Renal Tubular Acidosis in Children: “Don’t trip on the acid or drop the base.”

Written by: Priya John, Md Abdul Qader 

Infographics by Salar Bani Hani, Priya John

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Introduction

Renal tubular acidosis is an umbrella term of renal acidification disorders defined by either impaired proximal renal tubular bicarbonate (HOC3-) reabsorption, decreased distal renal tubular acid secretion, or both, resulting in hyperchloremic metabolic acidosis with a normal anion gap.

The human body produces around 1 meq/Kg of acid (H+) every day as a result of numerous metabolic processes and nutritional consumption. The three different forms of acids are carbonic acid (made from the reaction of created carbon dioxide and water), inorganic volatile acids (derived from sulfur-containing amino acids consumed), and organic acids (formed from metabolic processes like gluconeogenesis). The proximal renal tubules reabsorb 85-90% of the filtered bicarbonate, as well as 60% of the sodium, water, potassium, phosphate, glucose, amino acids, and low molecular weight proteins. Finally, the distal convoluted tubule and collecting duct (CD) regulate urine concentration and pH; alpha-intercalated cells control K+ and H+ secretion, whereas principal cells mediate Na+ reabsorption.

Physiology of renal acid-base homeostasis/ urinary acidification:

The proximal convoluted tubule (PCT) reabsorbs the majority of filtered bicarbonate. The remaining bicarbonate is reabsorbed by the thick ascending limb of the loop of Henle (TAL) and the B-intercalated cells of collecting ducts (CD). The distal convoluted tubule (DCT) contains alpha-intercalated cells that secrete H+ and K+, while principal cells reabsorb Na+, which is necessary for final urinary acidification. The main contributors to distal tubular H+ excretion and titratable acidity are inorganic phosphate in the form of H2PO4, and ammoniagenesis in the proximal tubules with conversion to ammonium (NH4+). The distal tubule has limited acid excretion capabilities but can generate a substantial pH gradient, up to 4.5, which can increase up to 10-fold with chronic metabolic acidosis, primarily by increased NH4+ excretion and partially by HPO4- released from bone. 

Figure: Pathophysiology and molecular basis of renal tubular acidosis.

Types of renal tubular acidosis 

Proximal RTA (Type II) is caused by impaired reabsorption of filtered bicarbonate and distal RTA (Type I) is due to impaired H+ secretion. On the other hand, type IV RTA is caused by impaired secretion of H+ and K+ by the collecting duct secondary to reduced aldosterone secretion or decreased responsiveness. Let’s examine the underlying etiologies and clinical presentations of RTAs.

Distal renal tubular acidosis:

Type 1 RTA-Distal RTA is characterized by a tubular defect in distal acidification resulting in acid retention. Hypocitraturia almost always accompanies distal RTA. 

The genetic causes of distal RTA include mutation of genes which affect either chloride-bicarbonate exchanger (AE1) or subunits of the H-ATPase pump. Here is a table that summarizes the causes of dRTA. 

Genetic causes

Autosomal recessive dRTA with deafness: ATP6V1B1 or FOXI1

Autosomal recessive dRTA without deafness: ATP6V0A4 and WDR72

Autosomal dominant distal RTA: SLC4A1

Secondary causes of dRTA

Sjogren’s syndrome

Autoimmune hepatitis/ primary biliary cirrhosis

Systemic lupus erythematosus 

Rheumatoid arthritis

Drugs that can cause dRTA

Ifosfamide (can cause pRTA with Fanconi syndrome)

Amphotericin B

Lithium carbonate

Ibuprofen 

Other conditions 

Hypercalciuric conditions: Hyperparathyroidism, vitamin D intoxication, Sarcoidosis, idiopathic hypercalciuria.

Others: Medullary sponge kidney, Obstructive uropathy, Kidney transplant rejection, Wilson disease.

Clinical presentation:

The clinical presentations of dRTA depend on the etiology. The genetic recessive form usually presents early in infancy, whereas the dominant form of dRTA usually presents at a later age. 

The main clinical presentation is hyperchloremic metabolic acidosis with moderate to severe hypokalemia, nephrocalcinosis, vomiting, failure to thrive, and rickets. Kidney stones are not as common in children compared to adults.

Augmented hydrogen ion permeability of the luminal membrane: Increased permeability of hydrogen ions results in a back leak of hydrogen ions from the lumen into the extracellular fluid which in turn causes decreased secretion of acid into the urine. Potassium and magnesium losses result secondary to increased basolateral membrane permeability of these ions.

In certain conditions of distal RTA, acid secretion and plasma bicarbonate are maintained within normal range. This is called “incomplete” dRTA, and is presumed due to decreased proximal tubule pH because of increased ammonium secretion and citrate reabsorption. Probable mechanisms behind proximal tubule acidosis are that the distal acidification defect is subtle and increased ammonium synthesis maintains bicarbonate in near normal levels. Another postulation is that an entirely different pathologic mechanism initiates acidosis in proximal tubules different from that distal acidification defect.

