MANAGEMENT AND TREATMENT OF

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1 CKD MANAGEMENT AND TREATMENT OF Chronic Kidney Disease Estimates suggest that 30 million Americans have some degree of chronic kidney disease. By 2030, more than 2.2 million people will require treatment for end-stage renal disease, causing a significant impact on healthcare costs in the United States. Nelson Kopyt, DO, FACP, FASN C hronic kidney disease (CKD) is a major public health concern that is underdiagnosed in the United States. 1 The early stages of CKD and the incidence and prevalence of kidney failure are increasing in the United States, due in part to the aging population and the rising rates of diabetes. 1-3 The 2007 report of the United States Renal Data System (USRDS) uses data up to 2005 from the National Health and Nutritional Examination survey, including people over the age of 20 years. The prevalence of the disease increased from 12.9 % in the 1988 to 1994 survey to 15.5% in the 1999 to 2004 survey. The total number of CKD patients is currently over 30 million people. Data is available from the United States Renal Data System at CKD is associated with increased risk for cardiovascular disease (CVD), progression to end-stage renal disease (ESRD), and sudden death. 1,2,4 The USRDS projects that by 2030 more than 2.2 million people will require treatment for ESRD, causing a significant impact on healthcare costs in the United States. 2 Emerging evidence suggests that early detection of CKD through risk assessment, periodic laboratory evaluations, and aggressive management of risk factors and sequelae associated with this condition, may prevent or delay the onset of CKD. 1-3 Morbidity and Mortality The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Advisory Board defines CKD as either (1) kidney damage for 3 or more months, indicated by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate 14 The Nurse Practitioner Vol. 32, No. 11 (GFR), manifested by abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging test results or (2) GFR lower than 60 ml/minute per 1.73 m 2 for 3 or more months, with or without kidney damage. 1 K/DOQI also established a five-stage classification system of CKD progression defined according to GFR and the presence or absence of kidney damage 1 (see Table: Stages and Prevalence of CKD. ) Although CKD is associated with a number of lifethreatening health outcomes, particular attention has addressed the relationship between CKD and CVD. In fact, CKD should be considered a CVD equivalent: CVD is a leading cause of death among patients with CKD and ESRD. 5 A recent study compared the claims of 1,091,201 Medicare patients 65 years or older, with and without CKD, from 1998 to 1999 and demonstrated significant associations between CKD and diabetes, age, CVD, other comorbid conditions; incidence of atherosclerotic vascular disease (AVD); incidence of heart failure (HF); and overall survival. 3 The risk for AVD and HF was greater than the potential need for renal replacement therapy in this CKD population. The increased risk for CVD among persons with CKD was also evident in a retrospective analysis of data on longterm survival rates for patients undergoing dialysis and hospitalized for a first acute myocardial infarction (AMI) between January 1977 and June Forty-one percent of patients survived for 1 year after AMI, and only 27% survived for 2 years. ESRD patients, 65 years or older, have significantly higher mortality rates after AMI and an average

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3 Stages and Prevalence of CKD (Adults 20 Years of Age and Older) 1 Stage Description 1 Kidney damage with normal or GFR >90 2 Kidney damage with mild decrease in GFR 3 Moderate decrease in GFR 4 Severe decrease in GFR 5 Kidney failure Note: GFR was measured in ml/min/1.73m 2. Data for stages 1 to 4 from the Third National Health and Nutrition Examination Survey (1988 to 1994) include 177 million adults 20 years of age and older. Data for stage 5 from USRDS (1998) include approximately 230,000 patients treated by dialysis and assume 70,000 additional patients not on dialysis. GFR estimated from serum creatinine using MDRD study equation based on age, sex, race, and calibration for serum creatinine. For stages 1 and 2, kidney damage was estimated by spot albumin-to-creatinine ratio of >17 mg/gram in men or >25 mg/gram in women on two measurements. Source: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002;39:S life expectancy of less than 1 year. 6 CKD patients have rates of all-cause mortality and cardiovascular events that increase as CKD progresses. 