Executive Summary and Recommendations
Renal Toxicity and Magnesium Deficiency associated with Cisplatin
M.E. Money, MD, FACP
354 Mill Street
Hagerstown, MD 21740
301-797-0210
5/11/15
Cisplatin renal toxicity pathophysiology1 and implication:










Onset in hours/days after initiation of treatment
Induction of renal vasoconstriction
Decrease in renal plasma flow
Localized inflammation
Oxidative stress
Tubular epithelial damage and cell apoptosis
Direct damage to proximal and distal tubules preventing reabsorption of
magnesium. (May occur without rise in serum creatinine or BUN).
25% of pts receiving cisplatin may develop acute renal failure, risk factors:
female, older age, smoker.2-5
Magnesium depletion has been shown to enhance the cisplatin-induced
nephrotoxicity.6
Cisplatin-associated anemia is proposed to be due to a deficiency in production of
erythropoietin by the kidneys.7
Magnesium
1. Overview8-10






Over 300 enzymes dependent on magnesium
Second most abundant intracellular cation, and 4th most abundant cation in the
body.
Normal body contains 22-26 grams of magnesium. 60% in bone, of which only
30% is exchangeable and functions as a reserve to stabilize the serum
concentration; 27% in muscle and soft tissue.
Serum magnesium accounts for only 0.3% of total body magnesium.
Normal range in serum: 1.7-2.4, carefully regulated by exchange from soft tissue
and bones (exact mechanism not fully understood).
Under normal conditions, 95% of magnesium in plasma (2 grams daily) is
reabsorbed by the kidneys, resulting in a loss of only approx 100 mg,
1
2. Hypomagnesemia clinical symptoms11,12







Electrolyte abnormalities: hypokalemia, hypocalcemia
Neuromuscular: carpopedal spasm, tetany, muscle cramps, muscle fasciculations,
muscle weakness, leg vibrations, general aching in legs
Neurologic: vertigo, aphasia, hemiparesis, depression, delirium, apathy,
choreoathetosis
Cardiovascular: tachycardia, ventricular arrhythmias, torsade de points, SVT,
General: anorexia (may be a very early symptom with sudden drop in serum mg),
fatigue, personality changes, impaired insulin sensitivity: glucose intolerance
Severe pain, fibromyalgia, tendonopathy.
A lot of the symptoms of hypomagnesmia may be attributed to the patient’s under
lying medical condition or chemotherapy without realizing that the culprit could
be a low magnesium
Effect of supplemental magnesium on cisplatin renal toxicity
 Kidera, et al: “The development of hypomagnesemia during cisplatin treatment
was significantly associated with a greater increase in serum creatinine level
(P=0.0025). Magnesium supplementation therapy was also associated with a
significantly reduced severity of renal toxicity (P=0.012)13
 Solanki, et al: Using cisplatin-induced AKI in physiologically relevant older
female mice: “Magnesium deficiency alone significantly induced basal and
cisplatin-mediated oxidative stress, whereas magnesium replacement attenuated
these effects.......magnesium replacement blocked the augmented platinum
accumulation after magnesium deficiency.”1
 Oka, et al: (lung cancer toxicity study): “High-volume hydration and Mg infusion
reduces the renal toxicity induced by cisplatin”.14
 Muraki, et al: (non-small cell lung cancer): “These results demonstrate that the
new hydration protocol comprising supplementation with magnesium without
furosemide could prevent the nephrotoxicity induced by cisplatin and pemetrezed
without affecting the treatment outcome.”15
2
Clinical Experience of a patient receiving IV magnesium with IP cisplatin
Pt is a BC Internist undergoing IP and IV chemotherapy, second round for relapse
ovarian cancer. Protocol consisted of IV Taxol at a dose of 135mg/m2 in 500 ml of
saline on day1; Cisplatin 75 mg/ m2 in 1 liter of NS along with 500-1000 cc of additional
saline IP on day 2, plus 2000 cc NS IV on day 2; additional 1000-1500 cc of saline on
day 3 and 9 for hydration; and Taxol 60 mg/ m2 IP on day 8. Serum magnesium was
routinely checked on days 1 and 8. IV magnesium was not administered unless serum
magnesium was low. However, as noted below, the patient observed that the urine output
after receiving IV magnesium on day 1 for cycle 4 was significantly less concentrated,
leading her to begin to request IV magnesium along with IP cisplatin for cycles 5 and 6.
The results are noted below:

