CKD–MBD｜慢性腎病礦物質與骨骼疾病

CKD–MBD大綱 · Outline

大綱

Outline

CKD–MBD framework · 簡介

One disease, three lenses — biochem, bone, vessel

Hormones & Ca–P balance · 生化

PTH · Vit D · FGF-23 — and how Ca, P go off-track

III

Bone & vascular calcification · 骨頭 & 血管

ROD · VC mechanism · inhibitors · calciphylaxis

治療 · Treatment

BCS targets · ROD treatment · binders · calcimimetics · Mg · Vit K · SNF472

Cases & take-home · 臨床案例

8 dialysis patients — applying the framework

I · Introduction定義 · Definition

04Renal Pathophysiology: The Essentials

CKD–MBD

A spectrum, not a single disease.

慢性腎病引起的礦物質與骨骼系統失衡，由生化、骨骼、與血管三個面向共同構成。

Initially asymptomatic; biochemically detected after eGFR < 30–40 mL/min. A non-traditional risk factor for cardiovascular disease.

01 · Biochemistry (BCS)

Ca, P, iPTH, Vit D, FGF-23, ALP

02 · Bone abnormalities

Renal osteodystrophy (ROD) & osteoporosis

03 · Vascular / soft-tissue calcification

CV mortality driver in dialysis patients

I · Introduction架構圖 · Framework

05KDIGO 2006 / 2017 · CKD–MBD

The three pillars

Three lenses on one disease.

BCS · 生化檢測

Biochemistry

CaCalcium
PPhosphorus
PTHParathyroid hormone
DVitamin D
FGFFGF-23
ALPAlkaline phosphatase

Bone · 骨骼

腎性骨病變 vs. 骨鬆

ROD

Renal osteodystrophy

Osteoporosis

Density & quality of bone

Bone biopsy

TMV classification (gold standard)

CV · 血管

心血管 / 軟組織鈣化

Vascular calcification

Intimal & medial (Mönckeberg)

Valvular / soft-tissue

Aortic, mitral, periarticular

Calciphylaxis

CUA — uremic small-vessel

II · BCS三個賀爾蒙 · Three hormones

三個賀爾蒙

Three hormones run the system.

PTH

Parathyroid hormone

副甲狀腺素 — responds to Ca, mobilises bone, drives renal vit-D activation.

Ca ↑ · P ↑↓

Target on dialysis: 150–650 pg/mL (2–9× ULN)

Vit D

Vitamin D (active)

活性維生素D — 1,25-(OH)₂D₃. Activated in kidney; raises gut Ca/P absorption.

Ca ↑ · P ↑ · PTH ↓

25(OH)D target: 25–80 ng/mL

FGF23

Fibroblast Growth Factor 23

A bone-derived phosphaturic hormone. Secreted by osteoblasts / osteocytes via α-Klotho.

P ↓ · active Vit D ↓

Rises earliest in CKD; suppresses 1α-hydroxylase.

All three are interdependent — dysregulation of one pulls the others off-target. As GFR falls, the cascade accelerates.

II · BCS · Hormone 1PTH

08Williams Textbook of Endocrinology

Parathyroid hormone

PTH — the calcium thermostat.

Blood 1–84 PTH = intact PTH (iPTH). Different assays give different numbers — targets are expressed as multiples of ULN.

Ca ↓

stimulates PTH release

Ca ↑

suppresses PTH

In normal kidneys, PTH is balanced. In renal failure, it pushes phosphate up.

Sites of PTH action

①

Bone

Resorption → release Ca / P

②

Kidney

↑ Vit D activation → Gut absorption (also directly stimulate intestine absorption)

③

Tubules

↑ Ca reabsorption · ↑ P excretion

II · BCS · Hormone 2Vitamin D

09臺北市醫師公會會刊 61:10, 2017

Two forms of Vit D

營養 vs. 活性 — same vitamin, two roles.

營養維生素D · Nutritional

Cholecalciferol / ergocalciferol

From sun & diet. Metabolized by liver 25-hydroxylase to storage form = 25(OH)D₃.

25(OH)D₃ reflects body Vit D stores 可自費檢驗
透過上游補充增加身體庫存
Pleiotropic effects beyond bone (活性的無!)

