Delayed Graft Function: State of the Art, November 10–11, 2000. Summit Meeting, Scottsdale, Arizona, USA

Abstract

Most cadaver and some live donor organ transplants manifest a degree of early dysfunction. In some cases they meet arbitrary criteria for delayed graft function (DGF), while others have ‘slow graft function’ (SGF) – impaired function which fails to meet DGF criteria. On November 10 and 11, 2000, 60 transplant clinicians met in Scottsdale to discuss the problem of early dysfunction of renal transplants – its pathology, causes, consequences, and management. The kidney transplant experience is of general interest because the database includes quantitative measurements of function and extensive experience with live donor organs. Some of the lessons from the kidney experience may be applicable to other organ transplants. The organizers of the summit surveyed kidney transplant units in the USA. About 60% of the surveyed units responded (42 centers representing 4200 renal transplants per year), including both large and small centers (> 300 and < 25 transplants per year.) Most preferred the name DGF, defined as the requirement for any dialysis in the first week. The term transplant acute tubular necrosis (ATN) is probably not suitable because other pathologic entities can cause poor initial function, as outlined below. Some centers used definitions of function based on urine output (e.g. > 1 L in the first 24 h) or fall in serum creatinine (e.g. a drop in creatinine of 20–30% over 24–48 h), reflecting glomerular filtration rate (GFR). The responding centers generally reported a DGF rate of 20–29% in cadaver kidneys, with some outliers (< 10% to > 50%). For the present discussion, DGF is defined as the requirement for dialysis in the first week unless otherwise stated, excluding obvious alternative explanations for poor function, e.g. ureteric obstruction. Solez et al. (1Solez K Racusen LC Olsen S Morphologic differences between acute tubular necrosis in transplanted and native kidneys.in: Solez K Racusen LC Acute Renal Failure: Diagnosis, Treatment and Prevention. Marcel Dekker, Inc.;, New York, NY1998: 3-12Google Scholar) reviewed the pathology of DGF. The usual findings are of ATN, similar to ATN in native kidneys. Transplant ATN differs from native kidney ATN in having fewer tubular casts, occasional necrosis of complete tubular cross-sections, less tubular dedifferentiation and regeneration, more calcium oxalate crystals, and more microcalcification and isometric vacuolization (possibly due to calcineurin inhibitor [CNI] toxicity). Other entities presenting as DGF are antibody-mediated rejection, cortical necrosis/infarction, endothelial damage, acute CNI toxicity, thrombotic microangiopathy, drug-induced interstitial nephritis, and fulminant disease recurrence. Injury is proinflammatory in rodent models and also in humans, since inflammation can promote immune recognition, and may contribute to the increased rejection observed in kidneys with DGF. However, caution must be exercised before extrapolating from rodent studies to humans. Experience in human native kidney ATN has shown that the animal models do not predict the behavior of human kidneys with acute injury (e.g. trials of atrial natriuretic factor and insulin-like growth factor-1). Cosio presented provocative data that DGF may be a manifestation of vascular dysfunction, and is associated with blood pressure alterations. Ojo, Hunsicker, and Cecka analysed the associations of DGF in the USRDS and UNOS scientific renal transplant registry. The frequency of DGF in cadaver transplants has declined only slightly, from about 29 to 23% over the past decade. In contrast, acute rejection rates have fallen more steeply, and the fall in acute rejection has probably accounted for the improvement in survival. The incidence of DGF is about 6% in kidneys from living donors, higher than is generally realized. The risk factors for DGF (Table 1) give an indication of causes. Five categories of risk factors predict DGF: donor tissue quality (age); brain death and other components of cadaver donation; preservation variables, particularly cold ischemia time (CIT); immune variables (PRA, transfusions, HLA mismatch, previous transplants); and recipient variables, such as medical status and race/ethnicity. These are the same general factors that influence graft survival.Table 1: The risk factors for delayed graft function (DGF)Ojo's analysis of the US Scientific Renal Transplant Registry Data (1990–98)aData source: US Scientific Transplant Registry, including only solitary cadaveric kidney transplants (CAD) from January 1990 to June 1998. n = 65 142.Hunsicker's