Beneficial Effects of Sodium-Glucose Cotransporter 2 Inhibitors in Cisplatin Nephrotoxicity

Abstract

Cisplatin remains a key chemotherapy for many solid tumors, but its dose-limiting nephrotoxicity affects up to one third of patients and has no effective pharmacologic prevention beyond hydration and magnesium supplementation. Preclinical studies highlight sodium-glucose cotransporter 2 (SGLT2) inhibitors as promising nephroprotective agents during cisplatin therapy, independent of glucose lowering. We conducted a PubMed search using predefined terms related to cisplatin nephrotoxicity and SGLT2 inhibitors, identifying seven nondiabetic rodent studies. Across these models, SGLT2 inhibitors consistently attenuated kidney injury through complementary mechanisms such as suppression of inflammatory, oxidative, and apoptotic pathways; activation of AMP-activated protein kinase–dependent autophagy; reduction of kidney platinum accumulation; and, uniquely, correction of cisplatin-induced hypomagnesemia, a clinically significant complication. Protective effects occurred without compromising cisplatin’s antitumor efficacy in vitro. Overall, these findings support SGLT2 inhibitors as a mechanistically versatile strategy that targets key injury pathways in platinum nephrotoxicity. Although prospective clinical application remains untested, the strong biologic rationale, reproducibility across models, and established safety of SGLT2 inhibitors in other populations underscore the urgency of translation. Future clinical trials should incorporate rigorous assessments of kidney function, tubular injury biomarkers, and urinary extracellular vesicle profiling to define the safety, efficacy, and mechanistic insights of SGLT2 inhibitors in cisplatin nephrotoxicity.

Introduction

Cisplatin is a cornerstone chemotherapy in treating multiple solid tumors, including testicular, ovarian, bladder, lung, and head and neck cancers. Its curative potential is well established, yet its use is often limited by dose-dependent nephrotoxicity, which affects up to 30% of patients and can cause lasting kidney damage and chronic hypomagnesemia.^1–4 AKI results from a multifactorial cascade involving direct tubular epithelial toxicity, inflammation, oxidative stress, and vascular dysfunction.^5,6 Current preventive measures, mainly aggressive intravenous hydration with magnesium sulfate and dose modifications, provide only partial protection, especially in high-risk patients.⁷ This persistent gap has prompted a search for adjunctive interventions that can protect kidney function without diminishing antitumor efficacy.

Among emerging candidates, sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their broad protective effects across diverse kidney diseases, including in nondiabetic populations.⁸ Originally developed for glycemic control, these agents improve kidney outcomes through mechanisms that extend well beyond glucose excretion, including modulation of tubular transport, optimization of mitochondrial efficiency, attenuation of oxidative stress, and restoration of tubuloglomerular feedback.^9,10 In addition, cisplatin can induce kidney magnesium wasting, which may further increase the risk of AKI and contribute to chronic morbidity.¹¹ The ability to correct hypomagnesemia, including in patients with or without diabetes, represents an additional therapeutic benefit of SGLT2 inhibitors.¹² This review synthesizes findings from seven distinct nondiabetic rodent models of cisplatin nephrotoxicity, highlighting convergent anti-inflammatory, autophagy-related, transporter-mediated, mitochondrial, and magnesium-handling mechanisms that together establish a foundation for translation.

Mechanisms of Platinum Nephrotoxicity

Cisplatin-induced nephrotoxicity is driven by a complex interplay of cellular and molecular mechanisms predominantly affecting the kidney tubular epithelium. The proximal tubule, especially the S3 segment, is the primary site of injury.^13,14 Cisplatin concentration in the kidney cortex is five times higher than in plasma because of the selective transport of cisplatin via organic ion transporters, including organic cation transporter 2.^1,15–17 It forms DNA adducts that trigger a cascade of cellular stress responses. When DNA repair is inadequate, this leads to cell cycle arrest, apoptosis, and necrosis.¹⁸ Besides nuclear DNA damage, mitochondrial DNA is also affected, impairing oxidative phosphorylation and disrupting ATP production. During mitochondrial dysfunction, reactive oxygen species damage lipids, proteins, and nucleic acids, intensifying cellular injury.^19–21 As part of an inflammatory response, cisplatin exposure induces the secretion of proinflammatory cytokines such as TNF-α, IL-1β, and monocyte chemoattractant protein-1, which attract leukocytes and promote tissue injury.^22,23 Damage to the thick ascending limb reduces the activity of sodium-potassium-chloride cotransporter 2 (NKCC2), impairing paracellular magnesium reabsorption.²⁴

