Pathogenesis and treatment of microalbuminuria in patients with diabetes: the road ahead

Abstract

The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low-level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin-angiotensin-aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS-blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end-stage renal disease or death.

Figure 1

 Mean levels of inflammatory markers in patients with type 2 diabetes with normoalbuminuria (mean urinary albumin excretion [UAE] 15.8 mg/d), microalbuminuria (mean UAE 158 mg/d), and macroalbuminuria (UAE 859 mg/d). Patients with normoalbuminuria were not receiving treatment with renin‐angiotensin‐aldosterone system (RAAS) blockers, but all patients with microalbuminuria or macroalbuminuria had received blockers of the RAAS for more than 76 months. All patients had a glomerular filtration rate >60 mL/min. ^aP<.01 for microalbuminuria or macroalbuminuria vs normoalbuminuria; ^bP<.0001 for microalbuminuria or macroalbuminuria vs normoalbuminuria; ^cP<.0001 for macroalbuminuria vs normoalbuminuria; ^dP<.0001 for macroalbuminuria vs microalbuminuria; ^eP<.01 for macroalbuminuria vs microalbuminuria or normoalbuminuria. hsCRP indicates high‐sensitivity C‐reactive protein; IL‐6, interleukin 6; TNF‐α, tumor necrosis factor α.

Figure 2

 Incidence of the composite end point, cardiovascular (CV) and all‐cause mortality, stroke, and myocardial infarction (MI) in the subgroup of 1063 patients with diabetes, hypertension, and left ventricular hypertrophy in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Events are presented by quintiles of the urinary albumin:creatinine ratio at baseline.

Figure 3

 The spectrum of urinary albumin excretion and intervention studies with angiotensin receptor blockers. IDNT indicates Irbesartan in Diabetic Nephropathy Trial IRMA 2, Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria‐2 RENAAL, Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan ROADMAP, Randomised Olmesartan and Diabetes Microalbuminuria Prevention.