ABSTRACT
Vertebral fractures (VFs) are the most common osteoporotic fractures in the general population, and they have been associated with high mortality, decreased quality of life, and high risk of subsequent fractures, especially when recent, multiple, or severe. Currently, VF diagnosis and classification determine fracture risk and the most appropriate anti-osteoporotic treatment. However, VFs are clearly underdiagnosed, especially in patients with chronic kidney disease (CKD), and CKD-associated osteoporosis has been disregarded until recently. VFs are associated with higher morbidity and mortality, and their prevalence and incidence differ depending on the grade of renal dysfunction (CKD G1-G5) and/or the type of renal replacement therapy (dialysis or transplantation). In addition to classical risk factors [such as higher age, female sex, reduced bone mineral density, diabetes and steroid use], various other factors have been associated with an increased risk of VFs in CKD, including CKD grade, haemodialysis vintage, time since renal transplantation, low or high intact parathyroid hormone and phosphate levels, and/or vitamin D and K1 deficiencies. Importantly, several clinical societies have recently modified their algorithms according to the fracture risk classification (including the presence of VFs) and determined the most appropriate anti-osteoporotic treatment for the general population. However, there are no specific guidelines addressing this topic in patients with CKD despite an important paradigm shift regarding the prognostic value of bone mineral density in 2017 after the publication of the CKD-Mineral and Bone Disorder Kidney Disease: Improving Global Outcomes guidelines. A proactive attitude towards diagnosis, treatment, and research is proposed to avoid therapeutic nihilism.
ABSTRACT
Sarcopenia and dynapenia are two terms associated with ageing that respectively define the loss of muscle mass and strength. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) introduced the EWGSOP2 diagnostic algorithm for sarcopenia, which integrates both concepts. It consists of 4 sequential steps: screening for sarcopenia, examination of muscle strength, assessment of muscle mass and physical performance; depending on these last 3 aspects sarcopenia is categorised as probable, confirmed, and severe respectively. In the absence of validation of the EWGSOP2 algorithm in various clinical contexts, its use in haemodialysis poses several limitations: (a) low sensitivity of the screening, (b) the techniques that assess muscle mass are not very accessible, reliable, or safe in routine clinical care, (c) the sequential use of the magnitudes that assess dynapenia and muscle mass do not seem to adequately reflect the muscular pathology of the elderly person on dialysis. We reflect on the definition of sarcopenia and the use of more precise terms such as "myopenia" (replacing the classic concept of sarcopenia to designate loss of muscle mass), dynapenia and kratopenia. Prospective evaluation of EWGSOP2 and its comparison with alternatives (i.e. assessment of kratopenia and dynapenia only; steps 2 and 4) is proposed in terms of its applicability in clinical routine, resource consumption, identification of at-risk individuals and impact on events.
Subject(s)
Sarcopenia , Sarcopenia/diagnosis , Humans , Aged , Muscle Strength , Renal Dialysis , Algorithms , Terminology as Topic , Muscle, Skeletal/physiopathologyABSTRACT
Chronic kidney disease-associated pruritus (CKD-aP) is a frequent complication, with an estimated prevalence of 24-37% in patients treated with hemodialysis. Its pathophysiology is complex and includes four interrelated axes: accumulation of uremic toxins, peripheral neuropathy, an imbalance in the opioid receptors balance, and abnormal activation of immune cells. This symptom which is associated with impaired quality of life is underestimated by caregivers and underreported by patients. Management is not uniformly codified. It includes the use of skin emollients, optimization of dialysis parameters and management of chronic kidney disease complications, and specifically the use of difelikefalin. Patients treated with hemodialysis have an increased risk of calcifications that can affect the arteries and heart valves. These calcifications are associated with decreased survival and several scores based on radiological examinations have been proposed for screening. Although recommended, this screening is rarely performed in dialysis centers. Prevention and treatment against the development of cardiovascular calcifications are the control of risk factors associated with atherosclerosis, control of phosphatemia, and new therapeutic strategies such as sodium thiosulfate, rheopheresis, vitamin K, magnesium supplementation or SNF-472, a calcium chelator currently in clinical development.
