Rta dr mahtab

DR MAHTAB
MBBS,DCH,DNB
GMSH 16 CHD

DEFINITION
 RTA IS DISEASE STATE CHARECTERIZE BY
NORMAL ANION GAP , METABOLIC ACIDOSIS IN
SETTING OF NORMAL OR NEAR NORMAL GFR.

RENAL TUBULAR ACIDOSIS
 First described clinically in 1935
 Confirmed as a renal tubular disorder in 1946
 Designated as RTA in 1951

2/27/2017 4
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

Basic terminology:
CLINICAL TERMINOLOGY CRITERIA
1. NORMAL pH
2. Acidemia
3. Alkaemia
4. Normal PaCO2
5. Respiratory acidosis (failure)
6. Respiratory
alkalosis(hyperventilation)
7. Normal HCO3
8. Metabolic acidosis
9. Metabolic alkalosis
1. 7.4(7.35-7.45)
2. pH < 7.35
3. pH > 7.45
4. 40(35-45mmHg)
5. PaCO2 >45mm Hg and low pH
6. PaCO2 <35mm Hg and high
pH
7. 24(22-26)
8. HCO3<22 mEq/L and low pH
9. HCO3>26 mEq/L and high pH

 The greater the concentration of H+, the more acidic a
solution is.
 The lower the concentration of H+, the more basic or
alkaline a solution becomes.
6
Neutral
Acidic Alkaline
71 14

7
Neutral
H+
HCO3
-
Alkaline
Acidic

8
KIDNEYS
Excrete / reabsorb H+ /
HCO3
-
LIVER
METABOLISM
PRODUCES H+
BLOOD BUFFERS
Protein,
Bicarbonate &
Phosphate
LUNGS
Eliminate CO2
METABOLISM
CO2
HCO3
-
H+
Protein buffers
synthesisedH+
H+

 3.RENAL REGULATION:
 Kidney regulates HCO3 by excreting non volatile-
fixed acids by following mechanisms:
1. Excretion of H+ ions by tubular secretion.
2. Reabsorption of filtered bicarbonate ion.

Anion Gap
 Described by Gamble in 1939
 Electroneutrality
 Na+, Cl-, and HCO3 are measured ions
Na + UC = Cl + HCO3 + UA
UC = Sum of unmeasured cations
UA = Sum of unmeasured anions
Anion Gap
UA - UC = Na - (Cl + HCO3); Anion Gap = Na - (Cl + HCO3)

 Anion Gap = Serum(Na+ + K+ )-(Cl- + HCO3-)
 Purpose of using anion gap: metabolic acidosis
resulting from bicarbonate loss can be differentiated
from accumulation of non volatile acid .
 Normal value : 4-11 mEq/L
 >20 is highly suggestive of presence of anion gap
 For every mEq of bicarb loss there is equal increase in
serum chloride levels so anion gap remains within
normal range
What is anion gap?

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

TYPES
Distal /classical type 1 RTA
Proximal / type 2 RTA
Hyperkalemic RTA / type 4 RTA
Type 3 ( combined proximal and distal
RTA )

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.

PATHOPHYSIOLOGY
 IMPAIRED H+ EXCRETION AT DISTAL TUBULES.
 DAMAGED AND IMPAIRED FUNCTIONING OF
ONE OR MORE TRANSPORTER OR PROTEIN Eg
H+/ATPase, H+/K+ ATPase, hco3-/cl- anion exchanger
 Inability to secrete H+ is compensated by secretion of
k+ so HYPOKALEMIA DEVELOP

 HYPERCALCINURIA IS USUALLY PRESENT LEAD
TO HYPERCALCINURIA LEDS TO
NEPHROCALCINOSIS OR NEPHROLITHIASIS
 CHRONIC METABOLIC ACIDOSIS IMPAIRE
URINARY CITRATE EXCRETION LED TO
HYPOCITRATURIA WHICH FURTHER INCREASE
RISK OF CALCIUM DEPOSITION IN TUBULES.

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

Secretory defects causing Distal RTA

Non secretory defects causing Distal RTA
 Gradient defect: backleak of secreted H+ ions. Ex.
Amphotericin B
 Voltage dependent defect: failure to generate and
maintain an appropriate electrical gradient to
favour h+ secretion ; hyperkalemic distal RTA
 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)

RISK FACTORS and etiology
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.

