Novel Therapies of Diabetic Nephropathy - SAGE Journals

Nephrology Reviews 2011; volume 3:e4

Novel therapies of diabetic nephropathy Harneet Kaur,1 Sharma Prabhakar2 1

Department of Medicine, New York Medical College, Valhalla, NY, USA; Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

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Economic burden

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Diabetes mellitus (DM) is the foremost cause of chronic kidney disease (CKD) in developed countries and is rapidly becoming

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Introduction

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Correspondence: Sharma S Prabhakar, Texas Tech University Health Sciences Center Lubbock, TX 79430, USA. Tel. 806.743.3155 - Fax: 806.743.3148. E-mail: [email protected]

Key words: diabetic nephropathy, biomarkers, therapy.

This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BYNC 3.0). ©Copyright H. Kaur and S. Prabhakar, 2011 Licensee PAGEPress, Italy Nephrology Reviews 2011; 3:e4 doi:10.4081/nr.2011.e4

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Received for publication: 14 February 2011. Accepted for publication: 31 March 2011.

Diabetic nephropathy is currently the most common cause of end stage renal disease not only in the Western hemisphere but also in the developing nations. While the available therapeutic options remain not very effective, there is a strong ongoing effort to understand the pathogenesis better and develop more useful biomarkers. As the pathogenic mediators and signaling pathways get better defined, the scope of novel pharmaceutical agents to address such mediating factors as therapeutic targets is advancing. This review provides, in addition to a brief synopsis of currently used strategies, a comprehensive review of potential therapies that have been evolving in the past decade with a specific focus on the promising agents.

population age and sex differences, average medical expenditure among people with diagnosed diabetes were 2.3 times higher than what expenditure would be in the absence of diabetes. Indirect costs were estimated at 58 billion US dollars (disability, work loss, premature mortality).3 Diabetic nephropathy (DN) refers to a characteristic set of structural and functional kidney abnormalities seen in patients with diabetes.4

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Acknowledgments: parts of the work quoted in this manuscript were funded by a grant from the American Heart Association-(Texas affiliate). We thank the Jane and Larry Woirhaye Renal Research Foundation for providing the funding for several of the experiments that were referenced in this manuscript. We also sincerely thank Patricia Faulkner for her secretarial assistance in the preparation of the manuscript.

the leading cause in developing countries.1 The prevalence of DM is increasing most rapidly in the developed countries and in developing countries undergoing transition from traditional to modern lifestyles. In the United States (US), estimates from national surveys have shown an 8-fold increase in the prevalence of diagnosed DM between 1958 and 20001 Approximately 23.5 million people or 10.7% of the US population over the age of 20 years, have DM, and about a third of those with diabetes are unaware that they have the disease. In addition, 15,000 youths in the US are newly diagnosed with Type 1 DM annually, and about 3,700 are newly diagnosed with Type 2 DM annually (based on 2002-03 data). This brings the rate of new cases among young people to 19 per 100,000 each year for type 1 DM and 5.3 per 100,000 for type 2. (CDC fact sheet 2007). Boyle et al.2 estimated that annual diagnosed incidence of DM will increase from about 8 cases per 1,000 in 2008 to about 15 in 2050. If we assume a low incidence and relatively high mortality due to DM, total diabetes prevalence of diagnosed and undiagnosed cases is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. However, if recent increases in incidence continue and the mortality stays relatively low, prevalence will increase to 33% by 2050. According to Boyle, these are the two extreme scenarios. A middle-ground scenario projects a prevalence of 25% to 28% by 2050.2 The greatest increase in prevalence of DM will occur in the population older than 75 years and among African Americans. Globally the burden of diabetes is expected to double between 2000 and 2030, with the greatest increases in prevalence expected to occur in the Middle East, sub-Saharan Africa, and India.1 The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men.

Abstract

The economic burden of this diabetes epidemic is also tremendous. In 2007, total estimated diabetes costs in the US (direct and indirect) were projected to be 174 billion US dollars. Direct medical costs were estimated at 116 billion US dollars. After adjusting for

[Nephrology Reviews 2011; 3:e4]

Epidemiology and financial implications

As the population of patients with diabetes of long duration grows, reports of a dramatically increasing burden of DN are appearing. This increased incidence is not only from developed countries but also from Africa, India, the Pacific Islands and Asia, where infectious disease previously posed the greatest threat. This increased risk and more rapid progression of DN also have also been reported in immigrants from developing to developed countries.1 In the US, DN accounts for 45% of prevalent kidney failure, up from 18% in 1980. In 2005, 46,739 people with diabetes began treatment for endstage kidney disease in the United States and Puerto Rico. In 2005, a total of 178,689 people with end-stage kidney disease due to diabetes were living on chronic dialysis or with a kidney transplant in the United States and Puerto Rico.3 In the Medicare program, non-dialysisrequiring chronic kidney disease, diabetes, and congestive heart failure account for close to two- thirds of all costs, and 4.2% of individuals with diabetes and chronic kidney disease account for 13.4% of expenditure. Approximately 60% of new hemodialysis patients in the United States have DM. Although the prevalence of renal replacement therapy remains comparatively low, rising prevalence rates may have substantial economic implications, especially when one considers that renal replacement therapy accounts for about 6% of current Medicare expenditure. Among dialysis patients, the presence of diabetes is associated with expenditure that is approximately 27% higher than in patients without diabetes.3

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The three major histological changes in the glomeruli in DN are mesangial expansion; glomerular basement membrane (GBM) thickening; and glomerular sclerosis. The last abnormality may have a nodular appearance (the Kimmelstiel-Wilson lesion), which often associated with hyaline deposits in the glomerular arterioles. These different histological patterns appear to have similar prognostic significance. The mesangial expansion and glomerulosclerosis do not always develop in parallel, suggesting that they may have a somewhat different underlying pathogenesis.5-8 Recently, Tervaert et al. classified DN pathologically into 4 classes. Class I, GBM thickening: isolated GBM thickening and only mild, non-specific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (KimmelstielWilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel–Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathological evidence that sclerosis is attributable to diabetic nephropathy.7

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Indications for a kidney biopsy in a patient with diabetes

range of 25 to 40%.13-17 In a systematic review of 28 studies involving 10,298 patients with type 2 diabetes, the prevalence of microalbuminuria was 26% at a mean diabetes duration of 10 years.13 ADVANCE trial involving 11,140 patients with type 2 diabetes reported a similar prevalence of 27% at eight years.14 The prevalence of microalbuminuria in patients with type 2 diabetes varies with ethnicity. It is higher in Asians and Hispanics than in Whites.16,17 At a mean duration of diabetes of almost eight years, the rate of microalbuminuria was significantly higher in Asians and Hispanics (43 vs 33 percent in whites). Additionally, there are also racial and ethnic differences in the rate of progression to macroalbuminuria. Interestingly, some patients with type 2 diabetes have microalbuminuria at the time of diagnosis.15,18,19 This issue was addressed in the United Kingdom Prospective Diabetes Study (UKPDS) which included approximately 5100 patients with newly diagnosed type 2 diabetes: 6.5% of the patients had microalbuminuria (and 0.7% had macroalbuminuria) at the time of diagnosis and the annual rate of progression from normoal buminuria to microalbuminuria was 2.0%.15 The rate of microalbuminuria at the time of diagnosis of type 2 diabetes may be higher in older patients.19 In addition to these clinical differences, there are aspects of the histopathology of the kidney that are different in the nephropathy of type I compared to type II diabetes. For example, the focal nodular glomerulosclerosis (Kimmelsteil Wilson lesion) that is common and characteristic of nephropathy of type I diabetes is rather uncommon in type II diabetes, being seen in only 30% while diffuse glomerulosclerosis is rather more common.

