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Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus

Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus
Author:
George L Bakris, MD
Section Editors:
Richard J Glassock, MD, MACP
David M Nathan, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Dec 2022. | This topic last updated: Sep 08, 2021.

INTRODUCTION AND DEFINITIONS — Increased urinary protein excretion may be an early clinical manifestation of diabetic nephropathy [1-6]. However, when assessing protein excretion, the urine dipstick is a relatively insensitive marker for initial increases in protein excretion, not becoming positive until protein excretion exceeds 300 to 500 mg/day (upper limit of normal less than 150 mg/day, with most individuals excreting less than 100 mg/day).

Using a specific assay for albumin is a more sensitive technique and is accepted today. 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 (the new terminology for what was formerly called "microalbuminuria") [2,7]. Albumin excretion above 300 mg/day (200 mcg/min) is considered to represent severely increased albuminuria (the new terminology for what was formerly called "macroalbuminuria" [2], clinical renal disease, or dipstick positive proteinuria) [8].

Although these cut-offs defining moderately increased albuminuria and severely increased albuminuria facilitate determining the risk for progression of nephropathy, the risk of developing overt diabetic nephropathy is probably directly related to albumin excretion rates at all levels.

The clinical significance, screening, and management of moderately increased albuminuria in patients with type 2 diabetes will be reviewed here. In addition to being a marker of cardiovascular risk, moderately increased albuminuria that is increasing when factors such as blood pressure and blood glucose are controlled is also associated with development of nephropathy in both diabetic and nondiabetic patients. As will be described below, moderately increased albuminuria is often present at diagnosis in patients with type 2 diabetes and reflects underlying cardiovascular disease [9].

The significance of moderately increased albuminuria in patients with type 1 diabetes, the mechanisms of moderately increased albuminuria, the association of moderately increased albuminuria with cardiovascular risk, and the treatment of overt diabetic nephropathy are discussed separately:

(See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus".)

(See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

(See "Treatment of diabetic kidney disease".)

DETECTION — Establishing the diagnosis of moderately increased albuminuria (formerly called "microalbuminuria") requires the demonstration of an elevation in albumin excretion (30 to 300 mg/day) that persists over a three- to six-month period. Fever, exercise, heart failure, infections, and poor glycemic control are among the factors that can cause transient moderately increased albuminuria [10]. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

Approach to detection — Measurement of the urine albumin-to-creatinine ratio in an untimed urinary sample is the preferred screening strategy for moderately increased albuminuria in all diabetic patients [1,3,8,10,11]. If an abnormal result (30 mg/g or higher) is noted in a patient who has previously had normal values, the test should be repeated twice more over a three- to six-month period to confirm that the albumin excretion is persistently elevated [1].

The urine albumin-to-creatinine ratio test 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. (See 'Screening' below.)

Urine albumin concentration — Although the 24-hour urine collection was the initial gold standard for the detection of moderately increased albuminuria [10,12], it has been suggested that screening can be more simply achieved by a timed urine collection or measurement of the urine albumin concentration on an early morning specimen to minimize changes in urine volume that occur during the day [10,13]. 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 [10].

There are also a variety of semiquantitative dipsticks, which have been used to test for moderately increased albuminuria if urine albumin excretion cannot be directly measured [3]. Guidelines on appropriate testing using dipsticks state that, of the available methods, the immunoturbidimetric assay is the most reliable and should be the standard for comparison because it has >95 percent sensitivity and specificity to detect very low levels of albuminuria [1].

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 [14]. 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 [10].

Urine 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 [11]. 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 moderately increased or severely increased albuminuria range over a three- to six-month period [2].

In one report, for example, 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 very 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 [13].

