A feline-focused review of chronic kidney disease-mineral and bone disorders - Part 1: Physiology of calcium handling.

Mineral derangements are a common consequence of chronic kidney disease (CKD). Despite the well-established role of phosphorus in the pathophysiology of CKD, the implications of calcium disturbances associated with CKD remain equivocal. Calcium plays an essential role in numerous physiological functions in the body and is a fundamental structural component of bone. An understanding of calcium metabolism is required to understand the potential adverse clinical implications and outcomes secondary to the (mal)adaptation of calcium-regulating hormones in CKD. The first part of this two-part review covers the physiology of calcium homeostasis (kidneys, intestines and bones) and details the intimate relationships between calcium-regulating hormones (parathyroid hormone, calcitriol, fibroblast growth factor 23, α-Klotho and calcitonin) and the role of the calcium-sensing receptor.

A feline-focused review of chronic kidney disease-mineral and bone disorders - Part 2: Pathophysiology of calcium disorder and extraosseous calcification.

Derangements in mineral metabolism are one of the main entities in chronic kidney disease-mineral and bone disorder (CKD-MBD). This is the second of a two-part review of the physiology and pathophysiology of calcium homeostasis in feline CKD-MBD. While dysregulation in calcium homeostasis is known to contribute to the development of vascular calcification in CKD, evidence characterising the relationship between serum calcium concentration and nephrocalcinosis and nephrolithiasis is limited. Recently, fibroblast growth factor 23 (FGF23) and α-Klotho have gained increased research interest and been shown to be important biomarkers for the prediction of CKD progression in human patients. However, conflicting evidence exists on their role in calcium homeostasis and vascular and soft tissue calcification. This review details the pathophysiology of calcium disorders associated with CKD-MBD and its implications on vascular and soft tissue mineralisation in human and feline patients. Further prospective studies investigating the clinical consequences of calcium disturbances in cats with CKD are warranted and this may provide additional insight into the pathophysiology of feline CKD-MBD.

Bone Mineral Density and Aortic Calcification: Evidence for a Bone-vascular Axis After Kidney Transplantation.

BACKGROUND: Chronic kidney disease mineral and bone disorders (CKD-MBD) and vascular calcification are often seen in kidney transplantation recipients (KTR). This study focused on the bone-vascular axis hypothesis, the pathophysiological mechanisms driving both bone loss and vascular calcification, supported by an association between lower bone mineral density (BMD) and higher risk of vascular calcification. METHODS: KTR referred for a dual-energy X-ray absorptiometry procedure within 6 mo after transplantation were included in a cross-sectional study (2004-2014). Areal BMD was measured at the proximal femur, and abdominal aortic calcification (AAC) was quantified (8-points score) from lateral single-energy images of the lumbar spine. Patients were divided into 3 AAC categories (negative-AAC: AAC 0; low-AAC: AAC 1-3; and high-AAC: AAC 4-8). Multivariable-adjusted multinomial logistic regression models were performed to study the association between BMD and AAC. RESULTS: We included 678 KTR (51 ± 13 y old, 58% males), 366 (54%) had BMD disorders, and 266 (39%) had detectable calcification. High-AAC was observed in 9%, 11%, and 25% of KTR with normal BMD, osteopenia, and osteoporosis, respectively (P < 0.001). Higher BMD (T-score, continuous) was associated with a lower risk of high-AAC (odds ratio 0.61, 95% confidence interval 0.42-0.88; P = 0.008), independent of age, sex, body mass index, estimated glomerular filtration rate, and immunosuppressive therapy. KTR with normal BMD were less likely to have high-AAC (odds ratio 0.24, 95% confidence interval 0.08-0.72; P = 0.01). CONCLUSIONS: BMD disorders are highly prevalent in KTR. The independent inverse association between BMD and AAC may provide evidence to point toward the existence, while highlighting the clinical and epidemiological relevance, of a bone-vascular axis after kidney transplantation.

Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review.

Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one's short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD.

Evaluation of anemia, malnutrition, mineral, and bone disorder for maintenance hemodialysis patients based on bioelectrical impedance vector analysis (BIVA).

BACKGROUND: ESRD (End-stage renal disease) treatment is a comprehensive medical process and requires numerous serological biochemical tests (SBTs) in diagnosis. To reduce these invasive, expensive, cumbersome, and time-consuming SBTs, there is a need to develop an alternative serological biochemical composition evaluation method. Bioelectrical impedance analysis (BIA) is affected by body's chemical and physical components, which might be correlated with serological biochemical composition and can be potentially used to evaluate biochemical composition in hemodialysis patient treatments. In this work, the relationship of classic and specific bioelectrical impedance vector analysis (BIVA) with major serological biochemical indexes in maintenance hemodialysis (MHD) patients was examined. METHODS: Bioelectrical and biochemical datasets were measured from 280 women and 408 men and formed 3872 effective biochemical-bioelectrical records in total. Statistical analysis was performed. RESULTS: The results show that BIVA vectors have strong relationship with phosphorus, hemoglobin, and PTH in both male and female groups. Strong correlation was also observed between Ca, albumin, CHOL, LDLC, and BIVA vectors in the male group. In the female group, a significant correlation was observed between classic BIVA values and NT-proBNP. SVM models are effective for classifying biochemical indexes. CONCLUSIONS: The obtained correlations and SVM classification models imply that BIVA can be used as a preliminary tool to evaluate and classify the degree of anemia, malnutrition, fluid overload, and mineral and bone disorder (MBD) in MHD patients by reducing the number of SBTs.

Bone and Mineral Metabolism in Children with Nephropathic Cystinosis Compared with other CKD Entities.

CONTEXT: Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD); however, systematic analyses are lacking. OBJECTIVE: To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across all stages of CKD. DESIGN: Cross-sectional multicenter study. SETTING: Hospital clinics. PATIENTS: Forty-nine children with NC, 80 CKD controls of the same age and CKD stage. MAIN OUTCOME MEASURES: Fibroblast growth factor 23 (FGF23), soluble Klotho, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, osteoprotegerin (OPG), biochemical parameters related to mineral metabolism, and skeletal comorbidity. RESULTS: Despite Fanconi syndrome medication, NC patients showed an 11-fold increased risk of short stature, bone deformities, and/or requirement for skeletal surgery compared with CKD controls. This was associated with a higher frequency of risk factors such as hypophosphatemia, hypocalcemia, low parathyroid hormone (PTH), metabolic acidosis, and a specific CKD stage-dependent pattern of bone marker alterations. Pretransplant NC patients in mild to moderate CKD showed a delayed increase or lacked an increase in FGF23 and sclerostin, and increased BAP, TRAP5b, and OPG concentrations compared with CKD controls. Post-transplant, BAP and OPG returned to normal, TRAP5b further increased, whereas FGF23 and PTH were less elevated compared with CKD controls and associated with higher serum phosphate. CONCLUSIONS: Patients with NC show more severe skeletal comorbidity associated with distinct CKD stage-dependent alterations of bone metabolism than CKD controls, suggesting impaired mineralization and increased bone resorption, which is only partially normalized after renal transplantation.

Skeletal and mineral metabolic effects of risedronate in a rat model of high-turnover renal osteodystrophy.

INTRODUCTION: High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined. MATERIALS AND METHODS: We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet. RESULTS: Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D. CONCLUSIONS: In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.

Adverse Effects of Autoclaved Diets on the Progression of Chronic Kidney Disease and Chronic Kidney Disease-Mineral Bone Disorder in Rats.

