Risk factors for microalbuminuria in black americans with newly diagnosed type 2 diabetes

Risk Factors for Microalbuminuria in Black Americans With Newly Diagnosed Type 2 Diabetes Kathryn A. Kohler, PhD, William M. McClellan, MD, David C. Ziemer, MD, David G. Kleinbaum, PhD, and John R. Boring, PhD ● We conducted a cross-sectional analysis to describe the prevalence of and risk factors for microalbuminuria among blacks with newly diagnosed type 2 diabetes. Black adults with diagnosed type 2 diabetes mellitus of 2 years’ duration or less who presented for care to the Grady Diabetes Clinic (Atlanta, GA) between January 1, 1994, and December 31, 1996, were eligible (n ⴝ 1,167). Information obtained at the initial visit included age; sex; body mass index (BMI); serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, C-peptide, serum creatinine, and hemoglobin A1c (HbA1c) levels; and seated systolic and diastolic blood pressures. Outcome was urine albumin-creatinine (Alb/Cr) ratio at the initial visit. Alb/Cr ratios were categorized as normal (Alb/Cr <25␮g/mg), microalbuminuric (Alb/Cr, 25 to 250 ␮g/mg), and macroalbuminuric (Alb/Cr >250 ␮g/mg). Patients with macroalbuminuria or creatinine levels of 2 mg/dL or greater were excluded. We used multiple linear regression to assess the joint association between HbA1c level, mean arterial pressure (MAP), and log-transformed Alb/Cr, controlling for other covariates. Of 1,044 patients studied, macroalbuminuria was present in 3.8%, and microalbuminuria, in 23.4%. Alb/Cr was independently associated with increased HbA1c level (P ⴝ 0.0070), MAP (P ⴝ 0.0001), BMI (P ⴝ 0.0156), log-transformed triglyceride levels (P ⴝ 0.0031), C-peptide level of 6.5 ng/mL or greater (P ⴝ 0.0007), serum creatinine level (P ⴝ 0.0068), and male sex (P ⴝ 0.0220). The relationship between HbA1c level and microalbuminuria was stronger in patients with lower BMIs. Microalbuminuria prevalence was high in this population of urban blacks with newly diagnosed type 2 diabetes. Risk factors associated with increased Alb/Cr included male sex, poor glycemic control, endogenous hyperinsulinemia, high blood pressure, elevated triglyceride levels, and obesity. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Albuminuria; diabetes mellitus type 2; blacks; human; insulin resistance; risk factors; diabetic nephropathy.

Editorial, p. 1054

P

ERSISTENT proteinuria develops in 30% to 40% of all patients with diabetes1,2 and is followed by end-stage renal disease (ESRD) in approximately 20% to 40% of the patients with type 1 diabetes3-5 and 3% to 8% of those with type 2 diabetes.2,6 Blacks with type 2 diabetes have an increased risk for developing microvascular complications, particularly nephropathy, compared with whites.7 For example, the incidence of diabetic ESRD is three times greater in black Americans than in whites. Type 2 diabetes accounts for most of this risk, and this excess risk persists even after controlling for hypertension.8-10 Microalbuminuria, a urinary albumin excretion (UAE) rate of 20 to 200 ␮g/min, is a predictor of clinical proteinuria and ESRD in patients with both type 1 and type 2 diabetes mellitus.11-13 Several studies have shown a high prevalence of microalbuminuria among persons with type 2 diabetes at initial diabetes diagnosis.14-20 The mechanisms underlying this premature development of microalbuminuria at the

presentation of type 2 diabetes mellitus have yet to be delineated. Several risk factors are commonly associated with microalbuminuria in persons with diabetes, including high blood pressure,14,15,21-24 long duration of diabetes,14,15,25,26 poor glycemic control,2,21,27 dyslipidemia,14,23,28,29 and male sex.23,24,30 However, it is unclear whether some of these physiologic factors precede and possibly initiate microalbuminuria or whether they are concurrent manifestations of underlying diabetic kidney disease. We investigated this issue by examining the

From the Department of Epidemiology, Rollins School of Public Health; Center for Clinical Evaluation Sciences, Program in Hypertension and Renal Disease Health Services Research; Emory University; and the Department of Medicine, Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA. Received September 20, 1999; accepted in revised form May 26, 2000. Address reprint requests to William M. McClellan, MD, Georgia Medical Care Foundation, 57 Executive Park South NE, Ste 200, Atlanta, GA 30329-2224. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3605-0003$3.00/0 doi:10.1053/ajkd.2000.19080

American Journal of Kidney Diseases, Vol 36, No 5 (November), 2000: pp 903-913

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associations between glycemic control (using hemoglobin A1c [HbA1c] level), mean arterial blood pressure (MAP), and microalbuminuria in an urban population of black Americans with newly diagnosed type 2 diabetes. PATIENTS AND METHODS

Study Population We studied black patients with type 2 diabetes from an economically disadvantaged urban population with low levels of literacy and poor health insurance coverage.14,31 Patients with a diabetes diagnosis for 2 years or less who presented to the Grady Diabetes Clinic (Atlanta, GA) for the first time between January 1, 1994, and December 31, 1996, were eligible for inclusion. Patients with both urine albumin and urine creatinine measurements at this visit were included in the analyses; patients with serum creatinine levels of 2 mg/dL or greater were excluded.

