CKD-Mineral Bone Disorder

Complex Pathograph 17 Renal Disease Metabolic Bone Disease

CKD-mineral and bone disorder (CKD-MBD) is the systemic complication syndrome of chronic kidney disease characterized by abnormalities of mineral metabolism, skeletal turnover/mineralization/volume or strength, and vascular or other soft-tissue calcification. Renal osteodystrophy refers specifically to the bone histomorphometric abnormalities of CKD-MBD seen on bone biopsy, not to the full CKD-MBD syndrome.

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1
Mappings
7
Pathophys.
4
Histopath.
6
Phenotypes
17
Pathograph
2
Genes
6
Medical Actions
3
Models
12
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0006946 renal osteodystrophy Not Yet Curated
skos:closeMatch MONDO
Closest available MONDO term in the current ontology snapshot maps only to the renal osteodystrophy bone component of CKD-MBD, not to the broader CKD-MBD syndrome.
⚙

Pathophysiology

7
Phosphate Retention and FGF23 Axis
As nephron mass declines, phosphate excretion per nephron increases via FGF23 and PTH-mediated suppression of proximal tubular sodium-phosphate cotransporters (NaPi-2a/NaPi-2c). FGF23 rises early in CKD (stage 2) before serum phosphate becomes overtly elevated. FGF23 requires the co-receptor alpha-Klotho, which is predominantly expressed in the kidney and declines with CKD progression, creating a vicious cycle.
Osteocyte CL:0000137 Proximal Tubular Epithelial Cell CL:0002306
RGS14 hgnc:9996
Phosphate Ion Homeostasis GO:0055062 Fibroblast Growth Factor Receptor Signaling GO:0008543
Proximal Tubule UBERON:0004134 Bone Tissue UBERON:0002481
Downstream
Secondary Hyperparathyroidism Hyperphosphatemia directly stimulates PTH secretion; FGF23 suppresses calcitriol removing PTH inhibition
Calcitriol Deficiency FGF23 suppresses 1-alpha-hydroxylase (CYP27B1) and upregulates 24-hydroxylase (CYP24A1)
Vascular Calcification Hyperphosphatemia and Klotho deficiency promote VSMC osteogenic transdifferentiation
Show evidence (3 references)
PMID:37258233 SUPPORT Human Clinical
"CKD-MBD manifests as hypocalcemia and hyperphosphatemia in the later stages of CKD; however, it initially develops much earlier in disease course. The initial step in CKD-MBD involves decreased phosphate excretion in the urine, followed by increased circulating concentrations of fibroblast..."
Confirms that FGF23 and PTH rise early in CKD as compensatory responses to decreased phosphate excretion, before overt hyperphosphatemia.
PMID:36821389 SUPPORT Model Organism
"phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production"
Identifies the molecular mechanism linking phosphate load to FGF23 production via a kidney-bone metabolic feedback loop involving G-3-P. Mouse and human data.
PMID:38541742 SUPPORT Human Clinical
"These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy"
Confirms mineral metabolism disturbances including FGF23 are observed early in CKD progression.
Kidney Glycolysis-G3P Phosphate Sensing
A recently discovered kidney-bone feedback loop: phosphate loading increases kidney-specific glycolysis and production of glycerol-3-phosphate (G-3-P) via GPD1. G-3-P enters the circulation and triggers FGF23 production in bone osteocytes. This places glycolysis at the nexus of mineral and energy metabolism, revealing that phosphate does not directly stimulate bone FGF23 expression but acts through a renal metabolic intermediate.
Proximal Tubular Epithelial Cell CL:0002306 Osteocyte CL:0000137
Glycolytic Process GO:0006096 Phosphate Ion Homeostasis GO:0055062
Kidney UBERON:0002113
Downstream
Phosphate Retention and FGF23 Axis G-3-P produced by kidney glycolysis circulates to bone and triggers FGF23 production
Show evidence (2 references)
PMID:36821389 SUPPORT Model Organism
"these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis"
Landmark study demonstrating that kidney glycolysis produces G-3-P as a phosphate-sensing signal to bone FGF23 production. Loss of GPD1 abolished phosphate-stimulated FGF23 in mice.
PMID:36821389 SUPPORT Model Organism
"phosphate does not directly stimulate bone FGF23 expression"
Overturns the assumption that phosphate directly acts on osteocytes, identifying an indirect kidney-mediated mechanism.
Secondary Hyperparathyroidism
Declining calcitriol synthesis (due to reduced 1-alpha-hydroxylase activity in damaged kidneys), hypocalcemia, hyperphosphatemia, and reduced calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression in parathyroid glands collectively stimulate PTH secretion. PTH levels spike above normal as early as CKD stage G2. Chronically elevated PTH drives high-turnover bone disease with increased osteoclastic resorption and extends to the cardiovascular system promoting vascular calcifications.
Parathyroid Chief Cell CL:0000446 Osteoclast CL:0000092 Osteoblast CL:0000062
CASR hgnc:1514
Parathyroid Hormone Secretion GO:0035898 Bone Resorption GO:0045453 Calcium Ion Homeostasis GO:0055074
Parathyroid Gland UBERON:0001132
Downstream
RANKL/OPG Imbalance Elevated PTH increases RANKL and suppresses OPG, driving osteoclastogenesis
Vascular Calcification Chronically elevated PTH promotes vascular calcifications
Bone Pain PTH-driven high-turnover bone disease causes diffuse bone pain
Left Ventricular Hypertrophy PTH and FGF23 directly cause left ventricular hypertrophy
Show evidence (4 references)
PMID:38785509 SUPPORT Human Clinical
"levels of PTH spike out of the normal range as early as stage G2 CKD, advancing it as a possible determinant of systemic damage"
Confirms PTH elevation begins very early in CKD, consistent with the updated trade-off hypothesis.
PMID:32961953 SUPPORT Human Clinical
"The decrease in serum calcium concentration is sensed by a specific membrane calcium-sensing receptor (CaSR) on parathyroid glands and is a potent stimulus for PTH release"
Directly supports CaSR as a parathyroid-gland mechanism modulating PTH release in CKD secondary hyperparathyroidism.
PMID:38785509 SUPPORT Human Clinical
"the altered mineral balance extends to the cardiovascular system, promoting vascular calcifications"
Elevated PTH drives not only bone resorption but also vascular calcification as a systemic consequence.
+ 1 more reference
Calcitriol Deficiency
The kidney is the primary site of 1-alpha-hydroxylation of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D (calcitriol). Progressive nephron loss reduces calcitriol production, impairing intestinal calcium absorption and skeletal mineralization. FGF23 further suppresses 1-alpha-hydroxylase and upregulates 24-hydroxylase, accelerating calcitriol depletion.
Vitamin D Metabolic Process GO:0042359
Kidney UBERON:0002113
Downstream
Secondary Hyperparathyroidism Reduced calcitriol removes VDR-mediated suppression of PTH gene transcription
Show evidence (2 references)
PMID:26303319 SUPPORT Human Clinical
"Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop."
Reviews the adaptive mechanisms maintaining mineral homeostasis in CKD, including the role of reduced calcitriol in hypocalcemia.
PMID:37258233 SUPPORT Human Clinical
"Simultaneously, the serum calcitriol concentration decreases as a result of FGF23 elevation."
Confirms that FGF23 elevation directly suppresses calcitriol production, linking the FGF23 axis to vitamin D deficiency.
Vascular Calcification
Hyperphosphatemia and elevated calcium-phosphate product promote osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells via RUNX2 and Pit-1/Pit-2 phosphate transporters. Loss of calcification inhibitors (fetuin-A, matrix Gla protein, pyrophosphate, osteoprotegerin) and Klotho deficiency further drive medial arterial calcification. Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as key mediators of phosphate toxicity, linking mineral stress to vascular inflammation and calcification. This is the major cause of cardiovascular mortality in CKD-MBD.
Vascular Smooth Muscle Cell CL:0000359
Osteogenic Transdifferentiation of Vascular Smooth Muscle Cells GO:0001649 ↑ INCREASED
Arterial Blood Vessel UBERON:0003509
Experimental models
Primary human vascular CPP bioassay model PRIMARY CELL CULTURE Recapitulates CPP-mediated vascular smooth muscle calcification and endothelial activation downstream of CKD mineral stress.
Downstream
Bone-Vascular Paradox (Sclerostin/Wnt Axis) Calcified arteries produce sclerostin and other factors that inhibit bone remodeling
Left Ventricular Hypertrophy Arterial stiffening from medial calcification increases cardiac afterload
Calciphylaxis Small vessel calcification and thrombosis cause painful skin necrosis
Show evidence (4 references)
PMID:39684805 SUPPORT Human Clinical
"several pathophysiological processes contribute to vascular calcifications, including osteochondrogenic differentiation of vascular cells, hyperphosphatemia and hypercalcemia, and the loss of specific vascular calcification inhibitors including pyrophosphate, fetuin-A, osteoprotegerin, and..."
Comprehensive description of vascular calcification as an active cell-mediated process involving osteochondrogenic differentiation and loss of endogenous inhibitors.
PMID:38541742 SUPPORT Human Clinical
"The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP)."
Confirms VSMC involvement and CPP formation as key components of CKD-MBD vascular calcification.
PMID:36107466 SUPPORT Human Clinical
"Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation."
Identifies CPPs as mediators of phosphate toxicity linking mineral stress to vascular damage.
+ 1 more reference
Bone-Vascular Paradox (Sclerostin/Wnt Axis)
Calcified arteries in CKD produce sclerostin and other factors that inhibit bone remodeling, explaining the paradox of simultaneous vascular calcification and low-turnover (adynamic) bone disease. Vascular osteoblastic/osteocytic transdifferentiation produces sclerostin that brakes Wnt-driven calcification in the vasculature but also suppresses skeletal bone formation. Anti-sclerostin antibody therapy improves bone but can worsen vascular calcification, highlighting the therapeutic complexity.
Vascular Smooth Muscle Cell CL:0000359 Osteocyte CL:0000137
Wnt Signaling Pathway GO:0016055 Bone Remodeling GO:0046849
Downstream
Decreased Bone Mineral Density Vascular sclerostin suppresses skeletal Wnt signaling and bone formation
Show evidence (3 references)
PMID:36776982 SUPPORT Human Clinical
"The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox."
Identifies the mechanism of the bone-vascular paradox where calcified arteries produce factors that inhibit skeletal bone remodeling.
PMID:36776982 SUPPORT Human Clinical
"Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy."
Vascular production of sclerostin through osteoblastic transdifferentiation of vascular cells links vascular calcification to bone disease.
PMID:36776982 SUPPORT Model Organism
"inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu"
Anti-sclerostin antibody demonstrates the paradox - improving bone worsens vascular calcification, confirming sclerostin's protective role in vasculature.
RANKL/OPG Imbalance
Elevated PTH increases RANKL expression by osteoblasts and osteocytes while suppressing osteoprotegerin (OPG), shifting the balance toward excessive osteoclastogenesis and bone resorption. Uremic toxins may independently alter RANKL/OPG signaling. Novel biologicals targeting RANKL (denosumab) and sclerostin are being explored in CKD-MBD but require careful consideration of the bone-vascular paradox.
Osteoclast Differentiation GO:0030316
Downstream
Decreased Bone Mineral Density Excessive osteoclastogenesis increases bone resorption, reducing BMD
Pathological Fractures Reduced BMD from RANKL-driven resorption increases fracture risk
Bone Pain High-turnover bone disease with excessive resorption causes bone pain
Show evidence (1 reference)
PMID:28540603 SUPPORT Human Clinical
"Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality."
Reviews the positioning of novel biologicals including denosumab (anti-RANKL) in CKD-MBD, discussing the RANKL/OPG axis as a therapeutic target.
✶

Histopathology

4
High-Turnover Renal Osteodystrophy (Osteitis Fibrosa)
Bone-biopsy pattern within the renal osteodystrophy component of CKD-MBD, driven by secondary hyperparathyroidism with excessive osteoclast-mediated bone resorption and disorganized new bone formation. The most common high-turnover pattern in dialysis patients.
Show evidence (1 reference)
PMID:34137924 SUPPORT Human Clinical
"42% had high turnover/hyperparathyroid bone disease and 23% had low turnover/adynamic bone disease"
Bone biopsy study of 26 dialysis patients using TMV classification showing hyperparathyroid/high-turnover disease as the most common renal osteodystrophy histologic pattern.
Low-Turnover Renal Osteodystrophy (Adynamic Bone Disease)
Bone-biopsy pattern within the renal osteodystrophy component of CKD-MBD characterized by suppressed bone formation and resorption, often from over-suppression of PTH or aluminum toxicity. Associated with increased fracture risk and vascular calcification.
Show evidence (1 reference)
PMID:34137924 SUPPORT Human Clinical
"42% had high turnover/hyperparathyroid bone disease and 23% had low turnover/adynamic bone disease"
Bone biopsy study confirms adynamic bone disease as a recognized renal osteodystrophy histologic pattern, present in 23% of dialysis patients.
Mixed Uremic Osteodystrophy
Bone-biopsy pattern within the renal osteodystrophy component of CKD-MBD with features of both high- and low-turnover disease, showing areas of increased resorption alongside defective mineralization.
Show evidence (1 reference)
PMID:28540603 SUPPORT Human Clinical
"Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD)"
Reviews the spectrum of renal osteodystrophy histologic patterns, including mixed forms, within the broader CKD-MBD framework.
Osteomalacia
Renal osteodystrophy pattern within CKD-MBD characterized by defective bone mineralization due to vitamin D deficiency or aluminum accumulation, with increased osteoid volume and decreased mineralization rate.
Show evidence (1 reference)
PMID:28646995 SUPPORT Human Clinical
"Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance"
KDIGO 2017 guideline recognizes osteomalacia as a distinct bone pathology within the bone component of CKD-MBD, requiring specific diagnostic and treatment approaches.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CKD-Mineral Bone Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Cardiovascular 2
Vascular Calcification VERY_FREQUENT Arterial calcification HP:0003207
Coronary artery calcification and peripheral arterial calcification are present in >80% of dialysis patients. Major driver of cardiovascular mortality.
Show evidence (1 reference)
PMID:38573243 SUPPORT Human Clinical
"as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis"
Highlights the clinical significance and therapeutic gap for vascular calcification in CKD.
Left Ventricular Hypertrophy FREQUENT Left ventricular hypertrophy HP:0001712
Secondary to arterial stiffening from vascular calcification and volume overload
Show evidence (1 reference)
PMID:37258233 SUPPORT Human Clinical
"FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification"
Directly links elevated FGF23 and PTH to left ventricular hypertrophy as a phenotypic manifestation of CKD-MBD.
Musculoskeletal 3
Pathological Fractures FREQUENT Pathologic fracture HP:0002756
Vertebral compression fractures, hip fractures. Risk 2-14x higher than age-matched controls without CKD.
Show evidence (2 references)
PMID:32961953 SUPPORT Human Clinical
"The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality."
Systematic review confirming increased fracture risk as a key consequence of CKD-MBD.
PMID:38785509 SUPPORT Human Clinical
"persistently high levels of PTH determine a reduction in mineral density and a concurrent increase in fracture risk"
Links elevated PTH to both reduced BMD and increased fracture risk.
Decreased Bone Mineral Density VERY_FREQUENT Reduced bone mineral density HP:0004349
Show evidence (1 reference)
PMID:32961953 SUPPORT Human Clinical
"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."
Systematic review defining bone mineral density abnormalities as a core component of CKD-MBD.
Calciphylaxis OCCASIONAL Calcinosis cutis HP:0025520
Calcific uremic arteriolopathy — painful skin necrosis from small vessel calcification and thrombosis. High mortality. Proxied to the broader HPO term calcinosis cutis because no exact calciphylaxis term was identified in the local HPO snapshot used for validation.
Show evidence (1 reference)
PMID:38573243 SUPPORT Human Clinical
"as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis"
Confirms calciphylaxis as a recognized CKD-MBD manifestation with no approved treatment.
Constitutional 1
Bone Pain FREQUENT Bone pain HP:0002653
Diffuse bone pain, especially in weight-bearing bones
Show evidence (1 reference)
PMID:32961953 SUPPORT Human Clinical
"Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD."
Confirms early bone structural changes in CKD that manifest as bone pain.
🧬

Genetic Associations

2
CASR (Modifier)
Gene: CASR hgnc:1514
Show evidence (1 reference)
PMID:35587600 SUPPORT Human Clinical
"SNVs adjacent to or within genes encoding the regulator of G protein-coupled signaling 14 (RGS14) and the calcium-sensing receptor (CASR) were associated with levels of mineral metabolites."
Candidate-variant analysis in 3027 CRIC participants supports CASR as a CKD-relevant modifier of mineral metabolism, but not as a primary causal gene for CKD-MBD.
RGS14 (Modifier)
Gene: RGS14 hgnc:9996
Show evidence (1 reference)
PMID:35587600 SUPPORT Human Clinical
"Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23, and lower prevalence of hyperparathyroidism."
This CRIC cohort result directly links RGS14 variation to key CKD-MBD laboratory features, supporting it as a disease-relevant modifier rather than a broad speculative pathway gene.
💊

