overview tubular and ca disorders rickets ... · rickets calciumdisorderscalcium disorders ......
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Tubular and Ca Tubular and Ca DisordersDisordersDr. Joshua KausmanDr. Joshua Kausman
Paediatric nephrologistPaediatric nephrologist
OVERVIEWOVERVIEWTubular disordersTubular disordersCorrelate with tubular physiologyCorrelate with tubular physiologyRicketsRicketsCalcium disordersCalcium disordersCalcium disordersCalcium disorders
PCT:PCT:Fanconi S (cystinosis)Fanconi S (cystinosis)XLH, pRTAXLH, pRTA
LOHLOHBartter SBartter SMg disorders (FHHNC)Mg disorders (FHHNC)
DCTDCTGitelman SGitelman SFHHFHH
CDCDDI, dRTADI, dRTAPseudohypoaldosternismPseudohypoaldosternism Thakker, April1999
NEJM 340:1177-87
Urinary Urinary Concentration/DilutionConcentration/Dilution
Urine tonicity when entering CD: ~50-100 mosm/kg
Maximum final urine tonicity: ~1000 mosm/kg
“Diuretopathies”S i l t Diuretopathies
Frusemide = BARTTER’S
Thiazide = GITELMAN’S
Spironolactone = Pseudohypoaldosteronism I
Amiloride ≠ LIDDLE
Spironolactone
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BARTTER AND GITELMAN SYNDROMES
•Incidence 1:50,000-1:100,000.
•Two of the ‘better-known’, genetically defined, tubular disorders.
•Autosomal recessive inheritance.
Transport in TAL of Transport in TAL of HenleHenle
3 Na+
2 K +
Na-K-ATPase
bloodlumen
+_
K+
Na+
K+
Na+
3 Na+
2 K +
Na-K-ATPase
bloodlumen
+_K+
+__ +K+
Na+
K+
Na+
3 Na+
2 K +
Na-K-ATPase
bloodlumen
+_K+
+__
+
Na+
K+
2 Cl-
NKCC2
K+
Na+
K+
Na+
+
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3 Na+
2 K +
Na-K-ATPase
bloodlumen
_K+
__ +++
Na+
K+
2 Cl-
NKCC2
++ K+
Na+
K+
Na+
+ROMK
+++
3 Na+
2 K +
Na-K-ATPase
bloodlumen
_K+
_ ++
Na+
K+
2 Cl-
NKCC2
++ K+
Na+
K+
Na+ROMK
+++
Cl-CLCKNB
3 Na+
2 K +
Na-K-ATPase
bloodlumen
_K+
_ ++
Na+
K+
2 Cl-
NKCC2
++ K+
Na+
K+
Na+ROMK
+++
Cl-CLCKNB
Barttin
3 Na+
2 K +
Na-K-ATPase
bloodlumen
_K+
_ ++
Na+
K+
2 Cl-
NKCC2
++ K+
Na+
K+
Na+ROMK
+++
Cl-CLCKNB
Barttin
Claudin16 (Paracellin)
Mg++
Ca++
Pathophysiology of Bartter Syndrome = Chronic Frusemide:1. Massive salt losses from LOH
2. Wash out medullary concentration gradient.
3. Distal tubule presented with NaCl+++ & water in the progressively salt and fluid depleted patient who can’t concentrate his urine.
4 Stimulation of Renin Angiotensin Aldosterone4. Stimulation of Renin- Angiotensin- Aldosterone.
hyperplasia of JG apparatus and PG secretion.
5. Increased Na reabsorption & increased K/H- Cl excretion.
6. Natriuresis and hypercalciuria. (N Mg in ~2/3 of cases)
7. Salt load causes paradoxical increase in volume depletion and excretion of KCl and HCl.
Findings include:- hypochloremic metabolic alkalosis- hypokalaemia- poly- and isosthenuria- hypercalciuria- elevated urinary prostaglandins (Hyper PGE-elevated urinary prostaglandins (Hyper PGEsyndrome)
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THE CLASSIC SYNDROME:
“Antenatal variant Bartter Syndrome/ Hyperprostaglandin E Syndrome”.
IU polyuria Polyhydramnios -> prematurity
Post-natal: salt-wasting/ hypoK alkalosis, hypercalciuria, nephrocalcinosis.
Hypokalaemia and alkalosis
FTT, fever and vomiting.
Normotensive hyperreninaemic hyperaldosteronism.
Hyperplasia of Juxtaglomerular apparatus.
Mg often normal.
CONFUSED CLINICAL CLASSIFICATION
1.Presenting age
2.K (May have normal K and be acidotic in NN period).
