Urinary albumin is a more sensitive marker for CKD due to diabetes, glomerular disease, and hypertension than is total urinary protein excretion.24“Standard” office dipstick urinalysis tools are not useful for detecting microalbuminuria because they detect total protein in the urine only at high levels (>500 mg/24 h). Both the NFK and the American Diabetes Association recommend using a microalbumin-sensitive dipstick or UACR in a spot urine sample for screening adults at risk for CKD and UACR for monitoring adult patients with CKD.9,24 First morning urine samples are preferred: timed or 24-hour urine samples are not necessary for screening and are much more cumbersome for patients.
There are a number of inexpensive easy-to-use methods for testing UAE in the primary care clinic that provide point-of-care results (Table II). The advantage of point of care testing is early identification of microalbuminuria, while it is still reversible, and the ability to modify treatment based on immediately available results. The authors believe that each of the currently available methodologies for urinary albumin screening provides a major step forward in promptly identifying elevated UAE. At the time of writing this communication, testing costs <$10 per test with the dipstick methodologies but insurance reimbursement has been erratic.
Table II. In-Office Albumin Tests
|Product Name||Test Description|
|HemoCue albumin 201 system (HemoCue, Angelholm, Sweden)||Urine is drawn into a reagent-lined microcuvette and read in analyzer in 90 s; range of albuminuria detection is 7–150 mg/L|
|Chemstrip Micral test strips (Roche Diagnostics, Indianapolis, IN)||1-Min dipstick reagent strip; color match result|
|Clinitek microalbumin reagent strips (Siemens Medical Solutions, Deerfield, IL)||Strips have 2 reagent areas (albumin and creatinine) making UACR calculation possible; used in Clinitek analyzers; hard copy report provided; results in 1 min|
|ImmunoDip test for microalbuminuria (Diagnostic Chemicals, San Diego, CA)||3-Min dipstick in a patented housing that allows for recording patient identification; color match result|
UAE can be elevated in certain conditions (eg, dehydration, hyperglycemia, systolic heart failure, and inflammatory states).25–27 It also is transiently increased as a result of strenuous exercise and during fever/infection.28 For example, 30 minutes following maximal exercise on a stationary bicycle, UAE is increased 20-fold from baseline in men aged 20 to 30 years and 3- to 7-fold in older men.29 UAE is increased during the febrile period but declines significantly 2 days postnormalization of body temperature.30 Interestingly, asymptomatic urinary tract infections are not associated with albuminuria, whereas symptomatic urinary tract infections are commonly associated with albuminuria.31 Consequently, to confirm the diagnosis of clinically significant microalbuminuria, clinicians should always ascertain elevated UAE measurements by rechecking a subsequent first morning urine sample, taking care that no confounding factors influence the UAE levels and obtaining at least 2 test results on separate occasions.
Ruling Out Other Disease States that Could Be Causing Albuminuria
Clinical experience suggests that all patients with hypertension, CKD, or diabetes should have UAE assessed at least annually. Because albuminuria can be caused by conditions other than hypertension, CKD, or diabetes, consideration of other disorders, such as immunoglobulin A nephritis is appropriate for patients with symptoms or signs that suggest consideration of an alternative diagnosis (Table III).32,33
Table III. Differential Diagnoses in the Etiology of Albuminuria in Patients With Hypertension, Diabetes, or Evidence of Target Organ Damage
|Diagnosis||Concurrent Conditions||Further Workup|
|Duration of diabetes||Refer to nephrologist if albuminuria worsens or renal function declines|
|Hypertensive nephrosclerosis||Typically <1 g/d proteinuria No other UA abnormalities||Refer to nephrologist if albuminuria worsens of renal function declines|
|Focal segmental glomerulosclerosis||Viral infection (HIV, parvovirus)||HIV antibody test|
|Minimal change disease (much less likely diagnosis in adults)||Chronic urinary reflux|
|Autoimmune disease (rash, joint pain)||dsDNA C3, C4|
|Vasculitis||Hepatitis C antibody|
|IgA nephropathy (recent URI?)||Serum cryoglobulins c-ANCA, p-ANCA|
|Membranous glomerulopathy||Hepatitis B/C||Hepatitis B surface antigen|
|Drugs (Gold/penicillamine/NSAID)|| |
|Lymphoproliferative disease (multiple myeloma, amyloid)||Bone pain + lytic lesions||Urine protein:creatinine ratio|
|Hypercalcemia||Urine/serum protein immunoelectrophoresis Bone marrow/fat pad biopsy|