活性維生素D · Active

1,25(OH)₂D₃ / 活性前驅 1α-(OH)D₃

Activated by kidney 1α-hydroxylase. The hormone form.

U-Ca® = 1,25(OH)₂D₃
Onealfa® = 1α-(OH)D₃
Drug for CKD-MBD therapy

II · BCS · Hormone 2Active Vit D — physiology & CKD use

11Renal Pathophysiology: The Essentials

Four sites of action

Active Vit D corrects low Ca/P and high PTH.

Activation in the kidney is driven by hypocalcaemia (via PTH) and hypophosphataemia.

Net physiological effect — raises Ca and P, feeds back to suppress PTH.

In CKD: 1α-hydroxylase fails → active Vit D must be replaced. But it also raises Ca/P load — use the lowest dose to keep PTH in range.

Clinical pearl · Hungry bone syndrome

After parathyroidectomy, even high-dose Ca + active Vit D may not correct severe hypoCa — without PTH, osteoclasts can't liberate Ca/P from bone.

① Small intestine

↑ Absorption of Ca / P

② Bone

↑ Resorption (+PTH)
→ release Ca / P

③ Kidney

↓ Renal Ca / P excretion

④ Parathyroid

Negative feedback → ↓ PTH

II · BCS · Hormone 3FGF-23

12Williams Textbook of Endocrinology

Fibroblast Growth Factor 23

FGF-23 — Bone speaks to the kidney.

骨頭分泌的排磷賀爾蒙 — a bone-derived phosphaturic hormone.

Stimulated by elevated phosphate; acts on kidney.
Member of FGF-19 subfamily (FGF-15/19/21/23) — no heparin-binding site, behaves like a hormone.
Secreted by osteoblasts & osteocytes — bone as an endocrine organ.
Binds FGFR with α-Klotho co-receptor for endocrine action.

Effects

Short term

↑ Renal phosphate excretion (phosphaturia)

(in normal kidney, also exerts negative feedback on PTH)

Long term

↓ 1α-hydroxylase → ↓ active Vit D → ↑ PTH

Disease links

ADHR · TIO · earliest BCS change in CKD

FGF-23 rises first in CKD and is the last to respond to treatment — it is simultaneously an early warning signal and the bridge between phosphate excess and cardiovascular risk.

II · Ca / PNormal Ca / P homeostasis

14basicmedicalkey.com / parathyroid-glands

A 24-hour balance

In health, what goes in comes out.

Blood Pool

Tight regulation by PTH / Vit D / FGF-23. Constant exchange with bone.

Gut & Intake

Absorption driven by active Vit D. High processed food = high P load.

Bone Reserve

99% Ca (1kg), 85% P (0.6kg). The body's primary mineral buffer.

Intake → Gut → Blood ⇌ Bone
└─ Feces └─ Urine

II · Ca / PPhosphate balance

15Tonelli M, NEJM 362:13, 2010

Health vs. kidney failure

In kidney failure, even strict diet runs positive.

Health · 健康人

balanced

Intake	1200 mg/day
Gut absorb	+800 mg/day
Feces	400 mg/day
Bone ↔ blood	0 mg/day (neutral)
Renal excretion	-800 mg/day

Net balance: 0

Kidney failure · 腎衰竭

positive +

Intake	900 mg/day (limited P diet)
Gut absorb	+400 mg/day (Ca 4#: 500 → 400 mg)
Feces	500 mg/day (Ca 4#: 400 → 500 mg)
Bone → blood	+40 mg/day 骨頭釋出
Renal excretion	0 (假設無尿)
Hemodialysis	-390 mg/day (-900 mg/session)

Net balance: +50mg/day (沉澱在心血管!)

II · Ca / PPathophysiology · the cascade

16Wolf M, JASN 21:9, 2010

時序 · 五指標

Five markers, one sequence — who moves first?

↑ FGF-23

Earliest change; phosphaturic compensation.
↓ 1,25(OH)₂D

Reduced activation in the kidney.
↑ PTH

Secondary hyperparathyroidism develops.
↑ Phosphate

Significant rise when GFR < 30 mL/min.
↓ Calcium

Stabilised by PTH; falls late (GFR < 20).

