Urinary Lactic Dehydrogenase: A Report Based on 250 Hospitalized Patients

Vol. 95, Jan. Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1966 by The Williams & Wilkins Co.

URINARY LACTIC DEHYDROGENASE: A REPORT BASED ON 250 HOSPITALIZED PATIENTS I

I

C. S. MIRABILE, G. N. BOWERS, JR.

AND

B. B. BERLIN

From the Departments of Urology ancl Pathology, Hartford Hospital, Hartford, Connecticut

reported as units per 8 hours and was calculated as follows:

It has been suggested that assays of urinary lactic dehyclrogenase (LDH) would be valuable in distinguishing benign from malignant urogenital diseases. 1 To help establish whether this new test should be done as a routine procedure, the following clinical and laboratory studies ·were performed.

Urine LDH activity @ 37C 11A340 mµ rr_1_l_._of~S_h_r_._u_n_·n_e . X mmute ml. of sample X

1IATERIAL AND METHODS

Patients of one of the Hartford Hospital staff urologists or cases seen by one of them in consultation were included in the study. All case histories were evaluated by the same urologist (B.B.B.). If the urologic evaluation was inadequate or a clinically diagnosed cyst or malignancy was not confinned by surgery, the case was not included. During an 8-hour period at night, urine specin1ens were collected, held at 4C in a sterile, chemically clean, glass bottle and processed the next working day. After centrifuging, the supernatant fluid was tested for protein and hemoglobin and then dialyzed against tap water as described by Dorfman and associates. 2 All urine specimens were examined microscopically for the presence of white blood cells (WEC), red blood cells (REC) and bacteria. If there were more than 10 WEC or REC per high power field, or if bacteria were noted, or if there was a positive test for hemoglobin, the specirn.en was considered contarn.inated. Urine LDH activity was measured on a 0.20 ml. sample of the dialyzed urine with a continuous spectrophotometric procedure utilizing pyruvate as the substrate. 3 Total activity was

wt. before dialyses . . X 1000 wt. after dialyses

STUDY OF NORMALS

The urinary LDH activity found 111 25 rn.en and 25 won1en all in good health was noted (table 1). Since the upper limit of normal was almost identical (16,000 and 15,000), 16,000 was used as the upper limit of normal for both sexes in our study. None of the urine specimens of normal individuals had positive reactions (1 plus or greater) for protein, hemoglobin, bacteria, WEC or REC (fig. 1, column 1). STUDY OF PATIENTS

The urinary LDH activities observed in 250 patients have been summarized graphically (fig. 1). In contrast to normals, two-thirds of the urine specimens from the 250 patients studied had a greater than 1-plus reaction for protein, hemoglobin, bacteria, WEC and REC. Interpretation of any elevated enzyme values is thus complicated by these additional factors, since each can release LDH into the urine. Kidney masses. The results in 55 patients referred for evaluation of a mass lesion of the kidney demonstrated by excretory urography or plain film. of the abdomen were noted (table 2). The final diagnosis, based on renal exploration with histological confirmation of either tumor or cyst, correlated with the urinary LDH values in only 37 of the 55 cases (67 per cent). There was 1 false negative (2 per cent, i.e. no elevation of urinary LDH in the presence of a malignancy) and 17 false positives (31 per cent, urinary LDH elevated with no malignancy found.) The 1 patient with a false-negative finding

Accepted for publication March 4, 1965. 1 yVacker, W. E. C. and Dorfman, L. E.: Urinary lactic dehydrogenase activity. I. Screening method for detection of cancer of kidneys and bladder. J. A. M.A., 181: 972-978, 1962. 2 Dorfman, L. E., Amador, E. and Wacker, W. E. C.: Urinary lactic dehydrogenase activity. III. Analytical validation of assay method. J. A. M. A., 184: 1-6, 1963. 3 Bowers, G. N., Jr. : Lactic dehydrogenase. In: Standard Methods in Clinical Chemistry. Edited by D. Seligson. New York: Academic Press, 1963, vol. 4, pp. IG3-172. 79

80

MIRABILE, BOWERS, JR. AND BERLIN TABLE

1

Sex

No.

