Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Semaglutide for treatment of obesity in hemodialysis patients waiting for a kidney transplant: new hope?

Obesity limits the access to kidney transplantation and increases the risk of complications and mortality posttransplantation. Usual noninvasive measures, including lifestyle changes and dietary education, do not provide long-term and consistent body weight reduction. In many cases, only bariatric surgery allows patients to significantly reduce body weight. We here report two cases of obese hemodialysis (HD) patients who were successfully treated with off-labeled semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA). The first patient had a body mass index (BMI) of 45.7 kg/m2 despite a history of partial gastrectomy. The second patient had a history of type 2 diabetes mellitus and a BMI of 36.5 kg/m2. Both patients started semaglutide at the maximal subcutaneous dose of 1 mg/week, which was clinically well tolerated. During the 9-month follow-up, body weight loss ranged from 6.5 to 9.0 kg, ∼1 kg/month. GLP-1RAs, such as semaglutide or liraglutide, could be a novel pharmacological alternative to bariatric surgeries for these HD patients.

Bone Fragility in Chronic Kidney Disease Stage 3 to 5: The Use of Vitamin D Supplementation.

Frequently silent until advanced stages, bone fragility associated with chronic kidney disease-mineral and bone disease (CKD-MBD) is one of the most devastating complications of CKD. Its pathophysiology includes the reduction of active vitamin D metabolites, phosphate accumulation, decreased intestinal calcium absorption, renal alpha klotho production, and elevated fibroblast growth factor 23 (FGF23) levels. Altogether, these factors contribute firstly to secondary hyperparathyroidism, and ultimately, to micro- and macrostructural bone changes, which lead to low bone mineral density and an increased risk of fracture. A vitamin D deficiency is common in CKD patients, and low circulating 25(OH)D levels are invariably associated with high serum parathyroid hormone (PTH) levels as well as with bone mineralization defects, such as osteomalacia in case of severe forms. It is also associated with a variety of non-skeletal diseases, including cardiovascular disease, diabetes mellitus, multiple sclerosis, cancer, and reduced immunological response. Current international guidelines recommend supplementing CKD patients with nutritional vitamin D as in the general population; however, there is no randomized clinical trial (RCT) evaluating the effect of vitamin D (or vitamin D+calcium) supplementation on the risk of fracture in the setting of CKD. It is also unknown what level of circulating 25(OH)D would be sufficient to prevent bone abnormalities and fractures in these patients. The impact of vitamin D supplementation on other surrogate endpoints, including bone mineral density and bone-related circulating biomarkers (PTH, FGF23, bone-specific alkaline phosphatase, sclerostin) has been evaluated in several RTCs; however, the results were not always translated into an improvement in long-term outcomes, such as reduced fracture risk. This review provides a brief and comprehensive update on CKD-related bone fragility and the use of natural vitamin D supplementation in these patients.

Longitudinal Bone Loss Occurs at the Radius in CKD.

INTRODUCTION: Chronic kidney disease (CKD) exposes to an increased incidence of fragility fractures. International guidelines recommend performing bone mineral density (BMD) if the results will impact treatment decisions. It remains unknown where bone loss occurs and what would preclude the longitudinal loss in patients with CKD. Here, we aimed to investigate factors influencing BMD and to analyze the longitudinal BMD changes. METHODS: In the NephroTest cohort, we measured BMD at the femoral neck, total hip, lumbar spine, and proximal radius, together with circulating biomarkers and standardized measured glomerular filtration rate (mGFR) by 51Cr-EDTA in a subset of patients with CKD stage 1 to 5 followed during 4.3 ± 2.0 years. A linear mixed model explored the longitudinal bone loss and the relationship of associated factors with BMD changes. A total of 858 patients (mean age 58.9 ± 15.2 years) had at least 1 and 477 had at least 2 BMD measures. RESULTS: At baseline, cross-sectional analysis showed a significantly lower BMD at femoral neck and total hip and a significant higher serum parathyroid hormone (PTH) along with CKD stages. Baseline age, gender, tobacco, low body mass index (BMI), and high PTH levels were significantly associated with low BMD. Longitudinal analysis during the mean 4.3 years revealed a significant bone loss at the radius only. BMD changes at the femoral neck were associated with BMI, but not CKD stages or basal PTH levels. CONCLUSIONS: CKD is associated with low BMD and high PTH in the cross-sectional analysis. Longitudinal bone loss occurred at the proximal radius after 4.3 years.

