Phyllis August

A randomized trial of therapies for type 2 diabetes and coronary artery disease.

BACKGROUND Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. METHODS We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention. RESULTS At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003). CONCLUSIONS Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

Genetic thrombophilias and preeclampsia: A meta-analysis

OBJECTIVE: To assess the relationship between the factor V Leiden (1691 G-A) single nucleotide polymorphism (SNP), the methylene tetrahydrofolate reductase (MTHFR) 677 C–T SNP, and the prothrombin 20210 G-A SNP and the risk of preeclampsia, by conducting a meta-analysis of all case-control studies with data on these polymorphisms and the risk of preeclampsia. DATA SOURCES: MEDLINE (1966 to November 2002), EMBASE (1980 to November 2002). Search terms included “preeclampsia,” “thrombophilia,” “factor V Leiden,” “protein C,” “MTHFR,” “methylenetetrahydrofolate reductase,” “homocysteine,” and “prothrombin gene 20210.” METHODS OF STUDY SELECTION: Case-control studies of genetic thrombophilias and preeclampsia were included. TABULATION, INTEGRATION, AND RESULTS: We identified 349 titles and reviewed 47 articles for inclusion and exclusion criteria. Thirty-one studies with 7,522 patients were included in the meta-analysis. Data from patients characterized as having severe preeclampsia were extracted and analyzed separately. The pooled odds ratio (OR) for the association of factor V Leiden and all cases of preeclampsia was 1.81 (95% confidence interval [CI] 1.14–2.87) and 2.24 (95% CI 1.28–3.94) for cases of severe preeclampsia. The pooled OR for the MTHFR 677 TT genotype and all preeclampsia was 1.01 (95% CI 0.79–1.29) and 1.38 (95% CI 0.93–2.06) for severe preeclampsia. The OR for the prothrombin 20210 polymorphism and all preeclampsia was 1.37 (95% CI 0.72–2.57) and 1.98 (.94–4.17) for severe preeclampsia. CONCLUSION: This meta-analysis suggests that the factor V Leiden SNP is associated with an increased risk of preeclampsia. Further studies are warranted to determine whether subgroups of high-risk women should be screened for this mutation.

Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts

BACKGROUND The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. METHODS We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. RESULTS A three-gene signature of 18S ribosomal (rRNA)-normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operating-characteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer-Lemeshow test indicated good fit (P=0.77). In an external-validation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P=0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti-interleukin-2 receptor antibodies from those who received T-cell-depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P=0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). CONCLUSIONS A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts. (Funded by the National Institutes of Health and others.).

Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: Deviations related to the development of superimposed preeclampsia*

A prospective longitudinal study of 25 pregnant women (30 pregnancies) with chronic hypertension, a group prone to development of preeclampsia, was conducted to explore the relationship between the renin-angiotensin-aldosterone system and the development of superimposed preeclampsia. In women with chronic hypertension in whom preeclampsia did not develop (17 pregnancies), blood pressure decreased and the renin-angiotensin-aldosterone system was stimulated, beginning in the first trimester and continuing throughout pregnancy as found previously in normotensive pregnant women (n = 58). Plasma estradiol and progesterone levels also increased progressively. In women with chronic hypertension in whom preeclampsia developed (13 pregnancies), blood pressure decreased and the renin-angiotensin-aldosterone system was stimulated in the first trimester as in the other groups. However, later in pregnancy significant differences were observed. Blood pressure began to rise in the second trimester. Initially the renin-angiotensin-aldosterone system remained stimulated, but in the early third trimester, when preeclampsia was diagnosed, plasma renin activity and urine aldosterone excretion decreased, and atrial natriuretic factor increased. These data provide information that may be useful in the recognition of superimposed preeclampsia, and in the investigation of its pathogenesis.

Update on the Use of Antihypertensive Drugs in Pregnancy

As the most common medical disorder of pregnancy, hypertension is reported to complicate 1 in 10 pregnancies1,2 and affects an estimated 240 000 women in the United States each year.3 Antihypertensive treatment rationale in this group represents a departure from the nonpregnant adult Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.4 First, during pregnancy, the priority regarding hypertension is in making the correct diagnosis, with the emphasis on distinguishing preexisting (chronic) from pregnancy induced (gestational hypertension and the syndrome of preeclampsia). Second, much of the obstetric literature distinguishes blood pressure (BP) levels as either mild (140 to 159/90 to 109 mm Hg) or severe (≥160/110 mm Hg), rather than as stages (as in Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; Table 1). Third, in contrast to hypertension guidelines in adults, which emphasize the importance of systolic BP, much of the obstetric literature focuses on diastolic rather than systolic BP, in part because of the lack of clinical trials to support one approach versus another. The focus of treatment is the 9 months of pregnancy, during which untreated mild-to-moderate hypertension is unlikely to lead to unfavorable long-term maternal outcomes. In this setting, antihypertensive agents are mainly used to prevent and treat severe hypertension; to prolong pregnancy for as long as safely possible, thereby maximizing the gestational age of the infant; and to minimize fetal exposure to medications that may have adverse effects. During pregnancy, the challenge is in deciding when to use antihypertensive medications and what level of BP to target. The choice of antihypertensive agents is less complex, because only a small proportion of currently available drugs have been adequately evaluated in pregnant women, and many others …

