Version May 2024
INTRODUCTION, TERMINOLOGY, AND DEFINITIONS — The urine dipstick is a relatively insensitive marker for albuminuria, not becoming positive until albumin excretion exceeds 300 to 500 mg/day. Using a specific assay for albumin is a more sensitive technique. The normal rate of albumin excretion is less than 30 mg/day (20 mcg/min); persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min) is called moderately increased albuminuria (formerly called "microalbuminuria") [1,2]. Albumin excretion above 300 mg/day (200 mcg/min) is considered to represent overt or dipstick positive proteinuria (also called severely increased albuminuria [formerly called "macroalbuminuria"]). (See "Definition and staging of chronic kidney disease in adults".)
The distinction between the terms "albuminuria" and "proteinuria" is discussed elsewhere in detail. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Definitions'.)
Initial studies demonstrated that moderately increased albuminuria may be the earliest clinical manifestation of diabetic nephropathy in patients with type 1 diabetes, and first begins to appear five years after diagnosis. This is no longer thought to be the case, as albuminuria levels are quite variable early in the course of disease [3-5]. In addition, many individuals with diabetes progress to end-stage kidney disease without ever having significantly elevated albuminuria [6,7]. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Natural history'.)
Moderately increased albuminuria is often present at diagnosis in patients with type 2 diabetes and may reflect underlying cardiovascular disease rather than diabetic kidney disease.
Yearly testing for albuminuria is recommended in patients with both type 1 diabetes (starting five years after disease onset) and type 2 diabetes (starting at disease onset). Assessment of albuminuria and estimated glomerular filtration rate are needed for kidney disease staging [8]. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus".)
In addition to being associated with diabetic nephropathy, moderately increased albuminuria is associated with cardiovascular disease in both patients with and without diabetes. These studies will be reviewed here.
DETECTION — Establishing the diagnosis of moderately increased albuminuria (formerly called "microalbuminuria") requires the demonstration of a persistent elevation in albumin excretion above 30 mg/day. Transient elevations in the excretion of albumin can be seen in the following settings [9] (see "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults"):
●Fever
●Infection
●Exercise
●Heart failure
●Nonspecific joint inflammation
●Poor glycemic control (hemoglobin A1c greater than 8 percent)
●Elevation in blood pressure (greater than 160/100 mmHg)
●Hyperlipidemia (LDL cholesterol greater than 120 mg/dL)
Urine albumin concentration — Although 24-hour urine collection is the gold standard for the detection of moderately increased albuminuria [9,10], it has been suggested that screening can be more simply achieved by a timed urine collection or an early morning specimen to minimize changes in urine volume that occur during the day [9]. moderately increased albuminuria is unlikely if the albumin excretion rate is below 20 mcg/min in a timed collection or the urine albumin concentration is less than 20 to 30 mg/L in a random specimen. Higher values (particularly those just above this range) may represent false positive results and should be confirmed by repeated measurements [9].
There are also a variety of semiquantitative dipsticks, such as Clinitek Microalbumin Dipsticks and Micral-Test II test strips, which can be used to test for moderately increased albuminuria if urine albumin excretion cannot be directly measured. The reported sensitivity and specificity of these tests range from 80 to 97 percent and 33 to 80 percent, respectively [11]. However, none of these approaches are recommended over formal quantitation [12].
The dipstick assessment, however, is the least sensitive and specific for determination of albuminuria [12]. One problem with measuring the urine albumin concentration or estimating it with a sensitive dipstick is that false negative and false positive results can occur since the urine albumin concentration is determined by the urine volume as well as the amount of albuminuria [13]. Thus, at a particular rate of albumin excretion, a substantial increase or decrease in urine volume will respectively lower and raise the urine albumin concentration. The confounding effect of the urine volume can be minimized by repeated measurements on early morning specimens [9].
