Treatment and Prevention of Diabetic Nephropathy

In the US, diabetic nephropathy is the leading cause of end-stage renal disease (ESRD), accounting for 40% of new cases; 20% to 40% of diabetes patients develop diabetic nephropathy.[1,2] Because there are more patients with type 2 than type 1 diabetes, over 50% of diabetic patients starting dialysis are type 2 patients.[2] Microalbuminuria (albumin in the range of 30 to 299 mg/24h) is the earliest clinical indication of nephropathy in diabetes patients.[2] Intensive treatment of diabetes, designed to maintain blood glucose levels in the normoglycemic range, can delay the onset and progression of microalbuminuria in both type 1 and type 2 diabetes patients.[1,3] High blood pressure (BP) and cholesterol are also risk factors for renal failure in diabetes patients, and tight BP regulation effectively slows the onset and progression of diabetic nephropathy.[4,5] In addition, lowering BP through use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) provides benefits over other antihypertensive agents in delaying the progression of diabetic nephropathy.[1,5,6,7,8] 

Therapeutic intervention and prevention of nephropathy has the greatest impact if instituted very early in the development of diabetes and its complications.[2,7] This article summarizes the current treatments for diabetic nephropathy and emphasizes the importance of early intervention.

Treatment of Nephropathy

The American Diabetes Association (ADA) treatment guidelines for diabetic nephropathy focus on reducing the risk and slowing the progression of nephropathy by controlling glucose levels and decreasing BP. The ADA provides recommendations for lifestyle modifications and pharmacologic interventions, such as ACE inhibitors and ARBs.[2] Because dyslipidemia is a risk factor for diabetic nephropathy, information regarding lipid control is provided in this article. Considerations for patients whose renal function declines, despite glucose and blood pressure regulation, are also included. 

Glucose Control

The Diabetes Control and Complications Trial (DCCT) showed that lowering blood glucose levels as close to normal as possible (A1C<7%) can produce a 34% reduction in occurrence of microalbuminuria.[3] The UK Prospective Diabetes Study (UKPDS) reported similar findings for type 2 patients.[9] Many organizations have developed recommendations regarding guidelines for glycemic control. Recommendations should be followed to achieve normoglycemia in both type 1 and type 2 diabetic patients. A summary of glycemic goals for the ADA, American Association of Clinical Endocrinologists (AACE), and Iternational Diabetes Federation (IDF) appears in Table 1.

Table 1. Glycemic goals

*More stringent goals (A1C<6%) may further reduce complications at the cost of increased risk of hypoglycemia.

†Self-monitored blood glucose reading

Blood Pressure Control

Hypertension is present in approximately one third of type 2 patients at the time of diabetes diagnosis, and manifestation of hypertension in type 1 patients generally occurs about the time microalbuminuria develops.[2] Both systolic and diastolic hypertension accelerate the progression of nephropathy, and aggressive antihypertensive therapy can greatly decrease the rate of renal function decline.[2] All patients with diabetes should have BP measured at the time of diagnosis or initial office evaluation and at each scheduled diabetes visit.[1] The goal of antihypertensive therapy in nonpregnant diabetic patients ≥18 years of age is BP <130/80 mm Hg. Initial treatment should consist of lifestyle modifications (weight loss, reduction of salt and alcohol intake, and physical activity) and, if appropriate, pharmacotherapy.[2] The stages of hypertension are described in Table 2.

Table 2. Classification of hypertension[12]

Only 11% of patients with diabetes achieve goal BP <130/80 mm Hg.[13] One of the key messages from the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) is that most patients with hypertension will require at least 2 antihypertensive medications to reach BP<140/90 mm Hg.[12] In the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), BP control was worse among diabetes patients than among other patient subgroups.[14] It is not surprising, then, that more than one half of patients with diabetes will require the use of 2 or more antihypertensive agents to achieve the ADA-recommended BP (<130/80 mm Hg).[12,14] An algorithm for hypertension management is presented in Figure 1. 

In summary, the ADA recommends the following interventions to achieve BP<130/80:[1]

• Systolic BP ≥140 mm Hg OR diastolic BP ≥90 mm Hg
  • Pharmacotherapy + lifestyle and behavioral therapy
• Systolic BP 130-139 mm Hg OR diastolic BP 80-89 mm Hg
  • Lifestyle and behavioral therapy alone for maximum of 3 months, then if target not achieved, ACE inhibitor or ARB
• All patients with diabetes and hypertension should be on either an ACE inhibitor or ARB
  • If further reduction needed, add thiazide diuretic.

ACE inhibitors and ARBs

Studies have shown profound benefits of ACE inhibitors and ARBs in reducing albuminuria and overall deterioration of kidney function. Due to the renal-protective effects of both classes of agents, the ADA recommends ACE inhibitors or ARBs as first-line therapy for hypertension and for the treatment of micro- and macroalbuminuria in diabetic patients who are not pregnant.[1] The ADA has also stated that ACE inhibitors are appropriate for managing persistent microalbuminuria in pediatric and adolescent patients with type 1 diabetes.[15] The National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines similarly indicate that ACE inhibitors or ARBs should be used to treat patients with diabetic kidney disease, even in the absence of hypertension.[16]  

Studies have demonstrated that the capacity of ACE inhibitors and ARBs to slow kidney damage may not be limited to their effects on BP.[6] Although researchers have not clearly identified the renal-protective mechanisms of ACE inhibitors and ARBs, several hypotheses have been proposed. In diabetes patients, localized hypertension due to altered renal hemodynamics may cause glomerular damage; ACE inhibitors and ARBs may prevent this damage by alleviating the constrictor effect of angiotensin II.[6] ACE inhibitors and ARBs may also prevent renal hypertrophy and preserve renal function by inhibiting the trophic actions of angiotensin II.[6] 

The renal-protective actions of ACE inhibitors and ARBs seem to be class effects, so the choice of therapeutic agent may depend on cost and tolerance considerations.[2] If either ACE inhibitors or ARBs are not tolerated, the other class should be substituted.[2] If neither ACE inhibitors nor ARBs are tolerated, physicians should consider other antihypertensive agents, such as non-dihydropyridine calcium channel blockers (non-DCCBs), β-blockers, or diuretics.[2] ACE inhibitors and ARBs are contraindicated for patients who are pregnant, but non-DCCBs may be used to reduce albuminuria during pregnancy.[1] Physicians should monitor potassium levels for hyperkalemia in patients using ACE inhibitors, ARBs, or diuretics.[1] In addition, ACE inhibitors may cause renal function to rapidly decline in patients with advanced renal disease or in older patients with bilateral renal artery stenosis.[2] Cough is also a side-effect of ACE inhibitors.[2]

Lipid Control

Dyslipidemia is considered a risk factor for diabetic nephropathy.[17,18] Moderately elevated lipid levels, especially when combined with high-normal BP and raised A1C levels, have been associated with progression of diabetic nephropathy.[4] Recent clinical trials have demonstrated that intensive cholesterol therapy reduces the risk of developing nephropathy and slows nephropathy progression. The GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) study demonstrated that diabetes patients allocated to atorvastatin therapy had a 10.9% increase in glomerular filtration rate (GFR).[19] Several other studies have been cited indicating the efficacy of HMG CoA reductase inhibitors (statins) in decreasing the progression of nephropathy, independent of their cholesterol lowering effects.[20] However, most data are based on short-term studies and need to be confirmed in long-term studies.[18] In the meantime, dyslipidemia in diabetic patients should be managed aggressively, according to current guidelines, in order to prevent macrovascular disease and potentially benefit microvascular complications.[18]

Table 3. Guidelines for the management of dyslipidemia

*Lower LDL goal of < 70 mg/dL may be appropriate for patients with diabetes and overt cardiovascular disease (CVD)

†>50 mg/dL may be appropriate for women

Lifestyle modification including nutritional therapy, increased physical activity, weight loss, and smoking cessation should allow some patients to achieve goal lipid levels. If not achieved, pharmacological therapy may be appropriate. Lowering LDL levels to <100 mg/dL is the primary goal of therapy. Lowering LDL cholesterol with statin treatment is associated with a reduction in cardiovascular events.[1] Lowering triglycerides and increasing HDL can be achieved with a fibrate or niacin. Combination therapy employing statins and fibrates or niacin may be necessary to achieve lipid targets.[1]

Other considerations

Protein restriction

Animal studies and some clinical studies have shown that protein restriction slows the decline of renal function. Current ADA guidelines indicate that protein intake should be limited to the adult Recommended Daily Allowance (RDA) of ≤0.8 g/kg body weight per day (~10% of daily calorie intake) in patients with overt nephropathy. Tighter restriction (0.6 g/kg body weight per day) may benefit some patients but may also result in nutritional deficiency and muscle weakness. The ADA therefore suggests consultation with a registered dietitian, who is familiar with dietary management in diabetes, when planning a protein-restricted diet.[2]

Specialist referral

Diabetic patients may also require treatment by a specialist for optimal management of diabetic nephropathy. The ADA recommends referral to a physician with expertise in diabetic renal when a patient's GFR has fallen to <60 mL/min/1.73m² or when managment of hyperkalemia or hypertension is difficult.[1] Consultation with a nephrologist earlier in disease progression, when the GFR is < 30 ml/min per 1.73m², may further benefit patient care.[1]

Prevention

American Diabetes Association treatment guidelines do not indicate a single treatment, such as a vaccine or medication, to prevent diabetic nephropathy. Instead, the guidelines emphasize a series of interventions to delay the onset and slow the progression of the complication.[1] Prevention, therefore, consists of taking measures to delay the onset of complications prior to the appearance of clinical symptoms. In the case of diabetic nephropathy, prevention begins with early diabetes detection. Estimates indicate approximately 6.2 million people in the US have diabetes and remain undiagnosed.[21] Type 2 diabetes is generally present for many years before a diagnosis is made; longer duration between disease onset and diagnosis increases the likelihood that complications, including nephropathy, will be present at diagnosis.[2] To promote early diagnosis, the ADA recommends diabetes screening in patients at high risk for diabetes, including all individuals age 45 and older.[1] If the initial screening is negative, repeated screening at 3-year intervals is considered appropriate, as significant diabetic complications are unlikely to develop within 3 years.[1]

Once a diabetes treatment program commences, controlling A1C levels below 7% can reduce the risk of microalbuminuria and slow the progression from micro-to macroalbuminuria.[3,4] In addition, controlling BP below 130/80 mm Hg has been shown to delay the development and progression of diabetic nephropathy. Several recent studies have implicated the emerging role of dyslipidemias in the development of diabetic nephropathy. Managing lipid levels with diet, exercise, and pharmacological therapy to achieve target goals may also decrease the risk of developing diabetic nephropathy.

Practice Pearls

Achieve target A1C levels <7%
Achieve target BP <130/80 mm Hg
Achieve target lipid profiles
Routine screening for microalbuminuria

References

1. American Diabetes Association. Standards of medical care in diabets. Diabetes Care. 2005; 28(suppl 1):S4-S36.
2. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83.
3. The Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progresion of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986.
4. Ravid M, Brosh D, Ravid-Safran D, Lezy Z, Rachmani R. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med. 1998; 158:998-1004.
5. UKPDS Group. Tight blood-pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ. 1998; 317:703-713.
6. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-1462.
7. Abbott K, Basta E, Bakris GL. Blood pressure control and nephroprotection in diabetes. J Clin Pharmacol. 2004; 44:431-438.
8. Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000; 57:601-606.
9. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
10. American Association of Clinical Endocrinologists and the American College of Endocrinology. Medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes self-management--2002 update. Endocr Pract. 2002; 8(suppl 1):40-82.
11. International Diabetes Federation. A desktop guide to type 2 diabetes mellitus. European Diabetes Policy Group 1999. Diabet Med. 1999; 16:716-730.
12. Chobanian AV, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA. 2003; 289:2560-2572.
13. Bakris GL, Weir MR. Achieving goal blood pressure in patients with type 2 diabetes: conventional versus fixed-dose combination approaches. J Clin Hypertens. 2003; 5:202-209.
14. Cushman WC, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). J Clin Hypertens. 2002; 4:393-404.
15. Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes. Diabetes Care. 2005;28:186-212.
16. National Kidney Foundation. Guideline 8: Pharmacological therapy: Diabetic kidney disease: K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Available at: http://www.kidney.org/professionals/kdoqi/guidelines%5Fbp/guide_8.htm. Accessed Januare 19, 2005.
17. Mulec H, Johnsen SA, Wiklund O, Bjorck S. Cholesterol: a renal risk factor in diabetic nephropathy? Am J Kidney Dis. 1993; 22:196-201.
18. Misra A, Kumar S, Kishore VN, Kumar A. The role of lipids in the development of diabetic microvascular complications: implications for therapy. Am J Cardiovasc Drugs. 2003; 3:325-338.
19. Athyros VG, et al. Statins and renal function in patients with diabetes mellitus. Curr Med Res Opin. 2003; 19:615-617.
20. Baghdasarian SB, Jneid H, Hoogwerf BJ. Association of dyslipidemia and effects of statins on nonmacrovascular diseases. Clin Ther. 2004; 26:337-351.
21. American Diabetes Association. All About Diabetes. Available at: http://www.diabetes.org/about-diabetes.jsp. Accessed June, 2006.