Renal osteodystrophy: something old, something new, something needed.

PURPOSE OF REVIEW: Renal osteodystrophy (ROD) is a complex disorder of bone metabolism that affects virtually all adults and children with chronic kidney disease (CKD). ROD is associated with adverse clinical outcomes including bone loss, mineralization and turnover abnormalities, skeletal deformities, fractures, cardiovascular events, and death. Despite current therapies, fracture incidence is 2-fold to 100-fold higher in adults and 2-fold to 3-fold higher in children when compared to without CKD. Limited knowledge of ROD pathogenesis, due to the lack of patient-derived large-scale multimodal datasets, impedes development of therapeutics aimed at reducing morbidity and mortality of CKD patients. The purpose of the review is to define the much needed infrastructure for the advancement of RDO treatment. RECENT FINDINGS: Recently, we created a large-scale data and tissue biorepository integrating clinical, bone quality, transcriptomic, and epigenomic data along with stored urine, blood, and bone samples. This database will provide the underpinnings for future research endeavors leading to the elucidation and characterization of the pathogenesis of ROD in CKD patients with and without dialysis. SUMMARY: The availability of an open-access NIH-funded resource that shares bone-tissue-based information obtained from patients with ROD with the broad scientific community represents a critical step in the process of discovering new information regarding unrecognized bone changes that have severe clinical complications. This will facilitate future high-impact hypothesis-driven research to redefine our understanding of ROD pathogenesis and pathophysiology and inform the development of disease-modifying and prevention strategies.

Overview of renal osteodystrophy in Brazil: a cross-sectional study.

INTRODUCTION: The epidemiologic profile of renal osteodystrophy (ROD) is changing over time and cross-sectional studies provide essential information to improve care and health policies. The Brazilian Registry of Bone Biopsy (REBRABO) is a prospective, nationalmulticenter cohort that includes patients with chronic kidney disease (CKD) undergoing bone biopsy. REBRABO aims to provide clinical information on ROD. The main objective of this subanalysis was to describe the profile of ROD, including clinically relevant associations. METHODS: From Aug/2015 to Dec/2021, 511 patients with CKD who performed bone biopsy were included in the REBRABO platform. Patients with no bone biopsy report (N = 40), GFR > 90 mL/min (N = 28), without asigned consent (N = 24), bone fragments inadequate for diagnosis (N = 23), bone biopsy indicated by a specialty other than nephrology (N = 6), and < 18 years old (N = 4) were excluded. Clinical-demographic data (e.g., age, sex, ethnicity, CKD etiology, dialysis vintage, comorbidities, symptoms, and complications related to ROD), laboratory (e.g., serum levels of total calcium, phosphate, parathormone, alkaline phosphatase, 25-hydroxyvitamin D, and hemoglobin), and ROD (e.g., histological diagnosis) were analyzed. RESULTS: Data from 386 individuals were considered in this subanalysis of REBRABO. Mean age was 52 (42-60) years; 198 (51%) were male; 315 (82%) were on hemodialysis. Osteitis fibrosa (OF) [163 (42%)], adynamic bone disease (ABD) [96 (25%)] and mixed uremic osteodystrophy (MUO) [83 (21%)] were the most frequent diagnosis of ROD in our sample; 203 (54%) had the diagnosis of osteoporosis, 82 (56%) vascular calcification; 138 (36%) bone aluminum accumulation, and 137 (36%) iron intoxication; patients with high turnover were prone to present a higher frequency of symptoms. CONCLUSIONS: A high proportion of patients were diagnosed with OF and ABD, as well as osteoporosis, vascular calcification and clinical symptoms.

[Diagnosis and treatment of osteoporosis in patients with chronic kidney disease : Joint guidelines of the Austrian Society for Bone and Mineral Research (ÖGKM), the Austrian Society of Physical and Rehabilitation Medicine (ÖGPMR) and the Austrian Society of Nephrology (ÖGN)]. / Diagnose und Therapie der Osteoporose bei Patienten mit chronischer Niereninsuffizienz : Gemeinsame Leitlinie der Österreichischen Gesellschaft für Knochen- und Mineralstoffwechsel (ÖGKM), der Österreichischen Gesellschaft für Physikalische Medizin und Rehabilitation (ÖGPMR) und der Österreichischen Gesellschaft für Nephrologie (ÖGN).