Medical Actions

6
Phosphate Binders
Action: phosphate binder therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: calcium carbonate CHEBI:3311 calcium acetate CHEBI:3310 lanthanum carbonate CHEBI:49701
Calcium-based (calcium carbonate, calcium acetate) or non-calcium-based (sevelamer, lanthanum carbonate, sucroferric oxyhydroxide) agents that bind dietary phosphate in the gut to reduce absorption.
Mechanism Target:
INHIBITS Vascular Calcification — Reduces intestinal phosphate absorption and endogenous calciprotein particle burden, attenuating phosphate-driven vascular calcification.
Show evidence (1 reference)
PMID:36107466 SUPPORT In Vitro
"High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro."
Supports a direct treatment edge from phosphate binders to the vascular calcification mechanism via reduced CPP burden and reduced pro-calcific serum activity.
Show evidence (1 reference)
PMID:36107466 SUPPORT In Vitro
"High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro."
Sucroferric oxyhydroxide reduces CPP formation and attenuates vascular calcification effects, supporting phosphate binder efficacy.
Active Vitamin D Therapy
Action: active vitamin D analog therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: calcitriol CHEBI:17823 paricalcitol CHEBI:7931
Calcitriol or active vitamin D analogs (paricalcitol, doxercalciferol) to suppress PTH, improve calcium absorption, and support bone mineralization. Must balance against risk of hypercalcemia and hyperphosphatemia.
Mechanism Target:
INHIBITS Secondary Hyperparathyroidism — Replaces deficient active vitamin D signaling and suppresses persistent secondary hyperparathyroidism.
Show evidence (1 reference)
PMID:29523679 PARTIAL Human Clinical
"There is insufficient data on whether to prefer vitamin D analogs compared with calcimimetics, but the available evidence suggests advantages with combination therapy."
Partially supports active vitamin D analog therapy as a treatment for secondary hyperparathyroidism, but the abstract frames the evidence comparatively rather than as a direct mechanistic PTH-suppression result.
Show evidence (1 reference)
PMID:29523679 SUPPORT Human Clinical
"There is insufficient data on whether to prefer vitamin D analogs compared with calcimimetics, but the available evidence suggests advantages with combination therapy."
Supports use of vitamin D analogs in CKD secondary hyperparathyroidism, noting combination therapy with calcimimetics may be optimal.
Calcimimetics
Action: calcimimetic therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: cinacalcet CHEBI:48390 etelcalcetide CHEBI:134700
Cinacalcet and etelcalcetide allosterically activate the calcium-sensing receptor on parathyroid cells, suppressing PTH secretion without raising serum calcium. First-line for secondary hyperparathyroidism in dialysis.
Mechanism Target:
INHIBITS Secondary Hyperparathyroidism — Activates the parathyroid calcium-sensing receptor to suppress PTH secretion and counter secondary hyperparathyroidism.
Show evidence (1 reference)
PMID:28097356 SUPPORT Human Clinical
"The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5%"
This randomized trial directly supports the mechanistic claim that calcimimetic therapy suppresses PTH in dialysis-associated secondary hyperparathyroidism, with cinacalcet achieving greater than 30% PTH reduction in most treated patients.
Show evidence (1 reference)
PMID:23121374 PARTIAL Human Clinical
"In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis."
The EVOLVE trial (n=3883) showed cinacalcet did not significantly reduce cardiovascular events in the primary ITT analysis, though secondary analyses suggested benefit after adjustment for baseline characteristics.
Parathyroidectomy
Action: parathyroidectomy Ontology label: surgical procedure MAXO:0000004
Surgical removal of hyperplastic parathyroid glands for refractory secondary or tertiary hyperparathyroidism unresponsive to medical therapy.
Mechanism Target:
INHIBITS Secondary Hyperparathyroidism — Removes hyperplastic parathyroid tissue when secondary hyperparathyroidism is refractory to medical therapy.
Show evidence (1 reference)
PMID:29523679 SUPPORT Human Clinical
"When parathyroid hormone level persists >800 pg/ml for >6 months, despite exhaustive medical interventions, monoclonal proliferation with nodular hyperplasia is likely present along with decreased expression of vitamin D and calcium-sensing receptors. Hence, surgical parathyroidectomy should be..."
Supports a direct treatment edge from parathyroidectomy to the secondary hyperparathyroidism mechanism in medically refractory disease.
Show evidence (1 reference)
PMID:29523679 SUPPORT Human Clinical
"When parathyroid hormone level persists >800 pg/ml for >6 months, despite exhaustive medical interventions, monoclonal proliferation with nodular hyperplasia is likely present along with decreased expression of vitamin D and calcium-sensing receptors. Hence, surgical parathyroidectomy should be..."
Defines indications for parathyroidectomy in refractory secondary hyperparathyroidism based on PTH thresholds and medical therapy failure.
Dialysis Optimization
Action: dialysis optimization Ontology label: hemodialysis MAXO:0000602
Adjustment of dialysate calcium concentration and extended/frequent dialysis sessions to improve phosphate and calcium clearance.
Show evidence (1 reference)
PMID:38573243 SUPPORT Human Clinical
"Conventional therapies targeted at CKD-mineral and bone disorder (MBD) modulation have yielded conflicting or inconclusive results."
Highlights that conventional CKD-MBD therapies including dialysis optimization have inconsistent effects on vascular calcification outcomes.
Kidney Transplantation
Action: kidney transplantation Ontology label: organ transplantation MAXO:0010039
Restores renal 1-alpha-hydroxylase activity and phosphate excretion. Most effective treatment for CKD-MBD, though persistent hyperparathyroidism (tertiary) may occur post-transplant.
Show evidence (1 reference)
PMID:33765230 SUPPORT Human Clinical
"Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations."
Reviews post-transplant CKD-MBD including persistent hyperparathyroidism, hypercalcemia, and ongoing bone disease despite restored renal function.
🔬

Biochemical Markers

10
Phosphate (Elevated)
Context: Impaired renal excretion, overtly elevated in CKD stages 4-5
Reference Ranges
Phosphate [Mass/volume] in Serum or Plasma 2.5–4.5 mg/dL (adults)
Reference interval from Tietz Clinical Guide to Laboratory Tests, 4th ed. (2006).
Show evidence (1 reference)
PMID:33784965 SUPPORT Human Clinical
"Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively"
Cross-sectional study of 85 patients quantifies the eGFR thresholds at which phosphate, PTH, and FGF23 become significantly elevated.
FGF23 (Elevated)
Context: Earliest biomarker, rises in CKD stage 2 before phosphate elevation
Show evidence (2 references)
PMID:33784965 SUPPORT Human Clinical
"a compensatory increase in circulating FGF23 concentrations commences before the occurrence of hyperphosphatemia"
Confirms FGF23 rises as an early compensatory mechanism in CKD before phosphate elevation.
PMID:37258233 SUPPORT Human Clinical
"increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion"
Reviews FGF23 as a key early biomarker in CKD-MBD pathogenesis.
Glycerol-3-Phosphate (G-3-P) (Elevated)
Context: Kidney glycolysis-derived metabolite that triggers FGF23 production in bone
Show evidence (1 reference)
PMID:36821389 SUPPORT Model Organism
"phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production"
Identifies G-3-P as a circulating metabolite produced by kidney glycolysis that signals to bone osteocytes.
PTH (Intact) (Elevated)
Context: Secondary hyperparathyroidism, spikes above normal as early as CKD stage G2
Reference Ranges
Parathyrin.intact [Mass/volume] in Serum or Plasma 15.0–65.0 pg/mL (adults)
Reference interval from Tietz Clinical Guide to Laboratory Tests, 4th ed. (2006). Reference range varies by assay generation; third-generation biointact PTH assays have different normal ranges.
Show evidence (2 references)
PMID:38785509 SUPPORT Human Clinical
"levels of PTH spike out of the normal range as early as stage G2 CKD, advancing it as a possible determinant of systemic damage"
Confirms PTH elevation begins in early CKD stage G2.
PMID:33784965 SUPPORT Human Clinical
"Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively"
Quantifies the eGFR threshold for significant PTH elevation at <29 mL/min/1.73m2.
Calcitriol (1,25-dihydroxyvitamin D) (Decreased)
Context: Reduced 1-alpha-hydroxylase activity and FGF23-mediated suppression
Reference Ranges
Calcitriol [Mass/volume] in Serum or Plasma 18.0–64.0 pg/mL (adults)
Reference interval from Mayo Clinic Laboratories.
Show evidence (1 reference)
PMID:33784965 SUPPORT Human Clinical
"while significant decreases in serum 1,25(OH)2D were observed at an eGFR of < 52 mL/min/1.73 m2 (95 % CI, 42.57-61.43)."
Demonstrates calcitriol decline occurs at eGFR <52, earlier than PTH or phosphate changes.
Calcium (Decreased)
Context: Reduced intestinal absorption from calcitriol deficiency
Reference Ranges
Calcium [Mass/volume] in Serum or Plasma 8.5–10.5 mg/dL (adults)
Hypocalcemia (–8.5 mg/dL) → Hypocalcemia Normal (8.5–10.5 mg/dL) Mild hypercalcemia (10.5–12.0 mg/dL) → Hypercalcemia Moderate hypercalcemia (12.0–14.0 mg/dL) → Hypercalcemia Severe hypercalcemia (14.0– mg/dL) → Hypercalcemia
Hypocalcemia: Total calcium below the reference interval; in CKD-MBD typically reflects calcitriol deficiency with reduced intestinal calcium absorption.
Mild hypercalcemia: Often asymptomatic; may follow over-correction with calcium-based binders or calcitriol/vitamin D analogues.
Moderate hypercalcemia: Symptomatic hypercalcemia (polyuria, constipation, fatigue); prompts review of calcium load and vitamin D therapy.
Severe hypercalcemia: Hypercalcemic crisis risk requiring urgent evaluation and treatment.
Normal interval from Tietz Clinical Guide to Laboratory Tests, 4th ed. (2006). Hypercalcemia severity tiers (mild 10.5-12, moderate 12-14, severe >14 mg/dL) follow standard clinical total-calcium grading; thresholds illustrate graded band interpretation and are not assay-specific cutoffs.
Show evidence (1 reference)
PMID:26303319 SUPPORT Human Clinical
"Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop."
Reviews calcium homeostasis in CKD, noting that hypocalcemia develops in advanced stages due to reduced calcitriol-mediated intestinal absorption.
Alkaline Phosphatase (Bone-Specific) (Elevated)
Context: Marker of osteoblastic activity and bone turnover
Show evidence (1 reference)
PMID:36510335 SUPPORT Human Clinical
"chronic kidney disease-mineral bone disorder"
Comprehensive review of bone turnover markers including bone ALP, confirming their utility in CKD-MBD diagnosis and management.
Sclerostin (Elevated)
Context: Produced by calcified vasculature; inhibits bone remodeling via Wnt pathway suppression
Show evidence (2 references)
PMID:33301619 SUPPORT Model Organism
"ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin"
Demonstrates that calcified arteries from CKD rats secrete sclerostin, which impairs bone metabolism through a vasculature-to-bone cross-talk.
PMID:36776982 SUPPORT Human Clinical
"Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy."
Confirms vascular production of sclerostin in CKD as a mediator of the bone-vascular paradox.
Alpha-Klotho (Decreased)
Context: FGF23 co-receptor; declines with CKD progression
Show evidence (1 reference)
PMID:27125746 SUPPORT Human Clinical
"Soluble αKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary αKlotho in even earlier CKD stage 1. Therefore soluble αKlotho is an early and sensitive marker of decline in kidney function."
Reviews Klotho decline beginning in CKD stage 1-2, establishing it as the earliest marker of kidney function decline.
Fetuin-A (Decreased)
Context: Calcification inhibitor; reduced levels increase CPP maturation and calcification propensity
Show evidence (1 reference)
PMID:36107466 SUPPORT In Vitro
"Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera."
Demonstrates fetuin-A role in CPP formation; removal of CPP (which contains fetuin-A complexes) reduces calcification.
🧫

Experimental Models

1
Primary human vascular CPP bioassay model PRIMARY_CELL_CULTURE namo:TwoDCellCulture
Primary human vascular cell assay using serum from dialysis patients to model calciprotein particle-driven vascular smooth muscle calcification and endothelial activation in CKD-MBD.
CKD-mineral bone disorder dialysis patient serum exposure calciprotein particle depletion vascular calcification
Vascular Smooth Muscle Cell CL:0000359 endothelial cell CL:0000115
Organism
human NCBITaxon:9606
Tissue
arterial blood vessel UBERON:0003509
Cell source
Primary human aortic smooth muscle cells and coronary artery endothelial cells exposed to serum from dialysis patients
Culture
Two-dimensional vascular cell bioassays with patient-serum exposure and CPP-removal perturbation
Publication
PMID:36107466
Pathograph links
Vascular Calcification Recapitulates CPP-mediated vascular smooth muscle calcification and endothelial activation downstream of CKD mineral stress.
Findings
Dialysis-patient serum induces vascular smooth muscle calcification and endothelial activation through a CPP-dependent mechanism in a primary human vascular assay
Show evidence (1 reference)
PMID:36107466 SUPPORT In Vitro
"Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera."
Supports this as a disease-relevant human vascular assay in which CKD-MBD patient serum and its CPP fraction drive the modeled vascular calcification phenotype.
Show evidence (1 reference)
PMID:36107466 SUPPORT In Vitro
"Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera."
Establishes a primary human vascular cell model that captures CPP-dependent calcific and inflammatory effects of CKD-MBD patient serum.
🧮

Computational Models

2
Peterson-Riggs Calcium Homeostasis and Bone Remodeling Model SBML COPASI KINETIC
Physiologically based ODE model of integrated calcium homeostasis and bone remodeling. Includes PTH, calcitriol, calcium, phosphate, and bone remodeling markers (osteoblasts, osteoclasts, RANKL/OPG). Describes hypoparathyroidism, hyperparathyroidism, renal insufficiency, PTH 1-34 administration, and RANKL inhibition. Foundation model for CKD-MBD simulations.
Repository ↗ PMID:19732857
Variable Model ID Unit Ontology Mappings Phenotype Thresholds
Plasma_Ca
Plasma calcium concentration
 P mg/dL Serum calcium Calcium
Plasma_PO4
Plasma inorganic phosphate concentration
 ECCPhos mg/dL Serum phosphate Phosphate
Plasma_PTH
Plasma intact parathyroid hormone concentration
 PTH pg/mL Intact PTH
Bone pain above 70
mild 70 moderate 100 severe 150
Plasma_Calcitriol
Plasma 1,25-dihydroxyvitamin D (calcitriol) concentration
 B pg/mL Serum 1,25-dihydroxyvitamin D Calcitriol
Proximal muscle weakness below 0.5
mild 0.5 moderate 0.25
BMD
Bone mineral density (relative to healthy baseline)
 Qbone relative
Reduced bone mineral density below 0.85
mild 0.85 moderate 0.7 severe 0.5
Pathologic fracture below 0.7
moderate risk 0.7 high risk 0.5
Short stature below 0.75
growth impairment 0.75
Osteoclasts
Osteoclast population
 OC relative
Osteoblasts
Osteoblast population
 OB relative
FGF23
Fibroblast growth factor 23
 FGF23 pg/mL Fibroblast growth factor 23
Soluble_Klotho
Soluble alpha-Klotho, FGF23 co-receptor shed from kidney
 sKlotho pg/mL
Vascular_Calcification
Vascular calcification burden
 VascCa relative
Arterial calcification above 50
mild 50 moderate 150 severe 300
Left ventricular hypertrophy above 100
mild 100 moderate 200
Calciphylaxis above 250
calciphylaxis risk 250
Sclerostin
Sclerostin, Wnt pathway inhibitor produced by osteocytes and calcified vasculature
 SOST pmol/L
CaPO4_Product
Calcium-phosphate product (derived quantity)
 CaPO4_product (mg/dL)^2
Findings
Model appropriately describes plasma PTH, calcitriol, calcium, phosphate, and bone remodeling markers across a broad range of clinical conditions
Show evidence (1 reference)
PMID:19732857 SUPPORT Computational
"These include changes in plasma parathyroid hormone (PTH), calcitriol, calcium and phosphate (PO4), and bone-remodeling markers as manifested by hypoparathyroidism and hyperparathyroidism, renal insufficiency, daily PTH 1-34 administration, and receptor activator of NF-kappaB ligand (RANKL) inhibition."
Directly lists the clinical biomarkers and conditions the model describes, confirming broad coverage of PTH, calcitriol, calcium, phosphate, and bone remodeling markers.
Renal insufficiency simulation reproduces secondary hyperparathyroidism and bone loss
Show evidence (1 reference)
PMID:19732857 SUPPORT Computational
"These include changes in plasma parathyroid hormone (PTH), calcitriol, calcium and phosphate (PO4), and bone-remodeling markers as manifested by hypoparathyroidism and hyperparathyroidism, renal insufficiency, daily PTH 1-34 administration, and receptor activator of NF-kappaB ligand (RANKL) inhibition."
Confirms that renal insufficiency is among the clinical conditions the model successfully reproduces, including the associated hyperparathyroidism.
Provides platform for hypothesis testing of PTH, vitamin D, and RANKL pathway interventions
Show evidence (1 reference)
PMID:19732857 SUPPORT Computational
"This model highlights the utility of systems approaches to physiologic modeling in the bone field. The presented bone and calcium homeostasis model provides an integrated mathematical construct to conduct hypothesis testing of influential system aspects"
Explicitly states the model provides a platform for hypothesis testing, supporting its use for evaluating PTH, vitamin D, and RANKL pathway interventions.
Key validatable outputs: serum Ca, PO4, PTH, calcitriol, BMD. Genetic-validation anchors include CASR and RGS14 loci from CKD cohort data. Clinically validatable against CRIC mineral-marker data.
Show evidence (1 reference)
PMID:19732857 SUPPORT Computational
"The model includes relevant cellular aspects with major controlling mechanisms for bone remodeling and calcium homeostasis and appropriately describes a broad range of clinical and therapeutic conditions."
Describes the physiologically based ODE model of calcium homeostasis and bone remodeling that serves as the foundation for CKD-MBD simulations.
Peterson-Riggs CKD-MBD Multiscale Extension SBML COPASI PHYSIOLOGICAL
Extension of the Peterson-Riggs calcium homeostasis model to simulate progressive CKD over a 10-year course, including evolution of secondary hyperparathyroidism from diminished renal phosphate clearance. Links bone remodeling markers with BMD formation and elimination rates. Includes simulated interventions with calcimimetics and calcitriol.
PMID:22232752 Base model: Peterson-Riggs 2010 (BIOMD0000000613)
Variable Model ID Unit Ontology Mappings Phenotype Thresholds
Plasma_Ca
Plasma calcium concentration, tracked over 10-year CKD progression
 P mg/dL Serum calcium
Plasma_PO4
Plasma phosphate, rising with declining renal clearance
 ECCPhos mg/dL Serum phosphate
Plasma_PTH
Plasma intact PTH, evolving secondary hyperparathyroidism trajectory
 PTH pg/mL Intact PTH
BMD_lumbar
Lumbar spine BMD, predicted loss at GFR stages 58, 39, and 16 mL/min
 Qbone g/cm2 Reduced bone mineral density
GFR
Glomerular filtration rate, declining over simulated CKD course
 GFR mL/min Estimated GFR
Bone_Remodeling_Marker
Bone remodeling markers (formation/resorption) linked to BMD dynamics
 U/L Serum alkaline phosphatase
Findings
Predicted lumbar spine BMD losses at GFR 58, 39, and 16 mL/min of -0.98%, -3.0%, and -6.5% respectively, compared to observed values of -0.5%, -4.0%, and -8.1%
Show evidence (1 reference)
PMID:22232752 SUPPORT Computational
"The composite model predicted lumbar spine BMD losses, relative to baseline, at months 28 (glomerular filtration rate = 58 mL/min), 50 (39 mL/min), and 120 (16 mL/min) of approximately -0.98%, -3.0%, and -6.5%, respectively, compared to the observed BMD values in corresponding renal function..."
Provides the exact predicted and observed BMD loss values at each GFR stage, directly supporting the finding statement.
Simulated calcimimetic intervention reduces PTH and attenuates BMD loss
Show evidence (1 reference)
PMID:22232752 PARTIAL Computational
"simulated interventions with a hypothetical calcimimetic agent and calcitriol are provided to show the utility of this model as a platform for evaluating therapeutics."
The abstract confirms that a calcimimetic intervention was simulated, but it does not report the specific PTH reduction or BMD attenuation claimed in the finding.
Simulated calcitriol intervention normalizes calcium but with risk of hyperphosphatemia
Show evidence (1 reference)
PMID:22232752 PARTIAL Computational
"simulated interventions with a hypothetical calcimimetic agent and calcitriol are provided to show the utility of this model as a platform for evaluating therapeutics."
The abstract confirms that a calcitriol intervention was simulated, but it does not report the specific calcium normalization or hyperphosphatemia risk claimed in the finding.
Multiscale model linking molecular/cellular bone remodeling to organ-level mineral homeostasis across progressive CKD stages. Validates against clinical BMD data stratified by GFR.
Show evidence (1 reference)
PMID:22232752 SUPPORT Computational
"A physiologically based, multiscale model of calcium homeostasis and bone remodeling was used to describe the impact of progressive loss of kidney function over a typical 10-year course of chronic kidney disease (CKD), including the evolution of secondary hyperparathyroidism (HPT) caused by..."
Describes the multiscale extension of the Peterson-Riggs model that simulates progressive CKD and evolution of secondary hyperparathyroidism.
{ }

