Effective regulation of acid–base status requires that the kidneys retain the ability to recover virtually all of the fi ltered bicarbonate, acidify the urine, and effectively excrete additional protons as ammonium. A defect in any one of these mechanisms leads to a normal anion gap acidosis known as renal tubular acidosis (RTA). RTA is classifi ed based on the location of the defect. Distal RTA (dRTA), also known as Type 1 RTA, occurs when distal acidifi cation and H + secretion are impaired. Distal RTA may be inherited as an autosomal dominant or recessive trait. Autosomal recessive dRTA often presents in infancy, whereas autosomal dominant dRTA may not present until adolescence or young adulthood. Mutations in the genes encoding carbonic anhydrase II, kidney anion exchanger 1 (kAE1), and subunits of the renal proton pump (H + -ATPase) have been identifi ed in patients with dRTA.(41) Sensorineural deafness is often found with genetic forms of dRTA in which the vacuolar proton pump is mutated. Amphotericin B can cause an acquired dRTA which is due to increased membrane permeability within the tubular cells of the distal nephron. Distal RTA is usually associated with hypokalemia. There is one form of hyperkalemic dRTA in which reduced sodium reab- sorption within the principal cells in the cortical collecting tubule leads to a voltage depen- dent defect in proton secretion. This can be seen with obstructive uropathy, sickle cell disease, severe volume depletion, and with drugs which inhibit sodium reabsorption, such as lithium, trimethoprim, and amiloride.
Distal RTA results from a decrease in urinary proton excretion. This leads to a high urine pH (>5.3), ineffective generation of ammonium, and the inability to excrete an acid load.
The result is a severe, progressive acidosis in which the serum bicarbonate can fall below 10 mEq/L. (Table 6-9 ) However, since proximal function is intact and the kidneys are able to recover the fi ltered bicarbonate, the fractional excretion of bicarbonate is low (<3% in adults, 5–10% in young children). Due to the severity of the acidosis, dRTA can present with recurrent episodes of vomiting and dehydration, poor feeding, constipation, and failure to thrive. Children frequently have kidney stones, nephrocalcinosis and hypercalciuria. Stone formation occurs as a result of the increased calcium and phosphorus release from the bone during buffering of acidemia, decreased tubular reabsorption of calcium and phosphorus leading to hypercalciuria and hyperphosphaturia, and low levels of urinary citrate (a stone inhibitor). A fi nal factor in stone formation is the high urine pH seen in distal RTA, which decreases the solubility of calcium phosphate, increasing the likelihood of stone formation.
Growth retardation is usually prominent. Hypokalemia, when present, can lead to severe muscle weakness. Distal RTA is almost always permanent, requiring life long treatment with an alkalinizing agent.
Proximal RTA (pRTA), also known as Type 2 RTA, is due to decreased capacity of the proximal tubule to reabsorb the fi ltered load of bicarbonate. As bicarbonate is lost in the urine, the serum bicarbonate falls, leading to a decrease in the amount of bicarbonate which is fi ltered. At some point, a threshold is reached where the proximal tubule is able to reab- sorb the remaining bicarbonate, and the serum bicarbonate stabilizes at a new steady state, usually at a level of 14–20 mEq/L. This can be demonstrated by determining the fractional excretion of bicarbonate in the face of bicarbonate loading. As serum bicarbonate increases above the threshold, spilling of bicarbonate in the urine results in a fractional excretion which is greater than 15–20%. Although huge amounts of bicarbonate may be lost, distal
A decreased extracellular pH, hypokalemia and a decreased ECV can lead to an increase in renal acid excretion.
