Minimal change disease medical therapy: Difference between revisions

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__NOTOC__
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{{Minimal change disease}}
{{Minimal change disease}}
{{CMG}}
{{CMG}}; {{AE}} {{VKG}}
 
==Overview==
==Overview==
Pharmacologic therapy using [[corticosteroid]]s is considered the mainstay of therapy for [[minimal change disease]].  According to the National Kidney Foundation (NKF) Kidney Disease – Improve Global Outcomes (KGIDO) guidelines in 2012, initial [[empirical]] treatment using [[corticosteroid]]s in patients presenting with [[nephrotic syndrome]] prior to a kidney biopsy is recommended. Notably also, the use of [[statin]]s for [[hyperlipidemia]] and [[ACE-I]] or [[ARB]] for [[proteinuria]] are both not recommended in patients presenting with the initial episode of MCD.
==Medical Therapy==
==Medical Therapy==
[[Prednisone]] is prescribed along with a blood pressure medication, typically an [[ACE inhibitor]] such as [[lisinopril]].  Often the liver is overactive with minimal change disease and over produces [[cholesterol]].  Therefore a [[statin]] drug is often prescribed for the duration of the treatment. When the urine is clear of protein, the drugs can be discontinued. 50% of patients will relapse and need further treatment.
* According to Children's Nephrotic Syndrome Consensus Conference Pharmacologic medical therapy is recommended among patients with [[minimal change disease]] are following
 
=== Initial therapy for children ===
*  '''Pediatric'''
** Preferred regimen (1): [[Prednisone]]  2 mg/kg per day for six weeks<ref name="pmid23871408">{{cite journal| author=Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH et al.| title=KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. | journal=Am J Kidney Dis | year= 2013 | volume= 62 | issue= 3 | pages= 403-41 | pmid=23871408 | doi=10.1053/j.ajkd.2013.06.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23871408  }} </ref><ref name="pmid279404602">{{cite journal |vauthors=Vivarelli M, Massella L, Ruggiero B, Emma F |title=Minimal Change Disease |journal=Clin J Am Soc Nephrol |volume=12 |issue=2 |pages=332–345 |date=February 2017 |pmid=27940460 |pmc=5293332 |doi=10.2215/CJN.05000516 |url=}}</ref>
*** Followed by alternate-day [[prednisone]] of 1.5 mg/kg for an additional six weeks.
 
==== First relapse ====
* Preferred regimen (1): [[Prednisone]]  2 mg/kg per day, until the urine protein tests shows negative results.<ref name="VivarelliMassella2017">{{cite journal|last1=Vivarelli|first1=Marina|last2=Massella|first2=Laura|last3=Ruggiero|first3=Barbara|last4=Emma|first4=Francesco|title=Minimal Change Disease|journal=Clinical Journal of the American Society of Nephrology|volume=12|issue=2|year=2017|pages=332–345|issn=1555-9041|doi=10.2215/CJN.05000516}}</ref>
 
==== Frequent relapses ====
* Preferred regimen (1):  [[Prednisone]] therapy of 2 mg/kg, until the urine protein tests shows negative results.
** Followed by alternate-day [[prednisone]] of 1.5 mg/kg for four weeks, then taper to 0.5 mg over a two month period.
 
==== Steroid-dependent disease ====
* [[Steroid]] dependence is defined as relapse during tapering of steroid therapy or within 4 weeks of [[steroid]] discontinuation.<ref name="pmid17699450">{{cite journal| author=Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G et al.| title=Adult minimal-change disease: clinical characteristics, treatment, and outcomes. | journal=Clin J Am Soc Nephrol | year= 2007 | volume= 2 | issue= 3 | pages= 445-53 | pmid=17699450 | doi=10.2215/CJN.03531006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699450 }} </ref><ref name="VivarelliMassella20173">{{cite journal|last1=Vivarelli|first1=Marina|last2=Massella|first2=Laura|last3=Ruggiero|first3=Barbara|last4=Emma|first4=Francesco|title=Minimal Change Disease|journal=Clinical Journal of the American Society of Nephrology|volume=12|issue=2|year=2017|pages=332–345|issn=1555-9041|doi=10.2215/CJN.05000516}}</ref><ref name="pmid27940460">{{cite journal |vauthors=Vivarelli M, Massella L, Ruggiero B, Emma F |title=Minimal Change Disease |journal=Clin J Am Soc Nephrol |volume=12 |issue=2 |pages=332–345 |date=February 2017 |pmid=27940460 |pmc=5293332 |doi=10.2215/CJN.05000516 |url=}}</ref><ref name="pmid2042651">{{cite journal |vauthors=Fujimoto S, Yamamoto Y, Hisanaga S, Morita S, Eto T, Tanaka K |title=Minimal change nephrotic syndrome in adults: response to corticosteroid therapy and frequency of relapse |journal=Am. J. Kidney Dis. |volume=17 |issue=6 |pages=687–92 |date=June 1991 |pmid=2042651 |doi= |url=}}</ref>
 
