Changes in Antibody Strength
At the index time point, adjusted HLA class I and class II antibody values were not different between those who received and did not receive transfusion (class I, P=0.96; class II, P=0.38). The proportion of patients with any change in class I and/or II antibody levels was substantively higher for those who received transfusion compared to those who did not receive transfusion (20.4% vs. 2.4%, P<0.001) (Fig. 2). Substantial increases in antibody strength, i.e., potentially crossmatch positive increases, were observed among 13.5% of those who received transfusion compared to 1.6% of those who did not receive transfusion. In the crossover cohort, the proportion of patients with any response was substantively higher in the group who received transfusion than in the group who did not receive transfusion (20.3% vs. 1.4%, P<0.001). Substantial increases in antibody strength were seen among 11.6% of those who received transfusion compared to none of those who did not receive transfusion in the crossover cohort (Fig. 2). The results were nearly identical when the analysis was limited to patients with additional specificity testing performed by the phenotype and/or single-antigen assays (see Figure S1, SDC, http://links.lww.com/TP/A896), when stratified by whether patients experienced any proinflammatory events (see Figure S2, SDC, http://links.lww.com/TP/A896) and by time between the transfusion event and the follow-up HLA antibody measurement (see Figure S3, SDC, http://links.lww.com/TP/A896). Aside from sex, the stratified analyses mirrored the overall population. Among females, 44.7% experienced an increase in antibody strength compared to 6.1% of males (see Figure S4, SDC, http://links.lww.com/TP/A896).
In the regression analyses, patients who received transfusion were at an elevated relative risk of having any HLA antibody response at the lower thresholds (odds ratio [OR]=10.4, 95% confidence interval [CI]=4.0–27.1). Similar estimates were observed for a potentially crossmatch positive antibody at the higher thresholds (OR =9.6, 95% CI=3.0–30.7) as shown in the Forrest plot in Figure 3 (estimates also provided in Table S1; see SDC, http://links.lww.com/TP/A896). The OR estimates remained unchanged after case-mix adjustment and were consistent across all subgroups where ORs could be estimated. The OR estimates for any antibody response were numerically much higher for black (OR=14.5, 95% CI=3.0–70.4) than for white patients (OR=8.5, 95% CI=2.5–29.4). The OR for any antibody response among females (OR=12.4, 95% CI=1.4–35.3) was numerically higher than for the overall population; no male patients who did not receive transfusion showed any antibody response so an OR could not be estimated. Although antibody levels declined gradually over time, analysis of posttransfusion samples for 20 patients with, on average, 5 additional measurements (standard deviation=4.1, interquartile range [IQR]=1–8) showed antibody persistence over the following year (see Figure S5, SDC, http://links.lww.com/TP/A896).
Changes in Antibody Breadth
The proportion of patients with an increase in changes in antibody breadth (CPRA) was greater among those who received transfusion than among the matched patients who did not receive transfusion (26.3% vs. 5.8%) and during the transfusion period (compared to the control period [38% vs. 2%]) in the crossover cohort (Fig. 4). Among patients who received transfusion, 15.2% (matched cohort) and 22% (crossover) experienced an increase in CPRA greater than 20 points; approximately 6% in both cohorts had a 50-point change or higher in CPRA. Increases in CPRA greater than 90 were observed among 4.7% of all who received transfusion (data not shown). Female patients who received transfusion, patients with some degree of sensitization before transfusions (i.e., non-zero CPRA at baseline), were more susceptible to increases in CPRA. Greater increases in CPRA were observed with increased time between the transfusion event and the follow-up HLA antibody measurement (see Figures S6–S8, SDC, http://links.lww.com/TP/A896 ).