Predictive value — The albumin-to-creatinine ratio obtained from a first morning void sample appears to provide the best predictive value for kidney disease progression [16]. This was shown in a subset analysis of the RENAAL trial in which methods of estimating protein excretion were compared in terms of their ability to predict renal outcomes, including the time of doubling of serum creatinine or end-stage kidney disease. Compared with urinary albumin excretion and urinary protein excretion from a 24 hour collection, and to urinary albumin excretion from a first morning void, the albumin-to-creatinine ratio from a first morning void demonstrated the strongest association with the risk for renal events (hazard ratios of 4.36 (3.50-5.45) versus 3.16 (2.60-3.86) for 24 hour urinary albumin excretion; 3.02 (2.53-3.62) for 24 hour urinary protein excretion; and 3.23 (2.67-3.91) for urinary albumin concentration from a first morning void). The superior predictive capability reflects both an increase in albumin and decrease in creatinine generation and excretion.

Limitations — There are three important caveats that must be considered to maximize the reliability of the urine albumin-to-creatinine ratio (see "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Limitations of the UPCR and UACR'):

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 a 1983 study, the best correlation with a 24-hour urine collection occurred with samples obtained after the first morning void and before bedtime [17]. By contrast, a later and larger study found the best correlation with the first morning void, although the difference compared to spot urine samples at other times was not significant [18].

Given the uncertainty, we have a slight preference for first morning void specimens. If this is inconvenient, specimens can be obtained at other times during the day. There are no data about the timing of repeat measurements as the patient's course is being monitored. If possible, it seems preferable to obtain the samples at approximately the same time of day.

Vigorous exercise can cause a transient increase in albumin excretion [19]. As a result, patients should refrain from vigorous exercise in the 24 hours prior to the test.

In addition to biologic variation in urine albumin excretion, laboratory variation can contribute; this leads to random variation (imprecision) and bias [20]. Laboratories can and should address the fact that some commercial methods are biased consistently high while others are biased consistently low [21]. Clinicians cannot circumvent bias by repeating the test. To help reduce laboratory variation, the National Kidney Disease Education Program (NKDEP) recommends that the total allowable imprecision should be less than 30 percent and that the bias of acceptable methods should be less than 15 percent [20]. Significant changes that correlate with kidney disease progression need to be at 30 percent or more [22,23].

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 [24]. The ratio also varies with sex [24] and with race/ethnicity in the United States [25], as creatinine excretion is significantly higher among Black patients who are not Hispanic and Mexican American patients than among White patients who are not Hispanic [25].

NATURAL HISTORY — The following data might be considered to represent the "natural history" of moderately increased albuminuria (formerly called "microalbuminuria") in patients with type 2 diabetes, since they were mostly obtained before the current era of recommended strict glycemic control, aggressive blood pressure control, and therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. (See 'Effect of interventions on albuminuria' below.)

Prevalence — The reported prevalence of moderately increased albuminuria among patients with type 2 diabetes approximately 10 years after the diagnosis ranges from 25 to 40 percent [26-30]. In a systematic review of 28 studies in type 2 diabetes (10,298 patients), the prevalence of moderately increased albuminuria was 26 percent at a mean diabetes duration of 10 years [26]. The prevalence was similar (27 percent at eight years) in the ADVANCE trial of 11,140 patients with type 2 diabetes that was published after the systematic review [27].

The prevalence of moderately increased albuminuria in patients with type 2 diabetes varies with ethnicity, being higher in Asian patients and Hispanic patients than in White patients [29,30]. The magnitude of this difference was illustrated in an international cross-sectional study of over 24,000 patients with type 2 diabetes without known albuminuria [30]. At a mean duration of diabetes of almost eight years, the rate of moderately increased albuminuria was significantly higher in Asian patients and Hispanic patients (43 versus 33 percent in White patients). As noted in the following section, there are also racial and ethnic differences in the rate of progression to severely increased albuminuria (formerly called "macroalbuminuria").

Some patients with type 2 diabetes have moderately increased albuminuria at the time of diagnosis [28,31,32]. This issue was addressed in the United Kingdom Prospective Diabetes Study (UKPDS) of approximately 5100 patients with newly diagnosed type 2 diabetes in which 6.5 percent had moderately increased albuminuria (and 0.7 percent had severely increased albuminuria) at the time of diagnosis [28]. The annual rate of progression from normal albumin excretion to moderately increased albuminuria was 2.0 percent.

