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Volume: 17 Issue: 3 June 2019


Impact of Primary Disease Nature in the Development of De Novo Donor-Specific Antibodies After Kidney Transplant and the Risk of Acute Rejection

Objectives: In this study, we explored the effect of the primary disease nature on development of de novo donor-specific antibodies after kidney transplant.

Materials and Methods: We retrospectively studied kidney transplant recipients based on their primary disease. Patients were divided according to autoimmune and nonautoimmune diseases. The frequency of de novo donor-specific antibodies posttransplant and the incidence of acute rejection were estimated. De novo donor-specific antibodies were determined by the Luminex (LAB Screen products, One Lambda, Inc., Canoga Park, CA, USA) assay.

Results: Our study included 228 patients: 92 with autoimmune diseases and 136 with nonautoimmune diseases. Similar rates of de novo donor-specific antibodies (10.9% vs 11.8%; P = .835) were shown in the 2 groups over a mean (standard deviation) follow-up of 56.5 (27.8) months. In the nonautoimmune group, presence of de novo donor-specific antibodies was associated with higher rates of biopsy-proven acute rejection (37.5% vs 8.3%; odds ratio = 6.6; 95% confidence interval, 1.985-21.945; P = .002) versus that shown in patients of the same group without de novo donor-specific antibodies. In the autoimmune group, biopsy-proven acute rejection rates were similar between patients with and without de novo donor-specific antibodies. Mean fluorescence intensity titers of de novo donor-specific antibodies were significantly higher in patients with nonautoimmune primary disease (P = .003).Overall, graft loss was shown to be significantly higher in patients with autoimmune than in patients with nonautoimmune diseases (P < .001), although not different between patients with de novo donor-specific antibody formation (P = .677).

Conclusions: No associations were shown between the frequency of de novo donor-specific antibody development after kidney transplant and the nature of the primary disease (autoimmune vs nonauto-immune). Detection of de novo donor-specific antibodies was associated with higher rates of biopsy-proven acute rejection among patients with nonautoimmune primary disease.

Key words : Alloimmunity, Autoimmunity, Graft survival, Outcome, Renal transplant


De novo formation of specific antibodies directed against donor human leukocyte antigens (HLA) is a major risk factor for reduced allograft survival after kidney transplant.1-4 Anti-HLA class II donor-specific antibodies (DSA) are the most frequent antibodies that occur de novo posttransplant in previously unsensitized renal transplant recipients.5-7 Risk factors for production of de novo DSAs have not been consistently explored or reported. However, HLA class II mismatches (HLA-DR, HLA-DQB, HLA-DQA, and HLA-DP mismatches) are considered to contribute to increased risk of graft loss.8,9 Other risk factors for de novo DSA, which could lead to subsequent acute rejection (AR), include retransplant, presence of HLA antibodies before kidney transplant, younger age, deceased-donor kidney transplant, no adherence, insufficient immunosuppression, and subclinical T-cell-mediated rejection.10

Diseases in renal transplant candidates that can cause end-stage renal disease (ESRD) include autoimmune diseases, which are characterized by abnormal immune responses to self-antigens which may be restricted to the kidney (eg, primary glomerulonephritides) or involve other organ tissues (eg, systematic autoimmune diseases, such as lupus). Many autoimmune diseases are thought to occur as a result of loss of immunogenic tolerance, defined as the ability to react to antigens and ignore self-antigens. Historically, research has focused on the cellular aspects of the alloimmune response after kidney transplant. Antibodies against self-antigens may also be related to the development of certain diseases (eg, obliterated bronchiolitis after lung transplant), which could lead to the development of chronic rejection.11 The precise mechanisms by which humoral autoimmunity induces rejection have not been fully described, but it has been shown that the lung is able to provide immune responses to induce graft dysfunction without secondary lymphoid tissues.