We evaluated the risk of transfusion-induced allosensitization among patients who were receiving chronic dialysis and awaiting their first transplant and found that nearly 14% of patients who received transfusion developed a biologically relevant increase in antibody strength compared to less than 2% of matched controls. Using a broader definition of antibody response at the lower assay thresholds, 20% of patients who received transfusion compared to less than 2% of patients who did not receive transfusion exhibited an antibody response. These results were nearly identical in our crossover population. These findings corresponded to a nearly 10-fold increased relative risk of broad sensitization and a 32-point mean increase in CPRA. These effects were more pronounced among females and blacks and were not explained by proinflammatory events such as surgeries or infections. There was a modest decline in antibody strength for both class I and II antibodies over the subsequent year among those patients with serial posttransfusion samples. These results provide strong evidence using contemporary antibody detection methods in the era of leukoreduced blood for a causal relationship between RBC transfusions and the development of allosensitization.
While it was recognized as early as 1954 that blood transfusions induce antibodies reactive with leukocytes (19), most studies were conducted with relatively insensitive and nonspecific cell-based assays (14, 20, 21) and results were equivocal, with some reporting significant antibody formation after a transfusion while others did not (22–24). Given the declining use of ESAs to treat anemia in patients receiving dialysis and the concomitant increase in transfusions, we sought to quantify the effect of transfusion on sensitization to HLA antigens using contemporary antibody assays. Our study is one of three to our knowledge that have examined transfusion-related sensitization using today’s antibody assays. In 2012, Balasubramaniam et al. (25) reported a 16.7% sensitization rate tested by single-antigen bead assays after receipt of leukodepleted blood transfusions among men awaiting primary kidney transplant, and this rate was four-fold higher than among patients who did not receive transfusion. More recently, Yabu et al. (26) observed a 20% sensitization rate for patients on dialysis awaiting primary transplant who received a single RBC transfusion relative to matched and self-controls. Our study used a similar design but included a demographically and regionally distinct population that contained a substantially higher percentage of black patients with results that essentially replicate the finding of a 20% sensitization rate and additionally provide estimates suggesting a nearly 10-fold increased RR of antibody response after a single RBC transfusion.
In our analyses, we used phenotype panels on the Luminex platform to evaluate changes in antibody strength as we have found that the MFI values from these assays yield superior correlations with actual crossmatch results than do single-antigen panels (27). There are many reasons why MFI values from single-antigen assays are frequently difficult to interpret when taken out of context: the values vary appreciably among the different antibody specificities; there is considerable variability between runs because of the high sensitivity of the assay; non-HLA antibodies can react with denatured antigens on the test beads, which has been shown to affect as much as 60% of some antigens; and the high sensitivity of the single-antigen assays has made it difficult to establish a threshold above which one can be sure that the reactivity is due to HLA-specific antibody (28, 29). A recent multicenter study in which all participating centers rigidly adhered to the same technique using test results from the same lots found that MFI values varied according to manufacturer, bead type, kit, and lot. While ROC analyses showed excellent consistency in antibody assignments between manufacturers (area under the curve>0.9), global normalization reduced MFI variation to levels near 20% (30). This 20% variability under very strict conditions substantiates our concern with using single-antigen data in this present study. We established a correlation for changes in antibody levels between the pooled antigen and phenotype tests (discussed in the Methods section) and determined that changes at the higher pooled antigen thresholds correlate with antibodies consistent with or approaching positive crossmatch levels. Recognizing that many centers use only single-antigen assays, we note that comparable single-antigen results yielded higher MFI values and varied according to different antibody specificities.
Like Yabu et al. (26), we also found that changes in HLA antibody levels after a transfusion corresponded to significant increases in CPRA, with nearly 40% of patients who received transfusion exhibiting a positive change and half were 20% or greater, translating to a sizable reduction in the potential number of available donor organs. Also notable was the absence of any change in CPRA among the comparator groups who did not receive transfusion, particularly during the self-control period in the crossover cohort. This effect on CPRA highlights the clinical and economic consequences of allosensitization because sensitized patients receive substantially fewer offers for a kidney translating into much longer wait times; have greater likelihood of dying while waiting; and, if transplanted, have reduced graft survival (2, 13, 31–33). Our findings also show that patients with some degree of sensitization are more likely to experience antibody increases after transfusion. Because 30% or more kidney transplant waitlist candidates have PRA/CPRAs greater than 20% (34), the clinical and economic consequences of transfusion may be even greater for these candidates.