A loosening prosthesis in a dialysis patient.

A haemodialysis patient with periprosthetic fractures and a history of corticosteroid use was referred for assessment for bone mineral disorders. Mixed renal osteodystrophy was diagnosed following a bone biopsy. Correction for vitamin D insufficiency did not improve the clinical signs, which prompted a potential diagnosis of hypophosphataemic osteomalacia to be considered. No causes for hypophosphataemia were found, except for phosphate dietary restrictions. Phosphorus supplementation was administered, resulting in an upturn in bone biochemical and histological parameters and increased bone mineral density, thus confirming the diagnosis of hypophosphataemic osteomalacia due to low phosphate intake. Characteristic features related to this diagnosis are shown from three repeated bone biopsies performed during the course of patient follow-up.

Cortical Bone Microarchitecture in Dialysis Patients.

BACKGROUND: The incidence of skeletal fractures is high in dialysis patients. Current available tools are insufficient to predict bone fragility. We analyzed the microarchitecture in patients on dialysis therapy using bone biopsies and peripheral microcomputed tomography. METHODS: We analyzed 12 trans-iliac bone biopsies of patients with recent fractures. Bone microarchitecture was assessed in the bone cores by histology (2D-), microcomputed tomography (3D-µCT), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia. RESULTS: Trabecular bone volume/tissue volume was similar in 2D histology and 3D-µCT (p = 0.40), while lower in HR-pQCT (p < 0.01). There was no correlation in trabecular microarchitectural indices between 2-histology and 3D-µCT, or HR-pQCT. The 3D-µCT cortical thickness (Ct.Th) were positively correlated with 2D (p < 0.05), but with HR-pQCT (p = 0.33). Ct.Th was lower in patients with ≥2 vertebral fractures than with one fracture. CONCLUSIONS: 3D-µCT is a reliable method for the measurement of cortical bone in bone biopsies. Prospective studies are awaited to address its value in discriminating fracture risk.

Valvular heart disease and calcification in CKD: more common than appreciated.

Ischaemic heart disease, sudden cardiac death and arrhythmias, heart failure, stroke and peripheral arterial disease make up >50% of the causes of death in advanced chronic kidney disease (CKD). Calcification of the vascular tree and heart valves is partially related to these complications and has received growing attention in the literature. However, the main focus of research has been on the pathophysiology and consequences of vascular calcification, with less attention being paid to valvular calcification (VC) and its impact on the survival of CKD patients. Although VC has long been seen as an age-related degenerative disorder with minimal functional impact, several studies proved that it carries an increased risk of death and clinical consequences different from those of vascular calcification. In dialysis patients, the annual incidence of aortic valve calcification is nearly 3.3% and the reported prevalence of aortic and mitral VC varies between 25% and 59%. Moreover, calcification of both valves occurs 10-20 years earlier in CKD patients compared with the general population. Therefore, the purpose of this review is to summarize the current knowledge on the pathophysiology and relevance of VC in CKD patients, and to highlight specific clinical consequences and potential therapeutic implications.