In the distal convoluted tubule, cisplatin decreases the abundance and phosphorylation of the sodium-chloride cotransporter (NCC), impairing tubular function.²⁵ These changes are accompanied by suppression of EGF signaling, downregulation of the transient receptor potential melastatin 6 (TRPM6) channel, and the consequent disruption of active transcellular magnesium uptake.^25,26 Injury to this segment also reduces the expression of cyclin M2, a basolateral magnesium efflux transporter, and FXYD (FXYD is named for the conserved Phe–X–Tyr–Asp amino acid motif) domain-containing ion transport regulator 2, a regulatory subunit of the Na⁺/K⁺-ATPase that supports the electrochemical gradient for magnesium transport.^27,28 Collectively, disruption of apical magnesium entry and basolateral efflux amplifies kidney magnesium wasting and systemic hypomagnesemia, underscoring several interconnected pathways amenable to therapeutic targeting.

Mechanistic Rationale for SGLT2 Inhibitors in Cisplatin Nephrotoxicity

SGLT2 inhibitors have emerged as potent kidney-protective agents across a spectrum of diseases, including those unrelated to glycemic status. Their benefits reflect a diverse set of biologic effects that act in concert to preserve nephron integrity and function.^29,30 Although the mechanism of the nephroprotective effect is not fully understood, SGLT2 inhibitors reduce sodium and glucose reabsorption, lowering the energy and oxygen demands for active transport.³¹ This improved metabolic efficiency can reduce mitochondrial strain and oxidative imbalance, creating a cellular environment more resilient to stress.^32,33 They also lead to increased sodium delivery to the macula densa, restore tubuloglomerular feedback, reduce intraglomerular pressure, and mitigate maladaptive hyperfiltration, processes that are particularly relevant in settings of ongoing injury.^31,34

Beyond their hemodynamic and metabolic effects, SGLT2 inhibitors also provide anti-inflammatory and antioxidative actions, thereby attenuating proinflammatory cytokine signaling and reactive oxygen species production.³⁵ They have also been shown to affect pathways involved in autophagy, apoptosis, and tubular transporter regulation, indicating their potential to modulate cellular survival mechanisms during injury.³⁶ Although their primary site of action is the proximal nephron, evidence indicates that SGLT2 inhibitors can influence more distal tubular function, including electrolyte handling, through mechanisms that are not yet fully understood.³⁷ These combined effects establish a complex foundation for kidney protection and pave the way for exploring their role in platinum-induced nephrotoxicity.

Preclinical Evidence Supporting SGLT2 Inhibitors in Cisplatin Nephrotoxicity

To identify relevant preclinical studies, we searched PubMed (January 1, 1970–December 31, 2025) using the following Boolean string: (cisplatin or carboplatin or oxaliplatin or platinum*) and (kidney or renal or nephrotoxicity or tubular or hypomagnesemia or magnesium) and (SGLT2 or dapagliflozin or empagliflozin or canagliflozin or sodium glucose cotransporter 2). No language restrictions were applied, and reference lists of retrieved articles were screened for additional reports. This search yielded 24 publications. Of these, seven studies met inclusion criteria as nondiabetic rodent models directly evaluating SGLT2 inhibitors during cisplatin exposure, and these form the focus of this mechanistic synthesis.^38–44 The remaining studies were excluded for predefined reasons, including lack of SGLT2 inhibitor intervention, absence of original data (reviews, editorials, or letters), or focus on cisplatin nephrotoxicity mechanisms unrelated to SGLT2 inhibitors. Five human studies examining SGLT2 inhibitors in the context of platinum-based chemotherapy were identified; all were retrospective in design. Three consisted of isolated case reports or small case series, which were excluded from detailed analysis because of inherent limitations, including lack of standardized exposure, absence of mechanistic end points, and limited generalizability.^45–47 Two larger retrospective observational studies were identified and are briefly reviewed separately to contextualize their findings.^48,49

Although heterogeneous in strain, dosing, and outcome measures, the seven included rodent studies converge on shared mechanistic themes. These converging pathways are summarized schematically in Figure 1, which integrates the major injury and protection axes engaged by SGLT2 inhibitors. Grouping the results by their predominant pathway helps clarify how SGLT2 inhibitors engage in specific injury cascades and frames their potential as a kidney-protective strategy during cisplatin therapy. These mechanisms operate across multiple nephron segments, including the proximal tubule, thick ascending limb, and distal convoluted tubule, which are illustrated in greater anatomic and transporter-level detail in Figures 2–4.