analysis of risk factors for DGF in UNOS DatabasebUNOS 1997 Center Specific Report Data Set, including transplants performed 1 January, 1988 to 30 April, 1994, and followed for periods up to 8.3 years. Population includes recipients of kidney transplants only, with data on cold ischemia time and ATN (54 698), with either known death or failure or at least 6-month follow-up (54 254), and with patient and graft survival to at least 6 months (46 653). Missing values estimated, with ‘missing’ flag.Donor age (10–40 years)Cold ischemia per 6 h1.145< 10 years1.16Peak PRA per 10%1.07641–55 years1.68Donor age per 10 years1.200> 55 years2.07Race/ethnicity (AA vs. White)1.555Cold ischemia time (12 h)Pre-transplant Tfs (> 10 vs. 0)1.75013–24 h1.38Recipient ponderosity/unit1.02125–36 h2.28Recipient sex (female vs. male)0.834> 36 h3.48Infant donor (yes vs. no)1.223PRA > 50% (PRA < 50%)1.21Total HLA mismatches (per mismatch)1.035Diabetic ESRD (vs. all others)1.03 (NS)African-American (AA) donor1.08 (NS)African-American recipient1.630-HLA mismatch (1 or more mismatch)0.80Duration of dialysis (per year)1.10a Data source: US Scientific Transplant Registry, including only solitary cadaveric kidney transplants (CAD) from January 1990 to June 1998. n = 65 142.b UNOS 1997 Center Specific Report Data Set, including transplants performed 1 January, 1988 to 30 April, 1994, and followed for periods up to 8.3 years. Population includes recipients of kidney transplants only, with data on cold ischemia time and ATN (54 698), with either known death or failure or at least 6-month follow-up (54 254), and with patient and graft survival to at least 6 months (46 653). Missing values estimated, with ‘missing’ flag. Open table in a new tab Halloran presented data that DGF shows strong pairing effects, i.e. kidneys from the same donor tended to behave the same. Thus the factors which exist before the kidneys are separated (donor age, brain death) play a large role in the occurrence of DGF, confirming previous studies (2Cosio FG Qiu W Henry ML et al.Factors related to the donor organ are major determinants of renal allograft function and survival.Transplantation. 1996; 62: 1571-1576Crossref PubMed Scopus (86) Google Scholar). In contrast, acute rejection episodes showed little pairing effect. The time taken to complete the vascular anastamoses predicts DGF and graft survival in some studies (3Halloran PF Aprile MA Farewell V et al.Early function as the principal correlate of graft survival: a multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine.Transplantation. 1988; 46: 223-228Crossref PubMed Scopus (204) Google Scholar) but is often not accurately recorded. The impact of the intraoperative variables is difficult to estimate because of poor standardized measurements. Immune parameters (PRA, HLA mismatches, previous transplants, transfusions, and positive flow cytometry cross-match) increase the risk of DGF. One mechanism for this association may be that antibody-mediated rejection produces a state of DGF. Thus pre-formed alloantibody that escapes detection in cross-matching, or appears rapidly post-transplant, can cause antibody-mediated rejection. This is difficult to recognize clinically and probably goes unrecognized in many centers. This could contribute to the increased rate of DGF in sensitized recipients. However, alloantibody alone may not explain all of the association between sensitization and DGF. Some interactions between the immune system and DGF are outlined in Table 2.Table 2: Role of delayed graft function (DGF) (‘acute tubular necrosis’, ATN) in graft survival early (< 6 months) and late (> 6 months) (multivariate model)Predictors of functional kidney transplant survival < 6 months (DGF included)Predictors of functional kidney transplant survival > 6 months (DGF included)Recipient ageRecipient race/ethnicityRecipient statusRecipient ageRecipient diagnosisLive donorDGFDonor ageTransplant dateTransplant dateDonor typeDonor weightRecipient race/ethnicityDGFHLA mismatchesHypertensionRecipient gender not CIT–HLA mismatches not CIT Open table in a new tab Kidneys that display DGF have a higher frequency of many adverse outcomes, including decreased functional graft survival (death censored), patient survival, and long-term function (e.g. 6-month GFR), and increased acute rejection. Delayed graft function is associated with the same reduction in graft survival and graft half-life as a full HLA mismatch. In cadaver transplants from 1994 to 1998, the half-life of kidneys with no DGF was 11.5 years, compared with 7.2 years with DGF. Hunsicker's multivariate analysis of factors affecting functional graft survival (Table 