Nephron 23: 205-209(1979)
Renal Tubular Necrosis following Cephalothin Bruce L. Thomas and Glenn C. Faith Department of Pathology, University of Wisconsin Medical School, Madison, Wise.
Key Words. Cephalothin • Acute tubular necrosis • Kidney • Renal failure • Rat ■Nephrotoxicity • Cephaloridine Abstract. Renal tubular necrosis was observed following intramuscular injections of cephalothin into rats. Lesions were consistently produced with 5.0 g/kg and were maximal in severity at the 2nd and 3rd days following injection. Renal tubular necrosis following cephalothin was similar in morphology to that produced by nephrotoxic doses (2.0 g/kg) of cephaloridine. The nephrotoxic potential of cephalothin has been demonstrated in the rat model and caution is urged in using large doses of cephalothin.
Cephalothin is an antibiotic thas has been used extensi vely for serious bacterial infections [1], Cephalothin is effective against a broad spectrum of both gram-positive and gram-negative bacteria, as well as penicillinase-produc ing bacteria. Since the incidence of clinical cross-allergenic ity with penicillin is low. cephalothin is an important alternate choise for patients that are allergic to penicillin. In addition, the nephrotoxic potential of cephalothin is far less than most other antibiotics that are used for serious, lifethreatening infections. The disadvantages of cephalothin [I] are allergic reac tions such as anaphylaxis, serum sickness, eosinophilia. fever, rashes, neutropenia. Coombs’ positive hemolytic anemia, painful intramuscular injections, phlebitis with intravenous use, sodium overloading, superinfections, and renal dysfunction. The early toxicology studies 12, 3] on cephalothin failed to demonstrate renal abnormalities. However, Perkins et at. [4] found that there was ‘focal cellular vacuolization and fragmentation’ in the proximal convoluted tubules of rabbits after 0.5g/kg of cephalothin, although no associa ted functional changes were documented. Siega [5] reported a rise in the mean serum creatinine from I. I to 1,5mg% in rabbits receiving 0.6g/kg of cephalothin. Subsequently, there have been several clinical reports [6-16] implicating cephalothin as a cause of acute renal failure. Common features in these clinical reports are large doses of cephalo thin. preexisting renal insufficiency, sepsis, hypotension, elderly patients, and the use of other nephrotoxic drugs.
This study was conducted to examine the effect of large doses of cephalothin on the morphology of the normal rat kidney. Materials and Methods Albino, male Sprague-Dawley rats, weighing approximately I50g, were allowed commercial ral food and water as desired. A single in jection of cephalothin sodium was given intramuscularly in the but tocks in dosages ranging from 1.0 to 5.0 g/kg. One control group received no injections and another control group received a compar able number of millicquivalcnts of sodium (i.e. 22 mEq Na kg) as 5% sodium chloride intramuscularly in a single injection. A fourth group of rats received a single injection of intramuscular cephaloridine in dosages ranging from 0.5 to 3.0 g/kg. The rats were given only one injection of their respective antibiotic or 5% sodium chloride, and then sacrificed at various time intervals ranging from I to 4 days after the injection. All rats were given ether anesthesia and laparotomy was per formed. The renal arteries and veins were clamped and both kidneys were removed, sliced, and immersed in cold fixative within 2 min after clamping the renal arteries. Specimens were fixed for 24 h in phosphate-buffered (0.1 M sodium phosphate) /^-formaldehyde (4%) and sucrose (4%). The tissues were processed for routine imbedding in paraffin, cut to 6 uni in thickness, and stained with hematoxylin and eosin (HE).
