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Renal Failure, 12(2), 93-97 (1990)

Folate Nephropathy Occurring During Cytotoxic Chemotherapy with High-Dose Folinic Acid and

5-Fluorouracil U. Metz-Kurschel*, E. Kurschelt, K. Wagner*, E. Aulbert?, N. Graben*, and Th. Philipp* *Department of Renal and Hypertensive Diseases and West German Tumor Center University Medical School, Essen, FRG

ABSTRACT

High-dose folinic acid with 5-jluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into jluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renul failure due to tubular obstruction. In order tofind out whether there are similar jindings in the clinical setting, we investigated 8 patients @ts.) with metastatic gastrointestinul cancer who were treated with this chemotherapy. We used thefollowing parameters: I . excretion of four urinary enzymes (DH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i. v. on days 1-5 and 5-jluorouracil400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. Wefound a constant decrease in the excretion of all 4 enzymesfrom n o d to subnormal d u e s which was statistically signijicant @ < .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-jluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.

93 Copyright @ 1990 @y Marcel Dekker, IN.

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INTRODUCTION High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer (1, 2). One of the mechanisms of action of 5-FU, the major drug in the treatment of gastrointestinal malignancies, is its conversion into fluorodeoxyuridylate (FdUMI’), which inhibits thymidilate synthetase (TS). TS is a key enzyme in the conversion of 2-deoxyuridylate (dUIdP) to thymidilate, an essential component of DNA (3, 4). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid (5, 6), thus it was atlractive to use high doses of folinic acid in combination with 5-FU to circumvent primary or secondary resistance in human gastrointestinal cancer. While nothing is known about the nephrotoxic potential of 5-FU, it is accepted that in anirnal trials high doses of folic acid (250-375 mg/kg b.w.) resulted in acute renal failure due to tubular obstruction (1 1). Since folinic acid is a derivative of the folic acid with identical pharmacokinetics, we were interested to find out whether there exists a correlate to folate nephropalhy. For this reason we investigated, during a phase I/II study, 8 patients (pts.) with metastatic gastrointestinal cancers who were treated with 5-FU and high-dose folinic aciid.

PATIENTS AND METHODS During a phase I/II study we investigated 8 pts. (female 3, male 5; age 27-62 years, median 54 years) with proven progressive metastatic gastroinfestinal cancers. All pts. had a Karnofsky status between 10 and 8. Therapy was delivered in an outpatient clinic. Treatment consisted of 5-day courses of folinic acid and 5-FU followed by drug-free intervals of 21 days. Folinic acid (leucovorin calcium) was administered in a dose of 200 mg/m2 by a 2-h intravenous infusion. Immediately afterwards, 5-FU was administered at a dose of 400 mg/m2 by i.v. infusion for a period of 15 min. Patients with severe nonmalignant diseases, impaired hepatic or renal function, or hematologic dysfunction; patients who were receiving antibiotics, corticosteroids, or non-steroidal antiinflammatory drugs; and patients on oral hypoglycemic agents or insulin for diabetes mellitus or prior treatment with nitrosoureas, cis-platinum, methotrexate, or mitomycin C were excluded from our study. At the start of the study all patients had normal levels

of serum creatinine, urinary enzymes, and protein; creatinine clearance was normal in all individuals. Investigations were carried out during 2 treatment cycles. In order to assess the nephrotoxic potential we used the following non-invasive methods: 1 . Analysis of the excretion of 4 urinary enzymes a. Lactate dehydrogenase (LDH, EC 1.1.1.27) b. Leucine aminopeptidase (LAP, EC 3.4.11.2) c. 7-Glutamyltransferase(GGT, EC 2.3.2.2) d. N-acetyl-fl-glucosaminidase(NAG, EC 3.2.1.30) 2. Determination of the excretion of total protein 3. Creatinine clearance

