Kidney-Heart Interactions (2005)

Heart disease accounts for approximately half of the deaths of patients with ESRD (1–3). In the past 5 yr, there has been increasing recognition of both coronary artery disease (CAD) and left ventricular hypertrophy (LVH) in ESRD patients, as these are the two typical presentations of heart disease in ESRD patients. It is also clear that many patients with chronic kidney disease (CKD) and a GFR of <60 ml/min are at risk for heart disease; many of these patients succumb to heart disease before reaching dialysis (4–6). This review includes a brief overview of the problem, a discussion of CAD and LVH, and an examination of the benefits of reducing BP and proteinuria on both the heart and the kidney and concludes with a brief section on treatment options for individuals with this disorder. Overview of the Problem of Cardiovascular Disease in Patients with Kidney Disease A growing awareness of heart disease in individuals with kidney disease as a major public health concern has increased sharply because of the revelation that there are millions of Americans with reduced kidney function (2). This fact, coupled with the understanding that many individuals with CKD do not reach dialysis because they die of heart disease (6), has expanded the concern about heart disease in both patients with CKD and patients with ESRD. Of interest is that whereas many superb prospective, randomized clinical trials have defined the scope of the appropriate therapy for heart disease in patients with normal kidney function, relatively few trials have addressed the issue in patients with kidney disease. Thus, the literature on cardiovascular disease (CVD) has focused on individuals without kidney disease, and guidelines regarding the management of heart disease in patients with ESRD in CKD, therefore, are largely opinion based (7). The two clinical presentations of heart disease in patients with kidney disease are atherosclerotic vascular disease (particularly CAD) and LVH. Atherosclerosis has been known to be a particular problem in patients with ESRD for >25 yr since Lindner et al. (8) hypothesized that there was accelerated atherogenesis in patients with ESRD. In the Lindner study, 60% of a cohort who underwent dialysis for 6.5 yr died and 14 of these deaths were attributed to complications of atherosclerosis. Subsequent postmortem and angiographic studies confirmed that the prevalence of atherosclerosis is increased dramatically in patients who are on dialysis when compared with age-matched individuals without kidney impairment (9–13). Of note, this increase in atherosclerosis and, in particular, CAD is progressive over a range of reduced GFR. This has been shown by Anavekar et al. (5) and by Beddhu et al. (14). The major increase in risk for heart disease and death occurs at a GFR of <50 to 60 ml/min (5,14) (Figure 1). A major problem with the issue of coronary disease is that in many patients, there is a high burden of coronary disease despite that the patient is asymptomatic. In a recent study by deFilippi et al. (15), 44% of a large cohort of asymptomatic hemodialysis patients had significant coronary disease. This was confirmed recently by Ohtake et al. (16), who showed that coronary disease (defined as >50% stenosis in the coronary artery) was present in as many as 53% of a cohort of asymptomatic dialysis patients. A second presentation of heart disease in this patient population is LVH. It is particularly important to understand this disorder in dialysis patients because as many as 80% of an incident dialysis population will have LVH as they begin dialysis (17). Individuals with LVH have both eccentric and concentric hypertrophy (18,19). Eccentric hypertrophy results from volume overload leading to cardiac myocyte dropout; LVH is characterized by a myocyte to arteriolar capillary mismatch. Concentric hypertrophy typically is the result of hypertension and increased afterload and is exacerbated by anemia, hyperparathyroidism, and high angiotensin II concentrations. Eccentric and concentric hypertrophy are relatively equivalent in prevalence in dialysis patients. The dominant LV physiology that accompanies heart disease in patients who are on dialysis is that of diastolic dysfunction (17,19). This physiology results in a sharp increase in LV diastolic pressure with modest increments in LV volume; the implication of the physiology is that patients have a lower threshold to pulmonary edema under these circumstances (Figure 2). Conversely, patients who undergo ultrafiltration on dialysis can experience a sharp fall in LV diastolic pressure under circumstances of a modest volume reduction, thereby risking sudden hypotension and hemodynamic instability. Patients with LVH also often have a reduction in systolic function, and the presence of this abnormality also exposes patients to the risk for sudden CV death (20). Cardiac arrhythmias and cardiac deaths are common in dialysis patients of all ages but are particularly problematic in patients who are older than 65 yr (21). There are many potential reasons for the problem of sudden death: Abnormalities in the coronary microcirculation; impaired coronary reserve; reduced aortic compliance; increased activity of the sympathetic nervous system; the increased plasma concentration of angiotensin II; and sudden changes in the concentrations of potassium, calcium, and magnesium (which occur normally during dialysis) all can contribute to this problem. Another recent contributor to the problem of sudden death in this patient population may be related to the degree of fibrosis in the hearts of individuals on dialysis (22). In a recent study by Aoki et al. (22), myocardial biopsies revealed abnormal cardiac myocyte anatomy and an interposition of dense fibrosis in the hearts of individuals who were on dialysis. Individuals with a higher fibrosis score had a shorter survival than individuals with a lower fibrosis score, suggesting that the presence of dense fibrosis denotes intrinsic myocardial damage and lowers the threshold for arrhythmias. In the aggregate, then, both CAD and LVH contribute to CV mortality in the dialysis population that dramatically exceeds that of the general population. This has been demonstrated in several recent publications and represents the major challenge for physicians who treat such patients. Figure 3 depicts this increase in CV mortality that occurs in this patient group graphically. Causes of Coronary Disease and LVH in CKD/ESRD A comprehensive discussion of all of the causes of heart disease in patients with CKD and ESRD is beyond the scope of this communication. This section provides a brief overview of several current issues that are relevant to the problem. It is known that patients with kidney disease have a high prevalence of other disorders that independently are associated with poor CV outcomes. For example, the high prevalence of diabetes in any CKD/ESRD cohort, the presence of hypertension in virtually all of the patients, the presence of LVH by electrocardiogram or echocardiography in the great majority of patients, that most patients have reduced physical activity and low exercise tolerance, that many patients have a lower-than-ideal HDL cholesterol concentration, that there is high oxidant stress in this group of individuals, and that many individuals have a high concentration of inflammatory biomarkers all contribute to the high prevalence of heart disease in this group. It should be acknowledged that patients in this group do have a lower prevalence of some traditional CV risk factors. For example, this group of patients is less typically obese, uses tobacco less frequently, and has less hypercholesterolemia (lower LDL levels) than the general population. Figure 4 is a schematic depiction of how many of the factors that contribute to heart disease in patients with kidney disease could result ultimately in LVH and CAD in patients with CKD and ESRD. A number of modifiable risk factors cited above are present in this patient group. Several uremia-related factors may also contribute to the problem; for example, anemia contributes to LVH, and a high calcium/phosphorus product will reduce aortic compliance that leads to an increased pulse wave velocity and an additional burden on the left ventricle. Vasoactive peptide concentrations (e.g., with endothelin and angiotensin II) are elevated and act as potent vasoconstrictors that exacerbate coronary vasoconstriction. The net result of all of these factors is an increased prevalence of coronary disease and LVH in this patient group. With regard to coronary disease in patients with ESRD, it is increasingly apparent that increased oxidant stress and inflammation are present, and this is reviewed in the following section. A number of nontraditional factors for coronary disease have also been identified in patients with CKD/ESRD. Hyperhomocysteinemia is associated with poorer survival in patients with coronary disease in the dialysis population (23). Recent studies on the ability of folic acid to lower the CV event rate by lowering homocysteine concentrations in patients with ESRD have been disappointing (24). For example, a recent study that used high-dose folic acid in 510 patients and had a mean follow-up of 24 mo did not detect any effect of folic acid on event-free survival (24). New prospective studies on this subject are under way and should reveal some insight into the best management of this problem. Another area of growing interest and focus has been the heightened recognition that arterial calcification in coronary vessels is very common in patients with CKD and ESRD (25,26). There is currently a debate over whether the calcification in coronary vessels that is detected by electron beam tomography (EBCT) in patients with CKD/ESRD denotes intraluminal narrowing of these vessels. Much of the calcification in these coronary vessels of patients with uremia resides in the media of the vessel, which does not result in intraluminal narrowing of the vessel. A recent study suggested that the calcification score of vessels obtained did not correlate with the severity of vessel stenosis by coronary angiography (27). However, another recent study suggested that the calcium score that is obtained by EBCT is reliable in defining the number of coronary vessels involved in an ESRD population (28). It is clear that the process of calcification in the coronary bed and other vascular beds is complicated; one new recently proposed factor that may have a major role to play in this calcification scheme is a substance called fetuin-A, which inhibits the mineralization of vascular smooth muscle cells both in vitro and in vivo (29). Even if the calcification of coronary vessels is not linked directly to intraluminal narrowing in