a 19-year - old female with no significant past medical history or medication use presented to our hospital in april 2010 with severe nephrotic syndrome characterized by marked fluid retention , heavy proteinuria ( protein : creatinine ratio of 1244 mg / mmol ) , hypoalbuminaemia ( 13
g / l ) and elevated total serum cholesterol ( 9.3 mmol / l ) .
renal function was preserved with a serum creatinine of 42 mol / l , and there was no haematuria evident on urine microscopy .
lupus and vasculitis markers , hepatitis serology and serum electrophoresis were negative . a renal biopsy was performed which revealed normal glomeruli , tubules and interstitium .
the patient was commenced on prednisolone 50 mg daily ( 1 mg / kg ) in addition to ramipril 5 mg daily , simvastatin 10 mg daily and warfarin therapy .
complete remission was achieved within 2 months and prednisolone dose was reduced to 25 mg daily .
soon after , and against medical advice , the patient abruptly ceased her prednisolone and within 72 h had a relapse of disease with recurrence of gross peripheral oedema , hypoalbuminaemia of 13
g / l ) and proteinuria of 1030 mg / mmol ( from 0.06 mg / mmol ) . despite recommencing high - dose steroids ( 60 mg / day )
, the disease thereafter remained refractory to steroid therapy with persistent gross oedema , nephrotic - range proteinuria and hypoalbuminaemia ( albumin of 9
g / l ) . after failing to respond to 3 months of high - dose steroids ,
the patient was commenced on cyclophosphamide . in light of the patient 's history of non - compliance and in an effort to reduce drug exposure and toxicity , pulse intravenous cyclophosphamide
was administered in incremental doses of 0.5 , 0.75 and 1.0 g / m 1 month apart . during this period
two months after the third pulse of cyclophosphamide was administered , there was no evidence of disease response with ongoing gross oedema , hypoalbuminaemia ( albumin 14
g / l ) and heavy proteinuria ( 1476 mg / mmol ) . at this point
, it was decided to trial the monoclonal anti - cd20 antibody rituximab ( rtx ) , with two doses of 500 mg given 2 weeks apart .
complete remission was rapidly induced within 1 month of rtx therapy with resolution of oedema , rising albumin to 31 g / l and absent proteinuria ( figure  1 ) .
1.changes in serum albumin ( g / l ) and urine protein : creatinine ratio ( mg / mmol ) over time , relative to treatment modality  .
changes in serum albumin ( g / l ) and urine protein : creatinine ratio ( mg / mmol ) over time , relative to treatment modality  . the patient has remained in complete remission for more than 32 months since the two doses of rtx were administered in february 2011 .
this is despite recovery of cd19 counts back to normal levels 24 months after treatment .
mcd is the most common cause of nephrotic syndrome in children and accounts for 1025% of cases in adults . close to 75% of cases
will respond initially to a course of high - dose glucocorticosteroids but relapse commonly occurs .
steroid - sparing agents like calcineurin inhibitors and cyclophosphamide are often used for frequently relapsing or steroid - dependent mcd . besides the significant adverse side effects of these agents , a large proportion of patients relapse after cessation of these medications . while there was some suggestion that oral cyclophosphamide may be more successful than iv cyclophosphamide in achieving disease remission in refractory mcd
, larger clinical trials have suggested that both forms of therapy are equivocal with respect to relapse rates and toxicity .
there are an increasing number of reports of success of rtx therapy for steroid- and cyclosporine ( csa)-dependent nephrotic syndrome in paediatric populations [ 4 , 5 ] .
a single rtx infusion also appeared to improve response to csa therapy and had significant steroid - sparing effects in children with steroid-dependent nephrotic syndrome ( sdns ) who had developed secondary resistance to csa . in a long - term follow - up study of 37 children who received rtx for sdns
, 26 patients remained in remission after 12 months and 7 remained in remission after 24 months without further maintenance immunosuppression .
however , response to rtx has been mixed in cases of steroid-resistant nephrotic syndrome ( srns ) in children .
reported the successful use of rituximab in five patients with srns , two of which had mcd .
.   carried out a multi - centre questionnaire - based study in which the response rate in children with srns was as high as 44% . in another case
series of four children with srns , including one case of mcd , all children failed to achieve sustained remission after a single dose of rituximab , despite complete b - cell depletion . in adults ,
the first case report of the efficacy of rtx in multi - relapsing mcd was published in 2007 . since
then there have been a number of reports of success with rituximab in steroid - dependent mcd [ 12 , 13 ] .
munyentwali et al .   analysed the outcome of 17 adult patients who were treated with rtx for steroid - dependent mcd over a mean follow - up period of 29.5 months .
after the first course of rtx , 11 patients ( 65% ) did not relapse after a mean follow - up of 26.7 months .
twelve of the 17 patients ( 70% ) were free of any immunosuppressant drugs at last follow - up .
there are minimal data available regarding the use of rtx in steroid - resistant mcd in adults .
the first case report , published in 2008 , describes an adult patient with steroid- and mycophenolate mofetil - resistant mcd who remained in complete remission 1 year after initiation of rtx therapy .
a further case report was of a 23-year - old patient with steroid- and csa - resistant mcd treated with two doses of rxt with sustained complete remission at the end of 1 year .
the second dose of rtx was given at 6 months in response to a recovery of b - cell counts .
a long - term follow - up study was published recently by bruchfeld et al .   on 16 adult patients with biopsy - proven mcd of which
13 were steroid dependent , 2 multi - relapsing and 1 steroid and multi - drug resistant . in this study , the rtx dose varied from 1000 to 2800 mg .
complete remission was achieved after initial rtx treatment in 13 patients . in the remaining cases ,
partial remission was achieved in all except the patient with steroid- and multi - drug - resistant disease .
relapses can often occur after the reappearance of cd19 cells , although this is not always the case [ 12 , 14 ] .
guigonis et al .   found a consistent association between relapses ( 3 of 22 paediatric patients ) and an increase in cd19 cells which occurred at a median time of 11 months ( range 839 months ) .
sellier - leclerc et al .   evaluated disease outcome after a minimum cd19 depletion period of 15 months obtained by repeated rtx infusion and found that it induced long - term remission even after definitive cd19 recovery in almost two thirds of the paediatric patients without the use of maintenance oral immunosuppressive drugs .
the rtx dosing has varied greatly in various reports including a single dose , doses of 500 or 1000 mg given at one or two time - points and 375 mg / m once weekly for 4 weeks . in the study by munyentwali et al .
we report a unique case of steroid- and cyclophosphamide - resistant mcd responding rapidly to two doses of rtx at 500 mg each , with sustained complete remission even after cd19 recovery .
as discussed , rtx has been shown to be efficacious in a growing number of small case series in steroid - sensitive and steroid - dependent mcd ; however , reported success of its use in multi - drug - resistant disease , particularly in adults , remains limited . in our case ,
clearly , a well - conducted multi - centred clinical trial of rtx for mcd is warranted either as a first - line agent or in cases of steroid - dependent and/or -resistant disease .
the results presented in this paper have not been published previously in whole or part , except in abstract format .
 we report a case of steroid- and cyclophosphamide - resistant nephrotic syndrome secondary to minimal - change disease occurring in an otherwise healthy 19-year - old female , responding rapidly to two doses of rituximab therapy . 
 complete disease remission has been sustained up to last follow - up ( 32 months ) despite cd19 recovery . 
 literature review suggests emerging evidence that rituximab may have a role to play in recurrent and/or refractory minimal - change disease . 
Case report
Discussion
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