Showing papers by "Raymond R. Townsend published in 2003"

The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods

Abstract: Insights into end-stage renal disease have emerged from many investigations but less is known about the epidemiology of chronic renal insufficiency (CRI) and its relationship to cardiovascular disease (CVD). The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for progression of CRI and CVD among CRI patients and develop models to identify high-risk subgroups, informing future treatment trials, and increasing application of preventive therapies. CRIC will enroll approximately 3000 individuals at seven sites and follow participants for up to 5 yr. CRIC will include a racially and ethnically diverse group of adults aged 21 to 74 yr with a broad spectrum of renal disease severity, half of whom have diagnosed diabetes mellitus. CRIC will exclude subjects with polycystic kidney disease and those on active immunosuppression for glomerulonephritis. Subjects will undergo extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 mo intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens will be collected annually. (125)I-iothalamate clearances and CVD evaluations including a 12-lead surface electrocardiogram, an echocardiogram, and coronary electron beam or spiral CT will be performed serially. Analyses planned in CRIC will provide important information on potential risk factors for progressive CRI and CVD. Insights from CRIC should lead to the formulation of hypotheses regarding therapy that will serve as the basis for targeted interventional trials focused on reducing the burden of CRI and CVD.

Pheochromocytoma: The Expanding Genetic Differential Diagnosis

Abstract: Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.

Common questions and answers in the management of hypertension. Residual risk.

Abstract: VOL. V NO. V SEPTEMBER/OCTOBER 2003 362 If you treat a hypertensive patient with medication and reduce his or her blood pressure to a value >140 mm Hg systolic, do you reduce his or her cardiovascular risk to the same level as that of someone who has similar nonhypertensive risk factors (such as elevated cholesterol level or cigarette use) and a similar systolic blood pressure value without medication, or is there a residual risk? A scenario of residual risk with specific numbers is available at the National Institutes of Health Web site.1 Users can try the same set of risk factor data with and without indication of current use of blood pressure medication for the same systolic pressure value. When the medication query box for hypertension is checked yes, 1% or 2% is added to the 10-year risk. One might wonder why this is so and what this phenomenon is called. It is known as residual risk. Why it is so takes a little explanation. Numerous prospective drug treatment trials, meta-analyses, consensus statements, and notably the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)2 demonstrate or support unequivocal reductions in cardiovascular outcomes with control of hypertension. By design, these reports usually lack an estimate of residual risk because treatment trials may not enroll subjects without antecedent hypertension. To address residual risk it would be desirable to prospectively follow a large cohort of subjects, treat hypertension and other risk factors aggressively if and when they develop, and compare the cardiovascular outcomes of those patients who required antihypertensive therapy with those who did not. Such a study has not been done per se, but information can be extrapolated from the existing literature. The Prospective Studies Collaboration confirmed the graded, linear relationship of “usual” blood pressure to renal, electrolyte, and cardiovascular outcomes,3 and Alderman et al.4 demonstrated the relatively high residual risk for patients with well-controlled blood pressure. In their study they found that in controlled hypertensive patients, risk factor prevalence continues to exert a strong influence on the risk of cardiovascular disease. In addition, data from the Framingham Study5 underscores this notion by showing that long-term time-averaged blood pressure is a more useful predictor of cardiovascular risk than a few casual or usual measurements. Consequently, the current 10-year cardiovascular disease risk calculator available on the National Institutes of Health Web site1 asks not only for current systolic blood pressure but also includes the question, “Are you currently on any medication to treat high blood pressure?” to control for long-term time-averaged blood pressure because those on medication presumably had higher systolic blood pressures in the past. The clinical implications of this phenomenon are at least two-fold. First is the acknowledgment that successful blood pressure control reduces but does not eliminate cardiovascular risk. Second is the support it lends for focusing even greater effort on those with “prehypertension,” as recommended by JNC 72 because prevention of hypertension, when possible, is probably the best defense against residual risk in hypertension treatment.

Management of chronic kidney disease in an academic primary care clinic.

