Biointact Parathyroid Hormone Research Articles

#2708 Impact of dialysis modality on bone phenotype

Abstract Background and Aims Literature data suggest that low bone turnover is the prevailing bone phenotype in patients treated with peritoneal dialysis (PD) and point to high sclerostin as the central culprit. Lack of adequate controls, diagnostic heterogeneity, and a changing mineral metabolism landscape and armamentarium call for a cautious interpretation and confirmation in contemporary patients. Method Laboratory parameters of mineral metabolism (biointact parathyroid hormone (PTH), fibroblast growth factor 23 [FGF23] and sclerostin), bone turnover markers (bone alkaline phosphatase [BALP], intact procollagen type I N-terminal propeptide [PINP], tartrate-resistant acid phosphatase 5b [TRAP5b]) and bone mineral density (BMD) were assessed in 636 non-diabetic kidney transplant candidates of whom 447 were treated with hemodialysis (HD) and 189 with PD. A bone biopsy was performed in 204 patients (n = 134 HD; n = 70 PD), with bone sclerostin expression assessed in a subset (n = 52). Results Patients treated with PD had lower levels of PINP (79.6 vs 99.5 ug/L; p < 0.01) and BALP (20.2 vs 23.7 ug/L; p = 0.04) compared to those treated with HD. Histomorphometric parameters of bone formation were numerically lower in patients treated with PD, but significance was not reached. Bone mineralization was impaired in HD patients (osteoid width: 7.90 vs 6.75 µM; p = 0.01; osteoid maturation: 9 vs 6 days; p = 0.03), while frank osteomalacia was rare in both modalities (6.0%, both groups). BMD was higher in patients treated with PD compared to HD at skeletal sites rich in cortical bone (Z-score midshaft radius −0.4 ± 1.3 vs −0.9 ± 1.7; p = 0.04). PTH levels were comparable (150 vs 144 pg/mL, PD vs HD), while patients treated with PD showed higher serum phosphate (4.9 ± 1.3 vs 4.5 ± 1.6 mg/dl; p < 0.01) and FGF23 levels (3852 pg/ml vs 2361 pg/ml; p = 0.01). Circulating (1.82 ng/mL, both groups) and bone tissue expression (205 ± 126 vs 206 ± 112 positive osteocytes per mm2) of sclerostin did not differ between groups. Conclusion Patients treated with PD present a lower bone turnover, better mineralization, and higher cortical BMD than counterparts treated HD. Overall, differences are marginal and most probably clinically irrelevant. We speculate that inferior phosphate control may be in the causal pathway.

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

Rationale & ObjectiveKidneys 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 DesignCase series. Setting & ParticipantsAdult patients with previous bilateral nephrectomy (anephric) not receiving active vitamin D therapy were evaluated at the time of (N=38) and 1 year after (N=25) kidney transplantation. Liquid chromatography–tandem mass spectrometry was used to measure vitamin D metabolites. Metabolic ratios were expressed CYP24A1 (24,25(OH)2D/25(OH)D) and CYP27B1 (1α,25(OH)2D/25(OH)D) as activities. Differences between evaluation timepoints were evaluated by paired Student’s t-test or Wilcoxon matched-pairs signed-rank test. FindingsAt time of transplantation, 1α,25(OH)2D was detectable in all patients (4 to 36 pg/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 PTH or FGF23. 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 3-5 fold. Also at 12 months after transplantation, 1α,25(OH)2D was positively correlated with PTH (rho=0.603, p=0.04), but not with levels of 25(OH)D or FGF23. LimitationsRetrospective, observational study design with a small cohort size. ConclusionsLow-normal levels of 1α,25(OH)2D was demonstrated in anephric patients, indicating production outside of 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.

Associations of Changes in Bone Turnover Markers with Change in Bone Mineral Density in Kidney Transplant Patients.

