Pediatric Examination and Board Review (216 page)

(A) type I RTA

(B) type II RTA

(C) type III RTA

(D) type IV RTA

(E) A and B only

11.
Rickets can accompany

(A) type I RTA

(B) type IV RTA

(C) type II RTA

(D) None of the above

(E) A and C only

12.
Nephrocalcinosis occurs

(A) more commonly in type I RTA

(B) more commonly in type II RTA

(C) more commonly in type IV RTA

(D) only in type I RTA

(E) commonly in type II and IV but never in type I RTA

13.
All of the following can cause type II or proximal RTA except

(A) valproic acid

(B) penicillin

(C) ifosfamide

(D) mercaptopurine

(E) sulfonamides

14.
All of the following can cause type I or distal RTA except

(A) analgesic abuse

(B) amphotericin B

(C) lithium

(D) amoxicillin

(E) vitamin D intoxication

15.
Type I or distal RTA can be caused by

(A) a bicarbonate reabsorption defect

(B) a proton pump failure in the cortical collecting duct

(C) a proton back leak into the cortical collecting duct cells

(D) all of the above

(E) B and C only

16.
Type II or proximal RTA can be caused by

(A) an HCO
₃
⁻
reabsorption defect

(B) an aldosterone deficiency

(C) a proton back leak into the cortical collecting duct cells

(D) insensitivity of the renal cortical collecting duct to aldosterone

(E) proton pump failure in the cortical collecting duct

17.
Type IV RTA can be caused by

(A) aldosterone deficiency

(B) a bicarbonate reabsorption defect

(C) insensitivity of the cortical collecting duct to aldosterone

(D) all of the above

(E) A and C only

18.
Type IV RTA in children that is caused by pseudohypoaldosteronism is best treated with

(A) mineralocorticoid-like fludrocortisone

(B) alkali supplementation

(C) vitamin D supplementation

(D) diuretics such as thiazides or furosemide

(E) none of the above

19.
Type IV RTA caused by hyporeninemic hypoaldosteronism is best treated with

(A) vitamin D and alkali supplements

(B) mineralocorticoid-like fludrocortisone

(C) angiotensin-converting enzyme (ACE) inhibitors

(D) angiotensin receptor-blocking agents

(E) none of the above

ANSWERS

1.
(B)
The serum anion gap is calculated as (serum sodium [cation; mEq/L] − serum chloride [anion; mEq/L] + serum bicarbonate [anion; mEq/L]). The anion gap is this case is [137 − (110 + 16)] = 11. Usually the anion gap is 10, with a normal range of 8-15. The serum chloride concentrate is also high. Therefore, this patient has a normal anion gap or hyperchloremic metabolic acidosis.

2.
(A)
The urine anion gap (UAG) is calculated as: urine sodium concentration (mEq/L) + urine potassium concentration (mEq/L) − urine chloride concentration (mEq/L). Under normal circumstances, there is minimal HCO
₃
⁻
in the urine. Therefore, it is not included in the equation.

3.
(A)
The UAG is an indirect measure of ammonium excretion in the urine. This calculation is employed because ammonium is difficult to measure. Ammonium excretion in the urine is one of the ways kidneys excrete protons (H
⁺
) to maintain acid-base homeostasis. Under normal circumstances, the UAG is a negative number (ie, the sum of the Na and K concentration is less than the Cl concentration) that represents the unmeasured ammonium cation (NH
₄
⁺
, ie, ammonium ion). Ammonium ions constitute almost all of the cations in the urine after Na and K are excluded. In this patient, the UAG is a positive number (+20). This is abnormally high and indicates no ammonium ion or the presence of another anion such as HCO
₃
⁻
(which has not been measured in the urine). The latter is present in excess in the urine in proximal RTA and is also not measured routinely in the urine. A positive UAG is therefore a result of decreased or impaired production of ammonium and an increased concentration of HCO
₃
⁻
in the urine due to excessive urinary losses. Both changes occur in proximal RTA. Once the serum bicarbonate falls below the renal threshold, bicarbonaturia ceases. The urine pH can then decrease to less than 5.5 as distal acidification in the cortical collecting duct continues to be normal in proximal RTA, which is characterized by HCO
₃
loss in the urine.

In gastroenteritis, a hyperchloremic metabolic acidosis can also occur and there is no increased serum anion gap (SAG). As a compensatory mechanism, the kidneys, if normal, would excrete more ammonium to excrete protons (H
⁺
) in an attempt to correct the metabolic acidosis. In this instance, one would expect the UAG to be more negative than normal. For example, the UAG may be more negative (eg, −60 or lower), suggesting increased urinary ammonium excretion.

4.
(C)
The UAG in this patient is positive (+20), suggesting decreased or absent ammonium in the urine. This suggests proximal RTA because the urine pH is also lower than 5.5, lower than that occurring in distal RTA. Patients with distal RTA have a proton pump disorder in the cortical collecting duct with inability to excrete hydrogen ions, and therefore they are not able to acidify urine to a pH of less than 5.5.

