1 Nature Reviews Nephrology 2012 Vol: 8(8):445-458. DOI: 10.1038/nrneph.2012.115

Childhood nephrotic syndrome—current and future therapies

The introduction of corticosteroids more than 50 years ago dramatically improved the prognosis of children with nephrotic syndrome. Corticosteroids remain the standard initial treatment for children with this disease, but a considerable proportion of patients do not respond and are therefore at risk of progressing to end-stage renal disease. Because of this risk, new therapeutic strategies are needed for steroid-resistant nephrotic syndrome. These strategies have historically focused on identifying effective alternative immunosuppressive agents, such as ciclosporin and tacrolimus, yet evidence now indicates that nephrotic syndrome results from podocyte dysfunction. Even conventional immunosuppressive agents, such as glucocorticoids and ciclosporin, directly affect podocyte structure and function, challenging the 'immune theory' of the pathogenesis of childhood nephrotic syndrome in which disease is caused by T cells. This Review summarizes the currently available treatments for childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome.

Mentions
Figures
Figure 1: Total rituximab dose does not seem to correlate with initial clinical response.The total rituximab dose based on the initial clinical response is shown for 70 children with SDNS and/or FRNS, SRNS, and post-tx NS. a | Good initial response (no or mild proteinuria and serum albumin >30 g/l); b | poor initial response (marked proteinuria and serum albumin <30 g/l). Individual doses were 375–750 mg/m2 and patients received as many as four doses, with doses given every 1–2 weeks. Abbreviations: FRNS, frequently recurring nephrotic syndrome; NS, nephrotic syndrome; SDNS, steroid-dependent nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; tx, transplantation. Permission obtained from Springer © Prytula, A. et al. Pediatr. Nephrol. 25, 461–468 (2010). Figure 2: Oral galactose induces remission of proteinuria in an adult with nephrotic syndrome resistant to multiple immunosuppressive agents.The clinical courses of proteinuria and serum creatinine are shown during various immunosuppressive regimens, before and following introduction of oral galactose. Doses: cyclophosphamide (initial course 125 mg daily [1.5 mg/kg]; 2nd course up to 100 mg daily); mycophenolate mofetil 500 mg twice daily; plasmapheresis three times weekly and ultimately once every 2 weeks; ciclosporin 50 mg twice daily, increased to 75 mg twice daily; ciclosporin (2nd course) 175 mg twice daily; oral galactose 10 g twice daily then 15 g twice daily. Permission obtained from Oxford University Press © De Smet, E., Rioux, J. P., Ammann, H., Deziel, C. & Querin, S. Nephrol. Dial. Transplant. 24, 2938–2940 (2009). Figure 3: Schematic of the canonical and alternate modes of action of thiazolidinediones.Traditionally, thiazolidinediones bind to their receptor, PPARγ, which dimerizes with the nuclear receptor RXR and acts on peroxisome proliferator response elements, together with co-activators, to promote the transcription of responsive genes (canonical pathway). Thiazolidinediones can also act on the glucocorticoid receptor directly (off-target pathway). In this off-target pathway, thiazolidinediones might imperfectly bind to and stimulate the glucocorticoid receptor through phosphorylation and nuclear translocation, possibly resulting in the expression of glucocorticoid-responsive genes. Thiazolidinediones may also modulate the glucocorticoid receptor pathway indirectly by binding to PPARγ, resulting in subsequent interaction between the two receptors directly or through the involvement of common cofactors. Thiazolidinediones may also deactivate mitogen-activated protein kinases via a nongenomic pathway, which subsequently modifies other cellular systems including the phosphorylation of the glucocorticoid receptor and PPARγ. Figure modified from the Nuclear Receptor Resource (http://www.nrresource.org) with the permission of Dr J. Vanden Heuvel, University Park, PA, USA. Abbreviations: GRE, glucocorticoid response element; PPARγ, peroxisome proliferator-activated receptor γ; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor. Figure 4: Following TGF-β binding, the TGF-β receptor is activated, resulting in downstream activation of pro-apoptotic p38 MAPK and MK2 signaling via activation of PKC.Accordingly, inhibition of PKCα, p38 MAPK, or MK2 would inhibit pro-apoptotic signaling in podocytes at different levels of the same pathway. Abbreviations: MAPK, mitogen-activated protein kinase; MK2, MAPK-activated protein kinase 2; PKC, protein kinase C; TGF-β, transforming growth factor β.
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References
  1. Arneil, G. C. The nephrotic syndrome. Pediatr. Clin. North Am. 18, 547-559 , .
    • . . . Although edema and proteinuria have been recognized clinically for more than 2,000 years, the initial description of children with nephrotic syndrome has been credited to Roelans in 1484,1 whereas the term 'nephrotic syndrome' was coined in 1929 by Henry Christian.2 Prior to the advent of glucocorticoids or antibiotics, the mortality of children with nephrotic syndrome was very high (~67%).3 The mortality rate first dropped markedly in 1939 to ~42% following the introduction of sulfonamides, and to ~35% in 1944 following the introduction of penicillin.3 Mortality fell even more dramatically in the 1950s to ~9% after the introduction of adrenocorticotropic hormone (ACTH) and cortisone, which caused a marked reduction in proteinuria in many patients . . .
  2. Cameron, J. S. in The Nephrotic Syndrome (eds Cameron, J. S., Glassock, R. J. & Whelton, A.) 3-56 (Marcel Dekker, Inc., New York, 1988) , .
    • . . . Although edema and proteinuria have been recognized clinically for more than 2,000 years, the initial description of children with nephrotic syndrome has been credited to Roelans in 1484,1 whereas the term 'nephrotic syndrome' was coined in 1929 by Henry Christian.2 Prior to the advent of glucocorticoids or antibiotics, the mortality of children with nephrotic syndrome was very high (~67%).3 The mortality rate first dropped markedly in 1939 to ~42% following the introduction of sulfonamides, and to ~35% in 1944 following the introduction of penicillin.3 Mortality fell even more dramatically in the 1950s to ~9% after the introduction of adrenocorticotropic hormone (ACTH) and cortisone, which caused a marked reduction in proteinuria in many patients . . .
    • . . . A randomized study in 54 children with SDNS reported that adding rituximab to glucocorticoids and calcineurin inhibitors enabled reduction in the doses of both medications, while yielding similar or better short-term (3-month) outcomes than standard dosing without rituximab.84 In a retrospective comparison of 23 children with SDNS, rituximab and tacrolimus were similarly effective in reducing relapse rates and glucocorticoid exposure.85 In another retrospective study of 30 children with SDNS treated with repeated doses of rituximab to maintain depressed CD19 levels for at least 15 months, long-term remission (~17 months) following complete CD19 recovery was noted in 19 (63%) of patients.86 In addition, a retrospective review of long-term outcomes for 37 children with SDNS found that 375 mg/m2 given weekly for 1–4 courses resulted in a sustained remission in 26 children (70%) for 12 months and, among 29 children followed for more than 2 years, 12 (41%) remained in remission.87 A randomized, double-blind, placebo-controlled, multicenter trial comparing rituximab with placebo infusions in children with SDNS is currently underway in Japan.88 . . .
    • . . . The most common dose used has been 375 mg/m2 weekly, and most treatments have been within the range of 1–4 weeks.74, 75, 77, 84 In addition, most children have complete B-cell depletion after only one dose.90 Moreover, in the largest retrospective study to date (70 children: 28 with SDNS and/or FRNS, 27 with SRNS and 15 with post-transplantation nephrotic syndrome), the total rituximab dose did not seem to correlate with the initial clinical response to therapy (Figure 1).74 Such findings, although far from conclusive, suggest that two doses of rituximab (with the second dose 1–2 weeks after the first), or perhaps even a single dose, is adequate to obtain the desired clinical benefits from this drug in children with nephrotic syndrome. . . .
  3. Arneil, G. C. & Lam, C. N. Long-term assessment of steroid therapy in childhood nephrosis. Lancet 2, 819-821 , .
    • . . . Although edema and proteinuria have been recognized clinically for more than 2,000 years, the initial description of children with nephrotic syndrome has been credited to Roelans in 1484,1 whereas the term 'nephrotic syndrome' was coined in 1929 by Henry Christian.2 Prior to the advent of glucocorticoids or antibiotics, the mortality of children with nephrotic syndrome was very high (~67%).3 The mortality rate first dropped markedly in 1939 to ~42% following the introduction of sulfonamides, and to ~35% in 1944 following the introduction of penicillin.3 Mortality fell even more dramatically in the 1950s to ~9% after the introduction of adrenocorticotropic hormone (ACTH) and cortisone, which caused a marked reduction in proteinuria in many patients . . .
  4. Minimal change nephrotic syndrome in children: deaths during the first 5 to 15 years' observation. Report of the International Study of Kidney Disease in Children. Pediatrics 73, 497-501 , .
    • . . . Children with corticosteroid-resistant disease have increased short-term mortality and are at a greater risk of mortality from end-stage renal disease than are those who do respond to treatment.4, 5 Although glucocorticoids have continued as the mainstay of therapy for nephrotic syndrome for more than 50 years, neither the target cell nor the mechanism of action of these agents in nephrotic syndrome has been clearly determined . . .
  5. Chavers, B. M., Li, S., Collins, A. J. & Herzog, C. A. Cardiovascular disease in pediatric chronic dialysis patients. Kidney Int. 62, 648-653 , .
    • . . . Children with corticosteroid-resistant disease have increased short-term mortality and are at a greater risk of mortality from end-stage renal disease than are those who do respond to treatment.4, 5 Although glucocorticoids have continued as the mainstay of therapy for nephrotic syndrome for more than 50 years, neither the target cell nor the mechanism of action of these agents in nephrotic syndrome has been clearly determined . . .
  6. Benoit, G., Machuca, E. & Antignac, C. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr. Nephrol. 25, 1621-1632 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
  7. Machuca, E., Benoit, G. & Antignac, C. Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum. Mol. Genet. 18, R185-R194 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
    • . . . However, since the first identification of a mutation in the podocyte protein nephrin,182 research has identified multiple mutations that can cause nephrotic syndrome.7, 8, 183 This new knowledge enables a more functionally relevant grouping of the causes of nephrotic syndrome (such as 'podocytopathies' for mutations directly affecting podocyte structure or function, or 'channelopathies' for mutations affecting an ion channel such as TRPC6).184 Eventually, we fully expect that this new knowledge will translate into new therapeutic approaches to treat nephrotic syndrome . . .
  8. Lowik, M. M., Groenen, P. J., Levtchenko, E. N., Monnens, L. A. & van den Heuvel, L. P. Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis-a review. Eur. J. Pediatr. 27, 27 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
    • . . . However, since the first identification of a mutation in the podocyte protein nephrin,182 research has identified multiple mutations that can cause nephrotic syndrome.7, 8, 183 This new knowledge enables a more functionally relevant grouping of the causes of nephrotic syndrome (such as 'podocytopathies' for mutations directly affecting podocyte structure or function, or 'channelopathies' for mutations affecting an ion channel such as TRPC6).184 Eventually, we fully expect that this new knowledge will translate into new therapeutic approaches to treat nephrotic syndrome . . .
  9. Savin, V. J. et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N. Engl. J. Med. 334, 878-883 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  10. Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952-960 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
  11. Hinkes, B. et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat. Genet. 38, 1397-1405 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
  12. Ozaltin, F. et al. Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am. J. Hum. Genet. 89, 139-147 , .
    • . . . One challenge in the treatment of childhood nephrotic syndrome is that it is clearly not a single disease; indeed, multiple genetic mutations have now been reported to cause nephrotic syndrome in children.6, 7, 8 Nevertheless, one or more circulating factors (for example, soluble urokinase receptor) seem to cause nephrotic syndrome in a subset of children and adults.9, 10 The majority of patients with genetic forms of childhood nephrotic syndrome are resistant to current immunosuppressive treatments, including corticosteroids.11, 12 The clinical response to treatment with corticosteroids separates children with nephrotic syndrome into two groups: a corticosteroid-resistant group (steroid-resistant nephrotic syndrome; SRNS), in which patients have a high risk of developing kidney failure, and a corticosteroid-sensitive group (steroid-sensitive nephrotic syndrome; SSNS), in which patients risk morbidity from relapses and corticosteroid exposure . . .
  13. Wei, C. & Reiser, J. Minimal change disease as a modifiable podocyte paracrine disorder. Nephrol. Dial. Transplant. 26, 1776-1777 , .
    • . . . Extensive research over the past decade has highlighted the crucial importance of the podocyte as a site of cellular injury in nephrotic syndrome.13, 14 These studies have revealed that numerous podocyte intracellular proteins and molecular pathways that regulate podocyte structure and function have crucial roles in the development of nephrotic syndrome and the response of patients to therapy . . .
  14. Schonenberger, E., Ehrich, J. H., Haller, H. & Schiffer, M. The podocyte as a direct target of immunosuppressive agents. Nephrol. Dial. Transplant. 26, 18-24 , .
    • . . . Extensive research over the past decade has highlighted the crucial importance of the podocyte as a site of cellular injury in nephrotic syndrome.13, 14 These studies have revealed that numerous podocyte intracellular proteins and molecular pathways that regulate podocyte structure and function have crucial roles in the development of nephrotic syndrome and the response of patients to therapy . . .