3.Hypercalciuria, nephrocalcinosis
4.Deafness
5.Renal failure
Variability due to nature of tubular defect
Cl channel vs ROMK vs NaKCC2 vs CaSR
BUT still no strict correlation b/w genotype & phenotype.
GENETIC CLASSIFICATION
*BS type 1: NKCC2 defect- 15q15-21. (SLC12A1).
*BS type 2: ROMK defect- 11q24-25. (KCNJ1).
(transient hyperkalaemia and acidosis in the neonate.)
*BS type 3: ClC-Kb defect- 1p36. (CLCKNB).
(milder, no nephrocalcinosis, diverse phenotypes possible)
*BS type 4: BARTTIN defect- 1p31. (BSND).
*BS type 5: Calcium-sensing Receptor Mutation.
*Gitelman synd.: NCCT defect- 16q13. (SLC12A3).
Subunit of the Cl channels, CLC-Ka & CLCKb.
Located on basolat memb of LOH & K-secreting cells of stria vascularis of inner ear.
Antenatal BS presentation, but with
BARTTIN DEFECT (BSND gene), “BS type 4”
less hypercalciuria & no n’calcinosis. N Mg.
Estevez et al Nov 2001, Nature
Calcium-sensing Receptor Mutation
Potent gain of function CaSR mutation ( L125P) leading to autosomal dominant hypocalcaemia.
Case described of this associated with Bartter-like syndrome (Vargas-Poussou et al, JASN 2002).
Thakker 1999 NEJM p1177
Classic Bartters Pseudohypoaldosteronism
Low BW + +
Acid base Alkalosis Acidosis
Polyhydramnios + +
P l i FTT ++ ++Polyuria, FTT ++ ++
Serum K low (except ROMK) high
Salt craving sometimes yes
PRA high high
P Aldosterone high very high
U Calcium high N
PRA on salt higher lower
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GITELMAN SYNDROME
NCCT DEFECT (Gitelman syndrome), 16q13.
Thiazide-sensitive sodium-chloride cotransporter (SLC12A3).
Pathophysiology of Gitelman Syndrome = Chronic Thiazide:
1. Salt losses from DCT.
2. Distal tubule excretes the 7% presented to it leading to mild fluid depletion.
3. Stimulation of Renin- Angiotensin- Aldosterone. (N PGE) g ( )BUT, Aldo normal due to hypokalaemic suppression.
4. NaCl and fluid retention/ K and H excretion.
5. Incr apical Ca reabsorption and Mg loss (not well defined).
Gitelman syndrome
Present in childhood or adolescence.
Less severe clinical presentation, but muscle cramps/ tetany common.
Salt-craving, nocturia & paraesthesia.
Normal BP.
Usually normal growth.Usually normal growth.
Low serum Mg, K. Alkalosis. Low urine calcium.
No correlation between biochemistry and symptoms.
Elevated PRA, normal Aldosterone.
GENOTYPE PHENOTYPE CORRELATION????
Konrad et al, JASN, 2003.
Disorder Locus Protein Onset Se K Se Mg U. Ca N'calcinosisAntenatal BS 15q15 NKCC2 Neonatal L/VL N VH YAntenatal BS 11q24 ROMK Neonatal Var. N VH YClassic BS 1p36 CLCKb Infanc VL N/L Var Rare
L=low, VL= very low, N= normal, H= high, VH= very high
Var= variable
Classic BS 1p36 CLC-Kb Infancy VL N/L Var. RareAntenatal BS/ deaf 1p31 Barttin Neonatal VL N N/H NGitelman S 16q NCCT Variable VL L L N
MANAGEMENT OF BARTTER SYNDROME
KCl supplementation.
NSAID Rx- Indomethacin (?COX-2).
Nutrition and fluids- Tube
Care during illness/ surgery
GH not indicated as expectation is for catch-up growth into normal range from mid-adolescence.
MANAGEMENT OF GITELMAN SYNDROME
Normal diet.
KCl supplementation +/- Mg as necessary.
Rarely, Spironolactone.
DENT’S DISEASE (1964)
Xp11.22 = ClC-5: aka’s…
1. X-linked recessive nephrolithiasis with renal failure (N. America)
2 X li k d i h h h t i i k t ith2. X-linked recessive hypophosphataemic rickets with hypercalciuria (France, Italy)
3. Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (Japan)
Evidence of a PCT defect (Fanconi-like).
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Dent’s Disease Rx:
Hypercalciuria: Low NaCl diet
Thiazide
Bone Disease: Oral Phosphate
Vitamin D (but watch U. Ca)
NEPHROGENIC DINEPHROGENIC DI
CongenitalCongenital-- Rare. 30 families in HollandRare. 30 families in Holland-- 15 15 million population.million population.Secondary/ acquired. Commoner.Secondary/ acquired. Commoner.