All special investigations were made in the second morning urine samples. To avoid any influence of circadian variations, urine for protein and enzyme analysis was collected in a 3-h period from 7:00 to 10:00 a.m. Immediately after the collection period the urine specimens for urinary enzyme determinations were prepared by gel filtration on Sephadex G 50 fine. Urinary enzymes were determined as described by Maruhn et al. (7). Enzyme activities were calculated as mU/3 h, correcting for the average adult body surface of 1.73 m2. Normal values were established from 100 healthy volunteers (8). Total protein excretion was measured by the biuret method (measurement of the concentration of the copperprotein complex at 546 nm on an Eppendorf photometer P 6 121, upper normal limit 300 mg/L) . Creatinine levels in serum and urine were determined by Jaffe’s method on Eppendorf photometer P 612 I . Statistics. Values were expressed as mean values f SD. Statistical comparison was made using Student’s t test. A p value of .05 or less was considered significant.

RESULTS Toxicity In all pts. toxicity was moderate; it consisted mainly in oral mucositis, diarrhea, dry skin rash, conjunctivitis, and lacrimation. No patient had fever or septicemia. Oral mucositis of moderate degree was detected in all pts. about 7 days after termination of chemotherapy. Diarrhea occurred in 2 pts. during the treatment-free interval, but no signs of hypovolemia were recorded. Patients who developed diarrhea were not identical with those who had a decrease of renal function. In all pts. toxicity resolved 1 week before the start of the next treatment cycle.

Folate Nephropathy

No specific treatment of toxic effects was necessary; no patient required hospitalization. Urinary Enzymes

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In all 8 patients we found a uniform decrease of the excretion of LDH, LAP, GGT, and NAG from normal to subnormal values (p < .05) during both treatment cycles. Between cycles 1 and 2, urinary enzymes returned to normal values (Figs. 1-3).

Protein Excretion

95

-I

mUl3h

Pat.3 Pal. 4

D

Pat. 5

Pat. 6

1000 0

3

1

5

day

Protein output was not altered significantly (data not shown). mUl3h

3000

2000

mU13h 3000

1

1000 2000

0 3

1

Fipre 2. LAP excretion in 8 patients treated with folinic acid and 5-flwrouracil.

1000

Creatinine Clearance

0

Three patients revealed impairment of renal function reflected by a decrease of the creatinine clearance from normal to pathological values (Table 1).

