Corticosteroid therapy for nephrotic syndrome in children. - PubMed - NCBI
Goals of treatment are to reduce proteinuria to normal levels thereby reducing symptoms and risk of complications. Some children with NS who respond to steroids eventually have a frequently relapsing or steroid-dependent course and may have significant side effects from cumulative corticosteroid therapy.
For these children, steroid-sparing medications are required. Treatment with mycophenolate mofetil is recommended as first-line therapy for treatment of frequently relapsing or steroid-dependent NS with steroid toxicity due to its favorable side effect profile compared to alternatives. Further randomized controlled trials are necessary to determine which agents are most effective and to determine methods to predict medication response in individual children. Most children with NS are treated initially with oral corticosteroids, and they can be clinically classified based on their ability to achieve remission i.
Older children are more likely to have steroid-resistant NS. Children with steroid-resistant disease may have an underlying genetic cause for NS, and providers should consider genetic testing in this population, depending on the age of the child [ 2 ]. While inherited causes of NS are often resistant to all therapies, there are reports of complete or partial remission in some children [ 3 ].
Further studies are required to understand the response to therapy in children with inherited NS. Children with frequently relapsing NS and steroid-dependent NS may have significant side effects from cumulative corticosteroid therapy so treatment with other agents is often required. Therapy for these children should be guided by a pediatric nephrologist. Clinical NS can be the result of a number of different pathologies on kidney biopsy. Kidney biopsies from patients with MCD have a normal appearance by light microscopy with effacement of podocyte foot processes visible by electron microscopy EM [ 5 ].
In addition to podocyte effacement by EM, biopsy samples from children with focal segmental glomerulosclerosis FSGS demonstrate light microscopic findings of segmental sclerosis within some glomeruli [ 6 ]. Children with FSGS on renal biopsy are less likely to go into remission with steroids than children with MCD and are more likely to have progressive chronic kidney disease [ 1 ].
In addition to loss of albumin in the urine, nephrotic patients lose components of the alternative complement pathway, including factors B and D that increase their susceptibility to infection with encapsulated organisms such as Streptococcus pneumoniae [ 9 , 10 , 11 , 12 ].
Children with active NS are at risk for thromboembolism for several reasons. Second, there is increased production of pro-coagulant factors by the liver [ 14 ]. Thus, successfully treating nephrotic syndrome to attain a remission is important in reducing the morbidity and mortality that go along with this disease.
This review will discuss treatments for steroid-sensitive NS and steroid-resistant NS. Goals of treatment are to attain remission with minimal medication side effects. Although used universally, the mechanism of action of corticosteroids in the treatment of NS is unknown.
It has been hypothesized that NS is a disorder of the immune system, with T-cell dysfunction resulting in the release of a circulating factor that causes podocyte foot process effacement and proteinuria [ 16 ]. Corticosteroids are presumed to act by suppression of a T-cell-mediated factor; however, the definitive identification of this circulating factor has remained elusive [ 17 ].
Alternately, corticosteroids may also have an effect on the podocyte directly through stabilization of the actin cytoskeleton and alteration of gene expression [ 18 , 19 ]. There are no randomized controlled trials examining the optimal dose or steroid treatment period for children who experience relapse.
Some children will require prolonged, alternate-day steroids in order to maintain remission [ 31 ]. Alkylating agents such as cyclophosphamide and chlorambucil are alternate agents for children with frequently relapsing NS and steroid-dependent NS and can induce a sustained remission in some children. Alkylating agents are not effective for children with steroid-resistant NS [ 33 , 34 , 35 ]. Its mechanism of action in NS is unknown but is presumably due to immunosuppressive effects on T-cells.
Concern about risks of severe side effects such as gonadal toxicity and increased incidence of malignancy limits the current use of chlorambucil despite its historic use in children with NS [ 36 ].
Children should be in remission with steroids before cyclophosphamide is started, and steroids should be continued at tapering doses during cyclophosphamide therapy [ 33 , 37 ]. Cyclophosphamide treatment can be associated with significant side effects. Fertility preservation strategies are available for treated patients [ 39 ]. White blood cell counts should be monitored along with dosing adjustments as necessary throughout treatment.
Cyclosporine and tacrolimus are calcineurin inhibitors that are commonly used as immunosuppressive agents in solid organ transplantation. Calcineurin inhibitors CNIs inhibit T-cell activation and may be exerting their effect in nephrotic syndrome through this mechanism. Alternately, cyclosporine has been shown to directly target the podocyte and stabilize the actin cytoskeleton responsible for maintaining cell shape [ 40 ]. Although the majority of studies in nephrotic syndrome have been performed with cyclosporine, tacrolimus appears to be equally efficacious [ 41 , 42 ].
Tacrolimus is administered at a starting dose of 0. The optimal duration of treatment for steroid-resistant children who attain a remission with CNIs is unknown, and relapse is common after discontinuing the medication, leading to prolonged therapy in many children. However, many children can successfully stop CNIs and maintain remission. Children with frequently relapsing or steroid-dependent NS can also be treated with CNIs at doses equivalent to those used for steroid-resistant NS.
Two randomized controlled trials of cyclosporine vs. Tacrolimus causes significantly less gingival hypertrophy and hypertrichosis and may be preferred for children for whom cosmetic side effects are a concern, particularly teenage girls.
