Dr. Tai Mostafa Al Akawy Consultant Pediatrician at Alexandria University Children Hospital, Faculty of medicine , Egypt

1. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬

2. RENAL TUBULAR
ACIDOSIS
DrTai al akawy
Consultant pediatrician
Alexandria university children hospital

3. RENAL TUBULAR ACIDOSIS
 First described clinically in
1935
 Confirmed as a renal
tubular disorder in 1946
 Designated as RTA in
1951
 Refers to disorders
affecting the overall
ability of the renal tubules
either to secrete
hydrogen ions or to
retain bicarbonate ions
 All types produce
hyperchloremic metabolic
acidosis
with a normal anion gap.

4. INTRODUCTION
 Lungs and Kidneys are responsible for Normal acid
base balance
 Alveolar ventilation removes CO2
 Kidneys reabsorb filtered Bicarbonate and excrete
a daily quantity of Hydrogen ion equal to that
produced by the metabolism of dietary proteins.
 Hydrogen ions are excreted primarily by
enhancing the excretion of ammonium ions in the
urine

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 Normal pH 7.35-7.45
 Narrow normal range
 Compatible with life 6.8 - 8.0
___/______/___/______/___
6.8 7.35 7.45 8.0
Acid Alkaline

6. 2/4/2015 6
Metabolic acidosis
 Excessive blood acidity caused by an over-
abundance of acid in the blood or a loss of
bicarbonate from the blood

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RESPONSES TO
ACIDOSIS AND ALKALOSIS
 Buffer system: temporary solution
 Respiratory mechanism provide short time
regulation
 Renal mechanism : permanent solution

9. Renal acid-base homeostasis may be
broadly divided into 2 processes
1. Proximal tubular absorption of HCO3
-
(Proximal acidification)
2. Distal Urinary acidification
 Reabsorption of remaining HCO3
- that
escapes proximally.
 Excretion of fixed acids & Ammonia.

10. Proximal tubule physiology
Multiple factors are of primary importance in
normal bicarbonate reabsorption
 The sodium-hydrogen exchanger in the
luminal membrane(NHE3).
 The Na-K-ATPase pump
 The enzyme carbonic anhydrase II & IV
 The electrogenic sodium-bicarbonate
cotransporter(NBC-1).

11. .

12. Excretion Of H+ Ions:
 Alpha-Intercalated Cells are thought to be the
main cells involved with H+ secretion in the
Collecting Tubules.
 This is accomplished by
-H+-K+-ATPase and
-H+-ATPase with
-Cl-/HCO3
- exchanger
- Na+ - K+ ATPase.

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NH4+ Excretion :

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16. Acidosis & anion gap
 Anion gap=[Na] – [Cl + Hco3]
 < 12 = normal or absence of anion gap
as in bicarbonate loss in {diarhea ,RTA,carbonic
anhydrase inhibitor , ureterosigmoidostomy}
 >20 =increased anion gap as
in{ lactic acidosis, DKA, inborn errors of
metabolism, uremia, poisoning with
(salicylate,methanol,ethanol)}

17. OUTLINE
 Renal tubular acidosis (RTA) is applied to a
group of transport defects in the reabsorption
of bicarbonate (HCO3-), the excretion of
hydrogen ion (H+), or both.
 The RTA syndromes are characterized by a
relatively normal GFR and a metabolic
acidosis accompanied by hyperchloremia and
a normal plasma anion gap.

18. INCIDENCE
 Predominant age: All ages
 Predominant sex: Male > Female (with
regard to type II RTA )

19. TYPES
 Distal / type 1 RTA
 Proximal / type 2 RTA
 Hypoaldosteronism / type 4 RTA
 Type 3 / mixed RTA (not in use)

20. Type 1-Distal RTA
Distal RTA (dRTA) is the classical form
of RTA. Inability of the distal tubule to
acidify the urine. Due to impaired
hydrogen ion secretion, increased backleak
of secreted hydrogen ions, or impaired
sodium reabsorption
Urine pH >5.5.

