Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

Abstract

Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria/albuminuria reduction, interruption of the renin-angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol lowering agents. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are urgently needed. This review highlights the available standard therapeutic approaches to manage progressive diabetic nephropathy, including markers for early diagnosis of diabetic nephropathy. Furthermore, we will discuss emerging strategies such as PPAR-gamma agonists, Endothelin blockers, vitamin D activation and inflammation modulation. Finally, we will summarize the recommendations of these interventions for the primary care practitioner.

INTRODUCTION

A large source of morbidity and premature mortality in diabetes mellitus (DM) relates to the development of late complications affecting multiple organ systems. One of these complications, diabetic nephropathy (DN), has become the leading cause of end stage renal disease (ESRD) in the United States.¹

DN is defined by persistent pathological albuminuria; 300 mg of urinary albumin excretion in a 24-hour collection and abnormal renal function as recognized by an abnormal plasma creatinine (PCr) level, glomerular filtration rate (GFR) or calculated creatinine clearance.²

Although both DM type-1(DMT1) and type-2 (DMT2) lead to DN, the course of DN has been better identified in DMT1. The earliest renal manifestation of diabetes is glomerular hyperfiltration, followed by a decline in GFR and increased albuminuria usually 5 or more years after the onset of DM. Finally, overt albuminuria develops and GFR continues to fall often, in association with the development of hypertension.³

The exact pathogenesis of DN is complex and not completely understood. Among the pathogenic factors are: hyperglycemia, increased systemic and glomerular pressure, increased activity of the renin-angiotensin-aldosterone-system (RAAS) and stimulation of several cytokines and growth factors by metabolic and hemodynamic factors. Several therapeutic interventions targeting these mechanisms have been developed and implemented with various degrees of success (Fig. 1).

Figure 1.

Pathogenesis of diabetic nephropathy and steps to slow its onset and progression. Abbreviations: RAAS, Renin-Angiotensin-Aldosterone System; GAC, Sulodexide; PKC, Protein Kinase C; TGF-β, Transforming growth Factor-beta.

Diabetic Nephropathy Markers

The early diagnosis of DN is imperative for adequate management of the disease. For years, measurement of urine albumin has been the mainstay for the detection of early DN.⁴ Although early reports indicated that as many as 80% of patients with elevated rates of microalbuminuria would progress to develop overt DN, recent studies suggest that the rate of progression from microalbuminuria to nephropathy is lower, in the range of 25-30%.^5,6 Perhaps more worrisome is the realization that some diabetic patients develop DN in the absence of microalbuminuria.⁷ In newly diagnosed diabetics, Zerbini et al.⁸ found that GFR began to decrease prior to the appearance of microalbuminuria. Thus, urinary albumin lacks both sensitivity and specificity to detect early DN. Measurements of cytokines such as connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α) and urinary podocytes have emerged as potential markers of progressive DN.^9–13 These markers merit ongoing study but are not yet available for clinical practice.

Additional promising markers are kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). In a recent cohort study,¹⁴ all patients with DMT1 and DMT2 had elevated urinary and serum levels of NGAL compared with matched control groups. More significantly, high levels of NGAL preceded the development of pathological albuminuria and reached higher levels in patients with overt DN. Additional studies demonstrated that NGAL represents a novel and independent risk predictor for progression and severity of renal disease. Furthermore, a recent study by Vaidya et al. showed that decreased urinary levels of KIM-1 and NAGL were associated with microalbuminuria regression in patients with DMT1.¹⁵ These data raise the possibility that NGAL may become a useful noninvasive tool for the early detection of incipient nephropathy and for estimating the severity of kidney involvement. However, until further results are available, periodic measurements of microalbuminuria and serum creatinine (for estimated GFR calculations) remain the standard of care for DN screening.

