Screening and Management of Diabetic Kidney Disease

Release Date: August 1, 2013

Expiration Date: August 31, 2015


Suzanne Albrecht, PharmD, MSLIS
Freelance Medical Writer
Woodstock, Illinois


The author has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.


To educate the pharmacist on the epidemiology, pathophysiology, screening, prevention, and management of diabetic kidney disease.


After completing this activity, the participant should be able to:

  1. Discuss the epidemiology of diabetes and diabetic kidney disease.
  2. Define diabetic kidney disease and discuss its pathophysiology.
  3. List the risk factors and management of diabetic kidney disease.
  4. Explain lifestyle modifications for the prevention and treatment of diabetic kidney disease.
  5. Identify emerging therapeutic strategies for the treatment of diabetic kidney disease.

ABSTRACT: Diabetes is the leading cause of chronic kidney disease and end-stage renal disease. Early recognition and diagnosis of diabetic kidney disease (DKD) can reduce morbidity and mortality. Understanding and managing the risk factors of DKD have been the primary interventions for prevention and treatment. The pathophysiology of DKD is complex, but with an increased understanding, new therapeutic targets are being recognized and investigated.

Diabetes is the seventh leading cause of death in the United States. An alarming 11.3% (25.6 million) of Americans aged 20 years or older were diagnosed with diabetes in 2011.1 The risk of diabetes increases with age. In that same year, 27% (10.9 million) of the population 65 years or older had diabetes.2 With the obesity epidemic, the prevalence of diabetes is expected to increase.

Diabetes is the most common cause of chronic kidney disease (CKD).3 According to data collected from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2010, approximately 40% of those with diabetes had CKD.4 Diabetes is also the most common cause of end-stage renal disease (ESRD), accounting for 44% of all new cases in 2008.1 Prediabetes and undiagnosed diabetes account for a large percentage of all CKD cases. Plantiga and colleagues found that over 40% of those with undiagnosed diabetes and nearly 18% of those with prediabetes had CKD.5 Despite these startling statistics, the incidence of diabetic kidney disease (DKD) is starting to decline, which is most likely due to earlier diagnosis and prevention.6


DKD is a microvascular complication of diabetes and a risk factor for cardiovascular mortality.7 DKD is defined as a progressive, irreversible reduction of kidney function that cannot be attributed to another etiology. Renal insufficiency (glomerular filtration rate [GFR] <60 mL/ min/1.73 m2) must last at least 3 months.3,8 DKD has typically been thought to be associated with albuminuria, but it is now well known that renal insufficiency can exist with normal albumin excretion.2,8 Furthermore, microalbuminuria can regress to normoalbuminuria. This often happens following the initiation of treatment for modifiable risk factors (e.g., hypertension or hyperlipidemia).2 Factors associated with microalbuminuria regression include a short duration of microalbuminuria, systolic blood pressure (BP) <115 mmHg, and better glycemic control (glycosylated hemoglobin) <8%) and lipid control (total cholesterol <198 mg/dL, triglycerides <145 mg/dL).2,6 DKD is often present at the time of initial diagnosis of type 2 diabetes.9


In the early stages of DKD, hemodynamic changes result in hyperperfusion, hyperfiltration, and intraglomerular hypertension.9,10 This is followed by the increased leakage of albumin from the glomerular capillaries (urinary albumin excretion [UAE]).9 Accompanying renal structural changes include increased basement membrane thickness, glomerular hypertrophy, glomerular sclerosis, expansion of the mesangial matrix (due to the accumulation of intraand extracellular proteins), and podocyte apoptosis.9,11 Advanced DKD is characterized by proteinuria, impaired renal function, decreasing GFR, and interstitial fibrosis.11

Hyperglycemia and microinflammation are responsible for the progression of DKD to ESRD.10 Many complex mechanisms contribute to the development and progression of DKD.9 These mechanisms are mediated by metabolic, hemodynamic, intracellular, and growth factors.11

Advanced Glycation End-products (AGEs): AGEs are present in the healthy kidney. They become a problem when they are overproduced, as in the case of chronic hyperglycemia. AGEs promote oxidative stress and inflammation. Increased levels of circulating AGEs are associated with the development of microvascular complications, including DKD. Specifically, increased AGE production is associated with renal and glomerular hypertrophy, albuminuria, mesangial matrix expansion, and glomerular sclerosis.11