21. DISTAL RTA
 Impairment of distal
acidification
 Inability to lower urine pH
maximally below 6.0 under
acid load
 Patho-mechanism is
inability to secrete H+
adequately (secretory
defect or classic distal RTA)
 Gradient defect
 Voltage dependent defect
 In children mainly a genetic
defect of the H+ pump

22. excreted
HCO3
-
Distal RTA or
RTA type 1
Acidification defect
H+
K+
Cl-

23. Distal RTA
 Loss of bicarbonate less than type 2 –
metabolic acidosis
 Absorption of chloride – hyperchloremia
 Loss of potassium – hypokalemia
 Decreased excretion of acids – high urinary
ph >5.5
 It is often associated with hypercalciuria,
hypocitraturia, nephrocalcinosis, and
osteomalacia

24.  The term incomplete distal RTA has been
proposed to describe patients with
nephrolithiasis but without metabolic acidosis.
 Hypocitraturia is the usual underlying cause.

25. Secretory defects causing Distal RTA

26. Non secretory defects causing Distal RTA
 Gradient defect: backleak of secreted H+
ions. Ex. Amphotericin B
 Voltage dependent defect: impaired distal
sodium reabsorption ex. Obstructive
uropathy, sickle cell disease, CAH, Lithium
and amiloride etc.
 This form of distal RTA is associated with
hyperkalemia (Hyperkalemic distal RTA)

27. Distal RTA
 A high urinary pH (5.5) is found in the
majority of patients with a secretory dRTA.
 Excretion of ammonium is low. This leads to a
positive urine anion gap.
 Urine PCO2 does not increase normally after a
bicarbonate load.
 Serum potassium is reduced. This is thought to
be due to decreased H+ and H-K-ATPase
activity.

28. RISK FACTORS
Genetics
Autosomal dominant or recessive. May
occur in association with other genetic
diseases (e.g., Ehlers-Danlos syndrome,
hereditary elliptocytosis, or sickle cell
nephropathy). The autosomal recessive
form is associated with sensorineural
deafness.

29. ETIOLOGY
• Genetic
• Sporadic
• Autoimmune diseases:
rheumatoid arthritis (RA), SLE
• Hematologic diseases:
Sickle cell disease, hereditary
elliptocytosis
• Medications:
Amphotericin B, lithium, K+-
sparing diuretics
• Toxins:
Toluene, glue
• Hypercalciuria, diseases
causing nephrocalcinosis
• Vitamin D intoxication
• Medullary cystic disease
• Glycogenosis type III
• Fabry disease
• Wilson disease
• Hypergammaglobulinemic
syndrome
• Obstructive uropathy
• Chronic pyelonephritis
• Chronic renal transplant
rejection
• Leprosy
• Hepatic cirrhosis
• Malnutrition

30. CLINICAL MANIFESTATIONS
 non-anion gap metabolic
acidosis
 growth failure
 nephrocalcinosis
 hypercalciuria

31. PROXIMAL RENAL TUBULAR ACIDOSIS
(type II)
 MAIN DEFECT
 Carbonic Anhydrase deficiency

32. Proximal RTA (Type 2)
 Caused by an
impairment of HCO3-
reabsorption in the
proximal tubules
 Most cases occur in
the context of
Fanconi’s syndrome
 Isolated proximal RTA
is rare.

33. Defect of the proximal tubule in
bicarbonate (HCO3) reabsorption.
Urine pH <5.5

35. 85% reabsorbed 15% reabsorbed
5% excreted
HCO3
HCO3
HCO3
HCO3
100%
Normal renal tubular function

36. 60% reabsorbed 15% reabsorbed
HCO3
HCO3
HCO3
25% HCO3
-
100%
K+
Proximal RTA or RTA type 2
Cl-
Decreased proximal tubule
efficiency

37.  Massive loss of bicarbonate – metabolic
acidosis
 Absorption of chloride - hyperchloremia
 Loss of potassium – hypokalemia
 Kidneys tries to compensate for the acidosis –
urine ph is low - < 5.5
 FEHCO3 increases(>15%)with administration
of alkali for correction of acidosis

38.  Patients with pRTA rarely develop
nephrocalcinosis or nephrolithiasis. This is
thought to be secondary to high citrate
excretion.
 In children, the hypocalcemia as well as the
HCMA will lead to growth retardation, rickets,
osteomalacia and an abnormal vitamin D
metabolism. In adults osteopenia is generally
seen.