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The earliest clinical evidence of DN is micro-albuminuria. This is defined as urinary albumin excretion of 30-299 mg/24 h in a 24-h urinary collection, 20-199 ug/min in a timed urine collection, or 30-299 ug/mg creatinine in a spot urine collection on at least two occasions within a three-to-six month period.4 A kidney biopsy is required to diagnose diabetic glomerulopathy definitively. However, in most cases careful screening of diabetic patients can identify people with DN without the need for kidney biopsy. The finding of elevated urinary albumin excretion is divided arbitrarily into: i) microalbuminuria, a modest elevation of albumin thought to be associated with stable kidney function, but a greater risk of macroalbuminuria and kidney failure; ii) macroalbuminuria, a higher elevation of albumin associated with progressive decline in glomerular filtration rate (GFR), an increase in systemic blood pressure, and a high risk of kidney failure.1 Substantial under-diagnosis of both DM and CKD leads to lost opportunities for prevention, and inadequate or inappropriate care of patients. This may contribute to disease progression. Nevertheless, diabetes care has improved on the whole. The benefits of meticulous management have become widely accepted and the use of angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and statins has increased in patients with diabetes.1

causes beyond diabetic nephropathy, This may often require a renal biopsy. Under such circumstances, it is not uncommon to find in the renal biopsy a non-diabetic glomerulopathy or vasculitis supervening over diabetic nephropathy.

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Diagnosis

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Usual criteria for suspecting and carrying out renal biopsy in type 1 diabetes mellitus are microhematuria, absence of diabetic retinopathy, uncharacteristic changes in renal function or immunological abnormalities. However, the validity of these clinical indications is not well established for type 2 diabetes mellitus and no formal criteria have been defined. Serra et al. used the criteria for type 1 diabetes and performed biopsies on 35 patients with type 2 diabetes. They reported that diabetic glomerulopathy is the most commonly found renal lesion in patients with type 2 diabetes with proteinuria biopsied according to type 1 diabetes criteria, even in patients with microhematuria or without retinopathy. In patients with microscopic hematuria, presence of RBC casts is an indication to consider renal biopsy since half of such patients eventually have a non-diabetic glomerulopathy. In addition, in type 2 diabetic subjects, an acute worsening of renal function and sudden increase in proteinuria or development of hematuria warrants investigation to exclude [page 24]

Impact on the kidney of type 1 versus type 2 diabetes In patients with type 1 diabetes, microalbuminuria usually develops 5 to 15 years after the onset of diabetes and then increases over time.9-11 Only, a small proportion of patients develop microalbuminuria within five years of onset of diabetes type.10,12 Newman and coauthors published a systematic review of nine longitudinal studies examining microalbuminuria in 7,938 patients with type 1 diabetes. They reported the overall prevalence of microalbuminuria as 28% at a mean duration of diabetes of 15 years.13 In another report, the prevalence of microalbuminuria reached 52% at 30 years.10 Patients with diabetes type 2 have a reported prevalence of microalbuminuria approximately ten years after the diagnosis in the [Nephrology Reviews 2011; 3:e4]

Treatment Management of DM Interventions that have been found useful in preventing or retarding the progression of DN include: i) strict glycemic control; ii) strict blood pressure control; iii) cessation of smoking; iv) control of hyperlipidemia; v) restriction of protein intake. Patients who develop endstage renal disease (ESRD) will require renal replacement therapy.4

Effects of glucose lowering and anti-hypertensive treatment on the course of diabetic nephropathy That hyperglycemia is an important initiator of many signaling pathways that result in renal and vascular injury in diabetes is by now widely acknowledged. However, such causeeffect relationship was demonstrated conclu-

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Blood pressure control Long-term and aggressive antihypertensive treatment induces a progressive reduction in the rate of decline in kidney function. Thus, this modality of treatment can postpone renal insufficiency in patients with DN. The primary goal of therapy for non-pregnant patients with DM over the age of 18 years is to achieve a blood pressure less than 130/80 mmHg for patients with proteinuria less than 1 g/day, and less than 125/75 mmHg for patients with more than 1 g/day of proteinuria. ACE inhibitors are recommended as first-line antihypertensive therapy for patients with type-I and type-2 DM. ARBs are now recommended as first-line therapy for patients with type-2 DM by the American Diabetes Association. Other agents that can be used include Beta blockers, calcium channel blockers, and diuretics.4

ACE inhibition versus angiotensin II (Ang II) receptor type 1 blockade in the reninangiotensin system RAS is one of the most important physiological regulators of renal function. ACE inhibitors selectively dilate efferent arterioles. This decreases arterial pressure and in turn reduces glomerular capillary pressure. In addition, Ang II causes mesangial cell growth and matrix production. Numerous animal studies and clinical trials have shown that ACE inhibitors significantly reduce the loss of kidney function in DN. They prevent progression of microalbuminuria to overt proteinuria. Also several studies evaluated the effect of ACE inhibitor on development and progression of DN. The landmark study by Lewis et al. examined the effect of captopril on the progression of DN in patients with type 1 DM. This was measured as the rate of decline in creatinine clearance and the combined end points of dialysis, transplantation, and death. Treatment with captopril was associated with 48% risk reduction for doubling the serum creatinine as compared to placebo.22 The results of the study were subsequently confirmed by the North American Microalbuminuria Study Group and EUCLID study group.32,33 They extended the observation by showing a protective effect of ACE inhibitors in patients with a variety of renal diseases, including glomerulopathies, interstitial nephritis, nephrosclerosis, and DN. The exception was polycystic kidney disease. Importantly, the protective effect of ACE inhibition was independent of the severity of renal insufficiency.34 The MICRO-HOPE (Heart Outcomes Prevention Evaluation) studied the benefit of ramipril in type 2 diabetics. Ramipril reduced the risk of overt nephropathy by 24%. Moreover, ramipril reduced urinary albumin excretion at one year and at the end of the study. Thus, ACE inhibitors have also been shown to be renoprotective in patients with type 2 DM.35 Angiotensin receptor blockers are equally effective in renal protection in diabetic

