INTRODUCTION AND DEFINITIONS — 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") [1]. In patients with diabetes, moderately increased albuminuria is a risk marker for cardiovascular disease and mortality [2], and (particularly in patients with type 1 diabetes) it may sometimes but not always be indicative of early diabetic nephropathy.
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" [1], overt albuminuria, or dipstick-positive albuminuria) [3].
Moderately increased albuminuria was thought to be an early clinical manifestation of diabetic nephropathy [4-8]. However, contemporary studies suggest that moderately increased albuminuria is not always indicative of kidney disease [9-11], although assessment of albuminuria over time is important to identify kidney disease development.
The clinical significance, screening, and management of moderately increased albuminuria in patients with type 1 diabetes will be reviewed here.
The significance of moderately increased albuminuria in patients with type 2 diabetes, 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 2 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, microalbuminuria) requires the demonstration of an elevation in albumin excretion that persists over a three- to six-month period. Fever, exercise, heart failure, and poor glycemic control are among the factors that can cause transient increases in albuminuria [12]. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)
Urine albumin concentration — Although the 24-hour urine collection was the initial gold standard for the detection of moderately increased albuminuria [12,13], 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 [12,14]. 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 [12].
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 [5]. The reported sensitivity and specificity of these tests range from 80 to 97 percent and 33 to 80 percent, respectively [15].
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 and the amount of albuminuria [16]. 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 [12].
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 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 [4]. 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 obtained over a three- to six-month period fall within the moderately or severely increased range [1,4].
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 [17]. 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 [14].
Limitations — There are three important caveats that must be considered to maximize the reliability of the urine albumin-to-creatinine ratio.
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 [18]. By contrast, a later and larger study found the best correlation with the first morning void, although the difference compared with spot urine samples at other times was not significant [19].
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 [20]. As a result, patients should refrain from vigorous exercise in the 24 hours prior to the test.
●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 Black patients and Hispanic American patients than among White patients [21].
Detection recommendation — 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 [3-5,12]. This test has the following advantages: it gives a quantitative result that correlates with the 24-hour urine values over a wide range of albumin 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. (See 'Screening' below.)
MECHANISMS — The glomerular capillary wall limits the filtration of anionic macromolecules such as albumin by size- and charge-selective properties. (See "Biology of glomerular podocytes" and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Types of proteinuria'.)
Studies in diabetic subjects with moderately increased albuminuria (formerly, microalbuminuria) demonstrate both an increase in the number of large pores (limiting size selectivity) and decreased staining for heparan sulfate (the major component of the charge barrier) [22-24]. These defects become more prominent with progression to overt albuminuria [23]. However, changes in charge selectivity may not be an important factor in the genesis of albuminuria [25,26]. Another possible mechanism of albuminuria, at least in type 1 diabetes mellitus, is decreased degradation of filtered albumin within the tubules [27] or impaired tubular uptake of filtered albumin [28].
NATURAL HISTORY — The following data might be considered to represent the "natural history" of moderately increased albuminuria (formerly, microalbuminuria) in patients with type 1 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 (ACE) inhibitors or angiotensin II receptor blockers (ARBs). (See 'Treatment' below.)
Long-term follow-up of patients with type 1 diabetes who have moderately increased albuminuria has shown that the likelihood of progression to overt nephropathy (defined as a positive urine dipstick for albumin, also called severely increased albuminuria [formerly called "macroalbuminuria"] or overt or clinical albuminuria) varies with the duration of diabetes and other risk factors. On the other hand, there is also an appreciable rate of spontaneous regression of moderately increased albuminuria to normoalbuminuria. These issues are discussed in the following sections.
Kidney biopsy findings in patients with type 1 diabetes and moderately increased albuminuria can range from relatively normal histology (most often seen in patients excreting less than 45 mg of albumin per day) to clear evidence of diabetic nephropathy [29]. Diabetic nephropathy is most likely to develop in patients with more prominent albuminuria, hypertension, and/or a reduction in creatinine clearance [7,29].