Angiotensin II (ANG II)/Renin-Angiotensin System (RAS): The systemic RAS regulates BP and fluid and electrolyte balance. There are some tissues, such as the kidneys, that have a localized and independently regulated RAS. Renin is produced in the renal juxtaglomerular cells and converted from angiotensinogen to angiotensin I (inactive form). The inactive angiotensin I (ANG I) is then converted to the biologically active angiotensin II (ANG II) by angiotensin-converting enzyme (ACE). ANG II adversely affects renal blood flow through vasoconstriction. Other untoward effects of ANG II include the promotion of cell proliferation, generation of reactive oxygen species (ROS), and stimulation of extracellular matrix expansion.12 Exactly how the RAS affects the structure and function of the kidneys is unclear. What is well established is the beneficial effects angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have on renal structure and function.11

Growth Hormone (GH) and Insulin-like Growth Factors (IGFs): In the kidney, GH and IGFs affect renal blood flow and tubular water, phosphate, and sodium absorption. The mechanisms by which GH and IGFs lead to DKD are complex, but evidence shows that they are involved in both early and late renal changes. In particular, IGF-I seems to play a role in early changes in structure and function of the kidney, such as renal and glomerular hypertrophy, mesangial expansion, increased UAE and GFR, and tubular integrity.11

Risk Factors

There are several risk factors associated with the development and progression of DKD (TABLE 1). Many of these are modifiable, and addressing these risk factors is the mainstay of DKD prevention and treatment.

Hyperglycemia: Hyperglycemia and the duration of diabetes are risk factors for the development and progression of DKD.3 The Diabetes Control and Complications study (DCCT) compared the incidence and rate of progression of diabetes complications in patients with type 1 diabetes using intensive glycemic control (insulin pump or 3 insulin injections per day achieving near normal glycemia) to conventional treatment (one to two insulin injections per day). Those assigned to conventional therapy had a higher risk of developing persistent microalbuminuria over time. Their cumulative incidences of persistent microalbuminuria were 14%, 33%, and 38% at 10, 20, and 30 years’ duration of diabetes, respectively. The intensive-treatment group had cumulative incidences of persistent microalbuminuria of 10%, 21%, and 25% at 10, 20, and 30 years, respectively.13

The DCCT study also looked at the rate of developing microalbuminuria with intensive treatment in participants with normoalbuminuria from the start, as well as the risk of progression of albuminuria in participants with existing albuminuria. In the intensive-treatment group with normoalbuminuria, there was a 34% lower risk of progressing to microalbuminuria when compared to those receiving conventional treatment. Participants with existing persistent microalbuminuria receiving intensive treatment had a 56% lower risk of progressing to a higher UAE than those using conventional treatment.14

Furthermore, in the Epidemiology of Diabetes Interventions and Complications (EDIC) cohort (a subset of the DCCT study), intensive glycemic control was associated with a higher incidence of regression to normoalbuminuria and a lower incidence of progression to macroalbuminuria, impaired GFR, and ESRD.13 The benefits continued to be observed at 7- and 8-year follow-up.15

The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines issued by the National Kidney Foundation recommend a target hemoglobin A1c(HbA1c) of approximately 7% to prevent or delay DKD, except for those at risk of hypoglycemia. There is an increased risk of hypoglycemia in those with DKD when compared to other patients with diabetes due to decreased clearance of antidiabetic agents (including insulin) and impaired gluconeogenesis.16

The management of glycemic control in patients with DKD is multifactorial and includes medications, appropriate diet and meal planning, and physical activity.16 Many medication doses need to be adjusted with renal dysfunction. This includes certain diabetes medications.