The form of incomplete dRTA (idRTA) was first described in 1959, and presented with nephrocalcinosis without significant systemic acidosis. So incomplete dRTA should be suspected in a child with nephrocalcinosis without significant systemic acidosis. 

Proximal renal tubular acidosis 

Type 2 RTA- Proximal RTA is characterized by defects in the reabsorption of bicarbonate with resultant bicarbonate wasting. The severity of acidosis is dependent on the ability of the distal tubule to reabsorb bicarbonate delivered by the proximal tubule. Most often acidosis is not severe in Type 2 RTA. Rarely it occurs as an isolated pRTA and is more commonly associated with other defects or with syndromes. 

Genetic forms of proximal RTA include mutations of the gene SLC4A4 which encode sodium bicarbonate cotransporter 1 (NBC1; a basolateral bicarbonate transporter) and carbonic anhydrase 2 (CA2) gene encodes CAII transporter cause an autosomal recessive pRTA. Secondary causes of pRTA are due to autosomal recessive or X-linked diseases, some of which include: Fanconi reno tubular syndrome, Dent disease, Lowe syndrome, Cystinosis, Tyrosinemia, Wilson disease, Galactosemia, Glycogen storage disease (1a & b), hereditary fructose intolerance Fanconi Bickel syndrome and mitochondrial disorders. 

The main differentiating features of pRTAs are generalized aminoaciduria and low molecular weight proteinuria which is often associated with glycosuria, phosphaturia, bicarbonaturia, natriuresis, kaliuresis and polyuria. Essentially, this is a failure of the proximal tubule to reabsorb a majority of the filtered substrate. Polyuria, polydipsia and faltering growth are the main presenting features. Features of rickets or osteomalacia and symptomatic hypokalemia (weakness and paralysis) are also not uncommon, but nephrocalcinosis is rare in pRTA.  

Type IV renal tubular acidosis

Type 4 RTA is a form of hyperkalemic hyperchloremic acidosis.This type of RTA is usually seen in mild to moderate chronic kidney disease often associated with type 2 diabetes in adults. The primary defect in this type of RTA is a defect in distal sodium reabsorption which impairs potassium and hydrogen secretion at the principal cell of connecting segment and cortical collecting tubule. There are 2 main types classified under type 4 RTA. They are voltage-dependent RTA and hypoaldosteronism.

Voltage-dependent RTA is caused by either increased proximal sodium reabsorption or decreased sodium intake which results in decreased distal delivery of sodium. Acquired or inherited defects in sodium transport mechanisms in the principal cells is another mechanism of voltage-dependent RTA. This subtype is characterized by the inability to lower the urine pH below 5.5 and normal aldosterone levels.

The following are the various conditions which produce voltage-dependent RTA.

1. Obstructive uropathy is the most common cause of voltage-dependent RTA. 

2. Sickle Cell anemia

3. Lupus nephritis can sometimes cause type 4 RTA secondary to the destruction of distal tubular cells by antigen-antibody complexes.

4. Drugs like amiloride and lithium can cause voltage-dependent RTA

Hypoaldosteronism can be due to reduced production or aldosterone resistance at the level of the kidney. The various causes of reduced aldosterone production include

1. Hyporeninemic hypoaldosteronism: This is commonly seen in chronic tubulointerstitial nephritis and mild to moderate chronic kidney disease of any cause. There is decreased renin production coupled with intrarenal defect with resultant decreased angiotensin 2 production which in turn results in decreased aldosterone production.

2. Primary adrenal insufficiency: This causes both decreased cortisol and aldosterone. The causes of primary adrenal insufficiency are autoimmune, infections, infiltration, drugs, trauma and hemorrhagic infarction.

3. Pseudohypoaldosteronism type 2: Gordon’s syndrome is characterized by hypertension, hyperkalemia, metabolic acidosis, normal kidney function and low renin and aldosterone levels.

4. Drugs

5. Diabetes mellitus: Decreased plasma renin activity is commonly evident in diabetic patients due to defective conversion of prorenin to renin. Fluid overload in these patients induces the release of atrial natriuretic peptide which suppresses the release of renin.

The following are the causes of aldosterone deficiency and resistance

1. NSAIDs, ACEi, Angiotensin II receptor blocker

2. Diminished aldosterone receptor function: Calcineurin inhibitor (tacrolimus, cyclosporin); Aldosterone receptor blocker (Spironolactone, eplerenone, finerenone)

3. Decrease ENaC channel function: Amiloride, triamterene, trimethoprim, pentamidine. 

Evaluation of RTA

All types of renal tubular acidosis are associated with normal anion gap metabolic acidosis. So, here are the steps of evaluation for the types of RTA.