  15. Churg, J., Habib, R. & White, R. H. Pathology of the nephrotic syndrome in children: a report for the International Study of Kidney Disease in Children. Lancet 760, 1299-1302 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  16. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J. Pediatr. 98, 561-564 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  17. Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int. 20, 765-771 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  18. Eddy, A. A. & Symons, J. M. Nephrotic syndrome in childhood. Lancet 362, 629-639 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  19. Rydel, J. J., Korbet, S. M., Borok, R. Z. & Sxhwartz, M. M. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am. J. Kidney Dis. 25, 534-542 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  20. Chun, M. J., Korbet, S. M., Schwartz, M. M. & Lewis, E. J. Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J. Am. Soc. Nephrol. 15, 2169-2177 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  21. Hodson, E. M., Willis, N. S. & Craig, J. C. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database of Systematic Reviews, Issue 4. Article No.: CD001533.doi: 10.1002/14651858.CD001533.pub4 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  22. Saadeh, S. A. et al. Weight or body surface area dosing of steroids in nephrotic syndrome: is there an outcome difference? Pediatr. Nephrol. 26, 2167-2171 , .
    • . . . Minimal-change disease (MCD) is the most common cause of nephrotic syndrome during childhood15 and corticosteroids induce remission in more than 90% of children with MCD.16 By contrast, the majority of children with the second most common etiology—focal segmental glomerulosclerosis (FSGS)15—do not respond to oral glucocorticoids.17 A child presenting with idiopathic nephrotic syndrome who does not enter remission following 1 month of corticosteroid therapy is typically classified as having SRNS.18 Evidence from adults, however, suggests that a prolonged (3–6-month) course of oral glucocorticoids improves their response rate.19, 20 In children with SSNS, compelling evidence from a systematic review indicates that a longer course of initial corticosteroids (minimum of 3 months) decreases the likelihood of subsequent relapses.21 Moreover, the dose of oral corticosteroids might also influence the number of relapses.22 The efficacy of glucocorticoids in idiopathic nephrotic syndrome might be attributable to the immunosuppressive effects of these agents, their direct action on the podocyte, or, potentially, a combination of these effects.23 . . .
  23. Ransom, R. F., Lam, N. G., Hallett, M. A., Atkinson, S. J. & Smoyer, W. E. Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int. 68, 2473-2483 , .
  24. Murnaghan, K., Vasmant, D. & Bensman, A. Pulse methylprednisolone therapy in severe idiopathic childhood nephrotic syndrome. Acta Paediatr. Scand. 73, 733-739 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced.28, 29, 30 Intravenous glucocorticoids may also improve the response of children with SRNS when combined with ciclosporin.31 . . .
  25. Hari, P., Bagga, A. & Mantan, M. Short term efficacy of intravenous dexamethasone and methylprednisolone therapy in steroid resistant nephrotic syndrome. Indian Pediatr. 41, 993-1000 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced.28, 29, 30 Intravenous glucocorticoids may also improve the response of children with SRNS when combined with ciclosporin.31 . . .
  26. Mori, K., Honda, M. & Ikeda, M. Efficacy of methylprednisolone pulse therapy in steroid-resistant nephrotic syndrome. Pediatr. Nephrol. 19, 1232-1236 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced.28, 29, 30 Intravenous glucocorticoids may also improve the response of children with SRNS when combined with ciclosporin.31 . . .
  27. Shenoy, M. et al. Intravenous methylprednisolone in idiopathic childhood nephrotic syndrome. Pediatr. Nephrol. 25, 899-903 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced.28, 29, 30 Intravenous glucocorticoids may also improve the response of children with SRNS when combined with ciclosporin.31 . . .
  28. Tune, B. M. et al. Intravenous methylprednisolone and oral alkylating agent therapy of prednisone-resistant pediatric focal segmental glomerulosclerosis: a long-term follow-up. Clin. Nephrol. 43, 84-88 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced.28, 29, 30 Intravenous glucocorticoids may also improve the response of children with SRNS when combined with ciclosporin.31 . . .
  29. Tune, B. M. & Mendoza, S. A. Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. J. Am. Soc. Nephrol. 8, 824-832 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced. . . .
  30. Mendoza, S. A. et al. Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents. Pediatr. Nephrol. 4, 303-307 , .
    • . . . High-dose intravenous glucocorticoids can sometimes induce remission of proteinuria in children with SRNS.24, 25, 26, 27 An 18-month protocol of intravenous glucocorticoids, with or without the alkylating agent cyclophosphamide, is effective in some children with SRNS.28, 29, 30 With this approach, all patients receive high doses of intravenous methylprednisolone, whereas cyclophosphamide is added only for patients who do not respond to intravenous methylprednisolone after the first 10 weeks, or who relapse as the frequency of intravenous methylprednisolone administration is reduced.28, . . .
  31. Ehrich, J. H. et al. Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated. Nephrol. Dial. Transplant. 22, 2183-2193 , .
  32. Vester, U., Kranz, B., Zimmermann, S. & Hoyer, P. F. Cyclophosphamide in steroid-sensitive nephrotic syndrome: outcome and outlook. Pediatr. Nephrol. 18, 661-664 , .
    • . . . Although cyclophosphamide is used more commonly in children with frequently relapsing nephrotic syndrome (FRNS; more than four relapses in a 12-month period or two relapses in the initial 6 months) or steroid-dependent nephrotic syndrome (SDNS; relapses during steroid taper or within 2 weeks of discontinuation),32 it is also used for treating children with SRNS . . .
  33. Plank, C. et al. Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie. Pediatr. Nephrol. 23, 1483-1493 , .
    • . . . In a randomized study of 32 children with SRNS, intravenous cyclophosphamide was inferior to ciclosporin in inducing remission.33 Cyclophosphamide had greater efficacy in children with SSNS who had polymorphisms in glutathione-S-transferase (which is important for cyclophosphamide metabolism) than in those who do not express these varients, potentially as a result of slower drug metabolism.34, 35 An alternative cytotoxic agent is chlorambucil, but a meta-analysis revealed an increased risk of seizures and severe bacterial infections with chlorambucil when compared with cyclophosphamide.36 . . .
    • . . . By contrast, only two of 12 patients in the placebo arm had a partial response and none had a complete remission.52 As mentioned earlier, in a nonrandomized trial, 65 children with SRNS (45 with MCD; 20 with FSGS) were treated with a combination of ciclosporin and prednisone, with 27 children (41%) achieving complete remission.54 In a randomized study published in 2008, ciclosporin was superior to intravenous cyclophosphamide in children with SRNS.33 The efficacy of ciclosporin might be enhanced when combined with intravenous glucocorticoids.31 The combination of mycophenolate mofetil and high-dose oral dexamethasone was compared with ciclosporin in a randomized clinical trial published in 2011.47 Although the remission rate was higher in the ciclosporin group than in the mycophenolate and dexamethasone group, this trend did not reach statistical significance. . . .
  34. Sharda, S. V. et al. Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome? Pediatr. Nephrol. 23, 2001-2006 , .
    • . . . In a randomized study of 32 children with SRNS, intravenous cyclophosphamide was inferior to ciclosporin in inducing remission.33 Cyclophosphamide had greater efficacy in children with SSNS who had polymorphisms in glutathione-S-transferase (which is important for cyclophosphamide metabolism) than in those who do not express these varients, potentially as a result of slower drug metabolism.34, 35 An alternative cytotoxic agent is chlorambucil, but a meta-analysis revealed an increased risk of seizures and severe bacterial infections with chlorambucil when compared with cyclophosphamide.36 . . .
  35. Vester, U., Kranz, B., Zimmermann, S., Buscher, R. & Hoyer, P. F. The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1. Pediatr. Nephrol. 20, 478-481 , .
    • . . . In a randomized study of 32 children with SRNS, intravenous cyclophosphamide was inferior to ciclosporin in inducing remission.33 Cyclophosphamide had greater efficacy in children with SSNS who had polymorphisms in glutathione-S-transferase (which is important for cyclophosphamide metabolism) than in those who do not express these varients, potentially as a result of slower drug metabolism.34, 35 An alternative cytotoxic agent is chlorambucil, but a meta-analysis revealed an increased risk of seizures and severe bacterial infections with chlorambucil when compared with cyclophosphamide.36 . . .
  36. Latta, K., von Schnakenburg, C. & Ehrich, J. H. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr. Nephrol. 16, 271-282 , .
  37. Dooley, M. A. et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N. Engl. J. Med. 365, 1886-1895 , .
    • . . . Mycophenolate mofetil has been used for the management of a variety of glomerular diseases, including lupus nephritis and IgA nephropathy,37, 38 but its mechanism of action in nephrotic syndrome remains unknown . . .
  38. Tang, S. C. et al. Long-term study of mycophenolate mofetil treatment in IgA nephropathy. Kidney Int. 77, 543-549 , .
    • . . . Mycophenolate mofetil has been used for the management of a variety of glomerular diseases, including lupus nephritis and IgA nephropathy,37, 38 but its mechanism of action in nephrotic syndrome remains unknown . . .
  39. Eugui, E. M., Almquist, S. J., Muller, C. D. & Allison, A. C. Lymphocyte-selective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand. J. Immunol. 33, 161-173 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  40. Ishikawa, H. Mizoribine and mycophenolate mofetil. Curr. Med. Chem. 6, 575-597 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  41. Senthil Nayagam, L. et al. Mycophenolate mofetil or standard therapy for membranous nephropathy and focal segmental glomerulosclerosis: a pilot study. Nephrol. Dial. Transplant. 23, 1926-1930 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  42. Cattran, D. C., Wang, M. M., Appel, G., Matalon, A. & Briggs, W. Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis. Clin. Nephrol. 62, 405-411 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  43. Moudgil, A., Bagga, A. & Jordan, S. C. Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions. Pediatr. Nephrol. 20, 1376-1381 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  44. Fujinaga, S. et al. Mycophenolate mofetil therapy for childhood-onset steroid dependent nephrotic syndrome after long-term cyclosporine: extended experience in a single center. Clin. Nephrol. 72, 268-273 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  45. de Mello, V. R. et al. Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephrotic syndrome. Pediatr. Nephrol. 25, 453-460 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  46. Gargah, T. T. & Lakhoua, M. R. Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome. J. Nephrol. 24, 203-207 , .
    • . . . Mycophenolate mofetil inhibits lymphocyte DNA synthesis and proliferation through the inhibition of inosine monophosphate dehydrogenase—a key enzyme in purine biosynthesis.39 This inhibition is restricted to T cells and B cells, however, as all other cell types have a 'salvage pathway' through which purines can still be synthesized in the presence of mycophenolate mofetil.40 In one randomized trial involving 33 adults with FSGS, mycophenolate mofetil and low-dose prednisone was as effective as standard oral corticosteroids in inducing remission.41 In a 6-month open-label study, use of mycophenolate mofetil in adults with FSGS who were resistant to other treatments resulted in a reduction in proteinuria in almost 50% of patients, but did not achieve complete remission in any.42 A number of uncontrolled studies have reported a good response to mycophenolate mofetil in children with SRNS or FRNS.43, 44 Indeed, in a retrospective study of 52 children who were resistant to corticosteroids and cyclophosphamide, 59.5% had either a complete or a partial remission in response to mycophenolate mofetil.45 Nevertheless, the response rate to mycophenolate mofetil in children is quite variable.46, 47 . . .
  47. Gipson, D. S. et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int. 80, 868-878 , .
  48. Fujinaga, S. et al. Single daily high-dose mizoribine therapy for children with steroid-dependent nephrotic syndrome prior to cyclosporine administration. Pediatr. Nephrol. 26, 479-483 , .
    • . . . The majority of case series describe its use in children with SDNS or FRNS,48 but it has also been used in children with SRNS.49 . . .
  49. Tanaka, H. et al. Mizoribine pulse therapy for a pediatric patient with steroid-resistant nephrotic syndrome. Tohoku J. Exp. Med. 205, 87-91 , .
  50. Borel, J. F. Mechanism of action of cyclosporin A and rationale for use in nephrotic syndrome. Clin. Nephrol. 35 (Suppl. 1), S23-S30 , .
    • . . . Ciclosporin prevents T-cell activation through inhibition of calcineurin-induced IL2 gene expression—a crucial early event in T-cell activation.50 However, ciclosporin also stabilizes the podocyte actin cytoskeleton, which might partly explain its effects in nephrotic syndrome.51 The efficacy of ciclosporin in SRNS has been demonstrated in placebo-controlled studies in both adults and children.52, 53 In a pediatric study, 12 children in the ciclosporin arm completed the 6-month protocol; four children had a complete remission and eight had a partial response . . .
  51. Faul, C. et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat. Med. 14, 931-938 , .
    • . . . Ciclosporin prevents T-cell activation through inhibition of calcineurin-induced IL2 gene expression—a crucial early event in T-cell activation.50 However, ciclosporin also stabilizes the podocyte actin cytoskeleton, which might partly explain its effects in nephrotic syndrome.51 The efficacy of ciclosporin in SRNS has been demonstrated in placebo-controlled studies in both adults and children.52, 53 In a pediatric study, 12 children in the ciclosporin arm completed the 6-month protocol; four children had a complete remission and eight had a partial response . . .
  52. Lieberman, K. V. & Tejani, A. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. J. Am. Soc. Nephrol. 7, 56-63 , .
    • . . . Ciclosporin prevents T-cell activation through inhibition of calcineurin-induced IL2 gene expression—a crucial early event in T-cell activation.50 However, ciclosporin also stabilizes the podocyte actin cytoskeleton, which might partly explain its effects in nephrotic syndrome.51 The efficacy of ciclosporin in SRNS has been demonstrated in placebo-controlled studies in both adults and children.52, 53 In a pediatric study, 12 children in the ciclosporin arm completed the 6-month protocol; four children had a complete remission and eight had a partial response . . .