THERAPEUTIC STRATEGIES FOR DN

 

Current Therapeutic Strategies for Diabetic Nephropathy

Available therapeutic options directed at delaying the progression of DN include intensive blood glucose (BG) control, improved blood pressure (BP) control, interruption of the RAAS using angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin type-1 (AT₁) receptor blockers (ARBs) along with dietary modification and cholesterol-lowering agents (Table 1).

Table 1.

Available Therapeutic Modalities in DN

Current therapy	Emerging therapy
1-Intensive glucose control	1-TZDs/PPAR-gamma agonists
a-Medication	2-ACE-2
b-Pancreatic transplantation	3-Endothelin blockers
2-Blood Pressure Control	4-AGEs inhibitors
a-Affecting RAAS:	5-Vitamin D activation
i. ACEi	6-Inflammation modulation
ii. ARBs
iii. Renin inhibitors
iv. Aldosterone inhibitors
b-Not affecting RAAS:
i. CCB
ii. Beta blockers
iii. Diuretics
3-Dyslipidemia and lipid-lowering drugs
4-Multifactorial intervention

Intensive Glucose Control

The Diabetes Control and Complications Trial (DCCT) performed more than 15 years ago was a milestone in our approach to delaying the onset and slowing the progression of DN.¹⁶ That study of 1441 patients with DMT1 over an 8-year period found that strict glycemic control reduced the incidence of albuminuria by 50% compared with standard therapy. This protective effect persisted for more than a decade after the completion of the trial.^17,18 The benefits of intensive glycemic control were not limited to delaying the onset and slowing the progression of DN but extended to decreasing the incidence of the cardiovascular diseases (CVD); the main cause of mortality in these patients.¹⁹

Likewise, the United Kingdom Prospective Diabetes Study (UKPDS) was designed as a randomized clinical trial comparing the effects of intensive diabetes treatment with four pharmacological mono-therapies, versus a diet control group on the complications of diabetes in about 4000 patients with DMT2 followed over 10 years.^20,21 It showed that intensive BG control by either sulphonylureas or insulin reduced the risk of microvascular complications.²² Each 1% reduction in HbA1c was associated with 21% reduction in the risk of any diabetes-related endpoints and 37% decrease in microvascular complications.^20,21

More recent randomized controlled studies in patients with DMT2 have yielded mixed results. The ADVANCE (Action in Diabetes and Vascular Disease)²³ trial showed that intensive glycemic control reduced albuminuria, nephropathy and the need for dialysis. Likewise, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, showed significantly lower rates of albuminuria (but not of more advanced nephropathy) in the intensive glycemic therapy group.²⁴ Contrary, the VADT (Veterans Affair Diabetic Trial)²⁵ did not show improvements in either nephropathy or retinopathy with intensive glycemic control. The lack of benefit in VADT may be explained by the longer duration of diabetes and the short follow-up time. However, the enthusiasm for strict glycemic control must be tempered by the observations in the ACCORD, ADVANCE and VADT trials that strict glycemic control had either a deleterious or no beneficial impact on major cardiovascular outcomes.

Another strategy in the management of DM is pancreas transplantation. Pancreas transplantation is usually performed in patients who have DMT1, although 6% of recipients are reported to have DMT2. The specific criteria for defining a candidate as having DMT1 or DMT2 are dependent on the transplant institution.^26,27 Pancreatic transplantation to achieve normal glycemic control has yielded promising results; reduction in proteinuria²⁸ and histologic improvements in diabetic glomerulopathy.^29–31

In summary, intensive glycemic treatment in both DMT1 and DMT2 reduces the risk and progression of early DN. The specific goal for HbA1c should be individualized considering the potential benefits and harms of different levels of HbA1c. A goal HbA1c of 7% appears reasonable with a target level set somewhat higher in older patients.³²

Blood Pressure Control

Both systolic and diastolic hypertension markedly accelerate the progression of DN. Normotensive patients with advanced DN show slower progression compared with hypertensive patients.^33–42

Non-pharmacologic approaches (dietary modifications especially and increased physical activity) are effective in reducing BP in non-diabetic individuals⁴³ and may have similar benefits for diabetic patients. However, pharmacologic approaches remain the mainstay for controlling BP in patients with DM.^44,45

