Pathological and Clinical Characterization of the ‘Troubled Transplant’: Data from the DeKAF Study

We are studying two cohorts of kidney transplant recipients, with the goal of defining specific clinicopathologic entities that cause late graft dysfunction: (1) prevalent patients with new onset late graft dysfunction (cross-sectional cohort); and (2) newly transplanted patients (prospective cohort). For the cross-sectional cohort (n = 440), mean time from transplant to biopsy was 7.5 ± 6.1 years. Local pathology diagnoses included CAN (48%), CNI toxicity (30%), and perhaps surprisingly, acute rejection (cellular- or Ab-mediated) (23%). Actuarial rate of death-censored graft loss at 1 year postbiopsy was 17.7%; at 2 years, 29.8%. There was no difference in postbiopsy graft survival for recipients with versus without CAN (p = 0.9). Prospective cohort patients (n = 2427) developing graft dysfunction >3 months posttransplant undergo ‘index’ biopsy. The rate of index biopsy was 8.8% between 3 and 12 months, and 18.2% by 2 years. Mean time from transplant to index biopsy was 1.0 ± 0.6 years. Local pathology diagnoses included CAN (27%), and acute rejection (39%). Intervention to halt late graft deterioration cannot be developed in the absence of meaningful diagnostic entities. We found CAN in late posttransplant biopsies to be of no prognostic value. The DeKAF study will provide broadly applicable diagnostic information to serve as the basis for future trials. We are studying two cohorts of kidney transplant recipients, with the goal of defining specific clinicopathologic entities that cause late graft dysfunction: (1) prevalent patients with new onset late graft dysfunction (cross-sectional cohort); and (2) newly transplanted patients (prospective cohort). For the cross-sectional cohort (n = 440), mean time from transplant to biopsy was 7.5 ± 6.1 years. Local pathology diagnoses included CAN (48%), CNI toxicity (30%), and perhaps surprisingly, acute rejection (cellular- or Ab-mediated) (23%). Actuarial rate of death-censored graft loss at 1 year postbiopsy was 17.7%; at 2 years, 29.8%. There was no difference in postbiopsy graft survival for recipients with versus without CAN (p = 0.9). Prospective cohort patients (n = 2427) developing graft dysfunction >3 months posttransplant undergo ‘index’ biopsy. The rate of index biopsy was 8.8% between 3 and 12 months, and 18.2% by 2 years. Mean time from transplant to index biopsy was 1.0 ± 0.6 years. Local pathology diagnoses included CAN (27%), and acute rejection (39%). Intervention to halt late graft deterioration cannot be developed in the absence of meaningful diagnostic entities. We found CAN in late posttransplant biopsies to be of no prognostic value. The DeKAF study will provide broadly applicable diagnostic information to serve as the basis for future trials. The two major problems in kidney transplantation today are late graft failure and the shortage of donor organs. These problems are interrelated; kidney allograft failure is currently the fourth leading cause of end stage renal disease in the United States and Canada, and recipients returning to the waiting list for deceased donor kidney transplantation contribute to the organ shortage. The use of modern immunosuppressive regimens has resulted in a significant decrease in acute rejection rates during the first year after kidney transplantation. In some studies, this has been associated with improvement in long-term outcome (1Matas AJ Humar A Payne WD et al.Decreased acute rejection in kidney transplant recipients is associated with decreased chronic rejection.Ann Surg. 1999; 230: 493-498Crossref PubMed Scopus (51) Google Scholar,2Hariharan S Johnson CP Bresnahan BA Taranto SE McIntosh MJ Stablein D Improved graft survival after renal transplantation in the United States, 1988 to 1996.N Engl J Med. 2000; 342: 605-612Crossref PubMed Scopus (1629) Google Scholar) at least partially due to better 1-year function (3Hariharan S McBride MA Cherikh WS Tolleris CB Bresnahan BA Johnson CP Post-transplant renal function in the first year predicts long-term kidney transplant survival.Kidney Int. 2002; 62: 311-318Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar). The stability of long-term function (the slope of the GFR) has also improved perhaps due to superior control of rejection with newer protocols (4Gourishankar S Hunsicker LG Jhangri GS Cockfield SM Halloran PF The stability of the glomerular filtration rate after renal transplantation is improving.J Am Soc Nephrol. 2003; 14: 2387-2394Crossref PubMed Scopus (97) Google Scholar,5Kasiske BL Gaston RS Gourishankar S et al.Long-term deterioration of kidney allograft function.Am J Transplant. 