Creatinine clearance in 118 diabetic outpatients

Creatinine Clearance in 118 Diabetic Outpatients By SIDNEY N. FRANKLIN With the aid of a computer the correlation between the usual clinical criteria, presumed to be associated with renal disease in diabetics, and renal function as measured by the endogenous creatinine clearance was evaluated in 118 diabetic out-patients. The criteria considered in this study included: age of patient, age at onset, duration of known diabetes, retinopathy, systolic and diastolic blood pressure, “qualitative” proteinuria, twenty-four hour urinary excretion of protein, blood urea nitrogen, “control of diabetes” and the presence of “other vascular disease.” Interpretation of these data indicated no significant correlation between “control of diabetes” as usually judged and renal function as

measured by the endogenous creatinine clearance. These data would further suggest that in maturity-onset diabetics one can not rely on the usual clinical criteria for the appraisal of renal function in diabetics. In juvenile diabetics the correlation, between the same clinical criteria, taken as a group but not individually, and the creatinine clearance values, was sign&ant. However, it would appear that serial determinations of endogenous creatinine clearance would provide a more accurate and practical measure of renal function than reliance upon these clinical indices. (Metabolism 16: No. 11, November, 10161023)

I

N THE MANAGEMENT of diabetic outpatients, it is common practice to assume the absence of significant renal impairment until the development of clinical criteria presumed to be associated with renal disease. Since renal failure has become an increasing cause of death in diabetics.‘--’ it would appear desirable to test the statistical validity of this practice. With the aid of a computer the correlation between the usual clinical criteria used to assess the presence of renal disease in diabetics, and glomerular filtration rate as measured by the endogenous creatinine clearance, was evaluated in 118 diabetic outpatients. Although the 24-hour endogenous creatinine clearance is not an exact measure of glomerular filtration rate in man, CX~this method was selected because of its practicality and its greater accuracy in approximating glomerular filteration rate than either blood urea nitrogen or serum creatinine concentration.“’ The criteria considered in this study included: age of patient, age at onset, duration of known diabetes, retinopathy, systolic and diastolic blood pressure, “qualitative” proteinuria, 24-hour urinary excretion of protein, blood urea nitrogen, “control of diabetes,” and the presence of “other vascular disease.” The results of the present study suggest that one cannot rely on the usual clinical criteria for appraisal of renal function in diabetics. It would appear that serial determinations of the endogenous creatinine clearance would offer a more accurate and practical method for achieving this purpose. _~__~.. .~ From the Diabetes Section, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pa. This investigation was supported, in part, by U.S. Public Health Serdce Training Grant TIAM 5245. Received for publication April 19, 1967. Diabetes Section. Department of SIDNEY N. FRANKLIN, M.D., F.A.C.P.: Associate, Medicine, Hospital of the University of Penn.sylvania, Philudelphia, Pa. 1016

CREATININE CLEARANCE IN DIABETIC OUTl?ATIENTS

1017

METHODS AND MATERIALS

300 outpatients

were seen in the Diabetes Clinic of the Hospital of the of the study, March 1965 through March 1966 Attempts were made to include all of the patients, but due to a lack of cooperation the final number of diabetics totalled 118. The patients were instructed in the technic of a 24-hour urine collection, were advised to drink six to eight glasses of water during the collection to ensure a minimum urine volume of I560 ml./24 hours, and were instructed to take their usual diet and dose of insulin or oral antidiabetic agent. Upon completion of the timed urine collection, a fasting blood sample was drawn for blood urea nitrogen and serum creatinine determinations. Serum and urine creatinine determinations were carried out by the method of Jaffe.” The edogenous creatinine clearance was calculated and corrected to a body surface of I.73 ma. Duplicate clearances for each patient were completed within one to four weeks. “Qualitative” urinary protein determinations were employed using sulfosalicylic acid, and the 24-hour urinary protein excretion was estimated by tungstic acid precipitation followed by the biuret reaction.” In the analysis of these data, the mean creatinine clearance for each of the 118 patients studied was designated as the dependent variable. Eleven clinical indices, as applied to each patient during the period of the study, were considerd as independent variables: age of patient, age at onset, duration of known diabetes, systolic and diastolic blood pressure, diabetic retinopathy, “qualitative” proteinuria, 24-hour urinary protein excretion, BUN, “control of diabetes,” and the presence of “other vascular disease.” For simplified computer purposes arbitrary gradings were assigned to systolic and diastolic blood pressure, degree of retinopathy, “qualitative” proteinuria, “control of diabetes,” and the presence of “other vascular disease.” In the remaining variables the absolute values were used in the analysis. Thus the systolic blood pressure (mean of six determinations during the period of study) was graded: 100-140 mm. Hg = 0; 141-160 mm. Hg =l; 161-180 mm. Hg = 2; 181 mm. Hg and over = 3. Likewise, the diastolic blood pressure values were graded: 60-90 mm. Hg = 0; 91-100 mm. Hg = 1; 101-110 mm. Hg = 2; and 111 mm. Hg or over = 3. Funduscopic examinations were done by a staff ophthalmologist, and retinopathy was graded: none = 0, mild retinopathy (microaneurisms, with or without punctate hemorrhages and minute exudates) = 1; moderate (many microaneurisms, dot and blot-like hemorrhages and waxy exudates) = 2; and severe retinopathy (preceding lesions plus retinitis proliferans ) = 3. “Qualitative proteinuria” was graded 0 to 4, corresponding to the mean of six determinations performed during the period of the study. In the computer analysis absolute values were used for the 24-hour urinary protein excretion. “Control of diabetes” was graded as: good = 0; fair = 1; and poor = 2. The criteria good control-aglycosuria in the majority of urines were essentially those of Marble? Approximately

