Assessing bone mineralisation in children with chronic kidney disease: what clinical and research tools are available?

Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a triad of biochemical imbalances of calcium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calcification. Maintaining optimal bone health in children with CKD is important to prevent long-term complications, such as fractures, to optimise growth and possibly also to prevent extra-osseous calcification, especially vascular calcification. In this review, we discuss normal bone mineralisation, the pathophysiology of dysregulated homeostasis leading to mineralisation defects in CKD and its clinical consequences. Bone mineralisation is best assessed on bone histology and histomorphometry, but given the rarity with which this is performed, we present an overview of the tools available to clinicians to assess bone mineral density, including serum biomarkers and imaging such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. We discuss key studies that have used these techniques, their advantages and disadvantages in childhood CKD and their relationship to biomarkers and bone histomorphometry. Finally, we present recommendations from relevant guidelines-Kidney Disease Improving Global Outcomes and the International Society of Clinical Densitometry-on the use of imaging, biomarkers and bone biopsy in assessing bone mineral density. Given low-level evidence from most paediatric studies, bone imaging and histology remain largely research tools, and current clinical management is guided by serum calcium, phosphate, PTH, vitamin D and alkaline phosphatase levels only.

Cytomegalovirus seropositivity is independently associated with cardiovascular disease in non-dialysis dependent chronic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of early death in patients with chronic kidney disease (CKD). Previous work has described an association between Cytomegalovirus (CMV) seropositivity and CVD amongst patients with dialysis dependent end stage renal disease. Whether CMV seropositivity is associated with CVD in non-dialysis dependent CKD has not been established. AIM: Investigate whether past CMV infection is associated with prevalent CVD in patients with non-dialysis dependent CKD. DESIGN: A retrospective observational study using the Renal Impairment in Secondary Care cohort, a study evaluating bio-clinical determinants of outcomes in patients with progressive CKD. METHODS: We assayed cryopreserved serum samples collected at inception for anti-CMV IgG antibodies from 764 patients with stages 2 to 5 CKD (pre-dialysis) and investigated its relationship with prevalent CVD. RESULTS: Median estimated glomerular filtration was 24 ml/min/1.73 m2 (IQR 19-32). Sixty-eight percent of patients were CMV seropositive. CMV seropositivity was associated with older age, non-Caucasian ethnicity, diabetes and higher social deprivation index score. On univariable analysis, CMV seropositivity correlated with higher systolic blood pressure (P = 0.044), prevalent CVD (P < 0.001), ischaemic heart disease (P < 0.001) and cerebrovascular disease (P = 0.022). On multivariable analysis, CMV seropositive patients nearly twice as likely to have CVD compared to seronegative patients [Odds Ratio (OR) = 1.998, CI 1.231-3.242, P = 0.005]. CONCLUSIONS: In patients with non-dialysis CKD, CMV seropositivity is independently associated with a higher prevalence of CVD.

Premature coronary artery disease and early stage chronic kidney disease.

A 30 year old asymptomatic male with stage 3 chronic kidney disease (CKD) secondary to Focal Segmental Glomerulosclerosis was found to have features of CKD associated cardiomyopathy including left ventricular hypertrophy (LVH) and focal sub-endocardial scarring on cardiac magnetic resonance imaging. There was also a significantly raised CT coronary calcium score and evidence of non-flow limiting coronary artery disease (CAD) on a CT coronary angiogram. Early stage CKD is a major risk factor for cardiovascular risk causing myocardial hypertrophy and fibrosis and coronary artery atheroma. Cardiovascular risk begins to increase from an eGFR of around 75ml/min/1.73m2. The pathophysiology of cardiovascular disease in CKD is under investigation but to date, treatment options are limited. Blood pressure control and statins have the strongest supportive evidence.

Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals.

