Novel Drug Treatment for Diabetic Nephropathy

Hong Kong J Nephrol • April 2011 • Vol 13 • No 1 19

Review Article

(DN)

Aliskiren

Ruboxistaurin C Pentoxifylline m-TOR

PAI-1

Avosentan

Novel Drug Treatment for Diabetic Nephropathy

Amitabh Dash,1 Rituparna Maiti,2 Tejaswi Kumar Akantappa Bandakkanavar,1 Bajrang Lal Pandey1

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In addition to the renin pathway, certain bioactive molecules are involved in its pathogenesis. Strategies to interrupt pathophysiological pathways are on the horizon. Aliskiren, a renin inhibitor, blocks the first step in the renin pathway. Protein kinase C over-expression is blocked by ruboxistaurin. Pentoxifylline and m-TOR inhibitors are anti-inflammatory agents in the pathogenesis of diabetic nephropathy. Inhibitors of advanced glycation, oxidative stress, and plasminogen activator inhibitor-1 have proved useful in animal models of diabetic nephropathy. Avosentan, an endothelin antagonist, decreases urinary albumin. Such targeted therapies have opened up avenues for researchers to develop agents that can halt and may even reverse the progression of diabetic nephropathy. [Hong Kong J Nephrol 2011;13(1):19–26]

Key words: diabetes mellitus, nephropathy, novel drugs

The burden of diabetes has increased worldwide and is expected to affect 380 million persons in 2025 [1,2]. Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), and approximately 30% of patients with type 1 diabetes (DM1) or type 2 diabetes (DM2) develop DN [3]. The phases of clinical progression have been described by Mogensen [4]: 1) hyperfiltration with renal hypertrophy, increased renal plasma flow, and glomerular filtration; 2) normoalbuminuria with early renal parenchymal changes (basement membrane thickening and mesangial expansion); 3) microalbuminuria with early hypertension; 4) overt proteinuria; and 5) ESRD.

Understanding the pathomechanism of DN has helped in designing a rational approach for optimal therapy and prevention of DN. Hyperglycemia can lead to the activa-tion of oxidative stress and increased production of reac-tive oxygen species (ROS). It can also lead to activation

of the proinflammatory transcription factor NF-κB, resulting in increased inflammatory gene expression, enhanced flux into the polyol and hexosamine pathways, and activation of protein kinase C (PKC), transforming growth factor-β (TGF-β), and the renin-angiotensin-aldosterone system (RAAS). There is also increased forma-tion of advanced glycation end-products (AGEs). These factors collectively result in cell injury and apoptosis of podocytes, and the accumulation of extracellular matrix proteins in the glomeruli and tubulointerstitium [5–9].

Protein kinase C-β has been shown to play an im-portant role in DN in in vivo models. PKC-β1 is an Akt S473 kinase, and TGF-β1 transcriptional upregulation requires epidermal growth factor receptor (EGFR)/PKC-β1/Akt signaling. Both PKC-β inhibition and PKC-β deletion suppress TGF-β1 upregulation and matrix expan-sion in diabetic glomeruli or kidneys. New therapeutic

1Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India and 2Department of Pharmacology, Prathima Institute of Medical Sciences, Karimnagar, Andhra Pradesh, India.Correspondence to: Dr. Amitabh Dash, E-13, Kalkaji, New Delhi 110019, India.E-mail: [email protected]

A. Dash, et al

20 Hong Kong J Nephrol • April 2011 • Vol 13 • No 1

approaches to DN may result from targeting components of this pathway, particularly the initial EGFR transactiva-tion [10]. Cell culture studies in podocytes have proven that hyperglycemia can activate the RAAS, resulting in podocyte apoptosis, which is a hallmark of DN [11–13].

Recent evidence indicates that, in addition to hyper-glycemia, altered insulin signaling plays an important role in podocyte malfunction and in microalbuminuria [14,15]. Cell culture studies showed that peroxisome proliferator-activated receptor gamma (PPAR-γ) activa-tion can block the effects of glucose and the RAAS in inducing podocyte apoptosis. Similar results are ob-tained in in vivo models of renal disease associated with both DM1 and DM2, where PPAR-γ agonists have been shown to be beneficial in preventing DN [13–16].