Le prurit associé à la maladie rénale chronique (MRC) est une complication fréquente, dont la prévalence est estimée entre 24 et 37 % chez les patients traités par hémodialyse. Sa physiopathologie est complexe et comprend quatre axes intriqués : l'accumulation des toxines urémiques, la neuropathie périphérique, un déséquilibre de la balance des récepteurs opioïdes et une activation anormale des cellules immunitaires. Ce symptôme est associé à une altération de la qualité de vie, mais il est pourtant sous-estimé par les soignants et sous-déclaré par les patients. La prise en charge n'est pas uniformément codifiée. Elle comprend l'usage d'émollients cutanés, l'optimisation des paramètres de dialyse et de la prise en charge des complications de la MRC, et de manière spécifique la difélikéfaline. Les patients traités par hémodialyse présentent un risque augmenté de calcifications qui peuvent toucher les artères et les valves cardiaques. Ces calcifications sont associées à une diminution de la survie et plusieurs scores s'appuyant sur les examens radiologiques ont été proposés pour le dépistage. Bien que recommandé, ce dépistage est peu réalisé dans les centres de dialyse. La prévention et le traitement contre le développement des calcifications cardiovasculaires reposent sur la correction des facteurs de risque associés à l'athérosclérose, le contrôle de la phosphatémie, et des nouvelles stratégies thérapeutiques comme le thiosulfate de sodium, la rhéophérèse, la vitamine K, la supplémentation en magnésium ou le SNF-472, qui est un chélateur du calcium en cours de développement clinique.
Subject(s)
Atherosclerosis , Vascular Calcification , Humans , Quality of Life , Vascular Calcification/etiology , Vascular Calcification/therapy , Pruritus/etiology , Pruritus/therapy , SkinABSTRACT
Aunque el fósforo es un elemento indispensable para la vida, en la naturaleza no se encuentra en estado nativo sino combinado en forma de fosfatos inorgánicos (PO43−), con niveles plasmáticos estrechamente regulados que se asocian a efectos deletéreos y mortalidad cuando estos se encuentran fuera de la normalidad. El interés creciente sobre el acúmulo de PO43− en la fisiopatología humana se originó en el papel que se le atribuyó en la patogenia del hiperparatiroidismo secundario a la enfermedad renal crónica. En este artículo revisamos los mecanismos por los cuales se justificaba dicho efecto y conmemoramos la importante contribución de un grupo español liderado por el Dr. M. Rodríguez, ahora hace justo 25 años, cuando demostraron por primera vez el efecto directo del PO43− sobre la regulación de la síntesis y secreción de hormona paratiroidea (manteniendo la integridad estructural de las glándulas paratiroides en su nuevo modelo experimental. Además de demostrar la importancia del ácido araquidónico (AA) y la vía de la fosfolipasa A2-AA como mediadora de respuestas en la glándula paratiroidea, estos hallazgos fueron predecesores de la reciente descripción del importante papel del PO43− sobre la actividad del receptor-sensor de calcio y alimentaron asimismo diversas líneas de investigación sobre la importancia de la sobrecarga de PO43−, no solo en la fisiopatología del hiperparatiroidismo secundario sino también en su papel patogénico sistémico. (AU)
Although phosphorus is an essential element for life, it is not found in nature in its native state but rather combined in the form of inorganic phosphates (PO43−), with tightly regulated plasma levels that are associated with deleterious effects and mortality when these are out of bounds. The growing interest in the accumulation of PO43− in human pathophysiology originated in its attributed role in the pathogenesis of secondary hyperparathyroidism in chronic kidney disease. In this article, we review the mechanisms by which this effect was justified and we commemorate the important contribution of a Spanish group led by Dr. M. Rodríguez, just 25 years ago, when they first demonstrated the direct effect of PO43− on the regulation of the synthesis and secretion of parathyroid hormone by maintaining the structural integrity of the parathyroid glands in their original experimental model. In addition to demonstrating the importance of arachidonic acid (AA) and the phospholipase A2-AA pathway as a mediator of parathyroid gland response, these findings were predecessors of the recent description of the important role of PO43− on the activity of the calcium sensor-receptor, and also fueled various lines of research on the importance of PO43− overload not only for the pathophysiology of secondary hyperparathyroidism but also of its systemic pathogenic role. (AU)
Subject(s)
Humans , Phosphorus , Cells , Parathyroid Hormone , Phosphates , Chronic Kidney Disease-Mineral and Bone Disorder , Parathyroid GlandsABSTRACT
The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.