Data At their intake visit to the Grady Diabetes Clinic, new patients underwent physical examination, an in-depth medical interview, laboratory testing, and diabetes education classes; findings were recorded on data collection sheets and entered into a relational database (FoxPro; Microsoft, Redmond, WA). Diabetes was confirmed using the standard American Diabetes Association criteria.32 Type 2 diabetes mellitus was diagnosed in patients with obesity and/or a strong family history of diabetes, no history of recurrent ketosis, diabetes management without insulin, no recurrent pancreatitis, and hyperglycemia in the absence of diabetogenic medications. Race was determined by observation by the nurse-provider or by direct questioning of the patient. Diabetes duration was estimated by asking patients when a health care provider first told them they had diabetes, excluding diabetes during pregnancy. Height and weight in light clothing were measured, and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. A single blood pressure measurement was performed; systolic and diastolic blood pressures were measured with an aneroid sphygmomanometer after the patients were sitting at rest for at least 3 minutes. MAP was calculated as diastolic blood pressure plus one third the difference between the systolic and diastolic blood pressures. Routine blood chemistry measurements were determined by the Grady clinical laboratory. HbA1c level at the intake visit was measured by high-performance liquid chromatography (DIAMAT; Biorad, Hercules, CA) and corrected for the proportion of hemoglobin A. Enzymatic assay (Hitachi 747/717; Hitachi Ltd, Tokyo, Japan; Boehringer Mannheim, Indianapolis, IN) measured total cholesterol and triglyceride levels. All lipids were measured as fasting levels. A precipitation technique (Reagent set HDL-C; Boehringer Mannheim) was used to separate high-density lipoprotein (HDL) cholesterol. C-peptide was measured by radioimmunoassay (INCSTAR Corp, Stillwater, MN). Patients were asked to provide a random morning urine specimen on arrival at the intake clinic visit. Urine albumin

content was measured using a Boehringer Mannheim nephelometric technique with a sensitivity of 0.18 mg/dL.33 Creatinine level was measured photometrically using the alkaline picric acid reaction. Albumin-creatinine (Alb/Cr) ratio from a random urine sample has been identified as a reliable and valid means of estimating albumin excretion rate (AER) in clinic settings.14,34-37 We calculated the Alb/Cr ratio from random urine samples, expressed as micrograms of albumin per milligram of creatinine. We divided subjects into three groups: normoalbuminuria (Alb/Cr ⬍25 ␮g/mg), microalbuminuria (Alb/Cr, 25 to 250 ␮g/mg), and macroalbuminuria and/or clinical nephropathy (Alb/Cr ⬎250 ␮g/mg).14

Statistical Methods Statistical analysis was performed using SAS computer software version 6.12 (SAS Institute, Cary, NC). Student’s t-test and Kruskal-Wallis test for nonparametric data were used to compare means of continuous variables in microalbuminuric and normoalbuminuric groups. Because of skewness, the Alb/Cr ratio was transformed using the natural log, and all analyses were performed using this transformed term, ln(Alb/Cr). Serum triglyceride levels were similarly log transformed to normalize their distribution. Along with simple linear regression, Pearson’s correlation coefficient (r) was computed to examine the linear correlation between ln(Alb/Cr) and each of the baseline clinical variables and the correlations between all pairs of clinical variables. Multiple linear regression was performed to assess the change in ln(Alb/Cr) with each of the clinical variables and to estimate the effect of each of the exposures on ln(Alb/Cr) while controlling for other clinical variables. Data are presented as mean ⫾ SD. We assessed the joint association of MAP and HbA1c level with the dependent variable ln(Alb/Cr), controlling for other covariates by using multiple linear regression. The mean value of ln(Alb/Cr) increased noticeably for C-peptide levels of 6.5 ng/mL or greater; thus, C-peptide level was dichotomized at this cut point. The two main exposures, MAP and HbA1c, were forced into the initial model as continuous variables. Nine potential confounders were added to the initial model: age, BMI, total cholesterol level, C-peptide level, diabetes duration, HDL cholesterol level, serum creatinine level, ln(triglycerides), and sex.

