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NDT Advance Access originally published online on May 15, 2006
Nephrology Dialysis Transplantation 2006 21(7):1761-1763; doi:10.1093/ndt/gfl222
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

Is tacrolimus for childhood steroid-dependent nephrotic syndrome better than ciclosporin A?

Jörg Dötsch, Katalin Dittrich, Christian Plank and Wolfgang Rascher

Kinder und Jugendklinik, University of Erlangen-Nürnberg, Germany

Correspondence and offprint requests to: Jörg Dötsch, MD, Kinder und Jugendklinik, University of Erlangen-Nürnberg, Loschgestrasse 15. 91054 Erlangen, Germany. Email: Joerg.Doetsch{at}kinder.imed.uni-erlangen.de

Keywords: calcineurin inhibitor; diabetes mellitus; immunosuppression; nephrotic syndrome; tacrolimus



   Immunosuppressive drugs in the treatment of severe steroid-dependent nephrotic syndrome (Figure 1)
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 Immunosuppressive drugs in the...
Is there a rationale...
 Tacrolimus treatment after...
 Adverse effects
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The dosage and 3 months duration of glucocorticoid treatment in steroid-sensitive childhood idiopathic nephrotic syndrome, mainly associated with the histological picture of minimal change glomerulopathy, is based on the evidence of randomized clinical trials with clear-cut end points [1–3]. Duration of up to 7 months of the therapy may even be more effective in achieving sustained remission. A further well-designed and adequately powered randomized controlled trial is, however, required. To avoid steroid toxicity, there is convincing evidence for the use of oral cyclophosphamide in patients with frequent relapses [4]. The evidence, however, is less stable for the treatment of steroid-dependent nephrotic syndrome (SDNS), i.e. recurrence of nephrotic syndrome within 2 weeks of cessation of steroid treatment [5,6]. One of the major concerns with regard to the use of alkylating agents such as cyclophosphamide or chlorambucil in children and adolescents is gonadotoxicity [7]. Therefore, ciclosporin A (CSA) has been advocated when toxic effects of prednisone and cyclophosphamide are expected. CSA results in a remission rate of 85% in children with SDNS, bearing, however, the risk of calcineurin inhibitor-induced nephrotoxicity [8].


Figure 1
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  		Fig. 1. Treatment options for steroid-sensitive nephrotic syndrome (SSNS) in childhood. The figure shows treatment options from initial treatment to the treatment of severe steroid-dependent nephrotic syndrome (SDNS). Evidence levels [25] are shown as follows: Level 1: Randomized clinical studies with robust clinical end point. Level 2: Randomized clinical studies with surrogate parameter as endpoint. Level 3: Non-randomized, controlled studies. Level 4: Therapy studies with beforeandafter comparison of case series with historical control group. Level 5: Case series with >10 patients. Level 6: Case reports with <10 patients.

 
Thus, alternative immunosuppressive drugs such as mycophenolate mofetil [9,10], rituximab [11] and sirolimus [12] are currently under investigation. Levamisol has been found to be of benefit in SDNS and has limited toxicity [13]. Data on the use of the calcineurin inhibitor tacrolimus (TAC) are scarce.



   Is there a rationale for the use of tacrolimus in patients with SDNS?
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 Immunosuppressive drugs in the...
 Is there a rationale...
Tacrolimus treatment after...
 Adverse effects
 Conclusions
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TAC and CSA, despite having distinct chemical structures and different cytosolic binding proteins, have almost identical cellular effects [14]. Both lead to calcineurin inhibition in T-cells, resulting in impaired production of cytokines that are important to enable T-cell progression from the G0 to the G1 state. Therefore, at first glance, TAC does not appear to have a theoretical superiority to CSA for use in any disease, including severe SDNS. Is there still a rationale for a study examining the switch in treatment from CSA to TAC? In fact, there are some aspects in favour of performing such a study:

  1. TAC has been shown to act in a distinct, if not superior, way to CSA in children with renal transplantation [15,16].
  2. TAC is successfully used in children with psoriasis, where CSA does not appear to be effective [17].
  3. In adults with focal segmental glomerulonephrosis and consecutive steroid-resistant nephrotic syndrome (SRNS) remission has been induced using TAC [18].
  4. TAC has been applied to maintain remission in eight paediatric patients with idiopathic SDNS and to induce remission in seven children with SRNS [19]. This group achieved complete remission in 81% of the patients and partial remission in 13%. However, the study is retrospective in nature, does not clearly discriminate between SDNS and SRNS and does not aim at comparing CSA and TAC.