Albumin-to-creatinine ratio — The confounding effect of variations in urine volume on the urine albumin concentration can be avoided by calculation of the urine albumin-to-creatinine ratio in an untimed urine specimen. A value 30 to 300 mg/g of creatinine (or, using standard [SI] units, 3.4 to 34 mg/mmol of creatinine) suggests that albumin excretion is between 30 and 300 mg/day and therefore that moderately increased albuminuria is probably present [14]. Values above 300 mg/g (or 34 mg/mmol) are indicative of severely increased albuminuria (formerly called "macroalbuminuria"). This classification system requires that at least two of three specimens fall within the high or very high albuminuric range [14].
In one report, 24-hour urine collections and random, single-void urine specimens for albumin and creatinine were obtained in 14 normal subjects, 13 with type 1 diabetes, and 12 with type 2 diabetes [15]. A close correlation was noted between the two measurements and the within-patient variability was small. A random albumin-to-creatinine ratio above 30 mg/g had a sensitivity of 100 percent for the detection of moderately increased albuminuria. Similar findings have been noted by others [16].
Limitations — There are three important caveats that must be considered to maximize the reliability of the urine albumin-to-creatinine ratio:
●Vigorous exercise can cause a transient increase in albumin excretion [17]. As a result, patients should refrain from vigorous exercise in the 24 hours prior to the test.
●The optimal time to measure the urine albumin-to-creatinine ratio is uncertain. The best data come from reports that primarily evaluated patients without diabetes. In an initial study, the best correlation with a 24 hour urine collection occurred with samples obtained after the first morning void and before bedtime [18]. By contrast, a later and larger study found the best correlation with the first morning void although the difference with collections at other times was not significant [19]. Given the uncertainty, we suggest that first morning void specimens are preferred and, if this cannot be done, serial specimens should always be obtained at the same time of day.
●The accuracy of the urine albumin-to-creatinine ratio will be diminished if creatinine excretion is substantially different from the expected value; this is particularly important in patients with borderline values. Albumin excretion will be underestimated in a muscular man with a high rate of creatinine excretion and overestimated in a cachectic patient in whom muscle mass and creatinine excretion are markedly reduced. The ratio also varies with race/ethnicity in the United States, as creatinine excretion is significantly higher among non-Hispanic Black Americans and Hispanic Americans than among non-Hispanic White Americans [20].
Recommendations — Measurement of the urine albumin-to-creatinine ratio in an untimed urinary sample is the preferred screening strategy for moderately increased albuminuria [9,14,21]. This test has the following advantages: it does not require early morning or timed collections, it gives a quantitative result that correlates with the 24-hour urine values over a wide range of protein excretion, it is simple to perform and inexpensive, and repeat values can be easily obtained to ascertain that moderately increased albuminuria, if present, is persistent.
CORRELATION OF MODERATELY INCREASED ALBUMINURIA (MICROALBUMINURIA) WITH CARDIOVASCULAR DISEASE — Post hoc analyses in different patient populations have suggested that, in addition to its relation to kidney disease, moderate increases in albuminuria (formerly called "microalbuminuria") over time are an important risk factor for cardiovascular disease and early cardiovascular mortality in patients with and without diabetes and/or hypertension [22-43]. Among patients with chronic kidney disease, observational studies have suggested a graded increase in coronary risk with the presence of overt proteinuria as measured with a urinary dipstick. (See "Chronic kidney disease and coronary heart disease".)
The following observations represent data from different groups of patients, ranging from those with cardiovascular disease to population-based cohorts.
Clinical trials — Among over 9000 participants at high risk for a cardiovascular event in the HOPE (Heart Outcomes Prevention Evaluation) trial, the presence of moderately increased albuminuria was associated with an increased relative risk of the primary aggregate end point (myocardial infarction [MI], stroke, or cardiovascular death) in those with and without diabetes (1.97 and 1.61, respectively) [24]. The risk of an adverse cardiovascular event increased progressively with increasing absolute levels of moderately increased albuminuria. (See "Goal blood pressure in adults with hypertension".)