By the time P and Ca move on labs, FGF-23 has already been rising for years — start screening from CKD stage 3, don't wait for the phosphate to break range.

III · Bone ROD · terminology

18Brenner and Rector's The Kidney

腎骨病變 · ROD terminology

How we describe a CKD bone.

骨切片三要素 · TMV

Turnover · 周轉

Referenced by iPTH + ALP

Mineralisation · 礦化

Defect = osteomalacia

Volume · 體積

Bone mass

Bone strength · 骨骼強度

Bone Density · 骨密度

DEXA — diagnoses osteoporosis

Bone Quality · 骨品質

Microarchitecture, turnover, mineralisation, microdamage

Bone biopsy · 骨切片

Gold standard — TMV; rarely performed clinically

III · BoneROD subtypes

192006 KDIGO CKD–MBD

Histological spectrum

ROD — five classic types, four clinical pictures.

Osteomalacia

骨質軟化 — defective mineralisation

Low turnover · ↓M

Adynamic bone

不活動型骨病變 — low turnover, normal M

↓PTH · over-suppression

HPT → OF

High-turnover spectrum

早期 SHPT 至纖維囊性骨炎 — severity gradient driven by PTH

↑→↑↑PTH · ± fibrosis

MUO

Mixed uremic

混合型腎性骨病變 — high turnover + ↓M

Overlap pattern

TMV biopsy is the reference — but in practice, PTH ± ALP positions most patients across this spectrum. Clinical osteoporosis in CKD is not equal to histological osteoporosis.

III · BoneDisease spectrum

20Comprehensive Clinical Nephrology

PTH × ALP

Two numbers position the bone.

ALP → bone turnover

Low PTH · High ALP

Osteomalacia

Mineralisation defect — Vit D, aluminum

High PTH · High ALP

Osteitis fibrosa

SHPT, fracture risk, brown tumours

Low PTH · Low ALP

Adynamic bone

Over-suppression — Ca-binders, calcimimetics, active Vit D

High PTH · Low ALP

Early SHPT

PTH rising, bone not yet fibrotic

iPTH → parathyroid drive

III · Vascular calcificationTwo patterns · 型態學

21Schlieper G et al, JASN 2016; Lanzer P et al, EHJ 2014

Vascular calcification · 起點

Two patterns, two stories.

In CKD, calcium leaves bone and finds the vessel wall. Where it lands changes the clinical consequence.

Intimal · 內膜型

Atherosclerotic

Lipid-rich plaque calcifies. Patchy, focal.

Population: general adults · diabetes · early CKD

Consequence: plaque rupture → MI · stroke · limb ischaemia

Medial · 中層型 (Mönckeberg)

Osteogenic

Diffuse circumferential "pipe-stem" calcification.

Population: CKD · dialysis · diabetes

Consequence: arterial stiffness → ↑ PWV · LVH · diastolic HF · CV mortality

Clinical pearl · Most dialysis patients have both, but medial calcification is the CKD-specific driver — and the one Ca-P imbalance accelerates.

III · Vascular calcificationMechanism · VSMC osteogenic switch

22Shanahan CM et al, Circ Res 2011; Paloian & Giachelli, AJP-Renal 2014

Why Ca-P matters

The vessel becomes bone.

High extracellular phosphate actively reprograms VSMCs into osteoblast-like cells — not passive precipitation.

P entry

High serum P enters VSMC via Pit-1 / Pit-2 Na-Pi cotransporters.

Phenotype switch

Loss of SM22α, gain of RUNX2 · Msx2 · Osterix · BMP-2. VSMC → osteoblast-like.

Matrix mineralisation

Cells secrete a bone-like ECM and matrix vesicles that nucleate hydroxyapatite.

Apoptosis & vesicles

High Ca/P triggers VSMC apoptosis. Apoptotic bodies serve as nucleation sites.

Inhibitor loss

↓ Fetuin-A · MGP · OPG · Pyrophosphate (PPi) — the brakes fail.

Self-amplification

Calcified VSMC release more vesicles → propagation. Established VC is largely irreversible.

