Treatment of steroid-resistant pediatric nephrotic syndromeChildren who suffer from steroid-resistant nephrotic stndrome SRNS require aggressive treatment to achieve remission. When intravenous high-dose methylprednisolone fails, calcineurin inhibitors, such as cyclosporine and tacrolimus, hephrotic used as the first line of treatment. A significant number of patients with SRNS progress to end-stage renal disease if remission is not achieved. For these children, renal replacement therapy can also be problematic; peritoneal dialysis may be accompanied by significant protein loss through the peritoneal membrane, and kidney allograft transplantation may be complicated by recurrence of SRNS. Stanozolol cycle side effects and rituximab were initially used for treatment of recurrent SRNS after transplantation; these are now under consideration as rescue kanagement for refractory SRNS. Although the prognosis of SRNS is complicated and unfavorable, intensive treatment management of steroid resistant nephrotic syndrome the early stages of the disease management of steroid resistant nephrotic syndrome achieve remission in more than half of the patients.
Treatment of steroid-resistant pediatric nephrotic syndrome
Received 16 September Published 11 April Volume Peer reviewers approved by Dr Amy Norman. Editor who approved publication: Patients with steroid-resistant nephrotic syndrome SRNS represent a challenging subset of patients with nephrotic syndrome who often fail standard immunosuppression and have a higher likelihood of progressing to end-stage renal disease.
Appropriate treatment of SRNS requires an adequate understanding of the historical treatment, renal histopathology, and genetics associated with the disease. The aim of this review is to present a comprehensive appraisal of the history, role of renal biopsy, genetics, and treatment of SRNS.
Nephrotic syndrome is a clinical condition characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Between and , the ISKDC carried out a prospective study of children from 24 participating clinics with primary nephrotic syndrome. The participants had a renal biopsy performed at the time of diagnosis before steroid therapy was begun.
Patients were also randomly assigned to 1 of 2 of the following relapse therapy treatments: Given the beneficial effect of standard prednisone therapy over short-course prednisone therapy, Ehrich and Brodehl, 10 in association with the German Pediatric Nephrology Working Group, conducted a controlled prospective multicenter study of 71 children comparing the efficacy and outcome of long prednisone therapy versus standard prednisone therapy for the initial treatment of childhood nephrotic syndrome.
Thanks to the contributions of the ISKDC and German Pediatric Nephrology Working Group, disparities between the short, standard, and long corticosteroid regimens for nephrotic syndrome were established Table 2. Long-course prednisone therapy for the initial presentation of SSNS is preferable to the standard regimen and short-course regimen because it leads to the highest percentage of sustained remission rates and reduces the rate of subsequent relapses.
Table 2 Comparative outcomes of steroid therapy for initial presentation of nephrotic syndrome. Additionally, recessive mutations in the kidney ankyrin repeat-containing protein KANK family proteins have been found to have essential roles in nephron function via regulation of Rho GTPase activity. In terms of the other histopathologic variants of MCD, which portend a steroid-resistant course, genes involved in the pathogenesis of diffuse mesangial sclerosis have been identified.
In summary, the role of the podocyte is crucial in understanding of the pathogenesis of nephrotic syndrome. The development, migration, basement membrane interaction, and regeneration of the podocyte are all critical processes in the maintenance of foot process integrity. Given the established association of 5 particular gene mutations in nonsyndromic FSGS, these genes will be explored in detail in the following sections, with emphasis being placed on the proposed mechanism of action leading to FSGS.
Congenital nephrotic syndrome will not be discussed in detail. However, data thus far suggest that podocin binds nephrin either directly or indirectly and thus may augment nephrin-induced stimulation of mitogen-activated protein kinases. Finally, of particular importance in the genetics of juvenile or adult-onset NS is the p. This variant, when found in association with one pathogenic NPHS2 mutation, represents the most frequently reported variant in Caucasians, particularly in Europeans with a frequency of 0.
ACTN4 , the gene that encodes alpha-actinin 4, is most prominently distributed in podocytes, with some distribution in renal vasculature. Alpha-actinin 4 is responsible for cross-linking bundles of actin filament in the slit diaphragm.
Mutations in this protein lead to decreased actin binding, formation of intracellular aggregates, and decreased protein half-life. Hinkes et al 15 have described a mutation in autosomal recessive nephrotic syndrome type 3, which leads to early-onset nephrotic syndrome.
The mutation causes a form of SRNS with the key histologic finding of diffuse mesangial sclerosis. More specifically, given that phospholipase C epsilon catalyzes the hydrolysis of membrane phospholipids to generate inositol 1,4,5-triplephosphate and diacylglycerol, the intracellular pathways of cell growth and differentiation are impaired by mutations in this protein.
TRPC6 encodes a calcium channel by the same name, which is located on the podocyte membrane and, in complex with podocin, regulates mechanosensation at the slit diaphragm. In response to phospholipase C activation, activation of TRPC6 leads to increased intracellular calcium concentration.
