tubulointerstitial nephritis is the most common renal manifestation of pss , while glomerulonephritis is unusual . membranous glomerulonephritis ( mgn ) is reported to be one of the most common pathological findings in patients with pss - related glomerulonephritis . systemic lupus erythematosus ( sle ) is generally diagnosed on the basis of clinical criteria . however , serological data are important for suggesting the possibility of sle , since antinuclear antibodies ( ana ) are closely associated with this condition , including anti - double - stranded dna ( anti - dsdna ) antibody and anti - smith ( anti - sm ) antibody [ 3 , 4 ] . in patients without these antibodies who meet the diagnostic criteria for sle , making an accurate diagnosis of lupus becomes more difficult and further investigation is needed . we report a patient who was considered to have mgn for many years , but in whom the final diagnosis was glomerulonephritis associated with pss . the relation between hyperthyroidism and exacerbation of proteinuria in this patient in march 2015 , a 36-year - old japanese woman was admitted to our hospital for exacerbation of proteinuria . she first presented to another hospital with massive proteinuria at the age of 19 years . ana was positive , and the complement titer was low . a renal biopsy specimen containing 20 glomeruli was obtained . light microscopy showed no global sclerosis and no definite spike formation on the glomerular basement membrane ( gbm ) ( fig 1 ) , but immunofluorescence revealed fine granular deposits of igg and c1q along the gbm . subepithelial electron - dense deposits ( edd ) were detected by electron microscopy ( em ) , but there were no mesangial edd or tubuloreticular inclusions . she was commenced on prednisolone ( psl ) at 50 mg daily , and also received steroid pulse therapy ( intravenous methylprednisolone at 0.5 g daily for 3 consecutive days ) and addition of cyclosporine a ( cya ) at 75 mg daily ( fig 2 ) . proteinuria relapsed ( 4 g daily ) temporarily during pregnancy , but thereafter decreased to less than 0.5 g daily . in november 2014 , proteinuria increased again to over 1 g daily . the dose of cya was increased to 150 mg daily , but proteinuria became worse . she did not drink alcohol , but had smoked 1 pack of cigarettes daily for 16 years from 20 years old . on admission in 2015 , the patient was 153 cm tall and weighed 54 kg . joint pain , neurological symptoms , and lupus - related skin lesions were all absent . laboratory findings were as follows ( table 1 ) : white blood cell count , 4,100/l ; red blood cell count , 3.67/10/l ; hemoglobin , 9.5 g / dl ; platelet count , 24.0/10/l ; total protein , 5.8 g / dl ; albumin , 2.7 g / dl ; serum urea nitrogen , 19 mg / dl ; serum creatinine , 0.59 mg / dl ; total cholesterol , 119 mg / dl ; and crp , 0.0 mg / dl . she was positive for anti - ss - a ( ro ) antibodies at a titer of 1 : 8 , but anti - dsdna antibody , anti - sm antibody , anti - ribonucleoprotein ( rnp ) antibody , anti - phospholipid antibodies ( including lupus anticoagulant and anticardiolipin antibodies ) , the direct coombs test , and anti - ss - b ( la ) antibody were all negative . serum c3 was 46 mg / dl ( normal : > 86 mg / dl ) , c4 was 7 mg / dl ( normal : > 18 mg / dl ) , and ch50 was 26 u / ml ( normal : > 30 u / ml ) . the serum level of igg was 1217 mg / dl , iga was 255 mg / dl and igm was 68.1 mg / dl . in addition , 24-h protein excretion was 4.65 g and creatinine clearance was 111 ml / min . light microscopy of the biopsy specimen contained 13 glomeruli , among which only 1 showed global sclerosis . diffuse thickening of the gbm and mesangial cell proliferation were revealed by periodic acid - schiff staining , while gbm spike formation was recognized on periodic acid methenamine - silver staining ( fig 3 ) . immunofluorescence revealed granular deposits of igg , iga , igm ( faint staining ) , c3 , c4 , and c1q along the gbm . on em , in addition to the previous subepithelial edd , new mesangial and subendothelial edd were noted . although mgn was diagnosed in 1997 , membranoproliferative glomerulonephritis ( mpgn ) with predominance of igg2 and igg4 deposits was revealed by the second renal biopsy . also , this patient was consistently negative for anti - dsdna antibody and anti - sm antibody , while being positive for anti - ss - a antibody . sicca syndrome was a definite diagnosis , because she had a positive schirmer test ( 4 mm after 5 min in both eyes ) and a positive rose bengal test . pss could also be diagnosed in this patient since her hypocomplementemia could be explained as due to cryoglobulinemia , because cryoglobulin was consistently positive at a low titer . however , renal biopsy did not show the typical histologic features of cryoglobulinemic glomerulopathy with predominance of igm deposits . the total cholesterol level usually increases in proportion to the level of proteinuria , but this patient 's total cholesterol decreased from 256 mg / dl ( 2 years previously ) to 119 mg / dl and showed an inverse relationship to proteinuria ( fig 2 ) . thyroid function tests gave the following results : thyroid - stimulating hormone ( tsh ) , 0.003 iu / ml ( normal : > 0.54 ) ; free thyroxine ( ft4 ) , 3.44 ng / dl ( normal : < 1.52 ) ; free triiodothyronine , 12.31 pg / ml ( normal : < 4.17 ) ; anti - tsh receptor antibody , 20.0 iu / l ( normal : < 2.0 ) . treatment with methiamazole was started on march 16 , but was discontinued after 2 weeks because of mild rash and leukopenia . urinary protein decreased to 0.4 g daily , serum c3 was 53 mg / dl , c4 was 14 mg / dl , and ch50 was 30 u / ml . psl was tapered from 7.5 to 4 mg daily , and cya was also reduced from 150 mg to 75 mg daily . as of december 2015 , her proteinuria remains under 0.5 mg daily . it seems likely that hyperthyroidism developed at 34 years old ( two years before diagnosis ) when the total cholesterol level decreased . light microscopy of the biopsy specimen contained 13 glomeruli , among which only 1 showed global sclerosis . diffuse thickening of the gbm and mesangial cell proliferation were revealed by periodic acid - schiff staining , while gbm spike formation was recognized on periodic acid methenamine - silver staining ( fig 3 ) . immunofluorescence revealed granular deposits of igg , iga , igm ( faint staining ) , c3 , c4 , and c1q along the gbm . on em , in addition to the previous subepithelial edd , new mesangial and subendothelial edd were noted . although mgn was diagnosed in 1997 , membranoproliferative glomerulonephritis ( mpgn ) with predominance of igg2 and igg4 deposits was revealed by the second renal biopsy . also , this patient was consistently negative for anti - dsdna antibody and anti - sm antibody , while being positive for anti - ss - a antibody . sicca syndrome was a definite diagnosis , because she had a positive schirmer test ( 4 mm after 5 min in both eyes ) and a positive rose bengal test . pss could also be diagnosed in this patient since her hypocomplementemia could be explained as due to cryoglobulinemia , because cryoglobulin was consistently positive at a low titer . however , renal biopsy did not show the typical histologic features of cryoglobulinemic glomerulopathy with predominance of igm deposits . the total cholesterol level usually increases in proportion to the level of proteinuria , but this patient 's total cholesterol decreased from 256 mg / dl ( 2 years previously ) to 119 mg / dl and showed an inverse relationship to proteinuria ( fig 2 ) . thyroid function tests gave the following results : thyroid - stimulating hormone ( tsh ) , 0.003 iu / ml ( normal : > 0.54 ) ; free thyroxine ( ft4 ) , 3.44 ng / dl ( normal : < 1.52 ) ; free triiodothyronine , 12.31 pg / ml ( normal : < 4.17 ) ; anti - tsh receptor antibody , 20.0 iu / l ( normal : < 2.0 ) . treatment with methiamazole was started on march 16 , but was discontinued after 2 weeks because of mild rash and leukopenia . urinary protein decreased to 0.4 g daily , serum c3 was 53 mg / dl , c4 was 14 mg / dl , and ch50 was 30 u / ml . psl was tapered from 7.5 to 4 mg daily , and cya was also reduced from 150 mg to 75 mg daily . as of december 2015 it seems likely that hyperthyroidism developed at 34 years old ( two years before diagnosis ) when the total cholesterol level decreased . patients with sle can be positive for various autoantibodies , including ana , anti - dsdna antibody , anti - sm