Hypertension (HTN): An increase in systolic BP is associated with DKD and may contribute to its progression.3,17 The rate of progression corresponds to the severity of HTN.17 Controlling BP may be the most effective intervention to prevent progression of nephropathy in patients with type 1 and type 2 diabetes. HTN in diabetic patients is defined as BP > 130/80 mmHg, and it has been shown that patients with diabetes who maintain a BP of < 130/80 mmHG rarely develop microalbuminuria, and the decrease of GFR is comparable to that of the nondiabetic population.18

Patients with type 1 and type 2 diabetes commonly have HTN. The difference is that HTN occurs later with type 1 diabetes and often marks the onset of DKD.17 With type 2 diabetes, HTN can occur before the onset of renal damage, which suggests that HTN is the result of insulin resistance.7

The target BP in patients with diabetes is 130/80 mmHg. The preferred antihypertensive agents are ACEIs or ARBs. If other agents are needed, a diuretic is preferred, followed by a beta-blocker or calcium channel blocker.17

ACEIs and ARBs have been shown to slow the progression of DKD in patients with type 1 and type 2 diabetes with microalbuminuria. These agents have beneficial effects on kidney function by slowing the increase in UAE, reducing UAE, and delaying the progression of microalbuminuria to macroalbuminuria. In particular, ACEIs are superior to other classes of antihypertensive agents in slowing the progression of DKD in patients with type 1 diabetes with HTN and macroalbuminuria. In patients with type 2 diabetes and HTN with macroalbuminuria, ARBs are superior to other classes of antihypertensive agents for delaying DKD progression.17

Most patients with diabetes will require multiple medications to control BP. The addition of a diuretic may potentiate the effects of an ACEI or ARB. The KDOQI recommends adding a diuretic to an ACEI or an ARB when multiple medications are required to achieve target BP.17

The three classes of antihypertensives that have been shown to reduce proteinuria are ACEIs, ARBs, and nondihydropyridine calcium channel blockers. Combination therapy with an ACEI and an ARB can decrease proteinuria more than either medication alone, but it is also associated with serious adverse reactions. KDOQI guidelines suggest that this dual therapy be reserved for those with controlled BP but persistently high macroalbuminuria or albumin-to-creatinine ratio (ACR) > 500 mg/g.17

Hyperlipidemia: Hyperlipidemia is common in those with DKD, and it increases the risk of cardiovascular events in this population. Low-density lipoprotein (LDL) cholesterol is of particular concern.16 DKD is associated with higher levels of LDL, intermediate-density lipoprotein (IDL), very-low-density lipoprotein (VLDL), and triglycerides, as well as decreased concentrations of high-density lipoprotein (HDL).19,20 Reduced levels of HDL are worrisome because HDL decreases the concentrations of markers of inflammation and cell-adhesion molecules, both of which are elevated in the early stages of DKD. These lipid abnormalities worsen as albuminuria increases, and renal function decreases due to impaired renal clearance of these lipoproteins.19

The mechanism by which lipoproteins cause renal injury is thought to begin with kidney exposure to oxidized LDL. The mesangial cells secrete chemotactic and adhesion molecules, which attract macrophages. Glomerular sclerosis and tubular fibrosis result from the infiltration of the macrophages. Next, the oxidized LDL is taken up by the macrophages, stimulating the release of ROS and cytokines such as transforming growth factor (TGF)-beta-1 and platelet-derived growth factor (PDGF). The cytokines induce the production of extracellular matrix proteins and mesangial expansion.19

The RAS is believed to contribute to renal injury through a complex pathway of reactions. ANG II promotes the oxidation of LDL and glomerular capillary hypertension, resulting in increased permeability of macromolecules and accumulation of mesangial lipids. ANG II also stimulates the release of chemokines and cytokines, leading to further infiltration and accumulation of lipids into the macrophages and resulting in glomerular and tubular interstitial injury.19

KDOQI guidelines recommend using HMG-CoA reductase inhibitors (statins) or statin-ezetimibe combinations to lower LDL and reduce the risk of cardiovascular events in those with DKD, including patients who have had a kidney transplant. Since statins do not reduce mortality and cardiovascular events, they are not recommended for dialysis patients.16

Statins work by blocking the enzyme 3-hydroxy-3methylglutaryl CoA (HMG-CoA), thereby inhibiting the rate-limiting step for cholesterol synthesis. This lowers lipids by increasing the uptake and degradation of LDL by the liver, preventing LDL oxidation, and decreasing cholesterol synthesis and accumulation. Statins exhibit pleiotropic (cholesterol-independent) protection against cardiovascular disease and DKD. Aside from their cholesterol-lowering properties, statins may have beneficial effects on oxidation, endothelial function, and inflammation.21

