Hope for CKD-MBD Patients: New Diagnostic Approaches for Better Treatment of CKD-MBD

Hocher, Berthold

doi:10.1159/000477244

Cited by 10 publications

(11 citation statements)

References 67 publications

(43 reference statements)

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“…T50, although strongly influenced by fetuin-A concentrations [1,3], is additionally a dynamic functional serum measure, more broadly affected by other determinantsserum phosphorus, magnesium, and bicarbonate [1,3,36], which are modifiable in CKD [37][38][39]. Thus CKD patients, including KTRs, with shorter duration T50, could be targeted for interventions already familiar to clinicians, which may improve (i.e., prolong) this index of serum calcification propensity [1,3,36].…”

Section: Resultsmentioning

confidence: 99%

“…Thus CKD patients, including KTRs, with shorter duration T50, could be targeted for interventions already familiar to clinicians, which may improve (i.e., prolong) this index of serum calcification propensity [1,3,36]. Phosphoruslowering treatments [37], and magnesium [38] or alkali [39] supplementation are examples of such individual therapies whose experimental capacity to prolong T50 might be considerably enhanced if administered in combination [1,3,36].…”

Section: Resultsmentioning

confidence: 99%

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Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

et al. 2018

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Background: “T50,” shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. Methods: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. Results: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20–2.89); fetuin-A, (HR 2.25; 95% CI 1.38–3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. Conclusions: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

et al. 2018

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“…Both negative as well as positive calcium balance pose possible health threats in CKD-MBD: negative balance might raise risk of osteoporosis as well as fracture, and positive balance might raise risk for extra-skeletal calcification and cardiovascular events. 16 There is substantial relationship between factors which influence calcium and phosphate regulation. These influences are more complicated in patients having impaired renal function.…”

Section: Introductionmentioning

confidence: 99%

Calcium levels and metabolic disturbance in renal disease patients receiving hemodialysis: a cross sectional study highlighting its association in dialysis patients

et al. 2019

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Background: The aim of this study was to determine the disturbances in Calcium and other mineral levels in patients on hemodialysis at Tabba Kidney Institute, Karachi, Sindh, Pakistan.Methods: A cross sectional observational study through convenient sampling technique was conducted from January 2017 to August 2017 at Tabba Kidney Institute, Karachi after obtaining ethical approval. 255 patients, all above 18 years of age and on hemodialysis were included in the study. Multi-organ failure patients on dialysis, other systemic diseased patients on hemodialysis were excluded. Demographic variables, mineral levels, symptoms and supplementations were recorded. SPSS version 20.0 was used for data analysis.Results: A total of 255 patients on hemodialysis were selected and divided into groups depending upon median years of hemodialysis below and above 5 years of hemodialysis. Median and IQR of calcium were 8.8 and 8.2-9.1 mg/dl for below 5 years, 8.6 and 8.1-9.1 mg/dl for above 5 years (P value=0.44). Median and IQR of phosphate were 4.9 and 3.9-5.7 mg/dl for below 5 years and 4.6 and 3.7-5.5 mg/dl for above 5 years (P value=0.21). Median and IQR of parathyroid hormone were 393 and 212-699 pg/ml for below 5 years and 329 and 128-657 pg/ml for above 5 years. (P value=0.13) Median and IQR of albumin were 4.0 and 3.6-4.2 mg/dl for below 5 years and 4.0 and 3.8-4.3 for above 5 years (P value=0.30). Total of 18 (10.9%) had para thyroidectomy.Conclusions: Present study showed that significant difference in mineral levels did not exist in patients on hemodialysis as regards to the duration of dialysis. However clinical features had a tendency to decrease as duration of dialysis increased to above 5 years. Para thyroidectomy and itching were two main significant findings in this study.

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“…Studies performed by leading research groups worldwide done about two decades ago clearly indicated that oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) have completely different biological properties (see reviews [19,20]). All these studies -over 20 in independent groups worldwide -indicate that PTH oxidation is critical for the biological activity of PTH.…”

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confidence: 99%

“…Huge clinical studies like the EVOLVE trail [13] used iPTH measurements as key inclusion criteria to identify patients with secondary hyperparathyroidism. Intact PTH (iPTH) measurements in these patients, however, do more describe oxidative stress rather than biological active PTH (iPTH correlates much better with biologically non-active oxidized PTH [oxPTH] than n-oxPTH, see references [19,20]). Thus including patients on the basis of iPTH is a poor clinical tool to select patients with secondary hyperparathyroidism.…”

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confidence: 99%

Need for better PTH assays for clinical research and patient treatment

Hocher

Zeng

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Parathyroid hormone (PTH) -a 84-amino acids containing peptide hormone secreted by the parathyroid gland -regulates the blood calcium level via GPCR binding and subsequent activation of intracellular signaling cascades [1]. Animal models of chronic kidney disease (CKD) clearly demonstrated that both too low and also too high PTH concentrations in these CKD model are causal for the development of both bone and cardiovascular diseases [2][3][4][5].Similarly, low PTH concentrations and in particular high PTH concentrations in CKD patients are associated with excess morbidity and mortality [6][7][8][9]. These studies led to the development of guidelines for the treatment of CKD patients [10,11] and the development of pharmaceutical tools to treat these abnormal status such as PTH analogues [12] for conditions of low PTH related situations as well a vitamin D analogues, calcimimetics and phosphorus binders for conditions with high PTH [13][14][15][16].Clinical research to develop new drugs for CKD-MBD patients, clinical use of these drugs and the monitoring of the efficacy requires reliable analytical tools to measure PTH. However, as of today, we are not able to define a clear cut-off value for PTH that is clearly associated with secondary hyperparathyroidism. We have instead complicated guidelines how PTH in patients on dialysis should look like (PTH should be 2-9 times higher than the upper detection limit of the individual assay used and physicians needs to consider PTH trends when adjusting therapy [10,11]). This complicated wording is simply necessary, because current PTH assays are unable to provide general applicable exact cut-offs. Moreover, in daily practice it is well known that PTH measurements in individual cases are often not fitting to the clinical situation [17]. One underlying reason that might contribute to the poor performance of current PTH assays is potential posttranslational modification of PTH -in particular oxidation at Met8 and Met18 of the PTH-1-84 molecule, since patients with CKD and in particular CKD patents on dialysis have a huge burden of oxidative stress [18].Oxidation of PTH has a huge impact on the biological activity of PTH. Studies performed by leading research groups worldwide done about two decades ago clearly indicated that oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) have completely different biological properties (see reviews [19,20]). All these studies -over 20 in independent groups worldwide -indicate that PTH oxidation is critical for the biological activity of PTH. PTH oxidation, however, has been so far ignored in the development of PTH assays that are used in current clinical practice.Therefore, assay system separating oxPTH from n-oxPTH were developed recently and it was demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients on dialysis [21][22][23][24]. The currently used PTH assays are called intact PTH (iPTH) assays. These are sandwich assays detecting the entire (intact) PTH molecule, but ignore PTH oxidat...

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Hope for CKD-MBD Patients: New Diagnostic Approaches for Better Treatment of CKD-MBD

Cited by 10 publications

References 67 publications

Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

Calcium levels and metabolic disturbance in renal disease patients receiving hemodialysis: a cross sectional study highlighting its association in dialysis patients

Need for better PTH assays for clinical research and patient treatment

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