Neurosyphilis mimicking giant cell arteritis both clinically and microscopically.

Temporal arteritis is usually caused by giant cell arteritis (GCA). However, inflammation of the temporal artery can also occur secondary to autoimmune diseases or infections.We present a remarkable case of a man in his 70s with biopsy proven temporal arteritis, who was later diagnosed with meningovascular neurosyphilis. The presentation of an acute onset monocular vision loss with inflammation of the temporal artery on biopsy appeared a GCA, misleading the physicians, as it turned out to be a manifestation of neurosyphilis.

Change in FGF23 concentration over time and its association with all-cause mortality in patients treated with haemodialysis or haemodiafiltration.

BACKGROUND: Previous studies in patients on haemodialysis (HD) have shown an association of fibroblast growth factor 23 (FGF23) with all-cause mortality. As of yet, the result of FGF23 lowering on mortality is unknown in this population. METHODS: FGF23 was measured in a subset of 404 patients from the Dutch CONvective TRansport STudy (CONTRAST study) [a randomized trial in prevalent dialysis patients comparing HD and haemodiafiltration (HDF) with clinical outcome] at baseline and Months 6 and 12. A substantial decline of FGF23 change over time was anticipated in patients randomized to HDF since HDF induces higher dialytic clearance of FGF23. The associations of both baseline FGF23 and 6-months change in FGF23 with all-cause mortality were analysed. In addition, the difference in FGF23 change between HD and HDF was explored. Furthermore, the role of dialysis modality in the association between FGF23 change and outcome was analysed. RESULTS: No association was observed between quartiles of baseline FGF23 and all-cause mortality. Over 6 months, FGF23 declined in patients on HDF, whereas FGF23 remained stable in patients on HD. A decrease in FGF23 was not associated with improved survival compared with a stable FGF23 concentration. However, increasing FGF23 was associated with a significantly higher mortality risk, both in crude and fully adjusted models [hazard ratio 2.01 (95% confidence interval 1.30-3.09)]. CONCLUSION: Whereas no association between a single value of FGF23 and all-cause mortality was found, increasing FGF23 concentrations did identify patients at risk for mortality. Since lowering FGF23 did not improve outcome, this study found no argument for therapeutically lowering FGF23.

Fibroblast growth factor 23: are we ready to use it in clinical practice?

Patients with chronic kidney disease (CKD) have a greatly enhanced risk of cardiovascular morbidity and mortality. Over the past decade it has come clear that a disturbed calcium-phosphate metabolism, with Fibroblast Growth Factor-23 as a key hormone, is partly accountable for this enhanced risk. Numerous studies have been performed unravelling FGF23s actions and its association with clinical conditions. As FGF23 is strongly associated with adverse outcome it may be a promising biomarker for risk prediction or, even more important, targeting FGF23 may be a strategy to improve patient outcome. This review elaborates on the clinical usefulness of FGF23 measurement. Firstly it discusses the reliability of the FGF23 measurement. Secondly, it evaluates whether FGF23 measurement may lead to improved patient risk classification. Finally, and possibly most importantly, this review evaluates if lowering of FGF23 should be a target for therapy. For this, the review discusses the current evidence indicating that FGF23 may be in the causal pathway to cardiovascular pathology, provides an overview of strategies to lower FGF23 levels and discusses the current evidence concerning the benefit of lowering FGF23.

Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3.

BACKGROUND: High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23. METHODS: In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383). RESULTS: A total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (ß = -0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (ß = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer. CONCLUSION: In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.

Fibroblast Growth Factor-23 and Risks of Cardiovascular and Noncardiovascular Diseases: A Meta-Analysis.

Background Fibroblast growth factor-23 (FGF-23) has been hypothesized to play a role in the increased risk of cardiovascular disease in patients with CKD.Methods We identified prospective studies reporting associations between FGF-23 concentration and risk of cardiovascular events. Maximally adjusted risk ratios (RRs) were extracted for each outcome and scaled to a comparison of the top versus bottom third of the baseline FGF-23 concentration, and the results aggregated.Results Depending on the assay used, median FGF-23 concentrations were 43-74 RU/ml and 38-47 pg/ml in 17 general population cohorts; 102-392 RU/ml in nine cohorts of patients with CKD not requiring dialysis; and 79-4212 RU/ml and 2526-5555 pg/ml in eight cohorts of patients on dialysis. Overall, comparing participants in the top and bottom FGF-23 concentration thirds, the summary RRs (95% confidence intervals [95% CIs]) were 1.33 (1.12 to 1.58) for myocardial infarction, 1.26 (1.13 to 1.41) for stroke, 1.48 (1.29 to 1.69) for heart failure, 1.42 (1.27 to 1.60) for cardiovascular mortality, and 1.70 (1.52 to 1.91) for all-cause mortality. The summary RR for noncardiovascular mortality, calculated indirectly, was 1.52 (95% CI, 1.28 to 1.79). When studies were ordered by average differences in FGF-23 concentration between the top and bottom thirds, there was no trend in RRs across the studies.Conclusions The similarly-sized associations between increased FGF-23 concentration and cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes, together with the absence of any exposure-response relationship, suggest that the relationship between FGF-23 and cardiovascular disease risk may be noncausal.