2) confirmed that DGF was significantly associated with graft loss, independent of other factors (Table 3). The effect of DGF on graft survival interacted with sensitization variables. When DGF was included in the model, either previous transfusions (< 6 months) or PRA (> 6 months) dropped out. Thus sensitization may operate by producing DGF: the effect of sensitization is lost when the kidney escapes DGF. Thus some of the impact of DGF on graft survival is due to forms of immune injury (rejection) manifesting as DGF.Table 3: Conceptual shifts in delayed graft function (DGF) and slow graft function (SGF)1.DGF is partly an outcome, partly a risk factor2.DGF reflects five influences: donor tissue quality (age); cadaver donation injury; preservation and implantation details; immune variables; and recipient variables3.DGF is a continuum with SGF: the cut-off for impact on survival or on acute rejection is probably between good function and SGF rather than between SGF and DGF4.Some risk factors (CIT) for DGF have little impact on graft survival. Thus injury is heterogeneous in its impact on graft survival5.Immune parameters increase DGF, in part by antibody-mediated renal injury. Better cross-matching may reduce this problem6.DGF increases acute rejection, but some impact of DGF is independent of rejection7.Improved immunosuppressive options are emerging for DGF: induction with anti-CD25 instead of polyclonals/anti-CD3, delayed introduction of CNIs, new CNI avoidance protocols using combinations of MMF, sirolimus/everolimus, FTY720, and others8.DGF is associated with powerful factors such as donor age, recipient race, and sensitization. Dissection of effects of DGF from the effects of these associated factors is difficult Open table in a new tab Although CIT is a powerful risk factor for DGF, it was not an independent risk factor for early or late graft survival in Hunsicker's multivariate analysis. This suggests that DGF is heterogeneous in its consequences: DGF due to immune factors or tissue quality (older donors) or brain death has more effect than DGF due to cold preservation time (CIT). This analysis contradicts some previous analyses (4Gjertson DW A multi-factor analysis of kidney graft outcomes at one and five years post-transplantation: 1996 UNOS update.in: Cecka JM Terasaki PI Clinical Transplants 1996. UCLA Tissue Typing Laboratory, Los Angeles, CA1997: 343-360Google Scholar). Cecka presented an analysis of paired kidneys from one donor, one with and one without DGF. This analysis focuses on the effects of DGF when the pair is discordant, which minimizes the effect of donor factors. In this comparison DGF is more deleterious for the graft survival and half-life than HLA mismatches, PRA, or acute rejection, and doubles the rate of early rejection. This analysis underscores that the effect of DGF is particularly ominous when the kidney pair is discordant, perhaps reflecting the impact of recipient variables. DGF is associated with increased risk of acute rejection, particularly early acute rejection. The high rate of DGF in African-Americans (AAs), and the high rate of acute rejection in AAs, makes this relationship complex. Hunsicker showed that AAs and DGF are independent risks for acute rejection. In Cecka's analysis of kidney pairs, the effect of DGF was stronger than the effect of acute rejection or PRA. The occurrence of DGF is associated with increased probability of patient death in the first 6 months, including death with a functioning graft (5Ojo AO Hanson JA Wolfe RA Leichtman AB Agodoa LY Port FK Long-term survival in renal transplant recipients with graft function. Delayed graft function does not reduce the survival of renal transplant allografts.Kidney Int. 2000; 57 (DOI: 10.1046/j.1523-1755.2000.00816.x): 307-313Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar). One explanation is comorbidities: frail recipients have an inability to perfuse kidney transplants and an increased risk of death for the same reason. Factors such as diabetes and obesity may independently increase DGF and also increase risk of cardiovascular events. Delayed graft function is associated with a reduction in eventual GFR, indicating permanent nephron loss (6Boom H Mallat MJ De Fijter JW Zwinderman AH Paul LC Delayed graft function influences renal function, but not survival.Kidney Int. 2000; 58 (DOI: 10.1046/j.1523-1755.2000.00235.x): 859-866Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar). Some long-term effects of DGF on survival reflect reduced GFR, because of the powerful relationship between GFR and graft survival. Many studies have shown increased rejection in DGF. In the UNOS database, DGF is associated with an increase in rejection. The incidence of acute rejection in the first 6 months is increased from 25% with no DGF to 40% with DGF. Is the adverse effect of DGF due to increased acute rejection? Some analyses find that DGF in the absence of rejection does not increase graft loss (6Boom H Mallat MJ De Fijter JW Zwinderman AH Paul LC Delayed graft function influences renal function, but not survival.Kidney Int. 2000; 58 (DOI: 10.1046/j.1523-1755.2000.00235.x): 859-866Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 7Marcen R Orofino L De Pascual J et al.Delayed graft function does not reduce the survival of renal transplant allografts.Transplantation. 