    • . . . By contrast, only two of 12 patients in the placebo arm had a partial response and none had a complete remission.52 As mentioned earlier, in a nonrandomized trial, 65 children with SRNS (45 with MCD; 20 with FSGS) were treated with a combination of ciclosporin and prednisone, with 27 children (41%) achieving complete remission.54 In a randomized study published in 2008, ciclosporin was superior to intravenous cyclophosphamide in children with SRNS.33 The efficacy of ciclosporin might be enhanced when combined with intravenous glucocorticoids.31 The combination of mycophenolate mofetil and high-dose oral dexamethasone was compared with ciclosporin in a randomized clinical trial published in 2011.47 Although the remission rate was higher in the ciclosporin group than in the mycophenolate and dexamethasone group, this trend did not reach statistical significance. . . .
  53. Cattran, D. C. et al. A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int. 56, 2220-2226 , .
    • . . . Ciclosporin prevents T-cell activation through inhibition of calcineurin-induced IL2 gene expression—a crucial early event in T-cell activation.50 However, ciclosporin also stabilizes the podocyte actin cytoskeleton, which might partly explain its effects in nephrotic syndrome.51 The efficacy of ciclosporin in SRNS has been demonstrated in placebo-controlled studies in both adults and children.52, 53 In a pediatric study, 12 children in the ciclosporin arm completed the 6-month protocol; four children had a complete remission and eight had a partial response . . .
  54. Niaudet, P. Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J. Pediatr. 125, 981-986 , .
    • . . . By contrast, only two of 12 patients in the placebo arm had a partial response and none had a complete remission.52 As mentioned earlier, in a nonrandomized trial, 65 children with SRNS (45 with MCD; 20 with FSGS) were treated with a combination of ciclosporin and prednisone, with 27 children (41%) achieving complete remission.54 In a randomized study published in 2008, ciclosporin was superior to intravenous cyclophosphamide in children with SRNS.33 The efficacy of ciclosporin might be enhanced when combined with intravenous glucocorticoids.31 The combination of mycophenolate mofetil and high-dose oral dexamethasone was compared with ciclosporin in a randomized clinical trial published in 2011.47 Although the remission rate was higher in the ciclosporin group than in the mycophenolate and dexamethasone group, this trend did not reach statistical significance. . . .
  55. Iijima, K. et al. Risk factors for cyclosporine-induced tubulointerstitial lesions in children with minimal change nephrotic syndrome. Kidney Int. 61, 1801-1805 , .
  56. Bowman, L. J. & Brennan, D. C. The role of tacrolimus in renal transplantation. Expert Opin. Pharmacother. 9, 635-643 , .
    • . . . An alternative calcineurin inhibitor is tacrolimus, although differences exist in its mechanism of action when compared with ciclosporin.56 Tacrolimus and ciclosporin have similar adverse effects but tacrolimus is seldom associated with the cosmetic adverse effects of hirsutism and gingival hyperplasia that affect the quality of life of many patients using ciclosporin . . .
  57. McCauley, J. et al. Pilot trial of FK 506 in the management of steroid-resistant nephrotic syndrome. Nephrol. Dial. Transplant. 8, 1286-1290 , .
    • . . . Tacrolimus has been used effectively in treating children with SRNS.57, 58, 59, 60, 61, 62 In one study, the relapse rate was lower with tacrolimus than with ciclosporin.61 . . .
  58. Gulati, S. et al. Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children. Nephrol. Dial. Transplant. 23, 910-913 , .
    • . . . Tacrolimus has been used effectively in treating children with SRNS.57, 58, 59, 60, 61, 62 In one study, the relapse rate was lower with tacrolimus than with ciclosporin.61 . . .
  59. Loeffler, K., Gowrishankar, M. & Yiu, V. Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. Pediatr. Nephrol. 19, 281-287 , .
    • . . . Tacrolimus has been used effectively in treating children with SRNS.57, 58, 59, 60, 61, 62 In one study, the relapse rate was lower with tacrolimus than with ciclosporin.61 . . .
  60. Westhoff, T. H., Schmidt, S., Zidek, W., Beige, J. & van der Giet, M. Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome. Clin. Nephrol. 65, 393-400 , .
    • . . . Tacrolimus has been used effectively in treating children with SRNS.57, 58, 59, 60, 61, 62 In one study, the relapse rate was lower with tacrolimus than with ciclosporin.61 . . .
  61. Choudhry, S. et al. Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial. Am. J. Kidney Dis. 53, 760-769 , .
  62. Bhimma, R., Adhikari, M., Asharam, K. & Connolly, C. Management of steroid-resistant focal segmental glomerulosclerosis in children using tacrolimus. Am. J. Nephrol. 26, 544-551 , .
    • . . . Tacrolimus has been used effectively in treating children with SRNS.57, 58, 59, 60, 61, 62 In one study, the relapse rate was lower with tacrolimus than with ciclosporin.61 . . .
  63. Garcia, C. D. et al. Plasmapheresis for recurrent posttransplant focal segmental glomerulosclerosis. Transplant. Proc. 38, 1904-1905 , .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  64. Bosch, T. & Wendler, T. Extracorporeal plasma treatment in primary and recurrent focal segmental glomerular sclerosis: a review. Ther. Apher. 5, 155-160 , .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  65. Pradhan, M., Petro, J., Palmer, J., Meyers, K. & Baluarte, H. J. Early use of plasmapheresis for recurrent post-transplant FSGS. Pediatr. Nephrol. 18, 934-938 , .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  66. Feld, S. M. et al. Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis in native kidneys. Am. J. Kidney Dis. 32, 230-237 , .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  67. Ginsburg, D. S. & Dau, P. Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis. Clin. Nephrol. 48, 282-287 , .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  68. Oliveira, L., Wang, D. & McCormick, B. B. A case report of plasmapheresis and cyclophosphamide for steroid-resistant focal segmental glomerulosclerosis: recovery of renal function after five months on dialysis. Ther. Apher. Dial. 11, 227-231 , .
    • . . . Many reports have described the use of plasmapheresis in the treatment of recurrent nephrotic syndrome following kidney transplantation in patients with FSGS.63, 64, 65 This strategy aims to remove a suspected soluble substance, such as a cytokine, which mediates FSGS recurrence.9 Interestingly, few studies have reported on the use of plasmapheresis in nephrotic syndrome occurring in native kidneys,64, 66, 67, 68 which is potentially related to the perceived invasive nature of plasmapheresis . . .
  69. Jayne, D. Role of rituximab therapy in glomerulonephritis. J. Am. Soc. Nephrol. 21, 14-17 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  70. Ruggenenti, P. et al. Rituximab for idiopathic membranous nephropathy: who can benefit? Clin. J. Am. Soc. Nephrol. 1, 738-748 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  71. Fervenza, F. C. et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 73, 117-125 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  72. Fornoni, A. et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci. Transl. Med. 3, 85ra46 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
    • . . . However, the novel finding in 2011 that rituximab binds directly to an acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B) on the surface of podocytes suggests an even more direct mechanism of action for this drug in nephrotic syndrome.72 In this report, the binding of rituximab to this 'off-target' podocyte protein prevented the downregulation of acid sphingomyelinase activity in cultured podocytes induced by sera from adults with recurrent FSGS, as well as restored actin stress fiber formation and podocyte viability.72 As potentially important as this finding has been, the mechanistic role of SMPDL3B in the regulation of podocyte structure and function remains to be determined.92 . . .
  73. Guigonis, V. et al. Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr. Nephrol. 23, 1269-1279 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  74. Prytula, A. et al. Rituximab in refractory nephrotic syndrome. Pediatr. Nephrol. 25, 461-468 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
    • . . . The most common dose used has been 375 mg/m2 weekly, and most treatments have been within the range of 1–4 weeks.74, 75, 77, 84 In addition, most children have complete B-cell depletion after only one dose.90 Moreover, in the largest retrospective study to date (70 children: 28 with SDNS and/or FRNS, 27 with SRNS and 15 with post-transplantation nephrotic syndrome), the total rituximab dose did not seem to correlate with the initial clinical response to therapy (Figure 1).74 Such findings, although far from conclusive, suggest that two doses of rituximab (with the second dose 1–2 weeks after the first), or perhaps even a single dose, is adequate to obtain the desired clinical benefits from this drug in children with nephrotic syndrome. . . .
    • . . . After successful induction of remission, nephrotic syndrome often recurs, but the time to relapse in SRNS has been highly variable, typically after 5–9 months (Table 2).74, 75 Relapses have often, but not always, been associated with repopulation of CD20+ B cells.90, 91, 92 Some children, however, remain in remission despite B-cell recovery, whereas others respond to rituximab despite an absence of B-cell depletion.74, 75 As a result, repeat dosing strategies have varied between those based on improvement or full recovery of CD20+ B-cell numbers and those based strictly on clinical relapse of nephrotic syndrome, regardless of B-cell numbers. . . .
  75. Gulati, A. et al. Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin. J. Am. Soc. Nephrol. 5, 2207-2212 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children. . . .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
    • . . . The largest series reported to date is a cohort study that included 33 children with SRNS who received 2–4 doses of rituximab.75 At 6 months after the last dose of rituximab, nine (27%) children had entered complete remission, seven (21%) had experienced a partial remission, and 17 (51%) had had no response . . .
    • . . . The most common dose used has been 375 mg/m2 weekly, and most treatments have been within the range of 1–4 weeks.74, 75, 77, 84 In addition, most children have complete B-cell depletion after only one dose.90 Moreover, in the largest retrospective study to date (70 children: 28 with SDNS and/or FRNS, 27 with SRNS and 15 with post-transplantation nephrotic syndrome), the total rituximab dose did not seem to correlate with the initial clinical response to therapy (Figure 1).74 Such findings, although far from conclusive, suggest that two doses of rituximab (with the second dose 1–2 weeks after the first), or perhaps even a single dose, is adequate to obtain the desired clinical benefits from this drug in children with nephrotic syndrome. . . .
    • . . . After successful induction of remission, nephrotic syndrome often recurs, but the time to relapse in SRNS has been highly variable, typically after 5–9 months (Table 2).74, 75 Relapses have often, but not always, been associated with repopulation of CD20+ B cells.90, 91, 92 Some children, however, remain in remission despite B-cell recovery, whereas others respond to rituximab despite an absence of B-cell depletion. . . .
  76. Bagga, A., Sinha, A. & Moudgil, A. Rituximab in patients with the steroid-resistant nephrotic syndrome. N. Engl. J. Med. 356, 2751-2752 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  77. Kari, J. A. et al. Rituximab for refractory cases of childhood nephrotic syndrome. Pediatr. Nephrol. 26, 733-737 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
    • . . . The most common dose used has been 375 mg/m2 weekly, and most treatments have been within the range of 1–4 weeks.74, 75, 77, 84 In addition, most children have complete B-cell depletion after only one dose.90 Moreover, in the largest retrospective study to date (70 children: 28 with SDNS and/or FRNS, 27 with SRNS and 15 with post-transplantation nephrotic syndrome), the total rituximab dose did not seem to correlate with the initial clinical response to therapy (Figure 1).74 Such findings, although far from conclusive, suggest that two doses of rituximab (with the second dose 1–2 weeks after the first), or perhaps even a single dose, is adequate to obtain the desired clinical benefits from this drug in children with nephrotic syndrome. . . .
  78. Suri, M., Tran, K., Sharma, A. P., Filler, G. & Grimmer, J. Remission of steroid-resistant nephrotic syndrome due to focal and segmental glomerulosclerosis using rituximab. Int. Urol. Nephrol. 40, 807-810 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  79. Kurosu, N. et al. Successful use of single-dose rituximab for the maintenance of remission in a patient with steroid-resistant nephrotic syndrome. Intern. Med. 48, 1901-1904 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  80. Peters, H. P., van de Kar, N. C. & Wetzels, J. F. Rituximab in minimal change nephropathy and focal segmental glomerulosclerosis: report of four cases and review of the literature. Neth. J. Med. 66, 408-415 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  81. Smith, G. C. Is there a role for rituximab in the treatment of idiopathic childhood nephrotic syndrome? Pediatr. Nephrol. 22, 893-898 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  82. Nakayama, M. et al. Rituximab for refractory focal segmental glomerulosclerosis. Pediatr. Nephrol. 23, 481-485 , .
    • . . . Rituximab is a chimeric monoclonal antibody that depletes CD20+ B cells and was originally developed to treat B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.69 In the past several years, rituximab has also been used to treat rheumatoid arthritis, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011), post-transplant lymphoproliferative disorder, lupus nephritis, membranous nephropathy,69, 70, 71 recurrence of nephrotic syndrome in patients with FSGS following transplantation,72 as well as nephrotic syndrome.73, 74, 75 Although reports of the use of rituximab to treat nephrotic syndrome have increased in the past 5 years, most have been anecdotal and in children.74, 75, 76, 77, 78, 79, 80, 81, 82, 83 . . .
  83. Sharma, A. P. & Filler, G. Role of mycophenolate mofetil in remission maintenance after a successful response to rituximab. Pediatr. Nephrol. 24, 423-424 , .
  84. Ravani, P. et al. Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Clin. J. Am. Soc. Nephrol. 6, 1308-1315 , .
    • . . . A randomized study in 54 children with SDNS reported that adding rituximab to glucocorticoids and calcineurin inhibitors enabled reduction in the doses of both medications, while yielding similar or better short-term (3-month) outcomes than standard dosing without rituximab.84 In a retrospective comparison of 23 children with SDNS, rituximab and tacrolimus were similarly effective in reducing relapse rates and glucocorticoid exposure.85 In another retrospective study of 30 children with SDNS treated with repeated doses of rituximab to maintain depressed CD19 levels for at least 15 months, long-term remission (~17 months) following complete CD19 recovery was noted in 19 (63%) of patients.86 In addition, a retrospective review of long-term outcomes for 37 children with SDNS found that 375 mg/m2 given weekly for 1–4 courses resulted in a sustained remission in 26 children (70%) for 12 months and, among 29 children followed for more than 2 years, 12 (41%) remained in remission.87 A randomized, double-blind, placebo-controlled, multicenter trial comparing rituximab with placebo infusions in children with SDNS is currently underway in Japan.88 . . .
