immunoglobulin a nephropathy ( igan ) is the most common glomerulonephritis , and the long - term prognosis of igan is variable because of the diversity of disease activity and long - term treatments among patients . many therapeutic regimens for igan have been reported , however , some patients still respond poorly to these regimens , especially in severe or advanced igan . patients who had massive proteinuria at the time of renal biopsy had a poor renal prognosis even if they received currently accepted intensive therapy . therefore , improved treatment regimens are required for those with therapy - resistant characteristics . in this report , we describe the renal pathological findings using the oxford - mest score   and the successful treatment course of an adult igan patient with nephrotic - level proteinuria at the time of diagnosis , and we discuss the potential effects of long - term coadministration of mizoribine ( mzr ) for adult igan treatment . a 41-year - old male patient was diagnosed with proteinuria and hematuria by medical examination in june 2009 , and he consulted us in november 2009 without receiving any treatment . laboratory testing revealed blood pressure ( bp ) 142/80 mm hg , 24-hour urinary protein excretion ( upe ) 3.91 g / day , number of urinary erythrocytes ( urbc ) 5099/high - power field ( hpf ) , granular cast ( + ) , serum creatinine 0.72 mg / dl , estimated glomerular filtration rate 96 ml / min/1.73 m , and serum iga 162 mg / dl . the percentages of glomeruli showing global sclerosis , mesangial hypercellularity , segmental glomerulosclerosis , endocapillary hypercellularity , and crescents were 4.2 , 41.7 , 4.2 , 16.7 , and 12.5% ( fibrocellular crescents 6.3% , fibrous crescents 6.3% ) , respectively . based on these clinicopathological findings , a diagnosis of primary iga nephropathy was made . in accordance with the oxford - mest score , in addition , numerous cd68-positive macrophages were observed in both glomeruli and interstitium ( fig . treatment with olmesartan 20 mg / day , dipyridamole 150 mg / day , and warfarin 1 mg / day was begun ( fig . 2 ) . because he had nephrotic - level proteinuria , we could not perform tonsillectomy before corticosteroid therapy . therefore , mzr 150 mg after each breakfast and corticosteroid therapy ( 500 mg methylprednisolone for three consecutive days in months 1 , 3 , and 5 , and 0.5 mg / kg prednisolone every other day ) were initiated 2 weeks later . the oral prednisolone dosage was reduced during the next month . under this regimen , the serum concentration of mzr 3 h after administration   was 0.85 g / ml . as his bp did not fall below 130/80 mm hg , amlodipine 5 mg / day after corticosteroid therapy , upe and urbc had decreased to 0.62 g / day and 59/hpf , respectively , and the risk that he might contract the infectious disease decreased . thereafter , olmesartan was increased from 20 to 40 mg / day , and his bp was 130/68 mm hg in october . urinary findings normalized 12 months after the beginning of treatment ( upe 0.17 g / day and urbc 14/hpf ) . at present , angiotensin ii ( angii ) inhibition and corticosteroid therapy are generally used for igan treatment . to improve efficacy , a combination of nationwide survey of tsp therapy for igan in japan reported a high rate of complete remission with tsp therapy , almost 50% . unfortunately , our patient had massive proteinuria and severe pathological findings initially , which are tsp therapy - resistant characteristics . adding low - dose azathioprine ( aza ) to corticosteroids for 6 months does not benefit igan treatment . in contrast , combination therapy including aza for 2 years was effective against childhood proliferative igan . instead of aza , mzr is frequently used for childhood igan because of its relative lack of toxicity . the immunosuppressive effects of mzr have been shown to be due to the inhibition of dna synthesis in the s phase of the cell cycle . renoprotective effects of mzr , such as amelioration of tubulointerstitial fibrosis by inhibition of tubular osteopontin expression   and inhibition of renal macrophage accumulation resulting in prevention of glomerulosclerosis and interstitial fibrosis   have also been demonstrated . clinically , mzr significantly reduced proteinuria and hematuria with histological improvement and caused fewer complications than the conventional immunosuppressants . moreover , a cocktail therapy using prednisolone , mzr , warfarin , and dipyridamole decreased upe , hematuria , and renal lesions in childhood igan . the effects of this mzr combination therapy were similar to those of the aza combination , and the side effects of the mzr combination were clearly milder than those of the aza combination . these reports suggest that long - term coadministration of mzr may improve the prognosis of adult igan . kaneko et al .   reported the effects of mzr and tsp combination therapy in igan patients with an average proteinuria being below 1 g / day . in their treatment regimen , the total dose of corticosteroids was reduced instead of administering mzr . because our patient had nephrotic - level proteinuria with severe pathological findings , we decided to administer mzr for a long period as part of the combination therapy . as a result first , numerous cd68-positive macrophages were observed in both glomeruli and interstitium in this patient ( fig . mzr has been reported to attenuate renal injury and macrophage infiltration [ 9 , 10 , 13 ] . kikuchi et al .   reported that both glomerulosclerosis and interstitial fibrosis were reduced by mzr via suppression of macrophage infiltration in non - insulin - dependent diabetic rat . furthermore , tanaka et al .   reported that intraglomerular macrophage infiltration and chronicity indices tended to decrease more in patients who received immunosuppressive treatment with mzr than in patients who received immunosuppressive treatment alone , in patients with severe lupus nephritis . although , corticosteroid has strong immunosuppressive and anti - inflammatory effects , it is considered that long - term coadministration of mzr may have additive and beneficial therapeutic effects in this patient . this effect was consistent with a previous study which showed antiproteinuric effect of the addition of low - dose eplerenone ( 2550 mg / day ) to renin - angiotensin system blockers in nondiabetic chronic kidney disease patients . recent studies suggested that aldosterone exerts deleterious effects in the vascular system and kidney independently of angiotensin ii . eplerenone reduced osteopontin and expression of proinflammatory molecules , with consequent attenuation of renal damage and inflammation . in this patient , there was no remarkable fall in blood pressure after administration of low - dose eplerenone ( fig . 2 ) , suggesting effects of eplerenone might be mediated by bp - independent mechanisms [ 14 , 15 , 16 , 17 ] . a prospective cohort study will be required to clarify the characteristics of regimen - sensitive patients .
a 41-year - old male patient was admitted to our hospital due to massive proteinuria and hematuria . 
 his 24-hour urinary protein excretion and the number of urinary erythrocytes were 3.91 g / day and 5099/high - power field , respectively . 
 a renal biopsy showed a severe pathological pattern of immunoglobulin a nephropathy ( igan ) that involved marked endocapillary proliferation and segmental sclerosis ( oxford - mest score : m0 , e1 , s1 , t0 ) . because he had nephrotic - level proteinuria with severe pathological findings , which are tonsillectomy and corticosteroid pulse therapy - resistant characteristics , he received mizoribine for a long period as part of the combination therapy using corticosteroid , tonsillectomy , dipyridamole , warfarin and renin - angiotensin - aldosterone system blockers . 
 twelve months after the beginning of treatment , his urinary findings were normal . in this report 
 , we describe the pathological findings and successful treatment course , and discuss the potential effects of long - term coadministration of mizoribine for adult igan treatment .