Bone loss after kidney transplantation is highly variable. We investigated whether changes in bone turnover markers associate with bone loss during the first post-transplant year. Bone mineral density (BMD) was measured at 0 and 12 months, with biointact parathyroid hormone, bone-specific alkaline phosphatase (BALP), intact procollagen type I N -terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) measured at 0, 3, and 12 months post-transplant ( N =209). Paired transiliac bone biopsies were available in a subset ( n =49). Between-group differences were evaluated by Student's t test, Wilcoxon signed-rank test, or Pearson's chi-squared test. Changes in BMD varied from -22% to +17%/yr. Compared with patients with no change (±2.5%/yr), patients who gained BMD had higher levels of parathyroid hormone (236 versus 136 pg/ml), BALP (31.7 versus 18.8 μ g/L), and Intact PINP (121.9 versus 70.4 μ g/L) at time of transplantation; a greater decrease in BALP (-40% versus -21%) and Intact PINP (-43% versus -13%) by 3 months; and lower levels of Intact PINP (36.3 versus 60.0 μ g/L) at 12 months post-transplant. Patients who lost BMD had a less marked decrease, or even increase, in Intact PINP (+22% versus -13%) and TRAP5b (-27% versus -43%) at 3 months and higher Intact PINP (83.7 versus 60.0 μ g/L) and TRAP5b (3.89 versus 3.16 U/L) at 12 months compared with patients with no change. If none of the biomarkers decreased by the least significant change at 3 months, an almost two-fold (69% versus 36%) higher occurrence of bone loss was seen at 12 months post-transplant. Bone loss after kidney transplantation was highly variable. Resolution of high bone turnover, as reflected by decreasing bone turnover markers, associated with BMD gain, while increasing bone turnover markers associated with bone loss.

#3325 EXTRARENAL CYP27B1 ACTIVITY CONTRIBUTES TO THE CIRCULATING POOL OF 1,25(OH)2D

Abstract Background and Aims Alterations of vitamin D metabolism are ubiquitous in patients with chronic kidney disease (CKD) and a key feature of the syndrome of CKD-mineral and bone disorder. A central paradigm in vitamin D metabolism is that the kidneys are the only relevant source of activation of vitamin D for systemic effects. However, various cells and tissues exhibit CYP27B1 activity and are capable of producing 1.25(OH)2D, which could contribute to the circulating pool [1]. This longitudinal, observational study challenges the dogma of the kidneys as the only source of 1.25(OH)2D, by investigating vitamin D metabolites in anephric patients free of active vitamin D therapy. Method Anephric patients free of active vitamin D therapy were included at time of kidney transplantation. A subset had a second study visit at 12 months post-transplant. Liquid chromatography–tandem mass spectrometry was used to measure 25(OH)D2/3, 1,25(OH)2D3 and 24,25(OH)2D3. Metabolic ratios of vitamin D metabolites over precursors were used as measures of CYP24A1 (24,25(OH) 2D3/ 25(OH)D3) and CYP27B1(1,25(OH)2D/ 25(OH)D3) activity. Biointact PTH (1-84) was measured by an in-house immunoradiometric assay [2] and FGF23 was measured by ELISA (Kainos Laboratories, Tokyo, Japan). Interleukin 6 (IL6), tumor necrosis factor-Α (TNF- Α) and interferon-Γ (IFN-Γ) were measured using an electrochemiluminescence multiplex immunoassay (Human Proinflammatory 1 V-plex, MSD, Maryland, US). Two independent laboratories performed confirmatory analyses of 1,25(OH)2D. Results All anephric patients (n = 38) had detectable (&amp;gt;2.5 pg/mL) levels of 1,25(OH)2D, with a median value of 13.5 pg/mL (range 3.9 to 35.7 pg/ml). There was a significant correlation between levels of 25(OH)D and 1,25(OH)2D (r = 0.583, p≪0.001), with 25(OH)D-levels explaining 34% of the variation in 1,25(OH)2D (Fig. 1). 1,25(OH)2D levels were not significantly correlated to PTH (rho = 0.279, p = 0.09) or FGF23 (rho = –0.280, p = 0.09), nor to any of the inflammatory markers; IL6 (rho = 0.068, p = 0.69), TNF-Α (rho = –0.264, p = 0.11), IFN-Γ (rho = –0.001, p = 0.99). To validate our findings, anonymized samples of 17 anephric patients and 17 CKD stage 5D with residual renal function were sent to two independent laboratories. The presence of 1,25(OH)2D was confirmed in all anephric patients. Twenty-five anephric patients underwent a successful kidney transplantation and were free of active vitamin D therapy at a study visit 12 months post-transplant. After kidney transplantation, 25(OH)D-level decreased, while levels of 1,25(OH)₂D and 24,25(OH) ₂D substantially increased. The metabolic ratios expressing CYP24A1 and CYP27B1 activity both increased (Fig. 2). At 12 months post-transplant, 1,25(OH)₂D-levels correlated with levels of biointact PTH (rho = 0.603, p = 0.002), but not with levels of FGF23 (rho = –0.262, p = 0.21). Conclusion Extrarenal CYP27B1 activity contributes to the circulating active vitamin D pool and may sustain low-normal levels of active vitamin D, even in anephric individuals. While renal CYP27B1 activity is hormonally regulated, extrarenal CYP27B1 activity seems to be mainly substrate dependent.