One-year safety and efficacy of intravenous etelcalcetide in patients on hemodialysis with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease, is characterized by elevated serum parathyroid hormone (PTH). Etelcalcetide is an intravenous calcimimetic that increases sensitivity of the calcium-sensing receptor to calcium and decreases PTH secretion. This open-label extension (OLE) trial evaluated the long-term effects of etelcalcetide for sHPT treatment in patients receiving hemodialysis. METHODS: This 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, placebo-controlled trials and one open-label, single-arm, 'switch' study from cinacalcet to etelcalcetide. The primary endpoint was to investigate the nature, frequency, severity and relation to treatment of all adverse events (AEs) reported throughout the trial. Secondary endpoints included the proportion of patients with >30% reduction from baseline in PTH and the percentage change from baseline in PTH, albumin-corrected calcium (Ca), phosphate (P) and the calcium-phosphate product (Ca × P).ClinicalTrials.gov identifier: NCT01785875; Amgen study: 20120231. RESULTS: Overall, 89.8% of the patients experienced one or more treatment-emergent AE. The most common were decreased blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the patients. Approximately 68% of patients achieved >30% reduction in PTH, and ∼56% achieved PTH ≤300 pg/mL. Mean percent changes from baseline ranged from -25.4% to -26.1% for PTH, -8.3% to -9.1% for Ca, -3.6% to -4.1% for P and -12.0% to -12.6% for Ca × P. CONCLUSIONS: Etelcalcetide effectively lowered PTH and its effect was sustained, while no new safety concerns emerged over a 1-year treatment period.

Osteoporosis, bone mineral density and CKD-MBD (II): Therapeutic implications. / Osteoporosis, densidad mineral ósea y complejo CKD-MBD (II): implicaciones terapéuticas.

Osteoporosis (OP) and chronic kidney disease (CKD) both independently affect bone health. A significant number of patients with CKD have decreased bone mineral density (BMD), are at high risk of fragility fractures and have an increased morbidity and mortality risk. With an ageing population, these observations are not only dependent on "renal osteodystrophy" but also on the associated OP. As BMD predicts incident fractures in CKD patients (partI), we now aim to analyse the potential therapeutic consequences. Post-hoc analyses of randomised studies have shown that the efficacy of drugs such as alendronate, risedronate, raloxifene, teriparatide and denosumab is similar to that of the general population in patients with a mild/moderate decline in their glomerular filtration rate (especially CKD-3). These studies have some flaws however, as they included mostly "healthy" women with no known diagnosis of CKD and generally with normal lab test results. Nevertheless, there are also some positive preliminary data in more advanced stages (CKD-4), even though in CKD-5D they are more limited. Therefore, at least in the absence of significant mineral metabolism disorders (i.e. severe hyperparathyroidism), the potential benefit of these drugs should be considered in patients with a high or very high fracture risk. It is an important change that the new guidelines do not make it a requirement to first perform a bone biopsy and that the risk/benefit ratio of these drugs may be justified. However, we must also be aware that most studies are not consistent and the level of evidence is low. Consequently, any pharmacological intervention (risk/benefit) should be prudent and individualised.

Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis. METHODS: Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy. FINDINGS: PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5-14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27-11%)) or mild iron overload (PDFF: 5% (0.30-11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 µmol/g, final 160 µmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 µmol/g, final: 45 µmol/g; P = 0.002). INTERPRETATION: Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients. TRIAL REGISTRATION NUMBER (ISRCTN): 80100088.

Bone, inflammation and the bone marrow niche in chronic kidney disease: what do we know?

Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone-vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease-mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases.

Lack of evidence does not justify neglect: how can we address unmet medical needs in calciphylaxis?

Calcific uraemic arteriolopathy (CUA), or calciphylaxis, is a rare disease predominantly occurring in comorbidity with dialysis. Due to the very low frequency of CUA, prospective studies on its management are lacking and even anecdotal reports on treatment remain scarce. Therefore, calciphylaxis is still a challenging disease with dismal prognosis urgently requiring adequate strategies for diagnosis and treatment.In an attempt to fill some of the current gaps in evidence on various, highly debated and controversial aspects of dialysis-associated calciphylaxis, 13 international experts joined the 1st Consensus Conference on CUA, held in Leuven, Belgium on 21 September 2015. The conference was supported by the European Calciphylaxis Network (EuCalNet), which is a task force of the ERA-EDTA scientific working group on Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). After an intense discussion, a 9-point Likert scale questionnaire regarding 20 items on calciphylaxis was anonymously answered by each participant. These 20 items addressed unsolved issues in terms of diagnosis and management of calciphylaxis. On the one hand, the analysis of the expert opinions identified areas of general consensus, which might be a valuable aid for physicians treating such a disease with less experience in the field. On the other hand, some topics such as the pertinence of skin biopsy and administration of certain treatments revealed divergent opinions. The aim of the present summary report is to provide some guidance for clinicians who face patients with calciphylaxis in the current setting of absence of evidence-based medicine.