Subject(s)
Bone Diseases , Hyperparathyroidism , Renal Insufficiency, Chronic , Calcium/metabolism , Humans , Hyperparathyroidism/metabolism , Parathyroid Hormone/metabolismABSTRACT
Although phosphorus is an essential element for life, it is not found in nature in its native state but rather combined in the form of inorganic phosphates (PO43-), with tightly regulated plasma levels that are associated with deleterious effects and mortality when these are out of bounds. The growing interest in the accumulation of PO43- in human pathophysiology originated in its attributed role in the pathogenesis of secondary hyperparathyroidism (SHPT) in chronic kidney disease. In this article, we review the mechanisms by which this effect was justified and we commemorate the important contribution of a Spanish group led by Dr. M. Rodríguez, just 25 years ago, when they first demonstrated the direct effect of PO43- on the regulation of the synthesis and secretion of parathyroid hormone by maintaining the structural integrity of the parathyroid glands in their original experimental model. In addition to demonstrating the importance of arachidonic acid (AA) and the phospholipase A2-AA pathway as a mediator of parathyroid gland response, these findings were predecessors of the recent description of the important role of PO43- on the activity of the calcium sensor-receptor, and also fueled various lines of research on the importance of PO43- overload not only for the pathophysiology of SHPT but also in its systemic pathogenic role.
Subject(s)
Hyperparathyroidism, Secondary , Renal Insufficiency, Chronic , Humans , Parathyroid Glands , Phosphates , Parathyroid Hormone , Hyperparathyroidism, Secondary/complications , Renal Insufficiency, Chronic/complicationsABSTRACT
BACKGROUND: Kidney failure with replacement therapy and hemodialysis are associated with a decrease in quality of life (QOL). Self-reported QOL symptoms are not always prioritized by the medical team, potentially leading to conflicting priorities with patients. Electronic patient-reported outcome measures (ePROMs) allow physicians to better identify these symptoms. The objective was to describe the prevalence of symptoms self-reported by hemodialysis (HD) patients. METHODS: A multicenter cross-sectional study was conducted in three HD centers. Patients were included if they were 18 years old or over treated with HD for at least 3 months in a center. Data were collected by the patient via a self-administered ePROMs questionnaire. Data included patient characteristics, post-dialysis fatigue and intensity, recovery time after a session, perceived stress, impaired sleep the day before the dialysis session, current state of health and the change from the past year. A multivariate analysis was conducted to identify relations between symptoms. RESULTS: In total, we included 173 patients with a mean age of 66.2 years, a mean ± SD hemodialysis duration of 48.9 ± 58.02 months. The prevalence of fatigue was 72%. 66% had a high level of stress (level B or C). Recovery time was more than 6 h after a HD session for 25% of patients and 78% declared they had a better or unchanged health status than the previous year. Sleep disturbance was associated with cardiovascular comorbidities (OR 5.08 [95% CI, 1.56 to 16.59], p = 0.007). CONCLUSIONS: Fatigue and stress were the main symptoms reported by HD patients. The patient's care teams should better consider these symptoms.
