Novel therapies of diabetic nephropathy Basil O. Burney, Rigas G. Kalaitzidis and George L. Bakris

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1 Novel therapies of diabetic nephropathy Basil O. Burney, Rigas G. Kalaitzidis and George L. Bakris Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago, Illinois, USA Correspondence to George L. Bakris, MD, University of Chicago School of Medicine, 5841 S. Maryland Avenue, MC 1027, Rm. P-328, Chicago, IL 60637, USA Tel: ; Current Opinion in Nephrology and Hypertension 2009, 18: Purpose of review Current therapies proven to slow the progression of diabetic nephropathy include blockade of the renin angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Given our better understanding of the pathophysiology of diabetic nephropathy, newer therapies to treat this condition are slowly emerging. Recent findings Animal studies and a single clinical trial demonstrate efficacy of the renin inhibitor, aliskiren, to decrease a marker of nephropathy progression, that is albuminuria. On the basis of animal study results, pyridoxamine, an inhibitor of advanced glycation and ruboxistaurin, a protein kinase C inhibitor showed promise as new agent to treat nephropathy. The clinical trial results were less than gratifying, however. Sulodexide, a glycosaminoglycan, works to reduce proteinuria presumably by restoring the already reduced glycoproteins present in the glomerular basement membrane. Like other agents, sulodexide also looked promising in animal studies, but failed to demonstrate albuminuria reduction in a large multicentre clinical trial (SUN-Micro-Trial). Summary This review summarizes newer therapies for slowing the progression of diabetic nephropathy. Aliskiren shows promise from small clinical studies, but we await the results of the multicentre, international ALTITUDE trial in about On the basis of the results of trials only, pyridoxamine may have a chance at further evaluation, but that is also unclear. Keywords diabetes, kidney, microalbuminuria, nephropathy, proteinuria, renal Curr Opin Nephrol Hypertens 18: ß 2009 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction Advanced diabetic nephropathy is the leading cause of glomerulosclerosis and end-stage renal disease worldwide [1]. A target of advanced nephropathy is to reduce albuminuria by at least 30% [2 ]. The earliest clinical evidence of nephropathy is an increase in microalbuminuria (defined as >30 mg/day) into the macroalbuminuria range (>300 mg/day). A number of clinical trials have demonstrated a slowed decline in kidney function using blockers of the renin angiotensin aldosterone system (RAAS) in concert with diuretics and calcium channel blockers [3]. Pathophysiology of diabetic nephropathy The pathophysiology of diabetic nephropathy is now better understood and targets have been established such as advanced glycation end products and membrane charge effects [4 ]. An early haemodynamic abnormality is glomerular hyperfiltration associated with intraglomerular hypertension; however, this alone does not predict nephropathy development [5]. Factors responsible for intraglomerular hypertension include activation of various vasoactive systems, such as the RAAS and endothelin systems. In response, secretion of profibrotic cytokines, such as transforming growth factor b (TGF-b) is increased and further haemodynamic changes occur, such as increased systemic and intraglomerular pressure [4 ]. Metabolic pathway involvement includes persistent hyperglycaemia leading to nonenzymatic glycosylation, increased protein kinase C (PKC) activity and abnormal polyol metabolism [4 ]. Oxidative stress [6] and increased secretion of inflammatory cells, such as cytokines, growth factors and metalloproteinase also plays an important role in the development of diabetic nephropathy [7,8]. A number of new studies focus on blocking some the aforementioned mechanisms to slow nephropathy. Studies have evaluated the effects blocking various pathways to see whether they are additive in the presence of already established RAAS blockade. These studies are summarized in the following sections of this paper ß 2009 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MNH.0b013e c51