|Polycystic kidney disease||Family history||Renal ultrasound|
Diabetes is the most common cause of albuminuria and the leading cause of end-stage renal disease in the United States. Diabetic nephropathy is characterized by hypertension, progressive albuminuria, and glomerulosclerosis, and can lead to a decline in glomerular filtration and ultimately to end-stage kidney disease if untreated. Renal biopsy is the gold standard for evaluating glomerular and tubular structure to establish the etiology of albuminuria, but is usually reserved for patients in whom a nondiabetic cause is suspected. In diabetics, because vascular basement membrane damage in the glomerulus usually occurs at the same time vascular damage in the retina is evolving (diabetic retinopathy), the absence of eye findings should direct consideration of other etiologies for albuminuria than simple diabetes. Findings that suggest a nondiabetic etiology for persistent albuminuria in a patient with diabetes include: (1) lack of retinopathy, (2) lack of autonomic neuropathy, and (3) presence of albuminuria at the time of diagnosis of diabetes (ie, albuminuria is more commonly seen in long-standing diabetes, rather than at the time of initial diagnosis).32
In patients with diabetes, differentiating between diabetes and less common etiologies of albuminuria requires a workup that can be initiated in the primary care setting. A careful patient history and physical examination may provide information that suggests alternative causes: rashes (autoimmune or systemic inflammatory disease), thrush (immunocompromised patients), or findings of liver disease (eg, ascites, splenomegaly) that may be associated with viral hepatitis. Initial laboratory testing should include a routine urinalysis with microscopic examination. The hematuria, pyuria, or casts may indicate either a glomerular or interstitial nephritis. Complete metabolic profile is appropriate to provide estimated glomerular filtration rate, creatinine (for CKD), and electrolytes. Complete blood cell count, liver function tests, and hemoglobin A1c level assessments should also be performed. In patients with nephrotic range albuminuria (urine albumin to creatinine ratio >3000 mg/g) or otherwise abnormal urinalysis, a serologic evaluation should include human immunodeficiency virus (HIV) antibody test (to assess for possible HIV-associated nephropathy), hepatitis B surface antigen, and hepatitis C antibody because either viral hepatitis can cause glomerulonephritis. Evidence also exists that hepatitis C is independently associated with albuminuria in older adults.34 An autoimmune workup including serum antinuclear antibody, antidouble strand DNA, complement 3, complement 4, and rheumatoid factor may help establish the diagnosis of systemic lupus erythematosus. Albuminuria is a universal finding in lupus nephritis, which occurs in almost 25% of patients with systemic lupus erythematosus. Other rare causes of albuminuria/proteinuria include paraproteinemias such as myeloma and amyloidosis. Supranormal serum total protein, especially when the serum albumin level is low, is indicative of excessive plasma globulin. In this setting, serum protein electrophoresis and 24-hour urine monitoring for protein electrophoresis and immunofixation are indicated to exclude multiple myeloma or other serious paraproteinemic states. Patients with abnormalities on these tests should be considered for referral to definitive diagnosis and treatment.
Autosomal dominant polycystic kidney disease is a relatively common cause of CKD and can present with hypertension and albuminuria. Family history and ultrasound examination of the kidney that reveals multiple bilateral cysts strongly suggests the presence of this condition.
In general, referral to a nephrologist for further evaluation should be considered whenever the PCC desires a second opinion on the etiology of albuminuria. Patients with abnormal laboratory data, as listed above, or deviation from the typical clinical course of diabetic nephropathy are more likely to have a nondiabetic etiology for albuminuria.
Failure to decrease proteinuria after treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) does not distinguish between the various proteinuric diseases but may be an indication of progressing renal disease that requires the involvement of a nephrologist. Patients with albumin excretion in the range of nephrotic syndrome and patients with stage 4 kidney disease should be referred promptly to a nephrologist for further evaluation. These groups may require more specialized testing and are more likely to develop complications that require further management considerations (eg, severe edema, anemia, hyperparathyroidism).