Obesity: Obesity may be an independent risk factor for CKD irrespective of the presence of type 2 diabetes. The mechanisms involved in obesity-related nephropathology are complex and not completely understood. However, the pathophysiology of DKD and obesityrelated CKD is strikingly similar.22 Like DKD, obesityrelated nephropathy begins with hyperfiltration and glomerular capillary hypertension. Glomerular hyperfiltration is thought to be partially due to increased sodium reabsorption in the proximal tubule.23 Increases in sympathetic tone and RAS activity also seem to stimulate sodium reabsorption in the proximal tubule.22

This is followed by glomerular hypertrophy and microalbuminuria. Elevated systolic BP adds to the progression of the disease to proteinuria, glomerular sclerosis, tubular interstitial fibrosis, and ultimately to ESRD.22

Weight loss will improve glycemic control and reduce cardiovascular risk by lowering BP, improving lipid profile, and reducing inflammation.9 Weight loss has beneficial effects on kidney function. The UAE and renal plasma flow (RPF) decrease. Proteinuria regression has also been observed following weight loss.23 Anti-obesity medications should be added to lifestyle modifications, if necessary, and bariatric surgery should be considered if the BMI is greater than 35.9

Smoking: Smoking is an independent risk factor for DKD development and progression in patients with both type 1 and type 2 diabetes.24,25 Specifically, there are four processes of DKD adversely affected by smoking: 1) The risk of developing microalbuminuria is increased; 2) the time between the onset of diabetes and the onset of microalbuminuria is shortened; 3) the time between microalbuminuria and progression to persistent proteinuria (overt DKD) is shortened; and 4) the rate of progression of DKD to ESRD is accelerated.24

Several mechanisms may contribute to the adverse relationship between smoking and DKD. These include increased BP and heart rate (HR); increased sympathetic tone, decreased GFR and RPF due to increased renal vascular resistance; and increased arteriosclerosis of the renal and intrarenal arteries and arterioles.24

Despite BP control and ACEI therapy, patients with type 2 diabetes with existing micro- or macroalbuminuria who smoke showed no slowing of the progression of DKD. Conversely, smoking cessation in this population exhibited a decline in the progression of DKD.26

Microalbuminuria: Microalbuminuria does not necessarily indicate the presence of DKD, but it is associated with endothelial dysfunction and an increase in cardiovascular risk.9 Microalbuminuria can lead to proteinuria and impaired renal function, and aside from being an early marker of kidney disease, it is an independent risk factor for all-cause mortality and cardiovascular events.3,9 Microalbuminuria can regress to normoalbuminuria. This is more common in patients with type 1 diabetes with a short duration microalbuminuria.3 Furthermore, about a third of patients with type 1 diabetes do not develop overt DKD.16

Most patients with diabetes with microalbuminuria also have HTN. The KDOQI guidelines recommend not using an ACEI or an ARB in the absence of HTN and albuminuria for the prevention of DKD. There is no evidence that these agents prevent the development of microalbuminuria in normotensive normoalbuminuric patients. ACEIs and ARBs are suggested for use in normotensive patients who have albuminuria levels > 30 mg/g and are at a high risk of progression. High-risk patients include those with increasing levels of microalbuminuria, macroalbuminuria, decreasing GFR, uncontrolled HTN, retinopathy, increased lipid levels or uric acid concentrations, or a family history of HTN, macrovascular disease, or DKD.16

Although the actual effective dose of an ACEI or ARB is unknown for normotensive patients with albuminuria, KDOQI guidelines recommend titrating the dose to the maximum approved (or tolerated) dose to treat HTN. Kidney function and potassium levels need to be monitored.16

The KDOQI does not recommend using a combination therapy of ACEI and ABR to lower albuminuria. The risks are too high (impaired renal function, hypotension, and hyperkalemia), even though the combination appears to reduce albuminuria levels.16

Albuminuria can result from other conditions and circumstances, and it is important to discern its etiology. Other causes include strenuous exercise within the past 24 hours, fever, high salt intake, infection, dehydration, hematuria, congestive heart failure, and very high BP and/or blood glucose.9 With albuminuria in the absence of retinopathy, another etiology should be investigated.

