Clinical characteristics associated with microalbuminuria in an adult diabetic population

Clinical Characteristics Associated with ~i~~~rniuuria in an Adult Diabetic Population

Paul Tung,

ABSTRACT

MD

Paulette

Ginier,

Seymour

R. Levin,

MD MD

Jeffrey D. Hershman Jerome

M. Hershman,

MD

Research and Medical Services, VA Wadsworth Medical Center, University of California, Los Angeles, California

A study was conductedto identify clinical characteristicswhich might distinguish individuals at risk for diabetic nephropathy. A cross-sectional survey measuring microatbuminuriain a population of 146 diabetic adults was performed and several clinical parameters among subgroupswith different clinical types of diabetes, based upon age of onset and insulin treatment, were examined. In 67 insulin-treated pa tients with onset of diabetesat or after the age of 66 who had elevated albuminexcretion rates,significantlygreaterduration of diabetes, age, blood pressure,serum creatinine,body mass index, and serum triglycerides were found. In this group of maturity onset insulfn-treated diabeticpatients,there was a significantlysmallerproportionof smokers in the microalbuminuriagroup than in the group with normal excretion.No such distinctionswere seen in 56 maturftyonset patients with and without microalbuminuriawho were not receivinginsulin. In 15 insulin dependentpatients with onset in early ad&hood, only age and durationdistinguishedthose with, or without, microatbumfnuria.Analysis of microalbuminuria,taking into accountdiabetestherapy and other clinical and demographicdata, may provide clues to the pathophysiology of renal disease in diabetes mellitus. (The Journal of Diabetes Complications4;1:15-20,199o.)

INTRODUCTION

Reprint requests to be sent to: Seymour R. Levin, MD, VA Wadsworth Medical Center, W111 K, Los Angeles, CA 90073. Submitted for publication March 1989, accepted in revised form June 1989.

Diabetic nephropathy, defined by persistent proteinuria detectable by chemical reagent strips, occurs in about 40% of diabetic patients and progresses to end-stage renal disease in a significant proportion of these patients. In spite of a large body of ongoing research on the pathophysiology and natural history of diabetic nephropathy, the reasons why nephropathy occurs in only a subset of individuals remains unknown. Viewed another way, it would be important to identify factors that protect some individuals from the development of nephropathy. While some putative protective characteristics would be immutable (e.g., genetic factors), others might be manipulated to prevent nephropathy. With the development of albumin assays which are sensitive down to the microalbuminuria range’ (defined as 20-200 p.g/min)‘, longitudinal studies have demonstrated that microalbuminuria is the earliest detectable clinical phase of diabetic nephropathy, and that most individuals with this early stage of nephropathy progress to overt proteinuria and clinical nephropathy.3‘6 Several clinical factors have been suggested to affect microalbuminuria including systemic hypertension,’ duration of diabetes4 and glycemic control.* Two major hypotheses concerning pathogenetic mechanisms have evolved from these studies. One holds that factors related primarily to metabolic control determine the development of nephropathy,9 while the other hypothesis proposes that intrarenal hemodynamic changes are of primary importance.1o Raskin and Rosenstock have emphasized the concept that a combination of hemodynamic and metabolic factors may determine the development of nephropathy.” Several studies have shown a significant correlation of albumin measured in spot urine specimens with that measured in 24 hr timed collections, especially if normalized to creatinine excretion.12-14 While certain qualifications must be made in extrapolating the results to timed collections, the 15

TUNG ET Al.

16

increased ease of collection of spot urine specimens compared to 24 hr collections, as well as collection errors that occur over prolonged periods, justify the use of single-voided specimens. We have undertaken a cross-sectional study of albuminuria in our VA diabetes clinic, employing a sensitive double-antibody radioimmunoassay applied to single-voided urine specimens. Our goals were 1) to investigate what clinical or laboratory data might differentiate individuals with normal and abnormal degrees of albumin excretion, and 2) to compare the prevalence of microalbuminuria among subgroups of diabetics, who were studied with regard to form of therapy, and clinical form of diabetes.

sured by the agar gel electrophoresis method (Corning Medical) without removal of the labile fraction (normal range: S.l%-7.1%). Single-voided urine specimens (in most cases not the first morning urine) were obtained in clinic and were frozen at -20°C and assayed at a later date for creatinine and albumin by a double antibody radioimmunoassay method (Diagnostic Products Corp). Statistical analysis utilized Student’s unpaired t-test for comparisons of means, and the Fisher’s exact test (two-sided p) for prevalence of smoking and relative prevalence of microalbuminuria.

