A New Perspective on Hyperphosphatemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

Steve Chen

P

PhosphatePhosphate

Reference Range:2.5 – 4.5 mg/L

PhosphatePhosphate

Hyperphosphatemia is phosphate > 5.2 mg/dl

PseudohyperphosphatemiaPseudohyperphosphatemia

Multiple Myeloma: paraproteins interferes colorimetric assay removal by SSA or Uf

Extreme hyperlyceridemia (TG)Hyperbilirubinemia ( B)In vitro Hemolysis:

storing plasma at 4’C overnight

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Serum POSerum PO44 > 5.2 mg/dL > 5.2 mg/dL EtiologyEtiology

– Decreased renal excretionDecreased renal excretion– Shift from ICF ECFShift from ICF ECF– Increased intakeIncreased intake– Most common with renal dysfunctionMost common with renal dysfunction– HypoparathyroidismHypoparathyroidism

Hyperphosphatemia

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Clinical Features (1)Clinical Features (1)– Although most patients with Although most patients with

hyperphosphatemia are hyperphosphatemia are asymptomatic, they occasionally asymptomatic, they occasionally report report hypocalcemichypocalcemic symptoms symptoms

– Other symptoms include bone and Other symptoms include bone and joint pain, pruritus, and rashjoint pain, pruritus, and rash

– These generally are These generally are uremicuremic symptoms symptoms

Hyperphosphatemia

Symptoms & signs of Symptoms & signs of Hypocalcemia Hypocalcemia – NeurologicalNeurological

Circumoral & digital paresthesiasCircumoral & digital paresthesias TetanyTetany Chvostek signChvostek sign Trousseau signTrousseau sign Impaired memory, Impaired memory, confusionconfusion HallucinationsHallucinations, dementia, dementia, seizures, seizures

Symptoms & signs of Symptoms & signs of HypocalcemiaHypocalcemia– CardiovascularCardiovascular

Heart failure; Heart failure; HypotentionHypotention VasoconstrictionVasoconstriction EKG abnormalitiesEKG abnormalities

– SkeletalSkeletal OsteodystrophyOsteodystrophy RicketsRickets OsteomalaciaOsteomalacia

Acute phosphate Acute phosphate nephropathynephropathy Markowitz et al: JASN 2007 Columbia Markowitz et al: JASN 2007 Columbia UniversityUniversity Definition: 1.16Definition: 1.16 ～～ 6.3% 6.3%

Baseline renal function: S-Cr > 1.3 mg/dl and Baseline renal function: S-Cr > 1.3 mg/dl and estimated C-Cr ≦60 ml/min; Worsening renal estimated C-Cr ≦60 ml/min; Worsening renal function(≧0.5function(≧0.5 ～～ 1.0mg/dl) 61.0mg/dl) 6 ～～ 12M after colonoscopy 12M after colonoscopy

Risk factors: Female/older/CHF/Diuretic use/ACEI useRisk factors: Female/older/CHF/Diuretic use/ACEI use Hydration: ≧72 ounces of clear liquids for 30Hydration: ≧72 ounces of clear liquids for 30 ～～ 45 ml 45 ml

OSP OSP Avoidance of anesthesia regimens: no oral Avoidance of anesthesia regimens: no oral intake for 4-6 Hrs intake for 4-6 Hrs Alternative agents in female: PEG Alternative agents in female: PEG (polyethylene glycol) (polyethylene glycol) Dose reduction or avoidance in the Dose reduction or avoidance in the elderly/risk factors elderly/risk factors

Daily UPiE <1500 mg/D: Renal > 1500 mg/D: Non-renal

GFR < 25 ml/min GFR > 25 ml/min (Glomerular) (Tubular)

AKI CKD

Hyperphosphatemia: DD

S-Ca : 8.5~10.5 Acromegaly/Insulinoma/IGF-1Tumoral calcinosisBiphosphonate

Pi load: GI Cellular Vitamin D

S-Ca > 10.4 Adrenal insufficiencyHyperthyroidism

S-Ca < 8.5Hypo-PTH (i-PTH ↓ or N)Pseudohypo-PTH (iPTH ↑)

Fractional Excretion of Pi Fractional Excretion of Pi

FE-Pi > 15% Non-renal : Massive phosphate ingestion (eg, laxative [Phospho-soda] abuse) Lysis of tissue and resulting release of intracellular phosphate

FE-Pi < 15% Renal: Renal failure Hypoparathyroidism

Hyperphosphatemia, renal Hyperphosphatemia, renal ( Pi > 5.2mg/dl )( Pi > 5.2mg/dl )

UPO4 < 1500mg/D : ↓renal excretion Ccr< 25ml/min: ↓renal infiltration

renal failure,acute/chronic Ccr>25ml/min: ↓tubular clearance

SCa<8.5mg/dl: hypoPTH/ PseudohypoPTH SCa 8.5 ～ 10.4: Acromegaly/Insulinoma/IGF-1; Tumoral calcinosis / Biphosphonate / Hypophosphatasia SCa>10.4mg/dl: Adrenal insufficiency/Hyperthyroidsim