Range of Activity

Mean

SD

M F

25 25

5 to 16,000 2 to 15,000

s,ooo+

9,000±

3,500 3,500

(normal LDH) had a mass in the kidney which was followed elsewhere for 5 years with no significant change in size. Repeat urinalysis failed to reveal any evidence of microscopic hematuria. Renal arteriograms suggested a cyst of the kidney with an avascular, sharplydefined mass. Surgical exploration disclosed a centrally necrotic tumor of the upper pole of the kidney with no gross evidence of communication with the renal pelvis or collecting system. Perhaps this lack of communication explains why the urinary LDH was not elevated. In contrast to this false-negative reading, one of the first patients to be studied had persistently

elevated urine LDH activities associated with hematuria arising from the left kidney. A filling defect in 1 calyx was demonstrated on retrograde pyelography. Because of the then current belief that elevated urine LDH activity was specific for carcinoma of the kidney and bladder, a left nephrectomy was performed elsewhere. Gross and histological examinations disclosed localized arteriolitis only; no tumor was found. In all 17 cases that had false-positive elevations in urinary LDH, 6 cases (35 per cent) had microscopically clear urine specimens with no significant proteinuria or hemoglobinuria. In the 31 cases with normal LDH levels, 14 (45 per cent) had clear urine specimens while 17 showed contamination. Bladder tumors. This group includes patients with lesions previously treated and undergoing followup studies, as well as those presenting for initial evaluation. As with kidney masses, th URINE ~

100

...

LDH X

xxxxxx 0

X

X

0 X

X

xx

X

~I

16

X

!I

10

X

ooxoo 00 0 0 0 000 0000 00

0

oxo

ooxxxoo

5

X

xx xx X xox

X X X

X

0 0

X

X

0

XXX

X OX

X

xox

0000000

oooxxooo

0000000

oxxo

0 0000

ooxxoo

0

00 0

X

X

oxo 0

• xx X

xxxx ox

0000000000

NO

DISEASE

...Eil!.lliQ.

X

0

xx xx xx

oxo

XXX

I0

X X

X

0

XX

0

xox

id;

BENIGN

INFLAMMATION

is:t....e. .

.!S.±..6.

0

0 XX

20

X X

XX

oxxxo

X 0 X X

30

o - - o o - - x x - - 16

o o·oo

000000000

0 00

X

x- - o xox

OX X 0

0

3

X

xooox

00000

31

X

X

50

X XXX

X

~·

xox 20

I 00

xx xx

X

30

CLEAN

X X

X

X X

CONTAMINATED

xx xx xx xx

X

X

X 0 X X 0 0

=

X X

" X

=

xxxxxx XX XXXX xx

X

50

X

0

ox

·x Q; PROSTATE

5

3

Frn. 1. Urinary LDH values from 50 normal individuals and 250 patients with various clinical conditions. Symbol O represents clean urine; X represents significant red or white cells, protein or hemoglobin contamination which makes interpretation more difficult. BPH = benign prostatic hypertrophy; Ca. prostate = carcinoma of prostate; Ca. K & B = carcinoma of kidney and bladder; benign K & B = benign non-inflammatory conditions of kidney and bladder.

81

URINARY LACTIC DEHYDROGENASE TABLE

2

Normal LDH Contaminated

7 malignant lesions 48 benign lesions

Clear

Abnormal LDH Contaminated

Urine

Urine

0

1

4

14 (45%)

11 (65%)

17 (55%)

TABLE

Urine

Clear Urine

2 6

(35%)

3

Normal LDH Abnormal LDH ConContamiClear tami- Clear nated Urine nated Urine Urine

15 malignant lesions 20 benign lesions

2

13

showed evidence of contamination, but surprisingly, a significant number had no elevation in the urinary LDH activity. Prostate. In adjacent columns on figure 1 the values obtained in patients with benign prostatic hypertrophy and cancer of the prostate are recorded. In all but 1 case with carcinoma, the urinary LDH was elevated when the prostatic urethra and bladder were involved in an inflammatory reaction. In the 1 case of prostatic carcinoma with normal urinary LDH, the urine was microscopically clear and no involvement of the mucosa was seen cystoscopically. DISCUSSION