RESULTS

Record review identified 1,167 eligible patients. Adequate information was available to calculate the Alb/Cr ratio for 1,055 of these patients (90.4%). Eleven patients with serum creatinine levels of 2 mg/dL or greater were excluded. Of the remaining 1,044 patients, 40 patients (3.8%) had clinical nephropathy (Alb/ Cr ⬎250 ␮g/mg) at the initial visit, 244 patients (23.4%) had microalbuminuria, and 760 patients (72.8%) had normoalbuminuria (Table 1). The 40 patients with clinical nephropathy were excluded from the remaining analyses. Mean Alb/Cr

MICROALBUMINURIA IN BLACKS WITH DIABETES

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Table 1. Prevalence of Microalbuminuria and Macroalbuminuria in Black Americans With Recent Onset Type 2 Diabetes All Albuminuria Group

No.

Women %

No.

%

Men No.

%

Normoalbuminuria 760 72.8 515 74.3 245 69.8 Microalbuminuria 244 23.4 155 22.4 89 25.4 Macroalbuminuria 40 3.8 23 3.3 17 4.8 Total 1,044 100 693 100 351 100 NOTE. Patients were treated at the Grady Health System Diabetes Clinic, January 1, 1994, to December 31, 1996. Normoalbuminuria, Alb/Cr less than 25 ␮g/mg; microalbuminuria, Alb/Cr of 25 to 250 ␮g/mg; and macroalbuminuria, Alb/Cr greater than 250 ␮g/mg.

ratios were 74.8 ␮g/mg in microalbuminuric patients and 7.85 ␮g/mg in normoalbuminuric patients. Distribution of Alb/Cr and ln(Alb/Cr) ratios are shown in Figs 1 and 2. Table 2 lists the clinical characteristics of the 1,004 patients without clinical nephropathy. The mean age of the patients was 51.3 ⫾ 13.5 years, mean BMI was 33.7 ⫾ 8.7 kg/m2, and 66.7% were women. The mean HbA1c level was 9.1% ⫾ 2.6%, and mean MAP was 93.5 ⫾ 11.3 mm Hg. In univariate analysis, patients with microalbuminuria had greater MAPs (P ⫽ 0.0027), Cpeptide levels (P ⫽ 0.0301), and triglyceride levels (P ⫽ 0.0034) compared with patients with normoalbuminuria (Table 3). Values for HbA1c, age, BMI, total cholesterol, diabetes duration,

Fig 1. Cr.

Distribution of Alb/

HDL cholesterol, and serum creatinine did not differ significantly between the two groups. The proportions of men and women with microalbuminuria were not statistically significantly different (26.7% versus 23.1%, respectively; P ⬎ 0.05). Pearson’s correlation coefficient also showed a statistically significant correlation between outcome, ln(Alb/Cr), HbA1c level (P ⫽ 0.0168), and MAP (P ⫽ 0.0001; Table 4). C-peptide level (P ⫽ 0.0022) and ln(triglycerides) (P ⫽ 0.0001) were also associated with ln(Alb/Cr). Conversely, there were no associations between ln(Alb/Cr) and age, BMI, total serum cholesterol level, diabetes duration, HDL cholesterol level, or serum creatinine level. As expected, many of the covariates significantly correlated with each other. Table 5 lists the variables and parameter estimates for the final multivariate model. Increased HbA1c level (P ⫽ 0.0070), MAP (P ⫽ 0.0001), BMI (P ⫽ 0.0156), ln(triglycerides) (P ⫽ 0.0031), C-peptide level of 6.5 ng/dL or greater (P ⫽ 0.0007), and male sex (P ⫽ 0.0220) were significant predictors of increased Alb/Cr. There was an inverse relationship between ln(Alb/ Cr) and serum creatinine level (P ⫽ 0.0068). The interaction term between HbA1c level and BMI was also statistically significant and remained in the final model. Despite a number of significant correlations between covariates in the model, the collinearity analysis showed no collinearity.

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Fig 2. Distribution ln(Alb/Cr).