BACKGROUND: Autoclaving rodent diets is common in laboratory animals, but autoclaving increases the formation of dietary advanced glycation end-products (AGE). We studied the effect of autoclaved (AC) diet alone or in combination with a diet high in bioavailable phosphorus on biochemistries of chronic kidney disease-mineral and bone disorder (CKD-MBD), intestinal gene expression, and oxidative stress. METHODS: Male CKD rats (Cy/+) and normal littermates were fed 1 of 3 diets: AC 0.7% phosphorus grain-based diet for 28 weeks (AC); AC diet for 17 weeks followed by non-autoclaved (Non-AC) 0.7% phosphorus casein diet until 28 weeks (AC + Casein); or Non-AC diet for 16 weeks followed by a Non-AC purified diet until 30 weeks (Non-AC + Casein). RESULTS: AC diets contained ~3× higher AGEs and levels varied depending on the location within the autoclave. Rats fed the AC and AC + Casein diets had higher total AGEs and oxidative stress, irrespective of kidney function. Kidney function was more severely compromised in CKD rats fed AC or AC + Casein compared to Non-AC + Casein. There was a disease-by-diet interaction for plasma phosphorus, parathyroid hormone, and c-terminal fibroblast growth factor-23, driven by high values in the CKD rats fed the AC + Casein diet. Compared to Non-AC + Casein, AC and AC + Casein-fed groups had increased expression of receptor of AGEs and intestinal NADPH oxidase dual oxidase-2, independent of kidney function. CONCLUSIONS: Autoclaving rodent diets impacts the progression of CKD and CKD-MBD, highlighting the critical importance of standardizing diets in experiments.

Chronic kidney disease-mineral bone disorder.

Chronic kidney disease-mineral bone disorder is typically seen in patients with advanced chronic kidney disease. It is managed primarily by renal physicians, but non-renal physicians are also likely to encounter patients undergoing treatment for this condition in both inpatient and outpatient settings so a basic understanding of the principles may be helpful. This article covers the fundamentals of the pathophysiology, diagnosis and treatment of chronic kidney disease-mineral bone disorder.

Correlation between serum sclerostin level and bone density status in children on regular hemodialysis.

Bone disease is frequently observed in chronic kidney disease (CKD) and increases a patient's risk for fracture. Sclerostin is an osteocyte-derived negative regulator of bone formation. We aimed to assess serum sclerostin level as a bone marker in children with CKD on regular hemodialysis (HD) and detect the association between this and bone density status. This cross-sectional comparative study was conducted on 25 children with CKD on HD and 25 age- and sex-matched healthy children, as controls. Their ages ranged from 4 to 18 years. Serum sclerostin levels were measured and dual-energy X-ray absorptiometry scan was performed in the same line with the traditional bone markers. There was a significant increase in serum sclerostin level in patients (1.754 ± 1.31 ng/mL) compared to controls (0.290 ± 0.074 ng/mL) with P = 0.001. Nine patients (36%) had low bone mineral density (BMD) with z score under -2.0, eight of whom had low BMD in both the neck of femur and lumbar spines. There was a significant increase in serum sclerostin levels in the patient-group with low BMD (2.38 ± 0.85 ng/mL) compared with patients with normal BMD (1.4 ± 0.98 ng/mL) (P = 0.001). A significant positive correlation was found between serum sclerostin level and alkaline phosphtase, parathormone with negative correlation with serum calcium. Sclerostin was 100% specific and sensitive in predicting CKD-mineral and bone disorder. Elevated sclerostin levels were consistent with low BMD and appear to be an independent predictor of reduced BMD in children on regular HD.

International variation in the management of mineral bone disorder in patients with chronic kidney disease: Results from CKDopps.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3-5 CKD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Prospective cohort study of 7658 adult patients with eGFR <60mL/min/1.73m2, excluding dialysis or transplant patients, participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, Germany, and the US. CKD-MBD laboratory markers included serum levels of phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25-D). MBD treatment data included phosphate binders and vitamin D (nutritional and active). Nephrologist survey data were collected on target MBD marker levels. RESULTS: Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60-20mL/min/1.73m2 and more sharply for eGFR<20. 25-D showed no relation to eGFR. Nephrologist survey data indicated marked variation in upper target P and iPTH levels. Among patients with P>5.5mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%-51%, and use of any (active or nutritional) vitamin D was 60%-87%. CONCLUSIONS: Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study.

