Traditional Chinese Medicine Intervenes in Signaling Pathways Associated with CKD-MBD： A Review / 中国实验方剂学杂志

Traditional Chinese medicine （TCM） has certain advantages in the treatment of chronic kidney disease-mineral and bone disorder （CKD-MBD）. In recent years， there have been many studies on the treatment of CKD-MBD by Chinese medicinal compounds and monomers. As revealed by literature retrieval， the research on the mechanism of Chinese medicine in intervening in signaling pathways related to CKD-MBD was mainly based on self-made Chinese medicinal compounds， and the action pathways involved fibroblast growth factor 23/Klotho （FGF23/Klotho） signaling pathway， Wnt/β-catenin signaling pathway， receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin （RANK/RANKL/OPG） system， and other signaling pathways. TCM can improve calcium and phosphorus metabolism and bone metabolism disorder， and regulate inflammatory reaction， oxidative stress， apoptosis， and autophagy by regulating this series of signaling pathways for the treatment of CKD-MBD. This paper introduced the research results of these signaling pathways and the mechanism of TCM in the treatment of CKD-MBD in order to provide ideas and references for the related research of Chinese medicine in the treatment of CKD-MBD.

Marcadores FGF-23 y Klotho en enfermedad renal crónica y su implicación cardiovascular, una revisión sistemática / FGF-23 and Klotho markers in chronic kidney disease and its cardiovascular implication, a systematic review

La principal causa de mortalidad en enfermedad renal crónica (ERC), en el 80% de pacientes se da por enfermedad cardiovascular asociada, los parámetros bioquímicos clásicos del metabolismo óseomineral aún no logran explicar la progresión patológica por tanto, se ha empezado a estudiar nuevos marcadores con relación al daño cardiovascular, donde se ha encontrado al marcador FGF-23 y su correceptor Klotho, implicados en la génesis del daño cardiovascular y enfermedad óseomineral asociada al fosforo, que en conjunto causan remodelamiento cardiovascular, lo que ha empezado aclarecer aún más esta dinámica fisiopatológica. Esta revision busca conocer la implicación de los marcadores FGF-23 y Klotho en ERC y el riesgo cardiovascular asociado y para ello realizó una revision sistemática de literatura, indagando en bases biomédicas como COCHRANE, Embase, LILACS, Scielo, Pub-Med, EBSCO, Hinari, Sociedades médicas, así como tesauros MeSH propios de esta investigación.

The main cause of mortality in chronic kidney disease (CKD), in 80% of patients, is due to associated cardiovascular disease, the classic biochemical parameters of bone-mineral metabolism will not yet be able to explain the pathological progression, therefore, new markers have begun to be studied in relation to cardiovascular damage, where the marker FGF-23 and its co-receptor Klotho have been found, involved in the genesis of cardiovascular damage and bone-mineral disease associated with phosphorus, which together cause cardiovascular remodeling , which has begun to further clarify this pathophysiological dynamic.This review seeks to know the implication of the FGF-23 and Klotho markers in CKD and the associated cardiovascular risk and for this purpose, a systematic review of the literature was carried out, investigating biomedical bases such as COCHRANE, Embase, LILACS, Scielo, Pub-Med, EBSCO, Hinari, Medical Societies, as well as MeSH thesauri specific to this research.

Analysis of the correlation between blood pressure fluctuation and hemodialysis-related complications in patients with maintenance hemodialysis / 上海交通大学学报（医学版）

Objective : To explore the correlation between blood pressure fluctuation and chronic kidney disease-mineral and bone disorder (CKD-MBD) in patients with maintenance hemodialysis (MHD). Methods ¡¤ From Jan. 2009 to Apr. 2015, 433 MHD patients in Hemodialysis Center of Renji Hospital, Shanghai Jiao Tong University School of Medicine were included, and their clinical data, treatment parameters during dialysis, lab examination indexes and drug applications were collected. According to the difference value of systolic blood pressure (SBP) during dialysis period, all the patients were divided into high fluctuation group of blood pressure (|△ SBP| ≥ 10 mmHg, n=234) and low fluctua-tion group of blood pressure (|△ SBP|<10 mmHg, n=199). The blood pressure fluctuation and its relationship with dialysis adequacy, bone metabolism indicator and nutrition indicator were analyzed between the two groups. Results ¡¤ Compared with the low fluctuation group of blood pressure, the patients in the high fluctuation group of blood pressure took higher proportion of β receptor blockers and Vit D, higher level of serum P and intact parathyroid hormone (iPTH), higher dialysis age, and lower Kt/V, ultrafiltration volume, body mass index (BMI) and serum albumin (ALB) level (all P<0.05). The blood pressure fluctuation between the patients with different serum P and iPTH levels was statistically significant (all P<0.05). There was no statistically significant difference in blood pressure fluctuation between the patients with different serum Ca levels. Multivariate Logistic regression analysis showed that dialysis age, serum P and iPTH levels were independent risk factors for blood pressure fluctuation of MHD patients, while Kt/V and ALB were protective factors. Con-clusion ¡¤ Blood pressure fluctuation in MHD patients during dialysis period is significantly correlated with CKD-MBD, nutritional status, dialy-sis age and dialysis adequacy.

