IN BREIF ABOUT RENAL TUBULAR ACIDOSIS (RTA) IN CHILDREN

1. RENAL TUBULAR
ACIDOSIS
DR KAMRUN NAHAR

2. What is renal tubular acidosis?
• The kidneys play a key role in preserving acid–base homeostasis in the
body by excretion of acid and regeneration of bicarbonate.
• RTA occurs when kidneys do not remove acids from blood into urine as
they should. The acid level in blood then becomes too high, a condition
called acidosis.
• Features:
- Inability to excrete enough acid or retain enough bicarbonate,
- in presence of normal renal function,
- persistent normal anion gap hyperchloremic metabolic acidosis.
• Incidence: Rare disease that is often misdiagnosed or undiagnosed
RTA is a group of renal tubular disorders due to defects in proximal
tubular reabsorption of bicarbonate ion (HCO3 - ), distal tubular
excretion of hydrogen ion (H+ ) or both, and is characterized by
hyperchloremic normal serum anion gap (AG) metabolic acidosis in
patients with relatively normal glomerular filtration rate (GFR).

3. ACID–BASE HOMEOSTASIS: ROLE OF
THE KIDNEY
 Bicarbonate reabsorption in the proximal tubule
• The proximal tubule is responsible for reabsorption of 85–90% of
filtered bicarbonate through secretion of protons (H+) through
sodium hydrogen exchangers and proton pumps (H+ATPase).
• In the lumen, the secreted H+ combine with HCO3
- to form H2CO3
(carbonic acid) which rapidly dissociates into CO2 and H2O (water), a
reaction catalyzed by carbonic anhydrase.
• The CO2 (carbon dioxide) generated diffuses freely into proximal
tubule cell and reacts with water to form carbonic acid, a reaction
catalyzed by carbonic anhydrase (CA II). Bicarbonate ions from the
dissociated carbonic acid exit through the basolateral membrane by
the sodium bicarbonate exchanger (NBCE1) [Figure 1].

4. Fig 1:
Bicarbona
reabsorpt
in proxima
tubule.

5.  Urinary acidification in the distal tubule
• The acidification of urine occurs in the distal collecting tubule and
collecting duct. The intercalated cells A (secrete H+), B (secrete
HCO3
-) and principal cells (reabsorb sodium, water, and secrete K+)
of the distal nephron play a pivotal role in fine tuning acid and base
excretion. The generated HCO3
- is transported to blood in exchange
for chloride by the basolateral Cl-/HCO3
- exchanger. The hydrogen
ions secreted into lumen by intercalated cells A are buffered by
titratable acids (phosphate) and ammonia and excreted in
urine [Figure 2].

6. Fig 2: Distal urinary acidification. NHE 3: Sodium hydrogen exchanger 3, NBC-1:
Sodium bicarbonate cotransporter, AE1: Anion exchanger, CA II: Carbonic anhydrase II,

8. FeaturesSuggestingTubularDisorders:
• Tubular dysfunction:
• failure to thrive
• polyuria, refractory rickets, hypokalemia and metabolic acidosis
• Non-specific features:
Features Suggestive of Renal Tubular Disorders
Clinical
• Growth retardation, failure to thrive
• Polyuria, polydipsia; preference for savory foods
• Refractory rickets
• Renal calculi, nephrocalcinosis
• Unexplained hypertension*
Laboratory
• Hyperchloremic metabolic acidosis
• Metabolic alkalosis with or without hypokalemia
• Hyponatremia with hyperkalemia
• Hypercalciuria with normal serum calcium
• * As in Liddle’s syndrome, syndrome of
apparent mineralocorticoid excess

9. Etiology in Children:
RTA is due to –
 Inherited
 Acquired
- that affects kidney's ability to absorb filtered
bicarbonate, or excrete ammonia or titratable acid.

10. Types of RTA:
• There are three main types of RTA.
• The most common pediatric forms of RTA are distal (type 1) and proximal (type 2).
• occurs if problem is at the end or distal part of tubules.
Type 1 RTA, or distal RTA
•Occurs if problem in the beginning or proximal part of the tubules.
Type 2 RTA, or proximal RTA
•occurs if tubules are unable to remove enough potassium,
•If interferes with kidney’s ability to remove acid from blood.
Type 4 RTA, or hyperkalemic RTA/ hypo-aldosteronism
• rarely used as a classification now as it is thought to be a combination of
type 1 and 2.
Type 3 RTA , mixed

