Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome

1. International Study of Kidney Disease in Children: Nephrotic syndrome in children:

prediction of histopathology from clinical and laboratory characteristics at time of

diagnosis. A report of the International Study of Kidney Disease in Children. Kidney

Int 13: 159-65, 1978. doi: 10.1038/ki.1978.23.

2. Kikunaga K, Ishikura K, Terano C, Sato M, Komaki F, Hamasaki Y et al.; Japanese

Pediatric Survey Holding Information of NEphrotic syndrome (JP-SHINE) study of

the Japanese Study Group of Renal Disease in Children: High incidence of idiopathic

nephrotic syndrome in East Asian children: a nationwide survey in Japan (JP-SHINE

study). Clin Exp Nephrol 21: 651-657, 2017. doi: 10.1007/s10157-016-1319-z.

3. International Study of Kidney Disease in Children: The primary nephrotic syndrome

in children. Identification of patients with minimal change nephrotic syndrome from

initial response to prednisone. J Pediatr 98: 561-564, 1981. doi: 10.1016/s00223476(81)80760-3.

4. Noone DG, Iijima K, Parekh R: Idiopathic nephrotic syndrome in children. Lancet

392: 61-74, 2018. doi: 10.1016/S0140-6736(18)30536-1.

5. KDIGO Clinical Practice Guideline for Glomerulonephritis: Chapter 3: Steroidsensitive nephrotic syndrome in children. Kidney Int Suppl 2: 163-171, 2012.

doi:10.1038/kisup.2012.16.

6. Ishikura K, Matsumoto S, Sako M, Tsuruga K, Nakanishi K, Kamei K, et al.;

Japanese Society for Pediatric Nephrology: Clinical practice guideline for pediatric

idiopathic nephrotic syndrome 2013: medical therapy. Clin Exp Nephrol 19: 6-33,

2015. doi: 0.1007/s10157-014-1030-x.

7. Hamasaki Y, Yoshikawa N, Nakazato H, Sasaki S, Iijima K, Nakanishi K, et al.; for

Japanese Study Group of Renal Disease in Children: Prospective 5-year follow-up

of cyclosporine treatment in children with steroid-resistant nephrosis. Pediatr

Nephrol 28: 765-771, 2013. doi: 10.1007/s00467-012-2393-4.

8. Ishikura K, Ikeda M, Hattori S, Yoshikawa N, Sasaki S, Iijima K, et al.: Effective and

safe treatment with cyclosporine in nephrotic children: a prospective, randomized

multicenter trial. Kidney Int 73: 1167-1173, 2008. doi: 10.1038/ki.2008.24.

9. Ishikura K, Yoshikawa N, Hattori S, et al.; for Japanese Study Group of Renal

Disease in Children: Treatment with microemulsified cyclosporine in children with

frequently relapsing nephrotic syndrome. Nephrol Dial Transplant 25: 3956-3962,

2010. doi: 10.1093/ndt/gfq318.

10. Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, et al.; Rituximab for

Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group: Rituximab

36

for childhood-onset, complicated, frequently relapsing nephrotic syndrome or

steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised,

placebo-controlled trial. Lancet 84: 1273-1281, 2014. doi: 10.1016/S01406736(14)60541-9.

11. Iijima K, Sako M, Kamei K, Nozu K: Rituximab in steroid-sensitive nephrotic

syndrome: lessons from clinical trials. Pediatr Nephrol 33: 1449-1455, 2018. doi:

10.1007/s00467-017-3746-9.

12. Kallash M, Smoyer WE, Mahan JD: Rituximab Use in the Management of Childhood

Nephrotic Syndrome. Front Pediatr 7: 178, 2019. doi: 10.3389/fped.2019.00178.

13. Guigonis V, Dallocchio A, Baudouin V, et al.: Rituximab treatment for severe steroidor cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases.

Pediatr Nephrol 23: 1269–1279, 2008. doi: 10.1007/s00467-008-0814-1.

14. Kamei K, Ito S, Nozu K, Fujinaga S, Nakayama M, Sako M, et al.: Single dose of

rituximab for refractory steroid-dependent nephrotic syndrome in children. Pediatr

Nephrol 24: 1321-1328, 2009. doi: 10.1007/s00467-009-1191-0.

15. Fujinaga S, Hirano D, Nishizaki N, Kamei K, Ito S, Ohtomo Y, et al.: Single infusion

of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome

after

long-term

cyclosporine.

Pediatr

Nephrol

25:

539-544,

2010.

doi:

10.1007/s00467-009-1377-5.

16. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: A

blinded, randomized clinical trial of mycophenolate mofetil for the prevention of

acute rejection in cadaveric renal transplantation. Transplantation 61: 1029-1037,

1996.

17. Vanrenterghem Y: The use of mycophenolate mofetil (Cellcept) in renal

transplantation. Contrib Nephrol 124: 64-69, 1998. doi: 10.1159/000059931.

18. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al.: Efficacy of

mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong

Kong-Guangzhou Nephrology Study Group. N Engl J Med 343: 1156-1162, 2000.

doi: 10.1056/NEJM200010193431604.

19. Lau KK, Jones DP, Hastings MC, Gaber LW, Ault BH: Short-term outcomes of

severe lupus nephritis in a cohort of predominantly African-American children.

Pediatr Nephrol 21: 655-662, 2006. doi: 10.1007/s00467-006-0060-3.

20. Afzal K, Bagga A, Menon S, Hari P, Jordan SC: Treatment with mycophenolate

mofetil and prednisolone for steroid-dependent nephrotic syndrome. Pediatr

Nephrol 22: 2059-2065, 2007. doi: 10.1007/s00467-007-0617-9.

37

21. Bagga A, Hari P, Moudgil A, Jordan SC: Mycophenolate mofetil and prednisolone

therapy in children with steroid-dependent nephrotic syndrome. Am J Kidney Dis

42: 1114-1120, 2003. doi: 10.1053/j.ajkd.2003.08.011.

22. Barletta GM, Smoyer WE, Bunchman TE, Flynn JT, Kershaw DB: Use of

mycophenolate mofetil in steroid-dependent and -resistant nephrotic syndrome.

Pediatr Nephrol 18: 833-837, 2003. doi: 10.1007/s00467-003-1175-4.

23. Fujinaga S, Ohtomo Y, Hirano D, Nishizaki N, Someya T, Ohtsuka Y,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, 2009.

24. Fujinaga S, Ohtomo Y, Umino D, Takemoto M, Shimizu T, Yamashiro Y, et al.: A

prospective study on the use of mycophenolate mofetil in children with

cyclosporine-dependent nephrotic syndrome. Pediatr Nephrol 22: 71-76, 2007. doi:

10.1007/s00467-006-0294-0.

25. Gellermann J, Querfeld U: Frequently relapsing nephrotic syndrome: treatment

with mycophenolate mofetil. Pediatr Nephrol 19: 101-104, 2004. doi:

10.1007/s00467-003-1300-4.

26. Hogg RJ, Fitzgibbons L, Bruick J, Bunke M, Ault B, Baqi N, et al.: Mycophenolate

mofetil in children with frequently relapsing nephrotic syndrome: a report from the

Southwest Pediatric Nephrology Study Group. Clin J Am Soc Nephrol 1: 11731178, 2006. doi: 10.2215/CJN.00550206.

27. Mendizabal S, Zamora I, Berbel O, Sanahuja MJ, Fuentes J, Simon J:

Mycophenolate

mofetil

in

steroid/cyclosporine-dependent/resistant

nephrotic

syndrome. Pediatr Nephrol 20: 914-919, 2005. doi: 10.1007/s00467-005-1877-x.

28. Okada M, Sugimoto K, Yagi K, Yanagida H, Tabata N, Takemura T:

Mycophenolate mofetil therapy for children with intractable nephrotic syndrome.

Pediatr Int 49: 933-937, 2007. doi: 10.1111/j.1442-200X.2007.02487.x.

29. Ulinski T, Dubourg L, Said MH, Parchoux B, Ranchin B, Cochat P: Switch from

cyclosporine A to mycophenolate mofetil in nephrotic children. Pediatr Nephrol 20:

482-485, 2005. doi: 10.1007/s00467-004-1778-4.

30. Ito S, Kamei K, Ogura M, Sato M, Fujimaru T, Ishikawa T, et al.: Maintenance

therapy with mycophenolate mofetil after rituximab in pediatric patients with

steroid-dependent nephrotic syndrome. Pediatr Nephrol 26: 1823-1828, 2011. doi:

10.1007/s00467-011-1886-x

38

31. Filler G, Huang SH, Sharma AP: Should we consider MMF therapy after rituximab

for nephrotic syndrome? Pediatr Nephrol 26: 1759-1762, 2011. doi:

10.1007/s00467-011-1894-x.

32. Larkins NG, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid

immunosuppressive medications for steroid-sensitive nephrotic syndrome in

children.

Cochrane

Database

Syst

Rev.

2020;4:CD002290.

doi:

10.1002/14651858.CD002290.pub5.

33. Kallash M, Smoyer WE, Mahan JD. Rituximab Use in the Management of Childhood

Nephrotic Syndrome. Front Pediatr. 2019;7:178. doi: 10.3389/fped.2019.00178.

34. Chan EY, Webb H, Yu E, Ghiggeri GM, Kemper MJ, Ma AL-T, et al: Both the

rituximab

dose

and

maintenance

immunosuppression

in

steroid-

dependent/frequently-relapsing nephrotic syndrome have important effects on

outcomes. Kidney Int 97: 393–401, 2020. doi: 10.1016/j.kint.2019.09.033.

35. Chan EY, Tullus K: Rituximab in children with steroid sensitive nephrotic syndrome:

in quest of the optimal regimen. Pediatr Nephrol. 2020 Jun 24. Online ahead of print.

doi: 10.1007/s00467-020-04609-0.

