George King, PharmD Candidate

Although no cure exists, pharmacologic and nonpharmacologic measures can help patients prevent onset or progression of diabetic nephropathy to preserve kidney function.

Diabetes is the seventh-leading cause of death in the United States and the primary cause of end-stage renal disease.

 Diabetic nephropathy is a longterm consequence of diabetes, estimated to affect 20% to 40% of patients with diabetes. 

 Although there is no cure for diabetic nephropathy, by understanding the pathophysiology, preventative strategies, and interventions to slow the progression of this disease, the pharmacist can be better prepared to advocate for kidney function preservation.

Although the exact cause of diabetic nephropathy is unknown, several mechanisms have been hypothesized. Hyperglycemia, the formation of advanced glycosylation products, activation of the renin-angiotensin- aldosterone system, and activation of cytokines are all thought to be contributing factors to the progression of disease.

Hyperglycemia appears to cause expansion and injury of the glomerular basement membrane of the kidneys by increasing the renal mesangial cell glucose concentration. Initially, the glomerular mesangium expands by cell proliferation and later by cell hypertrophy. Transforming growth factor beta (TGF-beta) is particularly important in causing the expansion and later fibrosis by stimulating the production of both collagen and fibronectin.

 Other cytokines that are present in the kidney are also under investigation for their role in diabetic nephropathy.

Advanced glycosylation products are formed as glucose binds reversibly—and eventually irreversibly&mdash;to proteins in the kidneys. The glycosylation products can eventually form complex cross-links over time as the hyperglycemia continues and can contribute to renal damage by stimulation of growth and fibrotic factors.

In diabetic nephropathy, the local renin-angiotensin system is activated. Angiotensin II is stimulated and results in constriction of the efferent arteriole of the glomerulus, which results in increased glomerular capillary pressures. Angiotensin II also stimulates renal mesangium expansion and fibrosis through activation of angiotensin II type 1 receptors, and increases the expression of TGF-beta and other growth factors.

Microalbuminuria (30-300 mg/L) may contribute to renal injury associated with diabetic nephropathy. An increase in glomerular permeability causes plasma proteins such as albumin to be secreted into the urine. A portion of these proteins is absorbed by the proximal tubular cells, which can trigger an inflammatory response that contributes to kidney damage. Macroalbuminuria (>300 mg/L), nephrotic syndrome, and eventually renal failure may occur during the later stages of diabetic nephropathy.

Diabetic nephropathy is preventable if appropriate corrective measures are taken. Once nephropathy is present, progression cannot be stopped; thus, it is important to screen patients appropriately. According to the National Kidney Foundation guidelines, screening for proteinuria with a standard urinalysis should begin at the time type 1 diabetes mellitus (T1DM) is diagnosed, due to the probability that diabetes has been present for numerous years prior to its detection. Screening in patients with type 2 diabetes mellitus (T2DM) should begin 5 years after the initial diagnosis. For both T1DM and T2DM, screening should continue annually thereafter.

 The gold standard for screening is the 24-hour urine collection, due to diurnal variation in protein excretion.

Optimizing glucose and blood pressure control has been shown to prevent diabetic nephropathy in both T1DM and T2DM.

Clinical trials have shown that the risk of developing microalbuminuria as well as nephropathy can be remarkably diminished with intensive glucose control in patients with diabetes.

A reduction in diabetic nephropathy can also be attributed to nonpharmacologic interventions and lifestyle modifications, including regular exercise, weight reduction, and smoking cessation.

  Interventions to reverse a sedentary lifestyle and promote weight loss have been shown to improve glucose control and may prevent the onset of T2DM itself.

 Similarly to poor glucose control, smoking has been linked to an increased risk of microvascular complications in patients with diabetes; proper counseling and smoking cessation should be implemented in these patients.

An intervention that may prevent or slow the progression of a kidney disease is protein restriction. A few studies have shown that restriction of protein to 0.6 g/ kg/day can slow the decline of the glomerulus filtration rate (GFR) and decrease urinary albumin excretion (UAE). Also, protein restriction could result in nutritional deficiencies and muscle weakness in some patients. Currently, the American Diabetes Association recommends protein intake similar to the adult recommended daily allowance of 0.8 g/kg/day. Further limitations may be necessary once the GFR has started to decline.

Pharmacologic Options to Slow Disease Progression 

Pharmacologic treatment methods are targeted at blood pressure reduction, tight glycemic control, and cholesterol management. Blood pressure control is the foundation for preventing the progression of diabetic nephropathy. A goal blood pressure of <130/80 mm Hg is recommended in all patients with diabetes, and further reduction to 125/75 mm Hg is suggested in patients with a UAE >1 g/day.

 In T1DM patients, angiotensin—converting enzyme inhibitors are recommended when microalbuminuria is noted, despite the blood pressure level. Angiotensin II receptor blockers (ARBs) are recommended for initial treatment in patients with T2DM with hypertension who show signs of microalbuminuria. Two clinical trials revealed that microalbuminuria was reversed in patients who received ARBs compared with the control group.

Prospective control trials have shown that tight glycemic control can reduce the occurrence of the microvascular complications of diabetes, including nephropathy. Average hemoglobin A1C levels <8% have been linked to further complications; therefore, it is recommended for diabetic patients to achieve hemoglobin A1C levels <7%. As always, hypoglycemia and weight gain are associated with more intense therapy. Patients with a lower life expectancy and comorbid conditions should set higher glycemic goals if hypoglycemia occurs frequently.

Lipid management not only protects from cardiovascular disease, it also decreases the progression of nephropathy in diabetic patients. Treatment goals include low-density lipoprotein cholesterol <100 mg/dL, high-density lipoprotein cholesterol >40 mg/dL, and triglycerides <150 mg/dL. These goals can be achieved with the assistance of cholesterol-lowering agents. Specifically, HMG-CoA reductase inhibitors have shown efficacy in preventing glomerulosclerosis by normalizing serum creatinine and decreasing urinary albumin excretion.

Blood glucose control is the foundation for preventing the microvascular complications of diabetes, including diabetic nephropathy. Pharmacists are key in preventing these complications by educating patients on the significance of blood glucose monitoring, the use of blood glucose monitors, and the importance of achieving their blood glucose goals. Pharmacists should highlight the importance of strict compliance with their medications, as tight glucose control has been shown to prevent nephropathy.

 For both oral hypoglycemic agents and insulin, focusing on administration times and dosing schedules is an important way to ensure tight glucose control.

Blood pressure control is another key factor in slowing the progression of this disease. Pharmacists can assist patients in this area by providing information on achieving optimal blood pressure, providing advice on choosing a home blood pressure monitor, and providing education on blood pressure goals.

By screening patient profiles, pharmacists can identify patients with diabetes. Through conversing with these patients, pharmacists can determine if they also have kidney disease. If patients are unsure, pharmacists can educate them on the importance of screening for nephropathy associated with diabetes in hopes of preventing further complications. It is crucial that pharmacists work with both the patient and physician to ensure that the patient is achieving optimal blood pressure, blood glucose, and lipid control, and that other cardiovascular risk factors such as obesity, smoking, and sedentary lifestyle are being addressed.

Pharmacists are the most accessible health care professionals and therefore play a critical role in patient care. For patients with diabetes, pharmacists have a significant responsibility in providing education on implementation of dietary and lifestyle modifications, medications, and use of monitoring devices. Patients’ appropriate control of their diabetes can be significantly influenced by proper education and counseling by their pharmacists.

Dr. Bridgeman is clinical assistant professor at Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey. Mr. King, Mr. Ondrejka, and Ms. Tracy are 2010 PharmD Candidates at the Ernest Mario School of Pharmacy.

1.      Xu J, Kochanek KD, Tejada-Vera B.  Deaths: Preliminary Data for 2007.  

2.      Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2005. Available at: www.cdc.gov/DIABETES/pubs/pdf/ndfs_2005.pdf. Accessed September 21, 2009.

3.       U.S. Renal Data System, USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009.

4.      Cooper M. Pathogenesis, prevention, and treatment of diabetic nephropathy. 

5.      McGowan TA, Ziyadeh FN. Clinical Course and Management of Diabetic Nephropathy. In: Greenberg A, ed. 

, 4th ed. Philadelphia: Saunders; 2005:243-44.

6.      Evans TC, Capell P. Diabetic Nephropathy. Clinical Diabetes 2000;18:7-16.

7.      Screening, Diagnosis, and Management of Diabetes-related Complications. In: Unger J. 

. Philadelphia: Lippincott Williams & Wilkins; 2007:563-7.

8.      Evans TC. American Diabetes Association. Standards of Medical Care in Diabetes-2008. 

9.      American Diabetes Association. Diabetic Nephropathy. 

10.   Nathan DM, Buse JB, Davidson MB, et al. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. 

11.  American Diabetes Association. Diabetic Nephropathy. 

George King, PharmD Candidate

Articles