In kidney transplant patients, immune responses directed against tissue-associated self-antigens have also been found to play a major role in chronic rejection.12-14 Moreover, a correlation between antibodies to angiotensin II receptor type 1 and allograft loss has been shown.14 However, about 50% of patients who develop antibodies to kidney-associated self-antigen angiotensin II receptor type 1, fibronectin, or collagen IV within the first year after kidney transplant did not have worse clinical outcomes.13 Another pathway by which these autoantibodies could contribute to rejection is the development of cryptic self-antigens. These are antigens that were previously hidden from the immune system and then become exposed due to tissue injury, such as during infection,12-14 or inflammation related to autoimmune diseases of the kidney.

One pathway in alloimmunity and autoimmunity is the T helper cell TH17, which clears pathogens not adequately handled by the T helper cells TH1 and TH2, thus contributing to autoimmune and inflam-matory diseases. TH17 and interleukin 6 have also been implicated in the development of rejection after solid-organ transplant.14 Together, these phenomena highlight the role that autoimmunity plays in rejection14 after transplant. Therefore, one question is whether a background of autoimmunity in kidney transplant recipients may predispose, facilitate, or trigger alloimmunity. Apart from the impaired intolerance mechanisms and the variety of effects involved in autoimmunity, including destruction of tissues and altered organ function, many such patients have also been exposed to considerable amounts of potent immunosuppressants pretrans-plant to achieve immunologic and clinical remission of the glomerular disease. Other kidney transplant recipients are immunosuppression naïve. It would be beneficial to know whether pharmacologic, long-term suppression of the immune system pretransplant plays a role in its subsequent ability to respond to alloimmune challenges after kidney transplant.

Here, we explored whether the primary disease nature might be associated with development of de novo DSAs after kidney transplant and its correlation, if any, with subsequent AR and graft function in the long term.

Materials and Methods

Study design and definitions
We retrospectively reviewed the medical records of all patients (N = 605) who underwent kidney transplant in our hospital between January 2005 and December 2011 and identified 269 patients in whom the primary disease was known. We excluded patients with simultaneous kidney-pancreas or liver-kidney transplant procedures, those with retransplant, those with ABO-incompatible kidney transplant, those who died or lost grafts due to a major surgical complication within month 1, patients with nonadherence issues, and those who were lost during follow-up.

The remaining cohort was divided into 2 groups, based on whether their primary disease was autoimmune in nature (group A) or not (group B). Group A included patients with biopsy-proven primary glomerulonephritis or glomerular diseases in the native kidney secondary to systemic autoimmune disorders, such as, pauci-immune small vessel vasculitis or systemic lupus erythematosus. Group B included patients with causes of ESRD that included obstructive uropathy, polycystic kidney disease, and congenital hypoplastic kidneys. Table 1 shows the distribution of ESRD causes per the study groups.

We recorded demographic, clinical, and laboratory characteristics related to donors and recipients in both groups, including age, donor source, duration of dialysis pretransplant, HLA mismatch, percentage of panel reactive antibodies (PRA) around the pretransplant period, and cold ischemia time. The observation period started on the day of kidney transplant and ended on the date of the most recent follow-up visit at the outpatient transplant clinic, the date of death with functioning graft, or the date of graft loss from any cause. Kidney transplant outcomes were compared between groups, including the frequency of development of de novo DSA posttransplant and the subsequent incidence of AR and graft function over the long term. Specifically, we recorded the level of graft function on day of first discharge after kidney transplant, at year 1 post-transplant, and at end of follow-up, as quantified by serum creatinine and estimated glomerular filtration rate, using the Modification of Diet in Renal Disease study equation.15

Primary outcomes of interest also included patient and graft survival assessed at the end of the observation period. Delayed graft function (DGF) was defined as the need for dialysis in the first week posttransplant. Suspicion of AR was indicated by an increase in serum creatinine of 25% or more from baseline, which was confirmed histopathologically by ultrasonographic-guided percutaneous biopsy. Rate of biopsy-proven AR (BPAR) in both groups was also evaluated. All patients with BPAR were treated on the basis of the histopathologic type, by either intravenous methylprednisolone (3-5 pulses, 500-1000 mg each) and subsequent oral tapering or rabbit antithymocyte globulin or both. Mortality was defined as death from any cause. All-cause graft loss was defined as the combination of mortality and death, censored at graft failure after resumption of dialysis. Cold ischemia time was time between application of cold perfusion solution after kidney procurement and time when renal tissue reached physiologic temperature during implantation. Graft failure was defined as the permanent decline of renal function requiring return to chronic dialysis. Medication nonadherence was confirmed by patient admission to clinic staff and/or by drug levels below detectable levels. Repeated failure to attend clinic visits or comply with laboratory evaluations (eg, blood draws for medication levels) was also defined as nonadherence.

