Investigator: Nadine D. Tanenbaum, MD

Location: School of Medicine, Duke University Medical Center Durham, North Carolina

Timeline: July 1, 2005 - July 1, 2006

Abstract
Background: Wegener's Granulomatosis (WG) is a rare systemic vasculitis that can affect almost any organ. Renal involvement occurs in at least 80% of patients. Kidney transplantation is a treatment option for those who reach end-stage renal disease. Small studies have demonstrated the success of transplantation in this population. Multiple aspects, however, regarding the long-term course of WG patients who undergo renal transplantation remain unknown. Information on the long-term allograft and patient survival in large numbers of patients, as well as on the incidences of acute allograft rejection and posttransplant malignancies, is lacking.
Hypotheses:
1. Patient and allograft survival may be different between WG transplant recipients and transplant recipients without WG.
2. WG transplant recipients and transplant recipients without WG may have different incidences of acute allograft rejection.
3. Patients with WG may be at greater risk than patients without WG for the development of posttransplant malignancies.
4. Specific risk factors can be identified that predispose certain WG transplant recipients to poorer outcomes.

Methods and Aims: Data will be extracted from the United Network for Organ Sharing database on 883 patients with WG who have undergone a total of 929 renal transplantations from January 1, 1988 through February 28, 2005. A group of 2787 patients matched for age, ethnicity, history of prior transplant, time of transplant, and center will serve as the control group. The aims of this study are to compare long-term patient and allograft survival rates, as well as to compare the incidences of acute allograft rejection and posttransplant malignancies between these two groups. Another aim is to identify predictors of adverse outcomes in the WG cohort.

Significance: Characterizing the course of WG transplant recipients and identifying risk factors for adverse outcomes may help us better define how to care for this population of patients.
The goal of this study is to examine the clinical course of a large population of patients with Wegener's granulomatosis (WG) who have undergone renal transplantation. In a preliminary data search on the United Network for Organ Sharing (UNOS) website, 883 WG patients in the United States from January 1, 1988 through February 28, 2005 have been identified who have received a total of 929 kidney transplants.
Specific aims
1. To compare long-term patient and renal allograft survival in renal transplant recipients with and without WG.
2. To compare the incidence of acute allograft rejection in renal transplant recipients with and without WG.
3. To determine the incidence and types of posttransplant malignancies in WG transplant recipients and to evaluate whether this risk is elevated compared to transplant recipients without WG.
4. To identify predictors for patient and renal allograft death, malignancy, and WG allograft recurrence in WG transplant recipients.

Characterizing the clinical course of WG transplant recipients and identifying risk factors for adverse outcomes may help us better define how to follow and care for this population of patients.

Methods
WG is a rare systemic anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis that can affect almost any organ. Untreated, the one year mortality rate is 80% [1]. Renal involvement, characterized by a pauci-immune necrotizing crescentic glomerulonephritis (GN), occurs in at least 80% of patients at some point in their course [2-4]. Between 11-43% of patients with WG or ANCA-associated GN develop end-stage renal disease (ESRD) and require chronic hemodialysis [3,5-8]. Among patients with ANCA-associated GN, the need for dialysis at diagnosis is a predictor of mortality with a significant difference in 5-year survival rates between patients with ESRD (61%) and those with preserved renal function (87%) [7].

In WG patients who reach ESRD, renal transplantation is treatment option. Case reports and small observational studies have demonstrated the success of transplantation in this population [9-13]. Multiple important aspects, however, regarding the course of WG patients who undergo renal transplantation remain unknown. Information is lacking regarding the long-term renal and patient survival in large numbers of patients, the risk of posttransplant malignancies, and the optimal immunosuppressive regimens. A better characterization of the incidence of disease recurrence and acute allograft rejection in this population is also needed.

