RESUMO
PURPOSE OF REVIEW: The aim of this review is to highlight recent evidence on the role of the gastrointestinal tract and gut microbiome on chronic kidney disease-mineral bone disorder (CKD-MBD) outcomes, including intestinal phosphorus absorption and sensing, and the effect of gut-oriented therapies. RECENT FINDINGS: Recent evidence has revealed a complex interplay among mineral metabolism and novel gut-related factors, including paracellular intestinal phosphate absorption, the gut microbiome, and the immune system, prompting a reevaluation of treatment approaches for CKD-MBD. The inhibition of NHE3 limits phosphate transport in the intestine and may lead to changes in the gut microbiome. A study in rats with CKD showed that the supplementation of the fermentable dietary inulin delayed CKD-MBD, lowering circulating phosphorus and parathyroid hormone, reducing bone remodeling and improving cortical parameters, and lowering cardiovascular calcifications. In non-CKD preclinical studies, probiotics and prebiotics improved bone formation mediated through the effect of butyrate facilitating the differentiation of T cells into Tregs, and Tregs stimulating the osteogenic Wnt10b, and butyrate was also necessary for the parathyroid hormone (PTH) bone effects. SUMMARY: Recent findings support multiple possible roles for gut-oriented therapies in addressing CKD-MBD prevention and management that should be further explored through clinical and translational studies.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Microbioma Gastrointestinal , Insuficiência Renal Crônica , Humanos , Ratos , Animais , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Hormônio Paratireóideo , Fósforo , Fosfatos , Minerais , Butiratos , Trato GastrointestinalRESUMO
PURPOSE OF REVIEW: Defining the optimal parathyroid hormone (PTH) target in chronic kidney disease (CKD) is challenging, especially for bone outcomes, due to the substantial variability in the skeleton's response to PTH. Although PTH hyporesponsiveness is as integral a component of CKD-mineral bone disorder as elevated PTH levels, clinical awareness of this condition is limited. In this review, we will discuss factors and mechanisms contributing to PTH hyporesponsiveness in CKD. This knowledge may provide clues towards a personalized approach to treating secondary hyperparathyroidism in CKD. RECENT FINDINGS: Indicates a link between disturbed phosphate metabolism and impaired skeletal calcium sensing receptor signaling as an important mediator of PTH hyporesponsiveness in CKD. Further, cohort studies with diverse populations point towards differences in mineral metabolism control, rather than genetic or environmental factors, as drivers of the variability of PTH responsiveness. IN SUMMARY: Skeletal PTH hyporesponsiveness in CKD has a multifactorial origin, shows important interindividual variability, and is challenging to estimate in clinical practice. The variability in skeletal responsiveness compromises PTH as a biomarker of bone turnover, especially when considering populations that are heterogeneous in ethnicity, demography, kidney function, primary kidney disease and mineral metabolism control, and in patients treated with bone targeting drugs.
Assuntos
Hiperparatireoidismo Secundário , Hormônio Paratireóideo , Insuficiência Renal Crônica , Humanos , Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/metabolismo , Remodelação Óssea/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismoRESUMO
PURPOSES OF REVIEW: With chronic kidney disease (CKD) progression, secondary hyperparathyroidism (sHPT) and mineral and bone metabolism disease (MBD) almost inevitably develop and result in renal osteodystrophy and cardiovascular disease (CVD). Together with active vitamin D, calcimimetics are the main therapy for sHPT in CKD. This review provides an overview of the therapeutic effects of oral cinacalcet and intravenous etelcalcetide on CKD-MBD and vascular disease, with a focus on pediatric dialysis patients. RECENT FINDINGS: Randomized controlled trials in adults and children demonstrate efficient lowering of parathyroid hormone (PTH) by the calcimimetics together with a reduction in serum calcium and phosphate when combined with low-dose active vitamin D, while therapy with active vitamin D analogs alone increases serum calcium and phosphate. Cinacalcet and etelcalcetide both improve bone formation and correct adynamic bone, i.e., have a direct bone anabolic effect. They decrease serum calciprotein particles, which are involved in endothelial dysfunction, atherogenesis, and vascular calcification. Clinical trials in adults suggest a modest slowing of the progression of cardiovascular calcification with cinacalcet. Calcimimetic agents represent a major pharmacological tool for improved control of CKD-MBD, by efficiently counteracting sHPT and allowing for better control of calcium/phosphate and bone homeostasis. Albeit definite evidence is lacking, the beneficial effects of calcimimetics on CVD are promising. Routine use of cinacalcet has been suggested in children.
