renal tubular acidosis - ipna onlineipna-online.org/media/junior classes/2014 - 1st ipna...

Renal Tubular Acidosis

Rosa Vargas-Poussou

Genetics Department

European Georges Pompidou Hospital - Paris

Protein metabolism

1 mmol/Kg/d Adult

1 – 3 mmol/kg/d Children

HCO3- + H+ H2CO3 CO2 + H2O

CO2

Cellular

respiration

Acid-base homeostasis

pH 7,38 - 7,42.

RVP – Porto - 2014

Reabsorption of 10 – 15 % of bicarbonate Ammonia recycling

Proton secretion Ammonia secretion

Kidney and acid-base status

Reabsorption of 80% of filtered bicarbonate Generation of ammonia

NH3

NAE = NH4+ + TA – HCO3

-

Net Acid Excretion (NAE)

NH4

H2PO4

H+

Urinary pH


Proton and ammonia secretion

Renal adaptation to acidosis

Bicarbonate reabsorption and ammonia generation

NH3

Net Acid Excretion = NH4+ + TA – HCO3

-

Urinary pH < 5.5


Unmeasured

anions

Cl-

HCO3-

Na + K - Cl > 0

Basal conditions

Urinary anion Gap

Ca++, Mg++

NH4+

K+

Na+

Unmeasured

cations

Na + K - Cl < 0

Normal renal response

Ca++, Mg++

NH4+

K+

Na+

> 75 mmol/d

Cl-

Unmeasured

anions

Na + K - Cl > 0

Ca++, Mg++

NH4+

K+

Na+ Cl-

HCO3-

Unmeasured

anions

Abnormal renal response

Net Acid Excretion = NH4+ + TA – HCO3

-

In Acidosis


Proton secretion

Renal Tubular Acidosis (RTA)

Bicarbonate reabsorption NH3


RTA – Common characteristics

Biological

• Hyperchloremic acidosis

normal anion gap

• Normal renal function

• Hypokalemia

Clinical

• Failure to thrive

• Polyuria

• Vomiting

• Dehydration

Calcium phosphate release

Rickets

Osteoporosis


Proximal Tubule

Reabsorption of :

Na+ 60%

Ca+2 60%

HCO3- 80%

Phosphate 80%

Na+

Na+

K+ Na+

Glucose

Phosphate

Amino acids

Na+

3HCO3-

H+ HCO3-

H2O CO2

CO2 H2O

H+ HCO3-

CAII CAIV H+

Glutamine

Glutamate

cetoglutarate

Glucose

NH4+

NH3

Na+

NH4+

NH3

NH4+

HCO3-

H+

NBCE1


-

H2CO 3

Ur pH

NHE3

B [HCO3-]

Excr. HCO3-

Filt. HCO3-

Reab. HCO3-

Excre

ted

HC

03-

22 mmol/L

H2CO3

> 5.5 if plasma HCO3-

is above the threshold

< 5.5 if plasma HCO3-

Is below the threshold

FE HCO3- =

U HCO3- /P HCO3

-

U Creat /P Creat

>15 %

x100


Proximal RTA - Causes

Reabsorption of :

Na+ 60%

Ca+2 60%

HCO3- 80%

Phosphate 80%

LMW proteins

HEREDITARY

Fanconi syndrome:

- Cystinosis

- Tyrosinemia, fructose

intolerance, Wilson

disease

- Dent/Lowe

Isolated autosomal

recessive pRTA

Dominant pRTA

Na+

Na+

K+ Na+

Glucose

Phosphate

Amino acids

Na+

3HCO3-

H+ HCO3-

H2O CO2

CO2 H2O

H+ HCO3-

H+

Glutamine

Glutamate

cetoglutarate

Glucose

NH4+

NH3

Na+

NH4+

NH3

NH4+

HCO3-

H+

CAII CAIV

NBCE1

H2CO 3

SECONDARY

- Autoimmune disease

- Drug toxicity (AC

inhibitors, anticancer,

antiretrovirals,

anticonvulsants, heavy

metals)

H2CO3


Isolated pRTA

Na+

Na+

K+ Na+

Glucose

Phosphate

Amino acids

Na+

3HCO3-

H+ HCO3-

H2O CO2

CO2 H2O

H+ HCO3-

H+

Glutamine

Glutamate

cetoglutarate

Glucose

NH4+

NH3

Na+

NH4+

NH3

NH4+

HCO3-

H+

Autosomal recessive

Cotransporter

Na+ /HCO3- (NBCE1)

Gene SLC4A4; 4q21

(Igarashi et al., 1999)

CAII CAIV

NBCE1

H2CO 3

Ocular abnormalities:

band kerathopathy,

cataracts, glaucoma.

