dipeptidyl peptidase ( dpp)-4 degrades incretin hormones , such as glucagon - like peptide ( glp)-1 , and reduces the glucose - dependent insulinotropic effects of incretins on pancreatic  cells .
dpp-4 inhibitors are a new class of anti - diabetic agents that improve glucose homeostasis by enhancing the actions of incretin hormones .
vildagliptin has a relatively shorter half - life than other dpp-4 inhibitors and therefore is preferably administered twice daily .
exposure to vildagliptin in patients with moderate - to - severe renal impairment is increased compared with that observed in control subjects .
however , the degree of exposure to vildagliptin does not correspond to the severity of renal impairment .
in contrast , the level of the primary metabolite of ( dpp)-4 ( m20.7 ) increases in association with declines of renal function ; however , increases in the level of this metabolite have no clinically relevant consequences since m20.7 is pharmacologically inactive [ 1 , 2 ] .
therefore , vildagliptin can be used without dose adjustment in patients with a creatinine clearance of > 50 ml / min .
although vildagliptin is , in principle , contraindicated in patients with moderate - to - severe renal impairment , a recent 24-week study suggested that vildagliptin ( 50 mg once daily ) therapy is effective and well tolerated in moderate - to - severe renal impairment patients and those on dialysis with type 2 diabetes mellitus ( t2 dm ) [ 3 , 4 ] .
dpp-4 is also known as adenosine deaminase complexing protein 2 or cd26 ( ec 3.4.14.5 ) and is expressed on the surface of several cell types , including lymphocytes and monocytes , where it exerts immunoregulatory effects .
in addition , dpp-4 substrates are proline- and alanine - containing peptides , including various growth factors , chemokines , neuropeptides and vasoactive peptides .
due to these off - target mechanisms , the use of dpp-4 inhibitors may result in unexpected side effects related to immunological responses . in this article
, we report the first case , to our knowledge , of sarcoid - like lung granulomas in a hemodialysis patient treated with vildagliptin .
a 70-year - old female began to receive hemodialysis for end - stage renal disease due to diabetic nephropathy in august 2010 .
her treatment regimen for t2 dm was changed from insulin injections to the oral administration of vildagliptin ( 50 mg / day ) in december 2011 . following the initiation of vildagliptin , the patient 's level of hba1c ranged between 6.0 and 6.3% , and no episodes of hypoglycemia were observed . in april 2012
, multiple nodular lesions were incidentally detected on chest computed tomography ( ct ) screening for lung cancer , without subjective symptoms ( figure  1a ) .
the patient had no pets , was not a smoker , had no experience of traveling overseas or allergies to drugs or foods .
a quantiferon - tb ( qft ) blood test was positive ; however , repeated sputum cultures and polymerase chain reaction assays were negative for tuberculosis ( tb ) .
the multiple nodular lesions increased in size on ct after 2 months ( figure  1c ) ; therefore , a ct - guided needle lung biopsy was performed , and granulomas without caseous necrosis were identified on a histological examination ( figure  2 ) .
no pathogenic microorganisms were detected on staining , including grocott 's methenamine silver and acid - fast staining .
furthermore , there was no evidence of tb on a culture of bronchial alveolar liquid ( bal ) .
because the presence of tb infection could not be completely excluded and the size of the granulomas progressively increased ( figure  1d ) , antituberculosis drugs , including rifampicin ( 450 mg / day ) , isoniazid ( 300 mg / day ) and ethambutol ( 250 mg / two days ) , were administered empirically starting in september 2012 . nevertheless , the granulomas further increased in size on follow - up ct performed 1 month later ( figure  1e ) .
therefore , we discontinued both the antituberculosis drugs and vildagliptin . following the discontinuation of vildagliptin ,
the size of the granulomas decreased within 1 month ( figure  1f ) , and most of the lesions were barely detectable after 4 months ( figure  1 g ) . 

multiple lung nodules were incidentally found in april 2012 ( a ) ; no lung nodules were seen in april 2011 ( b ) .
the size of the nodular lesions progressively increased in june 2012 ( c ) and september ( d ) . in spite of the initiation of antituberculosis drugs in september 2012
, the granulomas increased in size in october 2012 ( e ) . in november 2012 , 1 month after the discontinuation of antituberculosis drugs and vildagliptin , the size of the granulomas decreased ( f ) . in february 2013 ,
4 months after the discontinuation of these drugs , most of the granulomas were no longer detectable ( g ) . 