Source YAML

click to show 
name: CKD-Mineral Bone Disorder
creation_date: '2026-03-05T15:32:43Z'
updated_date: '2026-05-09T17:40:32Z'
category: Complex
parents:
- Renal Disease
- Metabolic Bone Disease
disease_term:
  preferred_term: CKD-mineral bone disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0006946
      label: renal osteodystrophy
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: Closest available MONDO term in the current ontology snapshot maps only to the renal osteodystrophy bone component of CKD-MBD, not to the broader CKD-MBD syndrome.
    tracked_issues:
    - url: https://github.com/monarch-initiative/mondo/issues/10128
      title: New term request — CKD-mineral and bone disorder (CKD-MBD)
      tracked_issue_role: ontology_term_request
      tracked_issue_status: OPEN
      notes: Upstream MONDO request for an exact CKD-MBD term; current mapping is a skos:closeMatch to renal osteodystrophy only.
description: >
  CKD-mineral and bone disorder (CKD-MBD) is the systemic complication syndrome of
  chronic kidney disease characterized by
  abnormalities of mineral metabolism, skeletal turnover/mineralization/volume or
  strength, and vascular or other soft-tissue
  calcification. Renal osteodystrophy refers specifically to the bone histomorphometric
  abnormalities of CKD-MBD seen on bone
  biopsy, not to the full CKD-MBD syndrome.
histopathology:
- name: High-Turnover Renal Osteodystrophy (Osteitis Fibrosa)
  description: >
    Bone-biopsy pattern within the renal osteodystrophy component of CKD-MBD, driven
    by secondary hyperparathyroidism with
    excessive osteoclast-mediated bone resorption and disorganized new bone formation.
    The most common high-turnover pattern
    in dialysis patients.
  context: Renal osteodystrophy histologic pattern within CKD-MBD
  evidence:
  - reference: PMID:34137924
    reference_title: "Bone Histomorphometry and (18)F-Sodium Fluoride Positron Emission Tomography Imaging: Comparison Between only Bone Turnover-based and Unified TMV-based Classification of Renal Osteodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 42% had high turnover/hyperparathyroid bone disease and 23% had low turnover/adynamic bone disease
    explanation: Bone biopsy study of 26 dialysis patients using TMV classification showing hyperparathyroid/high-turnover disease as the most common renal osteodystrophy histologic pattern.
- name: Low-Turnover Renal Osteodystrophy (Adynamic Bone Disease)
  description: >
    Bone-biopsy pattern within the renal osteodystrophy component of CKD-MBD characterized
    by suppressed bone formation and
    resorption, often from over-suppression of PTH or aluminum toxicity. Associated
    with increased fracture risk and vascular
    calcification.
  context: Renal osteodystrophy histologic pattern within CKD-MBD
  evidence:
  - reference: PMID:34137924
    reference_title: "Bone Histomorphometry and (18)F-Sodium Fluoride Positron Emission Tomography Imaging: Comparison Between only Bone Turnover-based and Unified TMV-based Classification of Renal Osteodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 42% had high turnover/hyperparathyroid bone disease and 23% had low turnover/adynamic bone disease
    explanation: Bone biopsy study confirms adynamic bone disease as a recognized renal osteodystrophy histologic pattern, present in 23% of dialysis patients.
- name: Mixed Uremic Osteodystrophy
  description: >
    Bone-biopsy pattern within the renal osteodystrophy component of CKD-MBD with
    features of both high- and low-turnover
    disease, showing areas of increased resorption alongside defective mineralization.
  context: Renal osteodystrophy histologic pattern within CKD-MBD
  evidence:
  - reference: PMID:28540603
    reference_title: "Positioning novel biologicals in CKD-mineral and bone disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD)
    explanation: Reviews the spectrum of renal osteodystrophy histologic patterns, including mixed forms, within the broader CKD-MBD framework.
- name: Osteomalacia
  description: >
    Renal osteodystrophy pattern within CKD-MBD characterized by defective bone mineralization
    due to vitamin D deficiency
    or aluminum accumulation, with increased osteoid volume and decreased mineralization
    rate.
  context: Renal osteodystrophy histologic pattern within CKD-MBD
  evidence:
  - reference: PMID:28646995
    reference_title: "Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance
    explanation: KDIGO 2017 guideline recognizes osteomalacia as a distinct bone pathology within the bone component of CKD-MBD, requiring specific diagnostic and treatment approaches.
pathophysiology:
- name: Phosphate Retention and FGF23 Axis
  description: >
    As nephron mass declines, phosphate excretion per nephron increases via FGF23
    and PTH-mediated suppression of proximal
    tubular sodium-phosphate cotransporters (NaPi-2a/NaPi-2c). FGF23 rises early in
    CKD (stage 2) before serum phosphate becomes
    overtly elevated. FGF23 requires the co-receptor alpha-Klotho, which is predominantly
    expressed in the kidney and declines
    with CKD progression, creating a vicious cycle.
  genes:
  - preferred_term: RGS14
    term:
      id: hgnc:9996
      label: RGS14
  cell_types:
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  - preferred_term: Proximal Tubular Epithelial Cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: Phosphate Ion Homeostasis
    term:
      id: GO:0055062
      label: phosphate ion homeostasis
  - preferred_term: Fibroblast Growth Factor Receptor Signaling
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
  locations:
  - preferred_term: Proximal Tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  - preferred_term: Bone Tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  evidence:
  - reference: PMID:37258233
    reference_title: "Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CKD-MBD manifests as hypocalcemia and hyperphosphatemia in the later stages of CKD; however, it initially develops much earlier in disease course. The initial step in CKD-MBD involves decreased phosphate excretion in the urine, followed by increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion.
    explanation: Confirms that FGF23 and PTH rise early in CKD as compensatory responses to decreased phosphate excretion, before overt hyperphosphatemia.
  - reference: PMID:36821389
    reference_title: "Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production
    explanation: Identifies the molecular mechanism linking phosphate load to FGF23 production via a kidney-bone metabolic feedback loop involving G-3-P. Mouse and human data.
  - reference: PMID:38541742
    reference_title: "Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy
    explanation: Confirms mineral metabolism disturbances including FGF23 are observed early in CKD progression.
  downstream:
  - target: Secondary Hyperparathyroidism
    description: Hyperphosphatemia directly stimulates PTH secretion; FGF23 suppresses calcitriol removing PTH inhibition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - serum phosphate elevation
    - calcitriol suppression by FGF23
  - target: Calcitriol Deficiency
    description: FGF23 suppresses 1-alpha-hydroxylase (CYP27B1) and upregulates 24-hydroxylase (CYP24A1)
    causal_link_type: DIRECT
  - target: Vascular Calcification
    description: Hyperphosphatemia and Klotho deficiency promote VSMC osteogenic transdifferentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - elevated calcium-phosphate product
    - Klotho deficiency
- name: Kidney Glycolysis-G3P Phosphate Sensing
  description: >
    A recently discovered kidney-bone feedback loop: phosphate loading increases kidney-specific
    glycolysis and production
    of glycerol-3-phosphate (G-3-P) via GPD1. G-3-P enters the circulation and triggers
    FGF23 production in bone osteocytes.
    This places glycolysis at the nexus of mineral and energy metabolism, revealing
    that phosphate does not directly stimulate
    bone FGF23 expression but acts through a renal metabolic intermediate.
  cell_types:
  - preferred_term: Proximal Tubular Epithelial Cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: Glycolytic Process
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: Phosphate Ion Homeostasis
    term:
      id: GO:0055062
      label: phosphate ion homeostasis
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:36821389
    reference_title: "Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis
    explanation: Landmark study demonstrating that kidney glycolysis produces G-3-P as a phosphate-sensing signal to bone FGF23 production. Loss of GPD1 abolished phosphate-stimulated FGF23 in mice.
  - reference: PMID:36821389
    reference_title: "Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: phosphate does not directly stimulate bone FGF23 expression
    explanation: Overturns the assumption that phosphate directly acts on osteocytes, identifying an indirect kidney-mediated mechanism.
  downstream:
  - target: Phosphate Retention and FGF23 Axis
    description: G-3-P produced by kidney glycolysis circulates to bone and triggers FGF23 production
    causal_link_type: DIRECT
- name: Secondary Hyperparathyroidism
  description: >
    Declining calcitriol synthesis (due to reduced 1-alpha-hydroxylase activity in
    damaged kidneys), hypocalcemia, hyperphosphatemia,
    and reduced calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression
    in parathyroid glands collectively
    stimulate PTH secretion. PTH levels spike above normal as early as CKD stage G2.
    Chronically elevated PTH drives high-turnover
    bone disease with increased osteoclastic resorption and extends to the cardiovascular
    system promoting vascular calcifications.
  genes:
  - preferred_term: CASR
    term:
      id: hgnc:1514
      label: CASR
  cell_types:
  - preferred_term: Parathyroid Chief Cell
    term:
      id: CL:0000446
      label: chief cell of parathyroid gland
  - preferred_term: Osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Parathyroid Hormone Secretion
    term:
      id: GO:0035898
      label: parathyroid hormone secretion
  - preferred_term: Bone Resorption
    term:
      id: GO:0045453
      label: bone resorption
  - preferred_term: Calcium Ion Homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  locations:
  - preferred_term: Parathyroid Gland
    term:
      id: UBERON:0001132
      label: parathyroid gland
  evidence:
  - reference: PMID:38785509
    reference_title: "The Molecular Mechanisms Underlying the Systemic Effects Mediated by Parathormone in the Context of Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: levels of PTH spike out of the normal range as early as stage G2 CKD, advancing it as a possible determinant of systemic damage
    explanation: Confirms PTH elevation begins very early in CKD, consistent with the updated trade-off hypothesis.
  - reference: PMID:32961953
    reference_title: "Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The decrease in serum calcium concentration is sensed by a specific membrane calcium-sensing receptor (CaSR) on parathyroid glands and is a potent stimulus for PTH release
    explanation: Directly supports CaSR as a parathyroid-gland mechanism modulating PTH release in CKD secondary hyperparathyroidism.
  - reference: PMID:38785509
    reference_title: "The Molecular Mechanisms Underlying the Systemic Effects Mediated by Parathormone in the Context of Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the altered mineral balance extends to the cardiovascular system, promoting vascular calcifications
    explanation: Elevated PTH drives not only bone resorption but also vascular calcification as a systemic consequence.
  - reference: PMID:37258233
    reference_title: "Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification
    explanation: Confirms direct cardiovascular effects of elevated PTH and FGF23.
  downstream:
  - target: RANKL/OPG Imbalance
    description: Elevated PTH increases RANKL and suppresses OPG, driving osteoclastogenesis
    causal_link_type: DIRECT
  - target: Vascular Calcification
    description: Chronically elevated PTH promotes vascular calcifications
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered mineral balance
    - cardiovascular system effects
  - target: Bone Pain
    description: PTH-driven high-turnover bone disease causes diffuse bone pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased bone resorption
  - target: Left Ventricular Hypertrophy
    description: PTH and FGF23 directly cause left ventricular hypertrophy
    causal_link_type: DIRECT
- name: Calcitriol Deficiency
  description: >
    The kidney is the primary site of 1-alpha-hydroxylation of 25-hydroxyvitamin D
    to active 1,25-dihydroxyvitamin D (calcitriol).
    Progressive nephron loss reduces calcitriol production, impairing intestinal calcium
    absorption and skeletal mineralization.
    FGF23 further suppresses 1-alpha-hydroxylase and upregulates 24-hydroxylase, accelerating
    calcitriol depletion.
  biological_processes:
  - preferred_term: Vitamin D Metabolic Process
    term:
      id: GO:0042359
      label: vitamin D metabolic process
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:26303319
    reference_title: "Pathophysiology of Calcium, Phosphorus, and Magnesium Dysregulation in Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop.
    explanation: Reviews the adaptive mechanisms maintaining mineral homeostasis in CKD, including the role of reduced calcitriol in hypocalcemia.
  - reference: PMID:37258233
    reference_title: "Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Simultaneously, the serum calcitriol concentration decreases as a result of FGF23 elevation.
    explanation: Confirms that FGF23 elevation directly suppresses calcitriol production, linking the FGF23 axis to vitamin D deficiency.
  downstream:
  - target: Secondary Hyperparathyroidism
    description: Reduced calcitriol removes VDR-mediated suppression of PTH gene transcription
    causal_link_type: DIRECT
- name: Vascular Calcification
  description: >
    Hyperphosphatemia and elevated calcium-phosphate product promote osteogenic transdifferentiation
    of vascular smooth muscle
    cells (VSMCs) into osteoblast-like cells via RUNX2 and Pit-1/Pit-2 phosphate transporters.
    Loss of calcification inhibitors
    (fetuin-A, matrix Gla protein, pyrophosphate, osteoprotegerin) and Klotho deficiency
    further drive medial arterial calcification.
    Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged
    as key mediators of phosphate toxicity,
    linking mineral stress to vascular inflammation and calcification. This is the
    major cause of cardiovascular mortality
    in CKD-MBD.
  cell_types:
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: Osteogenic Transdifferentiation of Vascular Smooth Muscle Cells
    description: >-
      Acquisition of a RUNX2-driven osteoblast-like differentiation program by vascular
      smooth muscle cells, producing ectopic medial arterial calcification. Bound to the
      GO osteoblast-differentiation process — the cell-fate switch that the cited evidence
      describes as "osteochondrogenic differentiation of vascular cells" — rather than the
      broad parent term "ossification" (GO:0001503), which denotes physiologic skeletal
      bone formation; no GO term specific to ectopic vascular calcification exists.
    modifier: INCREASED
    term:
      id: GO:0001649
      label: osteoblast differentiation
  locations:
  - preferred_term: Arterial Blood Vessel
    term:
      id: UBERON:0003509
      label: arterial blood vessel
  evidence:
  - reference: PMID:39684805
    reference_title: "Understanding Vascular Calcification in Chronic Kidney Disease: Pathogenesis and Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: several pathophysiological processes contribute to vascular calcifications, including osteochondrogenic differentiation of vascular cells, hyperphosphatemia and hypercalcemia, and the loss of specific vascular calcification inhibitors including pyrophosphate, fetuin-A, osteoprotegerin, and matrix GLA protein
    explanation: Comprehensive description of vascular calcification as an active cell-mediated process involving osteochondrogenic differentiation and loss of endogenous inhibitors.
  - reference: PMID:38541742
    reference_title: "Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP).
    explanation: Confirms VSMC involvement and CPP formation as key components of CKD-MBD vascular calcification.
  - reference: PMID:36107466
    reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation.
    explanation: Identifies CPPs as mediators of phosphate toxicity linking mineral stress to vascular damage.
  - reference: PMID:36107466
    reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera.
    explanation: Direct experimental evidence that CPPs in patient sera cause VSMC calcification and endothelial activation.
  downstream:
  - target: Bone-Vascular Paradox (Sclerostin/Wnt Axis)
    description: Calcified arteries produce sclerostin and other factors that inhibit bone remodeling
    causal_link_type: DIRECT
  - target: Left Ventricular Hypertrophy
    description: Arterial stiffening from medial calcification increases cardiac afterload
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - arterial stiffening
    - increased cardiac afterload
  - target: Calciphylaxis
    description: Small vessel calcification and thrombosis cause painful skin necrosis
    causal_link_type: DIRECT
- name: Bone-Vascular Paradox (Sclerostin/Wnt Axis)
  description: >
    Calcified arteries in CKD produce sclerostin and other factors that inhibit bone
    remodeling, explaining the paradox of
    simultaneous vascular calcification and low-turnover (adynamic) bone disease.
    Vascular osteoblastic/osteocytic transdifferentiation
    produces sclerostin that brakes Wnt-driven calcification in the vasculature but
    also suppresses skeletal bone formation.
    Anti-sclerostin antibody therapy improves bone but can worsen vascular calcification,
    highlighting the therapeutic complexity.
  cell_types:
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: Wnt Signaling Pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  - preferred_term: Bone Remodeling
    term:
      id: GO:0046849
      label: bone remodeling
  evidence:
  - reference: PMID:36776982
    reference_title: "Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox.
    explanation: Identifies the mechanism of the bone-vascular paradox where calcified arteries produce factors that inhibit skeletal bone remodeling.
  - reference: PMID:36776982
    reference_title: "Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy.
    explanation: Vascular production of sclerostin through osteoblastic transdifferentiation of vascular cells links vascular calcification to bone disease.
  - reference: PMID:36776982
    reference_title: "Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu
    explanation: Anti-sclerostin antibody demonstrates the paradox - improving bone worsens vascular calcification, confirming sclerostin's protective role in vasculature.
  downstream:
  - target: Decreased Bone Mineral Density
    description: Vascular sclerostin suppresses skeletal Wnt signaling and bone formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - sclerostin inhibition of Wnt pathway
    - suppressed osteoblast activity
- name: RANKL/OPG Imbalance
  description: >
    Elevated PTH increases RANKL expression by osteoblasts and osteocytes while suppressing
    osteoprotegerin (OPG), shifting
    the balance toward excessive osteoclastogenesis and bone resorption. Uremic toxins
    may independently alter RANKL/OPG signaling.
    Novel biologicals targeting RANKL (denosumab) and sclerostin are being explored
    in CKD-MBD but require careful consideration
    of the bone-vascular paradox.
  biological_processes:
  - preferred_term: Osteoclast Differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
  evidence:
  - reference: PMID:28540603
    reference_title: "Positioning novel biologicals in CKD-mineral and bone disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality.
    explanation: Reviews the positioning of novel biologicals including denosumab (anti-RANKL) in CKD-MBD, discussing the RANKL/OPG axis as a therapeutic target.
  downstream:
  - target: Decreased Bone Mineral Density
    description: Excessive osteoclastogenesis increases bone resorption, reducing BMD
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased osteoclast activity
    - excessive bone resorption
  - target: Pathological Fractures
    description: Reduced BMD from RANKL-driven resorption increases fracture risk
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced bone mineral density
    - impaired bone microarchitecture
  - target: Bone Pain
    description: High-turnover bone disease with excessive resorption causes bone pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased bone turnover
    - periosteal inflammation
phenotypes:
- category: Skeletal
  name: Bone Pain
  frequency: FREQUENT
  notes: Diffuse bone pain, especially in weight-bearing bones
  phenotype_term:
    preferred_term: Bone Pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:32961953
    reference_title: "Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD.
    explanation: Confirms early bone structural changes in CKD that manifest as bone pain.
- category: Skeletal
  name: Pathological Fractures
  frequency: FREQUENT
  notes: >
    Vertebral compression fractures, hip fractures. Risk 2-14x higher than age-matched
    controls without CKD.
  phenotype_term:
    preferred_term: Pathological Fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  evidence:
  - reference: PMID:32961953
    reference_title: "Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality.
    explanation: Systematic review confirming increased fracture risk as a key consequence of CKD-MBD.
  - reference: PMID:38785509
    reference_title: "The Molecular Mechanisms Underlying the Systemic Effects Mediated by Parathormone in the Context of Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: persistently high levels of PTH determine a reduction in mineral density and a concurrent increase in fracture risk
    explanation: Links elevated PTH to both reduced BMD and increased fracture risk.
- category: Skeletal
  name: Decreased Bone Mineral Density
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased Bone Mineral Density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:32961953
    reference_title: "Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Systematic review defining bone mineral density abnormalities as a core component of CKD-MBD.
- category: Cardiovascular
  name: Vascular Calcification
  frequency: VERY_FREQUENT
  notes: >
    Coronary artery calcification and peripheral arterial calcification are present
    in >80% of dialysis patients. Major driver
    of cardiovascular mortality.
  phenotype_term:
    preferred_term: Arterial Calcification
    term:
      id: HP:0003207
      label: Arterial calcification
  evidence:
  - reference: PMID:38573243
    reference_title: "New therapeutic perspectives for vascular and valvular calcifications in chronic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis
    explanation: Highlights the clinical significance and therapeutic gap for vascular calcification in CKD.
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  frequency: FREQUENT
  notes: Secondary to arterial stiffening from vascular calcification and volume overload
  phenotype_term:
    preferred_term: Left Ventricular Hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:37258233
    reference_title: "Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification
    explanation: Directly links elevated FGF23 and PTH to left ventricular hypertrophy as a phenotypic manifestation of CKD-MBD.
- category: Dermatologic
  name: Calciphylaxis
  frequency: OCCASIONAL
  notes: >