Agreement of Parathyroid Hormone Status Measured by Intact and Biointact Parathyroid Hormone Assays among Chronic Kidney Disease Patients and Its Correlation with Bone Turnover Parameters.

This study aimed to determine the agreement between intact parathyroid hormone (iPTH) and biointact parathyroid hormone (bio-PTH) assays and to correlate them with bone markers. This cross-sectional study included 180 patients with chronic kidney disease (CKD) stages 3b, 4 and 5D. We measured their iPTH, bio-PTH, 25-hydroxyvitaminD (25(OH)D), C-terminal telopeptide collagen (CTX), procollagen 1 intact N-terminal propeptide (P1NP), calcium, phosphate and alkaline phosphatase (ALP). Higher iPTH than bio-PTH concentrations were seen in CKD stages 3b, 4 and 5D (58[62] versus 55[67] pg/mL, 94[85] versus 85[76] pg/mL and 378[481] versus 252[280] pg/mL, respectively). Both PTH assays showed good agreement among all the subjects, with an intraclass correlation coefficient of 0.832 (P-value < 0.001). The Passing-Bablok showed that the equation for the bio-PTH was PTH = 0.64 iPTH + 15.80, with r = 0.99. The Bland-Altman plots showed increased bias with an increasing PTH concentration. Both PTH assays showed a high positive correlation with CTX and P1NP, a moderate correlation with phosphate, a low correlation with ALP and calcium, and a negligible correlation with phosphate and 25(OH)D. The iPTH and bio-PTH assays were in agreement, but their bias increased with the PTH concentration. The unacceptable large bias indicates that the two assays cannot be used interchangeably. They had a variable correlation with the bone parameters.

FC 076DIAGNOSTIC ACCURACY OF BONE TURNOVER MARKERS IN RENAL OSTEODYSTROPHY

Abstract Background and Aims A transiliac bone biopsy is the gold standard for diagnosing renal osteodystrophy, but is not recommended as part of routine clinical workup due to its invasive nature. Suitable non-invasive alternatives have yet to be established. The aim of this study was to investigate the diagnostic accuracy novel biochemical markers of bone remodeling compared to that of biointact parathyroid hormone (PTH) for bone turnover as evaluated by histomorphometry. Method Protocolled bone biopsies were performed in end-stage kidney disease patients (ESKD, n = 80) and kidney transplant recipients (n = 119). Full-length (1-84) PTH, bone-specific alkaline phosphatase (BsAP), intact N-terminal propeptide of type I collagen (P1NP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) were measured. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). Optimal diagnostic cutoffs were established in an exploration cohort (n=100), and subsequently validated in a separate subset of patients (n=99). Results Mean age was 55±13 years, two-thirds were men (67%), and 23% had diabetes mellitus. Post-transplant eGFR was 49 [IQR 39, 59] ml/min/1.73m². Bone turnover was low in 47 (24%), normal in 119 (60%), and high in 33 (17%) patients. All biomarkers differed significantly across categories of bone turnover (p &amp;lt; 0.001). The AUC of biointact PTH for high turnover was 0.82 (0.73, 0.91), which was not significantly different from AUC values for BsAP, Intact P1NP, and TRAP5b (0.87, 0.90, and 0.86, respectively). AUC of biointact PTH for low turnover was 0.71 (0.63, 0.78), which was significantly lower than the values for BsAP, Intact P1NP, and TRAP5b (0.79, 0.83, and 0.79, respectively; p &amp;lt; 0.05, all). Calculated optimal diagnostic cutoffs in the exploration cohort are shown in Table 1. Applying these cutoffs in the validation cohort revealed high negative predictive values for both high (92 - 96%) and low (82 - 90%) bone turnover. Positive predictive values were consistently low. Conclusion The diagnostic accuracies of BsAP, Intact P1NP and TRAP5b are sufficient to rule out both high and low bone turnover in CKD. Biointact PTH shows inferior performance, particularly in kidney transplant recipients.

European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates for serum biointact parathyroid hormone based on weekly samplings from 91 healthy participants.