PRIMARY
Sporadic or inherited (AR ,AD FORM ) AR A/W
EARLY ONSENT OR AR A/W LATE ONSET SND
SYNDROME A/W TYPE 1 RTA
 MARFAN SYNDROME
 WILSON DS
 EHLER DANLOS SYNDROME

 SECONDARY CAUSE
INTRINSIC RENAL DISEASE : INTERSTITIAL
NEPHRITIS,PYELONEPHRITIS,TRANSPLANT
REJECTION,SICKLE CELL NEPHROPATHY,LUPUS
NEPHRITIS,NEPHROCALCINOSIS
UROLOGICAL : OBSTRUCTIVE
UROPATHY,VUR,HEPATIC,CIRRHOSIS
TOXIN AND MEDICATION :AMPHOTERICIN
B,LITHIUM,CISPLATIN,TOULENE

CLINICAL MANIFESTATIONS
 non-anion gap metabolic acidosis
 growth failure ,ftt,polyuria,polydipsia
 Nephrocalcinosis,renal stone
 hypercalciuria
 hypokalemia - muscle weakness,neck
flopiness,transient paralysis
 AR d RTA HAVE SENSIRINEURAL DEAFNESS,
OVALOCYTOSIS,HEMOLYTIC ANEMIA
 AD d RTA PRESENT IS OLDER AGE OR DURIN
ADULTHOOD WITH MILDER DISEASE

Type 2-Proximal RTA
Defect of the proximal tubule in bicarbonate (HCO3)
reabsorption. Urine pH <5.5(DISTAL ACIDIFICATION IS
INTACT)
 PROPOSED MECHANISM IS DEFICIENT CARBONIC
ANHYDRASE ON BRUSH BORDER AND DEFECTIVE PUMP
SECRETION,
FUCTION OF NA+/K+ ATP ase
AR P RTA CAUSED BY MUTATION MUTATION IN GENE
CODING FOR SOD.BICARBONATE CO TRANSPORTER (
NCB1)

Proximal RTA (Type 2)
 Caused by an impairment of HCO3- reabsorption
in the proximal tubules

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

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

Proximal RTA
 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

ETIOLOGY AND RISK FACTOR
 Most cases occur as a part of Fanconi’s syndrome
 Isolated proximal RTA is rare.
FANCONI SYNDROME IS CHARECTERISE BY
GENERALISED PROXIMAL TUBULAR
DYSFUNCTION
Clinical manifestations -
phosphaturia, glycosuria, aminoaciduria, uricosuria,
and tubular proteinuria. The principal feature of
Fanconi's syndrome is bone demineralization due to
phosphate wasting.

RISK FACTORS
CAN BE INHERITED, PERSISTENT FROM BIRTH,AS
COMPONENT OF FANCONI SYNDROME
 CAUSE OF P RTA IS MAY AR CONDITION LIKE
CYSTINOSIS,LOWE DS,GALACTOSEMIA,WILSON DS,
HEREDETARY FRUCTOSE INTOLERANCE ETC

CLINICAL MANIFESTATIONS
 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

CLINICAL FEATURE
 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.

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
Cystinosis ( classic ex. Of Fanconi syndrome)

3 CLINICAL FORM
 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
Forms

 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.
Clinical Features of cystinosis

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

 Early initiation of therapy is important.
 correcting the metabolic abnormalities associated
with Fanconi syndrome or chronic renal failure.
 SPECEFIC THERAPY : 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
 RENAL TRANSPLANTATION FOR RENAL FAILURE

Mutation in OCRL1 of X chromosome(XLR)
Encodes PIBPase in golgi network
Accumulation of PIBP(phosphatidylinisotol polyphosphate 5
phosphatase protein)
1.Changes in protein trafficking
2.Defective actin cytosleleton polymerization
3.Altered cell signalling for endocytosis
Lowe Syndrome (oculocerebral
syndrome of lowe)

 Clinical feature :progressive growth failure present in
infancy, hypotonia, fanconi syndrome,significent
proteinuria,blindness, renal insuffiiency often develop,
charecteristic behavioural abnormalities
(tantrum,stereotypic movement ,obsession etc

Clinical Features•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

 Diagnosis is clinical,molecular testing for OCLR gene is
available.
 Prenatal Dx: slit lamp examination of mother(punctate
white opacities)
 Treatment is symptomatic
No specific therapy for renal ds and neurological deficit
-cataract extraction
-glaucoma control
-physical and speech therapy
-drugs to address behavioral problem
.
Diagnosis & Treatment