    Calcific uremic arteriolopathy — painful skin necrosis from small vessel calcification
    and thrombosis. High mortality.
    Proxied to the broader HPO term calcinosis cutis because no exact calciphylaxis
    term was identified in the local HPO
    snapshot used for validation.
  phenotype_term:
    preferred_term: Calciphylaxis
    term:
      id: HP:0025520
      label: Calcinosis cutis
  evidence:
  - reference: PMID:38573243
    reference_title: "New therapeutic perspectives for vascular and valvular calcifications in chronic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: as yet no medication has been approved to treat vascular or valvular calcification, or calciphylaxis
    explanation: Confirms calciphylaxis as a recognized CKD-MBD manifestation with no approved treatment.
biochemical:
- name: Phosphate
  presence: Elevated
  context: Impaired renal excretion, overtly elevated in CKD stages 4-5
  evidence:
  - reference: PMID:33784965
    reference_title: "Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)(2)D and normal FGF7 concentrations characterize patients with CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively
    explanation: Cross-sectional study of 85 patients quantifies the eGFR thresholds at which phosphate, PTH, and FGF23 become significantly elevated.
  biomarker_term:
    preferred_term: Phosphate Measurement
    term:
      id: NCIT:C64857
      label: Phosphate Measurement
  mappings_list:
  - preferred_term: Phosphate [Mass/volume] in Serum or Plasma
    term:
      id: LOINC:2777-1
      label: Phosphate [Mass/volume] in Serum or Plasma
  - preferred_term: hydrogenphosphate
    term:
      id: CHEBI:43474
      label: hydrogenphosphate
  reference_ranges:
  - loinc_term:
      id: LOINC:2777-1
      label: Phosphate [Mass/volume] in Serum or Plasma
    lower_bound: 2.5
    upper_bound: 4.5
    unit: mg/dL
    population: adults
    notes: "Reference interval from Tietz Clinical Guide to Laboratory Tests, 4th ed. (2006)."
- name: FGF23
  presence: Elevated
  context: Earliest biomarker, rises in CKD stage 2 before phosphate elevation
  evidence:
  - reference: PMID:33784965
    reference_title: "Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)(2)D and normal FGF7 concentrations characterize patients with CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a compensatory increase in circulating FGF23 concentrations commences before the occurrence of hyperphosphatemia
    explanation: Confirms FGF23 rises as an early compensatory mechanism in CKD before phosphate elevation.
  - reference: PMID:37258233
    reference_title: "Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion
    explanation: Reviews FGF23 as a key early biomarker in CKD-MBD pathogenesis.
  biomarker_term:
    preferred_term: Fibroblast Growth Factor 23
    term:
      id: NCIT:C104384
      label: Fibroblast Growth Factor 23
  mappings_list:
  - preferred_term: Fibroblast growth factor 23 [Mass/volume] in Serum or Plasma
    term:
      id: LOINC:54390-0
      label: Fibroblast growth factor 23 [Mass/volume] in Serum or Plasma
- name: Glycerol-3-Phosphate (G-3-P)
  presence: Elevated
  context: Kidney glycolysis-derived metabolite that triggers FGF23 production in bone
  evidence:
  - reference: PMID:36821389
    reference_title: "Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production
    explanation: Identifies G-3-P as a circulating metabolite produced by kidney glycolysis that signals to bone osteocytes.
  mappings_list:
  - preferred_term: sn-glycerol 3-phosphate
    term:
      id: CHEBI:15978
      label: sn-glycerol 3-phosphate
- name: PTH (Intact)
  presence: Elevated
  context: Secondary hyperparathyroidism, spikes above normal as early as CKD stage G2
  evidence:
  - reference: PMID:38785509
    reference_title: "The Molecular Mechanisms Underlying the Systemic Effects Mediated by Parathormone in the Context of Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: levels of PTH spike out of the normal range as early as stage G2 CKD, advancing it as a possible determinant of systemic damage
    explanation: Confirms PTH elevation begins in early CKD stage G2.
  - reference: PMID:33784965
    reference_title: "Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)(2)D and normal FGF7 concentrations characterize patients with CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively
    explanation: Quantifies the eGFR threshold for significant PTH elevation at <29 mL/min/1.73m2.
  biomarker_term:
    preferred_term: Parathyroid Hormone
    term:
      id: NCIT:C41027
      label: Parathyroid Hormone
  mappings_list:
  - preferred_term: Parathyrin.intact [Mass/volume] in Serum or Plasma
    term:
      id: LOINC:2731-8
      label: Parathyrin.intact [Mass/volume] in Serum or Plasma
  reference_ranges:
  - loinc_term:
      id: LOINC:2731-8
      label: Parathyrin.intact [Mass/volume] in Serum or Plasma
    lower_bound: 15.0
    upper_bound: 65.0
    unit: pg/mL
    population: adults
    notes: "Reference interval from Tietz Clinical Guide to Laboratory Tests, 4th ed. (2006). Reference range varies by assay generation; third-generation biointact PTH assays have different normal ranges."
- name: Calcitriol (1,25-dihydroxyvitamin D)
  presence: Decreased
  context: Reduced 1-alpha-hydroxylase activity and FGF23-mediated suppression
  evidence:
  - reference: PMID:33784965
    reference_title: "Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)(2)D and normal FGF7 concentrations characterize patients with CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: while significant decreases in serum 1,25(OH)2D were observed at an eGFR of < 52 mL/min/1.73 m2 (95 % CI, 42.57-61.43).
    explanation: Demonstrates calcitriol decline occurs at eGFR <52, earlier than PTH or phosphate changes.
  biomarker_term:
    preferred_term: 1,25-Dihydroxyvitamin D3 Measurement
    term:
      id: NCIT:C179754
      label: 1,25-Dihydroxyvitamin D3 Measurement
  mappings_list:
  - preferred_term: Calcitriol [Mass/volume] in Serum or Plasma
    term:
      id: LOINC:62290-2
      label: Calcitriol [Mass/volume] in Serum or Plasma
  - preferred_term: calcitriol
    term:
      id: CHEBI:17823
      label: calcitriol
  reference_ranges:
  - loinc_term:
      id: LOINC:62290-2
      label: Calcitriol [Mass/volume] in Serum or Plasma
    lower_bound: 18.0
    upper_bound: 64.0
    unit: pg/mL
    population: adults
    notes: "Reference interval from Mayo Clinic Laboratories."
- name: Calcium
  presence: Decreased
  context: Reduced intestinal absorption from calcitriol deficiency
  evidence:
  - reference: PMID:26303319
    reference_title: "Pathophysiology of Calcium, Phosphorus, and Magnesium Dysregulation in Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop.
    explanation: Reviews calcium homeostasis in CKD, noting that hypocalcemia develops in advanced stages due to reduced calcitriol-mediated intestinal absorption.
  biomarker_term:
    preferred_term: Calcium
    term:
      id: NCIT:C331
      label: Calcium
  mappings_list:
  - preferred_term: Calcium [Mass/volume] in Serum or Plasma
    term:
      id: LOINC:17861-6
      label: Calcium [Mass/volume] in Serum or Plasma
  - preferred_term: calcium(2+)
    term:
      id: CHEBI:22984
      label: calcium(2+)
  reference_ranges:
  - loinc_term:
      id: LOINC:17861-6
      label: Calcium [Mass/volume] in Serum or Plasma
    lower_bound: 8.5
    upper_bound: 10.5
    unit: mg/dL
    population: adults
    interpretation_bands:
    - name: Hypocalcemia
      upper_bound: 8.5
      unit: mg/dL
      abnormal_flag: LOW
      phenotype_term:
        preferred_term: Hypocalcemia
        term:
          id: HP:0002901
          label: Hypocalcemia
      interpretation: >-
        Total calcium below the reference interval; in CKD-MBD typically reflects
        calcitriol deficiency with reduced intestinal calcium absorption.
    - name: Normal
      lower_bound: 8.5
      upper_bound: 10.5
      unit: mg/dL
      abnormal_flag: NORMAL
    - name: Mild hypercalcemia
      lower_bound: 10.5
      upper_bound: 12.0
      unit: mg/dL
      abnormal_flag: HIGH
      severity: MILD
      phenotype_term:
        preferred_term: Hypercalcemia
        term:
          id: HP:0003072
          label: Hypercalcemia
      interpretation: Often asymptomatic; may follow over-correction with calcium-based binders or calcitriol/vitamin D analogues.
    - name: Moderate hypercalcemia
      lower_bound: 12.0
      upper_bound: 14.0
      unit: mg/dL
      abnormal_flag: HIGH
      severity: MODERATE
      phenotype_term:
        preferred_term: Hypercalcemia
        term:
          id: HP:0003072
          label: Hypercalcemia
      interpretation: Symptomatic hypercalcemia (polyuria, constipation, fatigue); prompts review of calcium load and vitamin D therapy.
    - name: Severe hypercalcemia
      lower_bound: 14.0
      unit: mg/dL
      abnormal_flag: CRITICAL_HIGH
      severity: SEVERE
      phenotype_term:
        preferred_term: Hypercalcemia
        term:
          id: HP:0003072
          label: Hypercalcemia
      interpretation: Hypercalcemic crisis risk requiring urgent evaluation and treatment.
    notes: >-
      Normal interval from Tietz Clinical Guide to Laboratory Tests, 4th ed. (2006).
      Hypercalcemia severity tiers (mild 10.5-12, moderate 12-14, severe >14 mg/dL)
      follow standard clinical total-calcium grading; thresholds illustrate graded
      band interpretation and are not assay-specific cutoffs.
- name: Alkaline Phosphatase (Bone-Specific)
  presence: Elevated
  context: Marker of osteoblastic activity and bone turnover
  evidence:
  - reference: PMID:36510335
    reference_title: "Bone Turnover Markers: Basic Biology to Clinical Applications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: chronic kidney disease-mineral bone disorder
    explanation: Comprehensive review of bone turnover markers including bone ALP, confirming their utility in CKD-MBD diagnosis and management.
  biomarker_term:
    preferred_term: Alkaline Phosphatase
    term:
      id: NCIT:C16276
      label: Alkaline Phosphatase
  mappings_list:
  - preferred_term: Alkaline phosphatase.bone [Enzymatic activity/volume] in Serum or Plasma
    term:
      id: LOINC:6768-6
      label: Alkaline phosphatase.bone [Enzymatic activity/volume] in Serum or Plasma
- name: Sclerostin
  presence: Elevated
  context: Produced by calcified vasculature; inhibits bone remodeling via Wnt pathway suppression
  evidence:
  - reference: PMID:33301619
    reference_title: "Chronic Kidney Disease-Induced Vascular Calcification Impairs Bone Metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin
    explanation: Demonstrates that calcified arteries from CKD rats secrete sclerostin, which impairs bone metabolism through a vasculature-to-bone cross-talk.
  - reference: PMID:36776982
    reference_title: "Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy.
    explanation: Confirms vascular production of sclerostin in CKD as a mediator of the bone-vascular paradox.
  biomarker_term:
    preferred_term: Sclerostin
    term:
      id: NCIT:C105078
      label: Sclerostin
- name: Alpha-Klotho
  presence: Decreased
  context: FGF23 co-receptor; declines with CKD progression
  evidence:
  - reference: PMID:27125746
    reference_title: "αKlotho and Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Soluble αKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary αKlotho in even earlier CKD stage 1. Therefore soluble αKlotho is an early and sensitive marker of decline in kidney function.
    explanation: Reviews Klotho decline beginning in CKD stage 1-2, establishing it as the earliest marker of kidney function decline.
  biomarker_term:
    preferred_term: Klotho Protein Measurement
    term:
      id: NCIT:C127624
      label: Klotho Protein Measurement
- name: Fetuin-A
  presence: Decreased
  context: Calcification inhibitor; reduced levels increase CPP maturation and calcification propensity
  evidence:
  - reference: PMID:36107466
    reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera.
    explanation: Demonstrates fetuin-A role in CPP formation; removal of CPP (which contains fetuin-A complexes) reduces calcification.
  biomarker_term:
    preferred_term: Alpha-2-HS-Glycoprotein
    term:
      id: NCIT:C113823
      label: Alpha-2-HS-Glycoprotein
genetic:
- name: CASR
  gene_term:
    preferred_term: CASR
    term:
      id: hgnc:1514
      label: CASR
  association: Modifier
  notes: >
    Common calcium-sensing receptor variation appears to modify mineral metabolism
    in CKD, especially serum calcium, rather
    than acting as a defining causal gene for CKD-MBD.
  evidence:
  - reference: PMID:35587600
    reference_title: "Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SNVs adjacent to or within genes encoding the regulator of G protein-coupled signaling 14 (RGS14) and the calcium-sensing receptor (CASR) were associated with levels of mineral metabolites.
    explanation: Candidate-variant analysis in 3027 CRIC participants supports CASR as a CKD-relevant modifier of mineral metabolism, but not as a primary causal gene for CKD-MBD.
- name: RGS14
  gene_term:
    preferred_term: RGS14
    term:
      id: hgnc:9996
      label: RGS14
  association: Modifier
  notes: >
    CKD-cohort variant associated with lower phosphate, lower FGF23, and lower prevalence
    of hyperparathyroidism, making
    it the clearest disease-relevant modifier signal in the current section.
  evidence:
  - reference: PMID:35587600
    reference_title: "Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23, and lower prevalence of hyperparathyroidism.
    explanation: This CRIC cohort result directly links RGS14 variation to key CKD-MBD laboratory features, supporting it as a disease-relevant modifier rather than a broad speculative pathway gene.
diagnosis:
- name: Mineral metabolism laboratory assessment
  description: >-
    Diagnosis and monitoring of CKD-mineral and bone disorder rely on serial
    assessment of phosphate, PTH, FGF23, calcium, and active vitamin D markers,
    because these biochemical abnormalities emerge as kidney function declines.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  markers: phosphate, PTH, FGF23, calcium, 1,25-dihydroxyvitamin D
  results: Elevated phosphate, FGF23, and PTH with reduced calcitriol in progressive CKD.
  evidence:
  - reference: PMID:33784965
    reference_title: "Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)(2)D and normal FGF7 concentrations characterize patients with CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main strength of the current study is the comprehensive measurement
      of mineral metabolism biomarkers, including full-length biologically
      active forms of FGF7 and FGF23 as well as 1,25(OH)2D, among patients
      with varying levels of eGFR.
    explanation: This human CKD study supports the core biochemical panel used for CKD-MBD assessment.
  - reference: PMID:33784965
    reference_title: "Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)(2)D and normal FGF7 concentrations characterize patients with CKD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant increases in serum iFGF23, PTH, and phosphate were
      observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 %
      CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI,
      19.25-25.51), respectively
    explanation: The measured biomarker changes support the expected laboratory pattern.
treatments:
- name: Phosphate Binders
  description: >
    Calcium-based (calcium carbonate, calcium acetate) or non-calcium-based (sevelamer,
    lanthanum carbonate, sucroferric oxyhydroxide)
    agents that bind dietary phosphate in the gut to reduce absorption.
  treatment_term:
    preferred_term: phosphate binder therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcium carbonate
      term:
        id: CHEBI:3311
        label: calcium carbonate
    - preferred_term: calcium acetate
      term:
        id: CHEBI:3310
        label: calcium acetate
    - preferred_term: lanthanum carbonate
      term:
        id: CHEBI:49701
        label: lanthanum(3+)
  evidence:
  - reference: PMID:36107466
    reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.
    explanation: Sucroferric oxyhydroxide reduces CPP formation and attenuates vascular calcification effects, supporting phosphate binder efficacy.
  target_mechanisms:
  - target: Vascular Calcification
    treatment_effect: INHIBITS
    description: Reduces intestinal phosphate absorption and endogenous calciprotein particle burden, attenuating phosphate-driven vascular calcification.
    evidence:
    - reference: PMID:36107466
      reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.
      explanation: Supports a direct treatment edge from phosphate binders to the vascular calcification mechanism via reduced CPP burden and reduced pro-calcific serum activity.
- name: Active Vitamin D Therapy
  description: >
    Calcitriol or active vitamin D analogs (paricalcitol, doxercalciferol) to suppress
    PTH, improve calcium absorption, and
    support bone mineralization. Must balance against risk of hypercalcemia and hyperphosphatemia.
  treatment_term:
    preferred_term: active vitamin D analog therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
    - preferred_term: paricalcitol
      term:
        id: CHEBI:7931
        label: paricalcitol
  evidence:
  - reference: PMID:29523679
    reference_title: "Parathyroidectomy in the Management of Secondary Hyperparathyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There is insufficient data on whether to prefer vitamin D analogs compared with calcimimetics, but the available evidence suggests advantages with combination therapy.
    explanation: Supports use of vitamin D analogs in CKD secondary hyperparathyroidism, noting combination therapy with calcimimetics may be optimal.
  target_mechanisms:
  - target: Secondary Hyperparathyroidism
    treatment_effect: INHIBITS
    description: Replaces deficient active vitamin D signaling and suppresses persistent secondary hyperparathyroidism.
    evidence:
    - reference: PMID:29523679
      reference_title: "Parathyroidectomy in the Management of Secondary Hyperparathyroidism."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: There is insufficient data on whether to prefer vitamin D analogs compared with calcimimetics, but the available evidence suggests advantages with combination therapy.
      explanation: Partially supports active vitamin D analog therapy as a treatment for secondary hyperparathyroidism, but the abstract frames the evidence comparatively rather than as a direct mechanistic PTH-suppression result.
- name: Calcimimetics
  description: >
    Cinacalcet and etelcalcetide allosterically activate the calcium-sensing receptor
    on parathyroid cells, suppressing PTH
    secretion without raising serum calcium. First-line for secondary hyperparathyroidism
    in dialysis.
  treatment_term:
    preferred_term: calcimimetic therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cinacalcet
      term:
        id: CHEBI:48390
        label: cinacalcet
    - preferred_term: etelcalcetide
      term:
        id: CHEBI:134700
        label: etelcalcetide
  evidence:
  - reference: PMID:23121374
    reference_title: "Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis.
    explanation: The EVOLVE trial (n=3883) showed cinacalcet did not significantly reduce cardiovascular events in the primary ITT analysis, though secondary analyses suggested benefit after adjustment for baseline characteristics.
  target_mechanisms:
  - target: Secondary Hyperparathyroidism
    treatment_effect: INHIBITS
    description: Activates the parathyroid calcium-sensing receptor to suppress PTH secretion and counter secondary hyperparathyroidism.
    evidence:
    - reference: PMID:28097356
      reference_title: "Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5%
      explanation: This randomized trial directly supports the mechanistic claim that calcimimetic therapy suppresses PTH in dialysis-associated secondary hyperparathyroidism, with cinacalcet achieving greater than 30% PTH reduction in most treated patients.
- name: Parathyroidectomy
  description: >
    Surgical removal of hyperplastic parathyroid glands for refractory secondary or
    tertiary hyperparathyroidism unresponsive
    to medical therapy.
  treatment_term:
    preferred_term: parathyroidectomy
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:29523679
    reference_title: "Parathyroidectomy in the Management of Secondary Hyperparathyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: When parathyroid hormone level persists >800 pg/ml for >6 months, despite exhaustive medical interventions, monoclonal proliferation with nodular hyperplasia is likely present along with decreased expression of vitamin D and calcium-sensing receptors. Hence, surgical parathyroidectomy should be considered
    explanation: Defines indications for parathyroidectomy in refractory secondary hyperparathyroidism based on PTH thresholds and medical therapy failure.
  target_mechanisms:
  - target: Secondary Hyperparathyroidism
    treatment_effect: INHIBITS
    description: Removes hyperplastic parathyroid tissue when secondary hyperparathyroidism is refractory to medical therapy.
    evidence:
    - reference: PMID:29523679
      reference_title: "Parathyroidectomy in the Management of Secondary Hyperparathyroidism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: When parathyroid hormone level persists >800 pg/ml for >6 months, despite exhaustive medical interventions, monoclonal proliferation with nodular hyperplasia is likely present along with decreased expression of vitamin D and calcium-sensing receptors. Hence, surgical parathyroidectomy should be considered
      explanation: Supports a direct treatment edge from parathyroidectomy to the secondary hyperparathyroidism mechanism in medically refractory disease.
- name: Dialysis Optimization
  description: >
    Adjustment of dialysate calcium concentration and extended/frequent dialysis sessions
    to improve phosphate and calcium
    clearance.
  treatment_term:
    preferred_term: dialysis optimization
    term:
      id: MAXO:0000602
      label: hemodialysis
  evidence:
  - reference: PMID:38573243
    reference_title: "New therapeutic perspectives for vascular and valvular calcifications in chronic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Conventional therapies targeted at CKD-mineral and bone disorder (MBD) modulation have yielded conflicting or inconclusive results.
    explanation: Highlights that conventional CKD-MBD therapies including dialysis optimization have inconsistent effects on vascular calcification outcomes.
- name: Kidney Transplantation
  description: >
    Restores renal 1-alpha-hydroxylase activity and phosphate excretion. Most effective
    treatment for CKD-MBD, though persistent
    hyperparathyroidism (tertiary) may occur post-transplant.
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:33765230
    reference_title: "Bone Mineral Disease After Kidney Transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations.
    explanation: Reviews post-transplant CKD-MBD including persistent hyperparathyroidism, hypercalcemia, and ongoing bone disease despite restored renal function.
datasets:
experimental_models:
- name: Primary human vascular CPP bioassay model
  description: >-
    Primary human vascular cell assay using serum from dialysis patients to model
    calciprotein particle-driven vascular smooth muscle calcification and endothelial
    activation in CKD-MBD.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: arterial blood vessel
    term:
      id: UBERON:0003509
      label: arterial blood vessel
  cell_types:
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  conditions:
  - CKD-mineral bone disorder
  - dialysis patient serum exposure
  - calciprotein particle depletion
  - vascular calcification
  cell_source: Primary human aortic smooth muscle cells and coronary artery endothelial cells exposed to serum from dialysis patients
