Medicine Newbie: Renal Tubular Acidosis (RTA)

Wednesday, 5 October 2011

Renal Tubular Acidosis (RTA)

Introduction

Renal tubular acidosis was first described in 1935 by Lightwood and 1936 by Butler et al. in children. Baines et al. first described it in adults in 1945.

Renal Tubular Acidosis (RTA) is a condition characterized by the inability of the kidneys to secrete hydrogen ions (acid) and therefore, cannot maintain acid-base balance.

Renal tubular acidosis is characterized by a normal anion gap and hyperchloremic metabolic acidosis; plasma potassium may be normal, low, or high, depending on the type of RTA.

Renal tubular acidosis (RTA) syndromes are nonuremic defects of urinary acidification. These syndromes differ from uremic acidosis, which is associated with a high anion gap and with enhanced proton secretion by each remaining nephron

MedIndia. Renal Tubular Acidosis is treated using alkaline agents like sodium bicarbonate and sodium citrate or potassium citrate. In some cases, treating the cause helps the patient recover from RTA. Vitamin D may be needed in some cases. The condition should be diagnosed early and treatment instituted to prevent complications. Regular monitoring is also necessary in these patients.

Types of RTA

There are 4 types of RTA based on their molecular mechanisms responsible for the defect in urinary acidification.

Type 1 or Classical Distal RTA
Type 2 or Proximal RTA
Type 3 is a combination of Types 1 and 2 (Type 3 is rare)
Type 4 disease or Hyperkalaemic RTA

Type 3 is rarely discussed. Most comparisons of RTA are limited to a comparison of types 1, 2, and 4.

Type 1 or Classical Distal RTA (dRTA)

Wikipedia. Distal RTA (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the cortical collecting duct (CCD) of the distal nephron. This failure of acid secretion may be due to a number of causes, and it leads to an inability to acidify the urine to a pH of less than 5.3. Because renal excretion is the primary means of eliminating acid from the body, there is consequently a tendency towards acidemia. There is an inability to excrete H⁺ while K⁺ cannot be reabsorbed, leading to acidemia (as H⁺ builds up in the body) and hypokalemia (as K⁺ cannot be reabsorbed). This leads to the clinical features of dRTA;

Normal anion gap metabolic acidosis/acidemia
Hypokalemia
Urinary stone formation (related to alkaline urine, hypercalciuria, and low urinary citrate).
Nephrocalcinosis (deposition of calcium in the substance of the kidney)
Bone demineralisation (causing rickets in children and osteomalacia in adults)

WebMD. The distal convoluted tubule and the collecting tubule reclaim about 15% of filtered bicarbonate, lower the urine pH to its final value, and titrate most of the nonbicarbonate urinary buffers. [What are these nonbicarbonate urinary buffers?]

FAR. There are 2 types of collecting tubules, cortical collecting tubule (CCT) and medullary collecting tubule (MCT). Acidification of urine occurs at these 2 locations, CCT and MCT. However, different factors govern these acidifications. CCT acidification (of urine) is governed by aldosterone and linked to sodium transport. Aldosterone increases this transepithelial voltage and hence CCT acidification. [Read on Aldosterone metabolism.] MCT acidification (of urine) is not inflenced by aldosterone or linked to sodium transport.

WebMD. In the cortical collecting tubule (CCT), acidification is indirectly coupled to sodium transport and is influenced by transepithelial voltage. Active sodium reabsorption in this nephron segment generates a negative electrical potential difference, which facilitates the active secretion of protons. [What is meant by active sodium reabsorption?]

Acidification in the medullary collecting tubule (MCT) is not influenced by sodium transport and occurs against an electrical gradient. The potential difference in this nephron segment is lumen-positive, most likely the result of active proton secretion. The absolute magnitude of proton secretion is greater in the MCT than in the CCT.

Hydrogen ion secretion is mediated by two proton pumps located in the intercalated cells, an H⁺-ATPase and an H⁺,K⁺-ATPase.

The H⁺-ATPase is regulated by aldosterone, while the H⁺,K⁺-ATPase responds inversely to the serum potassium level.

In the tubular lumen, the secreted hydrogen ions combine with ammonia and other urinary buffers and are excreted in urine. [Please refer to past year's lecture notes for these reactions.]

FAR. Note that the resultant level of potassium in blood is dependent on the nature and location of the renal tubular defect. In some defects, hypokalemia results; and in other defects, potassium level remains unperturbed, i.e., remains normal.

WebMD. Distal RTA (dRTA) can occur as a result of the following defects:

Impaired proton pump function
- Defective H⁺,K⁺-ATPase (classic hypokalemic dRTA) or
- Defective H⁺-ATPase (normokalemic dRTA),
Decreased potential difference in CCT (or "voltage-dependent" dRTA),
Aldosterone deficiency (or resistance),
Decreased capacity to maintain steep pH gradients (or "backleak" dRTA),
Rate-dependent dRTA, or
Abnormal anion exchange.

