Diabetic Nephropathy: Early Clues, Effective Management

In the Western world, diabetic nephropathy is the leading cause of progression to end-stage renal disease (ESRD). Moreover, the incidence of diabetic nephropathy is increasing. Because both the risk of the serum creatinine level doubling and the risk of proteinuria developing increase with the duration of the disease, the longer lifespan of patients with diabetes is resulting in a growing incidence of diabetic nephropathy.¹ For example, in 2003 the United States Renal Data System (USRDS) listed diabetic nephropathy as the cause of ESRD in 43% of patients in whom dialysis was initiated.² This was a 238% increase over the percentage of patients who started dialysis in 1990 in whom diabetic nephropathy was the cause of ESRD. Part of this sizable increase may result from improved treatments for diabetes-associated coronary artery disease and the consequent greater survival of patients with that complication.

In this article, we discuss strategies for identifying patients at greatest risk for diabetic nephropathy, the most effective approaches to risk factor modification, and treatment of early-stage nephropathy. We also describe settings in which consultation with a nephrologist is warranted.

NATURAL HISTORY

Overt diabetic nephropathy is defined as the presence of diabetes and albuminuria of more than 300 mg/d (Table 1) on at least 2 occasions that are separated by 3 to 6 months.³

Mogensen and colleagues⁴ described the natural history of kidney involvement in type 1 diabetes by dividing the progression into 5 stages (Figure). Stage 1 is characterized by a paradoxically elevated glomerular filtration rate (GFR) (hyperfiltration) and hypertrophy of the kidney (increased microvascular blood flow is seen in many tissues in hyperglycemia). Stage 2 is clinically similar to stage 1, but morphological lesions are present in the kidney on biopsy. Patients can remain in stage 2 for the remainder of their lives. However, those in whom nephropathy is destined to progress further will at this stage exhibit a loss of the normal nocturnal reduction in blood pressure (called "dipping"); this heralds the development of microalbuminuria (increased protein excretion in the range of 30 to 300 mg/d).⁵

Stage 3 is the stage of incipient nephropathy, and clinical manifestations begin to be evident. The primary manifestation is microalbuminuria with continued hyperfiltration and an increased GFR. Blood pressure, while typically still within the normal range, begins to rise.

Stage 4 is characterized by the presence of overt nephropathy: proteinuria of greater than 300 mg/d, hypertension, and a progressive decline in GFR if hypertension and diabetes are poorly controlled. Stage 5 is marked by the need for renal replacement therapy-either dialysis or transplantation.

Studies have shown that the cumulative risk of progression to overt nephropathy and renal failure is significant in type 1 and type 2 diabetes.¹ However, the unremitting progression seen in patients with type 1 diabetes is not always seen in patients with type 2 disease. In the latter, overt proteinuria may spontaneously regress to microalbuminuria or microalbuminuria to no detectable proteinuria.

RISK FACTORS

Risk factors for diabetic nephropathy are listed in Table 2.^6,7 The most critical of these are:

• Poor glycemic control.
• Hypertension.⁸

A family history of diabetic nephropathy or a first-degree relative with hypertension confers an increased risk as well.⁹ Intrauterine diabetes exposure has also been shown to portend an increased risk of diabetic nephropathy.¹⁰ Smoking is a predictor of the development of microalbuminuria and of progressive loss of renal function.¹¹ Fortunately, smoking cessation has a beneficial effect on the kidneys.¹² Genetic factors are involved in the development of nephropathy in both type 1 and type 2 diabetes; for example, there is a high incidence of diabetic nephropathy in Pima Indians. However, the specific genes responsible remain unknown.^13,14

SCREENING STRATEGIES

Because the excretion of small amounts of albumin characterizes the very earliest stages of diabetic nephropathy, screening for albuminuria is the centerpiece of most screening strategies (Algorithm). Begin screening patients with type 1 diabetes 5 years after diagnosis. In patients with type 2 diabetes, begin screening at the time of diagnosis of hyperglycemia, since the duration of disease is difficult to determine in these patients.^15,16

Initially, screen using a standard urine dipstick. Dipsticks provide quite specific but insensitive measures of albuminuria: they do not produce a positive result unless total protein excretion exceeds about 300 mg/d. A negative reading on a urine dipstick should be followed up by a more sensitive measurement of urinary albumin-usually an enzymatic study or radioimmunoassay at a full-service laboratory.

