Assessing cardiovascular risk in children with chronic kidney disease. B-type natriuretic peptide: a potential new marker

Elevated plasma B-type natriuretic peptide (BNP) level is a hallmark of altered left ventricular (LV) structure and function. Measurement of circulating BNP has proved to be a sensitive and specific diagnostic test for congestive heart failure (CHF) and coronary syndrome in adults. Further, BNP levels constitute a strong predictive marker for future cardiovascular (CV) events. In high CV risk populations, such as adults with hypertension or chronic kidney disease (CKD), increased BNP predicts CV morbidity and mortality in symptomatic or asymptomatic patients. However, caution is needed in interpreting plasma BNP levels, as they increase with both age and decreased renal function. Despite increasing evidence of the value of BNP in the medical literature in adults, data in children are limited to those with congenital heart disease. It is appropriate to analyze the potential application of this tool in children with CKD, a well-known factor for CV disease.     

Cardiovascular risk assessment in children with chronic kidney disease

Chronic kidney disease (CKD) is a major factor contributing to cardiovascular (CV) morbidity and mortality with the highest risk in patients on dialysis. An estimation of CV risk is important not only to identify potential modifiable risk factors but also to evaluate the effect of treatments aimed to reduce the risk. Non-invasive methods of measuring vascular changes and circulating biomarkers are available to assess the presence and severity of cardiovascular damage. These include measures of structural (carotid intima-media thickness and coronary artery calcification score) and functional (aortic pulse wave velocity, 24-h ambulatory blood pressure monitoring, ambulatory arterial stiffness index, heart rate variability and flow-mediated dilatation) changes in the vessel wall. In addition, a number of circulating biomarkers of vascular damage and its progression have been studied. Many of these tests are well validated as surrogate markers of future cardiovascular events and death in adult CKD patients, but need technical adaptation, standardization and validation for use in children. With our current state of knowledge, these are best reserved for research studies and scarce clinical resources may be better utilized for preventative strategies to reduce the modifiable risk factors for calcification from early CKD stages.     

Hypertension and kidney protection in the elderly: what is the evidence in 2007?

Hypertension and diabetes mellitus are the two most widely recognized risk factors for cardiovascular disease (CVD), chronic kidney disease (CKD), and end-stage renal disease (ESRD) requiring dialysis/transplantation; both become increasingly important as one ages. Common pathways and mechanisms are involved in the development of renal vascular lesions in both conditions, and effective treatments for each are now available to reduce morbidity, mortality and progression of organ damage. Although this review will focus primarily on the ability to protect the kidney and vasculature elsewhere by lowering blood pressure in the elderly, other approaches, specifically dietary restriction of protein, strict control of diabetes mellitus, and the management of the different dyslipidemias, must be used in conjunction with the antihypertensive agents to obtain optimum protection.     

The lipid story in chronic kidney disease: a long story with a happy end?

Cardiovascular (CV) morbidity and mortality increase with the severity of kidney disease, reaching 30 times higher mortality rates in dialysis patients compared with the general population. Although dyslipidemia is a well-established CV risk factor in the general population, the relationship between lipid disorders and CV risk in patients with chronic kidney disease (CKD) is less clear. Despite the clear evidence that statins reduce the risk of atherosclerotic events and death from cardiac causes in individuals without CKD, the use of statins in patients with kidney disease is significantly less frequent. For a long time, one of the explanations was the lack of a prospective, randomized, controlled study designed specifically to CKD patients. After recent publication of the data from Study of Heart and Renal Protection trial, given the safety and potential efficacy of statins, this lipid-lowering treatment should be administered more frequently to individuals with CKD stage 1–4, as well as those undergoing dialysis.     

Cardiovascular complications of pediatric chronic kidney disease

Cardiovascular disease (CVD) mortality is a leading cause of death in adult chronic kidney disease (CKD), with exceptionally high rates in young adults, according to the Task Force on Cardiovascular Disease. Recent data indicate that cardiovascular complications are already present in children with CKD. This review summarizes the current literature on cardiac risk factors, mortality and morbidity in children with CKD.     

Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Both in dialysis and in transplant patients, CVD remains the leading cause of death. There is accumulating evidence that the increase in CVD burden is present in patients prior to dialysis, due to both conventional risk factors as well as those specific to kidney disease. Of importance is that even in patients with mild kidney disease, the risk of cardiovascular events and death is increased relative to patients without evidence of kidney disease. The new classification system proposed by the National Kidney Foundation as part of the Dialysis Outcomes Quality Initiative (DOQI) process describes the five stages of kidney disease, as well as those complications associated with chronic kidney disease (CKD), in particular cardiovascular risk factors and disease. Patients with kidney disease are deemed to be at highest cardiovascular risk. CVD, defined as the presence of either congestive heart failure (CHF), ischemic heart disease (IHD), or left ventricular hypertrophy (LVH), is prevalent in cohorts with established CKD (8-40%). The prevalence of hypertension, a major risk factor for coronary artery disease (CAD) and LVH is high in patients with CKD (87-90%). At least 35% of patients with CKD have evidence of an ischemic event (myocardial infarction or angina) at the time of presentation to a nephrologist. The prevalence of LVH increases at each stage of CKD, reaching 75% at the time of dialysis initiation, and the modifiable risk factors for LVH include anemia and systolic blood pressure, which are also worse at each stage of kidney disease. Even under the care of nephrologists, a change in cardiac status (worsening of heart failure or anginal symptoms) occurs in 20% of patients. The presence of CVD predicts a faster decline of kidney function and the need for dialysis, after controlling for all other factors including glomerular filtration rate (GFR), age, and the presence of LVH. This article describes the new classification system for staging of CKD, defines and describes CVD in CKD, and reviews the evidence and its limitations with respect to the current understanding of CKD and CVD. Specifically, methodologic issues related to survival and referral bias limit our current understanding of the complex interaction of conventional and nonconventional kidney disease-specific risk factors. We identify the importance of well-conducted studies of patient groups with and without CVD, with and without CKD, in order to better understand the complex physiology so that treatment strategies can be appropriately applied.     

Hypertension in kidney transplantation

Arterial hypertension in renal transplant patients plays a major role in the progression to chronic allograft failure, and in morbidity and mortality associated with cardiovascular disease. Its cause is diverse, with contributions not only from donor and/or recipient factors, but it also is influenced strongly by the type of immunosuppressive regimen. Despite increased awareness of the adverse effects of hypertension in both graft and patient survival, long-term studies have shown that arterial hypertension in the transplant population has not been controlled adequately. Ambulatory blood pressure measurements provide the advantage of a better assessment of the diurnal blood pressure variation, a predictor of target organ damage and cardiovascular morbidity and mortality events. Although the available data do not support the recommendation of any class of antihypertensive medication as preferred agents for blood pressure management in the transplant population, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have shown beneficial effects beyond their antihypertensive effects. Clinical data in transplant recipients are emerging that suggest that applying interventions proven to be effective in reducing cardiovascular morbidity and mortality in the general population may be effective for the transplant population.     

Which drug should be used to treat patients with uncomplicated essential hypertension?

PURPOSE OF REVIEW: To review recent data and guidelines on selecting the initial antihypertensive drug. RECENT FINDINGS: The main driver of benefit from blood pressure-lowering therapy is blood pressure reduction, and there is little evidence supporting additional drug class-specific benefits in primary prevention of major cardiovascular outcomes. The results also confirm that in the patient with uncomplicated hypertension as well as in those patients with diabetes without nephropathy, initial therapy with 'newer therapies' (i.e. angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin receptor blockers) are effective, but not more effective than thiazide diuretics, at reducing stroke, coronary heart disease, morbidity or mortality, or all-cause mortality. SUMMARY: While compelling indications may exist for specific drug classes in those with specific target organ damage (i.e. heart failure, renal insufficiency, and coronary artery disease), thiazide diuretics remain unsurpassed in lowering blood pressure and in preventing hypertension-related clinical outcomes. Despite a more favorable metabolic profile, alpha-blockers are less effective in preventing cardiovascular disease, especially heart failure and stroke. Calcium channel blockers produce a similar reduction in blood pressure and cardiovascular disease outcomes compared with thiazide-type diuretics, although they are consistently less effective in preventing heart failure. In the absence of heart failure or renal disease, angiotensin-converting enzyme inhibitors have shown little advantage in clinical trials over diuretics in preventing cardiovascular disease and are not indicated as an initial therapy in Blacks.     

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.     

Cardiovascular Complications in Diabetic Kidney Disease

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). Due to an explosion in the incidence and the prevalence of Type 2 DM, the burden of CKD is expected to increase proportionately. Both DM and CKD are associated with a high incidence of cardiovascular (CV) morbidity and mortality, and it is important to understand the unique nature of CV disease in patients with the combination of these two conditions. In this report, we review the traditional and nontraditional risk factors that underlie the high risk of CV disease in this population, with a particular focus on vascular calcification, mineral metabolism, and therapeutic paradigms for the treatment of cardiovascular disease in this unique and high‐risk population.     

