Worldwide Early Impact of COVID-19 on Dialysis Patients and Staff and Lessons Learned: A DOPPS Roundtable Discussion.

As the worst global pandemic of the past century, coronavirus disease 2019 (COVID-19) has had a disproportionate effect on maintenance dialysis patients and their health care providers. At a virtual roundtable on June 12, 2020, Dialysis Outcomes and Practice Patterns Study (DOPPS) investigators from 15 countries in Asia, Europe, and the Americas described and compared the effects of COVID-19 on dialysis care, with recent updates added. Most striking is the huge difference in risk to dialysis patients and staff across the world. Per-population cases and deaths among dialysis patients vary more than 100-fold across participating countries, mirroring burden in the general population. International data indicate that the case-fatality ratio remains at 10% to 30% among dialysis patients, confirming the gravity of infection, and that cases are much more common among in-center than home dialysis patients. This latter finding merits urgent study because in-center patients often have greater community exposure, and in-center transmission may be uncommon under optimal protocols. Greater telemedicine use is a welcome change here to stay, and our community needs to improve emergency planning and protect dialysis staff from the next pandemic. Finally, the pandemic's challenges have prompted widespread partnering and innovation in kidney care and research that must be sustained after this global health crisis.

European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4-G5D.

Controlling the excessive fracture burden in patients with chronic kidney disease (CKD) Stages G4-G5D remains an impressive challenge. The reasons are 2-fold. First, the pathophysiology of bone fragility in patients with CKD G4-G5D is complex and multifaceted, comprising a mixture of age-related (primary male/postmenopausal), drug-induced and CKD-related bone abnormalities. Second, our current armamentarium of osteoporosis medications has not been developed for, or adequately studied in patients with CKD G4-G5D, partly related to difficulties in diagnosing osteoporosis in this specific setting and fear of complications. Doubts about the optimal diagnostic and therapeutic approach fuel inertia in daily clinical practice. The scope of the present consensus paper is to review and update the assessment and diagnosis of osteoporosis in patients with CKD G4-G5D and to discuss the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture. As such, it aims to stimulate a cohesive approach to the management of osteoporosis in patients with CKD G4-G5D to replace current variations in care and treatment nihilism.

Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population.

The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions. CKD should be regarded as an atypical disease in which both traditional and novel cardiovascular risk factors have effects on outcomes. But CKD can also be viewed conceptually as an accelerator of traditional cardiovascular risk factors. Findings from research into mineral bone disorder associated with CKD (CKD-MBD) could help the medical community to better understand the vascular actions of certain molecules, such as phosphates, fibroblast growth factor 23, parathyroid hormone, sclerostin, or vitamin D and their relevance to the management of different pathologies in the general population. Importantly, these components, which are recognised in nephrology, could help to explain residual risk of cardiovascular events in the general population. Thus, achieving a better understanding of CKD-MBDs could provide substantial insight into future treatments for arteriosclerosis and osteoporosis, which are strongly associated with ageing and morbidity in the general population.

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease.

The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non-genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25-hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

When, how, and why a bone biopsy should be performed in patients with chronic kidney disease.

In chronic kidney disease the excessive production of parathyroid hormone increases the bone resorption rate and leads to histologic bone signs of secondary hyperparathyroidism. However, in other situations, the initial increase in parathyroid hormone and bone remodeling may be slowed down excessively by a multitude of factors including age, ethnic origin, sex, and treatments such as vitamin D, calcium salts, calcimimetics, steroids, and so forth, leading to low bone turnover or adynamic bone disease. Both high and low bone turnover diseases actually are observed equally in chronic kidney disease patients treated by dialysis, and all types of renal osteodystrophy are associated with an increased risk of skeletal fractures, reduced quality of life, and poor clinical outcomes. Unfortunately, the diagnosis of these bone abnormalities cannot be obtained correctly by current clinical, biochemical, and imaging methods. Therefore, bone biopsy has been, and still remains, the gold standard analysis for assessing the exact type of renal osteodystrophy. It is also the unique way to assess the mechanisms of action, safety, and efficacy of new bone-targeting therapies.

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. METHODS: We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. RESULTS: We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. CONCLUSIONS: Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.

Phosphate handling: new genes, new molecules.

