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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