Results 16 rats received a single intramuscular injection of cephalothin ranging from 0.5 to 5.0g/kg. There were no pathological renal lesions in the 6 rats that received 0.5-3.0g/kg when sacrificed 24h after the injection. 4 rats
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Introduction
Thomas/Faith
206
(table I) that received 5.Og/kg were sacrificed after 24h and showed subcapsular tubular dilation and cytoplasmic vac uolization. cellular casts in the inner cortex, and minimal tubular necrosis in 1 (N o.3). 6 other rats were sacrificed at 48, 72, and 96h after a single injection of 5.0g/kg of cephalothin. Renal tubular necrosis (fig. 1,2) was present in 4 of these rats and various tubular casts were present in all 6 rats (tableI). Tubular necrosis was more frequent and severe at 72 h following the injection and usually limited to the subcapsular area. The glomeruli in all rats were normal. 8 control rats that received no injections or 5% sodium chloride had normal renal histology. 15 rats received a single intramuscular injection of cephaloridine ranging from 0.5 to 3.0g/kg. When the rats were sacrificed after 24 h, renal tubular necrosis was present
in the rats receiving 2.0 to 3.0g/kg. while the lower dosages (0.5-1.Og/kg) produced only cytoplasmic vacuolization of the tubular cells. Severe renal tubular necrosis developed at 48, 72, and 96h in 6 rats that received a single injection of 2.Og/kg of cephaloridine. Necrosis was more severe at 48-72h (fig.3) with a subcapsular distribution and large numbers of tubular casts. Tubular dilation and necrosis were less severe at 96h, but marked basophilia and mitoses of the tubular cells were present.
Discussion Large doses of intramuscular cephalothin are effective methods of inducing renal tubular necrosis in the rat. The renal pathology is very similar to that produced by toxic doses of cephaloridine. The common features are subcaps ular tubular dilation and tubular necrosis with a variety of casts. The renal lesion following cephalothin is not as severe, nor as predictable, as that following cephaloridine.
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Fig. ]. Rat kidney at 72 h after receiving 5.0 g kg of cephalothin. Low-power view of the outer cortex. There are foci of dilated subcapsular tubules that are lined by necrotic tubular epithelial cells and sloughed cellular debris in the lumens. * 500.
Fig. 2. High-power view of figure 1, demonstrating necrotic renal tubular epithelial cells, x 2,000.
Also, the nephrotoxic potency of cephalothin is much less than cephaloridine. There are several reasons that may explain why cepha lothin is less nephrotoxic than cephaloridine. Approxi mately 50% of cephalothin is bound to plasma protein [l]as compared to 0% binding of cephaloridine. Thus, the unbound serum concentration of cephalothin is much less than cephaloridine at the same dose. Also, 25% of cepha lothin is metabolized [1] to a weakly antibacterial Odesacetylcephalothin, whereas cephaloridine is not meta bolized to inactive compounds. Assuming that a reduction in nephrotoxicity may coincide with a reduction in the anti bacterial activity of the cephalothin metabolite, the neph rotoxic potential of cephalothin is further reduced in com parison to cephaloridine. Higher serum levels follow cepha loridine than an equivalent dose of cephalothin [17] and the half-life of cephaloridine [18] (1.5 h) is double the half-life of
207
cephalothin (0.8 h). Both antibiotics are filtered at the glomerulus, but the renal tubular secretion rate of cephalo thin is much greater than that of cephaloridine [19]. This tubular secretion of cephalolhin partially explains the short half-life of cephalothin. All of these factors decrease the effective free serum concentration of cephalothin relative to an equal dose of cephaloridine. Thus, a very large dose of cephalothin would have to be used before toxicities would be expected to occur. This situation could be produced by massive doses of cephalothin and/or a reduced blood clearance of cephalothin. In this study, the most consistent renal tubular lesions were attained with cephalothin doses of 5.0g/kg. This is a large dose if it is compared to the upper limit of the recommended human dose of 12g/70 kg or 171 mg/kg. However, an analogy to cephaloridine demonstrates that the nephrotoxic dose in rats [20:0.9-1.6g/kg] is 15-30 times the upper limit of the recommended human dose of 4g/70kg or 57 mg/kg. Thus, the rat is relatively resistant to the nephrotoxicity of the cephalosporins. By using the
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Renal Necrosis following Cephalolhin
Thomas, Faith
208
cephaloridine analogy and the pharmacological factors discussed previously, the nephrotoxic dose of cephalothin in the rat could be estimated to be between 2.5 and 5.0g/kg. Thus, the 5.0g/kg dose of cephalothin is relatively high, but is necessary to reveal the nephrotoxicity of cephalothin in the resistant rat kidney. Compared to this study, previous toxicology studies [2-5, 21-24] have used relatively smaller doses of cephalo thin (0.2-4.0g/kg). Venuto el al. [21] gave 0.3g/kg of cephalothin to rabbits with a reduced nephron population and achieved very high levels of cephalothin without adverse changes in the serum creatinine, although histolo gic studies were not done. Lawson el al. [22] demonstrated tubular necrosis in rats receiving 1.5g/kg of cephalothin alone, and at lower doses when the rats were pretreated with relatively nontoxic doses of glycerol and furosemide.