Iron-based phosphate binders: do they offer advantages over currently available phosphate binders?

Increased cardiovascular morbidity and mortality has been associated with the hyperphosphatemia seen in patients with end-stage chronic kidney disease (CKD). Oral phosphate binders are prescribed in these patients to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational cohorts they have shown to decrease all-cause and cardiovascular mortality risk. Different problems have been associated with currently available phosphate binders as positive calcium balance and impaired outcomes with calcium-based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. Several iron-based phosphate binders have undergone testing in clinical trials. Ferric citrate (JTT-751) and sucroferric oxyhydroxide (PA21) are the two iron-based binders that have passed to the clinical field after being found safe and effective in decreasing serum phosphate. Iron from ferric citrate is partially absorbed compared to sucroferric oxyhydroxide. Ferric citrate usage could result in an important reduction in erythropoiesis-stimulating agent (ESA) and IV iron usage, resulting in significant cost savings. Sucroferric oxyhydroxide was effective in lowering serum phosphorus in dialysis patients with similar efficacy to sevelamer carbonate, but with lower pill burden, and better adherence. Ferric citrate may be more suited for the treatment of chronic hyperphosphatemia in CKD patients requiring iron supplements but its use may have been hampered by potential aluminum overload, as citrate facilitates its absorption; sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplementation, with low pill burden.

Pro: cardiovascular calcifications are clinically relevant.

It is increasingly acknowledged that mineral and bone disorders (MBDs) contribute to the excessively high cardiovascular (CV) disease morbidity and mortality observed in patients with chronic kidney disease (CKD). There is ongoing debate as to whether screening for CV calcification, one of the hallmarks of CKD-MBD, should be implemented in clinical practice in patients with CKD. Issues to be considered in this controversy relate to prevalence, severity, relevance, and last but not least, modifiability and reversibility of vascular and valvular calcifications in the setting of CKD. The recent expansion of the armamentarium to treat CKD-MBD (calcium-free phosphate binders and calcimimetics) creates new opportunities. Mounting experimental and clinical evidence indicates that progression of CV calcification may indeed be attenuated. Whether this will translate into better outcomes remains to be proven. We acknowledge that hard outcome data so far are limited and, overall, yielded inconclusive results. Nevertheless, in an era in which personalized medicine has gained much popularity, we consider it reasonable, awaiting the results of additional studies, to screen for CV calcification in selected individuals. This policy may help to stratify CV risk and to guide therapy. We speculate that such an approach will ultimately improve outcomes and reduce health costs.

[Native vitamin D in dialysis patients]. / Place de la vitamine D native en dialyse.

Chronic kidney disease is frequent and usually responsible of mineral and bone disorder. These abnormalities lead to increased morbidity and mortality. To become active, native vitamin D needs a first hydroxylation in the liver, and a second one in the kidney. Next to its action on bone metabolism, vitamin D also possesses pleiotropic actions on cardiovascular, immune and neurological systems as well as antineoplastic activities. End-stage renal disease (ESRD) is also associated with a decrease in vitamin D activity by mechanisms including the increase of plasma phosphate concentration, secretion of FGF-23 and decrease in 1α-hydroxylase activity. The prevalence of 25 hydroxy-vitamin D deficiency depends on the chosen cut-off value to define this lack. Currently it is well established that a patient has to be substituted when 25 hydroxy-vitamin D level is under 30 ng/mL. The use and monitoring of 1.25 hydroxy-vitamin D is still not recommended in routine practice. The goals of vitamin D treatment in case of ESRD are to substitute the deficiency and to prevent or treat hyperparathyroidism. Interest of native vitamin D in first intention is now well demonstrated. This review article describes the vitamin D metabolism and physiology and also the treatment for vitamin D deficiency in ESRD population.

