Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study.

BACKGROUND: The CKD-associated decline in soluble α-Klotho (α-Klotho) levels is considered detrimental. Some studies suggest a direct induction of α-Klotho concentrations by growth hormone (GH). In the present study, the effect of exogenous GH administration on α-Klotho concentrations in a clinical cohort with mild chronic kidney disease (CKD) and healthy subjects was studied. METHODS: A prospective, single-center open case-control pilot study was performed involving 8 patients with mild CKD and 8 healthy controls matched for age and sex. All participants received subcutaneous GH injections (Genotropin®, 20 mcg/kg/day) for 7 consecutive days. α-Klotho concentrations were measured at baseline, after 7 days of therapy and 1 week after the intervention was stopped. RESULTS: α-Klotho concentrations were not different between CKD-patients and healthy controls at baseline (554 (388-659) vs. 547 (421-711) pg/mL, P = 0.38). Overall, GH therapy increased α-Klotho concentrations from 554 (405-659) to 645 (516-754) pg/mL, P < 0.05). This was accompanied by an increase of IGF-1 concentrations from 26.8 ± 5.0 nmol/L to 61.7 ± 17.7 nmol/L (P < 0.05). GH therapy induced a trend toward increased α-Klotho concentrations both in the CKD group (554 (388-659) to 591 (358-742) pg/mL (P = 0.19)) and the healthy controls (547 (421-711) pg/mL to 654 (538-754) pg/mL (P = 0.13)). The change in α-Klotho concentration was not different for both groups (P for interaction = 0.71). α-Klotho concentrations returned to baseline levels within one week after the treatment (P < 0.05). CONCLUSIONS: GH therapy increases α-Klotho concentrations in subjects with normal renal function or stage 3 CKD. A larger follow-up study is needed to determine whether the effect size is different between both groups or in patients with more severe CKD. TRIAL REGISTRATION: This trial is registered in EudraCT ( 2013-003354-24 ).

Phosphate Binding Therapy to Lower Serum Fibroblast-Growth-Factor-23 Concentrations in Chronic Kidney Disease: Rationale and Study Design of the Sevelamer on FGF23 Trial (SoFT).

BACKGROUND: Increased levels of phosphate and fibroblast growth factor-23 (FGF23) are strong predictors of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Preliminary data suggest that interventions lowering gastro-intestinal phosphate uptake lowers serum FGF23 concentrations and improves cardiovascular risk and subsequently survival. However, data are lacking about the magnitude of effects, the effect in different stages of CKD and whether there is a dose-effect relationship. METHODS: Therefore, the Sevelamer on FGF23 Trial (SoFT) is designed as an open-label, single-arm, clinical pilot study aiming to demonstrate the feasibility of a phosphate-restricted diet in combination with the phosphate binder sevelamer to induce an effective, predictable and sustained decrease in FGF23 level in patients with an estimated glomerular filtration rate (eGFR) of 15-90 or >90 ml/min/1.73 m2 with proteinuria >1.0 g in 24 h urine collection, despite optimally dosed RAAS blockade, without inducing hypophosphatemia using a forced uptitration treatment regimen aimed at restricting phosphate uptake.

Reduction of Oxidative Stress in Chronic Kidney Disease Does Not Increase Circulating α-Klotho Concentrations.

The CKD-associated decline in soluble α-Klotho levels is considered detrimental. Some in vitro and in vivo animal studies have shown that anti-oxidant therapy can upregulate the expression of α-Klotho in the kidney. We examined the effect of anti-oxidant therapy on α-Klotho concentrations in a clinical cohort with mild tot moderate chronic kidney disease (CKD). We performed a post-hoc analysis of a prospective randomized trial involving 62 patients with mild to moderate CKD (the ATIC study), all using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for 12 months. On top of that, the intervention group received anti-oxidative therapy consisting of the combination of pravastatin (40 mg/d) and vitamin E (α-tocopherol acetate, 300 mg/d) while the placebo was not treated with anti-oxidants. α-Klotho concentrations were measured at baseline and after 12 months of anti-oxidant therapy. Data were analysed using T-tests and Generalized Estimating Equations, adjusting for potential confounders such as vitamin D, parathyroid hormone, fibroblast-growth-factor 23 (FGF23) and eGFR. The cohort existed of 62 patients with an eGFR (MDRD) of 35 ± 14 ml/min/1.72 m2, 34 were male and mean age was 53.0 ± 12.5 years old. Anti-oxidative therapy did successfully reduce oxLDL and LDL concentrations (P <0.001). α-Klotho concentrations did not change in patients receiving either anti-oxidative therapy (476.9 ± 124.3 to 492.7 ± 126.3 pg/mL, P = 0.23) nor in those receiving placebo 483.2 ± 142.5 to 489.6 ± 120.3 pg/mL, P = 0.62). Changes in α-Klotho concentrations were not different between both groups (p = 0.62). No evidence was found that anti-oxidative therapy affected α-Klotho concentrations in patients with mild-moderate CKD.