Prevalence — The development of moderately increased albuminuria in patients with type 1 diabetes usually begins 5 to 15 years after the onset of diabetes and then increases over time [30-32]. A small proportion of patients develop moderately increased albuminuria within less than five years of disease onset [30,31]. In a systematic review of nine longitudinal studies examining moderately increased albuminuria in 7938 patients with type 1 diabetes, the overall prevalence of moderately increased albuminuria was 28 percent at a mean duration of diabetes of 15 years [33]. In another report, the prevalence of moderately increased albuminuria reached 52 percent at 30 years [31].
Risk factors — A number of independent factors have been noted in studies of patients with type 1 diabetes who developed moderately increased albuminuria in addition to the duration of diabetes. These include:
●Higher albumin excretion, even though the values are within the normal range [30,34-37]
●Worse glycemic control as evidenced by increased hemoglobin A1c values [30,34-41]
●Higher systolic or mean arterial pressure in most [30,32,35,40,41] but not all studies [34,35,39]
●Presence and severity of retinopathy [34,35]
●Higher total or LDL-cholesterol [36,40]
●History of smoking [42]
Although these observations do not prove a cause-and-effect relationship, they are compatible with an important role for glycemic and blood pressure control. Controlled clinical trials, most notably the Diabetes Control and Complications Trial (DCCT) and post-trial follow-up, strongly support a causal role for glycemic control in the pathogenesis of diabetic nephropathy (see 'Glycemic control' below). Patients with type 1 diabetes usually are not hypertensive if albumin excretion is normal [30,37]. The blood pressure typically begins to rise, initially within the normal range, at or within a few years after the onset of moderately increased albuminuria [30,37].
These temporal changes in blood pressure were illustrated in a prospective study of 277 patients with newly diagnosed type 1 diabetes [30]. The mean blood pressure at diabetes onset was 128/80 mmHg in the 79 patients who later developed moderately increased albuminuria, which was significantly higher than the value of 122/76 mmHg in the patients who did not go on to develop moderately increased albuminuria. At the time of progression to persistent moderately increased albuminuria, the mean blood pressure had increased to 140/84 mmHg, compared with 127/79 mmHg in the moderately increased albuminuria patients who regressed to normoalbuminuria.
The incidence of overt hypertension is approximately 15 to 25 percent in all patients with moderately increased albuminuria and increases as the patient progresses to overt nephropathy [43]. (See "Treatment of hypertension in patients with diabetes mellitus".)
Regression to normoalbuminuria — Moderately increased albuminuria reverts to normoalbuminuria in 15 to 65 percent of patients with type 1 diabetes (treated with insulin to maintain near-normal glycemia) over follow-up periods of approximately 5 to 30 years [9,30,33,44-48]. Independent risk factors for regression of moderately increased albuminuria include better glycemic control [30,44,45,47,49], lower blood pressure [30,44], lower serum cholesterol and triglyceride levels [44], recent onset of moderately increased albuminuria [44], a lesser degree of albuminuria [47], lower baseline glomerular filtration rate (GFR; ie, less glomerular hyperfiltration) [9,46], and, on kidney biopsy, smaller increases in glomerular basement membrane width [9].
The importance of these factors was illustrated in a prospective study of 386 patients with type 1 diabetes and persistent moderately increased albuminuria [44]. Regression of moderately increased albuminuria was observed in 58 percent over a total follow-up of eight years (and an average of 3.3 urinary samples per person). Regression was independently associated with the recent onset of moderately increased albuminuria and lower values of HbA1c (<8 percent), systolic blood pressure (<115 mmHg), total cholesterol (<198 mg/dL [5.12 mmol/L]), and triglycerides (<145 mg/dL [1.64 mmol/L]).
