increasing prevalence of diabetes worldwide , leading to a steep rise of patients with chronic complications , represents one of the major health problems of the current medicine . since both micro- and macrovascular complications contribute in the increasing morbidity and mortality of patients with type 2 diabetes , novel antidiabetic therapies are intensively studied with respect to their possible beneficial effects on the long - term complications beyond their glucose - lowering properties . incretin - based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain . these therapeutics either increase concentrations of endogenous glucagon - like peptide-1 ( glp-1 ) by the inhibition of its degradation ( dipeptidyl peptidase-4 inhibitors ) or directly stimulate glp-1 receptor ( glp-1 receptor agonists ) . stimulation of glp-1 receptor in turn increases insulin secretion and suppresses excessive glucagon release leading to improved glucose control . other numerous potential beneficial effects of incretin - based therapies have been suggested based mostly on experimental and small clinical studies including its beta - cell- and vasculoprotective actions and also numerous others pleiotropic positive effects such as neuroprotection and others . one of the interesting possibilities that have emerged from experimental studies is the protective effect of dpp-4 inhibitors on the diabetic kidney disease . here , we review the renal effects of dpp-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria . we will discuss potential mechanism of these effects , the differences between various dpp-4 inhibitors , and future perspectives of its use in patients with diabetic kidney disease . we performed a primary medline search using combinations of keywords : sitagliptin , vildagliptin , saxagliptin , linagliptin , exenatide , liraglutide , and glp-1 , dpp-4 with albuminuria , and we consequently used all relevant articles published in english language in this review . due to a limited number of results , we performed secondary searches using combinations of additional keywords like diabetic kidney disease and nephropathy . diabetic kidney disease ( dkd ) represents one of the most frequent microvascular complications of diabetes with an overall prevalence of approximately 40% in type 2 diabetes population . dkd is defined by the presence of albuminuria and decreased glomerular filtration rate ( gfr ) into 5 chronic kidney disease ( ckd ) stages . ckd stage 1 is characterized by normal gfr and urine findings ( mostly albuminuria ) or structural abnormalities of the kidney . patients with diabetic kidney disease , even in stage 1 , have a markedly increased risk of cardiovascular complications and hypoglycemia compared to patients without dkd [ 8 , 9 ] . numerous studies have shown that the risk of diabetic kidney disease is tightly linked to poor glucose control in both type 1 and type 2 diabetes [ 10 , 11 ] . the adverse effects of hyperglycemia are generally mediated through diverse metabolic pathways including increased reactive oxygen species formation , excessive production of advanced glycation end products ( ages ) , and the activation of polyol , protein kinase c ( pkc ) , and hexosamine pathways , respectively . activation of these pathways leads to a complex dysregulation of various effector molecules resulting in cellular damage and dysfunction . experimental studies have shown that some of these pathophysiological mechanisms are potentially modifiable by dpp-4 inhibition . activation of pkc in the kidney by hyperglycemia reduces glp-1 signaling while enhancing angiotensin ii and nuclear factor-b ( nf-b ) signaling pathways with subsequent development of glomerular endothelial dysfunction . this process that typically occurs in the early stages of diabetic kidney disease is characterized by decreased local production of nitric oxide and enhanced production of reactive oxygen species , proinflammatory and cell adhesive molecules including tumor necrosis factor- ( tnf- ) , plasminogen activator inhibitor-1 ( pai-1 ) , intercellular adhesion molecule-1 ( icam-1 ) , vascular cell adhesion molecule-1 ( vcam-1 ) , and others . increased expression of icam-1 on glomerular endothelial cells promotes local macrophage infiltration into glomeruli with subsequent development of local inflammation and increased production of the renal profibrotic cytokine transforming growth factor  ( tgf- ) . chronic overproduction of tgf- markedly contributes to local degenerative changes and progressive fibrosis in diabetic kidney . additional important players contributing to kidney damage especially in patients with type 2 diabetes include arterial hypertension and dyslipidemia that commonly cluster with glucose metabolism disturbances in these patients . the presence of microalbuminuria represents an important early sign of kidney damage in patients with diabetes . associations between microalbuminuria , increased risk of cardiovascular complications , and progressive renal impairment are well described but the underlying pathophysiological mechanisms are only partially understood . in general , the presence of microalbuminuria implies either dysfunction of the glomerular filtration barrier and/or dysfunction in tubular reabsorption . at the time of overt microalbuminuria , established glomerular