scholarly journals Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Philipp Tauber ◽  
Frederick Sinha ◽  
Raffaela S. Berger ◽  
Wolfram Gronwald ◽  
Katja Dettmer ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Models ◽  
Renal Injury ◽  
Extracellular Volume ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Disease Models ◽  
Diabetic Patients ◽  
High Salt Intake ◽  
Glomerular Damage

Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative. Previous studies showed that SGLT2 inhibitors reduce diabetic hyperfiltration, which is likely a key element in renoprotection. In line with this hypothesis, this study aimed to investigate the nephroprotective effects of the SGLT2 inhibitor empagliflozin (EMPA) in different mouse models with non-diabetic hyperfiltration and progressing CKD to identify the underlying diabetes-independent cellular mechanisms. Non-diabetic hyperfiltration was induced by unilateral nephrectomy (UNx). Since UNx alone does not result in renal damage, renal disease models with varying degrees of glomerular damage and albuminuria were generated by combining UNx with high NaCl diets ± deoxycorticosterone acetate (DOCA) in different mouse strains with and without genetic predisposition for glomerular injury. Renal parameters (GFR, albuminuria, urine volume) were monitored for 4–6 weeks. Application of EMPA via the drinking water resulted in sufficient EMPA plasma concentration and caused glucosuria, diuresis and in some models renal hypertrophy. EMPA had no effect on GFR in untreated wildtype animals, but significantly reduced hyperfiltration after UNx by 36%. In contrast, EMPA did not reduce UNx induced hyperfiltration in any of our kidney disease models, regardless of their degree of glomerular damage caused by DOCA/salt treatment. Consistent with the lack of reduction in glomerular hyperfiltration, EMPA-treated animals developed albuminuria and renal fibrosis to a similar extent as H2O control animals. Taken together, the data clearly indicate that blockade of SGLT2 has the potential to reduce non-diabetic hyperfiltration in otherwise untreated mice. However, no effects on hyperfiltration or progression of renal injury were observed in hypervolemic kidney disease models, suggesting that high salt intake and extracellular volume might attenuate the protective effects of SGLT2 blockers.

scholarly journals P0904EFFECT OF EMPAGLIFLOZIN ON SERUM MARKERS OF OSTEOCYTE AND OSTEOBLAST FUNCTION AND ALBUMINURIA IN DIABETIC AND NON-DIABETIC PATIENTS WITH CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Anna Masajtis-Zagajewska ◽  
Katarzyna Pä™czek ◽  
Tomasz Holub ◽  
Michal Nowicki
Keyword(s):  
Chronic Kidney Disease ◽  
Calcium Phosphate ◽  
Kidney Disease ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Creatinine Ratio ◽  
Urine Calcium ◽  
Ckd Stage ◽  
Calcium Phosphorus

Abstract Background and Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors are new class of oral antidiabetic drugs that show potent cardio- and nephroprotective actions. Despite having a favorable safety profile the treatment with SGLT2 inhibitors has been associated with several side-effects including increased risk of fractures. Although the pathomechanism of this complication has not been elucidated these drugs may inhibit tubular reabsorption of phosphate which may stimulate a secretion of fibroblast growth factor 23 (FGF23). The study was designed to assess the effect of SGLT2 inhibitor on markers of calcium-phosphate metabolism, bone turnover and early glomerular injury in diabetic and non-diabetic patients with stage 3 chronic kidney disease (CKD). Method 41 patients with chronic kidney disease including 23 without diabetes (13 M, 11F, age 52.9±0.7 years, estimated glomerular filtration rate (eGFR) 38.6±10.8 ml/min/1.73 m2) and 18 with type 2 diabetes (12 M, 6F, age 58.8±1.4 years, eGFR 38.8±7.7 ml/min/1.73 m2) were recruited. Main inclusion criteria were CKD stage 3 and urine albumin secretion >100 mg/g creatinine. All subjects received oral empagliflozin 10 mg once daily for 7 days. Serum calcium, phosphorus, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF23 and urine calcium, phosphate and albumin were measured at baseline and after 7 days of empagliflozin treatment. Results Plasma calcitriol, serum and urine calcium, phosphorus and BAP did not change significantly during the administration of empagliflozin. Urine phosphate/creatinine ratio was similar in both subgroups at baseline and did not change during empagliflozin administration. Plasma PTH was higher in non-diabetics than in diabetics both at baseline and after empagliflozin. The increase of PTH after empagliflozin tended to be higher in diabetic patients (p=0.07). There was only a trend towards an increase of serum FGF23 in both non-diabetic and diabetic subgroup (by 4.2±0.2 vs. 9.3±1.1 pg/mL, ns). BAP was significantly higher at baseline in diabetic patients but did not significantly change after empagliflozin in the subgroups. Albumin/creatinine ratio decrease after empagliflozin administration was significant only in non-diabetic patients (-62±17 vs. -2±8 mg/g in diabetic patients, p=0.03 for difference). Conclusion Our study showed no effect of short-time administration of empagliflozin on calcium-phosphate and bone metabolism markers in patients with both diabetic and non-diabetic CKD. Empagliflozin decreased albuminuria significantly only in non-diabetic CKD that may suggest a potentially greater nephroprotective effect of this SGLT2 inhibitor in non-diabetic than in diabetic nephropathy.