BACKGROUND: Inappropriate renal phosphate transport may alter serum phosphate concentration and bone mineralization, and it may also increase the risk of renal lithiasis or soft-tissue calcifications. Molecular identification of renal phosphate transporters and regulatory proteins has improved our knowledge of the mechanisms that control phosphate balance. This summary reviews recent findings regarding the consequences of mutations affecting several human genes encoding for phosphate transporters or regulatory proteins. Further, it describes the role played by the fibroblast growth factor 23-Klotho axis in phosphate homeostasis and its involvement in the pathophysiology of phosphate disturbances in chronic kidney diseases. CONCLUSIONS: This progress may allow development of new drugs that interfere with phosphate transporters, hormonal receptors or associated proteins to improve treatment and to help prevent secondary hyperparathyroidism.

[Calcimimetics: physiology, results of preclinical and clinical studies, and perspectives]. / Calcimimétiques: physiologie, résultats d'études cliniques et perspectives.

Secondary hyperparathyroidism is associated with an increased risk of skeletal fractures and mortality in dialysis patients. Classical treatments such as active vitamin D derivatives and surgical parathyroidectomy are efficient but have some limitations. Second generation calcimimetics allow to control serum PTH levels without increasing serum calcium phosphorus product. This article reviews the physiological bases of PTH regulation, the mode of action of calcimimetics and the results of preclinical and clinical studies evaluating the effect of calcimimetics on different biochemical, clinical and histological parameters.

The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.

BACKGROUND: This prospective, randomized, controlled trial compared the progression of vascular and cardiac valve calcification in 360 prevalent adult hemodialysis patients with secondary hyperparathyroidism treated with either cinacalcet plus low-dose vitamin D sterols or flexible doses of vitamin D sterols alone. METHODS: Eligible subjects were on hemodialysis for ≥ 3 months with parathyroid hormone (PTH) > 300 pg/mL or PTH 150-300 pg/mL with calcium-phosphorus product > 50 mg(2)/dL(2) while receiving vitamin D. All subjects received calcium-based phosphate binders. Coronary artery calcification (CAC) and aorta and cardiac valve calcium scores were determined both by Agatston and volume scoring using multi-detector computed tomography. Subjects with Agatston CAC scores ≥ 30 were randomized to cinacalcet (30- 180 mg/day) plus low-dose calcitriol or vitamin D analog (≤ 2 µg paricalcitol equivalent/dialysis), or flexible vitamin D therapy. The primary end point was percentage change in Agatston CAC score from baseline to Week 52. RESULTS: Median (P10, P90) Agatston CAC scores increased 24% (-22%, 119%) in the cinacalcet group and 31% (-9%, 179%) in the flexible vitamin D group (P = 0.073). Corresponding changes in volume CAC scores were 22% (-12%, 105%) and 30% (-6%, 133%; P = 0.009). Increases in calcification scores were consistently less in the aorta, aortic valve and mitral valve among subjects treated with cinacalcet plus low-dose vitamin D sterols, and the differences between groups were significant at the aortic valve. CONCLUSIONS: In hemodialysis patients with moderate to severe secondary hyperparathyroidism, cinacalcet plus low-dose vitamin D sterols may attenuate vascular and cardiac valve calcification.

Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients.

BACKGROUND: The ADVANCE (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects with Chronic Kidney Disease Receiving Haemodialysis) Study objective is to assess the effect of cinacalcet plus low-dose active vitamin D versus flexible dosing of active vitamin D on progression of coronary artery calcification (CAC) in haemodialysis patients. We report the ADVANCE Study design and baseline subject characteristics. METHODS: ADVANCE is a multinational, multicentre, randomized, open-label study. Adult haemodialysis patients with moderate to severe secondary hyperparathyroidism (intact parathyroid hormone [iPTH] >300 pg/mL or bio-intact PTH >160 pg/mL) and baseline CAC score >or=30 were stratified by CAC score (>or=30-399, >or=400-999, >or=1000) and randomized in a 1:1 ratio to cinacalcet (30-180 mg/day) plus low-dose active vitamin D (cinacalcet group) or flexible dosing of active vitamin D alone (control). The study had three phases: screening, 20-week dose titration and 32-week follow-up. CAC scores obtained by cardiac computed tomography were determined at screening and weeks 28 and 52. The primary end point was percentage change in CAC score from baseline to Week 52. RESULTS: Subjects (n = 360) were randomized to cinacalcet or control. Mean age was 61.5 years, 43% were women, and median dialysis vintage was 36.7 months (range, 2.7-351.5 months). The baseline geometric mean CAC score by the Agatston method was 548.7 (95% confidence interval, 480.5-626.6). Baseline CAC score was independently associated with age, sex, dialysis vintage, diabetes and iPTH. Subjects also had extensive aortic and valvular calcification at baseline. CONCLUSIONS: Subjects enrolled in ADVANCE have extensive CAC at baseline. The ADVANCE Study should help determine whether cinacalcet attenuates progression of vascular calcification.