Pathogenesis and management of vascular calcification in CKD and dialysis patients.

Patients with chronic kidney disease (CKD) have a predisposition to develop vascular calcification due to dysregulated homeostatic mechanisms, which lead to an imbalance in the circulatory promoters and inhibitors of vascular calcification, leading to a net calcification stress. These factors promote ectopic calcification and induce vascular smooth muscle cells to undergo osteogenic differentiation and actively calcify the vascular media. The article summarizes clinically relevant pathogenic mechanisms of vascular calcification in patients with CKD and in dialysis patients and summarizes novel therapeutic interventions. In addition to the management of traditional cardiovascular risk factors, patients with CKD-mineral and bone disorder need close attention in the management of the mineral metabolism to prevent adverse effects on the bone and vascular compartments. This article reviews current evidence and therapeutic guidelines in the management of mineral metabolism in CKD and dialysis.

[Osteoporosis and chronic kidney disease: review and new therapeutic strategies].

Osteoporosis affects a segment of the population in which Chronic Kidney Disease is also greatly represented. Nephropathic patients may present peculiar biochemical abnormalities related to Chronic Kidney Disease, defining the Mineral and Bone Disorder. This kind of anomalies, in the worst scenarios, configure the typical histomorphology patterns of Renal Osteodystrophy. Scientific Societies of Endocrinology have established therapy guidelines for patients with osteoporosis only based on the glomerular filtration rate and recommend avoiding the use of some drugs for the more advanced classes of nephropathy. However, there is no clear therapeutic approach for patients with advanced nephropathy and bone abnormalities. In this paper we propose a systematic review of the literature and present our proposal for managing patients with advanced nephropathy, based on eGFR and on presence of Mineral and Bone Disorder.

Bone matrix mineralization and osteocyte lacunae characteristics in patients with chronic kidney disease - mineral bone disorder (CKD-MBD).

OBJECTIVES: Little is known about bone mineralization and osteocyte lacunae properties in chronic kidney disease mineral bone disorder (CKD-MBD). METHODS: In this retrospective study, we measured the bone mineralization density distribution (BMDD) and osteocyte lacunar section (OLS) 2D-characteristics by quantitative backscatter electron imaging in Straumann drill biopsy samples from n=58 patients with CKD-MBD. Outcomes were studied in relation to serum parathyroid hormone (PTH), alkaline phosphatase (APH), histomorphometric bone turnover and treatment with cinacalcet or phosphate binders. RESULTS: Lower calcium concentrations in bone from high turnover (average degree of bone mineralization -6.2%, p<0.001) versus low turnover patients were observed. OLS-characteristics were distinctly different (p<0.01 to p<0.05) in patients with highest compared to those with lowest turnover. Patients with cinacalcet had different OLS-characteristics (p<0.05) compared to those without cinacalcet. Furthermore, patients with phosphate binders had differences in BMDD and OLS-characteristics (p<0.05) compared to patients without phosphate binders. CONCLUSIONS: Our findings suggest that in patients with CKD-MBD secondary hyperparathyroidism and increased bone turnover decrease the average degree of bone matrix mineralization. Conversely, density and lacunar size of the osteocytes are increased compared to adynamic bone disease pointing at distinct patterns of bone mineralization and osteocyte lacunar properties in these two disease entities.

GFR-Specific versus GFR-Agnostic Cutoffs for Parathyroid Hormone and Fibroblast Growth Factor-23 in Advanced Chronic Kidney Disease.