2005; 5: 1405Crossref PubMed Scopus (103) Google Scholar). In contrast, other large series, while noting a significant decrease in early rejection rates, have shown no significant improvement in long-term outcome (6Meier-Kriesche H-U Schold JD Kaplan B Long-term renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies?.Am J Transplant. 2004; 4: 1289-1295Crossref PubMed Scopus (532) Google Scholar,7Meier-Kriesche H-U Schold JD Srinivas TR Kaplan B Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.Am J Transplant. 2004; : 378-383Crossref PubMed Scopus (985) Google Scholar). There is no doubt that late graft loss continues to be a major challenge, with almost 4300 kidney transplant recipients returning to dialysis in the United States and Canada in 2005, most of them beyond 1 year after transplantation. Furthermore, improvements in graft survival have clearly plateaued with lower acute rejection rates and better early outcomes, but late graft loss remains an ongoing problem (8Available at: http://www.usrds.org. Accessed June 2009.Google Scholar). Determining the optimal treatment of recipients with late graft dysfunction (the troubled transplant) has been limited for a number of reasons: (a) deterioration of function can begin at any time following kidney transplantation and can be insidious; (b) there are likely many causes; (c) there are only a limited number of cases in any given year at a single institution; and, perhaps most importantly; (d) biopsy is usually done late in the clinical course (if at all), after the active phase of damage has occurred and only scar tissue is observable. The majority of these cases have been labeled ‘chronic rejection,’‘chronic allograft nephropathy’ (CAN) or, more recently, ‘interstitial fibrosis and tubular atrophy, no evidence of any specific etiology’ as represented by interstitial fibrosis and tubular atrophy (IF/TA) on biopsy (9Solez K Colvin RB Racusen LC et al.Banff’05 Meeting Report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’).Am J Transplant. 2007; 7: 518-526Crossref PubMed Scopus (926) Google Scholar). However, these terms do not represent specific entities from an etiologic, physiologic or pathologic point of view. To overcome these diagnostic shortcomings, the Long-Term Deterioration of Kidney Allograft Function (DeKAF) study is investigating ‘the troubled transplant’ phenotype with the aim of attributing dysfunction and/or loss to specific clinico-pathologic entities. By creating a multicenter consortium (so there are a sufficient number of patients) and doing biopsies early in the course of new-onset late graft dysfunction, we hope to overcome the above issues. Our goal is to show, with the use of early biopsy and appropriate analyses, that: (1) most chronic graft dysfunction and late graft failure can be attributed to well-understood entities that injure the nephron; (2) these disease processes or other sources of injury act at the time that deterioration is detected; (3) at least some of these entities are preventable and/or treatable and (4) the nihilism associated with the concept of chronic rejection, CAN, or IF/TA should be replaced by the assumption that therapy can prevent or slow progression in many cases. Defining specific entities will potentially allow development of intervention trials. In this first publication, we document the local pathologists’ diagnoses in two cohorts of recipients with new-onset late graft dysfunction and show that these previously stable grafts with new-onset late graft dysfunction have a relatively high rate of subsequent graft failure. We note a high prevalence of acute rejection in long-term allografts with new dysfunction. And we show that the diagnosis of CAN in late posttransplant biopsies is of no prognostic significance. DeKAF is a multicenter, observational study conducted at seven transplant centers in the United States and Canada, funded by the National Institutes of Health. Our hypotheses are that: (1) there are multiple, definable entities leading to late graft dysfunction; (2) these entities can be differentiated by means of clinical, serologic, and pathologic studies and (3) progressive late graft dysfunction is due to identifiable, currently operating injurious processes and not the consequence of a past injury. Our long-term goal is to understand and reduce long-term kidney transplant deterioration. A detailed description of the study can be found at http://www.clinicaltrials.gov (NCT00270712). Institutional Review Board approval was obtained at all participating sites. We are following two distinct populations of kidney transplant recipients: a cross-sectional cohort and a prospective cohort. The cross-sectional cohort (launched February 1, 2006) consists of recipients transplanted prior to October 1, 2005, having a last reported serum creatinine level ≤ 2 mg/dl between