An increase in risk was also noted a post hoc analysis from the LIFE trial of patients with hypertension and electrocardiographic evidence of left ventricular hypertrophy, the urine albumin-to-creatinine ratio was measured in 7143 nondiabetic subjects (median value 10.2 mg/g creatinine [1.16 mg/mmol]) and 1063 subjects with diabetes (median value 26.9 mg/g creatinine [3.05 mg/mmol]) [25]. For every 10-fold increase in the albumin-to-creatinine ratio, the risk of the composite end point of cardiovascular death, MI, or stroke increased by 57 percent and the risk of cardiovascular death by 98 percent among nondiabetics. The respective increases in risk for diabetics were 39 and 47 percent. A subsequent analysis of this trial showed that the risk of the composite end point of cardiovascular death, MI, or stroke was reduced among participants who had a substantial reduction in moderately increased albuminuria at the one-year follow-up [44].
Population-based studies — A number of population-based studies have identified moderately increased albuminuria as a significant predictor of cardiovascular risk [22,23,26,27,45]. In an analysis from the Prevention of Renal and Vascular End Stage Disease (PREVEND) study, urinary albumin excretion was measured in a general population sample of 40,548 participants who were followed for a median of 2.6 years [26]. There were 518 deaths (1.3 percent) of which 178 were cardiovascular deaths (0.4 percent). When adjusted for age and sex, there was a graded increase in the relative risk of cardiovascular mortality of 1.35 for each doubling of urinary albumin excretion. A potential limitation of this study is that the urine albumin concentration, rather than the albumin-to-creatinine ratio was used.
The mortality risk in postmenopausal females was evaluated in a population-based cohort study of 12,239 postmenopausal females [27]. Cardiovascular mortality was increased in those in the highest quintile of urinary albumin excretion (>21 mg/g creatinine [>2.41 mg/mmol]) compared with females without detectable albuminuria (13.2 versus 2.6 per 1000 years, age-adjusted rate ratio 4.4) [27]. This relationship was independent of diabetes and hypertension.
High-normal albuminuria — Higher levels of albumin excretion within the normal range, well under the above definitions for moderately increased albuminuria (≥30 mg/day [20 mcg/min] or urine albumin-to-creatinine ratio ≥30 mg/g), are associated with an increase in cardiovascular risk that is additive to conventional risk factors [28,29,46-49]. The following observations illustrated the range of findings:
●In the Third Copenhagen Heart Study, 2726 patients underwent a urine collection for measurement of albumin and were followed for the development of coronary heart disease or death [28]. Patients in the top quartile of urinary albumin excretion (>4.8 mcg/min [6.9 mg/day]) had an adjusted relative risk of death of 1.9 and of coronary heart disease of 2.0. Among the hypertensive participants, the cumulative incidence of heart disease (11 versus 5 percent) and mortality (28 versus 13 percent) were significantly increased with urinary albumin excretion ≥5 mcg/min (>7.2 mg/day) compared with values below 5 mcg/min. The adjusted relative risk for coronary heart disease and mortality were 2.0 and 1.9, after adjustment for other risk factors.
●Similar findings with very low levels of albuminuria were noted in a review from the Framingham Heart Study of 1568 nonhypertensive, nondiabetic individuals (mean age 55) [46]. At a median follow-up of six years, 54 participants developed a first cardiovascular event and 49 died. Participants with a urine albumin-to-creatinine ratio above the median (≥3.9 and ≥7.5 mg/g in males and females, respectively) had a significant increase in the risk of a first cardiovascular event (5.1 versus 1.8 percent, adjusted hazard ratio [HR] 2.92, 95% CI 1.57-5.44) and an almost significant increase in mortality (4.2 versus 2.0 percent, adjusted HR 1.75, 95% CI 0.95-3.22). The increase in risk remained significant in participants with a low or intermediate pretest probability of cardiovascular disease.
●Another report from the Framingham Heart Study demonstrated the association of high-normal albumin excretion with the risks of hypertension and blood pressure progression in 1499 nonhypertensive, nondiabetic individuals [29]. At a mean follow-up of 2.9 years, 15 percent developed hypertension and 33 percent progressed to a higher blood pressure category. The odds ratio in the highest quartile of urine albumin-to-creatinine ratio (>6.7 and 15.2 mg/g in males and females, respectively) compared with the lowest quartile was 1.93 and 1.45 for developing hypertension and progressive hypertension, respectively.
