immunoglobulin ( ig ) g4-related disease ( igg4-rd ) is characterized by increased serum igg4 levels , caused by the infiltration of igg4-positive cells into various organs [ 13 ] . renal involvement has been reported in 915  % of igg4-rd [ 4 , 5 ] . in the latest review , 37 cases of igg4-related kidney disease were reviewed . in all cases , tubulointerstitial nephritis ( tin ) was a dominant feature and glomerular involvement was reported in 24  % : 3 cases with membranous nephropathy ( mn ) , 1 with membranoproliferative glomerulonephritis , 4 with mesangial proliferative glomerulonephritis , and 1 with endocapillary proliferative glomerulonephritis . although igg4-related kidney disease does not include cases in which the glomerular lesion is the sole kidney lesion without tin [ 7 , 8 ] , a literature review revealed two case reports in which glomerular lesions were the only renal abnormalities associated with igag4-rd [ 9 , 10 ] . in these case reports , m - type phospholipase a2 receptor ( pla2r ) was identified as a possible target antigen in imn and autoantibodies against pla2r detected in serum samples from patients with imn were mainly of igg4 subclass . furthermore , type 2 helper t cells produce cytokines which stimulate b cells to produce igg4 in both igg4-rd   and imn . on the other hand , the patient presented with igg4-dominant deposit in the glomerular capillary wall and no associated tin . the degree of proteinuria and serum igg4 levels were associated and serum anti - pla2r antibody was negative . the patient is a 58-year - old japanese man with no previous medical history . in september 2010 , he presented with anorexia . urinalysis , renal function , serum total protein , and albumin levels were as follows : urinalysis : 3 + protein and 3 + occult blood , blood urea nitrogen 17  mg / dl ( 6.0  mmol / l ) , serum creatinine 0.67  mg / dl ( 51.1  mol / l ) , total protein 6.2  g / dl ( 62 g / l ) . enhanced computed tomography of the abdomen showed localized tumor on the pancreatic head with no kidney abnormalities . magnetic resonance cholangiopancreatography showed tumor on the pancreatic head without pancreatic duct dilation and stenosis . histological examination of the pancreas showed diffuse infiltration of plasma cells and lymphocytes without evidence of malignancy ( fig . immunohistochemistry for igg4 showed more than 10 labeling plasma cells in the high power field ( fig . the histological characteristics met the diagnostic criteria for type 1 autoimmune pancreatitis by the ministry of labor , health and welfare of japan .fig .  1 
 a , b pancreatic tissues , c  i kidney biopsy . a diffuse infiltration of plasma cells and lymphocytes in pancreatic tissue ( h&e , 40 ) . b immunohistochemistry on paraffin tissue for igg4 : the stain showed diffuse and dense labeling of infiltrated plasma cells ( 40 ) . c well - preserved structure of glomeruli were observed by light microscopic examination of the renal biopsy ( periodic acid - schiff stain , 40 ) . d no cellular infiltration was seen in the interstitium ( periodic acid - schiff stain , 10 ) . i electron microscopy showed subepithelial deposits 
 
 a , b pancreatic tissues , c  i kidney biopsy . a diffuse infiltration of plasma cells and lymphocytes in pancreatic tissue ( h&e , 40 ) . b immunohistochemistry on paraffin tissue for igg4 : the stain showed diffuse and dense labeling of infiltrated plasma cells ( 40 ) . c well - preserved structure of glomeruli were observed by light microscopic examination of the renal biopsy ( periodic acid - schiff stain , 40 ) . d no cellular infiltration was seen in the interstitium ( periodic acid - schiff stain , 10 ) . i electron microscopy showed subepithelial deposits after the surgery , the patient developed ascites and lower extremity edema . g / l ) and 24-h urinary protein excretion was 15.7  g. he also developed portal vein thrombosis . in december , he was transferred to our hospital for the evaluation of nephrotic syndrome . on admission , he was taking