METHODS

RESULTS

Albumin excretion rates as expressed here, are normalized to creatinine excretion. It was assumed that creatinine excretion was 1 mg/min; therefore microalbuminuria was defined as 20-200 kg albumin/mg creatinine. One hundred and seventy-five consecutive individuals seen in our diabetes clinic were evaluated for albuminuria. All but five were men. Thirty-five subjects (20%) had albuminuria of >200 kg albumin/mg creatinine. These were eliminated from further analysis as having a more advanced stage of nephropathy. The remaining 140 individuals were further characterized using data collected at the same clinic visit and comprise the subjects of this report. Blood pressure was recorded in the sitting position using the fifth Korotkoff sound as diastolic pressure. Fasting blood specimens were drawn for measurement of creatinine, glucose, triglycerides, and cholesterol by multichannel autoanalyzer. Glycohemoglobin (HgbAl) was mea-

The clinical characteristics of the total study population are listed in Table 1. When this population was divided by albumin excretion into normal (~20 kg/mg creatinine) and microalbuminuric (20-200 pg/mg creatinine) subgroups, the microalbuminuric patients had significantly greater age, duration of diabetes, and systolic blood pressure, and a lower percentage of smokers. Figure 1 demonstrates that the non-smokers had a higher mean urine alb/creat ratio than the smokers (39.2 ? 5.3 vs 23.7 5 5.7; p < 0.05). Further categorization was based upon method of treatment. One group was defined by the criterion of treatment without insulin; the clinical characteristics of this group are listed in Table 2. They typify Type 2 or non-insulin dependent diabetes mellitus (NIDDM), with late onset of diabetes (age 53 yrs) and have an obese habitus; body mass index (BMI) >27; BMI = weight (kg)/height(m).2 When this group was divided by albumin excretion into normal and microalbuminuric sub-

TABLE 1

Characteristics

of the Total Patient Population Albumin Excretion ALL 140 59.3

years Duration years Age at onset years Current smokers % Systolic blood pressure (SBP) mmHg Diastolic blood pressure (DBP) mmHg Body mass index Serum creatinine mg/dl HgbAl % Triglycerides mg/dl Cholesterol mg/dl Urine AlbKreat

dw Values are mean SEM.

pg/mg creatinine < 20 20-200 84 56.4

26.7

56 62.3 (1.0) 14.1 (1.4) 48.6 (1.8) 27 140.1 (2.7) 82.9 (1.4) 26.7

(0.5) 1.16 (0.10) 9.9 (0.3) 183.4 (20.0) 215.5 (5.1) 7.3 (0.6)

(0.6) 1.24 (0.05) 10.0 (0.3) 197.7 (19.3) 215.5 (6.7) 71.5 (6.4)

(0.8) 11.8

(A:;)

(0.8) 47.7 (1.1) 40 135.3 (1.8) 81.5 (0.9) 26.7

(0.9) 47.0

(0.4) * 1.19 (0.06) 9.9 (0.2) 188.8 (14.4) 215.5 (4.1) 33.0 (2.6)

(1.3) 48 132.0 (2.4) 80.6

(1.1)

< ,001 < ,001

< .05 < .05

< ,001

17

MICROALBUMINURIAIN ADULT DIABETICS

l

:

0

I I

f _L

i

NO

YES

CIGARETTE

SMOKER

FIG. 7 Distribution of urine albuminlcreatinine ratios among smokers and nonsmokers inthe total population. = ~~0.05 by unpaired

