Marc G. Vervloet

Cross Talk Between the Renin-Angiotensin-Aldosterone System and Vitamin D-FGF-23-klotho in Chronic Kidney Disease

There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.

Effects of Dietary Phosphate and Calcium Intake on Fibroblast Growth Factor-23

BACKGROUND AND OBJECTIVES Little is known about the influence of dietary phosphate intake on fibroblast growth factor-23 (FGF23) and its subsequent effects on vitamin D levels. This study addresses changes in intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23), phosphaturia, and levels of vitamin D on high and low phosphate and calcium intake. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Ten healthy subjects adhered to a diet low or high in phosphate and calcium content for 36 hours each with a 1-week interval during which subjects adhered to their usual diet. Serum phosphate, calcium, vitamin D metabolites, parathyroid hormone (PTH), and FGF23 levels (cFGF23 and iFGF23) were measured several times a day. Phosphate, calcium, and creatinine excretion was measured in 24-hour urine on all study days. RESULTS Serum phosphate levels and urinary phosphate increased during high dietary phosphate intake (from 1.11 to 1.32 mmol/L, P<0.0001 and 21.6 to 28.8 mmol/d, P=0.0005, respectively). FGF23 serum levels increased during high dietary phosphate/calcium intake (cFGF23 from 60 to 72 RU/ml, P<0.001; iFGF23 from 33 to 37 ng/L, P=0.003), whereas PTH declined. 1,25-dihydroxyvitamin D (1,25D) showed an inverse relation with FGF23. CONCLUSIONS Variation in dietary phosphate and calcium intake induces changes in FGF23 (on top of a circadian rhythm) and 1,25D blood levels as well as in urinary phosphate excretion. These changes are detectable the day after the change in the phosphate content of meals. Higher FGF23 levels are associated with phosphaturia and a decline in 1,25D levels.

Executive summary of the 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and why it matters

The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease.

Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial

IntroductionBecause of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI).MethodsIn this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied.ResultsOf the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P < 0.001). Filter survival times were superior for citrate (median 46 versus 32 hours, P = 0.02), as were the number of filters used (P = 0.002) and the off time within 72 hours (P = 0.002). The costs during the first 72 hours of prescribed CVVH were lower in citrate-based CVVH.ConclusionsRenal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs.Trial registrationClinicaltrials.gov NCT00209378. Registered 13th September 2005.

Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders.

Recent reports of several bone-derived substances, some of which have hormonal properties, have shed new light on the bone-cardiovascular axis. Deranged concentrations of humoral factors are not only epidemiologically connected to cardiovascular morbidity and mortality, but can also be causally implicated, especially in chronic kidney disease. FGF23 rises exponentially with advancing chronic kidney disease, seems to reach maladaptive concentrations, and then induces left ventricular hypertrophy, and is possibly implicated in the process of vessel calcification. Sclerostin and DKK1, both secreted mainly by osteocytes, are important Wnt inhibitors and as such can interfere with systems for biological signalling that operate in the vessel wall. Osteocalcin, produced by osteoblasts or released from mineralised bone, interferes with insulin concentrations and sensitivity, and its metabolism is disturbed in kidney disease. These bone-derived humoral factors might place the bone at the centre of cardiovascular disease associated with chronic kidney disease. Most importantly, factors that dictate the regulation of these substances in bone and subsequent secretion into the circulation have not been researched, and could provide entirely new avenues for therapeutic intervention.

High levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients: results from the NECOSAD study

BACKGROUND Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover, and it plays a role in cardiovascular calcification processes. Previous findings indicate that sclerostin regulation is disturbed in chronic kidney disease (CKD). The aim of this study was to assess the association of circulating sclerostin levels with mortality in dialysis patients. METHODS From a prospective cohort study of incident dialysis patients in the Netherlands, all patients with measured circulating sclerostin at 3 months after the start of dialysis (baseline) were included in the present analysis: n = 673, age 63 ± 14 years, mean serum sclerostin (ELISA) 1.24 ± 0.57 ng/mL. By Cox regression analyses, we assessed the association of sclerostin levels with cardiovascular and non-cardiovascular mortality both in the short (18 months) and long term (4-year follow-up). RESULTS Serum sclerostin levels in the entire cohort correlated with intact parathyroid hormone levels (r = -0.25, P < 0.001), age (r = 0.16, P < 0.001) and serum alkaline phosphatase (r = -0.13, P = 0.001). After adjustment for various clinical and biochemical parameters, patients in the highest sclerostin tertile had a significantly lower risk of cardiovascular death [hazard ratio 0.29, 95% confidence interval (CI) 0.13-0.62] and for all-cause mortality (0.39, 95% CI 0.22-0.68) within 18 months compared with patients of the lowest tertile. The association of sclerostin levels with outcome was less pronounced for long-term cardiovascular mortality and absent for non-cardiovascular mortality. CONCLUSIONS High levels of serum sclerostin are associated with lower short-term cardiovascular mortality in dialysis patients. The exact mechanisms of this association, e.g. how sclerostin influences or reflects uraemic vascular calcification, need to be investigated in further studies.

Fibroblast Growth Factor 23 and Cardiovascular Mortality after Kidney Transplantation

BACKGROUND AND OBJECTIVES Circulating fibroblast growth factor 23 (FGF23) is associated with adverse cardiovascular outcomes in CKD. Whether FGF23 predicts cardiovascular mortality after kidney transplantation, independent of measures of mineral metabolism and cardiovascular risk factors, is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The association between plasma C-terminal FGF23 and cardiovascular mortality was analyzed in a single-center prospective cohort of 593 stable kidney transplant recipients (mean age ± SD, 52 ± 12 years; 54% male; estimated GFR, 47 ± 16 ml/min per 1.73 m(2)), at a median of 6.1 (interquartile range, 2.7-11.7) years after transplantation. Multivariate Cox regression models were built, adjusting for measures of renal function and mineral metabolism; Framingham risk factors; the left ventricular wall strain markers midregional fragment of pro-A-type natriuretic peptide (MR-proANP) and N-terminal-pro brain natriuretic peptide (NT-proBNP); and copeptin, the stable C-terminal portion of the precursor of vasopressin. RESULTS In multivariate linear regression analysis, MR-proANP (β=0.20, P<0.001), NT-proBNP (β=0.18, P<0.001), and copeptin (β=0.26, P<0.001) were independently associated with FGF23. During follow-up for 7.0 (interquartile range, 6.2-7.5) years, 128 patients (22%) died, of whom 66 (11%) died due to cardiovascular disease; 54 (9%) had graft failure. FGF23 was associated with an higher risk of cardiovascular mortality in a fully adjusted multivariate Cox regression model (hazard ratio [HR], 1.88 [95% confidence interval (CI), 1.11 to 3.19]; P=0.02). FGF23 was also independently associated with all-cause mortality (full model HR, 1.86 [95% CI, 1.27 to 2.73]; P=0.001). Net reclassification improved for both cardiovascular mortality (HR, 0.07 [95% CI, 0.01 to 0.14]; P<0.05) and all-cause mortality (HR, 0.11 [95% CI, 0.05 to 0.18]; P<0.001). CONCLUSIONS Plasma FGF23 is independently associated with cardiovascular and all-cause mortality after kidney transplantation. The association remained significant after adjustment for measures of mineral metabolism and cardiovascular risk factors.