Assuntos
Doenças Cardiovasculares , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperparatireoidismo Secundário , Insuficiência Renal Crônica , Adulto , Humanos , Criança , Cinacalcete/uso terapêutico , Diálise Renal , Cálcio/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Calcimiméticos/uso terapêutico , Hormônio Paratireóideo , Vitamina D/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Minerais , Fosfatos/metabolismoRESUMO
RATIONALE & OBJECTIVE: Clinical trial data have demonstrated the efficacy of etelcalcetide for reducing parathyroid hormone (PTH) levels in hemodialysis (HD) patients. We provide a real-world summary of etelcalcetide utilization, dosing, effectiveness, and discontinuation since its US introduction in April 2017. STUDY DESIGN: New-user design within prospective cohort. SETTING & PARTICIPANTS: 2,596 new users of etelcalcetide from April 2017 through August 2019 in a national sample of adult maintenance HD patients in the US Dialysis Outcomes and Practice Patterns Study (DOPPS). PREDICTORS: Baseline PTH, prior cinacalcet use, initial etelcalcetide dose. OUTCOME: Trajectories of etelcalcetide dose, chronic kidney disease-mineral and bone disease (CKD-MBD) medications, and levels of PTH, serum calcium, and phosphorus in the 12 months after etelcalcetide initiation. ANALYTICAL APPROACH: Cumulative incidence methods for etelcalcetide discontinuation and linear generalized estimating equations for trajectory analyses. RESULTS: By August 2019, etelcalcetide prescriptions increased to 6% of HD patients from their first use in April 2017. Starting etelcalcetide dose was 15 mg/wk in 70% of patients and 7.5 mg/wk in 27% of patients; 49% of new users were prescribed cinacalcet in the prior 3 months. Etelcalcetide discontinuation was 9%, 17%, and 27% by 3, 6, and 12 months after initiation. One year after etelcalcetide initiation, mean PTH levels declined by 40%, from 948 to 566 pg/mL, and the proportion of patients with PTH within target (150-599 pg/mL) increased from 33% to 64% overall, from 0 to 60% among patients with baseline PTH ≥ 600 pg/mL, and from 30% to 63% among patients with prior cinacalcet use. The proportion of patients with serum phosphorus > 5.5 mg/dL decreased from 55% to 45%, while the prevalence of albumin-corrected serum calcium < 7.5 mg/dL remained at 1%-2%. There were increases in use of active vitamin D (from 77% to 87%) and calcium-based phosphate binders (from 41% to 50%) in the 12 months after etelcalcetide initiation. LIMITATIONS: Data are unavailable for provider dosing protocols, dose holds, or reasons for discontinuation. CONCLUSIONS: In the 12 months after etelcalcetide initiation, patients had large and sustained reductions in PTH levels. These results support the utility of etelcalcetide as an effective therapy to achieve the KDIGO-recommended guidelines for CKD-MBD markers in HD patients.
Assuntos
Doenças Ósseas , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperparatireoidismo Secundário , Insuficiência Renal Crônica , Adulto , Doenças Ósseas/complicações , Cálcio , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Estudos de Coortes , Humanos , Hiperparatireoidismo Secundário/etiologia , Minerais , Hormônio Paratireóideo , Peptídeos , Estudos Prospectivos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapiaRESUMO
BACKGROUND: Anemia and chronic kidney disease-mineral and bone disorder (CKD-MBD) are common and begin early in CKD. Limited studies have concurrently compared the effects of ferric citrate (FC) versus intravenous (IV) iron on CKD-MBD and iron homeostasis in moderate CKD. METHODS: We tested the effects of 10 weeks of 2% FC versus IV iron sucrose in rats with moderate CKD (Cy/+ male rat) and untreated normal (NL) littermates. Outcomes included a comprehensive assessment of CKD-MBD, iron homeostasis and oxidative stress. RESULTS: CKD rats had azotemia, elevated phosphorus, parathyroid hormone and fibroblast growth factor-23 (FGF23). Compared with untreated CKD rats, treatment with FC led to lower plasma phosphorus, intact FGF23 and a trend (P = 0.07) toward lower C-terminal FGF23. FC and IV iron equally reduced aorta and heart calcifications to levels similar to NL animals. Compared with NL animals, CKD animals had higher bone turnover, lower trabecular volume and no difference in mineralization; these were unaffected by either iron treatment. Rats treated with IV iron had cortical and bone mechanical properties similar to NL animals. FC increased the transferrin saturation rate compared with untreated CKD and NL rats. Neither iron treatment increased oxidative stress above that of untreated CKD. CONCLUSIONS: Oral FC improved phosphorus homeostasis, some iron-related parameters and the production and cleavage of FGF23. The intermittent effect of low-dose IV iron sucrose on cardiovascular calcification and bone should be further explored in moderate-advanced CKD.