candesartan , furosemide , spironolactone , warfarin , aspirin , famotidine , and voglibose . on examination other laboratory data were as follows ( reference range in parentheses ) : blood urea nitrogen : 13  mg / dl ( 4.6 mmol / l ) , serum creatinine : 0.7  mg / dl ( 53.4  mol / l ) , albumin : 1.8  g / dl ( 18 g / l ) , total cholesterol : 140  mg / dl , c - reactive protein : 0.01  mg / dl ( 9.52  nmol / l ) , hepatitis b surface antigen : negative , hepatitis c antibody : negative , antinuclear antibody : negative , c3 : 85.3 ( 65135 ) mg / dl , c4 : 22.0 ( 1335 ) mg / dl , igg : 934 ( 8701700 ) mg / dl ( 9.34 g / l ) , iga : 148 ( 110410 ) mg / dl ( 1480  mg / l ) , and igm : 70 ( 35220 ) mg / dl ( 700  mg his serum igg4 level was elevated to 377 ( 8105 )  mg / dl . in january 2011 light microscopy showed normocellular glomeruli with mild thickening of the glomerular capillary walls and normal mesangial matrix ( fig . intense igg4 staining was observed along the glomerular capillary walls and was absent in other components ( fig . enzyme - linked immunosorbent assay for pla2r was performed using 0.5  g of recombinant human pla2r ( 21663 amino acid ) per well as an antigen . , horseradish peroxidase - conjugated anti - human igg1g4 diluted 1:1500 was added ( igg1 , 3 , 4 : abcam , tokyo , japan and igg2 : invitrogen , yokohama , japan ) . absorbance at 450  nm was 0.093 for igg4 [ negative control ( healthy person ) 0.050 , positive control ( a patient with imn ) 1.677 ] . absorbance at 450  nm for igg13 was not significantly elevated compared with the negative control . the patient was treated with prednisolone ( 60  mg / day , tapered to 5  mg / day in 7  months ) and cyclosporine . there was improvement in the urine protein to creatinine ratio , but serum albumin remained low ( fig .  2 ) . three months later , cyclosporine was discontinued and monthly intravenous pulse cyclophosphamide was started ( fig . after the initiation of cyclophosphamide , there was improvement in the urine protein to creatinine ratio and serum albumin . his serum igg4 level decreased to 117  mg / dl , concomitantly with the improvement in proteinuria ( fig .  2 ) . his serum igg4 level increased to 187  mg / dl , concomitantly with the increase in proteinuria ( fig .  2 ) . there was improvement in the urine protein to creatinine ratio and his serum igg4 level was 75.6  mg / dl ( fig . the serum igg4 decreased in association with the resolution of proteinuria 
  the clinical course of membranous nephropathy ( mn ) and change in serum igg4 . this case has several distinct features compared with previous reports : ( 1 ) the severity of proteinuria was associated with the serum igg4 level ; ( 2 ) anti - pla2r antibody was negative ; ( 3 ) immunofluorescence staining showed igg4-dominant deposition among igg subclasses in the glomerular capillary wall ; ( 4 ) no associated tin was observed . a literature review revealed 10 cases of biopsy - proven mn associated with igg4-rd [ 9 , 10 , 1724 ] . a clinical feature of mn associated with igg4-rd is that the amount of proteinuria is variable ( 24-h urine protein excretion ranging from 1.4 to 15  g / day [ 9 , 10 , 1724 ] ) , and that it is associated with variable extra - renal involvement ( 5 with pancreatitis [ 9 , 1921 , 24 ] , 1 with possible pulmonary involvement , 1 with prostatitis , 1 with lymph node involvement , and 1 with periaortitis ) , and that about half will respond well to steroid mono - therapy and the rest seems to be refractory [ 9 , 10 , 1724 ] . in our case , the patient presented with type 1 autoimmune pancreatitis and mn . twenty - four - hour proteinuria was 15.7  g. the patient achieved partial remission after multiple combinations of immunosuppressants and steroids . a pathological feature of renal involvement of igg4-rd is usually tin , and mn was observed in only 8  % of cases . as far as we know , in the literature concerning mn associated with igg4-rd , only 2 cases were without tin [ 9 , 10 ] , and in one of them , igg4 