It has been suggested that osteopontin and macro-phage accumulation play a role in the tubulointerstitial injury of DN, and that inhibition of osteopontin expres-sion may be one of the mechanisms by which inhibition of the β isoform of PKC confers a renoprotective effect. There is also increasing evidence that epigenetic mech-anisms play a role in DN. Epigenetic alterations result in regulation of genes that are implicated in regulating the metabolism of diabetic complications, including AGEs and NF-κB [17–19]. The epigenetic mechanisms that constitute a metabolic memory response to episodes of transient hyperglycemia are therefore becoming major targets for the treatment and prevention of diabetic complications including DN.

TREATMENT OPTIONS

Based on its pathogenesis, the initial treatment of DN should be strict control of hyperglycemia, hypertension, dyslipidemia, proteinuria, and obesity and cessation of smoking. The beneficial role of thiazolidinediones (TZDs), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) in DN is already established. Over the past few years our understanding of the complexity of the patho-genesis of DN has grown as new mechanisms, compo-nents, and regulatory steps have been identified. Also, the potential of targeted therapies has been explored, resulting in many novel drugs for the treatment and prevention of DN.

NOVEL MOLECULES

Direct renin inhibitor: aliskirenThe central role of the RAAS in the pathogenesis of DN is widely accepted based largely on the attenuation of DN by ACEIs and ARBs. Because of insufficient sup-pression of the intrarenal RAAS, however, these agents

cannot stop disease progression. Theoretically, agents that more effectively suppress the RAAS should provide improved renal protection against DN. Direct renin in-hibitors, which act at the point of activation of the RAAS cascade, are such agents.

Aliskiren is an orally active, nonpeptide renin inhibi-tor that is highly specific for renin. It acts by binding to the active site of renin, thereby inhibiting catalytic activity. As renin acts at the rate-limiting step in the RAAS cas-cade, blockade of renin with aliskiren may inhibit the RAAS and reduce the feedback effects more completely than do ACEIs or ARBs. In addition, the blockade of renin may reduce activity at the (pro)renin receptor [(P)RR]. Therefore, aliskiren may provide superior renoprotection.

Azizi et al showed that in healthy human volunteers maintained on a high sodium diet a single 300 mg dose of aliskiren caused a reduction in PRA and angiotensin I and II levels within 1 hour of administration. In contrast, the ARB valsartan increased each of these parameters [20]. In streptozocin-induced diabetes mellitus in trans-genic Ren(2) rats, a model of advanced DN in humans, aliskiren reduced albuminuria and glomerulosclerosis to an extent similar to that produced by the ACEI perin-dopril. This effect was seen despite the fact that aliski-ren did not lower blood pressure as much as perindopril. The reduction in tubulointerstitial fibrosis was signifi-cantly greater in aliskiren-treated diabetic rats than in the perindopril-treated animals [21].

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliski-ren at a dosage of 300 mg/day to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 months among patients with DM2, hypertension, and albuminuria. The study con-cluded that aliskiren had a renoprotective effect that was independent of its blood pressure-lowering effect in patients with DM2 who were receiving the maximum recommended renoprotective treatment and optimal antihypertensive therapy [22].

Aliskiren may be antifibrotic because of its nonmu-tually exclusive (P)RR-mediated actions: 1) suppression of (P)RR gene expression, possibly resulting in fewer receptors and damping intracellular fibrotic pathways induced by (pro)renin; 2) preventing activation of pro-renin in renal tissue; and 3) negating the gain in catalytic activity of receptor-bound renin [23].

The results of these animal and human studies are highly encouraging. The results of a large outcome trial in diabetic nephropathy, ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints), are awaited. The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily re-duces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treat-ment (including ACEIs or ARBs). ALTITUDE is an in-ternational, randomized, double-blind, placebo-controlled,


Novel drug treatment for diabetic nephropathy

parallel group study that seeks to determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEI or ARB can reduce major morbidity and mortality in a broad range of high-risk patients with DM2 [24,25].