The European Biological Variation Study (EuBIVAS) was created by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Biological Variation to establish high-quality biological variation (BV) estimates for clinically important measurands. In this study, the aim was to deliver reliable BV estimates for the biointact parathyroid hormone (PTH 1-84). Serum samples were obtained from a population of 91 healthy individuals (38 men, 43 pre-menopausal women, and 10 post-menopausal women; 21-69 years) from 5 European countries, with all samples stored at -80 °C prior to analysis. PTH 1-84 analysis was performed at the San Raffaele Hospital (Milan, Italy) on the Roche Cobas e801. All samples from each individual were analysed in duplicate within a single run. CV-ANOVA was applied, after analysis of variance homogeneity and outliers, to obtain BV estimates for PTH 1-84 with 95% CIs. The within-subject BV [CVI (95% CI)] estimates were significantly different between men and women [13.0% (12.1-14.2%) and 15.2% (14.3-16.3%), respectively], while the between-subject estimates [CVG (95% CI)] were similar (men: 26.8% (21.4-35.1%), pre-menopausal women: 27.8% (22.7-36.1%)], allowing for delivery of updated analytical performance specifications and reference change values. Updated BV estimates for serum PTH 1-84 based on the large-scale EuBIVAS may be beneficial for the diagnosis and management of parathyroid glands and bone turnover pathologies.

Parathyroid hormone metabolism and signaling in health and chronic kidney disease

Circulating parathyroid hormone (PTH) shows a complex relationship with hard outcomes in subjects with chronic kidney disease (CKD). Moreover, intervention studies directly targeting PTH failed to yield unequivocal results. Disturbed PTH metabolism, posttranslational modifications of PTH, and end-organ hyporesponsiveness to PTH may explain the poor performance of PTH as an outcome biomarker and precise target of therapy in the setting of CKD, at least in the gray middle target zone. PTH fragments accumulate in CKD patients and may exert effects that are distinct from, if not opposite to biointact (1-84)PTH. Posttranslational modification of PTH and especially oxidation may alter the interaction of PTH with its receptor. Its clinical relevance, however, remains a matter of ongoing debate. Less controversial is the issue of end-organ hyporesponsiveness to PTH. This phenomenon, formally referred to as PTH resistance, has long been recognized in CKD, but factors and mechanisms contributing to it remain poorly defined. Subsequent evidence identified downregulation of the PTH receptor and competing downstream signals as underlying pathophysiologic mechanisms. End-organ hyporesponsiveness to PTH in CKD, along with important analytical and biological variability, renders defining the PTH target range in CKD challenging. Although this may still be accomplished at the population level, it may prove to be very difficult at the individual level. This is a disillusioning thought in an era of personalized medicine. Parallel to the search of a functional and readily available assay quantifying PTH signaling tone or sensitivity, additional biomarkers (or a panel of biomarkers) should be formally evaluated.

Clinical evaluation of two parathyroid hormone assays in the context of vitamin D supply in chronic kidney disease

Introduction: Parathyroid hormone levels provide important information in chronic renal failure. Aim: To compare parathyroid hormone levels measured by two assays in correlation with vitamin D supply. Method: Parathyroid hormone and 25-hydroxi-vitamin-D were determined in 104 patients (31 patients with chronic renal failure without renal replacement therapy, 36 patients treated with peritoneal dialysis and 37 patients treated with hemodialysis). Results: Good correlation was found between results of the two parathyroid hormone methods, but the intact parathyroid hormone levels were higher than the biointact values. 87% and 13% of the patients had vitamin-D deficiency and insufficiency, respectively. The frequency of serious vitamin-D deficiency was higher in the peritoneal dialysis than in the hemodialysis group. Intact parathyroid hormone levels were different in dialysed patients having vitamin-D-deficiency and insufficiency, and the difference was higher for the biointact than intact values. Negative correlation was detected between biointact parathyroid hormone and 25-hydroxivitamin-D in the hemodialysis group. Conclusions: Biointact parathyroid hormone levels better reflect the vitamin D supply and bone metabolism than intact levels, especially in hemodialysed patients. Orv. Hetil., 2013, 154(51), 2025–2036.

The relationship between intact PTH and biointact PTH (1–84) with bone and mineral metabolism in pre-dialysis chronic kidney disease (CKD)