[A new axis of phosphate balance control: fibroblast growth factor 23-Klotho]. / Un nouveau système de régulation du bilan du phosphate : Fibroblast Growth Factor 23-Klotho.

Serum phosphate concentration value is controlled by the kidney, which adapts phosphate reabsorption in the proximal tubule to the needs of the body and regulates intestine absorption of phosphate and calcium through calcitriol synthesis. Fibroblast Growth Factor 23 (FGF23) is a hormone that controls sodium-phosphate transporter and 1-alpha 25(OH) vitamin D hydroxylase expression in the renal proximal tubule. FGF23 is synthesized by bone cells in response to an increase in serum phosphate or calcitriol concentrations. The binding of FGF23 to a FGF receptor requires a protein named Klotho that is expressed in the kidney in the distal but not in the proximal tubule. The mechanism by which FGF23 controls proximal tubule function remains to be established. The alteration of the FGF23-Klotho axis in animal models and various human disorders is associated with abnormal control of body phosphate content confirming the major role played by these protein in phosphate homeostasis. This review details FGF23 and Klotho functions in normal conditions and in genetics or acquired disorders.

Klotho gene, phosphocalcic metabolism, and survival in dialysis.

The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress.

Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease.

Secondary hyperparathyroidism (SHPT) develops as a result of impaired calcium homeostasis when the failing kidneys disturb the complicated interactions between parathyroid hormone (PTH), calcium, phosphorus, and vitamin D. Twelve years ago, the calcium-sensing receptor (CaR) of the parathyroid gland was first cloned and identified as the principal regulator of PTH secretion. The activation of the CaR by small changes in extracellular calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and ultimately, bone turnover. The CaR became an ideal target for the development of calcimimetics, which are able to amplify its sensitivity to ec(Ca2+) suppressing PTH secretion. Cinacalcet HCl, a first-in-class calcimimetic, approved in both the United States and the European Union, offers a new therapeutic approach to the treatment of SHPT. The efficacy of cinacalcet HCl in treating SHPT in dialysis patients (n = 1,136) was studied in three similarly designed phase III clinical trials comparing patients receiving standard SHPT therapy plus cinacalcet HCl or plus placebo. Cinacalcet HCl, dosed from 30 to 180 mg/day, significantly reduced PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product in each of the three studies. Respective to the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI) recommended targets for bone and mineral metabolism, 41% of cinacalcet HCl-treated patients achieved both PTH and calcium-phosphorus product targets, compared with only 6% in the placebo group. Results from 2 recent phase IIIb studies (TARGET and CONTROL) conducted in the United States also showed that cinacalcet HCl can significantly reduce or maintain reduction in PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product. In addition, patients taking vitamin D at baseline of these 2 trials were able to see significant mean reductions in vitamin D dose. Further assessment of cinacalcet HCl trial data has shown some important effects in SHPT patient clinical outcomes. A combined post-hoc analysis of clinical events using data from 4 (n = 1,184) cinacalcet HCl phase II and III studies suggests that treatment with cinacalcet HCl has a beneficial effect on relative risks of parathyroidectomy, fracture, and hospitalization for cardiovascular complications. Nausea and vomiting occurred more often in patients taking cinacalcet HCl than in those taking a placebo. There were also transient episodes of hypocalcemia in 5% of cinacalcet HCl patients versus 1% of placebo patients. However, these episodes were rarely associated with symptoms. The development of calcimimetics has already changed the treatment of SHPT in renal patients. Its effectiveness on the control of PTH secretion, along with simultaneous reductions in calcium, phosphorus, and calcium-phosphorus product, give this agent an advantage over traditional therapies in all levels of severity of SHPT.

