INTRODUCTION

Renal tubular acidosis (RTA) refers to a group of disorders characterized by normal anion gap (hyperchloremic) metabolic acidosis with either hypokalemia or hyperkalemia and a relatively well preserved glomerular filtration rate (GFR).

• Normal anion gap metabolic acidosis with hypokalemia:

○ Proximal RTA (type 2 RTA) is caused by reduced tubular ability to reabsorb bicarbonate (HCO₃^–).

○ Distal RTA (type 1 RTA) is caused by defect in distal hydrogen (H⁺) excretion.

• Normal anion gap metabolic acidosis with hyperkalemia:

○ Type 4 RTA is due to either aldosterone deficiency or tubular resistance to the action of aldosterone. Less commonly this condition is caused by inherited or acquired defects in sodium (Na⁺) transport in the principal cells in collecting duct.

○ While type 4 RTA is the most common type of RTA, type 1 RTA is more common than type 2 RTA.

KIDNEY’S ROLE IN MAINTAINING ACID–BASE AND POTASSIUM BALANCE

The normal acid–base balance of the body depends on:

• Lungs: Alveolar ventilation removes carbon dioxide

• Kidneys: The tubules reclaim filtered HCO₃^– and excrete H⁺

The kidneys in a healthy adult filter about 4,200 mmol of HCO₃^– every day and all of it is reabsorbed in the renal tubules. While 85–90% of this HCO₃^– is reabsorbed in the proximal convoluted tubules (PCTs), the remaining 10–15% is reabsorbed in the distal nephron.

    Action of Carbonic Anhydrase in Reclaiming HCO₃^– in the Proximal Convoluted Tubule (Fig. 1)

The renal tubular cells similar to every cell in the body are deficient in Na⁺ due to the basolateral Na⁺-K⁺-ATPase extruding 3 Na⁺ from the cell and pulling in 2 K⁺ (Fig. 2). At the level of the glomeruli, with a GFR of 125 mL/min, healthy adults filter about 180 L of water over a day. More than 90% of the filtered water is reabsorbed in the tubules because water follows Na⁺, with the tubular cells being hungry for Na⁺ due to the intracellular deficiency.

Sodium bicarbonate (NaHCO₃) is freely filtered across the glomerular capillaries and dissociates in the lumen of PCT into Na⁺ and HCO₃^–; this Na⁺ is reabsorbed by the tubular cells in exchange for H⁺. In the tubular lumen, HCO₃^– combines with the H⁺ to form carbonic acid (H₂CO₃) under the influence of tubular carbonic anhydrase (CA). H₂CO₃ then splits into CO₂ and water. Water is lost in the urine while the CO₂ diffuses into the PCT cells and regenerates H₂CO₃ intracellularly after combining with H₂O. Aided by the intracellular CA, this H₂CO₃ then splits to form H⁺ and HCO₃^–. This H⁺ is secreted into the PCT lumen in exchange for Na⁺ while the HCO₃^– diffuses into the peritubular capillaries. The net result is that both Na⁺ and HCO₃^– (from the filtered NaHCO₃) are reabsorbed in the PCT cells. As the Na⁺ is reabsorbed, it drags along with it glucose, phosphate, uric acid, and amino acids.

An interference with the above would lead to bicarbonate loss in the urine causing type 2 RTA, as well as Na⁺ and the associated glucose, amino acids, phosphate, and uric acid loss in the urine, leading to glycosuria and proteinuria along with low plasma phosphate and uric acid (Fanconi syndrome).

An average healthy adult generates 50–70 mEq of acid per day from diet, most of which is excreted in the urine by tubular secretion. Excretion of this acid load requires urinary buffers to bind H⁺ as otherwise the urine would become supersaturated with excessive H⁺ and the pH would drop severely, inhibiting any more H⁺ secretion. Urine will not accept any more H⁺ from the tubules if its pH falls below 4.5.

