henoch - schnlein purpura nephritis ( hspn ) occurs in 2060  % of henoch - schnlein purpura ( hsp ) patients . the majority of the children with hspn present only hematuria and/or low - grade proteinuria , and have a good chance to recover with favorable renal prognosis . however , patients with > 50  % crescent formation , nephrotic syndrome , or renal insufficiency at onset are at a risk of poor outcome . previous studies have reported severe pediatric hspn patients treated with immunosuppressive agents , including corticosteroid , cyclophosphamide ( cyc ) , cyclosporin a ( csa ) , and azathioprine ( aza ) , but the data from these interventions are not conclusive , as discussed in the recent cochrane review . further , it was recently reported that a patient with severe hspn was successfully treated by intravenous cyclophosphamide therapy ( ivcy ) combined with cocktail therapy , proposing a new type of treatment for this subset of severe hspn patients [ 35 ] . we report a case of 6-year - old boy with hspn who presented with nephrotic syndrome and severe histopathological features ( > 50  % crescent formation ) . he was successfully treated with methylprednisolone pulse therapy ( mpt ) and ivcy followed by cocktail therapy ( prednisolone , aza , dipyridamole , and enarapril ) . a 6-year - old boy was admitted to our hospital 2  weeks after hspn onset , because proteinuria and hematuria had worsened . his family and medical history were unremarkable , and purpura , abdominal pain , or arthritis was not evident on physical examination . his blood pressure was 98/65  mmhg ; serum total protein level 4.5  g  dl , albumin 2.2  g  dl , blood urea nitrogen 8.0  mg  dl , serum creatinine 0.38  mg  dl , estimated glomerular filtration rate ( egfr ) by the schwartz formula   111  ml  min per 1.73  m , iga 138  mg  dl . dipstick urinalysis showed results of 3 + for occult blood and 3 + for protein . the early morning urine - protein to creatinine ratio was 19.2  g / g  cr . on initial biopsy , light microscopy revealed 29 glomeruli , diffuse mesangial proliferation , infiltration of polymorphonuclear leukocytes in glomerular capillaries , and presence of cellular crescents ( 16 of 29 glomeruli , 55  % ) and adhesions ( 6 of 29 glomeruli , 21  % ) immunofluorescence ( if ) showed predominant granular deposition of iga ( 3 + ) , c3 ( 3 + ) , igg ( + ) , and igm ( + ) in the mesangial areas ( fig .  1 ) . based on the histopathological findings , he was diagnosed with international study of kidney disease in children ( iskdc ) grade ivb.fig . d initial renal biopsy findings a light microscopy reveals diffuse global mesangial proliferation , and infiltration of polymorphonuclear leukocytes ( arrow ) . c , d immunofluorescence ( if ) analysis of iga and c3 showing predominant granular deposition in the mesangial area ; original magnification , 200 . panels e  h second renal biopsy findings e , f light microscopy revealed that the mesangial proliferation was extremely improved . g , h if analysis of iga and c3 , showing predominant granular deposition in the mesangial area , similar to the initial biopsy findings . however , the intensity is reduced ; original magnification , 200 
  renal biopsy findings . d initial renal biopsy findings a light microscopy reveals diffuse global mesangial proliferation , and infiltration of polymorphonuclear leukocytes ( arrow ) . c , d immunofluorescence ( if ) analysis of iga and c3 showing predominant granular deposition in the mesangial area ; original magnification , 200 . panels e  h second renal biopsy findings e , f light microscopy revealed that the mesangial proliferation was extremely improved . g , h if analysis of iga and c3 , showing predominant granular deposition in the mesangial area , similar to the initial biopsy findings . however , the intensity is reduced ; original magnification , 200 after obtaining written informed consent , the patient first received mpt ( 30  mg  kg  day for three consecutive days / week ) for 4  weeks , followed by cocktail therapy comprising oral prednisolone ( 2  mg  kg  day ) every other day , and dipyridamole ( 5  mg  kg  day ) . the patient was sequentially treated with ivcy ( 5001,000  mg  m once a month for 7  months ; total 6,000  mg  m ) , followed by aza ( 50  mg  day ) and enarapril ( 2.5  mg  day ) after 3  months , the dosage of prednisolone was decreased every alternate day by 1  mg  kg  day . the proteinuria resolved within 2  months of initiation of ivcy treatment , and hematuria , within 4  months ( fig .  