The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?

Hesp, Anne C.; Schaub, Jennifer A.; Prasad, Pottumarthi V.; Vallon, Volker; Laverman, Gozewijn D.; Bjornstad, Petter; Raalte, Daniël H. van

doi:10.1016/j.kint.2020.02.041

Cited by 119 publications

(95 citation statements)

References 119 publications

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“…Therefore, SGLT2i alleviates glomerular hypertension and hyperfiltration, thus reducing glomerular barotrauma and albuminuria. Of note, a potential additional consequence of attenuation of hyperfiltration is the decrease in oxygen (O2) demand for the active tubular transport of solutes, sodium in primis, with improved renal tissue oxygenation and prevention of fibrosis [ 39 , 40 ].…”

Section: Nephroprotection By Sglt2i In Diabetic Patients: From Benmentioning

confidence: 99%

Nephroprotection by SGLT2 Inhibition: Back to the Future?

Nicola

Gabbai

Garofalo

et al. 2020

JCM

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The introduction of sodium/glucose cotransporter 2 inhibitors (SGLT2i) has opened new perspectives for the management of diabetic population at risk of or with chronic kidney disease (CKD). More important, recent, large real-world studies have repositioned the nephroprotective efficacy of SGLT2i emerged from randomized trials within the frame of effectiveness. Furthermore, the salutary effects of these agents may extend to the nondiabetic population according to the positive results of current studies. Nevertheless, the clear benefits of these agents on the prevention of organ damage contrast with their unexpected, limited use in clinical practice. One potential barrier is the acute decline in glomerular filtration rate (GFR) commonly observed at the beginning of treatment. This phenomenon is reminiscent of the early response to the traditional nephroprotective interventions, namely blood pressure lowering, dietary protein and salt restriction and the inhibition of the renin–angiotensin system. Under this perspective, the “check-mark” sign observed in the GFR trajectory over the first weeks of SGT2i therapy should renew interest on the very basic goal of CKD treatment, i.e., alleviate hyperfiltration in viable nephrons in order to prolong their function.

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Section: Nephroprotection By Sglt2i In Diabetic Patients: From Benmentioning

confidence: 99%

Nephroprotection by SGLT2 Inhibition: Back to the Future?

Nicola

Gabbai

Garofalo

et al. 2020

JCM

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“…35 Hypoxia arises from a mismatch between oxygen demand and supply; diabetes and hyperglycaemia increase energy consumption of tubular cells as a result of upregulated sodium-glucose cotransport and glomerular hyperfiltration. 36 Oxidative stress-induced mitochondrial uncoupling further increases oxygen demand. 37 Despite the rise in oxygen consumption, oxygen delivery is inhibited in DKD due to multiple factors, such as loss of peritubular capillaries and interstitial fibrosis.…”

Section: Cellular and Molecular Biology Of Dkdmentioning

confidence: 99%

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

et al. 2021

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Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end-stage kidney disease (ESKD). Despite improvements in glycaemic control and blood pressure management with renin-angiotensin-aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression to ESKD in some patients. DKD is a heterogeneous disease entity in terms of its clinical manifestations, histopathology and the rate of progression, which makes it difficult to develop effective therapeutics. It was formerly considered that albuminuria preceded kidney function decline in DKD, but recent epidemiological studies revealed that a distinct group of patients presented kidney dysfunction without developing albuminuria.Other comorbidities, such as hypertension, obesity and gout, also affect the clinical course of DKD. The pathophysiology of DKD is complex and multifactorial, involving both metabolic and haemodynamic factors. These induce activation of intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy and epigenetic changes, which result in kidney inflammation and fibrosis. Recently, two groups of antidiabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, were demonstrated to provide renoprotection on top of their glucose-lowering effects. Several other therapeutic agents are also being developed and evaluated in clinical trials.

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“…In diabetes mellitus, renal perfusion for oxygen delivery can be reduced by hyperglycemia-associated microvascular injury. In addition, oxygen demand can be increased by the upregulation of sodium transport in the proximal tubule [ 130 ]. A mismatch between renal oxygen demand and oxygen delivery can occur in non-diabetic kidney disease as well.…”

Section: Sodium-glucose Transporter-2 Inhibitorsmentioning

confidence: 99%

Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

Chung

Kim

2021

Life

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New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, although metformin-associated lactic acidosis is a hindrance to its use in patients with kidney failure. New anti-diabetic agents, including glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, also produce cardiovascular or renal benefits in T2D patients. Their glucose-independent beneficial actions can lead to cardiorenal protection via hemodynamic stabilization and inflammatory modulation. Systemic hypertension is relieved by natriuresis and improved vascular dysfunction. Enhanced tubuloglomerular feedback can be restored by SGLT-2 inhibition, reducing glomerular hypertension. Patients with non-diabetic kidney disease might also benefit from those drugs because hypertension, proteinuria, oxidative stress, and inflammation are common factors in the progression of kidney disease, irrespective of the presence of diabetes. In various animal models of non-diabetic kidney disease, metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were favorable to kidney morphology and function. They strikingly attenuated biomarkers of oxidative stress and inflammatory responses in diseased kidneys. However, whether those animal results translate to patients with non-diabetic kidney disease has yet to be evaluated. Considering the paucity of new agents to treat kidney disease and the minimal adverse effects of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, these anti-diabetic agents could be used in patients with non-diabetic kidney disease. This paper provides a rationale for clinical trials that apply metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to non-diabetic kidney disease.

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The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?

Cited by 119 publications

References 119 publications

Nephroprotection by SGLT2 Inhibition: Back to the Future?

Nephroprotection by SGLT2 Inhibition: Back to the Future?

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

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