The Role of Immunoglobulin-G Subclasses and C1q in De Novo HLA-DQ Donor-Specific Antibody Kidney Transplantation Outcomes

Freitas, Maria Cecília S.; Rebellato, Lorita M.; Ozawa, Miyuki; Nguyen, Anh Thu; Sasaki, Nori; Everly, Matthew J; Briley, Kimberly P.; Haisch, Carl E.; Bolin, Paul; Parker, Kathryn; Kendrick, W.; Kendrick, Scott A.; Harland, Robert C.; Terasaki, Paul I.

doi:10.1097/tp.0b013e3182888db6

Cited by 166 publications

(129 citation statements)

References 25 publications

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“…However, the proportion of C1q+ dnDSAs was consistent with other studies. 15,19 As previously described, 15,17,18,21 we observed a correlation between DSA MFIs and their ability to bind C1q. We defined an MFI threshold that predicted C1q binding with very good sensitivity, specificity, and positive and negative predictive values.…”

Section: Discussionsupporting

confidence: 83%

“…[6][7][8][9]20 We also confirm previous results showing a poorer medium-term graft survival in patients with C1q+ dnDSAs compared with those with no dnDSAs or C1q2 dnDSAs. 15,19,20 Of note, we also observed in the original cohort that patients with C1q2 dnDSAs at 2 and 5 years had the same 10-year graft survival rates as those with C1q+ dnDSAs, whereas C1q2 dnDSAs detected only at 2 or 5 years had no significant effect on graft survival. Thus, a long exposure (here for at least 3 years) to C1q2 dnDSA could also be associated with graft loss.…”

Section: Discussionsupporting

confidence: 66%

“…[6][7][8][9] Because a fraction of dnDSA-positive patients escape rejection or graft dysfunction, 9,13 the current challenge is to identify clinically relevant dnDSAs in order to better stratify the individual immunologic risk. Several proposed approaches rely on serum dnDSA SAFB mean fluorescence intensity (MFI) strength, 14,15 IgG subclass analysis, 16 or complement-binding ability. 17,18 DSAs are deleterious via different pathways, but complement C4d deposition in peritubular capillaries reflects the central role of complement in AMR endothelial cell aggression.…”

mentioning

confidence: 99%

“…There is no consensus about the correlation between dnDSA SAFB MFI levels and C1q-binding ability. 15,17 Until recently, the prognostic value of C1q+ dnDSA had been assessed in only two studies, 15,19 but a large, recently held study showed that C1q+ dnDSA conferred a higher risk of kidney allograft loss than C1q2 dnDSA. However, that study described neither the kinetics of DSA ability to bind C1q over time nor the long-term effect of both C1q+ and C1q2 dnDSA.…”

mentioning

confidence: 99%

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Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

Guidicelli¹,

Guerville²,

Lepreux³

et al. 2016

Journal of the American Society of Nephrology

125

112

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C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity .6237 and .10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P,0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

Guidicelli¹,

Guerville²,

Lepreux³

et al. 2016

Journal of the American Society of Nephrology

125

112

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“…We performed predefined stratified analyses to examine for the effect of RMM on outcomes considering certain biologically anticipated risk groups. Given the increasing evidence that class 2 antigen differences 9-11 and class 2 HLA antibodies [18][19][20] specifically affect graft survival, the effect of class 2 RMM versus only class 1 was explored, and we found that the presence of class 2 RMM was associated with graft loss, specifically in sensitized recipients. This information may be of value in further refining the classification of immunologic risk in recipients with RMM, such that unsensitized recipients with class 2 RMM may be considered at lower risk than their sensitized counterparts.…”

Section: Discussionmentioning

confidence: 99%

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Tinckam

Rose

Hariharan

et al. 2016

JASN

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Kidney retransplantation is a risk factor for decreased allograft survival. Repeated mismatched HLA antigens between first and second transplant may be a stimulus for immune memory responses and increased risk of alloimmune damage to the second allograft. Historical data identified a role of repeated HLA mismatches in allograft loss. However, evolution of HLA testing methods and a modern transplant era necessitate re-examination of this role to more accurately risk-stratify recipients. We conducted a contemporary registry analysis of data from 13,789 patients who received a second kidney transplant from 1995 to 2011, of which 3868 had one or more repeated mismatches. Multivariable Cox proportional hazards modeling revealed no effect of repeated mismatches on all-cause or death-censored graft loss. Analysis of predefined subgroups, however, showed that any class 2 repeated mismatch increased the hazard of death-censored graft loss, particularly in patients with detectable panel-reactive antibody before second transplant (hazard ratio [HR], 1.15; 95% confidence interval [95% CI], 1.02 to 1.29). Furthermore, in those who had nephrectomy of the first allograft, class 2 repeated mismatches specifically associated with all-cause (HR, 1.30; 95% CI, 1.07 to 1.58) and death-censored graft loss (HR, 1.41; 95% CI, 1.12 to 1.78). These updated data redefine the effect of repeated mismatches in retransplantation and challenge the paradigm that repeated mismatches in isolation confer increased immunologic risk. We also defined clear recipient categories for which repeated mismatches may be of greater concern in a contemporary cohort. Additional studies are needed to determine appropriate interventions for these recipients. 27: 283327: -284127: , 201627: . doi: 10.1681 Kidney retransplantation is generally viewed to increase risk for immunologic damage and graft loss. The increased risk is attributed to the formation of T and B memory cells to mismatched HLA antigens in the original donors. Re-exposure to a repeated HLA antigen mismatched (RMM) in a subsequent donor potentially invokes alloimmune memory responses, resulting in earlier allograft damage and loss. J Am Soc NephrolThe nature and magnitude of this potential risk have changed with reanalysis over time. Whereas a number of studies have described worse allograft survival when repeated antigens are mismatched at the HLA-DR locus, 1-3 with RMM at class 1 (HLA-A or -B) not influencing outcomes, others have shown a beneficial effect of RMM on graft survival 4,5 or a neutral effect. 6,7 A more recent analysis showed an effect of class 1 RMM on graft survival, with no differences seen with class 2 RMM. 8

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Five‐year histological and serological follow‐up of operationally tolerant pediatric liver transplant recipients enrolled in WISP‐R

et al. 2016

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Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). While IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606) were followed for a total of five years (one year of IS withdrawal and four years off IS) with serial liver tests, auto- and allo-antibody assessments. Liver biopsies were performed two and four years off IS and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth muscle actin (SMA) expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells (LSECs) remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, three subjects showed intermittent de novo Class I DSA, four subjects showed persistent de novo Class II DSA and five subjects showed persistent pre-existing Class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity (MFI), rarely of the IgG3 subclass, and often capable of binding C1q. Conclusion Operationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage.

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The Role of Immunoglobulin-G Subclasses and C1q in De Novo HLA-DQ Donor-Specific Antibody Kidney Transplantation Outcomes

Abstract: The presence of de novo persistent, complement-binding DQ DSA negatively impacts kidney allograft outcomes. Therefore, early posttransplantation detection, monitoring, and removal of complement-binding DQ might be crucial for improving long-term kidney transplantation outcomes.

Cited by 166 publications

References 25 publications

Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

Five‐year histological and serological follow‐up of operationally tolerant pediatric liver transplant recipients enrolled in WISP‐R

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