Abstract: Background: Three million people in the United States are estimated to have chronic kidney disease (CKD). Management of these CKD patients in the outpatient primary care clinic setting has not been well studied. Hypothesis: Primary care management of CKD can be assessed and opportunities for improvement can be identified. Methods: Management of CKD based on available published literature and guidelines was assessed in a single primary care site of an academic hospital with 23,000 annual visits and 8,300 patients. Charts of patients seen between October 1, 1997 and March 25, 1999 with an elevated SCr ≧1.7 mg/dl on two separate measurements at least 6 months apart were reviewed for predefined indicators of CKD management. Results: Assessment identified several aspects of CKD management to be suboptimal: control of blood pressure, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, assessment of proteinuria, and renal consultation. Better management was found with respect to hemoglobin A1c measurement for diabetic patients. In general, CKD care was similar for diabetic and non-diabetic patients. CKD management was also similar regardless of level of creatinine clearance (≧50 vs. 50–30 vs. ≤30 ml/min). Conclusion: CKD care can be measured in an outpatient academic primary care clinic and opportunities to improve were identified.

Acid-Base and Electrolyte Disorders. A Companion to Brenner & Rector's The Kidney

Abstract: DuBose T and Hamm L. 574 pages. Philadelphia: WB Saunders; 2002. $110.00. ISBN 0721689566. Order at www.us.elsevierhealth.com/. Field of medicine: Internal medicine, nephrology, and intensive care unit medicine. Format: Hardcover book. Audience: Nephrologists, intensivists, internists, residents, and medical students. Purpose: To provide a concise, practical, and clinical yet physiologic approach to electrolyte and acid-base disturbances and their treatment. Content: The book consists of 28 chapters divided into five sections: acid-base, water, sodium, potassium, and divalent ions. Highlights: DuBose and Hamm have enlisted a group of recognized gurus and pack a lot of current information into this high-quality book. The practical recommendations for treatment of edema states contain the coveted maximum intermittent dose guidelines in a table for diuretic therapy stratified by renal function. The coverage of genetic disorders of the epithelial sodium channel is current and informative, given the emerging importance of genomics in all medical specialties. Chapter 27 covers disorders of phosphate metabolism. In addition to lucid writing, the approaches to treatment of phosphate disorders and the mechanisms by which hyperphosphatemia contributes to vascular calcification are worth reading. There is no cross-pollination between the primary source (Brenner and Rector's The Kidney) and this book; thus, it provides some new insights and does not serve as a vehicle to simply repeat the figures and tables of the parent work. Limitations: This book is not for the casual reader. It's best to read after completion of Nephrology 101 (an introduction to renal physiologysee your local medical school for details). A brief look at whole-body acid-base regulation (chapter 1) will prompt the reader to hold incoming calls for a while; you definitely will not be able to quickly brush up by scanning chapters like this one just before patient care rounds. Related reading: There are many texts on acid-base and electrolyte physiology, such as Rose and Post's Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th edition (McGraw-Hill; 2000), and Halperin and Goldstein's Fluid, Electrolyte, and Acid-Base Physiology: A Problem-Based Approach, 3rd edition (WB Saunders; 1999), as well as the pertinent online segments in UpToDate (www.uptodate.comrequires a subscription). Reviewer: Raymond R. Townsend, MD, Renal Electrolyte Hypertension Stone Division, University of Pennsylvania, Philadelphia, Pennsylvania.

Angiotensin and insulin resistance: conspiracy theory.

Abstract: Resistance to the metabolic effects of insulin is a contender for the short list of major cardiovascular risk factors. Since the elements of the syndrome of insulin resistance were first articulated together in 1988, numerous epidemiologic investigations and treatment endeavors have established a relationship between the metabolic disarray of impaired insulin action and cardiovascular disease. Angiotensin II, the primary effector of the renin-angiotensin system, has also achieved a place in the chronicles of cardiovascular risk factors. Conspiracy mechanisms by which angiotensin II and insulin resistance interact in the pathogenesis of cardiovascular disease are reviewed, with particular attention to recent developments in this engaging area of human research.

Guiding lights for antihypertensive treatment in patients with nondiabetic chronic renal disease: proteinuria and blood pressure levels?

