Renal calcification in children with renal tubular acidosis: What a paediatrician ‎should ‎know‎

Table 1 Comparison of different renal tubular acidosis types based on their etiology, pathogenesis, and key features.

Type of RTA		Type 1 RTA	Type 2 RTA	Type 3 RTA	Type 4 RTA
Prevalence		The most common type of RTA (1-2/100.000)	Less common than type 1 RTA (0.5/100.000)	Very rare	Slightly less common than type 1 RTA (1/100.000)
Location of defect		Distal nephron	Proximal nephron	Variable	Collecting duct
Etiology	Primary	Sporadic or hereditary (mutation of SLC4A1, H+-K+-ATPase, H+-ATPase)	Sporadic or hereditary (mutation of CA-IV, NHE-3, NBC-1)	Mutation in CA-II	PHA-1, PHA-2 (Gordon’s syndrome)
	Secondary	Autoimmune: Sjogren’s, SLE, RA, PBC; Nephrotoxins: Amphotercicn B, trimethoprim, lithium; Miscellaneous: Sarcoidosis, amyloidosis, obstructive uropathy	Autoimmune: Sjogren’s; Nephrotoxins: Tetracycline, topiramate, valproate, acetazolamide; Metabolic: Wilson’s disease, cystinosis, Lowe’s syndrome, galactosemia, chronic hypocalcemia; Hereditary fructose intolerance, tyrosinemia; Miscellaneous: Multiple myeloma, amyloidosis	Type 1 RTA with secondary proximal tubule dysfunction, type 2 RTA with secondary distal tubule dysfunction	Aldosterone deficiency or aldosterone resistance: Hypoaldosteronism, ACEIs, ARBs; Hyporeninemic hypoaldosteronism: Diabetes, sickle cell disease; Tubulointerstitial disease (eGFR: 20-50 ml/min); Drugs: Potassium sparing diuretics, NSAIDs, trimethoprim, pentamidine, cyclosporine, tacrolimus
Pathogenesis		Impaired hydrogen ion secretion & reduced bicarbonate reabsorption in the distal tubules	Impaired bicarbonate reabsorption in the proximal tubules	Impaired distal acidification and reduced bicarbonate reabsorption	Impaired hydrogen ion secretion and decreased potassium excretion due to reduced aldosterone activity
Degree of acidosis		Severe	Mild to moderate	Mild	Mild to moderate
Key features		Acidemia, hypobicarbonatemia, inability to acidify urine properly, and loss of bicarbonate ions in urine. Hypokalemia is common	Metabolic acidosis, loss of bicarbonate ions in urine, hypobicarbonatemia, electrolyte imbalances (e.g., hypokalemia, hypophosphatemia)	Metabolic acidosis, hypobicarbonatemia, variable features depending on the underlying systemic disease or medication	Metabolic acidosis, hyperkalemia, associated with hypoaldosteronism or resistance to aldosterone, potential electrolyte imbalances (e.g., hyponatremia, mild hyperchloremic acidosis)
Risk of renal calcification		High	Lower than type 1 RTA	Very low (variable)	Unknown

AE1: Anion exchanger 1; CA: Carbonic anhydrase; NHE-3: Sodium-hydrogen exchanger 3; NBC-1: Sodium-bicarbonate cotransporter 1; PHA: Pseudohypoaldosteronism; SLE: Systemic lupus erythematosus; RA: Rheumatoid arthritis; PBC: Primary biliary cirrhosis; ACE: Angiotensin converting enzyme; ARB: Angiotensin receptor blocker; RTA: Renal tubular acidosis.

Table 2 Acid load test in different types of renal tubular acidosis

Type of RTA	Urine pH	Fractional bicarbonate excretion
Type 1 RTA	Does not decrease	Normal or decreased
Type 2 RTA	Decreases	Increased
Type 3 RTA	Variable	Variable
Type 4 RTA	Does not decrease	Decreased

RTA: Renal tubular acidosis.