Determination of fibroblast growth factor 23

Background Fibroblast growth factor 23 (FGF-23) is a recently discovered hormone, which plays a key role in phosphate regulation. To investigate whether FGF-23 can be determined reliably, we validated the three available FGF-23 assays. Methods Currently, two intact FGF-23 assays (Kainos; Immutopics) and one C-terminal FGF-23 assay (Immutopics) are available. We determined intra- and inter-assay variation, linearity and matrix interference in these assays. Moreover, we compared assay results from healthy subjects with those of patient groups with expected high FGF-23 concentrations. Results Intra-assay variation was reasonably good in all three assays. Inter-assay variation and linearity were poor for the intact Immutopics assay but reasonable for both other assays. Immutopics assays gave best results in ethylenediaminetetraacetic acid (EDTA) plasma, while the Kainos assay showed comparable reproducibility in EDTA plasma and serum. Although the manual of the Kainos assay states that an automatic washing machine can be used, acceptable results were only found by manual washing. Patients with kidney disease and patients with hypophosphatemic osteomalacia had increased C-terminal FGF-23 concentrations compared with healthy controls. Conclusion Two assays of reasonable quality are available for FGF-23, the intact FGF-23 assay (Kainos) provided proper attention is paid to the washing procedure, and the C-terminal assay (Immutopics).

The role of vitamin D in cardiovascular disease: From present evidence to future perspectives

Vitamin D and its metabolites have wide-spread physiological roles far beyond the well described effects in skeletal biology. Many physiological processes are directly or indirectly regulated by vitamin D and in consequence, vitamin D deficiency is implicated in numerous disease conditions. Summarizing previous assumptions on the optimal vitamin D levels in humans these data point towards calcidiol levels of approximately 30 ng/ml as being sufficient. The role of vitamin D deficiency in cardiovascular disease is a relatively novel field of interest. Well substantiated experimental data describe convincingly regulatory effects of vitamin D regarding various cardiovascular risk factors such as hypertension and diabetes mellitus. Activation of the vitamin D receptor suppresses e.g. the renin-angiotensin system. These experimental data are strongly supported by epidemiological and observational human data that link vitamin D deficiency to the incidence, degree and prevalence of cardiovascular risk factors and disease conditions. In contrast to the in vivo data and to the homogenous non-interventional observations, we know much less about controlled prospectively evaluated supplementation of vitamin D as a potentially therapeutic agent on cardiovascular events. High quality, large, and randomized controlled trials aiming primarily on cardiovascular end-points are absent. Speculations about the vitamin D usage in prevention or therapy of cardiovascular disease need to take potential drawbacks of vitamin D overdosing into account: Vitamin D overdosing might induce hypercalcemia, hyperphosphatemia, and increases in fibroblast growth-factor 23. The limited evidence regarding vitamin D therapy currently prevents general recommendations for vitamin D application in cardiology.

A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock

Methylene blue increases blood pressure and myocardial function in septic shock mainly by inhibiting nitric oxide (NO) actions. However, a dose-dependency of methylene blue has not been established. Therefore, the compound is currently used as rescue treatment only. To evaluate dose-dependency, a prospective, randomized, double blind, single centre study was performed in 15 consecutive, mechanically ventilated patients with septic shock admitted to the intensive care unit, in whom methylene blue was infused at 1 mg/kg (n=4), 3 mg/kg (n=6) or 7 mg/kg (n=5) over 20 min. Hemodynamic parameters were measured before and after the infusion. Gastric tonometry was performed. Methylene blue treatment increased heart rate, cardiac index, mean arterial, pulmonary artery, pulmonary artery occlusion and central venous pressures, systemic vascular resistance, ventricular stroke work indices and O(2) delivery and uptake, and decreased lactate levels. Methylene blue had a dose-dependent effect on cardiac index, mean arterial, mean pulmonary artery and pulmonary artery occlusion pressures, left ventricular function, O(2) delivery and consumption and lactate levels. The drug dose-dependently increased the gastric-arterial blood PCO(2) gap. The data suggest that in human septic shock, methylene blue increases mean arterial blood pressure by an increase in cardiac index and systemic vascular resistance. The rise in cardiac index is caused by an increase in left ventricular filling and function, increasing tissue oxygenation, even at a dose of 1mg/kg. High doses of methylene blue may compromise splanchnic perfusion, even though further enhancing global hemodynamics, and should therefore, be avoided in future studies.