All patients were informed about the details of the various procedures and consented to the review of their medical records by the treating nephrologist.

HLA typing
Patients and donors were typed for HLA-A, HLA-B, HLA-C, DRB1, or DQB1 loci using commercially available serologic typing trays (Terasaki HLA Tissue Typing Trays, One Lambda, Inc., Canoga Park, CA, USA; and/or Lymphotype HLA, Bio-Rad, Hercules, CA, USA) and by low-resolution molecular methods (Labtype SSO, One Lambda). HLA-DPB1 and HLA-DQA1 typing was performed when HLA-DPB1 or HLA-DQA1 antibodies were detected in patient sera. To confirm allele-specific antibodies possibly or potentially recognizing a graft antigen, additional HLA typing of the donor with high-resolution molecular techniques was performed.

Anti-HLA antibody detection
Pretransplant screening
Screening for HLA antibodies included both the anti-human globulin complement-dependent micro-lymphocytotoxicity method (AHG-CDC) and the Luminex technique (LAB Screen products, One Lambda, Inc., Canoga Park, CA). Anti-HLA immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies were detected with the AHG-CDC method with and without addition of dithiothreitol to patient sera using trays precoated with a known panel of HLA phenotype T and B cells (Lymphoscreen ABC & DR, Bio-Rad). For the Luminex technique, patient serum samples were incubated with a panel of color-coded beads, coated with purified recombinant HLA antigens (LAB Screen PRA class I and II, One Lambda), which was followed by addition of secondary phycoerythrin-labeled antihuman IgG. HLA sensitization of each patient was expressed as percent PRAs. All PRA-positive pretransplant and posttransplant sera were further tested with single HLA antigen-coated beads (LAB Screen single antigen beads, One Lambda). LAB Screen assays, data analyses, and calculations were performed according to manufacturers’ instructions. Results were expressed as mean fluorescence intensity (MFI). HLA antibody specificity was considered positive if the normalized MFI was > 1000.

Posttransplant screening
Renal transplant reci-pients were typically monitored annually for anti-HLA antibodies and by clinical indication afterward. Two to 4 serum samples per patient were screened with the Luminex technique (LAB Screen PRA class I and II, One Lambda). All PRA-positive samples, as well as sera from patients with negative PRA but with acutely elevated serum creatinine (> 25% from baseline), were also analyzed for HLA antibody specificity with single antigen beads to define subthreshold levels of circulating DSAs. To identify the HLA DSA specificities, donor-recipient mismatched HLAs were compared with patient antibody profiles.

Crossmatch assays
Pretransplant crossmatching consisted of AHG-CDC and flow cytometry crossmatch analyses using T and B cells of the donor and pretransplant serum of the recipient. For AHG-CDC crossmatching, analyses used unseparated B and T cells taken from either living donor peripheral blood or deceased donor spleen. Sera were tested with and without dithiothreitol for detection of both anti-HLA IgG and IgM antibodies. Autologous AHG-CDC cross-matching was also done. For flow cytometry cros-s-match analyses, donor lymphocytes were incubated with recipient’s serum followed by addition of secondary fluorescence-labeled antihuman IgG and fluorescence-labeled anti-CD3/CD19 to identify the T- and B-cell populations. Results were analyzed with a cytometer (Beckman Coulter, Fullerton, CA, USA). All transplant recipients required a negative IgG AHG-CDC and T cell/B cell flow cytometry crossmatch to proceed to kidney transplant. A positive IgM CDC crossmatch was not a contra-indication for kidney transplant.