A higher rate of moderately increased albuminuria (17.9 percent) was noted in another report of over 3600 newly diagnosed patients who were recruited for the UKPDS [31]. The rate of moderately increased albuminuria was significantly higher in the 39 percent of patients with hypertension (24 versus 14 percent in those without hypertension). (See "Treatment of hypertension in patients with diabetes mellitus".)

The rate of moderately increased albuminuria at the time of diagnosis of type 2 diabetes may be higher in older patients. This was illustrated in a cross-sectional population study of older adults in Finland (age 65 to 74 versus a mean of 52 years in the previous two studies) [32]. Among 891 subjects who were free of diabetes at baseline, 69 developed diabetes at 3.5-year follow-up. Moderately increased albuminuria was present in 44 percent and hypertension in 68 percent of these patients; these values were significantly higher than in the subjects who did not develop diabetes (30 and 54 percent, respectively).

There are at least two possible explanations for the presence of moderately increased albuminuria at the time of diagnosis of type 2 diabetes: the patients had previously undiagnosed diabetes or some other disease (eg, benign nephrosclerosis) was responsible for the moderately increased albuminuria. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

Progression to severely increased albuminuria — As noted above, severely increased albuminuria (also called overt proteinuria, clinical renal disease, or dipstick positive proteinuria) is defined as albumin excretion greater than 300 mg/day or 200 mcg/min or a urine albumin-to-creatinine ratio greater than 300 mg/g of creatinine or, using standard (SI) units, 34 mg/mmol of creatinine.

Among the approximately 5100 patients (81 percent White patients) with newly diagnosed type 2 diabetes in the UKPDS described in the preceding section, the prevalence of severely increased albuminuria was 5.3 percent at 10 years after diagnosis, compared to 25 percent for moderately increased albuminuria [28]. The rate of progression from moderately to severely increased albuminuria was 2.8 percent per year, which is similar to the 20 to 40 percent rate within a 10-year period noted in other studies of mostly White patients [5,33,34].

In the systematic review cited above, patients with moderately increased albuminuria had a significantly higher risk than those with normoalbuminuria of progressing to severely increased albuminuria (relative risk 7.5, 95% CI 5.2-10.9) [26]. Other risk factors contributing to progression to severely increased albuminuria include higher baseline levels of albuminuria, worse glycemic control as estimated from the hemoglobin A1c concentration, higher blood pressure, and cigarette smoking [33-35].

Ethnicity may also be important as four- to five-year rates of progression to severely increased albuminuria as high as 37 to 42 percent have been described in Pima Indians and Israeli patients [36,37]. In addition to possible genetic differences, the patients in these two series were younger than in the studies described in the preceding paragraph, and the moderately increased albuminuria was almost certainly due to diabetes. In older patients, other causes for proteinuria (such as benign nephrosclerosis) that might progress more slowly than diabetic nephropathy could have accounted for the lower rate of progression to severely increased albuminuria.

Severely increased albuminuria in patients with type 2 diabetes is typically associated with a progressive reduction in glomerular filtration rate (GFR). In the Pima Indian study, for example, the initial mean GFR was 143 mL/min in patients with newly diagnosed diabetes, 155 mL/min in those with moderately increased albuminuria, and 124 mL/min in those with severely increased albuminuria (similar to the value in subjects with normal glucose tolerance) [36]. During four-year follow-up, the GFR increased by 18 percent in the patients with newly diagnosed diabetes, decreased by 3 percent in those with moderately increased albuminuria, and decreased by 35 percent in those with severely increased albuminuria. The mean rate of loss of GFR in patients with severely increased albuminuria was 0.93 mL/min per month, a rate similar to that observed in studies of severely albuminuric patients with type 1 diabetes (figure 1). (See "Treatment of diabetic kidney disease".)

Regression to normal albuminuria — As with type 1 diabetes, some patients with moderately increased albuminuria and type 2 diabetes regress to normal albuminuria. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Regression to normoalbuminuria'.)

