Machine learning based biomarker discovery for chronic kidney disease-mineral and bone disorder (CKD-MBD).

INTRODUCTION: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and some other complications. Although there are diagnostic criteria for CKD-MBD, in situations when conducting target feature examining are unavailable, there is a need to investigate and discover alternative biochemical criteria that are easy to obtain. Moreover, studying the correlations between the newly discovered biomarkers and the existing ones may provide insights into the underlying molecular mechanisms of CKD-MBD. METHODS: We collected a cohort of 116 individuals, consisting of three subtypes of CKD-MBD: calcium abnormality, phosphorus abnormality, and PTH abnormality. To identify the best biomarker panel for discrimination, we conducted six machine learning prediction methods and employed a sequential forward feature selection approach for each subtype. Additionally, we collected a separate prospective cohort of 114 samples to validate the discriminative power of the trained prediction models. RESULTS: Using machine learning under cross validation setting, the feature selection method selected a concise biomarker panel for each CKD-MBD subtype as well as for the general one. Using the consensus of these features, best area under ROC curve reached up to 0.95 for the training dataset and 0.74 for the perspective dataset, respectively. DISCUSSION/CONCLUSION: For the first time, we utilized machine learning methods to analyze biochemical criteria associated with CKD-MBD. Our aim was to identify alternative biomarkers that could serve not only as early detection indicators for CKD-MBD, but also as potential candidates for studying the underlying molecular mechanisms of the condition.

Post-Transplant Bone Disease in Kidney Transplant Recipients: Diagnosis and Management.

Kidney transplantation is the preferred gold standard modality of treatment for kidney failure. Bone disease after kidney transplantation is highly prevalent in patients living with a kidney transplant and is associated with high rates of hip fractures. Fractures are associated with increased healthcare costs, morbidity and mortality. Post-transplant bone disease (PTBD) includes renal osteodystrophy, osteoporosis, osteonecrosis and bone fractures. PTBD is complex as it encompasses pre-existing chronic kidney disease-mineral bone disease and compounding factors after transplantation, including the use of immunosuppression and the development of de novo bone disease. After transplantation, the persistence of secondary and tertiary hyperparathyroidism, renal osteodystrophy, relative vitamin D deficiency and high levels of fibroblast growth factor-23 contribute to post-transplant bone disease. Risk assessment includes identifying both general risk factors and kidney-specific risk factors. Diagnosis is complex as the gold standard bone biopsy with double-tetracycline labelling to diagnose the PTBD subtype is not always readily available. Therefore, alternative diagnostic tools may be used to aid its diagnosis. Both non-pharmacological and pharmacological therapy can be employed to treat PTBD. In this review, we will discuss pathophysiology, risk assessment, diagnosis and management strategies to manage PTBD after kidney transplantation.

Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, ßKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.

Chronic kidney disease mineral and bone disorder: A guide for general practice.

BACKGROUND: Chronic kidney disease mineral and bone disorder (CKD-MBD) is an important cause of morbidity, cardiovascular risk and mortality among patients with chronic kidney disease (CKD). The condition begins to manifest in stage 3a CKD. General practitioners play a crucial part in screening, monitoring and early management of this important problem, which is primarily managed in the community. OBJECTIVE: The aim of this article is to summarise the key evidence-based principles of the pathogenesis, assessment and management of CKD-MBD. DISCUSSION: CKD-MBD includes a spectrum of disease involving biochemical changes, bone abnormalities and vascular and soft tissue calcification. Management is centred on monitoring and controlling biochemical parameters with a variety of strategies to improve bone health and cardiovascular risk. The range of evidence-based treatment options is reviewed in this article.

Diagnosis and management of mineral and bone disorders in infants with CKD: clinical practice points from the ESPN CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce.

BACKGROUND: Infants with chronic kidney disease (CKD) form a vulnerable population who are highly prone to mineral and bone disorders (MBD) including biochemical abnormalities, growth retardation, bone deformities, and fractures. We present a position paper on the diagnosis and management of CKD-MBD in infants based on available evidence and the opinion of experts from the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce. METHODS: PICO (Patient, Intervention, Comparator, Outcomes) questions were generated, and relevant literature searches performed covering a population of infants below 2 years of age with CKD stages 2-5 or on dialysis. Clinical practice points (CPPs) were developed and leveled using the American Academy of Pediatrics grading matrix. A Delphi consensus approach was followed. RESULTS: We present 34 CPPs for diagnosis and management of CKD-MBD in infants, including dietary control of calcium and phosphate, and medications to prevent and treat CKD-MBD (native and active vitamin D, calcium supplementation, phosphate binders). CONCLUSION: As there are few high-quality studies in this field, the strength of most statements is weak to moderate, and may need to be adapted to individual patient needs by the treating physician. Research recommendations to study key outcome measures in this unique population are suggested. A higher resolution version of the Graphical abstract is available as Supplementary information.