Follow up a positive urine dipstick result by quantification with a spot albumin:creatinine ratio.¹⁷ The ratio negates the effect of urine volume (and thus of dilution) on a random, untimed collection. The ratio is based on the presumption that the average person excretes about 1 g of creatinine per day and less than 30 mg of albumin per day, resulting in a normal ratio of less than 0.03. The ratio will be lower in muscular persons whose daily excretion of creatinine is higher, and it will be higher in cachectic persons with low muscle mass.¹⁸

Transient proteinuria, which would result in false-positive values on either a dipstick or albumin:creatinine ratio test, can be found in the settings of fever, intense exercise, extremely poor glycemic control, urinary tract infection, and heart failure.^19-23 Thus, 2 positive values on a dipstick or albumin:creatinine test 3 months apart are required to make the diagnosis of either microalbuminuria or proteinuria.

PREVENTION AND TREATMENT

Various approaches have been used to modify the long-term course of nephropathy (Table 3).

Glycemic control. Attempts to prevent incipient diabetic nephropathy have generally relied on intense insulin therapy. The Diabetes Control and Complications Trial (DCCT) compared the effects of intense and conservative glycemic control in patients with newly diagnosed type 1 diabetes.²⁴ Over a 9-year period, patients in the intensive treatment arm who had mean glycosylated hemoglobin (HbA_1c) levels of 7% had a 35% to 45% lower risk of microalbuminuria than did patients in the conservative arm, in whom the mean HbA_1c level was 9%.²⁴

The United Kingdom Prevention of Diabetes Study (UKPDS) evaluated the effect of intensified insulin therapy in type 2 diabetes.²⁵ Although the difference between the mean HbA_1c in the conservative and intense treatment arms of this study was only 0.9% (7% vs 7.9%), progression to microalbuminuria and proteinuria occurred 25% less frequently in the patients who received intensified insulin therapy, and the doubling of creatinine levels was reduced by 50% with intensive therapy.²⁵ A 6-year study of nonobese patients with newly diagnosed type 2 diabetes found that in those who received intensive insulin therapy designed to achieve a HbA_1c level of 6.5%, the risk of microalbuminuria was 62% lower than in controls.²⁶ Studies evaluating the effect of glycemic control on the progression of diabetic nephropathy in patients who already have microalbuminuria have not yielded clear-cut results.²⁷

Control of hyperglycemia plays an important role in the treatment of diabetic nephropathy as well as in its prevention. Studies of patients with type 1 diabetes treated by pancreatic transplantation have yielded impressive and encouraging results regarding the effectiveness of good glycemic control. Currently, pancreas transplantation is indicated for patients with brittle type 1 diabetes who have frequent episodes of hypoglycemia and hypoglycemic unawareness. A welcome consequence of pancreatic transplantation has been a beneficial effect on the kidneys. One observational study showed that histological changes, such as glomerular and tubular expansion and even fibrosis, resolve over time.²⁸ Although it took about 10 years after transplantation to see some of these effects, the apparent improvement of what was thought to be irreversible end-stage glomerular sclerosis demonstrates the value of tight glycemic control, regardless of the degree of nephropathy.^28-31

Blood pressure lowering. Management of hypertension, along with glycemic control, is essential to both prevention and treatment of diabetic nephropathy; it also aids in the reduction of cardiovascular morbidity and mortality. In fact, control of hypertension is probably the single most important aspect of the treatment of diabetic nephropathy. Before angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) became available, a small study of intensive treatment of hypertension in patients with nephropathy showed an immediate drop in GFR, and over the subsequent 2 years, the rate of decline in renal function was significantly lower than it was in controls (0.39 mL/ min/mo vs 0.91 mL/min/mo).³² Since then, this benefit has been demonstrated in many other studies.

ACE inhibitors and ARBs are first-line therapy for hypertension in patients with diabetes, based on several trials; however, diuretics still play a prominent role as second agents.³³ A thiazide diuretic, such as hydrochlorothiazide at a dosage of 12.5 to 25 mg/d, is optimal for patients with an estimated GFR of greater than 60 mL/min. In patients with more advanced diabetic nephropathy, loop diuretics are more effective.