Abstract: In this issue, Jafar and colleagues address three questions about the management of patients with nondiabetic kidney disease and hypertension: Does the amount of urinary protein affect outcomes? Ar...

Blood pressure measurement: Common pitfalls-and how to avoid them

Abstract: The most common errors in measuring blood pressure (BP) are using the incorrect cuff size, not having the patient relax for 5 minutes before the measurement, and deflating the cuff too quickly. Observer bias may compound technical errors. When patients use the proper procedure, home BP measurements may be more reproducible than office measurements. Brachial artery-based monitors are more accurate than finger- or wrist-based instruments. To ensure that patients measure their BP correctly, observe their technique with their own monitors. Counsel patients to measure their BP at predetermined times and to have their monitors validated periodically.

The forgetful hypertensive patient.

Abstract: THE JOURNAL OF CLINICAL HYPERTENSION 89 With the growing importance of disorders like Alzheimer’s disease, and the natural apprehension that stalks patients each time they forget something, it is common to look for a correctable cause of memory slippage and a natural target is medication. This raises the question: Do antihypertensive drugs impair memory? Some antihypertensive medication package inserts mention memory loss in the adverse event sections. For example, several of the β blocker inserts include “short-term memory loss” under central nervous system effects. However, the effects of drugs are probably overshadowed by the substantial role that blood pressure itself plays in ultimate cognitive decline. There appear to be at least two lessons in this story. The first is that the cognitive decline evident in the 70-year-old patient is associated with blood pressures when the patient was 40 or 50 years old,1 underscoring hypertension as a risk factor for later cognitive decline and memory loss. The second lesson is that antihypertensive therapy generally helps, rather than attenuates, cognitive function preservation. This latter finding was evident in the Systolic Hypertension in Europe (Syst-Eur)2 study in which older subjects with systolic hypertension treated with a calcium channel blocker-based regimen compared with a placebobased regimen were found to have half the incidence of dementia over the next 4 years. At the recent 24th Congress of the European Society of Cardiology meetings two interesting additional studies have “raised the bar” with respect to this issue. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) used an angiotensin-converting enzyme inhibitor-diuretic regimen to treat patients who already had a stroke.3 In addition to reducing subsequent stroke occurrence, this study showed a protection of cognitive function in the treatment group. Interestingly, this protection extended even to the nonhypertensive patients treated with drug therapy. The Study on Cognition and Prognosis in the Elderly (SCOPE) trial tested the effectiveness of an angiotensin receptor blocker against a diuretic in 70–89-year-old hypertensives. The findings from the SCOPE trial are thought-provoking because it purports that angiotensin receptor blocker treatment has a strong favorable effect to preserve memory and cognitive function even at the extreme of age and in patients with some prior cognitive impairment.3 The last comment is that it isn’t clear that drug therapy for hypertension induces memory loss. In a most recent investigation specifically addressing this, data suggests that the jury is still out.4 If anything, when objectively tested, drug therapy appeared to maintain or improve cognitive function in hypertensives, and in this study two different β blockers were employed.4 However, we are learning that not all antihypertensive medications confer equal amounts of benefit despite similar degrees of blood pressure reduction, and it is probable that differences in outcomes like dementia will become increasingly evident as more is learned about the connections between elevated blood pressure and cognitive ability.