α-Klotho is unstable in human urine.

α-Klotho is an interesting new biomarker in kidney and cardiovascular disease. As α-Klotho is primarily expressed in renal epithelial tissue, various papers have reported α-Klotho concentrations in urine. As these studies did not address the reliability of urinary α-Klotho measurements and as urine is known to be a complex milieu, we investigated the stability of α-Klotho in both fresh catheter and fresh voided urine. α-Klotho was measured in these fresh urine samples and in the same samples under several other conditions. Storage of fresh catheter urine for 3 h at 37 °C, comparable to storage in the bladder, led to a 82% decrease in α-Klotho concentrations. Compared with fresh voided urine, α-Klotho concentrations decreased on an average of 45 and 82% after storage at -80 °C and -20 °C, respectively. An additional freeze-thaw cycle further decreased α-Klotho concentrations. The addition of a protease inhibitor or 0.1% albumin partly prevented degradation in fresh voided urine. Thus, α-Klotho is highly unstable in urine. Future studies showing results of urinary α-Klotho should mention conservation conditions and prove the reliability of the α-Klotho measurements.

The role of klotho on vascular calcification and endothelial function in chronic kidney disease.

Recent insights into novel roles of klotho in vascular biology make this primarily kidney-derived protein a possible candidate to form a link between chronic kidney disease and cardiovascular morbidity and mortality. Typical features of vascular dysfunction or structural abnormalities in the arterial wall are exacerbated in klotho-deficient states. Reported klotho functions include inhibition of local phosphate transport in vascular cells, phenotypic switches of vascular cellular elements into bone-forming cells, attenuation of matrix mineralization and calcification, and also preservation of endothelial functional properties and viability. To a large extent these insights rely on animal models of kidney or cardiovascular diseases. In this review the current state of knowledge on these issues is summarized, and we aim to provide a possible new perspective on cardiovascular disease in chronic kidney disease.

Dietary and pharmacological modification of fibroblast growth factor-23 in chronic kidney disease.

Increased levels of phosphorus and fibroblast growth factor-23 (FGF-23) are strong predictors of cardiovascular morbidity and mortality. From a physiological perspective and supported by some data, phosphorus is the main driver for FGF-23 secretion. Therefore, it is conceivable that interventions aiming at restriction of phosphorus uptake from the gastrointestinal tract may lower serum FGF-23 levels and improve cardiovascular risk and subsequently survival. It is not currently known to what extend phosphorus and FGF-23 are independent risk factors, and therefore both need to be targeted. However, their respective metabolisms are tightly connected. Control of phosphorus levels in chronic kidney disease (CKD) patients is attempted mainly by restriction of dietary intake and the use of phosphorus binders. In this review, it is outlined that not just the amount of dietary phosphorus intake is important but also its type (organic vs. inorganic), its source (animal vs. plant derived), and the protein-to-phosphorus ratio in the bioavailability of phosphorus from food. This qualitative aspect of diet is likely a neglected aspect of dietary counseling in CKD. However, in more advanced stages of CKD, dietary restriction of phosphorus alone is usually not sufficient to control hyperphosphatemia, and phosphorus binders are indicated. The inexpensive, calcium-containing dietary phosphorus binders are used commonly worldwide. However, they are not suitable for every patient because of the association with elevated serum calcium, increase in vascular and valvular calcification scores, and cardiovascular and all-cause mortality. The calcium content itself in these binders has recently been implicated to upregulate FGF-23. For that reason, the noncalcium, aluminum-free agents such as sevelamer and lanthanum are being advocated. However, these drugs do not have a clearly defined effect on circulating levels of FGF-23. Although it is conceivable that targeting FGF-23 may lead to improved clinical outcomes, this remains speculative. Therefore, more studies are needed to answer the question if this can be achieved with any of the phosphorus binders, or by another (additional) pharmacological intervention.

Ascites as the presenting symptom in a patient with Churg-Strauss syndrome.

A 67-year-old male presented with ascites, dyspnoea, peripheral edema and purpura. The history revealed asthma and nasal polyps. The laboratory tests showed an increased peripheral blood eosinophilic cell count. The ascitic fluid analysis showed features consistent with an eosinophilic peritonitis. A skin biopsy revealed eosinophilic vasculitis. Our patient was diagnosed with Churg-Strauss syndrome based on the medical history, laboratory and histology. This case describes ascites as the presenting symptom of Churg-Strauss syndrome.