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The preventive role of ACE inhibitors (ACEi) was first demonstrated in a large scale study by Edmond Lewis et al.22 In this study that involved type I diabetics, use of captopril was associated with a significant risk reduction of nephropathy compared to placebo. This effect was independent of blood pressure reduction. Renoprotective benefits with ACE inhibitors and ARBs compared to placebo have been reported in a number of trials.23-28 The magnitude of benefit can be illustrated by the results of a trial reported by Parving and coworkers in 2001: 590 hypertensive patients with type 2 diabetes and microalbuminuria were randomly assigned to either irbesartan (150 or 300 mg/day) or placebo and then followed for two years.29 The primary end point was the time from baseline to first detection of overt nephropathy (urine albumin excretion more than 200 µg/min [macroalbuminuria] and at least a 30% increase from baseline on two consecutive visits). This end point was significantly more common in the placebo group compared to irbesartan (14.9 vs 9.7 and 5.2% with 150 and 300 mg of irbesartan). Interestingly, this benefit was not related to differences in blood pressure. Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have similar efficacy in type 2 diabetic patients with microalbuminuria. The only randomized comparative trial (DETAIL) of these agents in type 2 diabetic patients compared enalapril to the ARB telmisartan in 250 patients with early nephropathy as defined by albuminuria (82% microalbuminuria and 18% macroalbuminuria to a maximum of 1.4 g/day) and a baseline GFR (measured isotopically) of approximately 93 mL/min per 1.73 m2.30 A greater fall in GFR of at least 10.0 mL/min per 1.73 m2 at five years was predefined as suggesting a clinically significant difference between the two treatment groups. At five years, there was a smaller decline in GFR with enalapril that was not significant (14.9 vs 17.9 mL/min per 1.73 m2 with telmisartan). Both groups had similar rates or findings for the secondary end points, which included annual changes in the GFR, blood pressure, serum creatinine concentration, urinary albumin excretion, end-stage kidney disease, cardiovascular events, and mortality. A limitation of the trial was that only 168 of the original 250 patients completed the trial. Nevertheless, the results are consistent with the conclusion that ACE inhibitors are at least as effective as ARBs in type 2 diabetics with microalbuminuria. In patients with type 2 diabetes and microalbuminuria, ACE inhibitor or an ARB is

recommended to slow or prevent progression to macroalbuminuria and overt diabetic nephropathy. The renal goal of ACE inhibitor therapy is a modest reduction in urine albumin excretion. There is evidence that suggests that addition of an ACEi to an ARB provides additional but significant effect in lowering proteinuria and also slowing the renal failure.31 However, the costs and increase in adverse effects particularly hyperkalemia, limit the routine use of combination therapy. A separate issue is whether ACE inhibitors or ARBs are effective as preventive therapy in normoalbuminuric type 2 diabetic patients who are either normotensive or hypertensive. This is yet to be proven.

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Effects of ACE inhibitors on the prevention of diabetic nephropathy

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sively by the DCCT study in which type I diabetics were treated either with intensive control or conventional therapy. Those treated with intensive insulin therapy had both primary and secondary prevention of nephropathy as well other microvascular complications of diabetes. Subsequently many other studies have validated such observations even in type II diabetes. Elevated systemic blood pressure is an important mechanism for renal injury in diabetes. Parving et al. first demonstrated that reducing blood pressure using diuretics and beta blockers, proteinuria can be reduced and well as slow down the decline of GFR can be slowed down.12 In more recent years, it has become clear that reduction of blood pressure with ACE inhibitors has a more profound effect on the indices of renal injury in diabetes. Glycemic control studies have shown that strict glycemic control delays the development of microalbuminuria, stabilizes or reduces protein excretion in patients with microalbuminuria and overt proteinuria, and slows the rate of progression to chronic renal failure. The Diabetes Control and Complications Trial (DCCT) compared conventional with intensive glycemic management in 1,441 type 1 diabetic patients. The mean glycosylated hemoglobin (HbA1c) achieved in the conventional arm was 9.1% as compared to 7.3% achieved in the intensive treatment arm.20,21 In the combined cohorts, intensive treatment reduced the development of microalbuminuria and clinical albuminuria by 39% and 56%, respectively. The overall DCCT results showed that the microvascular effects of hyperglycemia persisted for a considerable period after glucose levels had decreased. The benefits of intensive therapy were long-lasting and persisted beyond the period of shortest intervention.20,21

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Article reduced the rate of progression to ESRD in patients with type 1 diabetes. The National Kidney Foundation recommends that patients with GFR less than 29 mL/min per m2 should have a daily protein intake of 0.6 g/kg body weight4 More recently, a 4-year randomized controlled trial in 82 patients with type 1 diabetes with progressive DN showed that a moderately low-protein diet (0.9 g/kg−1/day−1) reduced the risk of ESRD or death by 76%, although no effect on GFR decline was observed40 The mechanisms by which a low-protein diet may reduce progression of DN are still unknown, but might be related to improved lipid profile and/or glomerular hemodynamics.41

ed microalbumin levels should be treated with an ACE inhibitor titrated to normalization of microalbumin excretion (if possible); ii) Patients should be educated about the importance of attention to glycemic control and avoidance or cessation of smoking in preventing and/or reversing diabetic nephropathy; iii) if hypertension exists, rigorous attention to normalization of blood pressure is important for reversal or delay of progression of nephropathy; iv) rigorous treatment of elevated LDL cholesterol may offer some benefit; v) if medical treatment is unsatisfactory, referral to a nephrologist should be considered.

Treatment of adolescents with diabetes to prevent diabetic nephropathy

Emerging therapies

The role of dietary protein restriction in CKD is best described as controversial. However, restriction of protein (0.6 g/kg body weight per day) and phosphorus (0.5 to 1 g per day) were shown to reduce the decline in GFR, lower blood pressure, and stabilize renal function compared with higher intakes. This was suggested by a randomized trial involving patients with type-I DM and overt DN. In addition, another study showed that restriction of protein intake to 0.8 g/kg body weight per day [page 26]

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Protein restriction

Extensive research is currently underway in this field and several new pathogenic mediators for DN have been discovered. These include: i) Renin; ii) Advanced Glycosylation end-products [AGE]; iii) Protein Kinase C [PKC]; iv) Transforming growth factor – Beta 1 [TGF-b 1]; v) Nitric Oxide [NO]; vi) vascular endothelial growth factor [VEGF]; vii) Oxidative stress (Table 1). In this current review we will focus on the role of these mediators and possible novel treatments using these approaches.

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The first sign of diabetic nephropathy in adolescents is microalbuminuria, an elevated albumin excretion rate (AER) as in adults. Hypertension, or even a rise in blood pressure within the normal range, may accompany progression to microalbuminuria, although the data is limited in children,24 or becomes manifest after the recognition of persistent microalbuminuria.35 However, hypertension generally precedes macroalbuminuria and overt proteinuria. Microalbuminuria is a sign of early nephropathy at a stage when nephropathy may be reversible with careful glycemic and blood pressure control.42,43 There is also some data that suggests that lowering LDL cholesterol may also provide benefits.42 Even in the absence of hypertension, therapy with an ACE inhibitor reverses increased albumin excretion or delays the rate of progression to macroalbuminuria.44-46 Thus, screening provides an opportunity to detect microalbuminuria early, to initiate ACE inhibitor and to encourage glycemic control during the reversible phase of diabetic nephropathy. Recommendations for diabetic nephropathy in adolescents are:47 i) annual screening for microalbuminuria should be initiated once the child is ten years of age and/or has had diabetes for five years; more frequent testing is indicated if values are increasing; ii) screening with a random spot urine sample analyzed for microalbumin-to-creatinine ratio; a timed overnight or a 24-h analysis can be done in followup, if indicated; iii) because exercise, smoking, and menstruation can affect the results and albumin excretion can vary from day to day, an abnormal value should be repeated; the diagnosis of persistent abnormal microalbumin excretion requires documentation of two of three consecutive abnormal values obtained on different days.47 Treatment: i) confirmed, persistently elevat-

