a new perspective on hypophosphatemia
TRANSCRIPT
A New Perspective on Hypophosphatemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrologist
Steve Chen
P
PhosphatePhosphate
Reference Range:2.5 – 4.5 mg/L
PhosphatePhosphate
Hypophosphatemia is phosphate < 2.5 mg/dl
PseudohypophosphatemiaPseudohypophosphatemia
Mannitol: interfere the action molybdate +Pi → phosphomolybdate removed by dialysis of serum
Bilirubin(>3mg/dl): interfere colorimetric assay
Acute leukemia in blast uptake at room temperature
Hypophosphatemia Hypophosphatemia ( < 2.5mg/dl )( < 2.5mg/dl )
Moderate Severe
S-Pi(mg/dl) 1.0~ 2.5 <1.0
Clinical S/S Usually not Organ dis-function
Pi depletion May not Usually present
Etiology of Etiology of hypophosphatemiahypophosphatemia
–Decreased oral intakeDecreased oral intake Malnutrition (Alcoholics)Malnutrition (Alcoholics)
–Excessive loss Excessive loss Renal or Non-renal Renal or Non-renal
–Redistribution from ECF to Redistribution from ECF to ICFICF Respiratory/Metabolic AlkalosisRespiratory/Metabolic Alkalosis
Amanzadeh J and Reilly RF Jr (2006) Hypophosphatemia: an evidence-based approach to its clinical consequences and management Nat Clin Pract Neprol 2: 136–148 doi:10.1038/ncpneph0124
Figure 1 Phosphate fluxes and causes of hypophosphatemia
Renal tubular defects→Pi↓Renal tubular defects→Pi↓ Fanconi syndrome Dent’s disease(XR-linked): CLC-5 XD-linked hypophosphatemic ricket: PHEX Hereditary hypophosphatemic ricket with
hypercalciuria Oncogenic osteomalacia Kidney transplantation Polyostotic fibrous dysplasia Panostotic fibrous dysplasia
Redistribution Redistribution Respiratory/Metabolic alkalosis Hormone effects
Insulin, Epinephrine Androgens Cortisol
Nutrient effects Glucose, Fructose, Xylitol AAs Glycerol, Lactate
Cellular uptake syndromes
Respiratory alkalosis→Pi↓Respiratory alkalosis→Pi↓
Respiratory alkalosis Intracellular alkalosis due to ↓PCO2Activation of intracellular glycolysis↑Phosphorylated carbonhydrate compoundsRedistribution of Pi Hypophosphatemia
Respiratory alkalosisRespiratory alkalosis Sepsis Heat stroke Neuroleptic malignant syndrome Hepatic coma Salicylate poisoning Gout Panic attacks Psychiatic depression Alcohol withdrawal
Cellular uptake syndromesCellular uptake syndromes
Recovery from hypothermia Burkitt lymphoma; histiocytic lymphoma Acute leukemia; chronic leukemia in blast crisis Treatment of pernicious anemia Erythopoietin therapy Hungry bones syndrome: S/P PTX Erythrodermic psoriasis
Hypophosphatemia Hypophosphatemia ( < 2.5mg/dl )( < 2.5mg/dl )
Moderate Severe
S-Pi(mg/dl) 1.0~ 2.5 <1.0
Clinical S/S Usually not Organ dis-function
Pi depletion May not Usually present
Severe hypophosphatemia Severe hypophosphatemia Prolonged use of phosphate-binding Antacids Chronic Alcoholism Respiratory Alkalosis Recovery from severe burns, DKA, major
OP,ARF, or Nutritional recovery syndrome Kidney Transplantation DM, poorly controlled Drug: Cisplatin, Ifosfamide, Foscarnet,
Acetaminophen intoxification
Symptoms & signs of Symptoms & signs of HypophosphatemiaHypophosphatemia– Progressive weakness and tremorsProgressive weakness and tremors– Circum-oral & fingertip paresthesiaCircum-oral & fingertip paresthesia– Absent DTRsAbsent DTRs– Mental depressionMental depression– Respiratory failureRespiratory failure
Amanzadeh J and Reilly RF Jr (2006) Hypophosphatemia: an evidence-based approach to its clinical consequences and management Nat Clin Pract Neprol 2: 136–148 doi:10.1038/ncpneph0124
Figure 2 Correlation between the decrease in maximal inspiratory pressures and the severity of hypophosphatemia
Reproduced with permission from Gravelyn TR et al. (1988) Hypophosphatemia-associated respiratory muscle weakness in a general inpatient population. Am J Med 84: 870–876. © (1988) Excerpta Medica, Inc.
