Response to: Pharmacological treatment of primary membranous nephropathy in 2016

Dear Editor,

We read with great interest the article of Van de Logt et al. entitled ‘Pharmacological treatment of primary membranous nephropathy in 2016’ [1]. Membranous nephropathy (MN) is an immune complex-mediated cause of nephrotic syndrome that may occur in all age groups, but shows low prevalence in the pediatric population [2]. Therefore, there are very limited studies that present data regarding the optimal treatment and no standardized pharmacological treatment approach is provided. The latest treatment recommendations that have been recently reported in the Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Guidelines include a brief section of the treatment in pediatric population [3]. Guidelines mainly refer to severe cases of pediatric MN and reported treatment is mostly based on adult recommendations [3].

In 2009, a major advance in our understanding of the pathophysiology of MN was made with the identification of the M-type phospholipase A2 receptor (PLA2R) as the primary antigenetic target [4]. Therefore, it was rationale that the use of anti-B cell therapy could be associated with favorable outcome. Rituximab is a chimeric monoclonal antibody, designed to bind specifically to the CD20 receptor, which presents in the cell membrane of pre-B cells and mature B cells, but not in the plasma cells [5]. As reported by Van de Logt et al., several uncontrolled trials mainly referred to adults but not to children or adolescents, have shown the efficacy of rituximab in severe cases of MN [1].

In regard to authors’ suggestion that rituximab should be offered to patients with persisting antibodies after previous immunosuppressive therapy with alkylating agents, mycophenolate mofetil, calcineurin inhibitors (CNIs) and it should be considered as monotherapy especially in patients with maintained renal function and severe nephrotic syndrome [1], we present the case of a 12-year-old adolescent girl with severe nephrotic syndrome due to MN that was resistant to treatment with corticosteroids, cyclosporine (CsA), and alkylating agent but responded to rituximab.

A 12-year-old girl, presented edema in both her eyelids and her ankles that exacerbated within 3 months. A heavy proteinuria (10 g/m²/24 h) was revealed, added to microscopic hematuria, hypoalbuminemia (albumin 1.53 g/dl), and hyperlipidemia (total cholesterol 385 mg/dl), with normal renal function (creatinine 0.69 mg/dl). The diagnosis of nephrotic syndrome was set and treatment with prednisone 60 mg/m²/day was initiated. Nephrotic range proteinuria persisted after 6 weeks of daily use of corticosteroids and three steroid pulses on alternate days. Due to steroid-resistant nephrotic syndrome a renal biopsy was performed revealing MN. Investigation for an underlying systemic disease or infection was negative and the diagnosis of primary MN was established.

Due to no signs of improvement, we started treatment with CsA in a dose of 3.5 mg/kg/day in combination with 40 mg/m²/day of prednisone on alternate days and lisinopril in a dose of 0.25 mg/kg/day. After 12 weeks of the above-mentioned treatment, nephrotic range proteinuria persisted and the patient continued to be dependent to weekly human albumin infusions. Therefore, an alteration of treatment approach was decided into a combination of the alkylating agent, cyclophosphamide 2 mg/kg/day with prednisone on alternate days and increased the dose of lisinopril to 0.5 mg/kg/day, according to the KDIGO 2012 suggestions. The use of cyclophosphamide has many adverse effects and one of the main risks is the gonadal damage [3]. The patient was treated with this combination for 9 weeks and the accumulative dose of cyclophosphamide reached up to 110 mg/kg, with no clinical or laboratory response.

After an overall period of treatment for 28 weeks, the patient still presented heavy proteinuria, microscopic hematuria, and hypoalbuminemia and was on frequent intravenous infusions of human albumin, despite the different treatment protocols that were used. The patient maintained normal renal function. Taking into account the resistance of our patient in any therapeutic protocol used and data of studies in adults which indicate the efficacy of rituximab in MN, we decided to use rituximab. The B cell monoclonal antibody was given to a single dose of 375 mg/m² in combination with CsA in a dose of 3.5 mg/kg/day and prednisone 0.5 mg/kg on alternate day. One week later the number of CD20 B lymphocytes was dramatically reduced to zero. Proteinuria gradually decreased and complete remission was achieved in a period of 2 months after rituximab infusion. Serum albumin, renal function, and blood pressure maintained in normal levels, while no side effects were noticed. Today, 8 months after the single rituximab infusion, the number of CD20 B lymphocytes remains zero and the patient is still in complete remission.