Silverblalt et al. [23] found an 'apparent increase in the prominence of lysosomes in the proximal tubular epithelial cells' in rats receiving 2.2g/kg of cephalothin. Kurmoto [24] demonstrated proliferation of the renal tubules of rats that were given 4.0g/kg of cephalothin, intraperitoneally, for 8 days. In summary, large doses of cephalothin (5.0g/kg) will produce renal tubular necrosis in the normal rat kidney. Cephalothin nephrotoxicity should be considered in pa tients that are receiving large doses of cephalothin or in patients with preexisting renal insufficiency that demon strate a decline in renal function while receiving cephalo thin.
Acknowledgements This investigation was supported by National Institutes of Health grant No.5-R0l-AM13755-02; the Upper Midwest Chapter of the National Kidney Foundation and the Department of Pathology, University of Wisconsin Medical School.
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Fig. 3. Rat kidney at 72 h after receiving 5.0 g/kg of cephaloridine. Low-power view of outer cortex with subcapsular tubular dilation and foci of necrotic tubular epithelial cells.
209
Renal Necrosis following Cephalothin
Rat No.
Time after cephalothin, h
Pathology
1
24
2
24
3
24
4 5
24 48
6
48
SC tubular dilation and cytoplasmic vacu olization SC tubular dilation and cytoplasmic vacu olization moderate SC tubular dilation and minimal tubular necrosis. Few cellular casts in IC large numbers of cellular casts in IC moderate number of cellular and hyaline casts in IC and OM severe SC tubular dilation and foci of tubular necrosis with a few hyaline and granular casts. Large numbers of cellular, hyaline, and granular casts in IC, OM and IM mild SC tubular dilation and foci of tubular necrosis. Occasional cellular casts in IC and
7
72
8
72
occasional hyaline casts in OM
9
10
96
96
severe SC tubular dilation and a moderate number of foci of tubular necrosis. A few cellular casts in 1C and a few granular and cellular casts in the IM moderate SC tubular dilation with hyaline and granular casts in theOC. Large numbers of cellular, hyaline, and granular casts in the fC and OM. Severe tubular and inter stitial necrosis at the tip of the papilla with interstitial edema and large numbers of cellular, hyaline, and granular casts occasional hyaline casts in OM and IM
9
10
II
12
13
14
15
16
17
18
19
SC = Subcapsular; OC = outer cortex; IC = inner cortex: OM = outer medulla; IM = inner medulla. 20
References