VC in CKD is an active, programmed disease of the vessel wall — not just calcium falling out of solution. Once established, the goal is to halt, not reverse.

III · Vascular calcificationDrivers — what tips the balance

23Vervloet & Cozzolino, Nat Rev Nephrol 2017

Promoters & protectors

A balance, not a single villain.

Promoters · 加速因子

↑ Phosphate — the central driver. Both serum and dietary load.

↑ Calcium load — Ca-based binders, high-Ca dialysate, active Vit D.

↑ FGF-23 — rises early; LVH & CV mortality marker.

↓ α-Klotho — CKD is a Klotho-deficient state; loss of FGF-23 co-receptor.

Uraemic toxins — indoxyl sulfate, p-cresyl sulfate drive VSMC senescence.

Inflammation · oxidative stress · diabetes · age

Protectors · 抑制因子

Fetuin-A — circulating Ca-P chaperone; low in dialysis = worse VC.

Matrix Gla protein (MGP) — locally inhibits crystal growth; Vit K dependent.

Pyrophosphate (PPi) — endogenous mineralisation brake; low in CKD.

Osteoprotegerin (OPG) — RANKL decoy; complex role.

Magnesium — competes with Ca; stabilises CPP; emerging therapeutic.

α-Klotho (when preserved) — anti-calcification.

CKD shifts the equilibrium: promoters rise, protectors fall. Targeting VC means moving both arms of the balance.

III · Vascular calcificationBiomarker — calciprotein particles & T50

24Pasch A et al, JASN 2012; Smith ER et al, JASN 2014; Bostom A et al, JAHA 2018

From snapshot to propensity

Serum Ca-P doesn't tell the whole story.

Two patients with identical Ca and P can have very different vessels. Calciprotein particles (CPP) and the T50 test measure the serum's intrinsic propensity to calcify.

Calciprotein particles (CPP)

Nano-aggregates of Ca · P · fetuin-A. The body's way of safely chaperoning excess mineral.

CPP-I (primary) — amorphous, soluble, safe.

CPP-II (secondary) — crystalline, pro-inflammatory, pro-calcifying.

In CKD, more I converts to II. Higher CPP-II correlates with arterial stiffness, VC progression, CV events.

T50 — serum calcification propensity

In-vitro time for CPP-I to mature into CPP-II. Shorter T50 = higher propensity to calcify.

↓ T50

independently predicts all-cause & CV mortality in HD, PD, and CKD 3–5 cohorts.

Modifiable by ↑ Mg, ↓ P, bicarbonate — useful as a functional read-out of "are my treatments helping?"

Not yet routine clinical care — but T50 is moving from research to bedside, and it reframes how we think about Ca-P targets.

III · Vascular calcificationImaging · 影像 & prognosis

25Kauppila LI et al, Atherosclerosis 1997; Block GA et al, KI 2007; Adragao T et al, NDT 2004

Look for it · measure it

Calcification seen predicts mortality.

Lateral abdominal X-ray

Kauppila 0–24 · aortic L1–L4 · score ≥ 7 → ↑ CV mortality

Pelvis & hand X-ray

Adragão 0–8 · iliac, femoral, radial, digital

CT — CACS

Agatston score · most sensitive; used in clinical trials

Functional — PWV

Carotid-femoral PWV · arterial stiffness; independent CV predictor

Prognostic weight

2–4×

CV mortality in dialysis patients with high VC burden vs. low.

KDIGO 2017 (3.2.1)

"In CKD G3a–G5D, a lateral abdominal X-ray can detect vascular calcification — reasonable alternative to CT." (2C)

Find it once — it changes how you weigh every subsequent Ca, P, Vit D, and binder decision.

III · Vascular calcificationBone–vessel axis

One system, two endpoints

Treating bone protects the vessel.

Bone · 骨骼

↑ High turnover

Excess Ca & P released into blood → vessel loading

↓ Low turnover · adynamic

Cannot buffer Ca load → Ca spills to vessel wall

Adynamic bone + Ca loading = highest VC risk

⇌

Ca ↑

P ↑

FGF-23 ↑

Klotho ↓

Vessel · 血管

VSMC trans-differentiation

Smooth muscle → osteoblast-like; loss of MGP, PPi, fetuin-A

↑ Arterial stiffness

Intimal & medial calcification → ↑ CV events & mortality

Optimising bone turnover is not just about fracture prevention — correcting adynamic bone is associated with slower VC progression.