    • . . . The most common dose used has been 375 mg/m2 weekly, and most treatments have been within the range of 1–4 weeks.74, 75, 77, 84 In addition, most children have complete B-cell depletion after only one dose.90 Moreover, in the largest retrospective study to date (70 children: 28 with SDNS and/or FRNS, 27 with SRNS and 15 with post-transplantation nephrotic syndrome), the total rituximab dose did not seem to correlate with the initial clinical response to therapy (Figure 1).74 Such findings, although far from conclusive, suggest that two doses of rituximab (with the second dose 1–2 weeks after the first), or perhaps even a single dose, is adequate to obtain the desired clinical benefits from this drug in children with nephrotic syndrome. . . .
  85. Sinha, A., Bagga, A., Gulati, A. & Hari, P. Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephrotic syndrome. Pediatr. Nephrol. 27, 235-241 , .
    • . . . A randomized study in 54 children with SDNS reported that adding rituximab to glucocorticoids and calcineurin inhibitors enabled reduction in the doses of both medications, while yielding similar or better short-term (3-month) outcomes than standard dosing without rituximab.84 In a retrospective comparison of 23 children with SDNS, rituximab and tacrolimus were similarly effective in reducing relapse rates and glucocorticoid exposure.85 In another retrospective study of 30 children with SDNS treated with repeated doses of rituximab to maintain depressed CD19 levels for at least 15 months, long-term remission (~17 months) following complete CD19 recovery was noted in 19 (63%) of patients.86 In addition, a retrospective review of long-term outcomes for 37 children with SDNS found that 375 mg/m2 given weekly for 1–4 courses resulted in a sustained remission in 26 children (70%) for 12 months and, among 29 children followed for more than 2 years, 12 (41%) remained in remission.87 A randomized, double-blind, placebo-controlled, multicenter trial comparing rituximab with placebo infusions in children with SDNS is currently underway in Japan.88 . . .
  86. Sellier-Leclerc, A. L. et al. Rituximab in steroid-dependent idiopathic nephrotic syndrome in childhood-follow-up after CD19 recovery. Nephrol. Dial. Transplant. 27, 1083-1089 , .
    • . . . A randomized study in 54 children with SDNS reported that adding rituximab to glucocorticoids and calcineurin inhibitors enabled reduction in the doses of both medications, while yielding similar or better short-term (3-month) outcomes than standard dosing without rituximab.84 In a retrospective comparison of 23 children with SDNS, rituximab and tacrolimus were similarly effective in reducing relapse rates and glucocorticoid exposure.85 In another retrospective study of 30 children with SDNS treated with repeated doses of rituximab to maintain depressed CD19 levels for at least 15 months, long-term remission (~17 months) following complete CD19 recovery was noted in 19 (63%) of patients.86 In addition, a retrospective review of long-term outcomes for 37 children with SDNS found that 375 mg/m2 given weekly for 1–4 courses resulted in a sustained remission in 26 children (70%) for 12 months and, among 29 children followed for more than 2 years, 12 (41%) remained in remission.87 A randomized, double-blind, placebo-controlled, multicenter trial comparing rituximab with placebo infusions in children with SDNS is currently underway in Japan.88 . . .
  87. Kemper, M. J. et al. Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol. Dial. Transplant. Link , .
    • . . . A randomized study in 54 children with SDNS reported that adding rituximab to glucocorticoids and calcineurin inhibitors enabled reduction in the doses of both medications, while yielding similar or better short-term (3-month) outcomes than standard dosing without rituximab.84 In a retrospective comparison of 23 children with SDNS, rituximab and tacrolimus were similarly effective in reducing relapse rates and glucocorticoid exposure.85 In another retrospective study of 30 children with SDNS treated with repeated doses of rituximab to maintain depressed CD19 levels for at least 15 months, long-term remission (~17 months) following complete CD19 recovery was noted in 19 (63%) of patients.86 In addition, a retrospective review of long-term outcomes for 37 children with SDNS found that 375 mg/m2 given weekly for 1–4 courses resulted in a sustained remission in 26 children (70%) for 12 months and, among 29 children followed for more than 2 years, 12 (41%) remained in remission.87 A randomized, double-blind, placebo-controlled, multicenter trial comparing rituximab with placebo infusions in children with SDNS is currently underway in Japan.88 . . .
  88. Iijima, K. Rituximab for childhood refractory nephrotic syndrome. Pediatr. Int. 53, 617-621 , .
  89. Magnasco, A. Rituximab in children with resistant idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. Link , .
    • . . . This favorable response to rituximab contrasts with the results of a randomized trial in which 31 children who were resistant to corticosteroids and calcineurin inhibitors were continued on a calcineurin inhibitor and low-dose corticosteroids.89 Half of these children also received two doses of rituximab . . .
  90. Sellier-Leclerc, A.-L. et al. Rituximab efficiency in children with steroid-dependent nephrotic syndrome. Pediatr. Nephrol. 25, 1109-1115 , .
    • . . . The most common dose used has been 375 mg/m2 weekly, and most treatments have been within the range of 1–4 weeks.74, 75, 77, 84 In addition, most children have complete B-cell depletion after only one dose.90 Moreover, in the largest retrospective study to date (70 children: 28 with SDNS and/or FRNS, 27 with SRNS and 15 with post-transplantation nephrotic syndrome), the total rituximab dose did not seem to correlate with the initial clinical response to therapy (Figure 1).74 Such findings, although far from conclusive, suggest that two doses of rituximab (with the second dose 1–2 weeks after the first), or perhaps even a single dose, is adequate to obtain the desired clinical benefits from this drug in children with nephrotic syndrome. . . .
    • . . . After successful induction of remission, nephrotic syndrome often recurs, but the time to relapse in SRNS has been highly variable, typically after 5–9 months (Table 2).74, 75 Relapses have often, but not always, been associated with repopulation of CD20+ B cells.90, 91, 92 Some children, however, remain in remission despite B-cell recovery, whereas others respond to rituximab despite an absence of B-cell depletion.74, 75 As a result, repeat dosing strategies have varied between those based on improvement or full recovery of CD20+ B-cell numbers and those based strictly on clinical relapse of nephrotic syndrome, regardless of B-cell numbers. . . .
  91. Kamei, K. et al. Single dose of rituximab for refractory steroid-dependent nephrotic syndrome in children. Pediatr. Nephrol. 24, 1321-1328 , .
    • . . . After successful induction of remission, nephrotic syndrome often recurs, but the time to relapse in SRNS has been highly variable, typically after 5–9 months (Table 2).74, 75 Relapses have often, but not always, been associated with repopulation of CD20+ B cells.90, 91, 92 Some children, however, remain in remission despite B-cell recovery, whereas others respond to rituximab despite an absence of B-cell depletion.74, 75 As a result, repeat dosing strategies have varied between those based on improvement or full recovery of CD20+ B-cell numbers and those based strictly on clinical relapse of nephrotic syndrome, regardless of B-cell numbers. . . .
  92. Ardelean, D. S. et al. Severe ulcerative colitis after rituximab therapy. Pediatrics 126, e243-e246 , .
  93. Chan, A. C. Rituximab's new therapeutic target: the podocyte actin cytoskeleton. Sci. Transl. Med. 3, 85ps21 , .
  94. Savin, V. J., McCarthy, E. T., Sharma, R., Charba, D. & Sharma, M. Galactose binds to focal segmental glomerulosclerosis permeability factor and inhibits its activity. Transl. Res. 151, 288-292 , .
    • . . . Galactose has been proposed as a novel treatment for nephrotic syndrome based on a study that demonstrated that galactose binds the FSGS permeability factor with high affinity and is able to alter glomerular permeability in vitro, as well as decrease this permeability activity after intravenous administration to patients.94 Subsequently, a case report in a single adult with nephrotic syndrome who was resistant to multiple immunosuppressants and plasmapheresis demonstrated that administration of oral galactose induced remission of nephrotic syndrome, in correlation with a reduction in permeability activity (Figure 2).95 In 2011, two children with SRNS who were also resistant to tacrolimus were reported to have partial remissions following treatment with oral galactose.96 Based in part on these findings, galactose has now been added to the Novel Therapies in Resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial for steroid-resistant FSGS,97 and is also being evaluated in a prospective clinical trial in children with SRNS.98 . . .
  95. De Smet, E., Rioux, J. P., Ammann, H., Deziel, C. & Querin, S. FSGS permeability factor-associated nephrotic syndrome: remission after oral galactose therapy. Nephrol. Dial. Transplant. 24, 2938-2940 , .
    • . . . Galactose has been proposed as a novel treatment for nephrotic syndrome based on a study that demonstrated that galactose binds the FSGS permeability factor with high affinity and is able to alter glomerular permeability in vitro, as well as decrease this permeability activity after intravenous administration to patients.94 Subsequently, a case report in a single adult with nephrotic syndrome who was resistant to multiple immunosuppressants and plasmapheresis demonstrated that administration of oral galactose induced remission of nephrotic syndrome, in correlation with a reduction in permeability activity (Figure 2).95 In 2011, two children with SRNS who were also resistant to tacrolimus were reported to have partial remissions following treatment with oral galactose.96 Based in part on these findings, galactose has now been added to the Novel Therapies in Resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial for steroid-resistant FSGS,97 and is also being evaluated in a prospective clinical trial in children with SRNS.98 . . .
  96. Kopac, M., Meglic, A. & Rus, R. R. Partial remission of resistant nephrotic syndrome after oral galactose therapy. Ther. Apher. Dial. 15, 269-272 , .
    • . . . Galactose has been proposed as a novel treatment for nephrotic syndrome based on a study that demonstrated that galactose binds the FSGS permeability factor with high affinity and is able to alter glomerular permeability in vitro, as well as decrease this permeability activity after intravenous administration to patients.94 Subsequently, a case report in a single adult with nephrotic syndrome who was resistant to multiple immunosuppressants and plasmapheresis demonstrated that administration of oral galactose induced remission of nephrotic syndrome, in correlation with a reduction in permeability activity (Figure 2).95 In 2011, two children with SRNS who were also resistant to tacrolimus were reported to have partial remissions following treatment with oral galactose.96 Based in part on these findings, galactose has now been added to the Novel Therapies in Resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial for steroid-resistant FSGS,97 and is also being evaluated in a prospective clinical trial in children with SRNS.98 . . .
  97. Novel therapies in resistant focal segmental glomerulosclerosis: www.fonttrial.org , .
    • . . . Galactose has been proposed as a novel treatment for nephrotic syndrome based on a study that demonstrated that galactose binds the FSGS permeability factor with high affinity and is able to alter glomerular permeability in vitro, as well as decrease this permeability activity after intravenous administration to patients.94 Subsequently, a case report in a single adult with nephrotic syndrome who was resistant to multiple immunosuppressants and plasmapheresis demonstrated that administration of oral galactose induced remission of nephrotic syndrome, in correlation with a reduction in permeability activity (Figure 2).95 In 2011, two children with SRNS who were also resistant to tacrolimus were reported to have partial remissions following treatment with oral galactose.96 Based in part on these findings, galactose has now been added to the Novel Therapies in Resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial for steroid-resistant FSGS,97 and is also being evaluated in a prospective clinical trial in children with SRNS.98 . . .
    • . . . The use of this agent in nephrotic syndrome stems from the reported roles of TNF in nephrotic syndrome and fibrosis.99, 100 To date, no reports have documented the use of adalimumab in nephrotic syndrome, although its efficacy when compared with galactose in the treatment of children with steroid-resistant FSGS is currently being tested as part of the FONT2 clinical trial noted above.97 Anecdotal reports, however, have shown associations between adalimumab use and both remission and induction of nephrotic syndrome.101, 102 Dosing strategies for the use of adalimumab in nephrotic syndrome were developed from phase I pharmacokinetic studies performed during the FONT1 clinical trial, and no serious adverse events were noted in the 10 patients studied.97, 103 Thus, although the potential for adalimumab in the treatment of nephrotic syndrome is still unknown, both its efficacy and toxicity in steroid-resistant FSGS are currently being evaluated, and should be available in the near future. . . .
  98. US National Library of Medicine. ClinicalTrials.gov [online], , .
  99. Suranyi, M. G., Guasch, A., Hall, B. M. & Myers, B. D. Elevated levels of tumor necrosis factor-alpha in the nephrotic syndrome in humans. Am. J. Kidney Dis. 21, 251-259 , .
    • . . . The use of this agent in nephrotic syndrome stems from the reported roles of TNF in nephrotic syndrome and fibrosis.99, 100 To date, no reports have documented the use of adalimumab in nephrotic syndrome, although its efficacy when compared with galactose in the treatment of children with steroid-resistant FSGS is currently being tested as part of the FONT2 clinical trial noted above.97 Anecdotal reports, however, have shown associations between adalimumab use and both remission and induction of nephrotic syndrome.101, 102 Dosing strategies for the use of adalimumab in nephrotic syndrome were developed from phase I pharmacokinetic studies performed during the FONT1 clinical trial, and no serious adverse events were noted in the 10 patients studied.97, 103 Thus, although the potential for adalimumab in the treatment of nephrotic syndrome is still unknown, both its efficacy and toxicity in steroid-resistant FSGS are currently being evaluated, and should be available in the near future. . . .
  100. Bustos, C., Gonzalez, E., Muley, R., Alonso, J. L. & Egido, J. Increase of tumour necrosis factor alpha synthesis and gene expression in peripheral blood mononuclear cells of children with idiopathic nephrotic syndrome. Eur. J. Clin. Invest. 24, 799-805 , .
