L Chan

Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes.

Background. Donor-specific antibodies (DSAs) after kidney transplantation have been associated with poor graft outcomes in multiple studies. However, these studies have generally used stored sera or a single cross sectional screening test to identify patients with DSA. We evaluated the effectiveness of a prospective DSA screening protocol in identifying kidney and kidney/pancreas recipients at risk for poor graft outcomes. Methods. From September 2007 through September 2009, 244 consecutively transplanted kidney and kidney/pancreas recipients without pretransplant DSA were screened for de novo DSA at 1, 6, 12, and 24 months and when clinically indicated. Results. DSA was detected in 27% of all patients by protocol or indication screening. Patients with DSA (DSA+) were significantly more likely to have experienced acute rejection (AR) compared with no DSA (DSA−) (29% vs. 9.5%, P<0.001), and lower estimated 2-year graft survival (83% vs. 98%, P<0.001). Only 3 of 19 DSA (+) patients with AR had DSA detected before the AR episode. When excluding patients with AR, 2-year graft survival was similar between DSA (+) and DSA (−) patients (100% vs. 99%) as was estimated glomerular filtration rate. Patients with DSA detected by protocol screening had similar outcomes compared with DSA (−), whereas those with DSA detected by indication experienced significantly worse outcomes. Conclusions. Patients with de novo DSA experience worse graft outcomes due to previous/concurrent episodes of AR. A prospective DSA screening protocol failed to identify patients at risk for AR or poor short-term graft outcomes.

Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients.

Background. Despite the prevalent use of rabbit antithymocyte globulin (rATG) as an induction agent in kidney transplantation, the appropriate dose for preventing acute rejection in high-risk patients is not known. Few studies have examined total exposure of rATG less than 6 mg/kg, with fewer studies examining lower dose rATG in patients with increased risk factors for acute rejection. Methods. We retrospectively analyzed outcomes of 83 kidney transplant recipients at increased risk for acute rejection (repeat transplant, African American race, and panel reactive antibody ≥20%) from July 2004 to July 2007 who were treated with rATG 1.5 mg/kg per day for 3 (n=39) or 4 (n=44) doses for induction to determine the impact of reduced-exposure rATG in the prevention of acute rejection. rATG was initiated intraoperatively and continued on consecutive days. All patients received triple maintenance immunosuppression including prednisone and calcineurin inhibitor. Patients requiring dialysis within 48 hr after transplant were excluded from analysis. Results. One-year acute rejection rates were 10% and 11% in the 3- and 4-dose cohorts, respectively, with 100% patient and graft survival at 1 year in both groups. Patients in the 3-dose cohort were discharged from the hospital sooner than the 4-dose cohort (median length of hospital stay, 3 vs. 4 days; P=0.004). Conclusions. Our results suggest that a 3- or 4-dose course of rATG (1.5 mg/kg/dose) provides excellent protection against acute rejection even in patients at increased risk, with the potential for cost savings from a reduction in hospital stay and medication administration.

High dose intravenous immunoglobulin therapy for donor-specific antibodies in kidney transplant recipients with acute and chronic graft dysfunction.

Background Postkidney transplant donor-specific antibodies (DSA) have been identified as important contributors to graft loss. Few therapeutic options exist and have been met with limited success. We report outcomes in patients with de novo DSA and graft damage treated with a protocol of high-dose intravenous immunoglobulin (IVIG). Methods Retrospective analysis of 28 kidney transplant recipients with de novo DSA and graft damage in the form of either chronic graft dysfunction (group 1, n=20) or a recent previous acute antibody-mediated rejection (AMR) episode (group 2, n=8) prescribed a standard regimen of high-dose (5 g/kg) IVIG dosed over 6 months. Results Mean fluorescence intensity (MFI) of 70 total DSA decreased by 12%at the end of treatment (T1, P=0.14) and by 18%at last follow up (T2, P=0.035) compared with treatment initiation (T0) MFI. The most robust effect was seen in class I DSA (37% decrease at T2 versus T0, P=0.05) and in DSA from patients in group 2 (52% decrease at T2 versus T0, P=0.008). Graft function stabilized in patients in group 2 but continued to decline in those in group 1. Conclusion High-dose IVIG resulted in modest DSA MFI reductions in patients with previous graft damage, with a larger effect occurring in class I DSA in patients with a previous acute AMR. There was no clinical treatment benefit in patients with ongoing chronic graft damage, whereas high-dose IVIG may reduce the risk of chronic graft dysfunction in those with an acute AMR event.

