In chronic kidney disease (CKD), high serum phosphate concentration is associated with cardiovascular disease and deterioration in renal function. In early CKD, the serum phosphate concentration is normal due to increased fractional excretion of phosphate. Our premise was that high phosphate intake even in patients with early CKD would result in an excessive load of phosphate causing tubular injury and accelerating renal function deterioration. In CKD 2–3 patients, we evaluated whether increased phosphaturia accelerates CKD progression. To have a uniform group of patients with early CKD, 95 patients with metabolic syndrome without overt proteinuria were followed for 2.7 ± 1.6 years. The median decline in eGFR was 0.50 ml/min/1.73 m2/year. Patients with a more rapid decrease in eGFR had greater phosphaturia. Moreover, the rate of decrease in eGFR inversely correlated with the degree of phosphaturia. Additionally, phosphaturia independently predicted renal function deterioration. In heminephrectomized rats, a high phosphate diet increased phosphaturia resulting in renal tubular damage associated with inflammation, oxidative stress and low klotho expression. Moreover, in rats with hyperphosphatemia and metabolic syndrome antioxidant treatment resulted in attenuation of renal lesions. In HEK-293 cells, high phosphate promoted oxidative stress while melatonin administration reduced ROS generation. Our findings suggest that phosphate loading in early CKD, results in renal damage and a more rapid decrease in renal function due to renal tubular injury.

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Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future.

CKD affects one in seven adults in Spain. The prevalence is higher than previously reported and similar to that in the United States. CKD was particularly prevalent in men, older people and people with cardiovascular disease. Prevalence of CKD increased considerably with the accumulation of CVRF, suggesting that CKD could be considered as a cardiovascular condition.

Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications.

The calcimimetic cinacalcet increases the sensitivity of the parathyroid calcium-sensing receptor to calcium and therefore should produce a decrease in the set point of the parathyroid hormone (PTH)-calcium curve. For investigation of this hypothesis, nine long-term hemodialysis patients with secondary hyperparathyroidism were given cinacalcet for 2 mo, the dosage was titrated per a protocol based on intact PTH and plasma calcium concentrations. Dialysis against low-and high-calcium (0.75 and 1.75 mM) dialysate was used to generate curves describing the relationship between PTH and calcium. Compared with precinacalcet levels, cinacalcet significantly reduced mean serum calcium, intact PTH and whole PTH (wPTH; all P Ͻ 0.001). The set points for PTH-calcium curves were significantly reduced, and both maximum and minimum levels of PTH (intact and whole) were significantly decreased. The calciummediated inhibition of PTH secretion was more marked after cinacalcet treatment. In addition, cinacalcet shifted the inverse sigmoidal curve of wPTH/non-wPTH ratio versus calcium to the left (i.e., less calcium was required to reduce the wPTH/non-wPTH ratio). In conclusion, cinacalcet increases the sensitivity of the parathyroids to calcium, causing a marked reduction in the set point of the PTH-calcium curve, in hemodialysis patients with secondary hyperparathyroidism.

In uremic patients, severe parathyroid hyperplasia is associated with reduced parathyroid calcium-sensing receptor (CaR) expression. Thus, in these patients, a high serum Ca concentration may be required to inhibit parathyroid hormone (PTH) secretion. This study compares the magnitude of reduction in CaR expression and the degree of the abnormality in Ca-regulated PTH release in vitro. A total of 50 glands from 23 hemodialysis patients with refractory hyperparathyroidism were studied. Tissue slices were incubated in vitro to evaluate (1) the PTH secretory output in a normal Ca concentration (1.25 mM) and (2) the PTH secretory response to high (1.5 mM) and low (0.6 mM) Ca concentration. Tissue aliquots were processed for determination of CaRmRNA expression. The results showed that, corrected for DNA, parathyroid tissue with lowest CaR expression secreted more PTH than that with relatively high CaR expression (146 ؎ 23 versus 60 ؎ 2 pg/g DNA; P < 0.01). Furthermore, glands with low CaR expression demonstrated a blunted PTH secretory response to both the inhibitory effect of high Ca and the stimulatory effect of low Ca. The study also showed that the larger the gland, the lower the CaRmRNA expression. Thus, large parathyroid glands produce a large amount of PTH not only as a result of the increased gland size but also because the parathyroid tissue secretory output is increased. These abnormalities in PTH regulation are related to low CaR expression.

P atients who have renal insufficiency develop secondary hyperparathyroidism (SHPT). High levels of parathyroid hormone (PTH) are associated with negative outcomes and play a key role in the development of chronic kidney disease-mineral and bone disorder (CKD-MBD). Excess PTH increases bone turnover, and as SHPT progresses, osteitis fibrosa develops. 1 However, due to bone resistance to PTH, a normal or moderately increased PTH concentration is not sufficient to maintain normal bone turnover. 2 Therefore, excessive suppression of PTH may exacerbate adynamic bone disease.