scholarly journals Sex-specific Effects of SGLT2 Inhibition in a Kidney with Reduced Nephron Number: Modeling and Analysis

2021 ◽  
Author(s):  
Anita Layton
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Male And Female ◽  
Renal Effects ◽  
Diabetic Kidney ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Sglt2 Inhibition

The kidney plays an essential role in regulating the homeostasis of electrolytes, acid-base species, and fluids. Kidney structure and function are significantly affected in diabetes. These pathophysiological changes include glomerular hyperfiltration and tubular hypertrophy, and ultimately leading to diabetic kidney disease. A class of medications that have shown promise in slowing the progression to diabetic kidney disease are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors target Na+ and glucose reabsorption along the proximal convoluted tubule, enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes. We postulate that both diabetes-induced and SGLT2 inhibition-induced changes in kidney may exhibit significant sex differences, because the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules, and (iii) study how those renal effects are altered in uninephrectomy. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes and/or uninephredctomy. The simulation results indicate that by inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis.

scholarly journals Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Kidney360 ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. 292-299
Author(s):  
David J. Leehey
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Standard Of Care ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Low Grade ◽  
Diabetic Kidney ◽  
Raas Blockade ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

scholarly journals Glomerular Diseases in Diabetic Patients: Implications for Diagnosis and Management

2021 ◽  
Vol 10 (9) ◽  
pp. 1855
Author(s):  
Nestor Oliva-Damaso ◽  
José María Mora-Gutiérrez ◽  
Andrew S. Bomback
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Treatment Strategies ◽  
Glomerular Disease ◽  
Diabetic Patients ◽  
Glomerular Diseases ◽  
Diabetic Kidney ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
New Treatment

The prevalence of diabetes continues to rise worldwide. In addition to rising rates of diabetic kidney disease, we are also seeing a parallel rise in nondiabetic kidney disease among patients with diabetes. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, membranous nephropathy, and other glomerular diseases. The management of diabetic kidney disease is rapidly evolving to include, beyond glycemic control and renin angiotensin inhibition, the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists. These and other new treatment strategies should be applicable to managing glomerular disease in diabetic patients to reduce toxicities associated with immunosuppression and, in particular, corticosteroids. The prevalence of glomerular disease in diabetic patients is underappreciated. Diagnosis and appropriately treating these diseases remain an important avenue to modify kidney outcomes in diabetic patients.

scholarly journals Role of sodium-glucose cotransporter 2 inhibition to mitigate diabetic kidney disease risk in type 1 diabetes

2020 ◽  
Vol 35 (Supplement_1) ◽  
pp. i24-i32 ◽  
Author(s):  
Daniël H van Raalte ◽  
Petter Bjornstad
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Risk ◽  
Unmet Need ◽  
Premature Death ◽  
Sglt2 Inhibitors ◽  
Diabetic Kidney ◽  
Sodium Glucose Cotransporter

Abstract Diabetic kidney disease (DKD) is a common complication of type 1 diabetes (T1D) and a major risk factor for premature death from cardiovascular disease (CVD). Current treatments, such as control of hyperglycaemia and hypertension, are beneficial, but only partially protect against DKD. Finding new, safe and effective therapies to halt nephropathy progression has proven to be challenging. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated, in addition to glycaemic lowering, impressive protection against DKD and CVD progression in people with type 2 diabetes. Although these beneficial cardiorenal effects may also apply to people with T1D, supporting data are lacking. Furthermore, the increased rates of euglycaemic diabetic ketoacidosis may limit the use of this class in people with T1D. In this review we highlight the pathophysiology of DKD in T1D and the unmet need that exists. We further detail the beneficial and adverse effects of SGLT2 inhibitors based on their mechanism of action. Finally, we balance the effects in people with T1D and indicate future lines of research.

Insulin Resistance Associated with Clinical Manifestations of Diabetic Kidney Disease (Glomerular Hyperfiltration, Albuminuria, and Kidney Function Decline)

2021 ◽  
Vol 18 ◽  
Author(s):  
María M. Adeva-Andany ◽  
Carlos Fernández-Fernández ◽  
Raquel Funcasta-Calderón ◽  
Eva Ameneiros-Rodríguez ◽  
Lucía Adeva-Contreras ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Urinary Albumin Excretion ◽  
Clinical Manifestations ◽  
Urinary Albumin ◽  
Diabetic Kidney ◽  
Patients With Diabetes ◽  
Kidney Function Decline