Our results corroborate previous findings regarding sensitization within demographic subpopulations. Data from the OPTN/SRTR have shown that sensitization is more common among female and black patients (35), and when transfused, their antibodies increase both in level and breadth (26, 36, 37). We found that sensitization after transfusion was substantially higher in female and black patients. This racial disparity has implications considering the recent evidence of increased transfusion particularly among black patients after implementation of the ESRD PPS (9).
Recent evidence also suggests that proinflammatory events (e.g., surgeries, infections) can provoke an antibody response (38–40). In the current analysis, a large proportion of the patients experienced a proinflammatory event proximate to the transfusion event, raising the possibility that these events might have confounded the observed antibody responses. However, our results remained unchanged when those patients and their matched controls were eliminated from the analysis. In addition, the issue of whether leukoreduction reduces the risk of sensitization remains an area of controversy. Our study, which was conducted from 2004 onward, provides indirect evidence that leukoreduction does not mitigate the risk of transfusion-associated sensitization. Our findings are consistent with those reported by Karpinski et al. (41) who showed that, even after a Canadian province uniformly adopted leukoreduction, there was no decrease in the level of allosensitization after RBC transfusion among kidney transplant candidates. Finally, given the available serial antibody measurements, we found that the antibody response persisted up to 1 year later.
The importance of minimizing the use of transfusion in patients with kidney disease, particularly potential transplant candidates, has long been recognized by the nephrology community and has been reinforced by recent updates to clinical practice guidelines for managing anemia of chronic kidney disease (42). The significant decline in transfusion among patients on dialysis over the past two decades coincident with the introduction and widespread adoption of ESAs has meaningfully affected sensitization in this population (2). However, the safety concerns raised by the high-hemoglobin target randomized controlled trials, the changes in ESA labeling, and the implementation of the ESRD PPS have all contributed to downward shifts in the use of ESAs (6, 7, 9, 43). This change in the management of anemia has resulted in falling hemoglobin levels and an increase in the use of transfusion (44). In this context, our findings reinforce the importance of weighing the benefits and risks of alternative therapies like ESAs when deciding on the course of anemia treatment for potential transplant candidates.
This study should be evaluated in light of the following limitations. Although our study population was from a relatively large single-center waitlist, it represents only a fraction of the entire waitlisted population and, therefore, may not generalize to all waitlist candidates. CPRA data were not available for all patients because only selected patient sera received further antibody specificity testing. Although we replicated the incidence of antibody responses limited to those with available CPRA data, we could not fully assess increases in antibody breadth in our entire study population. Lastly, we obtained transfusion data from Medicare claims, which are expected to have high specificity (low false positives) but only moderate sensitivity (modest number of false negatives). Hence, we may have misclassified some patients who did not receive transfusion; this would, under expectation, underestimate the true excess risk of sensitization after transfusion.
In conclusion, our findings indicate a causal relationship between RBC transfusions and clinically relevant HLA antibody development. The observed changes in HLA antibodies translated into a clinically meaningful increase in CPRA consistent with a ∼25% reduction in the pool of available donor organs. Importantly, the sensitizing effects of transfusion may differentially affect female and black patients, further limiting their access to transplantation. These findings should reinforce the importance of transfusion avoidance when clinically possible for patients on the transplant waitlist.
MATERIALS AND METHODS
Antibody data from Immunogenetics Laboratory at the Johns Hopkins University Comprehensive Transplant Center were merged with data from the USRDS. Sera are received monthly for antibody testing, with mean compliance rates of 65% to 80% among patients active on the renal waitlist. USRDS data capture demographic information, comorbid conditions, medication utilization, and encounters with the health care system including hospitalizations, surgeries, and general dialysis care. Deidentified patient antibody data were merged with the USRDS records, and subsequent data analyses were conducted after approval by the Johns Hopkins University Institutional Review Board and the USRDS.
