Hypertension-related Renal Disease Research Articles

A Classification Model to Predict the Rate of Decline of Kidney Function.

The African American Study of Kidney Disease and Hypertension (AASK), a randomized double-blinded treatment trial, was motivated by the high rate of hypertension-related renal disease in the African-American population and the scarcity of effective therapies. This study describes a pattern-based classification approach to predict the rate of decline of kidney function using surface-enhanced laser desorption ionization/time of flight proteomic data from rapid and slow progressors classified by rate of change in glomerular filtration rate. An accurate classification model consisting of 7 out of 5,751 serum proteomic features is constructed by applying the logical analysis of data (LAD) methodology. On cross-validation by 10-folding, the model was shown to have an accuracy of 80.6 ± 0.11%, sensitivity of 78.4 ± 0.17%, and specificity of 78.5 ± 0.16%. The LAD discriminant is used to identify the patients in different risk groups. The LAD risk scores assigned to 116 AASK patients generated a receiver operating curves curve with AUC 0.899 (CI 0.845–0.953) and outperforms the risk scores assigned by proteinuria, one of the best predictors of chronic kidney disease progression.

Mitochondria: a pathogenic paradigm in hypertensive renal disease.

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

The Effect of Aldosterone on the miRNA Content of a Murine Inner Medullary Collecting Duct Cell

MicroRNAs (miRNAs) are a family of small noncoding RNAs that have been shown to regulate gene expression by inhibiting translation or targeting specific mRNAs for degradation. miRNAs play important roles in the regulation of metabolism in the healthy cell and in the pathogenesis of many diseases including diabetic nephropathy and hypertension‐related renal disease.Aldosterone is the major known hormone responsible for sodium retention in the kidney collecting duct. Our working hypothesis is that aldosterone action alters the miRNA content in the inner medullary collecting duct resulting in increased translation and stabilization of mRNAs involved in sodium reabsorption.Here we report the miRNA landscape in mIMCD‐3 cells using Toray 3D‐GeneTM miRNA microarray analysis to evaluate 1080 miRNAs. Microarray analysis identified 35 highly expressed miRNAs, as well as several miRNAs whose levels appear to be affected by the presence of aldosterone. Two aldosterone responsive miRNAs affected levels of serum/glucocorticoid regulated kinase 1and sodium/potassium‐transporting ATPase subunit beta‐1 mRNA. Argonaute pull‐down experiments also demonstrated that endothelin‐1 mRNA is a target of the RNA‐induced silencing complex indicating miRNA action on this transcript.This work was supported by NIH NIDDK 1RO1DK082680 to B.D.C and C.S.W. and a 5T32DK076541–04 pre‐doctoral fellowship to M.E.J. Additional funding support and miRNA microarrays were provided by Toray Industries, Inc.

Abstract 161: Identification of Genetic Variants Associated with Kidney Injury That Leads to Increased Blood Pressure

Hypertension, diabetes and obesity, along with genetic predisposition, contribute to the growing number of chronic kidney disease patients. Our novel congenic model [S.SHR(11)] was developed through genetic modification of the Dahl salt-sensitive (S) rat, a model of hypertension related renal disease. The S.SHR(11) strain exhibits accelerated kidney injury compared to the already highly susceptible S rat. On either a low or high-salt diet, the S.SHR(11) model predominately exhibited more tubulointerstitial fibrosis compared to the S rat (17.1±1.29% vs. 12.9±1.22%). Increased α-SMA and macrophage infiltration was also observed. The S and S.SHR(11) had similar blood pressure (week 12), despite an early reduction in renal function in the S.SHR(11); however at an advanced age the S.SHR(11) demonstrated significantly higher blood pressure than the S (215±6.6 mm Hg vs. 183±5.9, respectively). This suggests that increased kidney injury is driving the development of hypertension later in life. Since these two animal models are identical with exception of chromosome 11, the causative genetic variants contributing to decreased renal function must reside within this region. The Dahl S and SHR genomes have been sequenced; this data provides a catalog of all the genetic variants between the two models. The 95% confidence interval of the genomic locus contains 28 non-synonymous SNP, with 15 of these SNP occurring within only three genes: Retnlg , Trat1 and Myh15. Two of these genes, Retnlg and Trat1, are known to play a role in immune response leading to our hypothesis that genetic variants in these genes alter protein function and lead to an increased immune response. Bone marrow transplant studies have been initiated to test our hypothesis and preliminary data shows that S rats who receive S.SHR(11) bone marrow have kidney function measurements similar to the S.SHR(11). The sequencing information has also lead to the development of nine new, more refined congenic strains. Through functional analysis of these new congenic animals, identification of the causative genetic variations will be expedited. In summary, we are employing a model of accelerated kidney disease to identify genes or genetic variants responsible for reduced kidney function and hypertension.