TGF-β1 DNA Polymorphisms, Protein Levels, and Blood Pressure

Transforming growth factor-beta1 (TGF-beta1), a multifunctional cytokine with fibrogenic properties, has been implicated in the pathogenesis of the vascular and target organ complications of hypertension. TGF-beta1 may also regulate blood pressure via stimulation of endothelin-1 and/or renin secretion. Herein we explored the hypothesis that circulating levels of TGF-beta1 protein (quantified using a TGF-beta1-specific sandwich ELISA) are correlates of blood pressure levels. This hypothesis was tested in 98 stable end-stage renal disease (ESRD) patients. (The use of ESRD patients as the study cohort eliminates renal function-dependent alterations in circulating levels of TGF-beta1 protein.) In addition, in view of the previously reported correlation among TGF-beta1 DNA polymorphisms and systolic blood pressure, TGF-beta1 codon 25 genotype and alleles were identified in 71 hypertensive subjects and 57 normotensives using amplification refractory mutation system polymerase chain reaction. Our studies demonstrate for the first time that TGF-beta1 levels (209+/-13 ng/mL, mean+/-SEM) are positive correlates (Pearson correlation analysis) of mean arterial pressure (P=0.008), systolic pressure (P=0.02), and diastolic pressure (P=0. 01). We also report that a higher percentage of hypertensives (92%) compared with normotensives (86%) are homozygous for the arginine allele at codon 25. Our observations support the idea that genetically determined TGF-beta1 protein concentrations may play a role in blood pressure regulation in humans.

Prevention of recurrent pulmonary edema in patients with bilateral renovascular disease through renal artery stent placement

Pulmonary edema and congestive heart failure (both referred to here as PE) have been reported to be complications of bilateral renal artery stenosis or unilateral stenosis in a solitary functioning kidney (both referred to as BRAS). The goals of this study were to determine whether a history of PE was more common in patients with BRAS than in those with unilateral stenosis and a normal contralateral kidney (URAS), and whether recurrent PE could be prevented by renal artery stent placement. We evaluated 90 consecutive patients with renovascular disease who were treated with percutaneous renal artery stent placement. History and clinical follow-up were obtained through chart review and phone contact with referring physicians. Mean follow-up was 18.4 months after stent placement. Twenty-three of 56 (41%) subjects with BRAS had a history of PE before revascularization, compared with four of 34 (12%) subjects with URAS (P = .05). Twenty-five of the 27 patients with history of PE had adequate clinical follow-up. Seventeen of the 22 (77%) subjects with BRAS and history of PE had no further PE after stent placement in one or both renal arteries. The five BRAS subjects with recurrent PE after stent placement had evidence of stent thrombosis or restenosis. In contrast, only one of three (33%) URAS subjects with a history of PE remained free of PE after stent placement. We conclude that PE is a common complication of BRAS, but not of URAS. In patients with BRAS, recurrent PE can be prevented by successful stent placement in one or both renal arteries.

β-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects

Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during beta-blockade have not been defined. This study quantifies the effects of beta-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of beta-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. Beta-blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. Beta-blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that beta-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during angiotensin converting enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, beta-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of beta-blockers has important implications for the treatment of cardiovascular disease.

A Simple Algorithm to Predict Incident Kidney Disease

BACKGROUND Despite the growing burden of chronic kidney disease (CKD), there are no algorithms (to our knowledge) to quantify the effect of concurrent risk factors on the development of incident disease. METHODS A combined cohort (N = 14 155) of 2 community-based studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, was formed among men and women 45 years or older with an estimated glomerular filtration rate (GFR) exceeding 60 mL/min/1.73 m(2) at baseline. The primary outcome was the development of a GFR less than 60 mL/min/1.73 m(2) during a follow-up period of up to 9 years. Three prediction algorithms derived from the development data set were evaluated in the validation data set. RESULTS The 3 prediction algorithms were continuous and categorical best-fitting models with 10 predictors and a simplified categorical model with 8 predictors. All showed discrimination with area under the receiver operating characteristic curve in a range of 0.69 to 0.70. In the simplified model, age, anemia, female sex, hypertension, diabetes mellitus, peripheral vascular disease, and history of congestive heart failure or cardiovascular disease were associated with the development of a GFR less than 60 mL/min/1.73 m(2). A numeric score of at least 3 using the simplified algorithm captured approximately 70% of incident cases (sensitivity) and accurately predicted a 17% risk of developing CKD (positive predictive value). CONCLUSIONS An algorithm containing commonly understood variables helps to stratify middle-aged and older individuals at high risk for future CKD. The model can be used to guide population-level prevention efforts and to initiate discussions between practitioners and patients about risk for kidney disease.

Abnormal 1,25-dihydroxyvitamin D metabolism in preeclampsia

We previously reported that preeclampsia is associated with hypocalciuria (N Engl J Med 1987; 316:715). The purpose of this study was to determine whether alterations in calcium regulatory hormones are present in preeclampsia and, if so, whether they are responsible for hypocalciuria. Thirty-two pregnant women were studied in the second and third trimesters of pregnancy (11 women with preeclampsia, nine with chronic hypertension, and 12 normotensive women). 1,25-Dihydroxyvitamin D, C-terminal parathyroid hormone, ionized calcium, and urinary calcium excretion were measured. 1,25-Dihydroxyvitamin D was significantly lower in the women with preeclampsia in the third trimester when the disease developed (37.8 +/- 15 pg/ml) than in women with chronic hypertension (75 +/- 15 pg/ml, p less than 0.05) and normal women (65 +/- 10 pg/ml, p less than 0.05). Parathyroid hormone was higher, but not significantly, in those with preeclampsia. Ionized calcium was not significantly different among the three groups. Urinary calcium excretion was abnormally low for pregnancy (less than 50 mg/24 hr) in all but one women with preeclampsia. We conclude that 1,25-dihydroxyvitamin D is reduced in preeclampsia and may lead to hypocalciuria by causing decreased intestinal absorption of calcium, stimulation of parathyroid hormone, and increased distal renal tubular resorption of calcium. The cause of reduced 1,25-dihydroxyvitamin D in preeclampsia is unknown and may be due to either diminished renal or placental production of the hormone.