Patient and renal allograft survival
One aim of this study is to compare differences in mortality and allograft survival between WG patients and patients without WG who receive a kidney transplant. The age of transplant recipients in this country is increasing. Patients older than 50 year now receive 47% of cadaveric transplants [14]. It is therefore likely that in the future clinicians will be confronted more frequently with the decision of whether renal transplantation in the often elderly WG patient is appropriate and whether WG patients will fare as well as patients without vasculitis. In the general transplant recipient population among patients age 60-74 years old, the estimate of additional years of life gained with a transplant compared to dialysis is about four years [15]. Small studies with fairly short follow-up in both WG patients and in patients with other types of vasculitides such as lupus suggest similar patient and graft survival when compared to patients without vasculitis [16-21]. In a group of 115 WG patients transplanted between 1982-1990, patient and allograft survival at 3 years of follow-up was similar between those with and without WG, although there was a trend towards a lower survival in the WG group [16]. Smaller studies that have followed patients up to 5 years have shown similar equivalent results [17-19]. However, the latter studies have consisted of less than 20 patients with either microscopic polyangiitis or WG [17-19]. Given its large cohort size and long length of follow-up, the proposed investigation is uniquely suited to address this issue in more detail. Furthermore, unlike most prior studies, this proposal includes patients only with WG. The course of renal disease in WG may differ from that associated with microscopic polyangiitis (MPA) or renal-limited vasculitis (RLV) [7].

Acute allograft rejection
Another aim of this study is to evaluate whether WG patients are at increased risk for acute allograft rejection. Acute allograft rejection is a major risk factor for chronic allograft nephropathy and ultimate graft loss [22-24]. Established risk factors for acute allograft rejection are the following: Black race, cadaveric transplant, second transplant recipients, elevated panel-reactive antibodies, increasing degree of HLA antigen mismatches, and possibly viral infections most notably CMV [25]. It is possible that ANCAs may cause subclinical neutrophil activation in WG transplant recipients, causing subsequent elevated levels of cytokines that might augment allograft rejection. Alternatively, the occurrence of rejection may predispose to recurrent allograft WG by cytokine-induced priming of ANCA antigens in the allograft. Demonstrating that WG transplant recipients have an elevated risk of acute allograft rejection in adjusted analyses would lend support to the idea that ANCA antibodies might be pathogenic in the rejection process and further studies, such as ANCA titer monitoring, could be proposed.

Malignancy in transplantation and WG
Patients with WG and ANCA-associated vasculitis are at increased risk for malignancies, especially bladder, skin, hematological, and possibly renal cell malignancies [26-33]. Much of this risk has been attributed to cyclophosphamide use. Of 1065 WG patients from a Swedish registry, 13% of deaths were secondary to a malignancy [27]. In some studies, the risk of bladder cancer in patients treated with cyclophosphamide has been about 30-fold greater than expected [26,31]. Other studies without available history on cyclophosphamide use have reported a 5-fold increase in bladder cancer risk [28]. The link between vasculitis and malignancies in general is incompletely understood. WG patients not treated with cyclophosphamide may also be at increased risk for malignancies. For example, Tatsis et. al. reported either preceding or concurrent diagnosis of malignancy in 23 patients also diagnosed with WG [32]. It is conceivable that there is a common genetic susceptibility for development of both WG and malignancy. It is also possible that the chronic immune stimulation of vasculitis predisposes to malignancy or inversely, that neoantigen exposure in malignancy may trigger the development of WG.