patients with CKD and ESRD, the increased vascular stiffness in the aorta increases pulse pressure, which, in turn, results in increased afterload and the burden of cardiac work (30). An increase in pulse wave velocity occurs as renal function decreases, suggesting that there is a continuum of an increased burden on the heart as renal function declines (30). In summary, vessel calcifications are common in patients with CKD and ESRD, particularly in the coronary vascular bed. Having coronary vessel calcifications on EBCT denotes a poorer prognosis than not having them, but there is still controversy over the degree of coronary luminal narrowing that can be ascribed to these calcifications in this patient group. Another subject of recent interest and study with regard to the cause of coronary disease has been the role of oxidant stress. In this regard, the accumulation of asymmetric dimethyl arginine has been shown to be a potent inhibitor of nitric oxide synthesis in endothelial cells (31). More problematic is the issue of whether antioxidant therapy can reduce CV events in patients with ESRD. In this regard, a recent study in which 134 patients who were on hemodialysis were followed for 14 mo received the potent antioxidant N-acetylcysteine (NAC; 600 mg twice daily) or a placebo. The primary end point in the study was a composite of myocardial infarction, CV death, coronary angioplasty, coronary artery bypass grafting, ischemic stroke, peripheral vascular disease, or peripheral vascular disease with amputations. The result of the study was mixed; 28% of the individuals in the NAC group reached one of the end points versus 47% of the individuals in the control group (P < 0.03) (32). However, for individual end points such as cardiac death, ischemic stroke, and peripheral vascular disease, there was no difference in the groups. Finally, there is increasing interest as to whether biomarkers can predict individuals who are at particular risk for CV death in the setting of CKD or ESRD. deFilippi et al. (15) suggested that a combination of high C-reactive protein cardiac troponin-T levels not only predicts CV death in patients with ESRD but also identifies the subpopulation of patients with ESRD and multivessel coronary disease (15) (Figure 5). Similarly, the use of N-terminal pro brain natriuretic peptide levels may have some utility in predicting outcome in patients with ESRD as well (33). As more pathophysiologic factors of importance are identified for LVH and coronary disease and more biomarkers are linked to these processes, it is likely that there will be an array of screening tests that will identify a particular patient’s particular risk for a CV death. Can Both Heart and Renal Disease Be Affected Favorably by Lowering of BP, Inhibition of the Renin Angiotensin System, and Lowering of Urinary Protein Excretion? Given that the prevalence of impaired kidney function continues to increase (34) in the context of higher BP and proteinuria (35,36), the question arises as to whether therapies that are directed at these abnormalities yield both a cardiac and a renal protective effect. This cardio–renal relationship is particularly evident in individuals with diabetes (37–39), a population of patients that accounts for the greatest proportion of the CKD/ESRD group (40). This section reviews the possibilities that interventions aimed at lowering BP via the inhibition of the renin-angiotensin system (RAS) and lowering protein excretion may be beneficial to both heart and kidney function. Is Lowering BP Equally Cardio- and Renoprotective? A large number of studies have repeatedly confirmed that treatment of increased BP decreases both cardiac and particularly cerebrovascular events in patients with diabetes (41–44) as well as those without diabetes (45,46). Such an effect of lowering BP is also one of the primary findings of a large meta-analysis that was performed by the Blood Pressure Lowering Treatment Trialist Collaboration that concluded, “Any commonly used regimen reduces the risk of total CV events and larger reductions in BP produce larger reductions in risk” (47). A similar protection afforded by decreasing BP on the progression of renal disease emerged from the analysis performed by Bakris et al. (48), who found a significant (P < 0.05) relationship between the achieved mean arterial pressure in 10 trials that were performed in patients with diabetes and the rate of decline in GFR in the same trials. The trials that demonstrated CV protection in individuals with diabetes were performed predominantly or almost exclusively in patients who had little or no underlying renal disease. Because the presence of renal disease per se, as noted above, imparts an added risk, it is unclear whether the results of those trials can be readily extrapolated to patients with impaired renal function. Furthermore, although target BP have been lowered progressively, it is not clear which component of the BP is important and whether the optimal BP is the same for the heart as it is for the kidney. In this regard, most CV trials have scant renal end points, and, conversely, renal trials are frequently devoid of CV outcome data. Recent trials in patients with overt diabetic nephropathy (49,50) monitored both renal and CV events, allowing perhaps for the first time the assessment of the effect of BP reduction on the CV and renal systems in the same