J., and Greene, J.A., jr .: Oliguria following transplantation of kidneys donated by blood relatives. Surgery Gynec. Obstet. 130: 29-36(1970). Benner, E.J.: Renal damage associated with prolonged adminis tration of ampicillin. cephaloridine, and cephalothin. Antimicrob. Agents Chemother. ¡969: 417-420 (1970). Pickering, M.J.: Spooner, G.R.:Ouesada, A. de, and Cade, J. R .: Declining renal function associated with administration of cephalothin. Sth. med. J., Nashville 63: 426-428 (1970). Campbell, M.H. and Naurer, W .J.: Recurrent oliguric renal failure during therapy with antibiotics. Wis. med. J. 69: 214-215 (1970) . Simpson, I.J.: Nephrotoxicity and acute renal failure associated with cephalothin and cephaloridine. N.Z. med. J. 74: 312-315 (1971) . Burton, J. R.: Lichtenstein, N.S.:Colvin, R. B., and Hyslop, N. E.. jr.: Acute renal failure during cephalothin therapy. J. Am. med. Ass. 229: 679-682(1974). Pasternak, D.P. and Stephens, B.G.: Reversible nephrotoxicity associated with cephalothin therapy. Archs intern. Med. 135: 599-602(1975). Carling, P.C.: Idelson, B.A.; Caseno, A.A.: Alexander, E.A., and McCabe, W. R.: Nephrotoxicity associated with cephalothin administration. Archs intern. Med. 135: 797-801 (1975). Engle, J.E .: Drago, J.: Carlin. B., and Schoolwerth. A .C .: Reversible acute renal failure after cephalothin. Ann. intern. Med. 83: 232-233 (1975). Perkins, R.L.; Saslaw, S., and Hackett, J.: Cephaloridine and cephalothin: comparative in vino evaluation. Am. J. med. Sci. 253: 293-299 (1967). Kunin, C. M. and Atuk, N.: Excretion of cephaloridine and cephalothin in patients with renal impairment. New Engl. J. Med. 274: 654-656 (1966). Tuano, S.B.; Brodie. J.L., and Kirby, W .M.; Cephaloridine versus cephalothin: Relation of the kidney to blood level differ ences after parenteral administration. Antimicrob. Agents Chemother. 1966: 101-106(1967). Atkinson, R. M.; Currie, J.P.: Davis, B.: Pratt, D .A .H .: Sharpe, H.M., and Tomich, E.G.: Acute toxicity of cephaloridine, an antibiotic derived from cephalosporin C. Toxic, appl. Pharmac. 8: 398-406(1966). Venuto, R.C.; Stein, J.H ., and Ferris, T. F.: Failure to demons trate nephrotoxicity of cephalothin in rabbits with reduced renal function. Proc. Soc. exp. Biol. Med. 139: 1065-1067 (1972). Lawson, D .H .: Macadam, R .F .: Singh, H.: Gavras, H.: Hartz, S .: Turnbull, D., and Linton, A. L.: Effect of furosemide on anti biotic-induced renal damage in rats. J. infect. Dis. 126: 593-600 (1972) . Silverblatt, F.; Harrison, W.O., and Turck, M.: Nephrotoxicity of cephalosporin antibiotics in experimental animals. J. infect. Dis. 128: suppl. I. pp. S367-S372 (1973). Kurmoto, M .: On the toxicity of massive dose of sodium cephal othin. Jap. J. Antibiot. 27: 746-765 (1974).