7 In addition, deaths attributable to cardiovascular events in CKD patients are significantly more common than deaths attributable to ESRD. 7 Several retrospective and prospective trials, including the Hypertension Detection and Follow-up Program Cooperative Group (HDFP), the Heart Outcomes and Prevention Evaluation (HOPE) study, the Hoorn Study, and the Cardiovascular Health Study (CHS), provided further evidence of the relationship between CVD and CKD The HDFP demonstrated that 8-year all-cause mortality increased as serum creatinine values increased. Death rates multiplied fivefold between patients with serum creatinine levels lower than 0.7 mg/dl and those with serum creatinine values higher than 2.5 mg/dl. The leading cause of death in this study was CVD. 7 The relationship between albuminuria and CVD was confirmed by the HOPE study, which demonstrated that even low albumin/creatinine ratios (lower than 0.5 mg/ mmol) were associated with significant increases in risk for CVD. 8,9 Results from the Hoorn Study confirmed that decreases in GFR from 90 to 60 ml/minute per were associated with a fourfold increase in CVD mortality. 10 Similarly, the CHS, a prospective, population-based study of persons older than 65 years of age (N = 5,808), demonstrated that those with elevated serum creatinine levels had significantly higher rates of all-cause mortality and cardiovascular mortality. Renal insufficiency was also associated with increased rates of incident CVD, AMI, stroke, angina, HF, or claudication; risk for death, CVD, and HF increased in a positive linear manner with increasing levels of serum creatinine. 11 Prevalence GFR N % >90 5, to 89 5, to 59 7, to <15 (or dialysis) Incidence and Prevalence Kidney disease is the ninth leading cause of death in the United States. It is estimated that over 30 million Americans have CKD and 106,000 have chronic kidney failure. 2,12 Data from the Renal Data Extraction and Referencing (Ren- DER) system indicate that the prevalence of chronic kidney failure increased 104% from 697 cases to 1,424 cases per million population between 1990 and Additionally, an estimated 800,000 people will require treatment by the year 2020 and 2.2 million persons will require treatment for ESRD by The prevalence of CKD increases with age, presence, and severity of hypertension (HTN), and diabetes. 12,13 Indeed, according to data from the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1994, onequarter of adults over 70 years of age in the United States had moderate or severe decreased kidney function. 13 Risk Factors RenDER data indicated that leading factors associated with increased risk for chronic kidney failure included diabetes and HTN, which accounted for approximately 60% of new cases of kidney failure. 12 Emerging data suggest that the metabolic syndrome is a strong and independent risk factor for CKD and microalbuminuria. 14 The metabolic syndrome is characterized by a constellation of clinical symptoms that include abdominal obesity, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL), HTN, and high fasting glucose levels. Elevated blood pressure (BP), hypertriglyceridemia, and elevated plasma glucose levels were each significantly associated with increased prevalence of CKD and microalbuminuria. Low HDL levels and abdominal obesity were significant predictors for the increased prevalence of CKD. 14 A community-based, longitudinal cohort (N = 2,738) enrolled in the Framingham Offspring Study provided additional information about CKD risk factors. Almost 10% of the sample had kidney disease at follow-up, and primary risk factors included older age, higher mean body mass index, higher total cholesterol level, higher prevalence of diabetes, and higher prevalence of HTN. Diabetes and older age more than doubled the risk for kidney disease. 15 During routine health encounters, the risk for CKD should be 18 The Nurse Practitioner Vol. 32, No. 11

4 Conditions that Indicate Need for CKD Screening History of diabetes Older adult (older than 60 years) Family history of CKD Hypertension Ethnicity (African-Americans, American Indians, Hispanics, Asians, Pacific Islanders) History of low-birth weight Exposure to nephrotoxic drugs Risk for CVD or history of CVD History of autoimmune disease History of recovery from acute kidney injury assessed with the use of sociodemographic characteristics, past medical history, family history, and BP measurement to determine who should be screened for CKD. Routine screening of patients for primary risk factors of CKD is important for early detection and treatment. The American Diabetes Association recommends screening to detect prediabetes and diabetes of patients 45 years of age or older and for patients younger than 45 years of age who have risk factors for diabetes. 16 BP monitoring at every routine visit and periodic lipid and kidney function assessments are recommended for patients with diabetes. 16,17 For all adults, routine BP monitoring is an important step in the prevention and control of hypertension HTN in the general population. 17 Proteinuria and HTN are significant CKD risk factors that promote more rapid progression of renal disease Proteinuria is also an indicator of the progressive loss of kidney function and is an independent predictor of increased risk for CVD and death. 5 Systolic BP and urinary protein excretion were related to risk for renal disease progression, with lower risk for disease exacerbation observed for patients with HTN, severe proteinuria at systolic BP readings from 110 to 129 mmhg, and urine protein levels lower than 2 grams/day. 18 Therefore, aggressive BP control has been established as an effective strategy to delay the progression of renal function loss among patients with kidney disease and/or proteinuria. 