scholarly journals Two-year longitudinal trajectory patterns of albuminuria and subsequent rates of end-stage kidney disease and all-cause death: a nationwide cohort study of biopsy-proven diabetic kidney disease

2021 ◽  
Vol 9 (1) ◽  
pp. e002241
Author(s):  
Masayuki Yamanouchi ◽  
Kengo Furuichi ◽  
Junichi Hoshino ◽  
Tadashi Toyama ◽  
Miho Shimizu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Incidence Rate ◽  
Diabetic Kidney Disease ◽  
Latent Class ◽  
Risk Profile ◽  
Stable Group ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
All Cause Mortality ◽  
End Stage

IntroductionData on the association between longitudinal trajectory patterns of albuminuria and subsequent end-stage kidney disease (ESKD) and all-cause mortality in diabetic kidney disease (DKD) are sparse.Research design and methodsDrawing on nationally representative data of 329 patients with biopsy-proven DKD and an estimated glomerular filtration rate above 30 mL/min/1.73 m2 at the time of biopsy, we used joint latent class mixed models to identify different 2-year trajectory patterns of urine albumin to creatinine ratio (UACR) and assessed subsequent rates of competing events: ESKD and all-cause death.ResultsA total of three trajectory groups of UACR were identified: ‘high-increasing’ group (n=254; 77.2%), ‘high-decreasing’ group (n=24; 7.3%), and ‘low-stable’ group (n=51; 15.5%). The ‘low-stable’ group had the most favorable risk profile, including the baseline UACR (median (IQR) UACR (mg/g creatinine): ‘low-stable’, 109 (50–138); ‘high-decreasing’, 906 (468–1740); ‘high-increasing’, 1380 (654–2502)), and had the least subsequent risk of ESKD and all-cause death among the groups. Although there were no differences in baseline characteristics between the ‘high-decreasing’ group and the ‘high-increasing’ group, the ‘high-decreasing’ group had better control over blood pressure, blood glucose, and total cholesterol levels during the first 2 years of follow-up, and the incidence rates of subsequent ESKD and all-cause death were lower in the ‘high-decreasing’ group compared with the ‘high-increasing’ group (incidence rate of ESKD (per 1000 person-years): 32.7 vs 77.4, p=0.014; incidence rate of all-cause death (per 1000 person-years): 0.0 vs 25.4, p=0.007).ConclusionsDynamic changes in albuminuria are associated with subsequent ESKD and all-cause mortality in DKD. Reduction in albuminuria by improving risk profile may decrease the risk of ESKD and all-cause death.

scholarly journals Retinopathy progression and the risk of end-stage kidney disease: results from a longitudinal Japanese cohort of 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease

2019 ◽  
Vol 7 (1) ◽  
pp. e000726 ◽  
Author(s):  
Masayuki Yamanouchi ◽  
Mikiro Mori ◽  
Junichi Hoshino ◽  
Keiichi Kinowaki ◽  
Takeshi Fujii ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Clinical Model ◽  
Renal Lesions ◽  
End Stage

ObjectiveThe predictive value of diabetic retinopathy on end-stage kidney disease (ESKD) has not been fully addressed in patients with type 2 diabetes and diabetic kidney disease.Research design and methodsWe studied 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease who were screened for diabetic retinopathy during the 1 month of kidney biopsy. We examined the association between retinopathy progression and renal lesions. We used Cox regression analyses to explore the risk of ESKD adjusting for known risk demographic and clinical variables. We assessed the incremental prognostic value of ESKD by adding diabetic retinopathy to the clinical variables.ResultsThe diabetic retinopathy progression positively correlated with all scores of renal lesions, especially with the glomerular-based classification (r=0.41), scores of interstitial fibrosis (r=0.41) and diffuse lesion (r=0.48). During a median follow-up of 5.7 years, 114 patients developed ESKD. Adjusting for known risk factors of ESKD, the HR for ESKD (patients with no apparent retinopathy as a reference) were 1.96 (95% CI 0.62 to 6.17) for patients with mild non-proliferative diabetic retinopathy (NPDR), 3.10 (95% CI 1.45 to 6.65) for patients with moderate NPDR, 3.03 (95% CI 1.44 to 6.37) for patients with severe NPDR, and 3.43 (95% CI 1.68 to 7.03) for patients with proliferative diabetic retinopathy, respectively. Addition of the retinopathy grading to the clinical model alone improved the prognostic value (the global χ2 statistic increased from 155.2 to 164.5; p<0.001), which is an improvement equivalent to the addition of the renal lesion grading to the clinical model.ConclusionsRetinopathy progression appeared to be associated with renal lesions and the development of ESKD. Our findings suggest that diabetic retinopathy and kidney disease share the same magnitude of disease progression, and therefore diabetic retinopathy may be useful for prognosticating the clinical course for diabetic kidney disease.