structural changes are present in diabetic kidney . studies have shown that local changes in glomerular morphology and the extent of matrix accumulation in glomeruli and interstitium correlate with extent of albuminuria . glomerular filtration barrier is characterized by three - layer structure : endothelium with glycocalyx , glomerular basement membrane , and podocytes . podocyte loss is one of the first changes contributing to increased glomerular permeability for albumin . nevertheless , albuminuria may also occur in the complete absence of structural changes of podocytes [ 21 , 22 ] . tubular dysfunction is another important player promoting albuminuria by lysosomal dysfunction which is promoted by renin - angiotensin system activation and tgf- overproduction . a number of experimental studies demonstrated that tgf- neutralization improved renal function and reversed morphological changes associated with disease progression in diabetic nephropathy models . tgf- is typically elevated in serum , urine , and glomerular tissue since early stages of both type 1 and 2 diabetes . its levels correlate with the degree of mesangial expansion , interstitial fibrosis , and renal dysfunction , but not with the extent of microalbuminuria . on the contrary , urinary levels of tnf- and vascular endothelial growth factor ( vegf ) tightly correlate with microalbuminuria [ 26 , 27 ] . both of these cytokines are upregulated in patients with type 2 diabetes [ 26 , 27 ] . albuminuria also positively correlates with markers of endothelial dysfunction and chronic low - grade inflammation including c - reactive protein [ 28 , 29 ] . the main action of dpp-4 inhibitors is to increase the levels of endogenous incretin hormones , especially glp-1 . dpp-4 inhibitors are known to exert also glp-1 independent effects as dpp-4 cleaves a wide range of other substrates such as neuropeptides , hormones , cytokines , and chemokines [ 6 , 30 ] . dpp-4 is also bound on the surface of many cell types including kidney proximal tubular cells and endothelial cells . microvesicle - bound dpp-4 secreted from tubular epithelial cells is found in urine and may be an early marker of renal damage before the onset of albuminuria . sun et al . also described higher urinary microvesicle dpp-4 levels in patients with diabetes compared to nondiabetic controls that positively correlated with extent of albuminuria in patients . upregulation of dpp-4 expression in renal glomeruli occurs during inflammation and usually accompanies the development of diabetes - induced glomerulosclerosis . renal effects of dpp-4 inhibitors appear to be , at least in part , mediated by increased glp-1 levels . in addition to pancreas , glp-1 receptor ( glp-1r ) is expressed in other numerous tissues including glomerular endothelial cells , mesangial cells , podocytes and also proximal tubular cells . studies have shown that glp-1 has anti - inflammatory properties and decreases ages production by activation of protein kinase a ( pka ) . the stimulation of nitric oxide ( no ) production and inhibition of production of angiotensin ii , pai-1 , icam-1 , and vcam-1 seems to be both glp-1 dependent and independent [ 3337 ] . several candidates for glp-1 independent effects of dpp-4 inhibitors in the kidney have been identified among known substrates of dpp-4 cleavage including high mobility group protein - b1 ( hmgb1 ) , meprin  , neuropeptide y ( npy ) , and peptide yy ( pyy ) . nevertheless , their exact role and importance in renoprotective effects of dpp-4 inhibitors has not yet been tested . hmgb1 is a known ligand of advances glycation end products receptor ( rage ) , as well as toll - like receptor 2 ( tlr2 ) and tlr4 , which are involved in the inflammatory process of diabetic nephropathy leading to nf-b activation . both npy and pyy are important mediators of various kidney functions including natriuresis [ 4044 ] . experimental studies have also shown that dpp-4 participates in the extracellular catabolism of proteins in the kidney such as catabolism / degradation proline - containing peptides . preclinical data suggesting nephroprotective effects of dpp-4 inhibitors are available for sitagliptin , vildagliptin , and linagliptin . the study with sitagliptin administration assessed its effects on metabolic profile and renal lesions in a rat model of type 2 diabetic nephropathy . sitagliptin treatment of diabetic rats lowered glycemia and ameliorated glomerular , tubulointerstitial , and vascular lesions . it also reduced kidney lipid peroxidation as measured by decreased malondialdehyde content . the study with vildagliptin light and electron microscopies of renal tissue revealed that vildagliptin treatment dose dependently inhibited interstitial expansion , glomerulosclerosis , and thickening of the glomerular basement membrane . the 24-week duration of hyperglycemia in untreated diabetic rats resulted in decrease of glp-1r staining . furthermore , increased urinary excretion rates of 8-oxo-2-deoxyguanosine ( major product of dna oxidation and marker of oxidative stress ) in diabetic rats were markedly attenuated by vildagliptin treatment . these results suggest prevention of oxidative dna damage and renal cell apoptosis by activating the glp-1r . diabetes was induced in endothelial nitric oxide synthase ( enos ) knockout mice which