In a multivariable analysis adjusting for known risk factors, the adjusted odds ratio for developing hypertension was 1.20 for every 1 standard deviation in urine albumin-to-creatinine ratio. Compared with those in the lowest urine albumin-to-creatinine ratio quartile, individuals in the highest quartile (males 6.6 mg/g, females 15.4 mg/g) had an adjusted odds ratio of 1.93 for developing hypertension and 1.45 for blood pressure progression.
ST and T wave changes — The presence of moderately increased albuminuria also enhances the predictive value of ST and T wave changes for cardiovascular disease. This was illustrated in another analysis from the population-based PREVEND study [30]. Among 7330 subjects, 1244 had ST-T changes; 885 had moderately increased albuminuria (mean albumin excretion 53 mg/day); and 223 had both. At a median follow-up of six years, the patients with both ST-T changes and moderately increased albuminuria compared with those with ST-T changes alone had marked increases in the incidence of all-cause mortality (7.2 versus 1.1 percent) and cardiovascular mortality (2.7 versus 0.5 percent). Moderately increased albuminuria had a greater impact on the risk of all-cause mortality than hypertension, hypercholesterolemia, cigarette smoking, obesity, or diabetes mellitus.
Possible mechanisms — How moderately increased albuminuria is associated with cardiovascular disease is not well understood. Moderately increased albuminuria in patients without diabetes appears to be a signal from the kidney that the vasculature, particularly the endothelium, is not functioning normally. As examples:
●Vasodilation in response to certain stimuli is relatively reduced in older "normal individuals" with moderately increased albuminuria compared with those with lower levels of albumin excretion [50].
●Among patients without diabetes with primary hypertension (formerly called "essential" hypertension), those with moderately increased albuminuria had higher plasma levels of von Willebrand factor (vWf) antigen than patients with normal albumin excretion [51]; furthermore, individual vWf and albumin excretion values were significantly correlated. vWf has been associated with occlusive thrombosis; thus, the increased plasma vWf levels might directly contribute to the enhanced cardiovascular risk.
Endothelial dysfunction is also present in patients with diabetes [32], and the degree of coronary endothelial dysfunction appears to be greater in patients with moderately increased albuminuria [52]. One important factor may be hyperglycemia-induced alterations in extracellular matrix, such as decreased density of heparan sulfate proteoglycans. This abnormality can lead to increased microvascular permeability, resulting in moderately increased albuminuria at the glomerulus and perhaps increased lipoprotein deposition in peripheral vessels.
The apparent association between moderately increased albuminuria and cardiovascular disease is in part related to an adverse risk factor profile in patients with and without diabetes [36,53-56]:
●In the Cardiovascular Health Study of almost 1100 older adults who did not have diabetes mellitus or hypertension, moderately increased albuminuria was associated with increasing age, increasing systolic blood pressure, and inflammatory markers (such as C-reactive protein levels) [53]. The importance of blood pressure was also noted in report of almost 8800 individuals without diabetes mellitus or hypertension in the Third National Health and Nutrition Examination Survey (NHANES) [54]. Compared with optimal blood pressure (<120/<80 mmHg), high-normal blood pressure (130 to 139/85 to 89 mmHg) was associated with a significant increase in the risk of moderately increased albuminuria (odds ratio 1.3 per 10 mmHg increase in systolic or diastolic pressure). (See "C-reactive protein in cardiovascular disease".)
●In a cross-sectional analysis of 1160 patients with type 1 diabetes in the Diabetes Control and Complications Trial, as progressive increases in albuminuria were associated with elevations in proatherogenic intermediate-density lipoprotein and small dense LDL particles [55].
●In a cross-sectional study of patients with type 2 diabetes with preserved kidney function (median GFR 87 mL/min per 1.73 m2), the urine albumin-to-creatinine ratio (ACR) was positively correlated with coronary and carotid artery calcification as defined by scores derived from computed tomography [56].
