NEPHROTOXIC EFFECTS OF KANAMYCIN: A PRELIMINARY REPORT

B y Mark Winfield and George 0. Crisp Medical Service, Veterans Administration Center, Los Angeles, C d y .

Morton H . Maxwell University of California at Los Angeles Medical Cmter, Los Angeles, Calg.

Charles R. Kleeman Metabolic Service, Veterans Administration Center and University of California at Los Angeles

Medical Center, Los Angeles, Ca-lif.

Introduction Kanamycin is a bactericidal antibiotic that apparently has a wide spectrum

including Micrococcus pyogenes, Mycobacterium tuberculosis, and Gram-negative bacilli. Therapeutic failures are frequently seen in infections caused by Diplococcus pneumoniae and Toxic effects in humans have not as yet been clearly evaluated. The present study was undertaken to investi- gate the nephrotoxicity of large intramuscular doses of kanamycin adminis- tered over relatively long periods of time.

Materials and Methods Twenty patients were studied before, during, and after kanamycin therapy.

Studies have been completed on sixteen, and incomplete data have been assembled on four. All the patients except one were being treated for various infections. The common denominator was that the patient was receiving kanamycin. All serum creatinine levels prior to administration of the drug were within normal limits (0.8 to 1.3 mg. per cent). The duration of therapy ranged from 6 to 31 days with a mean of 20.2 days. Total dosage ranged from 18.5 to 108 gm. with a mean of 46.5 gm. Nine patients were treated with SO mg./kg. and 10 received 25 mg./kg. One man received a combination of both dosages. Although it was originally planned to treat all patients for at least 30 consecutive days, in more than 50 per cent of the patients it was necessary to discontinue the drug sooner because of auditory toxicity. Renal function was evaluated by the following tests: inulin, creatinine, and para-amino hippurate (PAI-I) clearances, serum creatinine, PSP excretion, and urinalysis. The clearance tests were performed by methods previously described from this laboratory.h* These studies were undertaken in the postabsorptive state with patients in the supine position. Urine collections during the clearance periods were obtained by spontaneous voiding and by bladder catheterization when necessary. Examinations of qualitative proteinuria and urine sediments were performed on morning urine specimens examined within one half hour after voiding. Maximum urinary concentration was determined after over- night dehydration, and a 4-hour intravenous infusion of 240 cc. of 5 per cent glucose and water containing 4 milliunits of aqueous pitressin per ml. Maxi- mum urinary dilution was determined by measuring specific gravity and osmo-

140

R. B

. D

urat

ions

Dos

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w. P.

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atio

n

Dos

e

T. M

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n

Dos

e

c. s.

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Dos

e

__.__

lear

ance

cc./m

rn.

121.7

109.7

91.25

154.83

-

-

-

28

50

29

50

25

25

16

50

28

50

-

-

Inul

in

clea

ranc

e

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cc

./min

.

100.6

94.6

59.2

131.9

Bef

ore

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ing

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er

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Bef

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Bef

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Dur

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PAH

le

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ce

cc./m

in.

637.5

453.63

436.7

569.1

720.2

579.13

624.0

772.4

485.5

537.5

562.9

-

726.67

-

179.

0

* Dur

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per

cn

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2.6-1.4

0.8

0.8-1.3

0.85

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0.85-1.3

1.35

1.0

1.0-1.5

1.35-2.0

1.1

0.83-1.3

1.0-

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138.7

199.1

177.9

147.5

-

91.67

166.3

-

TAB

LE 1

CUM

ULA

TIV

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TA

130.3

122.6

105.7:

128.0

-

94.0

180.0

-

Spec

ific

grav

ity

Max

imal

co

ncen

trat

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1020 -

1013

1014 -

1024 (598)

1027 (760)

1020 (536)

1024 (690)

1027 (768)

1027 (747)

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(79

8)

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imal

di

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1004 -

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(79)

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min

2

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35.5

10.7

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39.0

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19.2

92.2

41.0

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15.6

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212.

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1.5

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1.3

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1.5

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26

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____-

Patient

0. u.

M. S.

N. P.

J. M.

T. B.

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W. T.

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x. n.

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___I_

Annals New York Academy of Sciences TABLE 2

Clearance

Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Iriulin PAH Ser. creat. Creat. Inulin P.4H Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat.