Is chronic kidney disease-mineral bone disorder (CKD-MBD) really a syndrome?

The concept of chronic kidney disease-mineral bone disorder (CKD-MBD) does not appear to fulfil the requirements for a syndrome at first glance, but its definition has brought some clear-cut benefits for clinicians and patients, including wider and more complex diagnostic and therapeutic approaches to the management of this challenging set of issues. Admittedly, not all components of CKD-MBD are present in all patients at all times, but these are highly interrelated, involving mineral and bone laboratory abnormalities, clinical and histological bone disease and finally, cardiovascular disease. The presence of typical biological bone ossification processes in an ectopic anatomical location in CKD has helped to define the existence of an unprecedented bone-vascular relationship, extending its interest even to other medical specialities. For now, we believe that CKD-MBD does not reach full criteria to be defined as a syndrome. However, this novel concept has clearly influenced current clinical guidelines. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF/KDOQI™) guidelines in 2003 for instance recommended that calcium-based phosphate binders should be avoided to treat hyperphosphataemia in the presence of cardiovascular calcifications. In 2009, the KDIGO and other guidelines reinforced and extended this recommendation by stating that it is reasonable to choose oral phosphate binder therapy by taking into consideration other components of CKD-MBD. Similarly, it is also considered reasonable to use information on vascular/valvular calcification to guide the management of CKD-MBD. Our current assumption as a working group 'CKD-MBD' is that CKD-MBD has the potential to be defined a true syndrome, such as a constellation of concurrent signs and symptoms that suggest a common underlying mechanism for these components as opposed to the term disease. The term 'syndrome' also implies that in any patient at risk due to the presence of one or a few components of the entire syndrome, the screening for additional components is highly recommended. However, it has not currently been demonstrated that there is an additive predictive value, which can be derived from identifying individual components. Despite all we have learned about this putative syndrome, we have been left with only a hypothetical framework about how to treat patients. So while we agree that the concept of CKD-MBD has influenced, and continues to influence, our current clinical hypotheses, definitive proof of a benefit of interventions in CKD-MBD is still lacking and a global-multiple therapeutic approach to treat simultaneously several components of CKD-MBD should be tested by well-designed new randomized controlled trials.

Pharmacologic role of vitamin D natural products.

Vitamin D is essential for maintaining a healthy mineral and bone metabolism. It stimulates calcium and phosphate absorption by the intestine, regulates bone metabolism, and negatively controls PTH secretion through the endocrine action of its active metabolite calcitriol. Vitamin D also possesses a variety of effects unrelated with mineral and bone metabolism, including the regulation of arterial blood pressure and the prevention of cardiovascular complications, modulation of immunological responses, regulation of insulin production and prevention against diabetes, protection against certain cancers, renoprotection, and other beneficial actions. This article provides an update review of the sources and pharmacological characteristics of natural vitamin D compounds, their most clinical uses, and their most important clinical results.

Sodium thiosulphate treatment of uraemic tumoral calcinosis.

OBJECTIVE: The objective of this study was to describe the efficacy of sodium thiosulphate (STS) in tumoral calcinosis (TC). METHODS: The methodology involved the reporting of four retrospective case reports of TC complicating end-stage renal disease (ESRD). RESULTS: We investigated STS treatment in four patients (two men; ages 46-70 years) with TC. ESRD was secondary to nephronophthisis (n = 1), membranoproliferative glomerulonephritis (n = 1), diabetic nephropathy (n = 1), and thrombotic microangiopathy (n = 1). TC developed 3-28 years after dialysis began and resulted in articular pain (n = 4) and stiffness (n = 1). It involved shoulders and hips and was diffuse in one patient. Several treatments were tried without success. STS 12.5-25 g was given intravenously after each dialysis session for 11-14 months. Pain and stiffness rapidly disappeared and TC showed partial or total regression. Side effects during infusion included increased blood pressure (n = 1), nausea (n = 1) and vomiting (n = 1). TC did not recur after treatment discontinuation with follow-up of 1.5-12 years. CONCLUSION: STS showed promising efficacy in this short series of TC. Further studies are warranted.