Graft biopsy policy and histopathologic evaluation
Graft biopsies were conducted when indicated by clinical results, including with presence of acute graft dysfunction (elevated serum creatinine levels of unknown cause after exclusion of obstructive uropathy by ultrasonography and toxic levels of calcineurin inhibitor [CNI] agents). Additional indications included proteinuria > 0.5 g/day or presence of glomerular erythrocyturia or any of these combinations. All biopsy specimens were evaluated by light microscopy and immunofluorescence for C4d according to the Banff 2007 criteria.15,16 A positive C4d was defined as focal or diffuse C4d in the peritubular capillaries by immunofluorescence. Acute cellular-mediated rejection was defined as a biopsy with C4d, transplant glomerulopathy or peritubular capillaritis.17 Acute cellular-mediated rejection was also assumed when moderate or severe transplant glomerulitis or peritubular capillaritis without C4d deposits in peritubular capillaries was present. If an episode of AR occurred together with acute T-cell-mediated rejection, it was also defined as AR.

Immunosuppressive regimens
Nearly all patients received induction treatment with an anti-CD25 agent (namely, basiliximab or daclizumab). Patients who received kidneys from expanded criteria donors or from those with cold ischemia times > 16 hours and/or higher likelihood of established DGF received induction treatment with rabbit antithymocyte globulin at a dose of 1.5 mg/kg, based on actual body weight, for 10 to 14 consecutive days. Doses were based on daily CD3 measurements and adjusted by white blood cell and/or platelet counts. All patients received glucocorticoids, 500 to 1000 mg of methyl-prednisolone on day of transplant, followed by a daily oral dose of 20 to 40 mg/day (depending on the immunologic risk), with gradual tapering afterward. Maintenance immunosuppression consisted of a calcineurin inhibitor (cyclosporine or tacrolimus) in combination with mycophenolate mofetil and low-dose methylprednisolone. Patients were maintained on cyclosporine with a C2 level of at 700 to 900 mg/dL for post-transplant year 1, which were then lowered to 500 to 700 mg/dL, and tacrolimus trough levels at 6 to 8 ng/mL during year 1, which were then lowered to 5 to 7 ng/mL. Patients at high immunologic risk were preferentially treated with tacrolimus and mycophenolic acid, and those with a history of malignancy were treated with an inhibitor of the mammalian target of rapamycin, at a goal of 6 to 8 ng/mL (if combined with mycophenolic acid) and 4 to 6 ng/mL (if combined with a calcineurin inhibitor).

Statistical analyses
Mean values and standard deviations were calculated for continuous variables, and categorical variables were presented as percentages. We used t tests to examine potential differences in continuous variables of interest between study groups. We used chi-square test to determine any associations between groups with respect to certain categorical variables. Logistic regression was applied to identify any differences in risk of AR between groups. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 17.0, IBM Corporation, Armonk, NY, USA). P < .05 was considered statistically significant.


Description of the study population
Of 269 patients identified with known causes of ESRD, 41 patients did not meet the inclusion criteria. Specifically, among excluded patients, 3 had simultaneous kidney-pancreas or liver-kidney transplants, 16 had retransplants, 11 had ABO-incompatible kidney transplant, 1 patient died and had graft loss due to surgical complication within month 1, and 3 had nonadherence issues, with some of these cases overlapping between these reasons. Figure 1 shows included patients (92 in group A and 136 in group B). Mean follow-up time (standard deviation) for the study groups was 56.5 (27.8) months. Demographics, baseline characteristics, and immunosuppressive regimens for kidney transplant recipients are displayed in Table 2. Patients in the 2 groups were similar with respect to age, sex, donor age and source, time in dialysis before transplant, and rates of PRA. Most patients received inductive immunosuppressive therapy with an anti-CD25 inhibitor, whereas the predominant regimen for maintenance therapy posttransplant included a CNI, a mycophenolate mofetil formulation, and glucocorticoids. The frequency of DGF was not different between study groups (Table 3).