2 108 Clinical nephrology Sulodexide Sulodexide is an oral formulation of highly purified mixture of glycosaminoglycans. It is composed of 80% fast-moving heparin sulphate and 20% dermatan sulphate and is the most extensively investigated glycosaminoglycans for diabetic patient [9 11]. It bears strong chemical similarity to heparin but does not have anticoagulation properties when given orally. Sulodexide has emerged as potential treatment of diabetic nephropathy as multiple studies demonstrate reductions in urinary albumin excretion with glycosaminoglycan therapy [12 14]. The precise physiology of the sulodexide-mediated nephroprotection in diabetic nephropathy is not clear, but several mechanisms have been described. In-vitro sulodexide has been shown to inhibit heparinase HPR-1 activity [15]. HPR-1, which is upregulated in high-glucose conditions, is responsible for decreasing the proteoglycan content of the glomerular basement membrane (GBM) by degrading heparin sulphate proteoglycans. As sulodexide is a mixture of glycosaminoglycans, it helps in restoring the glomerular glycoproteins present in GBM and mesangium. Another mechanism involves restoring the anionic heparin sulphate charge on the GBM by sulodexide and its related compounds. Finally, it suppresses high-glucose induced overexpression of TGF-b1 that is responsible for enhanced expression of mesangial matrix and collagens [16]. The efficacy of sulodexide in diabetes was evaluated in DiNAS study [17]. DiNAS was a randomized, double blind and placebo controlled trial involving 223 patients with microalbuminuria and macroalbuminuria who had type 1 or type 2 diabetes and stable blood pressure. Patients were randomized to sulodexide 50, mg daily and placebo for 4 months with a 4-month observation period after drug discontinuation. After 4 months of therapy, albuminuria decreased by 30, 49 and 74%, respectively, compared with the placebo group. Four months after drug discontinuation, albuminuria remained 69% lower in those randomized to 200 mg of sulodexide compared with the placebo group. There were no statistical differences in albuminuria reduction from placebo in the other groups. This sustained response suggested that some anatomical or structural change had occurred with sulodexide. Sulodexide was well tolerated and no major side-effects were seen in this study. A recent pilot study included 149 patients with type 2 diabetes and microalbuminuria, defined as an albumin/ creatinine ratio (ACR) between 20 and 300 mg/g creatinine. These patients were randomized to 200 and 400 mg of sulodexide versus placebo. The primary endpoint at 6 months was a 50% reduction in ACR or return to normoalbuminuria. This was achieved in 33.3, 18.4 and 15.4%, respectively [18 ]. Given the positive finding from these smaller studies, the sulodexide microalbuminuria trial (SUN-Micro-Trial) [19] was designed that evaluated the effects of sulodexide on diabetic nephropathy. It was a randomized, double blind, placebo controlled trial involving 1000 patients with diabetes and persistent microalbuminuria who were already receiving maximal RAAS blocking therapy. The primary endpoint was reduction in the urine albumin. However, this trial failed to achieve the primary endpoint. With the failure of this trial to demonstrate reduction of albuminuria in diabetic nephropathy, another already planned phase 4 trial, the SUN- Macro-Trial, was cancelled. Thus, a promising therapy tested early in its development on change in a marker of nephropathy progression, that is microalbuminuria failed to perform in an adequately powered study. Ruboxistaurin Overexpression of PKC is another key metabolic pathway involved in the pathogenesis of the diabetic nephropathy. PKC is a family of at least 12 isoforms that play an important role in signal transduction. PKC is activated in response to diacylglycerol, which is increased in hyperglycaemia [4 ]. Activated PKC causes kidney damage through number of mechanisms including generation of oxidants through activation of NADPH oxidase leading to oxidative stress [20] and signalling TGF-b to induce extracellular matrix production [21]. Ruboxistaurin (RTX) is an oral PKC-b inhibitor and, in animal studies, has been shown to normalize glomerular hyperfiltration, reduce extracellular matrix protein production and TGFb1 and ultimately decrease albuminuria [22]. In a recent pilot study of 123 patients with diabetic nephropathy and macroalbuminuria, patients were randomized to either 32 mg daily of RTX or placebo for 1 year [23]. Patients in both arms were continued on angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) during this trial. The primary endpoint was reduction in urinary albumin excretion. After 1 year, patients treated with RTX experienced 24% reduction in albuminuria as compared with those treated with placebo. This reduction in albuminuria appeared as early as 1 month following treatment initiation. In RTX group, kidney function assessed by estimated glomerular filtration rate (egfr) was stable, whereas in placebo group, there was a decline in egfr. However, this study had some limitations. It was underpowered to detect any significant differences in albumin creatinine ratio and egfr. Another limitation of this study was its small size study and limited duration of follow-up that further limited conclusions about safety of RTX. RTX has also been shown to reduce visual loss by 40% in patients with moderate to severe diabetic retinopathy