@<.OOl). When this insulin treated, maturity onset group was separated by level of albumin excretion, the microalbuminuric patients had significantly greater age, duration of diabetes, diastolic blood pressure, serum creatinine, and body mass index. There was a lesser proportion of current smokers in the microalbuminuric group. Figure 2 shows that the mean urine alb/creat ratio was higher in the nonsmokers compared with the smokers (50.2 + 9.2 vs. 17.4 * 6.6; pt< 0.01). A third group was defined by the criteria of treatment with insulin and onset of diabetes younger than age 30 years; the clinical characteristics of this group are listed in Table 4. These patients were defined clinically as having Type I diabetes (IDDM). They were thin (mean BMI 22.6) and young at onset, and were notable as having a prolonged duration of diabetes. When this group was separated by quantity of albumin excretion, the microalbuminuric group had significantly greater age, duration, and fasting serum triglyceride levels. The prevalence of microalbuminuria in all subgroups was about 40% (Table 5). There was no significant difference in prevalence among the different subgroups.

l

t-test

DISCUSSION groups, the subgroups were not found to differ in any of the measured parameters. A second group was defined by the criteria of onset at or after age 30 years and treatment with insulin (Table 3), referred to as the insulin treated, maturity onset group. They had a mean age at onset of 59.0, which was younger than the non-insulin treated group (pc.01) and had a lesser BMI

TABLE

2

Characteristics

In this random survey of an adult diabetic clinic population using single voided urine specimens, 35/l 75 (20%) patients had overt albuminuria, i.e., > 200 pg/mg creatinine (or greater than approximately 500 mg protein/24 hr, or 30 mgldl: the threshold of most reagent strips). In the remaining population (80%) we were able to identify clinical parameters, within different diabetes subgroups, that correlate with elevated rates of albumin excretion.

of Patients with NIDDM Albumin pg/mg

n Age years Duration years Age at onset years Current smokers % SEP mmHg DBP mmHg Body mass index Serum creatinine mg/dl HgbAl % Triglycerides mg/dl Cholesterol mg/dl Urine AlbKreat rgfmg Values are mean SEM.

Excretion creatinine

ALL

< 20

20-200

58 62.0

36 60.8

22 64.0

(1.1) 9.1

(1.3) 7.9

(2.0) 11.0

(1.0) 52.9 (1.4) 26 139.9 (2.6) 82.0 (1.4) 28.6 (0.6) 1.25 (0.14) 9.2 (0.3) 209.5 (25.1) 223.5 (5.9) 28.8 (3.6)

(1.2) 52.9 (1.6) 25 136.5 (3.8) 81.7 (1.8) 29.4 (0.8) 1.31 (0.23) 9.2 (0.4) 216.8 (36.7) 224.0 (7.5) 6.6 (0.8)

(1.6) 53.1

P

(2.6) 27 145.5 (3.1) 82.5 (2.3) 27.4 (0.9) 1.15 (0.06) 9.3 (0.3) 197.3 (27.0) 222.7 (9.5) 65.2 (9.5)

< .OOl

18

TUNG ETAL.

TABLE 3

Characteristics of Patients with Insulin Treated Maturity Onset Diabetes Mellitus Albumin pg/mg

years Duration years Age at onset years Current smokers % SBP mmHg DBP mmHg Body mass index Serum creatinine mg/dl HgbAl 56 Triglycerides mg/dl Cholesterol mg/dl Urine AlbKreat

Excretion creatinine

P

ALL

< 20

59.0 67

56.1 39

(1 .O) 10.2

(;:;)

Z.0 (1.2) 12.1

(0.8) 48.8 (1.0) 48 133.6

(0.9) 47.3 (1.3) 67 129.1

(1.4) 50.9 (1.5) 18 139.8

(2.7) 82.2

(3.5) 79.8

(4.3) 85.4

.02

(1.2) 26.0

(1.4) 25.0

(2.0) 27.3

.03

(0.5) 1.16 (0.04) 10.6

(0.7) 1.06 (0.02) 10.5

(0.7) 1.31 (0.10) 10.7

(0.4) 183.9 (19.7) 212.7

(0.5) 174.7 (24.9) 212.1

(6.3) 35.0

(8.1) 7.4

(4.2)

(0.9)

pg/mg

20-200

(0.5) 198.9 (32.5) 213.5 (10.1) 83.4 (10.8)

< ,001 < .05

< .Ol

< ,001

< .OOl

Values are mean SEM.