39. Clinical manifestations -
phosphaturia, glycosuria,
aminoaciduria, uricosuria, and
tubular proteinuria. The
principal feature of Fanconi's
syndrome is bone
demineralization due to
phosphate wasting.

40. -Autosomal dominant form is rare.
-Autosomal recessive form is
associated with ophthalmologic
abnormalities and mental
retardation.
Occurs in Fanconi syndrome, which is
associated with several genetic
diseases

42.  growth failure in the 1st year of life
 polyuria
 dehydration
 anorexia
 vomiting
 constipation
 hypotonia
 Patients with primary Fanconi
syndrome will have additional
symptoms
 Those with systemic diseases will
present with additional signs and
symptoms specific to their underlying
disease

43. Mutation in CTNS gene(17p)--encodes novel
protein:cystinosin(H+ driven cystine transporter)
Defect in metabolism of cystine
Accumulation of cystine crystals in major organs
Kidney, brain ,liver,eye,others

44.  Infantile /Nephropathic cystinosis
-1st 2 years of life
-severe tubular dysfuntion
-if no t/t then ESRD till first decade
 Adoloscents
-mild
-slower progression to ESRD
 Benign adult form with no kidney
involvement

45.  Diminished pigmentation: fair and blond
 Fanconi syndrome: polyuria, polydipsia
 Growth failure
 Rickets
 Fever: dehydration and decreased sweat production
 Ocular: photophobia, retinopathy, impaired visual
acuity
 Hepatosplenomegaly, delayed sexual maturation,
hypothyroidism
 Complications: CNS abnormalities, muscle weakness,
swallowing dysfunction, pancreatic insufficiency.

46.  Diagnosis:
1.Detection of cystine crystals in cornea
2.Increased leukocyte cystine content
3.Prenatal diag by CVS,amniocentesis

47.  Early initiation of therapy is important.
 correcting the metabolic abnormalities
associated with Fanconi syndrome or chronic
renal failure.
 cysteamine,which binds to cystine and
converts it to cysteine: facilitates lysosomal
transport and decreases tissue cystine.
 cysteamine eyedrops is required
 growth hormone for growth failure

48. Mutation in OCRL1 of X chromosome(XLR)
Encodes PIBPase in golgi network
Accumulation of PIBP
1.Changes in protein trafficking
2.Defective actin cytosleleton polymerization
3.Altered cell signalling for endocytosis

49. •Hypotonia with hyporeflexia
•Severe psychomotor
retardartion
•Bilateral cong Cataract
•Strabismus
•Infantile onset Glaucoma
•cheloids
•Frontal bossing
•Deep set eyes
•Chubby cheeks
•Fair complexion
Rachitic rosary
Fanconi syndrome

50.  Diagnosis is clinical,molecular testing for
OCLR gene is available.
 Prenatal Dx: slit lamp examination of
mother(punctate white opacities)
 Treatment is symptomatic
-cataract extraction
-glaucoma control
-physical and speech therapy
-drugs to address behavioral problem

51. Type 3 RTA-Combined
proximal and distal RTA
Extremely rare autosomal recessive syndrome
with features of both type I and type II
(juvenile RTA).