Classic dRTA is a syndrome of hypokalemia, hyperchloremic metabolic acidosis, inability to lower the urine pH below 5.5, nephrocalcinosis and nephrolithiasis, and osteomalacia or renal rickets. The clinical spectrum of dRTA is broad; no single pathogenetic mechanism exists.

"Backleak" dRTA is due to Amphotericin B therapy in patients with hypokalemic dRTA.

Type 2 or Proximal RTA

Wikipedia. Proximal RTA (pRTA) is caused by a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the urine can acidify to a pH of less than 5.3. pRTA also has several causes, and may occasionally be present as a solitary defect, but is usually associated with a more generalised dysfunction of the proximal tubular cells called Fanconi's syndrome where there is also phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria. The principal feature of Fanconi's syndrome is bone demineralization (osteomalacia or rickets) due to phosphate wasting.

WebMD. Proximal RTA can be divided in two categories, isolated bicarbonate wasting and generalized proximal tubule dysfunction (Fanconi's syndrome). Each type can be further divided according to whether it is accompanied by systemic or genetic disease.

Patients with proximal RTA generally have a plasma bicarbonate concentration more than 15 mmol/L; severe metabolic acidosis rarely develops. In fact, all the filtered bicarbonate will be completely reclaimed, and these patients will have normal distal nephron acidification. Thus, in patients with proximal RTA, urine is acidified normally during acidemia.

When plasma bicarbonate is raised by exogenous addition of alkali, the reduced proximal capacity to reabsorb bicarbonate leads to bicarbonaturia. After cessation of alkali administration, urinary bicarbonate wastage continues until the filtered load reaches the level at which the combined reabsorptive capacity of the proximal tubule and the distal tubule is no longer exceeded; urine bicarbonate concentration then becomes low and urine pH is appropriately acidic.

Isolated defects in proximal tubule bicarbonate reabsorption are rarely identified. Most patients with proximal RTA have multiple defects in proximal tubular function, including defective reabsorption of glucose, calcium, phosphate, citrate, uric acid, lysozymes, light-chain immunoglobulins, and amino acids.

Low serum potassium due to distal potassium wasting is a consistent finding in proximal RTA. This involves the renin-angiotensin-aldosterone system (RAAS). Kaliuresis is promoted by increased distal delivery of sodium bicarbonate and by hyperaldosteronism resulting from volume contraction. Plasma renin levels are typically elevated. The rate of kaliuresis is, therefore, proportional to the bicarbonate delivery to the distal nephron and also to the plasma bicarbonate concentration. Administration of alkali to correct acidosis in these patients leads to an exaggeration of the kaliuresis and potassium deficiency.

Patients with proximal RTA may have high urinary calcium excretion; however, nephrocalcinosis and renal calculi are rare. This may be due to the relatively normal rate of citrate excretion in these patients as compared with that of most acidotic patients.

Children with proximal RTA are likely to have growth retardation, rickets, osteomalacia, and abnormal vitamin D metabolism. In adults, osteopenia may develop but generally without pseudofractures.

Type 3 RTA - Combined proximal and distal RTA

Wikipedia. In some patients, their RTA shares features of both dRTA and pRTA. This rare pattern was observed in the 1960s and 1970s as a transient phenomenon in infants and children with dRTA, possibly in relation with some exogenous factor such as high salt intake, and is no longer observed. This form of RTA has also been referred to as juvenile RTA.

Combined dRTA and pRTA is also observed as the result of inherited carbonic anhydrase II deficiency. Mutations in the gene encoding this enzyme give rise to an autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, cerebral calcification, and mental retardation. It is very rare and cases from all over the world have been reported, of which about 70% are from the Magreb region of North Africa, possibly due to the high prevalence of consanguinity there. The kidney problems are treated as described above. There is no treatment for the osteopetrosis or cerebral calcification.

Type 4 RTA or Hyperkalaemic RTA

Wikipedia. Type 4 RTA is due to either a deficiency of aldosterone, or to a resistance to its effects. Type 4 RTA is not actually a tubular disorder at all nor does it have a clinical syndrome similar to the other types of RTA described above. It was included in the classification of renal tubular acidoses as it is associated with a mild (normal anion gap) metabolic acidosis due to a physiological reduction in proximal tubular ammonium excretion, which is secondary to hypoaldosteronism, and results in a decrease in urine buffering capacity. Its cardinal feature is hyperkalemia, and measured urinary acidification is normal, hence it is often called hyperkalemic RTA or tubular hyperkalemia.

Causes include: