it is currently the mainstay immunotherapy of relapsing - remitting multiple sclerosis ( ms ) .
we present a case of an ms patient who developed nephrotic - range proteinuria following ifn- treatment over a timespan of more than 9 years .
the histology was suggestive of membrano proliferative glomerulonephritis ( mpgn ) , but the absence of immune - complex deposition suggested a non - immune ifn--related disease .
this is a case report of a 37-year - old female who was referred to our renal outpatient clinic with the incidental finding of proteinuria determined by dipstick .
she had been on long - term ifn- 44 g three times weekly for most of this time .
she had a normal pregnancy 10 years previously ( a year prior to her ms diagnosis ) .
she denied haematuria , rash , arthralgia , weight loss , nose bleeds and haemoptysis . at the time of presentation in clinic
, she had a urine albumin creatinine ratio ( uacr ) of 268 mmol / l , equivalent to a protein leak of about 2.5 g/24 h. her serum creatinine ( cr ) was 60 mol / l , albumin 28 g / l , haemoglobin 11.5 g / dl , adjusted calcium 2.3 mmol / l , c - reactive protein ( crp ) of 2 mg / l and normal complement levels ( c3 0.98 g / l and c4 0.19
an angiotensin - converting enzyme ( ace ) inhibitor was introduced at this point ( figure  1 ) .
subsequently , urine culture , anti - glomerular basement membrane antibodies , myeloma screen , hepatitis b and c serology and human immunodeficiency virus were all negative .
the ultrasonography showed unequal size kidneys , the right kidney measuring 10 cm and the left 12.5 cm in length . 

, we represent the timing of biochemical parameters : serum creatinine levels , serum albumin levels , albuminuria ( expressed as uacr , urine albumin creatinine ratio ) and serum inflammatory markers as c - reactive protein ( crp ) .
our patient was on long - term ifn- treatment since the diagnosis of multiple sclerosis ( ms ) , 9 years prior to the clinic review . on july 2012 , she developed nephroticrange proteinuria with slight deterioration in kidney function and a drop in the serum albumin levels but normal crp .
at this point , an ace inhibitor was introduced and the renal biopsy date was arranged .
based on the biopsy results , ifn- was switched to glatiramer acetate , with progressive improvement of the proteinuria even after stopping the ace inhibitor .
above , we represent the timing of biochemical parameters : serum creatinine levels , serum albumin levels , albuminuria ( expressed as uacr , urine albumin creatinine ratio ) and serum inflammatory markers as c - reactive protein ( crp ) .
our patient was on long - term ifn- treatment since the diagnosis of multiple sclerosis ( ms ) , 9 years prior to the clinic review . on july 2012 , she developed nephroticrange proteinuria with slight deterioration in kidney function and a drop in the serum albumin levels but normal crp .
at this point , an ace inhibitor was introduced and the renal biopsy date was arranged .
based on the biopsy results , ifn- was switched to glatiramer acetate , with progressive improvement of the proteinuria even after stopping the ace inhibitor .
the renal biopsy showed 11 glomeruli with a general increase in the cellularity predominantly in the mesangium ( figure  2a ) .
the glomerular capillary basement membrane showed foci of basement membrane irregularity and few foci of 
the electron micrographs confirmed focal mesangial cell interposition ( figure  2d ) , with new basement membrane material deposited on the internal surface .
woolly accumulations of slightly electron - dense material , but these did not have the typical morphology of immune complex - type electron deposit ( figure  2c ) .
there were mild mesangial cell interposition and basement membrane irregularities , with no more than a hint of glomerular hyper cellularity .
the immunofluorescence showed a partly particulate deposition of predominantly c3 within the mesangium with a lesser deposition of igg , m and a. the renal biopsy report concluded that in the absence of immune - complex deposition ( or linear dense deposits ) , these findings justified a search for other possible causes of low - grade endothelial damage , such as the use of interferon therapy . 

( d ) by transmission electron microscopy , photograph showing interposition of mesangial cytoplasm . kidney biopsy specimen .
( b ) by methenamine silver stain , glomeruli showing reduplication of the glomerular basement .
unfortunately , following the renal biopsy , she bled and required embolization . in view of the biopsy report , ifn- was switched to glatiramer acetate ( copaxone ) 20 mg daily with a resultant progressive improvement of the proteinuria ( figure  1 ) .
we present the case report of a 37-year - old woman with nephrotic - range proteinuria secondary to mpgn - like glomerulonephritis without associated immune - complex deposition in the context of long - term ifn- therapy .
the complete remission of the proteinuria after cessation of ifn- treatment strongly suggests an aetiological role for ifn- in the development of the glomerulonephritis . to our knowledge , this is the second case of mpgn associated with ifn- therapy but the negative immune screen , normal inflammatory markers and the absence of immune complex deposition would imply a different pathway than that previously suggested .
its efficacy is thought to be related to its ability in restoring the impaired trafficking of inflammatory cells into the central nervous system and the modification of the pro - inflammatory / anti - inflammatory cytokine homeostasis .
the endogenous production of type i ifns ( ifn- and ifn- ) has a central role in the mediation of antiviral immunity and in many types of kidney diseases .
ifn treatment has been linked to different kinds of glomerulonephritis , including minimal change [ 3 , 4 ] , focal and segmental glomerulosclerosis ( fsgs ) [ 5 , 6 ] and collapsing fsgs .
glen et al . reported the largest cohort ( n = 11 ) of collapsing fsgs that developed in patients during treatment with different kinds of ifn .
in this patient cohort with collapsing fsgs , three patients were on ifn- for ms .
the median and mean duration of ifn therapy at the time of renal biopsy was 4.0 and 12.6 months , respectively , in this cohort .
typically , features of mpgn on light microscopy include mesangial hyper cellularity , endocapillary proliferation and capillary wall remodelling with the formation of double contours .
recently , it has been divided on the basis of pathophysiology , i.e. based on immune complex - mediation and complement mediation .
mpgn without immune - complexes or complement deposition has been described in thrombotic micro - angiopathies , thrombotic thrombocytopenic purpura or haemolytic  uraemic syndrome , atypical haemolytic  uraemic syndrome associated with complement abnormalities , the anti - phospholipid antibody syndrome , drug - induced thrombotic micro - angiopathies , nephropathy associated with bone marrow transplantation , radiation nephritis , malignant hypertension and connective - tissue disorders resulting from injury to the endothelial cells .
recently published a case report of a 40-year - old woman with ms on treatment with ifn- who developed nephrotic syndrome .
the kidney biopsy showed tubulo reticular inclusions and positive results for all five major immunofluorescence stains ( iga , igg , igm , c1q and c3 ) .
on the basis of these biopsy findings , together with other reports of sle induced by ifn [ 1214 ] , suggested that ifn- has the potential to induce and maintain immune complex  mediated mpgn .
this is in spite of normal complement levels and absence of serological or clinical findings of sle .
the pathway of how ifn- therapy triggered an mpgn - like glomerulonephritis without immune complex deposits is uncertain .
viral infections activate systemic antiviral immune responses interfering with systemic autologous ifn production and contributing to the triggering of glomerular diseases .
it has been reported that , ifn-4 , but not ifn-5 or ifn- , was increasingly expressed by intrinsic renal cells during autologous nephrotoxic serum nephritis and that the amount of renal ifn-4 expression correlated with proteinuria and renal excretory function .
adenovirus has been hypothesized as the trigger to make this ifn-4 over - expression functionally relevant .
although these described glomerulonephritis had immune complex deposits , the hypothesis of a viral infection triggering nephrotic syndrome could not explain its onset after several years of treatment ( 8 years in our patient , mean 12.6 months in glen et al .
it has been reported that ifn- significantly induced podocyte death and increased the permeability of podocyte monolayers and suppressed renal progenitor differentiation into mature podocytes . on the contrary
, there are some reports of amelioration of glomerular injury by recombinant ifn- treatment on animal models [ 19 , 20 ] .
therefore , further larger controlled , randomized trials should clarify the effect of ifn- on proteinuria .
on the other hand , the absence of immune - complex deposition in our patient 's renal biopsy may explain the complete remission of the proteinuria ( in contrast with the partial remission in patients reported by wallbach et al .   and glen et al . ) ,
, we report an ifn- related nephrotic - range proteinuria secondary to mpgn - like glomerulonephritis without immune complex deposits .
it is therefore our opinion that the complete remission of proteinuria after stopping ifn- therapy , together with the negative immune screen , normal inflammatory markers and the absence of immune complex deposition , would justify consideration of a different pathway for the development of glomerulonephritis not previously reported .
 we present a case report of a 37-year - old woman with multiple sclerosis ( ms ) who developed nephrotic - range proteinuria secondary to membrano proliferative glomerulonephritis ( mpgn)-like disease with mesangial c3 deposition without evidence of immune - complex deposition in the context of long - term interferon- ( ifn- ) therapy . 
 the complete remission of proteinuria following cessation of ifn- , strongly suggests causality . to our knowledge , this is the second case report of mpgn associated with ifn- use . 
 this being the case , the negative immune screen , normal inflammatory markers and the absence of immune complex deposits would imply a different pathway to that previously suggested . 
Introduction
Case report
Discussion
Conflict of interest statement