patient population. An analysis of the effect of achieved BP in the Irbesartan Diabetic Nephropathy Trial (IDNT) (51) sheds some light on the question at hand. This trial is a double blind, randomized, placebo-controlled trial performed in 209 clinics worldwide in patients with overt diabetic nephropathy (urinary protein and a concentration to Of the patients in the had at a In this group of patients, over a mean follow-up of yr, an of BP were per As is in Figure the risk for reaching a renal end point of or ESRD, by that the risk decreases as achieved systolic BP decreases from to The group did not have a risk from that of the to A in was associated with a 47% risk reduction for a renal end Furthermore, achieved is an risk factor for renal of the of to progression of renal disease were also in a trial of individuals without diabetes but were not in the of Kidney Disease and trial of individuals The revealed no significant between diastolic BP and renal An analysis of achieved BP and CV mortality in this same patient population provides a (Figure As is evident from the examination of Figure the risk for both mortality (Figure and CV mortality (Figure in the of patients was by a of and < There were only patients in this and an examination as to how these patients from the other patients revealed that they had a higher of heart disease and heart It is of that when the effect of levels of are in only those patients with an there is a significant protection for lowering to this for CV and heart but not for risk for myocardial or In to the effect of changes in on renal in were associated with an effect on the rate of myocardial and Thus, whereas the as in Figure increased at a per 10 to < the risk for to < The increased risk for coronary events the controversy of whether there is a effect. has been by some but by that at a there may be a effect in patients with underlying ischemic disease, as the coronary is particularly to a in The population in of patients with diabetes and overt nephropathy is very likely to be by such patients. Furthermore, it is of interest to that the trial that patients with hypertension and CAD also found a of lower with myocardial a meta-analysis of randomized trials also revealed a point at a of on mortality Because decreasing is associated with increasing pulse pressure, the that an in pulse pressure may be for these findings has been The findings in the cohort that revealed that an increase in CV events in patients with a low and an such a the effect of low and increased pulse pressure are to it is of interest that in both and the of low was not associated with an increase in suggesting that there is no effect of an increased pulse pressure and that the of a low are to the coronary In summary, therefore, as to BP, it that the progressive lowering of to is associated with renal protection and a in mortality and CV However, at an there is renal protection but an increase in CV and heart in patients who have more underlying cardiac disease. in that are with patients with a effect is at a for myocardial but not for renal The effect of low be readily from the increase in pulse the to an in cerebrovascular events an effect that most likely is by impairment in coronary artery Inhibition of Both Heart and studies that were in the and showed that the inhibition of reduces the risk for death and CV events myocardial and increases survival in patients with LV function Such particularly in related to heart were in both the of in with the Angiotensin II and which use angiotensin In fact, these two of and to a beneficial effect on CV both in patients with heart and in patients with on the of a large of suggesting a effect of on progressive cardiac fibrosis the use of such as with or have been found to mortality in patients with heart The effect of inhibition on the progression of renal disease has also been in individuals both with and without diabetes In fact, inhibition may the progression of diabetic renal disease at but not calcium the risk for from to Similarly, both and the rate of progression from to overt but the two do not to in the rate at which renal function is in these patients Finally, in patients with overt two studies have demonstrated a effect of on the rate of of GFR such protection is also afforded by is not as the results in have results Because the large trials did not have an inhibitor this question may well In with the above in cardiac there is increasing interest in the that of the could be in the progression of renal disease. This has in studies performed in but there are studies that an effect associated with inhibition et al. in an study a in protein excretion when patients with CKD received mg of for for the study of the effect of such on the progression of kidney disease with more clinical end The question that arises is whether there is an between lowering BP and to a This was in recent for both reduction in the rate of of renal function (51) and the risk for heart For the the analysis is in Figure It is of that at any of achieved the patients who were on the had renal than those who were to the treatment In fact, to the in a risk reduction (P < of reaching a renal end point beyond that achieved by lowering the The of lowering and treatment with the were and A similar effect was for lowering and to the in the of heart Thus, on the lowered the risk for heart by and lowering by did by