_______

RENAL HEMC _____

Before ( 1 )

381 115 368

1.2-1.5 66.7 90.5

396.0 1.3-1.5 108.6 103.1 738.2 1.4

123.8 88.0

467.5 1.4-1.8

93.1 92.2

640.4

83.7 71.3

356.0

1.1-1.3

1.97

1 .1 100.0 75.9

279.1 0.85

148.3 154.7 525.7

1.0-1.7 121.7 100.7 637.5

1 .o 154.83 131.9 569.1 0.8

138.7 130.3

1 .o 147.5 128.0 485.5

1 .o 166.3 180.0 726.67 1.1

629. a

CNAMICS

During (2)

- - - 1.4 __ - -

1.3-1.4 97.4 97.8

417 1.3-1.8 - - -

1.5-1.7 - - -

1.2-1.3 - - -

1.8-2.0 - - -

1.2 - - -

1.1-1.4 106.7 130.3 665.3 .84-1.1 109.7 94.6

453.63

142.15 157.5, 720.2

199.1 122.6 562.9

0.9-1.6

0.8-1.3

0.85-1.3

.-

- 1 . o-1 .5

0.83-1.3 _____-

After (3)

212 77

340 1.5-1.6 43.5 39.6

195.4

90.8 86.6

370.5 1 .o 82.2 36.8

259.2

85.7 75.7

374.5 1 .o 71 .O 52.0

316.0 1.65

196.0 183.0 688.0 1 .o

101.7

311.4 1.2

131.0 140.0 581.5 1.7 91.25 59.20

436.70

123.17 131.77 579.13 0.85

177.9 105.75 772.4 1.35 91.67 94.0

537.5 1.35-2 . O 122.5 152 .O 779.0 1.0-1.2

1.2-1.4

-

2.6-1.4

____

Percentage difference from control (1-3)

-44.3 -33.0 -7.6

-35.0 -56.0 -51.0

-16.0 -16.0 -50.0

-33.6 -58.1 -44.5

-7.9 -17.8 -44.6

-15.1 -27.0 -14.0

+26.4 +27.0 4-16.4

0

+11.5

-11.6 -9.5 +10.6

-

-25.0 -41 .O -31.4

-20.0 0

-2.0

+28.2

+22.7 -18.87

-38.0 -26.5 +11.0

-26.0 -15.5 +7.0

Patient

c. c.

A. L.

A. B.

Winfield et ul. : Nephrotoxic Effects

Clearance

Creat. Inulin PAH Ser. creat. Creat. Inalin PAH Ser. creat. Creat. Inulin PAH Ser. creat.

___ .- -___ ___

TABLE 2-Continued

Before (1)

148.3 154.7 529.0

1.3 133.5 152.7 725.0 1.2

189.0 174.0 729.0 1.2

145

During (2)

106.7 130.3 665.3

108.7 82.7

480.0 1.2-2.1 180.0 132.0 694.0 1 .o-1.5

1.3-1.7

,_

After (3)

131.0 140.0 548.7 1.8-1.5 54.3 54.0

309.0

143.0 124.0 626.0

2 .O-1.7

1.2-1.3

Percentage difference from control (1-3)

-11.67 -9.5 +3.7

-59.3 -64.6 -57.27

-24.3 -28.7 -14.1

lality of the most dilute hourly urine specimen obtained during a 5-hour period following the oral ingestion of 1500 cc.

Results and Conclusions The results are listed in TABLE 1 for the 16 patients on whom complete data

were obtained. It is readily apparent from these data and those of subsequent tables that parallel qualitative and quantitative changes were not observed for each major renal function that was measured.

On the basis of possible errors inherent in experimen- tal techniques and chemical analyses as well as physiological variability, a change in renal function was not considered significant unless it exceeded 20 per cent of the control value (TABLE 2). Of 17 patients in whom clearances were obtained before and after treatment with kanamycin, creatinine clearance was significantly decreased in 9 (52.9 per cent), inulin clearance in 8 (47 per cent), and PAH clearance in 6 (35.2 per cent). Arbitrarily selecting an incre- ment of 0.4 mg. per cent serum creatinine as significant, 7 of 20 patients (35 per cent) had a significant increase during treatment, 2 (10 per cent) remained elevated after cessation of therapy, and 5 returned to the pretreatment range within 6 weeks. This indicates that long-term follow-up is necessary to deter- mine the reversibility of renal toxicity.