From an initial sample of 2324 patients, 1342 adult patients were included who 1) were candidates for a primary transplant on the Johns Hopkins renal waitlist (2004–2010), 2) were receiving chronic dialysis, and 3) had at least two measurements for HLA antibodies separated by a mean of 30 days (median=30 days, interquartile range [IQR]=25–42 days). We limited our analysis to patient data from 2004 to 2010, a period during which most of transfused blood was leukoreduced (45). Of these, 110 received one or more RBC transfusions between two consecutive HLA antibody measurements. Each two consecutive HLA antibody measurements were considered a pair (e.g., measurements 1 and 2, 2 and 3, etc.). We identified all patients with one or more pairs with an intervening transfusion event; pairs without any intervening transfusion events were eligible for selection into the unexposed group.
Matched and Crossover Cohorts
Two cohorts of patients were identified: a matched cohort and a crossover cohort. Of the 110 patients who received transfusion, 89 were matched to 251 patients who did not receive transfusion; 69 were included in the crossover cohort (Fig. 1). The matched cohort consisted of all patients with a pair of HLA antibody measurements with an intervening transfusion event matched to individuals who had a pair of antibody measurements but without an intervening transfusion event. Each patient who received transfusion was individually matched to up to four patients who did not receive transfusion based on age (±2 years), sex, race (white, black, other), history of transfusion (yes/no), time on dialysis (±6 months), and calendar time (year of index HLA antibody measurement). The distribution of our matching ratio was 1:4 (45%), 1:3 (15%), 1:2 (18%), and 1:1 (22%). Twenty-one patients who received transfusion could not be matched owing to their lengthy/brief time on dialysis, older/younger age, and/or race. The first antibody measurement in any pair was considered the index (pre) and the second was considered the follow-up (post). For patients who received transfusion, the index was the antibody measurement immediately preceding the transfusion event, and for the patients who did not receive transfusion, the index was the first available antibody measurement as of the match date for the patient who received transfusion. The post sample was the HLA antibody with the maximum adjusted value during the follow-up period (median=77 days, IQR=32–166 days).
From the patients who received transfusion identified in the matched cohort, those who had at least one HLA antibody measurement preceding their index measurement were included in the crossover cohort. These patients had three consecutive HLA antibody measurements with a transfusion event occurring between the second and third (transfused period), but none occurring between the first and the second (control period).
The exposure in this investigation was an RBC transfusion event occurring in the inpatient or outpatient setting. Transfusion events were identified using codes defined by USRDS and previous studies (44, 46) (for description of codes used, see SDC, http://links.lww.com/TP/A896). Transfusion events were defined as one or more transfusion administrations occurring on a single day; information on the units of blood transfused was not available.
HLA Antibody Measurements
Patient sera were tested for HLA-specific antibodies using solid-phase immunoassays against pooled HLA class I and class II antigens, single HLA class I and class II phenotypes, and single HLA antigens on the Luminex platform (Lifecodes Immuncor, San Diego, CA; One Lambda, Thermo Fisher Scientific, Canoga Park, CA). All patient sera were routinely tested using the pooled antigen assays, and the results were used as the primary measure of changes in antibody strength and breadth. Interpretation of HLA antibody reactivity was made using an adjusted value that normalizes the antibody measurement to control values. The adjusted, normalized value was calculated using software provided by the manufacturer. When substantial changes were noted in serial patient samples, sera were then tested with the single HLA phenotype and/or single HLA antigen assays. As these were retrospective analyses, only a subset of patient sera had additional antibody testing performed with the phenotype or single antigen assays at the relevant time points. These data were used to evaluate changes in antibody specificity and to confirm changes in antibody strength. The breadth of the antibody response was measured as a calculated panel-reactive antibody value (CPRA) that represents the percentage of donors having HLA antigens corresponding to patient antibodies (47).
Criteria were established for changes in antibody strength in the pooled antigen assays based on correlations of the adjusted, normalized values from the pooled antigen assays with normalized MFI values from the HLA phenotype assays. Briefly, 67 and 72 sera were tested for class I and class II specific antibodies, respectively, on both the pooled antigen and phenotype platforms. The phenotype assay was used to establish the relative antibody strength based on prior correlations with crossmatch results, with MFI values greater than 6000 and greater than 10,000 for class I specific antibodies corresponding to positive flow cytometric and cytotoxicity crossmatch tests, respectively (27). The phenotype assay was used to evaluate antibody strength because it provides good correlation with crossmatch reactivity. It should be noted that comparable MFI values from single antigen assays correlating with positive crossmatch tests are substantially higher than those obtained with phenotype panels and the single antigen assay results yielded much lower correlations with crossmatch results (27).
