Authors' Reply: Acute Cisplatin Nephrotoxicity, Sodium-Glucose Cotransporter 2 Inhibitors, and Benefits Beyond Magnesium
Abstract
We thank Dr. Shah for his interest1 in our JASN article2 and his thoughtful comments. We acknowledge that our study did not clarify how sodium-glucose cotransporter 2 inhibitors (SGLT2i) affect Na+-K+-Cl− cotransporter 2 activity in the thick ascending limb, which warrants further investigation. In the distal convoluted tubule (DCT), the calcium-sensing receptor (CaSR) may sense luminal glucose and activate the With-No-Lysine[K] kinase 4-STE20/SPS1-related proline/alanine-rich kinase pathway, promoting sodium-chloride cotransporter (NCC) phosphorylation3 and possibly NCC stability, potentially contributing to the increased NCC abundance and DCT area observed in SGLT2i-treated models.1 Studies using DCT-specific CaSR knockout mice and ex vivo approaches with pharmacologic agents targeting CaSR and SGLT2 may be instrumental in exploring this mechanism. Dr. Shah suggested that the benefits of SGLT2i in our study may stem from a preventive effect on cisplatin-induced AKI, citing findings by Song et al.4 However, Song et al. used a single high-dose cisplatin injection (30 mg/kg), resulting in severe kidney injury (serum creatinine: 2.25 mg/dl; BUN: 171 mg/dl), with hyaline casts, vacuolization, and tubular lysis. By contrast, we used repeated low-dose cisplatin (2.5 mg/kg weekly for 5 weeks) to minimize injury. We found a modest, nonsignificant rise in serum creatinine (0.50±0.03 versus 0.43±0.01 mg/dl in controls), lower BUN levels (96±4 mg/dl) than Song et al., and no…
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