Renal autoregulation and passive pressure-flow relationships in diabetes and hypertension

We investigated renal hemodynamics in isolated, perfused kidneys from rat models of diabetes and hypertension. Autoregulation and passive vascular responses were measured using stepped pressure ramps in the presence of angiotensin II (pEC50) or papaverine (0.1 mM), respectively. Male diabetic heterozygote m(Ren2)27 rats were compared with three male control groups: nondiabetic, normotensive Sprague-Dawley (SD) rats; nondiabetic, hypertensive heterozygote m(Ren2)27 rats; and diabetic, normotensive SD rats. Kidney function (proteinuria, creatinine clearance) was monitored before induction and at monthly intervals. Vascular function was measured in vitro in rats of induction age (6-8 wk) and at 2 and 4 mo postinduction. Renal flow correlated with age, but not diabetes or the Ren2 gene. Kidney weight-specific and body weight-specific renal flow differed between diabetic and nondiabetic rats because diabetic rats had higher kidney but lower body weights. Kidneys from all groups showed effective autoregulation in the presence of angiotensin II. The autoregulatory pressure threshold of m(Ren2)27 rats was higher, and the autoregulation pressure range was wider, compared with SD rats. When vascular smooth muscle activity was blocked with papaverine, pressure-flow responses differed between groups and with time. The m(Ren2)27 rat groups showed higher renal vascular resistance at lower pressures, suggesting greater vascular stiffness. In contrast, diabetic SD rat kidneys demonstrated reduced vessel stiffness. Flow was impaired in diabetic m(Ren2)27 rats at 4 mo, and this correlated with a decline in creatinine clearance. The results suggest that the characteristic late decline in renal filtration function in diabetes- and hypertension-related renal disease follows changes in renal vascular compliance.

The Enigma of Hypertensive ESRD: Observations on Incidence and Trends in 18 European, Canadian, and Asian-Pacific Populations, 1998 to 2002

Despite improved treatment of hypertension and decreasing rates of stroke and coronary heart disease, the reported incidence of hypertensive end-stage renal disease (ESRD) increased during the 1990s. However, bias, particularly from variations in acceptance into ESRD treatment (ascertainment) and diagnosis (classification), has been a major source of error when comparing ESRD incidences or estimating trends. Age-standardized rates were calculated in persons aged 30 to 44, 45 to 64, and 65 to 74 years for 15 countries or regions (separately for the Europid and non-Europid populations of Canada, Australia, and New Zealand), and temporal trends were estimated by means of Poisson regression. For 10 countries or regions, population-based estimates of mean systolic blood pressures and prevalences of hypertension were extracted from published sources. Hypertensive ESRD, comprising ESRD attributed to essential hypertension or renal artery occlusion, was least common in Finland, non-Aboriginal Australians, and non-Polynesian New Zealanders; intermediate in most European and Canadian populations; and most common in Aboriginal Australians and New Zealand Maori and Pacific Island people. Rates correlated with the incidence of all other nondiabetic ESRD, but not with diabetic ESRD or community rates of hypertension. Between 1998 and 2002, hypertensive ESRD did not increase in Northwestern Europe or non-Aboriginal Canadians, although it did so in Australia. Despite the likelihood of classification bias, the probability remains of significant variation in incidence of hypertensive ESRD within the group of Europid populations. These between-population differences are not explained by community rates of hypertension or ascertainment bias.

