Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease.

BACKGROUND: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes. METHODS: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis. RESULTS: Across our population, median baseline eGFR was 32.3mls/min/1.73m2, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events. CONCLUSION: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.

Revascularization of atherosclerotic renal artery stenosis for chronic heart failure versus acute pulmonary oedema.

AIM: The aim of the study is to determine whether the apparent benefit of revascularization of renal artery stenosis for 'flash' pulmonary oedema extends to heart failure patients without a history of prior acute pulmonary oedema. METHODS: A prospective study of patients with renal artery stenosis and heart failure at a single centre between 1 January 1995 and 31 December 2010. Patients were divided into those with and without previous acute pulmonary oedema/decompensation. Survival analysis compared revascularization versus medical therapy in each group using Cox regression adjusted for age, estimated glomerular filtration rate, blood pressure and co-morbidities. RESULTS: There were 152 patients: 59% male, 36% diabetic, age 70 ± 9 years, estimated glomerular filtration rate 29 ± 17 mL/min per 1.73 m2 ; 52 had experienced previous acute pulmonary oedema (34%), whereas 100 had no previous acute pulmonary oedema (66%). The revascularization rate was 31% in both groups. For heart failure without previous acute pulmonary oedema, the hazard ratio for death after revascularization compared with medical therapy was 0.76 (0.58-0.99, P = 0.04). In heart failure with previous acute pulmonary enema, the hazard ratio was 0.73 (0.44-1.21, P = 0.22). For those without previous acute pulmonary oedema, the hazard ratio for heart failure hospitalization after revascularization compared with medical therapy was 1.00 (0.17-6.05, P = 1.00). In those with previous acute pulmonary oedema, it was 0.51 (0.08-3.30, P = 0.48). CONCLUSION: The benefit of revascularization in heart failure may extend beyond the current indication of acute pulmonary oedema. However, findings derive from an observational study.

The Association of Serum Free Light Chains With Mortality and Progression to End-Stage Renal Disease in Chronic Kidney Disease: Systematic Review and Individual Patient Data Meta-analysis.

OBJECTIVE: To clarify the associations between polyclonal serum free light chain (sFLC) levels and adverse outcomes in patients with chronic kidney disease (CKD) by conducting a systematic review and individual patient data meta-analyses. PATIENTS AND METHODS: On December 28, 2016, we searched 4 databases (MEDLINE, Embase, CINAHL, and PubMed) and conference proceedings for studies presenting independent analyses of associations between sFLC levels and mortality or progression to end-stage renal disease (ESRD) in patients with CKD. Study quality was assessed in 5 domains: sample selection, measurement, attrition, reporting, and funding. RESULTS: Five prospective cohort studies were included, judged moderate to good quality, involving 3912 participants in total. In multivariable meta-analyses, sFLC (kappa+lambda) levels were independently associated with mortality (5 studies, 3680 participants; hazard ratio [HR], 1.04 [95% CI, 1.03-1.06] per 10 mg/L increase in sFLC levels) and progression to ESRD (3 studies, 1848 participants; HR, 1.01 [95% CI, 1.00-1.03] per 10 mg/L increase in sFLC levels). The sFLC values above the upper limit of normal (43.3 mg/L) were independently associated with mortality (HR, 1.45 [95% CI, 1.14-1.85]) and ESRD (HR, 3.25 [95% CI, 1.32-7.99]). CONCLUSION: Higher levels of sFLCs are independently associated with higher risk of mortality and ESRD in patients with CKD. Future work is needed to explore the biological role of sFLCs in adverse outcomes in CKD, and their use in risk stratification.

The Associations of Blood Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin with Progression from CKD to ESRD.

BACKGROUND AND OBJECTIVES: Elevated levels of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are associated with negative outcomes in CKD. Our study aimed to explore the prognostic accuracy of blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for progression to ESRD, major adverse cardiovascular events, and death in a large cohort of adult patients with all-cause nondialysis-dependent CKD stages 3-5. We considered whether these factors improve prediction in relation to traditional biomarkers and clinical parameters. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were measured on baseline plasma samples from 1982 patients who were recruited to the Chronic Renal Insufficiency Standards Implementation Study between the start of June of 2002 and the start of June of 2013. Associations with study end points were assessed using Cox regression models, receiver operator characteristic curve analyses, and reclassification statistics. RESULTS: Over a median follow-up of 29.5 months (interquartile range, 14.9-53.5), 21.6% of patients progressed to ESRD, 27% died, and 6.6% suffered a major adverse cardiovascular event. Higher blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were independently associated with a greater risk for ESRD (hazard ratio, 1.25; 95% confidence interval, 1.10 to 1.43; P<0.001 and hazard ratio, 1.35; 95% confidence interval, 1.14 to 1.59; P≤0.001, respectively, per 1 SD higher biomarker concentration). There was no association with risk for cardiovascular events or death. The addition of biomarkers to our baseline risk model of traditional clinical characteristics and laboratory parameters did not significantly improve model discrimination or risk reclassification. CONCLUSIONS: In patients with moderate to severe CKD, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin blood levels are independent risk factors for progression to ESRD. Additional studies are needed to establish the utility and cost-effectiveness of these novel biomarkers in the clinical setting.