DEFINITION AND EPIDEMIOLOGY: Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded). Osteoporosis: compromised bone strength (low bone mass, disturbance of microarchitecture) predisposing to fracture. By definition, osteoporosis is diagnosed if the bone mineral density T­score is ≤ -2.5. Furthermore, osteoporosis is diagnosed if a low-trauma (inadequate trauma) fracture occurs, irrespective of the measured T­score (not graded). The prevalence of osteoporosis, osteoporotic fractures and CKD is increasing worldwide (not graded). PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD): Definition of CKD-MBD: a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; renal osteodystrophy; vascular calcification (not graded). Increased, normal or decreased bone turnover can be found in renal osteodystrophy (not graded). Depending on CKD stage, routine monitoring of calcium, phosphorus, alkaline phosphatase, PTH and 25-OH-vitamin D is recommended (2C). Recommendations for treatment of CKD-MBD: Avoid hypercalcemia (1C). In cases of hyperphosphatemia, lower phosphorus towards normal range (2C). Keep PTH within or slightly above normal range (2D). Vitamin D deficiency should be avoided and treated when diagnosed (1C). DIAGNOSIS AND RISK STRATIFICATION OF OSTEOPOROSIS IN CKD: Densitometry (using dual X­ray absorptiometry, DXA): low T­score correlates with increased fracture risk across all stages of CKD (not graded). A decrease of the T­score by 1 unit approximately doubles the risk for osteoporotic fracture (not graded). A T-score ≥ -2.5 does not exclude osteoporosis (not graded). Bone mineral density of the lumbar spine measured by DXA can be increased and therefore should not be used for the diagnosis or monitoring of osteoporosis in the presence of aortic calcification, osteophytes or vertebral fracture (not graded). FRAX can be used to aid fracture risk estimation in all stages of CKD (1C). Bone turnover markers can be measured in individual cases to monitor treatment (2D). Bone biopsy may be considered in individual cases, especially in patients with CKD G5 (eGFR < 15 ml/min/1.73 m2) or CKD 5D (dialysis). SPECIFIC TREATMENT OF OSTEOPOROSIS IN PATIENTS WITH CKD: Hypocalcemia should be treated and serum calcium normalized before initiating osteoporosis therapy (1C). CKD G1-G2 (eGFR ≥ 60 ml/min/1.73 m2): treat osteoporosis as recommended for the general population (1A). CKD G3-G5D (eGFR < 60 ml/min/1.73 m2 to dialysis): treat CKD-MBD first before initiating osteoporosis treatment (2C). CKD G3 (eGFR 30-59 ml/min/1.73 m2) with PTH within normal limits and osteoporotic fracture and/or high fracture risk according to FRAX: treat osteoporosis as recommended for the general population (2B). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) with osteoporotic fracture (secondary prevention): Individualized treatment of osteoporosis is recommended (2C). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) and high fracture risk (e.g. FRAX score > 20% for a major osteoporotic fracture or > 5% for hip fracture) but without prevalent osteoporotic fracture (primary prevention): treatment of osteoporosis may be considered and initiated individually (2D). CKD G4-5D (eGFR < 30 ml/min/1.73 m2 to dialysis): Calcium should be measured 1-2 weeks after initiation of antiresorptive therapy (1C). PHYSICAL MEDICINE AND REHABILITATION: Resistance training prioritizing major muscle groups thrice weekly (1B). Aerobic exercise training for 40 min four times per week (1B). Coordination and balance exercises thrice weekly (1B). Flexibility exercise 3-7 times per week (1B).

High prevalence of biochemical disturbances of chronic kidney disease - mineral and bone disorders (CKD-MBD) in a nation-wide peritoneal dialysis cohort: are guideline goals too hard to achieve? / Alta Prevalência de Distúrbios Bioquímicos Minerais e Ósseos na Doença Renal Crônica em uma coorte de diálise peritoneal nacional: as metas das diretrizes são muito difíceis de alcançar?

Abstract Introduction: Chronic kidney disease - mineral and bone disorders (CKD-MBD) are common in dialysis patients. Definition of targets for calcium (Ca), phosphorus (P), parathormone (iPTH), and alkaline phosphatase (ALP) and their treatment recommendations, are provided by international guidelines. There are few studies analyzing CKD-MBD in peritoneal dialysis (PD) patients and the impact of guidelines on mineral metabolism control. The aim of our study was to describe the prevalence of biomarkers for CKD-MBD in a large cohort of PD patients in Brazil. Methods: Data from the nation-wide prospective observational cohort BRAZPD II was used. Incident patients were followed between December 2004 and January 2011. According to KDOQI recommendations, reference ranges for total Ca were 8.4 to 9.5 mg/dL, for P, 3.5 to 5.5 mg/dL, for iPTH, 150-300 pg/mL, and for ALP, 120 U/L. Results: Mean age was 59.8 ± 16 years, 48% were male, and 43% had diabetes. In the beginning, Ca was 8.9 ± 0.9 mg/dL, and 48.3% were on the KODQI target. After 1 year, Ca increased to 9.1 ± 0.9 mg/dL and 50.4% were in the KDOQI preferred range. P at baseline was 5.2 ± 1.6 mg/dL, with 52.8% on target, declining to 4.9 ± 1.5 mg/dL after one year, when 54.7% were on target. Median iPTH at baseline was 238 (P25% 110 - P75% 426 pg/mL) and it remained stable throughout the first year; patients within target ranged from 26 to 28.5%. At the end of the study, 80% was in 3.5 meq/L Ca dialysate concentration, 66.9% of patients was taking any phosphate binder, and 25% was taking activated vitamin D. Conclusions: We observed a significant prevalence of biochemical disorders related to CKD-MBD in this dialysis population.

Resumo Introdução: Os distúrbios minerais e ósseos da doença renal crônica (DMO-DRC) são comuns em pacientes em diálise. A definição de metas para cálcio (Ca), fósforo (P), paratormônio (PTHi) e fosfatase alcalina (FA) e suas recomendações de tratamento são fornecidas por diretrizes internacionais. Há poucos estudos analisando o DMO-DRC em pacientes em diálise peritoneal (DP) e o impacto das diretrizes no controle do metabolismo mineral. O objetivo do nosso estudo foi descrever a prevalência de alterações nos marcadores para DMO-DRC em uma grande coorte de pacientes em DP no Brasil. Métodos: Foram utilizados dados da coorte observacional prospectiva nacional BRAZPD II. Pacientes incidentes foram acompanhados entre Dezembro de 2004 e Janeiro de 2011. De acordo com as recomendações do KDOQI, os intervalos de referência para Ca total foram de 8,4 a 9,5 mg/dL, para P, 3,5 a 5,5 mg/dL, para PTHi, 150-300 pg/mL, e para FA, 120 U/L. Resultados: A idade média foi de 59,8 ± 16 anos, 48% eram homens e 43% tinham diabetes. No início, o Ca era de 8,9 ± 0,9 mg/dL, e 48,3% estavam na meta do KODQI. Após 1 ano, o Ca aumentou para 9,1 ± 0,9 mg/dL e 50,4% estavam na faixa preferida do KDOQI. P basal era 5,2 ± 1,6 mg/dL, com 52,8% na meta, diminuindo para 4,9 ± 1,5 mg/dL após um ano, quando 54,7% estavam na meta. O PTHi basal mediano foi de 238 (P25% 110 - P75% 426 pg/mL) e permaneceu estável durante o primeiro ano; os pacientes dentro da meta variaram de 26 a 28,5%. No final do estudo, 80% estavam na concentração de 3,5 meq/L de Ca dialisato, 66,9% dos pacientes estavam tomando qualquer quelante de fosfato, e 25% estavam tomando vitamina D ativada. Conclusões: Observamos uma prevalência significativa de distúrbios bioquímicos relacionados ao DMO-DRC nesta população em diálise.

Osteoporosis and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Back to Basics.

Osteoporosis is defined as a skeletal disorder of compromised bone strength predisposing those affected to an elevated risk of fracture. However, based on bone histology, osteoporosis is only part of a spectrum of skeletal complications that includes osteomalacia and the various forms of renal osteodystrophy of chronic kidney disease-mineral and bone disorder (CKD-MBD). In addition, the label "kidney-induced osteoporosis" has been proposed, even though the changes caused by CKD do not qualify as osteoporosis by the histological diagnosis. It is clear, therefore, that such terminology may not be helpful diagnostically or in making treatment decisions. A new label, "CKD-MBD/osteoporosis" could be a more appropriate term because it brings osteoporosis under the official label of CKD-MBD. Neither laboratory nor noninvasive diagnostic investigations can discriminate osteoporosis from the several forms of renal osteodystrophy. Transiliac crest bone biopsy can make the diagnosis of osteoporosis by exclusion of other kidney-associated bone diseases, but its availability is limited. Recently, a classification of metabolic bone diseases based on bone turnover, from low to high, together with mineralization and bone volume, has been proposed. Therapeutically, no antifracture treatments have been approved by the US Food and Drug Administration for patients with kidney-associated bone disease. Agents that suppress parathyroid hormone (vitamin D analogues and calcimimetics) are used to treat hyperparathyroid bone disease. Antiresorptive and osteoanabolic agents approved for osteoporosis are being used off-label to treat CKD stages 3b-5 in high-risk patients. It has now been suggested that intermittent administration of parathyroid hormone as early as CKD stage 2 could be an effective management strategy. If confirmed in clinical trials, it could mitigate the retention of phosphorus and subsequently the rise in fibroblast growth factor 23 and may be beneficial for coexisting osteoporosis.

Bone turnover markers predict type of bone histomorphometry and bone mineral density in Asian chronic haemodialysis patients.