Figure 1.

Integrated mechanisms of cisplatin-induced kidney injury and protective effects of SGLT2 inhibitors. Cisplatin induces kidney injury through multiple, converging pathways within tubular epithelial cells, while SGLT2 inhibitors mitigate injury by engaging complementary protective mechanisms across nephron segments. (A) Inflammatory, oxidative, and apoptotic pathways. Cisplatin accumulation in tubular epithelial cells induces oxidative stress and inflammatory signaling, characterized by increased ROS, lipid peroxidation, and upregulation of proinflammatory cytokines including TNF-α, IL-1β, and IL-6. These processes amplify tubular injury and activate intrinsic apoptotic pathways, including caspase-3 cleavage. SGLT2 inhibitors attenuate inflammatory and oxidative signaling, restore antioxidant defenses, and suppress apoptotic cell death. (B) Autophagy and mitochondrial energy homeostasis. Cisplatin disrupts mitochondrial membrane potential and ATP production, leading to energy failure and accumulation of damaged mitochondria. SGLT2 inhibitors activate AMPK, suppress mTOR signaling, and promote autophagy and mitophagy, thereby preserving mitochondrial integrity, stabilizing ATP levels, and enhancing cellular stress tolerance. (C) Regulation of cisplatin uptake and survival signaling. Although cisplatin uptake is primarily mediated by basolateral transporters such as OCT2, SGLT2 inhibitors have been shown to reduce total kidney platinum accumulation by approximately 15%. SGLT2 inhibitors also activate prosurvival signaling pathways, particularly Akt phosphorylation, limiting apoptosis and promoting tubular epithelial cell survival. (D) Preservation of magnesium handling. Cisplatin disrupts tubular electrolyte transport, resulting in kidney magnesium wasting through injury to the thick ascending limb and distal convoluted tubule. SGLT2 inhibitors preserve transporter integrity and function, including NKCC2 phosphorylation, claudin-16–dependent paracellular transport, and TRPM6-mediated magnesium reabsorption, thereby mitigating cisplatin-induced hypomagnesemia. AMPK, AMP-activated protein kinase; mTOR, mechanistic target of rapamycin; NKCC2, sodium-potassium-chloride cotransporter 2; OCT2, organic cation transporter 2; ROS, reactive oxygen species; SGLT2, sodium-glucose cotransporter 2 (inhibitor); TRPM6, transient receptor potential melastatin 6.

Figure 2.

Proximal tubule: cisplatin-induced injury and protective mechanisms of SGLT2 inhibitors. Cisplatin is transported across the basolateral membrane of proximal tubule cells via OCT2, leading to intracellular accumulation. The drug forms DNA adducts in both the nucleus and mitochondria, thereby activating stress responses and promoting apoptosis and necrosis. Cisplatin-induced mitochondrial injury impairs oxidative phosphorylation, leading to a loss of membrane potential, reduced ATP generation, and increased ROS. The local production of inflammatory cytokines, including TNF-α, IL-1β, and IL-6, further amplifies tubular injury and cell death. SGLT2 inhibitors decrease sodium and glucose reabsorption in the proximal tubule, thereby reducing transport-related oxygen consumption, energy demand, and cellular stress. In an experimental model of cisplatin-induced injury, SGLT2 inhibitors limit apoptosis and preserve mitochondrial energetics by activating AMPK, which in turn inhibits mTOR, increases autophagy/mitophagy, stabilizes mitochondrial membrane potential, and promotes recovery of ATP levels. Engagement of Akt-dependent prosurvival signaling has also been observed. Approximately 15% reduction in total kidney platinum accumulation has been reported, and SGLT2 inhibitors have not been shown to impair cisplatin's antitumor activity in in vitro models. mTORC1, mechanistic target of rapamycin complex 1ATP; SGLT2i, SGLT2 inhibitor.

Figure 4.