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Distúrbio Mineral e Ósseo na Doença Renal Crônica , Insuficiência Renal Crônica , Animais , Biomarcadores , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Compostos Férricos , Óxido de Ferro Sacarado , Fatores de Crescimento de Fibroblastos/metabolismo , Homeostase , Ferro/uso terapêutico , Masculino , Minerais , Hormônio Paratireóideo , Fósforo , Ratos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Transferrinas/uso terapêuticoRESUMO
The effects of bone and mineral metabolism on skeletal formation, as well as vascular and soft tissue calcifications, define chronic kidney disease-metabolic bone disease (CKD-MBD). Treatment recommendations center on establishing adequate vitamin D status, phosphate control through diet restriction and phosphate binders, and the use of vitamin D analogs for specific indications. Several emerging bone-promoting therapies have now been studied in adults with CKD, including bisphosphonates and denosumab. These approaches are associated with improved bone mass and, in some cases, decreased fracture rates in adults with CKD-MBD and are of potential interest for some children with CKD-MBD. In children with CKD and immobilization and/or muscle weakness, bisphosphonates appear to be an effective treatment to increase bone mass; baseline assessment and careful monitoring of bone density and/or bone biopsy findings are important in consideration of any new bone therapies for children with CKD-MBD.
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Doenças Ósseas Metabólicas , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Insuficiência Renal Crônica , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Criança , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Denosumab , Difosfonatos , Humanos , Minerais , Fosfatos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Vitamina D/uso terapêuticoRESUMO
INTRODUCTION: Real-life data on the predialysis management of chronic kidney disease (CKD) is scarce. In this study, our aim was to investigate the current clinical practice and compliance among nephrologists with the KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guidelines. MATERIALS AND METHODS: In this multicenter cross-sectional study, we recruited stage 3 - 5 non-dialysis (ND) CKD patients and recorded the data related to CKD-MBD from two consecutive outpatient clinical visits 3 - 6 months apart. We calculated the therapeutic inertia for hyperphosphatemia, hypocalcemia, hyperparathyroidism, and hypovitaminosis D, in addition to overtreatment for hypophosphatemia, hypercalcemia, hypoparathyroidism, and hypervitaminosis D. RESULTS: We examined a total of 302 patients (male: 48.7%, median age: 67 years). The persistence of low 25-hydroxy vitamin D levels was the most common laboratory abnormality related to CKD-MBD (61.7%), followed by hyperparathyroidism (14.8%), hyperphosphatemia (7.9%), and hypocalcemia (0.0%). According to our results, therapeutic inertia seems to be a more common problem than overtreatment for all the CKD-MBD laboratory parameters that we examined. Therapeutic inertia frequency was highest for hypovitaminosis D (81.1%), followed by hypocalcemia (75.0%), hyperparathyroidism (59.0%), and hyperphosphatemia (30.4%). CONCLUSION: We concluded that CKD-MBD is not optimally managed in CKD stage 3 - 5 ND patients. Clinicians should have an active attitude regarding the correction of MBD even at the earlier stages of CKD.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperfosfatemia , Hipocalcemia , Falência Renal Crônica , Insuficiência Renal Crônica , Deficiência de Vitamina D , Humanos , Masculino , Idoso , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Hiperfosfatemia/terapia , Hiperfosfatemia/tratamento farmacológico , Estudos Transversais , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/tratamento farmacológico , Vitamina D/uso terapêutico , Deficiência de Vitamina D/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , MineraisRESUMO