Neurological abnormalities:

MR, basal ganglia

calcifications, migraine

headaches

Extrarenal manifestations

Others:

Enamel defects

Amylase and

lipase

H2CO3


Principal cell

Intercalated cells

Collecting duct

H2O H2O

Na +

K+ Aldosterone

K+

MR

ENaC

Cl-

K+

H+

CO2 H2O

HCO3 H+ HCO3

-

Na +

CAII

H+

(-) (+)

H+

K+ Na +

K+ Na +

Cl-

HCO3-

Cl- HCO3

-

Cl-

Cl-

HCO3-

Na +

B

A

Pendrin

NDCBE

NH3

NH4+

Urinary pH > 5.5

UAG : Na + K - Cl > 0


-

H2CO3

AE1

NH3 RhCG


Distal RTA

H2O H2O

Na +

K+ Aldosterone

K+

MR

ENaC

Cl-

K+

H+

CO2 H2O

HCO3 H+ HCO3

-

Na +

CAII

H+

(-) (+)

H+

K+ Na +

K+ Na +

Cl-

HCO3-

Cl- HCO3

-

Cl-

Cl-

HCO3-

Na +

Pendrin

NDCBE

NH3

NH4+

H2CO3

AE1

SECONDARY

- Autoimmune disease

- Drug toxicity

(amphotericin, vanadium)

Autosomal dominant

SLC4A1 (AE1)

HEREDITARY

Autosomal recessive

ATP6V1B1 (B1 subunit)

ATP6V0A4 (a4 subunit)

SLC4A1 (AE1)

NH3 RhCG


Cl-

K+

H+

CO2 H2O

HCO3

H+

HCO3-

ACII

H+

NH3 NH3

NH4+

K+

Cl-

K+ Na+

HCO3-

Cl-

Cl - Barttin

NH4+

NH3 H+

AE1

KCC4

CLC-Kb

SLC26A7 RhCG

Vacuolar H+ ATPase

H+ ATPase

B1 B1

B1

a4

ATP ADP+iP

H+

H+


B1 Subunit – ATP6V1B1 gene; 2p13. Protein: 513 amino acids

a4 Subunit – ATP6V0A4 gene; 7q33-34. Protein: 840 amino acids

*

*

*

*

Karet FE, 1999.

Mutations affect function and/or pump assembly

Smith AN, 2000


200 285

488

518

663

701

773

850

G

S

S

V A V

R

Alper SL, Exp Physiol, 2006

SLC4A1 gene - AE1exchanger

Band 3 kAE1

Dominant dRTA

Heterozygous

Recessive dRTA

With hematologic abnormalities

Without hematologic abnormalities

Blood group antigens

Spherocytosis

Ovalocytosis

Dominant dRTA

Recessive dRTA


dRTA – Characteristics

Biological

• Hyperchloremic acidosis

normal anion gap

• Positive UAG

• Ur pH > 5.5 in acidosis

• Normal renal function

• Hypokalemia

• Hypercalciuria

• Hypocitraturia

Clinical • Recessive inheritance

– Early manifestations

• Failure to thrive

• Polyuria

• Dehydration

• Vomiting, constipation

– If diagnosis after 1 year : failure to thrive, fortuitous discovery of nephrocalcinosis, rickets

– Sensorineural hearing loss • Enlarged vestibular aqueduct (EVA)

• Vertigo

– Haemolytic anaemia

• Dominant inheritance – Adolescent or adult

– Lithiasis, osteoporosis


Acidosis

Calcium phosphate release

Ca reabsorption

Citrate reabsorption

Hypercalciuria

Hypocitraturia

Alkaline pH

Nephrocalcinosis

Stones Salt wasting Polyuria

Secondary

hyperaldosteronism

Hypokalemia

K wasting

Physiopathology


Gueutin V et al, JCI, October 2013

Na and K wasting in dRTA

Mouse model of dRTA : invalidation of B1 subunit


dRTA and proximal tubular dysfunction

• Igarashi T, Pediatr Nephrol 1990 :

reversible LMW proteinuria

• Watanabe, Pediatr Nephrol, 2005 :

LMW proteinuria, aminoaciduria,

and phosphate and uric acid

wasting.

• Several similar reports in

patients with mutations in

ATP6V1B1 or ATP6V0A4

gene

• Hypokalaemia

• Acidosis

EMBO Molecular Medicine

Hennings JC et al. EMBO Mol Med. 2012 Volume 4, Issue 10,

a4 KO mice


http://onlinelibrary.wiley.com/doi/10.1002/emmm.v4.10/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201527/full

Age 1 month 5 months 14 months Clinical manifestations Failure to thrive

Urinary tract infection

Failure to thrive

Weight (kg) 3.390 6.055 9.270 Height (cm) 64.7 75

Treatment Sodium bicarbonate 2 g/day 2.25g/day Potassium citrate 2 g/day 1g/day 2.25g/day

Plasma/Blood pH 7.04 7.34 Sodium (133-146 mmol/L) 137 137 137

Potassium (3.5-5 mmol/L) 3.6 3.5 4 Chloride (90-117 mmol/L) 118 110 106 CO2t (18-25 mmol/L) 10 17 24 Calcium (2.20 -2.70 mmol/ L) 2.77 2.34 2.43

Phosphate 2.36 1.73 Creatinine (µmol/L) 31 19 Renin (2w-3m 11-72 pg/ml) (4m-1y 11-101 pg/ml)

82

274

Aldosterone (pmol/L) 1020 4590 Urines Citrate/creat (0.3-0.7 mmol/mmol) 0.12 Ca/creat (mmol/mmoL) 3.09 1.3 1.33

b2microglobuline/creat (0.006-0.08 mg/mmol) 16.82 1.35 <0.19 mg/L

Aminoaciduria Global moderate Glycosuria Negative <0.1 mmol/L RVP – Porto - 2014

Distal renal tubular acidosis Molecular genetics diagnosis

A. Recessive inheritance

ATP6V0A4 - 7q33-34 (44%)

ATP6V1B1 - 2p13 (56%)

Genetic

confirmation

n=155 families

81%

19% A. Dominant inheritance

SLC4A1 - 17q22


Sensorineural Hearing loss


Na+

Na+

K+ Na+

Glucose

Phosphate

Amino acids

Na+

3HCO3-

Proximal tubule

Principal cell

H2O

H2O

Na +

K+ Aldostérone

K+

RM

ENaC

Intercalated cells

H+ HCO3-

H2O CO2

CO2 H2O

H+ HCO3-

Cl-

K+

H+

CO2 H2O

HCO3 H+ HCO3

-

Collecting duct

Na +

CAII CAIV

CAII

H+

H+

Glutamine

Glutamate

cetoglutarate

Glucose

NH4+

NH3

Na+

NH4+

NH3

NH4+

HCO3-

H+

(-) (+)

H+

K+

Na +

K+

Na + Cl-

HCO3-

Cl- HCO3

-

Cl-

Cl-

HCO3-

Na +

B

A

H2CO 3

Combined proximal and distal RTA

Carbonic Anhydrase II Deficiency syndrome Osteopetrosis with RTA and brain calcification

Autosomal recessive disease

Increased bone density

Intracerebral calcification, mental retardation

Growth failure

Facial dysmorphism

Conductive deafness

NH3


Treatment

Proximal

• 10 - 20 mEq/kg per day

Distal

• 4-8 mEq/kg per day

Aims : • Correction of the biochemical abnormalities

• Promote growth

• Prevention of kidney stones and skeletal abnormalities

Sodium and potassium bicarbonate

Potassium citrate


Conclusions 1

Gene implicated in human pRTA

SLC4A4

Genes implicated in human dRTA

SLC4A1 (Dominant and Recessive)

ATP6V1B1 and ATP6V0A4 (Recessive)

Gene implicated in mixed RT

ACII (Osteopetrosis with RTA)


Conclusions 2

Recessive dRTA represents 81 % of cases

Similar frequency of a4 and B1 mutation in recessive dRTA

Phenotypic variability of hearing loss

More severe phenotype (age at diagnosis and metabolic

acidosis) in patients with a4 mutations


Physicians

FrenchTubulopathies Network

European countries

Patients and their families

Thanks


renal tubular acidosis - ipna onlineipna-online.org/media/junior classes/2014 - 1st ipna...

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