The Heart and the Kidney

Transcription

1 1 3 6 The Heart and the Kidney Martin R. Cowie The Epidemiologic Association Between the Kidney and the Heart The Burden of Chronic Kidney Disease The Association of Chronic Kidney Disease with Atherosclerosis Diabetic Renal Disease Chronic Heart Failure and the Kidney The Assessment of Kidney Disease in Patients with Cardiovascular Disease Slowing the Progression of Chronic Kidney Disease Screening for Chronic Kidney Disease Contrast-Induced Nephropathy Summary Key Points Death from cardiac causes is 10 to 20 times more common in patients with chronic renal failure than in ageand gender-matched individuals within the general population. Patients with decreased renal function do less well than those with normal renal function after acute coronary syndromes, including myocardial infarction, percutaneous coronary intervention, and coronary bypass surgery. Chronic kidney disease is an increasing public health problem in developed countries, due in part to greater prevalence of obesity and diabetes mellitus in populations that are living longer. Cohort studies have identified hypertension, diabetes, hyperlipidemia, obesity, and smoking as risk factors in the general population for the development of chronic kidney disease. Renal function is impaired in many patients with heart failure. Current management options for treatment of chronic kidney disease are based on the control of hypertension, proteinuria, hyperlipidemia, glucose, and smoking. Inhibition of the renin-angiotensin system is key to the preservation of glomerular function in chronic kidney disease, just as it is for cardiovascular function in heart failure. The interaction between the heart and the kidney is fundamental to the hemodynamic control of the cardiovascular system; both are key to blood pressure and fluid volume homeostasis. Both are vital organs, with complete failure of either being incompatible with life. More recently, it has become clear that the coexistence of both cardiac and renal dysfunction confers a poor prognosis, such that the existence of the cardiorenal syndrome has been proposed. 1 Increased activity of the renin-angiotensin system, oxidative stress, inflammation, and increased activity of the sympathetic nervous system are thought to be cornerstones of the pathophysiology in combined chronic renal and cardiac failure, leading to acceleration in decline of the function of both organs. This chapter describes the epidemiologic association between disease of the heart and the kidney, the best methods of assessing renal function in patients with cardiovascular disease, and the evidence base for treatment that delays the progression of renal disease and the associated atherosclerosis. Two renal pathologies frequently encountered in cardiologic practice, renal arterial disease and contrast-induced nephropathy, are also discussed. The Epidemiologic Association Between the Kidney and the Heart A large number of epidemiologic studies demonstrate the close association between the kidney and the heart. Death from cardiac causes is 10 to 20 times more common in patients with chronic renal failure than in age- and gendermatched individuals within the general population. 2 In endstage renal disease (ESRD), the prevalence of left ventricular hypertrophy (LVH) and coronary artery disease are 75% and 40%, respectively. 3 About half of ESRD patients suffer a myocardial infarction within 2 years after initiating dialysis therapy, and mortality in these patients is high. 4 Cardiovascular disease accounts for 40% of all deaths in patients with ESRD. 5 Even a slight decrease in kidney function is associated with a substantial increase in cardiovascular disease risk and mortality, independent of the other known risk factors

2 2820 chapter 136 Both proteinuria and a decline in glomerular filtration rate (GFR) are independent risk factors for the development of cardiovascular disease. 12 Importantly, most people with chronic kidney disease will die of cardiovascular causes before the renal dysfunction progresses to ESRD, 13 implying that aggressive identification and treatment of conventional risk factors for atherosclerosis is extremely important for such individuals. Patients with decreased renal function do less well than those with normal renal function after acute coronary syndromes, including myocardial infarction, percutaneous coronary intervention, 19 or coronary artery bypass surgery. 20 The Burden of Chronic Kidney Disease Chronic kidney disease (CKD) is an increasing public health problem in developed countries, due in part to the greater prevalence of obesity and diabetes mellitus in populations that are living longer. Diabetes is the major cause of ESRD in the industrialized world. 21,22 The worldwide rise in CKD is reflected in the increasing number of people with ESRD requiring renal replacement therapy dialysis or transplantation. Chronic kidney disease is characterized by a progressive decline in renal function, as measured by the decline in GFR. Guidelines published by the U.S. National Kidney Foundation in recommend a five-stage classification of CKD, based on renal excretory function (Table 136.1). Data from the third National Health and Nutrition Examination Survey (NHANES) in the United States suggest that up to 11% of the general adult population may have some degree of CKD. 24 Screening surveys in Australia, 25 Japan, 26 and Europe 27 report that between 6% and 11% of the general population have CKD. However, the NHANES data show that there are very few patients in the later stages of CKD; relatively few patients live to develop advanced renal disease or ESRD, largely because the risk of cardiovascular death is so substantial in patients with CKD. Data from a large managed care organization in the U.S. show that the rate of progression to renal replacement therapy is low, with many more patients dying before reaching ESRD (Table 136.2). 28 TABLE U.S. National Kidney Foundation recommended classification of stages of chronic kidney disease 23 Creatinine clearance Stage Description (ml/min/1.73 m 2 ) 1 Early renal damage pathologic 90 abnormalities or markers of damage including abnormalities in blood or urine tests or in imaging studies 2 Early renal insufficiency Moderate renal failure Severe renal failure End-stage renal failure <15 TABLE Rate of progression to renal replacement therapy compared with mortality over a 5-year period in a managed care organization database in the U.S. 28 National Kidney Foundation Stage of CKD year rate of progression to renal 1.1% 1.3% 19.9% replacement therapy 5-year mortality rate 19.5% 24.3% 45.7% The Association of Chronic Kidney Disease with Atherosclerosis The prevalence, incidence, and prognosis of clinical atherosclerotic cardiovascular disease (CVD) in patients with renal disease are not known with precision, but acceleration of atherosclerosis appears to begin early in the decline of renal function. In a representative sample of the U.S. population, renal insufficiency was independently associated with increased CVD-related and all-cause mortality rates. 