The frequency with which this occurs and predictors for regression were evaluated in a study of 216 Japanese patients with type 2 diabetes and moderately increased albuminuria [38]. At six years, regression occurred in 51 percent, while progression to severely increased albuminuria occurred in 28 percent. The following factors were independently associated with remission: a short duration of moderately increased albuminuria, better glycemic (hemoglobin A1c less than 7 percent) and blood pressure control (systolic pressure less than 129 mmHg), and the use of ACE inhibitors or angiotensin II receptor blockers, which have been shown in clinical trials to promote regression of moderately increased albuminuria. (See 'ACE inhibitors and ARBs' below.)

In a later follow-up at eight years, remission of moderately increased albuminuria or a 50 percent reduction in albumin excretion compared with no reduction was associated with significant reductions in death from and hospitalization for renal and cardiovascular events (adjusted risk 0.41) and reductions in the rate of decline in glomerular filtration rate [39]. Renal protection with remission of moderately increased albuminuria, as manifested by a slower rate of decline in glomerular filtration rate, was also noted in another study in which antihypertensive therapy and better glycemic control were again independent predictors of remission [40].

A much lower rate of regression to normal albuminuria in moderately albuminuric patients with type 2 diabetes (18 percent) was noted in the systematic review cited above [26].

Mortality — Moderately increased albuminuria appears to be associated with increased long-term mortality in patients with type 2 diabetes [26,28,33]. In the above systematic review, the relative risk for all-cause mortality was 1.9 (95% CI 1.7-2.1) compared with patients who had normal albuminuria; similar significant relative risks (2.0 and 2.3) were noted for cardiovascular and coronary heart disease mortality [26].

EFFECT OF INTERVENTIONS ON ALBUMINURIA — Glycemic and blood pressure control, particularly with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), renin inhibitors, and aldosterone receptor antagonists, reduce both moderately increased albuminuria (formerly called "microalbuminuria") and progression to severely increased albuminuria (formerly called "macroalbuminuria") [34,38,41]. Nondihydropyridine calcium channel blockers (diltiazem and verapamil) may also reduce albuminuria in hypertensive patients, while other classes of antihypertensive drugs have less or no antiproteinuric effect [42]. (See "Treatment of hypertension in patients with diabetes mellitus" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Drugs with little or no effect'.)

ACE inhibitors and ARBs are preferred agents in hypertensive patients with severely increased albuminuria but have not been shown to slow the progression of chronic kidney disease in hypertensive or normotensive individuals with moderately increased albuminuria [43,44]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

ACE inhibitors and ARBs — Antialbuminuric effects of ACE inhibitors and ARBs compared with placebo have been noted in a number of trials [37,45-49]. The potential magnitude of benefit can be illustrated by the results of a trial in which 590 hypertensive patients with type 2 diabetes and moderately increased albuminuria were randomly assigned to either irbesartan (150 or 300 mg/day) or placebo and then followed for two years [45].

The primary end point was the time from baseline to first detection of overt nephropathy (urine albumin excretion >200 mcg/min [severely increased albuminuria] and at least a 30 percent increase from baseline on two consecutive visits). This end point was significantly more common in the placebo group compared with irbesartan (14.9 versus 9.7 and 5.2 percent with 150 and 300 mg of irbesartan). This benefit was not related to differences in blood pressure, although the systolic blood pressure was 3 mmHg lower with 300 mg irbesartan than with placebo or 150 mg irbesartan (141 versus 144 mmHg), a difference that was statistically significant.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have similar efficacy in type 2 diabetic patients with moderately increased albuminuria. The only randomized comparative trial (DETAIL) of these agents in type 2 diabetic patients compared enalapril with the ARB telmisartan in 250 patients with early nephropathy as defined by albuminuria (82 percent moderately increased and 18 percent severely increased albuminuria to a maximum of 1.4 g/day) and a baseline glomerular filtration rate (GFR; measured isotopically) of approximately 93 mL/min per 1.73 m2 [50]. A greater fall in GFR of at least 10.0 mL/min per 1.73 m2 at five years was predefined as suggesting a clinically significant difference between the two treatment groups.