Current Status of Mineral and Bone Disorders in Transplant Recipients.

Most patients with end-stage kidney disease undergoing kidney transplantation are affected by the chronic kidney disease-mineral and bone disorder. This entity encompasses laboratory abnormalities, calcification of soft tissues, and the bone abnormalities of renal osteodystrophy that together result in an increased risk of fracture, cardiovascular events, and mortality. Although many biochemical disturbances associated with end-stage kidney disease improve in the first year after transplantation, hyperparathyroidism commonly persists, and residual changes of renal osteodystrophy are slow to resolve. When superimposed on common, traditional risk factors, post-transplant glucocorticoid treatment, the possibility of tubular disturbances and post-transplant chronic kidney disease, rates of incident fracture remain high. This review examines hormonal and biochemical changes before and after kidney transplantation, fracture risk assessment tools and imaging modalities, a staged approach to management and concerns associated with antiresorptive and anabolic therapies. A multidisciplinary approach is proposed as the best means to improve patient-level outcomes.

CKD-MBD biomarkers and CKD progression: an analysis by the joint model.

BACKGROUND: Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested. METHODS: We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction >30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up. RESULTS: In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P < .001)] and this was also true for repeated measurements of serum phosphate [HR (1 mg/dl) 1.3924 (range 1.1459-1.6918), P = .001], serum calcium [HR (1 mg/dl) 0.7487 (range 0.5843-0.9593), P = .022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P = .045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P = .006]. CONCLUSION: Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.

[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).

Manifestaciones craneofaciales en pacientes con osteodistrofia renal / Craneofacial manifestaciones in patients with renal osteodystrophy

Introducción: La osteodistrofia renal es una osteopatía metabólica difusa, relacionada con la insuficiencia renal crónica, que incluye diversas patologías en el sistema musculoesquelético. Se produce en respuesta a trastornos metabólicos generados por cambios electrolíticos, la inflamación crónica y la alteración hormonal. Estas variaciones modifican el proceso de remodelación ósea. Las manifestaciones clínicas incluyen alteración en el parénquima y estroma óseo, y van desde lesiones expansivas, produciendo deformidad, hasta fracturas patológicas del hueso. Objetivo: Relacionar las manifestaciones clínicas, imagenológicas e histológicas en el componente óseo cráneo facial para el diagnóstico de la osteodistrofia renal. Presentación de caso: Se presentan dos casos clínicos de pacientes con enfermedad renal crónica e hiperparatiroidismo secundario de base, con múltiples masas en maxilares que causan asimetría facial y alteración funcional. Las imágenes tomográficas revelan alteración en la morfología ósea cortical y trabecular. Ambos individuos evidenciaron alteraciones en niveles de hormona paratiroidea, fosfatasa alcalina, fósforo y calcio sérico. La histopatología comprobó tejido fibroóseo con hueso neoformado y gran vascularización, con células multinucleadas tipo osteoclastos sin presencia de hemosiderina. Pacientes manejados de forma interdisciplinaria entre medicina interna, endocrinología y cirugía maxilofacial. Conclusiones: Los pacientes con enfermedad renal crónica avanzada presentan alteración de la estructura y del metabolismo óseo y mineral. Tal situación puede comprometer el complejo óseo craneofacial. Los casos graves de osteodistrofia renal se caracterizan por una marcada expansión de los maxilares, que genera asimetría y rasgos de leontiasis. Las imágenes tomográficas asociadas a osteodistrofia renal presentan óseos trabeculares con expansión de cortical, que evidencia el recambio óseo inmaduro presente. La histopatología no es específica y puede ser similar a los casos de displasia ósea craneofacial. Ante lo anteriormente planteado es fundamental relacionar estos hallazgos con la clínica para definir un diagnóstico adecuado(AU)