Malignancy is more common in all renal transplant recipients compared to age- and gender-matched controls, in large part secondary to the intensity of the immunosuppressive regimen. Skin cancers, particularly squamous cell skin cancers, are most common. There is also an increased risk of lymphomas, especially non-Hodgkin’s lymphomas, as well as renal cell carcinomas, Kaposi sarcoma, anogenital and hepatocellular carcinomas. Interestingly, there is only a mild increase in the risk of more common cancers such as lung, prostate, and colorectal cancers [34,35]. Clear risk factors for the development of malignancies after transplantation are sun exposure (for skin cancers), history of pretransplant malignancies, increasing age, Epstein Barr virus (EBV) negative to positive seroconversion at the time of transplantation and exposure to antilymphocytic therapy (the latter two are risk factors mainly for lymphomas) [34,35]. Higher maintenance levels of cyclosporine and tacrolimus, lower CD4 counts (for skin cancer) and increasing length of dialysis pretransplant have also been implicated as risk factors [34,35]. Recent studies have suggested that the immunosuppressive medicine sirolimus, which binds to FK binding protein and modulates the mammalian target of rapamycin (mTOR) resulting in eventual cell cycle arrest in the G1-S phase, has antiproliferative properties and has been associated with less posttransplant malignancies. Unlike tacrolimus and cyclosporine, sirolimus blocks cytokine-driven T- and B-cell activation [36-38].

Understanding the risk of posttransplant malignancy in WG transplant recipients is another goal of this study. It is important to define this risk in order to identify whether specific posttransplant screening is warranted in this population. To the best of the principal investigator's knowledge, only one prior study with 8 WG and 7 MPA transplant recipients has investigated whether patients with ANCA-associated vasculitis are more prone to malignancies [39]. The results of this study suggest that the incidence of malignancy may be elevated. Risks of malignancies in patients with other types with vasculitis who may have received cyclophosphamide (eg. systemic lupus erythematosus (SLE) patients) have not been specifically investigated in the transplant setting.

Predictors of adverse outcomes: patient and renal allograft death, WG recurrent allograft disease, and malignancy
A final aim is to identify independent clinical predictors of four specific outcomes (patient and renal allograft death, WG recurrent allograft disease, and malignancy) in the group of WG transplant recipients. While many of these predictors are likely to be the same as in the general transplant population at large, attention here is drawn to several specific questions. In nontransplanted WG patients with newly-diagnosed GN, serum creatinine at diagnosis of renal dysfunction is the single most important predictor of renal outcome [40-42]. Presumably, this is true as well in the transplant population. Therefore, it is important to identify risk factors for WG allograft recurrence in this population in order to highlight those at risk so that an early diagnosis can be made. Recurrent disease in the allograft has been estimated to be 16%, with 40% of these cases resulting in graft failure [43]. Recurrence has been described up to 13 years after transplantation [44]. ANCA titers at transplant have not been shown to be predictive of allograft outcome or disease relapse [19,21,45]. Whether ANCA monitoring in a high risk subgroup is not known. It is conceivable but unproven that different immunosuppressive regimens may affect disease relapse rates. In one of the largest studies of 127 WG renal transplant recipients, Nachman et. al. reported a roughly 20% systemic disease relapse rate which was similar between patients treated with cyclosporine and without cyclosporine [45].

Whether disease relapse rates are lower in the era of tacrolimus, mycophenalate mofetil, and sirolimus use has not been studied. We intend to examine what is the incidence of recurrent allograft disease and whether certain immunosuppressive regimens may be associated with lower rates of recurrence. We also intend to examine whether occurrence of acute allograft rejection is an independent risk factor for recurrent disease (see also section above entitled acute allograft rejection).

Significance
• It is important to determine in a large study with long follow-up whether WG transplant recipients have equivalent patient and allograft survival to patients without WG in order to make the most appropriate decisions regarding transplantation.
• If WG is shown to be a risk factor for acute allograft rejection, this would lend support to the idea that ANCA antibodies might be pathogenic in the rejection process.
• As the age of patients receiving transplants increases and improving allograft survival necessitates longer duration of chronic immunosuppresion, it is essential to understand what, if any, the increased risk over others WG patients are at for the development of posttransplant malignancy.
• Finally, identifying independent predictors of poor outcomes in WG transplant recipients could be helpful in developing future predictive models to assist with patient care decisions.

A Pilot Project towards Establishment...

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Identification and characterization...