Subject(s)
Patient Reported Outcome Measures , Renal Dialysis , Self Report , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , France , Humans , Male , Middle AgedABSTRACT
El hiperparatiroidismo secundario es uno de los componentes integrales de las alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica (ERC) o complejo chronic kidney disease-mineral bone disorder. Se ha demostrado que en el desarrollo y progresión del hiperparatiroidismo secundario intervienen muchos factores, estrechamente interrelacionados, pero la presencia e importancia de la hiporrespuesta (o resistencia) a la acción de la hormona paratiroidea (PTH) es poco comprendida. En esta revisión analizaremos sus antecedentes, factores que intervienen, así como alguno de los mecanismos moleculares que podrían explicarla. La presencia de resistencia a la acción biológica de la PTH no es única en la ERC, ya que también se presenta para otras hormonas, habiéndose incluso usado el término de «uremia como una enfermedad de receptores». Esta hiporrespuesta a la PTH tiene importantes implicaciones clínicas, dado que no solo permite explicar parte de la patogenia progresiva de la hipersecreción de PTH e hiperplasia paratiroidea, sino también la creciente prevalencia de enfermedad ósea adinámica en la población con ERC. De este modo, subrayamos la importancia de controlar, sin normalizar completamente, los niveles de PTH en los distintos estadios de ERC, dado que un cierto incremento de sus niveles supone inicialmente una adaptación clínica. Futuros estudios a nivel molecular sobre la uremia, o la reciente descripción del efecto directo del fosfato sobre la actividad del receptor sensor de calcio como sensor de fosfato, podrían resultar valiosos incluso más allá de explicar la hiporrespuesta a la PTH en la ERC. (AU)
Secondary hyperparathyroidism (SHPT) is an integral component of the chronic kidney diseasemineral and bone disorder (CKDMBD). Many factors have been associated with the development and progression of SHPT but the presence of skeletal or calcemic resistance to the action of PTH in CKD has often gone unnoticed. The term hyporesponsiveness to PTH is currently preferred and, in this chapter, we will not only review the scientific timeline but also some of the molecular mechanisms behind. Moreover, the presence of resistance to the biological action of PTH is not unique in CKD since resistance to other hormones has also been described (uremia as a receptor disease). This hyporesponsiveness carries out important clinical implications since it explains, at least partially, not only the progressive nature of the pathogenesis of CKD-related PTH hypersecretion and parathyroid hyperplasia but also the increasing prevalence of adynamic bone disease in the CKD population. Therefore, we underline the importance of PTH control in all CKD stages, but not aiming to completely normalize PTH levels since a certain degree of SHPT may represent an adaptive clinical response. Future studies at the molecular level, i.e. on uremia, or the recent description of the calcium-sensing receptor as a phosphate sensor, may become of great value beyond their significance to explain just the hyporesponsiveness to PTH in CKD. (AU)
Subject(s)
Humans , Renal Insufficiency, Chronic , Hyperparathyroidism, Secondary , Parathyroid Hormone , Minerals/metabolism , PhosphatesABSTRACT
No disponible
Subject(s)
Humans , Terminology as Topic , Nephrology , Kidney , Consensus Development Conferences as Topic , Language , SpainABSTRACT
Secondary hyperparathyroidism (SHPT) is an integral component of the chronic kidney disease-mineral and bone disorder (CKD-MBD). Many factors have been associated with the development and progression of SHPT but the presence of skeletal or calcemic resistance to the action of PTH in CKD has often gone unnoticed. The term hyporesponsiveness to PTH is currently preferred and, in this chapter, we will not only review the scientific timeline but also some of the molecular mechanisms behind. Moreover, the presence of resistance to the biological action of PTH is not unique in CKD since resistance to other hormones has also been described ("uremia as a receptor disease"). This hyporesponsiveness carries out important clinical implications since it explains, at least partially, not only the progressive nature of the pathogenesis of CKD-related PTH hypersecretion and parathyroid hyperplasia but also the increasing prevalence of adynamic bone disease in the CKD population. Therefore, we underline the importance of PTH control in all CKD stages, but not aiming to completely normalize PTH levels since a certain degree of SHPT may represent an adaptive clinical response. Future studies at the molecular level, i.e. on uremia or the recent description of the calcium-sensing receptor as a phosphate sensor, may become of great value beyond their significance to explain just the hyporesponsiveness to PTH in CKD.