1998; 66: 461-466Crossref PubMed Scopus (87) Google Scholar), while others reach the opposite conclusion (8Shoskes DA Cecka JM Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection.Transplantation. 1998; 66: 1697-1701Crossref PubMed Scopus (352) Google Scholar, 9Kyllonen LE Salmela KT Eklund BH et al.Long-term results of 1047 cadaveric kidney transplantations with special emphasis on initial graft function and rejection.Transplant Int. 2000; 13: 122-128Crossref PubMed Google Scholar). However, in the large UNOS database, DGF with no acute rejection adversely affects graft survival. Even the single center experience saying that DGF with no rejection does not affect survival concurs that DGF impairs GFR (7Marcen R Orofino L De Pascual J et al.Delayed graft function does not reduce the survival of renal transplant allografts.Transplantation. 1998; 66: 461-466Crossref PubMed Scopus (87) Google Scholar), which should eventually translate into reduced long-term survival. Delayed graft function is an arbitrary definition and excludes many kidneys with SGF. Matas proposed that the deleterious associations of DGF are shared by kidneys with SGF. He reported a series of adult recipients in Minnesota with adverse risk factors, in which DGF occurred in 41% and SGF (serum creatinine > 3 and no dialysis in the first week) in 27%. Both SGF and DGF groups had increased rejection, impaired graft survival, and impaired 6-month serum creatinine (SGF, 2.3; DGF, 2.5). Thus kidneys with SGF despite dialysis independence have the same adverse associations as DGF: increased acute rejection, poor GFR, and reduced survival. This is an important concept. Interventions that convert DGF to SGF may not alter rejection or survival functions. To be worthwhile, interventions in DGF must restore, not SGF, but excellent function, a tall order considering the failure of so many therapies to improve function in injured kidneys. Southard reviewed organ preservation. Simple cold storage (flush at 4°C and preserve at 4°C, usually with UW lactobionate solution) is the principal method employed. The introduction of UW resulted in a decrease in DGF in a randomized trial and in clinical experience. The components of preservation included hypothermia, attention to physical factors (pH, osmotic strength, colloid, impermeants), and biochemical factors (substrates and antioxidants, inhibitors, vasoactive agents). The advantages of lactobionate include impermeance, chelation of calcium and iron, and inhibition of matrix metalloproteinases. Other important factors included glutathione, adenosine phosphate, and hydroxyethyl starch. Machine perfusion (continuous perfusion at about 1 mL/min per g flow rates, temperature 4− 8°C) uses a different preservative solution, such as UW-gluconate solution. Pulsatile perfusion decreases the rate of DGF, and a consensus at the meeting believed that pulsatile perfusion was desirable. However, whether pulsatile perfusion confers long-term benefit is not clear. If pulsatile perfusion simply converts DGF into SGF, it may not change the fundamental parameters of the kidney that determine its survival. Data on the effect of preservation strategies on long-term graft function and survival as opposed to DGF would be welcome. A variety of newer measures are being proposed either to prevent or reverse DGF. A partial list includes antagonists of selectins and adhesion molecules (e.g. anti-LFA-1, soluble P selectin ligand), prostaglandin E1, ICAM-1 antisense oligonucleotides or monoclonal antibodies, and trimetazidine. The use of peritoneal dialysis, or of biocompatible hemodialysis membranes, may help to reduce DGF. The survey revealed that baseline immunosuppression in most centers is four drug therapy: anti-CD25, CNI, mycophenolate mofetil (MMF), and steroid. Many centers report that they change their immunosuppression when faced with DGF or a high risk of DGF. The common change is to reduce or delay introduction of CNIs (29/42 centers) and to switch to a depleting antibody (e.g. thymoglobulin or anti-CD3). Several centers are in agreement that anti-CD25 can achieve good results in DGF without depleting polyclonals or anti-CD3. Studies in the 1980s showed that CNIs prolong but do not cause DGF (10Novick AC Hwei HH Steinmuller D et al.Detrimental effect of cyclosporine on initial function of cadaver renal allografts following extended preservation. Results of a randomized prospective study.Transplantation. 