DISCUSSION

The urban black Americans with type 2 diabetes in our study had a high prevalence of microalbuminuria despite short duration (ⱕ2 years) of diagnosed diabetes. Studies of other nonwhite type 2 diabetic populations have also noted a high prevalence of microalbuminuria; however, these studies did not focus solely on those with short diabetes duration.14,15,38,39 Few studies have examined microalbuminuria in black Americans with type 2 diabetes. Patients with type 2 diabetes are believed to have had the disease for an average of 4 to 7 years before diagnosis. In that time, untreated hyperglycemia may be one factor that initiates microvascular and macrovascular damage.40,41 Table 2. Variable

Population Characteristics Mean

SD Minimum Maximum

Alb/Cr (␮g/mg) 24.1 38.9 0.3 ln(Alb/Cr) 2.4 1.2 ⫺1.2 HbA1c (%) 9.1 2.6 2.9 MAP (mm Hg) 93.5 11.3 56.7 Sex (F/M) 670/334 Age (y) 51.3 13.5 19.0 BMI (kg/m2) 33.7 8.7 15.2 Cholesterol (mg/dL) 203.7 46.7 82 C-peptide (ng/dL) 2.8 1.3 0.4 Duration (y) 0.4 0.5 0 HDL (mg/dL) 43.3 13.5 2 Serum creatinine (mg/dL) 0.9 0.2 0.3 Triglycerides (mg/dL) 153.2 140.3 35

242.5 5.5 19.8 131.3 93.2 87.5 448 14.6 2 115 1.8 2,296

NOTE. Population included 1,004 black Americans with recent-onset type 2 diabetes from the Grady Health System Diabetes Clinic, January 1, 1994, to December 31, 1996.

of

Our finding of high microalbuminuria prevalence in newly diagnosed patients may reflect a longer interval between diabetes onset and diagnosis in this population. Alternatively, urban black Americans may be at increased risk for developing renal dysfunction earlier in the course of their diabetes. Table 6 summarizes three previous crosssectional studies of microalbuminuria prevalence in black Americans. Microalbuminuria prevalence ranged from 17% to 31% in these populations with diabetes mellitus of longer duration than among the newly diagnosed patients in our study. A previous study of a different cohort of patients from the Grady Diabetes Clinic found that microalbuminuria prevalence was 25% when restricting the analysis to those patients with diabetes duration less than 1 year.14 Conversely, Chaiken et al34 studied 218 black patients with type 2 diabetes and found that none of the 40 patients with duration of diagnosed diabetes less than 1 year had evidence of microalbuminuria. It is not clear whether the population studied was similar to our population with respect to socioeconomic and demographic characteristics, which might explain some of the disparities. The microalbuminuria prevalence of 23.3% in our patient population appears quite high considering that mean duration of diagnosed diabetes was only 5 months. Our results support the relationship between poor blood glucose control measured by greater initial HbA1c levels and microalbuminuria, reflected by greater Alb/Cr ratios. This contrasts with the prior study of patients from this clinic

MICROALBUMINURIA IN BLACKS WITH DIABETES Table 3.

Covariates in the Study Population

All

Normoalbuminuria

Microalbuminuria

P

9.1 ⫾ 2.6 93.5 ⫾ 11.3 51.3 ⫾ 13.5 33.7 ⫾ 8.7 203.7 ⫾ 46.7 2.8 ⫾ 1.3 0.9 ⫾ 0.2 0.4 ⫾ 0.5 43.3 ⫾ 13.5 153.2 ⫾ 140.3 4.9 ⫾ 0.5

9.0 ⫾ 2.6 92.9 ⫾ 11.1 51.2 ⫾ 13.3 33.4 ⫾ 8.1 202.4 ⫾ 45.1 2.7 ⫾ 1.2 0.9 ⫾ 0.2 0.4 ⫾ 0.5 43.5 ⫾ 13.4 141.5 ⫾ 92.5 4.8 ⫾ 0.5

9.3 ⫾ 2.5 95.4 ⫾ 11.7 51.6 ⫾ 14.0 34.5 ⫾ 10.3 207.3 ⫾ 51.3 3.0 ⫾ 1.7 0.9 ⫾ 0.3 0.4 ⫾ 0.4 42.9 ⫾ 13.8 189.5 ⫾ 229.6 5.0 ⫾ 0.6

0.1064 0.0027 0.6368 0.1562 0.1489 0.0301 0.6841 0.9826 0.6008 0.0034 0.0005

Variable

HbA1c (%) MAP (mm Hg) Age (y) BMI (kg/m2) Cholesterol (mg/dL) C-peptide (ng/mL) Creatinine (mg/dL) Duration (y) HDL cholesterol (mg/dL) Triglycerides (mg/dL) ln(triglycerides)

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NOTE. Data presented as mean ⫾ SD. P compares means in normoalbuminuric and microalbuminuric groups using appropriate t-test or Kruskal-Wallis test for nonparametric data.

