Kovesdy C.P.,Memphis Medical Center |
Kovesdy C.P.,University of Tennessee Health Science Center |
Lu J.L.,University of Tennessee Health Science Center |
Molnar M.Z.,University of Tennessee Health Science Center |
And 5 more authors.
JAMA Internal Medicine | Year: 2014
IMPORTANCE The effect of strict blood pressure control on clinical outcomes in patients with chronic kidney disease (CKD) is unclear. OBJECTIVE To compare the outcomes associated with a treated systolic blood pressure (SBP) of less than 120mmHg vs those associated with the currently recommended SBP of less than 140mmHg in a national CKD database of US veterans. DESIGN, SETTING, AND PARTICIPANTS Historical cohort study using a nationwide cohort of US veterans with prevalent CKD, estimated glomerular filtration rate less than 60 mL/min/1.73 m2, and uncontrolled hypertension, who then received 1 or more additional blood pressure medications with evidence of a decrease in SBP. Propensity scores were calculated to reflect each individual's probability for future SBP less than 120 vs 120 to 139mmHg. MAIN OUTCOMES AND MEASURES The effect of SBP on all-cause mortalitywas evaluated by the log-rank test, and in Cox models adjusted for propensity scores. RESULTS Using a database of 651 749 patients with CKD, we identified 77 765 individuals meeting the inclusion criteria. A total of 5760 patients experienced follow-up treated SBP of less than 120mmHg and 72 005 patients had SBP of 120 to 139mmHg. During a median follow-up of 6.0 years, 19 517 patients died, with 2380 deaths in the SBP less than 120mm Hg group (death rate, 80.9/1000 patient-years [95%CI, 77.7-84.2/1000 patient-years]) and 17 137 deaths in the SBP 120 to 139mmHg group (death rate, 41.8/1000 patient-years [95% CI, 41.2-42.4/1000 patient-years]; P > .001). The mortality hazard ratio (95%CI) associated with follow-up SBP less than 120 vs 120 to 139mmHg was 1.70 (1.63-1.78) after adjustment for propensity scores. CONCLUSIONS AND RELEVANCE Our results suggest that stricter SBP control is associated with higher all-cause mortality in patients with CKD. Confirmation of these findings by ongoing clinical trials would suggest that modeling of therapeutic interventions in observational cohorts may offer useful guidance for the treatment of conditions that lack clinical trial data. © 2014 American Medical Association. All rights reserved.
Richardson S.I.,Columbia University |
Freedman B.I.,Section on Nephrology |
Ellison D.H.,Oregon Health And Science University
Journal of the American Society of Hypertension | Year: 2013
The purpose of this review is to summarize the available information regarding salt sensitivity particularly as it relates to non-Hispanic blacks and Hispanics and to clarify possible etiologies, especially those that might shed light on potential treatment options. In non-Hispanic blacks, there is evidence that endothelial dysfunction, reduced potassium intake, decreased urinary kallikrein excretion, upregulation of sodium channel activity, dysfunction in atrial natriuretic peptide (ANP) production, and APOL1 gene nephropathy risk variants may cause or contribute to salt sensitivity. Supported treatment avenues include diets high in potassium and soybean protein, the components of which stimulate nitric oxide production. Racial heterogeneity complicates the study of salt sensitivity in Hispanic populations. Caribbean Hispanics, who have a higher proportion of African ancestry, may respond to commonly prescribed anti-hypertensive agents in a way that is characteristic of non-Hispanic black hypertensives. The low-renin hypertensive phenotype commonly seen in non-Hispanic blacks has been linked to salt sensitivity and may indicate an increased risk for salt sensitivity in a portion of the Hispanic population. In conclusion, increased morbidity and mortality associated with salt sensitivity mandates further studies evaluating the efficacy of tailored dietary and pharmacologic treatment in non-Hispanic blacks and determining the prevalence of low renin hypertension and salt sensitivity within the various subgroups of Hispanic Americans.
Freedman B.I.,Section on Nephrology
Nature Reviews Nephrology | Year: 2016
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. © 2016 Macmillan Publishers Limited.
Pirkle J.L.,Section on Nephrology |
Freedman B.I.,Section on Nephrology
Minerva Urologica e Nefrologica | Year: 2013
The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.
Wright J.T.,Case Western Reserve University |
Williamson J.D.,Sticht Center on Aging |
Whelton P.K.,Tulane University |
Snyder J.K.,U.S. National Institutes of Health |
And 13 more authors.
New England Journal of Medicine | Year: 2015
BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. METHODS We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. RESULTS At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensivetreatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensivetreatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensivetreatment group than in the standard-treatment group. CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. © 2015 Massachusetts Medical Society.
Murea M.,Section on Nephrology
Advances in Chronic Kidney Disease | Year: 2012
Metabolic end products accumulate in kidney failure, including uric acid (UA), a terminal product of purine catabolism. Hyperuricemia (HUA) can cause gout and has been increasingly linked with cardiovascular (CV) morbidity and mortality, outcomes that are highly prevalent in patients with kidney disease. Serum UA levels rise as glomerular filtration declines, whereas the frequency of gouty attacks declines and the incidence of CV death rises precipitously. Herein, we review the kinetics of UA metabolism in CKD and dialysis and discuss the possible mechanisms of gout mitigation in kidney failure and the potential contribution of hyperuricemic milieu to CV outcomes in patients with kidney disease. © 2012 National Kidney Foundation, Inc.
Palmer N.D.,Center for Genomics and Personalized Medicine Research |
Freedman B.I.,Section on Nephrology
Current Diabetes Reports | Year: 2012
Diabetic nephropathy (DN) is a devastating complication of type 1 and type 2 diabetes and leads to increased morbidity and premature mortality. Susceptibility to DN has an inherent genetic basis as evidenced by familial aggregation and ethnic-specific prevalence rates. Progress in identifying the underlying genetic architecture has been arduous with the realization that a single locus of large effect does not exist, unlike in predisposition to non-diabetic nephropathy in individuals with African ancestry. Numerous risk variants have been identified, each with a nominal effect, and they collectively contribute to disease. These results have identified loci targeting novel pathways for disease susceptibility.With continued technological advances and development of new analytic methods, additional genetic variants and mechanisms (e.g., epigenetic variation) will be identified and help to elucidate the pathogenesis of DN. These advances will lead to early detection and development of novel therapeutic strategies to decrease the incidence of disease. © Springer Science+Business Media, LLC 2012.
Freedman B.I.,Section on Nephrology |
Skorecki K.,Molecular Medicine Laboratory
Clinical Journal of the American Society of Nephrology | Year: 2014
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. © 2014 by the American Society of Nephrology.
Murea M.,Section on Nephrology |
Ma L.,Section on Nephrology |
Freedman B.I.,Section on Nephrology
Review of Diabetic Studies | Year: 2012
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.
Fervenza F.C.,Rochester College |
Glassock R.J.,University of California at Los Angeles |
Bleyer A.J.,Section on Nephrology
Clinical Journal of the American Society of Nephrology | Year: 2013
Presentation of the Nephrology Quiz and Questionnaire (NQQ) has become an annual tradition at the meetings of the American Society of Nephrology. It is a very popular session, judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, to those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. The topic presented here is GN. Cases representing this category, along with single best answer questions, were prepared by a panel of experts (Drs. Fervenza, Glassock, and Bleyer). The correct and incorrect answers were then briefly discussed after the audience responses and the results of the questionnaire were displayed. This article recapitulates the session and reproduces its educational value for a larger audience-that of the readers of the Clinical Journal of the American Society of Nephrology. Have fun. © 2013 by the American Society of Nephrology.