Tumoral calcinosis Tumoral calcinosis Tumoral calcinosis: uncommon benign characterized by large calcified

peri-articular soft tissue masses composed of calcium salts, usually located around large joints

Primary form: hereditary(AR): GALNT3, FGF-23, and Klotho, 3 genes whose proteins are important in promoting phosphate excretion and suppressing vitamin D synthesis. idiopathic: normally a single event with low incidence of recurrence

Secondary form: hyperparathyroidism vitamin D intoxication scleroderma uremia in the context of chronic renal failure.

Phosphate transport in PCTPhosphate transport in PCT

NaPi-2b mostly in small intestine

Progressively less abundant

Along the entire tubule

Regulation of phosphate Regulation of phosphate excretionexcretion

Increase↑ Decrease↓

PTH; PTH-rp; CalcitoninHigh phosphate intakepCO2↑Metabolic acidosisECV↑Fasting(glucagon)Acute renal denervationDopamine, DiureticGlucocorticoids; ANP; AminophyllineAlcoholAldosteronism, SIADH Hypo-Mg ; Hypo-K

Vitamin DPhsophate deprivationpCO2↓Metabolic alkalosisECV↓InsulinHyper-Ca; Hyper-MgGHThyroid hormoneAdrenal insufficiency

Hyperphosphatemia, non-renalHyperphosphatemia, non-renal(Pi > 5.2mg/dl(Pi > 5.2mg/dl))

UPO4 >1500mg/D: exogenous Pi loads: Vitamin D intoxication / Milk alkaline syndrome endogenous Pi loads: tumor lysis syndrome/rhabdomyolysis/hyperthermia/hemolysis

UPO4 >1500mg/D: redistribution of Pi acute metabolic or respiratory acidosis

Milk alkali syndrome from Sippy dietMilk alkali syndrome from Sippy dietLin et al, NDT 17: 708-14, 2002Lin et al, NDT 17: 708-14, 2002

Absorption of free Ca in upper intestinal tract: CaCO3+H (gastric secretion)→free Ca via trans-cellular pathway→CaCO3 by NaHCO3 in duodenum

Absorption of free Ca in downstream intestinal tract: CaCO3+H →free Ca via para-cellular pathway only if HPO4 deficiency→ Ca(PO4)2

Potential HCO3 load: CHO→H (bacterial fermentation)+ OA( non oxalate)

Triads: Hypercalcemia + Metabolic alkalosis + CKD; 1,25(OH)2VD low or low normal

Calcium(>4G/D) Alkali syndrome Calcium(>4G/D) Alkali syndrome Post-menopausal women: CaCO3(+VD3) Pregnant women: hyperemesis→ ECV→

Calcium via gut Transplant recipients/HD patients: CaCO3Patients with bulimia(anorexia nervosa):

food fetishes in Calcium Betel nuts chewers: a lime paste from

ground oyster: CaO + Ca(OH)2Thiazide users

Calcium Alkali syndrome Calcium Alkali syndrome

THAL

NKCC

ROMK

Na K ATP ase

Ca, Mg pH

Na/K

K

2Cl

CaSRNegative

Positive

Calcium Alkali syndrome Calcium Alkali syndrome

DCT

NCC

TRPV5

Na K ATP ase

pH pH

Na

Ca

Calcium flow

2Cl

CaSRPositive

PositiveCaSR

CaATPase

NCX

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

TreatmentTreatment– Treat the causesTreat the causes– Enhance renal excretion in patients with Enhance renal excretion in patients with

normal renal function: normal renal function: Hyperphosphatemia due to tumor lysis Hyperphosphatemia due to tumor lysis Forced Forced saline diuresis to enhance urinary losses saline diuresis to enhance urinary losses

– Restrict Phosphate intake: CKD/AKIRestrict Phosphate intake: CKD/AKI– Aluminum Carbonate/HydroxideAluminum Carbonate/Hydroxide

Absorbs phosphate secreted into gutAbsorbs phosphate secreted into gut– HemodialysisHemodialysis

Hyperphosphatemia

Regulation and action of FGF-23Regulation and action of FGF-23KI, 2008 ( Baylor University Medical Center, Dallas, Texas, USA)KI, 2008 ( Baylor University Medical Center, Dallas, Texas, USA)

FGF 23

Pi pool Bone

Kidney

↓Parathyroid ?

Pi

PiPi

1,25(OH)2D3

↓1σ hydroxylase

Klotho: anti-aging gene connects intermedin1–53 to suppression of vascular calcification in chronic kidney disease

MPG: Matrix γ-carboxyGlutamic acid Protein 

Hyperphosphatemic vascular calcification