was consistent with the highly significant effect of hypertension on microalbuminuria in the study of Goldschmid et al.14 Dasmahapatra et al15 also showed significant positive correlations between systolic and mean blood pressures and AER. These studies of black Americans with type 2 diabetes support the hypothesis that hemodynamic processes are intricately involved in the development and progression of nephropathy and thus underscore the importance of blood pressure management and antihypertensive therapy to prevent kidney disease in persons with diabetes. We found a strong positive association between C-peptide level and microalbuminuria among patients with C-peptide levels of 6.5 ng/mL or greater. Greater C-peptide level is a marker for greater endogenous insulin secretion.

with type 2 diabetes that, by means of stepwise linear regression, did not find that HbA1c level was significantly related to microalbuminuria.14 This may be caused by the use of a different algorithm for selecting variables in the regression analysis; alternatively, it may be a result of including patients with longer duration of diabetes. Dasmahapatra et al15 found no significant correlation between AER and glycated hemoglobin level in their entire population of 116 patients; however, the correlation was positive and significant when restricted to only patients with incipient nephropathy. Discrepancies among these three studies may also reflect the poor reproducibility of Alb/Cr ratios from random urine samples because daily variability can be as high as 40%.42 The positive relationship between higher blood pressure and greater Alb/Cr ratios in our study Table 4.

ln(Alb/Cr) HbA1c MAP Age BMI Cholesterol C-peptide Duration HDL Creatinine ln(triglycerides)

Pearson’s Correlation Coefficients Between Main Exposures, Covariates, and Outcome

ln(Alb/Cr)

HBA1c

MAP

Age

BMI

Cholesterol

C-Peptide

Duration

— 0.0755* 0.1362* 0.0298 0.0340 0.0605 0.0969* 0.0224 ⫺0.0206 ⫺0.0411 0.1420*

— ⫺0.1062* ⫺0.0649* ⫺0.0007 0.1266* ⫺0.0890* ⫺0.0646* ⫺0.0372 ⫺0.0471 0.1820*

— 0.1500* 0.1053* 0.1160* 0.0645* 0.0345 0.0856* 0.0591 0.0344

— ⫺0.2875* 0.1263* ⫺0.0356 ⫺0.0275 0.2261* 0.1731* ⫺0.0488

— ⫺0.0113 0.2121* ⫺0.0041 ⫺0.1597* ⫺0.0579 0.0478

— 0.0343 0.0353 0.2481* 0.0268 0.3296*

— 0.0027 ⫺0.2167* 0.1163* 0.3447*

— 0.0332 — 0.0053 ⫺0.0556 0.0637* ⫺0.3722*

NOTE. Main exposures are HbA1c level and MAP, and outcome is ln(Alb/Cr). *P ⬍ 0.05.

HDL

Creatinine

— 0.0416

908 Table 5.

KOHLER ET AL Results of Multiple Linear Regression

Variable

Intercept HbA1c MAP Age BMI Cholesterol C-peptide* Duration HDL cholesterol Serum creatinine ln(triglycerides) Sex† HbA1c ⫻ BMI

␤ˆ

SE (␤ˆ )

P

⫺8.5814 0.1535 0.0136 0.0037 0.0386 ⫺0.0003 1.1114 0.0330 0.0027 ⫺0.4946 0.2590 0.2132 ⫺0.0036

0.7837 0.0568 0.0035 0.0032 0.0159 0.0010 0.3287 0.0849 0.0035 0.1823 0.0873 0.0929 0.0017

0.0001 0.0070 0.0001 0.2404 0.0156 0.7783 0.0007 0.6977 0.4381 0.0068 0.0031 0.0220 0.0286

NOTE. Final model after backward elimination of interaction terms. Dependent variable is ln(Alb/Cr). *C-peptide: ⱖ6.5 ⫽ 1, ⬍6.5 ⫽ 0. †Sex: male ⫽ 1, female ⫽ 0.

These results suggest that in extremely hyperinsulinemic patients, there is a strong linear relation between C-peptide level and increasing levels of microalbuminuria, but this relation does not hold in patients with lower C-peptide levels. Because patients with low C-peptide clearance might have renal dysfunction, we also examined this relationship by controlling for serum creatinine level and found no difference. However, it is important to note that the median C-peptide level in our population was 2.5 ng/mL, and only 15 of our patients had C-peptide levels of 6.5 ng/mL or greater. When these patients were excluded, the final model remained virtually unchanged except that C-peptide level was no longer statistically Table 6.