5,19 Strong evidence suggests that BP control exerts a renoprotective effect by reducing the levels of urine protein and delaying the progression of renal disease. 20 Albuminuria and proteinuria are early indicators of kidney damage, especially among persons with diabetes. 2,21,22 Keane and colleagueset al. demonstrated that proteinuria causes renal inflammation and fibrosis and that increasing levels of proteinuria are positively correlated with increased CKD Screening Tests Basic metabolic profile GFR calculation according to abbreviated Modification of Diet in Renal Disease equation ( org/professionals/kdoqi/gfr_calculator.cfm) Urinalysis - If results are positive for protein, determine urine albumin-to-creatinine ratio - If results are negative for protein, determine microalbumin-to-creatinine ratio Define CKD stage and develop action plan risk for, and rate of progression to, ESRD. 21,22 Several community-based trials have also demonstrated that microalbuminuria is a significant independent risk factor for CVD and CKD in persons with and without diabetes. 8,9,23,24 For example, results from the HOPE trial confirm that microalbuminuria is present in 32.6% of subjects with diabetes and 14.8% of those without diabetes at baseline. 8 Baseline microalbuminuria is associated with a significantly increased risk for major cardiovascular events, all-cause mortality, and hospitalization for HF. 9 Data from the Prevention of Renal and Vascular End Stage Disease Study Group reveal that CVD- and non CVD-related deaths are associated with diabetes, hyperlipidemia, smoking, previous AMI, and elevated urinary albumin excretion levels. Elevated urinary albumin excretion levels increase the risk for CVD- and non-cvd related death, but the increased risk is significantly greater for CVD-related death. 23 Hypertension and CKD The relationship between HTN and progression of CKD is well established. 27 Uncontrolled HTN exacerbates damage to the renal system, can contribute to ESRD, and is also a consequence of CKD. 19 HTN is the most powerful single risk factor for CKD. 14 Multiple factors contribute to the pathophysiology of HTN, including mediators from the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). Loss of nephrons results in changes in renal hemodynamics, contributing to hypertrophy of the remaining nephrons, which is associated with decreased arterial resistance and increased glomerular plasma flow. 28 Management of Patients with Hypertension and CKD Therapeutic interventions and evidence-based guidelines recommend reducing BP to lower than 130/80 mmhg for patients with HTN and CKD. 2,29,30 BP control is also associated with less rapid decline in GFR. 2 Nadim and colleagues concluded that antihypertensive treatment with drugs that modulate RAAS in patients with CKD is the single most The Nurse Practitioner November

5 important treatment for this patient population because these medications reduce BP, decrease the excretion of urinary protein, and slow the progression of renal disease. 19 Pharmacologic management of HTN often requires a combination of two or three medications to achieve and sustain BP reductions to goal. The choice of medications includes those with complementary mechanisms of action, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, and loop or thiazide diuretics. 2,29-31 RAAS inhibitors, including ACE inhibitors and ARB medications, are the preferred treatment for HTN management in patients with diabetic kidney disease and those RAAS inhibitors are the preferred treatment for HTN management in patients with diabetic kidney disease. with nondiabetic renal disease with proteinuria. 2 Primary effects of RAAS blockade include vasodilation, enhanced endothelial and arterial function,and reductions in BP. 29,31,32 RAAS inhibition also decreases proteinuria and provides renoprotection, particularly in patients with diabetic nephropathy. 31,32 Guidelines issued by the National Kidney Foundation suggest that moderate-to-high doses of RAAS blockade compounds confer additional protective effects on the renal system compared with low doses of these medications. Furthermore, higher doses of RAAS inhibitors have been shown to achieve more significant reductions in proteinuria and microalbuminuria. 2,33 A brief review of clinical trials to evaluate the effect of RAAS blockade on CKD progression provides substantive evidence for the efficacy of this pharmacologic intervention. The Ramipril Efficacy in Nephropathy study was a prospective, double-blind, placebo-controlled trial that randomized 352 patients without diabetes to receive either an ACE inhibitor (ramipril [Altace]) or a placebo. The primary outcome measure assessed the effect of treatment on GFR rates. Urinary protein excretion was significantly reduced after 1 month of treatment for patients treated with ramipril, and this decrease was maintained at all follow-up evaluations up to 36 months. In contrast, urinary protein excretion did not change significantly in the placebo group. 