Renal Function (Microalbuminuria) Kory M. Ward Room 535 SAMP, The Ohio State University, 1583 Perty Street, Columbus, Ohio 43210-1234
Microalbuminuria is a term that represents the subclinical transition between normal albumin excretion and proteinuria and is defined as an albumin excretion rate of 30-300 mg/24 h (20200 pg/min, or 0.46-4.6 pmo1/24 h). Healthy individuals, with no abnormal albumin excretion will typically have an albumin excretion rate (AER) of less than 15 mg/day output. Those with AERs exceeding 300 mg/day have clinical proteinuria. Because of the early retrospective investigations in diabetic individuals, microalbuminuria has been demonstrated to have prognostic significance for future development of diabetic renal disease (B1, B2). More recently, clinical experience from prospective studies clearly verifies that persistent microalbuminuria provides a sensitive, but not specific identification of diabetic patients at risk of developing nephropathy (B3-B5). This expression of early diabetic renal disease is also called incipient diabetic nephropathy (B6). Although microalbuminuria was originally proposed as a “marker”for diabetic renal disease (B7-B10), it is now recognized as the earliest phase in the process (Bll-B13). Attention has also been recently given to the predictive power of microalbuminuria for cardiovascular mortality in both diabetic (Bl, B14B18) and nondiabetic (B19-BZ2) populations. It has become increasing clear that microalbuminuria is considered a generalized marker of vascular damage (B23). This slight elevation of urine albumin excretion, common in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependentdiabetes mellitus (NIDDM) , confers a higher risk of diabetic nephropathy, cardiovascular disease, morbidity and mortality, and early mortality (B24,B25). Measurement of AER in the normal and microalbuminuric range was first introduced as early as the 1960s with sensitive immunoassays (B26, B27). Not until 1986, however, did i”unoassays for low concentrations of albumin become available in the United States. The availability of these immunochemical methods coincided with the acceptance of leading groups studying diabetic nephropathy to recognize that conventional dipstick measurements for proteinuria failed to detect early elevation of the AER. This paper reviews the current concepts in the clinical significance of microalbuminuria in diabetic and in nondiabetic individuals. The prognostic significance,prevalence, and etiologic factors associated with this clinical condition are examined; treatment strategies are highlighted, and laboratory preanalytical, analytical, and postanalytical issues are summarized. DEFINING MICROALBUMINURIA Excretion of small amounts of albumin in the urine is normal. Studies have found that healthy individuals excrete less than 150 mg of total protein per 24 h (B28). Approximately one-third of this protein is albumin. This translates to an average 24h excretion of 16 mg in healthy nondiabetic subjects. By consensus, an AER of 30-300 mg (20-200 pg/min), measured in a 24h sample is indicative of microalbuminuria (B29). Strictly speaking, for an individual to be identified as having microalbuminuria,the excretion rate of 30-300 mg/day must occur on at least two out of three 24h specimens within a &month period (B30). Values greater than 300 mg/day are defined as mucroalbuminuria or
clinical albuminuria. Another term often used interchangeably with microalbuminuria is microproteinuria. Although this term has been used synonymously, it actually refers to the excretion of smaller sized proteins such as Brmicroglobulin. In addition, microalbuminuria has also been less specifically defined as “an increased excretion of albumin above the reference range for healthy nondiabetic individuals, but which is not detected by dipstick tests” (B31). Although this definition of microalbuminuria has been applied, the more accurate means of defining microalbuminuria is by reporting the urinary AER Formats for expressing AER include the following: micrograms per minute or second; milligrams per day; micromoles per day; milligrams of albumin to milligrams, grams, or millimoles of creatinine (as a ratio). The reference ranges for microalbuminuria by these various modes of reporting are as follows: (rate) 30-300 mg/24 h, 20-200 pg/min, 0.333.33 pg/s, or 0.46-4.6 pmo1/24 h; (ratio) 20-200 mg/g, 0.020.2 mg/mg, or 0.4-2.8 mg/mmol creatinine; (concentration) 30300 mg/L. PATHOPHYSIOLOGY The presence of microalbuminuria in early diabetic nephropathy is related to one or more general mechanisms and associated etiologic factors. The pathophysiology underlying microalbuminuria is related to hemodynamic alterations and structural and functional changes seen in the glomerular basement membrane (GBM) and the mesangium of the glomerulus. A number of pathologic derangements and structural alterations have been implicated in the development of diabetic nephropathy. These include (1) a genetic predisposition for the development of diabetic nephropathy, (2) hemodynamic alterations and renal hypertrophy, (3) systemic hypertension, and (4) metabolic control. There is no one universally acceptable hypothesis for the evolution of diabetic nephropathy. What is known, however, are the pathologic derangements that contribute to renal failure in diabetic individuals. Studies have shown that there is a definite genetic predisposition to the development of diabetic nephropathy (B32-B35). In patients who have a strong family history of renal disease, hypertension, or both, there is a greater tendency to develop diabetic nephropathy. Evidence to support this theory comes from clinical data from patients who have poor glycemic control. It is noteworthy that less than half of those diabetic individuals who have chronically poor glycemic control, as evidenced by a hemoglobin AI, value of greater than 8.5%(reference range 10->70 pg/min), and the length of followup (6- 14 years), the presence of microalbuminuria has been a good predictor of subsequent overt nephropathy, especially in patients with IDDM (B70).Retrospective studies of patients with diabetes of a l@yearduration and microalbuminuriahave shown
Table 1. Literature Survey of Predictive Value of Albumin Excretion Ratea no.
IDDM NIDDM
230
263
followup (years)
sensitivity
8 6
82
(%I
70
(%)
positive predictive value(%)
96 13
15 25
specificity
a Reproduced with permission from Winer RL. Microalbuminuria: a discussion of disease involvement; Monograph MA-1; Beckman Instruments, Inc.: Brea, CA, 1989.
that 80%will develop diabetic nephropathy, whereas only 4% of those IDDM patients with an AER of