scholarly journals Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity

2017 ◽  
Vol 313 (4) ◽  
pp. F951-F954 ◽  
Author(s):  
Danielle L. Saly ◽  
Mark A. Perazella
Keyword(s):  
Early Stage ◽  
Functional Decline ◽  
Healthcare Providers ◽  
Sglt2 Inhibitor ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Chip Technology ◽  
Urinary Glucose

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported “AKI” actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers.

scholarly journals Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

2021 ◽  
Vol 22 (9) ◽  
pp. 4374
Author(s):  
Tomoaki Takata ◽  
Hajime Isomoto
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Glycemic Control ◽  
Kidney Injury ◽  
Sglt2 Inhibitors ◽  
Pleiotropic Effects ◽  
Future Research ◽  
Diabetic Patients ◽  
Sodium Glucose Cotransporter ◽  
Stage Renal Disease

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.

scholarly journals Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Hiraku Kameda ◽  
Kumiko Yamashita ◽  
Yoshio Kurihara
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Creatinine Ratio ◽  
Sodium Glucose Cotransporter ◽  
Clinical Records

Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria. Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018

scholarly journals Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial

2020 ◽  
Vol 8 (7) ◽  
pp. 582-593 ◽  
Author(s):  
David Z I Cherney ◽  
Claire C J Dekkers ◽  
Sean J Barbour ◽  
Daniel Cattran ◽  
Abdul Halim Abdul Gafor ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Crossover Trial ◽  
Sglt2 Inhibitor ◽  
Diabetic Patients ◽  
Double Blind

scholarly journals Potential Impact on Lipoprotein Subfractions in Type 2 Diabetes

2019 ◽  
Vol 12 ◽  
pp. 117955141986681 ◽  
Author(s):  
Yuka Kamijo ◽  
Hideto Ishii ◽  
Tomohiko Yamamoto ◽  
Kunihisa Kobayashi ◽  
Hiroyuki Asano ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Sglt2 Inhibitor ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Lipoprotein Subfractions ◽  
Cholesterol Levels

Introduction: Recently, the sodium-glucose cotransporter2 (SGLT2) inhibitor empagliflozin has been shown to lower cardiovascular risk among diabetic patients. It is intriguing that some SGLT2 inhibitors have been found to increase low-density lipoprotein (LDL) cholesterol levels, while the relevance to high-density lipoprotein (HDL) cholesterol is unknown. Although the inhibitory effect of SGLT2 inhibitors on glucose reabsorption may accelerate compensatory lipid metabolism and subsequently reduce body weight and affect the lipid profile, much remains unclear about this mechanism. Therefore, we conducted this study to investigate in detail how canagliflozin affects lipoprotein fractions including LDL and HDL subclasses. Materials and Methods: This study is a multicenter prospective study. The participants were patients with 22 type 2 diabetes (60.7 ± 11.6 years, 59.1% of men) who had HbA1c ⩾ 7.0% and consented to participate in the study. They were administered 100 mg canagliflozin orally once per day. Biochemistry test and cholesterol levels of 20 lipoprotein fractions (G1-G20) using high performance liquid chromatography methods were examined before and after 12 weeks of treatment period. Results: Significant decreases were observed in the participants’ body weight (69.7 to 67.9 kg, P < .001), systolic blood pressure (129.3 to 119.5 mm Hg, P < .01), and HbA1c (8.5% to 7.4%, P < .001). Cholesterol levels in the 20 lipoprotein fractions increased for very large HDL (G14, G15) and large HDL (G16) ( P < .05). Conclusions: Reduction in body weight, improvement of blood glucose levels, and increases in very large HDL and large HDL subclasses were observed after canagliflozin treatment. These beneficial changes might contribute to subsequent suppression of cardiovascular outcomes.