1986; 42: 154-158Crossref PubMed Scopus (86) Google Scholar). CNIs also complicate the differential diagnosis of poorly functioning kidneys. As a result, many centers use protocols to minimize the effects of CNIs before function is established. The criteria used to guide the use of full doses of CNIs vary widely, e.g. urine output (either 1 or 2 L/24 h), a 20–30% drop in the serum creatinine, or an absolute level of serum creatinine < 3. Reports from several centers suggest that delayed introduction of CNIs does not measurably increase acute rejection. New CNI-free immunosuppression protocols are attracting interest, using combinations of anti-CD25, polyclonal ALG, MMF, sirolimus, everolimus, and new agents such as FTY720 and CTLA4Ig. A multicenter trial with 98 patients at low immunologic risk who received anti-CD25, MMF, and steroid demonstrated good outcomes but high rates of acute rejection (53% at 12 months). Vincenti presented early experiences with treating DGF with daclizumab, MMF, sirolimus, and prednisone. Three of eight cases have had rejection. It will be of interest to find out whether any protocols free of CNIs can achieve the same low rates of acute rejection now being regularly achieved with CNI-MMF protocols. The previous tendency has been to use ALG or anti-CD3 as prophylaxis in the context of high immunologic risk (e.g. highly sensitized) and in DGF, but increasingly anti-CD25 is replacing ALG and anti-CD3 for DGF, although not for the immunological risks. In the 1980s, prophylactic ALG and anti-CD3 improved graft survival (11Szczech LA Berlin JA Aradhye S Grossman RA Feldman HI Effect of anti-lymphocyte induction therapy on renal allograft survival: a meta-analysis.J Am Soc Nephrol. 1997; 8: 1771-1777Crossref PubMed Google Scholar), particularly when the immunologic risk was high. The use of ALG in DGF was probably beneficial in preventing graft loss (12Halloran PF Aprile M Farewell V Factors influencing early renal function in cadaver kidney transplants: a case-control study.Transplantation. 1988; 45: 122-127Crossref PubMed Scopus (115) Google Scholar). OKT3 was also beneficial in kidneys with prolonged CIT (13Abramowicz D Norman DJ Vereerstraeten P et al.OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: association with improvement in long-term survival.Kidney Int. 1996; 49: 768-772Abstract Full Text PDF PubMed Scopus (41) Google Scholar). ALG and anti-CD3 are still widely used for prophylaxis against acute rejection in kidneys with DGF and in kidneys with high immunologic risk. However, in the present era, with much lower rejection rates, the benefits of ALG/anti-CD3 are less clear: ALG/anti-CD3 prophylaxis reduces rejection but may not improve graft survival. Cecka showed that induction therapy with ALG or anti-CD3 decreases the rate of rejection in kidneys with DGF, almost to the level of kidneys with no DGF. However, induction did not affect graft survival. With no DGF, 3-year graft survival is 83%; with DGF, the 3-year survival is between 70 and 72%, with or without induction. Thymoglobulin is a popular ALG, which produces a ‘profound and durable beneficial lymphopenia’(14Brennan DC Flavin K Lowell JA et al.A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published erratum appears in Transplantation 1999; 67: 1386].Transplantation. 1999; 67: 1011-1018Crossref PubMed Scopus (311) Google Scholar). The Minneapolis experience indicates that intraoperative thymoglobulin is well tolerated, if the infusion is filtered and administered over a minimum of 6 h. Some still advocate the benefits of OKT3 in kidneys at risk of DGF. Abramowicz et al. (13Abramowicz D Norman DJ Vereerstraeten P et al.OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: association with improvement in long-term survival.Kidney Int. 1996; 49: 768-772Abstract Full Text PDF PubMed Scopus (41) Google Scholar) reported that OKT3 prophylaxis apparently improved long-term survival of renal grafts with prolonged cold ischemia times, compared with early introduction of cyclosporine. DGF is an important association of poor graft outcome in children (15Tejani AH Sullivan EK Alexander SR Fine RN Harmon WE Kohaut EC 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 (DOI: 10.1034/j.1399-3046.1999.00057.x): 293-300Crossref PubMed Scopus (67) Google Scholar). Pediatric kidney transplants represent special problems. In NAPTRCS, graft loss is increased by the absence of induction therapy (16Tejani AH Stablein DM Sullivan EK et al.The impact of donor source, recipient age, pre-operative immunotherapy and induction therapy on early and late acute rejections in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).Pediatr Transplant. 