34 Similarly, the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study confirmed the safety and effectiveness of another ACE inhibitor, benazepril, to delay the progression of renal disease in patients without diabetes but with mild-to-moderate renal insufficiency at study enrollment. Renal survival was significantly better in patients treated with benazepril than in the placebo group, and significantly fewer patients with mild or moderate renal insufficiency at baseline met the primary end point of doubled serum creatinine concentration or need for dialysis compared with the placebo group. 35 Clinical trials also demonstrated the efficacy of ACE inhibitors for the reduction of microalbuminuria and decreased risk for overt nephropathy in persons with diabetes. 36,37 The North-East Italy Microalbuminuria Study Group evaluated the effect of 6 months of treatment with ramipril or a placebo on microalbuminuria and BP levels among patients with type 2 diabetes, persistent microalbuminuria, and normal BP or mild HTN. Albumin excretion rates increased from a baseline median level of 65 mcg/minute to 83 mcg/minute at the 6-month follow-up among patients in the placebo group, whereas rates decreased from 62 mcg/ minute at baseline to 53 mcg/minute at 6 months in the ramipril group. 36 The Microalbuminuria, Cardiovascular, and Renal Outcome Heart Outcomes Prevention Evaluation (MICRO-HOPE) sub-study assessed the effect of ramipril on risk for overt nephropathy and demonstrated a 24% reduction in overt nephropathy (P = 0.027). 37 Ravid and colleagues conducted a randomized, double-blind, placebocontrolled trial with a 6-year follow-up of patients with diabetes and microalbuminuria who were randomly assigned to treatment with either an ACE inhibitor (enalapril) or a placebo. 38 Enalapril achieved a 12.5% absolute risk reduction in albuminuria. 38 Several trials have also demonstrated a favorable effect of ARB agents on renal outcomes. The Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensinconverting Enzyme Inhibitor in Nondiabetic Renal Disease study assessed the efficacy of monotherapy of an ACE inhibitor (trandolapril) and an ARB (losartan) at maximum dose and combination therapy in 336 Japanese patients with nondiabetic kidney disease. 39 Both monotherapies demonstrated a 40% reduction in proteinuria, while combination therapy demonstrated an additional 40% reduction and a significantly greater reduction in the progression of kidney disease. However, it should be noted that this was a very small study that used sub-maximal doses of the ACE inhibitor and ARB, and that further research is warranted. The primary end point for the Reduction of Endpoints in Noninsulin-Dependent Diabetes Mellitus with 20 The Nurse Practitioner Vol. 32, No. 11

6 Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a composite of a doubling of creatinine concentration from baseline, ESRD, or death. 40 The results of this study revealed significant reductions in doubling of the baseline serum creatinine concentration, ESRD, and death for diabetes patients with nephropathy who were treated with losartan. 40 The Irbesartan Diabetic Nephropathy Trial randomly assigned 1,715 diabetes patients with HTN and nephropathy to treatment with an ARB (irbesartan), a CCB (amlodipine), or placebo. The primary outcome measure was a composite of doubling of baseline serum creatinine levels, onset of ESRD, or death from any cause. The investigators reported a 20% reduced risk for reaching the primary end point in the irbesartan group compared with the placebo group and a 23% reduced risk compared with the CCB group. 41 Similarly favorable results for irbesartan were observed in a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 590 HTN patients with type 2 diabetes and microalbuminuria. Patients were followed up for a median of 2 years after randomization to placebo, 150 mg irbesartan,or 300 mg irbesartan.rates of overt nephropathy were significantly reduced by both doses of irbesartan compared with placebo. 42 Evidence also suggests RAAS blockade is a therapeutic option that significantly reduces cardiovascular death and events in patients with CKD. The HOPE trial demonstrated that ramipril significantly reduced rates of death from cardiovascular causes, myocardial infarction (MI), stroke, and death from any cause. 9,43 Among patients with diabetes, a favorable effect of ACE inhibitors on cardiovascular outcomes was reported in several trials, including the Collaborative Study, which evaluated the effect of captopril versus placebo on a combined end point of death, dialysis, and kidney transplantation. Captopril reduced the occurrence of the end point by one-half. 44 Further, the HOPE and MICRO- HOPE studies revealed that ramipril reduced the rate of cardiovascular end points in patients with type 2 diabetes without increasing adverse events. 