Kidney transplant outcomes
De novo donor-specific antibody formation

As shown in Table 3, the frequency of de novo DSA posttransplant was similar between groups (10.9% in group A and 11.8% in group B; P = .835) (Figure 2). Mean time (standard deviation) to de novo DSA detection overall was 20.9 (19.3) months from kidney transplant. However, MFI titers among patients with newly developed DSAs were found to be statistically different between groups, with mean MFI (standard deviation) of 2664.2 (2050.5) for patients with a primary disease of autoimmune origin versus 7266.4 (4724.2) for those with a primary disease of nonautoimmune origin (P = .003).

Biopsy-proven acute rejection
The follow-up time (standard deviation) of the 110 (44%) patients who underwent a graft biopsy was 56.5 (27.7) months, according to the clinical indications mentioned earlier. There were 31 occasions (13.45%) of BPAR. Twenty-five patients experienced 1 episode of BPAR, 5 had 2 episodes, and 1 had 3 episodes. The distribution of BPAR in accordance with detection of de novo DSA in each group is shown in Table 4. In group B patients, presence of de novo DSA was associated with higher rates of BPAR versus no detectable de novo DSA posttransplant (37.5% vs 8.3%; odds ratio [OR] = 6.6, 95% confidence interval [CI], 1.985-21.945; P = .002). Thus, group B patients with de novo DSAs were 6.6 times more likely to experience BPAR than group B patients without de novo DSAs. This phenomenon was not observed in group A patients. In contrast, among patients in group A, no differences in BPAR rates were shown between those with and without de novo DSA (OR = 1.3, 95% CI, 0.252-6.971; P = .738). We observed no differences in related risks between group A and group B patients without de novo DSA (OR = 0.5, 95% CI, 0.201-1.161; P = .104) (Table 5).

De novo donor-specific antibodies and kidney transplant maintenance regimen
When we compared the frequency of de novo DSA development among patients of group A who received maintenance therapy consisting of CNI, mycophenolic acid, and steroids versus group A patients who received a CNI plus an mTOR and steroids, no differences were shown (P = .555). Likewise, among group B patients, no differences were shown regarding DSA formation in patients who were maintained on a CNI, mycophenolic acid, and steroid regimen versus patients maintained on a CNI plus mTOR inhibitor and steroid regimen (P = .188). Further comparisons within each group regarding other regimens were not feasible due to the small number of patients.

Graft function
Renal function results at discharge and at year 1 posttransplant, represented by serum creatinine levels and estimated glomerular filtration rate, were not different between the 2 groups (Table 3). However, we observed a significant difference in graft function between the 2 groups at the end of our follow-up period, although graft function among patients with de novo DSA formation was similar at that point.

Graft loss
Graft loss was significantly higher in group A patients than in group B patients (21.1% vs 0; P < .001) within our mean follow-up of 56.45 months. Rate of graft failure was not significantly different among patients with de novo DSA formation in the 2 groups (3.6% vs 0; P = .677).


This is the first study, to our knowledge, that compared the frequency of de novo DSA development after kidney transplant on the basis of the primary disease. We explored the hypothesis that a past medical history of autoimmune disease (group A), either systematic or kidney targeted, which was the cause of ESRD, affected development of de novo DSA posttransplant. We found no differences in frequency of de novo DSA formation based on autoimmune versus nonautoimmune causes of ESRD. Interestingly, patients with a nonautoimmune primary disease (group B) and de novo DSA were 6.6 times more likely to experience BPAR than patients of the same group who did not develop de novo DSA posttransplant, a phenomenon not observed among group A patients. Moreover, the higher frequency of BPAR among group B patients with de novo DSA was associated with significantly higher MFI titers, whereas group A patients had relatively low titers of MFI and the frequency of BPAR was not influenced by the presence of de novo DSA. In addition, graft loss was found to be significantly higher in patients with autoimmune disorders as primary cause of ESRD, a difference attributed to factors not related to de novo DSA formation.