3 Novel therapies of diabetic nephropathy Burney et al. 109 after 3 years compared with placebo patients [24,25]. This was noted in PKC Diabetic Retinopathy study 2 (PKC-DRS2). However, in the same trial, investigators reported adverse event of diabetic nephropathy more frequently in patients receiving RBX than those receiving placebo [n ¼ 7 (2%) versus n ¼ 0; P ¼ 0.015]. Recently, a long-term, extensive and collective evaluation of three diabetic retinopathy trials compared the effects of RTX on kidney function [26 ]. The results demonstrate that there was no difference in the frequency of elevated urine albumin excretion, egfr or kidney outcomes in the two arms of the study. A recent drug safety analysis [27] of patients from different RBX studies failed to confirm an increased rate of diabetic nephropathy previously reported by investigators in PKC-DRS2 study. With these mixed results from different small clinical trials involving RTX, a large-scale randomized prospective trial is required to study the benefits and safety of RBX in patients with diabetic nephropathy. Unfortunately, due to the results of the retinopathy trial, the Food and Drug Administration required further testing and did not give approval for retinopathy, consequently, the company failed to develop the product further. Pyridoxamine There is increasing evidence to support the concept that advanced glycation end products (AGEs) are involved in the pathogenesis of diabetic nephropathy and other diabetes complication [28]. In diabetes, AGEs are formed by the modification of protein amino groups by glucose. The formation of AGEs increases not only by increase in oxidative substrate such as glucose in diabetes, but also by increase in reactive carbonyl species and reactive oxygen species. This important role of AGEs in the pathophysiology of diabetic kidney disease resulted in development of different compounds including pimagedine, tested in a clinical trial and, although efficacious, had safety issues [29] and more recently, pyridoxamine, an active inhibitor of AGEs [30]. The precise mode of pyridoxamine s action is still not clear, but it likely acts through three different mechanisms: inhibition of glycated proteins (Amadori products) breakdown, reduction of toxic effects of reactive oxygen species and scavenging of reactive carbonyl compounds [30]. Pyridoxamine has been studied extensively in rat models. In two previous rat models of type 1 and type 2 diabetes, pyridoxamine preserved kidney function [30 32]. A phase 2 trial PYR-206 studied the safety and efficacy of pyridoxamine. A total of 128 patients with diabetic nephropathy received either 50 mg of pyridoxamine or placebo for 6 months [33 ]. Another similar phase 2 trial PYR-205/207 included 84 patients with either type 1 or type 2 diabetes [33 ]. In these trials, patients were randomized to receive either pyridoxamine 250 mg or placebo in addition to standard of care therapy for diabetic nephropathy. As both trials were similar, merged data sets were published [33 ]. The data revealed a reduction of baseline serum creatinine of 48% in pyridoxamine group as compared with placebo group. Pyridoxamine group also decreased urinary excretion of TGF-b as compared with baseline. No change in urinary albumin excretion (UAE) was noted in either treatment or placebo groups. Moreover, there was no change in UAE in either group from baseline. The results of this integrated study suggested positive effects of pyridoxamine on slowing the progression of the diabetic kidney disease as witnessed by improvement in serum creatinine levels from baseline in the treatment group. These phase 2 trials demonstrate that pyridoxamine is well tolerated in patients and has a positive impact on the preservation of the renal function in patients with diabetic nephropathy. One must be cautious, however, in interpreting these small studies and a large trial such as that with sulodexide needs to be performed to assess the true benefit, if any. Aliskiren Aliskiren is a highly potent and orally effective renin inhibitor. It is responsible for inhibiting renin and, thus, decreasing angiotensin I and angiotensin II levels as well as aldosterone levels. Aliskiren also significantly reduces the expression of TGF-b, a protein which in conjunction with angiotensin 2 plays an important role in progression of renal fibrosis in diabetic nephropathy [4 ]. The antihypertensive effects of aliskiren are clear and it was approved for treatment for hypertension in 