: Clinical features of diabetic kidney disease include glomerular hyperfiltration, albuminuria, and kidney function decline towards End-Stage Kidney Disease (ESKD). There are presently neither specific markers of kidney involvement in patients with diabetes nor strong predictors of rapid progression to ESKD. Serum-creatinine-based equations used to estimate glomerular filtration rate are notoriously unreliable in patients with diabetes. Early kidney function decline, reduced glomerular filtration rate, and proteinuria contribute to identifying diabetic patients at higher risk for rapid kidney function decline. Unlike proteinuria, the elevation of urinary albumin excretion in the range of microalbuminuria is frequently transient in patients with diabetes and does not always predict progression towards ESKD. Although the rate of progression of kidney function decline is usually accelerated in the presence of proteinuria, histological lesions of diabetes and ESKD may occur with normal urinary albumin excretion. No substantial reduction in the rate of ESKD associated with diabetes has been observed during the last decades despite intensified glycemic control and reno-protective strategies, indicating that existing therapies do not target underlying pathogenic mechanisms of kidney function decline. Very long-term effects of sodium-glucose transporters-2 inhibitors and glucagon-like peptide-1 analogs remain to be defined. In patients with diabetes, glucagon secretion is typically elevated and induces insulin resistance. Insulin resistance is consistently and strongly associated with clinical manifestations of diabetic kidney disease, suggesting that reduced insulin sensitivity participates in the pathogenesis of the disease and may represent a therapeutic objective. Amelioration of insulin sensitivity in patients with diabetes is associated with cardioprotective and kidney-protective effects.

scholarly journals Association of UBE3C Variants with Reduced Kidney Function in Patients with Diabetic Kidney Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 210
Author(s):  
Ying-Chun Chen ◽  
Mei-Yi Wu ◽  
Zhi-Lei Yu ◽  
Wan-Hsuan Chou ◽  
Yi-Ting Lai ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Clinical Role ◽  
Diabetic Kidney ◽  
Factors Affecting ◽  
Patients With Diabetes ◽  
Stage Renal Disease ◽  
End Stage ◽  
Reduced Kidney Function

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence of ESRD in Taiwan remain the highest worldwide. Therefore, identifying genetic factors affecting kidney function would have valuable clinical implications. We performed microarray experiments and identified that ubiquitin protein ligase E3C (UBE3C) is differentially expressed in two DKD patient groups with extreme (low and high) urine protein-to-creatinine ratios. A follow-up genotyping study was performed in a larger group to investigate any specific variants of UBE3C associated with DKD. A total of 263 patients were included in the study, comprising 172 patients with DKD and 91 control subjects (patients with DM without chronic kidney disease (CKD)). Two UBE3C variants (rs3802129(AA) and rs7807(CC)) were determined to be associated with reduced kidney function. The haplotype analysis revealed that rs3802129/rs3815217 (block 1) with A/G haplotype and rs8101/rs7807 (block 2) with T/C haplotype were associated with higher risks of CKD phenotypes. These findings suggest a clinical role of UBE3C variants in DKD risk.

scholarly journals SGLT2 Inhibition for Diabetic and Non-diabetic Kidney Disease

2021 ◽  
Vol 96 (6) ◽  
pp. 455-462
Author(s):  
Mi-Yeon Yu ◽  
Gheun-Ho Kim
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Diabetic Kidney ◽  
Sglt2 Inhibition

Chronic kidney disease (CKD) can be progressive, and its prognosis is worse because of increased mortality when it is associated with diabetes and cardiac disease. The outcomes of diabetic kidney disease (DKD) need to be improved, despite multifactorial interventions including glucose and blood pressure (BP) control, and the use of renin-angiotensin system (RAS) inhibitors, statins, and aspirin. Recent clinical trials suggest that sodium-glucose cotransporter-2 (SGLT2) inhibitors offer additional cardiorenal protection in DKD and non-diabetic CKD on top of RAS inhibition. The action of SGLT2 inhibitors is derived from the proximal tubule of the kidney, but their systemic effects beyond glucose-lowering involve hemodynamic and non-hemodynamic mechanisms. First, SGLT2 inhibitors restore tubuloglomerular feedback and relieve glomerular hypertension and albuminuria. Second, natriuresis and renal glycosuria lead to fluid and weight loss, resulting in BP lowering and prevention of heart failure. Third, SGLT2 inhibitors have anti-inflammatory and anti-oxidative actions that can reduce renal and cardiac inflammation and fibrosis, probably via adenosine monophosphate-activated protein kinase and sirtuin-1 activation. Finally, the proximal tubular workload is relieved, accompanied by increased erythropoiesis. Hypoxia-inducible factor 1 may be stimulated by renal outer medullary hypoxia when tubular sodium transport shifts from the proximal convoluted tubule to the proximal straight tubule and thick ascending limb, due to SGLT2 inhibition. These effects may also be beneficial in non-diabetic CKD, and we anticipate that SGLT2 inhibitors will prove effective for albuminuria reduction and preservation of kidney function in primary kidney diseases, including glomerulonephritis.