January 1, 2005 and January 1, 2006, and subsequently developing graft dysfunction (defined as a ≥25% increase in creatinine level or new onset proteinuria leading to a biopsy). Inclusion and exclusion criteria are outlined in Table 1. At the time of biopsy, recipients were enrolled in the study and clinical data entered into the database. Patients in the cross-sectional cohort enroll at different times after transplant and at different times after January 2006; for example, a recipient with a baseline creatinine of 1.2 mg/dL is biopsied if the creatinine reaches 1.5 mg/dL (e.g. at year 2, 4 or at any time thereafter). This cohort provides an overview of the troubled kidney irrespective of the time from transplant. There is not a control group; however, the importance of this cohort is in defining distinct clinico-pathologic entities that may occur late posttransplant (and may be difficult to determine in an inception cohort [because of the need for long-term follow-up]).Table 1Inclusion criteria for the prospective and cross-sectional cohortsProspective cohort inclusion criteria:Kidney (or kidney-pancreas) transplant recipient, no more than 10 days posttransplant.No organs other than possibly a pancreas transplanted simultaneously with the qualifying kidney transplant.Cross-sectional cohort inclusion criteria:Kidney (or kidney-pancreas) transplant recipient prior to October 1, 2005.No organs other than the qualifying kidney or simultaneous kidney-pancreas.The last available serum creatinine drawn between January 1, 2005 and January 1, 2006 ≤2 mg/dL.Clinically indicated biopsy. Open table in a new tab Prospective cohort recipients are enrolled at the time of kidney or simultaneous kidney-pancreas transplant (provided no other organs are transplanted; Table 1). At the time of transplant (and consent), clinical information is entered into the database; baseline serum creatinine level is determined at 3 months posttransplant. Those demonstrating subsequent deterioration of graft function (defined as ≥25% increase in serum creatinine level over baseline or new onset proteinuria) undergo biopsy (hereafter referred to as the ‘index biopsy’). This cohort provides clinical information on all patients; there is a control group, without graft dysfunction, that is not biopsied. The prospective cohort was launched on October 1, 2005. For both cohorts, medical history, recipient and donor characteristics, and operative and postoperative information are collected at the time of enrollment. For both, follow-up data are collected every 6 months; additionally, in the prospective cohort, data collection occurs at 1 and 3 months posttransplant. Event-driven data collection is triggered by any of the following: a clinically indicated biopsy; a local diagnosis of treated acute rejection (biopsy-proven or treated without obtaining a biopsy); selected viral, fungal or mycobacterial infections; and graft failure (return to dialysis, retransplantation or death). To exclude the effects of permanent damage due to acute rejection, the creatinine reference point is reset for each participant 6 weeks after the initiation of therapy for acute rejection. The new value for the creatinine reference point is defined to be the average of up to three serum creatinine measurements taken at least 1 week apart and drawn between 6 and 12 weeks following initiation of treatment for acute rejection. Allograft biopsies read by the local pathologist are used to guide clinical care according to local protocols. Representative histologic sections (H&E, silver, PAS, trichrome stains and 11 unstained sections for additional studies) are to a for biopsies were by the pathologist the LC K Colvin RB et of renal allograft Int. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In biopsies were for and for in of atrophy and in of atrophy of was done as the 2005 K Colvin RB Racusen LC et of renal allograft and future J Transplant. PubMed Scopus Google Scholar). and were in the as and in of fibrosis and/or 1 = 2 = 3 = = in up to of 1 = 2 = and 3 = of collected at the time of each biopsy are at and to a in with information the and donor and the For both cohorts, we time from transplant to biopsy, renal local pathologists’ graft and slope of the of For the cross-sectional cohort, we rate of graft loss for with versus without a local diagnosis of are given as point with on the for the survival The was used to survival of the of creatinine was effects for each cohort. is from 3 posttransplant in the prospective cohort, while in the cross-sectional cohort, a is used to slope from biopsy to 6 postbiopsy and from 6 postbiopsy In each effects are included for the and each slope for the slope for the prospective cohort, and two slope effects in for the cross-sectional cohort, for each follow-up is for graft loss or of are potentially to for are on the to the with Patients (n = are of the transplant in Canada and the United States The time ± from transplant to biopsy was 7.5 ± 6.1 serum creatinine ± prior to January 2006 was ± mg/dL creatinine level at the time of graft biopsy was ± mg/dL cohort (n = cohort (n = at transplant ± ± ± transplant to index biopsy ± ± ± Open table in a new tab To in the cross-sectional cohort there have been graft after (and biopsy). 