Prevalence of Microalbuminuria in Blacks With Type 2 Diabetes

Publication Date

Population Size

Dasmahapatra et al15

1994

116

10.1 y

Goldschmid et al14

1995

466

5.3 y

Chaiken et al34

1997

218

Range, 1 mon32.6 y

Reference

significant. Thus, C-peptide level is likely only linearly related to ln(Alb/Cr) at the extremely high end of its distribution. Greater fasting triglyceride levels were positively associated with microalbuminuria in our patients; however, the small magnitude of this association is probably not clinically meaningful. Lipid level abnormalities, particularly elevated very low-density lipoprotein and triglyceride levels and low HDL level, are common in other populations with type 2 diabetes43 and correlated with diabetic nephropathy in several studies.17,21,23,44 Savage et al23 found that triglyceride and HDL levels were significantly related to both microalbuminuria and macroalbuminuria in univariate analyses of a large multiracial population of persons with type 2 diabetes. However, in multivariate analyses, only HDL level remained significant. Lee et al44 studied Koreans with type 2 diabetes and showed that patients with overt proteinuria had significantly greater total cholesterol and triglyceride levels and lower HDL levels than normoalbuminuric and microalbuminuric patients. Data from an Italian study support the findings with respect to HDL and triglyceride levels but did not support statistically significant differences in total cholesterol levels.21 The relationship between dyslipidemia and nephropathy is less clear in black Americans with type 2 diabetes. Dasmahapatra et al15 were unable to show a correlation between serum lipid levels and albuminuria, even after excluding patients administered lipid-lowering agents. Con-

Mean Diabetes Duration

Microalbuminuria Definition

24-h urine specimen, AER, 20-200 ␮g/min 24-h urine specimen,* AER, 30-300 mg/24 h ⬍3-h timed specimen,† Alb/Cr, 25-250 ␮g/mg Untimed morning specimen Alb/Cr, 30-300 ␮g/mg

Microalbuminuria Prevalence (%)

31 (overall) 26 (overall) 26 (duration ⬍1 y) 24 (overall) 25 (duration ⬍1 y) 17 (overall) 0 (duration ⬍1 y)

*Based on 122 patients with adequate 24-hour urine specimens. †Excludes 23 patients with clinical nephropathy and 5 patients without adequate data for calculation of Alb/Cr ratio.

MICROALBUMINURIA IN BLACKS WITH DIABETES

versely, Goldschmid et al14 found that total and low-density lipoprotein cholesterol levels were independently associated with the log of the Alb/Cr ratio in a multivariate analysis. However, triglyceride and HDL levels did not reach statistical significance. Our results showed a strong association only between triglyceride levels and Alb/Cr ratio. Serum creatinine level was inversely related to ln(Alb/Cr) in our population of recently diagnosed blacks with type 2 diabetes. In a similar population, Chaiken et al45 recently showed that patients with hyperfiltration (and thus possibly lower serum creatinine levels, although this was not specifically assessed) were more likely to have normal AERs than patients without hyperfiltration. We restricted our interest to patients with recently diagnosed type 2 diabetes; early diabetic nephropathy is characterized by increased glomerular filtration rate and normal or possibly lower serum creatinine levels. The early appearance of microalbuminuria is a poorly understood phenomenon of type 2 diabetes. The inverse relation between serum creatinine level and Alb/Cr in our study may reflect other mechanisms of renal damage, such as hypertension, that result in decreased glomerular filtration rate before the occurrence of macroalbuminuria. Greater BMI and male sex were also strongly related to greater Alb/Cr ratios in our study. This confirms the findings of Dasmahapatra et al15 in a group of 116 black Americans with type 2 diabetes. Interestingly, in a previous study of black American patients with type 2 diabetes from our clinic, BMI was not a statistically significant predictor of albuminuria in a multiple logistic regression analysis.14 The relationship between HbA1c level and microalbuminuria in our population was complicated by BMI. Our multivariate model showed a strong, positive linear relationship between ln(Alb/Cr) and HbA1c level in patients with lower BMI; this relationship was attenuated in patients with higher BMI. Patients on the high end of the BMI distribution are likely to be more insulin resistant than patients with lower BMI, which is consistent with the strong positive correlation we observed between BMI and C-peptide level (r ⫽ 0.21; P ⫽ 0.0001). Insulin resistance develops gradually and precedes the increase in blood