Several randomized controlled trials indicate that multiple antihypertensive agents, often more than three, are commonly required to achieve optimal BP control.^35,46–49 The optimal target BP for patients with DN has been long debated.⁵⁰ Early studies by the UKPDS group^20–22 suggesting that each 10 mmHg decrease in SBP is associated with a 13% reduction in microvascular complications, led investigators to believe that lower BP is better. The ADVANCE trial randomized hypertensive diabetic patients to a fixed combination of perindopril and indapamide vs. placebo when added to usual anti-hypertensive care.³⁷ Treatment with active agent was associated with a 5 mmHg reduction in SBP (135 vs. 140 mmHg) and a 14% reduction in mortality. Based on these and other findings, the American Diabetes Association⁵¹ and the Joint National Committee 7⁵² recommend a target BP of <130/80 mmHg for patients with diabetes. Several studies have investigated the benefit of even lower BP targets. The recent ACCORD trial failed to show a reduction in cardiovascular events but increased rates of hyperkalemia and renal dysfunction when targeting a SBP < 120 mmHg as compared with <140 mmHg.⁵³ A subgroup analysis of 6400 patients with diabetes in the INVEST study⁵⁴ and a cross-sectional analysis of patients in the Swedish National Diabetes Registry⁵⁵ also failed to show a reduction in mortality in patients with SBP < 130 vs. 130–139 mmHg. These recent observations do not support BP goals of <130/80 and even bring into question the need to reduce SBP below 140 mmHg.

Summary: The ADA and JNC 7 recommend reducing BP to <130/80 in patients with DM. However, given the difficulty in achieving this goal and the lack of strong evidence of benefit from reducing SBP to <130 vs. 140 mmHg, we believe that physicians should strive to achieve a target SBP of less than 140 mmHg in diabetic patients. A target of <130/80 mmHg can be pursued in younger patients, patients who tolerate their antihypertensive regimens well, patients with significant proteinuria (over 500 mg/day) and patients at particularly high risk of stroke.

Agents Affecting Renin-angiotensin-aldosterone-system

 

ACEi/ ARBs

Activation of the RAAS system plays a crucial role in the pathophysiology of DN. Several trials have established the efficacy of ACEi and ARBs in reducing the progression of DN.^56,57 The beneficial effects of RAAS blockade go beyond a reduction in systemic BP and include a reduction of intraglomerular pressure and proteinuria, thereby slowing progression of CKD.^56,57

A head to head comparison of ACEi (enalapril) and ARB (telmisartan) in patients with DMT2, hypertension and early-stage DN, did not reveal any differences between the two agents with respect to BP control, proteinuria or changes in GFR.⁵⁸ Thus, ACEi and ARBs appear to be equally effective in slowing the progression of DN. Other factors, such as cost or side-effects, should dictate the selection of either class of agents.

Two issues relating to the management of DN with ACEi and/or ARBs remain to be clarified; the roles of high-dose monotherapy and those of the combination of ACEi/ARBs. Higher doses of valsartan⁵⁹ (320–640 vs. 160 mg/day) or candesartan⁶⁰ (128 vs. 16 mg/day) produced significantly greater reductions in albuminuria as compared to conventional doses independent of BP effect. Although these results are encouraging, the long-term effects of high-dose ARB remain uncertain.

A second unresolved issue centers on the efficacy of combined therapy with both ACEi and ARBs in slowing DN. Small trials had reported greater reductions in proteinuria and even slowing of renal dysfunction in patients treated with combined therapy as compared to monotherapy.⁶¹ The enthusiasm for this approach was dampened by the ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) in which the combination therapy arm showed worse renal outcomes (doubling of the SCr and the need for dialysis), as compared with either of the monotherapy arms.⁶² Thus, unless new data emerge supporting the use of dual therapy with ACEi and ARBs, monotherapy with either agent will remain the first-line for patients with DN. Even so, combination ACEi and ARB seems reasonable for selected patients, such as those with no history of hypotension or major cardiac disease, who have persistent proteinuria on ACEi or ARB monotherapy. In such circumstances, referral to a nephrologist is appropriate.

