Second-Line Options for Nephrotic Syndrome
Second-Line Options for Nephrotic Syndrome
Although initially, many children with idiopathic nephrotic syndrome respond to steroid therapy, a repeated course for patients with relapses often causes significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, and so far, cyclophosphamide or levamisole have been regarded as first-choice options, although the latter is no longer available in many countries. Data are accumulating that mycophenolic acid may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and are often used after cytotoxic treatment, but long-term treatment is necessary, raising concerns regarding the accumulation of side effects. Still, some patients show a tendency to relapse even on this maintenance regimen and some even have a refractory course that creates a medical dilemma. For this situation, recent data have demonstrated an effect of monoclonal antibodies directed to B cells – rituximab, a drug that may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to initial steroid treatment need genetic testing and a renal biopsy, since focal segmental glomerulosclerosis may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors (mainly cyclosporine but also, recently, tacrolimus). Cyctotoxic treatment, especially intravenous cyclophosphamide, has been found to be effective in steroid-resistant nephrotic syndrome by some studies but is inferior to calcineurin inhibitors. In addition, mycophenolic acid and rituximab have been used in children with primary focal segmental glomerulosclerosis; however, response seems to be inferior in comparison with patients with steroid-sensitive nephrotic syndrome. Taken together, idiopathic nephrotic syndrome, including steroid-sensitive as well as steroid-resistant patients, is a potentially serious disorder. Although much progress has been made in recent years and a wide arsenal of immunological interventions is available, some patients have a treatment refractory course. Prospective studies or at least standardization of treatment for complicated cases is urgently needed.
The nephrotic syndrome (NS) in children is defined as massive proteinuria (>1 g/m/day), hypoalbuminemia (<25 g/l) and presence of edema. The most frequent cause in this age group is the so-called 'idiopathic' nephrotic syndrome (INS), of which there are two histological subtypes: the minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS). Studies of the International Study of Kidney Diseases in Children (ISKDC) have shown that a response to steroids can be expected in the majority of patients with MCNS, so nowadays, a renal biopsy is only performed in cases of steroid-resistant nephrotic syndrome (SRNS). This has been defined by the ISKDC as persisting proteinuria after a 4-week course of oral prednisone; recently, a short course of intravenous methylpredinsolone after 4 weeks of oral prednisone has become standard in many centers to exclude patients with delayed response (so-called late responders).
In patients with SRNS, the majority have FSGS or MCNS and other variants only represent approximately 10 (to 20)%. However, some clinical and histological overlap occurs. It should be noted that in the past decade, several genetic causes of SRNS (FSGS) have been identified (e.g., podocin mutations and WT1 mutations), that compromise up to 30% of children with SRNS; treatment of these entities will not be discussed in this article. In addition, these patients were included in all previous studies concerning SRNS and may have had a significant negative impact on the outcome. This is illustrated in Figure 1 with data from our own center, where those patients with genetic causes of INS had a deterioration of renal function much earlier than those with SRNS despite identical treatment with cyclosporine, suggesting that patients with acquired SRNS in fact have a better prognosis. The pathogenesis of sporadic SRNS is unclear, although an underlying immunological defect is suspected and is the rationale for the use of immunosuppressants or immunological interventions in this disorder.
(Enlarge Image)
Figure 1.
Patients with podocin mutations in steroid-resistant nephrotic syndrome progress to end-stage renal disease earlier (arrows). Prognosis in previous studies may have been affected negatively by inclusion of SRNS patients. Data taken from an unpublished series of 25 SRNS patients including 17 with FSGS and eight with MCNS treated with cyclosporine A at the University Children's Hospital, Hamburg, Germany.
FSGS: Focal segmental glomerulosclerosis; MCNS: Minimal change nephrotic syndrome; SRNS: Steroid-resistant nephrotic syndrome.
Data taken from [KEMPERETAL., UNPUBLISHEDDATA].
Patients with steroid-sensitive nephrotic syndrome (i.e., MCNS) may develop frequent relapses and, more importantly, steroid dependency. This results in repeated steroid treatment leading to steroid toxicity, thus requiring alternative treatments. This arsenal and the optimal sequence of these drugs will be discussed in the first part of this review. Patients with sporadic SRNS (FSGS) are usually more treatment refractory, and the progress in initial treatment as well as the treatment of subsequent problems will be discussed later.