(AU)Introduction: Renal osteodystrophy is a diffuse metabolic osteopathy, related to chronic renal failure, which includes various pathologies in the musculoskeletal system. It occurs in response to metabolic disorders generated by electrolyte changes, chronic inflammation and hormonal alteration. These variations modify the process of bone remodeling. Clinical manifestations include alteration in the parenchyma and bone stroma, and range from expansive lesions, producing deformity, to pathological fractures of the bone. Objective: Relate the clinical, imaging and histological manifestations in the skull-facial bone component for the diagnosis of renal osteodystrophy. Case Presentation: Two clinical cases of patients with chronic kidney disease and secondary underlying hyperparathyroidism are presented, with multiple masses in the jaws that cause facial asymmetry and functional alteration. Tomographic images reveal alteration in cortical and trabecular bone morphology. Both individuals showed alterations in levels of parathyroid hormone, alkaline phosphatase, phosphorus and serum calcium. Histopathology verified fibro-bone tissue with neoformed bone and great vascularization, with multinucleated osteoclast-like cells without the presence of hemosiderin. Patients were attended in an interdisciplinary way between internal medicine, endocrinology and maxillofacial surgery. Conclusions: Patients with advanced chronic kidney disease present alteration of the structure and bone and mineral metabolism. Such a situation can compromise the craniofacial bone complex. Severe cases of renal osteodystrophy are characterized by a marked expansion of the jaws, which generates asymmetry and traits of leonthiasis. The tomographic images associated with renal osteodystrophy present trabecular bones with cortical expansion, which evidences the immature bone turnover present. Histopathology is not specific and may be similar to cases of craniofacial bone dysplasia. Given the above, it is essential to relate these findings to the clinic to define an adequate diagnosis(AU)

An optimized machine learning framework for predicting intradialytic hypotension using indexes of chronic kidney disease-mineral and bone disorders.

Intradialytic hypotension (IDH) is the most common acute complication in hemodialysis (HD) sessions and is associated with increased morbidity and mortality in HD patients. To prevent the episode of IDH, it is critical to predict its occurrence. Chronic kidney disease-mineral and bone disorders (CKD-MBD) induce cardiac and vascular calcification, which impairs the compensatory mechanisms of blood pressure during HD. In this study, we proposed a feature selection framework called BSWEGWO_KELM to analyze 1940 records from 178 HD patients, which was based on an enhanced grey wolf optimization (GWO) algorithm and the kernel extreme learning machine (KELM). Then, global optimization experiments, together with feature selection experiments on public data sets and HD dataset, were performed to verify the effectiveness of the BSWEGWO_KELM method. The experimental results showed that the established BSWEGWO_KELM had the capability of screening out the key indicators such as dialysis vintage, mean arterial pressure (MAP), alkaline phosphatase (ALP), and intact parathyroid hormone (iPTH). Consequently, BSWEGWO_KELM can be applied as a practical and accurate method to predict IDH.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

Chronic Kidney Disease-Mineral Bone Disease Biomarkers in Kidney Transplant Patients.

BACKGROUND: Kidney transplant patients frequently suffer from Chronic Kidney Disease associated with Mineral Bone Disease (CKD-MBD), a complex condition that affects mainly kidney transplant patients. Post-transplantation bone disease is complex, especially in patients with pre-existing metabolic bone disorders that are further affected by immunosuppressive medications and changes in renal allograft function. Main biochemical abnormalities of mineral metabolism in kidney transplantation (KTx) include hypophosphatemia, hyperparathyroidism (HPTH), insufficiency or deficiency of vitamin D, and hypercalcemia. OBJECTIVE: This review aims to summarize the pathophysiology and main biomarkers of CKD-MBD in KTx. METHODS: A comprehensive and non-systematic search in PubMed was independently made, emphasizing biomarkers in mineral bone disease in KTx. RESULTS: CKD-MBD can be associated with numerous factors, including secondary HPTH, metabolic dysregulations before KTx, and glucocorticoid therapy in post-transplant subjects. Fibroblast growth factor 23 (FGF23) reaches normal levels after KTx with good allograft function, while calcium, vitamin D, and phosphorus, ultimately result in hypercalcemia, persistent vitamin D insufficiency, and hypophosphatemia, respectively. As for PTH levels, there is an initial tendency of a significant decrease, followed by a rise due to secondary or tertiary HPTH. In regard to sclerostin levels, there is no consensus in the literature. CONCLUSION: KTx patients should be continuously evaluated for mineral homeostasis and bone status, both in cases with successful kidney transplantation and those with reduced functionality. Additional research on CKD-MBD pathophysiology, diagnosis, and management is essential to guarantee long-term graft function, better prognosis, good quality of life, and reduced mortality for KTx patients.