Preemptive retransplant for BK virus nephropathy without concurrent transplant nephrectomy.

BK virus (BKV) nephropathy (BKVAN) has become an important cause of graft dysfunction after kidney transplant over the last decade (1). Consequently, consideration of retransplantation in the setting of BKVAN has become an increasingly pertinent issue. Questions of timing (preemptive vs. after progression to renal failure) and need for allograft nephrectomy remain unknown. Retransplantation has been reported in a total of 21 cases (2– 4), four of which were performed preemptively. All preemptive retransplants were performed with concurrent allograft nephrectomy because of concerns of possible BKV reinfection. We report for the first time a preemptive retransplant performed in a patient with BKVAN without simultaneous allograft nephrectomy. A 69-year-old woman had undergone living unrelated kidney transplant 5 years before presentation. Her first transplant was initially uneventful, but her baseline serum creatinine level increased during posttransplant months 8 to 14 from 1.3 to 4.0 mg/dL. A qualitative BKV blood polymerase chain reaction (PCR) was positive for BKV, and a biopsy demonstrated polyomavirusassociated interstitial nephritis with significant inflammation and fibrosis (retrospectively graded as b3 [5]). Five months after transition from tacrolimus/ mycophenolate/prednisone to low-dose sirolimus/leflunomide/prednisone, her viral PCR was undetectable, but she remained with a serum creatinine of 4.2 mg/dL (estimated glomerular filtration rate 12 mL/min). Leflunomide was discontinued, and she was placed on the transplant waiting list for retransplantation and maintained on sirolimus 2 mg daily (trough levels 4 – 8 ng/mL) and prednisone 5 mg daily with periodic monitoring of BKV. In the subsequent 4-year period, she remained clinically stable off of dialysis with an estimated glomerular filtration rate of 10 to 12 mL/min and BKV PCR that were undetectable, until she received a four-antigen mismatched deceased-donor kidney transplant. Three days before transplant, a screening BKV blood PCR had been undetectable. She received induction therapy with 1.5 mg/kg per day thymoglobulin for 3 days and was placed on tacrolimus, myfortic, and prednisone with immediate graft function. Figure 1 describes the clinical course of the patient. She experienced recurrent BKV viremia identified at 3 months posttransplant (after a steroid taper for gout) and underwent biopsy of both her first and second kidney transplants at posttransplant month 4 (BKV viremia 20,235 copies/mL). Neither kidney demonstrated SV40 staining for BKV despite examining two separate (totally four) cores including tissue at the corticomedullary junction from each kidney. Given the patchy distribution of BKV, the lack of findings may have reflected a sampling error or a potential uroepithelial source of BK viremia. Immunosuppression dose reduction resulted in a clearance of BKV viremia, and renal function remained stable throughout. This case is the first report of a successful preemptive kidney retransplant without graft nephrectomy in a patient with prior BKVAN. The clinical course highlights the need for ongoing monitoring of BKV replication both in the immediate posttransplant setting (to minimize the risk of development of BKVAN) and in the setting of the failing allograft (to dictate proper management and retransplant options). Critical to the decision making to not remove the failing allograft was the absence of BKV in blood at the time of retransplant. The success of our approach supports others’ FIGURE 1. Renal function and blood BK virus (BKV) polymerase chain reaction assessment after preemptive retransplant. Immunosuppression exposure is presented at monthly intervals. Despite stable renal function (serum creatinine [SCr] 0.8–0.9 mg/dL), the patient developed BK viremia prompting biopsy of both the failed allograft and functional second allograft. No BKV activity was identified in either biopsy by SV40 immunohistochemical staining. Decreased dosing of mycophenolate and tacrolimus resulted in clearance of BKV without clinical consequence.