Distal convoluted tubule: cisplatin-induced injury and protective mechanisms of SGLT2 inhibitors. Cisplatin suppresses EGF signaling in the distal convoluted tubule, resulting in downregulation of the TRPM6 channel, which mediates apical magnesium uptake. Tubular injury also reduces the expression of basolateral magnesium-handling proteins, including CNNM2 and FXYD2, the regulatory subunit of the Na⁺/K⁺-ATPase, thereby impairing maintenance of the electrochemical gradient required for transcellular magnesium extrusion. Concurrently, cisplatin decreases both the abundance and phosphorylation of the NCC, contributing to functional decline. Together, these alterations disrupt coordinated transcellular magnesium transport and promote kidney magnesium wasting. SGLT2 inhibitors alleviate metabolic and oxidative stress within distal tubular cells, preserving cellular integrity and transporter localization. By restoring EGF-TRPM6 signaling and maintaining basolateral transport, SGLT2 inhibitors recover TRPM6 protein expression and phospho-NCC levels. These coordinated effects support distal tubular structure, reestablish efficient transcellular magnesium reabsorption, and contribute to stabilization of serum magnesium levels after acute cisplatin-induced injury. CNNM2, cyclin M2; EGF(R), EGF (receptor); ERK, extracellular signal-regulated kinase; FXYD2, FXYD domain-containing ion transport regulator 2; MAPK, mitogen-activated protein kinase; NCC, sodium-chloride cotransporter.

Inflammatory, Oxidative, and Apoptotic Pathways

Abdelrahman et al. investigated the kidney-protective effects of canagliflozin in a nondiabetic mouse model of cisplatin-induced AKI.³⁸ In a mouse model, cisplatin was administered with or without prophylactic oral canagliflozin at two doses. Cisplatin exposure resulted in significant kidney dysfunction, increased urinary tubular injury markers, elevated circulating proinflammatory cytokines, depletion of endogenous antioxidant defenses, and severe tubular injury on histology. Canagliflozin treatment significantly mitigated these effects, improving kidney function, suppressing inflammatory cytokine production, restoring antioxidant capacity, and limiting histologic damage to mild focal tubular changes. These findings suggest that canagliflozin, with no consistent dose-dependent differences across biochemical, inflammatory, or histopathologic end points, attenuates cisplatin nephrotoxicity through combined anti-inflammatory and antioxidant mechanisms.

Farrokh–Eslamlou et al. further evaluated empagliflozin in a rodent model of cisplatin-induced AKI.³⁹ In a rat model, empagliflozin was administered at two doses beginning before cisplatin exposure and continued during injury induction. Consistent with the prior study, cisplatin caused marked kidney dysfunction accompanied by oxidative stress, inflammation, and extensive tubular injury. Empagliflozin administration dose-dependently improved kidney function, restored antioxidant activity, reduced lipid peroxidation and inflammatory signaling, and attenuated tubular damage on histologic examination. Empagliflozin alone had no measurable effect compared with sham-treated animals, indicating that its protective effects were specific to cisplatin-induced injury rather than baseline kidney physiology.

Abd Elmaaboud et al. further explored empagliflozin's effects with a focus on apoptotic signaling.⁴⁰ In a rat model, empagliflozin was administered either prophylactically before cisplatin exposure or therapeutically after injury onset, allowing direct comparison of preventive versus rescue treatment. Cisplatin exposure induced kidney dysfunction, oxidative stress, and prominent tubular apoptosis, as demonstrated by increased caspase-3 activation and histologic injury. Prophylactic empagliflozin administration markedly improved kidney function, restored antioxidant balance, reduced tubular necrosis, and strongly suppressed apoptotic signaling. By contrast, therapeutic administration after cisplatin exposure provided only partial biochemical improvement with persistent histologic injury and residual apoptosis, underscoring the importance of early intervention.

Alharbi and Aldubayan examined empagliflozin alone and in combination with linagliptin in a nondiabetic rodent model of cisplatin-induced kidney injury.⁴¹ In a rat model, cisplatin was administered with empagliflozin, linagliptin, or their combination to assess both individual and additive kidney-protective effects. Cisplatin administration produced kidney dysfunction and oxidative stress, which were significantly attenuated by empagliflozin. Linagliptin alone exerted modest protective effects, whereas combined therapy resulted in the greatest reduction in oxidative stress markers, suggesting potential additive or synergistic antioxidant effects.

Emerging evidence implicates ferroptosis as a contributor to cisplatin-induced AKI.⁵⁰ Ferroptosis is an iron-dependent, lipid peroxidation–driven form of regulated cell death characterized by GSH depletion and inactivation of GSH peroxidase 4, leading to the accumulation of membrane lipid peroxides in proximal tubular cells.⁵¹ Antiferroptotic drugs have been shown to ameliorate cisplatin-induced AKI in animal models.⁵² Notably, SGLT2 inhibitors have also been shown to suppress ferroptosis in models of diabetic kidney disease by activating AMP-activated protein kinase (AMPK)/NRF2 signaling and restoring the cysteine-glutathione–GSH peroxidase 4 antioxidant axis.^53–56 Although ferroptosis end points have not been systematically assessed in cisplatin-SGLT2 inhibitor studies to date, such a pathway may represent an additional mechanistic axis contributing to the observed nephroprotection and warrants further examination.