Subject(s)
Hyperparathyroidism, Secondary , Renal Insufficiency, Chronic , Uremia , Humans , Hyperparathyroidism, Secondary/complications , Hyperparathyroidism, Secondary/etiology , Parathyroid Hormone , Phosphates , Receptors, Calcium-Sensing , Renal Insufficiency, Chronic/complications , Uremia/complicationsABSTRACT
High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m2) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: -0.12, 0.26 and -0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.
Subject(s)
Chelating Agents/administration & dosage , Cresols/blood , Indican/blood , Indoleacetic Acids/blood , Renal Insufficiency, Chronic/drug therapy , Sevelamer/administration & dosage , Sulfuric Acid Esters/blood , Toxins, Biological/blood , Adsorption , Aged , Chelating Agents/chemistry , Cresols/chemistry , Double-Blind Method , Female , Gastrointestinal Tract/chemistry , Gastrointestinal Tract/metabolism , Humans , Indican/chemistry , Indoleacetic Acids/chemistry , Male , Middle Aged , Renal Insufficiency, Chronic/blood , Sevelamer/chemistry , Sulfuric Acid Esters/chemistry , UremiaABSTRACT
Alkaline phosphatases (APs) remove the phosphate (dephosphorylation) needed in multiple metabolic processes (from many molecules such as proteins, nucleotides, or pyrophosphate). Therefore, APs are important for bone mineralization but paradoxically they can also be deleterious for other processes, such as vascular calcification and the increasingly known cross-talk between bone and vessels. A proper balance between beneficial and harmful activities is further complicated in the context of chronic kidney disease (CKD). In this narrative review, we will briefly update the complexity of the enzyme, including its different isoforms such as the bone-specific alkaline phosphatase or the most recently discovered B1x. We will also analyze the correlations and potential discrepancies with parathyroid hormone and bone turnover and, most importantly, the valuable recent associations of AP's with cardiovascular disease and/or vascular calcification, and survival. Finally, a basic knowledge of the synthetic and degradation pathways of APs promises to open new therapeutic strategies for the treatment of the CKD-Mineral and Bone Disorder (CKD-MBD) in the near future, as well as for other processes such as sepsis, acute kidney injury, inflammation, endothelial dysfunction, metabolic syndrome or, in diabetes, cardiovascular complications. However, no studies have been done using APs as a primary therapeutic target for clinical outcomes, and therefore, AP's levels cannot yet be used alone as an isolated primary target in the treatment of CKD-MBD. Nonetheless, its diagnostic and prognostic potential should be underlined.
Subject(s)
Alkaline Phosphatase/physiology , Chronic Kidney Disease-Mineral and Bone Disorder/enzymology , Animals , Bone Remodeling , Chronic Kidney Disease-Mineral and Bone Disorder/complications , Diphosphates/metabolism , Humans , Inflammation , Isoenzymes , Parathyroid Glands/physiology , Parathyroid Hormone/metabolism , Phosphates , Phosphorus/metabolism , Proportional Hazards Models , Treatment Outcome , Vascular Calcification/complications , Vascular Calcification/enzymologyABSTRACT
BACKGROUND AND OBJECTIVES: Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m2, fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and α-klotho, were evaluated at baseline and 12 weeks after inclusion. RESULTS: Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m2) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m2, mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group (P=0.77). There was no significant difference in serum intact fibroblast growth factor 23, α-klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell significantly in the sevelamer group. CONCLUSIONS: In our double-blind, placebo-controlled, randomized study performed in normophosphatemic patients with CKD, a 12-week course of sevelamer carbonate significantly reduced phosphaturia without changing serum phosphorus but did not significantly modify serum C-terminal fibroblast growth factor 23 and intact fibroblast growth factor 23 or α-klotho levels.