multiple lung nodules were incidentally found in april 2012 ( a ) ; no lung nodules were seen in april 2011 ( b ) .
the size of the nodular lesions progressively increased in june 2012 ( c ) and september ( d ) . in spite of the initiation of antituberculosis drugs in september 2012
, the granulomas increased in size in october 2012 ( e ) . in november 2012 ,
1 month after the discontinuation of antituberculosis drugs and vildagliptin , the size of the granulomas decreased ( f ) . in february 2013 ,
4 months after the discontinuation of these drugs , most of the granulomas were no longer detectable ( g ) .
we herein reported a case of sarcoid - like lung granulomas in a patient under hemodialysis who was treated with vildagliptin . to the best of our knowledge ,
this is the first case of granulomatosis related to the use of a dpp-4 inhibitor . in general , the incidence of adverse effects of dpp-4 inhibitors is lower than that of other oral hypoglycemic agents , and this case represents a very rare adverse effect of vildagliptin .
the asymptomatic granulomas appeared following the initiation of treatment with vildagliptin and disappeared after its discontinuation .
it is well known that dialysis patients have an increased risk of tb compared with the general population , with an often atypical pattern of development . the current patient presented with positive findings for qft , with no evidence of tb on cultures of the sputum and balf or histology of the biopsy specimen .
although empiric therapy for tb was administered , the size of the granulomas did not change .
the patient 's laboratory findings and clinical course indicate that the granulomas were not caused by tb .
the occurrence of granulomatosis in patients treated with tumor necrosis factor ( tnf ) blockers has been previously reported .
it has also been speculated that modulation of the cytokine environment by anti - tnf therapy is related to the formation of granulomas .
it was recently reported that the inhibition of dpp-4/cd26 on t - cells by dpp-4 enzymatic inhibitors selectively suppresses lymphocyte proliferation and reduces the production of various cytokines , including interferon- , interleukin-17 and tnf- .
similarly , other dpp family members , such as dpp-8 and dpp-9 , play roles in immunoregulation .
in addition , it has been reported that glp-1 inhibits inflammatory pathways , thereby increasing the level of glp-1 via the inhibition of dpp-4 , which may affect the inactivation of inflammatory pathways .
therefore , the effects of dpp-4 inhibitors may mimic those of anti - tnf therapies under certain conditions .
discontinuation of the anti - tnf therapies results in the resolution of granulomatosis in most cases .
the granulomas also disappeared after the discontinuation of vildagliptin in the present case , suggesting similarities between the biological behavior of granulomas under these two conditions .
vildagliptin can be administered without dose adjustment in patients with a creatinine clearance of > 50 ml / min .
however , it has been reported that the plasma concentrations of vildagliptin and its metabolites are increased in patients with severe renal impairment [ 1 , 12 ] .
the accumulation of vildagliptin and its metabolites may affect the immune system and provoke unexpected side effects in dialysis patients with t2 dm . therefore , the use of non - renal excreted dpp-4 inhibitors , such as linagliptin , may reduce the risk of pharmacokinetic complications . since we ethically can not readminister the drug in this case , other possible causes of granulomas remain , for example , a late response to therapy for tb or the spontaneous regression of sarcoidosis .
in conclusion , the administration of dpp-4 inhibitors in patients undergoing hemodialysis is possibly linked with the new onset of sarcoid - like granulomatosis .
 it has been reported that the inhibition of dipeptidyl peptidase-4 ( dpp-4)/cd26 on t - cells by dpp-4 enzymatic inhibitors suppresses lymphocyte proliferation and reduces the production of various cytokines , including tumor necrosis factor ( tnf)-. a 72-year - old female with diabetic nephropathy on hemodialysis developed multiple lung nodules following the administration of vildagliptin . 
 a biopsy demonstrated the histology of granulomas without caseous necrosis . 
 the discontinuation of vildagliptin resulted in the disappearance of the granulomas within 4 months . 
 as granulomatosis often develops in patients under anti - tnf- therapy , the accumulation of dpp-4 inhibitors or its metabolites is possibly linked to unrecognized complications , such as sarcoid - like lung granulomas . 