Total Population In the entire group without overt proteinuria, those characteristics associated with microalbuminuria by comparison of means were: 1) prolonged duration of diabetes, 2) older age, and 3) higher systolic blood pressure (Table 1). Current smokers had a lower mean degree of albuminuria than nonsmokers (Figure 1).

2001

0

I

l

The roles of duration, age, and blood pressure have been noted previously in other studies.4*7,15 However, a negative relationship has not been previously described between smoking and microalbuminuria and nephropathy. This was most prominent in the patients who had an onset of diabetes over the age of 30, and were receiving insulin. NNIDM This clinically defined group typifies Type II diabetes which tended to be seen in those with an older age at onset and obesity. Comparisons of means between subgroups with normal albumin excretion and microalbuminuria disclose no significant differences in any of the clinical parameters measured (Table 2).

insulin Treated, Maturity Onset Diabetic Pafienls

0

ir’ NO

CIGARETTE

YES

SMOKER

F/G. 2 Distribution of urine albuminlcreatinine ratios among smokers and nonsmokers in the insulin treated adult onset diabetic population. = ~~0.01 by unpaired t-test. l

This group differs from the previous group in having a slightly younger age at onset and a lesser mean degree of obesity. In this grouping, of the clinical parameters between subgroups with normal and abnormal levels of albuminuria, the latter show significantly greater age, duration, diastolic blood pressure, body mass index, serum creatinine, and significantly lower percentage of current smokers. Current smokers in this subgroup had a lower mean degree of albuminuria, and this group influenced the significance of the data.

IDDM The clinical characteristics of this group, defined as insulintreated individuals with onset at age less than 30 years, are typical for Type I diabetes, with thin body habitus. In this group, the mean age, duration, and fasting serum triglycerides were

MICROALBUMINURIA INADULT DIABETICS

TABLE

4

Characteristics

19

of Patients with Insulin Dependent

Diabetes

Mellitus (IDDM)

Albumin Excretion < 20

ALL

years Duration years Age at onset years Current smokers % SBP mmHg DBP mmHg Body mass index

15 49.7

9 45.0

(2.4) 27.7 (2.5) 21.9

(3.6) 22.8

(0.8) 60 125.6 (3.8) 76.8

(0.8) 56 127.8 (4.7) 79.6

(3.4) 22.2

(3.4) 23.3 (0.9) 1.01 (0.06) 10.4

(2.3) 22.6 (0.8) 1.11 (0.07) 10.1

Serum creatinine mg/dl HgbAl % Triglycerides mg/di Cholesterol mg/dl Urine AlbKreat crg/mg

rg/mg creatinine 20-200

(0.6) 121.1 (13.1) 196.9 (11.0) 40.1

(0.5) 85.0 (16.2) 196.3 (11.8) 9.8

(5.9)

(1.4)

6 56.7 (2.6) 35.2 (3.7) 21.5 (1.6) 67 122.3 (6.3) 72.7

P

.03 .03

(2.4) 21.6 (1.5) 1.28 (0.17) 9.7 (1.3) 193.3 (22.1) 198.0 (15.9) 85.8 (14.9)

,003

< ,001

Values are mean SEM.

higher in the microalbuminuric subgroup compared with the subgroup with normal albumin excretion. Our study population is typical of the adult diabetic population in the great preponderance of Type II diabetes. However, the proportion of adult onset patients treated with insulin (54%) is greater than that reported in another survey.16 Our clinic population and, therefore, our study group, is unselected, however, on the basis of type of diabetes or difficulty in control. Several factors are known to increase proteinuria, including hematuria, congestive heart failure, exercise, and urinary tract infections. In our patients, hematuria was ruled out by reagent strip testing, and heart failure was not clinically apparent. However, the other two factors were not controlled. Exercise can increase protein excretion rates from normal to the microalbuminuria range, and in diabetic individuals may represent an early stage of microalbuminuria.” It is, however, unlikely that these patients engaged in exercise on the morning of the clinic. Urine cultures were not taken, but patients did not have symptoms of urinary tract infection. Nor is it likely that this group, predominantly men, had asymptomatic bacteriuria,

