Micke O1, Büntzel J2, Mücke R3, Kisters K4

1 Klinik f. Strahlentherapie u. Radioonkologie, Franziskus Hospital Bielefeld;
2 Klinik f. Hals-, Nasen- und Ohrenheilk., Südharzkrankenhaus Nordhausen
3 Strahlentherapeutische Klinik Lemgo, Klinikum Lippe
4 Medizinische Klinik I, St. Anna Hospital Herne; AK Trace Elements and Electrolytes - AKTE

Cisplatin is one of the most frequently chemotherapeutic agents used in radiochemotherapy in a large variety of
squamous cell carcinomas of the human body, especially head and neck cancers. Cisplatin induced tubulotoxicity is a well
described side effect. Besides the tubular damage with acute depression of renal function a cumulative renal damage is
observed. This leads to a pronounced magnesium (Mg) deficiency and a rising tubular proteinuria. Own clinical data of
patients receiving a combined radiochemotherapy containing of three cycles of 60 mg/m² body surface cisplatin showed
similar results: Serum Mg and creatinine levels as well as the scintigraphic renal clearance in 77 patients were analyzed
retrospectively and 10 further patients were investigated prospectively. Zinc, creatinine and Mg were measured in 24 hour
urine and serum before chemotherapy and at day 3 and 6 after application. In the retrospective analysis, Mg values
decreased, serum creatinine increased, and the scintigraphic clearance declined. In the prospective analysis, creatinine
values increased significantly from baseline returning to normal values at day 1 of the next cycle. Creatinine clearance
decreased from 98 ± 13 ml/min to 29 ± 5.1 ml/min at day 3 returning to 52.6 ± 14 at day 6. Fractional excretion of Mg
showed a linear increase from 2.36 % to 3.3 % at day 6 further increasing to 3.4 % and 5.3 % during the next cycle.
Fractional excretion of zinc was 2.1 to 2.6 % remaining constant. Overall, we found an acute decrease of creatinine
clearance nearly restored at day 6 after cisplatin application. Mg values decreased significantly between two cycles due to
increased excretion caused by an persisting tubular damage. Zinc values increased despite constant renal clearance,
implicating an increased liberation during radiochemotherapy. In the literature, there are several reports on a connection
of Mg and cisplatin nephrotoxicity, e.g. via a downregulation of the TRPM6/EGF pathway. Therefore, a potential
nephroprotective effect of Mg has been postulated. Preclinical experimental data in mice showed inconsistent results of
nephroprotection by Mg supplementation with a possible gender difference. Nevertheless three smaller clinical studies (2
prospective, 1 retrospective) revealed that a preloading with Mg can prevent cisplatin-induced nephrotoxicity. These
results were confirmed by an own pilot study with 10 patients receiving cisplatin radiochemotherapy and Mg
premedication. In these patients the decline of renal function was lesser compared to the above patients. Conclusion: The
main dose-limiting side effect of cisplatin chemotherapy is nephrotoxicity, which most commonly is manifested by acute
and chronic impairment of renal function with hypomagnesaemia. Premedication with Mg seems to have a protective
effect against cisplatin-induced nephrotoxicity.