Renin Inhibitors

The benefit of blocking the RAAS with ACEi and ARBs in a variety of kidney diseases, including DN, is now well established.^63–70 However, such treatment does not completely abrogate the progression of kidney disease.^69–71 This partial response has been attributed in part to feedback effects, such as angiotensin-escape and aldosterone-escape.^72,73

In light of these phenomena, alternative approaches to optimize the RAAS-blockade are being sought. The activity of renin, the rate-limiting-step in the RAAS cascade, is increased when either ACEi or ARBS are used for prolonged periods. Thus, direct inhibition of renin activity has potential advantages over ACEi and ARBs. Not only does renin inhibition lower BP through its action on the RAAS, it has also additional direct actions mediated through a renin receptor.⁷⁴ Aliskiren, an orally active non-peptidic renin inhibitor, decreases plasma renin activity, although renin concentration is increased.^75–77 Therefore, aliskiren may cause more complete RAAS-blockade and reduce the compensatory feedback as compared to ACEi/ARBs. Several short-term studies showed that aliskiren effectively lowers BP in non-diabetic^78,79 and diabetic⁸⁰ patients.

Parving et al.⁸¹ performed a prospective randomized study of aliskiren in 599 patients with DMT2, hypertension and proteinuria. They found that dual RAAS-blockade with aliskiren and losartan reduced albuminuria 20% more than losartan alone despite a very small difference in BP⁸¹. Thus, renin inhibitors may be effective in delaying the progression of DN. However, better outcome data on renal function itself, rather than surrogate end points as proteinuria, are needed.

Aldosterone Antagonists

The mineralocorticoid receptor antagonists’ spironolactone and eplerenone reduce proteinuria when administered alone with additional antiproteinuric benefits when given with ACEi or ARBs in patients with DMT1 and DMT2.^82–93 This additive antiproteinuric benefit is independent of further BP reduction.^86,87,93 The lack of sexual side-effects of eplerenone makes it a good alternative to spironolactone, particularly in men. These results, if supported by long-term outcomes, indicate that mineralocorticoid antagonists may be a valuable addition to our armamentarium to delay progression of DN with close monitoring of serum potassium and creatinine.

Agents that do not Interrupt Renin-Angiotensin-Aldosterone-System

As discussed, agents which interrupt the RAAS are recommended as first line treatment of hypertension in individuals with diabetes. However, the reduction in BP per se, rather than the choice of specific BP agents, is of paramount importance in delaying the progression of renal disease in DN.⁴⁴ Therefore, patients who are intolerant to ACEi and/or ARB, or who need further reduction of BP beyond what can be achieved with these drugs, will require treatment with other classes of antihypertensive agents.

Calcium Channel Blockers (CCB)

Parving and colleagues reviewed studies published from 1989–1996 comparing CCB to ACEi in patients with incipient and overt DN.⁹⁴ Eight studies examined a total of 160 (DMT1) and 54 (DMT2) patients treated with either dihydropyridine calcium-channel-blockers (DHPCCB) or ACEi.^95–102 All patients had microalbuminuric DN. While both groups demonstrated identical reductions in the mean arterial BP and beneficial effects on GFR, the groups receiving ACEi showed superior reductions in microalbuminuria. Similar results were observed in evaluating another eleven studies of patients with macroalbuminuric DN with a total of 177 patients (DMT1) and 76 patients (DMT2).^103–113 However, the ACCOMPLISH trial showed that the combination of amlodipine, a DHP CCB, with benazepril (ACEi), was superior to benazepril plus thiazide diuretic in reducing cardiovascular events¹¹⁴ and the progression of kidney disease¹¹⁵ in diabetes.