BACKGROUND: Abnormalities related to mineral and bone metabolism are a common finding in chronic kidney disease (CKD). Vitamin D compounds are often prescribed to CKD patients with the purpose to control secondary hyperparathyroidism and reduce the risk of high-turnover bone disease. However, data on the effect of vitamin D sterols on bone histology in non-dialysis CKD is limited. MATERIALS AND METHODS: A prospective controlled study was conducted on a cohort of 56 patients with CKD stages 3 and 4. 19 patients on calcitriol and 12 patients on cholecalciferol were compared to a group of 25 age- and sex-matched controls. Participants underwent a tetracycline double-labelled transiliac bone biopsy before starting therapy and again 12 months later. Changes from baseline in circulating biomarkers and bone histomorphometric parameters were analyzed. RESULTS: Low-turnover bone disease was the most common pattern of renal osteodystrophy on the initial biopsy. There was no difference in biochemical or histomorphometric values between the three study groups at baseline. Serum intact parathormone (iPTH) and bone formation rate decreased significantly in calcitriol-treated patients, with prevalence of low-turnover bone disease doubling from baseline. In contrast, no significant changes were noted in cholecalciferol-treated and control subjects. CONCLUSION: Calcitriol was effective in preventing secondary hyperparathyroidism and high-turnover bone disease. However, it was associated with an increased risk of developing or aggravating low-turnover bone disease. In the absence of a bone biopsy, calcitriol use in pre-dialysis CKD should be reserved for patients with a progressive rise in iPTH levels, in whom high-turnover bone disease is suspected.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperparatireoidismo Secundário , Insuficiência Renal Crônica , Vitamina D , Calcitriol , Colecalciferol , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Diálise/efeitos adversos , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/prevenção & controle , Hormônio Paratireóideo , Estudos Prospectivos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Esteróis/uso terapêutico , Vitamina D/uso terapêutico , VitaminasRESUMO
PURPOSE OF REVIEW: We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). RECENT FINDINGS: Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Fraturas Ósseas , Insuficiência Renal Crônica , Calcificação Vascular , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Feminino , Humanos , Masculino , Insuficiência Renal Crônica/complicações , Vitamina KRESUMO
OBJECTIVES: Research about the effects of magnesium (Mg) supplementation on chronic kidney disease-mineral bone disorder (CKD-MBD) among hemodialysis (HD) patients is controversial. Thus, we conducted a meta-analysis to examine Mg supplementation's effects on CKD-MBD in patients requiring dialysis. METHODS: The PubMed and EMBASE databases were searched for English language studies up to September 2020. The main indicators of our study were changes in serum Mg, calcium (Ca), phosphate, parathyroid hormone (PTH), and C-reactive protein levels, and carotid intima-media thickness (CIMT) after Mg supplementation. Mg efficacy was evaluated by weighted mean difference (WMD) and confidence intervals (CIs), and subgroup analyses of intervention type and intervention duration were also performed. RESULTS: Eight eligible studies comprising 309 HD patients were included in our meta-analysis. Mg supplementation alone produced a negative effect on serum PTH levels (WMD = -236.56; 95% CI -349.71 to -123.41) and CIMT (WMD = -0.18; 95% CI -0.34 to -0.01). A subgroup analysis based on intervention type showed a significant improvement in serum Mg (WMD = 1.08; 95% CI 0.51-1.64) and Ca (WMD = -0.50; 95% CI -0.77 to -0.23) levels when Mg was administered via dialysate and oral medication, respectively. Different intervention durations had no effect on serum Mg levels. Mg supplementation had no significant effect on serum phosphate (WMD = -0.25; 95% CI -0.64 to 0.14) and C-reactive protein levels (WMD = -0.02; 95% CI -2.80 to 2,76). CONCLUSIONS: Our results showed that Mg supplementation alone could improve CKD-MBD by regulating serum Ca and PTH metabolism and decreasing CIMT among HD patients.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Espessura Intima-Media Carotídea , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Suplementos Nutricionais , Humanos , Magnésio , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise RenalRESUMO
Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) frequently have low bone formation rates. A recent review suggested that adynamic bone disease is not always associated with negative outcomes and therefore antiresorptive medications could be used more often. However, there is currently no evidence to support an improvement in fracture risk or mortality in patients with CKD-MBD and low bone turnover who are treated with antiresorptive medication. There is reasonable pathophysiological evidence suggesting that it may even be harmful.