Ambulatory blood pressure during diseases of the kidney

During the last few years there has been a renewal of interest in blood-pressure-induced kidney damage due to a progressive increase in the incidence and prevalence of hypertension and vascular diseases as a cause of end-stage renal disease (ESRD). The need to prevent ESRD demands a continuation of effort to make the early identification of hypertensives who are at risk possible and to provide them with effective antihypertensive therapy. Since ambulatory blood pressure monitoring has been used successfully to assess blood pressure and identify risk markers for cardiovascular diseases, a logical approach would be to use it also to identify the risk markers for ESRD. Higher than normal percentages of non-dippers have been found among subjects with renal failure, during dialysis (haemofiltration, peritoneal dialysis and continuous ambulatory peritoneal dialysis), among cases of renovascular hypertension or cystic kidney disease and among cases of renal transplantation. Although this non-dipping pattern might be related to the presence of severe hypertension in some patients, such as those who have renovascular hypertension, in other cases the abnormal circadian variability is present with milder forms of hypertension or even in the absence of hypertension. Monitoring ambulatory blood pressure could offer advantages for protection of renal function during antihypertensive treatment of subjects with mild renal insufficiency. Furthermore, ambulatory blood pressure monitoring seems to have been prognostic for the development of proteinuria in a group of refractory hypertensives. Whether higher than normal nocturnal blood pressures and the non-dipping pattern are causes or consequences of renal disease should be addressed in prospective studies. The above notwithstanding, assessment of nocturnal blood pressure seems to be an important aid in the management of patients with hypertension-related renal disease and of patients who are susceptible to developing it.

Nephroprotective effect of antihypertensive drugs in essential hypertension.

Effective antihypertensive treatment has prevented target-organ involvement in hypertension, markedly reducing morbidity and mortality from strokes, coronary heart disease, cardiac failure, and hypertensive emergencies. However, the incidence of hypertension-related end-stage renal disease continues to increase, suggesting that therapeutic reduction in arterial pressure by itself is not sufficient to prevent the development of hypertensive renal failure. To examine experimental and clinical data concerning the protective effect of reduction of arterial pressure on the progression of hypertension-related renal disease, and the evidence indicating that some antihypertensive agents may afford more nephroprotection, over and above that attributable to reduction of arterial pressure. Results of numerous studies clearly indicate that adequate control of arterial pressure, irrespective of the antihypertensive agent used, slowed the progression of renal disease. Results of some studies suggest that lowering arterial pressure below the level that is usually considered adequate has an additional beneficial effect by slowing the progression of renal injury. Results of a number of studies evaluating nephroprotective effects of various drugs and regimens have indicated that certain agents, most notably angiotensin converting enzyme inhibitors and their combination with calcium antagonists, afford more protection than do others at similar levels of reduction of arterial pressure. Results of still other studies suggest that certain agents that exert greater nephroprotection are more efficient at controlling arterial pressure. Therefore, further data are needed before any final conclusion can be drawn. However, it is clear that, in order to establish nephroprotection in patients with essential hypertension, the problem should not be further complicated by additional comorbid diseases such as diabetes mellitus.