2007 [34]. Moreover, it has proven additive antihypertensive effects when used in combination with other blood pressure lowering agents [35 ]. Aliskiren decreases albuminuria, lowers blood pressure and normalizes serum creatinine in transgenic rats for human renin and angiotensinogen genes [36]. In another rat model, aliskiren in comparison with perindopril reduced blood pressure to the same extent as perindopril but attenuated tubulointerstitial fibrosis more than perindopril did, an important factor in diabetic nephropathy [37 ]. It also reduced albuminuria and glomerulosclerosis similar to the levels achieved by perindopril [37 ]. Feldman et al. [38] noted similar findings on blood pressure and albuminuria lowering as well as suppression of TGF-b in a different rat model. A small study of 15 patients with diabetes received 300 mg of aliskiren [39]. In this study, urinary albumin creatinine ratio (UACR) was reduced by 17% in 2 4 days and 44% at 28 days. Blood pressure also fell appropriately. This interesting observation was recently testing properly when dual

4 110 Clinical nephrology blockade of the RAAS system was studied in the Aliskiren in the Evaluation of proteinuria in Diabetes (AVOID) trial [40 ]. This was a randomized double-blind study involving 599 patients. Participants enrolled in this study entered into a 3-month open-label period where any previously administered drug that interfered with RAAS was discontinued, except beta-blockers. Treatment was initiated with 100 mg of losartan in all participants and then patients were randomly assigned to either aliskiren (150 mg for 3 months titrated to 300 mg for next 3 months) or placebo for total of 6 months. The primary outcome was reduction in UACR. A 20% reduction in UACR was observed in the aliskiren group when compared with placebo. About twice as many patients who received aliskiren had a more than 50% reduction in albuminuria compared with those receiving placebo. The results of these animal and human studies are very promising, and theresults of a large outcome trial in diabetic nephropathy, ALTITUDE [41] (Aliskiren Trial in Type 2 Diabetes using Cardiovascular and Renal Disease Endpoints) is awaited. This large-scale randomized placebo controlled trial will compare aliskiren at a dose of 300 mg daily to placebo in presence of conventional therapy in patients with type 2 diabetes who are at high risk for cardiovascular and renal mortality and morbidity. The primary endpoint of this study would be doubling of serum creatinine, onset of end-stage renal disease (ESRD), cardiovascular related death, myocardial infarction and stroke. Conclusion Current established treatments for diabetic nephropathy all involve blood pressure reduction on a base of RAASblocking therapy that includes ACEIs and ARBs. The last decade has seen new and interesting agents tested in the context of different pathophysiological mechanisms of diabetic nephropathy. These novel treatments were targeted to specific mechanisms in the pathogenesis of diabetic kidney disease. Out of the newer drugs, there is solid evidence to support renin inhibition, although outcome data are pending. All other innovations have failed to demonstrate clear benefit or in the case of pyridoxamine need more studies. On the basis of the available trial data, an updated paradigm for approaching a patient with diabetic nephropathy was recently published by the American Society of Hypertension [42 ]. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Rossing P. Diabetic nephropathy: worldwide epidemic and effects of current treatment on natural history. Curr Diab Rep 2006; 6: Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis 2007; 49: Comprehensive review of antihypertensive agents on changes in proteinuria in the context of kidney disease progression. 3 Khosla N, Bakris G. Lessons learned from recent hypertension trials about kidney disease. Clin J Am Soc Nephrol 2006; 1: Dronavalli S, Duka I, Bakris GL. The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 2008; 4: A review of cytokine and hormonal mechanisms involved in the development of diabetic nephropathy. 5 Forbes JM, Fukami K, Cooper ME. Diabetic nephropathy: where hemodynamics meets metabolism. Exp Clin Endocrinol Diabetes 2007; 115: Singh DK, Winocour P, Farrington K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat Clin Pract Nephrol 2008; 4: Ichinose K, Kawasaki E, Eguchi K. Recent advancement of understanding pathogenesis of type 1 diabetes and potential relevance to diabetic nephropathy. Am J Nephrol 2007; 27: A review that integrates the immune, inflammatory and hormonal factors that contribute to development to nephropathy. 