scholarly journals Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Kidney Disease-Related Genes in Patients with Diabetic Kidney Disease

2020 ◽  
Author(s):  
Jose Lazaro-Guevara ◽  
Julio Fierro Morales ◽  
A. Hunter Wright ◽  
River Gunville ◽  
Scott G. Frodsham ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
List Type ◽  
Next Generation ◽  
Diabetic Kidney ◽  
Pathogenic Variants ◽  
Patients With Diabetes ◽  
Disease Related Genes ◽  
Generation Sequencing

AbstractDiabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their kidney disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. Here, we set out to investigate the genetic basis of disease in non-diabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprised of 345 kidney disease-related genes. Our analysis identified rare diagnostic variants that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. Our findings suggest that rare variants in kidney disease-related genes in the context of diabetic pathophysiology may play a role in the pathogenesis of kidney disease in patients with diabetes.Key MessagesWhat is already known about this subject? For patients with diabetes and chronic kidney disease, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes; without histopathological confirmation, however, the underlying cause of their kidney disease is unclear.Next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease.What are the new findings? Using targeted NGS and a custom panel comprised of 345 kidney disease-related genes, we found that 22% of diabetic kidney disease patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel.Genetic variants suggestive of non-diabetic kidney disease were detected in 3% of the diabetic patients included in this study.How might these results change the focus of research or clinical practice? Our findings suggest that rare variants in kidney disease-related genes in the context of diabetic pathophysiology may play a role in the pathogenesis of kidney disease in patients with diabetes.Importantly, improved understanding of the underlying disease process in diabetic kidney disease could have major implications in terms of patient care and monitoring as well as for research studies in this field.

scholarly journals Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease

2021 ◽  
pp. 1-11
Author(s):  
Jose Lazaro-Guevara ◽  
Julio Fierro-Morales ◽  
A. Hunter Wright ◽  
River Gunville ◽  
Christopher Simeone ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Patients ◽  
Next Generation ◽  
Diabetic Kidney ◽  
Pathogenic Variants ◽  
Patients With Diabetes ◽  
Disease Related Genes ◽  
Generation Sequencing

<b><i>Introduction:</i></b> Diabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. <b><i>Methods:</i></b> Here, we set out to investigate the genetic basis of disease in nondiabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprising 345 kidney disease-related genes. <b><i>Results:</i></b> Our analysis identified rare diagnostic variants based on ACMG-AMP guidelines that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. <b><i>Discussion/Conclusion:</i></b> Our findings suggest that rare variants in kidney disease-related genes in a diabetic background may play a role in the pathogenesis of DKD and NDKD in patients with diabetes.

scholarly journals A Custom Target Next-Generation Sequencing 70-Gene Panel and Replication Study to Identify Genetic Markers of Diabetic Kidney Disease

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1992
Author(s):  
Sonia Mota-Zamorano ◽  
Luz María González ◽  
Nicolás Roberto Robles ◽  
José Manuel Valdivielso ◽  
Bárbara Cancho ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Study Groups ◽  
Gene Panel ◽  
Next Generation ◽  
Diabetic Kidney ◽  
Stage Renal Disease ◽  
The Impact ◽  
Generation Sequencing

Diabetic kidney disease (DKD) has been pointed out as a prominent cause of chronic and end-stage renal disease (ESRD). There is a genetic predisposition to DKD, although clinically relevant loci are yet to be identified. We utilized a custom target next-generation sequencing 70-gene panel to screen a discovery cohort of 150 controls, DKD and DKD-ESRD patients. Relevant SNPs for the susceptibility and clinical evolution of DKD were replicated in an independent validation cohort of 824 controls and patients. A network analysis aiming to assess the impact of variability along specific pathways was also conducted. Forty-eight SNPs displayed significantly different frequencies in the study groups. Of these, 28 with p-values lower than 0.01 were selected for replication. MYH9 rs710181 was inversely associated with the risk of DKD (OR = 0.52 (0.28–0.97), p = 0.033), whilst SOWAHB rs13140552 and CNDP1 rs4891564 were not carried by cases or controls, respectively (p = 0.044 and 0.023). In addition, the RGMA rs1969589 CC genotype was significantly correlated with lower albumin-to-creatinine ratios in the DKD patients (711.8 ± 113.0 vs. 1375.9 ± 474.1 mg/g for TC/TT; mean difference = 823.5 (84.46–1563.0); p = 0.030). No biological pathway stood out as more significantly affected by genetic variability. Our findings reveal new variants that could be useful as biomarkers of DKD onset and/or evolution.