   Tacrolimus treatment after ciclosporin. A failure in children with SDNS
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 Immunosuppressive drugs in the...
 Is there a rationale...
 Tacrolimus treatment after...
Adverse effects
 Conclusions
 References
 
In this issue of the journal, Sinha and coworkers reported the switch from CSA to TAC in 10 children with severe SDNS, in whom the first drug was withdrawn for ineffectiveness or adverse effects. Nine of the patients had minimal change glomerulopathy in the initial renal biopsy, and one patient had focal segmental glomerulonephrosis. Replacing TAC for CSA did not improve:

  1. the annual relapse rate of the nephrotic syndrome (NS), and
  2. the amount of glucocorticoids needed.

The limitation of this study is its retrospective approach and the design using TAC after CSA in a limited number of patients. Nonetheless, with respect to the data available on TAC treatment in severe childhood SDNS, the study by Sinha and coworkers is of great interest.

In our own retrospective study including five patients with severe SDNS and failure of cyclophosphamide and CSA, only one patient had a substantial improvement with TAC [20].



   Adverse effects
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 Immunosuppressive drugs in the...
 Is there a rationale...
 Tacrolimus treatment after...
 Adverse effects
Conclusions
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One of the most important adverse effects of TAC is the induction of insulin-dependent diabetes mellitus (IDDM). Under immunosuppressive therapy with TAC in children after renal transplantation, the incidence of IDDM is reported to be as high as 3% [21,22]. Sinha and coworkers describe one patient who developed permanent IDDM while taking TAC. We observed IDDM in two patients with SDNS treated with TAC. Diabetes occurred when, in addition to TAC, higher prednisone doses than in post-transplant patients were used to induce remission of the nephrotic syndrome [20]. Both nephrotic patients in this study had hypoalbuminaemia. TAC binds to erythrocytes (~80%) and plasma proteins (albumin and {alpha}-1-glycoproteins) (~20%), while only the free compound (1.2%) is pharmacologically active [23,24]. In the case of hypoalbuminaemia due to the relapse of NS, there may be a reduction of the bound TAC fraction by approximately 10%, resulting in an up to 10-fold rise of the free fraction. Total blood concentrations, however, remain almost constant. It therefore seems possible that, during a relapse or sustained proteinuria, stable total TAC concentrations mask high, or even toxic, levels of the free bioactive fraction. Other adverse effects of TAC such as hypertension and nephrotoxicity appear similar to CSA.



   Conclusions
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 Immunosuppressive drugs in the...
 Is there a rationale...
 Tacrolimus treatment after...
 Adverse effects
 Conclusions
References
 
There is currently no rationale for the use of TAC in place of CSA in children with SDNS and minimal change glomerulopathy, bearing in mind that all the studies performed so far are retrospective and based on a limited number of patients. In addition, the risk of drug-induced IDDM during TAC treatment of SDNS is rather discouraging.

In contrast, TAC might be more promising for the treatment of SRNS, e.g. in patients with focal segmental glomerulosclerosis [18]. Studies in this field might, therefore, be more interesting.

Conflict of interest statement. None declared.

(See related article by Sinha et al. Nephrol Dial Transplant 2006; 21:1848–1854.)



   References
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 Immunosuppressive drugs in the...
 Is there a rationale...
 Tacrolimus treatment after...
 Adverse effects
 Conclusions
 References
 