FGF-23 and Osteoprotegerin but not Fetuin-A are associated with death and enhance risk prediction in non-dialysis chronic kidney disease stages 3-5.

AIM: Numerous biomarkers have been shown to associate with clinical endpoints in chronic kidney disease (CKD). There is limited evidence whether biomarkers improve risk prediction in relation to clinical outcomes. Our study investigates whether a small suite of key chronic kidney disease-mineral and bone disorder biomarkers could be used to enhance risk assessment in CKD. METHODS: Fetuin-A, fibroblast growth factor-23 and osteoprotegerin were measured on baseline plasma samples from 463 patients recruited to the Chronic Renal Insufficiency Standards Implementation Study. The biomarkers were analysed in relation to progression to end stage kidney disease, death and major cardiovascular events. RESULTS: Over a median follow up of 46 months (interquartile range 21-69), fibroblast growth factor-23 was associated with risk for renal replacement therapy (hazard ratio (HR) 1.35, P = 0.05, 95% confidence interval (CI) 1.001-1.820), cardiovascular events (HR 1.74 P < 0.001, 95% CI 1.303-1.305) and death (HR 1.4 P = 0.005, 95% CI 1.109-1.767). Osteoprotegerin was associated with risk for death (HR 1.06, P = 0.03, 95% CI 1.006-1.117). There was no clear association between Fetuin-A and any of the clinical endpoints. The addition of biomarkers to risk models led to marginal improvement in model discrimination and reclassification. CONCLUSION: Biomarkers are often associated with clinical endpoints, and we observed such associations in our study of patients with advanced CKD. However, the markers analysed in our study were of limited benefit in improving the prediction of these outcomes. Any extra information biomarkers may provide to improve risk prediction in clinical practice needs to be carefully balanced against the potential cost of these tools.

Revascularisation of renal artery stenosis as a therapy for heart failure: an observational cohort study.

BACKGROUND: Heart failure contributes to 5% of all hospital admissions, and mortality is more than 50% at 4 years. 54% of patients with a left ventricular ejection fraction of less than 40% have renal artery stenosis. The potential benefit of revascularisation for heart failure is not established. We aimed to compare clinical outcomes for renal artery revascularisation with medical therapy for renal artery stenosis associated with heart failure as the first step towards validating revascularisation as a therapeutic option in heart failure. METHODS: In a prospective, longitudinal observational study at a single UK nephrology centre, we recruited patients with atherosclerotic renal artery stenosis (>50% as judged by CT, MR, or direct angiography). Endpoints were all-cause mortality and hospital admission for heart failure. Survival analyses were performed with Cox proportional hazard model adjusted for age, estimated glomerular filtration rate (eGFR), and cardiovascular comorbidities. Ethics approval was granted by South Manchester Research Ethics Committe. FINDINGS: 611 patients (152 [25%] with and 459 [75%] without heart failure) were recruited. Mean age was 70 years (SD 9), 348 (57%) were men, 183 (30%) had diabetes, and mean eGFR was 33 mL/min per 1·73 m(2) (SD 19). Patients with and without heart failure were similar with to sex, diabetes, and eGFR. 367 participants (60%) died over a follow-up of a mean of 4·3 years (SD 3·6). 87 patients without heart failure (19%) underwent revascularisation compared with 47 with heart failure (31%). The adjusted hazard ratio (HR) for death in heart failure compared with no heart failure was 1·9 (95% CI 1·5-2·5, p<0·0001). For patients without heart failure, the adjusted HR for death in revascularisation compared with receiving medical therapy was 0·8 (0·5-1·1, p=0·16). For heart failure, the HR was 0·6 (0·3-0·9, p=0·01). The HR for hospital admission for heart failure in revascularised patients was 0·2 (0·0-1·1, p=0·06). INTERPRETATION: Revascularisation of renal artery stenosis in heart failure is associated with a substantial reduction in all-cause mortality and hospital admission, although such observational data might be complicated by hidden confounders. These findings are encouraging for the development of a randomised trial of renal artery revascularisation versus medical therapy in heart failure, and suggest that investigation for renal artery stenosis should be considered more frequently in heart failure clinics. FUNDING: None.