  culture_system: Two-dimensional vascular cell bioassays with patient-serum exposure and CPP-removal perturbation
  publication: PMID:36107466
  modeled_mechanisms:
  - target: Vascular Calcification
    description: Recapitulates CPP-mediated vascular smooth muscle calcification and endothelial activation downstream of CKD mineral stress.
  findings:
  - statement: Dialysis-patient serum induces vascular smooth muscle calcification and endothelial activation through a CPP-dependent mechanism in a primary human vascular assay
    evidence:
    - reference: PMID:36107466
      reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera.
      explanation: Supports this as a disease-relevant human vascular assay in which CKD-MBD patient serum and its CPP fraction drive the modeled vascular calcification phenotype.
  evidence:
  - reference: PMID:36107466
    reference_title: "Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera.
    explanation: Establishes a primary human vascular cell model that captures CPP-dependent calcific and inflammatory effects of CKD-MBD patient serum.
computational_models:
- name: Peterson-Riggs Calcium Homeostasis and Bone Remodeling Model
  description: Physiologically based ODE model of integrated calcium homeostasis and bone remodeling. Includes PTH, calcitriol, calcium, phosphate, and bone remodeling markers (osteoblasts, osteoclasts, RANKL/OPG). Describes hypoparathyroidism, hyperparathyroidism, renal insufficiency, PTH 1-34 administration, and RANKL inhibition. Foundation model for CKD-MBD simulations.
  model_type: KINETIC
  repository_url: https://www.ebi.ac.uk/biomodels/BIOMD0000000613
  model_id: BIOMD0000000613
  model_software: COPASI
  model_format: SBML
  publication: PMID:19732857
  evidence:
  - reference: PMID:19732857
    reference_title: "A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The model includes relevant cellular aspects with major controlling mechanisms for bone remodeling and calcium homeostasis and appropriately describes a broad range of clinical and therapeutic conditions."
    explanation: "Describes the physiologically based ODE model of calcium homeostasis and bone remodeling that serves as the foundation for CKD-MBD simulations."
  findings:
  - statement: Model appropriately describes plasma PTH, calcitriol, calcium, phosphate, and bone remodeling markers across a broad range of clinical conditions
    evidence:
    - reference: PMID:19732857
      reference_title: "A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "These include changes in plasma parathyroid hormone (PTH), calcitriol, calcium and phosphate (PO4), and bone-remodeling markers as manifested by hypoparathyroidism and hyperparathyroidism, renal insufficiency, daily PTH 1-34 administration, and receptor activator of NF-kappaB ligand (RANKL) inhibition."
      explanation: "Directly lists the clinical biomarkers and conditions the model describes, confirming broad coverage of PTH, calcitriol, calcium, phosphate, and bone remodeling markers."
  - statement: Renal insufficiency simulation reproduces secondary hyperparathyroidism and bone loss
    evidence:
    - reference: PMID:19732857
      reference_title: "A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "These include changes in plasma parathyroid hormone (PTH), calcitriol, calcium and phosphate (PO4), and bone-remodeling markers as manifested by hypoparathyroidism and hyperparathyroidism, renal insufficiency, daily PTH 1-34 administration, and receptor activator of NF-kappaB ligand (RANKL) inhibition."
      explanation: "Confirms that renal insufficiency is among the clinical conditions the model successfully reproduces, including the associated hyperparathyroidism."
  - statement: Provides platform for hypothesis testing of PTH, vitamin D, and RANKL pathway interventions
    evidence:
    - reference: PMID:19732857
      reference_title: "A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "This model highlights the utility of systems approaches to physiologic modeling in the bone field. The presented bone and calcium homeostasis model provides an integrated mathematical construct to conduct hypothesis testing of influential system aspects"
      explanation: "Explicitly states the model provides a platform for hypothesis testing, supporting its use for evaluating PTH, vitamin D, and RANKL pathway interventions."
  notes: 'Key validatable outputs: serum Ca, PO4, PTH, calcitriol, BMD. Genetic-validation anchors include CASR and RGS14 loci from CKD cohort data. Clinically validatable against CRIC mineral-marker data.'
  variables:
  - name: Plasma_Ca
    dataset_identifier: P
    description: Plasma calcium concentration
    unit: mg/dL
    mappings_list:
    - preferred_term: Serum calcium
      term:
        id: LOINC:17861-6
        label: Calcium:MCnc:Pt:Ser/Plas:Qn
    - preferred_term: Calcium
      term:
        id: CHEBI:22984
        label: calcium(2+)
  - name: Plasma_PO4
    dataset_identifier: ECCPhos
    description: Plasma inorganic phosphate concentration
    unit: mg/dL
    mappings_list:
    - preferred_term: Serum phosphate
      term:
        id: LOINC:2777-1
        label: Phosphate:MCnc:Pt:Ser/Plas:Qn
    - preferred_term: Phosphate
      term:
        id: CHEBI:43474
        label: hydrogenphosphate
  - name: Plasma_PTH
    dataset_identifier: PTH
    description: Plasma intact parathyroid hormone concentration
    unit: pg/mL
    mappings_list:
    - preferred_term: Intact PTH
      term:
        id: LOINC:2731-8
        label: Parathyrin.intact:MCnc:Pt:Ser/Plas:Qn
    - preferred_term: Bone pain
      description: >-
        Thresholds calibrated to model steady-state PTH values, not clinical
        reference ranges. Clinical bone pain from osteitis fibrosa typically
        manifests at PTH >200-300 pg/mL in dialysis patients; model values
        run lower due to simplified bone resorption dynamics.
      term:
        id: HP:0002653
        label: Bone pain
      threshold: 70
      threshold_direction: above
      severity_scale:
      - threshold: 70
        name: mild
      - threshold: 100
        name: moderate
      - threshold: 150
        name: severe
  - name: Plasma_Calcitriol
    dataset_identifier: B
    description: Plasma 1,25-dihydroxyvitamin D (calcitriol) concentration
    unit: pg/mL
    mappings_list:
    - preferred_term: Serum 1,25-dihydroxyvitamin D
      term:
        id: LOINC:62290-2
        label: 1,25-Dihydroxyvitamin D:MCnc:Pt:Ser/Plas:Qn
    - preferred_term: Calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
    - preferred_term: Proximal muscle weakness
      term:
        id: HP:0003701
        label: Proximal muscle weakness
      threshold: 0.50
      threshold_direction: below
      severity_scale:
      - threshold: 0.50
        name: mild
      - threshold: 0.25
        name: moderate
  - name: BMD
    dataset_identifier: Qbone
    description: Bone mineral density (relative to healthy baseline)
    unit: relative
    mappings_list:
    - preferred_term: Reduced bone mineral density
      term:
        id: HP:0004349
        label: Reduced bone mineral density
      threshold: 0.85
      threshold_direction: below
      severity_scale:
      - threshold: 0.85
        name: mild
      - threshold: 0.70
        name: moderate
      - threshold: 0.50
        name: severe
    - preferred_term: Pathologic fracture
      term:
        id: HP:0002756
        label: Pathologic fracture
      threshold: 0.70
      threshold_direction: below
      severity_scale:
      - threshold: 0.70
        name: moderate risk
      - threshold: 0.50
        name: high risk
    - preferred_term: Short stature
      term:
        id: HP:0004322
        label: Short stature
      threshold: 0.75
      threshold_direction: below
      severity_scale:
      - threshold: 0.75
        name: growth impairment
  - name: Osteoclasts
    dataset_identifier: OC
    description: Osteoclast population
    unit: relative
  - name: Osteoblasts
    dataset_identifier: OB
    description: Osteoblast population
    unit: relative
  - name: FGF23
    dataset_identifier: FGF23
    description: Fibroblast growth factor 23
    unit: pg/mL
    notes: Extension model species (BIOMD0000000613.ext.ant)
    mappings_list:
    - preferred_term: Fibroblast growth factor 23
      term:
        id: LOINC:54390-0
        label: Fibroblast growth factor 23 [Mass/volume] in Serum or Plasma
  - name: Soluble_Klotho
    dataset_identifier: sKlotho
    description: Soluble alpha-Klotho, FGF23 co-receptor shed from kidney
    unit: pg/mL
    notes: Extension model species
  - name: Vascular_Calcification
    dataset_identifier: VascCa
    description: Vascular calcification burden
    unit: relative
    notes: Extension model species
    mappings_list:
    - preferred_term: Arterial calcification
      term:
        id: HP:0003207
        label: Arterial calcification
      threshold: 50
      threshold_direction: above
      severity_scale:
      - threshold: 50
        name: mild
      - threshold: 150
        name: moderate
      - threshold: 300
        name: severe
    - preferred_term: Left ventricular hypertrophy
      description: >-
        Model approximation: LVH is a consequence of arterial stiffening from
        vascular calcification, not a direct readout of calcification burden.
        VascCa serves as a proxy for arterial stiffness-driven cardiac remodeling.
      term:
        id: HP:0001712
        label: Left ventricular hypertrophy
      threshold: 100
      threshold_direction: above
      severity_scale:
      - threshold: 100
        name: mild
      - threshold: 200
        name: moderate
    - preferred_term: Calciphylaxis
      description: >-
        Model approximation: calcinosis cutis (calciphylaxis) involves small
        vessel disease distinct from medial arterial calcification. VascCa is
        used as a proxy for overall ectopic calcification burden.
      term:
        id: HP:0025520
        label: Calcinosis cutis
      threshold: 250
      threshold_direction: above
      severity_scale:
      - threshold: 250
        name: calciphylaxis risk
  - name: Sclerostin
    dataset_identifier: SOST
    description: Sclerostin, Wnt pathway inhibitor produced by osteocytes and calcified vasculature
    unit: pmol/L
    notes: Extension model species
  - name: CaPO4_Product
    dataset_identifier: CaPO4_product
    description: Calcium-phosphate product (derived quantity)
    unit: (mg/dL)^2
    notes: Extension model assignment rule
- name: Peterson-Riggs CKD-MBD Multiscale Extension
  description: Extension of the Peterson-Riggs calcium homeostasis model to simulate progressive CKD over a 10-year course, including evolution of secondary hyperparathyroidism from diminished renal phosphate clearance. Links bone remodeling markers with BMD formation and elimination rates. Includes simulated interventions with calcimimetics and calcitriol.
  model_type: PHYSIOLOGICAL
  base_model: Peterson-Riggs 2010 (BIOMD0000000613)
  model_software: COPASI
  model_format: SBML
  publication: PMID:22232752
  evidence:
  - reference: PMID:22232752
    reference_title: "Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "A physiologically based, multiscale model of calcium homeostasis and bone remodeling was used to describe the impact of progressive loss of kidney function over a typical 10-year course of chronic kidney disease (CKD), including the evolution of secondary hyperparathyroidism (HPT) caused by diminished renal phosphate clearance and increased plasma phosphate."
    explanation: "Describes the multiscale extension of the Peterson-Riggs model that simulates progressive CKD and evolution of secondary hyperparathyroidism."
  perturbations:
  - preferred_term: CASR
    term:
      id: hgnc:1514
      label: CASR
    modifier: INCREASED
  findings:
  - statement: Predicted lumbar spine BMD losses at GFR 58, 39, and 16 mL/min of -0.98%, -3.0%, and -6.5% respectively, compared to observed values of -0.5%, -4.0%, and -8.1%
    evidence:
    - reference: PMID:22232752
      reference_title: "Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The composite model predicted lumbar spine BMD losses, relative to baseline, at months 28 (glomerular filtration rate = 58 mL/min), 50 (39 mL/min), and 120 (16 mL/min) of approximately -0.98%, -3.0%, and -6.5%, respectively, compared to the observed BMD values in corresponding renal function groups, scaled to a 100-mL/min baseline, of -0.5%, -4.0%, and -8.1%, respectively."
      explanation: "Provides the exact predicted and observed BMD loss values at each GFR stage, directly supporting the finding statement."
  - statement: Simulated calcimimetic intervention reduces PTH and attenuates BMD loss
    evidence:
    - reference: PMID:22232752
      reference_title: "Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function."
      supports: PARTIAL
      evidence_source: COMPUTATIONAL
      snippet: "simulated interventions with a hypothetical calcimimetic agent and calcitriol are provided to show the utility of this model as a platform for evaluating therapeutics."
      explanation: "The abstract confirms that a calcimimetic intervention was simulated, but it does not report the specific PTH reduction or BMD attenuation claimed in the finding."
  - statement: Simulated calcitriol intervention normalizes calcium but with risk of hyperphosphatemia
    evidence:
    - reference: PMID:22232752
      reference_title: "Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function."
      supports: PARTIAL
      evidence_source: COMPUTATIONAL
      snippet: "simulated interventions with a hypothetical calcimimetic agent and calcitriol are provided to show the utility of this model as a platform for evaluating therapeutics."
      explanation: "The abstract confirms that a calcitriol intervention was simulated, but it does not report the specific calcium normalization or hyperphosphatemia risk claimed in the finding."
  notes: Multiscale model linking molecular/cellular bone remodeling to organ-level mineral homeostasis across progressive CKD stages. Validates against clinical BMD data stratified by GFR.
  variables:
  - name: Plasma_Ca
    dataset_identifier: P
    description: Plasma calcium concentration, tracked over 10-year CKD progression
    unit: mg/dL
    mappings_list:
    - preferred_term: Serum calcium
      term:
        id: LOINC:17861-6
        label: Calcium:MCnc:Pt:Ser/Plas:Qn
  - name: Plasma_PO4
    dataset_identifier: ECCPhos
    description: Plasma phosphate, rising with declining renal clearance
    unit: mg/dL
    mappings_list:
    - preferred_term: Serum phosphate
      term:
        id: LOINC:2777-1
        label: Phosphate:MCnc:Pt:Ser/Plas:Qn
  - name: Plasma_PTH
    dataset_identifier: PTH
    description: Plasma intact PTH, evolving secondary hyperparathyroidism trajectory
    unit: pg/mL
    mappings_list:
    - preferred_term: Intact PTH
      term:
        id: LOINC:2731-8
        label: Parathyrin.intact:MCnc:Pt:Ser/Plas:Qn
  - name: BMD_lumbar
    dataset_identifier: Qbone
    description: Lumbar spine BMD, predicted loss at GFR stages 58, 39, and 16 mL/min
    unit: g/cm2
    mappings_list:
    - preferred_term: Reduced bone mineral density
      term:
        id: HP:0004349
        label: Reduced bone mineral density
  - name: GFR
    dataset_identifier: GFR
    description: Glomerular filtration rate, declining over simulated CKD course
    unit: mL/min
    mappings_list:
    - preferred_term: Estimated GFR
      term:
        id: LOINC:98979-8
        label: Glomerular filtration rate/1.73 sq M.predicted:ArVRat:Pt:Ser/Plas/Bld:Qn:Creatinine-based formula (CKD-EPI 2021)
    notes: Input variable driving the simulation; CKD-EPI or MDRD equivalent
  - name: Bone_Remodeling_Marker
    description: Bone remodeling markers (formation/resorption) linked to BMD dynamics
    unit: U/L
    mappings_list:
    - preferred_term: Serum alkaline phosphatase
      term:
        id: LOINC:6768-6
        label: Alkaline phosphatase:CCnc:Pt:Ser/Plas:Qn
references:
- reference: DOI:10.1038/s41598-024-54812-4
  title: 'Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis'
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023.
    supporting_text: We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023.
    evidence:
    - reference: DOI:10.1038/s41598-024-54812-4
      reference_title: 'Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1093/ckj/sfad290
  title: Real-world usage of Chronic Kidney Disease – Mineral Bone Disorder (CKD–MBD) biomarkers in nephrology practices
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Real-world usage of Chronic Kidney Disease – Mineral Bone Disorder (CKD–MBD) biomarkers in nephrology practices
    supporting_text: Chronic 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.
    evidence:
    - reference: DOI:10.1093/ckj/sfad290
      reference_title: Real-world usage of Chronic Kidney Disease – Mineral Bone Disorder (CKD–MBD) biomarkers in nephrology practices
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic 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.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1093/ckj/sfae097
  title: The effect of parathyroid hormone lowering by etelcalcetide therapy on calcification propensity and calciprotein particles in hemodialysis patients
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: The effect of parathyroid hormone lowering by etelcalcetide therapy on calcification propensity and calciprotein particles in hemodialysis patients
    supporting_text: This study investigated whether parathyroid hormone (PTH) lowering with etelcalcetide, and the consequent effects on mineral and bone metabolism, could improve serum calcification propensity (T50 time) and decrease calciprotein particle (CPP) load in hemodialysis patients with secondary hyperparathyroidism.
    evidence:
    - reference: DOI:10.1093/ckj/sfae097
      reference_title: The effect of parathyroid hormone lowering by etelcalcetide therapy on calcification propensity and calciprotein particles in hemodialysis patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This study investigated whether parathyroid hormone (PTH) lowering with etelcalcetide, and the consequent effects on mineral and bone metabolism, could improve serum calcification propensity (T50 time) and decrease calciprotein particle (CPP) load in hemodialysis patients with secondary hyperparathyroidism.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1093/ckj/sfae143
  title: Application of artificial intelligence to chronic kidney disease mineral bone disorder
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease.
    supporting_text: The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease.
    evidence:
    - reference: DOI:10.1093/ckj/sfae143
      reference_title: Application of artificial intelligence to chronic kidney disease mineral bone disorder
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1093/ckj/sfz112
  title: Combinations of mineral and bone disorder markers and risk of death and hospitalizations in the international Dialysis Outcomes and Practice Patterns Study
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Combinations of mineral and bone disorder markers and risk of death and hospitalizations in the international Dialysis Outcomes and Practice Patterns Study
    supporting_text: Prior studies have developed a chronic kidney disease–mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA.
    evidence:
    - reference: DOI:10.1093/ckj/sfz112
      reference_title: Combinations of mineral and bone disorder markers and risk of death and hospitalizations in the international Dialysis Outcomes and Practice Patterns Study
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Prior studies have developed a chronic kidney disease–mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1093/cvr/cvae164
  title: Calciprotein particle counts associate with vascular remodelling in chronic kidney disease
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD).
    supporting_text: Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD).
    evidence:
    - reference: DOI:10.1093/cvr/cvae164
      reference_title: Calciprotein particle counts associate with vascular remodelling in chronic kidney disease
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD).
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1093/jbmr/zjae021
  title: 'Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study'
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population.
    supporting_text: Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population.
    evidence:
    - reference: DOI:10.1093/jbmr/zjae021
      reference_title: 'Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.1111/nep.14407
  title: Phosphorous metabolism and manipulation in chronic kidney disease
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Chronic kidney disease‐mineral bone disorder (CKD‐MBD) is a syndrome commonly observed in subjects with impaired renal function.
    supporting_text: Chronic kidney disease‐mineral bone disorder (CKD‐MBD) is a syndrome commonly observed in subjects with impaired renal function.
    evidence:
    - reference: DOI:10.1111/nep.14407
      reference_title: Phosphorous metabolism and manipulation in chronic kidney disease
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Chronic kidney disease‐mineral bone disorder (CKD‐MBD) is a syndrome commonly observed in subjects with impaired renal function.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.32948/ajsep.2024.05.20
  title: 'The relationship between vitamin D, chronic kidney disease, and mineral and bone disorder: a complex interplay comprehensive review'
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Chronic kidney disease (CKD) is a global health concern with a significant prevalence.
    supporting_text: Chronic kidney disease (CKD) is a global health concern with a significant prevalence.
    evidence:
    - reference: DOI:10.32948/ajsep.2024.05.20
      reference_title: 'The relationship between vitamin D, chronic kidney disease, and mineral and bone disorder: a complex interplay comprehensive review'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic kidney disease (CKD) is a global health concern with a significant prevalence.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.3389/fphys.2024.1356069
  title: Bone and bone derived factors in kidney disease
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: 'of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality.'
    supporting_text: 'of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality.'
    evidence:
    - reference: DOI:10.3389/fphys.2024.1356069
      reference_title: Bone and bone derived factors in kidney disease
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality.'
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.3390/jcm12196306
  title: Current and Emerging Markers and Tools Used in the Diagnosis and Management of Chronic Kidney Disease–Mineral and Bone Disorder in Non-Dialysis Adult Patients
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years.
    supporting_text: Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years.
    evidence:
    - reference: DOI:10.3390/jcm12196306
      reference_title: Current and Emerging Markers and Tools Used in the Diagnosis and Management of Chronic Kidney Disease–Mineral and Bone Disorder in Non-Dialysis Adult Patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
- reference: DOI:10.3803/enm.2024.1978
  title: Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease
  found_in:
  - CKD-Mineral_Bone_Disorder-deep-research-falcon.md
  findings:
  - statement: Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder.
    supporting_text: Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder.
    evidence:
    - reference: DOI:10.3803/enm.2024.1978
      reference_title: Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder.
      explanation: Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
📚