Amanzadeh J and Reilly RF Jr (2006) Hypophosphatemia: an evidence-based approach to its clinical consequences and management Nat Clin Pract Neprol 2: 136–148 doi:10.1038/ncpneph0124
Figure 3 Hypophosphatemia impairs the contractile properties of the diaphragm during acute respiratory failure
Reproduced with permission from Aubier M et al. (1985) Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 313: 420–424. © (1985) Massachusetts Medical Society. Pdi, increases in
transdiaphragmatic pressure.
↓↓Pi organic dysfunctionPi organic dysfunction
CNS: convulsion, coma,… Cardiovascular: CHF, HTNRenal: ↓GRF Derangement of pancreatic islets: IGTMusculoskeletal: rhabodomyolysisHematopoietic: hemolysis,
thrombocytopenia, ↓phagocytosis
Fractional excretion of PiFractional excretion of Pi
FE-Pi= C-Pi / C-Cr = U-Pi x P-Cr / U-Cr x P-Pi
In physiological response to hypophosphatemia, EF-pi=0
Urinary phosphate wasting: hypophosphatemia and FE-pi > 5%
FE of electolyteFE of electolyteFE of K >6.5%→ renal K wasting
in hypo-KFE of Pi >5.0% → renal Pi wasting
in hypo-PiFE of Mg>2.5%→ renal Mg wasting
in hypo-MgFE of Na> 1.0% → renal Na wasting
in hypo-NaFE of Ca>3.0% → renal Ca wasting
in hypo-Ca
TmP/GFRTmP/GFR
TRP(fractional reabsortion of Pi)=1-FE-Pi TmP/GFR=TRP x Plasma-Pi
if plasma Pi=Pi in glomerular filtrate if TRP 0.86≦
Age-related reference ranges for TmP/GFR 0.80 ~ 1.25mmol/L for adult
Amanzadeh J and Reilly RF Jr (2006) Hypophosphatemia: an evidence-based approach to its clinical consequences and management Nat Clin Pract Neprol 2: 136–148 doi:10.1038/ncpneph0124
Figure 4 Nomogram for derivation of normalized renal threshold phosphate concentration
Reproduced with permission from Walton RJ et al. (1975) Nomogram for derivation of renal threshold phosphate concentration. Lancet 2: 309–310. © (1975) Elsevier.
TmP/GFR indicationsTmP/GFR indicationsRB Payne, Ann Clin Biochem 1998RB Payne, Ann Clin Biochem 1998
Refeeding syndrome(↑Insulin/↓GH): ↓TmP/GFR if IV Kpi supply→TmP/GFR↑: intracellular Pi repletion
X-linked hypoPi ricket: ↓TmP/GFR if GH given →TmP/GFR↑: monitoring response to GH
Respiratory alkalosis:↓TmP/GFR( direct renal effect)
persistent ↓TmP/GFR→Pi replacement
Guidelines of TreatmentGuidelines of Treatment
TreatmentTreatment– Serum POSerum PO44 level < 1.0 mg/dL level < 1.0 mg/dL
IVIV replacement replacement 2.5-5 mg (0.08-0.16 mmol) / kg 2.5-5 mg (0.08-0.16 mmol) / kg IV IV over 6over 6
hours hours Check Check serum POserum PO44 after each dose after each dose
Indications for IV Pi supplyIndications for IV Pi supply
Moderate hypophosphatemia < 2.5 mg/dl if ongoing renal or GI loss of Pi
Moderate hypophosphatemia < 2.5 mg/dl(0.8 mmol/L) on a ventilator
Severe hypophosphatemia < 1.0 mg/dl (0.3 mmol/L) in a critically ill, intubated patients or Symptomatic hypophosphatemia
IV Pi preparations IV Pi preparations
Pi(mmol/ml) Na(meq/ml) K(meq/ml)
Potassium phosphate 3.0 0 4.4
Sodium phosphate 3.0 4.0 0
Neutral sodium phosphate
0.09 0.2 0
Neutral potassium phosphate
1.10 0.2 0.02
IV Pi supplyIV Pi supply Overtly symptomatic hypophosphatemia
hematological, cardiomyopathy, respiratory muscle weakness, altered mental status
IVF for 6 Hrs distributes in 40% TBWt Hebert et al, JCI 1996 310mg(10mmol) in 70Kg x 0.4=28L TBW ↑S-Pi 1.1mg/dl
