Diabetic Kidney Disease

300 mg per g (34 mg/mmol) is consistent with macroalbuminuria. An abnormal albumin:creatinine ratio in the microalbuminuric range should be confirmed with two additional first-void urine specimen over the next 3 to 6 months.

■ Diabetics with CKD may have elevated glomerular filtration rate (GFR) in the early stages; hence, GFR alone is not useful for screening purposes.

PREVENTION

■ Preventive measures include the use of an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in all diabetic patients with microalbuminuria or macroalbuminuria regardless of blood pressure (BP) (most such patients do have hypertension when 24-hour BP readings are obtained).

■ Diet, exercise, and weight loss are preventive of diabetes in all patient populations and are indicated for patients with DKD. Ophthalmologic evaluation, including a comprehensive dilated eye exam, should be performed yearly. Podiatric evaluation should be performed annually and the feet should be examined at each primary care visit.

DIFFERENTIAL DIAGNOSIS

CKD in diabetes could be caused by a number of disorders other than diabetes. Other considerations include the following:

■ Glomerulonephritis—The urinalysis in DKD typically shows proteinuria and a “bland sediment” (few cells and casts, no cellular casts). A more “active” sediment suggests glomerulonephritis.

■ Obstruction, infection, or stones should be ruled out with renal ultrasound, abdominal X-ray, or CT scan of the abdomen.

■ Multiple myeloma should be excluded by serum and urine protein electrophoresis and free light chain determinations if there is clinical suspicion (anemia or pancytopenia, hypercalcemia, lytic bone lesions, proteinuria with minimal albuminuria [see Chapter 3]).

■ Hepatitis should be ruled out in patients with IV drug abuse, transfusions, or risky sexual habits.

■ Patients with rash or arthritis should be tested for systemic lupus erythematosus or cryoglobulinemia (antinuclear antibodies, complements, cryoglobulins).

■ Renal artery stenosis should be considered in patients with refractory hypertension and vascular bruits, especially if there is acute renal failure associated with the initiation of a renin–angiotensin system (RAS) blocker.

■ Consider renal biopsy for an alternate diagnosis if the following are present:

■ Short duration of diabetes (especially in type 1)

■ Absence of retinopathy (in type 2)

■ Rapid decline in renal function

■ “Active” urine sediment

■ Evidence of another systemic disease

TREATMENT

■ Treatment of DKD should be comprehensive and should involve simultaneous evaluation and intervention at the level of hyperglycemia, hypertension, dyslipidemia, bone disease, anemia, nutrition, cardiovascular disease, physical fitness (exercise), and behavior (especially smoking) (Gaede et al., 1999).

■ Hyperglycemia: Intensive treatment of hyperglycemia can prevent DKD (development of microalbuminuria) as well as progression of microalbuminuria to macroalbuminuria (Reichard et al., 1993). It is controversial as to whether it can slow progression of CKD in established DKD (The DCCT Group, 1995; Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Research Group, 2003). Reversal of lesions of diabetic nephropathy after pancreas transplantation has been observed in type 1 diabetic patients (Fioretto et al., 1998). However, in the Veterans Affairs Diabetes Trial (VADT), intensive glycemic control had no significant overall effect on the progression of renal disease in type 2 diabetes, although it was associated with some protection against increasing albuminuria in patients with more advanced microvascular disease, lower baseline diastolic blood pressure, or higher baseline BMI and on worsening of GFR in patients with high baseline albuminuria (Agrawal et al., 2011). Recent results from the several clinical trials of intensive glucose control in type 2 diabetes, including Action in Diabetes and Vascular Disease (ADVANCE), Action to Control Cardiovascular Risk in Diabetes (ACCORD), and VADT have raised concern about the benefit versus risk of tight glycemic control in patients with advanced diabetic complications (Terry et al., 2012). Patients with CKD are at risk for hypoglycemia because of impaired clearance of medications such as insulin or sulfonylureas and because of impaired kidney gluconeogenesis. Metformin should not be used in patients with serum creatinine concentrations above 1.5 mg per dL (133 mcmol/L) because of a risk of lactic acidosis. Glyburide also should be avoided due to accumulation of active metabolites. Pioglitazone is not cleared by the kidney and will not cause hypoglycemia but may cause edema.

■ Hypertension: Treatment of hypertension reduces progression of DKD (Bakris et al., 2003; Lewis et al., 1999). BP should be maintained at 130/80 mm/Hg or below, as recommended by JNC 7 (Chobanian et al., 2003). First-line treatment should include ACE-inhibitors and ARBs, as they have been shown to be beneficial in preventing and slowing progression of DKD (Brenner et al., 2001; Barnett et al., 2004; Lewis et al., 1993, 2001). The beneficial effect of ACE-inhibitors and ARBs may be additive (Jacobsen et al., 2003); however, combined RAS blockade increases the risk of hyperkalemia (Pham et al., 2012). Addition of diuretics is usually necessary for BP control and helps to prevent hyperkalemia. Other useful agents are beta-blockers (carvedilol, more than metoprolol, has a beneficial effect on glycemic control as well as insulin resistance), nondihydropyridine calcium channel blockers (dihydropyridine calcium channel blockers such as amlodipine are not recommended as lone therapy because they worsen proteinuria and have not been shown to improve outcomes; however, they are acceptable if the patient is already on an ACE-I or an ARB).

■ Hyperlipidemia: Treatment of hyperlipidemia is essential, as studies have shown that the lower the low-density lipoprotein (LDL) is, the greater the cardiovascular benefit. The Study of Heart And Renal Protection (SHARP) trial has recently shown that patients with diabetes and CKD have a very high risk of cardiovascular events and derive substantial benefit from statins (although statins may not be helpful in patients with end-stage kidney disease) (Baigent et al., 2011). LDL should be maintained at least lower than 100 mg per dL and probably lower than 70 mg per dL (Grundy et al., 2004).

■ Other therapies: There are some data to support the claim that low-protein diets prevent decline in GFR and reduce progression of proteinuria (Hansen et al., 2002). Dietary protein restriction of 0.8 g per kg of ideal body weight is indicated for diabetics with kidney disease. High protein diets should be avoided. Cessation of smoking, low-dose aspirin, and limited intake of saturated fat, cholesterol, and sodium (2 to 3 g per day) are also recommended.

■ Prevention:

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