1998; 2: 318-324PubMed Google Scholar). Bartlett, Ferguson, and Kaplan reviewed experience with anti-CD25s in patients with DGF or at risk for DGF. Bartlett's protocol used basiliximab and tacrolimus for patients with DGF, with delayed tacrolimus introduction (about 10 d), for patients projected to have DGF based on donor characteristics. Patients with PRA > 60% received ATG and are excluded. In their study, the incidence of DGF was 44%, mostly in AAs. Two-year patient survival was 92% and graft survival 89% in the treated group, with acute rejection rate of 14% by 2 years. These results compared favorably with historical controls receiving OKT3. Basiliximab represented a significant saving compared with OKT3, with a similar length of stay. There were lower drug and laboratory costs with basiliximab with no compromise in efficacy, and reduced ICU stay. Rejection was greater in patients with DGF (23%) than in those with no DGF (8%), and also in AAs (18%) compared with Caucasians (8%). However, by multivariate analysis, rejection was significantly associated only with AAs and not with DGF. Ferguson presented the Ohio State experience with the delayed initiation of cyclosporine using anti-CD25 and MMF. Comparing anti-CD25 (basiliximab) to anti-CD3 induction at Ohio State University, in a retrospective analysis, the anti-CD25 group had less acute rejection (7%), with 97% graft survival. Delay of introduction of cyclosporine did not increase rejection rates. Kaplan reviewed the USA basiliximab induction study (17Kahan BD Rajagopalan PR Hall M Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group.Transplantation. 1999; 67: 276-284Crossref PubMed Scopus (468) Google Scholar). DGF was less in the basiliximab group (p = 0.07), and creatinine clearances were better. Similar effects were not seen in the other study of basiliximab (18Nashan B Moore R Amlot P Schmidt AG Abeywickrama K Soulillou JP Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group [published erratum appears in Lancet 1997; 350: 1484].Lancet. 1997; 350 (DOI: 10.1016/s0140-6736(97)09278-7): 1193-1198Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar) or in the pivotal daclizumab studies of daclizumab anti-CD25 (19Nashan B Light S Hardie IR Lin A Johnson JR Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group.Transplantation. 1999; 6: 110-115Crossref Scopus (298) Google Scholar, 20Vincenti F Kirkman R Light S et al.Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group [see comments].N Engl J Med. 1998; 338: 161-165Crossref PubMed Scopus (826) Google Scholar), raising doubts about whether the improved renal function was due to the anti-CD25. Kaplan also reviewed results of a multicenter study of basiliximab/cyclosporine vs. ATGAM with delayed cyclosporine (an open-label, randomized, multicenter). The incidence of DGF was 10 vs. 12%, and of poor function was 23 vs. 34%, respectively, in the anti-CD25 vs. ATGAM groups. At 6 months, biopsy proven rejection rates were around 20% in both groups, and the incidence of any rejection was about 30%. Adverse events, renal function, and length of stay were equal, supporting the utility of anti-CD25. The use of the anti-CD25 plus sirolimus has also been advocated in patients at high risk of DGF (21Hong JC Kahan BD Use of anti-CD25 monoclonal antibody in combination with rapamycin to eliminate cyclosporine treatment during the induction phase of immunosuppression.Transplantation. 1999; 68: 701-704Crossref PubMed Scopus (69) Google Scholar). Delayed graft function is a complex phenomenon in which donor age, brain death, preservation time, recipient factors, and immune mechanisms play a role (Table 3). DGF is both an outcome and a predictor of the subsequent course of a renal transplant. DGF can reflect several processes, which vary in their significance. Some types of injury presenting as DGF are benign while others have a lasting impact on function and outcome. Hunsicker's analysis showed that CIT may produce relatively benign injury, a finding in conflict with other analyses. In contrast, donor age, brain death, and immune variables are associated with increased DGF and have robust effects on function and survival.