Over the past decade, the clinical, serological, and pathological diagnosis of antibody-mediated injury has been improving. It was only in 2001 that Banff introduced acute antibody-mediated rejection (AMR) as a distinct entity (1). The current criteria include morphological evidence of tissue injury, C4d positivity, and the detection of donor-specific antibody (DSAb) (2); this will continue to be adapted with ongoing work into the molecular markers of AMR (3). The ability to correctly diagnose acute AMR is important to deliver appropriate therapy and reduce subsequent allograft loss (4, 5), acute AMR being a significant risk factor for the development of chronic rejection and transplant glomerulopathy (TG) (6, 7). There have been few studies analyzing factors predictive of poor outcomes after AMR in immunologically low-risk patients.
Alemtuzumab (Campath-1H) is a monoclonal anti-CD52 antibody, which is increasingly used as an induction agent in renal transplantation (8, 9). The CD52 antigen is expressed on B and T lymphocytes, natural killer cells, macrophages, monocytes, and neutrophils (10, 11). After administration, there is depletion of all affected mononuclear cells, with discordant recovery of the different cell types (12). Although initial hypotheses that such radical depletion would enable tolerance were unfounded (13), it has allowed successful transplantation in the setting of minimal maintenance immunosuppressive regimens (14, 15).
It has been reported that alemtuzumab is associated with an excess of AMR. However, these reports were limited to patients receiving calcineurin inhibitor (CNI)-free immunosuppressive regimens (16, 17). Randomized control trials assessing the efficacy of alemtuzumab and CNI monotherapy have shown equivalent results in allograft and rejection-free survival (18–20).
The aim of this study is to analyze the incidence, time course, risk factors, and outcomes of acute AMR in patients receiving a homogenous minimal maintenance immunosuppressive regimen. The recognition of factors associated with poor allograft survival will help to identify a subgroup of patients who might benefit from novel therapeutic options.
We retrospectively studied 469 patients who received an ABO compatible, crossmatch negative renal transplant. All patients received induction with alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) and maintenance immunosuppression with tacrolimus (Prograf; Astellas Pharma Inc., Tokyo, Japan) monotherapy. Overall, 100 of 469 patients (21.3%) experienced rejection, 52 of 469 (11.1%) developed acute cellular rejection (ACR) alone, and 48 of 469 (10.2%) of patients had biopsy-proven acute AMR. Thirty of 48 (62.5%) cases fulfilled the Banff criteria for definite AMR, whereas 18 of 48 (37.5%) were categorized as suspicious for AMR (1). The 369 of 469 (78.7%) patients who remained rejection free were used as our control group. The baseline demographics are shown in Table 1, this shows that patients with preformed DSAbs and those receiving a kidney with a higher mean human leukocyte antigen (HLA) or -DR locus mismatch are at increased risk of developing AMR. Thirteen of 48 (27.1%) of patients with AMR had preformed DSAbs compared with 33 of 369 (8.9%) of nonrejectors (NR) (P=0.0004). The mean HLA mismatch (A, B, DR) in the AMR group was 4.02±1.16, which was significantly higher than the nonrejectors who had a mean mismatch of 3.13±1.61 (P=0.001).
The median time to rejection in the AMR group was 1.55 months (0.2–31.7 months) compared with 5.77 months (0.4–44.57 months) in the patients with ACR (P=0.19). The mean tacrolimus levels at the time of AMR and ACR was 7.47±3.27 ng/mL and 6.55±2.30 ng/mL, respectively (P=0.09). The absolute lymphocyte count was significantly higher at the time of ACR (0.8±0.59×109/mL) than AMR (0.50±0.51×109/mL) (P=0.0078).