Correlates of health care satisfaction in inner-city patients with hypertension and chronic renal insufficiency

Barriers to effective health care are potential contributors to the increased prevalence of hypertension and hypertension-related renal disease observed in black patients. We have enrolled 333 primarily elderly (mean age 69 years) black (87%) patients with hypertension and chronic renal insufficiency into a prospective randomized trial testing the effect of intense multidisciplinary management on progression of chronic renal insufficiency. These patients have an average 6 years of education and $400–$800 monthly household income; 57% have diabetes. Our baseline data include the Patient Satisfaction Questionnaire administered by home interviewers who also recorded sociodemographic data, medications and questionnaires regarding medication compliance and symptoms related to anti-hypertensive drugs. Inpatient and outpatient vital signs, test results and diagnoses came from patients' computerized medical records. We used multiple linear regression to identify correlates of overall satisfaction. We also analyzed three subscales: access to care, financial aspects and interpersonal manner of physicians. We included only variables with univariate correlations ( P < 0.05) in the models. Decreased overall satisfaction correlated with more symptoms related to anti-hypertensive drugs ( P < 0.001), lower medication compliance ( P = 0.01), and higher diastolic blood pressure ( P = 0.08). Decreased satisfaction with access to care correlated with more symptoms related to anti-hypertensive drugs ( P < 0.001) and decreased medication compliance ( P = 0.08). Decreased satisfaction with financial aspects of care correlated with more symptoms related to anti-hypertensive drugs ( P < 0.001), lower medication compliance ( P = 0.01) and more proteinuria ( P = 0.02). Finally, decreased satisfaction with interpersonal manner of physicians correlated with lower medication compliance ( P < 0.001), lower albumin ( P = 0.01) and sodium ( P = 0.04), and higher diastolic blood pressure ( P = 0.04). These cross-sectional baseline data describe a group of mostly black inner-city patients with hypertension and chronic renal insufficiency in whom decreased satisfaction with care correlates with decreased medication compliance, increased symptoms related to anti-hypertensive drug therapy, higher diastolic blood pressure and more proteinuria. Our prospective study may help determine whether improving satisfaction improves compliance and blood pressure control, and forestalls complications in this high-risk population.

Renal hemodynamics in essential hypertension. Racial differences in response to changes in dietary sodium.

Previous studies have suggested striking racial differences in hypertension-related renal disease. To explore potential mechanisms responsible for these differences, we investigated changes in renal hemodynamics in white and black essential hypertensive patients in response to alterations in dietary sodium. Patients were untreated, age-matched, and blood pressure-matched white (n = 59) and black (n = 22) males with essential hypertension. Studies were conducted on an inpatient metabolic ward and included assessment of blood pressure, urinary sodium excretion, glomerular filtration rate, renal plasma flow, and renal blood flow after 5 days each of high and low salt diets. In response to high dietary salt intake, both white and black patients demonstrated significantly higher mean arterial pressure, renal plasma flow, and renal blood flow, and there were no racial differences in the changes in these parameters. However, whites and blacks differed significantly in glomerular filtration rate, with black hypertensive patients showing an increase in glomerular filtration rate (+17.3 +/- 5.3 mL/min per 1.73 m2, F = 7.586, P = .007) and white hypertensive patients showing no change (-0.2 +/- 3.3 mL/min per 1.73 m2) in response to high dietary sodium. These data demonstrate racial differences in the autoregulation of glomerular filtration rate in response to changes in dietary sodium. These differences suggest that glomerular hyperfiltration in response to a high salt diet may be a mechanism contributing to the racial disparity in hypertension-related renal disease.

The epidemiology of hypertension-related renal disease.

An increasing number of population-based studies and clinical trials have examined the role of blood pressure in renal disease. Recent reports indicate that elevations of blood pressure, even within the normotensive range, may result in renal damage. The available evidence suggests that blood pressure reduction diminishes and may completely prevent the progressive deterioration of renal function in persons with established renal insufficiency. Blood pressure reduction with an angiotensin-converting enzyme inhibitor may provide the best means of achieving this goal, but other antihypertensive medications may be equally effective. Nonpharmacologic interventions can be used to lower blood pressure in hypertensive persons and prevent the development of hypertension in those with blood pressure in the high-normal range. Other recent studies examined the role of environmental nephrotoxins, unrecognized viral infections, lower socioeconomic status, access to health care, and genetic factors as determinants of renal disease and hypertension in the general population. Despite their overall importance, known risk factors for hypertension-related renal disease fail to explain the excess risk of this entity in blacks and other racial minorities.

