Cardiovascular changes during chronic hypertensive states

It is well established that elevated blood pressure constitutes a major risk factor for coronary heart disease, arrythmias, heart failure, cerebrovascular disease, peripheral artery disease and renal failure. Blood pressure level and the duration of arterial hypertension (HTN) impact target organ damage. Many studies in adults have demonstrated the role of antihypertensive therapy in preventing cardiovascular (CV) events. The so-called hard end-points, such as death, myocardial infarction (MI) or stroke, are rarely seen in children, but intermediate target organ damage, including left ventricular hypertrophy, increased intima-media thickness and microalbuminuria, is already detectable during childhood. The goal of antihypertensive treatment is to reduce the global risk of CV events. In the adult population stratification of CV risk is based on blood pressure level, risk factors, subclinical target organ damage and established CV and kidney disease. Increased CV risk begins early in the course of kidney disease, and CV diseases are the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD). Children with CKD are especially prone to the long-term effects of CV risk factors, which result in high morbidity and mortality in young adults. To improve the outcome, pediatric and adult CKD patients require nephro- and cardioprotection.     

B-type natriuretic peptides are reliable markers of cardiac strain in CKD pediatric patients

Myocardial damage and strain are common in children with chronic renal failure. The most prevalent pathologies, as defined by echocardiography, are left ventricular hypertrophy (LVH), diastolic and systolic dysfunction, and altered LV geometry. Troponin I and T, as well as B-type natriuretic peptide (BNP) and its cleavage fragment NT-proBNP, are known to be good markers of myocardial damage and stress, respectively, in the general adult population and among those with chronic kidney disease (CKD). In this study we measured the levels of troponins I and T, BNP, and NT-proBNP in a group of children and young adults with CKD stages 3–5 and determined their respective correlations with echocardiographic and laboratory abnormalities. BNP and NT-proBNP levels and their log values correlated well with the following parameters: diastolic blood pressure, estimated glomerular filtration rate, time-averaged hemoglobin levels, and LV mass. Both BNP and NT-proBNP levels, but not those of either troponin, were found to be reliable surrogate markers of strained hearts, defined as having LVH or diastolic or systolic dysfunction, in the pediatric CKD stages 3–4 group. The log NT-proBNP value was also found to be a good marker of cardiac strain in the CKD stage 5 group of patients. Serum BNP and NT-proBNP threshold concentrations of 43 and 529 pg/ml, respectively, were found to have the best sensitivity and specificity in predicting strained hearts. Based on these findings, we conclude that both BNP and NT-proBNP levels, but not those of troponins I and T, can serve as inexpensive, simple, and reliable markers of stressed hearts in the pediatric CKD patient population.     

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.     

慢性肾脏病血清β-脑钠肽、同型半胱氨酸与心血管病变的关系

目的探讨血清β-钠肽（BNP）、同型半胱氨酸（Hcy）与慢性肾脏病（CKD）35期心血管事件的发生和病死率的关系。方法本组77例CKD患者,按NKF-DOQI指南分为CKD3期（A组）17例,CKD4期（B组）21例和CKD5期（C组）39例。正常对照组30例,观察各组临床表现、生化指标,血清BNP、Hcy等变化。同时,将77例患者根据Hcy数值分为升高组和正常组,观察其与心血管疾病（CVD）的相关性。结果与正常对照组比较,A、B、C组血肌酐（SCr）、尿素氮（BUN）、BNP明显升高,B组与A组比较,C组与B组比较,各组数值差异均有统计学意义。与Hcy正常组比较,Hcy升高组发生CVD明显增加,具有正相关关系。结论本研究显示,BNP和Hcy可作为慢性肾衰竭早期心血管损害的指标之一,BNP,Hcy与CVD发生及病死率的关系密切,BNP、Hcy越高,CVD的发生率越高,病死率也越高。     

Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease

BACKGROUND: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. PATIENTS AND METHODS: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. RESULTS: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = -0.756, p < 0.0001). CONCLUSIONS: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.     