One may expect that patients with autoimmune disorders, especially those who have reached ESRD because of the disease, would be more likely to develop de novo DSA posttransplant. This is because autoimmunity, as reported for patients with other types of organ transplant procedures,11-14,18 facilitated, triggered, or predisposed patients to alloimmunity.19 Among the various pathways implicated in the pathogenesis of autoimmune diseases,20,21 common mechanisms exist between glomerulonephritides and transplant rejection, which end up following the same kidney damage pathways.22 In addition, although antigens involved in transplant rejection and glomerular diseases are different, a number of factors involved in the effector response are similar. These are mainly those based on interactions between innate and adaptive immune mechanisms and on the strict cooperation between T and B cells.22 The common target for the allo- and autoimmune attacks are endothelial cells, which are richly found in the kidney.22 Complement participation in both processes is characteristic and can be activated via the classical pathway in some immune complex-mediated glomerulonephritides23 or uncontrolled activation of the alternative pathway due to genetic down-regulation of complement controllers23 in others. Overreactivity of complement cascade and deficient production of some complement components, ie, C1q, can trigger the development of lupus nephritis.24 However, the role of complement activation in AR is also pivotal, with capillary C4d deposition being a reliable marker of AR,22 but C4d deposits are difficult to detect even in the absence of circulating antibodies.25 This is the main reason why most of the available immunosuppressive agents used in kidney transplant have also been used in patients with primary or secondary glomerulonephritides and vice versa.

Although the assumption that the frequency of de novo development of DSA posttransplant is influenced by a background of autoimmunity was not confirmed, we found that BPAR was significantly more likely among those with a primary disease of nonautoimmune origin and de novo DSA in association with higher MFI titers. It has been repeatedly demonstrated that patients with de novo DSA at high strength have higher risk of AR.26 Therefore, DSA MFI titration is used for immunologic risk stratification27 of patients to guide their clinical management. Tang and associates showed that monitoring DSA posttransplant could identify patients at risk for AR.27 Salvade and associates found that a clinically relevant threshold of DSA anti-HLA antibodies between 4300 and 5300 was a significant outcome predictor.28 Patients with a primary disease of autoimmune origin in our study had significantly lower MFI titers, probably because they had been exposed to considerable amounts of immunosuppressive agents before transplant in combination or sequentially. Furthermore, among patients with glomerulonephritides, primary or secondary, those who progress to ESRD frequently have multiple renal relapses or treatment resistance, requiring continuous immunosuppressive therapy of increasing intensity, almost lifelong. Present medi-cations include glucocorticoids, alkylating drugs, purine synthesis inhibitors, CNIs, cyclophosphamide, and B-cell depletion with rituximab. Patients with systemic or kidney-targeted autoimmune disorders often receive cyclophosphamide, an agent acting through its metabolites that forms DNA crosslinks both between and within DNA strands, leading to cell apoptosis.28 Therefore, cyclophosphamide is a potent immunosuppressant, capable of inhibiting both humoral29 and cell-mediated immune responses,29,30 resulting in significant and often long-standing acquired immunodeficiency. Cyclophosphamide-based regimens have been associated with significant risk of comorbidities, including a well-documented and dose-dependent risk of cancer,30 with the time to event analysis indicating that the risk is particularly high 5 to 9 years after treatment initiation, implying a long-lasting or even irreversible effect in the immune system.30 Rituximab on the other hand has been associated with hypogammaglobulinemia,31 but the potential development of secondary immunodeficiency is not thoroughly studied in patients with autoimmune diseases.

Apart from the effects of prolonged immunosup-pression in patients with autoimmune disorders, it is also unclear whether all DSAs can cause AR. For instance, although the 10-year graft survival has been clearly shown to be lower among those with de novo DSAs compared with those without,8 some patients with newly formed DSAs are reported to do well, suggesting that not all DSAs may be pathogenic. Moreover, AR has been shown to be more common among patients with C1q-binding antibodies than in those with non-C1q-binding antibodies.32

Our present study also showed that graft function at end of follow-up was significantly lower among patients with autoimmune disorders, although this difference was not observed between subgroups of patients with de novo DSA. Likewise, graft loss was significantly higher among patients in group A. These differences in graft function and survival were not attributed to nonalloimmune factors related to kidney transplant. Interestingly, a much higher incidence of arterial hyalinosis was observed in biopsies of group B patients, possibly because of the de novo DSA that formed. Longer term follow-up may reveal additional loss or functional deterioration in group B.