New therapies for uremic secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease (CKD). It affects more than 300,000 end-stage renal disease patients treated by dialysis and probably more than 3 million patients with CKD worldwide. For a long time, traditional therapies for SHPT had consisted of correcting the hypocalcemia using calcium salts and vitamin D derivatives, preventing the hyperphosphatemia by calcium- or aluminum-containing intestinal phosphate binders, and recently by using no metal-containing intestinal phosphate binders; however, these therapies are limited by the occurrence of hypercalcemia, hyperphosphatemia, and the lack of specificity and long-term efficacy. Moreover, surgical parathyroidectomy (PTX), which remains the gold standard therapy, is not exempt from risk. PTX exposes patients to anesthesia risks, presurgical and postsurgical complications, and in many cases a permanent state of hypoparathyroidism. Thus, the medical treatment of SHPT became an ideal target for the development of new therapies and strategies. The purpose of this article is to provide an overview of these new therapies, including vitamin D analogs, intestinal phosphate binders, calcimimetics, parathyroidectomies, tyrosine kinase inhibitors, azydothymidine, anticalcineurins, N-terminal truncated parathyroid hormone fragments, bisphosphonates, calcitonin, osteoprotegerin, and others. The use of these new therapies alone or in combination may help to optimize the future treatment of SHPT in CKD patients.

[How to slow down parathyroid hormone (PTH) secretion without the risk of inducing an adynamic bone disease]. / Comment freiner au mieux la sécrétion d'hormone parathyroïdienne (PTH) sans risquer d'induire une ostéopathie adynamique?

Medical treatment for secondary hyperparathyroidism (HPTH-II) consists in correcting: hypocalcemia by providing a supply of calcium salts, vitamin D or its derivatives; hyperphosphatemia by a suitable diet and by using gastrointestinal phosphate-binders; metabolic acidosis by providing sodium bicarbonate. Very recently, this treatment armamentarium was expanded by the advent of a new therapeutic agent called a calcimimetic (cinacalcet HCL). Cinacalcet increases the calcium sensitivity of the calcium receptor (CaR) of parathyroid cells and thereby induces a rapid and sustained decrease in PTH secretion. When treatment with medical inhibitors proves to be ineffective or involves risks due to an increase in the calcium-phosphorus ion product and the occurrence or worsening of cardiovascular calcifications, it is then necessary to resort to surgical reduction of PTH production by surgical parathyroidectomy (PTX). The very high efficacy of medical inhibitory treatment of HPTH-II logically poses the problem of excessive inhibition of the secretion of PTH and its corollary, the increased risk of adynamic osteopathy. The primary purpose of this article is to provide the reader with an updated review of these problems consisting, on the one hand, of inhibiting PTH secretion and, on the other, of maintaining a sufficient level of bone remodeling to prevent any possible repercussions on other organs.

[What are the actual indications for a surgical parathiroidectomy?]. / Quelles sont les indications actuelles à retenir pour la parathyroïdectomie?

Secondary hyperparathyroidism (HPTH-II) is a major complication of chronic renal insufficiency (CRI). It affects more than 300,000 dialyzed CRI patients in the world and probably more than 3 million as yet non-dialyzed CRI patients. It results from an imbalance in the interaction between calcium, phosphorus, vitamin D and parathyroid hormone (PTH). In fact, CRI is accompanied by phosphorus retention and this accumulation of phosphorus induces an increased synthesis of FGF-23 (Fibroblast Growth Factor-23) which inhibits the activity of lalpha-hydroxylase and the synthesis of calcitriol. Moreover, the hyperphosphaturia induced by PTH and its stimulant effect on calcitriol synthesis and tubular calcium reabsorption are compromised by the reduction in the expression of the renal PTH receptor. All these changes lead to a negative calcium balance and a reduction in calcium-sensitive receptors and vitamin D receptors in parathyroid cells (CaR), thereby releasing the secretion of PTH and the proliferation of parathyroid cells. The chronic stimulation of PTH by these anomalies causes progressive hyperplasia of the parathyroid cells which may be transformed into a benign tumor with a monoclonal appearance. The usual medical treatment of HPTH-II consists in the correction of hypocalcemia by calcium salts and vitamin D and its derivatives, hyperphosphatemia by lifestyle and dietary changes and intestinal phosphorus chelating agents and metabolic acidosis. Very recently, this treatment armamentarium has been expanded by the advent of the calcimimetic agent, cinacalcet HCl. This product increases the calcium sensitivity of CaR in parathyroid cells leading to a rapid and sustained decrease in PTH secretion. However, it is still necessary to resort to surgical parathyroidectomy (PTX) when these treatments prove to be ineffective or involve risks because of adverse effects and in particular an increase in the calcium-phosphorus ion product and the occurrence or worsening of cardiovascular calcifications. The purpose of this article is to revise the current indications of PTX and to discuss changes and the current and future trends for treatment of HPTH-II by surgery alone or combined.