21 1 Weinstein, L. and Kaplan, K.: The cephalosporins. Ann. intern. Med. 72: 729-739(1970). 2 Lee, C.C.; Herr, E. B.,jr., and Anderson. R .C.: Pharmacological and toxicological studies on cephalothin. Clin. Med. 70: 1123— 22 1138(1963). 3 Kajimoto, Y.: Comparison of renal toxicity of cephalothin and cephaloridine in rabbits. Jap. J. Antibiot. 21: 124-130 (1968). 4 Perkins, R.L.; Apicella, M.A.; Lee, L; Cuppage, F .E., and 23 Saslaw, S.: Cephaloridine and cephalothin; comparative studies of potential nephrotoxicity. J. Lab. clin. Med. 71: 75-84 (1968). 5 Siega, K. : Study on renal and hepatic functions of rabbits follow 24 ing the administration of cephalothin and cephaloridine. Jap. J. Antibiot. 21: 336-341 (1968). 6 Rahal. J.J.: Meyers, B. R., and Weinstein, L.: Treatment of bacterial endocarditis with cephalothin. New Engl. J. Med. 279 Received: June 27, 1977 1305-1309(1968). Accepted: April 24, 1978 7 Thomas. B.L.: Renal function and cephalothin. New Engl. J. Med. 280: 505-506(1969). Bruce L. Thomas, MD, J.C. Blair Memorial Hospital, 8 Turcotte, J.G .: Herrmann, T.J.; Haig, O.; O’Dell, C., jr.; Cerny, Huntingdon, PA 16652 (USA)
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Table I. Pathology of rat kidneys after receiving a single intra muscular injection of 5.0 gm, kg of cephalothin
Renal Tubular Necrosis following Cephalothin Bruce L. Thomas and Glenn C. Faith Department of Pathology, University of Wisconsin Medical School, Madison, Wise.
Key Words. Cephalothin • Acute tubular necrosis • Kidney • Renal failure • Rat ■Nephrotoxicity • Cephaloridine Abstract. Renal tubular necrosis was observed following intramuscular injections of cephalothin into rats. Lesions were consistently produced with 5.0 g/kg and were maximal in severity at the 2nd and 3rd days following injection. Renal tubular necrosis following cephalothin was similar in morphology to that produced by nephrotoxic doses (2.0 g/kg) of cephaloridine. The nephrotoxic potential of cephalothin has been demonstrated in the rat model and caution is urged in using large doses of cephalothin.
Cephalothin is an antibiotic thas has been used extensi vely for serious bacterial infections [1], Cephalothin is effective against a broad spectrum of both gram-positive and gram-negative bacteria, as well as penicillinase-produc ing bacteria. Since the incidence of clinical cross-allergenic ity with penicillin is low. cephalothin is an important alternate choise for patients that are allergic to penicillin. In addition, the nephrotoxic potential of cephalothin is far less than most other antibiotics that are used for serious, lifethreatening infections. The disadvantages of cephalothin [I] are allergic reac tions such as anaphylaxis, serum sickness, eosinophilia. fever, rashes, neutropenia. Coombs’ positive hemolytic anemia, painful intramuscular injections, phlebitis with intravenous use, sodium overloading, superinfections, and renal dysfunction. The early toxicology studies 12, 3] on cephalothin failed to demonstrate renal abnormalities. However, Perkins et at. [4] found that there was ‘focal cellular vacuolization and fragmentation’ in the proximal convoluted tubules of rabbits after 0.5g/kg of cephalothin, although no associa ted functional changes were documented. Siega [5] reported a rise in the mean serum creatinine from I. I to 1,5mg% in rabbits receiving 0.6g/kg of cephalothin. Subsequently, there have been several clinical reports [6-16] implicating cephalothin as a cause of acute renal failure. Common features in these clinical reports are large doses of cephalo thin. preexisting renal insufficiency, sepsis, hypotension, elderly patients, and the use of other nephrotoxic drugs.
This study was conducted to examine the effect of large doses of cephalothin on the morphology of the normal rat kidney. Materials and Methods Albino, male Sprague-Dawley rats, weighing approximately I50g, were allowed commercial ral food and water as desired. A single in jection of cephalothin sodium was given intramuscularly in the but tocks in dosages ranging from 1.0 to 5.0 g/kg. One control group received no injections and another control group received a compar able number of millicquivalcnts of sodium (i.e. 22 mEq Na kg) as 5% sodium chloride intramuscularly in a single injection. A fourth group of rats received a single injection of intramuscular cephaloridine in dosages ranging from 0.5 to 3.0 g/kg. The rats were given only one injection of their respective antibiotic or 5% sodium chloride, and then sacrificed at various time intervals ranging from I to 4 days after the injection. All rats were given ether anesthesia and laparotomy was per formed. The renal arteries and veins were clamped and both kidneys were removed, sliced, and immersed in cold fixative within 2 min after clamping the renal arteries. Specimens were fixed for 24 h in phosphate-buffered (0.1 M sodium phosphate) /^-formaldehyde (4%) and sucrose (4%). The tissues were processed for routine imbedding in paraffin, cut to 6 uni in thickness, and stained with hematoxylin and eosin (HE).