Protein kinase C inhibitor: ruboxistaurinRuboxistaurin, an orally active selective inhibitor of the β-isoform of PKC, reduces the actions of vascular en-dothelial growth factor (VEGF) and attenuates the progression of diabetic retinopathy. Animal studies have shown it to normalize glomerular hyperfiltration and reduce TGF-β levels and proteinuria. Excess matrix, hypertrophy, and apoptosis are features of DN, and ruboxistaurin has been shown to attenuate histological injury, functional decline, and expression of the profi-brotic and proapoptotic growth factor TGF-β [26,27].

Kelly et al showed that both cell loss and VEGF overexpression were attenuated by administration of either perindopril or ruboxistaurin as single-agent treat-ment. A combination of the two provided additional, in-cremental improvement, reducing these manifestations of injury to levels seen in nondiabetic, normotensive, nontransgenic animals [28]. Ruboxistaurin has also been found to reduce osteopontin expression and consequent macrophage infiltration in diabetic rats [29]. A random-ized study showed that patients with DN treated with 32 mg of ruboxistaurin daily had a 24% greater reduction in albuminuria than those given a placebo, and they had a stable estimated glomerular filtration rate as well [30].

m-TOR inhibitor: rapamycin (sirolimus)A serine/threonine kinase, mTOR plays a pivotal role in mediating cell size, mass, proliferation, and survival. mTOR has also emerged as an important modulator of several forms of renal disease [31]. Studies have shown that the mTOR pathway is highly activated in progres-sive renal disorders including DN. Activation of mTOR signaling causes renal hypertrophy at an early stage of diabetes [32].

Diabetic db/db mice, which lack leptin receptor sig-naling, have been used as a model of ESRD associated with DN. It was demonstrated that p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice. Furthermore, systemic administration of rapa-mycin, a systemic and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunction. Rapamycin treatment also significantly reduced fat deposits and attenuated hyperinsulinemia, with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD, and that ra-pamycin could be an effective therapeutic agent for DN [33]. Yang et al concluded that rapamycin treatment can prevent the early renal structural changes of diabetes in experimental rats, and thus halt the early steps in the development of DN [34].

In another study in rats, sirolimus ameliorated renal inflammation, glomerular hypertrophy, and podocyte loss, as indicated by morphometric and immunohistological analyses. Sirolimus lowered the expression and activity of glomerular TGF-β and VEGF, which are considered central cytokines in the pathogenesis of DN. Based on its anti-inflammatory, antifibrotic, and podocyte-protective effects, sirolimus seems to be a superior treatment for preventing or ameliorating DN in the rat [35].

PentoxifyllineMetabolic and hemodynamic components are directly involved in the pathogenesis of DN, although there are convincing data indicating that inflammation participates in the diabetic complications as well. Renal expression of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6, is in-creased in DN and is significantly associated with urinary albumin excretion. Pentoxifylline administration has pre-vented this enhanced expression, leading to a decrease in urinary cytokine excretion and a reduction in albumin-uria. These findings provide a novel insight into the patho-genic mechanisms of DN, supporting the hypothesis that inflammatory mechanisms play a role in the renal injury secondary to diabetes mellitus [36]. A meta-analysis by McCormick et al concluded that pentoxifylline may decrease proteinuria in patients with DN [37].

A prospective, randomized, double-blind, placebo-controlled study evaluated the effect of pentoxifylline (1200 mg daily for 12 months) in 34 patients with es-tablished DN. The evaluated parameters were inflam-mation, proinflammatory cytokines, and urinary albumin excretion. Pentoxifylline treatment had a renoprotective effect determined by a significant reduction in urinary albumin excretion in both incipient and established DN patients. This effect was attributed to a reduction in serum C-reactive protein, IL-6, TNF-α, and leptin levels. Thus, pentoxifylline treatment caused regression and prevented the progression of renal damage [38].

The Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) study, an investigator-initiated, single-center, prospective, randomized, controlled, clini-cal trial funded by the Spanish Ministry of Science and Innovation is underway. It was initiated to provide evi-dence regarding the renoprotective benefit of pentoxifyl-line in patients with DN, in addition to interventions of proven efficacy (RAS blockade) [39].

