Alemtuzumab is a monoclonal antibody against CD52 that is being increasingly used in renal transplantation as a lymphocyte-depleting agent. Data on alemtuzumab use in resistant rejection episodes are scarce, especially in children. Here, we present a 14-year-old renal transplant patient with acute cellular and humoral rejection who was treated with pulse steroids, plasmapheresis, and intravenous immunoglobulin with no success. He had 2 previous rejection episodes that were treated with antithymocyte globulin. In the third episode, alemtuzumab was given as a rescue therapy, and the patient benefited from the treatment. No complications were observed. Alemtuzumab can be a treatment option in pediatric patients with refractory rejection episodes.
Key words : Children, Kidney transplantation, Monoclonal antibody, Resistant rejection
Alemtuzumab (Campath-1HR; Millennium, Cambridge, MA, USA) is a recombinant humanized rat monoclonal antibody against CD52 on T and B cells, natural killer cells, macrophages, dendritic cells, and monocytes. This antibody has been originally registered for treatment of multiple sclerosis and B-cell chronic lymphocytic leukemia. Several adult studies have demonstrated success of its off-label use for induction in renal transplantation.1,2 In adults, promising results with alemtuzumab as a rescue therapy for resistant rejection have also been reported.3,4 However, in pediatric patients, data on alemtuzumab use in renal transplantation are scarce.5 In this report, we present a pediatric renal transplant recipient with a resistant rejection episode who was successfully treated with alemtuzumab.
A 14-year-old boy with end-stage renal disease secondary to autosomal dominant polycystic kidney disease underwent preemptive living-related (aunt) kidney transplant. He was shown to have 5 antigens mismatched with his donor. The donor and recipient were seropositive for Epstein-Barr virus and cytomegalovirus (CMV). His class I and II panel reactive antibodies (PRA) were 0% before trans-plantation. The patient was put on triple immuno-suppression, including tacrolimus, mycophenolate mofetil, and steroids.
On day 1 posttransplant, the patient had fever, and antibiotics were started. He had a slow recovery of renal function, and Doppler ultrasonography on day 6 posttransplant showed increased resistivity index and decreased renal perfusion. His creatinine level was 5.8 mg/dL on day 9, and transplant biopsy was compatible with tubulointerstitial nephritis and possible borderline rejection. Some drug modifications for tubulointerstitial nephritis were done, and methyl--prednisolone pulses for 3 days were given.
On day 16 posttransplant, serum creatinine level was 5.4 mg/dL, and a Tc mercaptoacetyltriglycine scintigraphy was performed, which showed de-creased perfusion and delay in extraction function of the allograft. Antithymocyte globulin (ATG) was given for 4 days at 1.5 mg/kg/day for probable ongoing rejection. On day 22, with a serum creatinine level of 4.6 mg/dL, a second allograft biopsy was performed, which showed acute cellular rejection (Banff grade 2B, and C4d negative). Prednisolone dose was increased to 60 mg/day. On day 46 posttransplant, the patient was discharged with a serum creatinine of 1.5 mg/dL and glomerular filtration rate of 51 mL/min/1.73 m2.
Sixteen months after transplant, the patient was admitted to our clinic with fever. He had lower respiratory tract infection, and serum creatinine level was found to be elevated at 1.9 mg/dL. Due to ongoing creatinine elevation, renal biopsy was performed. The biopsy showed acute cellular and antibody-mediated rejection (Banff grade 1A ,C4d positive). Flow PRA was 0% for class 1 and 77% for class 2 with median fluorescence intensity (MFI) of 12906. He was noted to have donor-specific antibodies to 2 HLA antigens. He received pulse methylprednisolone for 3 days and subsequently 4 doses of ATG, with tapering doses of oral steroids. Serum creatinine decreased to 1.4 mg/dL after this treatment.
Six months later, the patient experienced a third rejection episode due to probable noncompliance to immunosuppressive therapy. Serum creatinine was 1.9 mg/dL, and allograft biopsy showed acute antibody-mediated and cellular rejection (Banff grade 1B, C4d positive). His flow PRA was 0% for class 1 and 29% for class 2 with MFI of 6952. The patient was treated with pulse methylprednisolone for 3 days, plasma exchange was performed for 4 days, and a total of 40 g (0.5 g/kg) of intravenous immunoglobulin was given over 4 days. After treatment, serum creatinine remained elevated at 2.1 mg/dL.
As a rescue therapy, 30 mg of alemtuzumab infusion was given once with paracetamol and diphen-hydramine premedication. No acute complications related to infusion were observed. Mycophenolate dose was tapered, and prophylaxis against CMV, fungal, and pneumocystic infections was started. The patient was discharged with a serum creatinine level of 1.6 mg/dL. During the following 8 months, he had no complaints, no severe infections, and no leukopenia. The patient was compliant with treatment, and creatinine level was 1.58 mg/dL at the last visit with a glomerular filtration rate of 72 mL/min/1.73 m2. Control MFI value for class II PRA decreased to 3650.
