Skeletal parathyroid hormone hyporesponsiveness: a neglected, but clinically relevant reality in chronic kidney disease.

PURPOSE OF REVIEW: Defining the optimal parathyroid hormone (PTH) target in chronic kidney disease (CKD) is challenging, especially for bone outcomes, due to the substantial variability in the skeleton's response to PTH. Although PTH hyporesponsiveness is as integral a component of CKD-mineral bone disorder as elevated PTH levels, clinical awareness of this condition is limited. In this review, we will discuss factors and mechanisms contributing to PTH hyporesponsiveness in CKD. This knowledge may provide clues towards a personalized approach to treating secondary hyperparathyroidism in CKD. RECENT FINDINGS: Indicates a link between disturbed phosphate metabolism and impaired skeletal calcium sensing receptor signaling as an important mediator of PTH hyporesponsiveness in CKD. Further, cohort studies with diverse populations point towards differences in mineral metabolism control, rather than genetic or environmental factors, as drivers of the variability of PTH responsiveness. IN SUMMARY: Skeletal PTH hyporesponsiveness in CKD has a multifactorial origin, shows important interindividual variability, and is challenging to estimate in clinical practice. The variability in skeletal responsiveness compromises PTH as a biomarker of bone turnover, especially when considering populations that are heterogeneous in ethnicity, demography, kidney function, primary kidney disease and mineral metabolism control, and in patients treated with bone targeting drugs.

Vitamin D Metabolites Before and After Kidney Transplantation in Patients Who Are Anephric.

RATIONALE & OBJECTIVE: Kidneys are vital for vitamin D metabolism, and disruptions in both production and catabolism occur in chronic kidney disease. Although vitamin D activation occurs in numerous tissues, the kidneys are the most relevant source of circulating active vitamin D. This study investigates extrarenal vitamin D activation and the impact of kidney transplantation on vitamin D metabolism in patients who are anephric. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Adult patients with previous bilateral nephrectomy (anephric) not receiving active vitamin D therapy evaluated at the time of (N=38) and 1 year after (n=25) kidney transplantation. ANALYTICAL APPROACH: Chromatography with tandem mass spectrometry was used to measure vitamin D metabolites. Activity of CYP24A1 [24,25(OH)2D/25(OH)D] and CYP27B1 [1α,25(OH)2D/25(OH)D] is expressed as metabolic ratios. Differences between time points were evaluated by paired t-test or Wilcoxon matched-pairs signed-rank test. RESULTS: At time of transplantation, 1α,25(OH)2D was detectable in all patients (4-36pg/mL). There was a linear relationship between 25(OH)D and 1α,25(OH)2D levels (r=0.58, P<0.001), with 25(OH)D explaining 34% of the variation in 1α,25(OH)2D levels. There were no associations between 1α,25(OH)2D and biointact parathyroid hormone (PTH) or fibroblast growth factor 23 (FGF-23). One year after transplantation, 1α,25(OH)2D levels recovered (+205%), and CYP27B1 activity increased (+352%). Measures of vitamin D catabolism, 24,25(OH)2D and CYP24A1 activity increased 3- to 5-fold. Also, at 12 months after transplantation, 1α,25(OH)2D was positively correlated with PTH (ρ=0.603, P=0.04) but not with levels of 25(OH)D or FGF-23. LIMITATIONS: Retrospective, observational study design with a small cohort size. CONCLUSIONS: Low-normal levels of 1α,25(OH)2D was demonstrated in anephric patients, indicating production outside the kidneys. This extrarenal CYP27B1 activity may be more substrate driven than hormonally regulated. Kidney transplantation seems to restore kidney CYP27B1 and CYP24A1 activity, as evaluated by vitamin D metabolic ratios, resulting in both increased vitamin D production and catabolism. These findings may have implications for vitamin D supplementation strategies in the setting of kidney failure and transplantation. PLAIN-LANGUAGE SUMMARY: Vitamin D activation occurs in multiple tissues, but the kidneys are considered the only relevant source of circulating levels. This study investigates vitamin D activation outside the kidneys by measuring vitamin D metabolites in 38 patients without kidneys. Active vitamin D was detectable in all patients, indicating production outside of the kidneys. There was a strong relationship between active and precursor vitamin D levels, but no association with mineral metabolism hormones, indicating that vitamin D production was more substrate dependent than hormonally regulated. One year after kidney transplantation, active vitamin D levels increased 2-fold and breakdown products increased 3-fold, indicating that production and degradation of the hormone recovers after kidney transplantation. These findings are relevant for future research into vitamin D supplementation in kidney failure.