TABLE

5

Distribution

of Microalbuminuria

since asymptomatic bacteriuria is not more common in diabetic men compared with nondiabetics.‘* Clinically significant prostatism or cystopathy was unlikely in all but a very small percentage of patients. Our data indicate that, for the entire population, duration of diabetes and age are important factors in albuminuria. This has been reported previouslfl and supports the notion of albuminuria and nephropathy as progressive, once the clinical setting for the development of nephropathy exists. Our results do not indicate a role for glycemic control in microalbuminuria in these patients with an overall diabetes duration of almost 12 years. There was no significant difference in glycohemoglobin between subgroups categorized on the basis of degree of microalbuminuria. In the group with IDDM, there were the expected significant differences in age and duration. Serum triglyceride concentration was greater in the albuminuric patients. Thus, this latter aspect, while interesting, would need to be assessed in a larger group with IDDM, with a wide spectrum of duration of diabetes. There were no trends toward differences in the smoking and non-smoking groups for the IDDM group.

Between Different Clinical Grouos Clinical group (% of group)

Degree of Insulin treated (rg/mg creatinine) < 20 20-200 Total

NIDDM

AODM

Type f

Total

(62%) 36 22 58 (38%)

39 (58%) 28 (42%) 67

9 (60%) 6 (40%) 15

84 (60%) 56 (40%)

. ._

1Al-l

20

TUNG fT Al.

Elevated blood pressure was a significant factor in the comparison-of-means analysis in only two groups; in the total population the systolic blood pressure was higher in the microalbuminuric group compared with normal albumin excretors, and in the insulin-treated maturity onset group the diastolic blood pressure was higher in the microalbuminuric group compared with normal albumin excretors. The role of the elevated blood pressure is not clear, but one possible explanation is that hemodynamic modulation of this early stage of nephropathy may be critical, as is proposed by the hyperfiltration hypothesis of glomerular disease.” Alternatively, early diabetic nephropathy may induce changes which cause systemic blood pressure elevation. The serum creatinine level was higher in patients with insulin-treated adult onset diabetes with microalbuminuria compared with those with normal albumin excretion, which suggests a slightly decreased creatinine clearance. However, in other studies, microalbuminuria has been associated with an increased glomerular filtration rate as measured by iothalamate clearance,5 and it has been shown that tubular creatinineexcretion increases with increasing proteinuria,lg making our finding unexpected in the face of these two changes which would theoretically decrease serum creatinine. There was a significantly greater proportion of cigarette smokers in the normal albuminuric subgroup of insulin-treated adult onset diabetic patients. In previously reported studies, cigarette smoking was associated with an increased prevalence of macroproteinuria in some studies,20*2’ or with a lack of association with proteinuria in other investigations.22.23 Nicotine decreases renal blood flow by a mechanism that involves both the alpha-adrenergic system and angiotensin ll.24 An hypothesis to explain our observations would propose physiologic differences in renal hemodynamics between the early microalbuminuric and more advanced macroproteinuric stages. One might then see a stage early in nephropathy in which the decreased renal blood flow due to nicotine is associated with decreased filtration pressure across the glomerular basement membrane; in this situation nicotine would lead to decreased microalbuminuria. Single urine specimens provide a practical way to screen populations, and are becoming accepted in studies of the progress of renal disease. 12-24,25 Laboratory and clinical features, as we have evaluated here, might be helpful in assessing the multiple factors that enter into the pathophysiology of diabetic renal disease. This is especially important in obtaining new information about the natural history of nephropathy in adult onset diabetes.26

Acknowledgments The authors are grateful to Anne Ryan, RN, for skilled nursing assistance, to Terry Reedy, PhD, for statistical advice, and to Diagnostic Products Corporation for providing the microalbumin RIA kits. This work was supported by grants from the Veterans Administration. PT was a trainee on NIH Training Grant #5T32DK07426_06Al.

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1963.