10 Data from the Cardiovascular Health Study in the U.S. suggest that once the GFR falls below 60 ml/min, the risk for cardiovascular (CV) events increases dramatically. 29 A recent publication from a population database of more than a million adults clearly demonstrates a strong association between GFR and the risk of death, CV events, and hospitalizations (Fig ). 13 Cohort studies have identified hypertension, diabetes, hyperlipidemia, obesity, and smoking as risk factors in the general population for the development of chronic kidney disease. 26,30 32 These factors are also well known to be risk factors for the development of atherosclerosis. Data from the Cardiovascular Health Study confirm that the classic CV risk factors do indeed explain a large part of the cardiovascular disease seen in patients with CKD. 33 Individuals with microalbuminuria, defined as a urinary excretion rate of 20 to 200 mg/l, have a 10- to 20-fold higher risk of developing nephropathy compared with subjects in whom microalbuminuria is absent. 34 Epidemiologic studies have indicated that microalbuminuria is also a powerful predictor of the risk of CVD, irrespective of the presence of diabetes Albuminuria is a predictor of cardiovascular and noncardiovascular mortality (Fig ): a twofold increase in urinary albumin excretion, even within the microalbuminuric range, is associated with a 29% increase in the risk of CV mortality [95% confidence interval (CI) 18 40%], and a 12% increase in non-cv mortality (95% CI 4 21%). 38 These observations have been confirmed in multiple racial and ethnic groups and hold for all ages. Albuminuria is also commonly associated with other surrogate measures of CVD, such as carotid intimal-medial thickness, 39 LVH, 40,41 and the metabolic syndrome. 40 In the Heart Outcomes Prevention Evaluation (HOPE) study, the urine albumin/creatinine ratio from a spot urine sample at the start of the study was the single factor most strongly associated with the subsequent development of cardiovascular events for individuals with and without diabetes. 36

3 the heart and the kidney 2821 Age-Standardized rate of death from any cause (per 100 person-yr) <15 Estimated GFR (ml/min/1.73 m 2 ) A No. of events 25,803 11, FIGURE Age-standardized rates of death for any cause (A), cardiovascular events (B), and hospitalizations (C) according to the estimated GFR among 1,120,295 ambulant adults insured by the Kaiser-Permanente Health Maintenance Organization in Northern California. A cardiovascular event was defined as hospitalization for coronary heart disease, heart failure, ischemic stroke or peripheral arterial disease. Age-Standardized rate of cardiovascular events (per 100 person-yr) <15 Estimated GFR (ml/min/1.73 m 2 ) B No. of events 73,108 34,690 18, Age-Standardized rate of hospitalization (per 100 person-yr) C No. of events <15 366, Estimated GFR (ml/min/1.73 m 2 ) 106,543 49,177 20, ,593 Cardiovascular death Urinary albumin concentration (mg/l) Urinary albumin concentration (mg/l) FIGURE Risk of cardiovascular death (left) and noncardiovascular death (right) by urinary albumin concentration in the general population. The shaded area represents those individuals with microalbuminuria. Hazard ratio Hazard ratio Non-cardiovascular death

4 2822 chapter 136 smoothed hazard Hazard of chronic renal failure among tpye 2 diabetic patients time since diagnosis (year) FIGURE Risk of developing chronic renal failure in people with type 2 diabetes mellitus. Diabetic Renal Disease The incidence of diabetes is rising. 42 The prevalence of diabetes for all age groups worldwide was estimated to be 2.8% in 2000, rising to 4.4% by The total number of people worldwide with diabetes is thus projected to rise from 171 million in 2000 to 366 million in Most of the epidemiologic knowledge about CVD in diabetes is derived from Caucasian populations. Studies in such populations consistently report a strong association between diabetes and the risk of coronary artery disease, 44 left ventricular systolic dysfunction (LVSD), 45 and heart failure. 46 Although the risk of CVD in the developed world has fallen in the past 50 years, in both people with diabetes and those without, those with diabetes still have a twofold increase risk of dying from CVD compared to nondiabetics. 47 The Diabetes Control and Complications Trial 48 and the U.K. Prospective Diabetes Study 49 established that poor control of diabetes accelerates the progression of diabetic nephropathy in both type 1 and type 2 diabetes. Recent data suggest that the risk of ESRD in people with type 1 diabetes is around 2% at 20 years from diagnosis, and 8% at 30 years. 50 Diabetic nephropathy is said to develop in about 40% of all subjects with type 2 diabetes, although recent data from Europe suggests that the risk of chronic renal failure as defined by a serum creatinine 2 mg/dl (177 μmol/l) is only 6% at 20 years from diagnosis, and 9% at 30 years (Fig ). 51 Chronic Heart Failure and the Kidney Chronic heart failure (CHF) is a clinical syndrome of fatigue, dyspnea, and fluid retention caused by a variety of responses to underlying cardiac dysfunction, which include neurohormonal activation, peripheral vasoconstriction, and salt and water retention. 52 The prevalence of CHF is increasing, due to improved survival from acute coronary events, and the aging of the population, with estimates of 1% to 2% of the general population living with this syndrome. 53,54 A large number of clinical, hemodynamic, and biochemical factors have been identified as related to prognosis in patients with CHF. 55 Biochemical markers, including serum sodium, urea, and creatinine, reflecting disease severity and underlying renal dysfunction, are consistently associated with prognosis. 56 The underlying left ventricular systolic function (typically measured as the ejection fraction), the functional severity of the syndrome (assessed using a scale such as the New York Heart Association functional class), and the etiology of the disease all carry independent prognostic value. Circulating neurohormones, particularly B-type natriuretic peptide, also provide independent prognostic information. 57,58 It has been suggested that the activation of the reninangiotensin system (RAS), which occurs when renal perfusion is reduced in CHF, is not primarily a response to preserve circulatory homeostasis, but a renal compensatory reaction to preserve renal function in the short term. 59 Angiotensin II appears to have deleterious effects on both heart and kidney (and also the vasculature) in the long-term, although it can be lifesaving in the face of acute volume loss (Table 136.3). The evidence that antagonism of the RAS is beneficial in the longer term in heart failure is extremely robust, and such therapies have also been shown to be beneficial in preserving renal function in the longer term also. This is discussed in more detail later in this chapter. Heart failure is associated with microalbuminuria, 69 just as is the acute phase of myocardial infarction. 70,71 The mechanism may be increased glomerular capillary pressure due to activation of the RAS, combined with increased capillary permeability. Renal function is impaired in many patients with heart failure. The U.S.-based registry of patients hospitalized with acute heart failure provides interesting insights into the syndrome. The typical duration of admission was 4 days, and the average age was 72 years. Renal function was frequently impaired, with 20% of patients having a serum creatinine TABLE The role of angiotensin II in producing end-organ damage via the type 1 receptor Organ Pathologic changes Diseases Brain Atherosclerosis Stroke Blood vessels Vasoconstriction Hypertension Vascular hypertrophy Endothelial dysfunction Heart Left ventricular Heart failure hypertrophy Fibrosis Myocardial infarction Remodeling Apoptosis Kidney Decreased glomerular Renal failure filtration rate Proteinuria Increased aldosterone release Glomerulosclerosis