* In the absence of steroid toxicity Prednisone still stands the preferred therapy.
* In the presence of [[steroid]] [[toxicity]] in patients with minimal change disease the following drugs may be used to treat the patients.
* Relative [[Contraindication|contraindications]] of [[Corticosteroid|corticosteroids]] include uncontrolled [[diabetes mellitus]], [[psychiatric disease]]s, and severe [[osteoporosis]]. In such cases, the use of alternative therapy is recommended.
** Preferred regimen (1): [[levamisole]]
** Preferred regimen (2): [[Mycophenolate]] Mofetil (MMF) 500-1000 mg twice daily, for 1-2 years
** Preferred regimen (3): [[cyclophosphamide]] 2-2.5 mg/kg/d for 8 weeks
*** [[Cyclophosphamide]] is contraindicated if [[fertility]] is of a concern.
** Preferred regimen (3): [[Calcineurin inhibitor|calcineurin]] inhibitors (ie, [[cyclosporine]] 3-5 mg/kg/d or tacrolimus
 
* According to the National Kidney Foundation (NKF) Kidney Disease – Improve Global Outcomes (KGIDO) guidelines in 2012, [[cyclophosphamide]] is recommended. In case relapse occurs despite [[cyclophosphamide]] or fertility is a concern, [[cyclosporine]] or [[tacrolimus]]. [[Mycophenolate mofetil]] (MMF) may be used, but is often reserved as last option.<ref name="pmid23871408" /><ref name="pmid1860266">{{cite journal |vauthors=Meyrier A, Condamin MC, Broneer D |title=Treatment of adult idiopathic nephrotic syndrome with cyclosporin A: minimal-change disease and focal-segmental glomerulosclerosis. Collaborative Group of the French Society of Nephrology |journal=Clin. Nephrol. |volume=35 Suppl 1 |issue= |pages=S37–42 |date=1991 |pmid=1860266 |doi= |url=}}</ref>
 
=== Initial therapy for adults ===
* Adults who are positive with [[minimal change disease]] present with [[edema]] and most commonly with [[hypertension]].<ref name="pmid11877569">{{cite journal |vauthors=Nakayama M, Katafuchi R, Yanase T, Ikeda K, Tanaka H, Fujimi S |title=Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome |journal=Am. J. Kidney Dis. |volume=39 |issue=3 |pages=503–12 |date=March 2002 |pmid=11877569 |doi=10.1053/ajkd.2002.31400 |url=}}</ref><ref name="pmid8941578">{{cite journal |vauthors=Mak SK, Short CD, Mallick NP |title=Long-term outcome of adult-onset minimal-change nephropathy |journal=Nephrol. Dial. Transplant. |volume=11 |issue=11 |pages=2192–201 |date=November 1996 |pmid=8941578 |doi= |url=}}</ref>
*  First-line [[therapy]] in adults with [[minimal change disease]]  low-[[sodium]] diet and [[Diuretic|diuretics]] for fluid removal.
* [[Angiotensin-converting enzyme]] ([[Angiotensin-converting enzyme|ACE]]) inhibitors or [[Angiotensin II receptor antagonist|angiotensin II receptor blocker]] ([[ARB]]) are of good choice to control [[hypertension]].And by using these drugs have an additional benefit like reducing urinary [[protein]] excretion.<ref name="pmid18580865">{{cite journal |vauthors=Galle J |title=Reduction of proteinuria with angiotensin receptor blockers |journal=Nat Clin Pract Cardiovasc Med |volume=5 Suppl 1 |issue= |pages=S36–43 |date=July 2008 |pmid=18580865 |doi=10.1038/ncpcardio0806 |url=}}</ref>
 
