SGLT2 Inhibition and Acute Kidney Injury Friend or Foe?

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic medications that have been demonstrated to improve cardiovascular outcomes in patients with diabetes. SGLT2 inhibitors regulate serum glucose levels by selectively blocking type 2 glucose transporters in the proximal convoluted tubules, thereby reducing the amount of glucose and sodium reabsorbed. Increased delivery of sodium and chloride to the macula densa induces tubuloglomerular feedback, leading to constriction of the renal afferent arteriole and to reduction of intraglomerular pressure and albuminuria. Also, these medications have been shown to reduce cellular oxidative stress and to improve energy balance. Whereas SGLT2 proteins are markedly distributed in the kidney and the gut, the beneficial effect of these medications on distant organs such as the cardiovascular system suggests that there may be additional anti-inflammatory and cardioprotective properties yet to be explored (1).

Three large randomized controlled trials, the Canagliflozin Cardiovascular Assessment Study (CANVAS) (2), the Empagliflozin Cardiovascular Outcome Event Trial in type 2 diabetes mellitus patients (EMPA-REG OUTCOME) (3), and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLAR-TIMI 58) (4) trial showed that SGLT2 inhibitors are associated with improved cardiovascular endpoints in patients with diabetes, such as decreases in myocardial infarction, cardiovascular mortality, and all-cause death. SGLT2 inhibitors have also proved to be beneficial in chronic kidney disease (CKD) patients by decreasing the rates of advanced CKD and kidney replacement therapy needs (5, 6).

Furthermore, the recent clinical trial “Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure” (DAPA-HF) (7), has shown that even nondiabetic patients may also benefit from the cardiometabolic effects provided by this group of medications. In addition, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (6) states that canagliflozin is safe and effective in reducing the rate of kidney function decline in patients with moderately advanced nephropathy and estimated GFR between 30 and 45 mL/min per 1.73 m2. Despite the promising body of evidence indicating that SGLT2 inhibitors are a new tool in the management of diabetic kidney disease (DKD), some concerns have been raised regarding their association with adverse kidney outcomes, including acute kidney injury (AKI), especially in the setting of excessive diuresis and/or reduction of renal blood flow resulting from severe afferent renal constriction (8). The purpose of this review is to discuss the role of SGLT2 inhibitors in AKI and to visit some of the putative mechanisms involved.

SGLT2 inhibitors: individual experience versus clinical evidence

In 2016, the U.S. Food and Drug Administration strengthened the existing warning on SGLT2 inhibitors, most notably canagliflozin and dapagliflozin, after a report of 101 patients in whom AKI developed after they began taking these medications without another identifiable culprit. AKI was seen within 1 month after the medication was started in approximately 50% of the cases. Although some of these patients experienced improvement after the medication was withheld, some of them required hospitalization and kidney replacement therapy. Thus, a warning label revision was added, and clinicians were requested to be judicious in the prescription of these medications.

Certainly, SGLT2 inhibitors could contribute to AKI by inducing volume depletion because of their natriuretic and osmotic properties, especially in patients who are already dehydrated or are exposed to medications that block the renin-angiotensin-aldosterone system, nonsteroidal anti-inflammatory drugs, or antibiotics, as in the stem case (9, 10). Furthermore, in the distal renal tubules, glucose can be exchanged for uric acid by luminal GLUT9, which becomes more active in the presence of glycosuria (11). This could result in increased tubular levels of uric acid, which may induce crystal deposition, inflammation, and oxidative stress, as shown in some preclinical models of tubular injury (12). Moreover, even though acute SGLT inhibition normalizes oxygen tension in the renal cortex, it may cause hypoxia in the renal medulla of anesthetized diabetic rats, rendering them susceptible to ischemic insults (13).

Although any of these mechanisms can contribute to the development of AKI in patients taking SGLT2 inhibitors, it is important to consider a few aspects of diabetes as a disease process.

First, patients with diabetes are at increased risk of AKI when they routinely use other substances such as antibiotics, nonsteroidal anti-inflammatory drugs, and contrast material. Second, diabetes per se confers an intrinsic susceptibility to AKI because of the chronic microvascular damage related to systemic inflammation and toxic effects associated with albuminuria. Third, despite the specific effects of SGLT2 inhibitors in different parts of the nephron, it is possible that compensatory mechanisms are responsible for the net benefit provided by these medications, including blood pressure control, natriuresis, and overall increased survival rates (1, 3, 5, 6). For example, erythropoietin (EPO) production by peritubular cells can increase as a response to decreased oxygen tension in the medulla, which could partially explain the rise in hematocrit levels in these patients (14). Ultimately, restoration of EPO levels could contribute to cardiovascular/renal tissue protection because of its immunomodulatory effects (15).

