Recruitment of African Americans with chronic renal insufficiency into a multicenter clinical trial: the african american study of kidney disease and hypertension

In patients with hypertensive nephrosclerosis, the African American Study of Kidney Disease and Hypertension (AASK) demonstrated the superiority of angiotensin-converting enzyme inhibitor therapy in blunting progression of renal disease compared with a b blocker and a dihydropyridine calcium channel blocker. In addition, the study found that a blood pressure treatment strategy that resulted in an achieved blood pressure of 128/78 mm Hg (low blood pressure goal) was no more effective in slowing the progression of renal disease than a strategy that resulted in a blood pressure of 141/85 mm Hg (usual blood pressure goal). AASK, which enrolled only African Americans with mild to moderate chronic renal insufficiency, also provided an opportunity to evaluate recruitment methods in minority populations. Eighty-three percent of patients were recruited through screening in clinical practice. To randomize 635 patients, 558,295 charts were reviewed (approximately 879 charts per randomized patient). More than half of the randomized patients (n=635 or 58%) were found by chart review. Sixty percent of women with creatinine levels considered within the normal range had at least mild chronic renal insufficiency. Screening in clinical practice was the most effective strategy to recruit participants with mild to moderate chronic renal insufficiency and hypertension into the clinical trial. This technique may also be an effective approach in trials of other essentially asymptomatic conditions.     

Risk factors for peripheral arterial disease among patients with chronic kidney disease

Patients with chronic kidney disease (CKD) have an increased risk for developing peripheral arterial disease (PAD). The aim of this study was to examine the cross-sectional association between novel risk factors and prevalent PAD in patients with CKD. A total of 3,758 patients with estimated glomerular filtration rates of 20 to 70 ml/min/1.73 m(2) who participated in the Chronic Renal Insufficiency Cohort (CRIC) study were included in the present analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, gender, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, estimated glomerular filtration rate, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios for a 1-SD higher level of risk factors were 1.18 (95% confidence interval [CI] 1.08 to 1.29) for log-transformed high-sensitivity C-reactive protein, 1.18 (95% CI 1.08 to 1.29) for white blood cell count, 1.15 (95% CI 1.05 to 1.25) for fibrinogen, 1.13 (95% CI 1.03 to 1.24) for uric acid, 1.14 (95% CI 1.02 to 1.26) for glycosylated hemoglobin, 1.11 (95% CI 1.00 to 1.23) for log-transformed homeostasis model assessment of insulin resistance, and 1.35 (95% CI 1.18 to 1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in patients with CKD.     

Fibroblast Growth Factor-23 and Cardiovascular Events in CKD

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2–4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m²). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2–4.CKD is an international public health epidemic that increases risk of premature death due to cardiovascular disease.^1–4 Rates of atherosclerotic disease are high in CKD, but risk of congestive heart failure is even more striking, with hazards approximately 3-fold higher than in non-CKD populations.^5,6 Excess risk of congestive heart failure in CKD is often attributed to hypertension and anemia.^6–9 However, aggressive control of these risk factors has not significantly improved heart failure outcomes in patients with CKD, suggesting additional mechanisms of disease.^10–12Fibroblast growth factor-23 (FGF-23) is secreted by osteocytes and regulates phosphate and vitamin D homeostasis by stimulating phosphaturia and inhibiting activation of vitamin D in the kidney.¹³ FGF-23 levels rise as kidney function declines, and higher levels are strongly associated with greater risk of death.^14–19 As a potential explanatory mechanism of FGF-23–associated mortality, multiple studies consistently demonstrated that higher FGF-23 levels are independently associated with greater risk of prevalent and incident left ventricular hypertrophy,^20–22 which is an important mechanism of cardiovascular disease in patients with CKD.⁸ In support of a causal role for elevated FGF-23 in the pathogenesis of left ventricular hypertrophy, FGF-23 stimulated pathologic hypertrophy of isolated cardiac myocytes and induced left ventricular hypertrophy in animals, independent of BP.²⁰ In contrast, observational studies reported conflicting results on the association of FGF-23 with arterial calcification, which is another prominent pattern of cardiovascular injury in CKD.²³ In the largest study to date, FGF-23 was not independently associated with coronary artery calcification in patients with CKD stages 2–4,²⁴ and laboratory studies failed to demonstrate a procalcification effect of FGF-23 on vascular smooth muscle cells.^24,25 These data suggest that direct effects of FGF-23 on cardiac remodeling, rather than the arterial vasculature, may underlie its association with mortality. We tested the hypotheses that elevated FGF-23 is a risk factor for cardiovascular disease events in patients with CKD stages 2–4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, and that FGF-23 is more strongly associated with risk of congestive heart failure compared with atherosclerotic events.     

Timing of dialysis initiation in transplant-naive and failed transplant patients

Over the past two decades, most guidelines have advocated early initiation of dialysis on the basis of studies showing improved survival in patients starting dialysis early. These recommendations led to an increase in the proportion of patients initiating dialysis with an estimated glomerular filtration rate (eGFR) >10 ml/min/1.73 m(2), from 20% in 1996 to 52% in 2008. During this period, the percentage of patients starting dialysis with an eGFR ≥15 ml/min/1.73 m(2) increased from 4% to 17%. However, recent studies have failed to substantiate a benefit of early dialysis initiation and some data have suggested worse outcomes for patients starting dialysis with a higher eGFR. Several reasons for this seemingly paradoxical observation have been suggested, including the fact that patients requiring early dialysis are likely to have more severe symptoms and comorbidities, leading to confounding by indication, as well as biological mechanisms that causally relate early dialysis therapy to adverse outcomes. Patients with a failing renal allograft who reinitiate dialysis encounter similar problems. However, unique factors associated with a failed allograft means that the optimal timing of dialysis initiation in failed transplant patients might differ from that in transplant-naive patients with chronic kidney disease. In this Review, we discuss studies of dialysis initiation and compare risks and benefits of early versus late initiation and reinitiation of dialysis therapy.     

Suppression of Grating Lobe Artifacts in Ultrasound Images Formed from Diverging Transmitting Beams by Modulation of Receiving Beams

In linear array transducers, owing to regular spacing of the array elements, grating lobes exist in transmission and reception. In ultrasonic imaging involving the use of diverging (unfocused) transmitting beams and steered receiving beams by linear transducer arrays, aperture apodization and spatial combination of steered receiving beams from multiple transmissions are not sufficient to suppress receive-grating lobe artifacts. To further suppress receive-grating lobe artifacts in reconstructed B-mode images, we propose a technique of modulating the receiving beams by a factor that is governed by the envelope of a corresponding signal, which is formed by filtering the receiving beam with a zero-phase low-pass filter with a cut-off frequency that is determined by the receiving beam steering angle. This technique suppressed receive-grating lobe artifacts without significant loss in spatial resolution in offline reconstructed B-mode images from simulation, phantom and in vivo imaging of the carotid artery. In a simulation of point scatterers, a relative reduction in grating lobe artifacts of 40 dB was realized in images from diverging beam scanning.