At five years, there was a smaller decline in GFR with enalapril that was not significant (14.9 versus 17.9 mL/min per 1.73 m2 with telmisartan). Both groups had similar rates or findings for the secondary end points, which included annual changes in the GFR, blood pressure, serum creatinine concentration, urinary albumin excretion, and rates of end-stage kidney disease, cardiovascular events, and mortality.

A limitation of the trial was that only 168 of the original 250 patients completed the trial. Nevertheless, the results are consistent with the conclusion that ACE inhibitors are at least as effective as ARBs in type 2 diabetics with moderately increased albuminuria.

Almost all of the moderately increased albuminuria trials involved hypertensive patients [45-48]. Only one major trial involved "normotensive" patients [37,49]. In this trial of 94 patients, enalapril was associated with stable albuminuria and serum creatinine, while increases in both parameters were noted with placebo at five and seven years. (See "Treatment of hypertension in patients with diabetes mellitus".)

Despite the antialbuminuric effects of ACE inhibitors and ARBs, the best available data indicate that these agents are not superior to other antihypertensive drugs in patients with moderately increased albuminuria. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Calcium channel blockers — Calcium channel blockers have less antialbuminuric effect than ACE inhibitors or ARBs, and the antialbuminuric effect is primarily seen with diltiazem and verapamil (which are useful to reduce proteinuria in hypertensive patients), not the dihydropyridines. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Drugs with little or no effect'.)

The difference between these drug classes in patients with type 2 diabetes and moderately increased albuminuria was evaluated in the MARVAL trial in which 332 such patients were randomly assigned to valsartan or amlodipine [51]. Albumin excretion was reduced by 44 percent with valsartan compared to 8 percent with amlodipine, a difference that was highly significant. There was no difference in blood pressure between the two groups during the course of the study. In addition, a study comparing lisinopril with diltiazem in hypertensive patients with type 2 diabetes and severe albuminuria found that both drugs reduced albuminuria to a similar degree [52].

Glucose control — A detailed discussion of glucose control, including glycemic targets, and the effect on renal outcomes in patients with type 2 diabetes is presented separately. (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Intensive combined risk factor modification therapy — The potential efficacy of intensive combined therapy in patients with type 2 diabetes and moderately increased albuminuria was examined in the Steno type 2 trial [53,54]. In this prospective study, 160 patients were randomly assigned to standard or multifactorial intensive therapy; the mean urine albumin excretion at baseline was 74 mg/day. The intensive regimen consisted of behavioral therapy (including advice concerning diet, exercise, and smoking cessation) and pharmacologic intervention (consisting of the administration of an ACE inhibitor and multiple other agents to attain several aggressive therapeutic goals, although the initial blood pressure and lipid goals were higher than current recommendations). The primary end point was progression to overt nephropathy at four years [53] and a composite cardiovascular end point at eight years [54].

At a mean follow-up of 7.8 years, intensive therapy reduced both microvascular and macrovascular disease [54]. With respect to diabetic nephropathy, there were significant improvements in albumin excretion (-20 versus +30 mg/day) and progression to severely increased albuminuria (20 versus 39 percent, relative risk 0.39). In contrast to these benefits, the glomerular filtration rate fell to the same degree in both groups (-30 versus -32 mL/min per 1.73 m2). The details of the protocol and overall results of this study are discussed elsewhere. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

SCREENING — The availability of effective therapy (as described in the next section) led to the recommendation that patients with type 2 diabetes should be screened for moderately increased albuminuria (formerly called "microalbuminuria") [11,55]. If not found at the initial screen, yearly screening for albuminuria is recommended [11]. (See 'Prevalence' above and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Monitoring for increased urinary albumin excretion'.)