References & Deep Research

References

12
DOI:10.1038/s41598-024-54812-4
Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis
1 finding
We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023.
"We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023."
Show evidence (1 reference)
DOI:10.1038/s41598-024-54812-4 SUPPORT Human Clinical
"We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1093/ckj/sfad290
Real-world usage of Chronic Kidney Disease – Mineral Bone Disorder (CKD–MBD) biomarkers in nephrology practices
1 finding
Real-world usage of Chronic Kidney Disease – Mineral Bone Disorder (CKD–MBD) biomarkers in nephrology practices
"Chronic 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."
Show evidence (1 reference)
DOI:10.1093/ckj/sfad290 SUPPORT Human Clinical
"Chronic 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."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1093/ckj/sfae097
The effect of parathyroid hormone lowering by etelcalcetide therapy on calcification propensity and calciprotein particles in hemodialysis patients
1 finding
The effect of parathyroid hormone lowering by etelcalcetide therapy on calcification propensity and calciprotein particles in hemodialysis patients
"This study investigated whether parathyroid hormone (PTH) lowering with etelcalcetide, and the consequent effects on mineral and bone metabolism, could improve serum calcification propensity (T50 time) and decrease calciprotein particle (CPP) load in hemodialysis patients with secondary..."
Show evidence (1 reference)
DOI:10.1093/ckj/sfae097 SUPPORT Human Clinical
"This study investigated whether parathyroid hormone (PTH) lowering with etelcalcetide, and the consequent effects on mineral and bone metabolism, could improve serum calcification propensity (T50 time) and decrease calciprotein particle (CPP) load in hemodialysis patients with secondary..."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1093/ckj/sfae143
Application of artificial intelligence to chronic kidney disease mineral bone disorder
1 finding
The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease.
"The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease."
Show evidence (1 reference)
DOI:10.1093/ckj/sfae143 SUPPORT Computational
"The global derangement of mineral metabolism that accompanies chronic kidney disease (CKD-MBD) is a major driver of the accelerated mortality for individuals with kidney disease."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1093/ckj/sfz112
Combinations of mineral and bone disorder markers and risk of death and hospitalizations in the international Dialysis Outcomes and Practice Patterns Study
1 finding
Combinations of mineral and bone disorder markers and risk of death and hospitalizations in the international Dialysis Outcomes and Practice Patterns Study
"Prior studies have developed a chronic kidney disease–mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA."
Show evidence (1 reference)
DOI:10.1093/ckj/sfz112 SUPPORT Human Clinical
"Prior studies have developed a chronic kidney disease–mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1093/cvr/cvae164
Calciprotein particle counts associate with vascular remodelling in chronic kidney disease
1 finding
Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD).
"Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD)."
Show evidence (1 reference)
DOI:10.1093/cvr/cvae164 SUPPORT Human Clinical
"Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD)."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1093/jbmr/zjae021
Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study
1 finding
Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population.
"Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population."
Show evidence (1 reference)
DOI:10.1093/jbmr/zjae021 SUPPORT Human Clinical
"Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.1111/nep.14407
Phosphorous metabolism and manipulation in chronic kidney disease
1 finding
Chronic kidney disease‐mineral bone disorder (CKD‐MBD) is a syndrome commonly observed in subjects with impaired renal function.
"Chronic kidney disease‐mineral bone disorder (CKD‐MBD) is a syndrome commonly observed in subjects with impaired renal function."
Show evidence (1 reference)
DOI:10.1111/nep.14407 SUPPORT In Vitro
"Chronic kidney disease‐mineral bone disorder (CKD‐MBD) is a syndrome commonly observed in subjects with impaired renal function."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.32948/ajsep.2024.05.20
The relationship between vitamin D, chronic kidney disease, and mineral and bone disorder: a complex interplay comprehensive review
1 finding
Chronic kidney disease (CKD) is a global health concern with a significant prevalence.
"Chronic kidney disease (CKD) is a global health concern with a significant prevalence."
Show evidence (1 reference)
DOI:10.32948/ajsep.2024.05.20 SUPPORT Human Clinical
"Chronic kidney disease (CKD) is a global health concern with a significant prevalence."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.3389/fphys.2024.1356069
Bone and bone derived factors in kidney disease
1 finding
of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality.
"of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality."
Show evidence (1 reference)
DOI:10.3389/fphys.2024.1356069 SUPPORT Human Clinical
"of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.3390/jcm12196306
Current and Emerging Markers and Tools Used in the Diagnosis and Management of Chronic Kidney Disease–Mineral and Bone Disorder in Non-Dialysis Adult Patients
1 finding
Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years.
"Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years."
Show evidence (1 reference)
DOI:10.3390/jcm12196306 SUPPORT Human Clinical
"Chronic kidney disease (CKD) is a significant public health concern associated with significant morbidity and has become one of the foremost global causes of death in recent years."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.
DOI:10.3803/enm.2024.1978
Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease
1 finding
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder.
"Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder."
Show evidence (1 reference)
DOI:10.3803/enm.2024.1978 SUPPORT Human Clinical
"Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder."
Deep research cited this publication as relevant literature for CKD-Mineral Bone Disorder.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 50 citations 2026-05-08T11:21:19.687609

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: CKD-Mineral Bone Disorder
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on CKD-Mineral Bone Disorder covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: CKD–Mineral and Bone Disorder (CKD-MBD)

Executive summary

Chronic kidney disease–mineral and bone disorder (CKD-MBD) is a systemic syndrome arising in CKD characterized by biochemical abnormalities (Ca–P–PTH–vitamin D/FGF23 axis), bone disease (renal osteodystrophy), and vascular/soft-tissue calcification, contributing to fractures and high cardiovascular morbidity/mortality. Recent 2023–2024 literature emphasizes (i) the bone–vascular axis and osteocyte/vascular transdifferentiation biology, (ii) real-world gaps in biomarker availability (FGF23/Klotho/CPP), and (iii) emerging markers (calciprotein particles, T50) and data-science/AI approaches for personalization. (williams2023updatesinthe pages 1-2, fusaro2024realworldusageof pages 1-3, lederer2024applicationofartificial pages 1-3, feenstra2024calciproteinparticlecounts pages 1-2)