Advanced glycation end-products inhibitorThe formation of advanced glycation end-products (AGEs) is closely linked to glycoxidative biology. By investigating the role of AGEs and their receptors (re-ceptors for AGEs, or RAGE) in the onset and progression of DN, future treatment strategies targeting the AGE-RAGE system have designed: 1) AGE formation inhibi-tor (ARBs, R-147176, aminoguanidine, benfotiamine,

A. Dash, et al


pyridoxamine); 2) AGE cross-link breaker (alagebrium); 3) RAGE antagonist (PPAR-γ antagonists); 4) AGE binder (Kremezin); 5) hypoxia-inducible factor (HIF) activator [40].

ARB derivative: R-147176A novel ARB derivative, R-147176, inhibits oxidative stress and AGEs, but has minimal affinity for the angio-tensin II type 1 receptor (AT1R), and thus little antihy-pertensive effect. The inhibition of AGEs formation, AT1R affinity, and the pharmacokinetic characteristics of newly synthesized ARB derivatives were assayed. R-147176 was eventually selected, as it strongly inhib-ited advanced glycation, but was 6,700 times less effec-tive than olmesartan in regard to AT1R binding. Despite a minimal effect on blood pressure, it showed significant renoprotection in spontaneously hypertensive/NIH-corpulent (SHR/NDmcr-cp) rats, as well as in Zucker dia-betic fatty rats. The renal benefits of ARB thus depend on inhibition of AGEs and oxidative stress by their chem-ical structure. This has opened a new avenue for treating normotensive or hypotensive patients with cardiovascu-lar diseases, including kidney disease [41].

PyridoxaminePyridoxamine is one of three natural forms of vitamin B6 and is an active inhibitor of AGEs. Investigation of the pyridoxamine mechanism of action demonstrated that pyridoxamine inhibits post-Amadori steps of the Maillard reaction by sequestering catalytic metal ions and blocking oxidative degradation of the Amadori intermediate. Pyridoxamine also has the capacity to scavenge toxic car bonyl products of sugar and lipid degradation, and to inhibit the ROS [42].

In a study by Murakoshi et al pyridoxamine amelio-rated lipid peroxidation and insulin resistance in KK-A(y)/Ta mice. This pleiotropic effect of pyridoxamine was related to CD36 expression in the kidney and adi-pose tissue [43]. Pyridoxamine was found to exert renoprotective effects and decrease renal pentosidine accumulation in experimental chronic allograft nephrop-athy (CAN), suggesting a detrimental role for renal AGE accumulation in the pathogenesis of renal damage in this nondiabetic model. These results indicate that inhibition of AGE formation might be a useful therapeutic adjunct to attenuate CAN [44].

The safety and efficacy of pyridoxamine was studied in a Phase II trial (PYR-206). A total of 128 patients with DN received either 50 mg of pyridoxamine or pla-cebo. In another trial (PYR-205/207), 84 patients with DM1 and DM2 were recruited. Patients were random-ized to 250 mg pyridoxamine treatment or placebo. The results of these two trials were merged and published. Although there was no change in urine albumin excretion, the pyridoxamine group had a 48% reduction in serum creatinine and reduced TGF-β [45].

BenfotiamineBenfotiamine (S-benzoylthiamine-O-monophosphate) is a synthetic S-acyl derivative of thiamine. Transketolase is an enzyme that directs the precursors of AGEs to a pen-tose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, re-sulting in a reduced level of AGEs in tissues [46]. A study by Stirban et al confirmed micro- and macrovascular endothelial dysfunction accompanied by increased oxi-dative stress following a real-life, heat-processed, AGE-rich meal in individuals with DM2. The authors suggested benfotiamine as a potential treatment [47].

Recent advances in understanding the biology of endothelial progenitor cells (EPCs) have highlighted their involvement in diabetes complications. Results of a study by Marchetti et al indicated that hyperglycemia impairs EPC differentiation, and that the process can be restored by benfotiamine administration via modulation of Akt/ FoxO1 activity [48]. In contrast, in a double-blind, randomized, placebo-controlled clinical trial on benfo-tiamine treatment in patients with DN, high-dose benfo-tiamine treatment for 12 weeks, in addition to ACEIs or ARBs, did not reduce urinary albumin excretion or KIM-1 (kidney injury molecule-1) excretion, despite improved thiamine status [49].