nU13h

3000

~-

I

~~~.cvcie I 2

DISCUSSION 2000

1000

0 1

3

5

day

pioUrr 1. LDH exmtion in 7 patients treated with folinic acid and 5-fluorowacil.

Application of high doses of folic acid (250-375 mg/kg b.w.) in rats impairs renal function and results in oliguria of variable duration. These events are mediated by the appearance of crystals of folate, mainly within the collecting ducts and in the tubular lumina immediately after the folate was given (9). This suggests that the oliguria is due to tubular obstruction and cell damage leading to a decreased number of functioning nephrons rather than to a direct, specific effect of the substance on the biochemical system in the renal tissue (10).

Metz-Kurschel et al.

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Histological findings after high doses of folic acid showed degeneration or necrosis of tubular epithelial cells adjacent to casts formed by folate crystals (9). The histological proven obstruction was paralleled by the reduced urinary excretion of LAP, LDH, GGT, and NAG 2000 (11, 12). With in vitro tests, inhibition of the enzymes by folic acid could be excluded. Pharmacokinetic studies demonstrated that high doses 1000 of folate and folinate are mainly ( =90 X) excreted by the kidneys (13). In our study the excretion of the four urinary enzymes 0 decreased in all patients during application of folinic acid. 1 3 Whether this is due to tubular obstruction is questionable, because the dosage of folinic acid used is much lower than in the animal studies (about 1/100 of the experimental mU/3h dosage). But the drop of the creatinine clearance is an in3000 1 I dicator that the renal excretory function was impaired. These findings might reflect a correlate of folate nephropathy in the clinical setting, although we have to consider an influence of 5-FUon the cellular proliferation of tubular epithelial cells. An influence of factors unrelated to therapy is unlikely, since all patients had a 1000 high Karnofsky index, which remained stable during the observation period. The toxicity observed during our study was mild or moderate; in particular, no episodes of severe mucositis or diarrhea occurred. Fever or sep0 ticemia, which would make the use of antibiotics necessary, was not observed. In conclusion, chemotherapy with high doses of folinic Figure 3. NAG excretion in 8 patients treated with folinic acid and 5-fluorouracil. acid and 5-FUis likely to produce subclinical and rarely clinical renal injury which seems to be similar to folate nephropathy.

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mUt3h 3000

Table 1

Address correspondence to Dr. U. Metz-Kurschel, Departmentof Renal and Hypertensive Diseases, University Medical School, Hufelandstr. 55, D-4300 Essen, FRG.

Creatinine Clearance in 8 Patients Treated with Folinic Acid and 5-Fluorouracil Creatinine clearance (mL /m:in/l.73 q m ) Cycle 1

REFERENCES

Cycle 2

Patients

Day 0

Day 5

Day 0

Day 5

1

98

95

102

98

2

102

105

100

105

3

112 95

52 92

108 92

58 98

5

94

48

95

50

6

115

62

107

58

7

97

102

95

96

92

95

95

95

4

8

1. Machover D, Goldschmidt F, Chollet P, Metzger G, Zittoun J, Marque J, Vandenbulcke J, Misset JL, Schwarzenberg L, Fourtillan JB,Gaget H, Mathe G: Treatmem of advand coloredal gland gastric adenocarcinomas with 5-fluomuracil and high-dose folinic acid. J Clin Onwl4:685-696, 1984. 2. Budd GT,Fleming TR, Bukowski RM,McCracken JD, Rivkin SF, O’Bryan RM,Balcerzak SP, MacDonald JS: 5-Fluorouracil and folinic acid in the treatment of metastatic cancer:a randomized comparison. A southwest oncology p u p wdy. J Clin Oncol5:272-277, 1987. 3. Pinedo HM, Peters GFJ: Fluorouracil: biochemistry and pharmacology. J Clin Oncd 10:1653-1664, 1988.

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Folate Nephropathy 4. Chabner BA: Pyrimidine antagonists. In BA Chabner (ed): Pharmacologic Principles of Cancer Treatment. Philadelphia, Saunders, 1982, pp 183-212. 5 . Santi DV, McHenry CS, Sommer H: Mechanism of action of thymidylate synthetase with 5-fluorouracil. Biochemistry 13:471-480, 1974. 6. Santi V: A biochemical rationale for the use of 5-fluorouracil in combination with leucovorin. In Proceedings of Symposium: The Current Staie of 5-Flwmuracil-Le1~ovorin ollcium Combination. New York, Park Row Publishers, 1984, pp 1-4. 7. Maruhn D, Fuck I, Mues G: Normal limits of urinary excretion of eleven enzyms. Clin Chem 22:1567-1574, 1976. 8. Maruhn D, Storzyk K, Gielow L Diurnal variations of urinary enzyme excretions. Clin Chim Actu 75~427-433, 1977. 9. Byrnes KA, Ghidoni JJ, Suzuki M, Thomas H, Mayfield ED: Response of the rat kidney to folic acid administration. 11.

97 Morphologic studies Lab Invest 2:191-200, 1972. 10. Byrnes KA, Ghidoni JJ, Suzuki M, Thomas H,Mayfield ED: Response of the rat kidney to folic acid administration. I. Biochemical studies. Lab Invest 2:184-190, 1972. 11. Schmidt U, Dubach UC: Acute rend failure in the folate treated rat: early metabolic changes in various structures of the nephron. Kidney Int 10:39-45, 1976. 12. Maruhn D, Paar D, Hartmann HG, Bock KD, Bomhard E, Lorke D.Enzyme patterns of rat urine in folateinduced a t e renal failure. In SS Brown, DS Davies (eds): Organ Directed Toxicity of Chemical Indices and Mechanisms (IUPAC). Oxford, Pergamon Press, 1981, pp 69-73. 13. Goodman Gilman A, Goodman LS,Gilman A: Folic acid. In A Goodman Gilman, LS Goodman, A Gilman ( 4 s ) : The Pharmacological Basis of Iherapeutics. New York,Macmillan, 1980, pp 1340-1346.

Folate nephropathy occurring during cytotoxic chemotherapy with high-dose folinic acid and 5-fluorouracil.

High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One...
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