Urinary mRNA Signatures as Predictors of Renal Function Decline in Patients With Biopsy-Proven Diabetic Kidney Disease

The clinical manifestations of diabetic kidney disease (DKD) are more heterogeneous than those previously reported, and these observations mandate the need for the recruitment of patients with biopsy-proven DKD in biomarker research. In this study, using the public gene expression omnibus (GEO) repository, we aimed to identify urinary mRNA biomarkers that can predict histological severity and disease progression in patients with DKD in whom the diagnosis and histologic grade has been confirmed by kidney biopsy. We identified 30 DKD-specific mRNA candidates based on the analysis of the GEO datasets. Among these, there were significant alterations in the urinary levels of 17 mRNAs in patients with DKD, compared with healthy controls. Four urinary mRNAs—LYZ, C3, FKBP5, and G6PC—reflected tubulointerstitial inflammation and fibrosis in kidney biopsy and could predict rapid progression to end-stage kidney disease independently of the baseline eGFR (tertile 1 vs. tertile 3; adjusted hazard ratio of 9.68 and 95% confidence interval of 2.85–32.87, p < 0.001). In conclusion, we demonstrated that urinary mRNA signatures have a potential to indicate the pathologic status and predict adverse renal outcomes in patients with DKD.

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COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.09100817 ◽

2018 ◽

Vol 13 (8) ◽

pp. 1162-1171 ◽

Cited By ~ 9

Author(s):

Yiting Wang ◽

Junlin Zhang ◽

Yingwang Zhao ◽

Shanshan Wang ◽

Jie Zhang ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Kidney Biopsy ◽

Genetic Effect ◽

Susceptibility Genes ◽

Rapid Progression ◽

Diabetic Kidney ◽

Protein Protein Interaction ◽

Pathogenic Variants ◽

Overt Proteinuria

Background and objectivesDespite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents.Design, setting, participants, & measurementsWhole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants.ResultsHNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein–protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY.ConclusionsThe genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.

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

Nutrients ◽

10.3390/nu13030789 ◽

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.

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Therapeutic Strategies for Diabetic Kidney Disease

Diabetology ◽

10.3390/diabetology2010003 ◽

2021 ◽

Vol 2 (1) ◽

pp. 31-35

Author(s):

Keiichiro Matoba

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Intensive Therapy ◽

Therapeutic Strategies ◽

Therapeutic Interventions ◽

Hemodynamic Changes ◽

Diabetic Kidney ◽

Global Epidemic ◽

Stage Renal Disease ◽

End Stage

Diabetic kidney disease (DKD) is a global epidemic leading to end-stage renal disease (ESRD) and susceptibility to cardiovascular disease, with few therapeutic interventions. A hallmark of DKD is the activation of the renin-angiotensin-aldosterone system and hemodynamic changes in glomerulus. Although intensive therapy with agents that targets those abnormalities lowers the risk of DKD progression, it does not completely abolish the risk of ESRD and cardiovascular events. Recent studies have illustrated the importance of renal inflammation, oxidative stress, and activated Rho-associated protein kinase (ROCK) signaling as essential pathogenesis for the development of DKD. In this commentary, these topics will be discussed.

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Diabetic kidney disease in thedb/dbmouse

AJP Renal Physiology ◽

10.1152/ajprenal.00315.2002 ◽

2003 ◽

Vol 284 (6) ◽

pp. F1138-F1144 ◽

Cited By ~ 267

Author(s):

Kumar Sharma ◽

Peter McCue ◽

Stephen R. Dunn

Keyword(s):

Diabetic Nephropathy ◽

Kidney Disease ◽

Mouse Model ◽

Renal Disease ◽

Mouse Models ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Matrix Expansion ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

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Gender Differences in Diabetic Kidney Disease: Focus on Hormonal, Genetic and Clinical Factors

International Journal of Molecular Sciences ◽

10.3390/ijms22115808 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5808

Author(s):

Annalisa Giandalia ◽

Alfio Edoardo Giuffrida ◽

Guido Gembillo ◽

Domenico Cucinotta ◽

Giovanni Squadrito ◽

...