There was no difference in patient survival between the nonrejectors, AMR group and ACR group, with patient survival being 95.9%, 94.1%, and 96.2%, respectively (P=0.54). Allograft survival, however, was inferior in the patients who developed AMR as shown in Figure 1, when compared with the NR group; allograft survival being 97.0% in the NR group and 70.2% in the AMR group (P<0.0001). Allograft survival in the ACR group was 84.6%, which was not statistically different from allograft survival in the AMR group (P=0.07). Of the 14 of 48 (29.2%) patients with AMR who lost their grafts, three were lost acutely during the first episode of AMR, four were lost due to TG, six grafts were lost due to resistant or ongoing rejection with or without complications (two pyelonephritis, one renal artery stenosis), and one patient developed ureteric complications.
There was a significant association between the presence of DSAbs and the development of acute AMR. Forty-two of 48 (87.5%) of patients with AMR had detectable DSAbs compared with 68 of 369 (18.4%) of patients who did not develop acute AMR during follow-up but who were DSAb positive on at least one occasion (odds ratio [OR], 30.99 [12.66–75.83], P<0.0001). DSAb-positive patients with AMR were more likely to have both CI+CII DSAbs (P<0.001). Of the nonrejectors, 32 of 68 (47.06%) had CI DSAbs, 32 of 68 (47.06%) had CII DSAbs, and 4 of 68 (5.88%) had both CI+CII DSAbs. In patients with AMR, 10 of 42 (23.81%) had CI DSAbs, 13 of 42 (30.95%) had CII DSAbs, and 19 of 42 (45.24%) had both CI+CII DSAbs. Patients with CII DSAbs at the time of AMR, whether alone or in combination with CI DSAbs were at increased risk of graft loss as shown in Figure 2 (P=0.014).
Thirty of 42 (71.4%) of DSAb-positive AMR cases had developed their DSAb de novo posttransplantation at a mean time of 8.96±9.44 months, 13 of 30 (43.3%) of these DSAb-positive cases had their antibody detected at the time of stable allograft function, at a median time of 7.6 months (0.53–28.87 months) prerejection episode. The risk of developing acute AMR after the detection of de novo DSAb in the setting of stable function was high (OR, 18.57 [6.64–51.96], P<0.0001). As a screening test subsequent AMR can be predicted with a sensitivity of 68.42% (43.45–87.42), specificity of 89.58% (85.81–92.64), positive predictive value of 27.08% (15.28–41.85), and negative predictive value of 98.05% (95.79–99.28).
Analysis of the impact of mean fluorescence index (MFI), using both the cumulative and the immunodominant value, revealed a significant association with outcome as shown in Figure 3. The mean cumulative MFI in the nonrejecting, AMR with graft survival and AMR with allograft loss groups was 1944±2378, 4917±5139, and 8785±9201, respectively (P<0.001). Similarly, the mean MFI of the immunodominant DSAb in each group was 1512±1623, 2753±1969, and 3878±2733, respectively (P<0.001). The presence of persistent DSAbs posttreatment was also associated with higher risk of allograft loss. Eleven of 14 (78.6%) graft losses had persistent DSAbs posttreatment (OR, 3.67 [0.87–15.55], P=0.08).
Thirty-nine of 48 (81.3%) of patients treated for AMR had focal or diffuse C4d. Thirty-seven of 140 (26.4%) of nonrejectors had C4d on an indication biopsy; therefore, C4d was significantly associated with acute AMR (OR, 12.06 [5.33–27.29], P<0.0001). Diffuse C4d was significantly associated with AMR (OR, 12.75 [5.52–29.42], P<0.0001), whereas focal C4d was not (OR, 1.62 [0.77–3.41], P=0.21).
The presence of diffuse C4d staining on the index AMR biopsy was associated with inferior allograft survival (P=0.019) as shown in Figure 2. There was no difference in outcome in those with focal C4d staining when compared with negative C4d (P=0.80).