scholarly journals Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

2020 ◽  
Author(s):  
Laura J Smyth ◽  
Jill Kilner ◽  
Viji Nair ◽  
Hongbo Liu ◽  
Eoin Brennan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Gene Annotation ◽  
Repeated Testing ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Long Duration ◽  
End Stage ◽  
Methylation Patterns

A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), which is the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n=862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p≤x10-8 and fold change ±2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by in silico functional data, and replication where possible, include; AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9, and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals, has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

scholarly journals Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
L. J. Smyth ◽  
J. Kilner ◽  
V. Nair ◽  
H. Liu ◽  
E. Brennan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Gene Annotation ◽  
Repeated Testing ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Long Duration ◽  
End Stage ◽  
Methylation Patterns

Abstract Background A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

scholarly journals Efficacy, safety and response predictors of adjuvant astragalus for diabetic kidney disease (READY): study protocol of an add-on, assessor-blind, parallel, pragmatic randomised controlled trial

BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e042686
Author(s):  
Kam Wa Chan ◽  
Alfred Siu Kei Kwong ◽  
Pun Nang Tsui ◽  
Simon Chi Yuen Cheung ◽  
Gary Chi Wang Chan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hong Kong ◽  
Kidney Disease ◽  
Adverse Events ◽  
Diabetic Kidney Disease ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Response Predictors ◽  
Randomised Controlled ◽  
End Stage

IntroductionDiabetic kidney disease (DKD) is a prevalent and costly complication of diabetes with limited therapeutic options, being the leading cause of end-stage kidney disease in most developed regions. Recent big data studies showed that add-on Chinese medicine (CM) led to a reduced risk of end-stage kidney disease and mortality among patients with chronic kidney disease (CKD) and diabetes. Astragalus, commonly known as huang-qi, is the most prescribed CM or used dietary herb in China for diabetes and DKD. In vivo and in vitro studies showed that astragalus ameliorated podocyte apoptosis, foot process effacement, mesangial expansion, glomerulosclerosis and interstitial fibrosis. Nevertheless, the clinical effect of astragalus remains uncharacterised. This pragmatic clinical trial aims to evaluate the effectiveness of add-on astragalus in patients with type 2 diabetes, stage 2–3 CKD and macroalbuminuria, and to identify related response predictors.Methods and analysisThis is an add-on, assessor-blind, parallel, pragmatic randomised controlled clinical trial. 118 patients diagnosed with DKD will be recruited and randomised 1:1 to receive 48 weeks of add-on astragalus or standard medical care. Primary endpoints are the changes in estimated glomerular filtration rate and urine albumin-to-creatinine ratio between baseline and treatment endpoint. Secondary endpoints include adverse events, fasting blood glucose, glycated haemoglobin, lipids and other biomarkers. Adverse events are monitored through self-complete questionnaire and clinical visits. Outcomes will be analysed by regression models. Subgroup and sensitivity analyses will be conducted for different epidemiological subgroups and statistical analyses. Enrolment started in July 2018.Ethics and disseminationThis study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West/East/Kowloon Central clusters (UW 16-553/HKEC-2019-026/REC (KC/KE)-19-0049/ER-4). We will report the findings in medical journals and conferences. The dataset will be available on reasonable request.Trial registration numberNCT03535935

scholarly journals Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Daiji Kawanami ◽  
Yuichi Takashi ◽  
Yoshimi Muta ◽  
Naoki Oda ◽  
Dai Nagata ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mineralocorticoid Receptor ◽  
Diabetic Kidney Disease ◽  
Current Knowledge ◽  
Mineralocorticoid Receptor Antagonists ◽  
Future Perspectives ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Fibrotic Process ◽  
End Stage