909

glucose levels in patients with type 2 diabetes.46 In heavier patients, a longer cumulative exposure to high levels of serum insulin might pose more of a threat to the renal endothelium than circulating glycosylated proteins. Conversely, patients with a lower BMI are less likely to have hyperinsulinemia and may thus be more sensitive to the nephrotoxic effects of glycated proteins. However, the roles of endogenous and exogenous insulin in the pathological state of diabetic renal disease are not clear. Although serum insulin levels have been associated with microalbuminuria progression, raising the possibility that endogenous insulin may be involved in glomerular injury,47 evidence from the Diabetes Control and Complications Trial has shown that tight blood glucose control with high levels of exogenous insulin protects the kidney from microalbuminuria progression.48 Another possibility is that patients with lower BMIs represent a subpopulation with characteristics intermediate between type 1 and type 2 diabetes. This group of patients may be more susceptible to hyperglycemiainduced kidney damage than patients with type 2 diabetes with the more traditional concomitant obesity. An interesting observation in our study was the association between microalbuminuria and a number of patient characteristics associated with metabolic syndrome X, or the insulin resistance syndrome (IRS).49 IRS describes a constellation of patient characteristics, including central obesity, increased triglyceride levels, decreased HDL cholesterol levels, glucose intolerance, and hypertension, that often occur in concert and are linked to increased risk for coronary heart disease. Hyperinsulinemia and/or insulin resistance may be the common factors behind these attributes. The prevalence of these characteristics was quite high in the black American patients with type 2 diabetes on our study, and these factors clearly correlated with each other. For example, C-peptide level positively correlated with ln(triglycerides) (r ⫽ 0.34; P ⬍ 0.0001) and BMI (r ⫽ 0.21; P ⬍ 0.0001) and negatively correlated with HDL level (r ⫽ –0.22; P ⬍ 0.0001). We also showed statistically significant relationships between nephropathy and greater MAP, poor glycemic control (measured by greater HbA1c levels), greater serum triglyceride levels, hyperinsulinemia (mea-

910

sured by greater C-peptide levels), and greater BMI, all components of IRS. Although these correlations suggest an association between microalbuminuria and IRS, several observations in our data are inconsistent. First, although BMI was significantly associated with microalbuminuria when controlling for other variables in the multiple linear regression analysis, mean BMI did not differ significantly between the normoalbuminuric and microalbuminuric groups. C-peptide levels were statistically significantly greater in the microalbuminuric patients, but the magnitude of the difference was quite small. In addition, HDL cholesterol levels were similar in the two groups. Some investigators have suggested that increased AERs may be another factor associated with IRS. Small experimental studies have examined the relationship between insulin resistance and albuminuria using hyperinsulinemic euglycemic clamp techniques.50-52 Niskanen and Laasko50 studied 22 persons with type 2 diabetes with elevated UAE rates and 18 persons with normal UAE. The mean glucose disposal rate was less in the group with elevated UAE after adjusting for hypertension, BMI, and sex, suggesting that even low levels of albuminuria were associated with impaired insulin action. Nosadini et al51 compared 28 persons with type 2 diabetes and 25 hypertensive patients without diabetes with two groups of healthy control subjects matched for age, sex, and weight. In the nondiabetic hypertensive group, whole-body glucose utilization was significantly less among patients with microalbuminuria compared with those with normal AERs. Similar findings held for the persons with diabetes and microalbuminuria versus those without microalbuminuria. In a study of 52 persons with type 2 diabetes and 19 controls without diabetes, Groop et al52 also showed impaired glucose metabolism among microalbuminuric patients. There has been little epidemiologic examination of the relationship between IRS and microalbuminuria. Recently, a population-based study of 622 white adults found that microalbuminuria was related to hypertension, type 2 diabetes, and waist-hip ratio, but not to other components of IRS.53 When only the 155 persons with type 2 diabetes were included, hypertension was the only variable associated with microalbumin-

KOHLER ET AL

uria. The investigators concluded that microalbuminuria was not a useful marker for IRS in whites. The small sample size for persons with diabetes may have hindered the ability to detect statistically significant associations between microalbuminuria and components of IRS. Alternatively, these associations may not exist in white populations, which typically have a lower prevalence of microalbuminuria than other racial/ ethnic groups. Several limitations to our study should be noted. First, the use of cross-sectional data limits our ability to draw causal inferences because the exposures and outcome were measured simultaneously. There is also the possibility of survivor bias because our data reflect only patients still alive during the study time frame of interest. Next, we had no marker for treated hypertension. Although some patients had information regarding the type of antihypertensive medication used, these data were incomplete. The inclusion of hypertension regardless of whether controlled as an independent risk factor for microalbuminuria might have altered our results. However, MAP was strongly associated with the Alb/Cr ratio in our study. We also used only one blood pressure measurement. Because blood pressure varies both diurnally and over longer periods of time, the use of a single measurement cannot fully describe the blood pressure patterns of a given patient and thus may have resulted in misclassification. Any misclassification that may have occurred was probably not associated with disease status because health care providers were not aware of patients’ Alb/Cr ratios while measuring blood pressure. The net result of nondifferential misclassification of exposure would be to attenuate our observed association between MAP and microalbuminuria. A similar weakness results from having only a single HbA1c measurement, which may reflect recent therapeutic changes rather than long-term hyperglycemia. Additionally, extremely elevated blood glucose levels may contribute to microalbuminuria that could potentially be resolved after a period of improved blood glucose control. Because of the cross-sectional design of our study, we were unable to assess how many of our patients initially classified as microalbuminuric remained in that category after improved glycemic control.