    • . . . The use of this agent in nephrotic syndrome stems from the reported roles of TNF in nephrotic syndrome and fibrosis.99, 100 To date, no reports have documented the use of adalimumab in nephrotic syndrome, although its efficacy when compared with galactose in the treatment of children with steroid-resistant FSGS is currently being tested as part of the FONT2 clinical trial noted above.97 Anecdotal reports, however, have shown associations between adalimumab use and both remission and induction of nephrotic syndrome.101, 102 Dosing strategies for the use of adalimumab in nephrotic syndrome were developed from phase I pharmacokinetic studies performed during the FONT1 clinical trial, and no serious adverse events were noted in the 10 patients studied.97, 103 Thus, although the potential for adalimumab in the treatment of nephrotic syndrome is still unknown, both its efficacy and toxicity in steroid-resistant FSGS are currently being evaluated, and should be available in the near future. . . .
  101. Gupta, A., Pendyala, P., Arora, P. & Sitrin, M. D. Development of the nephrotic syndrome during treatment of Crohn's disease with adalimumab. J. Clin. Gastroenterol. 45, e30-e33 , .
    • . . . The use of this agent in nephrotic syndrome stems from the reported roles of TNF in nephrotic syndrome and fibrosis.99, 100 To date, no reports have documented the use of adalimumab in nephrotic syndrome, although its efficacy when compared with galactose in the treatment of children with steroid-resistant FSGS is currently being tested as part of the FONT2 clinical trial noted above.97 Anecdotal reports, however, have shown associations between adalimumab use and both remission and induction of nephrotic syndrome.101, 102 Dosing strategies for the use of adalimumab in nephrotic syndrome were developed from phase I pharmacokinetic studies performed during the FONT1 clinical trial, and no serious adverse events were noted in the 10 patients studied.97, 103 Thus, although the potential for adalimumab in the treatment of nephrotic syndrome is still unknown, both its efficacy and toxicity in steroid-resistant FSGS are currently being evaluated, and should be available in the near future. . . .
  102. Nowak, B., Jeka, S., Wiland, P. & Szechinski, J. Rapid and complete resolution of ascites and hydrothorax due to nephrotic syndrome caused by renal amyloidosis in a patient with juvenile chronic arthritis treated with adalimumab. Joint Bone Spine 76, 217-219 , .
    • . . . The use of this agent in nephrotic syndrome stems from the reported roles of TNF in nephrotic syndrome and fibrosis.99, 100 To date, no reports have documented the use of adalimumab in nephrotic syndrome, although its efficacy when compared with galactose in the treatment of children with steroid-resistant FSGS is currently being tested as part of the FONT2 clinical trial noted above.97 Anecdotal reports, however, have shown associations between adalimumab use and both remission and induction of nephrotic syndrome.101, 102 Dosing strategies for the use of adalimumab in nephrotic syndrome were developed from phase I pharmacokinetic studies performed during the FONT1 clinical trial, and no serious adverse events were noted in the 10 patients studied.97, 103 Thus, although the potential for adalimumab in the treatment of nephrotic syndrome is still unknown, both its efficacy and toxicity in steroid-resistant FSGS are currently being evaluated, and should be available in the near future. . . .
  103. Joy, M. S. et al. Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group. Am. J. Kidney Dis. 55, 50-60 , .
    • . . . The use of this agent in nephrotic syndrome stems from the reported roles of TNF in nephrotic syndrome and fibrosis.99, 100 To date, no reports have documented the use of adalimumab in nephrotic syndrome, although its efficacy when compared with galactose in the treatment of children with steroid-resistant FSGS is currently being tested as part of the FONT2 clinical trial noted above.97 Anecdotal reports, however, have shown associations between adalimumab use and both remission and induction of nephrotic syndrome.101, 102 Dosing strategies for the use of adalimumab in nephrotic syndrome were developed from phase I pharmacokinetic studies performed during the FONT1 clinical trial, and no serious adverse events were noted in the 10 patients studied.97, 103 Thus, although the potential for adalimumab in the treatment of nephrotic syndrome is still unknown, both its efficacy and toxicity in steroid-resistant FSGS are currently being evaluated, and should be available in the near future. . . .
  104. Michalik, L. et al. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 58, 726-741 , .
    • . . . Thiazolidinediones are ligands of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ), which is known to modulate many metabolic and nonmetabolic processes, including adipogenesis, glucose homeostasis, inflammatory responses and apoptosis.104 In the past few years, the beneficial effects of thiazolidinediones on the kidneys have also been reported . . .
  105. Ma, L. J., Marcantoni, C., Linton, M. F., Fazio, S. & Fogo, A. B. Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats. Kidney Int. 59, 1899-1910 , .
    • . . . In addition to improvement of chronic kidney disease resulting from metabolic syndrome, thiazolidinediones reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in mouse and rat models, as well as in humans.105, 106, 107, 108, 109 The thiazolidinedione pioglitazone protected against progression of puromycin aminonucleoside (PAN)-induced glomerulosclerosis in vivo and against injury of cultured podocytes in vitro.106, 110 In addition, the thiazolidinedione rosiglitazone attenuated proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats.111 A meta-analysis in 2010 concluded that thiazolidinediones markedly decreased albuminuria and proteinuria in patients with diabetes mellitus, potentially through direct renal protective effects.108 . . .
  106. Yang, H. C., Ma, L. J., Ma, J. & Fogo, A. B. Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis. Kidney Int. 69, 1756-1764 , .
    • . . . In addition to improvement of chronic kidney disease resulting from metabolic syndrome, thiazolidinediones reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in mouse and rat models, as well as in humans.105, 106, 107, 108, 109 The thiazolidinedione pioglitazone protected against progression of puromycin aminonucleoside (PAN)-induced glomerulosclerosis in vivo and against injury of cultured podocytes in vitro.106, 110 In addition, the thiazolidinedione rosiglitazone attenuated proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats.111 A meta-analysis in 2010 concluded that thiazolidinediones markedly decreased albuminuria and proteinuria in patients with diabetes mellitus, potentially through direct renal protective effects.108 . . .
  107. Cha, D. R. et al. Peroxisome proliferator activated receptor alpha/gamma dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice. Diabetes 56, 2036-2045 , .
    • . . . In addition to improvement of chronic kidney disease resulting from metabolic syndrome, thiazolidinediones reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in mouse and rat models, as well as in humans.105, 106, 107, 108, 109 The thiazolidinedione pioglitazone protected against progression of puromycin aminonucleoside (PAN)-induced glomerulosclerosis in vivo and against injury of cultured podocytes in vitro.106, 110 In addition, the thiazolidinedione rosiglitazone attenuated proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats.111 A meta-analysis in 2010 concluded that thiazolidinediones markedly decreased albuminuria and proteinuria in patients with diabetes mellitus, potentially through direct renal protective effects.108 . . .
  108. Sarafidis, P. A., Stafylas, P. C., Georgianos, P. I., Saratzis, A. N. & Lasaridis, A. N. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am. J. Kidney Dis. 55, 835-847 , .
  109. Mao, Z. & Ong, A. C. Peroxisome proliferator-activated receptor gamma agonists in kidney disease--future promise, present fears. Nephron Clin. Pract. 112, c230-c241 , .
    • . . . In addition to improvement of chronic kidney disease resulting from metabolic syndrome, thiazolidinediones reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in mouse and rat models, as well as in humans.105, 106, 107, 108, 109 The thiazolidinedione pioglitazone protected against progression of puromycin aminonucleoside (PAN)-induced glomerulosclerosis in vivo and against injury of cultured podocytes in vitro.106, 110 In addition, the thiazolidinedione rosiglitazone attenuated proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats.111 A meta-analysis in 2010 concluded that thiazolidinediones markedly decreased albuminuria and proteinuria in patients with diabetes mellitus, potentially through direct renal protective effects.108 . . .
    • . . . Among the known molecular effects of the thiazolidinediones is the capacity of these agents to decrease the glomerular production of transforming growth factor (TGF)-β,113 a key mediator of renal injury.109 Of potential relevance to nephrotic syndrome, cultured podocytes treated with thiazolidinediones mimicked some podocyte responses to glucocorticoids, or had additive effects with them.112 This partial overlap of the molecular actions of thiazolidinediones and glucocorticoids on podocytes might account for some of the beneficial effects of thiazolidinediones in nephrotic syndrome . . .
  110. Kanjanabuch, T. et al. PPAR-gamma agonist protects podocytes from injury. Kidney Int. 71, 1232-1239 , .
    • . . . In addition to improvement of chronic kidney disease resulting from metabolic syndrome, thiazolidinediones reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in mouse and rat models, as well as in humans.105, 106, 107, 108, 109 The thiazolidinedione pioglitazone protected against progression of puromycin aminonucleoside (PAN)-induced glomerulosclerosis in vivo and against injury of cultured podocytes in vitro.106, 110 In addition, the thiazolidinedione rosiglitazone attenuated proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats.111 A meta-analysis in 2010 concluded that thiazolidinediones markedly decreased albuminuria and proteinuria in patients with diabetes mellitus, potentially through direct renal protective effects.108 . . .
    • . . . The renoprotective effects of thiazolidinediones result, at least in part, from their direct action on podocytes, seen in both cultured podocytes and in PAN-induced nephrotic syndrome in rats.110, 112 Thiazolidinediones induced complex responses in podocytes that may involve the canonical pathway (that is, PPARγ binding to responsive DNA elements), 'off-target' pathways such as activation of the glucocorticoid receptor, and nongenomic mechanisms independent of DNA binding, such as modulation of mitogen-activated protein kinase (MAPK) activity (Figure 3) . . .
  111. Liu, H. F. et al. Thiazolidinedione attenuate proteinuria and glomerulosclerosis in Adriamycin-induced nephropathy rats via slit diaphragm protection. Nephrology (Carlton) 15, 75-83 , .
    • . . . In addition to improvement of chronic kidney disease resulting from metabolic syndrome, thiazolidinediones reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in mouse and rat models, as well as in humans.105, 106, 107, 108, 109 The thiazolidinedione pioglitazone protected against progression of puromycin aminonucleoside (PAN)-induced glomerulosclerosis in vivo and against injury of cultured podocytes in vitro.106, 110 In addition, the thiazolidinedione rosiglitazone attenuated proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats.111 A meta-analysis in 2010 concluded that thiazolidinediones markedly decreased albuminuria and proteinuria in patients with diabetes mellitus, potentially through direct renal protective effects.108 . . .
  112. Agrawal, S., Guess, A. J., Benndorf, R. & Smoyer, W. E. Comparison of direct action of thiazolidinediones and glucocorticoids on renal podocytes: protection from injury and molecular effects. Mol. Pharmacol. 80, 389-399 , .
    • . . . The renoprotective effects of thiazolidinediones result, at least in part, from their direct action on podocytes, seen in both cultured podocytes and in PAN-induced nephrotic syndrome in rats.110, 112 Thiazolidinediones induced complex responses in podocytes that may involve the canonical pathway (that is, PPARγ binding to responsive DNA elements), 'off-target' pathways such as activation of the glucocorticoid receptor, and nongenomic mechanisms independent of DNA binding, such as modulation of mitogen-activated protein kinase (MAPK) activity (Figure 3) . . .
    • . . . Among the known molecular effects of the thiazolidinediones is the capacity of these agents to decrease the glomerular production of transforming growth factor (TGF)-β,113 a key mediator of renal injury.109 Of potential relevance to nephrotic syndrome, cultured podocytes treated with thiazolidinediones mimicked some podocyte responses to glucocorticoids, or had additive effects with them.112 This partial overlap of the molecular actions of thiazolidinediones and glucocorticoids on podocytes might account for some of the beneficial effects of thiazolidinediones in nephrotic syndrome . . .
  113. Kawai, T. et al. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-β. Lab. Invest. 89, 47-58 , .
    • . . . Among the known molecular effects of the thiazolidinediones is the capacity of these agents to decrease the glomerular production of transforming growth factor (TGF)-β,113 a key mediator of renal injury.109 Of potential relevance to nephrotic syndrome, cultured podocytes treated with thiazolidinediones mimicked some podocyte responses to glucocorticoids, or had additive effects with them.112 This partial overlap of the molecular actions of thiazolidinediones and glucocorticoids on podocytes might account for some of the beneficial effects of thiazolidinediones in nephrotic syndrome . . .
  114. Coulthard, L. R., White, D. E., Jones, D. L., McDermott, M. F. & Burchill, S. A. p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol. Med. 15, 369-379 , .
    • . . . The p38 MAPK pathway has crucial roles in inflammation, differentiation, senescence, tumorigenesis, and apoptosis, as well as in a variety of renal diseases.114, 115 p38 MAPK signaling is largely transmitted through phosphorylation and activation of MAPK-activated protein kinase 2 (MAPKAPK2, also known as MK2), a direct downstream substrate of p38 MAPK.116 . . .
  115. Grande, M. T. & Lopez-Novoa, J. M. Therapeutical relevance of MAP-kinase inhibitors in renal diseases: current knowledge and future clinical perspectives. Curr. Med. Chem. 15, 2054-2070 , .
    • . . . The p38 MAPK pathway has crucial roles in inflammation, differentiation, senescence, tumorigenesis, and apoptosis, as well as in a variety of renal diseases.114, 115 p38 MAPK signaling is largely transmitted through phosphorylation and activation of MAPK-activated protein kinase 2 (MAPKAPK2, also known as MK2), a direct downstream substrate of p38 MAPK.116 . . .
  116. Gaestel, M. Specificity of signaling from MAPKs to MAPKAPKs: kinases' tango nuevo. Front. Biosci. 13, 6050-6059 , .
  117. Stambe, C., Atkins, R. C., Hill, P. A. & Nikolic-Paterson, D. J. Activation and cellular localization of the p38 and JNK MAPK pathways in rat crescentic glomerulonephritis. Kidney Int. 64, 2121-2132 , .