The chief urinary buffers are ammonia-ammonium (NH₃ and NH₄⁺) and phosphate (HPO₄^-2 and H₂PO₄^-1).

TYPES 1 AND 2 RTA

Type 1 RTA is caused by inability of the distal tubules to secrete H⁺. The kidney characteristically cannot lower the urinary pH to <5.5 due to deficiency of H⁺ in the urine.

Na⁺ is reabsorbed in the tubules along with an anion, such as chloride (Cl^–) or bicarbonate (HCO₃^–), or in exchange for a cation, such as K⁺ or H⁺. As H⁺ secretion is impaired in type 1 RTA, the K⁺ secretion increases as a compensation leading to the hypokalemia.

While type 1 RTA may be inherited, acquired causes are more common and include Sjögren’s syndrome, systemic lupus erythematosus (SLE), hypergammaglobulinemic states, primary biliary cirrhosis, autoimmune hepatitis, hypercalciuria, obstructive uropathy, and renal transplantation (Table 1). Drugs like amphotericin can lead to type 1 RTA by causing excessive back leak of H⁺ in the distal tubules.

Sjögren’s syndrome has a very strong association with type 1 RTA and should be considered in the differential diagnosis even in the absence of sicca syndrome.

In type 2 RTA, the proximal tubule has a reduced capacity to reabsorb HCO₃^–. As the kidneys lose HCO₃^– and plasma HCO₃^– concentration falls, the filtered load of HCO₃^– decreases reaching a level that can be reabsorbed and a new steady state of serum HCO₃^– concentration is reached. Because of this ability of the kidney to decrease HCO₃^– excretion as well as compensatory increase in H⁺ secretion by the distal tubules, despite the aminoaciduria, urinary pH is <5.5. Reabsorption of Na⁺ (linked to reclaiming of HCO₃^–) in the proximal tubules helps to cotransport amino acid, glucose, uric acid, and phosphate. Type 2 RTA can occur as an isolated defect in HCO₃^– reabsorption or as a generalized defect in proximal tubular reabsorption with aminoaciduria, phosphaturia, glycosuria, and uric aciduria when the condition is termed Fanconi syndrome. The patient with Fanconi syndrome would present with normal anion gap metabolic acidosis with hypokalemia, urine pH <5.5, glycosuria, proteinuria, and low plasma phosphate and uric acid.

Although type 2 RTA may be familial, one must always suspect myeloma where the filtered immunoglobulin light chains by causing PCT cellular toxicity can lead to this condition. Other causes include Wilson’s disease, cystinosis, Lowe syndrome, outdated tetracycline, carbonic anhydrase inhibitors such as acetazolamide and topiramate, and lead or mercury poisoning (Table 2).

The metabolic acidosis in both types 1 and 2 RTA causes bones to release calcium salts to function as a buffer. This leads to progressive osteopenia and osteomalacia and also increased urinary calcium excretion. Under normal circumstances urinary citrate binds with calcium and makes it soluble. However, citrate is an effective alkaline buffer and hence in type 1 RTA, the proximal tubules tend to reabsorb increased amounts of citrate in an effort to combat the acidosis. The resultant deficiency of citrate in urine in type 1 RTA tends to make the urinary calcium insoluble. In addition, the alkaline urine markedly diminishes the urinary calcium solubility. The end result is increased incidence of nephrocalcinosis and nephrolithiasis in type 1 RTA.

As both types 1 or 2 RTA present with normal anion gap metabolic acidosis and hypokalemia, the only definitive way to distinguish between the two conditions is the urine pH (Table 3). Type 1 RTA is characteristically associated with urinary pH >5.5. In contrast, the urinary pH is usually <5.5 in type 2 RTA except when the patient is being treated with massive doses of alkali. Hypophosphatemia, hypouricemia, and glycosuria in the absence of raised blood glucose point toward Fanconi syndrome.