5 the heart and the kidney 2823 Numbers of patients > place to slow the loss of kidney filtration function and to treat and prevent cardiovascular events, which are the most common cause of death in patients with chronic kidney disease. Complications of reduced renal function can be detected and treated, and advance preparations made for renal replacement therapy as and when appropriate. Renal replacement therapy, either by dialysis or kidney transplantation, is beyond the scope of this chapter. International guidelines suggest that serum creatinine should be measured at least annually (and for many patients more frequently) in patients with CKD and those at high risk of developing silent renal disease such as those with heart failure, hypertension, diabetes mellitus, or atherosclerotic coronary, cerebral, or peripheral arterial disease. μmol/l FIGURE Frequency histogram of patients in the EuroHeart Heart Failure Survey, by serum creatinine concentration at time of admission to hospital. >2 mg/dl (177 μmol/l), and both blood urea nitrogen and serum creatinine were independent predictors of outcome, along with systolic blood pressure on admission. 72 In a large pan-european survey of similar patients (EuroHeart Heart Failure Survey), renal function was also impaired in a high proportion of patients, 73 with serum creatinine 150 μmol/l (1.7 mg/dl) in 16%, and 200 μmol/l (2.3 mg/dl) in 7% at the time of admission (Fig ). Renal function worsens in about a third of patients during an admission for decompensation of heart failure, if a rise in serum creatinine of 25 μmol/l (0.3 mg/dl) is taken as clinically meaningful Even such a comparatively small rise is associated with a worse prognosis and a longer length of hospital stay. 77,78 The Assessment of Kidney Disease in Patients with Cardiovascular Disease The current internationally recognized clinical practice guideline [Kidney Disease Outcome Quality Initiatives of the National (U.S.) Kidney Foundation] 23 suggests that once kidney disease is suspected, then 1. a specific (renal) diagnosis should be made, 2. the comorbidities assessed, 3. the severity of the renal disease assessed (expressed as estimated glomerular filtration rate and extent of proteinuria), 4. complications detected (such as bone disease or anemia), 5. the risk for loss of kidney function assessed, and 6. the risk of development of atherosclerotic cardiovascular disease assessed. Such an approach ensures a holistic assessment of the renal dysfunction; treatment can be aimed at the specific renal pathology and any associated morbidity, and measures put in Assessment of Glomerular Filtration Rate Glomerular filtration rate (GFR) can be measured by a variety of techniques. Historically, GFR was estimated in clinical practice using creatinine clearance based on a 24-hour urine collection and measurement of serum creatinine. This is unnecessary and often misleading. 79 Collections are often incomplete and creatinine clearance, in any case, is not synonymous with GFR. Serum creatinine concentration is dependent on both its rate of production and excretion. Production is related to muscle mass. Excretion is chiefly related to glomerular filtration, but also to tubular secretion, which becomes proportionally more important as filtration becomes more impaired. Serum creatinine may be higher than the usual quoted range in patients with normal renal excretory function but with high muscle mass (e.g., young males), but can be within the normal range despite marked impairment of glomerular function in patients with low muscle mass (e.g., elderly frail women). In modern clinical practice it is most usual to estimate GFR by using equations based on some or all of the following factors: age, gender, ethnicity, serum creatinine, and weight. The two most commonly used formulae are the Cockcroft- Gault 80 and the Modified Diet in Renal Disease formula (MDRD) 81 the latter existing also in a simpler version often termed MDRD2. 82 For practical purposes there is little to choose between the two equations, although the MDRD formula is slightly more complex but does not require patient weight. It is usual to correct GFR for body surface area, expressing it in terms of ml/min/1.73 m 2. The MDRD2 formula below to estimate GFR using plasma creatinine measured in mg/dl is automatically adjusted to a body surface area of m 2. Such adjustment for body surface area may underestimate GFR in obese subjects 83 : Estimated GFR = 186 [Plasma creatinine] [age] [0.742 if female] [1.212 if black] It is important to note that serum creatinine is higher in African Americans than in Caucasians, and the MDRD2 formula adjusts for this. It is not known whether adjustments should be made for other ethnic groups. If estimated GFR is >90 ml/min/1.73 m 2, then renal excretory function should be considered normal. In the range of 60 to 89 ml/min/1.73 m 2 renal disease should only be

6 2824 chapter 136 TABLE Staged classification for acute renal failure Change in serum creatinine Change in estimated GFR Urine output Risk % decrease <0.5 ml/kg/h for 6 hours Injury 2 50% decrease <0.5 ml/kg/h for 12 hours Failure 3 (or rise of at least 44 μmol/l 75% decrease to a level at or above 350 μmol/l) GFR, glomerular filtration rate. considered to be present if there is other evidence of this. Such evidence would be persistent microalbuminuria or proteinuria; persistent hematuria (after exclusion of urologic disease); structural abnormalities of the kidney (e.g., polycystic kidneys or reflux disease); or biopsy-proven glomerulonep hritis (in which case most patients will also have persistent hematuria or proteinuria). Estimating GFR in patients with heart failure, in whom weight may vary substantially over a short time course, and where there is substantial fluid retention, making body weight a poor reflection of underlying muscle mass, can be more difficult. Recent work suggests that the Cockcroft- Gault formula, using either actual or ideal body weight, systematically overestimates GFR, but that either the full MDRD or the simplified MDRD2 equations are better at identifying patients with renal dysfunction. 84 Serum Cystatin C as a Marker of Glomerular Filtration Rate Measurement of the low molecular weight protein cystatin C in serum shows promise for the future as a measure of glomerular filtration. 