Hyperglycemia, hypertension, hyperlipidemia, obesity, smoking, and albuminuria are all modifiable risk factors. Advanced age, male gender, and genetic makeup are nonmodifiable risk factors that can increase the likelihood of developing DKD.13


Since the earliest sign of DKD is microalbuminuria, even without clinical renal insufficiency, screening should consist of measuring urinary albumin. This can be done using a spot urine sample, a timed collection, or a 24-hour collection.2 Albuminuria may be absent even in advanced-stage DKD; therefore, kidney function should be assessed using serum creatinine (measured as albumin [mg]/creatinine [g]).9

According to the KDOQI guidelines, screening should start at the time of diagnosis for patients with type 2 diabetes and 5 years from diagnosis for those with type 1 diabetes. Screening should then be done annually, regardless of the results. Measuring the ACR using a spot urine sample should be part of the screening. Since early or advanced DKD can exist without elevated albuminuria, screening should also include an assessment of kidney function using the serum creatinine measurement. The serum creatinine can then be used to calculate the estimated glomerular filtration rate (eGFR).9 The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) recommends estimating GFR using the Modification of Diet in Renal Disease (MDRD) equation. The GFR ([measured as mL/min/1.73 m2] = 175 × [serum creatinine]-1.154 × [age]-0.203 × [0.742 if female] × [1.212 if African American]). This equation should not be used in persons under 18 years, persons with unstable creatinine conditions (e.g., pregnant women, those with serious comorbidities, and hospitalized patients), and persons with extremes of muscle mass and diet (e.g., body builders, paraplegics, obese patients, and patients with a musclewasting disease or who are taking creatinine supplements).27 The NIDDK has GFR calculators at www.

If the ACR is elevated, a diagnosis of urinary tract infection should be ruled out, and then the ACR should be measured twice more using a first-void specimen over the next 3 to 6 months. An ACR of 30 to 300 mg/g is called microalbuminuria. Macroabluminuria is an ACR greater than 300 mg/g. If two of the three samples are consistent for microor macroalbuminuria, that is sufficient to confirm the diagnosis.17 If the patient is found to have microor macroalbuminuria, he or she should be evaluated for the presence of microor macrovascular sequelae, specifically retinopathy.6

The presence of elevated albuminuria and retinopathy strongly suggests DKD. Long-term diabetes and neuropathy also suggest DKD versus another etiology.7 An alternative cause of CKD should be considered if the patient has any of any of the following conditions: absence of retinopathy, low or rapidly decreasing GFR, rapidly increasing proteinuria or nephrotic syndrome, refractory HTN, presence of active urinary sediment, signs or symptoms of another systemic disease, or a > 30% reduction of GFR within 2 to 3 months following the start of an ACEI or an ARB.17

DKD is then staged using the GFR value. Stage I is renal damage, with or without an increased GFR. When there is kidney damage with a mildly decreased GFR (60-89 mL/min/1.732), it is considered stage II. A moderately reduced GFR (30-59 mL/min/1.732) identifies stage III, which is furthered subdivided into stage IIIa and stage IIIb. Stage IV occurs when the GFR is between 15 and 29 mL/min/1.732. When there is kidney failure it is considered stage V. In stage V, the GFR is < 15 mL/min/1.732, or the patient requires dialysis.2,28

Diet Modifications

Salt is a modifiable risk factor for cardiovascular and renal disease.29 High sodium intake can have untoward effects on renal and cardiovascular health by two mechanisms.29,30 Sodium exacerbates hypertension, which increases the risk for both cardiovascular and renal disease. High sodium intake also diminishes the systemic RAS with a resulting decrease of renin, ANG II, and aldosterone plasma concentrations. It would seem logical that this blockade would be beneficial for cardiovascular and renal health, but those with type 2 diabetes and HTN exhibit a paradoxical reaction. The systemic and local tissue RAS does not respond normally to increased sodium intake. There is evidence that increased sodium intake negates the beneficial effects of ACEI therapy on proteinuria and left ventricular hypertrophy.29 To maximize the therapeutic and protective effects of ACEIs or ARBs, sodium intake must be moderated. Daily sodium restriction to less than 2.3 g/ day is recommended for patients with DKD.17 Certain foods to avoid are canned food, cured and smoked food, fast food, certain snacks, and certain condiments.30 Of importance is the potassium content in salt substitutes. Consumption of salt substitutes can increase potassium levels; careful monitoring is required.