Dyslipidemia, statins, and CKD patients' outcomes - review of the evidence in the post-sharp era

Hyperlipidemia in the general population is strongly associated with an increased incidence of major adverse cardiovascular (CV) events (MACE). It is well established that HMG-CoA reductase inhibitors (statins) reduce CV and all-cause mortality in the general population, as well as in patients with CV disease (CVD). However, such a finding has not been definitively confirmed in patients with chronic kidney disease (CKD). Given that CV risk gradually increases with increasing stages of CKD (and is even higher in dialysis patients), it is of major relevance and importance to identify whether CKD patients might also benefit from alteration of lipid fractions, and how this might best be achieved. Bearing in mind that animal model and preclinical evidence suggests dyslipidemia might also be a factor promoting worsening renal function, it could legitimately be asked whether treating it may also therefore have a nephroprotective effect.     

Abnormalities of vascular structure and function in pediatric hypertension

Hypertension is associated with adverse cardiovascular (CV) events in adults. Measures of vascular structure and function, including increased carotid intima–media thickness (cIMT) and elevated arterial stiffness predict hard CV events in adulthood. Newer data suggest that abnormalities in target organ damage are occurring in adolescents and young adults with high blood pressure. In this review, we discuss the techniques for measuring vascular dysfunction in young people and the evidence linking blood pressure levels to this type of target organ damage.     

Cardiovascular risk in chronic kidney disease

National Kidney Foundation guidelines define chronic kidney disease (CKD) as persistent kidney damage (confirmed by renal biopsy or markers of kidney damage) and/or glomerular filtration rate (GFR) <60 mL/min/1.73m2 for greater than three months. Patients with CKD experience higher mortality and adverse cardiovascular (CV) event rates, which remains significant after adjustment for conventional coronary risk factors. This progressive CV risk associated with worsening renal function may be explained by other factors that become increasingly important with renal decline. In this regard, more investigation of nonconventional factors that have received a lot of attention includes associations with inflammation, albuminuria, reduced vascular compliance, and homocysteine. In addition, individuals with CKD encounter the problem of "therapeutic nihilism," in which there is a lack of appropriate risk factor modification and intervention, despite established awareness of their high cardiovascular risk. Several studies suggest that these individuals derive as much, if not more, benefit from evidence-based cardiovascular therapies and strategies. Greater educational efforts are needed to reduce this therapeutic gap.     

Effects of oral alkali drug therapy on clinical outcomes in pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis

BackgroundMetabolic acidosis accelerates the progression of chronic kidney disease (CKD) and increases the mortality rate. Whether oral alkali drug therapy benefits pre-dialysis CKD patients is controversial. We performed a meta-analysis of the effects of oral alkali drug therapy on major clinical outcomes in pre-dialysis CKD patients.MethodsWe systematically searched MEDLINE using the Ovid, EMBASE, and Cochrane Library databases without language restriction. We included all eligible clinical studies that involved pre-dialysis CKD adults and compared those who received oral alkali drug therapy with controls.ResultsA total of 18 eligible studies, including 14 randomized controlled trials and 4 cohort studies reported in 19 publications with 3695 participants, were included. Oral alkali drug therapy led to a 55% reduction in renal failure events (relative risk [RR]: 0.45; 95% confidence interval [CI]: 0.25–0.82), a rate of decline in the estimated glomerular filtration rate (eGFR) of 2.59 mL/min/1.73 m² per year (95% CI, 0.88–4.31). There was no significant effect on decline in eGFR events (RR: 0.34; 95% CI: 0.09–1.23), proteinuria (standardized mean difference: −0.32; 95% CI: −1.08 to 0.43), all-cause mortality events (RR: 0.90; 95% CI: 0.40–2.02) and cardiovascular (CV) events (RR: 1.03; 95% CI: 0.32–3.37) compared with the control groups.ConclusionBased on the available and low-to-moderate certainty evidence, oral alkali drug therapy might potentially reduce the risk of kidney failure events, but no benefit in reducing all-cause mortality events, CV events, decline in eGFR and porteninuria.     