were used as an experimental model of nephropathy . the effect of linagliptin on the progression of nephropathy alone and in combination with the angiotensin receptor blocker telmisartan was tested . after 12 weeks of administration , linagliptin or telmisartan had no effect on glycemic control , while telmisartan reduced systolic blood pressure by 5.9  mmhg compared to no change in linagliptin group . combined treatment with linagliptin and telmisartan significantly reduced albuminuria compared with untreated diabetic mice , while monotherapy with either telmisartan or linagliptin had no effect . reduced glomerulosclerosis and normalization of tissue immune reactivity of malondialdehyde , a biomarker of oxidative stress , were seen in linagliptin and combined linagliptin / telmisartan group while angiotensin ii receptor blockade alone failed to reduce the markers of oxidative stress . another data suggesting possible nephroprotective effects of dpp-4 inhibitors come from the study on the experimental model of renal ischemia / reperfusion injury . in this study , vildagliptin was administered intravenously 15 minutes before surgery , and animals were sacrificed after 2 , 12 , and 48 hours of reperfusion . dpp-4 inhibition dose dependently decreased serum creatinine , tubular necrosis , serum malondialdehyde levels , and mrna expression of proinflammatory chemokine cxcl10 . these data suggest that the nephroprotection by dpp-4 inhibition was mediated by antiapoptotic , anti - inflammatory , and antioxidative changes . in addition to experimental data for dpp-4 inhibitors , animal studies suggest also possible nephroprotective effects of glp-1r agonists . both exendin-4   and liraglutide   ameliorated albuminuria decreased oxidative stress and inflammatory cytokines in a rat model of diabetic nephropathy . in the exendin-4 study , glomerular macrophage infiltration was prevented by suppression of icam-1 production on glomerular endothelial cells and by inhibition of proinflammatory cytokine release from macrophages . many diabetic patients develop diabetic kidney disease despite intensive efforts to achieve optimal control of blood pressure and glycemia . in addition to being a marker of renal damage , albuminuria has emerged as a predictive marker of increased risk of cardiovascular disease . according to current guidelines , the primary intervention in patients with detected albuminuria is the blockade of renin - angiotensin - aldosterone system ( raas ) with an angiotensin - converting enzyme inhibitor ( acei ) or angiotensin ii receptor blocker ( arb ) . proven additive effect of any antihyperglycemic agent on albuminuria lowering would be therefore of a high interest . first study indicating possible beneficial effect of a dpp-4 inhibitor on the kidney in man was a small observational study with sitagliptin . 36 patients with hba1c > 6.5% , despite lifestyle measures and antidiabetic treatment for at least 6 months , were enrolled and treated by sitagliptin ( 50  mg / day ) for 6 months . after 6 months of sitagliptin treatment , albuminuria measured by urinary albumin creatinine ratio ( uacr ) significantly decreased both in the patients with relatively modest microalbuminuria and the patients with more pronounced microalbuminuria at baseline . 82 subjects were enrolled to the 52-week , prospective , single - arm study where sitagliptin was added - on to sulphonylureas ( glimepiride or gliclazide ) with or without metformin . the secondary endpoints were changes in bmi , insulin secretory capacity , blood pressure , uacr , unresponsive rate , and hypoglycemia . after 52 weeks sitagliptin treatment reduced hba1c by 0.8% and uacr from 76.2  95.6  to 33.0  48.1  mg / g along with slight decreases in bmi blood pressure . in 2012 , a comprehensive analysis of randomized , double - blind , placebo - controlled trials ( duration 2452 weeks ) with linagliptin was published . the analysis included studies with both linagliptin monotherapy or add - on therapy to various glucose - lowering agents . inclusion criteria for the analysis were diabetic patients with persistent albuminuria defined as 30  uacr  3000  mg / g and stable treatment with ace inhibitor or angiotensin ii receptor blocker at baseline . the analysis included 168 patients treated with linagliptin and 59 patients on placebo , respectively . the endpoint of the analysis was the percentage change in geometric mean of uacr after 24 weeks of treatment compared to baseline values . placebo - corrected reduction of hba1c reached 0.71% blood pressure , and renal function remained unchanged . in linagliptin - treated group , uacr significantly decreased by 33% with a between - group difference versus placebo of 29% . interestingly , the degree of microalbuminuria reduction did not correlate with the magnitude of change in hba1c suggesting that the effects may have been independent of improvement in glycemic control . in a recently published meta - analysis of 13 linagliptin trials including 5466 patients focused on composite renal outcome , the hazard ratio of 0.84 in favor of linagliptin compared to placebo or comparator was found . the risk ratios for individual renal endpoints were 0.85 for microalbuminuria , 0.88 for macroalbuminuria , 0.44 for new onset of dkd , 0.77 for worsening of dkd , 0.93 for acute renal