Accelerated Kidney Transplant Rejection and Hypertensive Encephalopathy in a Pediatric Patient Associated With Antibodies Against Angiotensin Type 1 Receptor and HLA Class II

Donor-specific antibodies to human leukocyte antigens (HLAs) as well as antibodies to non-HLA targets are important causes for graft loss (1, 2). We report on the first pediatric case of accelerated acute C4d-positive kidney transplant rejection and malignant hypertension where both high-titer pre- and posttransplant angiotensin type 1 receptor antibodies (AT1R-Abs) and posttransplant high-titer HLA class II donor-specific alloantibodies were detected. The patient is a young girl with a WT1 gene mutation (p.H397P, OMIM 607102) (3). Steroid-resistant nephrotic syndrome due to a focal segmental glomerulosclerosis was diagnosed at the age of 15 months. Two months after her first hemodialysis (age of 9 years), she received a kidney transplant from her mother (HLA-typing of patient: HLA-A*02,*30; B*40,*18; DRB1*0301,-; DQB1* 0502,*0201; donor: HLA-A*25,*30; B*44, *18; DRB1*1501,*0301; DQB1*0602, *0201). HLA antibodies (complement-dependent cytotoxicity [CDC]/enzyme-linked immunosorbent assay [ELISA]) and the CDC crossmatches with separated donor T or B lymphocytes were negative before transplantation. Under primary immunosuppression with cyclosporine A, mycophenolate mofetil and prednisolone primary graft function was excellent with a creatinine level of 0.4 mg/dL on day 2 after transplantation. On day 3, she developed accelerated arterial hypertension with a maximum blood pressure of 180/120 mm Hg and hypertensive encephalopathy. A renal artery stenosis was excluded, and several antihypertensive drugs including Na nitroprusside were necessary. On day 5, creatinine increased to 2.1 mg/dL. Transplant biopsy showed a strong linear C4d staining of the peritubular capillaries with capillaritis and glomerulitis. Plasmapheresis treatment due to suspected AT1R-Ab-mediated rejection with malignant hypertension was initiated. AT1R-Abs were detected in very high titers before transplantation and at the time of rejection (Fig. 1A). The CDC crossmatch became positive with donor B cells but remained negative with donor T cells. The serum was strongly positive for HLA class II antibodies (B-Screen/ClassII-ID-ELISA; GTI, Aachen, Germany) directed against HLA DR2[15, 16], HLA-DR51, and HLA-DQ6, corresponding to the mismatches with the donor.FIGURE 1.: (A) Time course of serum creatinine, optical density (OD) of the enzyme-linked immunosorbent assay used for human leukocyte antigen (HLA) class II antibody screening and activity of angiotensin type 1 receptor antibodies. Day 0 is the date of transplantation. The days of renal biopsy, plasmaphereses, hemodialysis and administration of rituximab are indicated. (B) Retrospective HLA-antibody analysis of the pretransplant serum using a bead array assay. The fluorescence intensities of individual beads are given in a descending order. X1 to X8 are score values which are calculated with the automated “epitope analysis algorithm” of the HLA-Fusion software (One Lambda, CA). The positive reaction for the noninherited maternal antigen DR15 shows a weak reactivity level close to a cut-off of 1500 fluorescence units.Retrospective testing of the pretransplant serum in bead immunoassays (LabScreen single-antigen class II; One Lambda, Canoga Parc, CA) (4) identified weak anti-HLA-DR15 antibodies below the test cut-off (Fig. 1B). The Luminex crossmatch (Lifecodes donor-specific antibody; Geneprobe, Stamfort, CT) reacted negative. The treatment of rejection was in part described in a small case series (5). Briefly, the clinical course improved with intravenous immunoglobulin, 10 plasmaphereses, and rituximab (375 mg/m2 body surface area/6 hr) on day 10. Cyclosporine A was switched to tacrolimus (trough levels 8–10 ng/mL). Blood pressure normalized with high-dose ramipril (6 mg/m2 body surface area) and irbesartan (AT1R antagonist, 6 mg/kg body weight). Both antibodies disappeared around day 25 after transplantation. The patient was discharged 5 weeks after transplantation (creatinine 0.6 mg/dL, tacrolimus, mycophenolate mofetil, and low-dose steroids). The renal function remained stable (last follow-up at 30 months, creatinine 1.0 mg/dL). The hypertension is still under control with irbesartan. The patient's kidneys had been removed 2 month before and 2 months after transplantation. The case is remarkable for several reasons. The girl had had no blood transfusions or other classical immunizing events before. However, the rapid increase in HLA class II antibodies reminded of a secondary immune response. The antimaternal specificity and their retrospectively weak detection in the pretransplant serum suggest a preimmunization most likely during the fetal or peripartal period. The high-titer AT1R-Abs were associated with rapid-onset malignant hypertension and encephalopathy during the rejection period similar to the index case, where AT1R-Abs were originally described (6). Hypertension may act as a danger signal and is capable to enhance the expression of HLA class II antigens in kidney transplants (7), thereby increasing their exposure to the recipient's immune system. Although either type of antibody is principally able to trigger a humoral rejection alone, we propose that in our patient the synergy of AT1R and HLA class II antibodies contributed to the exceptionally rapid and severe onset of the clinical phenotype. AT1R gene has 14 described polymorphisms, and some of them act as “gain” or “loss” of function mutations implicated in receptor activation (8–10). Genotyping of the AGTR1 gene A1166C polymorphism, which is associated with adverse cardiovascular events and increased responsiveness of the AT1R to angiotensin II (11), showed that the mother is a heterozygous carrier of the A1166C variants, while the recipient is homozygous for the wild-type 1166A. Renal AT1R is instrumental for development of hypertensive responses (12). This observation is relevant in terms of a permissive genotype for the observed phenotype. This hypothesis is also in line with the observation of a moderate hypertension, which could be controlled by amlodipine alone before transplantation. Finally, we propose that high levels of AT1R-Abs aggravated hypertension and contributed to the rapid onset of the secondary immune response against HLA class II antigens in the recipient, who has been classified as “low-risk” by usual criteria. The evidence for the pathophysiologic role of AT1R-Abs in antibody-mediated rejection and autoimmune diseases is increasing (13, 14). Nevertheless, we are aware that it is difficult to definitely prove their role separately from HLA class II antibodies in this single case. Finally, the pathophysiologic reasoning, extended immunologic monitoring, and the immediate antirejection treatment reconstituted the function of the kidney. Reinhard Kelsch1 Anne Schulze Everding2 Eberhard Kuwertz-Bröking2 Eva Brand3 Bernd M. Spriewald4 Walter Sibrowski1 Martin Konrad2 Duska Dragun5 1 Institute of Transfusion Medicine and Transplantation Immunology University Hospital Münster Münster, Germany 2 Department of General Pediatrics Pediatric Nephrology University Hospital Münster Münster, Germany 3 Department of Internal Medicine D University Hospital Münster Münster, Germany 4 Department of Internal Medicine 5 University of Erlangen—Nürnberg Erlangen, Germany 5 Clinic for Nephrology and Intensive Care Medicine Charité Universitätsmedizin Berlin Berlin, Germany