By Banff grading, morphological features of tissue injury in AMR include acute tubular injury (type I), peritubular capillaritis and/or glomerulitis, and/or thrombosis (type II) or vascular involvement (type III) (1). Seven of 48 (14.6%) of patients histologically demonstrated type I AMR, 25 of 48 (52.1%) had type II, and 16 of 48 (33.3%) of patients had type III AMR. Analysis of the different types showed that there was a tendency for inferior graft survival in patients with histological type III (P=0.075) as shown in Figure 2. Table 2 shows the significance of specific histological features on graft survival by univariant analysis. Patients with thrombotic microangiopathy (HR 4.91 [1.14–21.16], P=0.03) and arteritis (HR 2.87 [0.9–9.18], P=0.075) were at risk of allograft loss secondary to AMR.
Patients with all three Banff criteria for AMR; DSAb, C4d positivity, and acute tissue injury had inferior graft survival compared with those cases, which were suspicious for AMR only, having acute tissue injury with C4d or DSAb as shown in Figure 2. Twelve of 30 (40%) of patients with definite AMR lost their graft compared with 2 of 18 (11.1%) of patients with suspicion only (P=0.042).
Six of 48 (12.5%) patients were dialysis dependent at the time of the diagnosis of AMR, three of these patients subsequently lost their grafts (P=0.34). Comparison of allograft function in the non-dialysis–dependent patients at the time of diagnosis showed no difference in the patients whose graft subsequently failed or survived (estimated glomerular filtration rate [eGFR] graft loss: 20.1±8.8; no graft loss: 23.1±11.1 mL/min/1.72m2; P=0.45). However, patients who lost their grafts had inferior function posttreatment (eGFR graft loss: 18.75±8.4; eGFR no graft loss: 37.2±19.8 mL/min/1.72m2; P=0.01).
Further AMR Episodes
Ten of 48 (20.8%) patients had more than one episode of acute AMR, of which 6 of 10 (60.0%) subsequently lost their graft. Eight of 38 (21.1%) of patients with a single episode of AMR lost their graft, and therefore allograft survival in these patients was superior to those with more than or equal to two episodes of AMR (78.6% and 40.0%, respectively, P=0.027).
Eight of 48 (16.7%) of patients had evidence of double contours at the time of index biopsy, a further 5 of 48 (10.4%) of patients with AMR had TG diagnosed on a subsequent indication biopsy, which was significantly higher than the patients with no rejection of whom only 5 of 369 (1.4%) patients had TG (OR, 27.04 [9.1–80.28], P<0.0001). CII DSAbs at the time of AMR was a risk factor for the development of TG; 12 of 13 (92.3%) of TG patients had CII DSAbs, compared with 19 of 35 (54.3%) of the patients with AMR who did not develop TG (P=0.018). There was no difference in allograft survival between the patients with AMR with TG (68.7%) when compared with those with no TG (71.4%) (P=0.91). However, longer follow-up will be required.
Multivariant analysis was performed looking at risk factors associated with allograft loss in patients with AMR using variables significant by univariant analysis, namely patients with all three criteria for AMR, diffuse C4d, CII DSAbs, TMA, and more than or equal to two episodes of AMR. Only diffuse C4d was found to be an independent significant poor prognostic factor (P=0.047; HR, 0.27 [0.08–0.98]).
In this large study, we have analyzed the risk factors and outcomes of acute AMR in patients receiving a homogenous minimal maintenance immunosuppressive regimen. AMR is not uncommon and is associated with inferior allograft survival.
The incidence of AMR has been reported to be between 4% and 8% in immunologically low-risk patients (13, 22). There have been concerns that there is an increased incidence of rejection with a humoral component in patients receiving alemtuzumab induction (16, 17). However, these findings appear to be limited to patients receiving CNI-free immunosuppressive regimens. Knechtle et al. (16) in a pilot study of 29 patients using alemtuzumab induction and sirolimus monotherapy resulted in 25% of the patients experiencing rejection, which was predominantly antibody mediated. Flechner et al. (17) then introduced mycophenolate mofetil (MMF) along with sirolimus in their study of 22 patients; however, there was still an unacceptable rate of rejection (8 of 22 [36.8%]). Reassuringly, three randomized controlled trials that include CNI monotherapy after alemtuzumab induction have demonstrated excellent medium term outcomes, with no heightened risk of rejection (18–20). Watson et al. (23) have further shown that such protocols also produce good long-term outcomes, with no increase in rejection episodes.