11. Hereditary causes of renal tubular acidosis.
Disorder Inheritance Gene
Chromoso
me Protein
Extrarenal
features
Distal RTA
Autosomal
dominant (AD)
Autosomal
dominant
SLC4A1 17q21-q22 Anion exchanger Hemolytic anemia
Autosomal
recessive (AR)
Autosomal recessive ATP6V1B1
ATP6V0A4
2q13
7q33-q34
H+ATPase Hearing
impairment
Proximal RTA
Cystinosis Autosomal recessive CTNS 17p13 Cystinosin Eyes, CNS,
endocrine
Dent’s disease
Type I
Type II
X linked CLCN5
OCRL1
(15%)
Xp11.22 Chloride channel Rare
Fanconi-Bickel AR SLC2A2 3q26.1–
q26.3
GLUT2 Hepatic
Galactosemia AD GALT 9p13 Galactose-1-phosphate
uridylyltransferase
Eye, hepatic, CNS
Hereditary
fructose
intolerance
Autosomal recessive ALDOB 9q22 Fructose-1 phosphate
aldolase
Hepatic
Lowe syndrome X linked OCRL1 Xq26.1 Phosphatidylinositol 4,5-
bisphosphate 5-phosphatase
CNS, eye
Tyrosinemia Autosomal recessive FAH 15q23-q25 Fumarylacetoacetate
hydrolase
Hepatic
Wilsons disease Autosomal recessive ATP7B 13q14.3-
q21.1
ATPase copper transporting
beta-polypeptide
Hepatic, CNS, eye

12. Who are at risk?
Genetic abnormality:
1. Autoimmune diseases e.g Sjögren’s syndrome or lupus
2. Fanconi syndrome
3. Medication history - treat HIV, viral hepatitis
4. In adults, type 2 RTA can be seen in multiple
myeloma, exposure to toxins, or certain medications. Rarely,
chronic rejection of a transplanted kidney.
5. If hormone aldosterone, cannot urinate freely because of an
obstruction, or had a kidney transplant, more likely to develop
type 4 RTA.

13. What are the complications of RTA?
Type 1 RTA Type 2 RTA Type 4 RTA
1. Growth failure
2. progressive kidney
disease (CKD)
3. bone diseases
4. kidney stones -
nephrolithiasis,
nephrocalcinosis; due
to
abnormal calcium depo
sits in kidneys.
5. Other conditions:
a. deafness
b. renal medullary cystic
disease
c. sickle cell anemia
d. Ehlers-Danlos syndrome
e. UTI
1. Growth failure
2. rickets
3. bone disease
4. dental disease
5. Hypokalemia - very low
potassium level can
develop during treatment
with alkali.
1. hyperkalemia: high
levels, can lead to muscle
weakness or heart
problems, such as slow
or irregular
heartbeats and cardiac
arrest

14. Diagnosis:
• Medical history
• Investigation:
If blood is more acidic and urine is less acidic than normal level; it should be RTA

15. Evaluation:
1. First step in evaluation of a child with
hypokalemia & metabolic acidosis is to
differentiate GI –HCO3 loss from RTA.
2. Presence of polyuria, preference for
savory foods, failure to thrive & rickets,
are suggestive of RTA.
3. GI losses can be differentiated from RTA
by estimating the urine anion gap.
- Negative urine anion gap indicates
increased renal NH4 + production
(extrarenal cause for metabolic acidosis),
- while positive gap suggests RTA.
RTA is can be categorized further
1) Proximal RTA - should evaluate for other
proximal tubule functions (phosphate,
electrolytes, glucose & amino acid
excretion) and screening for an
underlying etiology (e.g., Wilson
disease, cystinosis).
2) Distal RTA - include estimation of
urine calcium excretion, ultrasound for renal
calcification and work-up for secondary
causes (e.g., obstructive uropathy, reflux
nephropathy, chronic tubulo-interstitial
nephritis).

16. Signs and symptoms of RTA:
 Major signs:
o Type 1 RTA & type 2 RTA: Low levels of K & HCO3
Hypokalemia causes:
• extreme weakness
• irregular heartbeat
• paralysis
• Death
o Type 4 RTA: high K & low HCO3
• Symptoms include:
• abdominal pain fatigue that does not go away
• weak muscles
• not feeling hungry
• weight change
Hearing loss:
Mostly associated with DRTA
dx in between 3 months to 2 yrs.
It usually sensorineural type,
bilateral, asymmetrical, and
progressive occasionaly with a
conductive component.
Rickets -

17. Investigation:
• Low blood pH, high urine pH
• Serum electrolytes including
bicarbonate
• Ultrasound of KUB: To screen
out nephrocalcinosis (risk for
distal RTA).
Arvind Bagga et al
Urine pH measure:
• Freshly voided early morning urine
sample required
• Use pH meter.
• Urine should ideally be collected under
mineral oil to prevent dissipation of
CO2 and falsely elevated urine pH.
• Must exclude UTI as urea spitting
organisms are associated with falsely
high urine pH.
• Normal level: 4.5-5.3.