IVF for 6Hrs with maximum 2.5-5mg(0.08-0.16mmol)/Kg
Switch into oral form if S-Pi >2.0 ~ 2.5 mg/dl
PO Pi supplyPO Pi supply
Skim milk or low-fat(0.5%) milk : 0.9mg Pi/ml 1000 ~ 2000mg of Pi/D for 7 ~ 10 days
Oral preparations: K-phos Neutral: 250mg Pi + 1.1 meq K + 13 meq Na / tablet Neutra-Phos: 250mg Pi + 7.1 meq K + 7.1 meq Na /capsule Neutra-Phos K: 250mg Pi + 14.2 meq K /capsule
Dialysate Pi: Dialysate Pi: 4-8 4-8 mg/dlmg/dlFleet phospho-soda buffered saline laxative
comercially-available mixture 4.2 mmol of Pi per 1 cc
Dialysate Pi: 6.2mg/dl (2.0mmol/L) 92cc Fleet in 9.46L of B solution, diluted(1/20) into 190.4L
Dialysate Pi: 4mg/dl 60cc Fleet
Indications for dialysate PiIndications for dialysate Pi
Uremic pericarditis Hypercatabolic renal failureEthylene glycol poisoningLithium intoxificationVancomycin overdoseHypercalcemia&hypophosphatemiaIntensified HD for other ESRD conditions
Post IV Pi monitoring Post IV Pi monitoring
Complications of therapyComplications of therapy– HypocalcemiaHypocalcemia– Metastatic calcificationMetastatic calcification– HypotensionHypotension– HyperkalemiaHyperkalemia
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↓InsulinHyperCa; hyperMgGH; thyroid hormone
24,25(OH)2D3 24,25(OH)2D3
24,25(OH)2D3 from kidney while replete in 1,25(OH)2D3/Ca/Pi
Endogenous inhibitor of 1,25(OH)2D3Anabolic effects on boneClinical usefulness in treating
hyperparathyroidism
24, 25(OH)2D324, 25(OH)2D3J Nemere: KI 2007(Utah State University)J Nemere: KI 2007(Utah State University)
Ca/Pi absorption in Intestine
1,25(OH)D3 in Kidney Ca/Pi re-absorption 24-25(OH)2D3
PTH in Parathyroids
N
NAnabolic on Bone
FGF-23FGF-23AD hypo-phosphatemic rickets XL hypophosphatemia Tumor-induced osteomalacia (TIO): a para-
neoplastic syndrome (mesynchymal tumors) Case report: FGF 23 elevated in a patient
with metastatic prostate Ca and hypophosphatemia Casey et al: AJKD 2007
↓ 1αhydroxylase→ 1,25(OH)2D3 ↓↓Na-Pi co-transport in kidney
→Phosphaturia
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
Schematic representation of currently known inducers of FGF23 production
Nurr1: nuclear receptor-associated protein-1sKL: secreted Klotho
FGF 23 signaling in parathyroid cellFGF 23 signaling in parathyroid cell
Hiritaka Komaba et al: KI 77: 292-298, 2010
Membrane Klotho
FGF excess and deficiency
Y
Secondary excessNormal to high Pi; low 1,25DMarkedly high FGF23 • CKD• High Pi diet • Klotho deficiency ( faulty FGF23-Klotho
axis→ lack of inhibition of renal 1 α hydroxylase→ high 1,25D)
Primary excessSevere low Pi ; Inappropriate low 1,25DHigh FGF 23• ADHR• TIO: tumor induced osteolalacia • XLH• Fibrous dysplasia• IV iron
Secondary deficiencyNormal to low Pi; high 1,25DLow to undetectable FGF23•Low Pi diet•VD receptor deficieny• 1 α hydroxylase deficieny ( low 1,25D)•NaPi 2a deficiency•NaPi 2c deficiency(HHRH)
Primary deficiencySevere high Pi ; High 1,25DLow biologically active or un-detectable FGF 23
• Tumoral calcinosis • FGF 23 ablation
Secreted Klotho in regulation of ion Secreted Klotho in regulation of ion channelschannels
Na-dependent Pi transporter ↓TRPV5(epithelial Ca channel): ↑ ROMK K channel, distal nephron: ↑Intra-celluar signaling by insulin and IGF TRPC6: Ca channel in heart, vessel, kidney