Functional status and mortality in chronic kidney disease: results from a prospective observational study.

BACKGROUND/AIMS: Measures of functional status are used in the general population to aid prognostication but their use has not been explored in pre-dialysis chronic kidney disease (CKD). This analysis considers the association between the Karnofsky performance score (KPS) and all-cause mortality in a CKD stage 3-5 cohort. METHODS: Patients were selected from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a prospective observational study of outcome in CKD. Risk for death was assessed using multivariate Cox regression, and differences in progression of biochemical parameters were considered in a mixed-effects model. RESULTS: A total of 1,515 patients with a median follow-up time of 2.9 (1.5-4.8) years were considered. Baseline age was 60 ± 11 years and eGFR was 30 ± 12 ml/min/1.73 m(2). Patients with a reduced KPS had an increased risk for death. The hazard ratio (HR) for death was: KPS 90 group, HR 1.2 (95% CI 0.9-1.5), p = 0.1; KPS ≤ 80 group, HR 1.8 (95% CI 1.4-2.4), p < 0.001. In the mixed-effects model, the average annual loss of eGFR was greater in patients with a KPS ≤ 80 versus patients with a KPS >80 (5 vs. 3%, p = 0.008). CONCLUSION: A reduced KPS is independently associated with risk for mortality in patients with CKD stages 3-5. This may relate to a more rapid loss of eGFR.

Incidence and consequence of acute kidney injury in unselected emergency admissions to a large acute UK hospital trust.

BACKGROUND: AKI is common among hospital in-patients and places a huge financial burden on the UK National Health Service, causing increased length of hospital stay and use of critical care services, with increased requirement for complex interventions including dialysis. This may account for up to 0.6% of the total Health Service budget. To investigate the incidence and consequences of AKI, all unselected emergency admissions to a large acute UK single centre University Teaching Hospital over two separate 7 day periods were reviewed. METHODS: A retrospective audit of 745 case records was undertaken (54.6% male) including laboratory data post-discharge or death, with classification of AKI by RIFLE, AKIN and AKIB criteria. Participants were included whether admitted via their general practitioners, the emergency department, or as tertiary specialty transfers. Outcome measures were presence or absence of AKI recorded using each of the three AKI criteria, length of hospital stay (LOS), admission to, and LOS in critical care, and mortality. The most severe grade of AKI only, at any time during the admission, was recorded to prevent double counting. Renal outcome was determined by requirement for renal replacement therapy (RRT), and whether those receiving RRT remained dialysis dependent or not. RESULTS: AKI incidence was 25.4% overall. With approximately one third present on admission and two thirds developing post admission. The AKI group had LOS almost three times higher than the non AKI group (10 vs 4 days). Requirement for critical care beds was 8.1% in the AKI group compared to 1.7% in non AKI group. Overall mortality was 5.5%, with the AKI group at 11.4% versus 3.3% in the non AKI group. CONCLUSIONS: AKI in acute unselected hospital admissions is more common than existing literature suggests, affecting 25% of unselected admissions. In many this is relatively mild and may resolve spontaneously, but is associated with increased LOS, likelihood of admission to critical care, and risk of death. If targeted effective interventions can be developed it seems likely that substantial clinical benefits for the patient, as well as financial and structural benefits for the healthcare organisation may accrue.

Revascularization as a treatment to improve renal function.

An aging atherosclerosis-prone population has led to an increase in the prevalence of atherosclerotic renovascular disease (ARVD). Medical management of this disease, as with other atherosclerotic conditions, has improved over the past decade. Despite the widespread availability of endovascular revascularization procedures, there is inconsistent evidence of benefit in ARVD and no clear consensus of opinion as to the best way to select suitable patients for revascularization. Several published randomized controlled trials have attempted to provide clearer evidence for best practice in ARVD, but they have done so with varying clarity and success. In this review, we provide an overview of ARVD and its effect on renal function. We present the currently available evidence for best practice in the management of patients with ARVD with a particular focus on revascularization as a treatment to improve renal function. We provide a brief overview of the evidence for revascularization in other causes of renal artery stenosis.

The association of ECG and echocardiographic abnormalities with sudden cardiac death in a dialysis patient cohort.