85,86 This cysteine protease is produced by all nucleated cells at a constant rate (except in thyroid disease or when high doses of glucocorticoids are administered) and is therefore less dependent on muscle mass. Unlike creatinine it is not excreted by tubular secretion, and is more or less freely filtered at the glomerulus. Serum concentrations increase with milder degrees of reduction in GFR than does serum creatinine. It appears to give results closer to that given by such gold standard methods of measuring GFR as 51 Cr-labeled ethylenediaminetetraacetic acid (EDTA) clearance than methods based on the measurement of creatinine. Further validation of this marker is required. Acute Renal Failure Because of the time delay between reduction in GFR and a rise in serum creatinine, 87 a low threshold of suspicion should be maintained for acute renal failure, particularly in the context of acute illness. The severity of acute renal failure can only be judged by the rate of rise of serum creatinine or rate of fall of estimated GFR. The safest assumption is that a patient with a rising serum creatinine or reducing estimated GFR has zero GFR. A recent international consensus conference recommended the use of a staged classification during acute illness using the acronym RIFLE: risk, injury, failure, and loss of renal function, culminating in end-stage renal failure. 88 The classification is shown in Table Detection of Proteinuria An untimed or spot urine sample will detect proteinuria. An early morning sample is best, but this is not essential and a random sample is better than no sample. An early morning sample correlates best with 24-hour urinary protein excretion and helps prevent orthostatic (postural) proteinuria being labeled as pathologic. 23 If a dipstick test for protein or albumin is positive (1+ or greater), this corresponds to approximately 300 mg/l, and the degree of proteinuria should then be quantified. Historically, this has been done using 24-hour urine collections, but these are often unreliable and incomplete, and many now recommend a simple measurement of the protein/creatinine or albumin/creatinine ratio in an untimed urine sample. These correlate just as well with the risk of decline in glomerular function in nondiabetic CKD as 24-hour quantification 89 (Fig ). Beware a falsely positive dipstick test, due to dehydration, hematuria, heavy exercise, urinary infection, an extremely Log 24 hour urinary protein excretion rate (g/24 h) y = 0.948x r 2 = r = SDR = Ln spot morning urine protein:creatinine ratio FIGURE Correlation between a spot morning urine protein: creatinine ratio and 24 hour urine protein excretion in 177 nondiabetic patients with chronic kidney disease and persistent proteinuria.

7 the heart and the kidney 2825 TABLE Cut points for urinary albumin and protein excretion, based on the recommendations of the U.K. chronic kidney disease guidelines 127 Urineprotein : creatinine ratio, Urinary albumin : Urinary albumin Dipstick mg/mol (urine Urine total protein creatinine ratio, excretion μg/min reading protein mg/l) excretion, mg/24 h (g/24 h) mg/mmol (mg/24 h) Normal Negative <15 (<100) <150 (<0.150) <2.5 (males) <20 (<30) <3.5 (females) Microalbuminuria Negative <15 (<100) <150 (<0.150) (males) (30 300) (females) Trace protein Trace ( ) ( ) Clinical proteinuria ( ) ( ) >30 >200 (>300) (macroalbuminuria) ( ) ( ,499) Nephrotic range proteinuria ( 3000) 4500 ( 4.500) alkaline urine, or fever. Clinical context will aid interpretation, and multisticks will pick up hematuria, nitrites due to bacterial infection, and indicate urine ph. The specificity of stick-positive proteinuria for true pathologic proteinuria is below 70%. 90 Similarly, a false-negative dipstick test for proteinuria may occur with excess hydration or urine proteins other than albumin, such as immunoglobulin light chains or Tamm-Horsfall tubular glycoprotein. The recommended cut points for normality are shown in Table Detection of Hematuria Dipstick urinalysis is the method of choice for confirmation of macroscopic hematuria and detection of microscopic hematuria. Infection, trauma, and menstruation should be excluded as causes. Macroscopic hematuria, and microscopic hematuria in adults aged over 50 years, should be referred for urgent renal and urologic investigation. However, asymptomatic microscopic hematuria is found in up to 4% of the general population, 25,91 and in the absence of either hypertension or proteinuria, is unlikely to progress to chronic kidney disease. 92,93 Urinary Sediment, Renal Ultrasound, and Renal Biopsy If the serum creatinine is raised or there is proteinuria, then the urinary sediment should be examined microscopically. Red blood cell casts point toward glomerulonephritis, white blood cell casts to tubulointerstitial nephritis or glomerulonephritis, and eosinophilic casts toward allergic tubulointerstitial nephritis. The presence of casts should lead to imaging of the kidneys. In the first instance this is usually by ultrasound. Ultrasound facilitates measurement of renal size and echogenicity, and helps exclude hydronephrosis. There have been no population-based studies of the value of renal ultrasound in patients with CKD, and its main role may be in determining which patients should undergo renal biopsy: patients with small, echo-bright kidneys are most likely to have nephrosclerosis, which is not amenable to any specific treatment other than control of cardiovascular (CV) risk factors. Nephrotic syndrome or heavy proteinuria (urine protein/ creatinine ratio of 100 mg/mmol), milder proteinuria (urine protein/creatinine ratio of mg/mmol) accompanied by microscopic hematuria, or unexplained acute renal failure is generally accepted as an indication for renal biopsy. Detection of Complications of Chronic Kidney Disease If kidney function is more than mildly impaired (estimated GFR <60 ml/min/1.73 m 2 ), an assessment should be made for possible complications of renal disease, such as anemia, poor nutritional status (by assessment of dietary energy and protein intake, weight, serum albumin and total cholesterol), bone disease (by measurement of parathyroid hormone levels and serum calcium and phosphate levels), and overall functional status and well-being. Slowing the Progression of Chronic Kidney Disease Current management options for CKD are based on the control of hypertension, proteinuria, hyperlipidemia, glucose control, and smoking and are listed in Table Attention to such factors brings the additional benefit of reducing the risk of cardiovascular events, the main cause of death in patients with CKD. All cardiovascular physicians should be familiar with most of these management strategies, as they overlap substantially with the management of patients with, or at high risk of, atherosclerosis. Value of Inhibition of the Renin-Angiotensin System Inhibition of the RAS is key to the preservation of glomerular function in CKD, just as it is for cardiovascular function in heart failure. The use of either (and perhaps both) angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) slows down the progression of CKD and thus delays the time to dialysis. Such treatment also reduces the risk of vascular events in such patients, the major cause of mortality and morbidity.