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nephropathy. The reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (RENAAL) study36 showed that treatment with losartan was associated with a 25% decrease in the risk for doubling serum creatinine level. The risk of developing ESRD was also reduced by 28%. Two studies, Irbesartan in Patients with Diabetes and Microalbuminuria (IRMA-2) and Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study examined the effect of ARB’s in diabetic patients with microalbuminuria, but without overt DN.24,29 It is well known that in patients with type 2 DM presence of microalbuminuria increases the risk of developing DN 10 to 20 times. The IRMA-2 study showed that irbesartan significantly reduced the rate of progression of microalbuminuria to overt DN in patients with type 2 diabetes. Furthermore, the study discovered that irbesartan was associated with significantly more common restoration of normoalbuminuria as compared to standard therapy. All these effects were achieved independent of the systemic blood pressure. The more recent DETAIL study compared the renoprotective effects of ACE inhibitor enalapril and ARB telmisartan. In this head-to-head comparison, the authors showed that both treatments were equally effective in preventing the progression of renal dysfunction, measured as decline in the GFR.29 Other individual factors may better define the impact of ACE inhibitors on the progression of renal insufficiency. In particular, Rigat et al. described an insertion (I) and deletion (D) polymorphism in the ACE gene that correlates with ACE activity. ACE levels are highest in patients who are homozygous for the ACE D allele and lowest in patients homozygous for the ACE I allele.37 They are intermediate in those who are heterozygous. Yoshida et al.38 later reported a greater reduction in proteinuria in response to ACE inhibition in patients with IgA nephropathy who were homozygous for the D allele. In contrast to this, other investigators have suggested a worse response to therapy in patients who carry the D allele.39 Obviously, large-scale studies are needed to define the impact of genetic factors on the renal protective effects of ACE inhibition.

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Direct renin inhibitor – aliskiren It has been shown thus far that blockade of RAS with either ACE inhibitors or ARB is a key therapeutic strategy in slowing progression of DN. Interruption of the RAS may also be accomplished by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. Aliskiren is a direct renin inhibitor and thus decreases angiotensin II and aldosterone levels. Additionally, it decreases oxidative stress by suppressing angiotensin II induced NADPH activation. It has also been shown to reduce the expression of TGF-b levels. Aliskiren is a potent antihypertensive and antiproteinuric. Parving et al. reported the results of the AVOID trial in 2008.48 They evaluated the renoprotective effects of alkisiren in 599 patients in a multinational, randomized, double-blind study. Patients were randomly assigned to receive six months of treatment with aliskiren or placebo, in addition to losartan. The mean urinary albumin-to creatinine ratio was reduced by 20% in the group on 300 mg/day of aliskiren as compared with 12.5% of those who received placebo. The total numbers of adverse and serious adverse events were similar between groups.48

Advanced glycosylation end-products AGE’s (advanced glycosylation end-products) are generated as a result of the Maillard reaction. This is a series of sequential bio-

Article multi-ligand AGE-receptors (Figure 1). These receptors recognize a range of chemical structures. Several anti-AGE agents have been tested and shown to be renoprotective in experimental diabetic animal models.50

Aminoguanidine (Pimagedine) Aminoguanidine is the prototype of an AGE formation inhibitor which acts by scavenging intermediates in the advanced glycation catalytic process. In 1986, Brownlee et al. demonstrated that aminoguanidine administered to rats inhibited diabetes-induced accumulation of AGEs and abnormal cross-linking of arterial wall connective tissue protein. They concluded that hyperglycemia-induced increases in non-

enzymatic collagen cross-linking are prevented by aminoguanidine in vivo as well as in vitro.51 Subsequently, aminoguanidine has been shown in numerous animal models to inhibit the formation of AGEs and slow the progression of DN. In addition to being a nonspecific AGE inhibitor, aminoguanidine also inhibits other enzymes, such as nitric oxide (NO) synthase. This was demonstrated by Tilton et al.52 There also is evidence that aminoguanidine causes DNA damage through pro-oxidant activity.53 The first clinical study to evaluate aminoguanidine was ACTION (A Clinical Trial in Overt Nephropathy of Type 1 Diabetes) conducted by Bolton et al.54 This was a randomized, double-masked, placebo-

Table 1. Classification of novel agents for diabetic nephropathy. Examples

Direct renin inhibitor AGE formation inhibitors AGE Breakers AGE Receptor antagonists PKC beta inhibitor Glycosaminoglycans Endothelin receptor antagonists TGF- Inhibitors CTGF inhibitors VEGF inhibitors Anti-oxidant Others

Aliskiren Aminoguanidine, ALT-946, Pyridoxamine, thiamine Alagebrium, TRC4186, endogenous secretory RAGE, RAGE antibody Ruboxistaurin Sulodexide Avosentan Pirfenidone, SMP-534 anti-CTGF ab SU5416 Curcumin Pentoxifylline

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Class of Drugs

AGE, Advanced glycosylation end products; RAGE, transmembrane receptor for AGE; PKC, protein kinase C inhibitors; TGF, transforming growth factor – Beta; CTCF, connective tissue growth factor; VEGF, vascular endothelial growth factor.

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chemical reactions involving non-enzymatic glycation of proteins and lipids.49 AGEs are produced and accumulated as a result of prolonged hyperglycemia, dyslipidemia and oxidative stress in DM.50 About twenty-five AGEs have been chemically characterized. Some of these have been identified chemically as carboxymethyllysine and pentosidine among others.49 However, the identities of the AGEs contributing to the development of diabetic vascular complications have not been clearly determined. The first stable adduct between glucose and a protein is fructose-lysine or the Amadori product. This undergoes subsequent dehydration, oxidation, rearrangement and fragmentation reactions to form AGEs. Under physiological conditions, this reaction is can slow and occur during a period of months to years to generate AGEs. Over a person's lifespan, the amount and variety of AGE-modified tissue progressively increases. This is in part due to the time-dependence of the Maillard reaction but also reduced protein turnover associated with chronological aging, increased cross-linking and the resistance of AGE modified proteins to proteolytic digestion. A number of factors affect production of AGE. These include not just the reaction on a single amino group and sugar, but also interactions between Amadori products, protein and sugar fragmentation pools. Other factors may also influence the type and quantity of AGEs formed. For instance, time, temperature, pH, traces of transition metal ions, oxygen concentration and endogenous Maillard inhibitors (such as spermine and carnosine) may all result in changes to the observed product ratios. The formation of AGEs and their crosslinked products is a phenomenon of normal aging; however, it is accelerated in DM. AGEcross-linked products accumulate in patients with DM and have been implicated in the pathological process of diabetic complications. AGE-modification of proteins may impact on their structural and functional integrity. This is especially seen with matrix proteins, because of their slow turnover. Glucose-mediated cross-links between AGEs and target proteins also can occur, forming irreversible complexes which are resistant to proteolytic degradation. AGEs may also contribute to changes associated with aging in the cardiovascular system such as increased vascular and myocardial stiffness. AGEs increase gene expression of growth factors and cytokines, including transforming growth factor b (TGFb), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Eventually, these products cause glomerular and tubulointerstitial injury. AGEs have also been shown to directly generate reactive oxygen intermediates and quench nitric oxide. At least some of this AGE-mediated injury also occurs through the activation of

Figure 1. Role of advanced glycosylation end products in diabetic nephropathy: proposed mechanisms. AGE, advanced glycosylation end products; RAGE, transmembrane receptor for AGE; TGF b, Transforming growth factor – Beta; CTCF, connective tissue growth factor; TNF, tumor necrosis factor.