If detected, treatment is aimed at correcting underlying disorders such as hypertension, hyperglycemia, and dyslipidemia [9], and albuminuria should be assessed annually thereafter. Underlying progressive kidney damage is likely to be present if albuminuria continues to increase despite successful management of underlying disorders that can produce moderately increased albuminuria.

The KDIGO guidelines recommend use of the urine albumin-to-creatinine ratio on a spot urine sample for screening and that an elevated urine albumin-to-creatinine ratio should be confirmed in the absence of urinary tract infection with additional tests performed over at least a three-month interval [2]. The diagnosis of moderately increased albuminuria requires an elevated ratio be persistent for at least three months.

Moderately increased albuminuria in a patient with type 2 diabetes should be attributed to diabetes if diabetic retinopathy is present or the patient progresses to severely increased albuminuria (formerly called "macroalbuminuria") [11]. However, lack of retinopathy does not preclude diabetic nephropathy; in one study, for example, diabetic retinopathy was absent in 12 of 27 patients with biopsy-confirmed diabetic nephropathy [56].

Other causes of chronic kidney disease should be considered when there are findings that are not characteristic of diabetic nephropathy. These include (see "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Diagnosis'):

A low or rapidly decreasing glomerular filtration rate

Rapidly increasing protein excretion or acute onset of nephrotic syndrome

Refractory hypertension

Active urine sediment (eg, glomerular hematuria and red cell or other cellular casts)

Signs and/or symptoms of another systemic disease

More than a 30 percent reduction in glomerular filtration rate from baseline values after initiation of therapy with an ACE inhibitor or angiotensin II receptor blocker

PRIMARY PREVENTION — In addition to treating moderately increased albuminuria (formerly called "microalbuminuria") to prevent progressive disease, clinical trials have also demonstrated efficacy of ACE inhibitors and ARBs and of glycemic control for the primary prevention of moderately increased albuminuria and subsequent overt nephropathy in patients with type 2 diabetes.

Glycemic control — As noted above, worse glycemic control is a risk factor for both the development of moderately increased albuminuria and for progression to severely increased albuminuria (formerly called "macroalbuminuria") in patients with type 2 diabetes. Strict glycemic control is recommended in all patients because of its beneficial effects on the microvascular complications. The general benefits of strict glycemic control are discussed in detail elsewhere. (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Several randomized trials have demonstrated that strict glycemic control is effective for the primary prevention of moderately increased albuminuria [27,57,58]. The UKPDS evaluated the importance of strict glycemic control in 3867 patients with newly diagnosed type 2 diabetes [58]. The patients were randomly assigned to intensive or conventional therapy. Over 10 years, the average hemoglobin A1C value was 7.0 percent in the intensive therapy group, compared to 7.9 percent in the conventional therapy group (an 11 percent reduction).

At baseline, 6.5 percent of patients had moderately increased albuminuria, and 0.7 percent had severely increased albuminuria (defined as a urine albumin concentration above 300 mg/L) [28]. On analysis of these surrogate end points over time, intensive insulin therapy was associated at nine-year follow-up with a significantly lower rate of moderately increased albuminuria (19.2 versus 25.4 percent, relative risk 0.76, 95% CI 0.62-0.91) and a nonsignificantly lower rate of severely increased albuminuria (4.4 versus 6.5 percent, relative risk 0.67, 95% CI 0.42-1.07) [58].

Benefit from intensive therapy was also noted in the ADVANCE trial in which 11,140 patients with type 2 diabetes (mean duration eight years) were randomly assigned to intensive therapy to achieve a hemoglobin A1c below 6.5 percent or to standard therapy [27]. At a median follow-up of five years, the intensive and standard groups achieved mean hemoglobin A1c values of 6.5 and 7.3 percent, respectively. Intensive therapy was associated with a small but significant reduction in the rate of new-onset moderately increased albuminuria (23.7 versus 25.7 percent, relative risk reduction 9 percent).

