1. A New Perspective
on Hypocalcemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrology
Steve Chen
Ca

2. CalciumCalcium
Reference Range:
8.8 – 10.3 mg/L

3. CalciumCalcium
Hypocalcemia is total calcium < 8.5 mg/dl

4. CalciumCalcium
Hypocalcemia is ionized calcium < 2.125
mmol/L

5. Pseudo-hypocalcemiaPseudo-hypocalcemia
Transfer sample from tubes containing K-
EDTA
Sample stored at RT for extended time
Vasovagal episode
Usually accompanied with
pseudohyperkalemia

7. Etiology of Hypocalcemia(1)Etiology of Hypocalcemia(1)
– Common CausesCommon Causes
SShockhock
SSepsisepsis
RRenal failureenal failure
PPancreatitisancreatitis

8. Etiology of Hypocalcemia(2)Etiology of Hypocalcemia(2)
– MalignancyMalignancy
– EndocrineEndocrine
 HypoparathyroidismHypoparathyroidism
 Vitamin D deficiencyVitamin D deficiency
– DrugsDrugs
 Cimetidine, Phosphates, Dilantin, Phenobarbital, Glucagon,
Aminoglycosides, Cisplatin, Heparin, Theophylline,
Protamine, Norepinephrine, Loop diuretics, Glucocorticoids,
Magnesium Sulfate, Nitroprusside

9. Symptoms & signs ofSymptoms & signs of
HypocalcemiaHypocalcemia
 Clinical Features(1)Clinical Features(1)
– NeurologicalNeurological
 Circumoral & digital paresthesiasCircumoral & digital paresthesias
 TetanyTetany
 Chvostek signChvostek sign
 Trousseau signTrousseau sign
 Impaired memory, confusionImpaired memory, confusion
 HallucinationsHallucinations, dementia, seizures, dementia, seizures

10. Symptoms & signs ofSymptoms & signs of
HypocalcemiaHypocalcemia
 Clinical Features (3)Clinical Features (3)
-- GI: steatorrheaGI: steatorrhea
– MuscularMuscular
 Spasms, cramps, weaknessSpasms, cramps, weakness
– DermatologicDermatologic
 HyperpigmentationHyperpigmentation
 Coarse, brittle hairCoarse, brittle hair
 Dry, scaly skinDry, scaly skin

13. Symptoms & signs ofSymptoms & signs of
HypocalcemiaHypocalcemia
 Clinical Features (4)Clinical Features (4)
– CardiovascularCardiovascular
 Heart failure; HypotentionHeart failure; Hypotention
 VasoconstrictionVasoconstriction
 EKG abnormalitiesEKG abnormalities
– Prolonged QTProlonged QT
– SkeletalSkeletal
 OsteodystrophyOsteodystrophy
 RicketsRickets
 OsteomalaciaOsteomalacia

15. SCa < 8.5 mg/dl
SPi < 3.5 mg/dl SPi > 3.5 mg/dl
FECa
Renal loss
25(OH)D↓
VD deficiency
25(OH)D: N/1,25(OH)2D↓
VD dependent rickets: Type I
25(OH)D: N/1,25(OH)2D↑
VD dependent rickets: Type II
High
Low
GFR
PTH
Mg
Low
Low N/↑
Pseudo-hypo-
parathyroidism
Low
N
Primary/Secondary
hypoparathyroidism
Mg related
hypoparathyroidims
CRF

16. FE of electolyteFE of electolyte
FE of K >6.5%→ renal K wasting in hypoK
FE of Pi >5.0% → renal Pi wasting in hypoPi
FE of Mg>2.5%→ renal Mg wasting
in hypoMg
FE of Na> 1.0% → renal Na wasting
in hypoNa
FE of Ca>3.0% → renal Ca wasting
in hypoCa

17. Hypocalcemia: causesHypocalcemia: causes
Loss of circulating free calcium:
extravascular deposition: hyperphosphatemia; renal
failure; acute pancreatitis; osteoblastic metastasis;
hyngry bones syndrome
intravascular binding: citrate, lactate, foscarnet,
EDTA, acute respiratory alkalosis(↑Ca-albumin)
Hypoparathyroidism: S/P
PTX, thyroidectomy, or radical neck surgery
pseudohypoparathyroidism; idiopathic
Hypomagnesemia; severe hypermagnesemia
Vitamin D deficiency

19. Hungry bones syndromeHungry bones syndrome
 Severe form:
Profound hypocalcemia+↓Mg+↓Pi :
S/P PTX for severe osteodystrophy
 Mild form:
S/P thyrotoxicosis
accelerated bone formation in leukemia
osteoblastic metastasis
early healing of rickets or osteomalacia
 Calcitriol: 2 ～ 3μg/D(initial dose) with rapid
reduction after normocalcemia