Mineral and bone metabolism disorder in an adenine-induced rat model of chronic kidney disease / 中国比较医学杂志

Objective To investigate the characteristic changes of biochemical markers of mineral metabolism, vascular calcification, and renal osteodystrophy in an adenine-induced rat model of chronic kidney disease (CKD). Methods A total of 20 male Sprague Dawley rats (SD rats) were randomly divided into two groups: the normal group fed with a diet without adenine, and the CKD group fed with an adenine-containing diet (7. 5 g/kg) for the first 4 weeks and then a diet without adenine for the following 2 weeks. At the end of the 2nd week, serum biochemical markers were detected. At the end of the 6th week, the SD rats were sacrificed and serum biochemical markers were detected once again. The aortas were collected for pathological examination and detection of vascular calcium and phosphorus contents. Femurs and the fifth lumbar vertebrae were taken for bone mineral density (BMD) measurement and bone histomorphometric analysis. Results At the end of the 2nd and 6th weeks, compared with the normal control group, the levels of serum creatinine, urea nitrogen, phosphorus and parathyroid hormone (PTH) in the CKD group were significantly increased (P＜0. 05 or P＜ 0. 01), and the level of serum calcium was significantly decreased (P＜ 0. 05 or P＜ 0. 01). Medial layer vascular calcification of the aorta occurred in 50％ of the rats in the CKD group, but was not observed in the normal control group. Vascular calcium and phosphorus contents were significantly higher in the CKD group compared with the normal control group (P＜ 0. 05). The BMD of total femur, cortical and trabecular bone tissues of the femur, and the fifth lumbar vertebra was significantly decreased in the CKD group (P＜ 0. 05 or P＜ 0. 01). The histomorphometric analysis showed that both bone resorption and bone formation of the trabecular bone in the CKD group were increased, indicating a high bone turnover status. The volumes of both trabecular and cortical bones of rats in the CKD group were significantly lower than that of the normal control group (P ＜ 0. 05 or P ＜ 0. 01). However, the trabecular bone mineralization was not significantly different between the two groups. Conclusions The adenine-induced rat model of chronic kidney disease (CKD) established in this study shows reduced serum calcium and increased serum phosphorus and PTH, and medial layer vascular calcification of the aorta. With respect to renal osteodystrophy, this model shows a high trabecular bone turnover, normal trabecular bone mineralization, and low bone volume of cortical and trabecular bone, which meets the characteristics of osteitis fibrosa. This model may become a useful tool for future study of chronic kidney disease-mineral and bone disorder (CKD-MBD).

Osteoporosis management in patient with renal function impairment / Manejo da osteoporose no paciente com função renal comprometida

Aging is associated with decreases in bone quality and in glomerular filtration. Consequently, osteoporosis and chronic kidney disease (CKD) are common comorbid conditions in the elderly, and often coexist. Biochemical abnormalities in the homeostasis of calcium and phosphorus begin early in CKD, leading to an increase in fracture risk and cardiovascular complications since early stages of the disease. The ability of DXA (dual energy X-ray absorptiometry) to diagnose osteoporosis and to predict fractures in this population remains unclear. The management of the disease is also controversial: calcium and vitamin D, although recommended, must be prescribed with caution, considering vascular calcification risk and the development of adynamic bone disease. Furthermore, safety and effectiveness of osteoporosis drugs are not established in patients with CKD. Thus, risks and benefits of antiosteoporosis treatment must be considered individually.

