Dataset Information

The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder.

ABSTRACT: Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the 'intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that 'as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca²+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca²+ sensing receptor, and Klotho-fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an 'intestinal phosphatonin'. These observations suggest a possible 'phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-α-epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function.

SUBMITTER: Slatopolsky E

PROVIDER: S-EPMC3260962 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:BackgroundChronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice.MethodsA national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice.ResultsOne hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range.ConclusionResults point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Project description:Background and objectivesParathyroid hormone, calcium, and phosphate have been independently associated with cardiovascular event risk. Because these parameters may be on the same causal pathway and have been proposed as quality measures, an integrated approach to estimating event risks is needed.Design, setting, participants, & measurementsPrevalent dialysis patients were followed from August 31, 2005 to December 31, 2006. A two-stage modeling approach was used. First, the 16-month probabilities of death and composite end point of death or cardiovascular hospitalization were estimated and adjusted for potential confounders. Second, patients were categorized into 1 of 36 possible phenotypes using average parathyroid hormone, calcium, and phosphate values over a 4-month baseline period. Associations among phenotypes and outcomes were estimated and adjusted for the underlying event risk estimated from the first model stage.ResultsOf 26,221 patients, 98.5% of patients were in 22 groups with at least 100 patients and 20% of patients were in the reference group defined using guideline-based reference ranges for parathyroid hormone, calcium, and phosphate. Within the 22 most common phenotypes, 20% of patients were in groups with significantly (P<0.05) higher risk of death and 54% of patients were in groups with significantly higher risk of the composite end point relative to the in-target reference group. Increased risks ranged from 15% to 47% for death and from 8% to 55% for the composite. More than 40% of all patients were in the three largest groups with elevated composite end point risk (high parathyroid hormone, target calcium, and high phosphate; target high parathyroid hormone, target calcium, and high phosphate; and target high parathyroid hormone, target calcium, and target phosphate).ConclusionAfter adjusting for baseline risk, phenotypes defined by categories of parathyroid hormone, calcium, and phosphate identify patients at higher risk of death and cardiovascular hospitalization. Identifying common high-risk phenotypes may inform clinical interventions and policies related to quality of care.

Project description:BackgroundIn the general population, the trabecular bone score (TBS) represents the bone microarchitecture and predicts fracture risk independent of bone mineral density (BMD). A few studies reported that TBS is significantly reduced in dialysis patients. Chronic kidney disease-mineral and bone disorder (CKD-MBD) are accompanied by increased fracture risk, cardiovascular morbidity, and mortality. We investigated whether TBS is associated with comorbidity related to CKD-MBD or frailty in hemodialysis patients.MethodsIn this prospective observational study, TBS was obtained using the TBS iNsight software program (Med-Imaps) with BMD dual energy x-ray absorptiometry (DXA) images (L1-L4) from prevalent hemodialysis patients. A Tilburg frailty indicator was used to evaluate frailty, and hand grip strength and bio-impedance (InBody) were measured. A patient-generated subjective global assessment (PG-SGA) was used for nutritional assessment. The history of cardiovascular events (CVE) and demographic, clinical, laboratory, and biomarker data were collated. We then followed up patients for the occurrence of CKD-MBD related complications.ResultsWe enrolled 57 patients in total. The mean age was 56.8 ± 15.9 years (50.9% female). Prevalence of Diabetes mellitus (DM) was 40.4% and CVE was 36.8%. Mean TBS was 1.44 ± 0.10. TBS significantly reduced in the CVE group (1.38 ± 0.08 vs. 1.48 ± 0.10, p < 0.001). Multivariable regression analysis was conducted adjusting for age, sex, dialysis vintage, DM, CVE, albumin, intact parathyroid hormone, fibroblast growth factor 23, handgrip strength, and phosphate binder dose. Age (ß = - 0.030; p = 0.001) and CVE (ß = - 0.055; p = 0.024) were significant predictors of TBS. During the follow up period after TBS measurements (about 20 months), four deaths, seven incident fractures, and six new onset CVE were recorded. Lower TBS was associated with mortality (p = 0.049) or new onset fracture (p = 0.007, by log-rank test).ConclusionLower TBS was independently associated with increased age and CVE prevalence in hemodialysis patients. Mortality and fracture incidence were significantly higher in patients with lower TBS values. These findings suggest that TBS may indicate a phenotype of frailty and also a CKD-MBD phenotype reciprocal to CVE.

Project description:Information is limited regarding utilization patterns and costs for chronic kidney disease-mineral and bone disorder (CKD-MBD) medications in Medicare Part D-enrolled dialysis patients.Retrospective cohort study.Annual cohorts of dialysis patients, 2007-2010.Cohort year, low-income subsidy status, and dialysis provider.Utilization and costs of prescription phosphate binders, oral and intravenous vitamin D analogues, and cinacalcet.Using logistic regression, we calculated adjusted odds of medication use for low-income subsidy versus non-low-income subsidy patients and for patients from various dialysis organizations, and we report per-member-per-month and average out-of-pocket costs.Phosphate binders (?83%) and intravenous vitamin D (77.5%-79.3%) were the most commonly used CKD-MBD medications in 2007 through 2010. The adjusted odds of prescription phosphate-binder, intravenous vitamin D, and cinacalcet use were significantly higher for low-income subsidy than for non-low-income subsidy patients. Total Part D versus CKD-MBD Part D medication costs increased 22% versus 36% from 2007 to 2010. For Part D-enrolled dialysis patients, CKD-MBD medications represented ?50% of overall net Part D costs in 2010.Inability to describe utilization and costs of calcium carbonate, an over-the-counter agent not covered under Medicare Part D; inability to reliably identify prescriptions filled through a non-Part D reimbursement or payment mechanism; findings may not apply to dialysis patients without Medicare Part D benefits or with Medicare Advantage plans, or to pediatric dialysis patients; could identify only prescription drugs dispensed in the outpatient setting; inability to adjust for MBD laboratory values.Part D net costs for CKD-MBD medications increased at a faster rate than costs for all Part D medications in dialysis patients despite relatively stable use within medication classes. In a bundled environment, there may be incentives to shift to generic phosphate binders and reduce cinacalcet use.

Dataset Information

The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets