Diabetic Nephropathy:

Diabetic nephropathy, the leading cause of end-stage renal disease (ESRD) in the United States, affects 20% to 30% of patients with diabetes.¹ Early diagnosis and aggressive treatment may delay the progression of kidney disease.

Here we address questions that often arise in the management of diabetic kidney disease in the primary care setting, such as:

• What is the next step when an elevated albumin-creatinine ratio is detected?

• Which tests are recommended for monitoring the progression of diabetic nephropathy?

• When should patients be referred to a nephrologist?

We review screening and monitoring tests, discuss the workup of nondiabetic causes of albuminuria, and describe interventions that can slow or prevent the progression of renal disease. The Algorithm provides an overview of the management of diabetic nephropathy.

SCREENING

Annual screening for nephropathy is recommended in patients with diabetes who have no history of kidney disease.^1-3 Screening is initiated when type 2 diabetes is diagnosed because the onset of this disease often precedes the clinical diagnosis by 10 years; the onset of type 1 diabetes precedes the clinical diagnosis by 5 years.^1-3

Microalbuminuria, or incipient diabetic nephropathy, is the earliest sign of diabetic renal disease.³ Microalbuminuria is defined as an albumin-creatinine ratio between 30 and 300 µg/mg. Macroalbuminuria, or overt nephropathy, is defined as an albumin-creatinine ratio higher than 300 µg/mg. These values correlate with the amount of albumin excreted per day (300 µg/mg = 300 mg albumin/24 hours).

Albuminuria (albumin-creatinine ratio greater than 300 µg/mg) is an established risk factor for cardiovascular mortality^1,3 and a sign of progression to ESRD.^2,3 Eighty percent of patients with type 1 diabetes with microalbuminuria will progress to overt nephropathy in the absence of intervention.³ Overt nephropathy will develop in 50% of those patients in 10 years and in more than 75% by 20 years. Without treatment, 20% to 40% of patients with type 2 diabetes who have microalbuminuria progress to overt nephropathy and about 20% of those will progress to ESRD.³

Screening methods. The preferred method is measurement of the albumin-creatinine ratio in a random spot collection (normal values, less than 30 µg/mg). First morning voids or morning collections are most accurate, but voids at other times of the dayare acceptable.³

Another screening option is timed urine collection for albumin or total protein. However, because of frequent errors in collection, the difficulty of collection, and the accuracy and convenience of the albumin-creatinine ratio, this test is not often used.

The standard urine dipstick, which primarily detects albumin, is too insensitive for microalbuminuria screening because results become positive only after albumin levels exceed 300 mg/d.⁴ Semiquantitative urine albumin dipsticks may be used for screening for macroalbuminuria if urinary microalbumin measurement is not available.Note, however, that proteinuria in the absence of albuminuria is an important clue to the presence of paraproteinuria and warrants performance of urine and serum protein electrophoresis. Thus, both urine albumin and total protein should be assessed in select patients.

Increasing values in the normal range indicate progression to nephropathy.¹ If results are higher than 30 µg/mg, repeated testing is required before the diagnosis of diabetic nephropathy is made. False-positive results may be caused by exercise, urinary tract infection, congestive heart failure, and fever. Patients should not be screened after heavy exertion or during an acute illness. Two elevated results of 3 measurements over a 3- to 6-month period support the diagnosis of diabetic nephropathy.

Another useful parameter in screening for kidney disease and monitoring disease progression is measurement of serum creatinine to estimate the glomerular filtration rate (GFR). GFR can decline without accompanying albuminuria in a substantial number of patients.^1,5,6 Monitor GFR every 6 months in patients with kidney disease² and every 12 months in those with no disease.^1,2 There are convenient online calculators (eg, at www.nephron.com) that use the modification of diet in renal disease (MDRD) equation to estimate GFR.

Stages of renal disease. Five stages of kidney disease have been defined by the National Kidney Foundation's Kidney Disease Outcome Quality Initiative (Table).⁷ The grading system assists in patient education and communication with specialists.

FURTHER EVALUATION

In a patient with albuminuria, diabetic nephropathy is suggested by the following clinical picture²:

• Slow progression of albuminuria.

• Rising blood pressure (BP).

• Absence of hematuria.

• Presence of retinopathy.

• Elevated creatinine level and declining GFR.

If the nephropathy does not fit this pattern, further evaluation is warranted to identify a cause other than diabetes.

Diabetic nephropathy does not present with isolated microhematuria. Although microhematuria may accompany overt proteinuria in diabetic patients with nephropathy, the presence of red blood cells should prompt an investigation into nondiabetic causes of nephropathy, such as glomerulonephritis. More than 90% of patients with macroalbuminuria from diabetes also have at least mild retinopathy, including microaneurysms, flame hemorrhages, and hard or soft exudates. Patients with albuminuria and no retinopathy require further workup to evaluate for other causes of nephropathy.

Other causes of kidney disease. In a patient with moderate chronic kidney disease (GFR below 60 mL/min and/or albuminuria), further investigation may be warranted to confirm that diabetes is the cause.² Other causes of chronic renal insufficiency include prerenal disorders (dehydration, congestive heart failure); renal disorders (glomerulonephritis, hypertension, polycystic kidney disease, tubular necrosis, and interstitial nephritis); and postrenal disorders (obstruction).

