Defining Delayed Graft Function after Renal Transplantation: Simplest Is Best

Background : Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF.
Methods : The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined. ResultsThe incidence of DGF varied widely depending on the definition used (DBD; 24%–70%: DCD; 41%–91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF.
Conclusion : No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition—the use of dialysis in the first postoperative week—should be universally adopted as the definition of DGF clinically and as a study endpoint (read more)

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

The loading of peptide Ags onto MHC class I molecules is a highly controlled process in which the MHC class I–dedicated chaperone tapasin is a key player. We recently identified a tapasin-related molecule, TAPBPR, as an additional component in the MHC class I Ag-presentation pathway. In this study, we show that the amino acid residues important for tapasin to interact with MHC class I are highly conserved on TAPBPR. We identify specific residues in the N-terminal and C-terminal domains of TAPBPR involved in associating with MHC class I. Furthermore, we demonstrate that residues on MHC class I crucial for its association with tapasin, such as T134, are also essential for its interaction with TAPBPR. Taken together, the data indicate that TAPBPR and tapasin bind in a similar orientation to the same face of MHC class I. In the absence of tapasin, the association of MHC class I with TAPBPR is increased. However, in the absence of TAPBPR, the interaction between MHC class I and tapasin does not increase. In light of our findings, previous data determining the function of tapasin in the MHC class I Ag–processing and presentation pathway must be re-evaluated (read more)

Outcome of Kidney Transplantations Performed With Preformed Donor-Specific Antibodies of Unknown Etiology

The detection of preformed donor-specific alloantibodies (DSA) with multiplex-bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti-HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody-mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause-unk) at the time of transplantation. Twenty-one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement-dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause-unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m2, the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause-unk are able to mount AMR but have favorable 1-year outcomes (read more)

Unique B Cell Differentiation Profile in Tolerant Kidney Transplant Patients

Operationally tolerant patients (TOL) display a higher number of blood B cells and transcriptional B cell signature. As they rarely develop an allo-immune response, they could display an abnormal B cell differentiation. We used an in vitro culture system to explore T-dependent differentiation of B cells into plasma cells. B cell phenotype, apoptosis, proliferation, cytokine, immunoglobulin production and markers of differentiation were followed in blood of these patients. Tolerant recipients show a higher frequency of CD20+CD24hiCD38hi transitional and CD20+CD38loCD24lo naïve B cells compared to patients with stable graft function, correlating with a decreased frequency of CD20−CD38+CD138+ differentiated plasma cells, suggestive of abnormal B cell differentiation. B cells from TOL proliferate normally but produce more IL-10. In addition, B cells from tolerant recipients exhibit a defective expression of factors of the end step of differentiation into plasma cells and show a higher propensity for cell death apoptosis compared to patients with stable graft function. This in vitro profile is consistent with down-regulation of B cell differentiation genes and anti-apoptotic B cell genes in these patients in vivo. These data suggest that a balance between B cells producing IL-10 and a deficiency in plasma cells may encourage an environment favorable to the tolerance maintenance (read more)

Randomized Controlled Pilot Study of B Cell–Targeted Induction Therapy in HLA Sensitized Kidney Transplant Recipient

Optimal induction regimens for patients at high risk for antibody and/or cell–mediated rejection have not been established. This pilot, prospective, randomized study evaluated addition of B cell/plasma cell–targeting agents to T cell–based induction with rabbit antithymocyte globulin (rATG) in high immunologic risk renal transplant recipients. Patients were randomized to induction with rATG, rATG + rituximab, rATG + bortezomib or rATG + rituximab + bortezomib. Inclusion criteria were: (1) current cytotoxic panel reactive antibody (PRA) ≥20% or peak cytotoxic PRA ≥50% or (2) T or B cell positive flow crossmatch with donor-specific antibody (DSA) or (3) historical positive serologic or cytotoxic crossmatch or DSA to donor or (4) prior allograft loss with more than one acute rejection. Median overall follow-up was 496 days: 1-year and overall acute rejection were 25% and 27.5%, and 25% of patients developed de novo DSA within 1 year. One-year and overall patient survival were 97.5% and 92.5%, and 1-year and overall death-censored allograft survival were 97.5% and 95%. Renal allograft function posttransplant was similar among all arms. Eight of nine cases of peripheral neuropathy were mild, whereas one case was moderate and required a narcotic prescription. In conclusion, addition of rituximab and/or bortezomib to rATG induction has an acceptable safety/toxicity profile in a high immunologic risk renal transplant population (read more)

The impact of non-HLA antibodies directed against Endothelin-1 type A receptors (ETAR) on early renal transplant outcomes.