BACKGROUND: Cytomegalovirus (CMV) is a chronic infection that is widely distributed in the population. CMV infects a range of tissues, including endothelium, and viral replication is suppressed by the host immune system. Infection is associated with increased risk of mortality from vascular disease in older people, but the mechanisms behind this have not been determined. AIM: We investigated the association between CMV infection and cardiovascular phenotype in a cohort of healthy elderly donors. DESIGN: CMV serostatus and cardiovascular parameters were determined in the Lothian Birth cohort, which comprises 1091 individuals aged 70 years in whom many environmental, biochemical and radiological correlates of vascular function have been determined. METHODS: CMV serostatus was determined by enzyme-linked immunosorbant assay and correlated with a range of biochemical and phenotypic measures. RESULTS: Sixty-five percent of participants were CMV seropositive, which indicates chronic infection. The mean sitting systolic blood pressure (SBP) was 149.2 mmHg in CMV seropositive individuals compared with 146.2 mmHg in CMV seronegative subjects (SD 18.7 vs. 19.7; P < 0.017). This association between CMV infection and SBP was not attenuated after adjustment for a wide range of biological and socio-economic factors. CONCLUSIONS: These data show that CMV infection is associated with an increase in SBP in individuals at age 70 years. The magnitude is comparable to environmental variables such as obesity, diabetes or high salt intake. This is the first evidence to show that a chronic infection may be an important determinant of blood pressure and could have significant implications for the future management of hypertension.

Variability in cardiac MR measurement of left ventricular ejection fraction, volumes and mass in healthy adults: defining a significant change at 1 year.

OBJECTIVE: Variability in the measurement of left ventricular (LV) parameters in cardiovascular imaging has typically been assessed over a short time interval, but clinicians most commonly compare results from studies performed a year apart. To account for variation in technical, procedural and biological factors over this time frame, we quantified the within-subject changes in LV volumes, LV mass (LVM) and LV ejection fraction (EF) in a well-defined cohort of healthy adults at 12 months. METHODS: Cardiac MR (CMR) was performed in 42 healthy control subjects at baseline and at 1 year (1.5 T Magnetom® Avanto; Siemens Healthcare, Erlangen, Germany). Analysis of steady-state free precession images was performed manually offline (Argus software; Siemens Healthcare) for assessment of LV volumes, LVM and EF by a single blinded observer. A random subset of 10 participants also underwent repeat imaging within 7 days to determine short-term interstudy reproducibility. RESULTS: There were no significant changes in any LV parameter on repeat CMR at 12 months. The short-term interstudy biases were not significantly different from the long-term changes observed at 1 year. The smallest detectable change (SDC) for LVEF, end-diastolic volume, end-systolic volume and LVM that could be recognized with 95% confidence were 6%, 13 ml, 7 ml and 6 g, respectively. CONCLUSION: The variability in CMR-derived LV measures arising from technical, procedural and biological factors remains minimal at 12 months. Thus, for patients undergoing repeat annual assessment by CMR, even small differences in LV function, size and LVM (which are greater than the SDC) may be attributed to disease-related factors. ADVANCES IN KNOWLEDGE: The reproducibility and reliability of CMR data at 12 months is excellent allowing clinicians to be confident that even small changes in LV structure and function over this time frame are real.

The relationship between high-sensitivity CRP and polyclonal free light chains as markers of inflammation in chronic disease.

INTRODUCTION: Serum concentrations of polyclonal free light chains (FLC) represent the activity of the adaptive immune system. This study assessed the relationship between polyclonal FLC and the established marker of innate immunity, C-reactive protein (CRP), in chronic and acute disease. METHODS: We utilized four cross-sectional chronic disease patient cohorts: chronic kidney disease (CKD), diabetes, vasculitis and kidney transplantation; and a longitudinal intensive care case series to assess the kinetics of production in acute disease. RESULTS: There was a weak association between polyclonal FLC and high-sensitivity CRP (hs-CRP) in the study cohorts. A longitudinal assessment in acute disease showed a gradual increase in FLC concentrations over time, often when CRP levels were falling, demonstrating clear differences in the response kinetics of CRP and FLC in this setting. CONCLUSION: Polyclonal FLC and hs-CRP provide independent information as to inflammatory status. Prospective studies are now required to assess the utility of hs-CRP and polyclonal FLC in combination for risk stratification in disease populations.