慢性肾脏病非透析患者脑钠素与动脉粥样硬化及心功能的关系

目的 研究脑钠素（BNP）与慢性肾脏病（CKD）非透析患者动脉粥样硬化及心功能不全的关系。 方法 采用双抗夹心免疫荧光法检测203例CKD非透析患者与16例高血压患者对照组全血BNP水平，分析其与颈动脉超声结果、心脏彩超结果及既往心血管疾病史的关系。 结果 CKD非透析患者BNP水平与对照组相比显著升高[M（范围）：54.40(15.10～ 173.00) ng/L比9.35(7.35～15.00) ng/L，P < 0.01]。Spearman相关分析显示CKD患者BNP与颈动脉内膜中层厚度（IMT）、左室心肌重量指数（LVMI）等呈正相关。存在颈动脉斑块、左室肥厚或既往发生过心血管事件的患者血BNP水平显著增高。多元回归分析显示LVMI、既往心血管事件均是影响BNP水平的独立因素。 结论 CKD非透析患者BNP水平和动脉粥样硬化性疾病、左室肥厚及心功能不全相关，提示BNP水平可作为一项评价CKD非透析患者心功能及动脉粥样硬化的敏感生物学指标。     

Recent advances in pediatric dialysis: a review of selected articles

Important discoveries and studies that help inform us about the best methods to evaluate and manage children with end-stage renal disease (ESRD) continue to emerge. This review addresses a number of recent publications regarding important clinical issues for children with ESRD. Despite advances made in previous years, many clinical problems remain in the care of the pediatric dialysis patient. This review covers five topics of recent interest: three articles that address important patient outcome measures such as dialysis adequacy and hemoglobin; two articles that address growth failure in a chronic dialysis patients; five articles that address cardiovascular (CV) morbidity, mortality, and interventions to reduce CV risk in children; two articles that address mineral-bone disorder (MBD) and evidence that past strategies for MBD in children may have increased CV disease; and two articles that address nephrogenic systemic fibrosis, a recently described disorder in chronic kidney disease (CKD) patients that occurs in children as well as adults. Using a concise consistent format, each of the 14 key publications is summarized, and the "conclusion" for the practitioner is identified. The goal of this review is to highlight important work done in this area and focus attention on the important issues raised by each article.     

Intraindividual interleukin-6 variations on the cardiovascular prognosis of patients with chronic renal disease

In chronic kidney disease (CKD) patients on dialysis, plasma interleukin (IL)-6 levels predict mortality better than other markers. Impact of intraindividual changes of inflammatory markers on cardiovascular (CV) events in CKD patients is unknown. The aim of this study is to demonstrate the relation between CV outcomes and variations of C-reactive protein (CRP), IL-6, IL-1β, and tumor necrosis factor (TNF)-α in CKD. Ninety patients (mean age: 68.5 ± 12.8 years) at different stages (1-4) of CKD were evaluated. Serum CRP, IL-6, IL-1β, and TNF-α were measured basally and after taking statins or angiotensin II receptor blockers. Three patterns were defined for each marker (baseline, mean of two measurements, and variation of the marker: increase or decrease after 6 months). During follow-up (mean time: 72.7 ± 19.8 months), 14 patients died, 11 were included on dialysis program, and 29 suffered a CV event. Patients with persistently elevated IL-6 values had higher risk to develop CV events [OR = 1.21 (1.11-1.32), p = 0.001]. Mean of two measurements of IL-6 was a better predictor for events than a single measurement of IL-6, CRP, TNF-α, and IL-1β. A mean of two determinations of plasma IL-6 greater than 6 pg/mL and previous peripheral vascular disease was related to an increased risk for CV events [2.34 (1.05-5.22), p = 0.037 and 2.95 (1.27-6.93), p = 0.011, respectively] in an adjusted Cox regression model. IL-6 is a better inflammatory marker than CRP, TNF-α, and IL1β at predicting CV events in CKD nondialysis patients. Mean of two measurements is better than simple determinations at predicting CV outcome.     

Elevated serum parathyroid hormone is a cardiovascular risk factor in moderate chronic kidney disease

Introduction  

Over 8% of adults in the United States are estimated to have moderate (stages 3 and 4) chronic kidney disease (CKD), which is increasingly recognized as one of the independent predictors for cardiovascular (CV) disease and related mortality. Secondary hyperparathyroidism with elevated serum intact parathyroid hormone (iPTH) is associated with increased CV mortality in end-stage renal disease and this relationship is unclear in moderate CKD.     

Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease

Decreased nitric oxide (NO) production and/or impaired NO bioavailability may occur in patients with chronic kidney disease (CKD), and could contribute to the elevation of blood pressure, cardiovascular disease (CVD) and the progression of renal injury in these patients. However, the underlying molecular mechanisms for reduced NO action in patients with CKD remains to be elucidated. Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue found in plasma and various types of tissues, acting as an endogenous NO synthase inhibitor in vivo. Further, plasma level of ADMA is elevated in patients with CKD and found to be a strong biomarker or predictor for future cardiovascular events. In addition, plasma level of ADMA could predict the progression of renal injury in these patients as well. These findings suggest that elevation of ADMA may be a missing link between CVD and CKD. In this review, we discuss the molecular mechanisms for the elevation of ADMA and its pathophysiological role for CVD in high-risk patients, especially focusing on patients with CKD.     