Although the above findings do not prove a cause-and-effect relationship, they are generally compatible with a central role for glycemic, blood pressure, and lipid control in inducing regression of moderately increased albuminuria to normoalbuminuria.
Blockers of the renin-angiotensin system (RAS) such as ACE inhibitors and ARBs also reduce albumin excretion. However, when given to patients with moderately increased albuminuria, they do not prevent the progression of diabetic kidney disease [10,11]. Thus, these agents are of no added benefit in normotensive patients with type 1 diabetes and moderately increased albuminuria [50].
Changes in the degree of abnormal albumin excretion over time may correlate with the risk for a decline in kidney function [48,51-53]. In general, progression and stabilization of albuminuria are associated with high and intermediate risks, respectively, for a decline in GFR. However, the prognostic implications of remission of moderately increased albuminuria are less clear. In a large meta-analysis of patients with and without diabetes (and including both type 1 and type 2 diabetes), a 30 percent reduction in albuminuria over two years was associated with a 1 percent absolute reduction in the 10-year risk of end-stage kidney disease [51]. The following studies illustrate the range of findings in patients with type 1 diabetes:
●Among 1441 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and followed long term after trial completion, 423 developed moderately increased albuminuria (defined as albumin excretion of 30 to 299 mg/day); remission to normoalbuminuria occurred in 171 of these patients, and progression to severely increased albuminuria occurred in 180 patients [48]. Compared with patients who had persistent normoalbuminuria, the risk of developing a new reduction in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2 at 18 years was similarly increased in both patients with sustained moderately increased albuminuria (hazard ratio [HR] 5.26, 95% CI 2.43 to 11.4) and patients who remitted to normoalbuminuria (HR 4.36, 95% CI 1.80 to 10.6). The risk was highest among those who progressed to severely increased albuminuria (HR 54.4, 95% CI 30.8 to 95.9).
●Another study of 658 patients with type 1 diabetes reached a similar conclusion, except that patients who had remission of moderately increased albuminuria had a more favorable kidney prognosis [53]. At 8 to 12 years of follow-up, an early decline in GFR occurred in 68, 32, 16, and 9 percent of patients with progression, stabilization, or regression of moderately increased albuminuria, and normoalbuminuria, respectively.
Progression to severely increased albuminuria (macroalbuminuria) — As noted above, severely increased albuminuria (formerly called macroalbuminuria, also called overt albuminuria, clinical kidney disease, or dipstick positive albuminuria) 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, greater than 34 mg/mmol of creatinine. Severely increased albuminuria in patients with type 1 diabetes is usually first seen after 10 years of disease and then gradually increases over time [30,54].
The rate of progression from moderately to severely increased albuminuria varies with the duration of type 1 diabetes. In a series of 292 patients with type 1 diabetes who were followed for 20 to 40 years, the rate of development of severely increased albuminuria peaked at approximately 2.5 percent per year at a disease duration of 10 to 14 years and then gradually declined to 1 percent or less per year after 20 years [54]. The cumulative incidence of severely increased albuminuria, prior to the use of current preventive therapies, was 30 to 45 percent at 40 years [54,55].
Patients with type 1 diabetes who develop moderately increased albuminuria are at significantly increased risk for progression to severely increased albuminuria compared to those without moderately increased albuminuria [30,31,54,56-59]. The frequency with which severely increased albuminuria and progression occur was evaluated in a study of 277 patients with newly diagnosed type 1 diabetes [30]. The following findings were noted:
●At a median follow-up of 18 years, 79 patients (29 percent) developed persistent moderately increased albuminuria (defined as albumin excretion rate between 30 and 300 mg/day in at least two out of three consecutive 24-hour urine collections obtained yearly). Predictors of persistent moderately increased albuminuria included a 10-fold increase in albumin excretion at baseline, male sex, a 10 mmHg increased in mean arterial pressure, and a 1 percent increase in hemoglobin A1c. (See 'Risk factors' above.)