Assessment of patients with moderate chronic kidney disease includes urinalysis with microscopic evaluation (to examine the sediment); serum electrolytes; and renal ultrasonography to assess renal size, echogenicity, and hydronephrosis. Ultrasonography can help rule out such conditions as obstructive uropathy, reflux nephropathy, and polycystic kidney disease. Consider a nephrology consultation (and possible biopsy) for further evaluation of intrarenal causes or referral to a urologist for patients with postrenal causes of kidney failure.^2,3

The workup for nondiabetic causes of albuminuria includes urinalysis with evaluation of sediment and plasma blood urea nitrogen and creatinine levels.⁴ The sediment can help distinguish various causes of intrinsic renal disease associated with proteinuria, such as acute tubular necrosis (tubular casts); acute glomerulonephritis (red blood cell casts); and acute interstitial nephritis (white blood cell casts). A nephrology consultation is warranted for possible biopsy if glomerular disease is suspected. In patients younger than 30 years with proteinuria of less than 2 g/d, an evaluation for orthostatic proteinuria may be performed with a split urine test.⁸ Patients with progressing proteinuria despite maximal therapy should also have a complete blood cell count, tests for serum albumin and total protein, and renal ultrasonography before referral to a nephrologist for possible biopsy.⁴ Massive proteinuria with nephrotic syndrome or rapid progression of renal failure should also prompt consideration of diagnoses other than diabetic nephropathy and lead to a nephrology referral.

The American Diabetes Association (ADA) recommends referral to a nephrologist for patients with stage 3 to 5 kidney disease regardless of the cause.⁷ These patients are at risk for secondary complications of kidney failure, including fluid overload; electrolyte disturbances (hyperkalemia and acidosis); anemia; refractory hypertension; and bone disease. A nephrologist may also be able to help prepare the patient for dialysis access, including development of forearm muscle mass and preservation of vascular access sites.

MANAGEMENT

Control of hypertension and hyperglycemia are essential to slow the progression of diabetic nephropathy.^1,9 Management of hyperlipidemiaand implementation of lifestyle modifications, such as weight loss, reduction of salt and alcohol intake, smoking cessation, and exercise, are essential in the management of cardiovascular risk in patients who have diabetes.¹⁰

The National Kidney Foundation and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Blood Pressure recommend a BP goal below 130/80 mm Hg for patients with diabetes and for those with chronic kidney disease.^7,11 The United Kingdom Prospective Diabetes Group trial found that small decreases in levels of hemoglobin A_1c led to significant decreases in microvascular complications.⁹ A lowering of hemoglobin A_1c from 7.9% to 7% resulted in a significant decrease in renal complications.

ACE inhibitors/ARBs. These agents retard the progression of renal disease and have antiproteinuric and renoprotective effects. Therapy should be initiated with either agentonce microalbuminuria has been confirmed, even in normotensive patients.^1-3 Their renoprotective benefits--including slowing the decline of GFR, the progression of albuminuria, and in some studies, the development of ESRD--appear to be independent of BP-lowering effects.^3,11-16 Management of hypertension and hyperglycemia along with the administration ofangiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may result in remission of albuminuria.^17-22 Measureserum potassium and creatinine levels at baseline and in 2 to 4 weeks after initiation or dosage increase of an ACE inhibitor or ARB.^2,3

Patients with advanced renal disease--even without renal artery stenosis--may experience a rapid decline in renal function while taking ACE inhibitors. It is not clear if this also occurs with ARBs. The rise in serum creatinine levels is reversible and does not reflect structural injury. Therapy need not be altered if the creatinine level increases by less than 30%.^17,20

If a patient cannot tolerate ACE inhibitors, an ARB may be used. ACE inhibitors and ARBs are equally effective, although ARBs have been more extensively studied in patients with type 2 diabetes. Two small trials have suggested that the renoprotective effects are similar.^23,24

There are no data on how often microalbuminuria should be monitored once therapy with an ACE inhibitor or ARB is begun. The Veterans Health Administration/Department of Defense guidelines recommend that the albumin-creatinine ratio be monitored every 3 to 6 months to determine the effects of treatment.² Without intervention, the ratio would be expected to increase 10% to 30% per year. Treatment is considered successful if the ratio remains stable or decreases.² If treatment is unsuccessful, the dose of the ACE inhibitor or ARB should be increased to the maximum recommended dose while BP and levels of hemoglobin A_1c and lipids are optimized.²

With regard to primary prevention of nephropathy, a systematic review of 16 small studies suggests that ACE inhibitors decrease the incidence of microalbuminuria but do not affect the doubling time of creatinine in normotensive diabetic patients.¹⁶ The results of these studies should be interpreted cautiously, because the definition of normotensive varied somewhat. (Some participants had systolic BP between 130 and 140 mm Hg.)