University of Pennsylvania during the period

tested, 24-hour urine glucose less than five per cent of carbohydrate intake, no ketonuria, and the majority of blood glucose levels (approximately two to three hours after breakfast) not exceeding I30 mg. per cent. Fair control was designated: glycosuria in 24 hours not exceeding ten per cent of the total carbohydrate intake and the blood glucose levels not exceeding 150 mg. per cent. The inadequacies of this system for grading “control” are well recognized, but the criteria are similar to those generally employed in the management of diabetics.“+” “Other vascular disease” referred to the presence of coexisting peripheral vascular, coronary artery or cerebrovascular disease. It was graded: none = 0, and present = 1.

RESULTS AND DISCUSSION

A. General The

patients

were divided iuto two basic groups:

growth or early-onset

1018

SIDNEY

S.

FRAXELlh

diabetics, and maturity or late-onset diabetics. Each group was subdivided into males and females. There were 18 males and 27 females in the early-onset group and 17 males and 56 females in the late-onset group. The mean values for age of patients, age at onset, duration of diabetes, 24-hour urinary protein excretion, and blood urea nitrogen for each subgroup are recorded in Table 1. B. Distribution

of Creatinine

Clearance

Values

The distribution of the mean creatinine clearance values for each group are recorded in Table 2. In the early-onset group the values ranged from 6.3 to 134 ml./min. in the males and from 36.2 to 144 ml./min. in the females. In the maturity-onset diabetics the range was from 58 to 109 ml./min. in the males and from 13.5 to 121 ml./min. in the females. The mean values show a large degree of variability within each subgroup, as indicated by the standard deviations (Table 2. ) This is to be expected since each subgroup contains both diabetics with renal disease and those without. The somewhat lower mean creatinine clearance values in the late-onset group may in part be related to the greater mean age in this group, in accord with the reported decline of glomerular filtration rate with age in normal males.zl,“’ Eight patients in the combined groups, or roughly 7 per cent of the total. had clearance values between 040 ml./min., corresponding to a reduction of glomerular filtration rate of approximately 50 per cent or more based on Doolan’s normal values of 103 i 15.8 for males and 97 t 9.7 ml./min. for females. Fifty-seven patients, or 48 per cent of the total group. had relativeI> normal clearance values over 80 ml./min. Caution is required in the interpretation of creatinine clearance values. The reported wide range of normal values would appear to diminish the sensitivity of the procedure for the detection of lesser degrees of renal impairment;‘” however, serial determinations of creatinine clearance would minimize this disadvantage and would indicate a significant change in renal function as well. Although single sets of endogenous creatinine clearance values were employed in this study, the usefulness of the procedure was ap parent in the detection of definite renal impairment in some, normal renal function in others (as previously described), and the establishment of baseline values for the future study of each patient. C. Correlation of Clinical Data with Creatinine