scholarly journals Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1143
Author(s):  
Midori Sakashita ◽  
Tetsuhiro Tanaka ◽  
Reiko Inagi
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Stress Responses ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Therapeutic Agents ◽  
Metabolic Changes ◽  
Diabetic Kidney ◽  
Glucose Levels ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

scholarly journals Oxidized LDL Modifies the Association between Proteinuria and Deterioration of Kidney Function in Proteinuric Diabetic Kidney Disease

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 504
Author(s):  
Stefanos Roumeliotis ◽  
Panagiotis I. Georgianos ◽  
Athanasios Roumeliotis ◽  
Theodoros Eleftheriadis ◽  
Aikaterini Stamou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Secondary Outcome ◽  
Diabetic Kidney ◽  
Egfr Decline ◽  
Over Time

Proteinuria is characterized by low accuracy for predicting onset and development of diabetic kidney disease (DKD) because it is not directly associated with molecular changes that promote DKD, but is a result of kidney damage. Oxidized low-density lipoprotein (ox-LDL) reflects oxidative stress and endothelial dysfunction, both underlying the development of proteinuria and loss of kidney function in DKD. We aimed to investigate whether ox-LDL modifies the association between proteinuria and progression of DKD in a cohort of 91 patients with proteinuric DKD and diabetic retinopathy, followed for 10 years. The primary endpoint was a combined kidney outcome of eGFR decline ≥30% or progression to end-stage kidney disease. After the end of the study, we considered the percentage change of eGFR over time as our secondary outcome. Proteinuria was associated with both outcomes, and ox-LDL amplified the magnitude of this link (p < 0.0001 for primary and p < 0.0001 for secondary outcome, respectively). After adjustment for duration of diabetes, history of cardiovascular disease and serum albumin, ox-LDL remained a significant effect modifier of the association between proteinuria and eGFR decline over time (p = 0.04). Our study shows that in proteinuric DKD, circulating ox-LDL levels amplified the magnitude of the association between proteinuria and progression of DKD.

scholarly journals Dietary Phosphorus as a Marker of Mineral Metabolism and Progression of Diabetic Kidney Disease

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 789
Author(s):  
Agata Winiarska ◽  
Iwona Filipska ◽  
Monika Knysak ◽  
Tomasz Stompór
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mineral Metabolism ◽  
Careful Analysis ◽  
Diabetic Kidney ◽  
Dietary Phosphorus ◽  
Patients With Diabetes ◽  
Cv Disease ◽  
End Stage ◽  
Phosphorus Intake

Phosphorus is an essential nutrient that is critically important in the control of cell and tissue function and body homeostasis. Phosphorus excess may result in severe adverse medical consequences. The most apparent is an impact on cardiovascular (CV) disease, mainly through the ability of phosphate to change the phenotype of vascular smooth muscle cells and its contribution to pathologic vascular, valvular and other soft tissue calcification. Chronic kidney disease (CKD) is the most prevalent chronic disease manifesting with the persistent derangement of phosphate homeostasis. Diabetes and resulting diabetic kidney disease (DKD) remain the leading causes of CKD and end-stage kidney disease (ESRD) worldwide. Mineral and bone disorders of CKD (CKD-MBD), profound derangement of mineral metabolism, develop in the course of the disease and adversely impact on bone health and the CV system. In this review we aimed to discuss the data concerning CKD-MBD in patients with diabetes and to analyze the possible link between hyperphosphatemia, certain biomarkers of CKD-MBD and high dietary phosphate intake on prognosis in patients with diabetes and DKD. We also attempted to clarify if hyperphosphatemia and high phosphorus intake may impact the onset and progression of DKD. Careful analysis of the available literature brings us to the conclusion that, as for today, no clear recommendations based on the firm clinical data can be provided in terms of phosphorus intake aiming to prevent the incidence or progression of diabetic kidney disease.

Sign in / Sign up

Export Citation Format

Share Document