10 recipients with function and to dialysis or were The most of graft loss were CAN rejection and disease The rate of death-censored graft loss in the first year after biopsy was at 2 years, The slope of the of serum creatinine from biopsy to 6 months postbiopsy was mg/dL the slope following 6 months postbiopsy was mg/dL 1). The local pathologists’ and diagnoses of the biopsy are in Table shown is the mean time from transplant to biopsy for each biopsies with available of enrolled a or diagnosis of CAN, rejection, and transplant as and diagnoses were not biopsy and diagnoses in the prospective and cross-sectional as both and diagnoses cohort (n = cohort (n = from Mean ± from Mean ± rejection ± ± rejection ± ± tubular ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± as both and diagnoses Open table in a new tab there was no difference in subsequent graft survival between patients biopsy local diagnosis or was CAN (p = In the postbiopsy slope of versus time not between the two For with a local diagnosis of CAN, the slope from biopsy to 6 postbiopsy was ± mg/dL for without CAN, ± mg/dL (p = For with a local diagnosis of CAN, the slope from 6 months was ± mg/dL for without CAN, ± mg/dL (p = At time of a of biopsies have data available on determined for in = = and a for and in of tubular atrophy = were for as by a of at least was defined as Furthermore, of biopsies in of atrophy, in of atrophy and biopsies with determined in of atrophy, in of atrophy, and (n = 2427) are of the transplant in Canada and the United States For the prospective cohort, the mean slope of after 3 was ± of February 2, there have been graft recipients with and to dialysis or were of graft loss included rejection and nephropathy The rate of graft loss at 1 year posttransplant was at 2 years, The rate of death-censored graft loss at 1 year was at 2 years, the enrolled recipients, have index biopsy. The mean time from transplantation to index biopsy was 1.0 ± 0.6 years. The serum creatinine level at the time of biopsy was ± mg/dL The rate of index biopsy was 8.8% between months 3 and 1 year and 18.2% at year 2 the recipients with index biopsy, have graft and additional with The rate of graft loss at 6 months postbiopsy was graft survival is for having an index biopsy the (p For with graft survival and subsequently having an index biopsy, 1-year death-censored graft survival is For with graft survival and not biopsy, 1-year death-censored graft survival is The local pathologists’ and diagnoses of the index biopsy are in Table shown is the mean time from transplant to biopsy for each index a local pathologists’ or diagnosis of rejection of allograft of and of transplant recipients with acute rejection, creatinine level to baseline after treatment better postbiopsy graft survival versus creatinine level not to baseline graft dysfunction and graft loss major after renal transplantation. in serum creatinine have been associated with late graft dysfunction may also contribute to the and after a kidney transplant. of late graft dysfunction are defined (e.g. due to However, the majority of cases are attributed to the diagnoses of CAN, chronic rejection, and The DeKAF study was to the concept that the majority of cases of late graft dysfunction can be attributed to a single with a and rate of deterioration of renal In we the of terms as and hope to the of specific entities to the deterioration and loss of these The two cohorts in this study provide data new onset late graft dysfunction in (a) long-term recipients, and (b) new For the cross-sectional cohort, we the to a posttransplant progressive graft dysfunction can at any we will determine the rate of new onset graft dysfunction at posttransplant We recipients with graft dysfunction on the that biopsy early in the course is to the entities that may cause late graft and that late biopsies not likely to be of in The cross-sectional cohort provides information on the troubled kidney that graft dysfunction at any time posttransplant. The prospective cohort has the of a control group, as some recipients will late dysfunction; while will We will be to clinical for late graft dysfunction and for progression of deterioration for each diagnostic However, long-term follow-up will be To graft survival is death-censored