9,37,43 The impact of ARB pharmacologic compounds has not yet been evaluated in patients without diabetes. However, among those with diabetes, treatment with an ARB has achieved a reduction in HF rate. 40,41 The studies cited demonstrate the antiproteinuric and renal protective effects of ACE inhibitors and ARBs in patients with kidney disease, with or without diabetes, independently of the BP lowering effect in patients with HTN. It is clear that the RAAS has a profound effect on the development and progression of cardiovascular, cerebrovascular, and renal disease. It is interesting to note that only a 20% to 30% reduction in the progression of these diseases has been accomplished by modulating RAAS with ACE inhibitors or ARBs. This could be due to the effects of increased circulating angiotensin II stimulating type 2 receptors, following blockade of type 1 receptors by ARBs. It was previously reported that stimulation of angiotensin type 2 receptors was beneficial to patients and resulted in vasodilatation and increased nitric oxide production, thereby countering the negative effects of type 1 receptor stimulation. 45 Recent data indicate that stimulation of type 2 receptors may be deleterious and can lead to hypertrophy and fibrosis. 45 Indeed, clinical data suggest that stimulation of type 2 receptors may result in increased coronary atheroma, 46 which may explain the increased rate of MIs following treatment with ARBs. 47 Further,local tissue-based RAAS systems may not be inhibited by ACE inhibitors and ARB, due in part to increased levels of circulating renin following therapy with these classes of drugs. 48 Studies examining other mechanisms of modulating RAAS, such as blocking the effects of aldosterone, have also demonstrated positive results. 49,50 This approach must be used with appreciable caution and close laboratory monitoring given the reported increased morbidity and mortality associated with the increased use of spironolactone. 51 RAAS suppression with ACE inhibitors or ARB agents, either individually or in combination, also increases key components of the pathway, such as renin, angiotensin I, Early detection of CKD, along with lifestyle and pharmacologic interventions, can delay cardiovascular events and renal damage. and, with ARB use, angiotensin II levels. Increased renin levels under these conditions prompt the question whether greater clinical benefit can be expected with more complete RAAS suppression with upstream renin blockade. Direct renin inhibitors have been developed 52 and the first, aliskiren (Tekturna), has recently been approved for the treatment of HTN. Further research is needed to determine whether targeting RAAS at the point of activation by direct renin inhibition provides renal and cardiovascular protective benefits in addition to those observed with ACE inhibitors and ARBs. Conclusion Early detection and initiation of lifestyle and pharmacologic interventions for CKD can delay cardiovascular events The Nurse Practitioner November

7 Clinical Case Study A 35-year-old Hispanic man with type 1 diabetes (diagnosed at age 14) presents for routine follow-up care. The patient has a medical history of dyslipidemia and HTN. He reports smoking packs of cigarettes a month and moderate drinking. His mother has a history of type 2 diabetes, HTN, HF, AMI, and CKD requiring dialysis. His father has a history of HTN, chronic obstructive pulmonary disease, and stroke. The patient reports occasional episodes of blurred vision, intermittent edema, and arthritis in the right knee. Results of the physical examination include: pulse, 82 beats per minute; blood pressure, 148/92 mmhg; weight, 77 kg (165 lbs); and height, 178 cm (5 10 ). Examination of systems and major organs reveals the following: HEENT (head, eyes, ears, nose, throat): normocephalic; pupils equal, round, reactive to light, and accommodation Neck: no evidence of jugular venous distention, no carotid bruits, normal thyroid Cardiac: positive S 4, no rub or murmur Lungs: clear to auscultation and percussion Abdomen: flat, normal bowel sounds, no bruits, tenderness, or rebound Extremities: minimal edema Neurologic: normal Baseline laboratory results indicate the following: Hemoglobin A1C: 8.5% Fasting blood sugar: 225 mg/dl High-density lipoproteins: 31 mg/dl Low-density lipoproteins: 162 mg/dl Triglycerides: 165 mg/dl This patient has several risk factors for CKD including diabetes, HTN, positive family history, and Hispanic ethnicity. Screening for CKD is warranted. However, this patient has not undergone basic metabolic screening since age 24, when hospitalized for diabetic ketoacidosis. Screening for CKD is therefore performed and revealed the following: Serum creatinine: 1.8 mg/dl GFR: 46 ml/min per 1.73 m 2 Urinalysis: dip stick positive for protein (>300 mg/dl); no red or white blood cells present Urine albumin/creatinine ratio: 3,800 mg/gram creatinine This patient has stage III CKD with a 24.3% chance of mortality over a 5-year period. 25 Urinary protein level exceeding 3.5 grams is associated with a 57% likelihood of progression to ESRD in 2.1 years. 