The ACCORD trial demonstrated a decrease in moderately increased albuminuria but not in the primary composite outcome of dialysis or kidney transplantation, high serum creatinine (>3.3 mg/dL [291.72 micromol/L]), or retinal photocoagulation or vitrectomy to treat diabetic retinopathy [59]. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Introduction' and "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Microvascular disease'.)

ACE inhibitors or ARBs — There have been variable results related to the efficacy of ACE inhibitors [47,60-65] or ARBs [66-68] for the primary prevention of moderately increased albuminuria in clinical trials of patients with type 2 diabetes. This is due in part to variations in study design, specific antihypertensive agents administered, and type of individual enrolled, particularly normotensive and hypertensive patients.

The following findings have been noted in different trials of patients with type 2 diabetes with normal albumin excretion at baseline. The data are presented according to whether the baseline blood pressure is normal or elevated.

Normotensive patients — In different trials of normotensive patients with type 2 diabetes and normal albuminuria:

In the normotensive Appropriate Blood pressure Control in Diabetes (ABCD) trial of 480 patients, the rate of progression to moderately increased albuminuria was significantly lower with enalapril compared with placebo [61,62] and with nisoldipine compared with placebo, but after five years, there was no significant difference [62]. The rate of progression to moderately increased albuminuria was equivalent with enalapril and nisoldipine [62]. In addition, treating patients with normoalbuminuria with a renin-angiotensin system blocker does not change the natural history of diabetic nephropathy, but it may alter the progression of retinopathy [69-71]. (See "Diabetic retinopathy: Prevention and treatment".)

In DIRECT Protect-2, which included 725 normotensive patients with normal albuminuria, the rate of progression to moderately increased albuminuria was nonsignificantly lower with candesartan compared with placebo (29 versus 40 percent at 4.7 years, hazard ratio 0.73, 95% CI 0.48-1.10) [67]. However, the trial was underpowered to detect a difference of this magnitude.

These observations, coupled with information obtained from kidney biopsies in some studies [69,70], suggest that ACE inhibitors and ARBs do not change the natural history of kidney disease in such patients. We suggest not treating with an ACE inhibitor or ARB solely for the prevention of moderately increased albuminuria in such patients. These patients should be screened yearly for moderately increased albuminuria and an ACE inhibitor or ARB initiated if persistent moderately increased albuminuria is documented. (See 'Screening' above.)

Hypertensive patients — The effect of angiotensin inhibition for the prevention of moderately increased albuminuria has been evaluated in four randomized, placebo controlled trials of patients with type 2 diabetes and normal albuminuria. The BENEDICT trial also contained a verapamil arm, permitting a comparison between different antihypertensive drugs.

In the BENEDICT trial, 1204 patients with a mean baseline blood pressure of 150/87 mmHg were randomly assigned to trandolapril, verapamil, the combination of these medications, or placebo [64]. The rate of new-onset moderately increased albuminuria at three years or more was significantly lower with trandolapril alone or with verapamil (6.0 and 5.7 percent, respectively) than with verapamil alone or placebo (11.9 and 10.0 percent respectively).

In the ADVANCE trial of 11,140 patients, a fixed combination regimen of perindopril-indapamide significantly reduced the rate of new-onset moderately increased albuminuria (19.6 versus 23.6 percent) [47]. These patients had a mean baseline blood pressure of 145/81 mmHg, and perindopril-indapamide therapy was associated with a significantly greater mean reduction in blood pressure (5.6/2.2 mmHg compared with placebo).

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial randomly assigned 4447 patients type 2 diabetes and a mean baseline blood pressure of 136/81 mmHg to receive either olmesartan or placebo [72]. Olmesartan was associated with significant reductions in systolic blood pressure by 3.1 mmHg and in moderately increased albuminuria (8.2 versus 9.8 percent) compared with placebo. This possible increase in cardiovascular mortality with olmesartan has not been seen with other ARBs, and investigation by the Food and Drug Administration has found no cause for this secondary outcome [73].

The DIRECT Protect-2 trial included 1180 treated hypertensive patients with type 2 diabetes who had a mean baseline blood pressure of 139/75 mmHg [67]. Candesartan had no significant effect on the development of moderately increased albuminuria compared with placebo.