1. Serum anion gap (SAG): 

Can be calculated using the following formula: 

Anion GAP= Na+- [Cl-+ HCO3-]

SAG estimates the difference between unmeasured anions and cations and the normal value is 8-16 (mean+SD is 12+4) meq/L for measurements by flame photometry and colorimetry. Elevated SAG can be secondary to diabetic ketoacidosis, lactic acidosis, inborn errors of metabolism or ethylene glycol/methanol poisoning. On the other hand, low SAG can be due to hypoalbuminemia, hypercalcemia, hypermagnesemia, lithium or bromide intoxication. 

In the presence of hypoalbuminemia, SAG is corrected as,

Adjusted SAG= Measured SAG+ 2.3x (4- Serum albumin)

1. Urine anion gap (UAG):

UAG can depict the ammonia excretion in the renal tubule and can give a picture whether NH4+ excretion is high or abnormally low. In normal situations, NH4+ excretion in the urine is increased in the presence of metabolic acidosis (secondary to extrarenal loss of HCO3- secondary to diarrhoea) but in RTA, NH4+ excretion is low. 

UAG= [Na+ + K+] - Cl-

Urinary NH4+= 80- UAG

Considering the difference between urinary unmeasured anions and cations (without NH4) it remains at ~80 meq/L.  Normally UAG is positive (30-50 meq/L) due to excess unmeasured anions. In the non-kidney origin of metabolic acidosis (i.e., diarrhea), UAG becomes negative due to excess NH4+ excretion with Cl-. In the presence of hyperchloremic metabolic acidosis, a negative UAG represents adequate NH4+ excretion but in the case of RTA, UAG becomes positive. However, a recent paper has described urine ammonia is better determined if urine phosphate and sulfate are included in calculation of UAG in the case of chronic kidney disease. 

3. Urine pH: 

Metered urine pH is a useful indicator which represents distal acidification. Urine pH >5.3 in the presence of metabolic acidosis suggests defective distal acidification and in patients with pRTA, urine pH can be lower as <5.3 when plasma HCO3- level falls to a certain level when HCO3- reabsorption is complete. In patients with type IV RTA, urine pH can be lowered to <5.3. 

Na+ reabsorption in the cortical collecting duct plays a crucial role in creating the electronegative luminal potential to facilitate distal H+ and K+ secretion. So, urine pH should be interpreted in accordance with urinary Na+ as in case of diarrhea, cirrhosis or nephrotic syndrome, distal H+ secretion is low and urine pH is high. 

Figure: Differentiating investigations between various types of renal tubular acidosis.

4. Bicarbonate loading test

Sodium bicarbonate infusion is given as 0.5 mEq/ml at a rate of 3 mL/min and urine pH is measured 30-60 min apart & the test is terminated when consecutive 3 samples show urine pH >7.5. The Sodium bicarbonate can be given orally at a dose of 2-4 mEq/kg/day for 2-3 days to achieve similar urine pH.

1. Urine to blood CO2 gradient: In alkaline urine after bicarbonate loading), urine PCO2 increases because HCO3- reacts with distal H+ to form CO2. Urine PCO2 is more than 70mmHg in a urine pH of >7.5 and serum HCO2 >23-25 meq/L. In that case, urine to blood PCO2 gradient should be >20mmHg but in the case of distal RTA, the gradient is <10mmHg. 

2. Fractional excretion of Bicarbonate (FEHCO3)

Additional investigations:

1. Fractional excretion of phosphate

2. Transtubular potassium gradient (TTKG)

Genetic studies 

Figure: Inherited disorders causing renal tubular acidosis

Treatment: 

The primary goal of treatment is to provide adequate fluid and electrolyte supplementation, as well as nutritional support. The treatment of acidosis involves the use of alkali supplements, while patients with hyperkalemic RTA are recommended to stay away from alkalis and foods that contain potassium. The objective for acidosis correction in infants is >20 meq/L and >22 meq/L in older children and potassium citrate is preferred over sodium citrate or sodium bicarbonate because 

1. Sodium bicarbonate increases extracellular fluid volume while decreasing bicarbonate reabsorption, resulting in increased alkali needs.

2. Increased salt consumption worsens hypercalciuria. 

Alkali requirements decrease with age; newborns require 5-8 mEq/kg/day, children require 3-4mEq/kg/day, and adults require 1-2mEq/kg/day. Phosphate supplements, in addition to alkali supplements, are required for patients with Fanconi syndrome. Cystinosis patients require lifelong cysteamine supplements together with cysteamine eye drops or gel. Other tubular disorders require specific therapy and/or dietary modification.

Outcomes:

Patients with dRTA respond well to alkali therapy, however many children experience growth loss and their final height are impaired with dRTA and Fanconi syndrome. After adolescence, one-third of dRTA patients have a deterioration in renal function due to recurrent bouts of AKI related to volume depletion and nephrocalcinosis-associated renal fibrosis. Patients with cystinosis and Dent disease have a steady decline of kidney function, which occurs earlier in cystinosis.

Patients with RTA need long-term follow-up to monitor kidney function and growth. 

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.