Data obtained from animal and human studies confirm that non-dihydropyridine calcium-channel-blockers (NDHP CCBs) can reduce proteinuria and slow the progression of kidney disease in diabetics.^116–119 Bakris and colleagues showed that NDHP CCBs were comparable to ACEi and superior to beta-blockers in reducing proteinuria and delaying progression of renal disease in patients with DN.¹²⁰ This superiority of NDHP CCBs over beta-blockers was independent of BP control.¹²¹ These findings have been confirmed by other investigators.^122,123

Beta-Blockers and Diuretics

Relatively few studies have examined the effects of beta-blockers and diuretics in patients with DN. Nielson and colleagues showed that though ACEi were superior to beta-blockers in reducing proteinuria; both drugs equally reduced the decline in kidney function.¹²⁴ Likewise, the UKPDS study showed that ACEi and beta-blockers were equally effective in reducing both macrovascular and microvascular complications in DMT2.¹²⁵ Less is known regarding the effects of diuretics in DN. In one study, the diuretic agent indapamide was equivalent to enalapril in reducing microalbuminuria in hypertensive diabetic patients.¹²⁶ Although the GUARD study¹²⁷ showed that a combination of ACEi with hydrochlorothiazide resulted in a greater reduction in albuminuria than did the combination of ACEi and DHP CCB, the larger ACCOMPLISH study¹¹⁵ showed that the same combination of ACEi/hydrochlorothiazide was less effective than the ACEi/CCB combination in reducing the decline in GFR in high risk, mainly diabetic, hypertensive patients. These studies suggest that while beta-blockers and diuretics may be helpful in the management of DN, they should probably be used in combination with ACEi or ARBs.

Dyslipidemia and Lipid-Lowering Drugs

CVD is the leading cause of death in patients with advanced CKD.¹²⁸ Both DMT1¹²⁹ and DMT2¹³⁰ are associated with dyslipidemia; mainly hypertriglyceridemia. Several studies showed marked cardiovascular benefits for treating dyslipidemia in patients with DM.^131–138 Unfortunately, most of these studies excluded patients with CKD. Thus, direct data showing a benefit of lipid-lowering therapy on CVD in patients with CKD are limited. Post hoc analysis of the “Heart Protection Study” (HPS)¹³⁴ showed marginally significant reductions in the relative-risk of cardiovascular events in diabetic patients with CKD. Similar results were obtained from a post hoc analysis of the CARE (Cholesterol and Recurrent Events) study.¹³⁹ Although animal studies indicate that statins may slow the progression of DN; evidence in human trials is lacking.

Multifactorial Intervention

A recent Danish study¹⁴⁰ examined the impact of a multifactorial intervention on the risk of cardiac and renal outcomes in patients with DMT2 and microalbuminuria. Patients were treated with either conventional therapy or an intensive regimen consisting of tight glucose control, RAAS-blockers, aspirin, and lipid-lowering agents. The mean treatment period was 7.8 years followed by a mean of 5.5 year observation period. During the entire 13.3 years follow-up, 30% vs. 50% died in the intensive-therapy compared to the conventional therapy groups with an absolute risk-reduction of 20% death. Additionally, DN developed in 20 vs. 37 patients in the intensive-therapy group compared to the conventional therapy group (relative-risk: 0.44; 95% CI: 0.25-0.77; p = 0.004), with one patient in the intensive therapy group progressing to ESRD requiring dialysis as compared with six patients in the conventional therapy group (p = 0.04). This study highlights the need for targeting multiple pathways in order to reduce the burden of diabetic complications.