Membranous nephropathy is the most common cause of nephrotic syndrome in Caucasian adults; however, it is a rare histologic entity in children [6]. Approximately, 40−75% of patients with MN present with nephrotic syndrome. Hypertension may also be seen in a small subset of patients at presentation [7]. Children may present asymptomatic proteinuria or nephrotic syndrome, just as our patient [7]. The incidence of MN in children aged 1–12 years with nephrotic syndrome is reported to be 1% but increases to 22% in children between the ages of 13 and 19 years [8]. In pediatric population, ΜΝ is usually secondary due to infection from hepatitis B virus or systemic lupus erythematosus. In selected cohorts, secondary cases accounting for more than 75% of pediatric MN, especially below the age of 10 years, have been reported; therefore, our case is rare, complicating further the choice of treatment [7].

Renal function is almost always normal in children with MN at presentation and progression to renal failure is the exception [9]. The U.S. Renal Data System 2012 Annual Data Report found that 0.6% of incident cases of pediatric end stage kidney disease (ESKD) are due to MN, with a median age for reaching ESKD of 17 years [10]. Individually based decisions about treatment are therefore paramount in order to minimize the risk of progression to renal failure [2].

Due to the rarity of the disease in the pediatric population, there is no standardized approach to therapy. Children with primary MN will not usually require more than conservative therapy, but for children with severe symptomatic disease, the same drug combinations used in adults are suggested, with appropriate dosage adjustments [10].

After the discovery of autoantibodies in the pathogenesis of MN, the B cell depleting agent, rituximab was an attractive therapeutic option [11]. Unfortunately, still no evidence exists for its appropriate use in pediatric population [2]. Since the first report in 2002 [12], many prospective studies and a recent randomized controlled trial have shown that rituximab safely promotes the remission of nephrotic syndrome in approximately 65% of patients with MN [13].The issue of optimal rituximab dosing is still a matter of debate and different dosing schedules have been used. In the first report, rituximab was used in four weekly doses of 375 mg/m² [12]. In a recent prospective multicenter study, rituximab was infused on days 1 and 8 at the dose of 375 mg/m² [13]. As there is no consensus on rituximab therapeutic protocol, we decided to provide a single dose of rituximab in our patient, and to individualize next infusion taking into account patient’s clinical and laboratory profile. She achieved complete remission in a period of 2 months after rituximab infusion, earlier than the median time reported in different studies, which ranges from 7 to 12 months [11,14]. After 8 months of the single rituximab infusion, the number of CD20 B lymphocytes remains zero and the patient is still in complete remission on a minor dose of steroids and CsA. It is not yet clear, if after achieving initial remission with rituximab, a combination of CsA and minor steroids dose is a sufficient treatment to keep patient clear of proteinuria or the increase of B cells will be accompanied by relapse of proteinuria indicating that patient is ‘rituximab dependent.’ The above therapeutic approach of a single rituximab dose and periodical CD20 B lymphocytes profile have been considered as more cost effective considering that evidence is still lacking for the use of rituximab even in adult patients with primary MN [14,15]. Rituximab treatment in oncologic patients has been associated with major complications; however, recent study shows that it provides a rather safe profile in patients with MN [13].Considering its safety profile in pediatric population, there is still major concerns.

In conclusion, as well stated in the article of Van de Logt et al., treatment in patients with MN should be individualized, carefully weighing the short- and long-term benefits versus the adverse events [1]. In our case, rituximab was more effective to other treatment protocols that are traditionally used. It may be a promising and rather safe approach for MN therapy but there is also need for randomized control studies to establish the role and the risk–benefit ratio as compared to steroids/cyclophosphamide or CNI, both as first-line or second-line agent in the management of MN [15].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This letter was not funded.