The type and amount of protein and fats can also affect DKD. Excessive protein intake can cause an increase in UAE. Limiting protein intake to 20% or less of total caloric consumption does not appear to have an effect on DKD. UAE starts to rise when protein intake exceeds 20% of total daily energy.30

The KDOQI guidelines recommend protein intake of 0.8 g/kg body weight per day for stages I through IV DKD. Studies have shown that UAE can actually decrease and renal function can stabilize when following this guideline. In order to limit protein intake, there must be an increase of carbohydrate and fat consumption to meet daily energy requirements. With glycemic and lipid control being so paramount, it is difficult to determine the proper foods to eat and not tip the balance of any of these nutritional factors. Selecting the appropriate macronutrients focuses on quality, in addition to quantity, of dietary energy sources. There is some evidence that indicates protein from meat is more harmful than protein from vegetables and dairy products. The KDOQI guidelines recommend that 50% to 75% of total protein intake be from lean poultry, fish, and soy and vegetable sources.17

With decreased protein intake, proper nutrition must be maintained by increasing carbohydrate and fat intake. The KDOQI guidelines suggest that fat intake consist of an increase in omega-3 fatty acids and monounsaturated fats.17 Omega-3 polyunsaturated fatty acids (PUFAs) are well known to provide protection against cardiovascular disease, which is the leading cause of death in diabetes and DKD. Omega-6 PUFAs also seem to positively affect renal function and some risk factors for DKD. There is evidence that the omega-3 PUFA (alpha-linolenic acid) from fish oil and plant sources, along with the omega-6 PUFA (linoleic acid) from plant sources, has beneficial health effects against HTN, inflammation, glomerular sclerosis, and albuminuria.31 Simply substituting canola oil for vegetable oil is one strategy to increase omega-3 PUFAs and monounsaturated fats.17

Total carbohydrate consumption does strongly contribute to postprandial plasma glucose concentrations, but selecting the “right” type of carbohydrates can control glucose release and postprandial insulin spikes after a meal. Low glycemic foods, like those high in fiber, do not have the same glycemic effect as other types of food (processed or fast food).

A specially trained dietitian should be consulted to educate the patient on diet management. The diet for DKD is more complicated than that for either CKD or diabetes alone. The patient needs to be specifically educated on balancing macronutrient intake and sources.17


The mainstay of treatment has been blocking the RAS and controlling the modifiable risk factors.12 There are promising new agents, as well as existing agents, being investigated for the treatment of DKD.

ACEIs prevent the formation of ANG II and ARBs block the effects of ANG II, but they do not seem to cover the activity of the entire RAS cascade. There is a specific renin receptor found in the mesangial cells of the human kidney. Once renin is released into the circulation, it is taken up by tissues, where it either catalyzes the conversion of angiotensinogen to ANG I or binds to certain proteins. The renin-protein complex can then bind to the renin receptor in the kidneys. This binding of the renin-protein complex results in the conversion of angiotensinogen to ANG I at four times the rate of renin alone.12 This renin receptor may represent a new target for the treatment of CKD.

Aliskirin is a direct renin inhibitor that was approved by the FDA in 2007 for the treatment of HTN. By binding directly to the renin receptor, it blocks the conversion of angiotensinogen to ANG I. In studies, aliskirin has been shown to be as effective as ACEIs at reducing albuminuria, and the combination of the two drugs is more effective than either alone.12 Despite increased efficacy with the use of aliskirin plus an ACEI or an ARB, the KDOQI guidelines do not recommend using the two together because of an increased risk of adverse effects, such as hypotension, hyperkalemia, nonfatal stroke, and renal complications.16 Clinical trials are ongoing to determine whether aliskirin’s ability to directly block renin receptors translates into improved morbidity and mortality outcomes and what its role might be in DKD treatment.12

Pirfenidone is an antifibrotic agent that has shown promise in preliminary clinical studies. Pirfenidone has been shown to block TGF-beta activity and reduce ROS production. By this action, fibrosis may be reduced in the kidney.12,31

Bardoxolone methyl is an experimental agent undergoing clinical trials. Bardoxolone is an antioxidant inflammation modulator. An increase in GFR has been observed with this drug, and the benefits appear to be dose dependent. A clinical study is now being conducted to see if bardoxolone can slow progression to ESRD and cardiovascular death.31

Other agents currently being investigated include pentoxifylline (methyl xanthine derivative), ruboxistaurin (protein kinase C inhibitor), and paricalcitol (vitamin D analogue).31


The pathology of DKD is complex, but understanding the risk factors and their management can mitigate or prevent its development and progression. Patient care and therapeutic outcomes can be enhanced by proper pharmacist oversight and interventions. The pharmacist should counsel DKD patients on the management of modifiable risk factors, selection of OTC medications, and medication adherence. See TABLE 2 for counseling points.