BACKGROUND : Non-HLA antibodies (Abs) targeting vascular receptors are considered to have an influence on renal transplant injury. Anti-endothelin-1 type A receptor (anti-ETAR) antibodies were associated with cellular and antibody-mediated rejection and early onset of vasculopathy in heart transplant patients but their role in renal transplantation remains unclear. The aim of our study was to assess the incidence and importance of anti-ETAR antibodies and their impact on renal transplant during the first year observation.
METHODS: We evaluated the presence of anti-ETAR antibodies in 116 consecutive renal transplant recipients in pre- and post-transplant screening (before and in 1st, 3rd, 6th, 12th month after transplantation). Additionally, we assessed the presence of anti-HLA antibodies. Anti-ETAR antibodies were assayed by ELISA. The diagnosis of acute rejection was based on the Banff criteria.
RESULTS: Anti-ETAR antibodies were observed in 55 (47.4%) of the analyzed recipients before transplantation. The function of renal transplant was significantly worse in the anti-ETAR(+) group compared to the anti-ETAR(-) group during the first post-transplant year. One month after transplantation the serum creatinine in anti-ETAR (+) patients (pts) was 1.86±0.8mg/dl and 1.51±0.5 in anti-ETAR(-) pts (p=0.009). Twelve months after transplantation the difference between the groups was still observed 1.70±0.7 vs. 1.40±0.4 (p=0.04). Biopsy proven acute rejection was recognized in 8/55 (14.5%) in ETAR(+) and 9/61 (14.8%) in ETAR(-) patients but cases with mild to severe intimal arteritis (v1-v3) were more often observed in patients with the presence of anti-ETAR Abs 4/55 (7.2%) comparing with 1/61 (1.6%) in anti-ETAR(-) patients. The anti-ETAR antibody levels varied at different measurement intervals during the one-year follow-up.
CONCLUSIONS: The presence of anti-ETAR antibodies is associated with a worse renal transplant function during the first 12months after transplantation. Including anti-ETAR antibodies in the diagnostics of renal transplant recipient immune status should be considered to provide comprehensive assessment of humoral alloimmunity (read more)

Kidney paired donation in the presence of donor-specific antibodies

Incompatible donor/recipient pairs with broadly sensitized recipients have difficulty finding a crossmatch-compatible match, despite a large kidney paired donation pool. One approach to this problem is to combine kidney paired donation with lower-risk crossmatch-incompatible transplantation with intravenous immunoglobulin. Whether this strategy is non-inferior compared with transplantation of sensitized patients without donor-specific antibody (DSA) is unknown. Here we used a protocol including a virtual crossmatch to identify acceptable crossmatch-incompatible donors and the administration of intravenous immunoglobulin to transplant 12 HLA-sensitized patients (median calculated panel reactive antibody 98%) with allografts from our kidney paired donation program. This group constituted the DSA(+) kidney paired donation group. We compared rates of rejection and survival between the DSA(+) kidney paired donation group with a similar group of 10 highly sensitized patients (median calculated panel reactive antibody 85%) that underwent DSA(−) kidney paired donation transplantation without intravenous immunoglobulin. At median follow-up of 22 months, the DSA(+) kidney paired donation group had patient and graft survival of 100%. Three patients in the DSA(+) kidney paired donation group experienced antibody-mediated rejection. Patient and graft survival in the DSA(−) kidney paired donation recipients was 100% at median follow-up of 18 months. No rejection occurred in the DSA(−) kidney paired donation group. Thus, our study provides a clinical framework through which kidney paired donation can be performed with acceptable outcomes across a crossmatch-incompatible transplant (read more)