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

Design

Case presentation

A young girl with a WT1 gene mutation (p.H397P, OMIM 607102) received a kidney transplant from her mother, two months after her first hemodialysis at age 9. Graft function was excellent on day 2, with cyclosporine A, mycophenolate mofetil, and prednisolone utilized for primary immunosuppression. However, the patient developed hypertensive encephalopathy, with a maximum blood pressure of 180/120 mmHg, and received several antihypertensives to manage her arterial hypertension. Creatinine increased from 0.4 mg/dL after transplantation to 2.1 mg/dL on day 5. HLA class II antibodies were observable in serum, with AT1R-Abs detected at high levels prior to transplantation and at the time of rejection. Due to suspected AT1R-Ab-mediated rejection with malignant hypertension, plasmapheresis treatment was initiated.

The patient received intravenous immunoglobulin, 10 plasmaphereses, and rituximab (375 mg/m2 body surface area/6 hr) on day 10, and cyclosporine A was switched to tacrolimus (trough levels 8-10 ng/mL). The patient's blood pressure normalized after ramipril 6 mg/m2 body surface area and irbestartan 6 mg/kg body weight. On day 25 post-transplantation, the antibodies disappeared, and the patient was discharged 5 weeks post-transplantation on tacrolimus, mycophenolate mofetil, and low-dose steroids. At her last follow-up at 30 months, the patient's renal function continued to remain stable.

Study Author Conclusions

The evidence for the pathophysiologic role of AT1R-Abs in antibody-mediated rejection and autoimmune diseases is increasing. 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.

Acute kidney transplant rejection mediated by angiotensin II type 1 receptor antibodies in a pediatric hyperimmune patient

Design

Case presentation

A 13-year-old male patient who received a donor kidney transplant exhibited hypertension requiring treatment in the early post-transplantation phase, managed by amlodipine and carvedilol, and he was discharged on an immunosuppressive regimen comprised of cyclosporine, everolimus, and prednisone. Five months later, hypertension returned, and clonidine was adding to his medication list. His kidney function worsened, from a serum creatinine of 1.98 mg/dL at day 30 post-transplant to 3.2 mg/dL at five months, and acute C4d-negative cellular rejection was discovered in a renal biopsy. Despite administration of methylprednisolone pulses, the patient's serum creatinine and blood pressure continued to elevate, and so pulse steroid therapy was repeated, with cyclosporine and everolimus removed from the immunosuppressive regimen and changed to tacrolimus and mycophenolate mofetil. Still, the patient's renal function continued to worsen and progress to graft failure, and he was reintroduced on the waiting list for kidney transplantation, with the addition of HLA sensitization.

Three years after his initial kidney, the patient received a second donor kidney transplant. On postoperative day 10, renal function worsening was observed, and due to the patient being at risk for antibody-mediated rejection (AMR), methylprednisolone pulses plus plasmapheresis was initiated. A renal biopsy revealed acute humoral rejection with weakly positive staining for peritubular C4d. The patient was discharged after return to a serum creatinine of 1.5 mg/dL with amlodipine, although carvedilol was added once hypertension was noted three months later. A retrospective analysis of the serum from the first transplant found AT1R-Ab, and thus the patient was retroactively diagnosed with rejection secondary to AT1R-Ab. He was immediately started on losartan and rituximab (375 mg/m2), with observable improvement and creatinine levels of 1.3 mg/dL. By year 3 after losartan initiation, the patient's creatinine level sits at 1.02 mg/dL, with well-controlled blood pressure and no presentation of proteinuria.

Study Author Conclusions

Testing for AT1R-Ab in any hypertensive patient with acute rejection who tests negative or weakly positive for C4d and negative for HLA-DSA and who is refractory to therapy is highly advisable. Pre-transplant AT1R-Ab may be indicative of the outcome in patients whose first transplant failed. Prompt initiation of treatment with losartan—immediately after transplantation in patients with pre-existing AT1RAb—should be encouraged.