The reported incidence of de novo DSAbs postrenal transplant is highly variable, ranging from 5.5% to 24.2%, in cohorts not only receiving different immunosuppressive regimens but also using different screening methods (24, 25). There are few studies describing the development of DSAbs in patients receiving alemtuzumab induction. Cai et al. (26) in a study into anti-HLA antibody production with alemtuzumab induction and sirolimus maintenance showed 6 of 24 (25%) patients developed DSAbs of which four had biopsy-proven AMR. Shapiro et al. (27) described DSAb development aiding spaced weaning of tacrolimus monotherapy and 15% of stable patients on weaning developed DSAbs. The development of de novo DSAbs has been shown to be associated with AMR and allograft loss; however, the use of routine screening for DSAbs in predicting AMR remains controversial (28, 29). Gill et al. (28) did not find screening useful in identifying patients at risk of AMR. However, the number studied was small with only 11 patients developing anti-HLA antibodies; they also did not include sensitized patients or test for anti-DQ/DP antibodies. Contrary to this, Zhang et al. (29) found prospective screening in patients at increased risk of rejection helped to identify patients with AMR. DSAbs are may not only important in predicting AMR but they can also be used to guide the management of rejection. Our study has shown that DSAbs with high MFI at the time of AMR are associated with graft loss and that their persistence may be associated with graft failure, which has been shown by others (30, 31).
Although diffuse C4d staining has been found to be a specific indicator of AMR and a poor prognostic factor in acute rejection (32–34), the significance of focal C4d has been more controversial (35). Staining is dependent on the technique used, with immunohistochemistry being less sensitive than immunofluroscence (36). We found a strong correlation of diffuse C4d staining only on index biopsy with outcome. Lefaucheur et al. (5) looked at the relevance of persistent C4d post-AMR. All 21 patients studied had diffuse C4d on index biopsy, whereas 10 patients had persistent C4d on later biopsy and there was no association between C4d on follow-up biopsy and bad outcome (5). Histologically, like Lefaucheur et al., we found that patients with vascular involvement had a tendency to inferior outcome. Rafiq et al. (37) also showed that in high-risk patients, AMR with histological features showing acute tissue injury only was associated with superior outcome. Rafiq et al. were unable to differentiate between the other histological variants, whereas Lefaucheur et al. demonstrated that glomerulitis and capillaritis were also associated with poor prognosis.
A total of 27.1% of our patients with AMR developed TG and approximately one third of these patients have subsequently lost their grafts, which is likely to increase with follow-up (38). TG being progressive in nature and associated with reduced allograft survival (39–41). We found an association between TG and CII DSAbs, which has been shown by others (38, 42). Measures into the prevention of development of DSAbs or treatment of them when they occur in the setting of stable function should be the focus of further work.
The lack of randomized control trials in the treatment of acute AMR means that the most effective management protocol is unknown. Treatments usually used include a combination of antibody removal with plasmapharesis, intravenous (IV) immunoglobulin (43), rituximab (44), and optimizing tacrolimus, MMF, and corticosteroids (45). These patients with poor predictive factors may benefit from enhanced therapy or alternative agents such as bortezomib (46) and eculizumab (47).
In conclusion, this study shows that acute AMR is not uncommon and has an important consequential effect on allograft survival. Patients who satisfy the full Banff criteria for AMR are more likely to lose their grafts than those with suspicion alone. Patients who have HLA CII DSAbs, DSAbs of high MFI and persistent DSAbs posttreatment are at highest risk of graft loss. Also, patients with diffuse C4d on index biopsy have the worst allograft survival. Such patients might benefit from alternative therapies which are now available, which could be answered in the form of a multicenter randomized control trial.
MATERIALS AND METHODS
All 469 patients were transplanted at the Imperial College Kidney and Transplant Centre between 2005 and 2010. We excluded from our analysis patients who had received a simultaneous pancreas and kidney transplant or an ABO incompatible kidney transplant along with those patients who were transplanted across a positive flow cytometry crossmatch.