26 Treatment and management goals: Reduce BP to <130/80 mmhg. Reduce proteinuria. Reduce low-density lipoprotein and triglyceride levels. Reduce hemoglobin A1C to <7%. Treatment and management strategies: Initiate treatment with appropriate pharmacologic agents (combination of ACE inhibitor, ARB, beta-blocker, CCB, or diuretic). Initiate lifestyle modifications, such as the Dietary Approaches to Stop Hypertension diet and dietary changes to control blood glucose. Referral to a diabetes educator. Arrange a consultation with a nephrologist. Conduct regular follow-up visits to monitor BP, GFR, serum potassium levels, and proteinuria. and renal damage. Patients with known risk factors for CKD should undergo routine screening for proteinuria and albuminuria. The fundamental clinical goals for the treatment and management of CKD include aggressive control of HTN. This requires lifestyle modifications and treatment with multiple antihypertensive medications from complementary classes of drugs to achieve and maintain the desired BP target lower than 130/80 mmhg. Appropriate treatment of HTN has the potential to significantly reduce morbidity and mortality associated with CVD and renal disease. Prevention or reduction of proteinuria and albuminuria are significant clinical goals that correlate with clinical improvements in the progression of kidney disease, and that reduce the risk for cardiovascular events such as CHF, AMI, stroke, and death. Blockade of RAAS is the most effective intervention available to clinicians. RAAS inhibitors exert an independent, positive effect on renal function and significantly improve BP control. Agents that block RAAS slow the progression of kidney disease and reduce the incidence of CVD. The pharmacologic regimen should include a RAAS inhibitor with other compounds such as CCB, beta-blockers, or diuretics to achieve and maintain BP goals and to reduce cardiovascular comorbid conditions. The added use of direct renin inhibition may be on the horizon. REFERENCES 1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S Bakris GL. Protecting renal function in the hypertensive patient: clinical guidelines. Am J Hypertens Apr;18(4 Pt 2):112S- 119S. 3. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to J Am Soc Nephrol Feb;16(2): Kopyt NP Chronic kidney disease: the new silent killer. J Am Osteopath Assoc Mar;106(3): Kopyt N. Chronic kidney disease. In: Gotto AM, Jr., Toth PP, eds. Comprehensive management of high risk cardiovascular patients (fundamental and clinical cardiology). New York: Informa Healthcare USA, Inc.;2006: Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med Sep 17;339(12): Dennis VW. Coronary heart disease in patients with chronic kidney disease. J Am Soc Nephrol Nov;16 Suppl 2:S Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA Jul 25;286(4): Mann JF, Gerstein HC, Pogue J, et al. 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8 10. Henry RM, Kostense PJ, Bos G, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int Oct;62(4): Fried LF, Shlipak MG, Crump C, et al. Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol Apr 16;41(8): Centers for Disease Control and Prevention (CDC): state-specific trends in chronic kidney failure United States, Morb Mortal Wkly Rep Oct 8;53(39): Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey. Am J Kidney Dis Jan;41(1): Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med Feb 3;140(3): Fox CS, Larson MG, Leip EP, et al. Predictors of new-onset kidney disease in a community-based population. 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Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet Jan 22;355(9200): Ravid M, Brosh D, Levi Z, et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med Jun 15;128(12 Pt 1): Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-ii receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlled trial. Lancet Jan 11;361(9352): Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med Sep 20;345(12): Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. 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The clinical significance of a common, functional, X-linked angiotensin II type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease. Eur Heart J Mar;26(6): Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ Nov 27;329(7477): Azizi M. Renin inhibition. Curr Opin Nephrol Hypertens Sep;15(5): Pitt B, Rajagopalan S. Aldosterone receptor antagonists for heart failure: current status, future indications. Cleve Clin J Med Mar;73(3):257-60, Epstein M. Aldosterone blockade: an emerging strategy for abrogating progressive renal disease. Am J Med Nov;119(11): Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med Aug 5;351(6): Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet Oct 21;368(9545): ABOUT THE AUTHOR At the Lehigh Valley Hospital, in Allentown, PA, Dr. Nelson Kopyt is the Associate Chief of Nephrology. At Temple University, in Philadelphia, PA. Dr. Kopyt is a Clinical Professor of Medicine and is on the speaker s bureau at Novartis Pharmaceuticals. Editorial support for the development of this manuscript was provided by Novartis Pharmaceutical Corporation.Thanks extended to Denise L.Balog,PharmD, for editorial assistance. The Nurse Practitioner November