BACKGROUND: Although the levels of intact parathyroid hormone (iPTH) are well-controlled following the Kidney Disease Outcomes Quality Initiative guideline, the incidence of osteoporosis and fracture are still high in haemodialysis (HD) patients. This study was conducted to investigate the correlation between bone turnover markers, bone mineral density (BMD), and bone histomorphometry in HD patients. METHODS: Twenty-two chronic HD patients were enrolled. Serum levels of bone turnover markers were measured. Double tetracycline-labelled iliac crest bone specimens were evaluated using specialized a computer program (Osteomeasure). The types of bone histomorphometry were classified based on turnover, mineralization and volume. BMD and coronary artery calcification were also determined. RESULTS: Bone histomorphometry revealed osteitis fibrosa (50%), adynamic bone disease (45%) and mixed uremic osteodystrophy (5%). Serum iPTH level predicted high bone turnover with area under the receiver operating characteristic (ROC) of 0.833 (95% CI = 0.665-1.000, P = 0.008). Serum TRAP-5b also had ROC of 0.733 (95% CI = 0.517-0.950, P = 0.065). In addition, when using serum iPTH (cut-off 484.50 ng/mL) or serum TRAP-5b (cut-off 1.91 pg./mL) to predict high turnover, the sensitivity was 0.917. On the other hand, when both iPTH and TRAP-5B were above these cut-off, the specificity was 1.000. Low BMD and severe vascular calcification were commonly identified. However, there were no significant correlations between bone biomarkers and BMD or severe vascular calcification. CONCLUSION: Although iPTH levels were close to the target of Kidney Disease Outcomes Quality Initiative guideline, abnormal bone histomorphometry, BMD, and severe vascular calcification are still common. Bone biopsy is still crucially required as an accurate diagnostic tool in providing optimal guide for the treatment. © 2019 Asian Pacific Society of Nephrology.

Evaluation of prevalence, biochemical profile, and drugs associated with chronic kidney disease-mineral and bone disorder in 11 dialysis centers / Avaliação da prevalência, perfil bioquímico e drogas associadas ao distúrbio mineral ósseo-doença renal crônica em 11 centros de diálise

ABSTRACT Introduction: The diagnosis and treatment of mineral and bone disorder of chronic kidney disease (CKD-MBD) is a challenge for nephrologists and health managers. The aim of this study was to evaluate the prevalence, biochemical profile, and drugs associated with CKD-MBD. Methods: Cross-sectional study between July and November 2013, with 1134 patients on dialysis. Sociodemographic, clinical, and laboratory data were compared between groups based on levels of intact parathyroid hormone (iPTH) (< 150, 150-300, 301-600, 601-1000, and > 1001 pg/mL). Results: The mean age was 57.3 ± 14.4 years. The prevalence of iPTH < 150 pg/mL was 23.4% and iPTH > 601 pg/mL was 27.1%. The comparison between the groups showed that the level of iPTH decreased with increasing age. Diabetic patients had a higher prevalence of iPTH < 150 pg/mL (27.6%). Hyperphosphatemia (> 5.5 mg/dL) was observed in 35.8%. Calcium carbonate was used by 50.5%, sevelamer by 14.7%, 40% of patients had used some form of vitamin D and 3.5% used cinacalcet. Linear regression analysis showed a significant negative association between iPTH, age, and diabetes mellitus and a significant positive association between iPTH and dialysis time. Conclusion: The prevalence of patients outside the target for iPTH was 50.5%. There was a high prevalence of hyperphosphatemia (35.8%), and the minority of patients were using active vitamin D, vitamin D analogs, selective vitamin D receptor activators, and cinacalcet. These data indicate the need for better compliance with clinical guidelines and public policies on the supply of drugs associated with CKD-MBD.