    • . . . In rodent models of crescentic glomerulonephritis, activation of p38 MAPK was found in podocytes and other glomerular cells after disease induction, and inhibition of this signaling pathway was effective in reducing the severity of glomerular injury.117, 118, 119 In histological studies from adults with a variety of glomerular diseases, increased expression or activation of p38 MAPK isoforms in renal cells was reported and correlated with kidney dysfunction and histopathology, suggesting that p38 MAPK activation has an important role in human glomerulonephritis.120, 121 Similarly, increased p38 MAPK activation was observed in podocytes in biopsy samples from adults with various forms of nephrotic syndrome.119 . . .
  118. Sheryanna, A. et al. Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1β or IL-6. J. Am. Soc. Nephrol. 18, 1167-1179 , .
    • . . . In rodent models of crescentic glomerulonephritis, activation of p38 MAPK was found in podocytes and other glomerular cells after disease induction, and inhibition of this signaling pathway was effective in reducing the severity of glomerular injury.117, 118, 119 In histological studies from adults with a variety of glomerular diseases, increased expression or activation of p38 MAPK isoforms in renal cells was reported and correlated with kidney dysfunction and histopathology, suggesting that p38 MAPK activation has an important role in human glomerulonephritis.120, 121 Similarly, increased p38 MAPK activation was observed in podocytes in biopsy samples from adults with various forms of nephrotic syndrome.119 . . .
  119. Koshikawa, M. et al. Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome. J. Am. Soc. Nephrol. 16, 2690-2701 , .
  120. Stambe, C., Nikolic-Paterson, D. J., Hill, P. A., Dowling, J. & Atkins, R. C. p38 Mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: correlation with renal injury. J. Am. Soc. Nephrol. 15, 326-336 , .
    • . . . In rodent models of crescentic glomerulonephritis, activation of p38 MAPK was found in podocytes and other glomerular cells after disease induction, and inhibition of this signaling pathway was effective in reducing the severity of glomerular injury.117, 118, 119 In histological studies from adults with a variety of glomerular diseases, increased expression or activation of p38 MAPK isoforms in renal cells was reported and correlated with kidney dysfunction and histopathology, suggesting that p38 MAPK activation has an important role in human glomerulonephritis.120, 121 Similarly, increased p38 MAPK activation was observed in podocytes in biopsy samples from adults with various forms of nephrotic syndrome.119 . . .
  121. Polzer, K. et al. Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPKα. Ann. Rheum. Dis. 67, 602-608 , .
    • . . . In rodent models of crescentic glomerulonephritis, activation of p38 MAPK was found in podocytes and other glomerular cells after disease induction, and inhibition of this signaling pathway was effective in reducing the severity of glomerular injury.117, 118, 119 In histological studies from adults with a variety of glomerular diseases, increased expression or activation of p38 MAPK isoforms in renal cells was reported and correlated with kidney dysfunction and histopathology, suggesting that p38 MAPK activation has an important role in human glomerulonephritis.120, 121 Similarly, increased p38 MAPK activation was observed in podocytes in biopsy samples from adults with various forms of nephrotic syndrome.119 . . .
  122. Pengal, R. et al. Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury. Am. J. Physiol. Renal Physiol. 301, F509-F519 , .
    • . . . A study using cultured podocytes demonstrated that both p38 MAPK and MK2 are involved in cell injury, and that inhibition of either protein kinase protects podocytes from PAN-induced injury.122 Exposure of podocytes in vivo or in vitro to physiologically relevant concentrations of serum albumin also induced injury, and this response involved p38 MAPK and TGF-β.122, 123 . . .
    • . . . Indeed, research is already underway to develop inhibitors (including antisense oligonucleotides) with specificity towards these target protein kinases.122, 130, 131, 132, 133 Inhibitors of p38 MAPK and PKC are at the most advanced developmental stage and have been tested in clinical trials, albeit in the treatment of patients with conditions other than nephrotic syndrome.134, 135 . . .
  123. Yoshida, S., Nagase, M., Shibata, S. & Fujita, T. Podocyte injury induced by albumin overload in vivo and in vitro: involvement of TGF-β and p38 MAPK. Nephron Exp. Nephrol. 108, e57-e68 , .
  124. Sekar, M. C., Yang, M., Meezan, E. & Pillion, D. J. Angiotensin II and bradykinin stimulate phosphoinositide breakdown in intact rat kidney glomeruli but not in proximal tubules: glomerular response modulated by phorbol ester. Biochem. Biophys. Res. Commun. 166, 373-379 , .
    • . . . The various forms of protein kinase C (PKC) also have a role in both glomerular and tubular function.124, 125 In podocytes, different PKC isoforms seem to serve specific functions . . .
  125. Nowicki, S., Kruse, M. S., Brismar, H. & Aperia, A. Dopamine-induced translocation of protein kinase C isoforms visualized in renal epithelial cells. Am. J. Physiol. Cell. Physiol. 279, C1812-C1818 , .
    • . . . The various forms of protein kinase C (PKC) also have a role in both glomerular and tubular function.124, 125 In podocytes, different PKC isoforms seem to serve specific functions . . .
  126. Huber, T. B. et al. Loss of podocyte aPKCλ/ι causes polarity defects and nephrotic syndrome. J. Am. Soc. Nephrol. 20, 798-806 , .
    • . . . For example, deletion of atypical PKCλ/ι caused mislocalization of the slit diaphragm, podocyte polarity defects and nephrotic syndrome in mice,126 whereas the loss of PKCα had podocyte-protective effects in mice after diabetic injury.127 Compared with a wild-type podocyte cell line, a PKCα-deficient podocyte cell line exhibited enhanced activation of the antiapoptotic PI3K/AKT, ERK1/2 and Smad pathways after stimulation with TGF-β, whereas pro-apoptotic p38 MAPK signaling was reduced.128 In this study, PKCα was found to interact with the TGF-β receptor 1, resulting in promotion of its endocytosis with subsequent consequences for receptor recycling and degradation . . .
  127. Menne, J. et al. Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-α-deficient diabetic mice. Diabetes 53, 2101-2109 , .
    • . . . For example, deletion of atypical PKCλ/ι caused mislocalization of the slit diaphragm, podocyte polarity defects and nephrotic syndrome in mice,126 whereas the loss of PKCα had podocyte-protective effects in mice after diabetic injury.127 Compared with a wild-type podocyte cell line, a PKCα-deficient podocyte cell line exhibited enhanced activation of the antiapoptotic PI3K/AKT, ERK1/2 and Smad pathways after stimulation with TGF-β, whereas pro-apoptotic p38 MAPK signaling was reduced.128 In this study, PKCα was found to interact with the TGF-β receptor 1, resulting in promotion of its endocytosis with subsequent consequences for receptor recycling and degradation . . .
  128. Tossidou, I. et al. PKC-α modulates TGF-β signaling and impairs podocyte survival. Cell. Physiol. Biochem. 24, 627-634 , .
  129. Schiffer, M. et al. Apoptosis in podocytes induced by TGF-β and Smad7. J. Clin. Invest. 108, 807-816 , .
    • . . . p38 MAPK activation in podocytes is downstream of PKCα, and both protein kinases are activated by TGF-β.129 Thus, inhibition of PKCα, p38 MAPK, or MK2 would affect the same signaling pathway, although at different levels (Figure 4), and such inhibition seems to be an exciting potential strategy to treat nephrotic syndrome in both children and adults . . .
  130. Shen, G. X. Selective protein kinase C inhibitors and their applications. Curr. Drug Targets Cardiovasc. Haematol. Disord. 3, 301-307 , .
    • . . . Indeed, research is already underway to develop inhibitors (including antisense oligonucleotides) with specificity towards these target protein kinases.122, 130, 131, 132, 133 Inhibitors of p38 MAPK and PKC are at the most advanced developmental stage and have been tested in clinical trials, albeit in the treatment of patients with conditions other than nephrotic syndrome.134, 135 . . .
  131. Gaestel, M., Mengel, A., Bothe, U. & Asadullah, K. Protein kinases as small molecule inhibitor targets in inflammation. Curr. Med. Chem. 14, 2214-2234 , .
    • . . . Indeed, research is already underway to develop inhibitors (including antisense oligonucleotides) with specificity towards these target protein kinases.122, 130, 131, 132, 133 Inhibitors of p38 MAPK and PKC are at the most advanced developmental stage and have been tested in clinical trials, albeit in the treatment of patients with conditions other than nephrotic syndrome.134, 135 . . .
  132. Baier, G. & Wagner, J. PKC inhibitors: potential in T cell-dependent immune diseases. Curr. Opin. Cell. Biol. 21, 262-267 , .
    • . . . Indeed, research is already underway to develop inhibitors (including antisense oligonucleotides) with specificity towards these target protein kinases.122, 130, 131, 132, 133 Inhibitors of p38 MAPK and PKC are at the most advanced developmental stage and have been tested in clinical trials, albeit in the treatment of patients with conditions other than nephrotic syndrome.134, 135 . . .
  133. Wagner, E. F. & Nebreda, A. R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 9, 537-549 , .
    • . . . Indeed, research is already underway to develop inhibitors (including antisense oligonucleotides) with specificity towards these target protein kinases.122, 130, 131, 132, 133 Inhibitors of p38 MAPK and PKC are at the most advanced developmental stage and have been tested in clinical trials, albeit in the treatment of patients with conditions other than nephrotic syndrome.134, 135 . . .
  134. Yong, H. Y., Koh, M. S. & Moon, A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin. Investig. Drugs 18, 1893-1905 , .
    • . . . Indeed, research is already underway to develop inhibitors (including antisense oligonucleotides) with specificity towards these target protein kinases.122, 130, 131, 132, 133 Inhibitors of p38 MAPK and PKC are at the most advanced developmental stage and have been tested in clinical trials, albeit in the treatment of patients with conditions other than nephrotic syndrome.134, 135 . . .
  135. Roffey, J. et al. Protein kinase C intervention: the state of play. Curr. Opin. Cell. Biol. 21, 268-279 , .
  136. Niranjan, T., Murea, M. & Susztak, K. The pathogenic role of Notch activation in podocytes. Nephron Exp. Nephrol. 111, e73-e79 , .
  137. Barisoni, L. Notch signaling: a common pathway of injury in podocytopathies? J. Am. Soc. Nephrol. 19, 1045-1046 , .
    • . . . In this light it was not entirely surprising when abnormally increased Notch signaling was found in the glomeruli of patients with FSGS and diabetic nephropathy, and also in rodent models of glomerular disease.137, 138, 139 Niranjan and co-workers138 also demonstrated that transgenic mice conditionally overexpressing Notch-ICD in mature podocytes developed proteinuria and glomerulosclerosis, in association with p53 activation and podocyte apoptosis . . .
  138. Niranjan, T. et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat. Med. 14, 290-298 , .
    • . . . In this light it was not entirely surprising when abnormally increased Notch signaling was found in the glomeruli of patients with FSGS and diabetic nephropathy, and also in rodent models of glomerular disease.137, 138, 139 Niranjan and co-workers138 also demonstrated that transgenic mice conditionally overexpressing Notch-ICD in mature podocytes developed proteinuria and glomerulosclerosis, in association with p53 activation and podocyte apoptosis . . .
    • . . . Conversely, genetic deletion of downstream Rbpj in the podocytes of mice with diabetes protected against glomerular proteinuria, as did pharmacologic inhibition of the upstream γ-secretase in rats with PAN-induced proteinuria.138 In a similar study, ectopic expression of Notch-ICD in embryonic podocytes in mice was associated with proteinuria and glomerulosclerosis.140 Both studies also suggested that abnormally increased Notch signaling is associated with dedifferentiation of podocytes. . . .
    • . . . Notably, abnormally increased Notch signaling was associated with both apoptosis138 and cell cycle re-entry,140 which in turn were associated with a loss of mature podocyte characteristics . . .
  139. Walsh, D. W. et al. Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. Biochim. Biophys. Acta 1782, 10-21 , .
    • . . . In this light it was not entirely surprising when abnormally increased Notch signaling was found in the glomeruli of patients with FSGS and diabetic nephropathy, and also in rodent models of glomerular disease.137, 138, 139 Niranjan and co-workers138 also demonstrated that transgenic mice conditionally overexpressing Notch-ICD in mature podocytes developed proteinuria and glomerulosclerosis, in association with p53 activation and podocyte apoptosis . . .
  140. Waters, A. M. et al. Ectopic notch activation in developing podocytes causes glomerulosclerosis. J. Am. Soc. Nephrol. 19, 1139-1157 , .
    • . . . Conversely, genetic deletion of downstream Rbpj in the podocytes of mice with diabetes protected against glomerular proteinuria, as did pharmacologic inhibition of the upstream γ-secretase in rats with PAN-induced proteinuria.138 In a similar study, ectopic expression of Notch-ICD in embryonic podocytes in mice was associated with proteinuria and glomerulosclerosis.140 Both studies also suggested that abnormally increased Notch signaling is associated with dedifferentiation of podocytes. . . .
    • . . . Notably, abnormally increased Notch signaling was associated with both apoptosis138 and cell cycle re-entry,140 which in turn were associated with a loss of mature podocyte characteristics . . .
  141. Lasagni, L. et al. Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders. Stem Cells 28, 1674-1685 , .
    • . . . The Notch-mediated inappropriate proliferation of podocytes might even result in cell death by mitotic catastrophe.141 In the same study,141 Notch signaling was also shown to promote the proliferation of podocyte progenitors (parietal cells) and differentiation towards the podocyte lineage . . .
  142. Sharma, S., Sirin, Y. & Susztak, K. The story of Notch and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 20, 56-61 , .