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Pyridoxamine (PYR) is one of the three natural forms of pyridoxine (vitamin B6). In various studies, pyridoxamine limited the formation of AGEs and development of nephropathy in streptozotocin-diabetic rats without affecting glycemic control.57 It scavenges pathogenic reactive carbonyl species and inhibits the formation of AGEs from Amadori compounds.58,59 In animal models of DN, pyridoxine inhibited the increases in advanced lipoxidation end products (ALEs) in collagen, and significantly decreased the rise in plasma triglycerides, [page 28]

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AGE breakers This group of compounds decreases AGE accumulation by breaking the glycation crosslinks. Although there is controversy about the exact mode of action, thiazolium compounds have decreased renal AGE accumulation. In addition, the AGE breakers have an effect on putative mediators of renal injury, such as prosclerotic cytokines, extracellular matrix accumulation and oxidative stress.55 NPhenacylthiazolium bromide and particularly its more stabile derivative compound alagebrium (ALT-711; 3-phenacyl-4,5-dimethythiazolium chloride), have proved efficacious in retarding albuminuria and kidney structural damage in various pre-clinical studies in animal models. Combination therapy with alagebrium, and ramipril was tested for effects on kidney function in a diabetic rat model. The renal gene expression of AGE receptor 1 and soluble receptor for AGEs were markedly reduced by DM and normalized with alagebrium. It also reduced the DM induced renal mitochondrial oxidative stress. In the cytosol, both therapies were equally effective in reducing reactive oxygen species production. Increases in membranous PKC activity in dia-

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Pyridoxamine

betes were attenuated by both modalities of treatment, whereas diabetes-associated increases in nuclear factor-kappaB p65 translocation remained unaltered by any therapy. Thus, it is evident that RAS blockade and AGE inhibition have specific effects. However, many of their downstream effects appear to be similar, suggesting that their renoprotective benefits may ultimately involve common pathways and key points of convergence, which could be important targets for new therapies in DN. Alagebrium alone had a modest effect on urinary albumin excretion; however, a clear benefit of combination therapy was not shown.63 A clinical trial investigating the effect of alagebrium on DN has been terminated early because of financial constraints. Recently, Joshi et al. reported about the new AGE breaker TRC4186, a chloride salt. This was evaluated in an animal model of DM with progressive cardiac and kidney failure. TRC4186 even when administered alone, retarded the development of cardiac dysfunction and reduced the severity of renal dysfunction in this diabetic model with severe persistent hyperglycemia. This finding suggested that reduction in the AGE load with resultant attenuation of the pro-inflammatory state on one hand and an improvement in AGE-related dysfunction of myocardial metabolic and calcium handling apparatus on the other, possibly contributes to the beneficial effects on microvascular and cardiac determinants of hemodynamic and renal function in DM. TRC4186 is likely to complement the action of ACE inhibitors and / or ARBs, thus preventing progression of the pathology much more effectively than currently possible.64 AGE breakers appear to have promising effects on delaying the progression of DN. However, further clinical studies are required to confirm these.

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Thiamine Experimental studies have suggested that thiamine and benfothiamine (S-benzoylthiamine monophosphate), a vitamin B1 derivative, can also prevent or decrease kidney injury. These drugs decrease formation of AGE compounds and protein kinase C (PKC) activity in DN. Benfothiamine also inhibits DM induced hyperfiltration and development of microalbuminuria.61,62 Again, clinical trials are needed to prove this effect in humans.

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ALT-946 is a more potent and selective AGE formation inhibitor than aminoguanidine. It has minimal effects on NO synthesis and appears to have fewer toxic effects, although it has not been studied in as much detail. ALT946 reproduced the renoprotective effects of aminoguanidine in diabetic Sprague-Dawley rats by decreasing kidney AGE accumulation and albuminuria.55 It has also been studied in diabetic transgenic Ren-2 rats with severe DN and increased blood pressure. ALT-946 and aminoguanidine equally ameliorated glomerulosclerosis and medullary pathology; however, ALT-946 reduced cortical tubular degeneration more than aminoguanidine. Albumin excretion rate, which was elevated with DM, was reduced with ALT-946 but not aminoguanidine. AGE immunolabeling was increased in glomeruli and reduced with ALT946 and aminoguanidine. Thus, even in the context of renal injury which is primarily blood pressure- and/or angiotensin II-dependent, approaches that interfere with metabolic pathways such as inhibitors of AGE formation can be renoprotective in experimental models.56 However, additional clinical studies are needed to address the safety and efficacy of this drug.

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cholesterol, and creatinine. It also corrected hypertension and thickening of the vascular wall, and nearly normalized urinary protein and albumin excretion.57 In addition, several other pre-clinical studies indicate that oral pyridoxamine has efficacy in preserving kidney function in type 1 and 2 diabetic rat models. Two phase II studies (PYR-206 and PYR205/207) were conducted to determine the safety and tolerability of pyridoxamine in patients with type 1 and type 2 DM with overt proteinuria.60 PYR study-206 randomized 128 patients with DN to either 50 mg of PYR or placebo for six months. PYR 205/207 randomized 84 patients with DN on PYR 250 mg or placebo in addition to RAS blockade. Although not designed to test this end point, merged data sets showed a 48% reduction in serum creatinine in PYR treated groups versus placebo. Urinary albumin excretion was unaffected. In addition, a small decrease in urinary excretion of the profibrotic cytokine TGF-b was shown. Additional phase II and phase III studies are needed to prove this effect.

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controlled study performed on 690 patients with type 1 DM, DN and retinopathy with the primary end point of the time to doubling of serum creatinine. The secondary end points included evaluations of proteinuria, kidney function, and retinopathy. This study did not demonstrate a statistically significant beneficial effect of aminoguanidine on the progression of overt nephropathy resulting from type 1 DM. However, it was noteworthy in being the first clinical proof of the concept that inhibiting formation of AGEs can result in a clinically important attenuation of the serious complications of type 1 DM. Also, 3 patients receiving aminoguanidine in the study developed glomerulonephritis.54 Thus, it is unlikely that aminoguanidine has a future role in the treatment of DN because of its safety concerns and negative outcomes in the ACTION trial.

