In the JASN study by Jesus et al.,1 the investigators demonstrated that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) improved acute cisplatin (Cis)-induced hypomagnesemia and reduced kidney magnesium wasting associated with relative preservation of Na+-K+-Cl cotransporter 2 and NaCl cotransporter activity in the kidney tubules, indirectly assessed through channel phosphorylation and the natriuretic response to the diuretic challenge. More interestingly, SGLT2 inhibitors not only preserved TRPM6 expression but also prevented atrophy of the distal convoluted tubule (DCT).
The authors do not provide a convincing mechanism by which SGLT2 inhibitors could influence Na+-K+-Cl cotransporter 2 activity in the thick ascending limb of the loop of Henle but provide speculation that the restoration of the DCT area and TRPM6 expression may result from glycosuria-mediated activation of NaCl cotransporter through the luminal calcium-sensing receptor in the DCT.
I aim to highlight AKI associated with cisplatin toxicity in this study. The GFR, measured by FITC-sinistrin, decreased by nearly 40% in cisplatin-treated rats (0.68±0.05 versus 1.19±0.02 ml/min per 100 g body weight, P < 0.0001) but was relatively preserved with the administration of empagliflozin in these rats (FITC-GFR Cis versus Cis-EMPA P < 0.001), measured on day 24 (9 days after starting empagliflozin) of the 30-day study. Previous studies investigating acute cisplatin nephrotoxicity have shown that canagliflozin can significantly improve cisplatin-induced biochemical and histopathologic alterations,2 potentially by decreasing cisplatin uptake by nearly 15% in the proximal convoluted tubule cells of the kidney.3 Therefore, the prevention of acute cisplatin nephrotoxicity with SGLT2 inhibitors may explain the beneficial effects observed in nearly all studied aspects, with this study focusing specifically on magnesium homeostasis.
We must differentiate these findings from the previously demonstrated beneficial effects of SGLT2 inhibitors in managing chronic refractory hypomagnesemia associated with the historical use of platinum-based chemotherapy.4 Acute hypomagnesemia is common and often resolves after the completion of platinum-based therapy in many patients. However, chronic hypomagnesemia, while less prevalent, poses significant long-term management challenges.
This study thoughtfully paves the way for further clinical studies to investigate the effects of SGLT2 inhibitors on preventing AKI and hypomagnesemia during acute cisplatin therapy—two significant dose-limiting adverse effects. The authors' investigation in the field of onco-nephrology is commendable. At the same time, further research into the effects of SGLT2 inhibitors on chronic hypomagnesemia is needed to establish SGLT2 inhibitors as a novel class of medications for treating hypomagnesemia.
Footnotes
See related reply, “Authors’ Reply: Acute Cisplatin Nephrotoxicity, Sodium-Glucose Cotransporter 2 Inhibitors, and Benefits Beyond Magnesium,” on pages 1885–1886, and original article, “SGLT2 Inhibitors Blunt Kidney Magnesium Wasting in Acute Cisplatin-Induced Hypomagnesemia with Effects on the Thick Ascending Limb and Distal Convoluted Tubule,” on pages 1689–1701.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F240.
Author Contributions
Conceptualization: Chintan V. Shah.
Writing – original draft: Chintan V. Shah.
Writing – review & editing: Chintan V. Shah.
Funding
None.
References
- 1.Jesus EF Luchi WM Castro PC, et al. SGLT2 inhibitors blunt kidney magnesium wasting in acute cisplatin-induced hypomagnesemia with effects on the thick ascending limb and distal convoluted tubule. J Am Soc Nephrol. 2025;36(9):1689–1701. doi: 10.1681/ASN.0000000700 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Abdelrahman AM Al Suleimani Y Shalaby A, et al. Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on cisplatin-induced nephrotoxicity in mice. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(1):45–53. doi: 10.1007/s00210-018-1564-7 [DOI] [PubMed] [Google Scholar]
- 3.Song Z, Zhu J, Wei Q, Dong G, Dong Z. Canagliflozin reduces cisplatin uptake and activates Akt to protect against cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2020;318(4):F1041–F1052. doi: 10.1152/ajprenal.00512.2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Shah CV, Hammad N, Bhasin-Chhabra B, Rashidi A. SGLT2 inhibitors in management of severe hypomagnesemia in patients without diabetes: a report of 4 cases. Kidney Med. 2023;5(9):100697. doi: 10.1016/j.xkme.2023.100697 [DOI] [PMC free article] [PubMed] [Google Scholar]