8 2826 chapter 136 TABLE Lifestyle and pharmacological interventions to slow the progression of chronic kidney disease Diet Advise moderate protein restriction: g/kg daily if severe chronic renal disease 162 Advise low salt intake to optimize blood-pressure control and possibly decrease proteinuria 163 : mmol/day (4 6 g sodium chloride) Advise weight loss if obese, aiming for maintenance of normal body weight (BMI kg/m 2 ); this will help the control of blood pressure, and may reduce glomerular hyperfiltration and proteinuria 164,165 Blood-pressure control Lifestyle advice, including maintenance of normal body weight (BMI kg/m 2 ), low salt intake (60 80 mmol/day; 4 6 g sodium chloride), regular aerobic exercise, and limit alcohol intake to 3 units/ day for men or 2 units/day for women If proteinuria <1 g in 24 h, target systolic/diastolic blood pressure < /80 85 mmhg (mean arterial pressure 92 mmhg) If proteinuria >1 g in 24 h, target systolic/diastolic blood pressure <125/75 mmhg (mean arterial pressure 90 mmhg) Many patients will require more than one antihypertensive drug to achieve control of blood pressure. Treatment should include an ACE inhibitor for patients with proteinuria, diabetic patients with microalbuminuria, and patients with heart failure. Diuretic can be added to maximize effect. If ACE intolerant, an ARB should be substituted. If blood pressure requires additional treatment to ACE inhibitor + diuretic, then ARB can be added, or a nondihydropyridine calcium-channel blocker (more effective in reducing proteinuria than dihydropyridine CCBs); or β- or α-blocker Proteinuria Use an ACE inhibitor or ARB alone or in combination to maintain proteinuria at <1 g/24 hours; titrate to control proteinuria even if blood-pressure target is achieved Blood-glucose Trial evidence suggests that good glycemic control reduces the risk of microalbuminuria in patients with both type I control and 2 diabetes, 166,167 with suggestion of benefit in reduction in rate of progression to overt nephropathy; benefits also in diabetes for progression of retinopathy; maintain hemoglobin A 1c < 7 8% Dyslipidemia No specific evidence for patients with CKD but large trial (Study of Heart and Renal Protection) underway. 168 In presence of atherosclerosis use a statin according to international guidelines. Otherwise calculate global cardiovascular risk and target cholesterol as suggested by international guidelines. Smoking Use all measures to encourage smoking abstinence may reduce rate of decline of renal function 169 Angiotensin-converting enzyme inhibitors reduce physiologic levels of circulating angiotensin II by preventing its formation from the precursor angiotensin I. In contrast, ARBs specifically block the actions of angiotensin II at the level of the type 1 receptor. Although ACE inhibitors are effective, they do not provide a complete blockade of the RAS, as there are alternative pathways by which angiotensin II may be formed. Consequently, angiotensin II concentrations rise again after several months of treatment with an ACE inhibitor a phenomenon called escape. 94,95 By acting at the receptor level, ARBs provide a more complete blockade of the actions of angiotensin II. The mechanisms by which RAS inhibition offers potential benefit to the kidney and the cardiovascular system are shown in Table Activation of the RAS initially defends the kidney from underperfusion by raising blood pressure and constricting the efferent glomerular arteriole, thus raising intraglomerular capillary pressure and preserving GFR. Over time, this activation of the RAS damages the kidney by ischemia, glomerulosclerosis and tubulointerstitial fibrosis. Chronic kidney disease results from any pathologic process that leads to nephron injury and loss, with consequent glomerular capillary hypertension and hyperfiltration in the remaining nephrons. Although this helps to maintain GFR in the short term, over time the remaining nephrons are further damaged, a process that is accelerated by the RAS activation. 96,97 The clinical evidence for benefit of RAS inhibition by ACE inhibitors and ARBs in kidney disease comes from a number of randomized clinical trials, summarized in Tables and 136.9, respectively. Further studies of the renoprotective effects of ARBs are ongoing, for instance in the Programme of Research to Show Telmisartan End-Organ Protection (PROTECTION). 98 ON- TARGET will examine the impact of ramipril + telmisartan on a range of end points, including nephropathy, compared with ramipril. TRANSCEND will compare telmisartan compared with placebo in a similar study, but in ACEintolerant individuals. A large study of the impact of olmesartan compared with placebo in patients with type 2 diabetes and one other risk factor (ROADMAP) is planned to include renal end points. Other shorter term trials with valsartan compared with ACE inhibitor, or the combination, in both diabetic and nondiabetic nephropathy are also underway. TABLE Mechanisms of benefit of RAS inhibition to the kidney and cardiovascular system Mechanisms of benefit of RAS inhibition to the kidney Reduction in sodium and water reabsorption Reduction in proteinuria Reduction in glomerular and tubulointerstitial fibrosis Stabilization of renal function in chronic kidney disease Mechanisms of benefit of RAS inhibition to the cardiovascular system Reduction in elevated blood pressure Inhibition of vascular smooth muscle cell (VSMC) growth Regression of left ventricular (LV) hypertrophy Prevention of adverse remodeling of LV after myocardial infarction Prevention of heart failure after myocardial infarction Reduction in sympathetic nervous system activity Stabilization of atherosclerotic plaque Normalization of endothelial function Enhancement of fibrinolytic system