Clearance

The measure of correlation was expressed in terms of R” and multiple R”.“” As here employed, R’ was the degree of variability of the creatinine clearance (expressed as percent) that was explained by the variability of a single independent variable or clinical parameter. Multiple R” was employed when more than one independent variable were considered. The R2’s were adjusted for the degrees of freedom. An R2 of zero represented no correlation. whereas 100 per cent signified perfect correlation. In the first computer run two of the independent variables, “control of diabetes” and “other vascular disease” were found to be insignificant at the 0.01 level and so were discarded from subsequent analyses. In Table 3 are shown the multiple R”s for each group, expressing the corre-

CBEATIXIiKE

CLEABASCE

Table l.-Mean

I.019

IN DIABETIC OUTPATIENTS

Values of Clinical Data in 118 Diabetic Out-Patients Early Onset Male Mea

42.3 26.2 16.1 150.0 16.2

Age oi patient (Yrs.) Age at onset (Yrs.) Duration of diabetes (Yrs.) Proteinuria (mg./24 hrs.) BUN (mg./lOQ ml.)

Table Z-Distribution

(18)

Late onset

Female (27)

S. D.

Meal?

15.3 11.2 9.2 497.3 9.2

Male (17)

S. D.

14.5 44.4 10.6 26.7 8.7 17.1 584.4 1,116.2 7.3 16.2

of Creatinine Clearance

Mean

S. D.

Mean

S. D.

64.0 52.7 11.3 214.1 17.3

7.6 82 5.7 521.4 5.2

65.8 50.3 15.8 40.0 17.2

8.3 6.1 7.1 105.2 7.5

in 118 Diabetic

Early Onset

Creatinine Clearance

Female (56)

Out-Patients Total

Late onset

(ml./min.)

21&

Female

JIale

Felllale

@40

1 1 2 1 3 1 3 2 4

1 5 3 2 3 0 4 5 4

0 0 2 r 3” 5 1 1 0

6 6 6 6

11-50 5 l-60 61-70 71-80 81-90 91-100 101-I 10 111-150

Is Mean Standard deviation Range : Low High

86.5 32.1 6.3 134.0

27 81.2 30.0 36.2 144.0

1: 8 4 1

17

-56

77.3 14.4 58.0 109.0

72.7 22.7 13.5 121.0

812 13 14 14 20 16 12 9 118

lation between the combined clinical criteria and the mean creatinine clearance values. The values for the early-onset group were 82.7 per cent for males and 64.4 per cent for females, in contrast to 32.7 per cent and 38.9 per cent, respectively, in the late-onset group. Thus the correlation between the clinical criteria, taken as a whole, and the creatinine clearance was of a higher order in the early-onset group. These data would suggest that in juvenile diabetics one can place more reliance on these clinical criteria, taken collectively for the rough assessment of renal function, than in maturity-onset diabetics. In Table A one may observe the R2 for each of the clinical parameters within each group expressing the correlation of the single parameter with the mean creatinine clearance. Thus one can compare the relative importance of each independent variable. It was obvious that all of the R”‘s were low, signifying that no single parameter could be used to estimate the creatinine clearance. It should be noted that 24-hour proteinuria and blood urea nitrogen, two time-honored criteria for the assessment of renal disease in diabetics, correlated poorly with creatinine clearance, as indicated by the low R~‘s. The apparent lack of correlation between the mean creatinine clearance values and duration of diabetes, retinopathy, and proteinuria, as represen-

1020

SDJNEY S.

FRAKKLIN

Table 3.-Correlation of Combined Clinical Data with Creatinine Clearance by Multiple R” -. Multiple Ra * Male 82.7 32.7

Early Onset Late Onset Dependent

variable :

Independent variables : (taken as a group)

Creatinine

Clearance

1. Age of patient 2. 3. 4. 5. 6.

FemaIe 64.4 38.9

Age of onset Duration of disease Retinopathy Systolic B P Diastolic B P

7. 8. 9. ** 10. ** 11.

Qualitative proteinuria Quantitative proteinuria BUN Control Other vascular disease -

* Multiple R* =

100% (perfect correlation) 0% (no correlation)

** Omitted = Insignificant at 0.01 level of significance

Table 4.-Correlation of each Independent Creatinine Clearance by R’* Clinical Data (Independent Variables)

Male

Age of patient Age at onset Duration Systolic B P Diastolic B P Retinopathy Qualitative proteinuria Quantitative proteinuria BUN