Assuntos
Conservadores da Densidade Óssea , Doenças Ósseas , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , HumanosRESUMO
Patients with chronic kidney disease (CKD) have an increased fracture risk because of impaired bone quality and quantity. Low bone mineral density predicts fracture risk in all CKD stages, including advanced CKD (CKD G4-5D). Pharmacological therapy improves bone mineral density and reduces fracture risk in moderate CKD. Its efficacy in advanced CKD remains to be determined, although pilot studies suggest a positive effect on bone mineral density. Currently, antiresorptive agents are the most commonly prescribed drugs for the prevention and therapy of osteoporosis. Their use in advanced CKD has been limited by the lack of large clinical trials and fear of causing kidney dysfunction and adynamic bone disease. In recent decades, adynamic bone disease has evolved as the most predominant form of renal osteodystrophy, commonly associated with poor outcomes, including premature mortality and progression of vascular calcification. Evolving evidence indicates that reduction of bone turnover by parathyroidectomy or pharmacological therapies, such as calcimimetics and antiresorptive agents, are not associated with premature mortality or accelerated vascular calcification in CKD. In contrast, chronic inflammation, oxidative stress, malnutrition, and diabetes can induce low bone turnover and associate with poor prognosis. Thus, the conditions causing suppression of bone turnover rather than the low bone turnover per se may account for the perceived association with outcomes. Anabolic treatment, in contrast, has been suggested to improve turnover and bone mass in patients with advanced CKD and low bone turnover; however, uncertainty about safety even exceeds that of antiresorptive agents. Here, we critically review the pathophysiological concept of adynamic bone disease and discuss the effect of low bone turnover on the safety and efficacy of anti-osteoporosis pharmacotherapy in advanced CKD.
Assuntos
Doenças Ósseas Metabólicas , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Osteoporose , Insuficiência Renal Crônica , Densidade Óssea , Osso e Ossos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Humanos , Osteoporose/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Disturbances in mineral and bone metabolism are common in patients with chronic kidney disease (CKD), especially those undergoing dialysis. Renal osteodystrophy, which describes an alteration of bone morphology, is an important component of this systemic disorder and may explain the elevated risk of fracture which adversely affects morbidity and mortality. The most common form of renal osteodystrophy is high-turnover bone disease (osteitis fibrosa), which is induced by secondary hyperparathyroidism (SHPT). During the past decade, there has been considerable advances in the management of SHPT, with the introduction of the calcimimetic agents, the optimized use of nutritional and active vitamin D, and the accumulated experience with surgical parathyroidectomy. Studies supported that these advances could translate into improvement of renal bone disease and fracture prevention, as well as decreasing the risk of cardiovascular events and mortality. In this review, we summarize the available clinical evidence on the effect of old and new drugs on bone disorders in patients with CKD.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperparatireoidismo Secundário , Preparações Farmacêuticas , Insuficiência Renal Crônica , Calcimiméticos/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI-425, protects against MAC and improves survival probability in a CKD-mineral and bone disorder (MBD) mouse model. CKD-MBD mice were divided in three groups: vehicle, SBI-10, and SBI-30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high-phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14-20 weeks of age, mice in the SBI-10 and SBI-30 groups were given 10 and 30 mg/kg SBI-425 by gavage once a day, respectively, while vehicle-group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI-425 nearly halted the formation of MAC. Mice in the control, SBI-10 and SBI-30 groups exhibited 100% survival, which was significantly better than vehicle-treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI-425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD-MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Niacinamida/análogos & derivados , Sulfonamidas/farmacologia , Calcificação Vascular/prevenção & controle , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aorta/enzimologia , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/enzimologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Niacinamida/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Osteoblastos/patologia , Fatores de Tempo , Calcificação Vascular/enzimologia , Calcificação Vascular/etiologia , Calcificação Vascular/patologiaRESUMO
