Sodium/Glucose Cotransporter 2 Inhibitors and Magnesium Homeostasis: A Review.

Magnesium (Mg2+), also known as "the forgotten ion," is the second most abundant intracellular cation and is essential in a broad range of intracellular physiological and biochemical reactions. Its deficiency, hypomagnesemia (Mg2+<1.8mg/dL), is a prevalent condition and routinely poses challenges in its management in clinical practice. Sodium/glucose cotransporter 2 (SGLT2) inhibitors have emerged as a new class of drugs with treating hypomagnesemia as their unique extraglycemic benefit. The beneficial effect of SGLT2 inhibitors on magnesium balance in patients with diabetes with or without hypomagnesemia has been noted as a class effect in recent meta-analysis data from randomized clinical trials. Some reports have demonstrated their role in treating refractory hypomagnesemia in patients with or without diabetes. Moreover, studies on animal models have attempted to illustrate the effect of SGLT2 inhibitors on Mg2+homeostasis. In this review, we discuss the current evidence and possible pathophysiological mechanisms, and we provide directions for further research. We conclude by suggesting the effect of SGLT2 inhibitors on Mg2+homeostasis is a class effect, with certain patients gaining significant benefits. Further studies are needed to examine whether SGLT2 inhibitors can become a desperately needed novel class of medicines in treating hypomagnesemia.

SGLT2 Inhibitors in Management of Severe Hypomagnesemia in Patients Without Diabetes: A Report of 4 Cases.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors have demonstrated a class effect in improving serum magnesium levels in patients with diabetes. Additionally, recent reports have shown their promising beneficial effects in the treatment of refractory hypomagnesemia in patients with diabetes. However, their role in treating hypomagnesemia in patients without diabetes remains unexplored. Here, we report 4 cases of severe and refractory hypomagnesemia that showed dramatic improvement after initiating SGLT2 inhibitors in patients without diabetes. Case 1 had calcineurin inhibitor-associated severe hypomagnesemia. Cases 2, 3, and 4 had refractory hypomagnesemia associated with platinum-based chemotherapy with or without gastrointestinal losses. Case 1 was able to withdraw from high-dose oral magnesium supplementation. Cases 2 and 3 achieved independence from intravenous magnesium supplementation, whereas case 4 had decreased intravenous magnesium requirements. All the cases demonstrated sustainably improved serum magnesium levels. Withdrawal of SGLT2 inhibitors in case 4 resulted in worsening serum magnesium levels and intravenous magnesium requirements. The extraglycemic benefit of this group of medications not only suggests the need for further studies to better understand the effect of SGLT2 inhibitors on magnesium homeostasis but also supports expanded use in a larger patient population.

Sodium-Glucose Cotransporter 2 Inhibitors and Management of Refractory Hypomagnesemia Without Overt Urinary Magnesium Wasting: A Report of 2 Cases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitor have become widely used in patients with diabetes, heart failure, and kidney disease to improve clinical outcomes and diminish hospitalizations. They have also been associated with increased serum magnesium levels in patients with type 2 diabetes. The use of SGLT2 inhibitors resulted in improved magnesium homeostasis in a series of patients with refractory hypomagnesemia with urinary magnesium wasting. However, the role of SLGT2 inhibitors in patients with hypomagnesemia without urinary magnesium wasting remains unexplored. We report 2 cases with refractory hypomagnesemia without significant urinary magnesium wasting and dramatically improved serum magnesium levels after the initiation of SGLT2 inhibitors. Case 1 achieved independence from weekly intravenous magnesium infusions and reached sustainably greater serum magnesium levels with decreased oral magnesium supplementation and increased urinary fractional excretion of magnesium. Case 2 demonstrated improved serum magnesium levels with reduced oral magnesium supplementation without significant reduction in urinary fractional excretion of magnesium. These findings not only expand the use of SGLT2 inhibitors but also open the door for further studies to better understand the pathophysiology of how magnesium homeostasis is altered with inhibition of SGLT2.

Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI.

BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

Rescue Therapies for AKI in Onconephrology: Rasburicase and Glucarpidase.

Tumor lysis syndrome (TLS) and high-dose methotrexate (HD MTX) toxicity can present with potentially severe complications, including acute kidney injury, in patients with malignancy. Guidelines for using rasburicase and glucarpidase as rescue therapies for TLS and HD MTX toxicity, respectively, are widely used by clinicians intending to mitigate organ toxicity and decrease morbidity and mortality as a consequence of cancer therapy. This review discusses the pathogenesis of TLS and HD MTX-associated toxicity, to understand the mechanism of action of these therapeutic agents and to review the currently available evidence supporting their use.

Acute kidney injury in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.