Role of combination therapy with ACE inhibitors and calcium channel blockers in renal protection

Over recent years, a target blood pressure of 125/75 mm Hg has been sought in order to reduce the rate of chronic renal disease (CKD) progression and cardiovascular mortality. Some antihypertensive agents, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and calcium channel blockers also may be capable of reducing CKD progression because they halt some of the pathogenetic mechanisms involved in renal damage. The possibility that combination treatments with ACE inhibitors and calcium-channel blockers may confer additive or even synergistic renoprotective effects other than blood pressure control is not only fascinating, but also particularly important because multidrug antihypertensive regimens are required to obtain adequate blood pressure in the majority of patients with CKD. This combination may provide better blood pressure control, appears to be better tolerated with fewer side effects than either drug alone, and may exert a greater renoprotective effect in patients at risk for renal failure than either an ACE inhibitors or a calcium channel blocker. However, the current available data are too few to confirm this hypothesis. Cardiovascular disease accounts for more than 50% of the deaths of hemodialysis patients. Thus, care must be taken to prevent and treat the cardiovascular risk factors optimally from the early phase of CKD, and for this reason effective antihypertensive therapy is the most important treatment, not only in order to delay CKD progression, but also to reduce the burden of cardiovascular disease. In this perspective combination therapy with ACE inhibitors and calcium channel blockers can give further advantages.     

Cardiovascular care in end-stage renal disease

Cardiovascular disease (CVD) accounts for the majority of morbidity and mortality in patients with end-stage renal disease (ESRD). Chronic kidney disease, and ESRD as its most severe form, are now acknowledged to be independent risk factors for CVD. The spectrum of CVD includes accelerated atherosclerosis, myocardial disease and heart failure, cardiac arrhythmias, and valvular heart disease. In addition, CKD and ESRD are independent and powerful factors that complicate cardiovascular procedures and have been directly linked to increased mortality. This issue of Advances in Chronic Kidney Disease will explore the spectrum of risk and the opportunities to improve care in ESRD in outpatient management, during dialysis, after kidney transplantation, and in coronary revascularization.     

Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease

Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population.     

Heart rate as a risk factor for developing chronic kidney disease: longitudinal analysis of a screened cohort

Background  

High heart rate and chronic kidney disease (CKD) are both risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and the risk of developing CKD, however, has not been studied in a large screened cohort.     

Rationale and design of the MASTERPLAN study: Multifactorial approach and superior treatment efficacy in renal patients with the aid of nurse practitioners

BACKGROUND: Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease (CVD). In addition, patients with renal disease are exposed to a myriad of risk factors that increase their risk even further. The treatment of risk factors in these patients is paramount to reducing cardiovascular risk and for attenuating renal failure progression. It is well known that lifestyle interventions are difficult, and that medical treatment targets are seldom met. A multifactorial approach with the aid of nurse practitioners has shown to be beneficial for achieving treatment goals and reducing events in patients with diabetes mellitus and with heart failure. We propose that this will also hold for the CKD population. TRIAL DESIGN: A multicenter randomized clinical trial will be performed to study whether intensive medical care delivered by a nurse practitioner and a nephrologist will reduce cardiovascular risk compared to care provided by the nephrologist alone. The acronym MASTERPLAN describes the study: Multifactorial approach and superior treatment efficacy in renal patients with the aid of nurse practitioners. Eight hundred patients will be randomized to physician care or nurse practitioner support. For all patients the same set of guidelines and treatment goals will apply. Both groups will receive treatment according to current guidelines and have access to specific cardioprotective medication. Nurse practitioners will intensify therapy by promoting lifestyle intervention, and meticulous implementation of relevant guidelines. Patients will be followed-up for 5 yrs after baseline. Primary endpoints are all-cause mortality, cardiovascular morbidity and cardiovascular mortality.     

Cardiovascular morbidity and mortality after kidney transplantation

Kidney transplantation is the optimal treatment for patients with end stage renal disease (ESRD) who would otherwise require dialysis. Patients with ESRD are at dramatically increased cardiovascular (CV) risk compared with the general population. As well as improving quality of life, successful transplantation accords major benefits by reducing CV risk in these patients. Worldwide, cardiovascular disease remains the leading cause of death with a functioning graft and therefore is a leading cause of graft failure. This review focuses on the mechanisms underpinning excess CV morbidity and mortality and current evidence for improving CV risk in kidney transplant recipients. Conventional CV risk factors such as hypertension, diabetes mellitus, dyslipidaemia and pre‐existing ischaemic heart disease are all highly prevalent in this group. In addition, kidney transplant recipients exhibit a number of risk factors associated with pre‐existing renal disease. Furthermore, complications specific to transplantation may ensue including reduced graft function, side effects of immunosuppression and post‐transplantation diabetes mellitus. Strategies to improve CV outcomes post‐transplantation may include pharmacological intervention including lipid‐lowering or antihypertensive therapy, optimization of graft function, lifestyle intervention and personalizing immunosuppression to the individual patients risk profile.