21. Hypocalcemia in acuteHypocalcemia in acute
pancreatitispancreatitis
Extravascular deposition
Glucagon-stimulated calcitonin release
Inadequate PTH secretion

23. HypoparathyroidismHypoparathyroidism
S/P OP: permanent or intermittent
Hypomagnesemia(SMg<1mg/dl) in
malabsorption or chronic alcoholism
Severe hypermagnesemia in toxemia of
pregnancy( SMg> 6mg/dl)
Pseudo type1: Ia(AD, G-protein) Ib(↓receptor)
Pseudo type II: ↓cAMP-dependent PK

25. Vitamin D deficiencyVitamin D deficiency
Reduced VD intake or production:
bedridden state(no sun exposure)
steatorrhea or malabsorption
 Reduced availability of calcifediol(hepatic):
severe liver disease
use of Dilantin/phenobarbital
nephrotic syndrome(↓VD binding protein)
 Reduced production of calcitriol(renal):
chronic renal failure
VD-dependent ricket

27. Hypocalcemia in sepsisHypocalcemia in sepsis
Inadequate PTH or end-organ resistance
Inadequate VD
Hypomagnesemia
Glucagon-induced calcitonin release

29. Principles of treatmentPrinciples of treatment
 Symptomatic hypocalcemia – emergency
10 ml of 10% calcium gluconate IV over 10
minutes.
 Iv calcium should not be given with bicarbonate
or phosphate containing solution
 Serial calcium measurements
 Correction of co-existing alkalosis
Calcium suppy in long term

30. IV calcium supplyIV calcium supply
Symptomatic hypocalcemia (Sca<5.6mg/dl) :
heart failure, hypotention, bradycardia
convulsions, tetany,
paresthesias
 1 ～ 2 ampules(90mg/A), 10% Ca gluconate in 5
～ 10ml, 5% dextrose, IVF for 5 ～ 10minutes
10 ampules, Ca gluconate in 1L, 5%
dextrose, IVF: 50ml/Hr ( 45mg,calcium/Hr)
Calcium dose: 15mg/Kg IVF for 6 hr
Calcium space: 50 ～ 75%(?)

31. Adjuvant therapyAdjuvant therapy
Magnesium supply:
Hypocalcemia+Normal renal function+Normal
DTR
10% MgSo4, 2G, IVF for 10 minutes
10% MgSo4, 1G/100cc,fluid/Hr
Oral calcium and calcitriol( 0.5 ～ 1.0μg/D)
should initiated early

32. PO calcium supplyPO calcium supply
Calcium: 2 ～ 4G/D
Vitamin D indicated if insufficient response

33. PO Calcium preparationPO Calcium preparation
mg/Tb Ca,mg/Tb
CaCO3 500 200( 40% )
Ca gluconate 1000 90( 8% )
Ca lactate 300 60( 12% )

34. 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, Calcium, Magnesium3. Potassium, Calcium, Magnesium
 4. Sodium and Chloride4. Sodium and Chloride
– Consider impact of interventions overallConsider impact of interventions overall

36. Calcium handling in kidneyCalcium handling in kidney
 PCT: 60 ～ 65% of filtrate by para-cellular path
 THAL: 20% of filtrate by para-cellular path
paracellin-1 for Mg&Ca reabsortion
Simon et al, Science 1999
 DN: 10 ～ 15% by trans-cellular pathway
ECaC1, apical: VD ↑; lower pH ↓
Calbindin-D 28k: VD ↑;
estrogen↑; CsA↓
NCX1,basolateral: 70%
PMCA1b,basolateral: 30%
 Cl channel: PTH, Thiazide

38. TRPV5 cell surface abundanceTRPV5 cell surface abundance
Factors Cell surface abundance Proposed mode of action
Klotho + Modification channel glycosylation
Tissue kallikrein + PKC mediated channel phosphorylation
Acid pH - Dynamic plasma membrane trafficking
Ca - Channel recycling
Mg ND NA
PIP2 ND NA
WNK4 + ND (familial hyperkalemic
HTN/hypercalciuria)
ND: not determined; NA: not applicable
+, increase; -, decrease; =, no effect
WNK, With-No-Lysine(K): serine/threonine protein kinases

39. TRPV5 single channel activityTRPV5 single channel activity
Factors Single channel activity Proposed mode of action
Klotho ND NA
Tissue kallikrein ND NA
Acid pH - Proton binding to channel pH sensors
Ca - Feedback inhibition via channel C tail
Mg - Conformational change channel via
Mg binding
PIP2 + Stabilization channel open conformation
WNK4 =
ND: not determined; NA: not applicable
Kloth: anti-aging hormone