Projections of hypertension-related renal disease in middle-aged residents of the United States

<h3>Objective.</h3> —To establish nationwide projections for hypertension-related renal disease among middle-aged residents of the United States and compare disease burden in demographic subgroups. <h3>Design.</h3> —Integrated analysis of data from the US Census, the National Health and Nutrition Examination Survey of 1976 through 1980 (NHANES II), the 1971 through 1975 NHANES I Epidemiologic Follow-up Study, the Hypertension Detection and Follow-up Program trial, and the US Renal Data System. <h3>Population.</h3> —African-American and white residents of the United States, aged 30 to 69 years. <h3>Main Outcome Measures.</h3> —Incidence rates and counts of hypertension, hypertension-related hypercreatinemia, and hypertension-related end-stage renal disease (ESRD). <h3>Results.</h3> —Each year, approximately 1.8 million middle-aged Americans develop hypertension, 140000 develop hypertension-related hypercreatinemia, and 5300 develop hypertension-related ESRD. African Americans are at increased risk for hypertension (relative risk [RR], 1.6; population-attributable risk [PAR], 5%), hypercreatinemia if hypertensive (RR, 2.4; PAR, 18%), ESRD if hypertensive with hypercreatinemia (RR, 2.7; PAR, 32%), and hypertension-related ESRD overall (RR, 8.0; PAR, 44%). Compared with women, men are at increased risk for hypertension (RR, 1.3; PAR, 13%) and hypertension-related ESRD (RR, 1.6; PAR, 23%). Most cases of hypercreatinemia in hypertensives (73%) occur among those with mild hypertension. <h3>Conclusions.</h3> —Progression to ESRD is rare in persons with hypertension-related renal disease, and factors other than blood pressure probably play an important role. A large proportion of hypertension-related renal disease cases occur among population subgroups considered to be at low risk. Interventions that favorably influence factors associated with the progression of hypertension-related renal disease in African Americans, in men, and in persons with mild hypertension, hold the greatest potential for reducing the population burden of hypertension-related ESRD. (<i>JAMA</i>. 1993;269:1272-1277)

Projections of Hypertension-Related Renal Disease in Middle-aged Residents of the United States

To establish nationwide projections for hypertension-related renal disease among middle-aged residents of the United States and compare disease burden in demographic subgroups. Integrated analysis of data from the US Census, the National Health and Nutrition Examination Survey of 1976 through 1980 (NHANES II), the 1971 through 1975 NHANES I Epidemiologic Follow-up Study, the Hypertension Detection and Follow-up Program trial, and the US Renal Data System. African-American and white residents of the United States, aged 30 to 69 years. Incidence rates and counts of hypertension, hypertension-related hypercreatinemia, and hypertension-related end-stage renal disease (ESRD). Each year, approximately 1.8 million middle-aged Americans develop hypertension, 140,000 develop hypertension-related hypercreatinemia, and 5300 develop hypertension-related ESRD. African Americans are at increased risk for hypertension (relative risk [RR], 1.6; population-attributable risk [PAR], 5%), hypercreatinemia if hypertensive (RR, 2.4; PAR, 18%), ESRD if hypertensive with hypercreatinemia (RR, 2.7; PAR, 32%), and hypertension-related ESRD overall (RR, 8.0; PAR, 44%). Compared with women, men are at increased risk for hypertension (RR, 1.3; PAR, 13%) and hypertension-related ESRD (RR, 1.6; PAR, 23%). Most cases of hypercreatinemia in hypertensives (73%) occur among those with mild hypertension. Progression to ESRD is rare in persons with hypertension-related renal disease, and factors other than blood pressure probably play an important role. A large proportion of hypertension-related renal disease cases occur among population subgroups considered to be at low risk. Interventions that favorably influence factors associated with the progression of hypertension-related renal disease in African Americans, in men, and in persons with mild hypertension, hold the greatest potential for reducing the population burden of hypertension-related ESRD.