ObjectivesAbnormalities in PTH are implicated in the pathogenesis of bone abnormalities in chronic kidney disease (CKD)–mineral bone disorder (CKD–MBD). PTH concentrations are important in clinical decision and management. This emphasises the importance of providing an assay which measures biologically active PTH. We compared concentrations of intact PTH with biointact PTH (1–84) in CKD and end stage renal disease (ESRD) and investigated the relationship between the 2 PTH assays with bone and mineral laboratory parameters and bone mineral density (BMD) in CKD. Design and methodsWe assessed 140 patients (61 in ESRD and 79 with CKD stages 1–4) in this cross-sectional study. We measured biointact PTH (1–84) as well as routine biochemical parameters on all subjects. In the CKD cohort, bone turnover markers; bone alkaline phosphatase (BAP) and tartrate resistant acid phosphatase (TRACP)-5b and bone mineral density (BMD) were also determined. ResultsIn ESRD, intact PTH concentration was significantly higher compared to biointact PTH (1–84) (422 [443] v/s 266 [251] pg/mL, (p<0.001) with an average bias of 60%. In CKD, intact PTH concentration was also higher compared to biointact PTH (1–84) (79[55] v/s 68[49] pg/mL p<0.001) with an average bias of 18%. Only the biointact PTH (1–84) assay showed any significant correlation with serum calcium concentrations (r=−0.26, p<0.05) and phosphate (r=0.25, p<0.05) in CKD. Following multilinear regression analysis and adjustment for all significant co-variables, only eGFR, BAP and 25 (OH)vitamin remained significantly associated with intact PTH and biointact PTH (1–84). The strength of association was stronger between BAP and biointact PTH (1–84) (biointact PTH (1–84): p=0.007, intact PTH: p=0.01). In adjusted analyses, only biointact PTH (1–84) was significantly associated with BMD at the fore-arm (FARM) (p=0.049). ConclusionsThe study confirms the differences between intact PTH and biointact PTH (1–84) in ESRD. Whilst there may be similarities in the diagnostic ability of both intact and biointact PTH (1–84), our data suggest that biointact PTH (1–84) assay may better reflect bone metabolism and BMD in CKD. Further longitudinal studies are needed.

Clinical evaluation of two novel biointact PTH(1–84) assays in hemodialysis patients

ObjectivesIn chronic kidney disease–mineral and bone disorder (CKD-MBD), most treatment decisions are guided by parathyroid hormone (PTH) levels. Here, we aimed at assessing the technical and clinical performance of two novel automated biointact PTH(1–84) assays, from Roche Diagnostics (Ro) and DiaSorin (DS), in hemodialysis patients. Design and methodsWe recorded demographics, dialysis treatment characteristics, pharmacotherapy for CKD-MBD and laboratory work-up. Statistical methods included Passing–Bablok, and multiple linear regression. Results121 patients, dialyzing on average for 3.5years (range: 0.1–22.5), with serum phosphate 1.9±0.6mmol/L (mean±SD), participated in the study. Median serum concentration for intact PTH was 223ng/L (range: 5–2844), and for biointact PTH(1–84) was 136ng/L (Ro; range: 1–1644), respectively 138ng/L (DS; range: 4-1580). Both biointact assays were significantly correlated (r=0.98; Ro=0.87×DS+19.60). Bland–Altmann plots revealed an average bias ±2 SD of 10±27ng/L below 200ng/L, and −32±157ng/L above 200ng/L (Ro minus DS). The variably adjusted association between PTH and serum phosphate was very similar, regardless of the PTH assay, but this was not the case for PTH-derived measures (ratios biointact/intact; differences intact minus biointact). (Log)PTH concentrations as well as serum phosphate were significantly associated with serum creatinine, but only in patients with >0mL urine per day. ConclusionsResults from Roche and DiaSorin biointact PTH(1–84) assays were well correlated, but showed increased deviations at higher concentrations. Biointact PTH(1–84) levels are roughly two third of intact PTH. The association between PTH and serum creatinine may depend on residual renal clearance of PTH and/or serum phosphate.

Mineral metabolism in renal transplant recipients discontinuing cinacalcet at the time of transplantation: a prospective observational study

The calcimimetic cinacalcet is approved for treating secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Biochemical profiles and clinical outcomes in patients discontinuing cinacalcet at the time of transplantation are scarce. We performed a prospective observational cohort study, including 303 incident renal transplant recipients, of whom 21 were on cinacalcet treatment at the time of transplantation. Parameters of mineral metabolism and incidence of parathyroidectomy and nephrocalcinosis in patients discontinuing cinacalcet at the time of transplantation patients ("cinacalcet +") were compared to cinacalcet-naïve patients ("cinacalcet -"). Mean follow-up was 35.6 ± 15.8 months. At the time of transplantation, parameters of mineral metabolism were similar in both groups. Conversely, at month 3, serum ionized calcium (p = 0.0007), calcitriol (p = 0.02), biointact parathyroid hormone (p = 0.06) levels and urinary fractional excretion of phosphorus (p = 0.06) were higher, while serum phosphorus levels (p = 0.06) were lower in "cinacalcet +." Analysis based on matching at the time of initiation showed that the course of post-transplant mineral metabolism in cinacalcet-treated patients (median treatment period 12.5 months) vs. cinacalcet-naïve patients was identical. "Cinacalcet +" patients are characterized by a high-incidence proportion of both post-transplant nephrocalcinosis (45% at month 3) and parathyroidectomy (28.6%). No difference in renal function was observed between "cinacalcet +" and "cinacalcet-" patients. Cinacalcet does not affect the course of secondary hyperparathyroidism in patients awaiting kidney transplantation. Biochemical profiles and a high parathyroidectomy rate suggest rebound hyperparathyroidism in renal transplant recipients discontinuing cinacalcet at the time of transplantation, which may be related to the short exposure time specific to this population. Risk/benefit studies are urgently required to define the role of continued calcimimetic treatment in renal transplant recipients and to determine the optimal treatment of secondary hyperparathyroidism in patients listed for transplantation.