Alagebrium (ALT-711)Alagebrium (4,5-dimethylthiazolium), formerly known as ALT-711, is a novel cross-links breaker in AGEs. It has been studied in various models of diabetic compli-cations, and has been shown to attenuate diabetic renal disease, cardiac dysfunction, and atherosclerosis. In ad-dition to the ability of alagebrium to reduce tissue levels of AGEs, the drug appears to inhibit activation of certain PKC isoforms [50].

Methylglyoxal (MG), a highly reactive dicarbonyl compound, is a normal product of glucose, fatty acid, and protein metabolism. The clinical significance of MG lies in the fact that it reacts with and modifies certain proteins to form AGEs, leading to the vascular compli-cations of diabetes. Dhar et al showed that alagebrium pretreatment attenuated these effects of MG. In an in vitro assay, alagebrium reduced the amount of detectable MG. An acute in vivo effect of alagebrium against MG was possibly due to scavenging [51]. Based on their animal study, Peppa et al concluded that alagebrium may pre-vent, delay, and/or reverse established DN in db/db mice, by reducing the systemic AGE pools and facilitating urinary excretion of AGES [52].

Kremezin (AST-120)Oral adsorbent Kremezin reduces uremic toxins (e.g. in-doxyl sulfate) and retards the progression of chronic kidney disease (CKD). Kremezin binds to carboxymethyl lysine (CML) in vitro, one of the well-characterized digested



food-derived AGEs. Administration of Kremezin decreases serum AGE levels in nondiabetic patients in chronic renal failure (CRF). These findings suggest that digested food-derived AGEs such as CML may be a novel molecular target for oral adsorbent Kremezin, and that Kremezin could exert beneficial effects on CRF patients by adsorbing diet-derived AGEs and subsequently decreasing serum AGE levels [53]. Kremezin reduces the gene expression of TGF-β1, tissue inhibitor of metalloproteinase (TIMP)-1, and pro-α1(I) collagen in the kidneys. It delays the pro-gression of CRF by alleviating the overload of indoxyl sulfate on remnant proximal tubular epithelial cells [54].

Ueda et al found that Kremezin treatment signifi-cantly reduced mRNA levels of RAGEs, monocyte che-moattractant protein-1, and vascular adhesion molecule-1 in cultured human umbilical vein endothelial cells com-pared with their baseline levels. This study suggested that atheroprotective properties of Kremezin can be ascribed, at least in part, to its AGE-lowering ability via absorption of CML [55].

Plasminogen activator inhibitor-1 inhibitorsPlasminogen activator inhibitor-1 (PAI-1) can regulate TGF-β expression by binding to the urokinase plasmino-gen activator receptor and activating the extracellular-regulated signal kinase/mitogen-activated protein kinase (ERK/MAPK) pathway. Therefore, PAI-1 contributes to DN by regulating TGF-β and renal extracellular matrix production. Thus, it may be a therapeutic target in DN [56].

Several experimental and clinical studies support the role for PAI-1 in the renal fibrogenic process that occurs in chronic glomerulonephritis, DN, focal segmental glomerulosclerosis, and other fibrotic renal diseases. Inhibition of PAI-I activity or of PAI-I synthesis by specific antibodies, peptidic antagonists, antisense oligo-nucleotides, or decoy oligonucleotides has been obtained in vitro, but needs to be evaluated in vivo regarding the prevention or treatment of renal fibrosis [57].

Disruption of the PAI-I gene protects mice against DN. Some novel, orally active, small molecule substances—TM-5001, TM-5007, TM-5275—were identified [58,59]. In vitro, they specifically inhibited PAI-I activity and formation of a PAI-I–tissue plasminogen activator (t-PA) complex, and they enhanced fibrinolysis. Given to rats with Thy-I nephritis, they reduced proteinuria and me-sangial expansion, a benefit similar to that observed in the same model whose PAI-I molecule had been mutated [60]. Clinical benefits of PAI-I inhibitors in DN remain to be demonstrated. If confirmed, this molecule might expand our therapeutic armamentarium to prevent DN [61].