Complications of chronic kidney disease-associated mineral and bone disorders (CKD-MBD) are frequently observed in pediatric kidney transplant recipients and are associated with high morbidity, including growth failure, leg deformities, bone pain, fractures, osteonecrosis, and vascular calcification. Post-transplant CKD-MBD is mainly due to preexisting renal osteodystrophy and cardiovascular changes at the time of transplantation, glucocorticoid treatment, and reduced graft function. In addition, persistent elevated levels of parathyroid hormone (PTH) and fibroblast growth factor 23 may cause hypophosphatemia, resulting in impaired bone mineralization. Patient monitoring should include assessment of growth, leg deformities, and serum levels of calcium, phosphate, magnesium, alkaline phosphatase, 25-hydroxyvitamin D, and PTH. Therapy should primarily focus on regular physical activity, preservation of transplant function, and steroid-sparing immunosuppressive protocols. In addition, adequate monitoring and treatment of vitamin D and mineral metabolism including vitamin D supplementation, oral phosphate, and/or magnesium supplementation, in case of persistent hypophosphatemia/hypomagnesemia, and treatment with active vitamin D in cases of persistent secondary hyperparathyroidism. The latter should be done using the minimum PTH-suppressive dosages aiming at the recommended CKD stage-dependent PTH target range. Finally, treatment with recombinant human growth hormone should be considered in patients lacking catch-up growth within the first year after transplantation.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Transplante de Rim , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia , Transplante de Rim/efeitos adversos , Magnésio , Hormônio Paratireóideo , Fosfatos , Vitamina DRESUMO
OBJECTIVE: The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: A literature search on PubMed, Embase, and Cochrane Library databases was conducted up to 18 June 2021. Data acquisition and quality assessment were performed by two reviewers. Meta-analysis was performed to evaluate the serum biochemical parameters, adverse events, and patient-level outcomes of LC, non-LC PBs, and sevelamer for hyperphosphatemia in patients with CKD. Heterogeneity across studies was assessed utilizing the I2 statistic and Q-test, and a random effect model was selected to calculate the pooled effect size. RESULTS: A total of 26 randomized, controlled trials and 3 observational studies were included. Compared to the other groups, better control effect of serum phosphorus (RR = 2.68, p < 0.001), reduction in serum phosphorus (95%CI = -1.93, -0.99; p < 0.001), Ca × P (95%CI = -13.89, -2.99; p = 0.002), serum intact parathyroid hormone levels (95%CI = -181.17, -3.96, p = 0.041) were found in LC group. Besides, reduced risk of various adverse effects, such as hypotension, abdominal pain, diarrhea, dyspepsia, and a score of coronary artery calcification were identified with LC in comparison to calcium salt, non-LC PBs, or placebo group. Significantly lower risk in mortality with LC treatment vs. non-LC PBs was observed, while no significant difference was identified between LC and calcium salt groups. CONCLUSION: LC might be an alternative treatment for hyperphosphatemia in patients with CKD considering its comprehensive curative effect.
Assuntos
Hiperfosfatemia/tratamento farmacológico , Lantânio/uso terapêutico , Fosfatos/sangue , Insuficiência Renal Crônica/complicações , Sevelamer/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Humanos , Hiperfosfatemia/etiologia , Lantânio/efeitos adversos , Estudos Observacionais como Assunto , Hormônio Paratireóideo/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with the development of mineral and bone disorders (MBD), including renal osteodystrophy (ROD). ROD is a global disorder of bone strength that is associated with an increased fracture risk. The use of bisphosphonates for fracture risk reduction in CKD remains controversial. This review provides a synopsis of the state-of-the literature regarding the safety and potential antifracture benefits of bisphosphonates in CKD patients. RECENT FINDINGS: In preclinical studies of animals with CKD 3-4 and evidence of CKD-MBD, bisphosphonates resulted in changes in bone quality that improve bone strength. Bone turnover was generally reduced to a similar extent in animals with and without CKD. Post hoc analyses of randomized trials in patients with CKD 3-4 reported increases in bone mineral density (BMD) and fracture reduction that were similar in patients with and without CKD. There are no primary clinical trial data in patients with CKD-MBD. SUMMARY: In patients with CKD without evidence of CKD-MBD, the use of bisphosphonates should follow general population guidelines. The lack of data for patients with CKD 4-5D and evidence of CKD-MBD makes treatment decisions challenging. Clinical studies are urgently needed to provide data on the safety and antifracture benefits of bisphosphonates in these cohorts.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Difosfonatos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , HumanosRESUMO
INTRODUCTION: High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined. MATERIALS AND METHODS: We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet. RESULTS: Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D. CONCLUSIONS: In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.