Fibroblast growth factor-23 and mineral metabolism after unilateral nephrectomy

Fibroblast growth factor -23 (FGF-23) is a key regulator of mineral metabolism. It regulates renal phosphate (Pi) reabsorption and calcitriol synthesis, and has an inhibitory effect on parathyroid hormone (PTH) secretion. FGF-23 increases early in chronic kidney disease (CKD), but the regulation of FGF-23 in mild -to -moderate renal dysfunction is not fully understood. Nine healthy kidney donors underwent unilateral nephrectomy. Estimated glomerular filtration rate (eGFR) calculated from cystatin C and parameters of mineral metabolism: (Pi, ionized calcium, biointact PTH, intact FGF-23, calcitriol, and urinary excretion of calcium and Pi) were analysed before surgery, and one day, one week and three to six months after surgery. On the first post-operative day, PTH increased due to a decrease in the calcium level. One week after nephrectomy, the FGF-23 level increased from 31.8 ± 12.3 pg/mL to 55.8 ± 15.1 pg/mL, while PTH, Pi and calcium levels were unchanged compared towith baseline. On follow-up, eGFR improved compared with its one-week value, and PTH and FGF-23 were unchanged compared towith baseline. The calcitriol level decreased but was in the normal range at all points in time. The total amount of Pi in urine did not change, while the calcium excretion decreased significantly. Pi homeostasis after nephrectomy is maintained by PTH on the first day. When serum calcium is stabilized and food intake resumed, FGF-23 rises, possibly in response to the Pi- load in relation to GFR.

Fibroblast Growth Factor-23 in Early Chronic Kidney Disease

The discovery of fibroblast growth factor-23 (FGF-23) and the elucidation of its function as a phosphaturic and 1,25(OH)2VitD counter-regulatory hormone provides a new conceptual framework for the understanding of the pathogenesis of secondary hyperparathyroidism. This study aims to elucidate the complex associations between FGF-23, parathyroid hormone (PTH), 1,25(OH)2D, and phosphate in patients with early-stage chronic kidney disease (CKD) and to provide clinical evidence in favor of the new phosphate-centric paradigm for the pathogenesis of secondary hyperparathyroidism. Serum biointact PTH and FGF-23, 25(OH)D, 1,25(OH)2D, calcium, phosphate, 24-hour urine excretion of phosphate and calcium, and urinary fractional excretion of phosphate were determined in a cross-sectional study including 125 patients with CKD stages 1 to 3. Serum phosphate levels showed an inverse association with estimated GFR (eGFR), but were within the normal range in all but one patient. FGF-23 and PTH were inversely associated with eGFR, even in the subgroup of patients with CKD stages 1 and 2. High FGF-23 levels were significantly more prevalent than high PTH levels. The urinary fractional excretion of phosphate was highest in patients with both a high serum FGF-23 and PTH level. Increased FGF-23 and phosphate and decreased 25(OH)D were independently associated with decreased 1,25(OH)2D. Our data are in favor of the new paradigm for the pathogenesis of secondary hyperparathyroidism according to which a reduced phosphate excretion capacity is the principal abnormality that initiates secondary hyperparathyroidism.

Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients

The ADVANCE (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects with Chronic Kidney Disease Receiving Haemodialysis) Study objective is to assess the effect of cinacalcet plus low-dose active vitamin D versus flexible dosing of active vitamin D on progression of coronary artery calcification (CAC) in haemodialysis patients. We report the ADVANCE Study design and baseline subject characteristics. ADVANCE is a multinational, multicentre, randomized, open-label study. Adult haemodialysis patients with moderate to severe secondary hyperparathyroidism (intact parathyroid hormone [iPTH] >300 pg/mL or bio-intact PTH >160 pg/mL) and baseline CAC score >or=30 were stratified by CAC score (>or=30-399, >or=400-999, >or=1000) and randomized in a 1:1 ratio to cinacalcet (30-180 mg/day) plus low-dose active vitamin D (cinacalcet group) or flexible dosing of active vitamin D alone (control). The study had three phases: screening, 20-week dose titration and 32-week follow-up. CAC scores obtained by cardiac computed tomography were determined at screening and weeks 28 and 52. The primary end point was percentage change in CAC score from baseline to Week 52. Subjects (n = 360) were randomized to cinacalcet or control. Mean age was 61.5 years, 43% were women, and median dialysis vintage was 36.7 months (range, 2.7-351.5 months). The baseline geometric mean CAC score by the Agatston method was 548.7 (95% confidence interval, 480.5-626.6). Baseline CAC score was independently associated with age, sex, dialysis vintage, diabetes and iPTH. Subjects also had extensive aortic and valvular calcification at baseline. Subjects enrolled in ADVANCE have extensive CAC at baseline. The ADVANCE Study should help determine whether cinacalcet attenuates progression of vascular calcification.

Effect of Aggressive Osteodystrophy Management on Clinical Outcomes in Stage 5 Chronic Kidney Disease

The study investigated whether the type of bone disease management (aggressive versus conventional) had an impact on clinical outcomes, namely bone health measures (e.g., biointact parathyroid hormone [BiPTH], serum corrected calcium [cCa] level, serum phosphorus [phos] level, and corrected calcium-phosphorus product [cCaPO(4)]). Retrospective chart review of 173 closed medical records of maintenance hemodialysis patients on thrice-weekly therapy from January 1, 2005, through December 31, 2005. Two Conventional Management (i.e., control group) and three Aggressive Management (i.e., treatment group) dialysis facilities were enrolled. There was a significant interaction for group assignment and BiPTH levels (F = 4.12, P = .01), with the Aggressive Group trending toward lower BiPTH levels than the Conventional Group. The Conventional Group experienced a significantly lower mean annualized serum cCa level (F = 8.85, P = .003), and used non-calcium-based binders significantly more (P < .0005) than the Aggressive Group. In terms of serum phos level, the Aggressive Group had a significantly lower (F = 2.73, P = .05) value than the Conventional Group. No significant differences were reported for cCaPO(4) product (F = 1.87, P = .17). The percentage of the total sample that achieved target range for all bone health measures included 29.8% (n = 50). The study demonstrated that aggressive bone disease management appears to be as effective as traditional interventions in the treatment of mineral and bone metabolism disorders in chronic kidney disease.

Calcium Metabolism in the Early Posttransplantation Period

Information on the time course of serum calcium levels after renal transplantation is scanty, especially in the early posttransplantation period. Both the abrupt cessation of calcium-containing phosphorus binders and vitamin D (analogs) at the time of surgery and the recovery of renal function may be hypothesized to affect serum calcium levels in this period. In this prospective observational study, biointact parathyroid hormone, calcidiol, calcitriol, calcium, and phosphorus levels were monitored in 201 renal transplant recipients at the time of transplantation and 3 mo thereafter. In addition, the serum calcium nadir and peak in each individual patient within this time frame were identified and the urinary fractional calcium excretion was determined at month 3. Serum calcium levels followed a biphasic pattern with a significant decline during the first postoperative week, followed by a significant increase. High pretransplantation parathyroid hormone levels protect against hypocalcemia within the first postoperative week but put patients at risk for hypercalcemia later. These complications, occurring in 41 and 14% of the patients, respectively, most probably reflect inappropriate calcium release from the skeleton, rather than inappropriate renal calcium handling. Our data indicate that both hypo- and hypercalcemia are prevalent in the early posttransplantation period. Pretransplantation parathyroid function is an important predictor of posttransplantation calcium levels.

Absence of adynamic bone disease in African- Americans with CKD Stage 5 after 3 years of vitamin D therapy guided by iPTH and the PTH-(1-84)/N-terminally truncated PTH fragments ratio