Early Referral to Nephrologist

Primary care providers are on the front line in our battle against DN. The availability of several guidelines from professional societies, such as the American Diabetes Association, National Kidney Foundation and the American Society of Hypertension has helped a great deal in this fight. The coordinated effort among the different specialties; primary care provider, endocrinologist and nephrologist remains crucial for optimal patient outcomes. Early referral to nephrologists has been found to be associated with decreased rates of decline in GFR¹⁴¹ and mortality.¹⁴² In spite of that, it is still not uncommon for CKD patients to be seen by a nephrologist for the first time only one month before starting dialysis.^143,144 Similar trends were also noted in Europe, Australia, New Zealand and Canada. Ghossein et al. suggested that the greatest benefit to patients occurs when referral to nephrologist is initiated before the plasma creatinine concentration exceeds 1.5 to 2 mg/dL or GFR is less than 60 mL/min per 1.73 m2.¹⁴⁵

Summary: Strategies for the early identification and treatment of DN have evolved based on new clinical trials. The current evidenced-based approaches place emphasis on individualizing optimal glycemic control, BP control with RAAS-blockade as first-line agents, and optimization of traditional cardiovascular risk factors. Successful outcomes can be achieved with treatment that incorporates the aforementioned multifaceted interventions to slow the progression of diabetic renal disease and its associated complications (Table 2).

Table 2.

Antihypertensive Agents and Proteinuria Effect

Agents affecting RAAS	Proteinuric Effect
ACEI/ARB	Equally effective in reducing proteinuria and slowing DN progression56–58
Direct renin inhibit (aliskiren)	Comparable anti-proteinuria reduction to ACEI/ARB81
ACEI/ARB+direct renin inhibitor	Lower proteinuria by 20% more than monotherapy81
Aldosterone antagonists	Reduce proteinuria effectively82–93
ACEI/ARB+Aldosterone antagonists	Additive anti-proteinuric effect independent of BP control86,87,93
Agents not affecting RAAS	Proteinuric Effect
DHP CCB	Very effective BP control but inferior to RAAS blockade in reducing proteinuria95–102
NDHP CCB	Can reduce proteinuria. Some studies showing comparable anti-proteinuric effect to ACEI/ARB116–119
β-Blockers and diuretics	Inferior to RAAS and NDHP in reducing proteinuria but comparable in reducing decline in GFR124,126
Combination of RAAS±non-RAAS agents	Proteinuric Effect
ACEI+Diuretics	Greater proteinuric reduction but lesser BP reduction than ACEI+DHP CCB127
ACEI+DHP CCB	Better BP control but inferior in proteinuric control than ACEi+diuretics127

EMERGING THERAPEUTIC AGENTS FOR DIABETIC NEPHROPATHY

Thiazolidinediones / PPAR-Gamma Agonists

Thiazolidinediones (TZDs) exert their hypoglycemic activity by reducing insulin resistance.¹⁴⁶ Beyond their hypoglycemic actions, PPARЎ agonists exert a number of beneficial effects in diabetes including improvement in endothelial function,^147,148 reduction in pro-atherogenic inflammatory markers¹⁴⁹ and angiotensin-I and –II,¹⁵⁰ down regulation of AT₁ mRNA and protein in vascular smooth muscle cells,^151,152 decrease in urine endothelin-1 secretion,¹⁵³ attenuated lipid accumulation and its related injury in mesangial cells,^154,155 and inhibition of glomerular and tubular cell proliferation^156,157. Several animal^158–163 and human studies^{153,164–175} using various TZDs have demonstrated a reduction in proteinuria and BP. Unfortunately; most of these studies were of short duration averaging 1–9 months in the animal studies^158–163 and 3–12 months in human studies.^{153,164–175}

The use of TZDs has become less frequent due to higher rates of cardiovascular complications. A recent observational, retrospective, inception cohort of 227,571 Medicare patients who were treated with rosiglitazone or pioglitazone for a 12-month period and followed for up to 3 years after initiation of therapy showed rosiglitazone was associated with a higher risk of cardiovascular complications and all-cause mortality in patients 65 years or older compared with pioglitazone.¹⁷⁶ Rosiglitazone is currently restricted by the FDA to patients already benefiting from rosiglitazone or patients who cannot be controlled with other medications and are unwilling to use pioglitazone (http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm; accession date: September 21, 2011).

