Hemodialysis complications: focus on pruritus and vascular calcifications / Complications en hémodialyse : focus sur le prurit et les calcifications vasculaires

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.

Bodas de plata: 25 años de la primera demostración del efecto directo del fósforo en la célula paratiroidea / Silver jubilee: 25 years of the first demonstration of the direct effect of phosphate on the parathyroid cell

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)

Renal hyperparathyroidism.

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.

Silver jubilee: 25 years of the first demonstration of the direct effect of phosphate on the parathyroid cell.

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.

Patient-reported outcome measures in hemodialysis patients: results of the first multicenter cross-sectional ePROMs study in France.

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.

Hiporrespuesta o resistencia a la acción de la hormona paratiroidea en la enfermedad renal crónica / Hyporesponsiveness or resistance to the action of parathyroid hormone in chronic kidney disease

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 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. (AU)

Los riñones también hablan español / Kidneys also speak Spanish

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Hyporesponsiveness or resistance to the action of parathyroid hormone in chronic kidney disease.

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.

The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

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.

Alkaline Phosphatases in the Complex Chronic Kidney Disease-Mineral and Bone Disorders.

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.

Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

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.

Intravenous sodium thiosulfate for treating tumoral calcinosis associated with systemic disorders: Report of four cases.

Intravenous sodium thiosulfate (ivSTS) is a promising new therapeutic option for calciphylaxis related to end-stage renal disease. However, its effect on tumoral calcinosis (TC) complicating autoimmune connective-tissue diseases has been scarcely described. We report here 4 cases (3 adults and 1 child) of TC treated with ivSTS. TC was secondary to CREST syndrome, dermatomyositis (1 adult and 1 child) and systemic erythematous lupus and involved multiple sites in all cases. In all 4 patients, TC was responsible for joint pain, reduced mobility, inflammatory flares and skin fistulations. One patient experienced difficulty sitting due to the pain induced by calcified lesions on the buttock; another patient had major disability, moved only with wheelchair and was under opioid treatment for pain. For all patients, treatment with several medications before STS was unsuccessful. The 3 adults received at least 6 cycles of ivSTS (20g/d, 5 days/month) and the child received a daily infusion of 17g STS during 1 month then a 9-g/d infusion during 3 months. Two adults and the child showed clinical improvement with STS treatment and the third adult felt disappointed and stopped STS treatment after 6 months. The child also stopped STS after 6 months due to vomiting. In one patient, an intensive regimen of ivSTS (20g every 2 days) controlled recurrent flares and fistulations. Unfortunately, TC remained unchanged. Further studies are needed to decipher how STS modulates ectopic calcification, the optimal regimen and posology.

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism.

CKD and CKD-related mineral and bone disorders (CKD-MBDs) are associated with high cardiovascular and mortality risks. In randomized clinical trials (RCTs), no single drug intervention has been shown to reduce the high mortality risk in dialysis patients, but several robust secondary analyses point toward important potential beneficial effects of controlling CKD-MBD-related factors and secondary hyperparathyroidism. The advent of cinacalcet, which has a unique mode of action at the calcium-sensing receptor, represented an important step forward in controlling CKD-MBD. In addition, new RCTs have conclusively shown that cinacalcet improves achievement of target levels for all of the metabolic abnormalities associated with CKD-MBD and may also attenuate the progression of vascular and valvular calcifications in dialysis patients. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Tolerance of cinacalcet is limited by frequent secondary side effects such as nausea, vomiting, hypocalcemia and oversuppression of parathyroid hormone, which may cause some management difficulties, especially for those lacking experience with the drug. Against this background, this review aims to summarize the results of studies on cinacalcet, up to and including the publication of the recent ADVANCE and EVOLVE RCTs, as well as recent post hoc analyses, and to offer practical guidance on how to improve the clinical management of the most frequent adverse events associated with cinacalcet, based on both currently available information and personal experience. In addition, attention is drawn to less common secondary effects of cinacalcet treatment and advisable precautions.