Keyword(s):

Gender Differences ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Clinical Manifestations ◽

Current Evidence ◽

Sex And Gender ◽

Clinical Factors ◽

Diabetic Kidney ◽

And Gender ◽

The Impact

Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene–sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors.

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Diabetic Kidney Disease in Childhood and Adolescence: Conventional and Novel Renoprotective Strategies

EMJ Nephrology ◽

10.33590/emjnephrol/20-00077 ◽

2020 ◽

pp. 68-77

Author(s):

Samuel N Uwaezuoke ◽

Adaeze C Ayuk

Keyword(s):

Diabetes Mellitus ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Microvascular Complications ◽

Clinical Syndrome ◽

Clinical Staging ◽

Childhood And Adolescence ◽

Diabetic Kidney ◽

Haemodynamic Changes ◽

End Stage

Diabetic kidney disease (DKD) is defined as a clinical syndrome consisting of persistent macroalbuminuria, progressive decline in glomerular filtration rate (GFR), hypertension, increased cardiovascular disease events, and the associated mortality of these conditions. The disease evolves from the microvascular complications of poorly controlled Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). The pathogenic pathways comprise renal haemodynamic changes, ischaemia and inflammation, and overactive renin–angiotensin–aldosterone system (RAAS), through which several events cascade down from hyperglycaemia to renal fibrosis. Conventional and novel renoprotective strategies target modifiable DKD risk factors and specific stages of the pathogenic pathways, respectively. Although these strategies may slow DKD progression to end-stage kidney disease (ESKD), novel drugs are still undergoing trials for validation in human participants. This narrative review appraises these renoprotective strategies and highlights the current clinical staging and pathogenesis of the disease.

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Glycaemic Monitoring in Diabetic Kidney Disease – Is HbA1c Reliable?

Journal of Health Science and Medical Research ◽

10.31584/jhsmr.2021831 ◽

2021 ◽

Author(s):

Salbiah Binti Isa ◽

Rohayu Hami ◽

Alma’ Norliana JA ◽

Siti Salmah Noordin ◽

Tuan Salwani Tuan Ismail

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Glycated Albumin ◽

Glucose Monitoring ◽

Diabetic Control ◽

Haemoglobin A1c ◽

Diabetic Kidney ◽

Serum Fructosamine ◽

Potential Factors ◽

End Stage

Diabetic kidney disease (DKD) is a known complication of diabetes mellitus that increases patients’ risks of developing end-stage renal failure requiring dialysis treatment and vulnerability of fatal outcomes resulted from cardiovascular events. Therefore, a good diabetic control among patients with DKD is essential. Nevertheless, monitoring glycaemia in DKD is very challenging. The use of the gold standard glycaemic marker, haemoglobin A1c (HbA1c), is complicated by many hindrances associated with both biochemical and physiological derangements of DKD. Despite the constraints, the Kidney Disease Improving Global Outcome has recommended the use of HbA1c as a reliable glycaemic marker in DKD patients, whose estimated glomerular filtration rate is down to 30 millilitres/minute per 1.73 meter2 . In this article, we discuss the reliability and limitations of HbA1c as an advocated glycaemic marker in DKD. Considering that the reliability of HbA1c is highly dependent on the interpretation of the results, we also highlighted the common potential factors that can affect HbA1c interpretation in patients with DKD. The article also discusses the issues related to the utility of glycated albumin and serum fructosamine as alternative glycaemic biomarkers, and continuous glucose monitoring as a complementary marker to HbA1c in clinical practice. Understanding the HbA1c values and their limitations is important to ensure accurate interpretation of glycaemic status and to achieve optimal diabetic control in patients with DKD.

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