FGF-23 is elevated by chronic hyperphosphatemia

The Identification and characterization of FGF-23 has provided an opportunity to gain new insight into phosphorus metabolism. Circulating FGF-23 promotes renal excretion of phosphorus, and FGF-23 is measurable in the serum of normal subjects. Serum levels of FGF-23 are elevated in patients with renal phosphate wasting disorders such as tumor induced osteomalacia, X-linked hypophosphatemia and fibrous dysplasia. However, the factors that alter its serum concentration are not known. The study of serum FGF-23 is confounded by the fact that high serum calcium, PTH, and any other putative phosphotonins, have similar effects on serum and urine phosphorus. To circumvent the confounding effect of serum PTH and calcium, we studied serum FGF-23 and phosphate levels in patients with chronic hypoparathyroidism and hyperphosphatemia. Serum was collected in the morning after an overnight fast from three groups: 1) 9 patients with chronic hypoparathyroidism on stable treatment with calcium and calcitriol, 2) 9 patients with primary hyperparathyroidism, and 3) 77 normal controls. Patients with hypoparathyroidism had predictably higher levels of serum phosphorus than patients with hyperparathyroidism or normal controls (5.6 +/- 1.1, 3.1 +/- 0.6, and 3.1 +/- 0.5 mg/dL, mean +/- 1 SD, respectively (p < 0.01 for hypoparathyroid vs. either group)). They also had higher levels of FGF-23 (150 +/- 120 vs. 70 +/- 60, or 55 +/- 20 RIU/ml, respectively (p < 0.05 vs. either group)). In conclusion, serum FGF-23 levels are elevated in patients with hyperphosphatemia and chronic hypoparathyroidism, suggesting a feedback system in which serum FGF-23 responds to serum phosphorus and regulates it. However, in the setting of chronic hypoparathyroidism, the degree of elevation of FGF-23 is insufficient to normalize serum phosphorus.     

慢性肾脏病患者血浆成纤维细胞生长因子23与心血管疾病的关系

慢性肾脏病(CKD)患者心血管并发症发生率较普通人群增高,心血管疾病(CVD)是CKD进展的重要危险因子。CKD患者的矿物质与骨代谢异常(MBD)包括血清全段甲状旁腺激素(i PTH)升高、维生素D缺乏及高磷血症等,均为CVD的独立影响因素。成纤维细胞生长因子23(FGF23)能调节体内磷和维生素D代谢水平。血浆FGF23水平在CKD患者早期即进行性升高,一方面是机体对尿毒症状态的适应性变化,另一方面也是骨病与心血管并发症等病理过程的起始因素。血浆FGF23水平与CKD患者的左心室肥厚(LVH)、血管钙化、心血管功能异常及死亡率增加相关。现将FGF23的生理特点及其与CVD的关系、介导CVD的机制等作一综述。     

The role of statins in chronic kidney disease

Chronic kidney disease is associated with cardiovascular event rates that are at least as high as in patients with established atherosclerotic cardiovascular disease or in those with diabetes mellitus. Chronic kidney disease is therefore considered a cardiovascular disease risk equivalent. Treatment of dyslipidemia, which is very common in this population and reflects the pattern seen in the metabolic syndrome, reduces cardiovascular events in patients with chronic kidney disease. Thus, patients with chronic kidney disease should be evaluated and treated for dyslipidemia. Dyslipidemia is a risk factor for the development of impaired kidney function. Dyslipidemia is also associated with progressive renal disease in subjects with no overt renal disease, as well as those with diabetic and nondiabetic kidney disease. Although definitive randomized controlled trials are lacking, the collective evidence suggests that treatment of dyslipidemia is associated with less decline in renal function. The use of potent statins in high doses can lead to transient proteinuria via impairment of proximal tubular receptor--mediated endocytosis, in a dose-dependent manner. Over the long term, however, the use of statins results in a reduction in proteinuria and in the rate of decline of renal function. Several large definitive trials that are currently underway to examine the safety and efficacy of statins in cardiovascular and renal protection should provide more definitive answers on the role of these drugs in this very high risk population.     

