The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage

Heart rate dynamics during cardio-pulmonary exercise testing are associated with glycemic control in individuals with type 1 diabetes

IntroductionThis study investigated the degree and direction (kHR) of the heart rate to performance curve (HRPC) during cardio-pulmonary exercise (CPX) testing and explored the relationship with diabetes markers, anthropometry and exercise physiological markers in type 1 diabetes (T1DM).Material and methodsSixty-four people with T1DM (13 females; age: 34 ± 8 years; HbA1c: 7.8 ± 1% (62 ± 13 mmol.mol-1) performed a CPX test until maximum exhaustion. kHR was calculated by a second-degree polynomial representation between post-warm up and maximum power output. Adjusted stepwise linear regression analysis was performed to investigate kHR and its associations. Receiver operating characteristic (ROC) curve was performed based on kHR for groups kHR 0.20 in relation to HbA1c.ResultsWe found significant relationships between kHR and HbA1c (β = -0.70, P < 0.0001), age (β = -0.23, P = 0.03) and duration of diabetes (β = 0.20, P = 0.04). Stepwise linear regression resulted in an overall adjusted R2 of 0.57 (R = 0.79, P < 0.0001). Our data revealed also significant associations between kHR and percentage of heart rate at heart rate turn point from maximum heart rate (β = 0.43, P < 0.0001) and maximum power output relativized to bodyweight (β = 0.44, P = 0.001) (overall adjusted R2 of 0.44 (R = 0.53, P < 0.0001)). ROC curve analysis based on kHR resulted in a HbA1c threshold of 7.9% (62 mmol.mol-1).ConclusionOur data demonstrate atypical HRPC during CPX testing that were mainly related to glycemic control in people with T1DM

Long-term complications in youth-onset type 2 diabetes

BACKGROUND: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood. METHODS: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated. RESULTS: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up. CONCLUSIONS: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.)

Kidney oxygenation, perfusion and blood flow in people with and without type 1 diabetes

Background We used magnetic resonance imaging (MRI) to study kidney energetics in persons with and without type 1 diabetes (T1D). Methods In a cross-sectional study, 15 persons with T1D and albuminuria and 15 non-diabetic controls (CONs) underwent multiparametric MRI (3 Tesla Philips Scanner) to quantify renal cortical and medullary oxygenation (R-2*, higher values correspond to higher deoxyhaemoglobin concentration), renal perfusion (arterial spin labelling) and renal artery blood flow (phase contrast). Analyses were adjusted for age, sex, systolic blood pressure, plasma haemoglobin, body mass index and estimated glomerular filtration rate (eGFR). Results Participants with T1D had a higher median (Q1; Q3) urine albumin creatinine ratio (UACR) than CONs [46 (21; 58) versus 4 (3; 6) mg/g; P < .0001] and a lower mean +/- SD eGFR (73 +/- 32 mL/min/1.73 m(2) versus 88 +/- 15 mL/min/1.73 m(2); P = .12), although not significantly. Mean medullary R-2* was lower in T1D (34 +/- 6/s versus 38 +/- 5/s; P < .01) corresponding to a higher oxygenation. R-2* was not different in the cortex. Cortical perfusion was lower in T1D (163 +/- 40 versus 224 +/- 49 mL/100 g/min; P < .001). Renal artery blood flow was lower in T1D than in CONs (360 +/- 130 versus 430 +/- 113 mL/min; P = .05). In T1D, lower cortical oxygenation and renal artery blood flow were both associated with higher UACR and lower eGFR (P < .05). Conclusions Participants with T1D and albuminuria exhibited higher medullary oxygenation than CONs, despite lower cortical perfusion and renal artery blood flow. This might reflect perturbed kidney energetics leading to a higher setpoint of medullary oxygenation in T1D. Lower cortical oxygenation and renal artery blood flow were associated with higher UACR and lower eGFR in T1D.Peer reviewe

Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury.</p

Effects of dapagliflozin on volume status and systemic haemodynamics in patients with chronic kidney disease without diabetes:Results from DAPASALT and DIAMOND

Aims To assess the effect of sodium-glucose cotransporter-2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes. Materials and methods We performed a mechanistic open-label study (DAPASALT) to evaluate the effects of dapagliflozin on 24-hour sodium excretion, 24-hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo-controlled double-blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD. Results In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m(2), median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24-hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24-hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24-hour systolic BP decreased by -9.3 (95% confidence interval [CI] -19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash-out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m(2), median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI -5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L). Conclusions During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24-hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra-renal compensatory mechanisms to prevent excessive water loss

Kidney hemodynamic profile and systemic vascular function in adults with type 2 diabetes: Analysis of three clinical trials

Aims: Glomerular hyperfiltration plays a key role in the pathophysiology of diabetic kidney disease (DKD). Mechanisms underlying this adverse hemodynamic profile are incompletely understood. We hypothesized that systemic vascular pathology, including endothelial dysfunction and arterial stiffness, relates to glomerular hyperfiltration indicated by filtration fraction (FF). Methods: Baseline data of three trials of overweight adults with type 2 diabetes (TD2, n = 111) with relatively well preserved kidney function were analyzed. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and FF, were assessed with gold-standard clearance techniques. Systemic vascular resistance (SVR), an indicator of endothelial dysfunction, and pulse pressure (PP), a measure of arterial stiffness, were derived from continuous beat-to-beat monitoring. Results: SVR related negatively to GFR (β: −0.382, p < 0.001) and ERPF (β: −0.475, p < 0.001), and positively to FF (β:0.369, p < 0.001). Associations between SVR, ERPF and FF persisted after multivariable adjustments. PP was negatively related to ERPF (β: −0.252, p = 0.008), and positively to FF (β: 0.257, p = 0.006), of which the latter remained significant in multivariable regression. Conclusion: Parameters of systemic vascular pathology, including endothelial dysfunction and arterial stiffness, relate to an adverse kidney hemodynamic profile characterized by glomerular hyperfiltration, which predisposes to the development of DKD

Endogenous Fructose Metabolism Could Explain the Warburg Effect and the Protection of SGLT2 Inhibitors in Chronic Kidney Disease.

Chronic low-grade inflammation underlies the pathogenesis of non-communicable diseases, including chronic kidney diseases (CKD). Inflammation is a biologically active process accompanied with biochemical changes involving energy, amino acid, lipid and nucleotides. Recently, glycolysis has been observed to be increased in several inflammatory disorders, including several types of kidney disease. However, the factors initiating glycolysis remains unclear. Added sugars containing fructose are present in nearly 70 percent of processed foods and have been implicated in the etiology of many non-communicable diseases. In the kidney, fructose is transported into the proximal tubules via several transporters to mediate pathophysiological processes. Fructose can be generated in the kidney during glucose reabsorption (such as in diabetes) as well as from intra-renal hypoxia that occurs in CKD. Fructose metabolism also provides biosynthetic precursors for inflammation by switching the intracellular metabolic profile from mitochondrial oxidative phosphorylation to glycolysis despite the availability of oxygen, which is similar to the Warburg effect in cancer. Importantly, uric acid, a byproduct of fructose metabolism, likely plays a key role in favoring glycolysis by stimulating inflammation and suppressing aconitase in the tricarboxylic acid cycle. A consequent accumulation of glycolytic intermediates connects to the production of biosynthetic precursors, proteins, lipids, and nucleic acids, to meet the increased energy demand for the local inflammation. Here, we discuss the possibility of fructose and uric acid may mediate a metabolic switch toward glycolysis in CKD. We also suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors may slow the progression of CKD by reducing intrarenal glucose, and subsequently fructose levels

Hyperuricemia and chronic kidney disease: to treat or not to treat

Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD

Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.</p