All patients were transplanted on the basis of a negative T- and B-cell CDC crossmatch and a negative T-cell FCXM.
Detection of Anti-HLA DSAbs
Sensitization is defined by the presence of anti-HLA antibodies and the pretransplant sera of all patients were screened using LABScreen mixed beads (One Lambda, Inc., Canoga Park, CA). Patients with a positive screen had the specificity of their anti-HLA antibody identified using LABScreen single antigen beads. Posttransplant, patients were routinely screened for DSAbs at 3 and 6 months, and then 6 monthly intervals or when clinically indicated.
Each anti-HLA DSAb detected by the Luminex fluroanalyzer had its signal intensity recorded (by MFI). Our laboratory protocol is to type for HLA-A, -B, -Cw, -DR, and -DQ antigens. DP antigens are typed when anti-DP antibodies were detected in serum to allow classification of donor specificity.
All patients received induction with alemtuzumab 30 mg IV postoperatively and maintenance immunosuppression with tacrolimus to achieve a mean trough level of 5 to 8 ng/mL measured by HPLC-MS (High performance liquid chromatography with tandem mass spectrometry). Our steroid sparing protocol consists of methyl prednisolone (500 mg)IV preoperatively, followed by prednisolone 1 mg/kg/day (maximum 60 mg) for 3 days reduced to 0.5 mg/kg/day (maximum 30 mg) on day 4, and then discontinued after day 7.
Rejection was diagnosed by renal allograft biopsy and classified using Banff 2007 criteria (36). C4d staining was carried out by immunoperoxidase on paraffin sections using polyclonal rabbit anti-C4d antibody at 1/40 (Oxford Biosystems, BI-RC4D). The slides were subjected to 20-min microwave antigen retrieval then placed on the Biogenex i6000 autostainer. The Biogenex Non-Biotin detection kit was used. C4d was classified as negative (C4d0 and C4d1, peritubular capillary (PTC) staining of 0% and <10%, respectively), focal (C4d2, PTC staining of 11% to 50%) or diffuse (C4d3, PTC staining >50%) (34). Cases were diagnosed as AMR if they combined C4d focal or diffuse staining with any of the following histological features: acute tubular injury, peritubular capillaritis, glomerulitis, thrombotic microangiopathy, interstitial hemorrhage, or vascular necrosis along with the presence of a circulating DSAb. Cases were considered suspicious for AMR if they had features of acute tissue injury with C4d and no detectable DSAb or were DSAb positive but C4d negative.
All cases of AMR and suspicious for AMR were treated with a total of 2 g/kg IV immunoglobulin (Vigam; Bio Products Laboratory, Hertfordshire, UK) and plasmapheresis with an exchange volume of 50 mL/kg (maximum of 4.5 L) for 5 to 10 exchanges. Patients received 500 mg IV methyl prednisolone on three consecutive days along with the introduction of MMF (Cellcept; Roche, Nutley, NJ) to achieve a 12 hr predose mycophenolic acid level of 1.2 to 2.4 mg/L measured by HPLC-MS. After IV steroids, oral prednisolone was reintroduced (30 mg/day) and weaned to 10 mg by 3 months and continued thereafter. Patients had their tacrolimus dose increased to achieve a 12 hr trough level of 8 to 12 ng/mL.
Analyses were performed using the statistical package Medcalc version 10.4.3. Kaplan-Meier survival analysis was used to compare rejection-free survival and graft survival. Comparisons of means and frequencies of normally distributed variables were calculated using t tests and chi-squared/Fisher's exact tests. Multivariant analysis was achieved using Cox proportional hazards regression methods.
The authors thank the Auchi Dialysis Unit, Hammersmith Hospital, for providing the plasma exchange service used in the treatment of our patients. They acknowledge the work contributed by the transplant clinic staff, the Leslie Brent laboratory, and the Histocompatibility and immunogentics laboratory staff.
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