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 Therapeutic Advances in Diabetic Nephropathy

2022 ◽  
Vol 11 (2) ◽  
pp. 378
Author(s):  
Hanny Sawaf ◽  
George Thomas ◽  
Jonathan J. Taliercio ◽  
Georges Nakhoul ◽  
Tushar J. Vachharajani ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Treatment Options ◽  
The United States ◽  
Additional Treatment ◽  
Diabetic Kidney ◽  
Raas Blockade ◽  
Risk Factor Modification ◽  
Glucagon Like Peptide 1 ◽  
End Stage

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease.

scholarly journals NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease

2021 ◽  
Author(s):  
Komuraiah Myakala ◽  
Xiaoxin X Wang ◽  
Bryce A. Jones ◽  
Matthew D Hirschey ◽  
Xiaoping Yang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
The United States ◽  
Diabetic Kidney ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Mitochondrial Dna Damage ◽  
Patients With Diabetes

ABSTRACTBackgroundDiabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of all of the beneficial interventions implemented in patients with diabetes, there remains a need for additional therapeutic targets in diabetic kidney disease (DKD). Mitochondrial dysfunction and inflammation are increasingly recognized as important causes of the development and progression of DKD. However, the molecular connection between mitochondrial function, inflammation, and fibrosis remains to be elucidated.MethodsIn the present studies we tested the hypothesis that enhancing NAD metabolism could increase mitochondrial sirtuin 3 (SIRT3) activity, improve mitochondrial function, decrease mitochondrial DNA damage, and prevent inflammation and progression of DKD.ResultsWe found that treatment of db-db mice with type 2 diabetes with nicotinamide riboside (NR) prevented albuminuria, increased urinary KIM1 excretion, and several parameters of DKD. These effects were associated with increased SIRT3 activity, improved mitochondrial function, and decreased inflammation at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway.ConclusionsNR supplementation boosted the NAD metabolism to modulate mitochondrial function and inflammation and prevent progression of diabetic kidney disease.

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 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 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.

scholarly journals Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong-Yuan Chang ◽  
Xiao-Qian Li ◽  
Min Chen ◽  
Ming-Hui Zhao
Keyword(s):  
Kidney Disease ◽  
Protective Effect ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Membrane Attack Complex ◽  
Sglt2 Inhibitors ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Proximal Tubular Epithelial Cells ◽  
Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

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