Assessing the detrimental effects of any medication is very challenging without an appropriate control group to identify and remove confounding factors. From a physiologic perspective, SGLT2 inhibitors are expected to induce mild increments of serum creatinine because they tend to reduce intraglomerular pressure and consequently reduce the GFR (10). Often in clinical practice, sudden “creatininemia” raises caution among clinicians, who may in turn discontinue the “offending” agents, as in the case of the second patient in the stem problem. However, a recent post hoc analysis of a placebo-controlled clinical trial showed that serum creatinine increments in patients exposed to dapagliflozin were not associated with tubular injury, as measured by the urinary kidney injury molecule-1 (16). Furthermore, when compared with patients in the placebo-controlled group, patients using dapagliflozin presented a lower renal inflammatory profile, noted through the evaluation of urinary IL-6 levels (mean percentage change from baseline in the dapagliflozin group: −24 [95% CI 37.9 to −7], p = 0.01) (16). Moreover, in a propensity-matched cohort study, Nadkarni et al. (9) found that AKI was 60% less frequent among users of SGLT2 inhibitors when compared with the control group (adjusted hazard ratio: 0.4 [95% CI 0.2–0.7], p = 0.01) in the Mount Sinai cohort. Likewise, AKI was 50% less frequent in patients using SGLT2 inhibitors when evaluated in the counterpart Geisinger cohort (adjusted hazard ratio: 0.6 [95% CI 0.4–1.1], p = 0.09). Thus, whereas SGLT2 inhibitors have the potential to exacerbate AKI in patients who have other ongoing insults on an individual level, from a population standpoint, it appears that these agents confer net kidney-protective effects. Furthermore, they are not associated with an increased risk for AKI, which is consistent with the long-term kidney benefits on progressive DKD and kidney failure witnessed in the large randomized controlled trials (1719). Table 1 shows the reported incidence of AKI in major clinical trials.

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SGLT2 inhibitors, erythropoietin, and fibrosis: benefits from bench to bedside

SGLT2 inhibitors play a role in renal cell energy and oxygen preservation. Medications in this group decrease the absorption of glucose in the proximal tubules, a process that is otherwise energy dependent and that requires intense activity from the ATP-Na/K pump. Intracellular ATP depletion and oxygen consumption affect the energetic balance of renal tubular epithelial cells, thereby limiting their ability to recover from an insult (20). Furthermore, oxygen consumption and the generation of reactive oxygen species promote mitochondrial dysfunction and a dysregulated inflammatory state (21). The proximal tubules are especially vulnerable to hypoxic states and mitochondrial dysfunction, which can induce renal tubular epithelial cell apoptosis, necrosis, and epithelial cell transformation. The latter, which is largely influenced by oxidative stress and hypoxic conditions, involves the differentiation of resident peritubular fibroblasts that would otherwise produce EPO into activated myofibroblasts responsible for collagen synthesis (22). Therefore, SGLT2 inhibitors can ameliorate the cellular stress induced by hypoxia and inflammation-mediated fibrogenesis, which have been identified as key mechanisms of diabetic kidney disease (DKD). Furthermore, short-term canagliflozin treatment has been found to protect against in vivo myocardial ischemia-reperfusion injury in nondiabetic rats (23), a property that has been reproduced in the kidney by dapagliflozin (24).

The relationship between low EPO levels and progressive DKD has been previously assessed in clinical studies. Patients with diabetes have lower EPO levels than do nondiabetic individuals regardless of their kidney function. Furthermore, in a prospective analysis by Fujita et al. (25), low EPO levels—even below the upper normal limit (23.7 IU/L)—predicted rapid kidney function decline independently of other traditional prognostic factors such as hemoglobin level, estimated GFR, and urine albumin–creatinine ratio. Moreover, an indirect correlation between worsening glycosylated hemoglobin levels and EPO levels has also been demonstrated elsewhere. Therefore, it is presumed that SGLT2 inhibitors may alleviate cellular metabolic stress, reduce tissue tubular/peritubular inflammation, and allow to some extent the reversion of myofibroblasts to EPO-producing fibroblasts. The latter effects, along with cardiorenal axis regulation, may be associated with the relatively early cardiovascular and survival benefits provided by these medications in the acute and chronic settings (26).

Areas of uncertainty

Whereas the SGLT2 inhibitors show promise in the management of DKD, with no statistical data supporting an association with AKI, current labeling recommends dose reductions on the basis of estimated GFR, arguably because of the diminished glucose-lowering effect with reduced kidney function. Despite the statement in the CREDENCE study that the use of canagliflozin is safe and effective in improving cardiovascular outcomes in diabetic patients with an estimated GFR between 30 and 45 mL/min per 1.73 m2, it is unknown whether these results can be extrapolated to patients with more advanced stages of kidney disease (27). Also, it is unknown whether we can extrapolate the latter findings to other SGLT2 inhibitors because of the intraclass difference in pharmacodynamics. Additionally, more data from underrepresented populations and patients in extreme old age is needed because these populations have been shown to be at increased risk of AKI and higher lifetime risk of CKD. The benefit of using SGLT2 inhibitors in patients with active disease (e.g., infection, myocardial infarction) needs to be further investigated regardless of the AKI risk. Moreover, it is unknown whether patients with mild “permissible” serum creatinine increments experience better outcomes compared with those who do not show such increments. Further studies are needed to assess how permissible clinicians should be in their practice.

Conclusion

SGLT2 inhibitors have been demonstrated to improve cardiovascular and kidney outcomes and to reduce mortality rates among diabetic patients. Large meta-analyses and post hoc studies have failed to find an association between SGLT2 inhibitors and AKI. On the contrary, a potentially protective role has been suggested based on their cardiometabolic, cytoprotective, and anti-inflammatory properties, although this warrants further investigation. Although anecdotal cases of AKI after the initiation of SGLT2 inhibitors exist in the literature, other factors, including dehydration, infection, and nephrotoxins were poorly assessed. In a patient with signs of volume contraction, sepsis, or an active decompensating disease, it is reasonable to withhold the medication until the patient’s underlying medical problems have been solved (sick-days). However, SGLT2 inhibitors may be continued in patients in stable condition who show mild creatinine increments with no other obvious explanation. Follow-up and clinical judgment may be important in this scenario. Finally, clinicians should consider the use of SGLT2 inhibitors in the appropriate setting and based on the dose specifications available until additional data are obtained. Additional studies including patients from underrepresented populations, with a wider age range, and with more advanced kidney disease are warranted .

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October-November 2020 (Vol. 12, Number 10 & 11)