III · Vascular calcificationClinical impact of VC

27Kauppila LI et al, Atherosclerosis 1997; London GM et al, JASN 2003; Foley RN et al, AJKD 1998

Why it matters · 臨床後果

Stiff vessels steal from the heart.

Hemodynamic cascade

Medial calcification → ↑ Arterial stiffness

↑ Pulse wave velocity · loss of Windkessel buffer function

↑ Pulse pressure → LVH → HFpEF

↑ LV afterload; ↓ diastolic BP → subendocardial ischaemia, arrhythmia

Intimal calcification → Plaque instability

Atherosclerotic lesions more prone to rupture → ACS, stroke

Outcome data · 腎臟病患

~50%

of HD patient deaths are cardiovascular

10–30× higher CV mortality than age-matched general population

Aortic calcification score predicts CV death independently

Kauppila score ≥ 7 → ↑ all-cause & CV mortality in ESRD

PWV independently predicts mortality in CKD

Each 1 m/s rise in aortic PWV → ↑14% CV mortality risk

Vascular calcification is not a bystander — it is a direct mediator of the excess cardiovascular mortality seen in CKD.

III · Vascular calcificationEndogenous calcification inhibitors

28Luo G et al, Nature 1997 (MGP); Ketteler M et al, Lancet 2003 (fetuin-A); Lomashvili KA et al, JASN 2005 (PPi); Hu MC et al, JASN 2011 (Klotho)

What normally protects vessels

CKD dismantles the anti-calcification system.

MGP

Matrix Gla Protein

Most potent local VC brake. Produced by VSMCs & chondrocytes.

Requires Vit K for γ-carboxylation (activation). Warfarin blocks this.

CKD: subclinical Vit K deficiency → dp-ucMGP ↑

Fetuin-A

α2-Heremans-Schmid glycoprotein

Liver-derived. Coats CPPs — keeps Ca × P in solution, prevents crystal formation.

Negative acute-phase reactant — falls with inflammation.

CKD: chronic inflammation suppresses fetuin-A → less CPP buffering

Pyrophosphate

PPi · generated by ENPP1 from ATP

Directly blocks hydroxyapatite crystal growth at nucleation sites.

SNF472 (IP6) mimics PPi's crystal-blocking mechanism.

CKD: ↓ ENPP1 activity; ↑ ALP degrades PPi

Klotho

FGF-23 co-receptor · anti-ageing protein

Endocrine & local anti-calcific roles; regulates phosphate reabsorption.

Klotho-deficient mice develop severe medial VC spontaneously.

CKD: ↓↓ from early stages — first deficit to appear

Simultaneous loss of all four inhibitors creates a calcification-permissive milieu — even before mineral levels visibly rise on lab tests.

III · Vascular calcificationCalciphylaxis · CUA

29Nigwekar SU et al, NEJM 2018; Brandenburg VM et al, Nat Rev Nephrol 2018

Extreme form · 急性重症

Calciphylaxis — VC at its most lethal.

Calcific Uremic Arteriolopathy (CUA)

Calcification of subcutaneous arterioles → microvascular occlusion → ischaemic skin necrosis. Incidence 1–4% in dialysis; mortality 40–80% (sepsis from infected wounds).

Risk factors

Mineral imbalance

↑ Ca × P, SHPT, excess active Vit D or Ca binders

Warfarin use

Blocks Vit K → inhibits MGP activation

Patient factors

Female, obesity, DM, hypoalbuminaemia, liver disease

Lesion distribution

Proximal (trunk/thigh) = worse; distal (leg) = better prognosis

Management

Stop

Warfarin → switch to LMWH; Ca-based binders; excess active Vit D

Optimise dialysis

Intensify HD; ↓ dialysate Ca; strict P target; avoid hypercalcaemia

Add

Sodium thiosulfate (STS) IV 3×/wk during HD · chelates Ca deposits, antioxidant

Cinacalcet if SHPT; Vit K supplementation; wound care

SNF472 RCT in calciphylaxis — neutral on primary endpoint (wound healing)

Think calciphylaxis early: painful, violaceous, indurated skin lesions in a dialysis patient with warfarin or uncontrolled mineral balance — biopsy confirms, early action saves lives.