Assuntos
Remodelação Óssea , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Minerais/metabolismo , Ácido Risedrônico/uso terapêutico , Animais , Fenômenos Biomecânicos , Nitrogênio da Ureia Sanguínea , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiopatologia , Cálcio/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Creatinina/sangue , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Nefrectomia , Fragmentos de Peptídeos/sangue , Fósforo/sangue , Pró-Colágeno/sangue , Ratos Sprague-Dawley , Ácido Risedrônico/farmacologiaRESUMO
BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) management in patients with end-stage renal disease is important owing to the risk of cardiovascular diseases. In clinical practice, we manage patients not by monitoring the levels of biologically active ionized calcium (iCa) but by monitoring total serum calcium or corrected calcium (cCa). We previously reported that iCa/cCa ratio was different between patients with hemodialysis and those with peritoneal dialysis (PD). In PD patients, several factors are expected to affect iCa/cCa ratio. Therefore, modifying the strategy to achieve better CKD-MBD management might be necessary; however, no reports have studied this to date. Therefore, we investigated the factors influencing iCa/cCa ratio in PD patients. METHODS: This retrospective cross-sectional study examined background and laboratory data, including iCa, collected at routine outpatient visits. The patients were divided into the first, second, and third tertile of iCa/cCa ratio groups to compare patient background and laboratory data. Multiple regression analysis was used to investigate the factors influencing iCa/cCa ratio. We used multiple imputation to deal with missing covariate data. RESULTS: In total, 169 PD patients were enrolled. In PD patients with lower iCa/cCa ratio, PD duration was longer and pH was higher. Urine volume and weekly renal Kt/V were lower in the patients with lower iCa/cCa ratio than in those with higher iCa/cCa ratio. iCa/cCa ratio and weekly renal Kt/V were directly correlated (r = 0.41, p < 0.01), and weekly renal Kt/V and pH were independent factors affecting iCa/cCa ratio (t = 2.86, p < 0.01 and t = - 5.42, p < 0.01, respectively). CONCLUSIONS: iCa levels were lower in PD patients with lower residual renal function (RRF) even though their cCa levels were equal to those with maintained RRF, warranting caution in the assessment and management of CKD-MBD in PD patients.
Assuntos
Cálcio/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Falência Renal Crônica/sangue , Diálise Peritoneal , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Quelantes/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Cinacalcete/uso terapêutico , Estudos Transversais , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitamina D/uso terapêuticoRESUMO
Interventions that alter PTH levels in an animal model of chronic kidney disease have effects on the perfusion of bone and bone marrow. INTRODUCTION: Patients with chronic kidney disease (CKD) have accelerated bone loss, vascular calcification, and abnormal biochemistries, together contributing to an increased risk of cardiovascular disease and fracture-associated mortality. Despite evidence of vascular pathologies and dysfunction in CKD, our group has shown that cortical bone tissue perfusion is higher in a rat model of high-turnover CKD. The goal of the present study was to test the hypothesis that parathyroid hormone (PTH) suppressive interventions would normalize cortical bone vascular perfusion in the setting of CKD. METHODS: In two separate experiments, 35-week-old CKD animals and their normal littermates underwent intra-cardiac fluorescent microsphere injection to assess the effect of 10 weeks of PTH suppression (Experiment 1: calcium supplementation, Experiment 2: calcimimetic treatment) on alterations in bone tissue perfusion. RESULTS: In Experiment 1, CKD animals had serum blood urea nitrogen (BUN) and PTH levels significantly higher than NL (+ 182% and + 958%; p < 0.05). CKD+Ca animals had BUN levels that were similar to CKD, while PTH levels were significantly lower and comparable to NL. Both femoral cortex (+ 220%, p = 0.003) and tibial cortex (+ 336, p = 0.005) tissue perfusion were significantly higher in CKD animals when compared to NL; perfusion was normalized to those of NL in CKD+Ca animals. MicroCT analysis of the proximal tibia cortical porosity showed a trend toward higher values in CKD (+ 401%; p = 0.017) but not CKD+Ca (+ 111%; p = 0.38) compared to NL. Experiment 2, using an alternative method of PTH suppression, showed similar results as those of Experiment 1. CONCLUSIONS: These data demonstrate that PTH suppression-based interventions normalize cortical bone perfusion in the setting of CKD.