9 the heart and the kidney 2827 TABLE Summary of evidence from randomized clinical trials for benefit of ACE inhibition in chronic renal disease Trial Comparison Disease n Result Collaborative Study 170 Captopril 25 mg tds Type 1 diabetics, with 409 RRR 48% for doubling in serum vs placebo proteinuria 500 mg/day creatinine (p =.007) over median of + serum creatinine 3 years follow-up 2.5 mg/dl (221 μmol/l) RRR 50% for combined end point of (75% had hypertension) death or dialysis or renal transplant (p =.006) European Captopril 50 mg bd vs placebo Type 1 DM with 92 RRR 75% for development of overt Microalbuminuria microalbuminuria, but nephropathy over 2 years (p=.03) Captopril Study 171 not hypertensive The REIN trial 172 Ramipril mg/day Nondiabetic nephropathy 352 In group with >3 g/day proteinuria vs placebo (+ conventional (creatinine clearance 20 (n = 166), rate of decline in GFR 0.53 antihypertensive treatment) 70 ml/min/1.73 m 2 ) with [0.08] vs 0.88 [0.13] 70 ml/min per proteinuria >1 g/day month (p =.03); 50% RRR for doubling in serum creatinine or ESRD at mean follow-up of 16 months (p =.02). Effect persisted after correction for small difference in BP achieved in the two arms of the study Ravid et al. 173 Enalapril 10 mg/day Type 2 diabetics with 156 Absolute risk reduction of 12.5% vs placebo albuminuria <30 mg/day, [95% CI 2 23%; p =.04] for but not hypertensive development of microalbuminuria over 6 years; attenuated decline in GFR (1.5 ml/min vs 2.4 ml/min per year; p =.04) HOPE/MicroHOPE Ramipril 10 mg/day Diabetics, aged 55, 3577 RRR 24% [95% CI 3 40%] p = for Substudy 174 vs placebo previous CV event or at development of overt nephropathy least 1 other CV risk ( 300 mg albuminuria/day), with factor and no proteinuria effect seen in those who did and did nor HF nor low EF not have microalbuminuria at baseline AASK Trial 175 Factorial trial including African Americans 1094 Rate of decline in GFR not different comparison of ramipril aged 18 70, with among the three drugs, but ( mg/day) with hypertensive renal development of combined end point of metoprolol 65 ml/min/ disease (GFR: 20 ESRD, death or >50% decline in GFR 1.73 m 2 ) or amlodipine 65 ml/min/1.73 m 2 ) reduced in ramipril group compared (5 10 mg/day) with metoprolol (RRR 22% [95% CI 1 38%] p =.04) or amlodipine (RRR 38% [95% CI 14 56%] p =.004) over 3 to 6.4 y of follow-up RRR, relative risk reduction; DM, diabetes mellitus; CI, confidence interval; CV, cardiovascular; HF, heart failure; EF, ejection fraction. While the published studies have provided clear evidence that blocking the RAS and lowering blood pressure prevent kidney disease progression, the evidence that blocking the RAS reduces cardiovascular events perhaps over and above any blood pressure effect is more controversial, in part because larger trials and longer follow-up are needed to evaluate CVD events. Nevertheless, several trials in hypertensive patients that have included RAS blocking agents have demonstrated beneficial outcomes in cardiovascular endpoints, notably the Heart Outcomes Protection Evaluation (HOPE), 99 the Anglo- Scandinavian Cardiovascular Outcomes Trial (ASCOT), 100 the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE), 101 the Antihypertensive Lipid-Lowering Heart Attack Trial (ALLHAT), 102 and the Valsartan Antihypertensive Long-Term Use Evaluation Study (VALUE). 103 Achieving both a lower BP and blocking the RAS, either with an ACE inhibitor or an ARB-based regimen, provided consistent overall risk reduction in cardiovascular events. In addition, many of the surrogate measures commonly used to estimate CVD progression, such as reduction of albuminuria, new incidence of heart failure, or regression of LVH, were also more commonly evident when an RAS blocker was used as part of an equivalent blood pressure (BP)-lowering regimen. Incorporating an RAS blocker as part of a BP-lowering regimen reduces (or, more accurately, delays) the development of type 2 diabetes by approximately 25% to 30%. Treatment with an ACE inhibitor in the European Trial on Reduction of Cardiac Events with Perindopril (EUROPA) in stable coronary artery disease resulted in a 20% relative risk reduction of the primary combined end point of cardiovascular death, myocardial infarction, or cardiac arrest. 104 Similarly, ACE inhibitors or ARBs improve the outcome for patients with symptomatic or asymptomatic left ventricular systolic dysfunction, with greatest benefit in those with the most severe symptoms of heart failure The renin inhibitor aliskiren is currently undergoing moderate-sized phase II trials of safety and efficacy in a variety of disease states, including patients with hypertension, type 2 diabetes, and proteinuria. The evidence for the benefit of aldosterone blockade in patients with at least moderately severe chronic heart failure

10 2828 chapter 136 TABLE Summary of evidence from randomized clinical trials for benefit of ARBs in chronic renal disease Trial Comparison Disease n Results RENAAL 176 Losartan mg od Type 2 DM + nephropathy 1513 Over mean of 3.4 years, 16% RRR [95% vs placebo [urinary albumin: creatinine CI 2 28%] in primary end point of doubling ratio 300 mg/g or urinary in serum creatinine or ESRD or death protein 0.5 g/day, & serum (p =.02), with 25% RRR [8 39%] in creatinine betwee 1.3 and doubling of serum creatinine (p =.006) 3.0 mg/dl ( μmol/l)]; and 28% RRR [11 42%] of ESRD (p =.002). 93% using antihypertensive Difference persisted after correction for drugs at baseline differences in achieved BP. IDNT 177 Irbesartan 300 mg od or Type 2 DM + hypertension Over mean of 2.6 years, 20% RRR [95% amlodipine 10 mg od nephropathy [>900 mg CI 3 34%] in primary end point of doubling or placebo urinary protein/day and in serum creatinine or ESRD or death serum creatinine between compared with placebo (p =.02), or 23% 1 &3 mg/dl ( μmol/l) RRR [7 37%] compared with amlodipine in women or mg/dl (p =.006). Serum creatinine increased 24% ( μmol/l) in men] more slowly with ARB than with placebo (p =.008), and 21% more slowly than with amlodipine (p =.02). No difference in mortality. Effect independent of achieved blood pressure. MARVAL mg valsartan/day vs Type 2 DM + microalbuminuria 332 Over 24 weeks, urinary albumin excretion amlodipine 5 mg od (median urinary albumin rate was 56% [95% CI 50 63%] ofbaseline initially, with increase excretion rate of μg/ in valsartan group compared with 92% to control BP to 135/ min),with (65%) or without [82 104%] in amlodipine group (p <.001). 