Urine

2 2

11 3

0 2

urinary LDH was far from specific for malignant disease of the bladder. In 4 of 15 patients with malignant lesions (27 per cent) false-negative results were noted and in 5 of 20 patients with benign lesions (25 per cent) false-positive results were noted (table 3). To test the hypothesis that the test would be useful in following the clinical course of a patient with bladder carcinoma, 6 determinations were made over a period of a year in the same patient, both before and after surgery. The LDH activity reflected more closely the degree of cellular contamination of the urine, rather than the histologic findings or the clinical course of the patient (table 4). Inflammation of urinary tract. The last column in figure 1 demonstrates the scatter of urinary LDH values obtained in patients with inflammatory states of the bladder and kidney. This group includes nephritis, cystitis and acute urethritis. Almost every urine specimen in the group

This study of urine LDH in 250 hospitalized patients suggests that the test is often diagnostically more confusing than helpful to the clinician. One of the major difficulties with any LDH assay, whether of serum, body fluids or urine, arises from the ubiquitous distribution of this enzyme; especially its high concentration in the blood's cellular elements, white as well as red cells. Early in this study we were impressed by the inordinately high urine LDH activities in some patients in whom full urologic investigation and continued followup failed to demonstrate significant urologic disease. At first this was attributed to trauma and inflammation secondary to cystoscopic and retrograde pyelographic studies and, indeed, this usually seemed to be the best explanation. However, many of these urine specimens were negative for hemoglobin, protein or cellular elements. Conversely, many patients with well-defined urologic diseases, i.e. calculi, prostatic hypertrophy and inflammation whose urine specimens were positive for protein, hemoglobin or cellular elements, failed to demonstrate any elevation of urinary LDH. Gross contamination of urine was usually associated with elevated

TABLE

4

LDH

Clinical Status

Urine Findings

1-2-63

30,900

Grossly bloody

3-4-63

40,000

5-20-63 7-9-63 11-17-63 4-1-64

13,300 15,000 10,300 13,800

Preop. open fulguration resection, transitional cell carcinoma, grade 2 Postop. area of calcareous encrustation at site of fulguration and cystitis Decreasing area of encrustation Decreasing area of encrustation Normal appearing bladder Normal bladder

Date

ManyWBC 0cc. WBC 0cc. WBC Clear Clear

82

MIRABILE, BOWERS, JR. AND BERLIN

urinary LDH values; however, minor degrees gave neither high nor low values consistently. Thus, although the urinary LDH was elevated in a significantly high proportion of cases with carcinoma of the kidney or bladder, it was elevated in so many other cases which did not have carcinoma that its usefulness was limited. vVe can not tell whether or not concurrent determination of alkaline phosphatase, 4 or of the individual isozymes, 5 will make this test more specific. We believe the degree of contamination will continue to be a critical factor. Close to twothirds of the hospitalized cases presenting for urological evaluation had urinary contamination. We feel that this is one of the nmin drawbacks in 4

Amador, E., Zimmerman, T. S. and Wacker,

W. E.: Urinary alkaline phosphatase activity. I.

Elevated urinary LDH and alkaline phosphatase activities for the diagnosis of renal adenocarcinomas. J. A. M.A., 185: 769-775, 1963. 5 Macalalag, E. V., Jr. and Prout, G. R., Jr.: Confirmation of the source of elevated urinary lactic dehydrogenase in patients with renal tumor. J. Urol., 92: 416-423, 1964.

clinical usefulness of this test. The consensus of the practicing urologists who have familiarized themselves with the LDH assay during this study is that urine LDH values are not helpful in establishing the diagnosis of carcinoma nor are they helpful in the subsequent management of the patient. SUMMARY

Urine LDH assays were performed in 50 normal individuals and 250 patients hospitalized for urological complications. More often urinary LDH elevation reflected urinary contamination with cellular elements, or proteinuria rather than the presence of carcinoma. Urinary LDH was high in most of the grossly contaminated urine specimens, but this was not consistent. It might or might not be elevated in the moderately contaminated urine specimens or even in those urine specimens with no contamination. The test lacked diagnostic specificity and was more often confusing than helpful to the practicing urologist.