In this report, we present a pediatric patient who was successfully treated with alemtuzumab for a resistant third rejection episode. Chronic allograft nephropathy is known to be the most common cause of pediatric renal allograft failure.6 Acute rejection (AR) episodes contribute to chronic allography nephropathy development; therefore, it is important to reverse AR promptly. Late AR, which occurs 3 to 6 months posttransplant, has worse outcomes. For early AR, high-dose steroids are the first-line therapy and some monoclonal or polyclonal antibodies are used in steroid-resistant cases.7 For late AR, treatment modalities are still a matter of debate.
Alemtuzumab is considered as a promising option for late AR. It causes a rapid and sustained depletion of T and B lymphocytes and various cells of the innate immune system. It is increasingly being used off-label for the prevention and treatment of acute allograft rejection in solid-organ transplant.
In induction protocols, the main aim of its use is the maintenance of reduced immunosuppression. However, its role in AR has not been clearly defined. No randomized clinical trials exist for alemtuzumab use in AR, and dose levels for both induction and rejection (30 mg once or twice) are based on experience from chronic lymphocytic leukemia and multiple sclerosis.
Reducing exposure to steroids and preventing drug toxicity are especially important in children to protect their growth potential and prevent comorbidities. Alemtuzumab use for renal transplant induction in children is uncommon because most are not sensitized at the time of transplant, and there is a risk for Epstein-Barr virus (posttranplant lymphoproliferation) and CMV infections.8 However, few studies have reported its successful use in induction protocols of highly sensitized pediatric patients.9,10
In most centers, the first treatment modality for AR is pulse steroids, with antibody-depleting agents indicated for steroid-resistant cases.11 Generally, ATG is the preferred agent; however, especially in subsequent exposures, diminished activity and adverse reactions like serum sickness due to preformed antirabbit antibodies may be seen. Alemtuzumab has also been used as a second-line agent in steroid-resistant or severe AR. Clatworthy and associates compared the efficacy of alemtuzumab versus pulse methylprednisolone alone in adult patients with AR and showed comparable long-term outcomes; however, more infections were seen with alemtuzumab.12 In a small retrospective study that compared alemtuzumab with ATG for steroid-resistant AR in adult patients, similar treatment failure rates were shown (27% for alemtuzumab vs 40% for ATG).13 The single study of pediatric patients reported on 3 children who were treated with alemtuzumab for refractory late ARs; the patients had been treated with ATG for previous rejections.5 After 1 dose of alemtuzumab as a rescue therapy in the 3 children, 1 patient was successfully treated and 1 patient failed to respond. The third patient had recurrent rejection episodes at 5, 13, and 15 months after alemtuzumab use, which responded fully to retreatment with alemtuzumab in the first 2 episodes. There were no symptomatic viral infections in any of the patients during follow-up.
Our patient had delayed graft function after transplant and recurrent cellular and humoral rejection episodes during follow-up, which were possibly related to high mismatch rates with his donor, PRA/donor-specific antibody positivity, and noncompliance to immunosuppressive therapy. The patient required treatment with ATG and long-term steroid use. The last rejection episode was resistant to pulse methylprednisolone, plasma exchange, and intravenous immunoglobulin. Alemtuzumab was tried, and success was reached.
Complications related to alemtuzumab are of importance. Infusion-related cytokine release may present usually as headache, rash, nausea, hypo-tension, and fever. With premedication, choosing the subcutaneous route may lessen this effect. Due to prolonged depletion of T and B cells, infections may be observed. T- and B-cell depletion may continue for over a year; however, reconstitution of the cells of the innate immune system is faster.8 Prophylaxis against Herpesviridae and Pneumocystis jirovecii should be given until CD4+ T-cell count is over 200 cells/μL. A recent adult study showed that the significant association between opportunistic infections and antirejection therapy with alemtuzumab may also be attributed to increased immunosuppression after rejection.14 After alemtuzumab use, secondary autoimmune disorders like thyroid disease have been described in some adult patients.15 In our patient, during 8-month follow-up, no complications were so far observed.
In pediatric renal transplant recipients, alem-tuzumab may be a successful agent for resistant rejection episodes; however, the drug is presently being used off-label for this purpose. To expand the indication of alemtuzumab for solid-organ transplant, randomized controlled trials are needed. Proper antibacterial and antiviral prophylaxis and close monitoring for infections and other possible com-plications are mandatory for long-term follow-up.
DOI : 10.6002/ect.2018.0203
From the 1Department of Pediatrics, Division of Nephrology, and the
of Internal Medicine, Division of Nephrology, Ankara University School of
Medicine, Ankara, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Eda Didem Kurt-Sukur, Ankara University School of Medicine, Department of Pediatrics, Division of Nephrology, 06590 Cebeci, Ankara, Turkey
Phone: +90 3125956866