CORRELATION OF CARDIOVASCULAR DISEASE WITH MODERATELY INCREASED ALBUMINURIA (MICROALBUMINURIA) — The association between moderately increased albuminuria (formerly called "microalbuminuria") and cardiovascular disease also extends to the development of moderately increased albuminuria and/or progression to severely increased albuminuria among patients at high cardiovascular risk. This was shown in a retrospective analysis of the HOPE trial, in which 1859 of 7674 patients either developed new moderately increased albuminuria (1542 patients) or new clinical albuminuria (317 participants) [57]. Enrolled patients were at high risk for adverse cardiovascular outcome, which was defined as either:
●Evidence of vascular disease, including coronary heart disease (81 percent, with a prior history of myocardial infarction [MI] in 53 percent), stroke, or peripheral vascular disease
or
●Diabetes and at least one other coronary risk factor (serum total cholesterol above 200 mg/dL [5.2 mmol/L], low serum HDL cholesterol, hypertension [present in 56 percent], moderately increased albuminuria, or current smoking)
The administration of ramipril, compared with placebo, decreased the risk for progressive kidney function loss (odds ratio 0.87). It is not clear if the benefit was derived from angiotensin-converting enzyme (ACE) inhibition or from blood pressure lowering. (See "Goal blood pressure in adults with hypertension".)
In a subsequent meta-analysis of 41 treatment trials and 29,979 participants, a reduction in albumin excretion of 30 percent or more was associated with a 27 percent relative risk reduction in the incidence of doubling of serum creatinine or progression to kidney failure [58]. This finding has led the American Diabetes Association to suggest targeting a reduction in albuminuria of at least 30 percent [8].
SCREENING — We test for moderately increased albuminuria (formerly called "microalbuminuria") among patients with diabetes to screen for cardiovascular risk and to look for changes over time that would indicate the presence of nephropathy. Moderately increased albuminuria is often present at diagnosis in patients with type 2 diabetes. (See "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus".)
The value of measuring albumin excretion in patients with primary hypertension without diabetes is advocated by some to assess cardiovascular risk; however, it may not be cost effective in this context, and it does not have value as a screening tool for nephropathy in patients without diabetes with hypertension [17,18].
As described above, there is evidence of an increase in mortality risk with moderately increased albuminuria that is independent of diabetes [26,27,43]. Nevertheless, we do not screen for moderately increased albuminuria in the general population of patients without diabetes, since the value of screening in these patients is unclear; the ability of any therapies to provide benefit in this setting is unknown, and it is not cost effective [59].
TREATMENT — There is increasing evidence that even stage 3 chronic kidney disease (estimated glomerular filtration rate ≤60 mL/min) is associated with an increased risk of cardiovascular disease. As a result, chronic kidney disease is considered by many to be a coronary equivalent that should be managed according to secondary prevention goals. (See "Chronic kidney disease and coronary heart disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
The KDIGO guidelines suggest that moderately increased albuminuria (formerly called "microalbuminuria") alone that persists for more than three months falls within the definition of chronic kidney disease (see "Definition and staging of chronic kidney disease in adults"). Some authorities disagree, suggesting that isolated moderately increased albuminuria (without a reduction in glomerular filtration rate) represents generalized endothelial dysfunction and inflammation. Regardless, blockers of the renin-angiotensin system (eg, angiotensin-converting enzyme [ACE] inhibitors) are not appropriate in patients with normal blood pressure and only moderately increased albuminuria.
Even if moderately increased albuminuria does not, by itself, signify chronic kidney disease, it is clearly associated with an increase in cardiovascular risk as described above. Both moderately increased albuminuria and severely increased albuminuria are treated in patients with diabetes to slow the progression of diabetic nephropathy. Post hoc analyses of trials that enrolled patients with stage 3b and 4 chronic kidney disease showed that reducing albuminuria by 30 percent or more correlates with slowed progression of nephropathy. However, the ACCOMPLISH and ROADMAP trials failed to show a cardiovascular benefit from reduction in albuminuria. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Treatment of diabetic kidney disease" and "Treatment of hypertension in patients with diabetes mellitus".)