Angiotensin blockade. There has been much debate about whether drugs that target the renin-angiotensin-aldosterone system (RAAS) have an additional renoprotective effect beyond lowering systemic blood pressure-perhaps related to their ability to specifically reduce hydrostatic pressure in the glomerulus or to their blocking of fibrosis-stimulating pathways in the kidney.^34-37 A few randomized, controlled trials have shown that these agents have a small but significant benefit in patients with early diabetes who are still normotensive and have normal albumin excretion rates.^38,39 Whether this will translate into long-term renoprotection is still under active investigation.

In patients who have microalbuminuria and/or hypertension, abundant data show that ACE inhibitors and ARBs retard the progression or induce the regression of proteinuria in both type 1 and type 2 diabetes.^35-37

The Appropriate Blood Pressure Control in Diabetes (ABCD) study was a prospective, randomized, interventional trial of the effects over a 5-year period of intensive and moderate blood pressure control on the incidence and progression of nephropathy, retinopathy, cardiovascular disease, and neuropathy in normotensive and hypertensive patients with diabetes.⁴⁰ The mean blood pressure achieved in the hypertensive patients was 132/78 mm Hg in those who received intensive control and 138/86 mm Hg in those who received moderate control. The mean blood pressure achieved in the normotensive patients was 128/75 mm Hg with intensive control and 138/81 mm Hg with moderate control. Intensive control in hypertensive patients with diabetes was associated with a significant decrease in mortality compared with moderate control (5.5% vs 10.7%; P = .037). In normotensive patients who had diabetes, intensive control slowed the progression to overt nephropathy, retarded the progression of retinopathy, and reduced the incidence of stroke.

The ABCD study was also designed to compare the benefits of treatment with an ACE inhibitor (enalapril) and treatment with a calcium channel blocker (nisoldipine). This portion of the study was terminated prematurely because a significant increase in cardiovascular events was seen in the nisoldipine treatment group; these results suggested a potential cardiovascular benefit in patients with diabetes from treatment with an ACE inhibitor.

The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients (IRMA II) trial included 590 patients with hypertension, type 2 diabetes, persistent microalbuminuria, and an elevated serum creatinine level.⁴¹ Participants were randomly assigned to receive irbesartan (150 or 300 mg/d) or placebo; they were followed up for 2 years. All treatment arms had the same target blood pressure (less than 135/85 mm Hg), and the same classes of antihypertensive agents were allowed as additive therapy in all groups. The primary end point was progression to overt nephropathy, which was defined as persistent proteinuria (more than 200 µg/min-or an increase of more than 30% from baseline-over 2 consecutive measurements). Secondary end points included a change in albuminuria, a change in creatinine clearance, and regression to normoalbuminuria.

The mean blood pressures achieved were 144/83 mm Hg in the placebo group, 143/83 in the group that received 150 mg/d of irbesartan, and 141/83 mm Hg in the group that received 300 mg/d of irbesartan; all these values were above the intended target. Nonetheless, a significant decrease in systolic blood pressure was found in patients who received either dosage of irbesartan, compared with patients who received placebo (P = .0004).

Following adjustment for differences in blood pressure, a Cox proportional-hazards regression model demonstrated that the hazard ratio for development of overt nephropathy was 0.56 in the 150-mg group (P = .05) and 0.32 in the 300-mg group (P < .001) compared with placebo. Moreover, this difference was apparent after only 3 months of therapy. Albuminuria was reduced by 24% in the 150-mg group and by 37% in the 300-mg group, compared with a scant 2% in the placebo group. These results show that irbesartan has a dose-dependent effect on proteinuria (P < .001).

Many clinical trials have shown that ACE inhibitors and ARBs also slow the rate of decline of the GFR in stages 3 to 5 nephropathy in both type 1 and type 2 diabetes.^35,42,43 In fact, even in patients with very advanced chronic kidney disease, an ARB or an ACE inhibitor can delay progression to the need for renal replacement therapy, thus supporting continued use of these agents through even the advanced stages of kidney disease.⁴⁴

ACE inhibitors versus ARBs. Most studies of ACE inhibitors have been conducted in patients with type 1 diabetes, whereas most studies of ARBs have been conducted in those with type 2 diabetes. This has created debate and uncertainty regarding any class effect. A novel aspect of the Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study is that it demonstrated the "noninferiority" of the renoprotective effect of both telmisartan and enalapril, which suggests that either agent is effective.⁴⁵ In a recent meta-analysis, Kunz and colleagues⁴⁶ found a consistent 35% reduction in proteinuria with ARB therapy across varying degrees of proteinuria and with varying causes of proteinuric kidney disease. This effect was equivalent to that achieved with ACE inhibitors.