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

RTA IV
 RESULT FROM IMPAIRED ALDOSTERONISM
PRODUCTION (HYPOALDOSTERONISM)
 OR ,IMPAIRED RENAL RESPONSIVINESS(PESUDO
HYPOALDOSTERONISM)
 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

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

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

Clinical Features
 Growth failure(<1 YR)
 Polyuria
 Dehydration with salt wasting
 RARELY MAY PRESENT WITH Life threatning
hyperkalemia
 IF PSEDOHYPOALDOSTERONIS -
PYLONEPHRITIS ,UTI ( OTHER FEVER
,VOMATING,FOUL SMELLING URINE)

 BICARBONATE LOADING TEST : SODIUM
BICARBONATE IS GIVEN ORALLY OR AS IV
INFUSION ,URINE PH IS MONITOR SAMPLE
COLLECTED UNTIL URINE >7.5 ,AND PLASMA
HCO3- >22 TO 24 mEq/L
 FRACTIONAL EXCRETION OF HCO3 AND URINE
TO BLOOD CO2 GRADIENT ARE MEASURED.

DIAGNOSTIC APP TO RTA
 1. FIRST STEP CONFIRM PRESENCE OF NON
ANIONIC GAP METABOLIC ACIDOSIS
 IDENTIFY ELECTROLYTE ABN ,ASSESS RENAL
FUNCTION,R/O OTHER CAUSE OF HCO3 LOSS EG
DIARRHOEA (EXTREMELY COMMON) IN SUCH
CASE DX SHOULD BE DELAYED FR FEW DAYS
 sERUM ELECTROLYTE,BUN
,CALCIUM,PHOSPHORUS,CREATININE,PH -
VENOUS PUNCTURE
 IF AG IS PRESENT R/O LACTIC
ACIDOSIS,IEM,TOXIN INGESTION

 CONFIRM NON AG METABOLIC ACIDOSIS
 URINARY PH <5.5 P RTA
>6 D RTA
 URINE ANION GAP POSITIVE GAP - DRTA
NEGATIVE GAP - P RTA
 URINEANALYSIS OBTAINED TO DETERMINE
PRESENCE OF
GLYCOSURIA,PROTEINURIA,HEMATURIA, THESE
SUGGEST MORE GLOBAL TUBULAR DAMAGE AND
DYSFUNCTION
 RANDOM OR 24 HR URINE CALCIUM AND
CREATININE MEASUREMENT WILL IDENTIFY
HYPERCALCINEMIA
 USG FOR STRUCTURAL ANOMALIES,OBSTRUCTIVE
UROPATHY,NEPHROCALCINOSIS.

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

TREATMENT
 MAINSTAY IS BICARBONATE REPLACEMENT ;
P RTA 5- 20 eq /kg/24 hr
D RTA 2-3 mEq/KG/24 hr
Increased until bicarbonate level become normal ,alkali requirement
decreases after age of 5 years but are required life long , correction of
acidosis result in increase in the growth velocity.
In form sod bicarbonate or sod citrate solution
D RTA 2-4meq /kg/24 hr
 FANCONI SYNDROME PHOSPHATE SUPPLIMENT
 D RTA - MONITOR FR HYPERCALCINURIA,IF SYMPTOMATIC
HYPERCALCINURIA RECURRENT EPISODE OF
HEMATURIA,NEPHROCALCINOSIS,NEPHROLITHIASIS REQUIRE
THIAZIDE DIURETICS TO DECREASE CALCIUM EXCRETION

 TYPE 4 RTA WITH CHRONIC HYPERKALEMIA
REQUIRE SOD POTASSIUM EXCHANGE RESIN
(KAYEXALATE)
 PROGNOSIS DEPEND UPON THE UNDERLUING
CAUSE ISOLATED PROXIMAL RTA AND DISTAL
RTA
 PT WITH SYSTEMIC ILLNESS AND FANCONI
SYNDROME HAVING MORBIDITY Eg GROTH
FAILURE,RICKETS,AND SIGN AND SYMP OF
UNDERLYING DISEASE

 Nelson Textbook of Pediatrics 20th edition
 Pediatric Nephrology by RN Srivastava,A Bagga 6th
edition
References

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