the combination of both lowered the risk by 53% In summary, inhibition of the with an inhibitor or an provides both cardiac and renal The protection is most for heart Inhibition of provides survival in patients with low LV and may also have The heart and of inhibition is and to the obtained from lowering Is Lowering Protein Equally and analysis of risk factors that predict the progression of kidney disease points to the of proteinuria as an important of such an This was in a study in individuals with diabetes in the in study that also individuals without diabetes and in the and trials proteinuria also has been found to be a of CV events in these two trials as well as in other such as for in Heart and Thus, there is little question that proteinuria is a or a for renal and cardiac to be is whether lowering protein excretion per reduces the This was in a of the trials. in a reduction in protein excretion at mo was associated with a risk for reaching a renal end point than those who did not do In fact, the analysis that of the effect of the that was used was by lowering protein The reduction in protein excretion was also associated with a in CV events such that of the protein excretion in of the CV risk In regard to renal very similar emerged from the analysis of as a reduction in proteinuria at mo was associated with an reduction in reaching a renal end on this issue be it that lowering protein excretion is beneficial in the kidney and the heart as In summary, in the question as to whether is for the kidney is for the it is clear that lowering BP the but there may be levels of and which some increase in risk A BP of to be a target as of the is beneficial to both but the protection that is afforded by inhibition to been defined for the kidney. Finally, lowering protein to the progression of kidney disease and also may be but this will data. Treatment for LVH and CAD As at the relatively few studies have in randomized trials one for overt heart disease versus another in patients with CKD or ESRD. With regard to the management of LVH, two studies have the potential of a in this setting In the first of these the was used in ESRD patients with II and New Heart heart a there was some in the group as compared with the group In a follow-up of this patient group over several there was survival and in the group as compared with these studies that there may be a beneficial role for in the setting of heart in dialysis patients. It should be that in these the use of a was not as of individuals who were to the therapy were to of the With regard to the management of there is an debate of the of coronary artery bypass versus Several one study suggested that coronary artery bypass were associated with an survival compared with There are several reasons for such a result have been that many patients with more who a very high risk for death in the are from coronary artery bypass In have in recent The clinical and angiographic rate in patients who undergo interventions has been reduced dramatically recently This is as of with in this group of patients is For example, in one such of 10 patients who were on 10 of 10 patients had a very result that was for yr without any myocardial infarction, or the for target current in the population of patients with CKD and ESRD is to use a combination of and in patients with known coronary disease. The potential of in all patients with CKD and ESRD a randomized, prospective As above, there is no on whether are and new studies are to this A recent study of the in dialysis patients results over an follow-up of 4 yr the one cardiac events were reduced in the patients, but the of was increased in this group. This result to no significant effect on the composite end point of the findings will additional analysis and study, but is to use to reduce LDL cholesterol concentrations in with current guidelines (7). For patients with control is as is evident from the discussion on BP and protein the of in the patient population is a that the an inhibitor or an volume control via dialysis or dialysis is currently also more dialysis or dialysis will be and in patients in the is under study at management of calcium and is currently a combination of for the management of the and that the should be in the to as a and the LDL cholesterol should be lowered to in dialysis patients and in patients with known coronary of the of death at 3 yr from cardiovascular heart stroke, cardiac and the composite end to the GFR at in patients with diastolic heart and in control heart Cardiovascular mortality in general population and dialysis population factors that contribute to heart disease in patients with kidney angiographic multivessel coronary artery disease (CAD) by of the risk of reaching a renal end point by of achieved follow-up systolic BP The number of patients who were at risk for reaching a renal end point of or ESRD, defined as or renal is for of achieved follow-up systolic of the of mortality by of achieved follow-up The number of patients who are at risk for death by any cause is for of achieved follow-up of the of cardiovascular mortality by of achieved follow-up The number of patients who are at risk for death by any cause is for of achieved follow-up of myocardial by of achieved diastolic The number of patients who are at risk for death for of BP is at the of of achieved and treatment on the of reaching a renal end from with