Results 16 rats received a single intramuscular injection of cephalothin ranging from 0.5 to 5.0g/kg. There were no pathological renal lesions in the 6 rats that received 0.5-3.0g/kg when sacrificed 24h after the injection. 4 rats
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Introduction
Thomas/Faith
206
(table I) that received 5.Og/kg were sacrificed after 24h and showed subcapsular tubular dilation and cytoplasmic vac uolization. cellular casts in the inner cortex, and minimal tubular necrosis in 1 (N o.3). 6 other rats were sacrificed at 48, 72, and 96h after a single injection of 5.0g/kg of cephalothin. Renal tubular necrosis (fig. 1,2) was present in 4 of these rats and various tubular casts were present in all 6 rats (tableI). Tubular necrosis was more frequent and severe at 72 h following the injection and usually limited to the subcapsular area. The glomeruli in all rats were normal. 8 control rats that received no injections or 5% sodium chloride had normal renal histology. 15 rats received a single intramuscular injection of cephaloridine ranging from 0.5 to 3.0g/kg. When the rats were sacrificed after 24 h, renal tubular necrosis was present
in the rats receiving 2.0 to 3.0g/kg. while the lower dosages (0.5-1.Og/kg) produced only cytoplasmic vacuolization of the tubular cells. Severe renal tubular necrosis developed at 48, 72, and 96h in 6 rats that received a single injection of 2.Og/kg of cephaloridine. Necrosis was more severe at 48-72h (fig.3) with a subcapsular distribution and large numbers of tubular casts. Tubular dilation and necrosis were less severe at 96h, but marked basophilia and mitoses of the tubular cells were present.
Discussion Large doses of intramuscular cephalothin are effective methods of inducing renal tubular necrosis in the rat. The renal pathology is very similar to that produced by toxic doses of cephaloridine. The common features are subcaps ular tubular dilation and tubular necrosis with a variety of casts. The renal lesion following cephalothin is not as severe, nor as predictable, as that following cephaloridine.
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Fig. ]. Rat kidney at 72 h after receiving 5.0 g kg of cephalothin. Low-power view of the outer cortex. There are foci of dilated subcapsular tubules that are lined by necrotic tubular epithelial cells and sloughed cellular debris in the lumens. * 500.
Fig. 2. High-power view of figure 1, demonstrating necrotic renal tubular epithelial cells, x 2,000.