Several studies have shown that glomerulo-nephritis recurrence is an important factor of worse allograft outcome for kidney transplant recipients with ESRD due to long-term glomerulonephritis.

In a large and well-defined population, Briganti and associates32 demonstrated the importance of recurrent glomerulonephritis as cause of allograft loss after kidney transplant. Specifically, they showed that, in transplant recipients with a primary diagnosis of glomerulonephritis, recurrence was more frequent than AR as cause of allograft loss during the first 10 years after kidney transplant.32 Furthermore, certain types of glomerulonephritis in that study repre-sented the strongest risk factor for recurrence leading to allograft loss.32

Limitations of this study included its retrospective design and the small numbers of patients. However, patients with autoimmune disorders and ESRD are not so common, and the primary disease of kidney transplant recipients is often not known. In contrast, strength of this study was that all patients were from the same center, and thus therapeutic regimens and clinical practices were uniform.

In conclusion, we found that primary disease of an autoimmune versus nonautoimmune nature did not affect the frequency of de novo DSA development after kidney transplant. However, de novo DSA formation in patients with a nonautoimmune primary disease was associated with significantly higher rates of BRAR versus rates shown in patients without de novo DSA of the same group. This was not observed among patients with a primary disease of auto-immune origin.


  1. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378-383.
    CrossRef - PubMed
  2. Lee PC, Terasaki PI, Takemoto SK, et al. All chronic rejection failures of kidney transplants were preceded by the development of HLA antibodies. Transplantation. 2002;74(8):1192-1194.
    CrossRef - PubMed
  3. Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003;75(7):1034-1040.
    CrossRef - PubMed
  4. Issa N, Cosio FG, Gloor JM, et al. Transplant glomerulopathy: risk and prognosis related to anti-human leukocyte antigen class II antibody levels. Transplantation. 2008;86(5):681-685.
    CrossRef - PubMed
  5. Ntokou IS, Iniotaki AG, Kontou EN, et al. Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: high immunogenicity of HLA class II graft molecules. Transpl Int. 2011;24(11):1084-1093.
    CrossRef - PubMed
  6. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012;12(5):1157-1167.
    CrossRef - PubMed
  7. Everly MJ, Rebellato LM, Haisch CE, et al. Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation. 2013;95(3):410-417.
    CrossRef - PubMed
  8. Morath C, Opelz G, Zeier M, Susal C. Clinical relevance of HLA antibody monitoring after kidney transplantation. J Immunol Res. 2014;2014:845040.
    CrossRef - PubMed
  9. Burlingham WJ, Love RB, Jankowska-Gan E, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117(11):3498-3506.
    CrossRef - PubMed
  10. Bjerre A, Tangeraas T, Heidecke H, et al. Angiotensin II type 1 receptor antibodies in childhood kidney transplantation. Pediatr Transplant. 2016;20(5):627-632.
    CrossRef - PubMed
  11. Hesemann LE, Subramanian V, Mohanakumar T, Dharnidharka VR. De novo development of antibodies to kidney-associated self-antigens angiotensin II receptor type I, collagen IV, and fibronectin occurs at early time points after kidney transplantation in children. Pediatr Transplant. 2015;19(5):499-503.
    CrossRef - PubMed
  12. Taniguchi M, Rebellato LM, Cai J, et al. Higher risk of kidney graft failure in the presence of anti-angiotensin II type-1 receptor antibodies. Am J Transplant. 2013;13(10):2577-2589.
    CrossRef - PubMed
  13. Weber DJ, Wilkes DS. The role of autoimmunity in obliterative bronchiolitis after lung transplantation. Am J Physiol Lung Cell Mol Physiol. 2013;304(5):L307-311.
