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.

The influence of multiple episodes of acute kidney injury on survival and progression to end stage kidney disease in patients with chronic kidney disease.

BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are common syndromes associated with significant morbidity, mortality and cost. The extent to which repeated AKI episodes may cumulatively affect the rate of progression of all-cause CKD has not previously been investigated. In this study, we explored the hypothesis that repeated episodes of AKI increase the rate of renal functional deterioration loss in patients recruited to a large, all-cause CKD cohort. METHODS: Patients from the Salford Kidney Study (SKS) were considered. Application of KDIGO criteria to all available laboratory measurements of renal function identified episodes of AKI. A competing risks model was specified for four survival events: Stage 1 AKI; stage 2 or 3 AKI; dialysis initiation or transplant before AKI event; death before AKI event. The model was adjusted for patient age, gender, smoking status, alcohol intake, diabetic status, cardiovascular co-morbidities, and primary renal disease. Analyses were performed for patients' first, second, and third or more AKI episodes. RESULTS: A total of 48,338 creatinine measurements were available for 2287 patients (median 13 measures per patient [IQR 6-26]). There was a median age of 66.8years, median eGFR of 28.4 and 31.6% had type 1 or 2 diabetes. Six hundred and forty three (28.1%) patients suffered one or more AKI events; 1000 AKI events (58% AKI 1) in total were observed over a median follow-up of 2.6 years [IQR 1.1-3.2]. In patients who suffered an AKI, a second AKI was more likely to be a stage 2 or 3 AKI than stage 1 [HR 2.04, p 0.01]. AKI events were associated with progression to RRT, with multiple episodes of AKI progressively increasing likelihood of progression to RRT [HR 14.4 after 1 episode of AKI, HR 28.4 after 2 episodes of AKI]. However, suffering one or more AKI events was not associated with an increased risk of mortality. CONCLUSIONS: AKI events are associated with more rapid CKD deterioration as hypothesised, and also with a greater severity of subsequent AKI. However, our study did not find an association of AKI with increased mortality risk in this CKD cohort.

An exploration of patients' experiences of participation in a randomised controlled trial of the Manchester Acute Coronary Syndromes (MACS) decision rule.

BACKGROUND: As an important part of a pilot study to determine the feasibility of a large randomised controlled trial (RCT) comparing use of the Manchester Acute Coronary Syndromes (MACS) decision rule with standard care, we aimed to explore patient attitudes and potential barriers to participation in a trial of this nature. METHODS: We conducted a qualitative study nested within a pilot RCT comparing use of the MACS rule (which could enable some patients with chest pain to be discharged earlier) with standard care. Semi-structured interviews with consenting participants were conducted with reference to a bespoke topic guide. Interviews were audio recorded, transcribed verbatim and analysed using the Framework method with an inductive approach. RESULTS: The 10 interviewees expressed that participation in the trial was generally acceptable. All but one recommended participation to others. Participants who were in pain or anxious at the time of arrival reported that the initial invitation to participate in the trial was sometimes made too early. The approach was welcome, providing they had been given time to settle. Interviewees welcomed the opportunity that trial participation offered for them to play a more active role in their healthcare and to reduce unnecessary waiting time. Participants appeared to like the fact that participation in the trial might mean they could return home sooner and welcomed the provision of follow-up. Although several participants described being generally sceptical of medical research, they were amenable to participation in this trial. This appears to be because they agreed with the need for research in this field and perceived the intervention as non-invasive. CONCLUSIONS: Patients were positive about their participation in this RCT comparing the MACS rule with standard care. A number of areas for improving trial design were identified and should be considered in the planning of future large trials. TRIAL REGISTRATION: ISRCTN 86818215 RESEARCH ETHICS COMMITTEE REFERENCE: 13/NW/0081 UKCRN REGISTRATION ID: 14334.

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.

Associations of antiplatelet therapy and beta blockade with patient outcomes in atherosclerotic renovascular disease.