BACKGROUND: Cardiovascular mortality is greater in dialysis patients than the general population. More specifically, sudden cardiac death (SCD) accounts for 26% of dialysis patient deaths. However, SCD risk assessment tools used in the general population are not adequate for dialysis patients indicating that the hierarchy of pathopysiological factors appears to be different. The aim of this study was to use simple bedside tests to determine parameters independently predictive of cardiovascular mortality and SCD in dialysis patients. METHOD AND RESULTS: This was a sub-study of the Chronic Renal Insufficient Standards Implementations Study, a longitudinal cohort study of outcomes in CKD. ECG and echocardiographic abnormalities were assessed in a cross-section of prevalent dialysis patients. Patients were followed up until death or transplantation. Forward stepwise Cox regression then determined factors independently associated with all-cause, cardiovascular and SCD mortality. 323 patients were included (age 61.5 ± 14.6 years, 113 deaths, 66 cardiovascular deaths, 18 SCD). A number of factors were independently associated with all-cause mortality. These were age, time on dialysis, smoking, the difference between QRS and T-wave axes, resting heart rate, and pulmonary artery pressure (PAP) >35 mmHg. The only parameters predictive of SCD were elevated PAP (HR = 5.99, p = 0.05) and mitral regurgitation (HR = 6.71, p = 0.01). CONCLUSION: That PAP is associated with SCD in dialysis patients demonstrates that the pathophysiological mechanism is likely to be different in these patients compared to the general population. Because of this, a population specific approach to risk stratification is advisable.

Effect of CD40 and sCD40L on renal function and survival in patients with renal artery stenosis.

Activation of the CD40 receptor on the proximal tubular epithelium of the kidney results in fibrosis and inflammation in experimental models of kidney injury. Soluble CD40 ligand is released by activated platelets. The role of CD40-soluble CD40 ligand in patients with ischemic renal disease is unknown. Plasma levels of CD40 and soluble CD40 ligand were measured by enzyme-linked immunosorbent assay in a single center cohort of 60 patients with renal artery stenosis recruited from Salford Royal Hospital, Manchester, United Kingdom. A natural log transformation of CD40 and soluble CD40 ligand was performed to normalize the data. Estimated glomerular filtration rate was used as the primary indicator of renal function. By univariate analysis, low baseline levels of circulating CD40 (R(2)=0.06; P<0.05) and baseline creatinine (R(2)=0.08; P=0.022) were associated with loss of kidney function at 1-year follow-up, whereas soluble CD40 ligand was not (R(2)=0.02; P=ns). In a multiple linear regression model, CD40 (P<0.02) and baseline creatinine (P<0.01) continued to be significantly associated with a decline in renal function (model R(2)=0.17; P<0.005). Baseline CD40 levels were somewhat lower in patients who died during follow-up (survivors, 7.3±0.9 pg/mL, n=48 versus nonsurvivors, 6.7±1.0 pg/mL, n=12; P=0.06). The CD40/soluble CD40 ligand signaling cascade may be a novel mechanism contributing to the development and progression of renal injury in patients with atherosclerotic renal artery stenosis.

Meta-analysis of lipid-lowering therapy in maintenance dialysis patients.

BACKGROUND/AIMS: The use of lipid-lowering therapy (LLT) in patients on chronic dialysis is contentious. Here we present an aggregate data meta-analysis of randomised controlled trials (RCTs) comparing long-term LLT versus placebo in dialysis patients. METHOD: A search of Medline, Google Scholar, COCHRANE database, EMBASE, and cardiovascular and nephrology society proceedings was performed. Criteria for inclusion were RCTs of LLT versus placebo, in which LLT was demonstrated to significantly reduce low-density lipoprotein cholesterol, >12 months of follow-up, and at least one cardiovascular or mortality endpoint in an independently reported dialysis population. Meta-analysis was performed for atherosclerotic cardiovascular events, stroke and mortality using a random-effects method for odds ratio (OR) of risk. RESULTS: Three studies were included with 7,051 patients (3,541 treatment and 3,510 placebo). Twenty-five percent of the LLT patients suffered an atherosclerotic cardiovascular event versus 27% for placebo. The OR was 0.89 (95% CI: 0.80-0.99, p = 0.04). For stroke (haemorrhagic and non-haemorrhagic combined), the figures were 6.2% (LLT) versus 5.7% (placebo) [OR = 1.11 (95% CI: 0.85-1.46, p = 0.45)]. For all-cause mortality, the figures were 40 versus 42% [OR = 0.97 (95% CI: 0.88-1.06, p = 0.49)]. CONCLUSION: There was an overall significant reduction in risk for atherosclerotic cardiovascular events in dialysis patients treated with LLT compared to placebo. There was a numerical but not a statistical reduction in mortality. There was no statistically significant increase in risk of stroke as has been previously reported.