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 Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made Panel

2021 ◽  
Vol 11 ◽  
Author(s):  
Vincenza Precone ◽  
Rossella Cannarella ◽  
Stefano Paolacci ◽  
Gian Maria Busetto ◽  
Tommaso Beccari ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Male Infertility ◽  
Next Generation ◽  
Male Population ◽  
Pathogenic Variants ◽  
Custom Made ◽  
Number Of Genes ◽  
General Male Population ◽  
Generation Sequencing ◽  
Spermatogenic Failure

BackgroundInfertility affects about 7% of the general male population. The underlying cause of male infertility is undefined in about 50% of cases (idiopathic infertility). The number of genes involved in human spermatogenesis is over two thousand. Therefore, it is essential to analyze a large number of genes that may be involved in male infertility. This study aimed to test idiopathic male infertile patients negative for a validated panel of “diagnostic” genes, for a wide panel of genes that we have defined as “pre-diagnostic.”MethodsWe developed a next-generation sequencing (NGS) gene panel including 65 pre-diagnostic genes that were used in 12 patients who were negative to a diagnostic genetic test for male infertility disorders, including primary spermatogenic failure and central hypogonadism, consisting of 110 genes.ResultsAfter NGS sequencing, variants in pre-diagnostic genes were identified in 10/12 patients who were negative to a diagnostic test for primary spermatogenic failure (n = 9) or central hypogonadism (n = 1) due to mutations of single genes. Two pathogenic variants of DNAH5 and CFTR genes and three uncertain significance variants of DNAI1, DNAH11, and CCDC40 genes were found. Moreover, three variants with high impact were found in AMELY, CATSPER 2, and ADCY10 genes.ConclusionThis study suggests that searching for pre-diagnostic genes may be of relevance to find the cause of infertility in patients with apparently idiopathic primary spermatogenic failure due to mutations of single genes and central hypogonadism.

scholarly journals Next‐generation sequencing for the diagnosis of MYH9 ‐RD: Predicting pathogenic variants

2019 ◽  
Vol 41 (1) ◽  
pp. 277-290 ◽  
Author(s):  
Loredana Bury ◽  
Karyn Megy ◽  
Jonathan C. Stephens ◽  
Luigi Grassi ◽  
Daniel Greene ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Generation Sequencing

scholarly journals GLP-1 receptor agonists in diabetic kidney disease: from the patient-side to the bench-side

2018 ◽  
Vol 315 (6) ◽  
pp. F1519-F1525 ◽  
Author(s):  
Brad P. Dieter ◽  
Radica Z. Alicic ◽  
Katherine R. Tuttle
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Microvascular Complications ◽  
Renin Angiotensin System ◽  
Diabetic Kidney ◽  
Receptor Agonists ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide 1 ◽  
Patient Side ◽  
End Stage

Diabetic kidney disease (DKD), one of the most common and severe microvascular complications of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Since the development of renin-angiotensin system inhibition nearly three decades ago, no new therapeutic agents have received regulatory approval for treatment of DKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of newer antihyperglycemic agents, have shown promise for prevention of DKD onset and progression. This perspective summarizes clinical and experimental observations to give insight into biological mechanisms beyond glycemic control, such as natriuresis and anti-inflammatory actions, for preservation of kidney function in patients with diabetes.

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