Tacrolimus has the additional potential side effect of diabetes mellitus [ 52 ]. For this reason, minimizing the dose of CNI and duration of therapy to maintain remission is recommended. Mycophenolate mofetil MMF is a medication that suppresses the immune system through inhibition of B- and T-lymphocyte proliferation. Its mechanism of action in NS is also unknown, but presumed to work through immune suppression.
It is gaining popularity as a treatment for NS due to its favorable side effect profile compared to CNIs, specifically its lack of renal toxicity. The majority of studies using MMF have been performed in the frequently relapsing or steroid-dependent NS population.
Similar to treatment with CNIs, children with frequently relapsing or steroid-dependent NS frequently relapse after discontinuing MMF, and prolonged therapy may be necessary. MMF has also been used to treat steroid-resistant NS, although with somewhat less efficacy [ 57 , 58 ]. Side effects of MMF include stomach pain, diarrhea, leucopenia, and infection, although it is generally well tolerated [ 59 ]. MMF is teratogenic, so caution must be used when recommending this agent to women and girls of childbearing age [ 60 ].
Rituximab is a chimeric monoclonal antibody against CD20 on B cells that leads to B cell depletion after treatment. Alternately, rituximab may have a direct effect on podocyte structure and function as it has been found to bind directly to the sphingomyelin phosphodiesterase acid-like 3b SMPDL-3b protein on the surface of podocytes [ 61 ].
Rituximab has been found to be a useful drug to decrease relapse rates in children with frequently relapsing or steroid-dependent NS. A randomized controlled trial comparing 4-weekly doses of rituximab vs. Use of rituximab in clinical practice is limited by concern for side effects.
Potentially serious and life-threatening side effects include pulmonary fibrosis, Pneumocystis jiroveci pneumonia, malignancy, and progressive multifocal leukoencephalopathy [ 69 , 70 , 71 ].
Adrenocorticotropic hormone ACTH was initially used in the s to treat nephrotic syndrome and is the only US Food and Drug Administration-approved therapy for this indication [ 72 ]. ACTH fell out of favor for treatment of NS in the s after the widespread availability of inexpensive oral steroids. Disadvantages of ACTH over oral steroids in children include the need to be injected and high cost.
A current randomized trial of ACTH in children with frequently relapsing and steroid-dependent disease is ongoing and should shed light onto the efficacy and safety of ACTH in this population NCT Galactose is a monosaccharide sugar that binds to the focal sclerosis permeability factor in vivo and decreases its activity [ 73 ].
Further randomized controlled trials are necessary before galactose can be recommended for routine use. A second arm of the FONT II trial randomized seven pediatric and adult patients to treatment with adalimumab, an anti-TNF antibody, and found no patients with a favorable response to treatment [ 76 ].
Abatacept cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein is a costimulatory inhibitor that targets B CD While normally present on antigen-presenting cells, B has also been shown to be upregulated in podocytes in experimental nephrotic syndrome and possibly in a subset of patients with FSGS [ 77 , 78 ]. Abatacept treatment of four patients with recurrent nephrotic syndrome after transplant for FSGS and one patient with primary FSGS led to partial or complete remission in one case series; however, other reports have not demonstrated efficacy [ 78 , 79 ].
Further clinical trials are required to determine which, if any, patients would benefit from treatment with abatacept. In summary, a number of therapeutic options are available for treatment of children with NS. Careful consideration of potential complications should be discussed with families prior to prescribing treatments for NS.
Michelle Rheault has received researching funding from Amgen and Retrophin outside of the submitted work. This article does not contain any studies with human or animal subjects performed by any of the authors.
Updates and Approaches to Treatment. Part of the following topical collections: Topical Collection on Pediatric Nephrology. Corticosteroids Although used universally, the mechanism of action of corticosteroids in the treatment of NS is unknown. The Kidney Disease: No randomized controlled trials have been performed to examine different initial doses of prednisone. Unfortunately, a high percentage of children treated with this regimen have relapses of the disease, so a number of subsequent studies have been performed in an attempt to optimize the initial steroid course to minimize risk of relapse.
More recent randomized placebo-controlled trials have evaluated children with NS treated with 3 vs. Finally, studies have compared the 3 consecutive days per week steroid dosing to alternate day steroid dosing and found lower 1-year relapse rates for children treated with alternate-day steroids, leading to the widespread adoption of alternate-day dosing during the steroid taper [ 24 ]. Table 1 Recommended corticosteroid dose for children with nephrotic syndrome. Children with frequently relapsing NS and steroid-dependent NS can have high cumulative exposure to steroids and are at risk for developing steroid-associated side effects.
These can include short stature, cataracts, hyperglycemia, cushingoid appearance, obesity, hypertension, mood and sleep disorders, avascular necrosis of the hip, decreased bone density, and stomach ulcers [ 32 ]. Children receiving long-term steroids should be monitored for complications of their use, including yearly eye exams to exclude the development of cataracts.
Children with frequently relapsing NS and steroid-dependent NS who develop steroid-associated side effects should be offered steroid-sparing agents Table 2. Table 2 Maintenance agents for frequently relapsing or steroid-dependent NS. Compliance with Ethical Standards Conflict of interest Michelle Rheault has received researching funding from Amgen and Retrophin outside of the submitted work. Human and animal rights and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: The primary nephrotic syndrome in children.