In the aggregate, these trials suggest that ACE inhibitors and ARBs are effective in preventing the new onset of moderately increased albuminuria in hypertensive patients with type 2 diabetes and the BENEDICT trial provides support for these drugs being more effective than at least verapamil. None were designed to analyze effects on kidney function decline, and, in ROADMAP, mortality was increased despite reductions in albuminuria.

The treatment of hypertension in patients with diabetes is presented in detail elsewhere. (See "Treatment of hypertension in patients with diabetes mellitus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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Beyond the Basics topic (see "Patient education: Diabetic kidney disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Moderately increased albuminuria (the new term for what was formerly called "microalbuminuria") is defined as persistent urinary albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min). Severely increased albuminuria (the new term for what was formerly called "macroalbuminuria") refers to albumin excretion above 300 mg/day (200 mcg/min). (See 'Introduction and definitions' above.)

Among patients with type 2 diabetes, the reported prevalence of moderately increased albuminuria at 10 years is between 25 to 40 percent. Some patients have moderately increased albuminuria at the time of diagnosis, which may be due to previously undiagnosed diabetes or some other disease that is responsible for the moderately increased albuminuria. (See 'Prevalence' above.)

With type 2 diabetes, moderately increased albuminuria is associated with higher cardiovascular risk, possible progression to severely increased albuminuria, and increased long-term mortality. However, remission to normal albuminuria may occur. Factors associated with remission include short duration of moderately increased albuminuria, better glycemic control, better blood pressure control, and use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). (See 'Mortality' above and 'Regression to normal albuminuria' above.)

The preferred screening strategy for moderately increased albuminuria is measurement of the urine albumin-to-creatinine ratio in an untimed urinary sample. A value of 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. (See 'Urine albumin-to-creatinine ratio' above.)

We recommend that the urine albumin-to-creatinine ratio be measured yearly in patients with type 2 diabetes, although it is uncertain whether yearly testing should be continued in patients already treated with an ACE inhibitor or ARB. An elevated ratio should be confirmed with at least two additional tests performed over the subsequent three to six months, with confirmation of the diagnosis requiring at least two of three positive samples. (See 'Screening' above.)

Among patients with persistent moderately increased albuminuria and blood pressures above goal, we suggest therapy with an ACE inhibitor or ARB rather than other antihypertensive agents (Grade 2B). Other drugs are added as necessary. Issues related to goal blood pressure in patients with diabetes are discussed separately. (See 'ACE inhibitors and ARBs' above and "Treatment of hypertension in patients with diabetes mellitus".)

Data are limited on the value of treating moderately increased albuminuria with an ACE inhibitor or ARB in patients with type 2 diabetes who are normotensive, since no trials have been limited to patients who have a baseline blood pressure below 135/85 mmHg. In such patients, aggressive glycemic and lipid control are recommended, but angiotensin inhibition is not warranted solely to reduce albuminuria. (See 'ACE inhibitors and ARBs' above.)

There is sufficient evidence to not recommend ACE inhibitor or ARB therapy for primary prevention in patients with type 2 diabetes who have normal albumin excretion and who are normotensive. In addition, there is evidence that such therapy is not helpful. These patients should be screened yearly for moderately increased albuminuria and an angiotensin inhibition initiated if persistent moderately increased albuminuria is documented. (See 'Normotensive patients' above and 'Screening' above.)

Patients with type 2 diabetes who have normal albumin excretion and who are hypertensive should be treated to attain goal blood pressure. A detailed discussion of hypertension treatment in patients with diabetes is presented elsewhere. (See "Treatment of hypertension in patients with diabetes mellitus".)

Issues related to glycemic control, which is essential to minimize the renal and other microvascular complications of type 2 diabetes, are discussed in detail elsewhere. (See "Glycemic control and vascular complications in type 2 diabetes mellitus" and 'Glucose control' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David K McCulloch, MD, who contributed to an earlier version of this topic review.

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