The prospective cohort also will allow to the of entities (or of as defined in the cross-sectional cohort or to if recipients with graft dysfunction have different entities or a different for each and, will allow to determine clinical for graft dysfunction and For this cohort, the rate of development of late graft dysfunction was 8.8% between 3 and 1 by year To we have a number of to both our long-term study and to other studies of late kidney allograft deterioration. stable grafts that show new onset late graft dysfunction have a high rate of subsequent graft failure. In the cross-sectional cohort, we are clearly this of the mean serum creatinine level was ± mg/dL as of January 1, 2006, death-censored graft loss 1 year of subsequent development of graft dysfunction was at 2 years, 29.8%. In the prospective cohort, death-censored graft survival was for having index biopsies after 3 months posttransplant. loss was not biopsy, graft dysfunction as the of graft failure. we have the local pathologists’ of biopsies at the time of new onset late graft dysfunction. is of that biopsies from both cohorts relatively local diagnoses was in both in the cross-sectional cohort and in the prospective cohort. The of these biopsies will to the diagnosis of CAN, entities with different and a high of recipients in both cohorts were as having acute rejection. this was for the prospective cohort time from transplant to biopsy, 1.0 ± 0.6 it was a in the cross-sectional cohort new onset of dysfunction was relatively late posttransplant ± 6.1 of note was the that a of recipients in each cohort were with rejection. These the need to for a specific cause of late allograft dysfunction, as failure to rejection a significant number of patients of in and perhaps the most of our to is the in the cross-sectional cohort, the local diagnosis of CAN was of no prognostic Those with and without CAN of postbiopsy graft failure. There was also no difference with and without in the postbiopsy slope of versus for recipients with new onset late graft dysfunction, the diagnosis of CAN not a of patients with a different A and potentially is the high of in of interstitial atrophy and fibrosis and in of tubular atrophy has both these However, the additional studies to these to the Our data show that in biopsies with = both and are et reported that the was better than the in of in of graft outcome J S et is superior to the in outcome and the of in renal J Transplant. PubMed Scopus Google Scholar). of our study for recipients in the prospective cohort is to reset the baseline creatinine level after treatment of an acute rejection and to do a biopsy if the creatinine from that new and have shown that recipients creatinine not to baseline after rejection treatment have decreased graft and our data this H-U Schold JD Srinivas TR Kaplan B Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.Am J Transplant. 2004; : 378-383Crossref PubMed Scopus (985) Google D of on long-term kidney graft survival of rejection with PubMed Scopus Google et acute rejection is not a significant for the development of chronic rejection in renal allograft Int. 2000; PubMed Scopus Google Scholar). However, this provides no of the of the have shown no between serum creatinine level and the subsequent rate of deterioration of graft function over time (4Gourishankar S Hunsicker LG Jhangri GS Cockfield SM Halloran PF The stability of the glomerular filtration rate after renal transplantation is improving.J Am Soc Nephrol. 2003; 14: 2387-2394Crossref PubMed Scopus (97) Google The in allograft function long-term kidney transplant Am Soc Nephrol. 2003; 14: PubMed Scopus Google BL Gaston RS Gourishankar S et al.Long-term deterioration of kidney allograft function.Am J Transplant. 2005; 5: PubMed Scopus Google Scholar). In et an rate of subsequent rejection in creatinine level not to baseline H-U Schold JD Srinivas TR Kaplan B Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.Am J Transplant. 2004; : 378-383Crossref PubMed Scopus (985) Google Scholar). The of the DeKAF study is the of entities that cause late graft dysfunction, with the goal of developing intervention our consortium and reduce the of late graft dysfunction and For the prospective cohort, we have defined the rate of new onset graft dysfunction; for both cohorts, we have defined the rate of graft loss after new dysfunction, and the local biopsy We have shown that the local diagnosis of CAN is of no prognostic significance. Our data can be used as information for future of intervention to prevent or graft dysfunction in kidney transplant recipients will of clinically meaningful entities to better understand the phenotype of the We to our local are a in this And we for in of the

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