGF ',6,9 and reduces long-term graft survival rates. 6,24UNOS data show a striking increase in DGF with advancing donor age 22 (Fig 2). In these analyses, 15% of those who received kidneys from 20-year-old donors experienced DGF, and the percentage increased to 40% when the donor was aged older than 65 years. The number of functional nephrons declines with advancing age in healthy individuals,27 and we have postulated that older kidneys may be more stressed after transplantation to accommodate the load,2~ predisposing the kidney to hyperfiltration damage. However, advanced age does not correlate with a greater incidence of DGF when considering living donor kidneys (Fig 2). Time for more careful evaluation and selection of living donors in general, and older donors in particular, may result in simply choosing healthier kidneys. Conversely, the damaging effects of brain death may take a larger toll on the aging kidney. Damage to the more limited number of functional nephrons could further reduce the aging kidney's reserves,28 or the aging kidney might be slower or limited in its ability to repair damage39
Cecka, Shoskes,and Gjertson
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Donor Age Figure 2. Effect of donor age on the incidence of DGF among recipients of cadaver or IMng donor kidneys. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.) The relationship between donor age and DGF is complex, and unfortunately, rapid tests for accurately assessing the functional capacity of aging cadaver donor kidneys are not yet available. Cause of donor death. Kidneys from donors who died as a result of stroke yield poorer long-term survival rates than kidneys from younger donors who were victims of motor vehicle accidents. Stroke victims are generally older, and accident victims tend to be younger, but multivariate analyses also have identified the cause of donor death as a significant risk factor influencing graft survival6,3° when accounting for the disparate age distributions. The cause of donor death appears to be the dominant factor affecting graft losses within the first year, and advanced donor age has a much larger role in longterm graft outcome.30,3~ The relationship between cause of donor death and DGF from UNOS data is shown in Figure 3. Kidneys from donors who died in motor vehicle accidents had the lowest incidence of DGF (18%), whereas 30% of the kidneys from donors who died of stroke had DGF. Nearly half (45%) of the
400 non-heart-beating donor kidneys, with their attendant problems of longer warm ischemia times, had DGF. 32 The mechanism of death, clinical management of the donor before brain death, and underlying disease processes differ between donors for whom death resulted from a motor vehicle accident or stroke. Characterizing these differences ultimately may provide some insight into the interplay between brain death and cause of death. In the 1970s and 1980s, numerous groups studied the survival rates of kidneys from donors treated with transfusions, cytotoxic drugs, and steroids in an effort to determine whether the immunogenicity of the kidney could be modified before transplantation.33, 34 Although these early investigations did not yield compelling results that graft survival was improved by such interventions in the donor,35,36 it would probably be worthwhile to reexamine differential donor pretreatment in the modern immunosuppression era. Anti-inflammatory drugs, blood transfusions, or other treatments provided to the patient who later becomes a kidney
Clinical Impact of DGF
61
50 Figure 3. Effect of cause of donor death on the incidence of DGF among recipients of cadaver donor kidneys.Abbreviations: MVA, motor vehicle accident; NHBD, non-heartbeating donor. (Data from the UNOS ScientificRenal Transplant Registry for transplants performed between 1994 and 1998 as presented at Tramplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
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donor may affect the changes that occur during subsequent brain death and organ storage. For example, it was recently reported that pretreatment of donor Lewis rats with mycophenolate mofetil for 7 days before harvest prolonged cardiac graft survival after extended cold ischemiaP 7 The investigators proposed that donor pretreatment affects glycosylation or expression of adhesion molecules in the graft endothelium and prevents or reduces ischemia-reperfusion injury. Similarly, in a rodent renal ischemia model, mycophenolate mofetil and the bioflavonoids, quercetin and curcumin, were synergistic in reducing apoptosis and adhesion molecule expression and enhancing renal epithelial regeneration. 38
Ischemia-ReperfusionInjuries Cold ischemta time. Ischemia is the main cause of renal injury during and after donor surgery. Cessation of blood flow leads to anaerobic metabolism and loss of adenosine triphosphate-dependent ion transport. 39 Flushing with cold preservation solution slows the metabolic rate and enzyme activity, but prolonged storage offsets this measure to some degree. On reperfusion, vascular constriction restricts oxygen availability and obstructs capillary flow. Good success rates with kidneys transplanted up to approximately 36 hours after procurement has provided more flexibility in allocation, and very few cadaver kidney transplantations are performed under the stringent time constraints applied to heart and liver transplants. Although some have noted a significant impact of prolonged cold ischemia time
Stroke
NHBD