36. Lin DY, Wei LJ, Yang I, Ying Z: Semiparametric Regression for the Mean and Rate

Functions of Recurrent Events. J R Statist Soc B 62:711–730, 2000. doi:

10.1111/1467-9868.00259.

37. Basu B, Sander A, Preussler S, Sinha Mahapatra T, Schaefer F: IPN11036-82 Longterm efficacy of rituximab & MMF maintenance - therapy in childhood SDNS.

Abstracts of the 18th Congress of the International Pediatric Nephrology Association,

Venice

(Italy),

October

2019.

Pediatr

Nephrol

34:

1821-2260,

2019.

https://doi.org/10.1007/s00467-019-04325-4. Accessed September 12, 2020

38. Colucci M, Carsetti R, Cascioli S, Casiraghi F, Perna A, Ravà L, et al: B Cell

Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome. J Am

Soc Nephrol 27: 1811-1822, 2016. doi: 10.1681/ASN.2015050523.

39. Bashford-Rogers RJM, Bergamaschi L, McKinney EF, McKinney EF, Pombal DC,

Mescia F, et al.: Analysis of the B cell receptor repertoire in six immune-mediated

diseases. Nature 574: 122-126, 2019. doi: 10.1038/s41586-019-1595-3.

40. Ravani P, Lugani F, Pisani I, Bodria M, Piaggio G, Bartolomeo D, et al.: Rituximab

for very low dose steroid-dependent nephrotic syndrome in children: a randomized

controlled study. Pediatr Nephrol 35: 1437-1444, 2020. doi: 10.1007/s00467-02004540-4.

41. Nagano C, Sako M, Kamei K, Ishikura K, Nakamura H, Nakanishi K, et al.: Study

protocol: multicenter double-blind, randomized, placebo-controlled trial of rituximab

39

for the treatment of childhood-onset early-stage uncomplicated frequently relapsing

or steroid-dependent nephrotic syndrome (JSKDC10 trial). BMC Nephrol 20: 293,

2019. doi: 10.1186/s12882-019-1470-3.

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FIGURE LEGENDS

Figure 1. Study design. MMF: Mycophenolate mofetil, MZB: Mizoribine, CyA:

Cyclosporine, Tac: Tacrolimus. After rituximab was administered at a dose of 375 mg/m²

(maximum dose: 500 mg) once weekly for four weeks, on Days 1, 8, 15, and 22, MMF

was administered at a dose of 1,000–1,200 mg/m2/day (maximum 2 g/day) twice daily

after breakfast and dinner for 17 months (from Day 29 until Day 505). In the placebo

group, rituximab was provided in the same manner, and placebo was administered

instead of MMF. The follow-up period was defined as the time from Day 506 to the last

scheduled treatment date of the last enrolled patient. During the follow-up period,

investigators followed up all participants according to the specified schedule and

conducted a follow-up survey using routine clinical data.

Figure 2. Flow diagram.

Figure 3. Kaplan–Meier curves for treatment failure (frequent relapses, steroid

dependence or resistance, or use of immunosuppressive agents or rituximab)-free

survival. MMF: Mycophenolate mofetil. The times to treatment failure were not

statistically significantly longer throughout the study period (the treatment period and

follow-up period) among patients given MMF after rituximab than among patients

receiving rituximab monotherapy (hazard ratio (HR): 0.593, P=0.0694) (See also Table

3a). However, during the treatment period, rituximab followed by MMF decreased the

development of treatment failure by 80% compared with rituximab monotherapy (HR:

0.202) (See also Table 3b).

41

Figure 4. Kaplan–Meier curves or cumulative incidence-free function for

secondary outcomes. (a) Kaplan–Meier curves for relapse-free survival, (b)

Cumulative incidence-free function for frequent relapses, (c) Cumulative

incidence-free function for steroid-dependent relapses. MMF: Mycophenolate

mofetil. Times to relapse and those to each of component outcomes of treatment failure

such as frequent relapses and steroid dependent relapses were approximately 40%

longer (although not statistically significantly) among patients given MMF after rituximab

than among patients receiving rituximab monotherapy throughout the study (combined

treatment and follow-up) period [hazard ratio (HR): (a) 0.618, (b) 0.561, (c) 0.602] (See

also Table 5a, 6a, and 7a). However, during the treatment period, MMF after rituximab

decreased the occurrence of relapse, frequent relapses, and steroid-dependent relapses

by 70%–80% compared with rituximab monotherapy [(a) HR: 0.280, (b) HR: 0.202, (c)

HR: 0.220] (See also Table 5b, 6b, and 7b).

Figure 5. Peripheral B cell counts. Peripheral CD19-positive cell counts were

monitored until Day 505. Day 1 was the first day of rituximab administration. Boxes

represent the quartile range for each grouping and time period, straight lines (beard) are

connected from the top and bottom sides of the boxes to outliers within 1.5 times the

quartile range width, and red crosses and blue open circles represent outlying

observations in the MMF group and placebo group, respectively.

42

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