Antihypertensive drugs — Several studies have examined the effects of antihypertensive therapy on moderately increased albuminuria and clinical cardiovascular outcomes. Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are equally effective in reducing albuminuria [60]. However, ACE inhibitors and ARBs should not be used in combination. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)
In the PREVEND IT trial, 846 normotensive patients with "normal" serum cholesterol (mean total cholesterol 223 mg/dL [5.8 mmol/L]), mean LDL cholesterol 154 [4.0 mmol/L], and moderately increased albuminuria [15 to 300 mg/24 hours] were randomly assigned to fosinopril or placebo and to pravastatin or placebo [61]. This was largely a primary prevention study since only 3.4 percent had a history of a prior cardiovascular event.
At follow-up of almost four years, fosinopril significantly lowered urinary protein excretion and was associated with a nonsignificant trend toward a lower rate of the primary end point of cardiovascular mortality or hospitalization for cardiovascular morbidity (hazard ratio [HR] 0.60, 95% CI 0.33-1.10). Similar findings were noted in two post hoc subset analyses of the LIFE trial; reductions in baseline albuminuria, which were more pronounced with losartan than atenolol, were associated with enhanced cardiovascular benefits [44,62].
Reduced albumin excretion with ACE inhibitors is well described in patients without diabetes, while the possible cardiovascular benefit in PREVEND IT may have resulted from a significantly lower blood pressure (129/76 versus 132/78 mmHg for placebo), rather than a specific effect of angiotensin inhibition. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
The IMPROVE trial was performed in an attempt to determine if combining an ACE inhibitor with an ARB reduced albuminuria more than an ACE inhibitor alone [63,64], although subsequent studies have found that combination therapy is potentially harmful and should not be used. IMPROVE randomly assigned 405 hypertensive patients with moderately increased albuminuria and increased cardiovascular risk to ramipril alone or ramipril plus irbesartan. The primary end point was the reduction in albumin excretion rate by week 20; cardiovascular outcomes were not assessed in this trial.
The following findings were noted:
●Combined therapy with ramipril and irbesartan was no more effective than ramipril alone in reducing albumin excretion in all patients with albuminuria.
●Subgroup analyses showed that combined therapy was more effective than ramipril alone in reducing albumin excretion rate in patients with overt nephropathy (defined as albuminuria >200 mcg/min). The small number of patients and the large 95% CIs in both groups suggest that these data be interpreted with caution.
●A greater reduction in both systolic and diastolic blood pressure was achieved in patients who received the combination of ramipril and irbesartan.
●The incidence of adverse effects was similar in both treatment groups.
Statin therapy — In the pravastatin arm of the PREVEND IT trial, pravastatin significantly lowered both total cholesterol (223 to 185 mg/dL [5.8 versus 4.8 mmol/L]) and LDL cholesterol (158 to 119 mg/dL [4.1 versus 3.1 mmol/L]), while there was no change in the placebo group [61]. Pravastatin therapy did not reduce albumin excretion and was associated with a nonsignificant 13 percent reduction in the primary cardiovascular end point (5.0 versus 5.7 percent, HR 0.87, 95% CI 0.49-1.57) [61]. However, this study was underpowered for the cardiovascular outcome, and other primary prevention trials in patients with similar baseline lipid levels have shown a significant cardiovascular benefit from statin therapy.
Recommendations — In the absence of clear data, the following represents our usual approach in patients without diabetes who are noted to have moderately increased albuminuria (see 'Screening' above):
●Testing for moderately increased albuminuria should be repeated once or twice to make certain that it is a persistent abnormality. Possible inflammatory causes should be sought, such as periodontal disease.
●Among patients with persistent moderately increased albuminuria who are hypertensive, we would use an ACE inhibitor or ARB because of the greater ability to reduce albuminuria, but there are no data demonstrating an outcome benefit in this group, and, hence, blood pressure control is the key approach. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
●Goal blood pressure depends upon the level of cardiovascular risk and tolerability of the antihypertensive regimen. (See "Goal blood pressure in adults with hypertension".)