CRFCRFCRFCRFDrugsDrugs-- Li, Li, TetracyclinesTetracyclinesMetabolicMetabolic-- High Ca, low KHigh Ca, low KObstruction/ dysplasia/ chronic PNObstruction/ dysplasia/ chronic PN
Renal insensitivity to ADH/ VP.Renal insensitivity to ADH/ VP.
Countercurrent MechanismCountercurrent MechanismEffect of ADHEffect of ADH
Congenital NDICongenital NDI
Present from birth onwards, breast feeding, may Present from birth onwards, breast feeding, may delay presentation (lower solute).delay presentation (lower solute).PC: dehydration, seizures (> with Rx), PC: dehydration, seizures (> with Rx), constipation fever En resis/constipation fever En resis/noct rianoct ria laterlaterconstipation, fever. Enuresis/constipation, fever. Enuresis/nocturianocturia later.later.Usu have mild FTTUsu have mild FTT-- ? LOA due to fluid ? LOA due to fluid volumes required.volumes required.Cognitive impairment if Cognitive impairment if unRx’dunRx’d..DxDx-- PolyuriaPolyuria, ↑Na, U. , ↑Na, U. osmosm <200 (N>800).<200 (N>800).
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Congenital NDICongenital NDI
Genetics.Genetics.90% XLR (Xq28). V2 receptor defect.90% XLR (Xq28). V2 receptor defect.10% AR>>AD. AQP2 channel defect.10% AR>>AD. AQP2 channel defect.
Diagnosis of PolyuriaDiagnosis of PolyuriaCause Onset P Na Max. Uosm
with dehydration
Uosm after ADH
%↑ Uosm after ADH
Central DI Usu Sudden
Usu >143
< 300 > 300 > 50
Partial Usu Usu < 600 > 300 9 – 50central DI Sudden >143 Nephrogenic DI
Usu Gradual
Usu >143
< 300 < 300 9– 50
Primary polydipsia
Usu Gradual
Usu <137
500–800 500–800
< 9
Normal - 135–45 > 800 > 800 < 9
MJA 2004 p354
Calcium homeostasisCalcium homeostasis Calcium homeostasisCalcium homeostasis
Renal tubular Ca reabsorption:Renal tubular Ca reabsorption:PCTPCT--65%, TALH65%, TALH--20%, DCT20%, DCT--10%, CD10%, CD--1.5%1.5%
Ca reciprocal relationship with:Ca reciprocal relationship with:Ph hPh hPhosphatePhosphatepHpH
Symptoms common with ↑ or ↓ Ca levelsSymptoms common with ↑ or ↓ Ca levels
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1,251,25--Vit D novel actionsVit D novel actions
1. Regulation of hormone secretion1. Regulation of hormone secretion
2. Modulation of immune response 2. Modulation of immune response
3 Inhibition of cell division3 Inhibition of cell division3. Inhibition of cell division3. Inhibition of cell division
4. Induction of cell differentiation4. Induction of cell differentiation
Phosphate homeostasisPhosphate homeostasis
Level decreases with ageLevel decreases with age8080--97% reabsorbed by 97% reabsorbed by renal tubule (PCTrenal tubule (PCT--80%)80%)TRPTRP T PT P/GFR/GFRTRP, TRP, TmPTmP/GFR/GFRDerangements rarely Derangements rarely cause clinical symptomscause clinical symptoms
N = 1.15-2.44 mmol/l
PTH homeostasisPTH homeostasis
PulsatilePulsatileRapid response to Rapid response to iCaiCa, long, long--living cellsliving cellsImportant signalling controlsImportant signalling controls
CaSRCaSRVitVit DDCaCaPhosPhosOthersOthers-- Mg!Mg!
Konrad, Weber JASN 14: 249-260, 2003
Konrad, Weber JASN 14: 249-260, 2003
Singh 2003 Arch Dis Child
Others:
Transient NN hypoparathyroidism!:
Prem
Asphyxia
IODM
Hyperphosphataemia
Decreased bone mobilisation
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Ca Sensing receptor disorders
CASR located in parathyroid gland and TAL/DCT nephron segments (basolateral membrane).
Also in medullary CD (?mediates hyperCa inhibition of VP).