2 ) . tonsillectomy was then performed as an add - on therapy 7  months after initiation of ivcy treatment in order to maintain remission.fig . after initial renal biopsy , treatment with mpt , followed by cocktail therapy ( oral prednisolone , and dipyridamole ) was unsuccessful , after which he was treated by ivcy therapy followed by azathioprine and enarapril . after this , proteinuria and hematuria gradually improved and the patient achieved complete remission within 7  months of the onset of hspn . mpt methylprednisolone pulse therapy , ivcy intravenous cyclophosphamide therapy , psl prednisolone , aza azathioprine , ob occult blood , rbx renal biopsy 
  patient s clinical course . after initial renal biopsy , treatment with mpt , followed by cocktail therapy ( oral prednisolone , and dipyridamole ) was unsuccessful , after which he was treated by ivcy therapy followed by azathioprine and enarapril . after this , proteinuria and hematuria gradually improved and the patient achieved complete remission within 7  months of the onset of hspn . mpt methylprednisolone pulse therapy , ivcy intravenous cyclophosphamide therapy , psl prednisolone , aza azathioprine , ob occult blood , rbx renal biopsy the second renal biopsy was performed 22  months after the first biopsy to confirm treatment efficacy . physical examination did not reveal any remarkable findings . blood pressure and biochemical test results were normal : serum total protein 6.4  g  dl , albumin 4.4  g  dl , blood urea nitrogen 11.2  mg  dl , serum creatinine 0.42  mg  dl , egfr 112  ml  min per 1.73  m , cystatin c 0.89  mg light microscopy revealed 54 glomeruli , focal segmental mesangial proliferation , and presence of adhesions ( 7 of 54 glomeruli , 13  % ) . the if showed predominant granular deposition of iga ( 2 + ) , c3 ( + ) , igg ( + ) , and igm ( + ) in the mesangial areas ; however , with less intensity ( fig .  1 ) . medication except enarapril was tapered off 24  months after hspn onset ( fig .  2 ) . within 5  years of onset , blood pressure , urinary findings , and renal function were normal ( serum creatinine , 0.67  mg  dl and cystatin c , 0.67  mg cyc is used in pediatric renal diseases primarily for rapidly progressive glomerulonephritis , lupus nephritis , and nephrotic syndrome . despite uncontrolled study , early treatment with oral psl and cyc ( 2  mg / kg / day for 8  weeks ) was found to be effective in nine children with clinically severe forms of hspn . at the latest follow - up ( mean interval 78  months ) , all except two showed negative proteinuria while no patient showed renal impairment . however , randomized study by tarshish et al .   showed that oral cyc ( 90  mg / m / day for 42  days ) as single therapy was less effective than supportive therapy for histopathologically severe hspn patients . at final follow - up ( mean time , 3.71  years ) , 3 out of 28 patients ( 11.0  % ) in the oral cyc group and 4 out of 28 patients ( 14.3  % ) in the control group progressed to end - stage renal disease . no differences in outcome were found between the treatment trial and the control group . on the other hand , rasche et al .   prospectively reported that ivcy ( 750  mg  m once a month for 6  months ) and low dose oral prednisolone is effective in decreasing proteinuria and preserving renal function in patients with advanced progressive iga nephropathy , which is similar to hspn . the loss of renal function per year significantly reduced from 16  % before therapy to 4  % after therapy . another prospective study by tumlin et al .   has shown that ivcy ( 500750  mg  m once a month for 6  months ) combined with mpt reduced proliferative lesions and proteinuria , and stabilized renal function in patients with the crescentic iga nephropathy . to determine the long - term efficacy of the treatment , 12 treated patients were compared to 12 historical controls matched for the severity of iga on initial biopsy . after 36  months , the incidence of end - stage renal disease in the treated group was lower ( 1/12 ) than that in the historical controls ( 5/12 ) . furthermore , in two recent reports , ivcy was effective in treating adults with hspn who were resistant to various treatments [ 3 , 5 ] . lpez meiller et al . , used 1000  mg  m once a month for 6  months , and namba et al . , used 375  mg  m once a month for 5  months to treat hspn in adults . in addition , there is another report that showed the efficacy of ivcy ( 500750  mg  m once a month for 16  months ) combined with corticosteroids , and angiotensin - converting enzyme inhibitor / angiotensin receptor blocker for pediatric patients with severe hspn and iga nephropathy . further , the meta - analysis by groot et al .   