a new perspective on hypophosphatemia

A New Perspective on Hypophosphatemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

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