In light of these confirmatory data, clinicians may confidently decide to initiate therapy with an ACE inhibitor or an ARB based on the patient's insurance formulary. Up-titrate the dose and monitor the patient's serum creatinine and potassium levels on an interim basis. The antiproteinuric effect of therapy can be assessed as early as 6 to 8 weeks; at that point, titrate the dosage to keep proteinuria under 500 mg/d.

Combination therapy. Several studies have examined the effect of combinations of ACE inhibitors and ARBs on both proteinuria and blood pressure in patients with diabetic nephropathy. In the Candesartan and Lisinopril Microalbuminuria (CALM) study, combination treatment with candesartan (an ARB) and lisinopril (an ACE inhibitor) resulted in a greater reduction in urinary albumin excretion and lower blood pressure in patients with hypertension and type 2 diabetes than did either agent alone.⁴⁷ Other studies have shown similar benefits of combination therapy regarding urinary albumin excretion but no difference in blood pressure between combination therapy and monotherapy groups.⁴⁸

A recent meta-analysis confirmed the beneficial effect of dual RAAS blockade (an ACE inhibitor and an ARB) on proteinuria.⁴⁶ Thus, we recommend that you begin with monotherapy and titrate to the maximum dosage of the agent. If proteinuria remains greater than 500 mg/d, add a drug from the other class. The addition of a second RAAS-blocking agent mandates close monitoring of serum creatinine and potassium levels.

Direct blockade of aldosterone is another therapeutic approach that targets the RAAS. Studies have shown that progressive deterioration of renal function correlates with increased serum and urine aldosterone concentrations.⁴⁹ Moreover, molecular studies have shown that aldosterone exacerbates histological correlates of disease progression, such as fibrosis.⁵⁰ Still, although a few small trials have suggested a benefit from add-on therapy with such aldosterone antagonists as spironolactone, a significant clinical concern is that complete blockade of the RAAS in a patient with advanced nephropathy may result in severe hyperkalemia.⁵¹

Monitoring therapy. One of the proposed mechanisms of the renoprotective effect of ACE inhibitors and ARBs is the reduction of glomerular hyperfiltration and hypertension. Such a mechanism may explain why a 10% to 20% increase in serum creatinine level is frequently observed following the addition of one of these agents or an increase in the dosage. However, an increase in the creatinine level of more than 30% is worrisome; it may indicate the presence of other renal pathology, such as renal artery stenosis, and should be evaluated accordingly.

In addition to the creatinine level, serum potassium must be monitored closely as well, because ACE inhibitors and ARBs have a hyperkalemic effect. Educate patients with advanced kidney disease about the need to avoid potassium-rich foods and salt substitutes. All nephrologists endorse dietary potassium restriction in such patients, and some even prescribe daily enteral cationic exchange resins (ie, sodium polystyrene) to allow for the continued administration of an ACE inhibitor or ARB.

WHEN TO REFER

Referral to a nephrologist is indicated when the patient reaches chronic kidney disease stage 3, which is defined by the presence of one or more of the following:

• An estimated GFR of less than 60 mL/min.
• Difficulty lowering either blood pressure or proteinuria below the target threshold.
• An acute, rapid rise in creatinine (a rise of more than 20% in less than 6 months).

An abundance of evidence shows that the rate of decline in renal function slows in patients who are referred to nephrologists early. Early referral also provides monitoring and management of secondary complications of advanced chronic kidney disease, such as anemia and renal osteodystrophy, which begin to manifest at this stage.

If it becomes evident that a patient will eventually need renal replacement therapy, the guidance of a nephrologist can help ensure that such therapy will have the best possible outcome. Preemptive (before dialysis) transplantation is associated with the best graft survival; thus, it is imperative that a patient who will receive a renal transplant from a living relative avoid any dialysis treatments.⁴⁴ If a patient is to enter a long-term dialysis program, his or her survival is enhanced by having a functioning arteriovenous fistula at the time of the first dialysis treatment.⁵² Thus, early referral to a nephrologist for early fistula creation or preparation for a preemptive transplant is a crucial component of care.

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