Angiotensin-Converting Enzyme-2 (ACE2)

ACE2 is a recently discovered homologue of ACE. ACE2 is abundantly expressed in the kidney where it may counter-balance the classical RAAS.¹⁷⁷ Whereas ACE promotes formation of angiotensin-II, ACE2 metabolizes angiotensin-II to angiotensin 1–7, and angiotensin-I to angiotensin 1-9.¹⁷⁸ Angiotensin 1–7 has vasodilatory effects on the kidney,¹⁷⁹ suggesting a possible protective role of ACE2 in kidney diseases.

Few studies have addressed the potential role of ACE2 in the pathogenesis of DN. Ye et al. showed that while ACE expression was increased in diabetic mouse glomeruli, the glomerular immunostaining for ACE2 was attenuated.¹⁸⁰ Furthermore, the administration of MLN-4760, a specific ACE2-inhibitor, resulted in worsening albuminuria in a diabetic mouse model.¹⁸⁰ These findings suggest a protective role for ACE2 in early DN and that maneuvers aimed at upregulation of ACE2 activity may have a therapeutic potential.

Endothelin (ET) Blockers

First described by Yanagisawa et al.¹⁸¹ more than 20 years ago, the ET system is a family of 21-amino acid peptides with powerful vasoconstrictor and pressor properties. The renal ET system is activated in patients with DN as well as in rat models of diabetes-induced damage^182–184 leading to exacerbation of proteinuria, glomerular capillary hypertension, an increase in glomerular permeability, and excessive protein filtration.¹⁸⁵ Moreover, it was shown that altered ET-1 production may contribute to hypertension.^186,187

Several human studies demonstrated a correlation between plasma or urinary levels of ET-1 and markers of DN, such as hyperfiltration, mesangial expansion, macro- and/or microalbuminuria, and uremia.^188–192 In addition, interventional studies using endothelin-receptor-blockers have yielded encouraging results^193–198 in rodent models of DMT1^195,198 or DMT2.^196,197 Honing et al.¹⁹⁹ reported reversal of proteinuria in 10 patients with DMT1 after treatment with the ET-antagonist; atrasentan for 12 weeks. The antiproteinuric effect of ET-antagonism was confirmed in a study of avosentan.²⁰⁰ When the avosentan-treated patients were followed up after 3- and 6-months in the ASCEND (Avosentan on Doubling of Serum Creatinine, End-stage Renal Disease and Death in Diabetic Nephropathy) phase III clinical trial, substantial reductions in albuminuria were seen.²⁰¹ Unfortunately, drug-related adverse events including fluid retention, led to early termination of the ASCEND trial.²⁰¹ Much more work will be needed to determine the safety and effectiveness of ET antagonists in preventing or treating DN in humans.

Advanced Glycation Endproducts (AGEs) Inhibitors

AGEs are a heterogeneous group of compounds that can alter the structure and function of tissue proteins and stimulate cellular responses associated with diabetic complications. AGEs are excreted by the kidneys and tend to increase in the setting of renal impairment.²⁰² Receptors for AGE (RAGE) specifically recognize proteins that bound AGE, and enable macrophages to stimulate the removal and replacement of senescent macromolecules that have been cross-linked and denatured by long-term exposure to glucose.²⁰³ This AGE-RAGE interaction may play a role in the pathologic process associated with the AGE accumulation. Thus, interventions aiming at inhibiting the formation of AGE, reversing the cross-linking of already formed AGE, and/or interfering with AGE/RAGE interactions, may have beneficial effects in delaying, preventing, or reversing long-term diabetic complications.

Preclinical studies evaluated the effect of the AGE inhibitor; Pimagedine (PG) on renal function in diabetic animals yield promising results.²⁰⁴ Therefore, two major multicenter clinical trials were initiated to evaluate the use of PG in patients with DMT2²⁰⁴ (ACTION II) and DMT1²⁰⁵ (ACTION I). Unfortunately, due to PG side-effects, its clinical development has been suspended.²⁰⁶

Other AGE inhibitors (Pyridoxamine) and cross-link breaker (Alagebrium) have been studied. Both agents are well-tolerated in man,^207–209 but their efficacy in preventing or slowing of DN remains to be established.