  1. Arbeitsgemeinschaft für Pädiatrische Nephrologie. Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Lancet 1988; 1: 380–383[Medline]
  2. Dötsch J, Rascher W, Plank C. Therapie des idiopathischen nephrotischen syndroms im kindesalter. Monatsschrift Kinderheilkd 2004; 152: 265–272[CrossRef]
  3. Hodson EM, Craig JC, Willis NS. Evidence-based management of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2005; 20: 1523–1530[Medline]
  4. International Study of Kidney Disease in Children. Prospective, controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome. Lancet 1974; 2: 423–427[CrossRef][Medline]
  5. Arbeitsgemeinschaft für Pädiatrische Nephrologie. Effect of cytotoxic drugs in frequently relapsing nephrotic syndrome with and without steroid dependence. N Engl J Med 1982; 306: 451–454[Abstract]
  6. Bargman JM. Management of minimal lesion glomerulonephritis: evidence-based recommendations. Kidney Int 1999; 70: 3–16
  7. Latta K, Schmalenburg C, von Ehrich JHH. A metaanalysis of cytotoxic treatment of frequently relapsing nephrotic syndrome in children. Pediatr Nephrol 2001; 16: 271–282[CrossRef][Web of Science][Medline]
  8. Niaudet P, Habib R. Ciclosporine in the treatment of idiopathic nephrosis. J Am Soc Nephrol 1994; 5: 1049–1056[Abstract]
  9. Hogg RJ, Fitzgibbons L, Buick J et al. Clinical trial of mycophenolate mofetil (MMF) for frequent relapsing nephrotic syndrome in children. Pediatr Nephrol 2004; 19: C66[CrossRef]
  10. Bagga A, Hari P, Moudgil A, JNordan SC. Mycopenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome. Am J Kidney Disease 2003; 42: 1114–1120[CrossRef][Web of Science][Medline]
  11. Benz K, Dötsch J, Rascher W, Stachel D. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 2004; 19: 794–797[Medline]
  12. Tumlin JA, Miller D, Near M, Selvaraj S, Hennigar R, Guasch A. A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2006; 1: 109–116
  13. British Association for Paediatric Nephrology. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. Lancet 1991; 337: 1555–1557[CrossRef][Medline]
  14. Meyrier A. Treatment of idiopathic nephrosis by immunophillin modulation. Nephrol Dial Transplant 2003; 6: 79–86
  15. Kari JA, Trompeter RS. What is the calcineurin inhibitor of choice for pediatric renal transplantation?. Pediatr Transplant 2004; 8: 437–444[Medline]
  16. Filler G, Webg NJA, Milford DV et al. Four-year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. ciclosporine microemulsion. Pediatr Transplant 2005; 9: 498–503[CrossRef][Web of Science][Medline]
  17. Steele JA, Choi C, Kwong PC. Topical tacrolimus in the treatment of inverse psoriasis in children. J Am Acad Dermatol 2005; 53: 713–716[Medline]
  18. Duncan N, Dhaygude A, Owen J et al. Treatment of focal segmental glomerulosclerosis in adults with tacrolimus monotherapy. Nephrol Dialysis Transplant 2004; 3062–3067
  19. Loeffler K, Gowrishankar M, Yiu V. Tacrolimus therapy in pediatric patients with treatment resistant nephrotic syndrome. Pediatr Nephrol 2004; 19: 281–287[CrossRef][Medline]
  20. Dittrich K, Knerr I, Rascher W, Dötsch J. Transient insulin-dependent diabetes mellitus in children with steroid-dependent idiopathic nephrotic syndrome during tacrolimus treatment. Pediatric Nephrol (in press).
  21. Trompeter R, Filler G, Webb NJ et al. Randomized trial of tacrolimus versus ciclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002; 17: 141–149[CrossRef][Web of Science][Medline]
  22. Al-Uzri A, Stablein DM, A Cohn R. Posttransplant diabetes mellitus in pediatric renal transplant recipients: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001; 72: 1020–1024[CrossRef][Medline]
  23. Venkataramanan R, Jain A, Warty VS. Pharmacokinetics of FK506 in transplant patients. Transplant Proc 1991; 23: 2736–2740[Medline]
  24. Beysens AJ, Wijnen RNH, Beuman GH, van der Heyden J, Kootstra G, van As H. FK 506: monitoring in plasma or whole blood?. Transplant Proc 1991; 23: 2745–2747[Web of Science][Medline]
  25. Cattran DC. Evidence-based recommendations for the management of glomerulonephritis. Introduction. Kidney Int 1999; [Suppl 70]1–2

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Treatment of severe steroid-dependent nephrotic syndrome (SDNS) in children with tacrolimus
Manish D. Sinha, Rebecca MacLeod, Emma Rigby, and A. Godfrey B. Clark
NDT 2006 21: 1848-1854. [Abstract] [FREE Full Text]  




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