deposit was seen in the tubular basement membrane , suggesting some tubular involvement . in 7 cases examined with immunofluorescence staining for igg subclasses , igg4 staining was dominant in glomeruli in 4 [ 10 , 2123 ] , igg2 and igg3 were dominant in 2 cases [ 9 , 18 ] , and no glomerular staining was seen in one case . igg4 staining was also observed in plasma cells in the interstitium [ 17 , 2123 ] or tubular basement membrane , except for one case . our case was not associated with tin and igg4-dominant staining was seen only in the glomeruli , not in the interstitium . during renal biopsy , three cores of specimens were obtained , most of which were cortex , and tin was not observed in any of the specimens . the diagnosis of imn is usually by the exclusion of secondary causes , but several features could help the differentiation of idiopathic from secondary mn . anti - pla2r antibody was positive in 68.581.7  % of imn , whereas it was positive in only 012.2  % of secondary mn [ 12 , 2628 ] . however , in these studies , the possibility could not be excluded that the coincidental occurrence of imn with the associated disease was considered to be secondary [ 2527 ] . immunofluorescence study in imn usually shows igg4-dominant glomerular deposit , whereas igg2 or igg3 is dominant in secondary mn . the absence of circulating anti - pla2r antibody was suggestive of secondary mn in our case . also , the association of serum igg4 levels and the degree of proteinuria in our case suggests secondary mn . the level of serum igg usually decreases in a background of nephrotic syndrome , but in our case , the igg4 levels increased at the onset and during the relapse of nephrotic syndrome . this even more strongly suggests the association of serum igg4 levels and the degree of proteinuria due to membranous nephropathy , although more cases need to be studied in order to draw definite conclusions . interestingly , immunofluorescence microscopy showed intense igg4 staining along the glomerular capillary walls in our case , which is usually a feature of imn . cravedi et al .   also reported a case in which increased serum igg4 was followed by the onset of mn and anti - pla2r was negative . in their report , the serum igg4 level decreased after the treatment with rituximab , but proteinuria persisted and igg3 staining was dominant in the glomeruli , observations which are different from our case . in summary , we reported a case of mn without tin associated with igg4-rd . the association of serum igg4 and proteinuria and negative anti - pla2r antibodies suggested that mn was secondary to igg4-rd . our case suggests the possible role of igg4 in the pathogenesis of mn more clearly than previous cases . the antigen against igg4 in our case needs to be identified in a future study .
we report a case of membranous nephropathy associated with type 1 autoimmune pancreatitis . a 58-year - old man presented with anorexia . 
 work - up revealed a mass in the pancreatic head , which was subsequently resected . 
 pathological examination showed diffuse infiltration of immunoglobulin ( ig ) g4-positive plasma cells , which was compatible with the diagnosis of type 1 autoimmune pancreatitis . 
 serum igg4 was elevated . 
 he developed nephrotic syndrome around the time of the surgery . 
 kidney biopsy confirmed the diagnosis of membranous nephropathy . 
 immunofluorescent staining showed predominant glomerular igg4 deposit among igg subclasses . 
 tubulointerstitial nephritis , which is usually a dominant feature of renal involvement in igg4-related disease , was not observed . 
 the patient was treated with prednisolone and several immunosuppressants . during the course 
 , the degree of proteinuria was associated with the serum igg4 level . 
 serum antibody against phospholipase a2 receptor was negative . 
 these findings together with igg4-dominant glomerular deposit suggest that igg4 may play a unique role in the pathogenesis of secondary membranous nephropathy caused by igg4-related diseases .