Abstract and Introduction
Abstract
Although initially, many children with idiopathic nephrotic syndrome respond to steroid therapy, a repeated course for patients with relapses often causes significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, and so far, cyclophosphamide or levamisole have been regarded as first-choice options, although the latter is no longer available in many countries. Data are accumulating that mycophenolic acid may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and are often used after cytotoxic treatment, but long-term treatment is necessary, raising concerns regarding the accumulation of side effects. Still, some patients show a tendency to relapse even on this maintenance regimen and some even have a refractory course that creates a medical dilemma. For this situation, recent data have demonstrated an effect of monoclonal antibodies directed to B cells – rituximab, a drug that may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to initial steroid treatment need genetic testing and a renal biopsy, since focal segmental glomerulosclerosis may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors (mainly cyclosporine but also, recently, tacrolimus). Cyctotoxic treatment, especially intravenous cyclophosphamide, has been found to be effective in steroid-resistant nephrotic syndrome by some studies but is inferior to calcineurin inhibitors. In addition, mycophenolic acid and rituximab have been used in children with primary focal segmental glomerulosclerosis; however, response seems to be inferior in comparison with patients with steroid-sensitive nephrotic syndrome. Taken together, idiopathic nephrotic syndrome, including steroid-sensitive as well as steroid-resistant patients, is a potentially serious disorder. Although much progress has been made in recent years and a wide arsenal of immunological interventions is available, some patients have a treatment refractory course. Prospective studies or at least standardization of treatment for complicated cases is urgently needed.
Introduction
The nephrotic syndrome (NS) in children is defined as massive proteinuria (>1 g/m/day), hypoalbuminemia (<25 g/l) and presence of edema. The most frequent cause in this age group is the so-called 'idiopathic' nephrotic syndrome (INS), of which there are two histological subtypes: the minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS). Studies of the International Study of Kidney Diseases in Children (ISKDC) have shown that a response to steroids can be expected in the majority of patients with MCNS, so nowadays, a renal biopsy is only performed in cases of steroid-resistant nephrotic syndrome (SRNS). This has been defined by the ISKDC as persisting proteinuria after a 4-week course of oral prednisone; recently, a short course of intravenous methylpredinsolone after 4 weeks of oral prednisone has become standard in many centers to exclude patients with delayed response (so-called late responders).
In patients with SRNS, the majority have FSGS or MCNS and other variants only represent approximately 10 (to 20)%. However, some clinical and histological overlap occurs. It should be noted that in the past decade, several genetic causes of SRNS (FSGS) have been identified (e.g., podocin mutations and WT1 mutations), that compromise up to 30% of children with SRNS; treatment of these entities will not be discussed in this article. In addition, these patients were included in all previous studies concerning SRNS and may have had a significant negative impact on the outcome. This is illustrated in Figure 1 with data from our own center, where those patients with genetic causes of INS had a deterioration of renal function much earlier than those with SRNS despite identical treatment with cyclosporine, suggesting that patients with acquired SRNS in fact have a better prognosis. The pathogenesis of sporadic SRNS is unclear, although an underlying immunological defect is suspected and is the rationale for the use of immunosuppressants or immunological interventions in this disorder.
(Enlarge Image)
Figure 1.
Patients with podocin mutations in steroid-resistant nephrotic syndrome progress to end-stage renal disease earlier (arrows). Prognosis in previous studies may have been affected negatively by inclusion of SRNS patients. Data taken from an unpublished series of 25 SRNS patients including 17 with FSGS and eight with MCNS treated with cyclosporine A at the University Children's Hospital, Hamburg, Germany.
FSGS: Focal segmental glomerulosclerosis; MCNS: Minimal change nephrotic syndrome; SRNS: Steroid-resistant nephrotic syndrome.
Data taken from [KEMPERETAL., UNPUBLISHEDDATA].
Patients with steroid-sensitive nephrotic syndrome (i.e., MCNS) may develop frequent relapses and, more importantly, steroid dependency. This results in repeated steroid treatment leading to steroid toxicity, thus requiring alternative treatments. This arsenal and the optimal sequence of these drugs will be discussed in the first part of this review. Patients with sporadic SRNS (FSGS) are usually more treatment refractory, and the progress in initial treatment as well as the treatment of subsequent problems will be discussed later.
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