If this normal anion-gap metabolic acidosis were a result of gastroenteritis with normal renal function, one would expect a more negative than normal UAG. Such a finding suggests increased urinary ammonium excretion by the kidneys as a compensatory mechanism to maintain acid-base homeostasis.

5.
(C)
Nephrocalcinosis occurs commonly with distal RTA and rarely with proximal RTA. In distal RTA, nephrocalcinosis is caused by persistent metabolic acidosis and buffering of the acidosis by bones. Calcium is released into the serum leading to hypercalciuria. There is also decreased citrate excretion in distal RTA. Citrate in the urine inhibits stone formation. These changes in distal RTA make nephrocalcinosis and renal calculus formation more likely in distal RTA. As mentioned, nephrocalcinosis can occur in proximal RTA as well, and therefore a renal ultrasound may be useful in detecting nephrocalcinosis.

6.
(
D
) Proximal RTA can be primary, which includes genetically determined proximal RTA that can be autosomal recessive or dominant. Proximal RTA can also be secondary to several disorders, including metabolic disorders such as cystinosis, galactosemia, glycogen storage disease, and carbonic anhydrase deficiency. It can also be associated with drugs and toxins and heavy metal poisoning including lead toxicity. It can also occur as an isolated bicarbonate reabsorption defect with consequent HCO
₃
⁻
loss in the urine or as a part of Fanconi syndrome, a generalized disorder of proximal tubules leading not only to bicarbonaturia but also glycosuria, aminoaciduria, and phosphaturia.

7.
(E)
Treatment of both proximal and distal RTA consists of alkali supplementation with either oral sodium bicarbonate or sodium citrate. Citrate is converted to bicarbonate by the liver and therefore requires normal liver function. Because both types of RTA can be associated with hypokalemia, supplementation with potassium citrate or potassium chloride may also be needed. Dietary sodium restriction helps to enhance proximal tubular reabsorption of Na and HCO
₃
⁻
and decreases the alkali supplementation requirements. Prostaglandin synthesis inhibitors are not known to play a role in the treatment of RTA.

8.
(C)
Type III RTA, originally described as mixed type I and type II RTA, is no longer recognized. In young infants and premature infants there can be a transient physiologic proximal tubular immaturity leading to increased urinary HCO
₃
⁻
losses during infancy. Children with type I RTA resulting from a hydrogen ion secretion defect thus also have increased urinary HCO
₃
⁻
losses. Therefore the term
mixed
or
type III RTA
was used in the older literature. However, this bicarbonaturia tends to resolve as the tubules mature but the distal acidification defect persists. Therefore the patients who were first described as having mixed RTA were actually children with distal RTA and a physiologic proximal tubular immaturity that resolved with time.

9.
(D)
Only type IV RTA causes hyperkalemia. In children, this could be the result of pseudohypoaldosteronism (with normal or high serum aldosterone levels but insensitivity or relative lack of aldosterone receptors in the principal cell of the cortical collecting duct, hence the term
pseudohypoaldosteronism
) and in adults because of mineralocorticoid deficiency as a result of hyporeninemic hypoaldosteronism. Other causes of hypoaldosteronism leading to type IV RTA include Addison disease, congenital adrenal hyperplasia, and effects of drugs such as ACE inhibitors, heparin, and cyclosporine.

10.
(E)
Hypokalemia occurs with type I and II RTA. In type I RTA there is a proton pump disorder with failure of hydrogen ion excretion. Therefore another cation must be excreted with the anions delivered in the filtrate to the cortical collecting duct; this cation is usually K. In type II RTA there is an excess of urine anions (HCO
₃
⁻
in this case) that have to be excreted in combination with cations like K. This leads to increased excretion of K in the cortical collecting duct and hypokalemia. Both primary type I and II RTA can have autosomal recessive or autosomal dominant inheritance. Patients with both type I and II RTA can present with vomiting, anorexia, constipation, polyuria, polydipsia, or growth retardation. Both conditions have associated hypokalemia with muscle weakness.

11.
(E)
Rickets can occur in both type I and type II RTA. It is not seen in type IV RTA.

12.
(A)
Although nephrocalcinosis can occur in both type I and type II RTA, it is much more common in type I RTA (distal RTA). This is because of the following:

1. Persistent metabolic acidosis, which is seen in type I RTA compared with type II (proximal RTA) where blood pH tends to fluctuate more than in type I RTA.

2. Increased serum calcium because of calcium released from the bone as a result of buffering of persistent metabolic acidosis by the bones.

3. Decreased citrate excretion in the urine or hypocitraturia because of the distal tubular defect in type I RTA. Citrate and magnesium in the urine are known inhibitors of stone formation. In type I RTA, the previously mentioned factors lead to an increased incidence of nephrocalcinosis.