Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study

BMC Cancer. 2019 Dec 2;19(1):1170. doi: 10.1186/s12885-019-6398-2.


Background: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer.

Methods: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α1-microglobulin, β2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment.

Results: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline.

Conclusions: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.

Keywords: Chemotherapy; Cisplatin; Nephrotoxicity; Urinary megalin.

Publication types

  • Observational Study

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / urine*
  • Aged
  • Antineoplastic Agents / adverse effects*
  • Biomarkers / metabolism
  • Biomarkers / urine
  • Cisplatin / adverse effects*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glomerular Filtration Rate
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Kidney Tubules, Proximal / physiopathology
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism*
  • Male
  • Middle Aged
  • Prospective Studies
  • Thoracic Neoplasms / drug therapy
  • Thoracic Neoplasms / pathology
  • Thoracic Neoplasms / urine


  • Antineoplastic Agents
  • Biomarkers
  • LRP2 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Cisplatin