Central pulse pressure in patients with chronic kidney disease and in renal transplant recipients.

Patients with chronic kidney disease (CKD) and renal transplant recipients (RTR) have increased cardiovascular risk. The value of measuring central pulse pressure (cPP) over brachial pulse pressure (pPP) is not known. Central PP was measured in 597 patients (364 CKD:233 RTR). In multivariate analysis, age and female gender positively correlated with cPP; heart rate and estimated glomerular filtration rate negatively correlated with cPP. Associations for age, heart rate and gender persisted after additional adjustment for pPP and aortic wave reflection. This model accounted for 91% of the variability in cPP, with pPP alone accounting for 74%. Results were similar when both patient groups were analysed separately. A subset of patients with CKD had aortic pulse wave velocity (PWV) and left ventricular mass index (LVMI) measured. There were no differences in the univariate correlations between PWV (r=0.368 vs 0.315; P=0.4) or LVMI (r=0.125 vs 0.163; P=0.7); nor in the multivariate models created for PWV (P=0.1) or LVMI (P=0.1) when either cPP or pPP were used. This study demonstrates that in these patients most of the variability in cPP can be explained by pPP. Additionally, cPP does not appear to provide additional information beyond pPP in determining PWV and LVMI.

Understanding the effects of chronic kidney disease on cardiovascular risk: are there lessons to be learnt from healthy kidney donors?

Chronic kidney disease (CKD) is now a recognized global public health problem. It is highly prevalent and strongly associated with hypertension and cardiovascular disease (CVD); far more patients with a glomerular filtration rate below 60 ml min(-1) per 1.73 m(2) will die from cardiovascular causes than progress to end-stage renal disease. A better understanding of the complex mechanisms underlying the development of CVD among CKD patients is required if we are to begin devising therapy to prevent or reverse this process. Observational studies of CVD in CKD are difficult to interpret because renal impairment is almost always accompanied by confounding factors. These include the underlying disease process itself (for example, diabetes mellitus and systemic vasculitis) and the complications of CKD, such as hypertension, anaemia and inflammation. Kidney donors provide an ideal opportunity to study healthy subjects without manifest vascular disease who experience an acute change from having normal to modestly impaired renal function at the time of uninephrectomy. Prospectively examining the cardiovascular consequences of uninephrectomy using donors as a model of CKD may provide useful insight into the pathophysiology of CVD in CKD and, therefore, into how the CVD risk associated with renal impairment might eventually be reduced.

A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project.

BACKGROUND: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project. OBJECTIVE: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines. SEARCH STRATEGY: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. SELECTION CRITERIA: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded. DATA COLLECTION AND ANALYSIS: This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines. MAIN RESULTS: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil. CONCLUSIONS: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids. RECOMMENDATIONS: RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.

Is lowering phosphate exposure the key to preventing arterial stiffening with age?

Cardiovascular disease remains the leading cause of death world wide. Although atheroma is clearly important, the role of arteriosclerotic vascular disease is often overlooked. Arteriosclerosis causes increased arterial stiffness, with consequent systolic hypertension and left ventricular hypertrophy. Serum phosphate is increasingly being recognised as a cardiovascular risk factor and has been implicated in the development of arteriosclerosis and arterial calcification. Its determinants are unclear, but both diet and minor reductions in renal function may be important. Diets in affluent populations are high in phosphate because of increased consumption of animal protein and the use of phosphate-containing preservatives. This viewpoint suggests that the consumption of a phosphate-rich diet, exacerbated by the high prevalence of chronic kidney disease found in ageing populations, accelerates the development of arteriosclerosis. It is hypothesised that reducing phosphate intake will attenuate the progression of arterial stiffness with major beneficial effects upon cardiovascular mortality and morbidity.

