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

Our plain-English summary of Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study, by S. Shoji, M. Hosojima, H. Kabasawa, et al (BMC Cancer, 2019).

The study

• Authors: S. Shoji, M. Hosojima, H. Kabasawa, R. Kondo, S. Miura, S. Watanabe, N. Aoki, R. Kaseda, S. Kuwahara, N. Tanabe, Y. Hirayama, I. Narita, T. Kikuchi, H. Kagamu, A. Saito
• Journal: BMC Cancer
• Published: 2019;19(1):1170
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This prospective observational study, done at one hospital in Japan, followed 45 patients who were new to chemotherapy and scheduled to receive at least 60 mg/m2 of the cancer drug cisplatin. Of these, 33 had non-small cell lung cancer, 10 had small cell lung cancer and 2 had malignant pleural mesothelioma. Before and after the first course, the authors measured urinary megalin, a kidney tubule receptor, including its ectodomain form (A-megalin), along with other urine markers of kidney injury. They also tracked kidney function (eGFR). An adverse kidney event was defined as an eGFR fall of more than 10 mL/min/1.73 m2, and it occurred in 24 patients (53.3%). Higher A-megalin before treatment was correlated with a larger eGFR fall (r = −0.458, P = 0.002). The highest A-megalin quarter had a higher event risk than the lowest (hazard ratio 7.243, 95% confidence interval 1.545 to 33.962). After adjusting for baseline kidney function, the ratio was 4.39 (0.911 to 21.134), which the authors called marginally significant. Other urine markers showed no correlation. The authors concluded that A-megalin levels are correlated with cisplatin kidney damage. They noted the study was small and single-institution.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: prospective observational study
• Who was studied: 45 consecutive chemotherapy-naïve patients with intact kidney function at Niigata University Medical and Dental Hospital, Japan: 33 with non-small cell lung cancer, 10 with small cell lung cancer, 2 with malignant pleural mesothelioma
• Exposure: Cisplatin chemotherapy at 60 mg/m2 or more (mean dose 76.0 mg/m2); urinary A-megalin, C-megalin and other kidney injury markers measured before and after the first course. Asbestos exposure was not studied.
• Main results:
  • 24 of 45 patients (53.3%) had an adverse kidney event (eGFR decline greater than 10 mL/min/1.73 m2) during 564 person-days of follow-up
  • Baseline urinary A-megalin was negatively correlated with change in eGFR (r = −0.458, P = 0.002)
  • eGFR decline was associated with baseline A-megalin quartile on Kaplan–Meier curves (P = 0.038)
  • Highest vs lowest A-megalin quartile: crude hazard ratio 7.243 (95% CI 1.545–33.962) for eGFR decline
  • Adjusted for baseline eGFR, the highest vs lowest quartile hazard ratio was 4.39 (95% CI 0.911 to 21.134, P = 0.065), described as marginally significant
  • Other baseline urinary markers showed no correlation with eGFR decline
• The authors' conclusion: The authors concluded that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity and may be a novel predictor of it
• Limitations the authors state:
  • Single-institution study with a limited number of patients
  • Relationship with long-term kidney dysfunction was not examined
  • Adverse event defined as eGFR decline greater than 10 mL/min/1.73 m2 rather than standard acute kidney injury criteria, which few patients met

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Nephrotoxicity, Tubule, Monoclonal Antibody, Biomarker, Chemotherapy, Small Cell Lung Cancer, Non-Small Cell Lung Cancer.

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