In distal RTA, decreased urinary proton excretion leads to severe, progressive acidosis which can be accompanied by kidney stones or nephrocalcinosis.
function is intact so the ability to acidify the urine is retained once a steady state has been reached. Thus, despite a low serum pH, the urine pH can be less than 5.3. Features of pRTA include growth retardation, recurrent vomiting and failure to thrive. Unlike distal RTA, prox- imal RTA is rarely associated with stones or nephrocalcinosis. Rickets and osteomalacia may occur in association with phosphate wasting. The proximal dysfunction of Type 2 RTA can be accompanied by generalized proximal dysfunction, which is also known as Fanconi syndrome. In Fanconi syndrome, there can be loss of glucose, amino acids, potassium, and phosphorus in the urine in addition to the bicarbonate wasting. Therapy for pRTA often requires large amounts of bicarbonate (10–15 mEq/kg/day) because increasing levels of serum bicarbonate result in a fi ltered load that is above the reabsorptive capacity and most is lost in the urine. In addition, if there is phosphate wasting and bone disease, phosphate and Vitamin D supplementation may be required. Isolated, idiopathic pRTA in children, particu- larly in males, may be transient, resolving within a few years.
Type 4 RTA is usually caused by insuffi cient aldosterone synthesis or resistance to aldos- terone. Aldosterone resistance often stems from a defect in the receptor or from tubular damage. Type IV RTA may be isolated or occur in patients with renal parenchymal disease.
It may be transient in infancy and early childhood. Typically, acidosis is mild, with a serum bicarbonate >15 mEq/L. Proximal bicarbonate recovery is intact, so the fractional excretion of bicarbonate is low. Inherited defects leading to Type 4 RTA include congenital adrenal hyperplasia with salt wasting, isolated hypoaldosteronism, and pseudohypoaldosteronism (due to a defect at the aldosterone receptor level). An acquired Type 4 RTA can be due to tubular damage resulting from obstructive nephropathy, tubulointerstitial nephritis, sickle cell disease, kidney transplant rejection, lupus nephritis, and from such drugs as cyclosporine.
This is distinguished from the dRTA hyperkalemic form by the ability to reduce the urine pH. The lack of aldosterone action results in an inability to effectively secrete protons and potassium, leading to acidosis and hyperkalemia. In addition, the accompanying hyper- kalemia directly impairs ammonia production. The hyperkalemia is often out of proportion to the degree of renal impairment. The clinical presentation of Type 4 RTA is varied and depends on the degree of hyperkalemia and whether salt wasting is present. Type 4 RTA is diagnosed by measuring serum aldosterone and renin levels, although some forms involve resistance to aldosterone (pseudohypoaldosteronism). Treatment depends on the underlying cause. In the case of aldosterone defi ciency, mineralocorticoid replacement can result in cor- rection of both the hyperkalemia and the acidosis.
DISTAL RTA (TYPE 1) PROXIMAL RTA (TYPE 2)
ALDOSTERONE DEFICIENCY/
RESISTANCE (TYPE 4) Serum potassium Normal/low Normal/low High
High with voltage defect
Urine pH when acidotic >5.3 Variable (< 5.3 when below threshold)
<5.3
Serum bicarbonate (untreated)
Low(can be < 10 mEq/L) 14–20 mEq/L >15 mEq/L Fractional excretion of
bicarbonate with normal serum bicarbonate
<3% (adults) >15–20% <3%
<5–10% (young children)
Associated conditions Nephrocalcinosis Rickets Renal stones
Clinical course Usually requires lifelong therapy
Can be transient Variable, depends on underlying cause
TABLE 6-9
TYPICAL FEATURES OF RENAL TUBULAR ACIDOSIS (RTA)
Adapted from: Rose and Post ( 2001 )
In proximal RTA, loss of fi ltered bicarbonate leads to a milder acidosis; however, it is diffi cult to treat, requiring massive doses of bicarbonate.
