Genetic methodologies are improving our understanding of the pathophysiology in diverse diseases. Breakthroughs have been particularly impressive in nephrology, for which marked disparities exist in ...rates and etiologic classifications of end-stage kidney disease between African Americans and European Americans. Discovery of the apolipoprotein L1 gene (APOL1) association with focal segmental glomerulosclerosis, human immunodeficiency virus (HIV)-associated nephropathy, lupus nephritis, sickle cell nephropathy, and solidified glomerulosclerosis, as well as more rapid failure of transplanted kidneys from donors with APOL1 renal-risk genotypes, has improved our understanding of nondiabetic nephropathy. Environmental factors acting through natural selection in sub-Saharan African populations likely underlie this association. This article describes the discovery of chromosome 22q renal-risk variants and their worldwide distribution, reviews the epidemiology and pathology of APOL1-associated nephropathies, and explores several proposed mechanisms of kidney injury identified in cell culture and animal models. Detection of APOL1 associations with kidney diseases and delineation of injury pathways brings hope for effective treatment for these kidney diseases.
Abstract
Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or ...reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.
This scientific statement reviews and discusses the microvascular complications of diabetes on an organ-by-organ basis.
Molecular genetics have revolutionized the understanding of susceptibility to the broad spectrum of kidney diseases with light microscopic appearance of FSGS, particularly in populations with recent ...African ancestry. These disorders include idiopathic FSGS, HIV-associated nephropathy, severe lupus nephritis, sickle cell nephropathy, and the primary kidney disorder focal global glomerulosclerosis, which had historically been ascribed to systemic hypertension. FSGS was once thought to include a multitude of unrelated disorders with similar histologic appearance. However, variation in the apolipoprotein L1 gene locus is now known to account for the vast majority of such cases in African Americans as well as nearly all the excess risk for FSGS and related forms of progressive nondiabetic nephropathy in populations with recent African ancestry, relative to European ancestry. Inheriting two coding apolipoprotein L1 gene nephropathy risk variants is necessary for susceptibility to CKD; however, these variants alone are insufficient to produce disease. This work reviews the evidence supporting second hits or modifying factors that affect risk for apolipoprotein L1 gene-associated nephropathy and produce the protean manifestations of this common and complex syndrome. Targeting modifiable second factors will lead to preventive therapies for slowing progression of nondiabetic nephropathy in many patients possessing two apolipoprotein L1 gene risk variants. This model of genetic risk coupled with modifiable second hits will serve as a paradigm applicable to patients with CKD of various etiologies as well as a host of other complex disorders.
Effects of Intensive BP Control in CKD Cheung, Alfred K; Rahman, Mahboob; Reboussin, David M ...
Journal of the American Society of Nephrology,
09/2017, Volume:
28, Issue:
9
Journal Article
Peer reviewed
Open access
The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood ...Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group;
=1330) or <140 mm Hg (standard group;
=1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio HR, 0.81; 95% confidence interval 95% CI, 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD (
values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (-0.47 versus -0.32 ml/min per 1.73 m
per year;
<0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.
An improved understanding of the pathogenesis in apolipoprotein L1 (APOL1) gene-associated chronic kidney disease (CKD) arose from observations in kidney transplantation. APOL1 genotyping could soon ...improve the safety of living kidney donation in individuals with recent African ancestry and alter the allocation of deceased donor kidneys.
This article reviews the potential mechanisms that underlie development of APOL1-associated nephropathy. Roles for circulating APOL1 protein versus intrinsic renal expression of APOL1 are discussed, as well as the requirement for modifying genetic and/or environmental factors.
Abundant evidence supports local kidney production of APOL1 renal-risk variant protein in the development of nephropathy; this is true in both native kidney disease and after renal transplantation. Only a minority of kidneys from individuals with APOL1 high-risk genotypes will develop CKD or manifest shorter renal allograft survival after transplantation. Therefore, modifying factors that explain why only a subset of kidneys develops nephropathy remain critical to identify. It appears likely that environmental exposures, as opposed to major APOL1-second gene interactions, will prove to be stronger modifiers of the risk for nephropathy.