Cycles 1-3: decreased, concentrated urine for days 2-4, disproportionate to
expected considering fluid administration and oral intake of >2000 cc on day 1,
>4000cc on day 2, and >2000 cc on day 3. Estimated urine output 500-1000cc for
days 2-4. Diuresis did not begin until evening of day 3 and into days 4-5.
 Cycle 4, serum magnesium on day 1 was 1.0, and consequently 4 gm of
magnesium as administered. The patient consequently observed less concentrated
urine output sooner than on the prior 3 cycles, leading her to do a literature
research regarding the influence of magnesium on kidney function in relationship
to cisplatin.
 For cycle 5, after research on the benefit of IV magnesium, she requested and
received 2 gm of IV magnesium even with a serum magnesium level of 1.7.
Consequently nonconcentrated urine output on day 2-3 for 24 hrs after receiving
IP cisplatin was >3500 compared to 500-800 cc for cycles 1-3. Abdomen was
markedly less tender and less swollen compared to cycles 1-4.
 For cycle 6, her serum magnesium on the day for IP cisplatin was 1.6 (lower limit
of normal). She received 2 gm of IV magnesium. Total urine output for the next
23 hrs was 4950 (nonconcentrated pale urine) and total IV, oral, and IP intake
during the same time period was approximately 4800 cc. She experienced less
abdominal distention and pain for the next 3 days than experienced for cycles 1-3.
3
Recommendations
 Check the magnesium level on Day 1 of each cycle and administer
appropriate magnesium if low. However, administer 2-4 gm of IV
magnesium on the day of cisplatin treatment for each cycle as long as
the pt’s BUN and Creatinine are normal, even if the serum magnesium
level is normal. The administration of magnesium improves urine
output by preventing renal vasoconstriction and the inflammatory
response of the cisplatin to the renal tubules.
 Monitor serum magnesium levels on Day 3 and every 2-3 days to
keep the level normal. Renal loss may be significant daily in spite of
oral magnesium. Levels below 1.4 may not cause the typical
symptoms as represented in the textbooks but affect the patient’s
quality of life.
 Do not assume the patient’s symptoms of: severe anorexia,
tachycardia, weakness, dizziness, leg vibrations or pain, etc are due to
dehydration or the chemotherapy agent. It very may be from a rapidly
decreasing serum magnesium level. These symptoms may resolve
after magnesium therapy.

If a patient has significant hypomagnesemia, oral replacement therapy
will probably not work due to a structural damage on the renal tubules
resulting in the loss. The use of amiloride 5 – 10 mg bid is
recommended with close monitoring of serum magnesium and
potassium, but it may still not prevent the renal loss and
administration of 4 gm of IV magnesium frequently may be
necessary.
4
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Solanki MH, Chatterjee PK, Gupta M, et al. Magnesium protects against
cisplatin-induced acute kidney injury by regulating platinum accumulation. Am J
Physiol Renal Physiol. Aug 15 2014;307(4):F369-384.
Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in
cisplatin-induced nephrotoxicity. Exp Toxicol Pathol. May 2009;61(3):223-242.
Daugaard G, Abildgaard U. Cisplatin nephrotoxicity. A review. Cancer
Chemother Pharmacol. 1989;25(1):1-9.
Sanchez-Gonzalez PD, Lopez-Hernandez FJ, Lopez-Novoa JM, Morales AI. An
integrative view of the pathophysiological events leading to cisplatin
nephrotoxicity. Crit Rev Toxicol. Nov 2011;41(10):803-821.
Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review.
Am J Med Sci. Aug 2007;334(2):115-124.
Lajer H, Kristensen M, Hansen HH, et al. Magnesium depletion enhances
cisplatin-induced nephrotoxicity. Cancer Chemother Pharmacol. Nov
2005;56(5):535-542.
Wood PA, Hrushesky WJ. Cisplatin-associated anemia: an erythropoietin
deficiency syndrome. The Journal of clinical investigation. Apr 1995;95(4):16501659.
Fawcett WJ, Haxby EJ, Male DA. Magnesium: physiology and pharmacology. Br
J Anaesth. Aug 1999;83(2):302-320.
Jahnen-Dechent WK, M. Magnesium basics. J Clin Kidney. 2012 2012;5([Suppl
1]):i3-i14.
Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev.
May 2003;24(2):47-66.
Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev. Feb
1999;25(1):47-58.
Lopez-Saca JM, Lopez-Picazo JM, Larumbe A, Urdiroz J, Centeno C.
Hypomagnesemia as a possible explanation behind episodes of severe pain in
cancer patients receiving palliative care. Support Care Cancer. Feb
2013;21(2):649-652.
Kidera Y, Kawakami H, Sakiyama T, et al. Risk factors for cisplatin-induced
nephrotoxicity and potential of magnesium supplementation for renal protection.
PLoS One. 2014;9(7):e101902.
Oka T, Kimura T, Suzumura T, et al. Magnesium supplementation and high
volume hydration reduce the renal toxicity caused by cisplatin-based
chemotherapy in patients with lung cancer: a toxicity study. BMC Pharmacol
Toxicol. 2014;15:70.
Muraki K, Koyama R, Honma Y, et al. Hydration with magnesium and mannitol
without furosemide prevents the nephrotoxicity induced by cisplatin and
pemetrexed in patients with advanced non-small cell lung cancer. J Thorac Dis.
Dec 2012;4(6):562-568.
5