MICROALBUMINURIA IN BLACKS WITH DIABETES

We reanalyzed the data, excluding 53 patients with HbA1c levels at the 95th percentile of our distribution (ⱖ13.7%) or greater and 3 patients with missing initial HbA1c values. Exclusion of these patients with extremely high initial blood glucose levels did not alter our results (data not shown). The use of a single Alb/Cr ratio may have misclassified the microalbuminuric status of some patients. The Alb/Cr ratio may vary substantially from day to day and can be transiently increased because of factors including fever, exercise, elevated blood pressure, urinary tract infection, congestive heart failure, posture, and extreme hyperglycemia.42,54 Ideally, several Alb/Cr measurements over time should be used to identify patients with persistent microalbuminuria. Misclassification of normoalbuminuria and microalbuminuria in our study is likely to be random and independent of the main exposures, diluting any differences between the two groups. Misclassification may have been minimized by our use of a slightly higher cut point for microalbuminuria than is typically used (25 to 250 ␮g/mg versus 20 to 200 ␮g/mg), reducing the influence of misclassification of patients with Alb/Cr ratios slightly greater than the traditional cut point. In conclusion, among black Americans with newly diagnosed type 2 diabetes, we found a high prevalence of microalbuminuria that was associated with HbA1c level and blood pressure. Increased triglyceride levels, male sex, BMI, and high C-peptide levels were also significantly associated with increased albumin excretion, whereas serum creatinine level was inversely related to albuminuria. The link between these components of IRS and incipient nephropathy warrants additional epidemiologic investigation. Patients with type 2 diabetes and microalbuminuria are at increased risk for developing progressive renal insufficiency and ESRD and are at risk for early mortality, primarily from cardiovascular disease.41,55 Screening patients with newly diagnosed diabetes with the Alb/Cr ratio from a random urine sample can identify patients with the earliest signs of kidney damage so that intervention can be initiated in this highrisk group. Such screening strategies should account for variability in UAE and the influence of

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blood glucose control and other factors noted by using an algorithm such as that recommended by the American Diabetes Association.41 Although screening may increase costs of care, nearly a quarter of the black American patients with diagnosed type 2 diabetes of less than 2 years’ duration in our population had microalbuminuria and could thus benefit from early identification and intervention to avoid or delay morbidity and mortality from renal and cardiovascular causes. REFERENCES 1. Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR: The changing natural history of nephropathy in type I diabetes. Am J Med 78:785-794, 1985 2. Ballard DJ, Humphrey LL, Melton LJ, Frohnert PP, Chu PC, O’Fallon WM, Palumbo PJ: Epidemiology of persistent proteinuria in type II diabetes mellitus. Diabetes 37:405-412, 1988 3. Andersen AR, Christiansen JS, Andersen JK: Diabetic nephropathy in type I (insulin-dependent) diabetes: An epidemiological study. Diabetologia 25:496-501, 1993 4. Borch-Johnsen K, Nissen H, Henriksen E, Kreiner S, Salling N, Deckert T, Nerup J: The natural history of insulin-dependent diabetes mellitus in Denmark. 1. Longterm survival with and without late diabetic complications. Diabetes Med 4:201-210, 1987 5. Krolewski AS, Warram JH, Rand LI, Kahn CR: Epidemiologic approach to the etiology of type I diabetes mellitus and its complications. N Engl J Med 317:1390-1398, 1987 6. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 27:167-194, 1996 7. Tull ES, Roseman JM: Diabetes in African Americans, in Diabetes in America. Bethesda, MD, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, NIH pub no. 95-1468 1995, pp 613-630 8. Tierney WM, McDonald CJ, Luft FC: Renal disease in hypertensive adults: Effect of race and type II diabetes mellitus. Am J Kidney Dis 13:485-493, 1989 9. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J: End-stage renal disease in AfricanAmerican and white men: 16-Year MRFIT findings. JAMA 277:1293-1298, 1997 10. Brancati FL, Whittle JC, Whelton PK, Seidler AJ, Klag MJ: The excess incidence of diabetic end-stage renal disease among blacks. JAMA 268:3079-3084, 1992 11. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356-360, 1984 12. Gall MA, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving H: Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes 44:1303-1309, 1995 13. Mogensen CE: Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidney Int 31:673-689, 1987 14. Goldschmid MG, Domin WS, Ziemer DC, Gallina DL, Phillips LS: Diabetes in urban African-Americans. II. High prevalence of microalbuminuria and nephropathy in African-Americans with diabetes. Diabetes Care 18:955961, 1995

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