Recommended calcium intake in adults and children with chronic kidney disease-a European consensus statement.

Mineral and bone disorders (MBD) are common in patients with chronic kidney disease (CKD), contributing to significant morbidity and mortality. For several decades, the first-line approach to controlling hyperparathyroidism in CKD was by exogenous calcium loading. Since the turn of the millennium, however, a growing awareness of vascular calcification risk has led to a paradigm shift in management and a move away from calcium-based phosphate binders. As a consequence, contemporary CKD patients may be at risk of a negative calcium balance, which, in turn, may compromise bone health, contributing to renal bone disease and increased fracture risk. A calcium intake below a certain threshold may be as problematic as a high intake, worsening the MBD syndrome of CKD, but is not addressed in current clinical practice guidelines. The CKD-MBD and European Renal Nutrition working groups of the European Renal Association (ERA), together with the CKD-MBD and Dialysis working groups of the European Society for Pediatric Nephrology (ESPN), developed key evidence points and clinical practice points on calcium management in children and adults with CKD across stages of disease. These were reviewed by a Delphi panel consisting of ERA and ESPN working groups members. The main clinical practice points include a suggested total calcium intake from diet and medications of 800-1000 mg/day and not exceeding 1500 mg/day to maintain a neutral calcium balance in adults with CKD. In children with CKD, total calcium intake should be kept within the age-appropriate normal range. These statements provide information and may assist in decision-making, but in the absence of high-level evidence must be carefully considered and adapted to individual patient needs.

Natural History of Bone Disease following Kidney Transplantation.

BACKGROUND: Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year. METHODS: We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism. RESULTS: Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P<0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P<0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip. CONCLUSIONS: Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950.

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.

Traditional and Non-traditional Risk Factors for Osteoporosis in CKD.

Osteoporosis is a state of bone fragility with reduced skeletal resistance to trauma, and consequently increased risk of fracture. A wide range of conditions, including traditional risk factors, lifestyle choices, diseases and their treatments may contribute to bone fragility. It is therefore not surprising that the multi-morbid patient with chronic kidney disease (CKD) is at a particularly high risk. CKD is associated with reduced bone quantity, as well as impaired bone quality. Bone fragility in CKD is a composite of primary osteoporosis, accumulation of traditional and uremia-related risk factors, assaults brought on by systemic disease, and detrimental effects of drugs. Some risk factors are modifiable and represent potential targets for intervention. This review provides an overview of the heterogeneity of bone fragility in CKD.

Patterns of renal osteodystrophy 1 year after kidney transplantation.

BACKGROUND: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation. METHODS: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously. RESULTS: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization. CONCLUSIONS: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant.

Association between circulating proprotein convertase subtilisin/kexin type 9 levels and prognosis in patients with severe chronic kidney disease.

BACKGROUND: Chronic kidney disease is a risk factor for premature development of coronary atherosclerosis and mortality. A high level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently recognized cardiovascular risk factor and has become the target of effective inhibitory treatment. In 167 kidney transplantation candidates, we aimed to: (i) compare levels of PCSK9 with those of healthy controls, (ii) examine the association between levels of PCSK9 and low-density lipoprotein cholesterol (LDL-c) and the degree of coronary artery disease (CAD) and (iii) evaluate if levels of PCSK9 predict major adverse cardiac events (MACE) and mortality. METHODS: Kidney transplant candidates (n = 167) underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) before transplantation. MACE and mortality data were extracted from the Western Denmark Heart Registry, a review of patient records and patient interviews. A group of 79 healthy subjects were used as controls. RESULTS: Mean PCSK9 levels did not differ between healthy controls and kidney transplant candidates. In patients not receiving lipid-lowering therapy, PCSK9 correlated positively with LDL-c (rho = 0.24, P < 0.05). Mean PCSK9 was similar in patients with and without obstructive CAD at both CCTA and ICA. In a multiple regression analysis, PCSK9 was associated with neither LDL-c (ß=-6.45, P = 0.44) nor coronary artery calcium score (ß=2.17, P = 0.84). During a follow-up of 3.7 years, PCSK9 levels were not associated with either MACE or mortality. CONCLUSIONS: The ability of PCSK9 levels to predict cardiovascular disease and prognosis does not seem to apply to a cohort of kidney transplant candidates.