1. Disease information

1.1 What is CKD-MBD?

Recent authoritative definitions converge on CKD-MBD as a systemic syndrome linking mineral dysregulation to bone and cardiovascular pathology. A CKJ 2024 AI-focused review defines CKD-MBD as: “the collective skeletal and cardiovascular organ damage resulting from the deranged mineral metabolism that complicates CKD.” (https://doi.org/10.1093/ckj/sfae143; advance publication June 2024) (lederer2024applicationofartificial pages 1-3)

A 2024 Clinical Kidney Journal survey paper states: “Chronic 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.” (https://doi.org/10.1093/ckj/sfad290; published 2024) (fusaro2024realworldusageof pages 1-3)

A 2024 overview emphasizes the broader systemic scope: CKD-MBD involves dysregulation of bone turnover/mineralization/strength with soft-tissue and vascular calcification, driven by disturbances in calcium, phosphate, PTH, vitamin D, FGF-23, and Klotho that occur early in CKD. (https://doi.org/10.3390/life14030418; March 2024) (izzo2024chronickidneydisease pages 1-2, izzo2024chronickidneydisease pages 2-4)

1.2 Key identifiers and codes

A single, definitive ontology/ICD code set for CKD-MBD was not retrieved in the current evidence corpus, and should not be guessed. The corpus supports standard naming, synonyms, and related component terms (renal osteodystrophy). See artifact below. (ketteler2017executivesummaryof pages 4-5, fusaro2024realworldusageof pages 1-3)

Concept (identifier type) Identifier/Code Label Notes/Source
Preferred disease name — Chronic kidney disease–mineral and bone disorder (CKD-MBD) KDIGO 2017 and recent reviews use CKD-MBD as the standard term for the systemic disorder of mineral and bone metabolism due to CKD (https://doi.org/10.1016/j.kint.2017.04.006, 2017; https://doi.org/10.1093/ckj/sfad290, 2024; https://doi.org/10.1093/ckj/sfae143, 2024) (ketteler2017executivesummaryof pages 4-5, fusaro2024realworldusageof pages 1-3, lederer2024applicationofartificial pages 1-3)
Core definition — Systemic disorder of mineral and bone metabolism due to CKD KDIGO-linked review states CKD-MBD is “defined as a systemic disorder of mineral and bone metabolism due to CKD” manifested by abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover/mineralization/volume/growth/strength; and vascular or other soft-tissue calcification (Bone Reports review summarizing KDIGO; https://doi.org/10.1016/j.bonr.2018.07.002, 2018). Recent reviews restate this as a complex disorder linking mineral dysregulation, bone disease, and vascular calcification (https://doi.org/10.3390/life14030418, 2024; https://doi.org/10.1093/ckj/sfae143, 2024) (izzo2024chronickidneydisease pages 1-2, lederer2024applicationofartificial pages 1-3)
Abbreviation — CKD-MBD Widely used abbreviation in guideline and review literature (https://doi.org/10.1016/j.kint.2017.04.006, 2017; https://doi.org/10.1093/ckj/sfad290, 2024) (ketteler2017executivesummaryof pages 4-5, fusaro2024realworldusageof pages 1-3)
Related component term — Renal osteodystrophy KDIGO executive summary clarifies renal osteodystrophy is one component of CKD-MBD and refers specifically to “abnormal bone histology,” not the entire syndrome (https://doi.org/10.1016/j.kint.2017.04.006, 2017) (ketteler2017executivesummaryof pages 4-5)
Common synonym/near-synonym — CKD-related mineral and bone disorder Used interchangeably in some reviews, but CKD-MBD remains preferred standard nomenclature (https://doi.org/10.1093/ckj/sfae143, 2024; https://doi.org/10.3390/jcm12196306, 2023) (lederer2024applicationofartificial pages 1-3, fusaro2023currentandemerging pages 5-6)
Common synonym/near-synonym — Mineral and bone disorder in chronic kidney disease Plain-language inversion of CKD-MBD used in reviews/surveys; same syndrome (https://doi.org/10.1093/ckj/sfad290, 2024; https://doi.org/10.3390/life14030418, 2024) (fusaro2024realworldusageof pages 1-3, izzo2024chronickidneydisease pages 1-2)
Related pathobiology phrase — Bone–vascular axis / bone–vascular paradox Not a synonym for the disease itself, but a mechanistic framing commonly used for CKD-MBD linking low bone turnover/remodeling abnormalities with vascular calcification (https://doi.org/10.3389/fphys.2023.1120308, 2023; https://doi.org/10.3390/life14030418, 2024) (williams2023updatesinthe pages 1-2, izzo2024chronickidneydisease pages 1-2)
MONDO not retrieved in current corpus — No MONDO identifier was available in the retrieved evidence corpus; should not be guessed (fusaro2024realworldusageof pages 1-3, ketteler2017executivesummaryof pages 4-5)
MeSH not retrieved in current corpus — No MeSH identifier for CKD-MBD was directly retrieved in the current evidence corpus; related historical indexing may use broader bone/kidney disorder terms, but not confirmed here (fusaro2024realworldusageof pages 1-3, ketteler2017executivesummaryof pages 4-5)
ICD-10 not retrieved in current corpus — No single ICD-10 code for CKD-MBD was directly retrieved in the current corpus; syndrome is typically represented across CKD, mineral metabolism, bone disorder, and hyperparathyroidism coding domains rather than a single dedicated code (not confirmed from current evidence) (fusaro2024realworldusageof pages 1-3, izzo2024chronickidneydisease pages 1-2)
ICD-11 not retrieved in current corpus — No directly retrieved ICD-11 identifier in the current corpus (fusaro2024realworldusageof pages 1-3, izzo2024chronickidneydisease pages 1-2)
OMIM not retrieved in current corpus — No OMIM entry was retrieved; CKD-MBD is a complex acquired syndrome rather than a single-gene Mendelian disease entity in the reviewed sources (izzo2024chronickidneydisease pages 1-2, lederer2024applicationofartificial pages 1-3)
Orphanet not retrieved in current corpus — No Orphanet identifier was retrieved in the current evidence corpus (fusaro2024realworldusageof pages 1-3)
Evidence source type — Aggregated disease-level resource and cohort/review literature Information here is derived from disease-level guidelines/reviews and clinical cohorts/surveys rather than individual-patient EHR extraction alone (KDIGO 2017 guideline/update; Italian nephrologist survey; recent reviews) (https://doi.org/10.1016/j.kint.2017.04.006, 2017; https://doi.org/10.1093/ckj/sfad290, 2024; https://doi.org/10.3390/life14030418, 2024) (ketteler2017executivesummaryof pages 4-5, fusaro2024realworldusageof pages 1-3, izzo2024chronickidneydisease pages 1-2)

Table: This table summarizes the core disease definition, standard terminology, related terms, and identifier availability for CKD-MBD using only the retrieved evidence corpus. It is useful for populating a knowledge-base entry while clearly marking identifiers that were not directly retrieved.

1.3 Synonyms and alternative names

Commonly used alternatives include “mineral and bone disorder in chronic kidney disease,” “CKD-related mineral and bone disorder,” and the component term “renal osteodystrophy” (a bone histology entity within CKD-MBD). (ketteler2017executivesummaryof pages 4-5, fusaro2024realworldusageof pages 1-3)

1.4 Evidence source type

Information here is derived primarily from aggregated disease-level guidelines/reviews and cohorts/surveys (KDIGO guideline update, observational cohorts, biomarker trials), not individual-patient EHR extraction. (wheeler2017kdigo2017clinical pages 13-16, neri2019detectinghighriskchronic pages 1-2, thiem2023effectofthe pages 1-3)

2. Etiology

2.1 Disease causal factors (mechanistic)

CKD-MBD is an acquired, CKD-driven systemic syndrome caused by reduced kidney function leading to disturbed phosphate excretion, impaired vitamin D activation, altered calcium homeostasis, endocrine adaptations (PTH/FGF23), and downstream bone remodeling abnormalities and calcification biology. Reviews highlight that phosphate stress is central (“phosphorocentric hypothesis”), with feedback actors including vitamin D, PTH, CPPs, FGF-23 and Klotho. (https://doi.org/10.1111/nep.14407; Oct 2024) (izzo2024chronickidneydisease pages 2-4)

2.2 Risk factors

Evidence from a large CKD cohort (CRIC) indicates multiple modifiable and CKD-related factors are associated with hip/vertebral fractures. In 3939 participants, baseline diabetes, lower BMI, steroid use, proteinuria, and elevated PTH were associated with fracture risk; time-updated lower eGFR, lower serum calcium, and lower bicarbonate were also associated. (https://doi.org/10.1093/jbmr/zjae021; advance access Feb 4, 2024) (hsu2024riskfactorsfor pages 1-2)

In dialysis populations, combinations of Ca/P/PTH abnormalities define high-risk CKD-MBD phenotypes with increased mortality and hospitalization, consistent with CKD-MBD as a risk-enrichment syndrome. (neri2019detectinghighriskchronic pages 1-2, fuller2020combinationsofmineral pages 1-2)

2.3 Protective factors

Protective factors are incompletely defined in the retrieved corpus. One recent systematic review/meta-analysis suggests physical exercise may beneficially modulate the Klotho–FGF23 axis, reporting decreased FGF23 and increased Klotho in pooled RCT data (though this pertains to CKD broadly and is not limited to CKD-MBD endpoints). (https://doi.org/10.7150/ijms.90195; Jan 2024) (simic2024boneandbone pages 1-2)

2.4 Gene–environment interactions

Not retrieved in current corpus at a specificity appropriate for CKD-MBD knowledge base annotation.

3. Phenotypes

3.1 Core phenotype domains

CKD-MBD phenotypes cluster into: 1) Laboratory abnormalities: hyperphosphatemia (or phosphate stress), hypocalcemia/hypercalcemia, elevated iPTH, low active vitamin D, elevated FGF23, Klotho deficiency (often investigational). (lederer2024applicationofartificial pages 1-3, izzo2024chronickidneydisease pages 2-4, fusaro2024realworldusageof pages 1-3) 2) Skeletal abnormalities / renal osteodystrophy (bone turnover/mineralization/strength). (izzo2024chronickidneydisease pages 1-2, ketteler2017executivesummaryof pages 4-5) 3) Vascular and soft-tissue calcification and related cardiovascular sequelae. (izzo2024chronickidneydisease pages 1-2, williams2023updatesinthe pages 1-2)

3.2 Quantitative clinical phenotype data (fracture outcomes)

In CRIC (n=3939), fracture incidence for hip/vertebral fractures was 2.4 events per 1000 person-years (95% CI 2.0–2.9) over mean 11.1 years; fracture hazard was highest in kidney failure treated with dialysis vs eGFR≥60 (HR 4.53; 95% CI 1.77–11.60). (hsu2024riskfactorsfor pages 1-2)

3.3 Quality-of-life impact

Direct QoL instrument statistics (e.g., EQ-5D, PROMIS) were not retrieved in the current corpus; however, fractures and cardiovascular disease are consistently identified as major morbidity drivers in CKD-MBD reviews and cohorts. (simic2024boneandbone pages 1-2, neri2019detectinghighriskchronic pages 1-2)

3.4 HPO term suggestions (non-exhaustive; ontology IDs not validated in corpus)

Not retrieved in current corpus; should be mapped during curation using validated HPO resources. Phenotypic concepts to map include: hyperparathyroidism, hyperphosphatemia, hypocalcemia/hypercalcemia, vitamin D deficiency, renal osteodystrophy, osteoporosis/low bone mineral density, vascular calcification.

4. Genetic / molecular information

4.1 Causal genes and pathogenic variants

CKD-MBD is primarily a complex acquired syndrome secondary to CKD rather than a Mendelian disorder; no causal gene/variant lists were retrieved in the current corpus. (izzo2024chronickidneydisease pages 1-2, lederer2024applicationofartificial pages 1-3)

4.2 Key molecular mediators emphasized in 2023–2024 literature

Key endocrine and signaling mediators include: - PTH and parathyroid hyperplasia in secondary hyperparathyroidism (SHPT), linked to fractures and mortality in advanced CKD. (https://doi.org/10.3803/enm.2024.1978; June 2024) (simic2024boneandbone pages 1-2) - FGF23–Klotho axis as a phosphate/vitamin D regulator and potential mediator of off-target organ effects (causality for outcomes remains under investigation). (simic2024boneandbone pages 1-2) - Wnt signaling / sclerostin (SOST) framing the bone–vascular paradox; vascular-derived sclerostin may function as a brake on Wnt-driven calcification, complicating therapeutic inhibition strategies. The 2023 update review states: “inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification”, arguing that a better target is reducing vascular osteoblastic/osteocytic transdifferentiation. (https://doi.org/10.3389/fphys.2023.1120308; Jan 2023) (williams2023updatesinthe pages 1-2)

4.3 Suggested GO / CL terms

Ontology term IDs were not retrieved in the corpus; however, mechanistic processes supported here include endothelial activation, inflammation, extracellular matrix remodeling, ossification, and osteogenic transdifferentiation of vascular smooth muscle cells. (feenstra2024calciproteinparticlecounts pages 1-2, williams2023updatesinthe pages 1-2)

5. Environmental information

5.1 Lifestyle / nutrition

The corpus emphasizes phosphate loading and calcium load as contributors to vascular calcification biology, but does not provide detailed exposure-response estimates for lifestyle factors.

5.2 Exercise as a potential modifier

A 2024 meta-analysis of 4 RCTs (n=272) reported exercise decreased FGF23 (MD −102.07 pg/mL; p=0.001) and increased Klotho (MD 158.82 pg/mL; p=0.001). (simic2024boneandbone pages 1-2)

6. Mechanism / pathophysiology

6.1 Causal chain (simplified)

Declining kidney function → phosphate retention/phosphate stress → compensatory endocrine changes (↑FGF23, ↑PTH, ↓calcitriol) and altered calcium balance → disturbed bone remodeling/turnover (renal osteodystrophy; osteoporosis phenotypes) and generation of calciprotein particles (CPP) → vascular smooth muscle cell osteogenic programming, endothelial activation/inflammation/ECM remodeling → vascular calcification and cardiovascular complications, contributing to mortality. This integrated, systemic framing is emphasized in 2023–2024 literature. (izzo2024chronickidneydisease pages 2-4, izzo2024chronickidneydisease pages 1-2, feenstra2024calciproteinparticlecounts pages 1-2)

6.2 Vascular calcification and CPP biology (2023–2024 developments)

A 2024 Cardiovascular Research study linking imaging, vascular transcriptomics and CPP measures reports that CKD is characterized by systemic vascular calcification with increased calcification propensity and CPP counts, and vascular tissue shows enrichment of “endothelial activation, inflammation, extracellular matrix (ECM) remodelling, and ossification” processes; CPP counts were significantly associated with vascular remodeling markers. (https://doi.org/10.1093/cvr/cvae164; online ahead Aug 5, 2024) (feenstra2024calciproteinparticlecounts pages 1-2)

Mechanistic-interventional evidence in dialysis patients supports CPP reduction as a plausible therapeutic axis: in a randomized crossover secondary analysis (n=28), high-dose sucroferric oxyhydroxide reduced primary CPP by −62% and secondary CPP by −38% versus washout, and reduced inflammatory cytokines (including IL-6 and IL-8); serum from treated patients induced less vascular calcification and endothelial activation in vitro. (https://doi.org/10.1093/ndt/gfac271; NDT 2023) (thiem2023effectofthe pages 1-3)

6.3 AI and systems modeling (2024)

A 2024 CKJ review argues that guideline-era therapies targeting surrogate biochemical targets have not changed cardiovascular outcomes and proposes a combined mathematical modeling + machine learning approach for hypothesis generation, in-silico trials, and therapy personalization. It reiterates the biochemical signature as “high serum phosphate, low calcium, high parathyroid hormone (PTH), low active vitamin D (calcitriol), and high fibroblast growth factor 23 (FGF23).” (https://doi.org/10.1093/ckj/sfae143; June 2024) (lederer2024applicationofartificial pages 1-3)

7. Anatomical structures affected

7.1 Organ level (supported in corpus)

  • Bone/skeleton (renal osteodystrophy; osteoporosis phenotype) (izzo2024chronickidneydisease pages 1-2, ketteler2017executivesummaryof pages 4-5)
  • Vasculature (arterial media calcification; remodeling) (feenstra2024calciproteinparticlecounts pages 1-2, izzo2024chronickidneydisease pages 1-2)
  • Cardiovascular system (CVD risk and mortality association emphasized) (williams2023updatesinthe pages 1-2, izzo2024chronickidneydisease pages 1-2)

7.2 Tissue/cell level

  • Vascular smooth muscle cells (VSMCs) undergoing osteogenic transdifferentiation in uremic milieu (review framing). (izzo2024chronickidneydisease pages 1-2)
  • Vascular tissues exhibit transcriptomic enrichment for endothelial activation/inflammation/ECM remodeling/ossification. (feenstra2024calciproteinparticlecounts pages 1-2)

7.3 UBERON / CL suggestions

Ontology IDs not retrieved; map bone tissue, arterial media, VSMCs, endothelial cells during curation.