Of 16 patients, 6 (37.5 per cent) exhibited a reduction in maximal specific gravity exceeding 0.004 (TABLE 3). Three patients (18.7 per cent) were unable to dilute their urine to within 0.004 of the control value. The pattern of change in urinary osmolality confirms these changes in concen- trating and diluting ability.

Pre- and posttreatment PSP tests were done in 13 patients, and 3 (23 per cent) showed more than 20 per cent loss of function.

Urinalysis. Proteinuria of significance appeared in only 2 (10 per cent) of the 20 patients and persisted in 1 (5 per cent), TABLE 4. Microscopic hema- turia was noted in 6 (30 per cent), but only 4 (20 per cent) of these could be definitely attributed to the drug.

Renal hcmodynamics.

Tubular function.

Significant cylindruria was not observed.

Pati

ent

R. B

.

w. F

.

T. M

.

L. R

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c. s.

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60

.0

1027

(96

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1004

19

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92.2

10

24 (

690)

10

18 (

495)

35

.0

87.0

10

27 (

747)

10

05 (

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38.0

71

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1023

(70

3)

1006

(13

7)

19.0

64

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1021

(64

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1028

(86

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1007

(1

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1033

50.0

91

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(65

) 23

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45.3

Dur

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Aft

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I Pa

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t i;

1013

10

05

1024

(59

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~' 11. S

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10.7

39

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Ii

l0l0

-

I 10

20 (

536)

10

04 (7

8)

41 .o

87

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1027

(76

8)

1015

(37

9)

15.6

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o

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(1

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44.0

70

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20 (

630)

R

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(1

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148 Ten (50 per cent) of the 20 patients sustained hearing loss of mild to severe

degree, with 2 (10 per cent) losing acuity in the conversational range. All of the patients who had auditory loss demonstrated renal toxicity as well. Seven of these 10 subjects received doses of 50 mg./kg. and 3 received 25 mg./kg., showing a positive correlation between dosage and auditory toxicity.

Although all patients showed some evidence of nephrotoxicity (significant decrease in a t least 1 parameter of renal function), of the 10 with the most severe damage, 7 were receiving 50 mg./kg. and 3 received 25 mg./kg. This demonstrates a correlation between dosage and renal toxicity as well. Neither auditory nor renal toxicity seemed to be related to duration of therapy or total dosage.

Annals New York Academy of Sciences

Summary Renal impairment of varying magnitude was noted during or after treatment

with kanamycin, a new antibiotic, in 100 per cent of 20 men who received the drug. Toxicity occurred in the hemodynamic and tubular functions, but did not necessarily involve all aspects in a given case. Auditory loss occurred in 10 (50 per cent) of the patients, all of whom had concurrent renal damage. Less toxicity was seen with the lower dosage of the drug (25 mg./kg.) than with 50 mg./kg. The duration and reversibility of this renal toxicity have not been fully evaluated.

References 1. UMEZAWA, H., M. UEDA, K. MAEDA, K. YAGASHITA, S. KONDO, Y. OKAMI, R. UTAHARA,

Y . OSATO, K. NITTA & T. TAKEUCHI. Production and isolation of a new anti- biotic, kanamycin.

2. GOIJREVITCII, I\., G. A. HUNT & J. LEIN. 1958. Antibacterial activity of kanamycin. Antibiotics & Chemotherapy. 8: 149.

3. DICKISON, H. L. & D. E. TISCH. A preliminary report upon the pharmacology of kanamycin. Trans. 17th Conf. Chemotherapy of Tuberculosis. : 391.

4. CRON, M. J., D. L. JOIINSON, F. M. PALERMITI, Y . PERRON, H. D. TAYLOR, I>. F. WHITE- HEAD & T. R. HOOI’ER. 19.58. Kanamycin. I. Characterization and acid hydrolysis studies.

5 . KI.EEMAN, C. R., M. H. MAXWELL & R. KOCKNEY 1957. Production of hypertonic urine in humans in the probable absence of antidiuretic hormone (ADH). Proc. SOC.

19.57. J. Antibiotics Japan. Ser. A. 10: 181.

1958.

(Communication to the editor.) J. Am. Chem. SOC. 80: 752.

Exptl. Biol. Metl. 96: 189.

thyrotoxicosis with hypercalcemia. 6 . KLEEMAN, C. R., S. TUTTLF. & S. H. BASC~TT. 19.58. Metabolic observations in a case of

J. Clin. Endocrinol. Metabolism. 18: 477.