==== Non Immunosuppressive therapies ====
* [[Glucocorticoid]] therapy with  [[prednisone]] or [[prednisolone]] in [[minimal change disease]] (MCD) patients.<ref name="pmid19494796">{{cite journal |vauthors=Meyrier AY |title=Treatment of focal segmental glomerulosclerosis with immunophilin modulation: when did we stop thinking about pathogenesis? |journal=Kidney Int. |volume=76 |issue=5 |pages=487–91 |date=September 2009 |pmid=19494796 |doi=10.1038/ki.2009.204 |url=}}</ref><ref name="pmid23431071">{{cite journal |vauthors=Hogan J, Radhakrishnan J |title=The treatment of minimal change disease in adults |journal=J. Am. Soc. Nephrol. |volume=24 |issue=5 |pages=702–11 |date=April 2013 |pmid=23431071 |doi=10.1681/ASN.2012070734 |url=}}</ref><ref name="pmid3747335">{{cite journal |vauthors=Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams DG |title=Adult-onset minimal change nephrotic syndrome: a long-term follow-up |journal=Kidney Int. |volume=29 |issue=6 |pages=1215–23 |date=June 1986 |pmid=3747335 |doi= |url=}}</ref>
* [[Glucocorticoid]] have antiproteinuric effect on the [[glomerular filtration]] barrier apart from the [[Immunosuppression|immunosuppressive]] effect.<ref name="pmid4916790">{{cite journal |vauthors=Black DA, Rose G, Brewer DB |title=Controlled trial of prednisone in adult patients with the nephrotic syndrome |journal=Br Med J |volume=3 |issue=5720 |pages=421–6 |date=August 1970 |pmid=4916790 |pmc=1701394 |doi= |url=}}</ref>
** Preferred regimen (1): [[prednisone]] 60 mg/day for eight weeks.
* In MCD patients who are treated with low-dose [[prednisone]] had shown [[Remission (medicine)|remission]] of [[proteinuria]] in 75% of the patients.<ref name="pmid49167902">{{cite journal |vauthors=Black DA, Rose G, Brewer DB |title=Controlled trial of prednisone in adult patients with the nephrotic syndrome |journal=Br Med J |volume=3 |issue=5720 |pages=421–6 |date=August 1970 |pmid=4916790 |pmc=1701394 |doi= |url=}}</ref>
'''Rituximab'''
* [[Rituximab]] is used in both adults and children patients who are positive for minimal change disease.<ref name="pmid23338210">{{cite journal |vauthors=Sinha A, Bagga A |title=Rituximab therapy in nephrotic syndrome: implications for patients' management |journal=Nat Rev Nephrol |volume=9 |issue=3 |pages=154–69 |date=March 2013 |pmid=23338210 |doi=10.1038/nrneph.2012.289 |url=}}</ref><ref name="pmid21762648">{{cite journal |vauthors=Hoxha E, Stahl RA, Harendza S |title=Rituximab in adult patients with immunosuppressive-dependent minimal change disease |journal=Clin. Nephrol. |volume=76 |issue=2 |pages=151–8 |date=August 2011 |pmid=21762648 |doi= |url=}}</ref>
 
* A human [[Monoclonal antibodies|monoclonal antibody]] that identifies the [[CD20]] on B-lymphocytes.<ref name="pmid23739238">{{cite journal |vauthors=Ravani P, Ponticelli A, Siciliano C, Fornoni A, Magnasco A, Sica F, Bodria M, Caridi G, Wei C, Belingheri M, Ghio L, Merscher-Gomez S, Edefonti A, Pasini A, Montini G, Murtas C, Wang X, Muruve D, Vaglio A, Martorana D, Pani A, Scolari F, Reiser J, Ghiggeri GM |title=Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome |journal=Kidney Int. |volume=84 |issue=5 |pages=1025–33 |date=November 2013 |pmid=23739238 |pmc=3816123 |doi=10.1038/ki.2013.211 |url=}}</ref><ref name="pmid18465150">{{cite journal |vauthors=Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H, Raynaud N, Taque S, Ronco P, Bouissou F |title=Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases |journal=Pediatr. Nephrol. |volume=23 |issue=8 |pages=1269–79 |date=August 2008 |pmid=18465150 |doi=10.1007/s00467-008-0814-1 |url=}}</ref><ref name="pmid21566104">{{cite journal |vauthors=Ravani P, Magnasco A, Edefonti A, Murer L, Rossi R, Ghio L, Benetti E, Scozzola F, Pasini A, Dallera N, Sica F, Belingheri M, Scolari F, Ghiggeri GM |title=Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial |journal=Clin J Am Soc Nephrol |volume=6 |issue=6 |pages=1308–15 |date=June 2011 |pmid=21566104 |pmc=3109926 |doi=10.2215/CJN.09421010 |url=}}</ref>
 