Acute antibody-mediated rejection in ABO-compatible pediatric liver transplant recipients: case series and review of the literature

Design

Case presentation #5

A 6-month-old male patient who received an ABO-identical whole graft lung transplant had an uneventful postoperative course, and was discharged on post-operative day (POD) 18 with steroids and tacrolimus as maintenance immunosuppression. However, the patient was readmitted POD 38 for elevated AST and ALT, which suggested acute cellular rejection (ACR). Despite a steroid pulse for mild ACR, elevation of AST and ALT continued. Results of HLA antibody testing showed de novo donor-specific antibodies (DSA) to DQ7 and DQ9. Minimum improvement after treatment with high-dose intravenous immunoglobulin (IVIG) and the addition of mycophenolate mofetil to his immunosuppression therapy led to rituximab initiation; however, liver biopsy showed progression of ACR in severity, with lobular inflammation and graft dysfunction. A repeat biopsy after anti-thymocyte globulin showed extensive necrosis that may have been secondary to severe antibody-mediated rejection (AMR) or fulminant hepatitis caused by recurrent disease. The patient was treated with a 5-day course of plasmapheresis, then IVIG, but continued deterioration of his liver led to a re-transplantation.

The patient experienced persistent complications after his retransplant. Immunosuppression was comprised of another steroid pulse and taper (induction) and steroids, tacrolimus, and mycophenolate mofetil as his maintenance, alongside high-dose IVIG weekly. The patient's presentation was thought to be due to recurrent AMR, based on detectable non-HLA antibodies (endothelial cell and angiotensin II type 1 receptor). Despite rituximab, bortezomib, and plasmapheresis therapy, the patient's graft continued deteriorating, and the patient passed away on POD 144.

Study Author Conclusions

AMR following ABO-compatible LTx is likely more common than previously thought and may be under-diagnosed. The clinical presentation can be variable in terms of timing and degree of graft injury. Accurate diagnosis of liver AMR is essential given that it commonly leads to graft failure, even when recognized and treated. Treatment should be individualized based on patient clinical status. At a minimum, use of IVIG and additional B-cell modulating therapies should be considered. Eculizumab may also be a reasonable option. Ultimately, future multicenter studies are needed to characterize the optimal treatment and long-term outcomes following liver AMR.

Accelerated rejection, thrombosis, and graft failure with angiotensin II type 1 receptor antibodies

Design

Case presentation

A 7-year-old boy with end-stage renal disease from posterior urethral valves had received a renal transplant at 9 months old. Following this, complications included BK nephropathy, chronic severe hypertension, development of anti-HLA DSA, and chronic AMR, resulting in graft failure at 6.5 years. Prior to the patient's second transplant, hypercoagulability work up was mostly negative, as well as infectious disease workup. Due to the patient's severe hypertension following the first transplant, clinicians suspected angiotensin II type 1 receptor antibodies (AT1R-Abs). Per the institution's protocol, Luminex SAB MICA-Ab test, enzyme-linked immunosorbent-based AT1R-Ab test, and flow cytometry-based anti-endothelial cell crossmatch (ECXM) were conducted, as well as routine pre-transplant HLA antibody testing. While testing negative for ECXM and MICA-Ab, the patient was found to have high AT1R-Ab of 109.55 U/ml (normal < 10 U/mL). 

The patient underwent pre-transplant desensitization, including 3 days of plasmapheresis, 3 days of intravenous immunoglobulin (IVIG; 1 g/kg), and one dose of rituximab (375 mg/m2), which resulted in AT1R-Ab level reduction to 33.76 U/mL. The patient was induced with thymoglobulin (ATG; 1.5 mg/kg), and maintained on steroid-based immunosuppression with tacrolimus and mycophenolate mofetil. 

The patient initially did well post-transplantation, a nadir serum creatinine (Cr) of 0.4 mg/dL on day 2 post-transplant and hypertension of 130 s/90s improving with losartan (1 mg/kg). However, due to increase in his Cr and persistent AT1R-Ab of 27.96 U/mL, plasmapheresis was performed on days 6-9, resulting in decreased Cr and AT1R-Ab (12.87 U/mL). The patient was discharged on day 10 post-transplant with a Cr of 0.5 mg/dL and ATIR-Ab level of 13 U/mL, but unfortunately readmitted 5 days later with hematuria, graft tenderness, fever, rising Cr and AT1R-Ab level of 17 U/mL; HLA class I and II DSAs were negative. A renal ultrasound was conducted, finding normal flow in the main renal artery and vein. The patient was treated with methylprednisolone pulse (5 mg/kg), plasmapheresis, ATG (1.5 mg/kg), and eculizumab (600 mg).