IV · TreatmentTreatment targets · BCS

CKD–MBD · 生化檢測標準

The four numbers to know.

Analyte	Normal	Dialysis target	Note
Ca 血鈣	2.15 – 2.58 mM 8.5 – 10.5 mg/dL	= normal range	Avoid hypercalcaemia.
P 血磷	2.5 – 5.0 mg/dL	3.5 – 5.5 mg/dL	~ 10 % above normal.
iPTH	15 – 68 pg/mL	150 – 650 pg/mL	2–9× ULN.
25(OH)D 維生素D	25 – 80 ng/mL	≥ 25 ng/mL	<10 severe deficiency · >80 overdose.

25(OH)D testing is out-of-pocket in Taiwan (NTD 920).

IV · TreatmentTreatment philosophy · 個人建議

Guiding principles

Treat patients, not Ca × P.

BCS first · diagnose by the numbers

Bone disease is hard to confirm — biopsy is rare. Combine biochemistry with clinical inference.
Diet control for (almost) every dialysis patient

Phosphate-additives, protein source, and adherence drive the lab numbers.
Read each value, then read the whole picture

Know what the patient is already on — dose, pill count, dialysate. Adjust stepwise; follow the trend. Don't fixate on Ca × P.
Treat the parathyroid & the bone

Manage the symptoms and the disease — not just the analyte.
Look for VC — let it tighten every Ca decision

Once vascular calcification is documented (lateral X-ray, Kauppila), shift away from Ca-based binders, lower dialysate Ca, and reassess active Vit D dosing.

IV · Targeting VCStrategy · five levers

Targeting vascular calcification

Five places to push.

Established VC is largely irreversible — so the goal is to slow progression. Every CKD-MBD decision can be re-framed as "does this add to, or subtract from, the vascular Ca-P load?"

Lower P ★

The single most important lever.

Diet · additives · binders · NHE3 inhibitor (tenapanor) · adequate dialysis.

Limit Ca load

Prefer non-Ca binders · cautious active Vit D · individualised dialysate Ca.

Control PTH

Calcimimetics over Vit D when Ca / P are not low — avoids Ca-P load.

Boost protectors

Magnesium · Vit K (mechanism strong, evidence developing).

Novel direct anti-VC

SNF472 (myo-inositol hexaphosphate) · investigational crystal poisons.

IV · Targeting VCBinders & calcimimetics — does it change VC?

34Treat-to-Goal 2002 · DCOR 2007 · IMPROVE-CKD 2020 · LANDMARK 2021 · EVOLVE 2012 · ADVANCE 2011

Evidence · what the trials show

The Ca-vs-non-Ca question.

Trial	Comparison	VC endpoint	Result	Signal
Treat-to-Goal Chertow 2002	Sevelamer vs Ca-based	CACS & aortic CT	+	Less CACS progression with sevelamer
DCOR Suki 2007	Sevelamer vs Ca-based	All-cause mortality	—	Neutral; signal in age ≥ 65 subgroup
IMPROVE-CKD Toussaint 2020	Lanthanum vs placebo (CKD 3b–4)	PWV, aortic CT	—	Neutral — P-lowering pre-dialysis did not slow VC
LANDMARK Ogata 2021	Lanthanum vs Ca carbonate (HD)	Composite CV events	—	No difference between binder types
EVOLVE Chertow 2012	Cinacalcet vs placebo (HD, SHPT)	CV death & MACE	±	Neutral (ITT); signal in lag-censored analysis
ADVANCE Raggi 2011	Cinacalcet + low-dose Vit D vs Vit D alone	CACS, aortic CT	+	Attenuated CACS progression

Take-home · Non-Ca binders slow VC imaging progression; hard CV endpoints remain elusive. Calcimimetics help most where Ca-P load is high. Pick the right patient — earlier is better.