antibody , anti - rnp antibody , anti - ro antibody , and anti - la antibody . among these , anti - ds dna antibody is most commonly associated with lupus nephritis ( ln ) , and its titer is usually correlated with disease activity . anti - sm antibody has also been reported to show a relation with renal disease , and this association is stronger when anti - sm antibody is positive together with anti - dsdna antibody . ln has not been reported in patients negative for both anti - dsdna and anti - sm antibodies . our patient had no deposits of igg1 and igg3 , which was inconsistent with typical ln . anti - ss - a ( ro ) antibody is more commonly associated with pss , although it is also detected in patients with ln . renal biopsy was done in 9 patients and 3 of them had chronic glomerulonephritis , including mgn , mesangioproliferative glomerulonephritis with c3 deposits , and cryoglobulinemic glomerulonephritis with igm deposits . cortez et al .   reported a 31-year - old caucasian woman with pss who developed nephrotic syndrome . renal biopsy revealed type i mpgn with fine granular deposits of igm and c3 , while em demonstrated scattered subendothelial granular dense deposits . however , this case differs from our patient who showed predominance of igg deposition , including igg2 and igg4 . renal biopsy was done in 41 patients , among whom 1 had mgn and 2 had mesangial proliferative nephritis . deposition of igg , igm , and c3 was noted , but em findings were not reported . performed a prospective cohort study of 261 patients with pss , and reported that palpable purpura , a decrease in c4 level , and mixed monoclonal cryoglobulinemia were significant predictors of glomerulonephritis in patients with pss . moreover , mpgn with deposition of igm and c3 has been reported in 6 patients . according to these previous reports , cryoglobulinemic glomerulopathy with predominant deposition of igm were the typical features of glomerulonephritis in patients with pss , but igg subclass staining was not done in patients with glomerulopathies such as mgn and mpgn . only a few case reports have described treatment using corticosteroids with or without cyclophosphamide for pss with renal disease , but such regimens have generally achieved good clinical outcomes . hyperthyroidism is considered to promote proteinuria , and vargas reported that hyperthyroidism may be related to glomerular hyperfiltration , since it resolved after treatment of the thyroid disease . there has also been a case report that graves disease can induce mgn . in conclusion , we evaluated glomerulonephritis in a patient with pss . renal biopsy at the onset of nephrotic range proteinuria revealed mgn , but repeat renal biopsy at the relapse of heavy proteinuria 16 years later showed mpgn with mesangial and subendothelial deposits as well as subepithelial deposits . in addition , igg subclass analysis identified predominant deposition of igg2 and igg4 . furthermore , this patient was consistently negative for anti - dsdna antibody and anti - sm antibody , while she was positive for anti - ss - a antibody . this patient 's nephropathy was considered to be closely related to pss . because her proteinuria subsided soon after remission of hyperthyroidism , it seems that hyperthyroidism also contributed to exacerbation of proteinuria , probably via acceleration of hyperfiltration . the present report adhered to the declaration of helsinki , and the patient gave her consent for the case report to be published .
we report a case of glomerulopathy in a 36-year - old japanese woman with primary sjgren syndrome ( pss ) . 
 the first renal biopsy suggested membranous glomerulonephritis . 
 however , repeat biopsy was performed after 16 years because of increased proteinuria , revealing membranoproliferative glomerulonephritis with mesangial deposits , subendothelial deposits , and subepithelial deposits . 
 immunofluorescent studies showed predominant deposition of igg2 and igg4 . 
 this patient was positive for antinuclear antibody and anti - ss - a antibody . 
 sicca syndrome was confirmed by a positive schirmer test and positive rose bengal test . 
 therefore , pss - related glomerulopathy was considered to be the most likely diagnosis .