Prevalence of complications in children with chronic kidney disease according to KDOQI

The Kidney Disease Outcome and Quality Initiative (KDOQI) Group recommended guidelines for the monitoring and treatment of chronic kidney disease (CKD) in 2002. These recommendations were based on the prevalence of known complications as seen in adults. In children, the exact prevalence of these complications is unknown. We therefore conducted a cross-sectional study of 366 patients with CKD in a single center to analyze the prevalence of these complications across all stages of kidney disease. Patients were categorized to their KDOQI stage of CKD according to their estimated renal function as determined from serum cystatin C. Fifty seven percent of patients had CKD stage 1, 29.0% stage 2, 10.4% stage 3 and 4.1% stages 4+5. Uropathies (31%) were the most prevalent causes of CKD. Glomerular disease accounted for 27%. The overall prevalence of complications was as follows: hypertension 70.2%, anemia 36.6%, proteinuria 11.5%, and metabolic bone disease 16.9%. Metabolic bone disease and anemia occurred frequently, even with a glomerular filtration rate >60 ml/min/1.73 m2. Growth failure (11.5%) was also common and is not a component of the KDOQI guidelines for CKD in children. The prevalence of all complications increased with worsening stage of kidney disease (all P-values significant). In summary, this study supports the KDOQI guidelines in defining and staging CKD in children. This study also highlights the differences in the causes and complications that occur in CKD between adults and pediatrics. We recommend modification of the KDOQI guidelines for children to reflect the differences described in this paper.     

Brain natriuretic peptide and right heart dysfunction after heart transplantation

Heart transplantation (HT) should normalize cardiac endocrine function, but brain natriuretic peptide (BNP) levels remain elevated after HT, even in the absence of left ventricular hemodynamic disturbance or allograft rejection. Right ventricle (RV) abnormalities are common in HT recipients (HTx), as a result of engraftment process, tricuspid insufficiency, and/or repeated inflammation due to iterative endomyocardial biopsies. RV function follow‐up is vital for patient management as RV dysfunction is a recognized cause of in‐hospital death and is responsible for a worse prognosis. Interestingly, few and controversial data are available concerning the relationship between plasma BNP levels and RV functional impairment in HTx. This suggests that infra‐clinical modifications, such as subtle immune system disorders or hypoxic conditions, might influence BNP expression. Nevertheless, due to other altered circulating molecular forms of BNP, a lack of specificity of BNP assays is described in heart failure patients. This phenomenon could exist in HT population and could explain elevated BNP plasmatic levels despite a normal RV function. In clinical practice, intra‐individual change in BNP over time, rather than absolute BNP values, might be more helpful in detecting right cardiac dysfunction in HTx.     

Urotensin II in end-stage renal disease: an inverse correlate of sympathetic function and cardiac natriuretic peptides

BACKGROUND: Urotensin II (UTN) is a peptide highly conserved across species with disparate effects on the vascular system and it is currently unclear whether high plasma UTN levels play a vasculotoxic or a vasculoprotective role. METHODS: In this study, we investigated the relationship between plasma UTN and sympathetic activity and cardiac natriuretic hormones in 191 hemodialysis (HD) patients without clinical evidence of heart failure. RESULTS: Plasma UTN was significantly higher in patients with end-stage renal disease (ESRD) (median: 6.5 ng/mL) than in age matched healthy subjects (median: 3.1 ng/mL) (p<0.001). On univariate analysis, UTN was inversely related to heart rate (r=-0.24), dialysis treatment duration (r=-0.27), norepinephrine (r=-0.28), neuropeptide Y (NPY) (r=-0.66), brain natriuretic peptide (BNP) (r=-0.41) and atrial natriuretic peptide (ANP) (r=-0.28) (all p<0.008). Of note, in multiple regression analyses these associations maintained strength similar to that of the corresponding unadjusted correlation coefficients. CONCLUSIONS: The inverse links between UTN and neuro-hormonal factors indicate that UTN down-regulation in the presence of high sympathetic activity and high BNP could be a counter-regulatory response aimed at mitigating cardiovascular (CV) damage or that UTN itself acts as a protective factor.     