* [[Rituximab]] is used in the treatment on another diseases along with MCD, [[membranous nephropathy]], [[Focal segmental glomerulosclerosis|FSGS]].
* In severe steroid-dependent minimal change disease patients [[rituximab]] is efficient and safe.<ref name="pmid23325085">{{cite journal |vauthors=Munyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R, Deschênes G, Ronco PM, Plaisier EM, Dahan KY |title=Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease |journal=Kidney Int. |volume=83 |issue=3 |pages=511–6 |date=March 2013 |pmid=23325085 |doi=10.1038/ki.2012.444 |url=}}</ref>
* In MCD patients [[rituximab]] may be considered as a radical [[therapeutic]] agent for patients with [[steroid]]-dependent MCNS.<ref name="pmid25546674">{{cite journal |vauthors=Iwabuchi Y, Takei T, Moriyama T, Itabashi M, Nitta K |title=Long-term prognosis of adult patients with steroid-dependent minimal change nephrotic syndrome following rituximab treatment |journal=Medicine (Baltimore) |volume=93 |issue=29 |pages=e300 |date=December 2014 |pmid=25546674 |pmc=4602588 |doi=10.1097/MD.0000000000000300 |url=}}</ref>
 
==References==
==References==
{{reflist|2}}
{{reflist|2}}
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[[Category:Needs content]]
[[Category:Nephrology]]
[[Category:Disease]]
[[Category:Disease]]
[[Category:Kidney diseases]]
[[Category:Kidney diseases]]
[[Category:Urology]]
[[Category:Urology]]

Latest revision as of 14:52, 13 June 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Overview

Pharmacologic therapy using corticosteroids is considered the mainstay of therapy for minimal change disease. According to the National Kidney Foundation (NKF) Kidney Disease – Improve Global Outcomes (KGIDO) guidelines in 2012, initial empirical treatment using corticosteroids in patients presenting with nephrotic syndrome prior to a kidney biopsy is recommended. Notably also, the use of statins for hyperlipidemia and ACE-I or ARB for proteinuria are both not recommended in patients presenting with the initial episode of MCD.

Medical Therapy

  • According to Children's Nephrotic Syndrome Consensus Conference Pharmacologic medical therapy is recommended among patients with minimal change disease are following

Initial therapy for children

  •  Pediatric
    • Preferred regimen (1): Prednisone  2 mg/kg per day for six weeks[1][2]
      • Followed by alternate-day prednisone of 1.5 mg/kg for an additional six weeks.

First relapse

  • Preferred regimen (1): Prednisone  2 mg/kg per day, until the urine protein tests shows negative results.[3]

Frequent relapses

  • Preferred regimen (1):  Prednisone therapy of 2 mg/kg, until the urine protein tests shows negative results.
    • Followed by alternate-day prednisone of 1.5 mg/kg for four weeks, then taper to 0.5 mg over a two month period.

Steroid-dependent disease

  • Steroid dependence is defined as relapse during tapering of steroid therapy or within 4 weeks of steroid discontinuation.[4][5][6][7]

Initial therapy for adults

Non Immunosuppressive therapies

Rituximab

  • Rituximab is used in both adults and children patients who are positive for minimal change disease.[17][18]