O envelhecimento associa-se tanto ao declínio da qualidade óssea quanto da filtração glomerular. Consequentemente, osteoporose e doença renal crônica (DRC) são comorbidades frequentes em idosos, e muitas vezes coexistem. Anormalidades bioquímicas na homeostase do cálcio e do fósforo surgem precocemente na DRC, causando aumento do risco de fraturas e de complicações cardiovasculares desde fases precoces da doença. A capacidade da densitometria (DXA) em diagnosticar osteoporose e predizer fraturas nessa população é questionável. O manejo da doença é também controverso; cálcio e vitamina D são recomendados com cautela, devido ao risco de calcificações vasculares e de doença óssea adinâmica. Além disso, a segurança e a eficácia dos medicamentos para osteoporose ainda não estão estabelecidas em pacientes com DRC. Assim, riscos e benefícios do tratamento para osteoporose devem ser considerados individualmente nesses pacientes.

Chronic Kidney Disease-mineral Bone Disorder and Active Vitamin D Analogs for Treating Severe Hyperparathyroidism in Children Receiving Chronic Peritoneal Dialysis

PURPOSE: The aims of this study were to assess the clinical and laboratory profiles of chronic kidney disease-mineral bone disorder (CKD-MBD) and to assess the effects of treatment of active vitamin D analogs on severe hyperparathyroidism (SHPT) in pediatric patients on chronic peritoneal dialysis. METHODS: This is a retrospective study included 53 patients who had been undergoing dialysis for more than 1 year, between January 2003 and December 2012. RESULTS: Even after treatment with phosphate binders and active vitamin D analogs, the mean+/-standard deviation of the percentage of time during peritoneal dialysis that the patients' serum concentrations of phosphorus, corrected total calcium, and parathyroid hormone (PTH) fell within the Kidney Disease Outcomes Quality Initiative recommended ranges was 25.06+/-17.47%, 53.30+/-23.03%, and 11.52+/- 9.51%, respectively. Clinical symptoms or radiological signs of CKD-MBD were observed in 10 patients (18.9%). There were significant differences in percentage of time that the serum intact PTH concentration was outside of the recommended range between patients with and without symptoms or signs of CKD-MBD (below recommended range, 11.74+/-7.37% vs. 40.77+/-25.39%, P<0.001; above the recommended range, 63.79+/-27.86% vs. 37.09+/-27.76%, P=0.022). Of the 25 patients with SHPT, high-dose alfacalcidol treatment was required in 13 patients that controlled SHPT in 7 of these patients, without marked complications. CONCLUSION: Despite our efforts to manage CKD-MBD, patients' met the recommended ranges from relevant guidelines at a low frequency. The treatment of high-dose active vitamin D analogs was required in about half of the patients with SHPT and effective in about half of them.

Estudo da prevalência de óbitos de pacientes com doença renal crônica associada à doença mineral óssea / Study of the prevalence of deaths of patients with chronic kidney disease associated with bone mineral disease

Introdução: Os disturbios na homeostase do cálcio, do fósforo e do paratormônio (PTH) ocorrem precocemente nos pacientes com doença renal crônica (DRC) e desempenham papel fundamental na fisiopatologia das doenças ósseas que acometem esses pacientes. As desordens do metabolismo mineral e ósseo são modificáveis e podem reduzir os fatores de risco associados a essas alterações que aumentam o risco de mortalidade em pacientes sob diálise. objetivo: identificar e quantificar casos de distúrbio mineral e ósseo (DMO) em pacientes com DRC que vieram a óbito no período de janeiro de 2004 a julho de 2008. Método: foram revisados 87 prontuários médicos dos pacientes que faziam hemodiálise e foram a óbito durante esse período. Foi realizado um registro retrospectivo de dados pessoais, laboratoriais, de morbidade e mortalidade. Resultados: a taxa de mortalidade anual média dos pacientes com DRC, atendidos no período estudado, foi de aproximadamente 16,7%. Do total de óbitos, a prevalecencia de DMO-DRC foi de 67,8%. A principal causa de óbito foi a doença cardiovascular (26,4%) e a doença de base, 52,9%, foi a nefropatia diabética. Dos pacientes que foram a óbito, 45% se apresentaram com os valores de fósforo acima de 5,5mg/dL, 38% com valores de PTH acima de 300pg/mL, 40% com valores de albumina inferior a 3,5g/L e 40,2% com valores de fosfatase alcalina acima de 126 U/L. Conclusão: Os marcadores bioquímicos são úteis para avaliar não apenas o risco de mortalidade na população com DRC, mas também o uso adequado do tipo de tratamento para esse grupo distinto de pacientes.