●The 79 patients with persistent moderately increased albuminuria were followed for a median of 7.5 years at which time progression to persistent severely increased albuminuria (albumin excretion rate greater than 300 mg/day on 24-hour urine collection) occurred in 27 (34 percent), and permanent regression to normoalbuminuria occurred in 13 (16 percent), which was spontaneous (ie, in the absence of ACE inhibitors) in 10. (See 'Regression to normoalbuminuria' above.)
●None of the patients who developed severely increased albuminuria spontaneously regressed to moderately increased albuminuria or normoalbuminuria.
Other smaller studies reported variable rates of progression of moderately to severely increased albuminuria: 7 of 8 at 14 years from the diagnosis of moderately increased albuminuria [58], 12 of 14 at 10 years [56], and 5 of 18 at 10 years [60].
These disparate findings may be due in part to the time at which moderately increased albuminuria begins after the onset of type 1 diabetes. It has been suggested that almost all patients who develop moderately increased albuminuria within the first 10 years progress to severely increased albuminuria [31]. By contrast, progression to severely increased albuminuria may occur in only approximately 30 to 50 percent of patients with later onset moderately increased albuminuria [31,60].
The risk of developing severely increased albuminuria is much lower in patients with type 1 diabetes who do not develop moderately increased albuminuria after 10 to 15 years [56-59]. In one series, for example, there were 55 patients seen in 1967 who had not developed moderately increased albuminuria at a mean diabetes duration of nine years; these patients were reevaluated at 14 and 23 years. Severely increased albuminuria developed in only 2 of the 55 patients at a 14-year follow-up in 1981 [58] and in 5 of 53 at 23-year follow-up in 1990 [59]. The patients with moderately increased albuminuria at the initial evaluation also had an increased rate of cardiovascular death at 23-year follow-up. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)
Similar findings were noted in another study of patients with a mean type 1 diabetes duration of 12 years [56]. At a mean follow-up of 10 years, severely increased albuminuria developed in none of 29 patients without moderately increased albuminuria at study entry.
The magnitude of the difference in risk of developing severely increased albuminuria in patients with or without moderately increased albuminuria was evaluated in the systematic review of 7938 patients with type 1 diabetes cited above [33]. The relative risk of severely increased albuminuria in patients with compared to without moderately increased albuminuria was 7.5 (95% CI 5.4-10.5). The patients with moderately increased albuminuria also had a significantly greater fall in GFR over time, and there was a significant benefit from ACE inhibitor therapy in reducing the risk of progression from moderately to severely increased albuminuria. (See 'Angiotensin inhibition' below.)
In addition to the presence of moderately increased albuminuria and the duration of diabetes at the time of diagnosis of moderately increased albuminuria, other risk factors for the development of severely increased albuminuria in patients with type 1 diabetes include worse glycemic control as evidenced by increased A1c values and higher degrees of moderately increased albuminuria [47].
Moderately increased albuminuria (microalbuminuria) and GFR — It was initially thought that moderately increased albuminuria (formerly called "microalbuminuria") precedes the loss of glomerular filtration rate (GFR) in patients with type 1 diabetes. However, some patients with normoalbuminuria or moderately increased albuminuria have significant reductions in GFR prior to the development of severely increased albuminuria [49,53,59,61,62]. The frequency with which this occurs was evaluated in a study of 267 and 301 type 1 diabetic patients with normoalbuminuria and moderately increased albuminuria, respectively [53]. The patients were followed for 8 to 12 years with serial measurements of albumin excretion and estimation of the GFR (using the serum cystatin C concentration, which is more accurate than the serum creatinine concentration). (See "Assessment of kidney function".)
Loss of kidney function, which was defined as an estimated decrease in GFR of more than 3.3 percent per year, occurred in 9 percent of patients with normoalbuminuria and 16 percent with regression of moderately increased albuminuria. Loss of kidney function occurred much more frequently (32 and 68 percent) in patients with stable or progressive moderately increased albuminuria, respectively.