Table 3 Comparison of clinical and laboratory data between type 1 and type 2 renal tubular acidosis

Feature		Type 1 RTA	Type 2 RTA
Prevalence		More common than type 2 RTA	Less common than type 1 RTA
Cause		Usually isolated, inherited, autosomal recessive forms are associated with hearing loss	Usually secondary to a systemic disease, most often metabolic disease, e.g., Fanconi syndrome
Clinical features	Nephrocalcinosis	Often present	Occasionally present
	Polyuria (increased urine output)	Common	Common
	Polydipsia (increased thirst)	Common	Common
	Dehydration	Less common	Less common
	Bone abnormalities	Usually, severe	Variable
	Failure to thrive (children)	Occasional	Uncommon
	Rickets/osteomalacia (children)	Occasional	Uncommon
	Metabolic acidosis	Severe acidosis; is easily corrected with bicarbonate supplementation	Usually milder but difficult to correct; requires high doses of bicarbonate supplementation
Laboratory Finding	Serum HCO3- (bicarbonate)	Decreased	Decreased
	Serum potassium	Low	Normal/low
	Urine pH	> 5.5	< 5.5
	Fractional excretion of bicarbonate	< 5%	> 15%
	Urine-blood PCO2	< 20 mmHg	> 20 mmHg
	Phosphaturia and hypophosphatemia	Absent	Present (variable)
	Tubular defects – low-molecular-weight proteinuria, aminoaciduria, glycosuria	Absent	Present (variable)
	Hypercalciuria	Often present	Occasionally present

RTA: Renal tubular acidosis.

Table 4 Genetic causes of different types of renal tubular acidosis

Gene involved	Inheritance	Location of gene	RTA type caused	Affected protein	Main clinical feature
SLC4A1 gene	AD	17q21-q22	Type 1 RTA	AE1	Type 1 RTA, hereditary spherocytosis
	AR
CA2 gene	AR	8q21.2	Type 1 RTA, type 3 RTA	CA II	Osteopetrosis, brain calcification, RTA
ATP6V1B1	AR	2q13	Type 1 RTA	H+-ATPase	Sensorineural deafness
ATP6V0A4		7q33-q34
SLC4A2 gene	AR	7q36.1	Type 2 RTA	AE2	PBC
SLC4A4 gene	AR	4q13.3	Type 2 RTA	(NBC)	Ocular abnormalities
SLC2A2 gene	AR	3q26.2	Type 2 RTA	GLUT2	Fanconi-Bickel syndrome, NIDDM
CLCN5 gene	X-linked recessive	Xp11.23	Type 2 RTA	H+/Cl- exchanger	Dent disease type 1, HHR
OCRL1 gene	X-linked recessive	Xq26.1.	Type 2 RTA	OCRL enzyme	Dent disease, type 2, LOCRS
NR3C2 (MR) gene	AD	4p	Type 4 RTA	MLR NRC	PHA1, hyperkalemia, salt wasting & hypotension
SCNN1A, SCNN1B, and SCNN1G genes	AR	SCNN1A (12p3). SCNN1B, & SCNN1G located in (16p12-p13)	Type 4 RTA	ENaC	Liddle syndrome, sodium loss from the kidneys and other organs, including the sweat glands, salivary glands, and colon

AD: Autosomal dominant; AE1: Anion exchanger 1 protein; AE2: Anion exchanger 2 protein; AR: Autosomal recessive; CA II: Carbonic anhydrase II; ENaC: Epithelial sodium channels located on the luminal membrane of the collecting tubule; GLUT2: Glucose transporter 2; HHR: Hereditary hypophosphatemic rickets; OCRL: Lowe oculocerebrorenal syndrome; MLR NRC: The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, MR: Mineralocorticoid receptor, group C; NBC: Sodium bicarbonate cotransporter, which regulates bicarbonate secretion, absorption, and intracellular pH. NIDDM: Noninsulin-dependent diabetes mellitus, PBC: Primary biliary cirrhosis; PHA1: Primary pseudohypoaldosteronism type 1; RTA: Renal tubular acidosis.

Table 5 Comparison of different imaging modalities in nephrocalcinosis due to RTA

Modality	Advantages	Limitations
X-ray	Readily available; Cost-effective; Quick initial assessment; Suitable for detecting large, dense stones	Limited sensitivity for smaller or radiolucent stones; No detailed anatomical information
Ultrasound	Can be used to assess kidney size, shape, and echogenicity; Non-invasive; Real-time imaging; Widely available; Initial assessment of kidney stones and medullary cyst	Reduced sensitivity for smaller or deeply located calcifications; Limited anatomical details
CT	Excellent spatial resolution; Detailed cross-sectional images; Highly sensitive for detecting kidney stones and calcifications; Assesses impact on kidney function and urinary tract	Involves exposure to ionizing radiation; Contrast agents may be contraindicated in some patients; Not suitable for all patients due to contrast use
MRI	No ionizing radiation; Detailed images of the extent of calcification and surrounding soft tissue damage; Multiplanar imaging capability; Can provide information on tissue characteristics and perfusion	It may not be as readily available as other modalities; Limited sensitivity for detecting small or faint calcifications

CT: Computed tomography; MRI: Magnetic resonance imaging.