Secondary hyperparathyroidism is a frequent complication of chronic kidney disease (CKD). The goal of treatment is to achieve circulating levels of parathyroid hormone (PTH) associated without oversuppression of bone turnover. This is commonly achieved by treatment with vitamin D analogs. Doses of vitamin D compounds are usually monitored by measurement of circulating levels of PTH. To prospectively assess the effects on bone histology of two different protocols for dosing vitamin D. African-American patients from the same geographic area, managed by the same team of physicians in three dialysis clinics were studied. Patients were treated with vitamin D for 3 years and underwent bone biopsies for assessment of bone turnover. Dosing of vitamin D during the 3 years prior to the biopsy was done following two different guidelines. One group was treated following K/DOQI guidelines adapted to the bio-intact PTH assay (Protocol A), the other group was managed (Protocol B) following K/DOQI guidelines for intact PTH and/or the ratio of PTH-(1-84)/N-terminally truncated fragments (PTH ratio). Levels of circulating PTH and/or PTH ratio. Prevalence of low bone turnover. Qualitative and quantitative assessment of bone histology after tetracycline labeling. 7 out of 22 patients managed following Protocol A were found to have low bone turnover (32%) by bone histology. None of the 21 patients managed by Protocol B for guidance of vitamin D therapy, had low bone turnover. Lack of bone biopsy at the beginning of study. This report indicates that the additional information provided by the PTH ratio represents a distinct advantage in avoiding low bone turnover over the use of a single PTH assay to guide vitamin D dosing in African-American patients with CKD Stage 5 on dialysis.

The Association of Race With Erythropoietin Dose in Patients on Long-term Hemodialysis

Medicare data indicate that black hemodialysis patients receive greater doses of erythropoietin (EPO) than white patients when achieving similar hemoglobin levels. We confirmed and evaluated this observed association between race and EPO dose. Cross-sectional cohort study. Primary Medicare-insured white (57%) and black (43%) adult long-term hemodialysis patients treated by Fresenius Medical Care who received EPO from January 1 to 31, 2004 (N = 44,721). White/black race. Average weekly EPO dose. Associations between race and baseline demographic and laboratory variables were evaluated by using logistic and linear regression models. Correlates of log-transformed weekly EPO dose were determined using linear regression models. Black patients received 12.6% more EPO than white patients (95% limits, 10.9% to 14.3%; P < 0.001). This racial difference in EPO dose was observed across similar hemoglobin levels despite fewer catheters (P < 0.001) and fewer prior hospitalization events in black patients (P = 0.002). Black patients were younger and had larger body size and greater albumin and biointact parathyroid hormone levels, but lower equilibrated Kt/V and white blood cell counts (all P < 0.001). In the 95th percentile of EPO dose (those receiving > 60,000 U/wk), there was a greater proportion of black patients (6% of total black population compared with only 4% in all white patients; P < 0.001). The difference in EPO dose between black and white patients was modified by age and was significant at ages younger than 45 and 65 years or older. Observational study limited to white and black adult Medicare patients only, correlating with EPO doses from a single month, without adjustment for comorbid conditions. Black patients were administered approximately 12% greater EPO doses than white patients while achieving similar hemoglobin levels. We identified variables that differed across race that may explain this difference, but they were either not actionable or presented limited opportunity for intervention. Additional studies are needed to define a physiological (or pathological) basis for these observations.

Vitamin C deficiency and secondary hyperparathyroidism in chronic haemodialysis patients

Maintenance haemodialysis patients often suffer from secondary hyperparathyroidism and serum parathyroid hormone levels may be influenced by nutritional variables. We examined serum bio-intact parathyroid hormone (BiPTH) and plasma vitamin C in 117 chronic haemodialysis patients. Plasma vitamin C was measured by high-performance liquid chromatography with electrochemical detection, on samples collected before start of the dialysis treatment. Plasma vitamin C showed a significant positively skewed distribution, ranging from <2 microM to >300 microM. We found 15% (n = 17) of the patients with severe vitamin C deficiency (<10 microM), 66% (n = 77) in the range 10-80 microM, and 19% (n = 23) with plasma vitamin C >80 microM, the upper limit of normal for non-renal disease population. High plasma vitamin C was associated with lower plasma BiPTH (P = 0.005, one-way analysis of variance), and this association persisted after stepwise multiple regression for other factors known to influence PTH. Low vitamin C levels were also associated with increased serum alkaline phosphatase, a further indicator of the impact of vitamin C status on bone metabolism. Patients who reported dietary vitamin C intake of >or=100 mg/day had lower BiPTH (P = 0.015), consistent with findings from plasma measurements of vitamin C. This novel observation of the interaction between PTH and vitamin C may result from effects of vitamin C on cAMP-linked signalling pathways in bone and parathyroid gland. This finding does not yet warrant therapeutic intervention with supplemental vitamin C to remedy secondary hyperparathyroidism. However, further research may indicate a key interaction between vitamin C and the parathyroid hormone linked signalling pathways, and may uncover mechanisms of therapeutic importance.