Cause of Death on long-term kidney graft survival,4° others have not.4~,42However, the effect of cold ischemia on DGF is clear. A recent study of 31 sequentially transplanted kidney pairs noted a significantly greater incidence of DGF among recipients of the second kidney, even though the difference in cold ischemia time was only 5 hours. 43 Cold ischemia was the most important predictor of DGF identified in analyses of the US Renal Data System database. ~ Recent analyses of UNOS data show that the correlation between cold ischemia time and the incidence of DGF is almost linear, indicated by the broad bars in Figure 4. Overall DGF incidence ranged from 14% when the kidney was transplanted within 12 hours to more than 45% when kidneys were transplanted after more than 48 hours of cold ischemia time. The effects of cold ischemia time and donor age were approximately additive in this analysis. Less than 10% of those who received kidneys from donors aged 19 to 30 years (open bars) and underwent transplantation in less than 12 hours experienced DGF. When the donor was older (closed bars), more than 20% had DGF, even witli short cold ischemia times. When cold ischemia time was 36 to 48 hours, more than half the recipients of older kidneys experienced DGF compared with less than 30% of those who received younger donor kidneys. Ischemia apparently produces less damage in younger donor kidneys than in those from donors aged older than 50 years. Donor age and duration ofischemia have been shown to act synergistically in their effects on chronic allograft dysfunction in an animal model.~ Thus, the
Cecka, Shoskes, and Gjertson
62
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Figure 4. Effectof cold ischemia time on the incidence of DGF among recipients of cadaver donor kidneys. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
processes that lead to injury of the donor kidney, such as brain death, ischemia, and reperfusion, have more pronounced effects on older donor kidneys. Pu/sat//e perfits/on. Evaluating kidneys from expanded and nonheart-beating donors, pulsatile perfusion of kidneys before transplantation either in lieu of or subsequent to simple cold storage offers some advantages in reducing the incidence of DGF and improving long-term graft survival. 45,46 As the fraction of nonideal donors continues to grow, the costeffectiveness of pulsatile perfusion is likely to improve because the savings from a reduction in the incidence of DGF would offset the additional costs of perfusion. One study of 30 donors considered marginal because of advanced age, cessation of heartbeat, and other criteria compared the early function rates for kidneys preserved by pulsatile perfusion with those of the mate kidneys and more ideal kidneys maintained by simple cold storage. 46 The results showed a significant improvement in early graft function (10% DGF) in the perfused kidneys compared with nearly 30% DGF in those stored without perfusion. A survey of 44 centers showed that 11 of the 12 centers that reported using pulsatile perfu-
sion for some or all of their kidneys had a lower incidence of DGF than the centers using ice storage. 47 Marginal kidney viability, particularly when the donor is at the extremes of acceptability, can be assessed using perfusion parameters before transplantation. Pharmacologic agents can be delivered to the kidney more effectively using this approach, as well. 48 Because the fraction of nonideal donors continues to grow, the cost-effectiveness ofpulsatile perfusion is likely to improve. The savings from a reduction in the incidence of DGF would offset the additional costs of perfusion.
Recipient Factors DGF has been observed more frequently in sensitized patients or those who underwent retransplantation and is more common when the donor and recipient are poorly mismatched for H I A antigens. 2 DGF also complicates management of the patient during the period of nonfunction, particularly in regard to monitoring immunosuppression and recognizing rejection episodes. The increased risk for immune injury for sensitized patients coupled with the potential masking of rejection by DGF predisposes
ClinicalImpact ofDGF the sensitized patient to more severe rejection. The degree of immune injury is determined in part by the severity of rejection in the early posttransplantation period. However, when alloantigen-driven responses exacerbate preexisting injuries to the donor kidney associated with brain death and ischemia, the status of the transplanted kidney will affect the degree of injury that is sustained as well. Sens/t/zation. The presence of preformed anti/-ILA antibodies has been associated with DGF for many years despite donor-specific cross-match tests designed to avoid transplantation in the face of antibodies that react with the donor's ~ antigens. The development and use of more sensitive crossmatch tests to detect even very low levels of donorreactive antibodies (reviewed in49) can reduce this source of immune injury. However, even among recent cadaveric kidney recipients, the presence of broadly reacting antibodies was associated with an increased incidence of DGF, shown in Figure 5. Donor-reactive anti-HLA antibodies are still missed or are permitted in some broadly sensitized patients, leading to DGF. From the perspective of optimal use of the scarce resource, ie, cadaver kidneys, the clear potential for antibody-mediated injury to the kidney should be avoided when possible, particularly in the patient who underwent retranplantation. Early rejection. DGF significantly increases the risk for early rejection episodes. Most studies have noted a greater incidence of rejection when graft function is delayed, and DGF may also predispose to multiple rejections,s° We recently examined the influence of DGF on rejection using UNOS data. To minimize the influence of donor-related factors, we
63
