A comprehensive review for medical students and deep learners

1. A New Perspective on
Hypophosphatemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrologist
Steve Chen
P

2. PhosphatePhosphate
Reference Range:
2.5 – 4.5 mg/L

3. PhosphatePhosphate
Hypophosphatemia is phosphate < 2.5 mg/dl

4. 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

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

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

9. 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

10. RedistributionRedistribution
 Respiratory/Metabolic alkalosis
 Hormone effects
Insulin, Epinephrine
Androgens
Cortisol
 Nutrient effects
Glucose, Fructose, Xylitol
AAs
Glycerol, Lactate
 Cellular uptake syndromes

11. Respiratory alkalosis→Pi↓Respiratory alkalosis→Pi↓
Respiratory alkalosis
Intracellular alkalosis due to ↓PCO2
Activation of intracellular glycolysis
↑Phosphorylated carbonhydrate compounds
Redistribution of Pi
Hypophosphatemia

12. Respiratory alkalosisRespiratory alkalosis
 Sepsis
 Heat stroke
 Neuroleptic malignant syndrome
 Hepatic coma
 Salicylate poisoning
 Gout
 Panic attacks
 Psychiatic depression
 Alcohol withdrawal

13. 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

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

16. Symptoms & signs ofSymptoms & 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

17. 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.

18. 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.

19. ↓↓Pi organic dysfunctionPi organic dysfunction
CNS: convulsion, coma,…
Cardiovascular: CHF, HTN
Renal: ↓GRF
Derangement of pancreatic islets: IGT
Musculoskeletal: rhabodomyolysis
Hematopoietic: hemolysis,
thrombocytopenia, ↓phagocytosis

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

24. 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.

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

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

29. IV Pi preparationsIV 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

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

36. Phosphate transport in PCTPhosphate transport in PCT
NaPi-2b mostly in small intestine
Progressively less abundant
Along the entire tubule

38. Regulation of phosphateRegulation of phosphate
excretionexcretion
Increase↑ Decrease↓
PTH; PTH-rp; Calcitonin
High phosphate intake
pCO2↑
Metabolic acidosis
ECV↑
Fasting(glucagon)
Acute renal denervation
Dopamine, Diuretic
Glucocorticoids; ANP; Aminophylline
Alcohol
Aldosteronism, SIADH
Hypo-Mg ; Hypo-K
Vitamin D
Phsophate deprivation
pCO2↓
Metabolic alkalosis
ECV↓
Insulin
HyperCa; hyperMg
GH; thyroid hormone

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

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

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

52. Renal hypophosphatemiaRenal hypophosphatemia:: adult onsetadult onset
Pi
disturbance
Adult
onset
Disease
association
XLH-R/O isolated
PHEX mutation
rare,
asymptmatic
elderly
Vitamin D↓
ADH-R/O isolated
FGF23 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

53. Renal phosphate wasting disordersRenal phosphate wasting disorders
Tenenhouse 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)

54. Membrane-bound
endopeptidase
Phosphatonin

55. Tumor Induced Osteomalacia
Phosphatonin
Membrane-bound
endopeptidase

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

58. Renal hypophosphatemiaRenal hypophosphatemia
AD
proximal
tubulopathy
Dent
disease
Fanconi
syndrome
HypoPemic
hypercalciuric
rickets
(HHRH)
Renal
hypoPemic
rickets
Familial AD XL all AR XL
CRF
Nephrocalcinosis
Kidney stones
-
-
+
+
+
+
+/-
+/-
+/-
-
-
-
-
-
-
HypoKemia
Type II RTA
Hypercalciuria
-
-
↑
+
-
↑
+
+
↓/↑
-
-
↑
-
-
↓
1,25-VitD3
i-PTH
↑
↓
↑
↓
N/↓
N/↑
↑
↓
↓
N/↑
Bone osteomalacia R
osteoma
lacia
R
osteomalacia
R R

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

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

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