85 mm Hg or below (35%)hypertension 30% of valsartan group reverted to normoalbuminuria compared with 14% in amlodipine group (p =.01). No difference in achieved blood pressure in the two groups. IRMA2 179 Irbesartan 150 mg or Type 2 DM + hypertension Over 2 years of follow-up, 70% RRR [95% 300 mg od vs placebo microalbuminuria (urinary CI 39 86%]in risk of diabetic nephropathy albumin excretion rate of (urinary albumin excretion rate >200 μg/min μg/min), with serum + >30% increase in excretion from baseline) creatinine 1.5 mg/dl in 300-mg group (p <.001),compared with (133 μmol/l) in men or 1.1 mg/ placebo. Statistically nonsignificant (p =.08) dl (97 μmol/l) in women decrease for 150 mg group (RRR 39%). No clinically significant difference in achieved BP in the three arms. DETAIL 180 Telmisartan 80 mg/day Type 2 DM + early nephropathy 250 Over 5 years, telmisartan was not inferior to compared with (urinary albumin excretion enalapril in terms of the primary end point enalapril 20 mg/day* rate of μg/min & of percentage reduction in GFR from serum creatinine <1.6 mg/dl baseline. No difference between groups in (141 μmol/l))+ hypertension change in secondary end points of serum creatinine, urinary albumin excretion or blood pressure from baseline. BENEDICT 181 Trandolapril 2 mg od Type 2 DM + hypertension Over a minimum of 3 years follow-up versus verapamil normoalbuminuria trandolapril or the combination slowed the 240 mg SR od vs onset of microalbuminuria ( 20 μg/minin combination (2 mg + two overnight samples) compared with 180 mg SR) vs placebo placebo (p =.01), whereas verapamil produced similar results to placebo. Percentages with microalbuminuria were 5.7% (combination), 6.0% (trandolapril), 11.9% (verapamil), 10% (placebo). RRR, relative risk reduction; CI, confidence interval; DM, diabetes mellitus; GFR, glomerular filtration rate. or heart failure after acute myocardial infarction is robust. 67,68 Patients with more than mild chronic renal failure were excluded from such studies, due to concerns about hyperkalemia. Work in animal models suggests that there may be a role for aldosterone blockade in preserving renal function, 105,106 but as yet no clinical trials have been published. Treatment of Anemia to Preserve Kidney and Heart Function Anemia becomes increasingly common in patients with CKD as the renal function deteriorates. A prospective study from several renal centers in Canada reported a prevalence of anemia of 25% in those with a GFR >50 ml/min/1.73 m 2,

11 the heart and the kidney 2829 rising to between 44% and 51% at a GFR of 25 to 49 ml/ min/1.73 m 2, and 87% in those with a GFR below 25 ml/ min/1.73 m 2, 107 With a similar definition of anemia of hemoglobin <12 g/dl in men and 11 g/dl in women, data from NHANES III in the U.S. reported somewhat lower figures with anemia in 1% of those with a GFR above 60 ml/min/ 1.73 m 2, 9% of those with a GFR around 30 ml/min/1.73 m 2, and 33% in men with a GFR around 15 ml/min/1.73 m 2 in men and 67% of women with a GFR of that level. 108 Anemia is associated with a marked increase in the risk of the development of LVH and heart failure, and is associated with increased mortality. 109,110 The mechanism of cardiac injury is likely to be volume overload and perhaps also a reduction in myocardial oxygen supply. 111 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative in the U.S. recommends that the target hemoglobin in a patient with CKD should be between 11 and 12 g/dl (corresponding to a hematocrit of between 33% and 36%). 23 If no other cause for anemia is found (such as blood loss, folate/b 12 deficiency, hypothyroidism, hemolysis) and the CKD is at least moderate [serum creatinine >2 mg/dl (177 μmol/l)], then it is generally safe to assume that is due to erythropoietin deficiency. Measurement of serum erythropoietin is usually unnecessary. Adequate iron stores are required to permit an optimal response to erythropoietin therapy, and should be assessed by measurement of serum iron, ferritin, transferrin saturation, and mean cell hemoglobin concentration. Oral iron therapy is unlikely to replete iron stores in patients with CKD, and most patients will require intravenous iron on a regular basis. For patients on dialysis, the treatment of anemia and maintenance of hemoglobin by regular iron and erythropoietin therapy reduces morbidity and the need for hospitalization or blood transfusion, and greatly improves quality of life. 112 The evidence that such treatment also delays progression of renal failure (and thus the avoidance of renal replacement therapy) and reduces the risk of cardiovascular events in patients not on dialysis is less secure and is the subject of several randomized clinical trials It is increasingly recognized that anemia may arise as part of the heart failure syndrome. Within a large cohort of patients hospitalized with heart failure in Canada, 17% had anemia, with 53% of these being ascribed to the anemia of chronic disease. 116 The risk of CKD among those with anemia was more than double that of those without anemia. A similar prevalence of anemia among patients admitted with heart failure has also been reported from a U.K. hospital, with 44% of those with anemia having evidence of CKD [serum creatinine 160 μmol/l (1.8 mg/dl)]. 117 Anemia confers an increased risk of rehospitalization and mortality in patients with heart failure, independent of other clinical and demographic factors, with reports of a 13% increase in the mortality risk for each 1 g/dl decrease in hemoglobin. 118,119 The association with mortality is particularly strong in patients with low estimated GFR. 120 The mechanism of anemia may be related to underlying renal failure and erythropoietin deficiency or be due to inhibition of the effect of erythropoietin on the bone marrow as part of the inflammatory response triggered in severe heart failure, or most likely a combination of these factors. 121 The term cardiorenal-anemia syndrome has been coined to describe the vicious cycle of heart failure and renal failure causing anemia, which then accelerates the deterioration in the function of both organs, leading to further anemia. 122 Small observational and randomized studies have suggested that the treatment of such anemia (by intravenous iron and erythropoietin therapy) may lead to marked improvement in left ventricular function, symptoms, quality of life, and risk of hospitalization Large randomized trials are underway to test such claims and to determine whether treatment of anemia will also improve prognosis for patients with heart failure. Screening for Chronic Kidney Disease The potential exists for earlier detection of CKD, with intervention to delay the progression of both the CKD and the almost inevitable coexisting atherosclerosis, thus reducing morbidity and mortality. It has been argued that population screening for microalbuminuria (or reduced GFR) could help identify those at greatest need for CVDreduction measures, such as greater scrutiny and control of blood pressure (particularly with incorporation of RASblocking drugs), and better lipid and glucose control. 126 There has been no large trial of the value of population-wide screening for CKD, but even in conservative health care systems screening for chronic kidney disease is recommended in patients with clinically manifest CVD, diabetes, or hypertension. 