成纤维细胞生长因子23与慢性肾脏病患者心血管疾病的关系

心血管疾病是慢性肾脏病(CKD)患者最常见的致死原因.成纤维细胞生长因子23(FGF23)在CKD患者中明显升高,且与左心室肥厚和心血管事件发生率密切相关.其机制包括FGF23激活肾素-血管紧张素-醛固酮系统和非klotho依赖左心室肥厚等.目前针对降低FGF23干预性治疗尚无定论,低磷饮食、磷结合剂与西那卡塞可降低CKD患者FGF23水平,但其有效性还需进一步的临床研究加以证实.     

Obesity, anemia, and cardiovascular risk in patients with chronic kidney disease: Overview and pathophysiologic insights

Obesity is a well-established risk factor for cardiovascular disease (CVD) and is increasingly being recognized as a risk factor for chronic kidney disease (CKD). Anemia that is associated with rapid CKD progression is also associated with increased CVD risk. The common soil hypothesis linking obesity, anemia, CKD, and CVD includes increased inflammation and oxidative stress. We present an overview of CKD and CVD risk associated with obesity and anemia highlighting the pathogenetic pathways linking these rapidly growing disorders. We also discuss the therapeutic strategies for obesity reduction and anemia treatment and their impact on CVD and CKD risk, highlighting the contemporary issues and questions raised by recent clinical trials.     

Atherosclerosis in chronic kidney disease: the role of macrophages

Patients with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease and loss of renal parenchyma accelerates atherosclerosis in animal models. Macrophages are central to atherogenesis because they regulate cholesterol traffic and inflammation in the arterial wall. CKD influences macrophage behavior at multiple levels, rendering them proatherogenic. Even at normal creatinine levels, macrophages from uninephrectomized Apoe(-/-) mice are enriched in cholesterol owing to downregulation of cholesterol transporter ATP-binding cassette subfamily A member 1 levels and activation of nuclear factor κB, which leads to impaired cholesterol efflux. Interestingly, treatment with an angiotensin-II-receptor blocker (ARB) improves these effects. Moreover, atherosclerotic aortas from Apoe(-/-) mice transplanted into renal-ablated normocholesterolemic recipients show plaque progression and increased macrophage content instead of the substantial regression seen in recipient mice with intact kidneys. ARBs reduce atherosclerosis development in mice with partial renal ablation. These results, combined with the clinical benefits of angiotensin-converting-enzyme (ACE) inhibitors and ARBs in patients with CKD, suggest an important role for the angiotensin system in the enhanced susceptibility to atherosclerosis seen across the spectrum of CKD. The role of macrophages could explain why these therapies may be effective in end-stage renal disease, one of the few conditions in which statins show no clinical benefit.     

Inflammation in chronic kidney disease: the role of cytokines

Chronic kidney disease (CKD) is a serious public health problem whose prevalence has increased in the last few years. Its progression is associated with high morbidity and mortality. Several factors are associated with the onset and progression of CKD, such as obesity, hypertension and diabetes mellitus. Beyond these factors, there is evidence of a pathophysiological role for inflammation in CKD. Several cytokines and chemokines have been detected in the plasma and urine of patients at early stages of CKD, and have also been related to CKD complications. The expression of these mediators and renal injury may be influenced by drugs such as angiotensin-converting enzyme inhibitors, statins and antagonists of cytokine receptors. Modulation of the immune-inflammatory response can become a target for CKD treatment. The aim of this study was to review the scientific evidence on the role of inflammation in CKD, especially the effects of cytokines and chemokines.     

Interplay between metabolic dysfunction-associated fatty liver disease and chronic kidney disease: Epidemiology,pathophysiologic mechanisms,and treatment considerations