Introduction: The disturbances in the homeostasis of calcium, phosphorus and parathyroid hormone (PTH) occur early in patients with chronic kidney disease (CKD) and play a key role in the pathophysiology of bone diseases that affect these patients. Disorders of bone and mineral metabolism are modifiable and can reduce the risk factors associated with these changes that increase the risk of mortality in patients on dialysis. goal: to identify and quantify cases of mineral and bone disorder (BMD) in patients with CKD who died during the period from January 2004 to July 2008. METHODS: We reviewed medical records of 87 patients who were hemodialysis and died during that period. We conducted a retrospective record of personal data, laboratory, morbidity and mortality. Results: The average annual mortality rate of patients with CKD treated during the study period was approximately 16.7%. Of the total deaths, to prevailence of CKD-MBD was 67.8%. The main cause of death was cardiovascular disease (26.4%) and underlying disease, 52.9% were diabetic nephropathy. Of the patients who died, 45% presented with P values ​​above 5.5 mg / dL, 38% of patients with PTH above 300pg/mL, 40% with albumin values ​​below 3.5 g / L and 40.2% with alkaline phosphatase values ​​above 126 U / L. Conclusion: Biochemical markers are useful to evaluate not only the risk of mortality in people with CKD, but also the use of appropriate treatment for this distinct group of patients.

Visão geral da doença óssea na doença renal crônica (DRC) e nova classificação / Bone disease in chronic kidney disease (CKD): general view and new classification

Os distúrbios na homeostase do cálcio, do fósforo, do calcitriol e do paratormônio ocorrem precocemente nos pacientes com doença renal crônica (DRC) e desempenham papel fundamental na fisiopatologia das doenças ósseas que acometem esses pacientes. Essa síndrome antes conhecida pelo nome“osteodistrofia renal” (ODR) foi modificada pelo KDIGO (Kidney Disease: Improving Global Outcomes), recebendo uma denominação mais ampla que reúne as alterações clinicas, bioquímicas e ósseas, além das calcificações extra-ósseas, freqüentemente observadas na doença renal crônica. Essa síndromerecebeu o nome “distúrbio mineral e ósseo da doença renal crônica” (DMO-DRC) e o termo ODR ficou reservado para as alterações na histologia ósseaavaliadas por biópsia.

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, calcitriol, and parathyroid hormone (PTH) homeostasis that play animportant role in the pathophysiology of renal bone disease and are an important cause of morbidity. These disturbances have traditionally been termed renalosteodystrophy and classified based on bone biopsy. “Kidney Disease: Improving Global Outcomes” (KDIGO) recommended that the term renal osteodystrophy should be used exclusively to define alterations in bone histology associated with CKD, and proposed a new term to describe the syndrome of biochemical,bone and extra-skeletal calcification abnormalities that occur in these patients. The new term is CKD-MBD (CKD-Mineral and Bone Disorder).

Clinical analysis of serum biochemical parameter changes in patients with chronic kidney disease-mineral and bone disorder / 中国实用内科杂志

Objective To provide guide for clinical diagnosis,classification and treatment of chronic kidney disease-mineral and bone disorder(CKD-MBD).Methods A total of 56 patients with chronic renal insufficiency were divided into three different groups:CKD4 period,CKD5 period and long-term hemodialysis(over 5 years).Their serum calcium,phosphorus,iPTH,bAP,and TRACP levels,and the bone mineral density were examined.Results The incidences of CKD-MBD in the three groups were 36.4%,73.0%,and 87.5%,respectively.High-turnover bone disease accounted for 65.79%,and the low-turnover bone disease accounted for 34.21%.The bAP and TRACP activity was significantly increased in patients with high-turnover bone disease and decreased in those with low-turnover bone disease.Conclusion CKD-MBD is a common complication of patients with chronic renal failure,with the main type being high-turnover bone disease,but the low-turnover bone disease can not be ignored.TRACP and bAP are the sensitive indicators of osteoblasts and osteoclast activity,and they could be used to identify high or low turnover bone disease.TRACP and bAP,together with serum calcium,phosphorus,iPTH,bone mineral density changes,can be used for a comprehensive analysis of bone metabolic state,so as to guide the diagnosis,sub-typing,drug selection and comprehensive treatment of CKD-MBD.