Sclerostin is not associated with cardiovascular event or fracture in kidney transplantation candidates
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BACKGROUND: Sclerostin, a bone-derived protein, has been linked to cardiovascular calcifications in chronic kidney disease (CKD). The aim of this study was to investigate the associations between sclerostin and mineral and bone disorder in CKD, specifically whether sclerostin levels could predict cardiovascular event, fracture, or all-cause mortality. MATERIALS AND METHODS: Kidney transplantation candidates (n = 157) underwent computed tomography scans of the chest, abdomen, and pelvis. Calcification scores were calculated for coronary arteries, thoracic aorta, and the aortic and mitral valves. Volumetric bone mineral density (BMD) was measured at the spine and hip. Sclerostin and markers of bone turnover were determined from fasting blood samples. RESULTS: Compared to patients with a calcification score of 0, sclerostin levels were higher in patients with calcifications at the coronary arteries (+23%, p < 0.001) and the thoracic aorta (+27%, p = 0.001), but not in patients with calcifications at the aortic (+1%, p = 0.85) or mitral (+8%, p = 0.20) valves. During a median follow-up of 3.7 years, 28 patients had a major cardiovascular event, 19 patients sustained a fragility fracture, and 32 patients died. Sclerostin levels above the median did not predict major cardiovascular event (p = 0.15), fracture (p = 0.58), or mortality (p = 0.65). CONCLUSION: Sclerostin was positively associated with the presence of vascular calcifications, but was not predictive of events associated with mineral and bone disorder in a cohort of kidney transplantation candidates.
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Vertebral Bone Mineral Density Measured by Quantitative Computed Tomography With and Without a Calibration Phantom: A Comparison Between 2 Different Software Solutions.

Quantitative computed tomography (CT) can be used to quantify bone mineral density (BMD) in the spine from clinical CT scans. We aimed to determine agreement and precision of BMD measurements by 2 different methods: phantom-less internal tissue calibration and asynchronous phantom-based calibration in a cohort of patients with chronic kidney disease (CKD). Patients with CKD were recruited for CT angiography of the chest, abdomen, and pelvis. BMD was analyzed by 2 different software solutions using different calibration techniques; phantom-based by QCT Pro (Mindways Inc.) and phantom-less by Extended Brilliance Workspace (Philips Healthcare). Intraoperator reanalysis was performed on 53 patients (36%) for both methods. An interoperator reanalysis on 30 patients (20%) using the phantom-based method and 29 patients (19%) using the phantom-less method was made. XY- and Bland-Altman plots were used to evaluate method agreement. Phantom-based measured BMD was systematically higher than phantom-less measured BMD. Despite a small absolute difference of 3.3 mg/cm3 (CI: -0.2-6.9 mg/cm3) and a relative difference of 5.1% (CI: 2.2%-8.1%), interindividual differences were large, as seen by a wide prediction interval (PI: -47-40 mg/cm3). The Bland-Altman plot showed no systematic bias, apart from 5 outliers. Intraoperator variability was high for the phantom-less method (5.8%) compared to the phantom-based (0.8%) and the interoperator variability was also high for the phantom-less method (5.8%) compared to the phantom-based (1.8%). Despite high correlation between methods, the between-method difference on an individual level showed great variability. Our results suggest agreement between these 2 methods is insufficient to allow them to be used interchangeably in patients with CKD.

Bone turnover markers are associated with bone density, but not with fracture in end stage kidney disease: a cross-sectional study.

BACKGROUND: Fracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates. METHODS: Volumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures. RESULTS: The fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z-score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z-score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z-score. CONCLUSIONS: Bone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov with identifier NCT01344434 .

Effect of Intravenous Contrast on Volumetric Bone Mineral Density in Patients with Chronic Kidney Disease.

Volumetric bone mineral density (vBMD) can be measured from clinical computed tomography (CT) scans, facilitating screening for osteoporosis. However, use of X-ray contrast media may influence vBMD analyses, and previous studies reported as much as a 30% increase in lumbar spine (LS) vBMD after contrast administration. At the total hip (TH), an increase of only 4.1% was reported, indicating less sensitivity to contrast enhancement at this site. This study aimed to investigate the changes in vBMD after intravenous contrast media administration at both the LS and proximal femur in patients with chronic kidney disease. Seventy-one patients underwent CT angiography of the chest, abdomen, and pelvis as part of the cardiac workup before kidney transplantation. vBMD of the LS and proximal femur were calculated before and after administration of 95 mL ioversol intravenously. XY- and Bland-Altman plots and paired Student's t-test were used to evaluate changes in vBMD. After contrast media administration vBMD increased both at the LS and proximal femur. Although the absolute difference was comparable, the relative difference was almost twice as high at the LS (10.2% [6.1-14.1]) compared to the TH (5.9% [2.4-9.3], p <0.001) and femoral neck (FN) (5.3% [0.5-9.9], p <0.001). Women had a greater increase in LS-vBMD than men (13.4 ± 8.0 vs 9.8 ± 4.8 mg/cc, p = 0.02). Based on FN T-scores, 11 patients (16%) changed osteoporotic status after contrast enhancement. In conclusion vBMD of the spine and hip increased after contrast media administration in a cohort of patients with chronic kidney disease. FN T-scores from contrast-enhanced clinical CT scans should therefore be interpreted with caution. The proximal femur may be the preferred region for vBMD analysis from clinical CT scans, as sensitivity to contrast enhancement seem less at this site. These results may not be applicable to other patient populations.