[Nephrology Reviews 2011; 3:e4]

AGE receptor antagonists AGEs mediate their effects both directly and indirectly through receptor-dependent mechanisms. They bind to the transmembrane receptor for AGE (RAGE) and result in protein synthesis-dependent sustained activation of nuclear factor-κB (NF-κB), induction of cellular oxidant stress and expression of heme oxygenase type I with consequences for a range of cellular functions at the local site of tissue damage. By these mechanisms, RAGE is involved in the development of diabetic microvascular complications.65,66 Thus, RAGE is a potential target to prevent AGE effects. Administration of the soluble isoform of RAGE or anti-RAGE antibodies for RAGE inhibition could have a beneficial effect in DN. Yamamoto et al. reported in 2005 about endogenous secretory RAGE (esRAGE) as a decoy receptor. esRAGE protected AGEinduced vascular cell injuries as a decoy receptor and was actually detected in human

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Protein kinase C inhibitors Recent studies have identified that activation of PKC initiated by hyperglycemia is associated with many vascular abnormalities in retinal, renal, and cardiovascular tissues. Among the various PKC isoforms, the betaand delta-isoforms are activated preferentially in the vasculatures of diabetic animals, although other PKC isoforms are also increased in the renal glomeruli and retina. The glucose-induced activation of PKC

findings. Thus, the effect on albuminuria was long-lasting and additive to the ACE inhibitory effect. This strongly suggested that a chemical/anatomical change was induced in renal tissues by sulodexide. Major adverse effects were not seen.76 Thus in studies that enrolled a relatively small number of patients, sulodexide seemed to be effective in DN. However, a large adequately powered clinical study did not confirm those promising findings. (ClinicalTrials.gov Identifier: NCT00130208)

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Endothelin receptor antagonists Endothelin-1, a multifunctional peptide, is produced by the kidney and may regulate a variety of renal functions. The renal medulla is the major site of endothelin-1 synthesis and receptor expression in the kidney. In vitro, endothelin-1 inhibits sodium or water transport in the collecting duct and thick ascending limb via autocrine pathways. Endothelin-1 can also increase medullary blood flow. These effects of endothelin-1 are mediated by nitric oxide and cyclooxygenase metabolites which are produced by most medullary cells. It is one of the most potent endogenous vasoconstrictors and correlates with decreased kidney function and albuminuria.77 DN is associated with enhanced renal synthesis of endothelins. A number of pre-clinical reports suggested that endothelin might be an appropriate target to decrease DM-related albuminuria.78 Avosentan (SPP301) is a new orally available endothelin 1 antagonist. Wenzel at al. conducted a randomized, placebo-controlled, double-blind, parallel-design and dosage-range study of the effect of the avosentan on urinary albumin excretion rate (UAER) in patients with DN: 286 patients with macroalbuminuria, and BP less than 180/110 mmHg were randomized to 12 weeks of avosentan or placebo, in addition to standard ACE inhibitors/ARBs. Avosentan as an addition to standard ACEI/ARB treatment decreased UAER in patients with DN and macroalbuminuria.79 Thus far, avosentan has been the only endothelin antagonist studied for proteinuria. A large phase III trial, ASCEND, evaluated the renoprotective effect of avosentan. It showed substantial decreases in albuminuria from baseline. However, this study was stopped because of drug-related adverse events (ClinicalTrials.gov Identifier: NCT00120328). Overall, endothelin receptor antagonists appear to be additive therapeutic drugs to combine with currently approved antiproteinuric medications. However, additional clinical studies are required to evaluate their efficacy and safety.

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Glycosaminoglycans Glycosaminoglycans are important components of plasma membranes. They are important determinants of GBM permeability. An emerging body of evidence supports the notion that glomerular capillary wall and mesangial alterations in DN involve pathobiochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic, revealed that the administration of heparin and other anionic glycoproteins effectively prevented the biochemical alterations that promote albuminuria.73 Sulodexide (Glucurono-2-amino-2-deoxyglucoglucan sulfate) is a highly purified oral form of glycosaminoglycans mixture (80% heparin sulphate and 20% dermatan sulphate). Unlike heparin, sulodexide has no anticoagulant properties. It has reduced proteinuria in various studies.74,75 The exact mechanism for this renoprotection has not been fully explained yet. It is believed that sulodexide restores the anionic heparin sulphate charge on the GBM. Additionally, it also inhibits heparinase-1 (HPR-1), which is upregulated by high glucose. This decreases proteoglycans in GBM. Finally, it is also hypothesized that sulodexide inhibits tumor growth factor beta 1 (TGF-b1). The Di.N.A.S. study was a randomized, doubleblind trial which evaluated the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 albuminuric diabetic patients with serum creatinine of 150 mmol/L and under and stable blood pressure and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/day, 100 mg/day, or 200 mg/day sulodexide daily or placebo for four months (T0 to T4), with 4-month followup after drug suspension (T4 to T8). Treatment with 200 mg/day sulodexide for four months significantly reduced log albumin excretion rate which was maintained till T8. Subanalysis by type of diabetes (type1 vs type 2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar

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Pentoxifylline Pentoxifylline (PTF) is a methylxanthine derivative with hemorheological properties that has favorable effects on microcirculatory blood flow. In vivo, it also functions as a phosphodiesterase inhibitor.69 PTF has been used in the treatment of patients with circulatory abnormalities, including diabetic patients. Also, the renoprotective and antiproteinuric effects of pentoxifylline have been observed in animal studies. In addition, PTF has also been recognized as an important immunomodulator with significant anti-TNF(tumor necrosis factor)-alpha properties, and it has been used in subjects with sepsis or human immunodeficiency virus infection. Several studies have reported that PTF decreased serum TNF-alpha concentrations as well as reducing TNF-alpha messenger RNA levels. Thus, it is possible to hypothesize that the proinflammatory cytokines such as TNF-alpha may play a significant role in renal damage of DN. Furthermore, PTF reduced proteinuria in these patients, and the anticytokine activity of this drug may be a further explanation for its antiproteinuric effect.69 A number of clinical trials evaluating pentoxifylline in patients with DN have been conducted. In a recent meta-analysis reviewing all randomized controlled trials, pentoxifylline was shown to be an efficacious antiproteinuric agent in patients with DN.70 Thus, additional research is needed to determine if long-term use of pentoxifylline could be a pharmacological alternative for delaying or preventing the development of DN.

increased the production of extracellular proteins. The blocking of PKC-beta isoforms has been shown to decrease albuminuria, structural injury, and TGF-beta expression in animal models of DM.71 Use of PKC beta inhibitor (ruboxistaurin) in a small patient population of type 2 DM showed a significant reduction in albuminuria, decreased glomerular and interstitial fibrosis. Although reduction in albuminuria and changes in estimated glomerular filtration rate (eGFR) did not significantly differ between the placebo and ruboxistaurin groups in the phase II trial, the study was not powered to determine such a difference. More clinical studies with a larger sample size are needed to clarify the exact role.72

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circulation. esRAGE may be related to individual variations in resistance to the development of diabetic vascular complications suggesting that it could decrease AGE-induced vascular injury.67 Also it has been shown that, RAGE antibody administration significantly reduced the increase in urinary albumin excretion, kidney weight, and creatinine clearance in animal models of DN. The renal effects of RAGE-ab administration in mice were seen without impact on body weight, blood glucose or food consumption. Although there have been no clinical studies, RAGE inhibition appears to be a promising target to overcome DN.68

[Nephrology Reviews 2011; 3:e4]

Antifibrotic agents and growth factor inhibitors Characteristic morphological lesions of DN include glomerular hypertrophy, thickening of [page 29]