RESUMO Introdução: O diagnóstico e tratamento do distúrbio mineral ósseo-doença renal crônica (DMO-DRC) é um desafio para os nefrologistas e gestores de saúde. O objetivo deste estudo foi avaliar a prevalência, perfil bioquímico, e drogas associadas a DMO-DRC. Métodos: Estudo transversal entre julho e novembro de 2013, em 11 centros com 1134 pacientes em diálise. Dados sociodemográficos, clínicos, e laboratoriais foram comparados entre os grupos, com base em níveis do paratormônio intacto (PTHi) (< 150,151-300, 301-600,601-1000, e > 1001 pg/mL). Resultados: A idade média foi de 57,3 ± 14,4 anos, 1071 pacientes estavam em hemodiálise, e 63 em diálise peritoneal. A prevalência de PTHi < 150 pg/mL foi 23,4% e PTHi > 601 pg/mL foi de 27,1%. A comparação dos grupos mostrou que o nível de PTHi diminuiu com o aumento da idade. Pacientes diabéticos apresentaram uma maior prevalência de PTHi < 150 pg/mL (27,6%). Carbonato de cálcio foi usado por 50,5%, Sevelamer por 14,7%, 40% dos pacientes utilizaram alguma forma de vitamina D, e 3,5% utilizaram cinacalcet. A hiperfosfatemia (> 5,5mg/dL) foi observada em 35,8%. A análise de regressão linear mostrou uma associação negativa significativa entre PTHi, idade, e diabetes mellitus e uma associação positiva significativa com o tempo em diálise. Conclusão: A prevalência de pacientes fora do alvo para PTHi foi de 50,5%. Houve uma alta prevalência de hiperfosfatemia e um baixo uso de vitamina D ativa, análogos da vitamina D, ativadores seletivos da vitamina D, e cinacalcet. Estes dados chamam a atenção para a necessidade de uma maior conformidade com as diretrizes e políticas públicas sobre o fornecimento de medicamentos associados à DMO-DRC.

Vitamin D and renal outcome: the fourth outcome of CKD-MBD? Oshima Award Address 2015.

Bone fracture, cardiovascular events, and mortality are three outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD), and the umbrella concept originally described for dialysis patients. The reported association of serum phosphorus or fibroblast growth factor 23 (FGF23) levels with renal outcome suggests that the fourth relevant outcome of CKD-MBD in predialysis patients is renal outcome. We found that proteinuria of 2+ or greater with a dipstick test was associated with low vitamin D status due to urinary loss of 25-hydroxyvitamin D (25D). Moreover, active vitamin D or its analogues decrease proteinuria. Given our finding that maxacalcitol does not repress renin, the reduction of proteinuria by this agent is likely due to direct upregulation of the nephrin and podocin in podocytes. Moreover, this agent downregulates the mesenchymal marker desmin in podocytes and blocks transforming growth factor-beta autoinduction, leading to attenuation of renal fibrosis in a unilateral ureteral obstructive (UUO) model. These facts are reminiscent of the suppression of epithelial-mesenchymal transition (EMT) by vitamin D. EMT blockage may explain our finding that vitamin D prescription in renal transplant recipients is associated with a lower incidence of cancer. We also reported that low vitamin D status and high FGF23 levels predict a worse renal outcome. However, administration of massive doses of 25D exacerbates renal fibrosis in UUO kidneys in 1alpha-hydroxylase knockout mice. Moreover, FGF23 inhibits 1alpha-hydroxylase in proximal tubules and monocytes. Taken together, local 1,25(OH)2D in the kidney tissue but not 25D seems to protect the kidney.

Update on the role of bone biopsy in the management of patients with CKD-MBD.

Patients with chronic kidney disease (CKD) are at increased risk of fractures. The fracture risk steadily increases along with the progression of renal disease to become several-fold higher in end-stage renal disease (ESRD) patients as compared to age and sex-matched controls. Renal osteodystrophy (ROD) is a heterogeneous group of metabolic bone diseases complicating progressive chronic kidney disease. Bone biomarkers and bone imaging techniques may help to assess bone health and predict fractures in CKD, but do have important inherent limitations. The gold standard for the diagnosis and specific classification of renal osteodystrophy (ROD) remains the (quantitative) histomorphometric analysis of the bone biopsy. By informing on bone turnover and mineralization, a bone biopsy may help guide prevention and treatment of ROD and its consequences. This review aims to present an update on epidemiological and procedural aspects, clinical indications, and histomorphometric analysis of bone biopsies and to define the role of bone biopsy in current CKD-MBD care.

Study of chronic kidney disease-mineral bone disorders in newly detected advanced renal failure patients: A Hospital-based cross-sectional study.