Intraindividual Interleukin-6 Variations on the Cardiovascular Prognosis of Patients with Chronic Renal Disease

In chronic kidney disease (CKD) patients on dialysis, plasma interleukin (IL)-6 levels predict mortality better than other markers. Impact of intraindividual changes of inflammatory markers on cardiovascular (CV) events in CKD patients is unknown. The aim of this study is to demonstrate the relation between CV outcomes and variations of C-reactive protein (CRP), IL-6, IL-1β, and tumor necrosis factor (TNF)-α in CKD. Ninety patients (mean age: 68.5 ± 12.8 years) at different stages (1–4) of CKD were evaluated. Serum CRP, IL-6, IL-1β, and TNF-α were measured basally and after taking statins or angiotensin II receptor blockers. Three patterns were defined for each marker (baseline, mean of two measurements, and variation of the marker: increase or decrease after 6 months). During follow-up (mean time: 72.7 ± 19.8 months), 14 patients died, 11 were included on dialysis program, and 29 suffered a CV event. Patients with persistently elevated IL-6 values had higher risk to develop CV events [OR = 1.21 (1.11–1.32), p = 0.001]. Mean of two measurements of IL-6 was a better predictor for events than a single measurement of IL-6, CRP, TNF-α, and IL-1β. A mean of two determinations of plasma IL-6 greater than 6 pg/mL and previous peripheral vascular disease was related to an increased risk for CV events [2.34 (1.05–5.22), p = 0.037 and 2.95 (1.27–6.93), p = 0.011, respectively] in an adjusted Cox regression model. IL-6 is a better inflammatory marker than CRP, TNF-α, and IL1β at predicting CV events in CKD nondialysis patients. Mean of two measurements is better than simple determinations at predicting CV outcome.     

Determinants of B-type natriuretic peptide plasma levels in the chronic phase after heart transplantation.

Determinants of B-type natriuretic peptide (BNP) plasma levels in the chronic phase after heart transplantation remain unclear. BNP was measured in 105 stable long-term heart transplant recipients with normal left ventricular function by echocardiography and correlated with clinical, demographic and hemodynamic parameters. Multivariate analysis revealed a significant correlation of BNP with female recipient gender (P = 0.006), time post-transplant (P =0.006), donor age (P = 0.007), angiographic signs of transplant vasculopathy (TVP) (P = 0.03), serum creatinine level (P = 0.04), and a strong trend for diastolic dysfunction (P = 0.09). Donor gender, recipient age, cyclosporin A blood levels, rejection history, and pulmonary artery pressure had no independent effect on BNP. BNP after heart transplantation appears to be influenced both by established general determinants (female gender, renal function) and transplant-specific determinants such as time post-transplant, donor age and potentially also TVP. In order to determine the value of BNP as a potential surrogate marker of TVP serial intraindividual measurements appear appropriate.     

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.     

C-type natriuretic peptide levels in cor pulmonale and in congestive heart failure.

BACKGROUND--C-type natriuretic peptide (CNP) is a recent addition to the family of natriuretic peptides which includes atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whilst the levels of ANP and BNP are increased in conditions such as congestive heart failure and cor pulmonale, abnormal levels of CNP in these conditions have not been reported. METHODS--Plasma levels of CNP were measured by specific radioimmunoassay in 12 young normal controls, 12 elderly normal controls, 12 patients with NYHA grade III-IV congestive heart failure, and in 16 patients with hypoxaemic cor pulmonale. RESULTS--Mean (SE) plasma levels of CNP were similar in young normal controls (0.46(0.03) pmol/l), elderly normal controls (0.43(0.05) pmol/l), and in patients with congestive heart failure (0.33(0.2) pmol/l). In patients with cor pulmonale, however, plasma levels of CNP were raised (1.39(0.27) pmol/l) 3.2-fold compared with age-matched controls. CONCLUSIONS--In cor pulmonale the increased plasma levels of CNP were not as great as the previously observed increases in levels of ANP (5.6-fold) or BNP (18.5-fold) in comparable patients. CNP may therefore be less important than ANP or BNP as a circulating counter-regulatory peptide in conditions of overactivity of the renin angiotensin system.     

World Kidney Day 2016: Averting the legacy of kidney disease—focus on childhood

World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early, or who are small-for-date newborns, have a relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy-makers, and caregivers about the needs and possibilities surrounding kidney disease in childhood.     

Puberty and chronic kidney disease

Puberty is a period of dramatic physiologic changes when children become adults. Chronic kidney disease (CKD), like many disorders, may delay or blunt the onset and outcomes of puberty. These include attainment of adult height and reproductive capacity. Although nutrition and treatment effects may contribute to these phenomena, increasing evidence supports direct biological effects of CKD on the neurohypophyseal axis that controls these systems. Although CKD affects puberty, this life period also impacts the progression of CKD. Diabetes mellitus, posterior urethral valves, reflux nephropathy, and hypoplasia all appear to accelerate with sexual maturation. Potential mechanisms include increases in blood pressure and body size as well as altered endocrine physiology. Better understanding of the interactions of puberty and CKD may lead to better outcomes for children with CKD as well as longer preservation of native kidney function.     

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.