CLINICAL NOTE

Microalbuminuria in Clinical Practice

Trond Jenssen, MD, PhD, is a Specialist and Consultant in at Oslo University Hospital Rikshospitalet, and he also holds a position as Professor of Medicine at the University of Tromsø, Norway. He has served on several scientific and clinical advisory boards in internal medicine both nationally and internationally. His main focus in research has been on cardiovascular risk assessment, including , in the general population and in clinical subpopulations. A substantial number of his published papers have been on risk assessments in persons with renal disease and/or .

TROND JENSSEN, MD, PHD Professor of Medicine. Department of Nephrology, Oslo University Hospital Rikshospitalet, and Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø

THE HISTORY MECHANISMS

In the early 1980s it was reported that The filtrating capillaries (glomeruli) of the prevent large amounts of albumin excretion of small amounts of albumin leaking into the due to the size of the fenestraes, and the fact that the basement in the urine () membrane is negatively charged, as is the albumin molecule as a whole. When the of persons with diabetes predicted integrity of the basement membrane is disrupted, it becomes largely positively 5-10 years charged, and albumin leaks into the urinary space. This is what happens when later. 1,2 Microalbuminuria also turned significant albuminuria first occurs in patients with or diabetes. Later out to be associated with subsequent on, the size of the fenestraes may enlarge, and larger proteins appear in the urine. cardiovascular disease (CVD) in Thus, microalbuminuria has converted to a more unselected . persons with ,2 and in The sequence is as follows: 3 4 non-diabetic persons with or without Normoalbuminuria -> Microalbuminuria -> Proteinuria hypertension. It is not clear why leakage of albumin in the glomeruli should lead to cardiovascular Furthermore, in population based disease. It is currently speculated that microalbuminuria describes a basement cohorts microalbuminuria turns out to membrane distortion in the whole vascular tree. This, in turn, activates growth be a stronger determinant of CVD and factors and inflammatory processes in the vessel wall leading to atherosclerosis. stroke than the .5 It is recommended that urinary albumin excretion should be measured in MEASUREMENT OF MICROALBUMINURIA persons at future risk of CVD or renal disease, regardless of whether they have diabetes or not. The excretion of albumin in the urine may vary by +/- 25% on a daily basis, whereas the excretion of water may vary by more than 100% depending on the intake of fluids. The urinary concentration of albumin is more a measurement of water diuresis rather than a measurement of albumin excretion itself. The gold standard method has therefore been to measure 24-hr urinary excretion of albumin. MEASUREMENT OF MICROALBUMINURIA

However, this may also lead to erroneous estimates, since RECOMMENDATIONS correct sampling of urine over 24 hours may be difficult 1. Since the measurements of ACR may vary from one day to accomplish. The current guidelines recommend that to another, each patient should provide three samples the urinary albumin concentration (measured as mg/L) is from 3 separate days. At least two of these samples corrected by the urinary concentration (measured should be in the pathological range in order to diagnose as mmol/L or g/L) in morning urine. This gives the urinary microalbuminuria. albumin-creatinine ratio (ACR). The correction for urinary creatinine concentration is prudent, since creatinine is 2. Fever, protein-enriched meals or physical activity within excreted in the urine at a rather constant rate independently the previous 12 hrs may transiently induce increased ACR. of pathological processes in the basement membrane. This is normal. Morning urine measurements give somewhat lower and more 3. may produce spuriously high ACR. Bacteriuria reproducible measurements than measurements in random should be eliminated before final assesment of ACR. urine samples. Measurements in random samples can, however, 4. Patients with microalbuminuria or proteinuria should be be used for screening purposes. treated with an ACE inhibitor or an angiotensin receptor Women have a smaller muscle mass than men, and thus, they blocker, unless contraindications prohibit it. Dosage are excreting less creatinine in the urine. It has therefore been should be titrated so that the ACR is reduced. Most often recommended that women should have a higher reference this requires higher doses than those necessary to reduce range for ACR than men. In the daily clinic, however, it is the blood pressure itself. Consequently, not only blood sufficient to apply the so-called “rule of 3” regardless of gender,6 pressure, but also ACR should be monitored in that all thresholds are a product of 3: during treatment. 5. In patients without diabetes it is not documented that the SI UNITS: incidence of or cardiovascular disease is lowered by actively reducing ACR with pharmaceutical ALBUMIN-CREATININE RATIO 0-2.9 mg/mmol: NORMAL ALBUMIN EXCRETION agents. However, measurement of ACR should still be performed to assess the overall cardiovascular risk. ALBUMIN-CREATININE RATIO 3-30 mg/mmol: MICROALBUMINURIA 6. The definition of microalbuminuria (ACR 3-30 mg/mmol, ALBUMIN-CREATININE RATIO ≥ 31 mg/mmol: or 30-300 mg/g) was originally established according to PROTEINURIA the risk of developing proteinuria in patients with type 1 CONVENTIONAL UNITS: or type 2 diabetes.1,2 The risk of developing cardiovascular

ALBUMIN-CREATININE RATIO 0-29 mg/g: disease starts at much lower levels of ACR, and without NORMAL ALBUMIN EXCRETION any definite threshold. The risk in an individual patient

ALBUMIN-CREATININE RATIO 30-300 mg/g: is therefore best assessed over time with repeated MICROALBUMINURIA measurements, e.g., when ACR changes from

ALBUMIN-CREATININE RATIO ≥ 301 mg/g: low to high levels. PROTEINURIA 7. How often should ACR be measured?

The ACR also reflects an estimate of the 24-hr urinary PATIENTS WITH DIABETES WITHOUT ONCE A YEAR albumin excretion. If measured in SI units, the 24-hr albumin MICROALBUMINURIA OR PROTEINURIA: excretion (in mg) is estimated by multiplying the ratio by 10, e.g., ACR of 30 mg/mmol equals albumin excretion of 300 mg/ PATIENTS WITH DIABETES AND 2-4 TIMES/ YEAR 24 hours. If measured in conventional units, the 24-hr urinary INCREASED ACR: albumin excretion is estimated directly by the ratio itself. PATIENTS WITHOUT DIABETES, ONCE A YEAR The AfinionTM ACR test provides a simple, fast and reliable BUT WITH INCREASED CV RISK: point of care test for determination of albumin, creatinine and PATIENTS WITH NEITHER NO albumin/creatinine ratio (ACR) in human urin. DIABETES NOR CV RISK: RECOMMENDATIONS

FOR MORE INFORMATION ABOUT THIS TEST PLEASE VISIT ABBOTT.COM/POCT

1. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. NEJM 1984;311:89-93. 2. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. NEJM 1984;310:356-60. 3. Ljungman S, Wikstrand J, Hartford M et al. Urinary albumin excretion – a predictor of risk of cardiovascular disease. A prospective 10-year follow-up of middle- aged non-diabetic normal and hypertensive men. Am J Hypertens 1996;9:770-8. 4. Arnlov J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and non-diabetic individuals: The Framingham Heart Study. Circulation 2005;112:969-75. 5. Solbu MD, Kronborg J, Jenssen TG, Njølstad I, Løchen ML, Mathiesen EB, Wilsgaard T, Eriksen BO, Toft I. Albuminuria, metabolic syndrome and the risk of mortality and cardiovascular events. Atherosclerosis 2009;204:503-8. 6. Hartmann A, Jenssen T, Midtvedt K, et al. Protein/ creatinine concentration ratio: a simple method for proteinuria assessment in clinical practice. Tidsskr Nor Lægeforen 2002;122:2180-3. © 2019 Abbott. All Rights Reserved. ™ indicates a trademark of the Abbott group of companies. 10003885-2 01/19