Other microvascular complications — Among patients with type 1 diabetes, the prevalence of other microvascular complications, such as retinopathy and neuropathy, increases with the degree of albuminuria. This was illustrated in a study of 981 patients who had type 1 diabetes for five or more years [63]. Proliferative retinopathy was present in 12 percent of patients with normoalbuminuria, 28 percent with moderately increased albuminuria, and 58 percent with severely increased albuminuria. The comparable rates of impaired vibratory sense were 21, 31, and 50 percent, respectively.
Mortality — Moderately increased albuminuria is associated with increased long-term mortality in patients with type 1 diabetes [2,33,59]. In the systematic review of 7938 patients cited above, the relative risk for all-cause mortality was 1.8 (95% CI 1.5-2.1) compared to patients with normoalbuminuria, with a suggestion of a similar relative risk for cardiovascular mortality [33,64].
TREATMENT — The presence of moderately increased albuminuria does not establish a diagnosis of diabetic nephropathy; rather, moderately increased albuminuria is a marker of increased inflammation and a predictor of cardiovascular events [2,65]. In several studies moderately increased albuminuria provided similar outcome results to elevated C-reactive protein [66-69].
Glucose control — As mentioned above, worse glycemic control is a risk factor for the development of moderately increased albuminuria in patients with type 1 diabetes and may also be a risk factor for disease progression in patients with moderately increased albuminuria who are treated with ACE inhibitors [70-72]. (See 'Risk factors' above.)
Strict control of the serum glucose concentration (A1C less than 7.5 percent) can slow the rate of progression or even reduce albuminuria in these patients, compared to a common increase in albumin excretion in conventionally treated patients [73-75]. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
As described below, intensive compared with conventional insulin therapy in the Diabetes Control and Complications Trial (DCCT) was associated with a significant 39 percent adjusted risk reduction in the development of new onset moderately increased albuminuria in the 1365 patients with normal albumin excretion at study entry [73]. (See 'Glycemic control' below.)
There were only 73 patients in DCCT with moderately increased albuminuria at baseline, and too few of these patients progressed to severely increased albuminuria (formerly called "macroalbuminuria") to demonstrate significant benefit from intensive insulin therapy. However, the magnitude of the treatment effect of intensive insulin therapy was similar to that in the much larger population of patients without moderately increased albuminuria at baseline.
Issues related to glycemic control are discussed in detail elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
Angiotensin inhibition — Albumin excretion is lowered and progression to severely increased albuminuria is reduced by blood pressure control, with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) [33,76-79]. ACE inhibitors and ARBs prevent progression of albuminuria with similar efficacy and in a dose-dependent manner [80-83]; therefore either drug type can be given if there is evidence of progressively increasing albuminuria (to above 300 mg/day) or if the patient becomes hypertensive. The renal goal of renin-angiotensin system (RAS) blocker therapy is to reduce blood pressure and slow nephropathy progression among those with established albuminuria levels above 300 mg/day. (See "Treatment of hypertension in patients with diabetes mellitus".)
The effects of RAS blocker therapy in patients with moderately increased albuminuria has been evaluated in numerous randomized prospective trials. In two different trials, for example, 317 patients with type 1 diabetes, moderately increased albuminuria, and a normal blood pressure were randomly assigned to captopril or placebo [77,78]. Progression to overt albuminuria was markedly reduced at two years in the patients treated with captopril (7.6 versus 23.1 percent). In one of these trials, albumin excretion fell by 9.6 percent per year in patients receiving captopril compared to an increase of 14.2 percent per year with placebo [77]. However, RAS blockers do not change the natural history of kidney disease in patients with type 1 diabetes, moderately increased albuminuria, and normal blood pressure [50]. (See 'Primary prevention' below.)