Collectively, these studies demonstrate that cisplatin-induced kidney injury is characterized by robust activation of inflammatory, oxidative, and apoptotic pathways, predominantly affecting the proximal tubule (Figures 1A and 2). Across models, SGLT2 inhibitors consistently attenuated cytokine signaling, oxidative stress, and tubular apoptosis, with prophylactic administration providing greater protection than postinjury treatment. Although these findings establish a convergent protective phenotype, interpretation is limited by the use of tumor-free rodents, acute high-dose cisplatin exposure, and short experimental timeframes, which constrain conclusions regarding durability of protection and oncologic relevance.

Autophagy and Mitochondrial Energy Homeostasis

Preservation of mitochondrial integrity and activation of adaptive survival programs such as autophagy represent a complementary protective strategy in cisplatin-induced kidney injury. Park et al. investigated whether canagliflozin mitigates cisplatin nephrotoxicity through AMPK activation, autophagy induction, and maintenance of mitochondrial function in both in vivo and in vitro models.⁴² In the mouse model, canagliflozin was administered prophylactically before cisplatin exposure. Cisplatin exposure caused acute kidney dysfunction, severe tubular injury, increased apoptosis, and mitochondrial impairment, characterized by loss of membrane potential, reduced ATP production, and increased reactive oxygen species. Canagliflozin administration significantly improved kidney function, reduced histologic injury, and suppressed tubular apoptosis. In parallel in vitro experiments, cisplatin exposure markedly reduced viability of human proximal tubular cells and induced mitochondrial dysfunction and apoptotic signaling. Canagliflozin dose–dependently restored cell viability, reduced apoptotic markers, and preserved mitochondrial membrane potential and ATP levels. By contrast, dapagliflozin and empagliflozin did not confer similar protection in vitro, suggesting a drug-specific mechanism rather than a class effect under these experimental conditions. Mechanistically, canagliflozin uniquely activated AMPK through inhibition of mitochondrial respiratory complex I, leading to suppression of mechanistic target of rapamycin signaling and induction of autophagy and mitophagy, as evidenced by increased LC3-II and Beclin-1 and reduced p62 accumulation. Pharmacologic inhibition of either AMPK or autophagy abolished the protective effects of canagliflozin, confirming that AMPK-dependent autophagy is essential for cytoprotection.

While these data highlight a potentially unique off-target property of canagliflozin, the comparative lack of protection by other SGLT2 inhibitors was demonstrated only in vitro and was not tested in vivo. Still, the findings indicate that canagliflozin preserves mitochondrial energy homeostasis and limits cisplatin-induced tubular injury by promoting adaptive mitochondrial quality control rather than solely suppressing downstream oxidative stress (Figure 1B).

Regulation of Cisplatin Uptake and Activation of Survival Pathways

Limiting tubular cisplatin uptake while activating prosurvival signaling represents another protective axis of SGLT2 inhibitors (Figure 1C). Song et al. investigated whether canagliflozin attenuates cisplatin-induced nephrotoxicity through modulation of platinum handling and activation of cytoprotective signaling pathways in vivo and in vitro.⁴³ In the mouse model, canagliflozin was administered prophylactically before cisplatin exposure, and complementary in vitro experiments examined proximal tubular cell responses to cisplatin with or without canagliflozin pretreatment. In vivo, cisplatin administration caused severe kidney dysfunction, extensive tubular injury, and marked apoptosis. Canagliflozin pretreatment significantly improved kidney function, reduced histologic injury, and suppressed apoptotic signaling, including cleaved caspase-3 expression. These protective effects were associated with increased phosphorylation of Akt and an approximately 15% reduction in total kidney platinum content, quantified using whole-kidney homogenates. In cultured primary proximal tubular cells, canagliflozin similarly improved cell viability and reduced intracellular platinum accumulation by approximately 9%. Pharmacologic inhibition of Akt signaling abolished the cytoprotective effects of canagliflozin, indicating that Akt activation is required for protection. Importantly, canagliflozin did not diminish cisplatin-induced cytotoxicity in tested cancer cell lines, supporting the specificity of its protective effects to kidney tubular cells.