18. Treatment:
 Alkali therapy: sodium bicarbonate (drinking solution) or sodium citrate
[ususally in combination of NaHCO3 & KHCO3)
Indication: For all types of RTA.
Dose: 1-3 meq/kg/day
Use: lower blood acid level, prevent bone disorders and kidney stones,
and grow normally.
• Type 1 RTA (Distal RTA):
• Potassium supplements, Infants may need but rarely in older children and
adults. [alkali therapy prevents kidneys from excreting potassium into urine]
• Type 2 RTA (Proximal RTA):
- Alkali solution (sodium bicarbonate or potassium citrate)
- Additional Vitamin D supplements (To prevent bone problems).
• Type 4 RTA: may need to lower the potassium levels
• Researchers don’t yet know whether a diet low in acidic foods can have a
positive effect on RTA.

19. Other treatment:
Specific therapy for an underlying disorder
• Cysteamine for cystinosis,
• D-penicillamine for Wilson disease and
• Lactose free diet in galactosemia
Correction of acidosis reduces urinary K+ and prevents
hypokalemia, and patients may not require potassium
supplementation in the long run. However, in presence of
hypokalemia potassium citrate is preferred.

20. Prognosis
• Distal RTA: depends on nephrocalcinosis at diagnosis.
Other wise long term prognosis is favorable.
• Proximal RTA:
- Good.
Follow-up includes
Regular assessment for growth and blood levels of
electrolytes, pH and bicarbonate.

21. Rickets in RTA:
• Rickets, a metabolic disease restricted to an age group before
epiphyseal growth plate fusion, and is diagnosed by typical skeletal
deformities and characteristic radiological features.
• Commonest etiology of rickets worldwide is nutritional deficiency of
vitamin D and/or calcium, followed by primary renal phosphate
wasting disorders.
• Two most common disorders associated with metabolic acidosis and
rickets are chronic kidney disease and renal tubular acidosis (RTA)

22. • RTA is an important cause of rickets, particularly ‘resistant rickets’, as the
diagnosis is often missed initially and the patients are being wrongly treated
with other agents without any benefit.
• Usually common in dRTA and relatively uncommon in pRTA, and absent in
incomplete dRTA.
The definition of refractory rickets is not universally accepted, however, absence of
radiological healing lines after 3–4 weeks of adequate Calcium and Vit D suggests
non-nutritional rickets.
Rickets in RTA is multifactorial.
Systemic acidosis is associated with defective mineralization of cartilages and bones due to
increased solubility of mineral phase. During acidosis, calcium and phosphate are mobilized
from bones for purpose of buffering by enhanced osteoclastic resorption. Enhanced activity
of osteoclasts is associated with influx of calcium and phosphate into circulation. These
molecules are subsequently excreted through kidneys due to - a) increased filtered load and
b) reduced proximal tubular reabsorption (secondary to systemic acidosis).
Hypercalciuria results in secondary hyperparathyroidism that further aggravates
hypophosphatemia due to renal phosphate loss. In addition, pRTA itself may be associated
with phosphaturia and low renal 1α-hydroxylase activity, which leads to impaired
conversion of 25-hydroxy vit D to calcitriol (1, 25-dihydroxy vit D), active form of vit D.
RicketsinRTA:cont.

23. Approach to refractory rickets:

24. Diagnosis:
Clinical survey including -
• Peripheral extremities, cranium, spine and eyes is of utmost
importance.
Investigation: [ as baseline for all children with rickets]
• serum calcium, phosphate,
• S. albumin,
• ALP,
• PTH (by second generation assay),
• 25-hydroxy vit D,
• creatinine and
• arterial blood gas analysis
• Urine pH [ fresh morning sample]; preferably with a pH meter
Defects occur in proximal tubular
reabsorption of phosphorus and conversion
of 25 (OH) D2 to 1,25 (OH)2 D3 is defective.

25. Figure 5: 4.5-year-old girl with dRTA was treated with alkali therapy. Note the
complete clinical (B) and radiological (D) recovery after 1.5 years of treatment. A
and C represent features at presentation.

26. Management:
1. Phosphorus supplementation: [ Joulie’s solution] [ dibasic
sodium phosphate]
dose: 1-3 gm elemental phosphorus in 4-5 times a day for
whole life
Joulie’s solution contains 30.4 mg/ml elemental phosphate.
2. Oral calcitriol [ 1,25 (OH)2 D3] supplementation:
30-70 µg/kg/day in two divided doses.
3. Appropriate correction of acidosis with bicarbonate and
phosphate supplementation.

27. Figure 6: Residual deformity after 3 years of alkali therapy in a boy diagnosed with dRTA at 16
years of age. The growth plates are fused and the boy is posted for corrective osteotomy.
Figure 2: (A)dRTA in a 16-year-old boy with rickets and bilateral
nephrocalcinosis (C). Metaphyseal changes are seen in B.

28. Prognosis:
• Early diagnosis and proper management of RTA leads to
complete clinical and radiological recovery with rickets
secondary to RTA.
• If diagnosed late, deformity might be permanent, once growth plates
are fused, that ultimately require corrective osteotomy.

29. Figure 5: 4.5-year-old girl with dRTA was treated with alkali therapy. Note the complete clinical (B) and radiological
(D) recovery after 1.5 years of treatment. A and C represent features at presentation.

30. THANK YOU………….