CKD-Mineral Bone Disorder - Disorder Mechanisms

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Mappings

MONDO

MONDO:0006946 renal osteodystrophy Not Yet Curated

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.

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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 link Proximal Tubular Epithelial Cell link

Phosphate Ion Homeostasis link Fibroblast Growth Factor Receptor Signaling link

Proximal Tubule link Bone Tissue link

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 link Osteocyte link

Glycolytic Process link Phosphate Ion Homeostasis link

Kidney link

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 link Osteoclast link Osteoblast link

Parathyroid Hormone Secretion link Bone Resorption link Calcium Ion Homeostasis link

Parathyroid Gland link

Show evidence (3 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: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.

PMID:37258233 SUPPORT Human Clinical

"FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification"

Confirms direct cardiovascular effects of elevated PTH and FGF23.

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 link

Kidney link

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 link

Ossification link

Arterial Blood Vessel link

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.

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 link Osteocyte link

Wnt Signaling Pathway link Bone Remodeling link

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 link

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.

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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.

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Pathograph

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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.

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Genetic Associations

2

CASR (Modifier)

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)

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.

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Treatments

6

Phosphate Binders

Action: phosphate binder therapy Ontology label: pharmacotherapy MAXO:0000058

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 MAXO:0000058

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 MAXO:0000058

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.

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Biochemical Markers

10

Phosphate (Elevated)

Context: Impaired renal excretion, overtly elevated in CKD stages 4-5

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

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

Show evidence (1 reference)

PMID:33784965 SUPPORT Human Clinical

"a significant decrease in serum 1,25(OH)2D concentrations was 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

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.

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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.

Organism

human ↗

Tissue

arterial blood vessel ↗

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.

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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
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: '2026-04-07T03:28:00Z'
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.
  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.
  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: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: Ossification
    term:
      id: GO:0001503
      label: ossification
  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
- 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
- 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: a significant decrease in serum 1,25(OH)2D concentrations was 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
- 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+)
- 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
  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
  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.
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: MAXO:0000058
      label: pharmacotherapy
  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: MAXO:0000058
      label: pharmacotherapy
  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: MAXO:0000058
      label: pharmacotherapy
  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