In a systematic review of 13 randomized controlled trials, ACE inhibitors prevented progression of established microalbuminuria in normotensive diabetic patients with microalbuminuria, but this effect was not clearly separate from the BP-lowering effects.²²

Several small, short-term trials that examined the combination of ACE inhibitors and ARBs in patients with types 1 and 2 diabetes suggest that the combination is more effective in reducing albuminuriathan maximum doses of ACE inhibitors alone in the setting of progressing microalbuminuria.^17,25,26 Another study that involved patients with diabetes found combination treatment to be well tolerated and more effective than either class alone in reducing BP but not in slowing the progression of microalbuminuria.²⁴ Given the limited evidence for decreased progression of microalbuminuria with combination therapy, the primary focus should be on BP control and early use of an ACE inhibitor or an ARB.^1-3

Other antihypertensives.

Agents from other classes may be used if goal BP is not achieved with ACE inhibitor or ARB monotherapy in hypertensive diabetic patients with nephropathy. Thiazide diuretics are a good second choice; they are cost- effective and reduce the risk of cardiovascular disease.

²⁷

Nondihydropyridine calcium channel blockers and b-blockers may be added if necessary. Note that there is limited evidence for decrease in progression of microalbuminuria or reduction in the rate of decrease of GFR with nondihydropyridine calcium channel blockers.

^1,17

Reassess BP every 4 to 6 weeks until control is achieved.

³

If microalbuminuria progresses after the addition of other antihypertensives, it may be reasonable to try a combination of an ACE inhibitor and an ARB.

^17,25,26

Antidiabetic agents. There is limited evidence that peroxisome proliferator-activated receptor-gamma agonists, including thiazolidinediones, reduce albuminuria. Larger studies of longer duration are required to confirm the renoprotective effects of these agents.¹⁷

Caution is advised when prescribing most sulfonylureas in patients with impaired renal function because of the risk of accumulation and prolonged hypoglycemia.²⁸ Metformin is contraindicated in patients with impaired renal function (creatinine level higher than 1.5 mg/dL in males and 1.4 mg/dL in females)because of the risk of lactic acidosis.

Protein restriction. The ADA recommends protein restriction (less than 0.8 g/kg/d) in patients with macroalbuminuria.^1-3 Further restriction to 0.6 g/kg/d may be useful for slowing the decline in GFR in certain patients. Most protein restriction studies have been small and have involved mainly patients with type 1 diabetes. Compliance with a low-protein diet is difficult for patients with diabetes who are already on a restricted diet to achieve glycemic, hypertensive, and lipid goals.

References:

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American Diabetes Association. Standards of medical care in diabetes.

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2006;29: S4-S42.

2.

Veterans Health Administration and Dept of Defense. Management of diabetes mellitus in primary care. Clinical practice guideline. 2003. Available at: www.oqp.med.va.gov/cpg/DM/DM3_cpg/content /introduction.htm. Accessed on April 20, 2006.

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Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes.

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4.

Rose BD, Fletcher SW. Proteinuria: the primary care approach

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Kramer HJ, Nguyen QD, Curhan G, Hsu C. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.

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Tsalamandris C, Allen TJ, Gilbert RE, et al. Progressive decline in renal function in diabetic patients with and without albuminuria.

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Kidney Disease Outcomes Quality Initiative (K/ DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.

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Carroll MF, Temte JL. Proteinuria in adults: a diagnostic approach.

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Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. NIH Publication 02-5215. September 2002.

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Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

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13.

Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

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14.

Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.

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Kasiske BL, Kalil RSN, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis.

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16.

Strippoli GF, Craig M, Craig JC. Antihypertensive agents for preventing diabetic kidney disease.

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17.

Rose BD, Bakris GL. Treatment and prevention of diabetic nephropathy. UpToDate. 2005.

18.

Perkins BA, Ficociello LH, Silva KH. Regres-sion of microalbuminuria in type 1 diabetes.

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19.

Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.

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20.

Thorp ML. Diabetic nephropathy: common questions.

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21.

Hovind P, Rossing P, Tarnow L, et al. Remission of nephrotic range albuminuria in type 1 diabetic patients.

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22.

Lovell HG. Angiotensin converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria.

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23.

Barnett AH, Bain SC, Bouter P, et al. Angio- tensin-receptor blockade versus converting- enzyme inhibition in type 2 diabetes and nephropathy (DETAIL).

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24.

Mogensen CE, Steen N, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study.

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25.

Rossing K, Jacobsen P, Pietraszek L, Hans-Henrik P. Renoprotective effects of adding angiotensin II receptor blockade to maximal recommended doses of ACE inhibitor in diabetic nephropathy.

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26.

Jacobsen P, Andersen S, Jensen BR, Parving HH. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.

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Furberg CD, Wright JT, Davis BR, et al. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting inhibitor or calcium channel blocker vs diuretic. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

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28.

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EVIDENCE-BASED MEDICINE:

• Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet. 2000;355:253-259.

• Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.

RELEVANT GUIDELINES:

• Veterans Health Administration and Dept of Defense. Management of diabetes mellitus in primary care. Clinical practice guideline. 2003. Available at: www.oqp.med.va.gov/cpg/DM/DM3_cpg/content/introduction.htm. Accessed on April 20, 2006.