BACKGROUND: In the majority of patients with advanced chronic kidney disease (CKD), values of parathyroid hormone (PTH1-84) and fibroblast growth factor 23 (FGF-23) exceed the normal reference range, potentially as an appropriate adaptation to reduced glomerular filtration rate (GFR). We tested whether GFR-specific cutoffs for PTH1-84 and FGF-23 could better identify patients with inappropriately high PTH1-84 and FGF-23 for their degree of CKD and thereby improve prognostication of clinical outcomes compared to a uniform threshold. METHODS: Prospective pan-Canadian cohort of 1,812 patients with mean estimated GFR (eGFR) 28.9 mL/min/1.73 m2 followed for a median of 52 months. Repeated log-rank tests were used to identify optimal cutoffs for PTH1-84 and FGF-23 within eGFR strata (<20, 20-29 and ≥30 mL/min/1.73 m2) that maximally differentiated high- and low-risk populations for (1) cardiovascular (CV) events (fatal or nonfatal myocardial infarction, coronary revascularization, stroke, heart failure) and (2) renal events (initiation of chronic renal replacement therapy). In multivariable models, we examined the association between -GFR-specific cutoffs and outcomes and compared their added prognostic value to existing uniform thresholds. RESULTS: Risk-based cutoffs for PTH1-84 and FGF-23 increased in a graded fashion with decreasing eGFR. Among patients with eGFR <20 mL/min/1.73 m2, CV risk-based cutoffs for PTH1-84 and FGF-23 were 3.4 and 5.5 times the upper limit of normal, respectively, and reclassified 31.9 and 35.1% of patients when added to a multivariable base model for CV events. In contrast, the addition of PTH1-84 and FGF-23 to the base model using uniform cutoffs failed to reclassify such patients. Similar findings were demonstrated for renal outcomes. CONCLUSION: GFR-specific risk-based cutoffs for PTH1-84 and FGF-23 may facilitate more meaningful risk stratification in advanced CKD than current GFR-agnostic reference ranges derived from healthy adults. This may be most applicable in those with severely reduced GFR.

Parathyroid suppression therapy normalizes chronic kidney disease-induced elevations in cortical bone vascular perfusion: a pilot study.

Interventions that alter PTH levels in an animal model of chronic kidney disease have effects on the perfusion of bone and bone marrow. INTRODUCTION: Patients with chronic kidney disease (CKD) have accelerated bone loss, vascular calcification, and abnormal biochemistries, together contributing to an increased risk of cardiovascular disease and fracture-associated mortality. Despite evidence of vascular pathologies and dysfunction in CKD, our group has shown that cortical bone tissue perfusion is higher in a rat model of high-turnover CKD. The goal of the present study was to test the hypothesis that parathyroid hormone (PTH) suppressive interventions would normalize cortical bone vascular perfusion in the setting of CKD. METHODS: In two separate experiments, 35-week-old CKD animals and their normal littermates underwent intra-cardiac fluorescent microsphere injection to assess the effect of 10 weeks of PTH suppression (Experiment 1: calcium supplementation, Experiment 2: calcimimetic treatment) on alterations in bone tissue perfusion. RESULTS: In Experiment 1, CKD animals had serum blood urea nitrogen (BUN) and PTH levels significantly higher than NL (+ 182% and + 958%; p < 0.05). CKD+Ca animals had BUN levels that were similar to CKD, while PTH levels were significantly lower and comparable to NL. Both femoral cortex (+ 220%, p = 0.003) and tibial cortex (+ 336, p = 0.005) tissue perfusion were significantly higher in CKD animals when compared to NL; perfusion was normalized to those of NL in CKD+Ca animals. MicroCT analysis of the proximal tibia cortical porosity showed a trend toward higher values in CKD (+ 401%; p = 0.017) but not CKD+Ca (+ 111%; p = 0.38) compared to NL. Experiment 2, using an alternative method of PTH suppression, showed similar results as those of Experiment 1. CONCLUSIONS: These data demonstrate that PTH suppression-based interventions normalize cortical bone perfusion in the setting of CKD.

