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.

Glycosylflavonoids from Cecropia pachystachya Trécul are quorum sensing inhibitors.

The Cecropia genus is widely distributed in Latin America including at least 60 species, and some of them are commonly used in traditional medicine for the treatment of several diseases. We used Cecropia pachystachya Trécul to search for quorum sensing (QS) inhibitors compounds and found that the aqueous extract of C. pachystachya leaves is a promising source of substances with this activity. Using as biosensor Chromobacterium violaceum ATCC 31532 and Escherichia coli pSB403, the compounds chlorogenic acid (2), isoorientin (3), orientin (4), isovitexin (6), vitexin (7), and rutin (9) were identified as QS inhibitors. None of these compounds inhibited the growth of neither the used biosensors nor the microorganisms Staphylococcus aureus ATCC 23591, Escherichia coli ATCC 25922 and Saccharomyces cerevisiae, used here as growth inhibition controls. Along with the rutin, here we presented for the first time the QS-inhibition potential of the C-glycosyl flavonoids. The prospective of this evidence lead to the use of these compounds as antipathogenic drugs or antifoulants.

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.

Percutaneous radiological gastrostomy: single-puncture double-anchor technique.

PURPOSE: We evaluated technical success, safety and effectiveness of percutaneous radiological gastrostomy (PRG) with a modified technique: single puncture and double anchor. MATERIALS AND METHODS: From January 2008 to June 2011, 163 patients underwent PRG with a single-puncture double-anchor technique. The stomach was punctured with a 17-gauge Chiba needle, and gastropexy was performed by placing two anchors in the gastric lumen. Finally, a 12-F Wills-Oglesby percutaneous gastrostomy catheter was inserted. Technical success and complications at 30 days were evaluated on the basis of imaging and patients' medical records. RESULTS: PRG was successfully completed in all 163 patients. Only a single puncture was required in all patients. The average PRG procedure time was 9 min. Three patients had major complications: haemorrhage (n=2) and pneumoperitoneum (n=1). Ten patients had minor complications: tube malfunction/breakage (n=9), and leakage through the insertion site (n=1). Two patients died 30 days after the procedure. CONCLUSIONS: Single-puncture double-anchor PRG is a fast, safe and effective technique.

Severe acute alcoholic hepatitis and hepatorenal syndrome: role of transjugular intrahepatic portosystemic stent shunt.

Acute Alcoholic Hepatitis (AAH) is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. Mild to moderate forms of AAH frequently respond to alcoholic abstinence, whereas severe AAH is characterized by a poor prognosis. Up to 40% of these patients die within 6 months upon symptoms onset. This high rate of mortality is due to different factors: liver failure, severe infections, and portal hypertension with variceal bleeding and hepatorenal syndrome (HRS). In AAH, HRS is a common complication that leads to the death of more than 90% of the patients within 3 months, unless they had been liver transplanted. Transjugular Intrahepatic Portosystemic Stent Shunt (TIPS) has been increasingly used in the management of portal hypertension and its complications, and, it might become a valuable option in patients with HRS awaiting LT. This study has taken into consideration 9 consecutive patients affected by severe AHH with HRS suitable for TIPS. We have determined serum creatinine, blood urea nitrogen, serum sodium, sodium urinary excretion and urine volume in all patients, before the intervention, 7 days and 30 days after TIPS. Seven patients were transplanted within 6 months. After TIPS, the renal function improved with significant reduction in serum creatinine and increase in urine volume. We can conclude that TIPS is a valuable option in patients with severe AAH complicated by HRS and are waiting for liver transplantation.

MDCT findings of aortic branch artery pseudoaneurysms associated with type B intramural haematoma.

PURPOSE: The purpose of this study was to evaluate prevalence, morphological characteristics and evolution of aortic branch artery pseudoaneurysms associated with type B aortic intramural haematoma (IMH) using multidetector computed tomography (MDCT). MATERIALS AND METHODS: We enrolled 14 patients (nine men; mean age 64.6±9.6; range 42-75 years) with a diagnosis in the acute phase of type B IMH without evidence of intimal tear. All patients underwent clinical and MDCT follow-up. RESULTS: Twenty-two pseudoaneurysms in six patients (6/14, 43%) were observed at MDCT. In the majority of patients (5/6, 83%) the pseudoaneurysms were multiple and involved the branches of the descending thoracic aorta (14/22, 64%), mainly the intercostal arteries (11/22, 50%). At a mean follow-up of 10.6±8.7 months, 21 pseudoaneurysms showed resolution, reduction or dimensional stability (95%), whereas only one increased in size (5%). CONCLUSIONS: Aortic branch artery pseudoaneurysms associated with IMH may be considered a benign disease, as the majority of cases resolved or did not change in size, with haematoma resorption. However, because a dynamic change in pseudoaneurysms in the acute and subacute phases was frequently observed, close clinical and imaging follow-up is mandatory.

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.

Percutaneous embolization of periduodenal varix due to portal hypertension in a patient with kidney-pancreas transplantation: a case report.

Kidney-pancreas transplantation is a valid therapeutic option for patients with insulin-dependent diabetes mellitus. However, vascular complications associated with pancreas transplantation are not uncommon. Herein we have reported a 32-year-old woman with a history of insulin-dependent diabetes mellitus and celiac disease. She underwent liver transplantation for acute hepatitis. After 7 years, the patient developed end-stage kidney disease beginning hemodialysis and being listed for a kidney-pancreas transplantation, which was successfully performed when she was 29 years old with enteric diversion (Roux intestinal loop reconstruction). Five years after kidney-pancreas transplantation, she was admitted to our hospital with serious intestinal bleeding and poor liver function. The ultrasound showed a pattern like a arteriovenous fistula near the head of the pancreas. Computed Tomography was not diagnostic; an arteriogram showed the presence of a mesenteric varix and a mesenteric-caval shunt through the duodenum of the pancreatic graft. The liver biopsy and portal pressure gradient showed portal hypertension and liver cirrhosis. To obtain time a waiting a new liver, the patient underwent percutaneous embolization of the mesenteric varix through jugular access. The procedure was uneventful. The patient was successfully transplanted 2 months later. Pancreas function was always satisfactory.