Two conservative threshold levels for assessing changes in antibody strength were defined from the above correlations. Changes in the adjusted values of 25 to 49 and 30 to 59, respectively, for class I and class II specific antibodies, were considered as moderate changes in antibody strength that would correspond to MFI values below a positive crossmatch level. This level of reactivity was sufficiently high to rule out any changes due to day-to-day variation in test results, which has been established in our laboratory as between 4.9% and 6.6% using a robotic liquid handling system (29). Because the moderate changes were well above the range that might be due to inherent test variability, such changes were indicative of some increase and/or broadening of patient sensitization. Changes in the adjusted values for class I and class II specific antibodies greater than 50 and greater than 60, respectively, were considered substantial and potentially “biologically significant” because changes in these ranges correlated with MFI values that approached or were consistent with positive crossmatch assays.
Demographic characteristics including age, sex, race, and primary cause of ESRD were ascertained from the Medical Evidence form (CMS 2728). Comorbidities including heart failure, atherosclerotic heart disease, cancer, and cerebrovascular disease were identified from inpatient and outpatient Medicare claims in the 1-year period preceding the index HLA antibody measurement using established methods (48). Proinflammatory events, including major surgeries and infections, were identified before and after the index measurement.
Summary statistics for continuous variables (mean, standard deviation, median) and categorical variables (count [n], percent [%], 25th/75th percentile) were used to characterize patients and changes in HLA antibody levels from the index to follow-up measurement. Baseline patient characteristics were compared using Pearson χ2 analysis and Student t-test, as appropriate. Changes in HLA class I and II antibody levels from index to the follow-up measurements were compared using Pearson χ2 analysis in the matched cohort and Wilcoxon sign rank test in the crossover cohort.
Logistic regression analysis was used to estimate ORs and 95% CIs for the effect of a single transfusion event on the development of an antibody response. The primary analysis evaluated “any” response defined as an increase at either the lower or the higher pooled antigen assay cutoff values for HLA class I or II antibodies evaluated together and separately. A secondary analysis evaluated increases only at the higher thresholds, which were more likely clinically relevant. Patients who did not receive transfusion served as the reference group in all analyses. Statistical adjustment was made for residual imbalances in patient characteristics between patients who received and did not receive transfusion. Because not all sera received additional specificity testing, analyses were replicated in the subset of patients for whom antibody specificities were determined for the CPRA calculation. Subgroup analyses were conducted within strata of age (<40, 40 to <50, ≥ 50 years), sex (male/female), and race/ethnicity (white/black/other) and according to whether patients experienced a proinflammatory event (yes/no) between the antibody measurements because proinflammatory events may stimulate an antibody response (38).
Changes in CPRA for patients who received and did not receive transfusion in the matched cohort and during the transfusion and control periods in the crossover cohort were compared using Pearson χ2 analysis and the Wilcoxon sign rank test, respectively. Analyses were conducted for the overall population and according to demographic characteristics, the presence of concurrent proinflammatory events, and baseline level of sensitizations (CPRA=0 vs. CPRA >0).
Lastly, among those patients who experienced an increase in HLA antibodies after a transfusion, we examined changes in HLA class I and II antibody levels for up to 1 year using generalized estimating equations (see more detailed description in the SDC, http://links.lww.com/TP/A896). For all analyses, P<0.05 was considered statistically different. All analyses were done using SAS, version 9.2 (Cary, NC), and all analyses were performed on limited data sets in compliance with the provisions of the Health Insurance Portability and Accountability Act.
The authors thank Fangfei Chen and Corina Bigham for their assistance with the statistical programming for this study.
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Transfusion; Sensitization; HLA antibody; Calculated panel-reactive antibody; Kidney transplantation; Dialysis
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