IV · Targeting VCEmerging — Magnesium · Vit K · SNF472

35MAGICAL-CKD · JASN 2023; iPACK-HD · NDT 2023; VitaVasK · CKJ 2022; CALIPSO · Circulation 2020

What's next

Direct anti-calcification therapy.

Magnesium

Mg²⁺

Mechanism: competes with Ca for crystal nucleation · stabilises CPP · lengthens T50.

Evidence: low serum Mg predicts mortality & VC in dialysis. MAGICAL-CKD — Mg supplementation did not slow CACS progression in CKD 3–4 (neutral, JASN 2023).

Bedside: Mg-containing binders, or higher dialysate Mg, are reasonable in selected patients.

Vitamin K2

MK-7

Mechanism: activates MGP via γ-carboxylation — MGP is the local VC brake.

Evidence: dp-ucMGP elevated in CKD = subclinical Vit K deficiency. VitaVasK · iPACK-HD · K4Kidneys — biomarker improves; hard VC endpoints mixed-to-neutral.

Mechanism beautiful, clinical signal still weak. Don't withhold warfarin alternative when needed.

SNF472

IP6

Mechanism: IV myo-inositol hexaphosphate — binds growing hydroxyapatite crystals, blocks growth.

Evidence: CALIPSO — slowed coronary & aortic valve CACS progression in HD over 52 wk. Calciphylaxis trial neutral on primary endpoint.

Not yet approved for VC; first-in-class direct anti-calcification agent.

The field is moving from "manage the labs" to "directly modify the vessel." Routine practice will look different in 5 years.

IV · Targeting boneRenal osteodystrophy — treatment

36KDIGO 2017 CKD-MBD guideline; Jamal SA et al, Lancet 2011 (denosumab in CKD); Cunningham J et al, CJASN 2011 (etelcalcetide)

ROD · 骨骼疾病治療

Treat bone by its type, not just the PTH.

Low turnover · Adynamic

Goal: let PTH rise toward target — stop suppressing further

↓ Ca load → non-Ca binders; lower dialysate Ca (1.25 mmol/L)

Reduce or stop active Vit D if iPTH suppressed (< 150); reduce/stop cinacalcet if over-suppressing

Mildly elevated P stimulates PTH mechanistically — but DO NOT target this intentionally: adynamic bone cannot buffer excess P → VC risk↑. Letting P drift slightly by reducing Ca-binders is an acceptable side effect, not a treatment strategy.

High turnover · SHPT

Calcimimetics — cinacalcet PO or etelcalcetide IV · ↓ PTH, Ca, P; cinacalcet has GI side effects

Active Vit D analogs — calcitriol / paricalcitol (VDR agonists) · monitor Ca & P; paricalcitol = less hypercalcaemia

Combination — calcimimetic + low-dose Vit D analog: complementary, reduces side effects of each

PTX — refractory SHPT; iPTH persistently > 800 with VC progression or uncontrolled Ca × P; watch for hungry bone post-op

Fracture prevention · 骨折預防 = 建議骨質疏鬆治療

Denosumab (RANKL inhibitor) — preferred in ESRD; beware of hypocalcaemia; ignore post-dose iPTH fluctuations; avoid if adynamic bone

Bisphosphonates — CKD 1–3: standard use; CKD 4: cautious; CKD 5D: avoid (accumulate, not cleared, may worsen adynamic bone)

Bone biopsy is the gold standard for ROD typing; in practice, PTH trend + ALP + clinical context guide the decision.

V · CasesLong-term anuric HD · Patients 1 – 8

舉例 · clinical decisions

Eight patients, eight different moves.

All long-term, anuric HD patients on diet control. Labs alone don't decide — clinical context, trend, and medication history drive the move.