●We recommend aspirin therapy and suggest consideration of a statin in patients who also have other risk factors for cardiovascular disease. The goal LDL cholesterol concentration is well below 100 mg/dL (2.6 mmol/L). (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)
●Albumin excretion should be monitored at regular intervals. Issues related to blood pressure and LDL cholesterol goals in patients with atherosclerotic cardiovascular disease are discussed in detail separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Goal blood pressure in adults with hypertension".)
The management of patients with diabetes who have moderately increased albuminuria is discussed separately. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus".)
SUMMARY AND RECOMMENDATIONS
●Moderately increased albuminuria (formerly called "microalbuminuria") is defined as persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min). Moderately increased albuminuria (≥30 mg/day [20 mcg/min] or urine albumin-to-creatinine ratio ≥30 mg/g) is a marker associated with increased risk of cardiovascular disease that is additive to conventional risk factors in all patients regardless of diabetes status. (See 'Introduction, terminology, and definitions' above and 'Correlation of moderately increased albuminuria (microalbuminuria) with cardiovascular disease' above.)
●Measurement of the urine albumin-to-creatinine ratio in an untimed urinary sample is the preferred screening strategy for moderately increased albuminuria. In order to maximize the reliability of the urine albumin-to-creatinine ratio, patients should refrain from vigorous exercise in the 24 hours prior to the test since vigorous exercise can cause a transient increase in albumin excretion. In addition, the accuracy of the albumin-to-creatinine ratio will be diminished if creatinine excretion is substantially different from the expected value, such as in a muscular or cachectic individual. (See 'Detection' above.)
●The mechanism by which moderately increased albuminuria is associated with cardiovascular disease is not well understood. However, moderately increased albuminuria appears to be a signal that the vasculature, particularly the endothelium, is not functioning normally. Among patients with diabetes, the degree of coronary endothelial dysfunction appears to be greater in patients with moderately increased albuminuria and may be related to hyperglycemia-induced alterations in extracellular matrix, such as decreased density of heparan sulfate proteoglycans. This abnormality can lead to increased microvascular permeability, resulting in moderately increased albuminuria at the glomerulus and perhaps increased lipoprotein deposition in peripheral vessels. (See 'Possible mechanisms' above.)
●We test for moderately increased albuminuria among patients with diabetes to screen for cardiovascular risk and to look for changes over time that would indicate the presence of nephropathy. We also screen for moderately increased albuminuria among patients without diabetes at increased risk for chronic kidney disease and cardiovascular disease, such as those with hypertension and the metabolic syndrome. We do not screen for moderately increased albuminuria in the general population of patients without diabetes without any such risk factors, since the value of screening in these patients is unclear; the ability of any therapies to provide benefit in this setting is unknown, and it is not cost effective. (See 'Screening' above.)
●The KDIGO guidelines suggest that moderately increased albuminuria alone that persists for more than three months falls within the definition of chronic kidney disease. (See 'Treatment' above.)
●It is not certain that treatment specifically aimed at lowering albumin excretion in nondiabetics with moderately increased albuminuria is beneficial. In the absence of clear data, the following represents our usual approach in patients without diabetes who have moderately increased albuminuria. (See 'Screening' above.)
•Testing for moderately increased albuminuria should be repeated at least twice to make certain that it is a persistent abnormality. Possible inflammatory causes should be sought, such as periodontal disease. Albumin excretion should be monitored at regular intervals.
•Among patients with persistent moderately increased albuminuria who are hypertensive, an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) lowers albuminuria more than other drugs but has not been shown to reduce cardiovascular events more than other antihypertensive agents in this group. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
•Goal blood pressure depends upon cardiovascular risk and tolerability of therapy. (See "Goal blood pressure in adults with hypertension".)
•Issues related to blood pressure and LDL cholesterol goals in patients with atherosclerotic cardiovascular disease are discussed in detail separately. (See 'Recommendations' above and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Goal blood pressure in adults with hypertension".)
•We recommend aspirin therapy and suggest consideration of a statin in patients who also have other risk factors for cardiovascular disease. The goal LDL cholesterol concentration is well below 100 mg/dL (2.6 mmol/L). (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)
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