Subsequently, biopsy results found acute cellular rejection (ACR) IB with endarteritis and C4d-negative AMR characterized by glomerulitis, and peritubular capillaritis; due to C4d-negativity, eculizumab was discontinued. While Cr and oliguria improved with initial treatment, the patient developed acute pain and anuria, followed by renal artery thrombosis with resultant allograft loss on post-transplant day 21.

Study Author Conclusions

This case highlights the risk of allograft thrombosis in addition to vascular rejection associated with AT1R-Ab. Further studies are needed to better characterize the mechanisms of AT1R-Ab pathogenesis and to establish safe levels of AT1R-Ab both pre- and post-transplantation. Additionally, the role of anti-coagulation, more extensive plasmapheresis to levels below 10 U/mL, and immunomodulatory therapy with such agents as tocilizumab and bortezomib, warrant further investigation in controlled trials.

Kidney re-transplantation in a child across the barrier of persisting angiotensin II type I receptor antibodies

Design

Case presentation

A male patient had received his first kidney transplant at age 3.2 years old; the patient had a past history of chronic kidney disease stage 5 in infancy due to obstructive uropathy. The patient's initial course of immunosuppressives included cyclosporin A microemulsion (CsA), mycophenolate mofetil (MMF), and methylprednisolone. Seven days after transplant, the patient experienced acute T cell–mediated rejection with mild to moderate intimal arteritis. Despite stable graft function for 6 years the patient experienced progressive decline along with severe arterial hypertension. A biopsy then revealed chronic transplant glomerulopathy with partial glomerular sclerosis, interstitial fibrosis and tubular atrophy (IFTA), mild tubulitis, and arterial intimal fibrosis of new onset. AT1R-Ab were initially measured with a bioassay and serum concentration of AT1R-Ab was markedly elevated (112 U/L, reference range <10 U/L). Endothelin type A receptor antibodies (ETAR-Ab) were also measured with a sandwich ELISA. Despite interventions with methylprednisolone, tacrolimus, and candesartan, graft function rapidly declined. Histology showed severe transplant glomerulopathy and severe IFTA, with AT1R-Ab concentration peaking at 276 U/mL 16 months after transplantectomy, then slowly decreasing to 55 U/mL over 2 years, where it remained persistently elevated at approximately 20 U/mL in the following years. It was hypothesized that the patient's recurrent shunt thromboses may have been related to elevated AT1R-Ab. 

At age 13, the patient received a 2nd kidney allograft. Due to persistently elevated AT1R-Ab prior to transplantation, the patient underwent desensitization with 15 plasmapheresis sessions (three sessions per week over 5 weeks, each time 150% exchange of plasma volume with human albumin 5%), followed by three infusions of intravenous immunoglobulin G (IVIG), per institutional protocol. As a result, AT1R-Ab titer decreased from 19.8 to 9.5 U/mL and the ETAR antibody titer from 56 to 9.5 U/mL. The patient received immunosuppressive induction therapy with intravenous IV thymoglobulin (3x) and three sessions of plasmapheresis in the first 10 days post-transplant. Immunosuppressive maintenance therapy consisted of tacrolimus (initial dose 0.3 mg/kg per day), MMF (1200 mg/m2 per day), and methylprednisolone, as well as candesartan (0.15 mg/kg body weight per day), which was resumed on day 10 post-transplant. Iloprost (0.5 ng/kg/min infused over 6 hours) was initiated x 7 days to improve renal microcirculation. 

While initial graft function was deemed to be excellent, by day 17 interstitial borderline rejection was observed, resulting in increased tacrolimus exposure. On day 87 post-transplant, the patient exhibited rapid decline in transplant function, as well as an increase in AT1R-Ab and ETAR-Ab. Antirejection therapy included methylprednisolone pulse therapy, six sessions of plasmapheresis, and one dose of rituximab (375 mg/m2). He also received vasodilatory therapy with iloprost (initially once weekly and thereafter every second week) and three additional sessions of plasmapheresis, as well as four weekly doses of high-dose IVIG 1 g/kg body weight per dose. Ultimately, over the following years, the patient's serum creatinine slowly increased. After a total of 4 years with a functioning graft, the patient had to resume chronic hemodialysis. 

Study Author Conclusions