8 Raptis AE, Viberti G. Pathogenesis of diabetic nephropathy. Exp Clin Endocrinol Diabetes 2001; 109 (Suppl 2):S424 S Achour A, Kacem M, Dibej K, et al. One year course of oral sulodexide in the management of diabetic nephropathy. J Nephrol 2005; 18: Dedov I, Shestakova M, Vorontzov A, Palazzini E. A randomized, controlled study of sulodexide therapy for the treatment of diabetic nephropathy. Nephrol Dial Transplant 1997; 12: Solini A, Vergnani L, Ricci F, Crepaldi G. Glycosaminoglycans delay the progression of nephropathy in NIDDM. Diabetes Care 1997; 20: Myrup B, Hansen PM, Jensen T, et al. Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus. Lancet 1995; 345: Skrha J, Perusicova J, Pont uch P, Oksa A. Glycosaminoglycan sulodexide decreases albuminuria in diabetic patients. Diabetes Res Clin Pract 1997; 38: Sorrenti G, Grimaldi M, Canova N, et al. Glycosaminoglycans as a possible tool for micro- and macroalbuminuria in diabetic patients. A pilot study. J Int Med Res 1997; 25: Maxhimer JB, Somenek M, Rao G, et al. Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients. Diabetes 2005; 54: Ceol M, Gambaro G, Sauer U, et al. Glycosaminoglycan therapy prevents TGF-beta1 overexpression and pathologic changes in renal tissue of longterm diabetic rats. J Am Soc Nephrol 2000; 11: Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol 2002; 13: Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria. Nephrol Dial Transplant 2008; 23: Clinical trial results that demonstrates effects of sulodexide in diabetic nephropathy. 19 Lambers Heerspink HJ, Fowler MJ, Volgi J, et al. Rationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy. Diabet Med 2007; 24: Hudson BI, Bucciarelli LG, Wendt T, et al. Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders. Arch Biochem Biophys 2003; 419: Chu S, Bohlen HG. High concentration of glucose inhibits glomerular endothelial enos through a PKC mechanism. Am J Physiol Renal Physiol 2004; 287:F384 F Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000; 14: Tuttle KR, Bakris GL, Toto RD, et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 2005; 28: The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 2005; 54:

5 Novel therapies of diabetic nephropathy Burney et al Aiello LP, Davis MD, Girach A, et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 2006; 113: Tuttle KR, McGill JB, Haney DJ, et al. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin J Am Soc Nephrol 2007; 2: A review of studies with this PKC-b inhibitor in diabetes. 27 McGill JB, King GL, Berg PH, et al. Clinical safety of the selective PKC-beta inhibitor, ruboxistaurin. Expert Opin Drug Saf 2006; 5: Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol 2003; 14:S254 S Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004; 24: Voziyan PA, Hudson BG. Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage. Cell Mol Life Sci 2005; 62: Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int 2003; 63: Degenhardt TP, Alderson NL, Arrington DD, et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int 2002; 61: Williams ME, Bolton WK, Khalifah RG, et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol 2007; 27: Results of clinical trials with pyridoxamine in people with diabetic nephropathy. 34 Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renininhibitor, provides dose-dependent antihypertensive efficacy and placebolike tolerability in hypertensive patients. Circulation 2005; 111: Oparil S, Yarows SA, Patel S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, doubleblind trial. Lancet 2007; 370: The study shows the effects of a renin inhibitor added to an angiotensin receptor blocker on blood pressure reduction. 36 Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 2005; 46: Kelly DJ, Zhang Y, Moe G, et al. Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia 2007; 50: A series of studies in animal models that demonstrate effects on renin inhibition on inflammatory and clinical effects of a renin inhibitor. 38 Feldman DL, Jin L, Xuan H, et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 2008; 52: Persson F, Rossing P, Schjoedt KJ, et al. Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int 2008; 73: Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358: The study shows the antiproteinuric effects of adding a renin inhibitor to an angiotensin receptor blocker in type 2 diabetes. 41 Gaddam KK, Oparil S. Renin inhibition: should it supplant ACE inhibitors and ARBs in high risk patients? Curr Opin Nephrol Hypertens 2008; 17: Bakris G, Sowers JR, on behalf of the American Society of Hypertension: Treatment of Hypertension in Patients with Diabetes: An Update. J Clin Hypertens (Greenwich) 2008; 10: Updated approach to treat hypertension in diabetic nephropathy from the American Society of Hypertension.