[Chronic kidney disease - Mineral bone disorders: Physiopathology and guidelines]. / Troubles minéraux et osseux dans la maladie rénale chronique : physiopathologie, conséquences et prise en charge.

Chronic Kidney Disease (CKD) is associated with a strong impact on phosphocalcic homeostasis, due to the chronic reduction in glomerular filtration rate (GFR) (phosphate excretion decrease), the inhibition of calcitriol synthesis and dietary restrictions. CKD-Mineral and Bone Disorders (CKD-MBD) must be monitored in CKD patients with biological work-up associated with bone markers and bone density dual X-ray absorptiometry. Adapted diet (phosphate restriction, normalization of calcium intake) and medications (vitamin D, phosphate binders, calcimimetics) help to correct CKD-MBD. Serum parathormone must be kept between 2 to 9 times the usual values, to limit renal osteodystrophy and avoid tertiary hyperparathyroidism. CKD patients are also at risk of artery calcifications, which can significantly increase the morbidity and mortality of the affection. Bisphosphonates may be used after correction of biological abnormalities, in patients with estimated GFR above 30ml/min/1,73m2. Even if transplantation aims to normalize kidney function, kidney transplant recipients remain at risk of CKD-MBD. Biology and bone density dual X-ray absorptiometry must be regularly assessed, especially in the few months following the transplantation. More studies are needed to know if treatments of CKD-MBD are well tolerated in severe CKD and if they are associated with a decrease of bone fracture and vascular calcifications.

Manifestations of hyperparathyroidism in the jaws: Concepts, mechanisms, and clinical aspects.

Hyperparathyroidism is one of the most common endocrine disorders worldwide. In countries where routine biochemical screening is not common, symptomatic hyperparathyroidism predominates. Its manifestations include skeletal alterations, calcification of soft tissues, kidney stones, and functional alterations in other systems. Notably, jaw alterations can be the first clinical sign of hyperparathyroidism, including brown tumor, renal osteodystrophy, osteitis fibrosa, and leontiasis ossea, and knowing such conditions is of core importance for the multidisciplinary diagnosis and management of hyperparathyroidism. We aimed to perform a concise review, systematizing the concepts and mechanisms underlying hyperparathyroidism and associated gnathic alterations. In addition, a detailed description of the clinical aspects of the jaw manifestations is presented.

Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy.

RATIONALE & OBJECTIVE: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies. TESTS COMPARED: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b). OUTCOME: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99). RESULTS: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis. LIMITATIONS: The single-center approach and heterogeneity of the study cohort are main limitations of this study. CONCLUSIONS: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease.

Clinical Prediction of High-Turnover Bone Disease After Kidney Transplantation.

Bone histomorphometric analysis is the most accurate method for the evaluation of bone turnover, but non-invasive tools are also required. We studied whether bone biomarkers can predict high bone turnover determined by bone histomorphometry after kidney transplantation. We retrospectively evaluated the results of bone biopsy specimens obtained from kidney transplant recipients due to the clinical suspicion of high bone turnover between 2000 and 2015. Bone biomarkers were acquired concurrently. Of 813 kidney transplant recipients, 154 (19%) biopsies were taken at a median of 28 (interquartile range, 18-70) months after engraftment. Of 114 patients included in the statistical analysis, 80 (70%) presented with high bone turnover. Normal or low bone turnover was detected in 34 patients (30%). For discriminating high bone turnover from non-high, alkaline phosphatase, parathyroid hormone, and ionized calcium had the areas under the receiver operating characteristic curve (AUCs) of 0.704, 0.661, and 0.619, respectively. The combination of these markers performed better with an AUC of 0.775. The positive predictive value for high turnover at a predicted probability cutoff of 90% was 95% while the negative predictive value was 35%. This study concurs with previous observations that hyperparathyroidism with or without hypercalcemia does not necessarily imply high bone turnover in kidney transplant recipients. The prediction of high bone turnover can be improved by considering alkaline phosphatase levels, as presented in the logistic regression model. If bone biopsy is not readily available, this model may serve as clinically available tool in recognizing high turnover after engraftment.