    • . . . Potentially 'druggable' steps for inhibition of Notch signaling include inhibition of the γ-secretase-mediated cleavage of the Notch receptor, or inhibition of ligand binding with selective antibodies.142 Of particular interest is that γ-secretase inhibitors have already been developed and used in clinical trials, albeit only so far for the treatment of cancer.143 Furthermore, in patients whom have already lost podocytes following glomerular injury, stimulation of Notch signaling in progenitor cells may be indicated as a future therapeutic approach, with the goal to support their proliferation and differentiation into mature podocytes . . .
  143. Purow, B. Notch inhibition as a promising new approach to cancer therapy. Adv. Exp. Med. Biol. 727, 305-319 , .
    • . . . Potentially 'druggable' steps for inhibition of Notch signaling include inhibition of the γ-secretase-mediated cleavage of the Notch receptor, or inhibition of ligand binding with selective antibodies.142 Of particular interest is that γ-secretase inhibitors have already been developed and used in clinical trials, albeit only so far for the treatment of cancer.143 Furthermore, in patients whom have already lost podocytes following glomerular injury, stimulation of Notch signaling in progenitor cells may be indicated as a future therapeutic approach, with the goal to support their proliferation and differentiation into mature podocytes . . .
  144. Araya, C. et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr. Nephrol. 3, 3 , .
    • . . . Numerous studies have suggested the involvement of various cytokines in the pathogenesis of nephrotic syndrome.144, 145, 146, 147, 148, 149 Although no single cytokine has been shown to have a direct causative role in nephrotic syndrome, several studies have suggested a potentially important role for IL-13 . . .
  145. Assadi, F. Neonatal nephrotic syndrome associated with placental transmission of proinflammatory cytokines. Pediatr. Nephrol. 26, 469-471 , .
    • . . . Numerous studies have suggested the involvement of various cytokines in the pathogenesis of nephrotic syndrome.144, 145, 146, 147, 148, 149 Although no single cytokine has been shown to have a direct causative role in nephrotic syndrome, several studies have suggested a potentially important role for IL-13 . . .
  146. Jiang, H. K., Luo, G. & Jiang, H. Interleukin-18 expression in peripheral blood mononuclear cells in children with steroid-resistant nephrotic syndrome [Chinese]. Zhongguo Dang Dai Er Ke Za Zhi 11, 337-340 , .
    • . . . Numerous studies have suggested the involvement of various cytokines in the pathogenesis of nephrotic syndrome.144, 145, 146, 147, 148, 149 Although no single cytokine has been shown to have a direct causative role in nephrotic syndrome, several studies have suggested a potentially important role for IL-13 . . .
  147. Kanai, T. et al. Elevated serum interleukin-7 level in idiopathic steroid-sensitive nephrotic syndrome. Pediatr. Int. 53, 906-909 , .
    • . . . Numerous studies have suggested the involvement of various cytokines in the pathogenesis of nephrotic syndrome.144, 145, 146, 147, 148, 149 Although no single cytokine has been shown to have a direct causative role in nephrotic syndrome, several studies have suggested a potentially important role for IL-13 . . .
  148. Souto, M. F. et al. Immune mediators in idiopathic nephrotic syndrome: evidence for a relation between interleukin 8 and proteinuria. Pediatr. Res. 64, 637-642 , .
    • . . . Numerous studies have suggested the involvement of various cytokines in the pathogenesis of nephrotic syndrome.144, 145, 146, 147, 148, 149 Although no single cytokine has been shown to have a direct causative role in nephrotic syndrome, several studies have suggested a potentially important role for IL-13 . . .
  149. van den Berg, J. G. & Weening, J. J. Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome. Clin. Sci. 107, 125-136 , .
    • . . . Numerous studies have suggested the involvement of various cytokines in the pathogenesis of nephrotic syndrome.144, 145, 146, 147, 148, 149 Although no single cytokine has been shown to have a direct causative role in nephrotic syndrome, several studies have suggested a potentially important role for IL-13 . . .
  150. Yap, H. K. et al. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J. Am. Soc. Nephrol. 10, 529-537 , .
    • . . . For example, IL13 expression was reported to be elevated in CD4+ and CD8+ T cells in children with SSNS during a relapse.150 Similarly, IL-13 serum levels and peripheral blood mononuclear cell IL13 mRNA levels were found to be increased in children with SRNS when compared with levels in healthy individuals, and both IL-13 gene and protein expression was reduced by methylprednisolone therapy.151 By contrast, in another study, treatment with prednisolone resulted in a further increase in IL-13 levels, but only in those children with SSNS.152 In rat studies, IL-13 protein overexpression led to renal injury that resembled minimal-change nephrotic syndrome, thus providing further support for a potentially causative role of IL-13 in nephrotic syndrome.153 In summary, growing evidence suggests that inhibition of IL-13 is a potentially effective therapy for, at least, SSNS . . .
  151. Jiang, H. K., Jiang, H., Luo, G. & Sun, G. L. Interleukin-13 expression before and after pulse treatment with methylprednisolone in children with steroid-responsive nephrotic syndrome [Chinese]. Zhongguo Dang Dai Er Ke Za Zhi 9, 533-536 , .
    • . . . For example, IL13 expression was reported to be elevated in CD4+ and CD8+ T cells in children with SSNS during a relapse.150 Similarly, IL-13 serum levels and peripheral blood mononuclear cell IL13 mRNA levels were found to be increased in children with SRNS when compared with levels in healthy individuals, and both IL-13 gene and protein expression was reduced by methylprednisolone therapy.151 By contrast, in another study, treatment with prednisolone resulted in a further increase in IL-13 levels, but only in those children with SSNS.152 In rat studies, IL-13 protein overexpression led to renal injury that resembled minimal-change nephrotic syndrome, thus providing further support for a potentially causative role of IL-13 in nephrotic syndrome.153 In summary, growing evidence suggests that inhibition of IL-13 is a potentially effective therapy for, at least, SSNS . . .
  152. Tain, Y. L., Chen, T. Y. & Yang, K. D. Implications of serum TNF-β and IL-13 in the treatment response of childhood nephrotic syndrome. Cytokine 21, 155-159 , .
    • . . . For example, IL13 expression was reported to be elevated in CD4+ and CD8+ T cells in children with SSNS during a relapse.150 Similarly, IL-13 serum levels and peripheral blood mononuclear cell IL13 mRNA levels were found to be increased in children with SRNS when compared with levels in healthy individuals, and both IL-13 gene and protein expression was reduced by methylprednisolone therapy.151 By contrast, in another study, treatment with prednisolone resulted in a further increase in IL-13 levels, but only in those children with SSNS.152 In rat studies, IL-13 protein overexpression led to renal injury that resembled minimal-change nephrotic syndrome, thus providing further support for a potentially causative role of IL-13 in nephrotic syndrome.153 In summary, growing evidence suggests that inhibition of IL-13 is a potentially effective therapy for, at least, SSNS . . .
  153. Lai, K. W. et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J. Am. Soc. Nephrol. 18, 1476-1485 , .
    • . . . For example, IL13 expression was reported to be elevated in CD4+ and CD8+ T cells in children with SSNS during a relapse.150 Similarly, IL-13 serum levels and peripheral blood mononuclear cell IL13 mRNA levels were found to be increased in children with SRNS when compared with levels in healthy individuals, and both IL-13 gene and protein expression was reduced by methylprednisolone therapy.151 By contrast, in another study, treatment with prednisolone resulted in a further increase in IL-13 levels, but only in those children with SSNS.152 In rat studies, IL-13 protein overexpression led to renal injury that resembled minimal-change nephrotic syndrome, thus providing further support for a potentially causative role of IL-13 in nephrotic syndrome.153 In summary, growing evidence suggests that inhibition of IL-13 is a potentially effective therapy for, at least, SSNS . . .
  154. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088-1098 , .
    • . . . Fortunately, an IL-13 antibody (lebrikizumab) has already been developed and demonstrated to be effective for the treatment of asthma.154 Thus, treatment of nephrotic syndrome using lebrikizumab or alternative IL-13 inhibitors represents yet another possible future therapeutic approach for nephrotic syndrome. . . .
  155. Chakrabarti, A., Chen, A. W. & Varner, J. D. A review of the mammalian unfolded protein response. Biotechnol. Bioeng. 108, 2777-2793 , .
    • . . . Stress-induced disturbance of protein folding in the endoplasmic reticulum, called the unfolded protein response (UPR), is recognized as the underlying pathologic mechanism of a growing number of acquired and inherited diseases, including neurologic and muscular degeneration, cardiac diseases, cancer, immune and inflammatory disorders, and diabetes.155 The UPR is a complex signaling program of stress adaption by maintaining protein folding homeostasis . . .
  156. Markan, S. et al. Up regulation of the GRP-78 and GADD-153 and down regulation of Bcl-2 proteins in primary glomerular diseases: a possible involvement of the ER stress pathway in glomerulonephritis. Mol. Cell. Biochem. 324, 131-138 , .
    • . . . In kidney biopsy samples from adults with nephrotic syndrome associated with FSGS, crescentic glomerulonephritis, membranous glomerulonephritis, and membranoproliferative glomerulonephritis, indicators of the UPR, such as heat shock 70 kDa protein 5 (HSPA5, also known as GRP78) and DNA-damage-inducible transcript 3 (DDIT3, also known as GADD-153), were found to be upregulated when compared with patients with MCD, whereas the apoptosis regulator Bcl-2 was downregulated.156 Moreover, in glomeruli from rats with PAN-induced nephrotic syndrome, the expression of HSPA5 was upregulated, together with increased phosphorylation of eukaryotic translation initiation factor 2 subunit 1 (eIF2α; another indicator of the UPR), suggesting involvement of this response in renal injury.157 Notably, the UPR was regulated by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and proteinuria in this model was prevented by inhibition of mTORC1 with everolimus—a derivative of the currently clinically available mTOR inhibitor, sirolimus . . .
  157. Ito, N. et al. mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome. Lab. Invest. 91, 1584-1595 , .
    • . . . In kidney biopsy samples from adults with nephrotic syndrome associated with FSGS, crescentic glomerulonephritis, membranous glomerulonephritis, and membranoproliferative glomerulonephritis, indicators of the UPR, such as heat shock 70 kDa protein 5 (HSPA5, also known as GRP78) and DNA-damage-inducible transcript 3 (DDIT3, also known as GADD-153), were found to be upregulated when compared with patients with MCD, whereas the apoptosis regulator Bcl-2 was downregulated.156 Moreover, in glomeruli from rats with PAN-induced nephrotic syndrome, the expression of HSPA5 was upregulated, together with increased phosphorylation of eukaryotic translation initiation factor 2 subunit 1 (eIF2α; another indicator of the UPR), suggesting involvement of this response in renal injury.157 Notably, the UPR was regulated by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and proteinuria in this model was prevented by inhibition of mTORC1 with everolimus—a derivative of the currently clinically available mTOR inhibitor, sirolimus . . .
  158. Cybulsky, A. V. et al. Complement C5b-9 membrane attack complex increases expression of endoplasmic reticulum stress proteins in glomerular epithelial cells. J. Biol. Chem. 277, 41342-41351 , .
  159. Kitamura, M. Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces. Am. J. Physiol. Renal Physiol. 295, F323-F334 , .
    • . . . The UPR has also been suggested to have a role in some inherited forms of nephrotic syndrome, caused by mutations in nephrin, podocin and α-actinin-4.159, 160 In vitro, expression of mouse mutant Lys256Glu α-actinin-4 (corresponding to human Lys255Glu) in podocytes induced endoplasmic reticulum stress, as indicated by induction of HSP90B1 and DDIT3 expression, with simultaneous impairment of the ubiquitin–proteasome system, formation of aggresomes (which is triggered by many mutant proteins), and induction of apoptosis.161 . . .
  160. Henderson, J. M., Alexander, M. P. & Pollak, M. R. Patients with ACTN4 mutations demonstrate distinctive features of glomerular injury. J. Am. Soc. Nephrol. 20, 961-968 , .
    • . . . The UPR has also been suggested to have a role in some inherited forms of nephrotic syndrome, caused by mutations in nephrin, podocin and α-actinin-4.159, 160 In vitro, expression of mouse mutant Lys256Glu α-actinin-4 (corresponding to human Lys255Glu) in podocytes induced endoplasmic reticulum stress, as indicated by induction of HSP90B1 and DDIT3 expression, with simultaneous impairment of the ubiquitin–proteasome system, formation of aggresomes (which is triggered by many mutant proteins), and induction of apoptosis.161 . . .
  161. Cybulsky, A. V. & Kennedy, C. R. Podocyte injury associated with mutant α-actinin-4. J. Signal Transduct. 2011, 563128 , .
  162. Liu, X. L. et al. Defective trafficking of nephrin missense mutants rescued by a chemical chaperone. J. Am. Soc. Nephrol. 15, 1731-1738 , .
    • . . . Alternative approaches might include the use of low-molecular mass compounds that reduce misfolding and protein aggregation, such as sodium 4-phenylbutyrate162 or (−)-epigallocatechin-3-gallate,163 which is a secondary plant metabolite. . . .
  163. Ehrnhoefer, D. E. et al. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum. Mol. Genet. 15, 2743-2751 , .
    • . . . Alternative approaches might include the use of low-molecular mass compounds that reduce misfolding and protein aggregation, such as sodium 4-phenylbutyrate162 or (−)-epigallocatechin-3-gallate,163 which is a secondary plant metabolite. . . .