Also, the nephrotoxic potency of cephalothin is much less than cephaloridine. There are several reasons that may explain why cepha lothin is less nephrotoxic than cephaloridine. Approxi mately 50% of cephalothin is bound to plasma protein [l]as compared to 0% binding of cephaloridine. Thus, the unbound serum concentration of cephalothin is much less than cephaloridine at the same dose. Also, 25% of cepha lothin is metabolized [1] to a weakly antibacterial Odesacetylcephalothin, whereas cephaloridine is not meta bolized to inactive compounds. Assuming that a reduction in nephrotoxicity may coincide with a reduction in the anti bacterial activity of the cephalothin metabolite, the neph rotoxic potential of cephalothin is further reduced in com parison to cephaloridine. Higher serum levels follow cepha loridine than an equivalent dose of cephalothin [17] and the half-life of cephaloridine [18] (1.5 h) is double the half-life of
207
cephalothin (0.8 h). Both antibiotics are filtered at the glomerulus, but the renal tubular secretion rate of cephalo thin is much greater than that of cephaloridine [19]. This tubular secretion of cephalolhin partially explains the short half-life of cephalothin. All of these factors decrease the effective free serum concentration of cephalothin relative to an equal dose of cephaloridine. Thus, a very large dose of cephalothin would have to be used before toxicities would be expected to occur. This situation could be produced by massive doses of cephalothin and/or a reduced blood clearance of cephalothin. In this study, the most consistent renal tubular lesions were attained with cephalothin doses of 5.0g/kg. This is a large dose if it is compared to the upper limit of the recommended human dose of 12g/70 kg or 171 mg/kg. However, an analogy to cephaloridine demonstrates that the nephrotoxic dose in rats [20:0.9-1.6g/kg] is 15-30 times the upper limit of the recommended human dose of 4g/70kg or 57 mg/kg. Thus, the rat is relatively resistant to the nephrotoxicity of the cephalosporins. By using the
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Renal Necrosis following Cephalolhin
Thomas, Faith
208
cephaloridine analogy and the pharmacological factors discussed previously, the nephrotoxic dose of cephalothin in the rat could be estimated to be between 2.5 and 5.0g/kg. Thus, the 5.0g/kg dose of cephalothin is relatively high, but is necessary to reveal the nephrotoxicity of cephalothin in the resistant rat kidney. Compared to this study, previous toxicology studies [2-5, 21-24] have used relatively smaller doses of cephalo thin (0.2-4.0g/kg). Venuto el al. [21] gave 0.3g/kg of cephalothin to rabbits with a reduced nephron population and achieved very high levels of cephalothin without adverse changes in the serum creatinine, although histolo gic studies were not done. Lawson el al. [22] demonstrated tubular necrosis in rats receiving 1.5g/kg of cephalothin alone, and at lower doses when the rats were pretreated with relatively nontoxic doses of glycerol and furosemide.
Silverblalt et al. [23] found an 'apparent increase in the prominence of lysosomes in the proximal tubular epithelial cells' in rats receiving 2.2g/kg of cephalothin. Kurmoto [24] demonstrated proliferation of the renal tubules of rats that were given 4.0g/kg of cephalothin, intraperitoneally, for 8 days. In summary, large doses of cephalothin (5.0g/kg) will produce renal tubular necrosis in the normal rat kidney. Cephalothin nephrotoxicity should be considered in pa tients that are receiving large doses of cephalothin or in patients with preexisting renal insufficiency that demon strate a decline in renal function while receiving cephalo thin.
Acknowledgements This investigation was supported by National Institutes of Health grant No.5-R0l-AM13755-02; the Upper Midwest Chapter of the National Kidney Foundation and the Department of Pathology, University of Wisconsin Medical School.
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Fig. 3. Rat kidney at 72 h after receiving 5.0 g/kg of cephaloridine. Low-power view of outer cortex with subcapsular tubular dilation and foci of necrotic tubular epithelial cells.
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Renal Necrosis following Cephalothin
Rat No.