Am I More Likely to Develop Diabetes If I Have High Blood Pressure

Abstract: THE JOURNAL OF CLINICAL HYPERTENSION 175 Three recent hypertension trials have pointed out a disparity in the likelihood of diabetes developing when ramipril,1 captopril,2 or losartan3 are used in comparison with either conventional β blocker therapy,3 diuretic therapy,2 or placebo.1 In the treatment of high blood pressure the recognition that insulin resistance, a precursor to type 2 diabetes, commonly occurs in hypertensive patients4 represents more evidence in favor of a greater chance of diabetes if a person is hypertensive. But, how often do patients with hypertension develop diabetes? The reason we muse about such issues relates to the well-known and substantial additional cardiovascular risk that the presence of diabetes attaches to the hypertensive patient. In a recent prospective cohort study that included more than 12,000 adults, the development of type 2 diabetes was nearly 2.5-times more likely in patients with hypertension compared with normotensive counterparts.5 Other studies, such as those of Hayashi et al.6 and Grodzicki et al.7 corroborate this finding on different continents. This isn’t all that surprising when we consider that a large number of patients with hypertension are above ideal body weight and often have evidence of insulin resistance.4 However, more distressing is the concern regarding how often diabetes develops as a result of antihypertensive therapy and whether the background of the patients (overweight, insulin resistant) places them at higher risk of drug-induced (or is it drug enabling?) diabetes. This is a much more challenging question. In the afterglow of the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT), this probably is not the best time to resurrect an old controversy about the effect of diuretics (and β blockers) on glucose metabolism; however, there does appear to be a relationship between diuretic8 and β blocker4 usage and diabetes development. In ALLHAT it was evident that diureticbased therapy did have somewhat higher glucose levels at the end of the study compared with either calcium channel blocker or angiotensin-converting enzyme (ACE)-inhibitor treatment.8 What do we do with this information? There are several possibilities. First, we share this knowledge with patients hoping it motivates them when we suggest they make lifestyle changes that could both reduce blood pressure levels and diabetes risk. Second, we make a mental note to watch their biochemical values a little more closely (and perhaps more often) after initiating therapy and avoid the tendency to attribute complaints of urinary frequency to the diuretic without at least considering that the diuretic effect may be osmotic rather than thiazide-based. Whether the use of an ACE inhibitor or an angiotensin receptor blocker should be preferred in the hypertensive at risk for diabetes is best left for the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). But we should remember the ALLHAT results, which reported benefit of diuretic therapy in both diabetics and nondiabetics.

Is Funduscopy Clinically Useful in the Evaluation of the Hypertensive Patient

Abstract: THE JOURNAL OF CLINICAL HYPERTENSION 421 In the last two decades, all disciplines of medicine have witnessed a surge of emphasis on evidencebased medicine. Increasingly, components of the physical examination that had traditionally been viewed as essential are being scrutinized under the magnifying glass of “clinical evidence.” Consequently, practitioners who are under considerable time constraints are condensing their physical exams, deleting those items that lack sufficient data supporting their routine use. This raises the issue of whether examination of the retina is clinically useful in the evaluation of the hypertensive patient. In 1850, Hermann von Helmholtz invented the ophthalmoscope. Nine years later Liebreich was the first to describe abnormalities of the retina in a patient with probable hypertension. Subsequently, the spectrum of hypertensive retinopathy was described to include grades I (focal arteriolar constriction), II (generalized arteriolar constriction), III (flame-shaped hemorrhages, cotton wool spots, and yellow-white exudates), and IV (papilledema accompanied by hemorrhages and exudates). More recently, a revised classification of hypertensive retinopathy has been proposed, consisting of only two grades: I (arteriolar narrowing, focal constriction, and arteriovenous nicking) and II (hemorrhages and exudates, with or without disc edema).1 It is often difficult to detect early change of grade I retinopathy, i.e., focal constriction or arteriolar narrowing. The prevalence of hypertensive retinopathy has only recently been described. The Beaver Dam Eye Study1 and the Blue Mountains Eye Study3 have reported a prevalence of retinopathy of 8%–10% among nondiabetic hypertensive patients. The incidence increases with age and severity (or poor control) of hypertension. The clinical significance of hypertensive retinopathy was not apparent until 1939, when a group of physicians at the Mayo Clinic classified hypertensive patients based on the severity of retinal disease and showed that those with more severe disease had higher morbidity and mortality. Subsequent reports have shown a correlation between the presence of hypertensive retinopathy and lower glomerular filtration rates as well as with the presence of left ventricular hypertrophy. Though there are case reports of hypertensive retinopathy progressing to blindness,4 either directly (via retinal infarction, retinal hemorrhage, disc edema, or vitreous hemorrhage) or indirectly (via infarction of the visual cortex or optic nerve, occlusion of retinal vessels, or raised intracranial blood pressure), hypertensive retinopathy is not a major cause of blindness. Most of the case reports are in patients with severe, malignant hypertension, including those whose blood pressures were lowered too rapidly. Thus, hypertensive retinopathy might be viewed as more of a marker for other cardiovascular outcomes, rather than as a true cardiovascular outcome in its own right. It is grouped together with “true” cardiovascular outcomes under the category of “target organ damage” in the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), though the authors recommend antihypertensive therapy based on bloodpressure level without regard to the presence or Is Funduscopy Clinically Useful in the Evaluation of the Hypertensive Patient?