The evolving understanding of the pathogenesis in APOL1-associated nephropathy will identify biomarkers predicting nephropathy in individuals at high genetic risk and lead to novel therapies to prevent or slow native CKD progression and prolong survival of transplanted kidneys. In the interim, the National Institutes of Health-sponsored "APOL1 Long-term Kidney Transplantation Outcomes" Network will determine whether APOL1 genotyping in individuals with recent African ancestry improves outcomes and safety in kidney transplantation.
Faced with a global epidemic of type 2 diabetes (T2D), it is critical that researchers improve our understanding of the pathogenesis of T2D and related vascular complications. These findings may ...ultimately lead to novel treatment options for disease prevention or delaying progression. Two major paradigms jointly underlie the development of T2D and related coronary artery disease, diabetic nephropathy, and diabetic retinopathy. These paradigms include the genetic risk variants and behavioral/environmental factors. This article systematically reviews the literature supporting genetic determinants in the pathogenesis of T2D and diabetic vasculopathy, and the functional implications of these gene variants on the regulation of beta-cell function and glucose homeostasis. We update the discovery of diabetes and diabetic vasculopathy risk variants, and describe the genetic technologies that have uncovered them. Also, genomic linkage between obesity and T2D is discussed. There is a complementary role for behavioral and environmental factors modulating the genetic susceptibility and diabetes risk. Epidemiological and clinical data demonstrating the effects of behavioral and novel environmental exposures on disease expression are reviewed. Finally, a succinct overview of recent landmark clinical trials addressing glycemic control and its impact on rates of vascular complications is presented. It is expected that novel strategies to exploit the gene- and exposure-related underpinnings of T2D will soon result.
Unrelated disease processes commonly occur in non-diabetic individuals with mild-to-moderate hypertension and low level or absent proteinuria who present with chronic kidney disease: primary ...glomerulosclerosis in those with recent African ancestry, and arteriolar nephrosclerosis with resultant glomerular ischaemia potentially related to hypertension and vascular disease risk factors in other cases. Unfortunately, nephrologists often indiscriminately apply a diagnosis of 'hypertensive nephrosclerosis' to patients in either scenario, which implies that the hypertension is causative of their renal disease. Although nephropathies that are associated with variants in the apolipoprotein L1 gene (APOL1) often cause secondarily elevated blood pressure, they belong to the spectrum of focal segmental glomerulosclerosis and are not initiated by systemic hypertension. Because genetic testing for APOL1 variants and other glomerulosclerosis-associated gene variants is available and can provide a precise definition of disease pathogenesis, we believe that the term 'hypertensive nephrosclerosis' should now be abandoned and replaced with either gene-based (for example, APOL1-associated) glomerulosclerosis or arteriolar nephrosclerosis. Precision medicine will be key to improving diagnostic accuracy in this field. Discrimination of these disparate disorders has the potential to eradicate primary forms of glomerulosclerosis that are associated with APOL1 renal-risk variants.
More than 5 million African-Americans, and millions more in Africa and worldwide, possess apolipoprotein L1 gene (APOL1) high-risk genotypes with an increased risk for chronic kidney disease. This ...manuscript reviews treatment approaches for slowing the progression of APOL1-associated nephropathy.
Since the 2010 discovery of APOL1 as a cause of nondiabetic nephropathy in individuals with sub-Saharan African ancestry, it has become apparent that aggressive hypertension control, renin-angiotensin system blockade, steroids and conventional immunosuppressive agents are suboptimal treatments. In contrast, APOL1-mediated collapsing glomerulopathy due to interferon treatment and HIV infection, respectively, often resolve with cessation of interferon or antiretroviral therapy. Targeted therapies, including APOL1 small molecule inhibitors, APOL1 antisense oligonucleotides (ASO) and inhibitors of APOL1-associated inflammatory pathways, hold promise for these diseases. Evolving therapies and the need for clinical trials support the importance of increased use of APOL1 genotyping and kidney biopsy.
APOL1-associated nephropathy includes a group of related phenotypes that are driven by the same two genetic variants in APOL1. Clinical trials of small molecule inhibitors, ASO, and inflammatory pathway inhibitors may improve outcomes in patients with primary forms of APOL1-associated nephropathy.
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