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TGF-b inhibitors

CTGF inhibitors

Despite the established role of TGF- b in DN, data on use of TGF- b inhibition on progression of DN are limited. Sharma et al. studied Pirfenidone (PFD; 5-methyl-1-phenyl-2(1H)-pyridone), a low molecular weight synthetic molecule that exerts dramatic antifibrotic properties in cell culture and various animal models of fibrosis. PFD has emerged as a promising oral treatment with few adverse effects in open-label clinical studies.80 A 4-week therapy with perfinindone decreased mesangial expansion and fibrosis but not urinary albumin excretion in animal models. SMP-534, another antifibrotic agent is also being studied. SMP-534 ameliorated the increase in extracellular matrix production in kidneys of db/db mice, possibly through inhibition of TGF-b action.81 In another experiment, SMP-534 ameliorated the progression of glomerular fibrosis in the diabetic (db/db) mouse strain, whereas losartan did not. Several AGE inhibitors, including aminoguanidine, alagebrium, pyridoxamine, and OPB-9195, also decrease TGF-b levels. Overall, TGF-b inhibitors are an important area of drug discovery research. Clinical trials have been initiated but results are not yet known.78,81 Bone morphogenic proteins (BMPs) are members of the TGF-b superfamily and are highly regulated in the kidney. The kidney expresses multiple BMPs, among which BMP7 is most abundant and reveals specific function. It is expressed primarily in the glomeruli (podocytes), thick ascending limb, distal convoluting tubule and collecting duct.82 BMP-7 reversed TGF-1-induced epithelial-to-mesenchymal transition (EMT) in renal tubular epithelial cells and mammary ductal epithelial cells. Thus, systemic administration of recombinant human BMP-7 can lead to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury.83 Inhibition of gremlin (one of the antagonists of BMP-7) induced therapeutic effects on the diabetic kidney by allowing the efficient binding of endogenous BMP-7 to receptors without inhibition. In addition, gremlin can increase DNA synthesis and cell counts and accelerate cell cycle progression of vascular smooth muscle cells. It is possible that gremlin may regulate cell growth via a BMP-7-independent pathway. Thus, gremlin may be recognized as a novel therapeutic target in either a BMP-7 dependent or a BMP-7 independent way.82 Finally, emerging evi-

Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of matricellular proteins whose expression is induced by a number of factors including TGFb. It has been associated with fibrosis in various tissues including the kidney. CTGF is not only induced by TGF- b but is also a major promoter of its biological activity. It promotes many profibrotic effects of TGF-b. It is up-regulated in most models of DN. Anti-CTGF therapies in experimental DN resulted in decrease in urinary albumin excretion in db/db mice and GBM thickness.84 Adler et al. recently reported the results of a phase I clinical study evaluating anti-CTGF ab (FG3019). Treatment of microalbuminuric DN subjects was well tolerated and associated with a decrease in albuminuria. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.85

VEGF (vascular endothelial growth factor) is a main regulator of blood vessel growth and plays an important role in promoting endothelial survival and maintaining the microvasculature. Loss of capillaries is strongly associated with the progression of CKD to ESRD.90 There is evidence that increased production of VEGF from podocytes causes glomerular hypertrophy and is associated with proteinuria.91 In several kidney disease animal models, VEGF expression in the kidney is decreased and administration of VEGF is protective. Recent clinical observations revealed that blocking VEGF by endogenous inhibitor (soluble Flt-1) in preeclampsia and monoclonal antibody against VEGF in cancer patients cause proteinuria and renal dysfunction. However, plasma VEGF levels in DN patients are increased and blocking VEGF improved DN in animal models. Deleterious effects of VEGF have been demonstrated in atherosclerosis and sepsis, which are frequent complications in CKD patients. Although administrating VEGF or novel drugs that activate the VEGF pathway may improve the progression of CKD, careful monitoring will be required when CKD patients have complications of diabetes, atherosclerosis or sepsis.90 On the other hand, inhibition of VEGF by SU5416 ameliorated albuminuria in an experimental model of DN.92 Thus, VEGF might be a critical kidney survival factor; thus, more experiments are, therefore, required to confirm this issue and the role of VEGF in DN.

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Abnormalities of renal NO (nitric oxide) generation have been linked to pathogenesis of renal disease in diabetes. Notwithstanding the complexity and confusions related to the published data in this field, it is clear that whereas in the early phases of DN the NO production and NO synthase (NOS) isoform expression in the kidney is up-regulated, there is a progressive decline in NO production and specifically NO bioavailability in the kidney with advancing renal failure.86 Awad et al. published in 2004, the results of monitoring NO in renal interstitial fluid in animal models of DN. They proved that NO levels decreased after development of DN. ARBs reversed this effect and caused an increase in NO.87 Similarly, Prabhakar et al. concluded that ZSF1 rats represented the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability. In addition, the NOS expression is down-regulated and so is the total renal NO production.88 Other studies89 in experimental diabetes have demonstrated that decreased renal NO levels are a consequence of increased oxidative stress, primarily as a result of enhanced expression of superoxide dismutase and catalase. Thus, NO and / or NOS are targets for drug development for treatment and/or prevention of DN.

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dences have shown that these two developmental genes, BMP-7 and gremlin may serve as therapeutic targets for the treatment of DN, which, then, has important implications for the future development of therapeutic strategies targeting these two molecules. Clinical trials are awaited with BMP-7.82

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the basement membrane, and mesangial expansion. This leads to glomerulosclerosis, tubulointerstitial fibrosis and, eventually, loss of kidney parenchyma. Several growth factors which are normally expressed in the kidney have been implicated in the pathogenesis of DN.

[Nephrology Reviews 2011; 3:e4]

Alternative and complementary therapies for diabetic nephropathy Exercise and yoga The American Diabetes Association recommends a minimum of 30 minutes of moderateintensity aerobic physical activity five days per week, or vigorous-intensity aerobic physical activity for 20 minutes 3 times per week is recommended for healthy adults aged 18 to 65. Currently, there is no clinical evidence to suggest that vigorous exercise increases the rate of progression of diabetic nephropathy. In fact, some studies have shown that aerobic exercise actually decreased urine protein excretion.93 Additionally, it has been demonstrated that resistance training may have a beneficial effect on muscle mass, nutritional status, functional capacity, and glomerular filtration rate. Therefore, the American Diabetes Association feels that there is no need to restrict exercise in patients with diabetic nephropathy. A more recent study that examined the effects of yoga and conventional exercise showed findings that suggest better glycemic and blood pressure control obtained in type 2 diabetic patients after Hatha yoga than conventional PT exercises.94

Article Table 2. Conventional and potential therapies in diabetic nephropathy. Drug

Mechanism of action

In vitro studies

Clinical trials

Outcomes

Clinical use

Aliskiren

Direct renin inhibitor

Yes

AVOID Trial

More phase III studies needed.

Yes. Inhibits diabetesinduced accumulation of advanced glycosylation products and abnormal cross-linking of arterial wall connective tissue protein Renoprotective effect in diabetic Sprague-Dawley rats by decreasing kidney AGE accumulation and albuminuria. Limits the development of nephropathy in streptozotocin-diabetic rats without affecting glycemic control.

ACTION Trial

Reduced the mean urinary albumin-to creatinine ratio by 20%. Study did not demonstrate a statistically significant beneficial effect. 3 patients developed glomerulonephritis.

Decrease the formation Inhibits diabetes induced of AGE compounds hyperfiltration and PKC activity and development of microalbuminuria. Decrease AGE Efficacious in retarding accumulation by albuminuria and kidney breaking the glycation structural damage cross-links. in animal models. Decrease AGE Retards the development accumulation of cardiac dysfunction and by breaking the reduces the severity of renal glycation cross-links. dysfunction in a diabetic model with severe persistent hyperglycemia. Reduces the increase in urinary albumin excretion, kidney weight, and creatinine clearance in animal models. Hemorheological Renoprotective and properties. antiproteinuric effects Also functions as have been observed in animal a phosphodiesterase studies. inhibitor. PKC beta inhibitor Blocking of PKC-beta isoforms decreases albuminuria, structural injury, and TGF-beta expression. Glycosaminoglycans Administration of heparin and mixture other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria.