Selective Vitamin D Activation

Paricalcitol, a vitamin D receptor activator, reduced albuminuria and slowed progression of kidney disease in mice, so de Zeeuw et al., assessed the role of paricalcitol in reducing albuminuria in 281 patients with DN.²¹⁰ They found that paricalcitol, when given in a dose of 2 μg/day, reduced albuminuria by −18% to −28%, with comparable side effects to the placebo arm of the study. This was only a short 24-week study leaving questions about the long-term cost of the drug as well as the safety of using paricalcitol which may aggravate adynamic bone disease.

Inflammation Modulation

Recently, an orally available synthetic triterpenoid, Bardoxolone methyl, has shown promising results in DN. Bardoxolone methyl exerts potent anti-oxidant and anti-inflammatory activity via induction of the Nrf2 transcription factor. A Phase 2 trial of bardoloxone methyl treatment for 8 weeks in 20 patients with moderate-severe CKD and DMT2 demonstrated improved renal function as evidenced by increased eGFR paralleled by a significant reduction in serum creatinine and BUN.²¹¹ A subsequent trial examined the effect of bardoloxone methyl (25–150 mg/d) administered for 52 weeks to 227 patients with moderate to severe CKD and DMT2.²¹² Bardoloxone methyl produced a significant increase in GFR of 8–11 ml/min/1.73 m². The improvement in GFR was evident by 8–12 weeks of treatment and persisted for the entire 52-week treatment period. Likewise, bardoloxone treatment reduced the proportion of patients who experienced a 25% fall in GFR from 13% in the placebo group to only 2% in treatment group. Although hard outcomes, such as dialysis dependency and death, were not evaluated, these results are very encouraging and justify further study of bardoxolone methyl and related compounds.

Summary: Although none of these recent interventions are ready for use in patients, it is encouraging that active research is ongoing to prevent DN. It is not clear whether these emerging strategies will be more effective than, or additive to, current therapeutic approaches in improving the renal and CVD outcomes in diabetes.

SUMMARY AND CONCLUSIONS

Primary care physicians (PCP) remain the front line defenders in our fight against diabetic nephropathy. There are several important roles that the PCP can play before consulting a nephrologist. First, the PCP should strive for optimal glycemic and BP control as a means to prevent or delay the development of diabetic nephropathy. Second, the PCP should periodically screen patients with diabetes for signs of early renal involvement. The ADA²¹³ currently recommends annual screening for the presence of microalbuminuria in type 1 diabetic patients with diabetes duration of 5 years and in all type 2 diabetic patients, starting at diagnosis and during pregnancy. Due to the inadequacies of microalbuminuria, it is also recommended that the serum creatinine should be measured at least annually for the estimation of glomerular filtration rate (eGFR) in all adults with diabetes regardless of the degree of urine albumin excretion. Third, once nephropathy is detected, a team approach should be adopted between the PCP, nephrologist, dietitian and endocrinologist to ensure optimal management focused on multiple risk factor interventions. Optimum individualized glucose control in both DMT1 and DMT2 remains a crucial target for DM therapy. A goal of HbA1c of 7% appears acceptable for most patients. Optimal BP management is associated with reduced microvascular complications. The ADA and JNC 7 recommend reducing BP to <130/80 in patients with DM, which seems a reasonable goal for young patients and for patients who can tolerate this goal well, as well as patients with evidence of microvascular disease. Agents which block the RAAS system have a superior reno-protective effect in patients with DN. Currently; there are tremendous ongoing efforts by laboratory and clinical researchers to gain a better understanding of the pathophysiology of DN, to identify better markers for early diagnosis of the disease, and to develop better therapeutic approaches to combat this devastating disease.