References

  1. 1.0 1.1 Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH; et al. (2013). "KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis". Am J Kidney Dis. 62 (3): 403–41. doi:10.1053/j.ajkd.2013.06.002. PMID 23871408.
  2. Vivarelli M, Massella L, Ruggiero B, Emma F (February 2017). "Minimal Change Disease". Clin J Am Soc Nephrol. 12 (2): 332–345. doi:10.2215/CJN.05000516. PMC 5293332. PMID 27940460.
  3. Vivarelli, Marina; Massella, Laura; Ruggiero, Barbara; Emma, Francesco (2017). "Minimal Change Disease". Clinical Journal of the American Society of Nephrology. 12 (2): 332–345. doi:10.2215/CJN.05000516. ISSN 1555-9041.
  4. Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G; et al. (2007). "Adult minimal-change disease: clinical characteristics, treatment, and outcomes". Clin J Am Soc Nephrol. 2 (3): 445–53. doi:10.2215/CJN.03531006. PMID 17699450.
  5. Vivarelli, Marina; Massella, Laura; Ruggiero, Barbara; Emma, Francesco (2017). "Minimal Change Disease". Clinical Journal of the American Society of Nephrology. 12 (2): 332–345. doi:10.2215/CJN.05000516. ISSN 1555-9041.
  6. Vivarelli M, Massella L, Ruggiero B, Emma F (February 2017). "Minimal Change Disease". Clin J Am Soc Nephrol. 12 (2): 332–345. doi:10.2215/CJN.05000516. PMC 5293332. PMID 27940460.
  7. Fujimoto S, Yamamoto Y, Hisanaga S, Morita S, Eto T, Tanaka K (June 1991). "Minimal change nephrotic syndrome in adults: response to corticosteroid therapy and frequency of relapse". Am. J. Kidney Dis. 17 (6): 687–92. PMID 2042651.
  8. Meyrier A, Condamin MC, Broneer D (1991). "Treatment of adult idiopathic nephrotic syndrome with cyclosporin A: minimal-change disease and focal-segmental glomerulosclerosis. Collaborative Group of the French Society of Nephrology". Clin. Nephrol. 35 Suppl 1: S37–42. PMID 1860266.
  9. Nakayama M, Katafuchi R, Yanase T, Ikeda K, Tanaka H, Fujimi S (March 2002). "Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome". Am. J. Kidney Dis. 39 (3): 503–12. doi:10.1053/ajkd.2002.31400. PMID 11877569.
  10. Mak SK, Short CD, Mallick NP (November 1996). "Long-term outcome of adult-onset minimal-change nephropathy". Nephrol. Dial. Transplant. 11 (11): 2192–201. PMID 8941578.
  11. Galle J (July 2008). "Reduction of proteinuria with angiotensin receptor blockers". Nat Clin Pract Cardiovasc Med. 5 Suppl 1: S36–43. doi:10.1038/ncpcardio0806. PMID 18580865.
  12. Meyrier AY (September 2009). "Treatment of focal segmental glomerulosclerosis with immunophilin modulation: when did we stop thinking about pathogenesis?". Kidney Int. 76 (5): 487–91. doi:10.1038/ki.2009.204. PMID 19494796.
  13. Hogan J, Radhakrishnan J (April 2013). "The treatment of minimal change disease in adults". J. Am. Soc. Nephrol. 24 (5): 702–11. doi:10.1681/ASN.2012070734. PMID 23431071.
  14. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams DG (June 1986). "Adult-onset minimal change nephrotic syndrome: a long-term follow-up". Kidney Int. 29 (6): 1215–23. PMID 3747335.
  15. Black DA, Rose G, Brewer DB (August 1970). "Controlled trial of prednisone in adult patients with the nephrotic syndrome". Br Med J. 3 (5720): 421–6. PMC 1701394. PMID 4916790.
  16. Black DA, Rose G, Brewer DB (August 1970). "Controlled trial of prednisone in adult patients with the nephrotic syndrome". Br Med J. 3 (5720): 421–6. PMC 1701394. PMID 4916790.
  17. Sinha A, Bagga A (March 2013). "Rituximab therapy in nephrotic syndrome: implications for patients' management". Nat Rev Nephrol. 9 (3): 154–69. doi:10.1038/nrneph.2012.289. PMID 23338210.
  18. Hoxha E, Stahl RA, Harendza S (August 2011). "Rituximab in adult patients with immunosuppressive-dependent minimal change disease". Clin. Nephrol. 76 (2): 151–8. PMID 21762648.
  19. Ravani P, Ponticelli A, Siciliano C, Fornoni A, Magnasco A, Sica F, Bodria M, Caridi G, Wei C, Belingheri M, Ghio L, Merscher-Gomez S, Edefonti A, Pasini A, Montini G, Murtas C, Wang X, Muruve D, Vaglio A, Martorana D, Pani A, Scolari F, Reiser J, Ghiggeri GM (November 2013). "Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome". Kidney Int. 84 (5): 1025–33. doi:10.1038/ki.2013.211. PMC 3816123. PMID 23739238.
  20. Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H, Raynaud N, Taque S, Ronco P, Bouissou F (August 2008). "Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases". Pediatr. Nephrol. 23 (8): 1269–79. doi:10.1007/s00467-008-0814-1. PMID 18465150.
  21. Ravani P, Magnasco A, Edefonti A, Murer L, Rossi R, Ghio L, Benetti E, Scozzola F, Pasini A, Dallera N, Sica F, Belingheri M, Scolari F, Ghiggeri GM (June 2011). "Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial". Clin J Am Soc Nephrol. 6 (6): 1308–15. doi:10.2215/CJN.09421010. PMC 3109926. PMID 21566104.
  22. Munyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R, Deschênes G, Ronco PM, Plaisier EM, Dahan KY (March 2013). "Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease". Kidney Int. 83 (3): 511–6. doi:10.1038/ki.2012.444. PMID 23325085.
  23. Iwabuchi Y, Takei T, Moriyama T, Itabashi M, Nitta K (December 2014). "Long-term prognosis of adult patients with steroid-dependent minimal change nephrotic syndrome following rituximab treatment". Medicine (Baltimore). 93 (29): e300. doi:10.1097/MD.0000000000000300. PMC 4602588. PMID 25546674.

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