demonstrated that in patients with wegener s granulomatosis and microscopic polyangiitis , ivcy is more effective in preventing relapses and has significantly lower risk of infections and leucopenia than oral cyc . for these reasons , we judged that , although the evidence about the long - term renal prognosis of ivcy is insufficient , ivcy was effective for achieving prompt complete remission and maintaining the remission . therefore , we selected a similar ivcy treatment regimen ( 5001,000  mg  m once a month for 7  months ; total 6,000  mg  m ) and not the oral cyc treatment regimen . in our patient , histopathology indicated disease of grade iskdc ivb and he developed nephrotic syndrome at the onset ; so it was predicted that renal prognosis was very poor . few papers have reported about the long - term renal prognosis of severe hspn patient treated with various immunosuppressive drugs . niaudet et al .   reported that mpt followed by oral prednisolone ( 3.5  months ) was effective for severe hspn , but about 10  % of patients in their study progressed to end - stage renal disease at the latest follow - up , 116  years after the initiation of therapy . dual therapy with aza and oral steroids resulted in similar outcomes at follow - up after 32  months . in addition , shenoy et al .   have reported the efficacy of treatment protocol comprising daily steroids and oral cyc ( 22.5  mg / kg / day for 812  weeks ) followed by aza . after a mean follow - up period of 7  years following presentation , 14.8  % had progressed to end - stage kidney failure . from the above - mentioned reports , we judged that the effect of mpt and cocktail therapy ( steroid , aza , and oral cyc ) are insufficient for our patient . therefore , it was necessary for further immunosuppressive therapies to be provided as well as ivcy for maintaining complete remission and preserving renal function . our patient underwent tonsillectomy as an add - on therapy when there was no urinary abnormality . in the recent reports , tonsillectomy was associated with a favorable renal outcome of iga nephropathy in terms of clinical remission and delayed renal deterioration even in non - steroid - treated patients . it was also reported that tonsillectomy and mpt compared with mpt alone has a favorable effect on long - term renal survival in patients with iga nephropathy . there have been some reports on the efficacy of combination of tonsillectomy and mpt in treating severe hspn in adults and children [ 1719 ] . it was concluded that tonsillectomy appeared to contribute to the prevention of hspn relapses and the maintenance of the renal function . in another study , inoue et al . reported that tonsillectomy alone might be able to prevent the complications of hspn , thereby contributing to early recovery from hsp in children . however , there are no studies with discussion about whether monotherapeutic tonsillectomy is effective or not for long - term renal prognosis for hspn , and even igan , when urinary findings are normal . hence , further studies about the efficacy of monotherapeutic tonsillectomy for severe hspn patients without urinary abnormality are needed . further , csa therapy is performed in combination or as an add - on therapy with corticosteroids . there have been a few case reports suggesting that csa may have a beneficial effect in children with severe hspn [ 2123 ] . however , the effect is restrictive , and the optimal dose , target trough level concentration , and duration of csa treatment are not known in the treatment of hspn . the most common side effects of csa were hirsutism ( 82  % ) , gingival hypertrophy ( 45  % ) , and transient elevation in serum creatinine ( 45  % ) . the csa nephrotoxicity for hspn , which is characterized by arteriolopathy and striped interstitial fibrosis with tubular atrophy , is not well studied yet . the cyc is known to cause oncogenicity and gonadal dysfunction , which is influenced by