Urinary GM2AP coincides with renal cortical damage and grades cisplatin nephrotoxicity severity in rats

Toxicology. 2024 Nov:508:153919. doi: 10.1016/j.tox.2024.153919. Epub 2024 Aug 11.

Abstract

Nephrotoxicity, including electrolytic disorders and acute kidney injury (AKI), limits the clinical dosage and utility of platinated antineoplastics such as cisplatin. Cisplatin nephrotoxicity embodies a tubulopathy involving the medullary S2 and S3 segments of the proximal and the distal tubules. Higher dosage extends damage over the cortical S1 segment and intensifies overall injury. However, the standard diagnosis based on plasma creatinine as well as novel injury biomarkers lacks enough pathophysiological specificity. Further granularity in the detection of renal injury would help understand the implications of individual damage patterns needed for personalized patient handling. In this article, we studied the association of urinary ganglioside GM2 activator protein (GM2AP) with the patterns of tubular damage produced by 5 and 10 mg/kg cisplatin in rats. Our results show that GM2AP appears in the urine only following damage to the cortical segment of the proximal tubule. The information provided by GM2AP is not redundant with but distinct and complementary to that provided by urinary neutrophil gelatinase-associated lipocalin (NGAL). Similarly, treatment with 150 mg/kg/day gentamicin damages the renal cortex and increases GM2AP urinary excretion; whereas renal ischemia, which does not affect the cortex, has no effect on GM2AP. Because of the key role of the cortical proximal tubule in renal function, we contend GM2AP as a potential diagnostic biomarker to stratify AKI patients according to the underlying damage and follow their evolution and prognosis. Prospectively, urinary GM2AP may help grade the severity of platinated antineoplastic nephrotoxicity by forming part of a non-invasive liquid biopsy.

Keywords: GM2AP; acute kidney injury; acute tubular injury; cisplatin; cortical necrosis; urinary biomarker.

MeSH terms

  • Acute Kidney Injury* / chemically induced
  • Acute Kidney Injury* / pathology
  • Acute Kidney Injury* / urine
  • Animals
  • Antineoplastic Agents* / toxicity
  • Biomarkers* / urine
  • Cisplatin* / toxicity
  • G(M2) Activator Protein*
  • Gentamicins / toxicity
  • Kidney Cortex* / drug effects
  • Kidney Cortex* / metabolism
  • Kidney Cortex* / pathology
  • Lipocalin-2 / urine
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Severity of Illness Index

Substances

  • Cisplatin
  • Biomarkers
  • Antineoplastic Agents
  • G(M2) Activator Protein
  • Gentamicins
  • Lipocalin-2
  • Lcn2 protein, rat