Changes in Bone Histomorphometry after Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Over the past decade, the management of CKD-mineral and bone disorder has changed substantially, altering the pattern of bone disease in CKD. We aimed to evaluate the natural history of kidney bone disease in contemporary kidney transplant recipients and patients on dialysis. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Sixty one patients on dialysis who were referred to kidney transplantation participated in this prospective cohort study during November 2009 and December 2010. We performed baseline bone biopsies while the patients were on dialysis and repeated the procedure in 56 patients at 2 years after kidney transplantation or 2 years after baseline if transplantation was not performed. Measurements of mineral metabolism and bone turnover, as well as dual energy x-ray absorptiometry scans, were obtained concurrently. RESULTS: A total of 37 out of 56 participants received a kidney transplant, of which 27 underwent successful repeat bone biopsy. The proportion of patients with high bone turnover declined from 63% at baseline to 19% at 2 years after kidney transplantation, whereas the proportion of those with low bone turnover increased from 26% to 52%. Of 19 participants remaining on dialysis after 2 years, 13 underwent successful repeat biopsy. The proportion of patients remaining on dialysis with high bone turnover decreased from 69% to 31%, and low bone turnover increased from 8% to 38%. Abnormal bone mineralization increased in transplant recipients from 33% to 44%, but decreased in patients remaining on dialysis from 46% to 15%. Trabecular bone volume showed little change after transplantation, but low bone volume increased in patients remaining on dialysis. Bone mineral density did not correlate with histomorphometric findings. CONCLUSIONS: Bone turnover decreased over time both in patients remaining on dialysis and in kidney transplant recipients. Bone mineral density and bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens.

Associations of plasma fibroblast growth factor 23 and other markers of chronic kidney disease-Mineral and bone disorder with all-cause mortality in South African patients on maintenance dialysis: A 3-year prospective cohort study.

INTRODUCTION: Few studies have linked high levels of plasma C-terminal fibroblast growth factor 23 (FGF23) with poor clinical outcomes in patients on maintenance haemodialysis (MHD), while the association between intact FGF23 and mortality in this group of patients remains inconclusive. Therefore, the aim of this study was to evaluate the association between plasma levels of intact FGF23 and mortality in dialysis patients. METHODS: A prospective multicenter study involving patients undergoing dialysis at three dialysis centers in Johannesburg was undertaken between 1st October 2014 and 31st December 2017. RESULTS: The study comprised 165 chronic dialysis patients (111 blacks, 54 whites) with a mean age of 46.6 ±14.2 years. During a three year follow up period, there were 46 deaths (1.03 per 100 person-years). The median plasma FGF 23 level was 382 pg/ml (interquartile range [IQR], 145-2977). In adjusted multivariable analyses, there was a non-statistically significant increase in the risk of mortality with higher quartiles of FGF 23 levels: the adjusted hazard ratios (HR) for the second, third and fourth quantiles were HR 3.20 (95% CI, 0.99-10.35; P = 0.052), HR 2.43(95% CI,0.65-9.09; P = 0.19), and HR 2.09 (95% CI, 0.66-7.32; P = 0.25),respectively. Corrected serum calcium 2.38-2.5 mmol/l [HR 2.98 (95% CI, 1.07-8.29; P = 0.04] and > 2.50 mmol/l [HR 5.50 (95% CI, 1.84-16.48; P = 0.002] were independently associated with increased risk of death. Likewise, patients with intact parathyroid hormone > 600 pg/ml had a 3.46-fold higher risk of death (HR 3.46, 95% CI, 1.22-9.82 P = 0.019). These findings persisted in time -dependent analyses. CONCLUSION: Higher levels of intact FGF 23 appear not to be independently associated with all-cause mortality in our dialysis patients, while hypercalcaemia and severe hyperparathyroidism were found to be independent predictors of mortality in this cohort of patients.