Other antihypertensive drugs — Whether other antihypertensive drugs are as effective as ACE inhibitors or ARBs in preventing progressive albuminuria in patients with diabetes and moderately increased albuminuria is unproven. This issue was addressed in a trial that randomly assigned 42 normotensive patients with type 1 diabetes and moderately increased albuminuria (mean 64 mcg/min at baseline) to perindopril, slow-release nifedipine, or placebo [84]. At three years, median albumin excretion had fallen to 23 mcg/min in the perindopril group compared with the rising values of 122 and 112 mcg/min in the other two groups.
Studies in patients with overt albuminuria have found that only diltiazem and verapamil may have as prominent antialbuminuric activity as ACE inhibitors in patients with diabetes. (See "Treatment of diabetic kidney disease".)
SCREENING — The availability of effective therapy (as described in the preceding section) led to the recommendation in the 2007 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines on diabetes and chronic kidney disease and 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines that patients with type 1 diabetes should be screened for moderately increased albuminuria (formerly, microalbuminuria) [4,85,86]. Screening can be deferred for five years after the onset of disease in type 1 diabetes because moderately increased albuminuria is uncommon before this time [4,30,31]. If not found at the initial screen, yearly screening for moderately increased albuminuria is recommended [4]. (See 'Prevalence' above.)
The KDOQI and KDIGO guidelines recommend use of the urine albumin-to-creatinine ratio on a spot urine sample for screening in diabetic patients and that an elevated urine albumin-to-creatinine ratio should be confirmed in the absence of urinary tract infection with at least two additional tests performed over the subsequent three to six months [4]. The diagnosis of moderately increased albuminuria requires an elevated ratio on at least two of the three samples.
The guidelines concluded that moderately increased albuminuria in patients with type 1 diabetes should be attributed to diabetes if the diabetes duration is at least 10 years and/or if diabetic retinopathy is present [4]. (See 'Other microvascular complications' above.)
The guidelines also noted that other causes of chronic kidney disease should be considered when there are findings that are not characteristic of diabetic nephropathy. These include:
●A low or rapidly decreasing glomerular filtration rate (GFR)
●Rapidly increasing albumin excretion or acute onset of nephrotic syndrome
●Refractory hypertension
●Active (nephritic) urine sediment (eg, dysmorphic hematuria and red cell or other cellular casts)
●Signs and/or symptoms of another systemic disease
●More than a 30 percent reduction in GFR after initiation of therapy with an ACE inhibitor or angiotensin II receptor blocker (ARB)
(See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Diagnosis'.)
PRIMARY PREVENTION — Both strict glycemic control and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs) have been evaluated for primary prevention of moderately increased albuminuria (formerly called "microalbuminuria") in patients with type 1 diabetes.
Glycemic control — Strict glycemic control is recommended in all patients with type 1 diabetes because of its beneficial effects on microvascular complications. The general benefits of strict glycemic control, including the effect of strict glycemic control on the prevention of kidney disease, is presented elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
ACE inhibitors or ARBs — A number of clinical trials have evaluated the efficacy of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for the primary prevention of moderately increased albuminuria in patients with type 1 diabetes mellitus. Four randomized, placebo-controlled trials of 256 to 3326 patients with type 1 diabetes and normoalbuminuria (Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial [AdDIT], Renin Angiotensin System Study [RASS], Examining Use of Ticagrelor in Peripheral Artery Disease [EUCLID], and Diabetic Retinopathy Candesartan Trials [DIRECT]) showed no benefit from angiotensin inhibition [10,79,87,88]. We therefore do not administer these drugs for primary prevention.
Lack of efficacy was illustrated by the results from the DIRECT Program, which included 3326 patients with type 1 diabetes who were randomly assigned to candesartan (16 to 32 mg/day) or placebo [88]. DIRECT was designed to assess the effect of candesartan on preventing the development or progression of diabetic retinopathy. The patients were also normoalbuminuric at baseline, which permitted assessment of the effect of candesartan on albumin excretion. The mean duration of diabetes was 6.7 years in the prevention arm and 11 years in the protection against progression arm.