glomerulus
Renal hypophosphatemiaRenal hypophosphatemia: : adult onsetadult onset Pi disturbance
Adult onset
Disease association
XLH-R/O isolatedPHEX mutation
rare, asymptmatic elderly
Vitamin D↓
ADH-R/O isolatedFGF23 mutataion
? Vitamin D↓
OHO (Oncogenic hypo-Pi osteomalacia)
isolated phosphatonnin
usual Vitamin D↓Mesynchymal tumor
Fanconi syndrome
isolated or complex
Para-neoplastic
Vitamin D↓LCDD; Cd
Renal phosphate wasting disordersRenal phosphate wasting disordersTenenhouse et al, JASN 14: 240-47, 2003Tenenhouse et al, JASN 14: 240-47, 2003
PHEX mutations (Phosphate regulating gene with homology to Endopeptidases on X chromosome): loss of PHEX function on osteoblasts, osteocytes, odontoblasts→ phospaturic hormone↑/Pi-conserving hormone↓
FGF-23 (a phosphaturic factor): ↓type II-a Na/Pi in BBM (ADH: ↓pro-protein convertase→FGF-23 ↑)
Phosphatonin candidates: FGF-23 FRP-4 (frizzled related protein 4) mepe (matrix extracellular phosphoglycoprotein)
Membrane-bound endopeptidase
Phosphatonin
Tumor Induced Osteomalacia
Phosphatonin
Membrane-bound endopeptidase
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
Renal hypophosphatemiaRenal hypophosphatemiaAD proximal tubulopathy
Dent disease
Fanconi syndrome
HypoPemic hypercalciuric rickets (HHRH)
Renal hypoPemic rickets
Familial AD XL all AR XL CRFNephrocalcinosisKidney stones
--+
+++
+/-+/-+/-
---
---
HypoKemiaType II RTAHypercalciuria
--↑
+-↑
++↓/↑
--↑
--↓
1,25-VitD3i-PTH
↑↓
↑↓
N/↓N/↑
↑↓
↓N/↑
Bone osteomalacia Rosteomalacia
Rosteomalacia
R R
Renal phosphate wasting disorders Renal phosphate wasting disorders Tenenhouse et al, JASN 14: 240-47, 2003Tenenhouse et al, JASN 14: 240-47, 2003 1,25(OH)2D↑
Hypercalciuria Primary defect
XLHHypGy
-- -- --
No No No
PHEX 3’Phex del.5’Phex del.
ADH -- No FGF-23
OHO -- No Phosphatonins
HHRHNpt2-/-
+ +
Yes Yes
? Npt2
Renal phosphate wastingRenal phosphate wasting+Family history XL >Hypophosphatemic Rickets>AD Hypophosphatemic Rickets>Hereditary Hypophosphatemic Riskets with hypercalciuria
+ proximal RTA/Glycosuria/AAciduria (Fanconi syndrome) >Wilson’s disease>Heavy metal >Cystiuria>Hereditary fructose intolerance >Multiple myeloma
+ prior normal Pi/Normal Ca/25(OH)VD; low 1,25(OH)2VD (TIO)Definite diagnosis: remission after resection of tumorOsteomalacia by TC labeled iliac crest bone biopsy
Post-transplant hypophosphatemiaPost-transplant hypophosphatemiaMoshe levi, KI 2001Moshe levi, KI 2001
↓Intestinal phosphate absorption ↓Renal phosphate reabsorption: ↓TmP/GFR
PTH level and activity↑ 1,25(OH)2D3↓ Glucocorticoids Cyclosporin: ↓Npt in animal model ↑Phosphatonin(bone-derived humeral factor) ↓PHEX(bone-derived membrane protein) Stanniocalcin ↓type1/↑type2
ELECTROLYTE DISORDERSELECTROLYTE DISORDERS
Things to rememberThings to remember– Treat the patient, not the lab valueTreat the patient, not the lab value– Rate of correction should mirror rate of Rate of correction should mirror rate of
changechange– Correct in orderly fashionCorrect in orderly fashion
1. Volume1. Volume 2. pH2. pH 3. Potassium, Phosphate, Calcium, Magnesium3. Potassium, Phosphate, Calcium, Magnesium 4. Sodium and Chloride4. Sodium and Chloride
– Consider impact of interventions overallConsider impact of interventions overall
Key Points