127 Renal Arterial Disease Renal arterial disease may be present in as many as 10% of apparently healthy potential live kidney donors, although it is usually not more than mild to moderate, and in 80% of cases relates to fibromuscular dysplasia rather than atherosclerosis. 128 A population-based study in the United States suggests that the prevalence of hemodynamically significant renal artery stenosis in the post-retirement population is 6.8%, as defined by a Doppler duplex sonography peak systolic velocity of at least 1.8 m/s. 129 Some 90% of cases were unilateral, with increasing age, low serum high-density lipoprotein (HDL) cholesterol, and raised systolic blood pressure associated with the presence of disease. The prevalence is higher among those undergoing coronary angiography or peripheral arterial angiography around 20% in the former and 45% in the latter groups. 130 Among hypertensive patients referred for coronary angiography to one U.S. center, renal arterial disease with a stenosis of at least 50% was found in 19% of cases, of which 40% had a stenosis greater than 70% (high grade), and 20% had bilateral disease. 131 It is unclear how rapidly renal atherosclerotic arterial disease progresses. Although rare, progression to total occlusion can occur. The likelihood of progression is greater in

12 2830 chapter 136 more severe stenoses, those with diabetes, and those with hypertension. 132 Such progression may lead to increasing renal dysfunction, and it is argued that renal revascularization will prevent or delay this. Recent observational studies suggest that the rate of progression of renal dysfunction without revascularization may actually be slow (perhaps occurring in 10% to 15% of people over 5 years), with death from other vascular events ( competing risk ) being common, and the renal dysfunction may increase because of other pathologies, such as diabetes. 133,134 Clinical Presentations Renal arterial disease is usually asymptomatic. Nearly all patients have arterial disease elsewhere the aorta, the coronaries, or the carotid circulation being typical sites. Classically, when the degree of renal arterial stenosis reaches a critical level, a chain of events is unleashed that leads to a rise in systemic arterial pressure, deterioration in renal function, and possibly stroke or heart failure. Rapid deterioration in renal function can occur if blood pressure is reduced rapidly in patients with severe renal arterial disease, due to a reduced transcapillary filtration pressure in the glomerulus. This is termed functional renal insufficiency and is most likely to occur when blood pressure is lowered by the use of ACE inhibitors or ARBs. However, where the stenosis is unilateral, the change in serum creatinine may be very small or not evident. When the entire functioning renal mass is at risk, due to a solitary functioning kidney with stenosis or high-grade stenoses to both kidneys, the change in kidney function can be profound. Interestingly, even when ACE inhibition is given to patients at high risk of renal arterial disease and with modestly impaired renal function [serum creatinine between 1.4 and 2.3 mg/dl (124 to 203 μmol/l)], there is no evidence of a significant rise in serum creatinine, but a clinically important 20% reduction in subsequent cardiovascular events, 135 albeit in the context of a clinical trial. Modern guidelines suggest that ACE inhibitors should be used in such patients at risk of functional renal insufficiency, with general cardiovascular benefit and benefit in terms of preservation of renal function in the longer term. 136 It is vitally important to monitor serum creatinine and potassium levels and avoid excessive diuretic use or volume depletion before commencing the ACE inhibition. The clinical syndrome of flash pulmonary edema was described in 1988 by Pickering and colleagues, 137 with acute and unprovoked development of pulmonary edema in patients with either bilateral renal artery stenosis or unilateral stenosis to a single functioning kidney. Patients may or may not have coexisting coronary disease, and absolute proof of the link between the pulmonary edema and the renovascular disease comes only with a lack of recurrence after renal artery angioplasty or surgical revascularization. Interestingly, the flash episodes usually occur at night and may relate to nocturnal dips in blood pressure in hypertensive patients, with consequent reduced pressure natriuresis. 138 Imaging Selective renal arteriography is the gold standard for diagnosis of renal arterial disease, but is not suitable as a first diagnostic test. Less invasive tests are usually preferred, but both duplex Doppler ultrasonography and captopril enhanced renography may miss hemodynamically significant renal arterial disease, particularly in routine clinical practice. The negative predictive value of a normal captopril renogram is dependent on the pretest probability of disease, and thus in patients without any vascular disease may approach 100%, but falls to as low as 60% in those with extensive arterial disease. 139 It has been suggested that lateralization of tracer to the affected kidney in the captopril renogram predicts a beneficial response to percutaneous revascularization. 140 Experienced centers can achieve very high sensitivity and specificity (around 90% for both) for hemodynamically significant renal arterial disease using Doppler ultrasonography, 141,142 but this is unlikely to reflect the situation in centers where such studies are performed infrequently. Computed tomography (CT) angiography involves the administration of iodinated contrast intravenously (typically 150 ml), but provides pictures of similar quality to intraarterial angiography, and at a similar risk of contrast-induced nephropathy. 143 Meta-analysis suggests that both CT angiography and gadolinium-enhanced three-dimensional magnetic resonance angiography may be more reliable than either Doppler ultrasonography or captopril-enhanced renography in screening for renal arterial disease, although individual studies included in the meta-analysis varied widely. 144 Figure shows the details of renal artery stenosis picked up on a gadolinium-enhanced three-dimensional magnetic resonance angiogram in a patient with extensive atherosclerosis and moderate chronic kidney disease. FIGURE Three-dimensional gadolinium-enhanced magnetic resonance image of left renal artery stenosis (posterior view).