Mutations alter Ca set-point for stopping PTH secretion:
(i ti t i ti t l )(inactivate= raise, activate = lower)
CaSRCaSR
1.1. LOSS OF FUNCTION:LOSS OF FUNCTION:1.1. Familial Hypocalciuric HypercalcaemiaFamilial Hypocalciuric Hypercalcaemia2.2. Severe NN HypoparathyroidismSevere NN Hypoparathyroidism
2.2. GAIN OF FUNCTIONGAIN OF FUNCTIONAA1.1. AD Hypercalciuric hypocalcaemia AD Hypercalciuric hypocalcaemia
2.2. Bartter S Type 5Bartter S Type 53.3. Idiopathic HypercalciuriaIdiopathic Hypercalciuria
3.3. Ab to EC DOMAIN CaSRAb to EC DOMAIN CaSR1.1. Autoimmune Hypocalciuric HypercalcaemiaAutoimmune Hypocalciuric Hypercalcaemia2.2. Autoimmune hypoparathyroidismAutoimmune hypoparathyroidism
HypocalcaemiaHypocalcaemia--Clinical FeaturesClinical Features
BoneBone--muscle: Pain, cramps, muscle: Pain, cramps, laryngospasmlaryngospasm, , tetanytetanyCNSCNS p r th ip r th i S/ZS/Z rprp p d l p mp d l p mCNS: CNS: paraesthesiaeparaesthesiae, S/Z, , S/Z, carpocarpo--pedal spasm, pedal spasm, IC IC Ca’nCa’n, irritability, depression, psychosis, irritability, depression, psychosisCardiac: Cardiac: ↑↑QQ--T, arrhythmiasT, arrhythmiasOther: cataracts, dentalOther: cataracts, dental
RicketsRickets
DefinitionDefinitionGrowing skeletonGrowing skeleton↓ mineralisation↓ mineralisation
L Vi i DL Vi i DLow Vitamin DLow Vitamin DCa deficiencyCa deficiencyLow PhosphateLow Phosphate
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Not all rickets is Vitamin D
Hypophosphataemia
1. Tubular P wasting:
• Generalised
• Specific defect
2. Inadequate intake
X-Linked Hypophosphataemic Rickets (XLH)
X-linked dominant disorder
Prevalence 1:20,000
G ti d f t PHEX X 22 1 (1995)Genetic defect: PHEX, Xp22.1 (1995)
PHEX: Phosphate-regulating gene with
Homologies to
Endopeptidases on the
X-chromosome
PHEX gene product(s) cleave phosphatonins
(FGF-23, MEPE, FRP4, others).
PHEX deletion →
1 Ph h t i1. Phosphaturia
2. Abnormal vitamin D metabolism
3. Abnormal bone mineralisation
Associated disorders- ADHR, TIO
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Biochemical features:
Serum P LOW
Serum Ca Normal
PTH Normal/ high → Sec HPT
ALP Normal/ high
25VitD Normal
1,25 VitD NORMAL/ SLIGHTLY LOW
Radiologically:Rickets in lower limbs esp knees and hips.Axial skeleton often dense spine.Nephrocalcinosis in up to 80%.
Importance of P in neonates
VITAMIN D USELESS IFVITAMIN D USELESS IF
LOW CALCIUMLOW CALCIUM
CALCIUM USELESS IFCALCIUM USELESS IF
LOW PHOSPHATELOW PHOSPHATE
CAUSES OF CAUSES OF HYPERCALCAEMIAHYPERCALCAEMIA
VITAMIN D AND VITAMIN D AND HYPERCALCAEMIAHYPERCALCAEMIA1. Excess VIT D intake1. Excess VIT D intake
MilkMilk--alkali S.alkali S.2 VIT D Sensitivity2 VIT D Sensitivity
Immobilisation/ bone disease Dehydration
2. VIT D Sensitivity2. VIT D Sensitivitye.g. hyperthyroidism, e.g. hyperthyroidism, hypoadrenocorticismhypoadrenocorticism
3. Increased 13. Increased 1--HydroxylationHydroxylatione.g. e.g. sarcoidsarcoid, , phosphate depletion, phosphate depletion, ? Williams syndrome? Williams syndrome
HypercalcaemiaHypercalcaemia--Clinical FeaturesClinical Features
Renal: Renal: nDInDI, stones/ , stones/ calcinosiscalcinosis, HT, HTBoneBone--muscle: Pain, muscle: Pain, myopathymyopathyGI: PUD, pancreatitis, N&V, constipationGI: PUD, pancreatitis, N&V, constipationCNS: ↓CNS: ↓conscconsc state, depression, H/Astate, depression, H/ACardiac: ↓QCardiac: ↓Q--T, T, BradycardiaBradycardia
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Evaluation hypercalcaemia in infants NN persistent hypercalcaemia
Management
1. Reduce intake- diet, Rx with vit D/ Ca2. Increase excretion:
1. FLUIDS! N. Saline 1.5-2.5 x maintenance.2. Frusemide
3. Specific therapies:1. Calcitonin2. Steroids3. Bisphosphonates4. Calcimimetics5. Parathyroidectomy6. Dialysis