40. Modes of TRPV5 regulationModes of TRPV5 regulation

41. ECaC1 homologuesECaC1 homologues
Muller et al, NDT 2001Muller et al, NDT 2001
Sequence
similarities
tissue
distribution
Chromosome
7q35
hECaC1 80% Kidney>GI Evolution
gene
duplication
hCaT1 80% GI>kidney hECaC2

42. TRP V 5 knockout mice modelTRP V 5 knockout mice model
 Transient receptor potential channels (TRP): Gate-keeper
proteins
 TRP V5 in kidney: ECaC 1
 TRP V6
 Hypercalciuria
 Diuresis: CaSR, apical in principal cells + Ca in lumen ﹡
→AQP2
 Acid urine: CaSR, apical in intercalated cells + Ca in
lumen → H+APTase
 Hyperphosphaturia
Rene Bindels: Radboud University Nijmegen Medical Center,
Netherlands

44. Hypercalciuric stone disease: XLHypercalciuric stone disease: XL
O Devuyst and Y Prison: KI 2008(Belgium)O Devuyst and Y Prison: KI 2008(Belgium)
Dent’s disease:
CLCN5/CLC-5/ Cl/H exchanger
PT/TAL/IC α
Renal:
Trafficking defect: endocytosis
PT dysfunction: Fanconi syndrome
Nephrocalcinosis, stones
Impaired urine acidification
Renal failure
Extra-renal:
Rickets
Lowe’s disease
OCRL/OCRL1/
Phosphatidylinositol 4,5-
biphosphate 5-phosphatase
PT
Renal:
PT dysfunction: Fanconi syndrome
Proximal RTA
Nephrocalcinosis, stones
Extra-renal:
Mental retardation, growth delay
Cataract, rickets, cryptorchidism
Neuromuscular/behavior
abnormality

45. Hypercalciuric stone disease: ADHypercalciuric stone disease: AD
O Devuyst and Y Prison: KI 2008(Belgium)O Devuyst and Y Prison: KI 2008(Belgium)
AD Hypocalcemia
( Bartter syndrome V)
CASR/CaSR/ calcium sensing
receptor
PT/TAL/DCT/CD
Renal: gain-of-function
Low serum PTH
Hypocalcemia, Hypercalciuria
Nephrocalcinosis, stones
Salt-losing nephropathy;
Hypokalemia (CaSR→ ROMK↓)
Extra-renal: basal ganglia
calcifications, seizures
Distal RTA (RTA I)
SLC4A1/ AE1/ Cl/HCO3
exchanger
ICα
Renal:
Impaired anion exchange in IC α
Metabolic acidosis
Hypercalciuria
Nephrocalcinosis, stones
Extra-renal:
Osteomalacia, rickets
Growth retardation

46. Hypercalciuric stone disease; ARHypercalciuric stone disease; AR
O Devuyst and Y Prison: KI 2008(Belgium)O Devuyst and Y Prison: KI 2008(Belgium)
 Ante-natal Bartter’s syndrome I: NKCC2/ Na-K-2Cl
cotransporter 2
Hyperprostaglandin E syndrome
 Ante-nasal Bartter’s syndrome II: ROML/ K channel
Hyperpostagladin E syndrome
2
 Bartter’s syndrome III: CLC-Kb/ Cl channel
 Familial hypomagnesemia with hypercalciuria and
nephrocalcinosis: FHHNC
 Distal RTA with progressive nerve deafness: ATP6V1B1/
B1 subunits of proton pump
 Distal RTA with preserved hearing/late onset hearing loss:
ATP6V0A4 / A4 subunits of proton pump

47. FHHNCFHHNC
 CLND 16/ Claudin-16/ paracellin-1 tight junction
protein
 TAL, DCT
 Renal:
Impaired paracellular transport of Ca/Mg:
calcium and magnesium wasting
Nephrocalcinosis, stones
Renal failure
 Extra-renal:
Convulsions, tetany, chondrocalcinosis,
neuro-muscluar manifestations

48. Function of CIC 5: Cl/H exchangerFunction of CIC 5: Cl/H exchanger
PT cell
Coated
vesicle
Recycling
endosome
LMW
H+ Cl/H
CLLate endosome
Lysosome

49. Functional loss of ClC-5Functional loss of ClC-5
Trafficking defect in PT cells
Generalized PT cell dysfunction-Renal
Fanconi syndrome
LMW proteinuria: DBP-25(OH)D3; PTH
Internalization of NaPi-IIa: phosphaturia
↑1 α hydroxylase: ↑1,25(OH)2D3
Hypercalciuria, nephrocalcinosis, stones