  1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet; 2011. Accessed April 4, 2013.
  2. Reutens A. Epidemiology of diabetic kidney disease. Med Clin N Am. 2013;97:1-18.
  3. Pyram R, Kansara A, Banerji M, Loney-Hutchinson L. Chronic kidney disease and diabetes. Maturitas. 2012;71:94-103.
  4. United States Renal Data System. USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Epidemiology of Diabetic Kidney Disease 13. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2011.
  5. Plantiga L, Crews D, Coresh J, et al. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin Am Soc Nephrol. 2010;5:673-682.
  6. Gross J, de Azevedo M, Silveiro S, et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:176-188.
  7. Van Buren P, Toto R. The pathogenesis and management of hypertension in diabetic kidney disease. Med Clin N Am. 2013;97:31-51.
  8. Wylie E, Satchell S. Diabetic nephropathy. Clin Med. 2012;5:480-482.
  9. Bakris G. Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc. 2011;86:444-456.
  10. Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci. 2013;124:139-152.
  11. Schrijvers B, De Vriese A, Flyvbjerg. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004;25:971-1010.
  12. De Cléves A, Sharma K. New pharmacological treatments for improving renal outcomes in diabetes. Nephrology. 2010;6:371-380.
  13. De Boer I, Rue T, Cleary P, et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Cohort. Arch Intern Med. 2011;171:412-420.
  14. Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47:1703-1720.
  15. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on the development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290:2159-2167.
  16. Bilous R, Gonzalez-Campoy J, Mauer M, et al. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850-866.
  17. Aschner P, Bakris J, Bilous R, Caramori M, et al. Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kid Dis. 2007;49(suppl 2):S1-S179.
  18. Giunti S, Barit D, Cooper M. Mechanisms of diabetic nephropathy: role of hypertension. Hypertension. 2006;48:519-526.
  19. Rutledge J, Ng K, Aung H, Wilson D. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol. 2010;6:361-370.
  20. Rosario R, Prabhakar S. Lipids and diabetic nephropathy. Curr Diabetes Rep. 2006;6:455-462.
  21. Danesh F, Kanwar Y. Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy. FASEB J. 2004;18:805-815.
  22. Maric-Bilken C. Obesity and diabetic kidney disease. Med Clin North Am. 2013;97:59-74.
  23. Bayless G, Weinrauch L, D’Elia J. Pathology of obesity-related renal dysfunction contributes to diabetic nephropathy. Curr Diabetes Rep. 2012;12: 440-446.
  24. Ritz E, Ogata H, Orth S. Smoking: a factor promoting onset and progression of diabetic nephropathy. Diabet Metab. 2000;26:54-63.
  25. Sawicki P, Didjurgeit U, Muhlhauser I, et al. Smoking is associated with progression of diabetic nephropathy. Diabetes Care. 1994;17:126-131.
  26. Chuahirun T, Simoni J, Hudson C, et al. Cigarette smoking exacerbates and its cessation ameliorates renal injury in type 2 diabetes. Am J Med Sci. 2004;327:57-67.
  27. Estimating GFR. United States Department of Health and Human Services: National Kidney Disease Education Program website. www.nkdep.nih. gov/lab-evaluation/gfr/estimating.shtml. Updated February 6, 2013. Accessed April 29, 2013.
  28. Levey A, de Jong P, Coresh J, et al. The definition, classification and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17-28.
  29. Charytan D, Forman J. You are what you eat: dietary salt intake and renin angiotensin blockade in diabetic nephropathy. Kidney Int. 2012;82: 257-259.
  30. Franz M, Wheeler M. Nutrition therapy for diabetic nephropathy. Curr Diabetes Rep. 2003;3:412-417.
  31. Shapiro H, Theilla M, Attal-Singer J, Singer P. Effects of polyunsaturated fatty acid consumption in diabetic nephropathy. Nat Rev Nephrol. 2010;7:110-121.

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