The recently proposed nomenclature change from non-alcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease (MAFLD) has resulted in the reappraisal of epidemiological trends and associations with other chronic diseases. In this context, MAFLD appears to be tightly linked to incident chronic kidney disease (CKD). This association may be attributed to multiple shared risk factors including type 2 diabetes mellitus, arterial hypertension, obesity, dyslipidemia, and insulin resistance. Moreover, similarities in their molecular pathophysiologic mechanisms can be detected, since inflammation, oxidative stress, fibrosis, and gut dysbiosis are highly prevalent in these pathologic states. At the same time, lines of evidence suggest a genetic predisposition to MAFLD due to gene polymorphisms, such as the PNPLA3 rs738409 G allele polymorphism, which may also propagate renal dysfunction. Concerning their management, available treatment considerations for obesity (bariatric surgery) and novel antidiabetic agents (glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter 2 inhibitors) appear beneficial in preclinical and clinical studies of MAFLD and CKD modeling. Moreover, alternative approaches such as melatonin supplementation, farnesoid X receptor agonists, and gut microbiota modulation may represent attractive options in the future. With a look to the future, additional adequately sized studies are required, focusing on preventing renal complications in patients with MAFLD and the appropriate management of individuals with concomitant MAFLD and CKD.     

维生素D与慢性肾脏病患者的免疫调节功能

维生素D缺乏在慢性肾脏病患者中很常见,且与患者预后相关。维生素D不仅参与矿物质代谢,也在免疫调节中发挥重要作用。因为尿毒症毒素、营养不良、透析器生物相容性及维生素D甲状旁腺素轴等因素,慢性肾脏病患者往往存在免疫功能失调。本文就维生素D在固有免疫、适应性免疫中的作用展开探讨,着重对维生素D参与调节慢性肾脏病患者的免疫功能方面进行综述。     

The role of melatonin in patients with chronic kidney disease undergoing haemodialysis

Patients with chronic kidney disease including those undergoing haemodialysis have deranged sleep-wake pattern. In large part this is due to an abnormal circadian cycle of melatonin, a hormone secreted by the pineal gland in the evening and induces sleep. Subjects undergoing automated peritoneal dialysis or nocturnal haemodialysis have better sleep profile compared to those on daytime dialysis. Studies have shown that exogenous melatonin improves sleep-wake cycle in daytime haemodialysis patients. However, large randomised controlled trials are needed in order to establish its role in this patient population.     

The adaptation and relationship of FGF-23 to changes in mineral metabolism in Graves' disease

OBJECTIVE: The aim of this study was to observe the changes in bone and mineral metabolism and to confirm the regulation of fibroblast growth factor-23 (FGF-23) in untreated Graves' disease. PATIENTS AND MEASUREMENTS: The study comprised 39 patients, with or without Graves' disease. The Graves' disease group was made up of 21 newly diagnosed patients, enrolled before starting treatment. Their disease was determined by biochemical and radiological means. The control group was composed of 18 people who were proven to be euthyroid without any diseases affecting bone and mineral metabolism. FGF-23, calcium, phosphate, PTH, 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels and bone turnover markers were compared between these groups. RESULTS: Serum calcium and phosphate, plasma FGF-23 and free T4 were significantly higher in the Graves' disease group than in the healthy control group (P < 0.05). The bone turnover markers serum osteocalcin and C-terminal cross-linked telopeptide of type 1 collagen (s-CTx) were also significantly elevated in the Graves' disease group, and had a positive correlation with free T4 levels. However, there was no significant decrease in PTH and 1,25(OH)2D in the Graves' disease group. Plasma levels of FGF-23 exhibited a positive correlation with serum phosphate levels and with free T4 levels (P < 0.05). CONCLUSIONS: These findings suggest that FGF-23 is physiologically related to serum phosphate homeostasis, as indicated indirectly by the changes in bone and mineral metabolism, in untreated Graves' disease.     

Obesity and chronic kidney disease

Obesity is associated with the early onset of glomerulomegaly, hemodynamic changes of a hyperfiltering kidney, and increased albuminuria, which are potentially reversible with weight loss. However, pathologic lesions of focal segmental glomerulosclerosis develop in experimental models of sustained obesity, and are observed in morbidly obese humans presenting with massive proteinuria. In addition, several observational, cross sectional and longitudinal studies document that obesity is as an independent risk factor for the onset, aggravated course, and poor outcomes of chronic kidney disease, even after adjustment for confounding co-morbidities including metabolic syndrome, diabetes and hypertension, the major causes of chronic kidney disease. Early dietary intervention to reduce weight, and where necessary bariatric surgery, should be considered in the management of overweight and obese chronic kidney disease (CKD) patients.