We aim to evaluate the disturbances in mineral metabolism, abnormalities in bone mineral density (BMD), and extraskeletal calcification in newly detected, untreated predialysis stage 4 and 5 chronic kidney disease (CKD) patients at a tertiary care hospital in North India. This is cross-sectional observational study. A total of 95 (68 males, 27 females) newly detected patients underwent clinical evaluation, biochemical assessment [serum calcium, phosphorus, alkaline phosphatase (ALP), albumin, creatinine, intact parathyroid hormone (iPTH), 25- hydroxyvitamin D (25(OH)D)], BMD measurement (at spine, hip, and forearm) by dual-energy X-ray absorptiometry (DXA), lateral abdominal radiograph [for abdominal aortic calcification (AAC)], skeletal survey (to look for any abnormality including fractures), and echocardiography [for any cardiac valvular calcification (CVC)]. Symptoms related to CKD-mineral bone disorder were seen in 33.6% of the study patients. Prevalence of hypocalcemia, hyperphosphatemia, hyperparathyroidism, and hypovitaminosis D was 64.2%, 81.1%, 49.5%, and 89.5%, respectively. CVC was seen in 22.1% of patients on echocardiography, mostly involving the mitral valve. Patients with CVC were more likely to be males and smokers. There was no significant difference in iPTH levels between patients with or without CVC. AAC was seen in 10.5% of patients on lateral abdominal X-ray. Patients with AAC had higher levels of iPTH, phosphorus, and ALP and lower levels of calcium compared to patients without AAC. BMD by DXA showed a low bone mass in 41.05% of our patients and was more prevalent in CKD stage 5. Most of the study patients had hyperparathyroidism and low 25(OH)D levels. Our study shows that newly detected, naïve Indian CKD patients have a high prevalence of disturbances of mineral metabolism including hyperparathyroidism, Vitamin D deficiency, abnormal BMD, and valvular and vascular calcification, even before initiating dialysis.

Bone Quality in Chronic Kidney Disease: Definitions and Diagnostics.

PURPOSE OF REVIEW: In this paper, we review the epidemiology, diagnosis, and pathogenesis of fractures and renal osteodystrophy. RECENT FINDINGS: The role of bone quality in the pathogenesis of fracture susceptibility in chronic kidney disease (CKD) is beginning to be elucidated. Bone quality refers to bone material properties, such as cortical and trabecular microarchitecture, mineralization, turnover, microdamage, and collagen content and structure. Recent data has added to our understanding of the effects of CKD on alterations to bone quality, emerging data on the role of abnormal collagen structure on bone strength, the potential of non-invasive methods to inform our knowledge of bone quality, and how we can use these methods to inform strategies that protect against bone loss and fractures. However, more prospective data is required. CKD is associated with abnormal bone quality and strength which results in high fracture incidence.

Differentially expressed miR-3680-5p is associated with parathyroid hormone regulation in peritoneal dialysis patients.

Mineral and bone disorder (MBD) is observed universally in patients with chronic kidney disease (CKD). Detrimental MBD-related skeletal changes include increased prevalence of fracture, cardiovascular disease, and mortality. MicroRNAs (miRNAs) have been identified as useful biomarkers in various diseases, and the aim of this study was to identify miRNAs associated with parathyroid hormone level in peritoneal dialysis (PD) patients. Fifty-two PD patients were enrolled and grouped by their intact parathyroid hormone (iPTH) level; 11 patients had low iPTH (<150 pg/mL) and 41 patients had high iPTH (≥150 pg/mL). Total RNA was extracted from whole blood samples. Total RNA from 15 patients (7 and 8 patients in the low and high iPTH groups, respectively) underwent miRNA microarray analysis, and three differentially upregulated (>2-fold change) miRNAs previously associated with human disease were selected for real-time quantitative PCR (qPCR) analysis. Interaction analyses between miRNAs and genes were performed by using TargetScan and the KEGG pathway database. Microarray results revealed 165 miRNAs were differentially expressed between patients with high iPTH levels and low iPTH levels. Of those miRNAs, 81 were upregulated and 84 were downregulated in patients with high iPTH levels. Expression levels of miR-1299, miR-3680-5p, and miR-548b-5p (previously associated with human disease) in 52 patients were analyzed by using qPCR. MiR-3680-5p was differentially expressed in low and high iPTH patients (P < 0.05). The predicted target genes of miR-3680-5p were USP6, USP32, USP46, and DLT, which are involved in the ubiquitin proteolysis pathway. This pathway has roles in PTH and parathyroid hormone related protein degradation and proteolysis. The mechanisms involved in the associations among low PTH, adynamic bone disease, miR-3680-5p, and the target genes should be explored further in order to elucidate their roles in CKD-MBD development.

Important abnormalities of bone mineral metabolism are present in patients with coronary artery disease with a mild decrease of the estimated glomerular filtration rate.

Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is characterized by increased circulating levels of parathormone (PTH) and fibroblast growth factor 23 (FGF23), bone disease, and vascular calcification, and is associated with adverse outcomes. We studied the prevalence of mineral metabolism disorders, and the potential relationship between decreased estimated glomerular filtration rate (eGFR) and CKD-MBD in coronary artery disease patients in a cross-sectional study of 704 outpatients 7.5 ± 3.0 months after an acute coronary syndrome. The mean eGFR (CKD Epidemiology Collaboration formula) was 75.8 ± 19.1 ml/min/1.73 m(2). Our patients showed lower calcidiol plasma levels than a healthy cohort from the same geographical area. In the case of men, this finding was present despite similar creatinine levels in both groups and older age of the healthy subjects. Most patients (75.6 %) had an eGFR below 90 ml/min/1.73 m(2) (eGFR categories G2-G5), with 55.3 % of patients exhibiting values of 60-89 ml/min/1.73 m(2) (G2). PTH (r = -0.3329, p < 0.0001) and FGF23 (r = -0.3641, p < 0.0001) levels inversely correlated with eGFR, whereas calcidiol levels and serum phosphate levels did not. Overall, PTH levels were above normal in 34.9 % of patients. This proportion increased from 19.4 % in G1 category patients, to 33.7 % in G2 category patients and 56.6 % in G3-G5 category patients (p < 0.001). In multivariate analysis, eGFR and calcidiol levels were the main independent determinants of serum PTH. The mean FGF23 levels were 69.9 (54.6-96.2) relative units (RU)/ml, and 33.2 % of patients had FGF23 levels above 85.5 RU/ml (18.4 % in G1 category patients, 30.0 % in G2 category patients, and 59.2 % in G3-G5 category patients; p < 0.001). In multivariate analysis, eGFR was the main predictor of FGF23 levels. Increased phosphate levels were present in 0.7 % of the whole sample: 0 % in G1 category patients, 0.3 % in G2 category patients, and 2.8 % in G3-G5 category patients (p = 0.011). Almost 90 % of patients had calcidiol insufficiency without significant differences among the different degrees of eGFR. In conclusion, in patients with coronary artery disease there is a large prevalence of increased FGF23 and PTH levels. These findings have an independent relationship with decreased eGFR, and are evident at an eGFR of 60-89 ml/min/1.73 m(2). Then, mild decreases in eGFR must be taken in consideration by the clinician because they are associated with progressive abnormalities of mineral metabolism.

Chronic kidney disease-mineral and bone disorder (CKD-MBD): a new term for a complex approach.

The global widespread of the chronic kidney disease (CKD) is a worldwide health problem. Its increasing incidence and prevalence and adverse outcomes (including decreased quality of life, increased morbidity and mortality) represents a huge challenge for all recent health are systems. Reflecting this situation, the new, global initiative (KDIGO) was established to enhance communication and clinical decision-making, promote the use of evidence based medicine and facilitate clinical research. The new definition, evaluation and classification of "renal osteodystrophy"; has been one of the first outcome of this initiative, suggesting the topic of chronic kidney disease--mineral and bone disorder (CKD-MBD) to be a hot problem of recent nephrology. The new terminology is consistent with a recent view on this topic and describes CKD-MBD as a complex syndrome, including abnormal mineral and PTH metabolism, altered bone structure as far as extra-skeletal calcifications.

Renal osteodystrophy after successful renal transplantation: a histomorphometric analysis in 57 patients.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. It corrects most of the metabolic abnormalities that cause renal osteodystrophy. Nevertheless, renal osteodystrophy persists in many transplant recipients. The aim of this study was to investigate frequency and histomorphometric pattern of bone disease after renal transplantation. Bone biopsy specimens were taken from the iliac crest of 57 patients, including 28 women (26-70 years old) and 29 men (27-67 years old). Indications for biopsy were hypercalcemia, elevation of parathyroid hormone, and, in 19 cases, without suspected bone abnormalities based on laboratory parameters. The mean time of dialysis prior to renal transplantation was 43 months (range, 6-91 months in women and 10-111 months in men) and the mean interval between transplantation and bone biopsy was 53.5 months (range, 4-191 months in women and 5-90 months in men). Fourteen patients were treated with either 25-hydroxyvitamin D3 and/or 1-alpha hydroxyvitamin D3 or 1,25 dihydroxyvitamin D3, 3 with phosphate-binding agents. The immunosuppression consisted of cyclosporine, azathioprine, and prednisolone. The cumulative dosage of corticosteroids was 5569+/-5305 mg. For static and dynamic histomorphometry, we used American Society of Bone and Mineral Research nomenclature. Mild osteitis fibrosa and osteitis fibrosa, the most frequent forms of renal osteodystrophy, were observed in 13. (22.8%) and 14 patients (24.6%), respectively. Mixed uremic osteodystrophy was found in 7 patients (12.3%), adynamic renal bone disease in 3 patients (5.3%), and osteomalacia in 2 patients (3.5%). In 13 patients (22.8%), reduced bone mass and structural damage without typical signs of renal osteodystrophy, such as endosteal fibrosis or osteoclasia, were detected, and 5 patients (8.7%) showed normal histomorphometric parameters. We concluded that renal osteodystrophy, especially forms with high bone turnover, persisted in many patients after successful renal transplantation. This finding may be due to preexisting conditions, such as duration of dialysis and degree of hyperparathyroidism. Bone disease is increased by corticosteroid and immunosuppressive therapy after renal transplantation and requires close monitoring.

Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation.

Hypercalcemia in persistent secondary hyperparathyroidism after kidney transplantation is considered to result from increased bone resorption. Bone biopsies' studies, however, have never been performed in these patients. Bone biopsies after double tetracycline labeling were obtained from 17 patients with hypercalcemic hyperparathyroidism and an estimated glomerular filtration rate > 30 mL/min/1.73 m2. Serologic bone markers, calcitriol, intact fibroblast growth factor-23 (iFGF-23), and serum and 24h urine concentration of calcium and phosphate were measured in all patients. Tubular maximum for phosphate corrected for GFR (TmP/GFR), and the fractional excretion of calcium (FeCa) were calculated. High-turnover renal osteodystrophy (ROD) was present in nine and low-turnover ROD in eight patients. The bone formation rate was significantly associated with bone alkaline phosphatase, c-telopeptide and osteocalcin. In patients with high turnover ROD, osteocalcin was also significantly higher than in patients with decreased bone formation. The FeCa was normal or below normal in 14/17 patients. TmP/GFR was below normal in all patients. Neither intact PTH nor iFGF-23 was associated with TmP/GFR, FeCa or any histomorphometric bone parameter. We conclude that hypercalcemia of posttransplant hyperparathyroidism can be associated with high or low turnover bone disease. Decreased calcium excretion suggests an additive tubular effect on hypercalcemia.

The prevalence of radiological markers of renal osteodystrophy in patients with chronic renal failure in Enugu.

OBJECTIVES: To study the prevalence of renal osteodystrophy in Chronic renal failure patients in Enugu, using radiological methods. SUBJECTS AND METHODS: Ninety adult patients (56 male and 34 female) were recruited from the renal clinics of the University of Nigeria Teaching Hospital, Enugu over a period of twelve consecutive months. A structured questionnaire was administered and a physical examination carried out at the initial interview. This was followed by other investigations including renal ultrasonography, plain radiographs and laboratory investigations including serum electrolytes, urea and creatinine, calcium and phosphate, total alkaline phosphate and creatinine clearance estimation. RESULTS: There was no obvious relationship between bone pain (a symptom of renal osteodystrophy) and the presence ofradiological features of renal osteodystrophy. The findings of the study showed that renal osteodystrophy, demonstrable by radiography is relatively uncommon, existing in only 3 subjects (3.35%). Among the 3 subjects, 2 showed radiological features of osteitis fibrosa cystica (one male and one female), while the other subject (one female) had radiological features of osteoporosis. All these subjects belonged to group 3 and had been on maintainance haemodialysis for more than 6 months. Other forms of renal osteodystrophy were not demonstrated. CONCLUSION: Renal osteodystrophy is probably not as common in Nigerian patients as in Caucasians and there may be reasons for this.

New worldwide trends in presentation of renal osteodystrophy and its relationship to parathyroid hormone levels.

AIMS: Abnormal mineral metabolism in chronic renal disease is associated with bone disease and extraskeletal calcifications. High turnover, hyperparathyroid bone disease, the most common form of renal osteodystrophy, has been the target for aggressive therapy. More recently, an increasing occurrence of low turnover bone disease has been reported. The present study was undertaken to evaluate the current prevalence of different forms of bone disease in a large population on chronic hemodialysis and its relationship to parathyroid hormone (PTH) levels. METHODS: Ninety-six chronic hemodialysis patients underwent double tetracycline-labeled bone biopsy. Serum PTH levels were obtained in 52 patients at the time of biopsy. Bone formation rate (BFR/BS) was plotted vs. PTH levels in all patients and in subgroups with PTH ranges between 0-150, 150-500 and 500 - 1,200 pg/ml. RESULTS: The histomorphometric data showed that 40% of all patients were affected by osteitis fibrosa cystica (OFC). In the remaining 60%, various forms of low-turnover bone disease were observed. There was no correlation between PTH and BFR/BS in all patients (r = 0.28) and in subgroups whose PTH levels ranged between 150 - 500 and 500 - 1,200 pg/ml (r = 0.027, r = 0.21), respectively. A close correlation between PTH and BFR/BS (r = 0.84, p < 0.05) was found only in the subgroup with a PTH level ranging low-turnover bone disease. The predictive between 0 - 150 pg/ml. CONCLUSIONS: The histomorphometric findings present a wide spectrum of renal osteodystrophy with a shift towardsvalue of PTH is limited as high-turnover osteodystrophy may present with low PTH levels and that with low turnover may occur with high PTH levels. In the latter parathyroidectomy should be avoided. We share the view that bone biopsy remains the "gold standard" diagnostic tool for renal osteodystrophy.