At a mean follow-up of approximately 4.7 years, there was no difference between the candesartan and placebo groups in either the rate of developing moderately increased albuminuria (6 versus 5 percent and 16 versus 16 percent [hazard ratio, abbreviated as HR, 1.08 and 1.03] in the prevention and progression arms, respectively) or in the annual rate of increase in urinary albumin excretion.
Lack of prevention of moderately increased albuminuria was also noted in the RASS, which included 285 normotensive normoalbuminuric patients with type 1 diabetes (mean duration 11 years) [10]. In addition, kidney biopsy was performed at study onset and at five years in 90 percent of the patients. Treatment with either losartan or enalapril had no effect compared to placebo on the fraction of glomerular volume occupied by the mesangium (the primary study end point) or other histologic findings seen in diabetic nephropathy. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Pathology'.)
In summary, there is no evidence that ACE inhibitors or ARBs are effective for the primary prevention of moderately increased albuminuria in patients with type 1 diabetes who are normoalbuminuric and normotensive. These patients should be screened yearly for moderately increased albuminuria, and angiotensin inhibition should be initiated if hypertension is present and moderately increased albuminuria is documented. (See 'Screening' above and "Treatment of hypertension in patients with diabetes mellitus".)
The effect of angiotensin inhibition on retinopathy outcomes are presented elsewhere. (See "Diabetic retinopathy: Prevention and treatment", section on 'Prevention'.)
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.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Diabetic kidney disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Moderately increased albuminuria (formerly, microalbuminuria) is defined as persistent urinary albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min). Severely increased albuminuria (formerly, macroalbuminuria) refers to albumin excretion above 300 mg/day (200 mcg/min). (See 'Introduction and definitions' above.)
●Moderately increased albuminuria generally develops 5 to 15 years after the onset of type 1 diabetes. The reported prevalence is approximately 30 percent at 15 years and 50 percent by 30 years. (See 'Prevalence' above.)
●Risk factors associated with the development of moderately increased albuminuria include increased albumin excretion at baseline, poor glycemic control, hypertension, presence and severity of retinopathy, and elevated total or LDL-cholesterol. (See 'Risk factors' above.)
●Moderately increased albuminuria regresses to normoalbuminuria in a significant proportion of patients. Risk factors that favor the regression of moderately increased albuminuria include better glycemic control, lower blood pressure, lower serum cholesterol and triglycerides, recent onset and lower levels of albuminuria, and less glomerular hyperfiltration. (See 'Regression to normoalbuminuria' above.)
●Moderately increased albuminuria is associated with a higher risk for developing severely increased albuminuria, retinopathy, neuropathy, and for overall mortality. (See 'Natural history' 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 albumin-to-creatinine ratio be measured yearly in all patients who have had type 1 diabetes for five years or more. 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 hypertensive patients with persistent moderately increased albuminuria, we recommend treatment with an angiotensin-converting enzyme (ACE) inhibitor rather than other antihypertensive agents (Grade 1B). The renal goal of ACE inhibitor therapy is to reduce blood pressure and slow nephropathy progression among those with established diabetic nephropathy. Other drugs are added as necessary to attain the goal blood pressure. (See 'Angiotensin inhibition' above and "Treatment of hypertension in patients with diabetes mellitus".)
●There is no evidence supporting angiotensin inhibition for the primary prevention of moderately increased albuminuria in patients with type 1 diabetes who are normoalbuminuric and normotensive. Such patients should be screened yearly for moderately increased albuminuria and an ACE inhibitor initiated if persistent moderately increased albuminuria is documented. (See 'ACE inhibitors or ARBs' above and 'Screening' above.)
●Issues related to glycemic control, which is essential to minimize both the kidney and extrarenal complications of type 1 diabetes, are discussed in detail elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David K McCulloch, MD, who contributed to an earlier version of this topic review.
