Update of pathophysiology and management of diabetic kidney disease

Lin, Yi‐Chih; Chang, Yu-Hsing; Yang, Shan-Yi; Wu, Kwan Dun; Chu, Tzong‐Shinn

doi:10.1016/j.jfma.2018.02.007

Cited by 363 publications

(300 citation statements)

References 121 publications

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“…DN is the leading cause of ESRD in the world, with a complex pathophysiology involving both glucotoxicity and lipotoxicity, triggering oxidative stress and inflammation [106, 107]. T2D patients have a positive correlation between serum FGF21 levels and urinary albumin excretion.…”

Section: Fgf21 and Diabetic Nephropathymentioning

confidence: 99%

Fibroblast growth factor 21 in chronic kidney disease

et al. 2018

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Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD.

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Section: Fgf21 and Diabetic Nephropathymentioning

confidence: 99%

Fibroblast growth factor 21 in chronic kidney disease

et al. 2018

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“…The DM and DN are the main causes of end stage renal disease (ESRD) in the USA, with prevalence of 800 million people 3 . The DN is chronic microvascular complication of DM, presenting as clinical syndrome, manifesting with persistent albuminuria [urine albumin/creatinine ratio (UACR) > 300 mg/g], arterial hypertension, decreasing of glomerular filtration rate and increased cardiovascular events 4 . Considering high direct and indirect costs for treating ESRD patients with renal transplantation or hemodialysis, continuous research are conducting to prevent or slow progression of DN.…”

Section: Introductionmentioning

confidence: 99%

Effect of vitamin D on proteinuria, lipid status, glicoregulation and C-reactive protein in patients with type-2 diabetes mellitus

et al. 2020

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Background/Aim. Vitamin D insufficiency/deficiency is often present in patients with type-2 diabetes mellitus (DM) and could present a risk factor for rapid progression of diabetic nephropathy and for higher incidence of cardiovascular events. The aim of this study was to examine the influence of vitamin D supplementation on proteinuria, cholesterol, triglycerides, C-reactive protein (CRP) and hemoglobin A1c in patients with type-2 DM and vitamin D insufficiency/deficiency. Methods. This prospective, cohort study included 90 patients with type-2 DM and vitamin D insufficiency/deficiency divided into 3 equal groups: with normal proteinura, with microproteinuria and with macroproteinuria. Therapy included six months of supplementation with cholecalciferol drops: first two months with 20,000 IU twice weekly, than if level of vitamin D was below normal the same dose was given next four months. If the level of vitamin D was normal 5,000 IU was given twice weekly. At the begining and at the end of the study the levels of urea, creatinine, fasting blood glucose, calcium, phosphorus, cholesterol, triglycerides, CRP, hemoglobin A1c, intact parathyroid hormone, 24-hour urine protein and creatinine clearance were determined. Levels of calcium, phosphorus and vitamin D were also checked 2 months after beginning of therapy due to possible correction of cholecalciferol dose. Results. The lowest level of vitamin D before therapy was found in patients with macroproteinuria, while at the end of the study the significantly higher level of vitamin D was found in all three groups. After 6 months of therapy a significant decrease of 24-hour urine protein, cholesterol, triglycerides, hemoglobin A1c in all three groups, and CRP in patients with normal proteinuria and microproteinuria were found. Significantly negative correlation between vitamin D and 24-hour urine protein, cholesterol and CRP was found in patients with macroproteinuria. Also, significantly negative correlation was found between vitamin D and hemoglobin A1c, in patients with normal proteinuria, vitamin D and CRP in patients with microproteinuria. Conclusion. A preventive use of high-dose cholecalciferol supplementation in patients with type-2 DM (with or without proteinuria) decreases cholesterol, triglycerides, proteinuria, CRP and hemoglobin A1c.

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“…In animal studies, drugs that inhibit inflammatory factors show beneficial effects on DKD. For example, the phosphodiesterase inhibitor pentoxifylline attenuates the development of DKD through inhibiting TNF-α (DiPetrillo & Gesek, 2004;) and the anti-inflammation drug bardoxolone methyl normalizes glomerular filtration rate (GFR) in type 2 diabetic patients via inhibition of nuclear factor-kappa B signalling (Pergola et al 2011;Lin et al 2018). However, how inflammation develops in DKD remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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Update of pathophysiology and management of diabetic kidney disease

Cited by 363 publications

References 121 publications

Fibroblast growth factor 21 in chronic kidney disease

Fibroblast growth factor 21 in chronic kidney disease

Effect of vitamin D on proteinuria, lipid status, glicoregulation and C-reactive protein in patients with type-2 diabetes mellitus

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

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