Time after cephalothin, h
Pathology
1
24
2
24
3
24
4 5
24 48
6
48
SC tubular dilation and cytoplasmic vacu olization SC tubular dilation and cytoplasmic vacu olization moderate SC tubular dilation and minimal tubular necrosis. Few cellular casts in IC large numbers of cellular casts in IC moderate number of cellular and hyaline casts in IC and OM severe SC tubular dilation and foci of tubular necrosis with a few hyaline and granular casts. Large numbers of cellular, hyaline, and granular casts in IC, OM and IM mild SC tubular dilation and foci of tubular necrosis. Occasional cellular casts in IC and
7
72
8
72
occasional hyaline casts in OM
9
10
96
96
severe SC tubular dilation and a moderate number of foci of tubular necrosis. A few cellular casts in 1C and a few granular and cellular casts in the IM moderate SC tubular dilation with hyaline and granular casts in theOC. Large numbers of cellular, hyaline, and granular casts in the fC and OM. Severe tubular and inter stitial necrosis at the tip of the papilla with interstitial edema and large numbers of cellular, hyaline, and granular casts occasional hyaline casts in OM and IM
9
10
II
12
13
14
15
16
17
18
19
SC = Subcapsular; OC = outer cortex; IC = inner cortex: OM = outer medulla; IM = inner medulla. 20
References
J., and Greene, J.A., jr .: Oliguria following transplantation of kidneys donated by blood relatives. Surgery Gynec. Obstet. 130: 29-36(1970). Benner, E.J.: Renal damage associated with prolonged adminis tration of ampicillin. cephaloridine, and cephalothin. Antimicrob. Agents Chemother. ¡969: 417-420 (1970). Pickering, M.J.: Spooner, G.R.:Ouesada, A. de, and Cade, J. R .: Declining renal function associated with administration of cephalothin. Sth. med. J., Nashville 63: 426-428 (1970). Campbell, M.H. and Naurer, W .J.: Recurrent oliguric renal failure during therapy with antibiotics. Wis. med. J. 69: 214-215 (1970) . Simpson, I.J.: Nephrotoxicity and acute renal failure associated with cephalothin and cephaloridine. N.Z. med. J. 74: 312-315 (1971) . Burton, J. R.: Lichtenstein, N.S.:Colvin, R. B., and Hyslop, N. E.. jr.: Acute renal failure during cephalothin therapy. J. Am. med. Ass. 229: 679-682(1974). Pasternak, D.P. and Stephens, B.G.: Reversible nephrotoxicity associated with cephalothin therapy. Archs intern. Med. 135: 599-602(1975). Carling, P.C.: Idelson, B.A.; Caseno, A.A.: Alexander, E.A., and McCabe, W. R.: Nephrotoxicity associated with cephalothin administration. Archs intern. Med. 135: 797-801 (1975). Engle, J.E .: Drago, J.: Carlin. B., and Schoolwerth. A .C .: Reversible acute renal failure after cephalothin. Ann. intern. Med. 83: 232-233 (1975). Perkins, R.L.; Saslaw, S., and Hackett, J.: Cephaloridine and cephalothin: comparative in vino evaluation. Am. J. med. Sci. 253: 293-299 (1967). Kunin, C. M. and Atuk, N.: Excretion of cephaloridine and cephalothin in patients with renal impairment. New Engl. J. Med. 274: 654-656 (1966). Tuano, S.B.; Brodie. J.L., and Kirby, W .M.; Cephaloridine versus cephalothin: Relation of the kidney to blood level differ ences after parenteral administration. Antimicrob. Agents Chemother. 1966: 101-106(1967). Atkinson, R. M.; Currie, J.P.: Davis, B.: Pratt, D .A .H .: Sharpe, H.M., and Tomich, E.G.: Acute toxicity of cephaloridine, an antibiotic derived from cephalosporin C. Toxic, appl. Pharmac. 8: 398-406(1966). Venuto, R.C.; Stein, J.H ., and Ferris, T. F.: Failure to demons trate nephrotoxicity of cephalothin in rabbits with reduced renal function. Proc. Soc. exp. Biol. Med. 139: 1065-1067 (1972). Lawson, D .H .: Macadam, R .F .: Singh, H.: Gavras, H.: Hartz, S .: Turnbull, D., and Linton, A. L.: Effect of furosemide on anti biotic-induced renal damage in rats. J. infect. Dis. 126: 593-600 (1972) . Silverblatt, F.; Harrison, W.O., and Turck, M.: Nephrotoxicity of cephalosporin antibiotics in experimental animals. J. infect. Dis. 128: suppl. I. pp. S367-S372 (1973). Kurmoto, M .: On the toxicity of massive dose of sodium cephal othin. Jap. J. Antibiot. 27: 746-765 (1974).
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Table I. Pathology of rat kidneys after receiving a single intra muscular injection of 5.0 gm, kg of cephalothin
