5. HypophosphatemiaHypophosphatemia ( < 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
6.
7. Etiology ofEtiology of
hypophosphatemiahypophosphatemia
–Decreased oral intakeDecreased oral intake
Malnutrition (Alcoholics)Malnutrition (Alcoholics)
–Excessive lossExcessive loss
Renal or Non-renalRenal or Non-renal
–Redistribution from ECF to ICFRedistribution from ECF to ICF
Respiratory/Metabolic AlkalosisRespiratory/Metabolic Alkalosis
8. 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
14. HypophosphatemiaHypophosphatemia ( < 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
15. Severe hypophosphatemiaSevere 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
21. 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%
22. FE of electolyteFE of electolyte
FE of K >6.5%→ renal K wasting
in hypo-K
FE of Pi >5.0% → renal Pi wasting
in hypo-Pi
FE of Mg>2.5%→ renal Mg wasting
in hypo-Mg
FE of Na> 1.0% → renal Na wasting
in hypo-Na
FE of Ca>3.0% → renal Ca wasting
in hypo-Ca
23. 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
25. TmP/GFR indicationsTmP/GFR indications
RB 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
26.
27. Guidelines of TreatmentGuidelines of Treatment
TreatmentTreatment
– Serum POSerum PO44 level < 1.0 mg/dLlevel < 1.0 mg/dL
IVIV replacementreplacement
2.5-5 mg (0.08-0.16 mmol) / kg2.5-5 mg (0.08-0.16 mmol) / kg IVIV over 6over 6 hourshours
CheckCheck serum POserum PO44 after each doseafter each dose
28. 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
30. 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
31. 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
32. Dialysate Pi:Dialysate Pi: 4-84-8 mg/dlmg/dl
Fleet 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
33. Indications for dialysate PiIndications for dialysate Pi
Uremic pericarditis
Hypercatabolic renal failure
Ethylene glycol poisoning
Lithium intoxification
Vancomycin overdose
Hypercalcemia&hypophosphatemia
Intensified HD for other ESRD conditions
34. Post IV Pi monitoringPost IV Pi monitoring
Complications of therapyComplications of therapy
– HypocalcemiaHypocalcemia
– Metastatic calcificationMetastatic calcification
– HypotensionHypotension
– HyperkalemiaHyperkalemia
35.
36. Phosphate transport in PCTPhosphate transport in PCT
NaPi-2b mostly in small intestine
Progressively less abundant
Along the entire tubule
40. 24,25(OH)2D324,25(OH)2D3
24,25(OH)2D3 from kidney while replete in
1,25(OH)2D3/Ca/Pi
Endogenous inhibitor of 1,25(OH)2D3
Anabolic effects on bone
Clinical usefulness in treating
hyperparathyroidism
41. 24, 25(OH)2D324, 25(OH)2D3
J 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
N
Anabolic
on Bone
42. FGF-23FGF-23
AD 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
43. Regulation and action of FGF-23Regulation and action of FGF-23
KI, 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
Pi
Pi
1,25(OH)2D3
↓1σ hydroxylase
44. Schematic representation of currently
known inducers of FGF23 production
Nurr1: nuclear receptor-associated protein-1
sKL: secreted Klotho
45. FGF 23 signaling in parathyroid cellFGF 23 signaling in parathyroid cell
Hiritaka Komaba et al: KI 77: 292-298, 2010
Membrane Klotho
46.
47.
48. FGF excess and deficiency
Y
Secondary excess
Normal to high Pi; low 1,25D
Markedly high FGF23
• CKD
• High Pi diet
• Klotho deficiency ( faulty FGF23-Klotho
axis→ lack of inhibition of renal 1 α
hydroxylase→ high 1,25D)
Primary excess
Severe low Pi ; Inappropriate low 1,25D
High FGF 23
• ADHR
• TIO: tumor induced osteolalacia
• XLH
• Fibrous dysplasia
• IV iron
Secondary deficiency
Normal to low Pi; high 1,25D
Low to undetectable FGF23
•Low Pi diet
•VD receptor deficieny
• 1 α hydroxylase deficieny
( low 1,25D)
•NaPi 2a deficiency
•NaPi 2c deficiency(HHRH)
Primary deficiency
Severe high Pi ; High 1,25D
Low biologically active or un-detectable FGF 23
• Tumoral calcinosis
• FGF 23 ablation
49.
50. Secreted Klotho in regulation of ionSecreted 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
57. Regulation and action of FGF-23Regulation and action of FGF-23
KI, 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
Pi
Pi
1,25(OH)2D3
↓1σ hydroxylase
59. Renal phosphate wasting disordersRenal 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
XLH
Hyp
Gy
--
--
--
No
No
No
PHEX
3’Phex del.
5’Phex del.
ADH -- No FGF-23
OHO -- No Phosphatonins
HHRH
Npt2-/-
+
+
Yes
Yes
?
Npt2
60. Renal phosphate wastingRenal phosphate wasting
+Family history
XL
>Hypophosphat
emic Rickets
>AD
Hypophosphate
mic Rickets
>Hereditary
Hypophosphate
mic Riskets with
hypercalciuria
+ proximal
RTA/Glycosuria/A
Aciduria (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 tumor
Osteomalacia by
TC labeled iliac
crest bone biopsy
61.
62. Post-transplant hypophosphatemiaPost-transplant hypophosphatemia
Moshe 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
63.
64. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
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 changeRate of correction should mirror rate of change
– 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