To assess whether reduced platinum accumulation alone accounted for the observed protection, the authors compared apoptosis after full-dose cisplatin plus canagliflozin with apoptosis after proportionally reduced cisplatin dosing. Although the degree of functional and histologic protection exceeded what would be expected from reduced platinum exposure alone, this comparison assumes a linear relationship between administered cisplatin dose and kidney platinum accumulation. Given the transporter-mediated and potentially saturable nature of cisplatin uptake, and the absence of direct measurement of kidney platinum levels in the reduced-dose comparator group, this approach cannot definitively disentangle downstream cytoprotective signaling from altered cisplatin handling. Interpretation is further limited by the absence of a comparator intervention that selectively reduces tubular cisplatin accumulation and by the lack of direct assessment of cisplatin transporter activity. Within these experimental constraints, the findings support a model in which canagliflozin attenuates cisplatin-induced nephrotoxicity through a combination of modestly reduced kidney platinum accumulation and activation of Akt-mediated survival signaling, thereby limiting tubular apoptosis.

Preservation of Magnesium Handling

Unlike prior experimental models that primarily emphasized proximal tubular injury, Jesus et al. addressed a clinically important and often underappreciated consequence of cisplatin nephrotoxicity; kidney magnesium wasting.⁴⁴ Hypomagnesemia is common during cisplatin therapy, occurring in approximately 76% of patients acutely and persisting in up to 50% long term.^27,28,57,58 Mechanistically, cisplatin disrupts coordinated magnesium handling across multiple nephron segments, impairing paracellular reabsorption in the thick ascending limb and active transcellular uptake in the distal convoluted tubule (Figure 1D and Figures 3 and 4).^24–27

Figure 3.

Thick ascending limb: cisplatin-induced injury and protective mechanisms of SGLT2 inhibitors. Cisplatin causes tubular cell injury, mitochondrial dysfunction, and oxidative stress in the thick ascending limb, leading to loss of NKCC2 phosphorylation. Reduced NKCC2 activity diminishes the lumen-positive transepithelial voltage, which is essential for driving paracellular magnesium transport. Concurrently, cisplatin disrupts tight junction architecture by decreasing claudin-16 abundance and altering the claudin-16/19 complex that forms the paracellular magnesium pore. These alterations markedly reduce magnesium reabsorption, resulting in kidney magnesium wasting and systemic hypomagnesemia. SGLT2 inhibitors preserve tubular cell integrity and transporter function, maintaining NKCC2 expression and phosphorylation and thereby generating luminal voltage. SGLT2 inhibitors also restore tight junction composition, including claudin-16 abundance and claudin-16/19 balance, facilitating recovery of paracellular magnesium permeability. Through these coordinated effects, SGLT2 inhibitors stabilize electrochemical driving forces and limit urinary magnesium loss after acute cisplatin-induced kidney injury.

Jesus et al. investigated whether SGLT2 inhibitors reduce kidney magnesium wasting in a rodent model of acute cisplatin-induced hypomagnesemia.⁴⁴ In a mouse model, dapagliflozin or empagliflozin was administered prophylactically and continued after cisplatin exposure. Cisplatin-induced marked hypomagnesemia with increased fractional magnesium excretion, accompanied by downregulation and mislocalization of key magnesium transporters and proteins in both the thick ascending limb and distal convoluted tubule, including claudin-16, TRPM6, cyclin M2, and FXYD domain-containing ion transport regulator 2. Treatment with dapagliflozin or empagliflozin blunted the cisplatin-induced rise in fractional magnesium excretion, preserved serum magnesium levels, and restored NKCC2 activity/phosphorylation as well as claudin-16 abundance and the expression and function of TRPM6, TRPM7, and NCC. In parallel, SGLT2 inhibitor treatment partially preserved kidney function, as evidenced by improved GFR, reduced serum urea, stabilization of creatinine, and preservation of kidney mass.

The same group subsequently extended these findings using a prolonged low-dose cisplatin exposure model in which empagliflozin was initiated after hypomagnesemia was established. Sustained cisplatin exposure resulted in persistent magnesium loss accompanied by thick ascending limb dysfunction and structural and molecular alterations in the distal convoluted tubule, including reduced NKCC2 phosphorylation, diminished claudin-16 abundance, decreased TRPM6 protein and mRNA, and lowered total and phosphorylated NCC. Empagliflozin administration rapidly improved serum magnesium, reduced fractional magnesium excretion, and restored thick ascending limb and distal convoluted tubule transporter function, as demonstrated by recovery of NKCC2 and NCC phosphorylation, improved diuretic responsiveness, relative preservation of TRPM6, and expansion of distal convoluted tubule area. Although serum creatinine changes were modest, cisplatin exposure was associated with a nearly 40% reduction in measured GFR, which was relatively preserved with empagliflozin treatment.