  164. Mishra, O. P. et al. Antioxidant status of children with idiopathic nephrotic syndrome. Pediatr. Nephrol. 26, 251-256 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  165. Pavlova, E. L., Lilova, M. I. & Savov, V. M. Oxidative stress in children with kidney disease. Pediatr. Nephrol. 20, 1599-1604 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  166. Kamireddy, R. et al. Oxidative stress in pediatric nephrotic syndrome. Clin. Chim. Acta 325, 147-150 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  167. Ece, A. et al. Paraoxonase, total antioxidant response, and peroxide levels in children with steroid-sensitive nephrotic syndrome. Pediatr. Nephrol. 20, 1279-1284 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  168. Ghodake, S. R. et al. Role of free radicals and antioxidant status in childhood nephrotic syndrome. Indian J. Nephrol. 21, 37-40 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  169. Agardh, C. D., Stenram, U., Torffvit, O. & Agardh, E. Effects of inhibition of glycation and oxidative stress on the development of diabetic nephropathy in rats. J. Diabetes Complications 16, 395-400 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  170. Sawant, S. U., Chandran, S., Almeida, A. F. & Rajan, M. G. Correlation between oxidative stress and thyroid function in patients with nephrotic syndrome. Int. J. Nephrol. 2011, 256420 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  171. Duann, P. et al. Superoxide dismutase mimetic preserves the glomerular capillary permeability barrier to protein. J. Pharmacol. Exp. Ther. 316, 1249-1254 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  172. Nakakura, H., Ashida, A., Hirano, K. & Tamai, H. Oxidative stress in a rat model of nephrosis can be quantified by electron spin resonance. Pediatr. Nephrol. 19, 266-270 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  173. Marshall, C. B., Pippin, J. W., Krofft, R. D. & Shankland, S. J. Puromycin aminonucleoside induces oxidant-dependent DNA damage in podocytes in vitro and in vivo. Kidney Int. 70, 1962-1973 , .
    • . . . Oxidative stress occurs in both children and adults with various kidney diseases, including glomerulonephritis, acute kidney injury, chronic kidney disease, diabetic nephropathy, and nephrotic syndrome, possibly in conjunction with hyperlipidemia.164, 165, 166, 167, 168, 169, 170 Reactive oxygen species (ROS) have been suggested to have a role in the pathogenesis of nephrotic syndrome through actions such as impairing the integrity of the glomerular basement membrane or reducing podocyte proteoglycan de novo synthesis.171 PAN treatment in vivo and in vitro increases ROS concentrations, lipid peroxidation, and DNA damage, which all contribute to oxidative injury in podocytes.172, 173 In response, podocytes induce anti-oxidative enzymes, apparently in an attempt to maintain redox homeostasis.174 . . .
  174. Vega-Warner, V., Ransom, R. F., Vincent, A. M., Brosius, F. C. & Smoyer, W. E. Induction of antioxidant enzymes in murine podocytes precedes injury by puromycin aminonucleoside. Kidney Int. 66, 1881-1889 , .
  175. Kinugasa, S. et al. Selective albuminuria via podocyte albumin transport in puromycin nephrotic rats is attenuated by an inhibitor of NADPH oxidase. Kidney Int. 80, 1328-1338 , .
  176. Alvarez, B., Carballal, S., Turell, L. & Radi, R. Formation and reactions of sulfenic acid in human serum albumin. Methods Enzymol. 473, 117-136 , .
    • . . . Oxidative injury of podocytes in nephrotic syndrome might also be caused indirectly through increased exposure to oxidized serum albumin.175 Albumin is the most abundant protein in serum, and is susceptible to oxidation in oxidative stress situations, which can result in alterations in its structure and possibly its function.176, 177 Serum albumin is also known to be more oxidized in patients with FSGS than in healthy individuals.177, 178 Following endocytotic uptake and transport through podocytes, such oxidized serum albumin can potentially injure podocytes in nephrotic syndrome.175 . . .
  177. Candiano, G. et al. The oxido-redox potential of albumin methodological approach and relevance to human diseases. J. Proteomics 73, 188-195 , .
    • . . . Oxidative injury of podocytes in nephrotic syndrome might also be caused indirectly through increased exposure to oxidized serum albumin.175 Albumin is the most abundant protein in serum, and is susceptible to oxidation in oxidative stress situations, which can result in alterations in its structure and possibly its function.176, 177 Serum albumin is also known to be more oxidized in patients with FSGS than in healthy individuals.177, 178 Following endocytotic uptake and transport through podocytes, such oxidized serum albumin can potentially injure podocytes in nephrotic syndrome.175 . . .
  178. Bruschi, M. et al. Analysis of the oxido-redox status of plasma proteins. Technology advances for clinical applications. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 879, 1338-1344 , .
    • . . . Oxidative injury of podocytes in nephrotic syndrome might also be caused indirectly through increased exposure to oxidized serum albumin.175 Albumin is the most abundant protein in serum, and is susceptible to oxidation in oxidative stress situations, which can result in alterations in its structure and possibly its function.176, 177 Serum albumin is also known to be more oxidized in patients with FSGS than in healthy individuals.177, 178 Following endocytotic uptake and transport through podocytes, such oxidized serum albumin can potentially injure podocytes in nephrotic syndrome.175 . . .
  179. Lee, H. S. et al. Dietary antioxidant inhibits lipoprotein oxidation and renal injury in experimental focal segmental glomerulosclerosis. Kidney Int. 51, 1151-1159 , .
    • . . . Indeed, a few reports using the radical scavenger edaravone or dietary supplementation with the antioxidants probucol and vitamin E in a rat model of PAN-induced nephrosis179, 180 or children181 with nephrotic syndrome have provided modest evidence in support of this approach. . . .
  180. Matsumura, H., Ashida, A., Hirano, K., Nakakura, H. & Tamai, H. Protective effect of radical scavenger edaravone against puromycin nephrosis. Clin. Nephrol. 66, 405-410 , .
    • . . . Indeed, a few reports using the radical scavenger edaravone or dietary supplementation with the antioxidants probucol and vitamin E in a rat model of PAN-induced nephrosis179, 180 or children181 with nephrotic syndrome have provided modest evidence in support of this approach. . . .
  181. Tahzib, M., Frank, R., Gauthier, B., Valderrama, E. & Trachtman, H. Vitamin E treatment of focal segmental glomerulosclerosis: results of an open-label study. Pediatr. Nephrol. 13, 649-652 , .
    • . . . Indeed, a few reports using the radical scavenger edaravone or dietary supplementation with the antioxidants probucol and vitamin E in a rat model of PAN-induced nephrosis179, 180 or children181 with nephrotic syndrome have provided modest evidence in support of this approach. . . .
  182. Kestilä, M. et al. Positionally cloned gene for a novel glomerular protein-nephrin-is mutated in congenital nephrotic syndrome. Mol. Cell 1, 575-582 , .
    • . . . However, since the first identification of a mutation in the podocyte protein nephrin,182 research has identified multiple mutations that can cause nephrotic syndrome.7, 8, 183 This new knowledge enables a more functionally relevant grouping of the causes of nephrotic syndrome (such as 'podocytopathies' for mutations directly affecting podocyte structure or function, or 'channelopathies' for mutations affecting an ion channel such as TRPC6).184 Eventually, we fully expect that this new knowledge will translate into new therapeutic approaches to treat nephrotic syndrome . . .
  183. Chiang, C. K. & Inagi, R. Glomerular diseases: genetic causes and future therapeutics. Nat. Rev. Nephrol. 6, 539-554 , .
    • . . . However, since the first identification of a mutation in the podocyte protein nephrin,182 research has identified multiple mutations that can cause nephrotic syndrome.7, 8, 183 This new knowledge enables a more functionally relevant grouping of the causes of nephrotic syndrome (such as 'podocytopathies' for mutations directly affecting podocyte structure or function, or 'channelopathies' for mutations affecting an ion channel such as TRPC6).184 Eventually, we fully expect that this new knowledge will translate into new therapeutic approaches to treat nephrotic syndrome . . .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  184. McCarthy, H. J. & Saleem, M. A. Genetics in clinical practice: nephrotic and proteinuric syndromes. Nephron Exp. Nephrol. 118, e1-e8 , .
    • . . . However, since the first identification of a mutation in the podocyte protein nephrin,182 research has identified multiple mutations that can cause nephrotic syndrome.7, 8, 183 This new knowledge enables a more functionally relevant grouping of the causes of nephrotic syndrome (such as 'podocytopathies' for mutations directly affecting podocyte structure or function, or 'channelopathies' for mutations affecting an ion channel such as TRPC6).184 Eventually, we fully expect that this new knowledge will translate into new therapeutic approaches to treat nephrotic syndrome . . .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  185. Pei, Y. INF2 is another piece of the jigsaw puzzle for FSGS. J. Am. Soc. Nephrol. 22, 197-199 , .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  186. Akilesh, S. et al. Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J. Clin. Invest. 121, 4127-4137 , .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  187. Hasselbacher, K. et al. Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney Int. 70, 1008-1012 , .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  188. Santin, S. et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 6, 1139-1148 , .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  189. Hinkes, B. G. et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119, e907-e919 , .
    • . . . Examples of affected genes include NPHS1, NPHS2, CD2AP, PLCE1, LAMB2, ACTN4, TRPC6, INF2, and ARHGAP24, with mutations causing nonsyndromic forms of nephrotic syndrome.183, 184, 185, 186, 187 Mutations in these genes collectively account for the majority of all cases in the first year of life and a sizeable minority of cases of childhood nephrotic syndrome.188, 189 The genetic cases of nephrotic syndrome are generally characterized by earlier onset proteinuria presenting in infancy and throughout childhood, resistance to steroids and other treatments, and an unremitting clinical course progressing to end-stage renal disease. . . .
  190. Schlondorff, J., Del Camino, D., Carrasquillo, R., Lacey, V. & Pollak, M. R. TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am. J. Physiol. Cell. Physiol. 296, C558-C569 , .
    • . . . Sustained excessive calcium influx through this channel has been reported to be a common pathway in many glomerulopathies that originate in podocytes, with downstream consequences of NFAT-dependent transcription and activation of NF-κB signaling.190, 191A number of nephrotic syndrome-associated mutations in the TRPC6 gene are now known, and most of them seem to increase receptor activity compared with the wild-type receptor.191 Interestingly, ciclosporin can downregulate TRPC6 mRNA expression in podocytes by nonimmune mechanisms,192, 193 and this approach may be effective in patients with mutations resulting in elevated TRPC6 activity . . .
  191. Dryer, S. E. & Reiser, J. TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am. J. Physiol. Renal Physiol. 299, F689-F701 , .
    • . . . Sustained excessive calcium influx through this channel has been reported to be a common pathway in many glomerulopathies that originate in podocytes, with downstream consequences of NFAT-dependent transcription and activation of NF-κB signaling.190, 191A number of nephrotic syndrome-associated mutations in the TRPC6 gene are now known, and most of them seem to increase receptor activity compared with the wild-type receptor.191 Interestingly, ciclosporin can downregulate TRPC6 mRNA expression in podocytes by nonimmune mechanisms,192, 193 and this approach may be effective in patients with mutations resulting in elevated TRPC6 activity . . .
  192. Bensman, A. & Niaudet, P. Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr. Nephrol. 25, 1197-1199 , .
    • . . . Sustained excessive calcium influx through this channel has been reported to be a common pathway in many glomerulopathies that originate in podocytes, with downstream consequences of NFAT-dependent transcription and activation of NF-κB signaling.190, 191A number of nephrotic syndrome-associated mutations in the TRPC6 gene are now known, and most of them seem to increase receptor activity compared with the wild-type receptor.191 Interestingly, ciclosporin can downregulate TRPC6 mRNA expression in podocytes by nonimmune mechanisms,192, 193 and this approach may be effective in patients with mutations resulting in elevated TRPC6 activity . . .
  193. Nijenhuis, T. et al. Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway. Am. J. Pathol. 179, 1719-1732 , .
    • . . . Sustained excessive calcium influx through this channel has been reported to be a common pathway in many glomerulopathies that originate in podocytes, with downstream consequences of NFAT-dependent transcription and activation of NF-κB signaling.190, 191A number of nephrotic syndrome-associated mutations in the TRPC6 gene are now known, and most of them seem to increase receptor activity compared with the wild-type receptor.191 Interestingly, ciclosporin can downregulate TRPC6 mRNA expression in podocytes by nonimmune mechanisms,192, 193 and this approach may be effective in patients with mutations resulting in elevated TRPC6 activity . . .
  194. Gipson, D. S. et al. Differential risk of remission and ESRD in childhood FSGS. Pediatr. Nephrol. 21, 344-349 , .
    • . . . Moreover, failure to respond clinically to either glucocorticoids or these alternative treatments results in a greatly increased risk of end-stage renal disease (>50% within 4 years of diagnosis of SRNS).194 In this context, new therapies to treat childhood nephrotic syndrome are urgently required . . .
  195. Redmond, E. M., Guha, S., Walls, D. & Cahill, P. A. Investigational Notch and Hedgehog inhibitors-therapies for cardiovascular disease. Expert Opin. Investig. Drugs 20, 1649-1664 , .
  196. Woolf, A. S. & Pitera, J. E. in Pediatric Nephrology (eds Avner, E. D., Harmon, W. E., Niaudet, P. & Yoshikawa, N.) 3-3 (Lippincott Williams & Wilkins, Philadelphia, 2009) , .
  197. Kopan, R., Cheng, H. T. & Surendran, K. Molecular insights into segmentation along the proximal-distal axis of the nephron. J. Am. Soc. Nephrol. 18, 2014-2020 , .
  198. Chen, L. & Al-Awqati, Q. Segmental expression of Notch and Hairy genes in nephrogenesis. Am. J. Physiol. Renal Physiol. 288, F939-F952 , .
  199. McCright, B. et al. Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128, 491-502 , .
  200. Cheng, H. T. et al. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 134, 801-811 , .
  201. Cheng, H. T. & Kopan, R. The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int. 68, 1951-1952 , .
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