failure , and 0.77 for death , respectively . although none of the studies was primarily designed to test the effect of linagliptin on microalbuminuria and renal function , they collectively suggest its possible nephroprotective effects . furthermore , two small studies with sitagliptin and the experimental studies described previously open the possibility that nephroprotection might be a class effect of dpp-4 inhibition . on the other hand , dpp-4 inhibitors have different pharmacokinetics , and their nonglucose lowering effects may vary in man due to different concentrations in various organs and due to distinct substrate selectivity of binding to dpp-4 enzyme . in general , all long - term studies with antidiabetic agents suggest that good glucose control can prevent or delay the development of microvascular complications in both type 1 and type 2 diabetes [ 10 , 11 ] . in short - term studies , the specific influence of different antidiabetic medications on microalbuminuria might differ substantially . in a small 16 weeks study comparing glp-1r agonist exenatide with glimepiride , no differences in improvement of glucose control were found but a 24-hour urinary albumin was reduced by 40% in exenatide group compared to 5% reduction in glimepiride group . furthermore , urinary tgf- and type iv collagen in the exenatide group were also significantly reduced compared to no change in glimepiride - treated group . another antidiabetic medication affecting microalbuminuria is thiazolidinediones that share several mechanisms of action with incretin - based therapies including amelioration of increased activation of protein kinase c pathway in glomerular mesangial cells , improvement of impaired endothelial function , inhibition of mesangial and tubular cell proliferation by suppressing tgf- expression , anti - inflammatory actions by attenuation of interleukin-1 , 6 , and tnf - alpha in renal mesangial cells , and reduction of oxidative stress in the kidney [ 59 , 60 ] . in a 52-week , open - label , cardiac safety study comparing rosiglitazone to glyburide , only the rosiglitazone group showed a significant reduction of albuminuria from baseline . for patients with microalbuminuria at baseline , reductions in uacr did not correlate with reductions in hba1c or fasting plasma glucose but showed strong correlation with changes in mean 24 h systolic and diastolic blood pressures in rosiglitazone - treated patients . another small randomized study comparing pioglitazone versus metformin in patients with baseline albuminuria treated with raas blockade showed similar effects . after 52 weeks of treatment , the changes in uacr from baseline were 8.3% in pioglitazone group and + 4.2% in metformin group ( p = 0.01 ) with similar glycemic and blood pressure changes in both arms . these results suggest that metformin does not share the albuminuria - lowering potential of thiazolidinediones and incretin - based therapies . collectively , these data suggest a possibility of specific and glucose - lowering independent effects of incretin - based therapies and thiazolidinediones on the renal damage in patients with diabetes . nevertheless , larger trials designed primary on testing renal outcomes are necessary to confirm this interesting possibility . the results of published preclinical and clinical studies suggest that dpp-4 inhibitors may have a potential to lower albuminuria and to also possess other more complex nephroprotective properties . possible mechanisms underlying these effects include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction in the kidney . effects of dpp-4 inhibitors may be both glp-1 dependent and glp-1 independent . at the moment , the data are too scarce and incomplete to make definite conclusions with respect to dpp-4 inhibitors induced nephroprotection . ongoing studies , such as the marlina study comparing , prospectively , the effects of linagliptin to placebo on albuminuria may shed some light in this field . furthermore , numerous ongoing long - term cardiovascular trials with dpp-4 inhibitors can bring novel crucial information about relationships among glucose control and macrovascular and microvascular complications and further elucidate the role of albuminuria in these processes .
incretin - based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain . 
 other numerous potential beneficial effects of incretin - based therapies have been suggested based mostly on experimental and small clinical studies including its beta - cell- and vasculo - protective actions . 
 one of the recently emerged interesting features of dipeptidyl peptidase-4 ( dpp-4 ) inhibitors is its possible protective effect on the diabetic kidney disease . here , we review the renal effects of dpp-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria , as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications . 
 mechanisms underlying possible nephroprotective properties of dpp-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction . 
 effects of dpp-4 inhibitors may be both glucagon - like peptide-1 ( glp-1 ) dependent and independent . ongoing prospective studies focused on the nephroprotective effects of dpp-4 inhibitors 
 will further clarify its possible role in the prevention / attenuation of diabetic kidney disease beyond its glucose lowering properties .