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide. Mineralocorticoid receptor (MR) plays an important role in the development of DKD. A series of preclinical studies revealed that MR is overactivated under diabetic conditions, resulting in promoting inflammatory and fibrotic process in the kidney. Clinical studies demonstrated the usefulness of MR antagonists (MRAs), such as spironolactone and eplerenone, on DKD. However, concerns regarding their selectivity for MR and hyperkalemia have remained for these steroidal MRAs. Recently, nonsteroidal MRAs, including finerenone, have been developed. These agents are highly selective and have potent anti-inflammatory and anti-fibrotic properties with a low risk of hyperkalemia. We herein review the current knowledge and future perspectives of MRAs in DKD treatment.

Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of End Stage Kidney Disease in Diabetes

2021 ◽  
pp. ASN.2021010105
Author(s):  
Eiichiro Satake ◽  
Pierre-Jean Saulnier ◽  
Hiroki Kobayashi ◽  
Manoj Gupta ◽  
Helen Looker ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Axon Guidance ◽  
Diabetic Kidney Disease ◽  
Umbilical Vein ◽  
Micro Rna ◽  
Circulating Mirnas ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
End Stage ◽  
Circulating Levels

Background Mechanisms underlying the progression of diabetic kidney disease to end-stage kidney disease (ESKD) are not fully understood. Methods We performed global micro-RNA (miRNA) analysis in plasma in two cohorts encompassing 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease and targeted proteomics analysis in plasma in four cohorts encompassing 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsies from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. Results In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, miR-328-3p), which were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins—most notably EFNA4 and EPHA2—were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsies. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. Conclusions This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.

scholarly journals Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Yue-Yu Gu ◽  
Fu-Hua Lu ◽  
Xiao-Ru Huang ◽  
Lei Zhang ◽  
Wei Mao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Therapeutic Targets ◽  
Diabetic Complication ◽  
End Stage Kidney Disease ◽  
Diabetic Kidney ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
End Stage

Diabetic kidney disease (DKD) is the most common diabetic complication and is a leading cause of end-stage kidney disease. Increasing evidence shows that DKD is regulated not only by many classical signaling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation, and non-coding RNA (ncRNAs). In this review, we focus on our current understanding of the role and mechanisms of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the pathogenesis of DKD. Of them, the regulatory role of TGF-β/Smad3-dependent miRNAs and lncRNAs in DKD is highlighted. Importantly, miRNAs and lncRNAs as biomarkers and therapeutic targets for DKD are also described, and the perspective of ncRNAs as a novel therapeutic approach for combating diabetic nephropathy is also discussed.

scholarly journals Mitophagy in Diabetic Kidney Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaofeng Zhang ◽  
Jing Feng ◽  
Xia Li ◽  
Dan Wu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Therapeutic Approaches ◽  
End Stage Kidney Disease ◽  
Common Cause ◽  
Diabetic Kidney ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
End Stage

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease worldwide and is the main microvascular complication of diabetes. The increasing prevalence of diabetes has increased the need for effective treatment of DKD and identification of new therapeutic targets for better clinical management. Mitophagy is a highly conserved process that selectively removes damaged or unnecessary mitochondria via the autophagic machinery. Given the important role of mitophagy in the increased risk of DKD, especially with the recent surge in COVID-19-associated diabetic complications, in this review, we provide compelling evidence for maintaining homeostasis in the glomeruli and tubules and its underlying mechanisms, and offer new insights into potential therapeutic approaches for treatment of DKD.

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