52. RTA Type IV
• Deficiency of aldosterone
• Pseudohypoaldosteronism or end organ target
resistance

53. Adolsterone
Water
K+
Na
Na+
H+
Cl-
RTA IV:
Hypoaldosteronism or
pseudohypoaldosteronism
H20

54. RTA IV
• End organ target failure or low aldosterone:
– Loss of sodium – hyponatremia
– Retention potassium - hyperkalemia
• Absorption of chloride – hyperchloremia
• Decreased excretion of acids – metabolic
acidosis
• Loss of fluid - dehydration

55. Type IV RTA
ACUTE CHRONIC
OBSTRUTIVE
UROPATHY
•ACUTE PYELONEPHRITIS
•ACUTE URINARY
OBSTRUCTION
ALDOSTERONE
UNRESPONSIVENESS
ACIDOSIS
HYPERKALEMIA

56. ETIOLOGY
 Medications: Nonsteroidal anti-inflammatory
drugs, angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers,
heparin/LMW heparin, calcineurin inhibitors
(tacrolimus, cyclosporine) (1)
 Diabetic nephropathy
 Obstructive nephropathy
 Nephrosclerosis due to hypertension
 Tubulointerstitial nephropathies
 Primary adrenal insufficiency
 Pseudohypoaldosteronism(end-organ
resistance to aldosterone)
 Sickle cell nephropathy

57.  Growth failure
 Polyuria
 Dehydration with salt wasting
 Life threatning hyperkalemia
Clinical Features

58. Lab diagnosis of RTA
 RTA should be suspected when metabolic
acidosis is accompanied by hyperchloremia
and a normal plasma anion gap (Na+ - [Cl- +
HCO3-] = 8 to 16 mmol/L) in a patient
without evidence of gastrointestinal HCO3-
losses and who is not taking acetazolamide or
ingesting exogenous acid.

59. History collection
 Often asymptomatic (particularly
type IV)
 Failure to thrive in children
 Anorexia, nausea/vomiting
 Weakness or polyuria (due to
hypokalemia)
 Rickets in children
 Osteomalacia in adults
 Constipation
 Polydipsia

60.  confirm the presence of and nature of the
metabolic acidosis.
 assess renal function.
 rule out other causes of metabolic acidosis,
such as diarrhea ( which is extremely
common) .
 identify electrolyte abnormalities (K,Na,Cl)
 blood urea nitrogen, calcium, phosphorus,
and creatinine and pH

61.  the anion gap should be calculated
using the formula [Na+] - [Cl- + HCO3-].
Values of less than 12 demonstrate the
absence of an anion gap.
 True hyperkalemic acidosis is consistent
with type IV RTA, whereas the finding of
normal or low potassium suggests type I
or II .
 urine pH may help distinguish distal from
proximal causes. A urine pH of less than
5.5 in the presence of acidosis suggests
proximal RTA, whereas patients with distal
RTA typically have a urine pH of more
than 6.0.

62. The urine anion gap ([Urine Na + Urine
K] - Urine Cl) is sometimes calculated
to confirm the diagnosis of distal RTA.
A positive gap suggests distal RTA. A
negative gap is consistent with
proximal tubule bicarbonate wasting
(or gastrointestinal bicarbonate
wasting).

63.  # acid loading test with use of
ammonium chloride with finding of
further fall in serum bicarbonate
without decline of urine PH below 6.0
without development of –ve urine
anion gap is proof of distal RTA

64. # A urinalysis should also be obtained
to determine the presence of
glycosuria, proteinuria, or hematuria
suggesting the possibility of more
global tubular damage or dysfunction
.
# Random or 24-hr urine calcium and
creatinine measurements will
identify hypercalciuria

65.  # A renal ultrasound should be
obtained to identify underlying
structural abnormalities such as
obstructive uropathies as well as to
determine the presence of
nephrocalcinosis.

66. Ultrasound examination of a child with distal renal tubular
acidosis demonstrating medullary nephrocalcinosis

68. Fractional excretion of bicarbonate
 Urine ph monitoring during IV administration
of sodium bicarbonate.
 FEHCO3 is increased in proximal RTA >15%
and is low in other forms of RTA.

69.  Urine pH
 Urine anion gap
 Urine Pco2
 TTKG
 Urinary citrate

70.  In humans, the minimum urine pH that can be
achieved is 4.5 to 5.0.
 The urine pH must always be evaluated in
conjunction with the urinary NH4+ content to
assess the distal acidification process
adequately .
 Urine sodium should be known and urine
should not be infected.