In the kidney, TRPC6 is expressed in renal tubules and glomeruli, with predominance in podocytes. Thus far, 11 different mutations in the TRPC6 gene have been identified in 8 families from different ethnic backgrounds. Although previously ascribed only as a genetic cause of late-onset autosomal dominant FSGS, a group of Italian investigators have suggested that the TRPC6 variants can also be detected in children with early-onset and sporadic SRNS 4 of 33 patients.
The CD2AP protein is expressed in podocytes and interacts with fyn and synaptopodin, thus maintaining the cytoskeletal architecture of the podocyte. Syndromic forms of SRNS are far less frequent and may be due to mutations in genes encoding various components involved in glomerular basement integrity. Mutations in NPHS1 are responsible for most cases of congenital nephrotic syndrome.
Additionally, there may be some difficulty in distinguishing between true steroid resistance and noncompliance with steroid therapy. Although there are no specific treatment guidelines based on genetic variants of SRNS, recent data suggest that cyclosporine therapy may be more effective in nongenetic forms of SRNS as opposed to genetic forms of SRNS, 35 possibly encouraging providers to more frequently request genetic testing in SRNS patients.
Additionally, given the poor response to immunosuppressive therapy in genetic forms of SRNS, identification of mutations via genetic screening may assist clinicians in deescalating further immunosuppression options and spare children from significant side effects associated with these medications. More specifically, Benoit et al 34 have suggested a systematic approach to genetic testing based on age at diagnosis, histopathologic findings, and mode of inheritance Figure 1.
Figure 1 Systematic approach to genetic testing in children with steroid-resistant nephrotic syndrome. The presence of a circulating serum factor associated with SRNS has long been sought. In a seminal paper by Savin et al, 36 the association between a circulating factor and disease activity was evaluated in patients with recurrent FSGS. Serum samples were analyzed in patients with FSGS pre- and postrenal transplant to evaluate if the serum samples of patients with recurrent FSGS increased glomerular-capillary permeability to albumin.
A permeability value was assigned to each sample, with the lower permeability values indicating poor glomerular-capillary permeability to albumin and higher permeability values indicating increased glomerular-capillary permeability to albumin. Patients were then stratified according to their permeability value, with the relative risk of recurrent FSGS being 5 times higher in patients with pretransplantation values of at least 0. Of note, this association did not hold true for the 9 children with SSNS who were tested.
Plasmapheresis in patients with recurrent FSGS lowered the level of serum activity and decreased proteinuria. More recently, the soluble urokinase-type plasminogen activator receptor suPAR has been suggested as a potential circulating factor in FSGS. Reiser et al 38 reported that circulating suPAR could activate B3 integrin on podocytes as a means of inducing proteinuria.
Following failure of standard steroid therapy for nephrotic syndrome, the Tune-Mendoza protocol may serve as a useful adjunct to treatment of SRNS. Oral cyclophosphamide therapy over a week time course has been used in combination with steroids for the treatment of steroid-dependent nephrotic syndrome. Calcineurin inhibitors have long been used in the treatment of SRNS, with the preponderance of data existing for therapy with cyclosporine. Studies have shown that cyclosporine in combination with steroids is effective in retaining remission and reducing relapse rates in patients with SRNS.
Tacrolimus serves as an alternative to cyclosporine with a slightly more attractive side effect profile as there is less hypertrichosis and gum hypertrophy. However, other side effects, including tremor, hypertension, and diabetes, have been reported. At a dose of 0. Data are largely retrospective 52 or from single-center experience with a low number of patients. Adverse effects of MMF include abdominal pain, diarrhea, infection, metabolic acidosis, and hyperlipidemia.
Rituximab is a monoclonal antibody directed against the cell surface antigen CD20 expressed on B lymphocytes. It has gained acceptance as a treatment for refractory cases of childhood nephrotic syndrome and, in recent years, is gaining recognition as a first-line steroid-sparing agent in the treatment of children with steroid-dependent nephrotic syndrome.
More recently, various investigators have published retrospective data evaluating the efficacy of rituximab used in combination with other immunosuppressive therapies in the treatment of SRNS. Kidney transplantation is the most ideal renal replacement therapy for children with SRNS. Children with SRNS run the risk of recurrence of nephrotic syndrome following transplantation. Recurrence of nephrotic syndrome, if not controlled, can cause delayed graft function, acute rejection, and diminished allograft survival.
The majority of information regarding posttransplant outcomes comes from pediatric patients with FSGS, the most common histopathologic finding in patients with SRNS. Dependent on the local practices of renal transplantation programs, plasmapheresis may be part of the pre- or postoperative protocol in patients with SRNS.
Many advances have been made in the study of this particular set of patients previously destined to rapidly progress to ESRD. In particular, the genetic profile of such patients has proved critical in unraveling the pathophysiologic mechanisms of disease and in guiding therapeutic options.
With further research in the field, it is likely that new mechanisms will be implicated in the pathophysiology of SRNS and further treatment options can be elucidated to optimize treatment of this disease. Nephrotic syndrome in the Netherlands: Early identification of frequent relapses among children with minimal change nephrotic syndrome.
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Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.
Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. Tejani A, Stablein DH.