Low-molecular-weight glycosaminoglycan polysaccharides: sulodexideA primary alteration in DN consists of decreasing the concentration of glycosaminoglycans (GAGs) in the

glomerular extracellular matrix. This evidence has prompted interest in using exogenous GAGs, specifi-cally sulodexide, in the treatment of DN [62].

Sulodexide is a commercially available compound consisting of heparin sulfate (80%) and dermatan sulfate (20%). Sulodexide is degraded in the digestive tract into GlcNAc building blocks, leading to an increase in the precursors available for GAG synthesis [63].

The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose range-finding trial to evaluate the extent and duration of the hypoalbumin-uric effect of oral sulodexide in diabetic patients. The study concluded that a 4-month course of high doses of sulodexide significantly and dose-dependently alleviated albuminuria in DM1 and DM2 patients and micro- or macroalbuminuric patients with or without concomitant ACE inhibition [64]. In another trial, sulodexide micro-albuminuria (SUN-Micro-Trial) given to 1000 patients with diabetes and persisting microalbuminuria on maxi-mum RAAS blockade failed to show a reduction in urine albumin. Further studies are needed on this molecule before its utility for DN can be determined [65].

PirfenidonePirfenidone (PFD) [5-methyl-1-phenyl-2-(IH)-pyridone] is a low-molecular-weight synthetic molecule that exerts dramatic antifibrotic properties in cell culture and various animal models of fibrosis [66,67]. In cell culture studies of mouse mesangial cells, PFD decreased TGF-β pro-moter activity, reduced TGF-β protein secretion, and inhibited TGF-β-induced Smad2 phosphorylation, 3TP-lux promoter activity, and generation of ROS. In the db/db mouse, PFD promoted resolution of the mesangial matrix when administered after the onset of nephropathy. For identification of novel pathways of PFD relevant to DN, proteomic studies of the whole kidneys followed by bioinformatic analyses revealed RNA processing as a novel mechanism of PFD action. In support of PFD play-ing a role in mRNA translation, PFD was found to regu-late the activity of eukaryotic initiation factor (eIF4E), a key mRNA cap structure-binding protein, in mesangial cells in culture [68].

Endothelin-A receptor antagonist: avosentanThe endothelin system regulates a number of renal functions, and can induce proteinuria by various mech-anisms. Plasma and urinary endothelin-1 (ET-1) levels are elevated in patients with diabetes, and correlate with reduced renal function, increased blood pressure, albu-minuria, and the severity and duration of diabetes.

Avosentan is a nonpeptidergic, once-daily, orally available endothelin-A (ETA) antagonist that is currently in clinical development for the treatment of DN. Endo-thelin antagonists have shown anti-inflammatory, anti-fibrotic, and antiproteinuric effects in experimental studies.

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ASCEND was a multicenter, placebo-controlled trial that aimed to investigate the effects of the ETA receptor antagonist avosentan in patients with DN. In this study, 25 mg and 50 mg of avosentan daily substantially re-duced the albumin/creatinine ratio compared with that induced by placebo. They found that avosentan reduced albuminuria when added to standard treatment in people with DM2 and overt nephropathy, but it induced sig-nificant fluid overload and congestive heart failure as well [69,70]. Wenzel et al conducted a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study on the effect of the ETA antagonist avosentan on the urinary albumin excretion rate (UAER) in 286 pa-tients with DN. The study revealed that avosentin given in addition to standard ACEI/ARB treatment decreases UAER in patients with DN [71].

CONCLUSION

During the past half-century, a global pandemic of kid-ney failure attributed to diabetes mellitus has provoked continuously changing treatment strategies based on the belief that micro- and macrovascular complications of diabetes are preventable. In diabetic patients with overt nephropathy, multiple pharmacological interventions have represented a promising pathway to preventing progres-sion to ESRD. This review addressed some of the more promising therapeutic agents for delaying the progres-sion of diabetic kidney disease. The diversity of therapies currently in development reflects the pathogenic com-plexity of diabetic nephropathy. These novel agents, target-ing several culprit areas, should provide additional, much needed benefits, but translation of these experimental achievements to the clinical world is still limited or lack-ing. We look forward to witnessing successful manage-ment of diabetic nephropathy in the near future.

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Novel Drug Treatment for Diabetic Nephropathy

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