Plasma n-3 Polyunsaturated Fatty Acids and Bone Mineral Density in Renal Transplant Recipients.

OBJECTIVE: Renal transplant recipients (RTR) suffer high rates of bone loss and increased risk of fracture. Marine n-3 polyunsaturated fatty acids (n-3 PUFA), found mainly in fish and seafood, may have beneficial effects on bone and are positively associated with bone mineral density (BMD) in healthy elderly. The aim of this study was to investigate if this association prevails despite the more complex causes of bone loss in RTR. DESIGN, SUBJECTS, AND METHODS: A total of 701 RTR were included in a cross-sectional analysis. BMD of lumbar spine, proximal femur, and distal forearm were measured by dual energy x-ray absorptiometry scan, and blood samples were drawn in the fasting state for measurement of plasma fatty acid composition 10 weeks posttransplant. Multiple linear regression analysis was used to assess the association between plasma marine n-3 PUFA levels and BMD. RESULTS: Mean age was 52.2 years, and two-thirds were men. Based on femoral neck T-scores, 26% of patients were osteoporotic and 52% osteopenic. Z-scores increased significantly across quartiles of marine n-3 PUFA levels, and marine n-3 PUFA was a positive predictor of BMD at total hip and lumbar spine after multivariate adjustment. No association was found between n-6 PUFA content and BMD. CONCLUSIONS: Plasma marine n-3 PUFA levels were positively associated with BMD at the hip and lumbar spine 10 weeks posttransplant.

Diagnosis and therapeutic decisions of osteoporosis in chronic kidney disease.

A 63-yr-old woman with end-stage CKD secondary to glomerulonephritis, on hemodialysis therapy, presented with scoliosis, back pain, and progressive loss of physical function for which corrective surgery was planned. Optimization of bone health was requested by the surgeon as a DXA scan had revealed osteoporosis at spine, hip, and forearm. Due to previous subtotal parathyroidectomy and normal parathyroid hormone and bone-specific alkaline phosphatase levels, a low bone turnover state was suspected. An iliac bone biopsy was performed and revealed low bone turnover, a mineralization defect, and severe osteoporosis. The patient was treated with calcium and intensified vitamin D supplementation, followed by a 2-yr course of teriparatide. Monitoring of bone turnover markers indicated a bone anabolic response to therapy, and a repeat DXA showed increases in BMD at spine and hip. A repeat biopsy at end of treatment showed normal bone turnover and mineralization. This case demonstrates the complicated bone health of patients with advanced CKD. As there are no randomized trials for fracture pretention in patients with CKD, care must be individualized and is often based on expert opinion. The use of bone biopsy is safe and informative in guiding therapy.

Ten tips on how to assess bone health in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) experience a several-fold increased risk of fracture. Despite the high incidence and the associated excess morbidity and premature mortality, bone fragility in CKD, or CKD-associated osteoporosis, remains a blind spot in nephrology with an immense treatment gap. Defining the bone phenotype is a prerequisite for the appropriate therapy of CKD-associated osteoporosis at the patient level. In the present review, we suggest 10 practical 'tips and tricks' for the assessment of bone health in patients with CKD. We describe the clinical, biochemical, and radiological evaluation of bone health, alongside the benefits and limitations of the available diagnostics. A bone biopsy, the gold standard for diagnosing renal bone disease, is invasive and not widely available; although useful in complex cases, we do not consider it an essential component of bone assessment in patients with CKD-associated osteoporosis. Furthermore, we advocate for the deployment of multidisciplinary expert teams at local, national, and potentially international level. Finally, we address the knowledge gaps in the diagnosis, particularly early detection, appropriate "real-time" monitoring of bone health in this highly vulnerable population, and emerging diagnostic tools, currently primarily used in research, that may be on the horizon of clinical practice.