Although the involvement of a pediatric nephrologist is recommended if a diagnosis of renal tubular acidosis is suspected, there are a number of relatively simple tests which are useful as the fi rst steps in the investigation. When RTA is suspected, the fi rst step is simulta- neous measurement of blood and urine. Evaluation of serum pH with a blood gas allows for confi rmation that there is in fact systemic acidemia, rather than a respiratory disturbance with metabolic compensation. Measurement of serum electrolytes, including Na, K, Cl, HCO 3, BUN, and creatinine, allows for detection of renal insuffi ciency, hyperkalemia/
hypokalemia and calculation of the anion gap to confi rm a normal anion gap acidosis. The serum anion gap can be calculated from the following equation:
Aniongap Na= +−(Cl−+HCO )3−
Normally, unmeasured anions result in an anion gap of 5–11 mEq/L. With renal or stool losses of NaHCO 3 , there is increased renal reabsorption of NaCl in order to maintain extra- cellular volume. The result is an elevation of serum Cl - without an elevation of the anion gap (since both Na + and Cl - increase, resulting in a normal anion gap hyperchloremic metabolic acidosis). If there is an elevated anion gap, this implies that an unmeasured anion is contrib- uting to the acidosis and this should be investigated further.
Close examination of the urine can provide additional information which is useful in the evaluation of RTA. Urine pH can be helpful in differentiating between the different types of RTA, but it is important to remember that a low urine pH is not inconsistent with RTA.
Urinalysis, urine electrolytes and urine amino acid evaluation allow for detection of gluco- suria, phosphaturia, aminoaciduria, and evaluation of urinary sodium handling. Urine elec- trolytes can be used to calculate the urine net charge, which gives an estimate of urinary ammonium excretion.
Urine net charge (mEq/L) = urine Na (U+ Na) + urine K (U ) - urine Cl (U )+ K − Cl Since the major cation which is not measured is ammonium, the urine net charge is indica- tive of urinary ammonium excretion. In the case of systemic acidemia, the appropriate renal response is ammonium generation to allow for excretion of the acid load. In this case, a large number of Cl - ions should be present to balance the unmeasured cation ammonium, leading to a negative urine net charge, typically −30 to −50 mEq/L. Confi rmation of a negative urine net charge is consistent with intact distal urinary acidifi cation mechanisms. If there is a nor- mal anion gap with a negative urine net charge, the differential diagnosis includes pRTA, acetazolamide use and other sources of bicarbonate loss, such as stool losses. A urine net charge that is positive (>0 mEq/L) implies low distal acidifi cation and is consistent with renal causes of acidosis such as dRTA and Type 4 RTA. In order to evaluate the urine anion gap, there must be adequate distal sodium delivery with a urine sodium >25 mEq/L. Low distal sodium delivery, such as occurs with hypovolemia, causes a reversible form of dRTA which will correct with volume repletion as sodium delivery to the distal segment increases.
The urine net charge is not a useful tool when there are unmeasured anions present, such as in ketoacidosis or with drugs which are excreted as anions, such as penicillin and aspirin.
(43) In these situations, the amount of ammonium may be estimated by examining the urine osmolal gap, comparing the calculated and measured urine osmolality (U osm ). Since ammo- nium salts (NH 4 + and its associated anion) represent the major unmeasured osmoles, the amount of ammonium can be estimated by using the following equation.
Urine NH4+= ½ (Measured Uosm – CalculatedUosm)
If U Na and U K are in mEq/L but U urea and U glu are in mg/dL, the following equation can be used to convert all variables to mmol/L.
osm Na K urea glu
4
[U – (2 U 2
Urine NH mmo U U / 2.8 U / 18)
l / L)
2 ( ]
+ × + × + +
=
Type 4 RTA is usually caused by insuffi cient aldosterone synthesis or resistance to aldosterone. Lack of aldosterone action results in an inability to effectively secrete protons and potassium, leading to acidosis and hyperkalemia.
With renal or stool losses of NaHCO 3 , increased renal reab- sorption of NaCl leads to a non-anion gap hyperchloremic metabolic acidosis.
Low distal sodium delivery, such as occurs with hypovolemia, causes a reversible form of dRTA which will correct with volume repletion as sodium delivery to the distal segment increases.
Since NH 4 + salts are the major unmeasured osmoles in the urine, the osmolal gap is refl ective of urine ammonium excretion. If there is systemic acidemia, the appropriate renal response is generation of ammonium with a urinary ammonium value greater than 75 mEq/
dL. A urine NH 4 + which is less than 25 mEq/L is consistent with RTA with inadequate ammonium production.