8. Temporal development

8.1 Onset and progression

Biochemical perturbations and endocrine adaptations can occur early (often from CKD stage 3) and progress with declining eGFR; bone and vascular complications accumulate, with highest fracture hazard observed in kidney failure/dialysis populations. (izzo2024chronickidneydisease pages 2-4, hsu2024riskfactorsfor pages 1-2)

9. Inheritance and population

9.1 Epidemiology (CKD burden)

A 2024 overview summarizes global CKD burden as 697.5 million affected worldwide, 35.8 million DALYs, and 1.2 million deaths in 2017, with CKD mortality increasing 41.5% from 1990 to 2017. (https://doi.org/10.3390/life14030418; 2024) (izzo2024chronickidneydisease pages 1-2)

9.2 CKD-MBD population-risk statistics from cohorts

In a 35,721-patient international dialysis cohort (EuCliD), there were 126.7 deaths/1000 person-years and CKD-MBD phenotype-specific adjusted mortality HRs ranged 1.07 to 1.59 across Ca/P/PTH phenotype combinations. (neri2019detectinghighriskchronic pages 1-2)

10. Diagnostics

10.1 Standard biochemical testing and monitoring (KDIGO 2017)

KDIGO 2017 recommends monitoring serum calcium, phosphate, PTH, and alkaline phosphatase starting in CKD G3a, and optionally measuring 25(OH)D with correction of deficiency/insufficiency per general-population strategies. Suggested monitoring frequencies are stage-based (see table image citation and details below). (wheeler2017kdigo2017clinical pages 13-16, wheeler2017kdigo2017clinical media ed681c34)

Visual evidence (KDIGO monitoring frequency table/summary): (wheeler2017kdigo2017clinical media ed681c34)

KDIGO suggested monitoring intervals (adult CKD) include: - CKD G3a–G3b: Ca and phosphate every 6–12 months; PTH based on baseline and progression. - CKD G4: Ca and phosphate every 3–6 months; PTH every 6–12 months. - CKD G5/G5D: Ca and phosphate every 1–3 months; PTH every 3–6 months. - CKD G4–G5D: alkaline phosphatase every 12 months (more often if PTH elevated). - 25(OH)D: “might be measured” with repeat testing based on baseline and interventions. (wheeler2017kdigo2017clinical pages 13-16, wheeler2017kdigo2017clinical media ed681c34)

10.2 Bone and vascular imaging tools

The 2024 overview notes multiple approaches for vascular calcification detection (e.g., lateral plain X-ray, Kauppila and Adragao scores, pulse wave velocity, and pQCT). (izzo2024chronickidneydisease pages 1-2)

10.3 Emerging markers/tools

A 2023 review on non-dialysis CKD highlights a need for additional markers beyond late-stage dialysis practice and discusses emerging markers including CPP/T50 approaches in CKD-MBD management contexts. (https://doi.org/10.3390/jcm12196306; Sep 2023) (fusaro2023currentandemerging pages 5-6)

10.4 Real-world implementation of diagnostic testing (2024)

A 2024 Italian survey (n=106 nephrologists) provides a real-world snapshot of biomarker availability and guideline use: - Hospital labs could support requests for ionized calcium (99.1%), PTH (99.1%), ALP (99.1%), 25(OH)D (94.3%), but only 1,25(OH)2D (57.5%). - Most labs did not support FGF-23 (intact 88.7% unavailable; C-terminal 93.4% unavailable) or Klotho (95.3% unavailable; soluble 97.2% unavailable). - Guideline usage for starting SHPT therapy varied: KDOQI used by 51.9% vs KDIGO by 37.7%. (https://doi.org/10.1093/ckj/sfad290; 2024) (fusaro2024realworldusageof pages 1-3)

Biomarker (CHEBI/protein where applicable) What it reflects in CKD-MBD KDIGO 2017 monitoring recommendation Common real-world availability / implementation notes Key evidence citation (URL/year)
Calcium (ionized/serum calcium; CHEBI:29108) Core mineral homeostasis abnormality; tends to decrease with CKD progression, and both hypo- and hypercalcemia are linked with CKD progression and higher cardiovascular mortality; integrated with phosphate and PTH for treatment decisions (izzo2024chronickidneydisease pages 2-4, wheeler2017kdigo2017clinical pages 16-18) Monitor from CKD G3a onward. Suggested intervals: G3a–G3b every 6–12 mo; G4 every 3–6 mo; G5/G5D every 1–3 mo. Use serial assessments of phosphate, calcium, and PTH together rather than single values (wheeler2017kdigo2017clinical pages 13-16, wheeler2017kdigo2017clinical pages 16-18, wheeler2017kdigo2017clinical media ed681c34) Italian survey: ionized calcium available in 99.1% of hospital laboratories; widely implemented routine biomarker (fusaro2024realworldusageof pages 1-3) KDIGO update https://doi.org/10.1016/j.kint.2017.04.006 (2017); survey https://doi.org/10.1093/ckj/sfad290 (2024) (ketteler2017executivesummaryof pages 4-5, fusaro2024realworldusageof pages 1-3)
Phosphate / phosphorus (CHEBI:18367) Phosphorocentric driver of CKD-MBD; linked to bone osteodystrophy, vascular calcification, CKD progression, ESKD, and all-cause/CV mortality; early compensatory rises in FGF23/PTH initially maintain normophosphatemia (izzo2024chronickidneydisease pages 2-4, izzo2024chronickidneydisease pages 1-2) Monitor from CKD G3a onward at same intervals as calcium: G3a–G3b every 6–12 mo; G4 every 3–6 mo; G5/G5D every 1–3 mo. Treatment should focus on progressively or persistently elevated phosphate and lower elevated phosphate toward the normal range; avoid phosphate loading (wheeler2017kdigo2017clinical pages 13-16, wheeler2017kdigo2017clinical pages 16-18, fusaro2023currentandemerging pages 5-6) Routine lab marker; widely available. In real-world practice, phosphate control is guideline-driven but implementation is heterogeneous; advanced CPP/T50 tools are not routine substitutes for serum phosphate (fusaro2024realworldusageof pages 1-3, fusaro2023currentandemerging pages 5-6) Review https://doi.org/10.1111/nep.14407 (2024); KDIGO https://doi.org/10.1016/j.kint.2017.04.006 (2017) (izzo2024chronickidneydisease pages 2-4, ketteler2017executivesummaryof pages 4-5)
Intact PTH / parathyroid hormone (PTH; UniProt P01270) Central marker of secondary hyperparathyroidism and bone turnover disturbance; rises from CKD stage 3; associated with fractures, vascular events, and mortality in observational studies (izzo2024chronickidneydisease pages 2-4, fusaro2023currentandemerging pages 5-6) Monitor from CKD G3a onward. Suggested intervals: G3a–G3b based on baseline level and CKD progression; G4 every 6–12 mo; G5/G5D every 3–6 mo. In CKD G5D, maintain iPTH approximately 2–9× assay ULN and use trends rather than single measurements (wheeler2017kdigo2017clinical pages 13-16, wheeler2017kdigo2017clinical pages 16-18, fusaro2023currentandemerging pages 5-6) Italian survey: PTH available in 99.1% of hospital laboratories. Most clinicians used KDOQI (51.9%) vs KDIGO (37.7%) to start sHPT treatment, showing heterogeneous implementation (fusaro2024realworldusageof pages 1-3) Roles review https://doi.org/10.3803/enm.2024.1978 (2024); KDIGO https://doi.org/10.1016/j.kint.2017.04.006 (2017) (fusaro2024realworldusageof pages 1-3, ketteler2017executivesummaryof pages 4-5)
Alkaline phosphatase, total and bone-specific if available (ALP; bone ALP/BSAP) Surrogate marker of bone turnover; bone-specific ALP can help evaluate turnover alongside PTH; treatment decisions should consider abnormal alkaline phosphatase among other CKD-MBD markers (ketteler2017executivesummaryof pages 4-5, wheeler2017kdigo2017clinical pages 13-16) Monitor alkaline phosphatase beginning in CKD G3a; suggested in G4–G5D every 12 mo, more often if PTH elevated. Serum PTH or bone-specific ALP may be used to evaluate bone disease because markedly high or low values predict underlying bone turnover (wheeler2017kdigo2017clinical pages 13-16) Italian survey: ALP available in 99.1% of laboratories; bone-specific assays were not specifically quantified, suggesting standard total ALP is the practical routine marker (fusaro2024realworldusageof pages 1-3) KDIGO guideline pages summarized in https://doi.org/10.1016/j.kint.2017.04.006 (2017); real-world survey https://doi.org/10.1093/ckj/sfad290 (2024) (wheeler2017kdigo2017clinical pages 13-16, fusaro2024realworldusageof pages 1-3)
25-hydroxyvitamin D / 25(OH)D (calcidiol; CHEBI:28940) Nutritional vitamin D status; deficiency/insufficiency is common in CKD and contributes to CKD-MBD pathogenesis and SHPT (izzo2024chronickidneydisease pages 2-4) In CKD G3a–G5D, 25(OH)D levels may be measured; repeat testing should depend on baseline values and interventions. Correct deficiency/insufficiency as in the general population (wheeler2017kdigo2017clinical pages 13-16, wheeler2017kdigo2017clinical media ed681c34) Italian survey: 25(OH)D available in 94.3% of laboratories, supporting moderate-to-high real-world implementation (fusaro2024realworldusageof pages 1-3) Vitamin D review https://doi.org/10.32948/ajsep.2024.05.20 (2024); KDIGO update https://doi.org/10.1016/j.kint.2017.04.006 (2017) (fusaro2024realworldusageof pages 1-3, wheeler2017kdigo2017clinical pages 13-16)
1,25-dihydroxyvitamin D / calcitriol (CHEBI:28934) Active vitamin D deficiency is part of the biochemical signature of CKD-MBD; suppressed early by rising FGF23 and reduced renal activation capacity, promoting SHPT and impaired mineral balance (lederer2024applicationofartificial pages 1-3, izzo2024chronickidneydisease pages 2-4) No routine stage-specific monitoring interval retrieved from KDIGO evidence here; KDIGO recommendations cited in retrieved reviews emphasize use of nutritional vitamin D in earlier CKD and reserving calcitriol/analogs for more advanced disease/SHPT rather than routine serial assay-based targeting (izzo2024chronickidneydisease pages 2-4, wheeler2017kdigo2017clinical pages 16-18) Italian survey: 1,25(OH)2D available in only 57.5% of laboratories, indicating substantially lower real-world availability than 25(OH)D (fusaro2024realworldusageof pages 1-3) AI review https://doi.org/10.1093/ckj/sfae143 (2024); survey https://doi.org/10.1093/ckj/sfad290 (2024) (lederer2024applicationofartificial pages 1-3, fusaro2024realworldusageof pages 1-3)
FGF23 / fibroblast growth factor 23 (UniProt Q9GZV9) Early osteocyte-derived phosphaturic hormone; rises early in CKD, suppresses calcitriol, reflects phosphate stress, and is associated with mortality and vascular calcification severity in observational studies (izzo2024chronickidneydisease pages 2-4, simic2024boneandbone pages 1-2) Not part of standard KDIGO 2017 routine monitoring panel in retrieved text; considered an emerging/non-routine biomarker rather than a guideline-mandated serial test (wheeler2017kdigo2017clinical pages 13-16, fusaro2023currentandemerging pages 5-6) Italian survey: intact FGF23 unavailable in 88.7% of laboratories and C-terminal FGF23 unavailable in 93.4%, indicating poor routine implementation despite mechanistic importance (fusaro2024realworldusageof pages 1-3) FGF23/Klotho review https://doi.org/10.3803/enm.2024.1978 (2024); survey https://doi.org/10.1093/ckj/sfad290 (2024) (fusaro2024realworldusageof pages 1-3, simic2024boneandbone pages 1-2)
Klotho / α-Klotho (UniProt Q9UEF7) Anti-aging co-receptor for FGF23; deficiency begins early in CKD and is linked to phosphate retention, FGF23 resistance, vascular calcification, and CKD-MBD progression (izzo2024chronickidneydisease pages 2-4, simic2024boneandbone pages 1-2) No KDIGO 2017 routine monitoring recommendation retrieved; currently investigational/controversial as a biomarker because assays and standardization remain limited (wheeler2017kdigo2017clinical pages 13-16, simic2024boneandbone pages 1-2) Italian survey: Klotho unavailable in 95.3% of labs and soluble Klotho unavailable in 97.2%, showing minimal clinical implementation (fusaro2024realworldusageof pages 1-3) Klotho meta-analysis https://doi.org/10.1038/s41598-024-54812-4 (2024); survey https://doi.org/10.1093/ckj/sfad290 (2024) (fusaro2024realworldusageof pages 1-3, simic2024boneandbone pages 1-2)
Calciprotein particles / calcification propensity T50 (CPPs/T50; mineral-protein nanoparticles, not a single CHEBI entity) Emerging markers of phosphate toxicity and mineral buffering; higher CPP burden and lower T50 indicate greater calcification propensity and associate with vascular remodeling, inflammation, endothelial activation, and ossification in CKD (izzo2024chronickidneydisease pages 1-2, fusaro2023currentandemerging pages 5-6) No KDIGO 2017 routine monitoring recommendation retrieved; CPP/T50 are emerging research tools, not standard guideline biomarkers (fusaro2023currentandemerging pages 5-6, wheeler2017kdigo2017clinical pages 13-16) Not included in routine hospital lab menus in the Italian survey; CPP/T50 are discussed as emerging markers/tools rather than standard practice. Proof-of-principle studies show high-dose sucroferric oxyhydroxide reduced primary CPP by 62% and secondary CPP by 38%, while etelcalcetide reduced CPP fractions without significantly changing T50 (fusaro2023currentandemerging pages 5-6) CPP vascular study https://doi.org/10.1093/cvr/cvae164 (2024); sucroferric oxyhydroxide https://doi.org/10.1093/ndt/gfac271 (2023); etelcalcetide https://doi.org/10.1093/ckj/sfae097 (2024) (fusaro2023currentandemerging pages 5-6, izzo2024chronickidneydisease pages 1-2)

Table: This table summarizes the main laboratory and emerging biomarkers used in CKD-MBD, what they represent biologically, how KDIGO 2017 recommends monitoring the standard markers, and what recent real-world evidence shows about laboratory availability and implementation.

11. Outcome / prognosis

11.1 Mortality and hospitalization risk (dialysis)

  • In the EuCliD dialysis cohort (n=35,721), mortality was 126.7 deaths/1000 person-years and hospitalization incidence 203.9/1000 person-years, with phenotype-dependent adjusted mortality HRs up to 1.59. (neri2019detectinghighriskchronic pages 1-2)
  • In international DOPPS hemodialysis patients, having 2–3 markers above target (Ca/P/PTH composite) was associated with higher mortality (USA HR 1.41, 95% CI 1.10–1.82) vs all markers in target; in age ≥65 the HR was 1.82 (95% CI 1.28–2.58). (fuller2020combinationsofmineral pages 1-2)

11.2 Fracture outcomes (non-dialysis CKD and kidney failure)

CRIC reports 2.4 hip/vertebral fractures per 1000 person-years; fracture hazard is markedly increased in kidney failure on dialysis (HR 4.53). (hsu2024riskfactorsfor pages 1-2)

12. Treatment

12.1 KDIGO 2017 treatment principles (selected)

KDIGO 2017 emphasizes treatment based on serial assessments of phosphate, calcium and PTH considered together, and suggests: - Lower elevated phosphate toward the normal range and focus phosphate-lowering treatment on hyperphosphatemia. - Avoid hypercalcemia. - In adults receiving phosphate-lowering treatment, restrict calcium-based phosphate binders. - In CKD G5D, maintain iPTH roughly 2–9× the assay ULN; options include calcimimetics, calcitriol, vitamin D analogs, or combination when PTH-lowering therapy is needed. (wheeler2017kdigo2017clinical pages 16-18, wheeler2017kdigo2017clinical pages 13-16, ketteler2017executivesummaryof pages 4-5)

12.2 Therapeutic innovation and mechanistic interventions (recent literature)

  • CPP-focused effects of phosphate binders (2023): sucroferric oxyhydroxide reduced CPP fractions and attenuated inflammatory/pro-calcific serum effects in vitro. (thiem2023effectofthe pages 1-3)
  • Data-science/AI for personalization (2024): proposed as an approach to address heterogeneity and improve targeting beyond surrogate biochemical targets. (lederer2024applicationofartificial pages 1-3)

12.3 MAXO suggestions

Not retrieved in the current corpus; map standard actions such as phosphate binder therapy, calcimimetic therapy, vitamin D supplementation/analogs, dialysis prescription changes, and parathyroidectomy during ontology curation.

13. Prevention

Primary prevention of CKD-MBD is primarily prevention/mitigation of CKD progression and early control of mineral metabolism disturbances. KDIGO’s emphasis on early monitoring from CKD G3a and trend-based management supports secondary prevention of complications. (wheeler2017kdigo2017clinical pages 13-16)

14. Other species / natural disease

Not retrieved in current corpus.

15. Model organisms

Not retrieved in current corpus for CKD-MBD-specific models; mechanistic literature referenced in reviews indicates animal studies exist (e.g., sclerostin/Wnt, erythropoiesis/FGF23), but model details were not extracted from the retrieved pages. (simic2024boneandbone pages 1-2, williams2023updatesinthe pages 1-2)

Appendix: Key 2023–2024 sources (with dates/URLs as available in corpus)

  • KDIGO CKD-MBD guideline update (2017): https://doi.org/10.1016/j.kint.2017.04.006 (July 2017) (ketteler2017executivesummaryof pages 4-5)
  • Fusaro et al., CKJ real-world biomarker usage survey: https://doi.org/10.1093/ckj/sfad290 (2024) (fusaro2024realworldusageof pages 1-3)
  • Lederer et al., AI in CKD-MBD: https://doi.org/10.1093/ckj/sfae143 (June 2024) (lederer2024applicationofartificial pages 1-3)
  • Izzo et al., CKD-MBD and vascular calcification overview: https://doi.org/10.3390/life14030418 (March 2024) (izzo2024chronickidneydisease pages 1-2)
  • Hsu et al., CRIC fracture risk factors: https://doi.org/10.1093/jbmr/zjae021 (Feb 2024) (hsu2024riskfactorsfor pages 1-2)
  • Feenstra et al., CPP counts and vascular remodeling: https://doi.org/10.1093/cvr/cvae164 (Aug 2024 online ahead) (feenstra2024calciproteinparticlecounts pages 1-2)
  • Thiem et al., sucroferric oxyhydroxide effects on CPP/inflammation: https://doi.org/10.1093/ndt/gfac271 (2023; advance access Sept 2022) (thiem2023effectofthe pages 1-3)
  • Williams et al., osteocytic proteins/bone–vascular paradox update: https://doi.org/10.3389/fphys.2023.1120308 (Jan 2023) (williams2023updatesinthe pages 1-2)

References

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