The inclusion of both acute and prolonged cisplatin exposure models represents a meaningful advancement over prior work; however, all experiments were conducted in tumor-free rodents, limiting direct clinical extrapolation. Kidney platinum accumulation and cisplatin transport pathways were not directly assessed, precluding definitive determination of whether preserved magnesium handling reflects altered cisplatin pharmacokinetics or downstream protection from tubular injury. The authors' proposed involvement of NCC activation via glycosuria-dependent signaling is biologically plausible but should be interpreted cautiously because sustained NCC activation in other contexts is associated with hypertension, whereas SGLT2 inhibitors consistently lower BP in clinical trials, suggesting a restorative rather than supraphysiologic effect.^59–62

Mechanistically, these findings suggest that SGLT2 inhibitors preserve magnesium handling in cisplatin-induced hypomagnesemia through coordinated effects on both the thick ascending limb and distal convoluted tubule. Such benefits could also result from preventing or reducing cisplatin-induced acute tubular injury by decreasing platinum uptake and attenuating inflammatory and oxidative stress through SGLT2 blockade.^58,63,64 Whether the magnesium-sparing effect itself mediates the observed kidney protection or whether both result from upstream changes in cisplatin handling is unknown and requires further investigation.

Evidence in Human Studies

Kidney-on-a-Chip Model

The most mechanistically informative human relevant evidence derives from a translational study by Cohen et al., which combined a vascularized human proximal tubule kidney-on-a-chip platform with retrospective clinical data.⁴⁸ In this microphysiologic model, cisplatin disrupted proximal tubular epithelial polarity at subtoxic concentrations, leading to intracellular glucose accumulation and lipogenesis as an early metabolic driver of injury. Pharmacologic inhibition of glucose reabsorption with empagliflozin attenuated these metabolic derangements, delayed injury onset, and increased the estimated nephrotoxic threshold for cisplatin by approximately three-fold. This platform leverages primary human cells and physiologic flow to detect early, human-specific tubular stress responses that precede overt cell death or creatinine elevation. However, it is limited to short-term proximal tubular injury and does not assess systemic pharmacokinetics, distal nephron effects, whole-organ integration, or oncologic efficacy.

Observational Studies

Human clinical data are limited to two small retrospective observational studies with discordant findings. In the clinical component of the study by Cohen et al., 19 cisplatin-treated patients and an additional subset of cyclosporine-treated patients were concurrently treated with an SGLT2 inhibitor.⁴⁸ In the cisplatin cohort, SGLT2 inhibitor use was associated with lower serum creatinine and uric acid levels, and higher estimated GFR compared with nonusers. By contrast, Ishigami et al. evaluated cisplatin-associated AKI in a single-center cohort of 167 patients with diabetes, including 33 SGLT2 inhibitor users, and observed no reduction in creatinine-defined AKI incidence, with cisplatin dose emerging as the dominant risk factor.⁴⁹ Both studies are constrained by retrospective design and limited power, underscoring the need for larger, mechanistically informed prospective trials to determine whether SGLT2 inhibitors confer clinically meaningful nephroprotection during platinum-based chemotherapy.

Cautionary Remarks

Although preclinical studies demonstrate that SGLT2 inhibitors can attenuate cisplatin-induced kidney injury, all were conducted in tumor-free rodent models, limiting direct translational inference. Malignancy can alter kidney hemodynamics, tubular metabolism, inflammatory signaling, and drug pharmacokinetics, potentially modifying both injury mechanisms and therapeutic responses.^65–68 In addition, existing studies have not directly established whether the observed kidney protection reflects on-target SGLT2 inhibition or off-target effects. A recent heart failure model showed that pharmacologic SGLT2 inhibition can confer benefit independent of SGLT2 itself, as genetic SGLT2 knockout did not fully recapitulate drug effects despite similar metabolic phenotypes.⁶⁹ These findings raise the possibility that non-SGLT2 dependent pathways contribute to kidney protection, underscoring the need for cisplatin nephrotoxicity models incorporating kidney-specific or global SGLT2 knockout alongside pharmacologic inhibition.

Clinically, SGLT2 inhibitors are widely prescribed and generally well tolerated in CKD, heart failure, and diabetes, making them attractive candidates for repurposing in oncology-adjacent settings. However, their use during active platinum-based chemotherapy has not been prospectively evaluated. In a retrospective observational study, patients with cancer receiving chemotherapy who were treated with SGLT2 inhibitors experienced higher rates of diabetic ketoacidosis, mycotic genitourinary infections, and weight loss compared with patients receiving dipeptidyl peptidase-4 inhibitors, potentially reflecting vulnerability during periods of reduced oral intake, gastrointestinal toxicity, and immunosuppression.⁷⁰ The effects of SGLT2 inhibitors on chemotherapy pharmacokinetics, antitumor efficacy, and long-term oncologic outcomes therefore remain incompletely characterized and warrant careful evaluation in future trials.

Future Directions for Clinical Translation

Preclinical animal studies first demonstrated that intravenous magnesium sulfate attenuates cisplatin nephrotoxicity by reducing intratubular cisplatin accumulation, a mechanistic observation subsequently supported by multicenter observational clinical data linking magnesium sulfate administration to lower incidence and severity of cisplatin-associated kidney injury.^7,71 Building on this established translational paradigm, SGLT2 inhibitors represent a compelling candidate strategy because they may reduce tubular cisplatin stress while simultaneously exerting convergent kidney-protective effects through multiple complementary pathways (Figures 1–4). This multimodal profile provides a strong rationale for prospective clinical investigation. As of 2025, no completed prospective clinical trials have evaluated SGLT2 inhibitors for the prevention of cisplatin-induced nephrotoxicity. However, one randomized, double-blind, placebo-controlled phase 2 trial (NCT07018622; Dapagliflozin Attenuates Renal Magnesium Loss in Cisplatin-Induced Nephrotoxicity) is designed to evaluate the short-term prophylactic use of dapagliflozin in patients receiving platinum-based chemotherapy. The primary end point is the change in urinary kidney injury molecule-1 at 72 hours, with secondary outcomes including additional tubular injury biomarkers, AKI incidence, electrolyte disturbances (including magnesium), and safety assessments.

An early-phase clinical trial should prioritize feasibility, safety, and detection of biologic signal rather than definitive efficacy. Primary end points should remain pragmatic and clinically meaningful. Safety assessments should include (1) infection risk and other SGLT2 inhibitor–associated adverse events in patients receiving chemotherapy relative to background rates and (2) evaluation of any effect on cisplatin antitumor efficacy or oncologic outcomes. Efficacy end points should focus on (1) reduction in clinically significant AKI and (2) prevention of cisplatin-associated acute and chronic hypomagnesemia.

In parallel, although novel biomarkers should not replace clinical end points in early trials, they may provide valuable mechanistic insight. Secondary or exploratory analyses should assess the effects of SGLT2 inhibitors on established tubular injury markers (e.g., kidney injury molecule-1, N-acetyl-β-D-glucosaminidase, or neutrophil gelatinase–associated lipocalin) and emerging noninvasive approaches such as urinary extracellular vesicle profiling.^72–74 Complementary evaluation of magnesium handling and homeostasis, including indirect indices of NKCC2, claudin-16, TRPM6, EGF, and NCC activity, may further clarify whether observed clinical effects reflect altered tubular transport, structural protection, or both, thereby strengthening causal inference.

Summary

Across seven preclinical studies in nondiabetic rodent models of cisplatin-induced kidney injury, SGLT2 inhibitors conferred multifaceted kidney protection (Figures 1–4). These benefits include reducing inflammation, activating autophagy via AMPK, decreasing cisplatin uptake, promoting Akt-mediated survival signaling, correcting magnesium wasting, and possibly an antiferroptotic effect. Prophylactic treatment was more effective than rescue therapy, highlighting the importance of early intervention. While current approaches rely mainly on hydration and magnesium supplementation, SGLT2 inhibitors offer a mechanistically versatile option for kidney protection during cisplatin therapy. The convergence of these complementary protective pathways provides a strong biologic rationale for clinical translation.

Supplementary Material

kidney360-7-1150-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B591.

Author Contributions

Conceptualization: Chintan V. Shah.

Data curation: Akash Mathavan, Akshay Mathavan, Chintan V. Shah.

Investigation: Akash Mathavan, Akshay Mathavan.

Project administration: Chintan V. Shah.

Supervision: Chintan V. Shah.

Validation: Chintan V. Shah.

Visualization: Akash Mathavan, Akshay Mathavan.

Writing – original draft: Akash Mathavan, Akshay Mathavan.

Writing – review & editing: Chintan V. Shah.

Funding

None.