Can I Stop Taking This Blood Pressure Medicine

Abstract: VOL. V NO. III MAY/JUNE 2003 234 Although great emphasis is placed in clinical practice on methods to encourage patients to continue (or even increase) their antihypertensive medication, patients often ask if they “really need this drug.” Hypertension is usually not curable, and if untreated leads to premature target organ damage, so our usual response is to assure patients that they really do need this (or these) drug(s). Possibly, though, an occasional patient who was started on antihypertensive medication no longer needs drug therapy. How might you suspect that? The question is not without interest in the literature. Several studies have addressed antihypertensive drug withdrawal in treated patients. A recent systematic review of these studies1 confirms what we have used as rule-of-thumb indicators to predict which patients could be considered for step-down therapy (less medication) or drug discontinuation. In many patients hypertension is weight-related. If someone has lost 15 pounds (or more), and had modest elevations in blood pressure before therapy, that patient may be a candidate for drug reduction. The same is true regarding salt intake, though my experience has been that weight loss is a more potent blood pressure reduction measure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)2 also supports antihypertensive drug reduction particularly in conjunction with successful lifestyle modification. Patients with consistently low blood pressures in the office (I use a rough guide of <120 mm Hg systolic in nondiabetics) may be candidates for drug reduction. Well-controlled hypertensive patients on a single drug, particularly in a low dose, may also be candidates for drug reduction or a trial of discontinuation. The study I remember most clearly which addresses the role of dietary factors and medication reduction3 showed that hypertensive patients who remained normotensive after discontinuing drug therapy did so when they were well coached and successful at lifestyle modification (about one half of the patients were still off medication at 3 years; this was group I in the study). When no targeted attempt was made to intervene with lifestyle changes about five out of six patients became hypertensive again within 3 years after discontinuing drug treatment (this was group II in the study; they functioned as the control group). The important thing in pursuing drug reduction is vigilant monitoring, either through one’s office or in the patient’s home if they take home blood pressures. Nothing is without risk; although, the cardiovascular risks are small in otherwise healthy hypertensive patients without target organ damage. Keep in mind that it may take months or even years for hypertension to recur. Motivation is a wonderful thing. Some patients maintain lifestyle changes indefinitely and are still controlled on less medicine, or even off drug therapy, for a long time.

Comprehensive Proteomic Analysis of Breast Cancer Cell Membranes Reveals Unique Proteins with Potential Roles in

Abstract: Proteins associated with cancer cell plasma membranes are rich in known drug and antibody targets as well as other proteins known to play key roles in the abnormal signal transduction processes required for carcinogenesis. We describe here a proteomics process that comprehensively annotates the protein content of breast tumor cell membranes and defines the clinical relevance of such proteins. Tumor-derived cell lines were used to ensure an enrichment for cancer cell-specific plasma membrane proteins because it is difficult to purify cancer cells and then obtain good membrane preparations from clinical material. Multiple cell lines with different molecular pathologies were used to represent the clinical heterogeneity of breast cancer. Peptide tandem mass spectra were searched against a comprehensive data base containing known and conceptual proteins derived from many public data bases including the draft human genome sequences. This plasma membrane-enriched proteome analysis created a data base of more than 500 breast cancer cell line proteins, 27% of which were of unknown function. The value of our approach is demonstrated by further detailed analyses of three previously uncharacterized proteins whose clinical relevance has been defined by their unique cancer expression profiles and the identification of proteinbinding partners that elucidate potential functionality in cancer.