selected 3,250 kidney pairs from the same donor when 1 kidney functioned immediately and the other had DGF. Less than 10% of the transplant recipients with early function had a reported rejection episode before their hospital discharge, compared with nearly a quarter of those who had DGF, shown in Figure 6. This strong association between early acute rejection and DGF frames the debate regarding the longterm influence of DGF. Most agree that DGF affects 1-year graft survival and that DGF and rejection together lead to a poor long-term outcome. But does DGF affect long-term survival in the absence of rejection? Large multicenter database studies, using the need for dialysis in the first posttransplantation week as a surrogate for delayed function, found that DGF in the absence of rejection had a significant detrimental effect on long-term graft survival. ~,5 When analyzed with many other factors, including rejection, in a Cox regression model, DGF alone still remained a significant risk factor for 5-year graft survival. ~ Others (using more precise definitions) found that DGF had a negative impact on long-term survival only in conjunction with acute rejection episodesg.5~-53or when DGF was prolonged.54 Interpreting these conflicting results is difficult; in part because the analyses include variables known pretransplantation (such as donor age) and early graft outcomes (such as DGF and rejection) as components in the mix when assessing their impact on another outcome (long-term survival). The ranking of factors depends heavily on the specific mix and types of variables included in each study. Slow graft function, defined as an elevated serum
50 Figure 5. Effect of recipient sensitization status on the incidence of DGF among recipients of cadaver donor kidney transplants. Abbreviation: PRA, percentage of panel-reactive antibodies.(Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
40
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Figure 6. Incidence of acute rejection episodes before hospital discharge for recipients of 3,250 paired kidneys in which 1 kidney functioned immediately and the contralatera] kidney had DGF. (Data from the UNOS Scientific Renal Transplant Registry for transplants performed between 1994 and 1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17,
25
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creatinine level day 3 but without the need for dialysis) 5 resulted in an increased incidence of acute rejection that was less than that observed in patients with DGF. There was no effect of slow graft function on long-term survival in the absence of rejection.
2ooo.)
When UNOS Registry transplantations were stratified with regard to DGF and rejection before hospital discharge, DGF had a deleterious effect on graft survival except when the discharge serum creatinine level was less than 2.5 mg/dL. 3 These results support
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Years Posttransplant Figure 7. Comparison of graft survival rates stratified by donor type and DGF. (Based on data reported to the UNOS Scientific Renal Transplant Registry for transplants performed between 1994-1998 as presented at Transplant 2000, the First Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, Chicago, IL, May 13-17, 2000.)
Clinical Impact of DGF
the idea that injury occurs by degree. Some injury is reversible and may not affect long-term survival when it is reversed. Patient smwival can also be affected by DGF. 56-59 Increased deaths noted in pediatric recipients 56 and in the U N O S data 57 occurred early in the posttransplantation period, and it was suggested that difficulties treating patients with delayed function and overimmunosuppression in an attempt to salvage the graft may have contributed to the increased mortality. These results should raise caution because we transplant more older donor kidneys with a greater likelihood of DGF, often to older recipients who may be more vulnerable to immunosuppressive drugs. 6° A cornucopia of powerful new immunosuppressants have provided the means to effectively control the immune response, and as a result, both longterm and short-term graft survival rates have improved significantly during the past decade. 6t,62 Although there remains much to accomplish on this front, attacking the many other processes that injure the donor kidney before transplantation and that can affect long-term graft function is also an important goal. If we could devise measures to eliminate DGF among cadaver kidneys, what could we expect? The result might be similar to the results obtained with living donor transplants, shown in Figure 7. Actuarial survival values are similar through the first 5 years after transplantation. The half-life for cadaveric transplants remains somewhat lower. In the longterm, success would not be as good as with living donor grafts, but recipients of cadaver grafts tend to be older, and most long-term differences are likely caused by deaths among older patients. Eliminating or reducing the incidence of D G F among recipients of cadaver kidneys would still be better than what we have today, because 25% of cadaver kidneys do not function right away.
Summary DGF is an early manifestation of the cumulative damage or injury to the transplanted kidney caused by brain death, ischemia, or preservation and reperfusion, as well as immune assaults in the immediate posttransplantation period. Type and degree of injury may determine the ultimate consequences in terms of the clinical course, ranging from primary nonfunction to an accelerated chronic rejection process and later graft dysfunction and loss, to no longterm effect when damage is sufficiently reversed.
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The factors that contribute to DGF are often the same as those that influence chronic rejection, 6~ suggesting that D G F may be a harbinger of later graft dysfunction. The health and functional reserve of the donor kidney may be key components for gauging the impact of these injuries and their relationship to DGF. Our understanding of the types of injuries and damage that occur before transplantation is still rather primitive, but the potential for intervention in the brain-dead donor and during the pretransplantation interval offers an.exciting opportunity for new research to prevent or reverse the initial damage to the kidney graft, c'4 DGF can serve as an important early marker for the success of these endeavors.
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