Chemotherapy agents can also cause increased systemic toxicity due to delayed drug excretion especially in pts with CKD. Other nephrotoxic agents-NSAIDS, aminoglycosides. So renal function should be carefully re-assessed frequently and dosing adjusted as needed
Bifunctional??
Pt Cl Cl NH3 NH3
In 2002, Ishida et al showed that deletion of Ctrl, high affinity copper transporter results in reduced intracellular accumulation of cisplatin in yeast which is associated by increased resistance to cisplatin toxicity. It is interesting to note that CTrl is also highly expressed in proximal tubular cells.
Females may have increased toxicity due to lower unbound cisplatin clearance- found to 15% less in women according to a study.( OR 2.0) Smoking-speculative- may be due to increased oxidative stress( OR2.5) Hypoalbuminemia- increased plasma concentrations of unbound cisplatin( OR 3.4) Paclitaxel- unknown but OR(4.0)
A study “ Magnesium depletion enhances cisplatin-induced nephrotoxicity” in cancer chemotherapy and pharmacology, 2005 has shown. Conducted in rats. Mechanism unknown. Mg deprivation is believed to cause oxidative stress and cell death and cause pro-inflammatory stress response which could contribute.
In a study published in Annals of Internal medicine in 1982- “ Intraperitoneal cisplatin with systemic thiosuplhate protection” Seventeen patients with intraperitoneal tumors were treated by 4-hour intraperitoneal dialysis with cisplatin alone, or in combination with an intravenous neutralizing agent, sodium thiosulfate. Cisplatin alone, 90 mg/m2 body surface area intraperitoneally, produced nephrotoxicity. When intraperitoneal cisplatin therapy was combined with intravenous thiosulfate treatment, the dose of cisplatin could be escalated to 270 mg/m2 body surface area without causing an increase in serum creatinine levels or undue myelosuppression. NAC- again a thiol-believed to act on death receptor and mitochondrial apoptotic pathways.. One case report used it as salvage therapy with benefit. Theophylline-one small study Glycine-animal studies Coreg-rats studies-preventing mitochondrial dysfunction induced by cisplatin. Was shown earlier to be protective against doxorubicin cardiotoxicity-associated with free radical production. PPAR: mice.antiinflammatory
Both were ovarian carcinoma pts treated previously with cisplatin and received IP carboplatin, with normal baseline renal function. Creatinine increased upto 9.5 in both. One pt required HD briefly. Creatinine decreased to 4.6 and 2 respectively.
Renal salt wasting reported in a child treated with carboplatin and etoposide- resolved later- likely due to proximal tubular dysfunction.
Mesna vs hyperhydration for prevention of hemorrhagic cystitis in BMT- journal of oncology-1991.
Pathogenesis poorly understood. Fanconi’s syndrome---proximal tubular dysfunction leading to loss of bicarbonate, amino acids, glucose, potassium,phosphate,uric acid,magnesium,sodium in urine. Glomerular and distal tubular toxicity also may be seen.
Classified as an antibiotic. Causes crosslinking of DNA and inhibits DNA synthesis.
Relatively high incidence of proteniuria suggests possible ancillary role for adaptive hyperfiltration response to reduced nephron number either due to nephrectomy or replacement by tumor.