    CrossRef - PubMed
  14. Nakagiri T, Inoue M, Minami M, Shintani Y, Okumura M. Immunology mini-review: the basics of T(H)17 and interleukin-6 in transplantation. Transplant Proc. 2012;44(4):1035-1040.
    CrossRef - PubMed
  15. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753-760.
    CrossRef - PubMed
  16. Amico P, Honger G, Mayr M, et al. Clinical relevance of pretransplant donor-specific HLA antibodies detected by single-antigen flow-beads. Transplantation. 2009;87(11):1681-1688.
    CrossRef - PubMed
  17. Muro M, Llorente S, Marin L, et al. Acute vascular rejection mediated by HLA antibodies in a cadaveric kidney recipient: discrepancies between FlowPRA, ELISA and CDC vs luminex screening. Nephrol Dial Transplant. 2005;20(1):223-226.
    CrossRef - PubMed
  18. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. J Am Soc Nephrol. 1999;10(11):2426-2439.
  19. Jaeger C, Brendel MD, Hering BJ, Eckhard M, Bretzel RG. Progressive islet graft failure occurs significantly earlier in autoantibody-positive than in autoantibody-negative IDDM recipients of intrahepatic islet allografts. Diabetes. 1997;46(11):1907-1910.
    CrossRef - PubMed
  20. Bonelli M, Savitskaya A, Steiner CW, et al. Phenotypic and functional analysis of CD4+ CD25- Foxp3+ T cells in patients with systemic lupus erythematosus. J Immunol. 2009;182(3):1689-1695.
    CrossRef - PubMed
  21. Bonelli M, Savitskaya A, von Dalwigk K, et al. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int Immunol. 2008;20(7):861-868.
    CrossRef - PubMed
  22. Ponticelli C, Salvadori M, Coppo R. The kidney, a victim and culprit of autoimmune and alloimmune responses. Nephron Clin Pract. 2011;119(3):c200-204.
    CrossRef - PubMed
  23. Chen M, Daha MR, Kallenberg CG. The complement system in systemic autoimmune disease. J Autoimmun. 2010;34(3):J276-286.
    CrossRef - PubMed
  24. Lood C, Gullstrand B, Truedsson L, et al. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum. 2009;60(10):3081-3090.
    CrossRef - PubMed
  25. Haas M. The significance of C4d staining with minimal histologic abnormalities. Curr Opin Organ Transplant. 2010;15(1):21-27.
    CrossRef - PubMed
  26. O'Leary JG, Kaneku H, Susskind BM, et al. High mean fluorescence intensity donor-specific anti-HLA antibodies associated with chronic rejection postliver transplant. Am J Transplant. 2011;11(9):1868-1876.
    CrossRef - PubMed
  27. Tang MY, Wang QH, Wang J, et al. Strength of donor-specific antibodies with the use of Luminex single-antigen beads is a reliable predictor of acute rejection in living-relative kidney recipients. Transplant Proc. 2015;47(2):309-312.
    CrossRef - PubMed
  28. Salvadé I, Aubert V, Venetz JP, et al. Clinically-relevant threshold of preformed donor-specific anti-HLA antibodies in kidney transplantation. Hum Immunol. 2016;77(6):483-489.
    CrossRef - PubMed
  29. Penn I. Malignancy after immunosuppressive therapy. Clin Immunother. 1995;4:207-218.

  30. van Vollenhoven RF, Emery P, Bingham CO, 3rd, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis. 2013;72(9):1496-1502.
    CrossRef - PubMed
  31. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215-1226.
    CrossRef - PubMed
  32. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med. 2002;347(2):103-109.
    CrossRef - PubMed

Volume : 17
Issue : 3
Pages : 304 - 312
DOI : 10.6002/ect.2018.0054

PDF VIEW [363] KB.

From the 1Department of Nephrology and Transplantation Unit, Laiko Hospital, National and Kapodistrian University of Athens, Faculty of Medicine; the 2Department of Pathology, National and Kapodistrian University of Athens, Faculty of Medicine; the 3National Tissue Typing Center, “Gennimatas Hospital;” and the 4Transplantation Unit, Laiko Hospital, Athens, Greece
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Sophia Lionaki, Ag Thoma 17, 11527, Athens, Greece
Phone: +30 2107456859