Association of kidney function, vitamin D deficiency, and circulating markers of mineral and bone disorders in CKD.

BACKGROUND: Vitamin D (25 hydroxyvitamin D [25(OH)D]) deficiency is common in patients with chronic kidney disease (CKD). Neither the relation of this deficiency to the decrease in glomerular filtration rate (GFR) nor the effects on CKD mineral and bone disorders (MBD) are clearly established. STUDY DESIGN: Cross-sectional analysis of baseline data from a prospective cohort, the NephroTest Study. SETTING & PARTICIPANTS: 1,026 adult patients with all-stage CKD not on dialysis therapy or receiving vitamin D supplementation. PREDICTORS: For part 1, measured GFR (mGFR) using (51)Cr-EDTA renal clearance; for part 2, 25(OH)D deficiency at <15 ng/mL. OUTCOMES & MEASUREMENTS: For part 1, 25(OH)D deficiency and several circulating MBD markers; for part 2, circulating MBD markers. RESULTS: For part 1, the prevalence of 25(OH)D deficiency was associated inversely with mGFR, ranging from 28%-51% for mGFR ≥60-<15 mL/min/1.73 m(2). It was higher in patients of African origin; those with obesity, diabetes, hypertension, macroalbuminuria, and hypoalbuminemia; and during winter. After adjusting for these factors, ORs for 25(OH)D deficiency increased from 1.4 (95% CI, 0.9-2.3) to 1.4 (95% CI, 0.9-2.1), 1.7 (95% CI, 1.1-2.7), and 1.9 (95% CI, 1.1-3.6) as mGFR decreased from 45-59 to 30-44, 15-29, and <15 (reference, ≥60) mL/min/1.73 m(2) (P for trend = 0.02). For part 2, 25(OH)D deficiency was associated with higher age-, sex-, and mGFR-adjusted ORs of ionized calcium level <1.10 mmol/L (2.6; 95% CI, 1.2-5.9), 1,25 dihydroxyvitamin D concentration <16.7 pg/mL (1.8; 95% CI, 1.3-2.4), hyperparathyroidism (1.8; 95% CI, 1.3-2.4), and serum C-terminal cross-linked collagen type I telopeptides concentration >1,000 pg/mL (1.6; 95% CI, 1.0-2.6). It was not associated with hyperphosphatemia (phosphate >1.38 mmol/L). LIMITATIONS: Cross-sectional analysis of the data prevents causal inferences. CONCLUSIONS: 25(OH)D deficiency is related independently to impaired mGFR. Both mGFR decrease and 25(OH)D deficiency are associated with abnormal levels of circulating MBD biomarkers.

Effectiveness of cinacalcet in patients with recurrent/persistent secondary hyperparathyroidism following parathyroidectomy: results of the ECHO study.

BACKGROUND: Progressive secondary hyperparathyroidism (sHPT) is characterized by parathyroid gland hyperplasia which may ultimately require parathyroidectomy (PTX). Although PTX is generally a successful treatment for those patients subjected to surgery, a significant proportion develops recurrent sHPT following PTX. ECHO was a pan-European observational study which evaluated the achievement of KDOQI(TM) treatment targets with cinacalcet use in patients on dialysis. Previously published results showed that cinacalcet plus flexible vitamin D therapy lowered serum PTH, phosphorus and calcium in the clinical practice with similar efficacy as seen in phase III trials. METHODS: This subgroup analysis of ECHO describes the real-world cinacalcet treatment effect in patients with recurrent or persistent sHPT after PTX (n = 153) compared to sHPT patients without prior history of PTX (n = 1696). RESULTS: Both groups of patients had substantially elevated serum PTH with comparable sHPT severity at baseline. After 12 months of cinacalcet treatment, 20.3% (26/128) of patients with prior PTX and 18.2% (253/1388) of patients without prior PTX achieved serum PTH and Ca × P values within the recommended KDOQI(TM) target ranges. CONCLUSIONS: Our data support the successful use of cinacalcet in patients with recurrent/persistent sHPT after PTX.