Pt	Ca (mM)	P (mg/dL)	iPTH (pg/mL)	Treatment suggestion
1	1.90	5.7	500	Ca-based binder (low Ca) > non-Ca binder
2	2.20	6.0	350	Non-Ca binder > Ca-based binder
3	2.20	5.3	900	Active Vit D or calcimimetics
4	2.70	5.3	350	Low-Ca dialysate + ↓ Ca binder dose (or switch to non-Ca)
5	2.70	6.5	350	Low-Ca dialysate + non-Ca binder
6	2.70	6.5	1000	Calcimimetics + low-Ca dialysate ± non-Ca binder > consider PTX
7	1.90	2.5	650	Active Vit D
8	1.90	2.5	30	Stop binder · diet ± high-Ca dialysate · (post-PTX: high-Ca dialysate + Ca + Vit D)

HIGH P

P > 5.5 — pick binder by Ca status.

HIGH Ca

Ca > 2.58 — stop Ca load, lower dialysate Ca.

HIGH PTH

iPTH > 650 — Vit D or calcimimetics.

Same numbers, different patient → different plan. Trend, medications and clinical state must inform the move.

ClosingKey takeaways · 重點回顧

Key takeaways

What to carry home.

VC is the CKD-MBD endpoint that kills

~50% of dialysis mortality is CV. Medial calcification is the CKD-specific pattern.

Ca-P drives VC actively

High P switches VSMC to osteoblast-like cells. Not passive precipitation — a programmed phenotype change.

Promoters & protectors

P · Ca · FGF-23 · toxins push. Fetuin-A · MGP · PPi · Mg · Klotho hold the line.

Look for VC — it changes everything

Lateral abdominal X-ray (Kauppila) is enough. Once you see it, every Ca-load decision tightens.

Treat bone by type, treat vessels directly

Adynamic bone: ↓ Ca load, let PTH recover. SHPT: calcimimetics or Vit D analogs. Non-Ca binders first when VC is present.

New toolbox — and know calciphylaxis

Mg · Vit K · SNF472 target the vessel directly. Painful ischemic skin in a dialysis patient = calciphylaxis — stop warfarin, add STS, act fast.

鈣磷失衡與血管鈣化

Outline

A spectrum, not a single disease.

Three lenses on one disease.

Three hormones run the system.

PTH — the calcium thermostat.

營養 vs. 活性 — same vitamin, two roles.

Vit D acts far beyond bone.

Active Vit D corrects low Ca/P and high PTH.

FGF-23 — Bone speaks to the kidney.

In health, what goes in comes out.

In kidney failure, even strict diet runs positive.

Five markers, one sequence — who moves first?

How we describe a CKD bone.

ROD — five classic types, four clinical pictures.

Two numbers position the bone.

Two patterns, two stories.

The vessel becomes bone.

A balance, not a single villain.

Serum Ca-P doesn't tell the whole story.

Calcification seen predicts mortality.

Treating bone protects the vessel.

Stiff vessels steal from the heart.

CKD dismantles the anti-calcification system.

Calciphylaxis — VC at its most lethal.

The four numbers to know.

Treat patients, not Ca × P.

Five places to push.

The Ca-vs-non-Ca question.

Direct anti-calcification therapy.

Treat bone by its type, not just the PTH.

Eight patients, eight different moves.

What to carry home.

鈣磷失衡 與 血管鈣化

Outline

A spectrum, not a single disease.

Three lenses on one disease.

Three hormones run the system.

PTH — the calcium thermostat.

營養 vs. 活性 — same vitamin, two roles.

Vit D acts far beyond bone.

Active Vit D corrects low Ca/P and high PTH.

FGF-23 — Bone speaks to the kidney.

In health, what goes in comes out.

In kidney failure, even strict diet runs positive.

Five markers, one sequence — who moves first?

How we describe a CKD bone.

ROD — five classic types, four clinical pictures.

Two numbers position the bone.

Two patterns, two stories.

The vessel becomes bone.

A balance, not a single villain.

Serum Ca-P doesn't tell the whole story.

Calcification seen predicts mortality.

Treating bone protects the vessel.

Stiff vessels steal from the heart.

CKD dismantles the anti-calcification system.

Calciphylaxis — VC at its most lethal.

The four numbers to know.

Treat patients, not Ca × P.

Five places to push.

The Ca-vs-non-Ca question.

Direct anti-calcification therapy.

Treat bone by its type, not just the PTH.

Eight patients, eight different moves.

What to carry home.

鈣磷失衡與血管鈣化