Aortic distensibility and arterial-ventricular coupling in early chronic kidney disease: a pattern resembling heart failure with preserved ejection fraction.

OBJECTIVES: To examine arterial and left ventricular function and their interaction in patients with early-stage chronic kidney disease (CKD). DESIGN AND SETTING: Cross-sectional observational study in a university teaching hospital. PATIENTS: 117 patients with stage 2 (60-89 ml/min/1.73 m(2)) or stage 3 (30-59 ml/min/1.73 m(2)) non-diabetic CKD, without overt cardiovascular disease were compared with 40 controls. INTERVENTIONS: Aortic distensibility and left ventricular mass were assessed using cardiac magnetic resonance imaging. Systolic and diastolic ventricular function and arterial-ventricular elastance (stiffness) were assessed by transthoracic echocardiography. MAIN OUTCOME MEASURES: Arterial stiffness as measured by aortic distensibility and arterial elastance. Left ventricular mass, left ventricular systolic and diastolic function, including end-diastolic and end-systolic elastance and their relationship with arterial elastance. RESULTS: Compared with controls, patients with CKD 2 and CKD 3 had reduced aortic distensibility (4.12 (1.3) vs 2.94 (1.8) vs 2.18 (1.8)x10(-3) mm Hg, p<0.01), increased arterial elastance (1.4 (1.3) vs 1.65 (0.40) vs 1.74 0.48) mm Hg, p<0.05) and increased end-systolic (1.88 (0.48) vs 2.43 (0.83) vs 2.42(0.78) mm Hg/ml, p<0.05) and end diastolic elastances (0.07 (0.04) vs 0.11 (0.04) vs 0.12 (0.04, p<0.01). Aortic distensibility was positively correlated with estimated glomerular filtration rate (r = 0.349, p<0.01) and indices of elastance were inversely correlated (r = 0.284, p<0.05). Systolic function was not impaired in patients with early CKD compared with controls but diastolic filling velocities (Em) were reduced (8.1 (0.9) vs 7.9 (0.6) vs 7.5 (0.7) cm/s, p<0.01) while mean left atrial pressure (E/Em) was increased (5.6 (1.1), vs 7.4 (1.8) vs 8.0 (2.4), p<0.01) and end-diastolic elastance was increased. CONCLUSIONS: Early-stage CKD is characterised by reduced aortic distensibility and increases in arterial, ventricular systolic and diastolic stiffness; arterial-ventricular coupling is preserved. This pattern of pathophysiological abnormalities resembles that seen in heart failure with preserved ejection fraction and may account for the high levels of cardiovascular morbidity and mortality in patients at all stages of CKD. TRIAL REGISTRATION NUMBER: NCT00291720.

The treatment of coronary artery disease in patients with chronic kidney disease.

Premature cardiovascular disease is the largest cause of mortality, and a major cause of morbidity, in patients with chronic kidney disease (CKD). Patients with end-stage kidney disease (ESKD) are at extreme risk, but cardiovascular event rates are increased even in early CKD. There is little controlled trial evidence on which to base treatment, as most therapeutic trials have excluded CKD patients. Current treatment strategies are therefore based upon small prospective studies or retrospective analyses of controlled trials and registry data. It is thus unclear whether CKD patients benefit from modern secondary preventive treatments in the same manner as patients with normal renal function. There is a need for randomized trials to identify effective drugs to prevent and treat coronary artery disease in CKD. Revascularization by CABG in CKD has been widely reported in registry data to provide better results than medical treatment or angioplasty. Recent angioplasty data in patients with CKD, however, show improving results, and the risks of CABG in CKD remain high. It is not clear which revascularization technique has a better outcome in patients 'equally suitable' on angiographic criteria for either procedure. The high rate of late adverse cardiovascular events after both CABG and angioplasty accentuates the need for effective secondary preventive therapy disease in these high-risk patients.