0.5 5.2 21 .o 9.6 29.3 17.8 8.1 35.2 30.0 *R’=

Early Onset F.Z.lUile R= (%I

3.5 1.3 1.5 18.7 0.1 6.6 24.6 26.5 36.4

Variable with

Male

3.5 0.2 5.0 3.0 5.3 6.0 4.2 5.6 9.2

Late Onset F‘Xl& R” (%I

1.0 0.5 1.0 5.8 1.0 17.3 0.2 3-./ 21.0

100% (perfect correlation) 0% ( no correlation)

of the other data, is graphically displayed in Figures l-3. It is apparent in Figure 1 (creatinine clearance correlated with duration of diabetes) that only in the male early-onset group was there any significant correlatic-:. In the first eight years of diabetes (total early-onset group), the clearance values were relatively normal, but beyond that period the distribution diverged. In seven early-onset diabetics who had their disease more than 16 years, the clearance values were all unexpectedly over 100 ml./min. In Figure 2 the correlation between the creatinine clearance values and diabetic retinopathy is illustrated. Patients who had no demonstrable retinopathy exhibited highly variable clearances, ranging from just below 50 to over 100 ml./min., indicative of poor correlation. Those patients with moderate or severe retinopathy had clearances ranging from 6 ml./min. to normal; however, in the severe retinopathy groups most of the clearance values were below 50 ml./min. tative

CREATININE

CLEARANCE

early

onset

Y 150 ? C sQ5

1021

OUTPATIENTS

IN DIABETIC

* *

.:

l---A-,-

16

Fig. l.-Creatinine

24 Years

32

IX 40

duration

C-l-l-I~-Ix 0

8

16

24

32

40

of disuse

clearance correlated with duration of diabetes. earLy

onset Y

Fig. 2.-Creatinine

clearance correlated with diabetic retinopathy.

Likewise, in Figure 3 (creatinine clearance correlated with 24-hour urinary protein excretion) great variability in creatinine clearance (below SO to over 100 ml./min.) was observed in those patients with no significant proteinuria. However, in four out of five gatients with over 2.0 grams of urinary protein per 24 hours, the clearance values were below 50 ml./min. These data indicate that the usual clinical indices do not provide an accurate assessment of renal function in maturity-onset diabetics. In juvenile diabetics the correlation between the same clinical criteria, taken as a group but not individually, and the mean creatinine clearance does provide a better gross estimate of the presence or absence of impaired glomerular filtration. It is obvious that in studies designed to evaluate the efficacy of present

1022

SIDNEY

24

Fig. 3.-Creatinine excretion.

clearance

hour

correlated

Proteinurea

S.

FRASELlN

(mg)

with twenty-four

hour urinary protein

diabetic therapy, in preventing the development of clinically significant renal disease reliance must be placed upon the serial determinations of specific aspects of renal function such as the endogenous creatinine clearance. In the present study the measure of endogenous creatinine clearance was restricted to two determinations per patient performed within a period of one month; therefore, no information concerning the progression of renal disease was provided. It was of interest that there was no apparent correlation between the quality of diabetic control as presently assessed and the glomerular filtration rate as approximated by the endogenous creatinine clearance. ACKNOWLEDGMENTS The assistance F. D. W. Lukens acknowledged.

of Mr. A. A. Whyte in the statistical analysis of the data and of Dr. and Dr. A. I. Winegrad in the preparation of the manuscript is gratefull!

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pany, 1963. Doolan, P. D., Alpen, E. L., and Theil, G. B.: A clinical appraisal of the plasma concentration and endogenous clearance of creatinine. Amer. J. Med. 32:65, 1962. Richard, H. J.: Clinical Chemistry. New York, Harper and Row, 1965, pp. 287-289. Richard, H. J.: Clinical Chemistry. New York, Harper and Row, 1965, pp. 179-186. Marble, A.: Therapy: Criteria and control. In: Diabetes Mellitus Diagnosis and Treatment. New York, American Diabetes Association, 1964. White, P.: Standards for control. In: Jo&n, E. P., Root, H. F., White, P., and Marble, A. (Eds. ) : The Treatment of Diabetes Mellitus, 10th Ed. Philadelphia, Lea & Febiger, 1959, p. 673. VanPilsum, J. F., and Seljeskog, E. L.: Long-term endogenous creatinine clearances in man. Proc. Sac. Exp. Biol. Med. 97:270, 1958. Davies, D. F., and Shock, N. W.: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J. Clin. Invest. 29:496, 1950. Ezekiel, M., and Fox, K. A.: Methods of Correlation and Regression Analysis, Linear and Curvilinear, 3rd Ed. New York, John Wiley and Sons, Inc., 1959.