NORMAL ANION GAP (HYPERCHLOREMIC) METABOLIC ACIDOSIS IN DIARRHEA

Chronic diarrheal states may present with normal anion gap metabolic acidosis and hypokalemia and hence simulate RTA. The mechanism is as follows:

• Metabolic acidosis: Due to fecal loss of bicarbonate-rich pancreatic secretions
• Hypokalemia: Hypovolemia can lead to activation of renin–angiotensin–aldosterone system (RAAS) with the resultant tubular loss of K⁺ under the influence of aldosterone.

The urine anion gap (UAG) calculation helps to differentiate between RTA type 1 and extrarenal causes of normal anion gap acidosis such as diarrheal states, being positive in the former and negative in the latter.

UAG (in mEq/L or mmol/L) = Urine (Na⁺ + K⁺ – Cl^–)

The UAG is positive (between 20 and 90) in healthy individuals because the dietary and hence urinary Na⁺ and K⁺ is normally more than Cl^–. With metabolic acidosis from any cause, the kidney will respond by excreting a heavy load of H⁺ which will also need increased ammonia to buffer the H⁺. Since ammonia in the urine exists as NH₄Cl, this leads to increased urinary Cl^– with the result that the UAG becomes negative. In type 1 RTA since the defect is in the secretion of H⁺ and therefore there is no need for extra ammonia and hence urinary NH₄Cl remains low and UAG remains positive.

    Management

Treatment of both types 1 and 2 RTA consists of potassium replacement and alkali therapy. One should be careful when administering NaHCO₃ because the resultant Na⁺ loss in urine may increase K⁺ secretion and thus exacerbate hypokalemia. In this setting, it is advisable to replace K⁺ before the acidosis is corrected. Potassium citrate is often useful in these patients.

As explained above, type 1 RTA patients have low urinary citrate which makes them more predisposed to recurrent urinary stones. Potassium citrate can be useful in this patient group too.

Type 2 RTA often needs much bigger doses of alkali because of the tendency of the kidneys to excrete more HCO₃^– as the serum HCO₃^– concentration increases.

TYPE 4 RTA (HYPERKALEMIC DISTAL TUBULAR ACIDOSIS)

Type 4 RTA is the most common among the RTAs and patients present with normal anion gap metabolic acidosis and hyperkalemia.

Under normal circumstances, secretion of H⁺ and K⁺ in the collecting duct is dependent on the intraluminal negativity generated as a consequence of aldosterone-induced reabsorption of the Na⁺. With hypoaldosteronism or tubular unresponsiveness to aldosterone, less Na⁺ is reabsorbed and hence less H⁺ and K⁺ are secreted into the tubules.

Hyperkalemia in itself causes decreased tubular secretion of H⁺ by decreasing renal ammonia generation; ammonia is one of the chief buffers for H⁺ in the urine. Ammonia is derived from breakdown of glutamine by phosphate-dependent glutaminase (PDG) in the PCT cells. Hyperkalemia decreases PDG activity and therefore decreases ammonia production which in turn interferes with the tubular capacity to secrete H⁺.

The etiology of type 4 RTA can be divided in three groups based on the pathophysiology:

1. Aldosterone deficiency: Hyporeninemic hypoaldosteronism is common in diabetes mellitus. Other causes of hypoaldosteronism include nonsteroidal anti-inflammatory drug (NSAID) use, calcineurin inhibitors (cyclosporine and tacrolimus), angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) groups of drugs, and heparin or low molecular heparin.

2. Tubular unresponsiveness or resistance to aldosterone: This is seen with:

a. Potassium-sparing diuretics by either antagonizing the action of aldosterone by competing for the aldosterone receptor (spironolactone and eplerenone) or closing the sodium channels in the luminal membrane (amiloride and triamterene).

b. Antibiotics: Trimethoprim and pentamidine can cause type 4 RTA by closing the epithelial sodium channels in the collecting tubule with the resultant inability to excrete K⁺ and H⁺.