scholarly journals Aging-associated renal disease in mice is fructokinase dependent

2016 ◽  
Vol 311 (4) ◽  
pp. F722-F730 ◽  
Author(s):  
Carlos A. Roncal-Jimenez ◽  
Takuji Ishimoto ◽  
Miguel A. Lanaspa ◽  
Tamara Milagres ◽  
Ana Andres Hernando ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Knockout Mice ◽  
Renal Injury ◽  
Disease Process ◽  
High Salt ◽  
Mesangial Matrix ◽  
Wild Type ◽  
High Salt Intake ◽  
Matrix Expansion

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

MO654REAL LIFE EXPERIENCE AFTER 20 MONTHS USING SGLT2 INHIBITORS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Renata Carvalho ◽  
Bárbara Ribeiro ◽  
Joana Medeiros ◽  
José Mário Bastos ◽  
Raquel Vaz ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Glycated Hemoglobin ◽  
Patient Adherence ◽  
Laboratory Data ◽  
Sglt2 Inhibitors ◽  
Initial Increase ◽  
Urinary Concentration ◽  
Diabetic Patients ◽  
Kidney Protection ◽  
Mean Time

Abstract Background and Aims Diabetic kidney disease (DKD) develops in almost half of diabetic patients and is the leading cause of chronic kidney disease (CKD). SGLT2 inhibitors (SGLT2i) have consistently shown to confer kidney protection in patients with type 2 diabetes (T2D). The recent KDIGO guidelines suggest their use as a first line medication along with metformin. After the study CREDENCE was published, in mid-2019, DKD patients at the Nephrology outpatient department of the Hospital of Braga were started on SGLT2i. We aimed at assessing these patients’ clinical and laboratory data after the introduction of the new drug. Method We collected data on age, gender, weight, blood pressure (BP) values, the use of renin-angiotension-aldosterone system inhibitors (RAASi), kidney function, glycated hemoglobin (HbA1c), glycosuria, proteinuria and albuminuria at baseline and during the two next patient assessments. Data was analyzed using SPSS®. Results Twenty-nine DKD patients who started SGLT2i between May 2019 and August 2020 were followed. Mean age was 71.2±13.5 years, 22 patients were male and their mean weight was 86.9±13.9 kg. They had had T2D for a mean of 15.9±10.3 years and a significant percent had end organ damage: 34% had diabetic retinopathy, 24% complaints suggestive of neuropathy, 51% had documented heart failure and 27% had cerebral vascular disease. Most were hypertensive with a mean BP of 156±19/83±11mmHg and 72.4% were taking RAASi. One third were treated with insulin. Most patients were started on canagliflozin (n=28) and one patient started empagliflozin. After starting the drug, patients were evaluated at a mean time of 141±55 days and had a second reevaluation at a mean time of 254±72 days. On the first evaluation they showed a significant reduction in the mean systolic BP to 140±15.1mmHg (p=0.001). Glycated hemoglobin decreased from a mean of 7.4±1.3% to 7.1±1.1% although this difference was not significant (p=0.4). Protein-creatinine urinary ratio was significantly reduced from a median value of 1.48 (IQR 0.24-1.85) to 0.93 (IQR 0.40-1.56). Mean serum creatinine increased significantly from baseline until the first evaluation at 1.96±0.49 to 2.27±0.66mg/dL (p=0.00) but remained stable on the second evaluation (2.29±0.79mg/dL). Seventy percent of the patients developed significant glycosuria (urinary concentration &gt;500mg/dL) after starting SGLT2i. When asked about adherence, most non-glycosuric patients admitted not having started the drug. Conclusion Despite having a weak effect in the reduction of HbA1c, SGLT2i are an exciting drug for kidney protection in DKD. Patient adherence is easy to assess based on glycosuria. In our experience and based on this criterion drug compliance was acceptable (at least 70%) and we were able to reinforce instructions among non-compliant patients. Some of the benefits of SGLT2i were evident soon after they were started such as the improvement in BP and proteinuria. The initial increase in plasma creatinine was expected due to reduction in intraglomerular pressure and hyperfiltration and was noticeable only on the first assessment. We expect to continue SGLT2i use DKD patients.

Sign in / Sign up

Export Citation Format

Share Document