71.  Urine AG = Urine (Na + K - Cl).
 The urine AG has a negative value in most
patients with a normal AG metabolic acidosis.
 Patients with renal failure, type 1 (distal) renal
tubular acidosis (RTA), or hypoaldosteronism
(type 4 RTA) are unable to excrete ammonium
normally. As a result, the urine AG will have a
positive value.

72.  Measure of distal acid secretion.
 In pRTA, unabsorbed HCO3 reacts with
secreted H+ ions to form H2CO3 that
dissociate slowly to form CO2 in MCT.
 Urine-to-blood pCO2 is >20 in pRTA.
 Urine-to-blood pCO2 is <20 in distal RTA
reflecting impaired ammonium secretion.

73.  Trans-tubular potassium gradient
 TTKG is a concentration gradient between the
tubular fluid at the collecting tubule and the plasma.
 TTKG = [Urine K ÷ (Urine osmolality / Plasma
osmolality)] ÷ Plasma K.
 Normal value is 8 and above.
 Value <7 in a hyperkalemic patient indicates
hypoaldosteronism.

74.  The proximal tubule reabsorbs most (70-90%)
of the filtered citrate.
 Alkalosis enhances citrate excretion, while
acidosis decreases it.

79.  correction of the acidemia with oral sodium
bicarbonate, sodium citrate or potassium citrate.
This will reverse bone demineralization
 Hypokalemia and urinary stone formation and
nephrocalcinosis can be treated with potassium
citrate tablets
 Patients with proximal RTA often require large
quantities of bicarbonate, up to 20 mEq/kg/24 hr
in the form of sodium bicarbonate or sodium
citrate solution

80.  The base requirement for distal RTAs is generally in
the range of 2-4 mEq/kg/24 hr.
 Patients with Fanconi syndrome generally require
phosphate supplementation .
 Patients with distal RTA should be monitored for the
development of hypercalciuria. Symptomatic
hypercalciuria, nephrocalcinosis, or nephrolithiasis
may require thiazide diuretics to decrease urine
calcium excretion.
 Patients with type IV RTA may require chronic
treatment for hyperkalemia with sodium-potassium
exchange resin

81.  Administration of sufficient bicarbonate to reverse
acidosis stops bone dissolution and the
hypercalciuria.
 Proximal RTA is treated with both bicarbonate and
oral phosphate supplements to heal bone disease.
 Vitamin D is needed to offset the secondary
hyperparathyroidism that complicates oral
phosphate therapy
 The mainstay of therapy in all forms of RTA is
bicarbonate replacement .

84. increased

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Glassock RJ (eds). Baltimore,Williams &Wilkins Co,Vol 1, 2nd Ed, 1988, p 382
 SlyWS,Whythe MP, SundaramV, et al: Carbonic anhydrase II deficiency in 12 families
with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis
and cerebral calcification. N Engl J Med 1985; 313:139-145
 Albright F, Burnett CH, ParsonW: Osteomalacia and late rickets. the various etiologies
met in the United States with emphasis on that resulting from a specific form of renal
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 Halperin ML, Goldstein MB, Haig AJ, et al: Studies on the pathogenesis of type 1
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 DuBoseTD Jr, Caflisch CR:Validation of the difference in urine and blood CO 2 tension
during bicarbonate loading as an index of distal nephron acidification in experimental
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 CavistonTL, CampbellWG,Wingo CS, et al: Molecular identification of the renal H+,
K+-ATPases. Semin Nephrol 1999; 19:431-437

86.  Sabatini S, Kurtzman NA: Enzyme activity in obstructive uropathy: basis for salt wastage
and the acidification defect. Kidney Int 1990; 37:79-84
 Dafnis E, Sabatini S, Kurtzman NA: Effect of lithium and amiloride on collecting tubule
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 Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies.Nephrol.
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And
 NelsonTextbook of Pediatrics 19th edition
 IAPTextbook of Pediatrics 5th edition
 Pediatric Nephrology by RN Srivastava,A Bagga 5th edition
 Dr.Tai Al Akawy