Lipid-lowering therapy in chronic kidney disease: is there a role for ezetimibe?

The use of lipid-lowering therapy (LLT) in chronic kidney disease (CKD) results in a reduction in atherosclerotic cardiovascular events but not mortality. The risk reduction for patients on dialysis appears to be less than in pre-dialysis CKD. These findings may be due to the higher rate of non-atherosclerotic cardiovascular disease found in end-stage disease. Because of this, the role of LLT is less clear in CKD than in the general population. This review outlines the results of recent trials of LLT, particularly Ezetimibe, and implications for patients with CKD. The evidence in favour of lipid lowering in CKD comes largely from the SHARP study. This study used combined simvastatin and Ezetimibe to reduce cholesterol. Though the benefits of statins are well proven, there is no evidence that Ezetimibe independently reduces cardiovascular events in any population. Data which support the use of Ezetimibe show only that it effectively reduces cholesterol. Surrogate end-point data are contentious. Some studies suggest benefit whilst others suggest off-target effects that question the validity of Ezetimibe in the absence of quality cardiovascular outcome data.

How accurately do nephrologists predict the need for dialysis within one year?

BACKGROUND/AIMS: Knowing when patients with chronic kidney disease will need dialysis can improve patient counselling and timing of vascular access. We aimed to assess the accuracy of clinician judgement in predicting the need for dialysis within 12 months. METHODS: We asked the nephrologists in a dedicated pre-dialysis clinic to predict the time until initiation of dialysis for patients. We compared predicted with actual time to dialysis and the accuracy of predictions made by different grades of clinician. Multivariate logistic regression compared clinical parameters that correlated with predicted and actual time to dialysis. RESULTS: One hundred and eighty-four patients were included. The sensitivity of clinician judgement as a predictor of dialysis within 12 months was 95% and the specificity was 62%. Consultants were correct in 71% of cases and trainees in 68% of cases. Estimated glomerular filtration rate (eGFR) was the only independent correlate of predicted time to dialysis [odds ratio (OR) = 1.6 per 1 ml/min/1.73 m(2) reduction, p < 0.001]. eGFR was also associated with actual time to dialysis (OR = 1.6 per 1 ml/min/1.73 m(2), p < 0.001) along with age (OR = 0.94 per year increase, p = 0.005) and itch (OR = 3.7, p = 0.048). CONCLUSION: Clinical judgement is sensitive but not specific in predicting the need for dialysis. Educating the clinicians may improve the specificity of judgement and improve the accuracy of prognostic information given to patients.

Thermally controlled preferential molecular aggregation state in a thiacarbocyanine dye.

Herein we report the experimental and theoretical study of the temperature dependence of a thiacarbocyanine dye in its monomer, H- and J-aggregates states. We demonstrate the ability to control the ratio of monomer, H- and/or J-aggregates with heat. We link such a control to the conformation dependence of the molecule. An alternative way to gain access to the dominating species without changing the concentration as a complete switching mechanism between all the present species is proposed. The results presented in this work lead to a better understanding of thiacarbocyanine dye's behavior.

Linear and nonlinear optical characterizations of a monomeric symmetric squaraine-based dye in solution.

The photophysical properties of a symmetric squaryllium dye, namely, 2,4-bis[4-(N,N-dibutylamino)-2-hydroxyphenyl] squaraine (SQ), in its monomer form in acetone solution, have been thoroughly studied by means of one-photon absorption (1PA) and two-photon absorption (2PA), excitation anisotropy, fluorescence emission, fluorescence quantum yield, and excited state absorption. The results show that there is a strong one-photon allowed absorption band in the near IR region associated with intramolecular charge transfer. Higher one-photon allowed and forbidden singlet excited states were also revealed by absorption and excitation anisotropy. A relatively high fluorescence quantum yield (0.44) was measured for this dye. The nonlinear optical characterization of SQ in solution confirms the ability of squaraine dyes to be used as good two-photon absorbers. Additionally, it was found that this dye presents both saturable and reverse saturable absorption effects. Density functional theory calculations of the 1PA and 2PA electronic spectra of SQ were carried out to support the experimental data. A detailed analysis of the symmetry and energy of the orbitals involved in the lowest five electronic transitions is presented and discussed in relation to the behavior observed experimentally.