2. Moaensen CE: Microalbuminuria as a oredictor of clinicai diabetic nethropathy. Kidney Int 31:673-689,‘1987. 3. Parving H-H, Oxenboll B, Svendsen PAa, Sandahl Christiansen JS. Andersen AR: Earlv detection of oatients at risk of develooina diabetic nephropathy.‘A longitudinal study of urinary albtimi; excretion. Acta fndocrinollOO:55&555, 1982. 4. Viberti GC, Jarett RJ, Mahmud U, et al: Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1 :I 430-l 432,1982. 5. Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-deDendent oatients. N Enal J Med 311:8%93. 1984. 6. Mogensen dE: Microslbuminuria pr&%ts clinical piot&urii and early mortality in maturity-onset diabetes. N Engl J Med310:35& 360,1984. 7. Mogensen CE: Antihypertensive treatment inhibiting the progression of diabetic nephropathy. Acta Endocrinol 94(Suppl 238\:103-111.1980. 6. ThgKroc Coll&&&e Study Group: Blood Glucose Control and the Evolution of Diabetic Retinooathv and Albuminuria. N Enal I J Med 311:365-372,1984. ’ ’ 9. Viberti GC: Determinants of renal failure in the diabetic patient, in Keen H, Legrain M, (eds), Prevention and Treatment ofDiabetic Nephropathy, Lancaster, MTP Press Ltd., 1983, pp. 91-105. 10. Hostetter TH, Rennke HG, Brenner BM: The case of intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72:375-380, 1982. 11. Raskin P, Rosenstock J: Blood glucose control and diabetic complications. Ann Intern Med 105:254-263, 1986. 12. Shaw AB, Risdon P, Lewis-Jackson JD: Protein creatinine index and Albustix assessment of proteinuria. Br Med J 287:929-932, 1983. 13. Nathan DM, Rosenbaum C, Protasowicki VD: Single void urine samples can be used to estimate quantitative microalbuminuria. Diabetes Care lo:41 4-418,1987. 14. Cowell CT, Rogers S, Silink M: First morning urinary albumin concentration is a good predictor of 24-hour urinary albumin excretion in children with Type I (insulin-dependent) diabetes. Diabetologia 29:97-99, 1986. 15. Rowe DJF, Hayward M, Bagga H, Betts P: Effect of glyceamic control and duration of disease on overnight albumin excretion in diabetic children. Br MedJ 289:957-959. 1984. 16. Krolewski AS, Warram JH, Christlieb AR: Onset, course, complications, and prognosis of diabetes mellitus, in Marble A, Krall LP, Bradley RF, Christlieb AR, Soeldner JS (eds). Joslin’s Diabetes Mellitus, 72th ed. Philadelphia, Lea & Febiger, 1985, pp. 251277. 17. Mohamed A, Wilkin T, Leatherdale BA, Rowe D: Resoonse of urinary albumin to submaximal exercise in newly diagnosed non-insulin dependent diabetes. Br Med J 288:1342-l 343,1984. 18. Kass EH: Bacteriuria and the diagnosis of infections of the urinary tract. Arch lntem Med 100:709, 1957. 19. Shemesh 0, Golbetz H, Kriss JP, Myers BD: Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Intern 28:830-838,1985. 20. Muhlhauser I, Sawicki P, Berger M: Cigarette-smoking as a risk factor for macroproteinuria and proliferative retinopathy in Type 1 (insulin-dependent) diabetes. Diabetalogia 29:50&502, 1986. 21. Telmer S, Christiansen JS, Anderson AR, Nerup J, Decker? T: Smoking habits and prevalence of clinical diabetic microangiopathy in insulin-dependent diabetics. Acta Med Stand 215:63-68, 1984. 22. West KM, Ahuya MMS, Bennett PH, et al: Interrelationships of microangiopathy, plasma glucose and other risk factors in 3,583 diabetic oatients: A multinational studv. Diabetologia 22:412420,198i. 23. West KM, Erdreich LS, Stober JA: Absence of a relationship between smokina and diabetic anaiooathv. _. I Diabetes Care 3:250-252,1980.24. Hock CE, Passmore JC: Mechanisms mediating canine renal vasoconstriction induced by nicotine infusion. Life Sci 37:19972003,1985. 25. Watts GF, Shaw KM, Polok A: The use of random urine to screen for microalbuminuria, in the diabetic clinic. Prac Diabetes 3:8688,1986. 26. Tung P, Levin SR: Nephropathy in non-insulin dependent diabetes mellitus. Am J Med 85(Suppl5A):131-136,1988.