Alagebrium

Merged data sets Further phase II and phase III show a 48% reduction in studies are needed to prove serum creatinine in PYR this effect. treated groups vs. placebo. Urinary albumin excretion was unaffected. NA To be determined.

Not yet

Yes

Terminated early due to financial constraints.

To be determined but unlikey.

No

NA

Further clinical studies are required.

Roboxistaurin

Sulodexide

Avosentan (SPP301)

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TRC4186

Two phase II studies (PYR-206 and PYR-205/207)

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To be determined.

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Limits the formation of AGEs. Inhibits the increases in ALEs.

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Not yet

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More potent and selective AGE formation inhibitor than aminoguanidine

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Unlikely to have a future role.

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Aminoguanidine AGE formation inhibitor

Endothelin 1 antagonist

Endothelin is one of the most potent endogenous vasoconstrictors and correlates with decreased kidney function and albuminuria.

No clinical studies NA

A number of clinical An efficacious trials have been antiproteinuric agent conducted. in patients with diabetic kidney disease.

Additional research is needed.

Phase II

More clinical studies with a large number of patients are needed to clarify the exact role. Unlikely to have a future role.

Significant reduction in albuminuria, glomerular and interstitial fibrosis.

Di.N.A.S. study and Was promising in initial phase III trials. studies. However, a large adequately powered clinical study did not confirm those promising findings. Wenzel et al. Decreased UAER Studies are required and ASCEND Trial in patients with to evaluate the efficacy diabetic nephropathy and safety in diabetic and macroalbuminuria. nephropathy. ASCEND; stopped because of drug-related adverse events.

Continued next page

[Nephrology Reviews 2011; 3:e4]

[page 31]

Article Table 2. Continued from previous page. Drug

Mechanism of action

In vitro studies

Pirfenidone and SMP 534

Antifibrotic and TGF-b inhibitors

Anti-CTGF antibody

Anti-CTGF therapy

Decreases mesangial Underway expansion and fibrosis but not urinary albumin excretion in animal models. Led to decrease in UAE in db/db Adler et al. mice and GBM thickness. Phase 1

SU5416

VEGF Inhibitor

Curcumin

Clinical trials

Ameliorated albuminuria in an Not yet experimental model of diabetic nephropathy. Anti-inflammatory, Yes. Lowers BUN and plasma Not yet anti-oxidant and creatinine/body weight ratio antifibrotic properties in diabetic animals.

Outcomes

Clinical use

NA

Clinical trials have been initiated but results are not yet known.

Treatment was well tolerated and associated with a decrease in albuminuria. NA

Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study. To be determined.

NA

Not yet

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Herbal and food derivatives Curcumin Curcumin, the active component in Tumeric Rhizomes (Curcuma Long Linn), was originally used in traditional Indian medicine over 3,000 years ago. Curcumin has been shown to possess anti-inflammatory, anti-oxidant and antifibrotic properties in many tissues in in vivo and in vitro studies. Recent literature has suggested that diferuloylmethane (curcumin) prevented and reversed myocardial hypertrophy and decreased inflammation

[page 32]

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betic effects for some time now. Mishra et al. have investigated its effects on nephropathy in diabetes in rodent models of type 1 diabetes. Early stage of diabetic nephropathy was induced by administration of alloxan (150 mg/kg, I. P.). Cinnamon oil was administered at varying doses (5, 10, 20 mg/kg; I. P.) while the level of fasting blood glucose, total cholesterol, high density lipoprotein, urea, thiobarbituric acid reactive substances, reduced glutathione, and catalase were determined. These parameters in cinnamon oil treated groups were compared with those of standard (glipizide; 10 mg/kg) and vehicle treated groups in order to investigate if cinnamon oil confers a significant protection against diabetic nephropathy. Histological studies of the kidney proved the protective effect of cinnamon oil by reducing the glomerular expansion, eradicating hyaline casts, and decreasing the tubular dilatations.102 The authors concluded that the volatile oil from cinnamon contains more than 98% cinnamaldehyde and that it confers significantly dose-dependent, protection against alloxan-induced renal damage. While the mechanism of its action remains unclear, it is believed to be mostly due to its antidiabetic and antioxidant effects leading to reduced formation of AGEs.

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Obesity is often associated with diabetes mellitus and also with nephropathy independent of diabetes (often focal sclerosis). However, the impact of weight loss in diabetic subjects with nephropathy on renal function and proteinuria remains a subject of intense investigation. Short-term studies recently reported that weight reduction using dietary therapy for four weeks resulted in a significant reduction in systolic pressure, proteinuria, and serum creatinine in obese patients with diabetic nephropathy.95 Longer studies involving larger group of patients need to be evaluated to validate such conclusions. Smoking has been shown in many previous studies to effect diabetic complications. Recent studies demonstrated that smokers have increased systolic blood pressures and proteinuria amongst diabetics with nephropathy96 More recent work by Chihuran et al. has shown that renal function declines faster in smokers than non-smokers with type 2 DN undergoing treatment to improve blood pressure, including ACE inhibitors. Cigarette smoking remains a risk factor for renal function decline in type 2 DN despite currently recommended therapy.97

and fibrosis in murine models of heart failure. Tikoo et al. have shown that curcumin treatment prevented the development of DN by significantly lowering blood urea nitrogen and plasma creatinine/body weight ratio in diabetic animals.98 Various biological actions of curcumin are mediated by inhibiting cell proliferation,99 oxidative stress and inflammation.100 Several other investigators have also shown that the anti-inflammatory property of curcumin can significantly improve kidney function in animals with chronic renal failure. Curcumin is remarkably well tolerated in both humans and animals. Its low toxicity in humans and animals makes this compound suitable to be used alone or with other agents to improve renal function. Curcumin is a multifaceted compound which can affect other proinflammatory cytokines, adhesion molecules, transforming growth factor-b and is also a potent antioxidant. However, the potential beneficial role of curcumin in DN has not been investigated. Results from our laboratory have demonstrated that curcumin has distinct salutary effects on the development and progression of diabetic nephropathy in animal models. When ZSF rats, a model of nephropathy in type II diabetes were given drinking water containing curcumin for an 18-week period, the decline of renal function and proteinuria were ameliorated significantly. Mechanistically these effects were mediated by reduced expression of growth factors and mediators incriminated in diabetic nephropathy notably vascular endothelial growth factor and transforming growth factor-b.101 While these exciting observations remain to be demonstrated in clinical studies in humans, such data offer scope for potential alternate therapies in diabetic nephropathy. Cinnamon Cinnamon has been known for its antidia-

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Life style modifications

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AGE, advanced glycosylation end products; RAGE, transmembrane receptor for AGE; PKC, protein kinase C inhibitors; TGF b, transforming growth factor – Beta; CTCF, connective tissue growth factor; VEGF, vascular endothelial growth factor.

[Nephrology Reviews 2011; 3:e4]

Conclusions During the last three decades, considerable progress has been made in delaying the progression of CKD as the frequency of DN continues to increase. Our current treatment is sub-optimal. As reviewed (Table 2), there are several ongoing treatment options for DN in clinical trials and some of them appear promising. These therapies are important and sig-

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