What is the significance of an elevated urine albumin-to-creatinine ratio with normal urine creatinine and albumin levels?

From the Guidelines

An elevated urine albumin-to-creatinine ratio (ACR) with normal individual albumin and creatinine levels is a significant indicator of early kidney damage and increased risk of kidney disease progression, as supported by the most recent guidelines 1. This finding suggests that while the absolute values of albumin and creatinine fall within normal ranges, their ratio is disproportionate, reflecting subtle increases in albumin excretion that might not be detected when looking at albumin levels alone. The ACR is particularly valuable because it accounts for variations in urine concentration by indexing albumin to creatinine.

Key Points to Consider:

• Early detection of an elevated ACR is crucial as microalbuminuria often precedes overt proteinuria and significant kidney function decline, especially in conditions like diabetic nephropathy and hypertensive kidney disease.
• The ACR is a continuous measurement, and differences within the normal and abnormal ranges are associated with renal and cardiovascular outcomes 1.
• When an elevated ACR is detected, further evaluation is recommended, including confirmation with repeat testing, comprehensive kidney function assessment, and investigation of underlying causes such as diabetes, hypertension, or glomerular diseases.
• Early intervention with medications like ACE inhibitors or ARBs, along with tight control of blood pressure and blood glucose in diabetic patients, can significantly slow disease progression and protect kidney function 1.

Recommendations:

• Repeat testing to confirm the presence of an elevated ACR, as there can be variability in albumin excretion 1.
• Comprehensive kidney function assessment, including estimation of glomerular filtration rate (eGFR) and evaluation of underlying causes of kidney disease.
• Investigation of underlying causes, such as diabetes, hypertension, or glomerular diseases, to guide targeted interventions.
• Early intervention with medications like ACE inhibitors or ARBs, and tight control of blood pressure and blood glucose in diabetic patients, to slow disease progression and protect kidney function.

From the FDA Drug Label

The RENAAL study was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0 mg/dL in females or males ≤60 kg and 1.5 to 3. 0 mg/dL in males >60 kg and proteinuria [urinary albumin to creatinine ratio ≥300 mg/g])

The significance of an elevated urine albumin-to-creatinine ratio with normal urine creatinine and albumin levels is not directly addressed in the provided drug labels. However, it is mentioned that an elevated urinary albumin to creatinine ratio ≥300 mg/g is an indicator of nephropathy in type 2 diabetic patients 2.

• Key points:
  • Elevated urinary albumin to creatinine ratio is associated with nephropathy in type 2 diabetic patients.
  • Losartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease.
  • The provided drug labels do not directly address the significance of an elevated urine albumin-to-creatinine ratio with normal urine creatinine and albumin levels.

From the Research

Significance of Elevated Urine Albumin-to-Creatinine Ratio

• An elevated urine albumin-to-creatinine ratio (UACR) with normal urine creatinine and albumin levels is associated with increased risk of cardiovascular events and chronic kidney disease progression 3, 4, 5.
• Studies have shown that even high-normal albuminuria is reportedly associated with cardiovascular events and increased risk of initiating chronic kidney disease (CKD) 3, 4.
• A UACR cutoff point of >10 mg/g could significantly predict the cumulative incidence and progression of CKD in patients with type 2 diabetes mellitus 4.
• Higher UACR within normal range is associated with increased risk of all-cause mortality and cardiovascular mortality, with a larger association among women and younger participants 5.

Risk Factors and Associations

• Hypertension and age are independent risk factors that increase UACR 3.
• UACR is significantly correlated with systolic and diastolic blood pressures and pulse pressure 3.
• Elevated UACR within normal range is associated with higher all-cause and cardiovascular mortality risk across almost all subgroups, including participants without comorbidities 5.
• The Canadian Diabetes Association Clinical Practice Guidelines recommend a threshold for abnormal urine albumin-to-creatinine ratios of 2.0 mg/mmol for both men and women 6.

Diagnostic Performance

• The diagnostic performance of random urine samples using albumin concentration vs ratio of albumin to creatinine for microalbuminuria screening in patients with diabetes mellitus is comparable 7.
• The albumin concentration (UAC) and the ratio of albumin to creatinine (ACR) yield high sensitivity and specificity for the detection of microalbuminuria, with no differences in sensitivity, specificity, or diagnostic odds ratios between the two tests 7.