cumulative dose , sex , and age . gonadal dysfunction affects boys more than girls , and in the puberty stage than in prepuberty . according to a meta - analysis of renal disease and malignant tumor in prepubertal boys , the minimum cumulative dose causing gonadal dysfunction is 300400  mg  kg . our patient was prepubertal and the cumulative dose he received was 6,000  mg  m ( approximately 200  mg  kg ) , which can be considered safe . however , it is recently reported that gonadal dysfunction can occur even when less than 300400  mg / kg of cyc is administered . therefore , careful informed consent is necessary . nevertheless , malignancy is rare , with only one report of association between malignancy and cyc in a 6-year - old boy with nephrotic syndrome who developed bladder cancer after 4  years of treatment with 49.5  g cyc . in addition , combination of enough hydration and administration of mesna is established in preventing hemorrhagic cystitis . the importance and efficacy of a prompt treatment has been well demonstrated in achieving complete remission in patients with severe hspn [ 7 , 27 , 28 ] . all these reports suggest that the early suppression of disease activity by immunosuppressant or elimination of circulating immune complexes is essential for attaining clinical remission of hspn . however , even after such aggressive and prompt therapeutic approaches , a subset of hspn patients do not respond well and may progress to end - stage renal failure through successive flare - ups [ 2729 ] . we observed that only mpt was not effective in our patient and hence , treated him with ivcy combined with cocktail therapy ( psl , aza , dipyridamole , and ace inhibitor ) . as a result , he achieved complete remission promptly , and on the second biopsy , the histopathological findings had significantly improved ( crescents had disappeared ) . after 5  years of the onset of hspn , complete remission and normal renal function are maintained only by ace inhibitor . however , renal impairment sometimes occurs among patients with transient resolution of renal manifestations , especially for histologically severe hspn . , our case demonstrated that mpt plus ivcy treatment combined with cocktail therapy could not only achieve early complete remission but also maintained remission and normal renal function . therefore , it appears that ivcy combined with cocktail therapy as add - on therapy to mpt is effective in treating severe hspn , which could not be promptly treated with other agents . our case provides a theoretical ground for the use of ivcy in the treatment of severe hspn , together with an anecdotal evidence of its efficacy . however , further clinical trials are necessary to confirm whether ivcy is effective in treating severe hspn .
henoch - schnlein purpura ( hsp ) is a common self - limited vasculitis in children . 
 the long - term prognosis depends on renal involvement . in severe henoch - schnlein purpura nephritis ( hspn ) 
 patients , > 50  % have crescent formation and nephrotic syndrome that are important predicted outcomes . therefore , for such patients , an aggressive immunosuppressive therapy is needed to prevent the progression . however , there is no consensus for an appropriate therapeutic regimen for severe pediatric hspn patients . in this paper 
 , we have reported on a 6-year - old boy who presented with hspn with nephrotic syndrome and severe histopathological abnormalities ; he was diagnosed with international study of kidney disease in children ( iskdc ) grade ivb . despite treatment with methylprednisolone pulse therapy , followed by oral prednisolone and dipyridamole ; the nephrotic syndrome persisted . 
 subsequently , intravenous cyclophosphamide therapy ( ivcy ) ( 5001,000  mg  m2 once a month for 7  months ; total 6,000  mg  m2 ) was administered , followed by azathioprine and enarapril . within 7  months of disease onset 
 , complete remission was achieved . 
 after 22  months of the initial renal biopsy , the second biopsy was performed to confirm treatment efficacy . 
 histopathological findings improved , and iskdc grade iiia was diagnosed . even after 5  years of hspn onset , complete remission and normal renal function is maintained . 
 although our evidence is restricted to single patient , we have shown that mpt and ivcy combined with cocktail therapy may be an effective treatment for severe pediatric hspn .