Randomized trials have shown a neutral effect of percutaneous revascularization compared with optimal medical therapy in patients with atherosclerotic renovascular disease (ARVD). However, there are few data to define what constitutes optimal medical therapy. We present a retrospective analysis of 529 ARVD patients. Separate analyses were performed comparing outcomes in patients prescribed/not prescribed beta blocker and antiplatelet agents. Analyses were adjusted for effects of baseline covariates on probability of treatment and on clinical outcome. Over a median follow-up period of 3.8 years, antiplatelet therapy was associated with a reduced risk for death (relative risk, 0.52 [95% confidence interval {CI}: 0.31-0.89]; P = .02). Beta blocker therapy was associated with a reduced for death (relative risk, 0.45 [95% CI: 0.21-0.97]; P = .04) and nonfatal cardiovascular events (relative risk, 0.74 [95% CI: 0.60-0.90]; P = .003). Although limited by small patient numbers, this study suggests that in ARVD, treatment with antiplatelet therapy and beta blockade may associate with a prognostic benefit.

Risks for mortality and renal replacement therapy in atherosclerotic renovascular disease compared with other causes of chronic kidney disease.

AIM: Patients with atherosclerotic renovascular disease (ARVD) have an increased risk for death and likelihood of initiating renal replacement therapy (RRT) compared with the general population. No data exist to describe prognosis in ARVD compared with other causes of chronic kidney disease (CKD). We compare patient outcomes between ARVD and other causes of CKD. METHODS: Patients were selected from two prospective observational cohort studies of outcome in ARVD and CKD. Multivariate Cox regression was used to compare risk for RRT and death (both prior to and following initiation of RRT) between patients with ARVD and other causes of CKD. RESULTS: Of 1472 patients (563 (38%) ARVD, 909 (62%) non-ARVD), 242 (16%) progressed to RRT and 640 (44%) died over a median follow-up period of 4.1 (2.4-5.6) years. Patients with ARVD had an increased risk for death (HR 1.5 (1.2-1.8), P < 0.001) but not for RRT (HR 1.0 (0.7-1.4), P = 0.9). The largest increase in risk for death was observed relative to renal limited diseases, e.g. pyelonephritis (HR 2.4 (1.3-4.5), P = 0.004) and interstitial/infiltrative disease (HR 2.2 (1.3-4.5), P = 0.02). Following initiation of RRT, patients with ARVD had a significantly increased risk for death compared with patients without ARVD (HR 3.3 (2.2-5.0), P < 0.001). CONCLUSIONS: Patients with ARVD as a cause of CKD have an increased risk for death both prior to and following initiation of RRT. Further work should seek to identify modifiable risk factors relevant to prognosis.

Where now in the management of renal artery stenosis? Implications of the ASTRAL and CORAL trials.

PURPOSE OF REVIEW: The neutral findings of Angioplasty and Stenting for Renal Artery Lesions and Cardiovascular Outcomes in Renal Artery Lesions trials have shown that unselected revascularization does not improve outcomes in atherosclerotic renovascular disease (ARVD). This review highlights recent translational, clinical and epidemiological studies and suggests directions for future research. RECENT FINDINGS: Imaging studies show that the degree of renal artery stenosis is not the most important determinant of outcome and response to therapies in ARVD. Porcine models have established a better understanding of the microvascular and inflammatory changes that occur in ARVD. Biomarkers of inflammation and cardiovascular dysfunction may be informative but do not yet help assess prognosis or response to treatment. Stem cell therapies show promise in animal models but have yet to translate into clinical practice. Analysis of patient subgroups with high-risk presentations of ARVD has provided new insights into treatment response and may guide future studies. SUMMARY: It is time to reframe thinking and research in ARVD. We need better ways to identify patients likely to benefit from revascularization and to improve response to treatment in these individuals. Many preclinical studies show promise, but these are often small scale and difficult to replicate. Future work should focus on establishing an international disease registry as a foundation for collaborative research.

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.