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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
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