Bone and mineral disorders occur frequently in kidney transplant recipients and are associated with a high risk of fracture, morbidity, and mortality. There is a broad spectrum of often overlapping bone diseases seen after transplantation, including osteoporosis as well as persisting high-or low-turnover bone disease. The pathophysiology underlying bone disorders after transplantation results from a complex interplay of factors, including preexisting renal osteodystrophy and bone loss related to a variety of causes, such as immunosuppression and alterations in the parathyroid hormone-vitamin D-fibroblast growth factor 23 axis as well as changes in mineral metabolism. Management is complex, because noninvasive tools, such as imaging and bone biomarkers, do not have sufficient sensitivity and specificity to detect these abnormalities in bone structure and function, whereas bone biopsy is not a widely available diagnostic tool. In this review, we focus on recent data that highlight improvements in our understanding of the prevalence, pathophysiology, and diagnostic and therapeutic strategies of mineral and bone disorders in kidney transplant recipients.

Renal osteodystrophy is common in advanced CKD, but characterization of bone turnover status can only be achieved by histomorphometric analysis of bone biopsy specimens (gold standard test). We tested whether bone biomarkers and high-resolution peripheral computed tomography (HR-pQCT) parameters can predict bone turnover status determined by histomorphometry. We obtained fasting blood samples from 69 patients with CKD stages 4-5, including patients on dialysis, and 68 controls for biomarker analysis (intact parathyroid hormone [iPTH], procollagen type 1 N-terminal propeptide [PINP], bone alkaline phosphatase [bALP], collagen type 1 crosslinked C-telopeptide [CTX], and tartrate-resistant acid phosphatase 5b [TRAP5b]) and scanned the distal radius and tibia of participants by HR-pQCT. We used histomorphometry to evaluate bone biopsy specimens from 43 patients with CKD. Levels of all biomarkers tested were significantly higher in CKD samples than control samples. For discriminating low bone turnover, bALP, intact PINP, and TRAP5b had an areas under the receiver operating characteristic curve (AUCs) of 0.82, 0.79, and 0.80, respectively, each significantly better than the iPTH AUC of 0.61. Furthermore, radius HR-pQCT total volumetric bone mineral density and cortical bone volume had AUCs of 0.81 and 0.80, respectively. For discriminating high bone turnover, iPTH had an AUC of 0.76, similar to that of all other biomarkers tested. The biomarkers bALP, intact PINP, and TRAP5b and radius HR-pQCT parameters can discriminate low from nonlow bone turnover. Despite poor diagnostic accuracy for low bone turnover, iPTH can discriminate high bone turnover with accuracy similar to that of the other biomarkers, including CTX.

Renal osteodystrophy (ROD) is a heterogeneous group of metabolic bone diseases complicating progressive chronic kidney disease (CKD). Bone biomarkers and bone imaging techniques may help to assess bone health and predict fractures in CKD but do have important inherent limitations. By informing on bone turnover and mineralization, a bone biopsy may help to guide prevention and treatment of ROD and its consequences. According to a recent survey conducted among European nephrologists, bone biopsies are performed rather exceptionally, both for clinical and research purposes. Obviously, clinical research in the field of ROD is threatened by vanishing clinical and pathological expertise, small patient cohorts and scientific isolation. In March 2016, the European Renal Osteodystrophy (EU-ROD) initiative was created under the umbrella of the ERA-EDTA CKD-mineral and bone disorder (MBD) Working Group to revitalize bone biopsy as a clinically useful tool in the diagnostic workup of CKD-MBD and to foster research on the epidemiology, implications and reversibility of ROD. As such, the EU-ROD initiative aims to increase the understanding of ROD and ultimately to improve outcomes in CKD patients.

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BackgroundVascular calcification (VC) and renal osteodystrophy are important complications of advanced chronic kidney disease (CKD). High resolution peripheral quantitative computed tomography (HRpQCT) is able to assess bone microstructure in renal osteodystrophy and lower leg arterial calcification (LLAC) is usually seen as an incidental finding. LLAC can be a useful quantitative assessment of VC in CKD but the relationship between LLAC and vascular biomarkers and bone is unknown. We aimed to assess the relationship between LLAC and biomarkers, bone turnover and microstructure. MethodsIn this cross-sectional study, fasting blood samples were taken from 69 CKD stages 4-5D patients and 68 healthy controls. HRpQCT of distal tibia and radius were performed. 43 CKD patients had trans-iliac bone biopsy after tetracycline labelling. ResultsLLAC was more severe in CKD than controls (median [

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide; and commonly used resorption markers serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen and tartrate resistant acid phosphatase type 5b. BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable components (e.g., age, gender, ethnicity) and controllable components, particularly relating to collection conditions (e.g., fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics; and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget’s disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.

BACKGROUND: Hyperphosphatemia is a risk factor for vascular calcifications (VCs) and VCs belong to mineral bone disorders (MBD) in chronic kidney disease (CKD) patients. Vitamin Kdependent proteins such as Matrix Gla Protein (MGP) and Bone Gla Proteins (BGP or osteocalcin) can inhibit VCs and regulate bone mineralization. OBJECTIVE: To evaluate whether the phosphate binder, sevelamer, could influence vitamin K levels in hemodialysis (HD) patients. METHODS: In a secondary analysis of the VItamin K Italian (VIKI) study, we evaluated the relationship between vitamin K status, VFs and VCs in 387 HD patients with/without sevelamer. Levels of serum vitamin 25(OH)D, alkaline phosphatase (ALP), vitamin k vitamers: K1 and K2 or menaquinone (MK, including: MK4, MK5, MK6 and MK7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. RESULTS: No significant differences were observed between sevelamer-treated and untreated patients for main clinical characteristics. Lower MK4 levels (0.45 vs. 0.6 ng/mL, p=0.01) and a higher MK4 deficiency was observed in sevelamer-treated patients (13.5% vs. 5.4%, p=0.005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (Odds Ratio; OR: 2.64, 95% CI: 1.25-5.58, p=0.011) and aortic calcification (OR: 8.04, 95% CI: 1.07-60.26, p=0.04). In the same multivariate logistic regression model, sevelamer significantly amplified the effect of total BGP levels on the odds of fractures so that in sevelamer-treated patients, the OR of VFs was about 3 times higher in patients with total BGP <150 µg/L compared to those with total BGP ≥150 µg/L (OR: 3.15, 95% CI: 1.46-6.76, p=0.003), whereas no such effect was found in those untreated (total BGP <150 µg/L vs. total BGP ≥150 µg/L: OR: 1.21, 95% CI: 0.66-2.23, p=0.54] (p=0.049 for effect modification by sevelamer). CONCLUSION: These data suggest that sevelamer could interfere with MK4 levels in HD patients and its use in patients with low BGP levels (<150 µg/L) could increase bone fragility in CKD patients.

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