Impact of fractional phosphate excretion on the relation of FGF23 with outcome in CKD patients.

BACKGROUND: Cardiovascular risk is increased in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) has emerged as an important, independent predictor of outcome in CKD patients. High FGF23 may, however, be a reflection of renal tissue resistance to its actions, reflected by low fractional excretion of phosphate (FePi). We evaluated the modifying effect of FePi on the association between FGF23 and outcome in patients with CKD stage 3-4. METHODS: An analysis was performed in a subset of 166 adult patients of two participating centers of the MASTERPLAN trial of whom urine samples at baseline were available to calculate FePi. Outcome was defined as a composite of death, renal failure (defined as need for renal replacement therapy or doubling of serum creatinine) and cardiovascular events (myocardial infarction, cerebrovascular accident, percutaneous transluminal coronary angioplasty or coronary artery bypass graft. Patients were categorized by FGF23 and FePi. A product term was added to Cox regression and RERIs were calculated. RESULTS: Patients had a median estimated glomerular filtration rate (eGFR) of 36 ml/min/1.73 m(2) [interquartile range (IQR) 27-44], serum phosphate 1.04 mmol/l (IQR 0.92-1.20), FGF23 140 RU/ml (IQR 81-236) and FePi 0.32 (IQR 0.25-0.44). A total of 96 events occurred during 5 years of follow up. LnFGF23 was a significant, independent predictor for the composite outcome [hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.53-2.95]. FePi did not modify the relation between FGF23 and outcome in these patients with CKD. CONCLUSIONS: Our study shows that FGF23 itself, but not its renal tissue resistance as reflected by FePi, is an important risk factor for clinical events in subjects with CKD stage 3-4.

Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients.

BACKGROUND: Dialysis patients suffer from a high burden of cardiovascular disease (CVD). Partly this is due to progressive deterioration of calcium-phosphate homeostasis. Previous studies suggested that besides FGF-23, low levels of Klotho, a protein linked to aging, might constitute a key factor in this detrimental relationship. The purpose of the present study was to determine the relationship between serum Klotho (sKlotho) and the presence of CVD in dialysis patients. METHODS: Plasma levels of sKlotho were measured in a cohort of dialysis patients and related to left ventricular (LV) dysfunction (defined as a LV ejection fraction<45%) and LV mass using echocardiography. Coronary artery disease (CAD) and calcification score were assessed using computed tomography angiography. Abdominal aortic calcification score (AACscore) was measured by abdominal X-ray. RESULTS: We included 127 dialysis patients, 67±7 years old, 76% male, 67% on hemodialysis, median sKlotho 460 pg/mL (25th-75th percentile 350-620 pg/mL). Patients with a low sKlotho (<460 pg/mL) showed significantly more CAD (81% versus 61%; p=0.02) and LV dysfunction (19% versus 3%; p<0.01). However, after adjusting for confounders, sKlotho was not independently associated with the presence of CVD or the AACscore. CONCLUSIONS: In the present cohort of dialysis patients, sKlotho was not independently associated with CVD. However, patients with a low sKlotho level (<460 pg/mL) did show CAD and LV dysfunction more frequently. Therefore, while sKlotho might be a marker for CVD in dialysis patients, the current data does not support a direct cardioprotective effect of sKlotho.

Time-averaged level of fibroblast growth factor-23 and clinical events in chronic kidney disease.

BACKGROUND: A single time-point fibroblast growth factor-23 (FGF23) level is a strong, well-established risk factor for clinical events in chronic kidney disease (CKD). This study investigated whether repeated measurements of FGF23 after 2 years, allowing the calculation of time-averaged FGF23 and the rate of change in FGF23, provided a better prediction of clinical events in CKD than a single time-point value. METHODS: A post-hoc analysis was performed in a subset of 439 adult patients with a median estimated glomerular filtration rate of 36 (interquartile range 28-48) mL/min per 1.73 m(2) of the prospective multicentre MASTERPLAN study, in which paired samples to measure FGF23 were available. The primary outcome was defined as a composite of myocardial infarction, stroke and cardiovascular mortality and secondary end points, which were overall mortality, congestive heart failure (CHF) and start of renal replacement therapy. Only events occurring after Month 24 were included in the analysis. RESULTS: Analysis of different FGF23 measures showed that a single time-point value and time-averaged FGF23 were positively associated with the primary end point, and also with overall mortality, start of renal replacement therapy and CHF. The adjusted hazard ratios of a single value of FGF23 and of time-averaged FGF23 for the composite end points were 1.71 (CI 1.20-2.43) and 1.91 (CI 1.29-2.82), respectively. Change in FGF23 was not associated with any outcome except for the initiation of renal replacement therapy. CONCLUSIONS: Our study confirms that FGF23 is an important cardiovascular risk factor. Two measurements of FGF23 have no added value over a single value to predict the cardiovascular outcome. This study demonstrates that, under routine clinical practice, the variability of FGF23 in 2 years' time is small. Concomitantly, this study showed no benefit of consecutive FGF23 testing for estimating the risk of a clinical event in an individual patient.