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Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients.

Djamali A, Muth BL, Ellis TM, Mohamed M, Fernandez LA, Miller KM, Bellingham JM, Odorico JS, Mezrich JD, Pirsch JD, D'Alessandro TM, Vidyasagar V, Hofmann RM, Torrealba JR, Kaufman DB, Foley DP - Kidney Int. (2013)

Bottom Line: The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year.The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection.A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Wisconsin, Madison, Wisconsin 51703, USA. axd@medicine.wisc.edu

ABSTRACT
In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

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Kaplan-Meier survival curve for rejection free probability in patients with or without post-reperfusion C4d stainingC4d (+) patients were at significantly greater risk for antibody-mediated or mixed rejection.
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Figure 3: Kaplan-Meier survival curve for rejection free probability in patients with or without post-reperfusion C4d stainingC4d (+) patients were at significantly greater risk for antibody-mediated or mixed rejection.

Mentions: To determine the effects of transplantation on DSA, we first examined the changes in DSA over time. We evaluated MFImax and MFIsum per class, and for both class I and II, at the time of transplant, 1 week, 1 month, 3 months and 12 months. Table 4 and Figure 1 show that DSA increased after transplantation despite immunosuppression and desensitization strategies. Class II antibodies were the primary cause of this rise in DSA. Next, we discovered that the association between the rise in DSA and acute rejection was stronger at 1 week than at 1 month, 3 months and 12 months (Tables 5). We confirmed these findings by examining the predictive value of delta DSA at 1 week for any episode of acute rejection (Table 6). We noted that patients with delta MFI values higher than 500, 1,000 and 3,000 MFI, had a 1.9 to 10.8 times greater risk of subsequent rejection, regardless of class or type of DSA (Max or Sum). Notably, there was a linear relationship between MFImax and MFIsum at 1 week (MFImax = −84.95 + 0.37 MFIsum, R2=0.82, p < 0.001). Mean time to acute rejection in patients with a 1 week rise in MFImax > 500 and MFIsum > 500 was 1.45±0.4 and 1.60±0.4 months after transplant, respectively, suggesting a true predictive ability. Multivariate cox regression analyses confirmed the strong association of delta DSA at 1 week with acute rejection (Table 7). Separate multivariate regression analyses demonstrated a similar association between antibody-mediated rejection and delta DSA at 1 week (HR=3.7, 95% CI 1.69 to 8.10, p=0.002 for MFImax > 500), African American race (HR=13, 95% CI 3.9 to 42.9, p < 0.0001) and C4d staining in post-reperfusion biopsies (HR=7, 95% CI 3.0 to 16.6, p < 0.0001). Out of all these variables, only 1 week MFImax > 500 was associated with acute cellular rejection (HR=2.90, 95% CI 1.07 to 7.70, p=0.03), suggesting a cross talk between cellular and humoral immune response.


Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients.

Djamali A, Muth BL, Ellis TM, Mohamed M, Fernandez LA, Miller KM, Bellingham JM, Odorico JS, Mezrich JD, Pirsch JD, D'Alessandro TM, Vidyasagar V, Hofmann RM, Torrealba JR, Kaufman DB, Foley DP - Kidney Int. (2013)

Kaplan-Meier survival curve for rejection free probability in patients with or without post-reperfusion C4d stainingC4d (+) patients were at significantly greater risk for antibody-mediated or mixed rejection.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672254&req=5

Figure 3: Kaplan-Meier survival curve for rejection free probability in patients with or without post-reperfusion C4d stainingC4d (+) patients were at significantly greater risk for antibody-mediated or mixed rejection.
Mentions: To determine the effects of transplantation on DSA, we first examined the changes in DSA over time. We evaluated MFImax and MFIsum per class, and for both class I and II, at the time of transplant, 1 week, 1 month, 3 months and 12 months. Table 4 and Figure 1 show that DSA increased after transplantation despite immunosuppression and desensitization strategies. Class II antibodies were the primary cause of this rise in DSA. Next, we discovered that the association between the rise in DSA and acute rejection was stronger at 1 week than at 1 month, 3 months and 12 months (Tables 5). We confirmed these findings by examining the predictive value of delta DSA at 1 week for any episode of acute rejection (Table 6). We noted that patients with delta MFI values higher than 500, 1,000 and 3,000 MFI, had a 1.9 to 10.8 times greater risk of subsequent rejection, regardless of class or type of DSA (Max or Sum). Notably, there was a linear relationship between MFImax and MFIsum at 1 week (MFImax = −84.95 + 0.37 MFIsum, R2=0.82, p < 0.001). Mean time to acute rejection in patients with a 1 week rise in MFImax > 500 and MFIsum > 500 was 1.45±0.4 and 1.60±0.4 months after transplant, respectively, suggesting a true predictive ability. Multivariate cox regression analyses confirmed the strong association of delta DSA at 1 week with acute rejection (Table 7). Separate multivariate regression analyses demonstrated a similar association between antibody-mediated rejection and delta DSA at 1 week (HR=3.7, 95% CI 1.69 to 8.10, p=0.002 for MFImax > 500), African American race (HR=13, 95% CI 3.9 to 42.9, p < 0.0001) and C4d staining in post-reperfusion biopsies (HR=7, 95% CI 3.0 to 16.6, p < 0.0001). Out of all these variables, only 1 week MFImax > 500 was associated with acute cellular rejection (HR=2.90, 95% CI 1.07 to 7.70, p=0.03), suggesting a cross talk between cellular and humoral immune response.

Bottom Line: The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year.The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection.A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Wisconsin, Madison, Wisconsin 51703, USA. axd@medicine.wisc.edu

ABSTRACT
In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

Show MeSH
Related in: MedlinePlus