A woman with generalised weakness, hypokalaemia, and metabolic acidosis

Short answer

Distal renal tubular acidosis.

Long answer

Renal tubular acidosis comprises a group of disorders that result from tubular damage without glomerular damage. Primary and acquired forms have been described. There are three major types: type 1 or distal renal tubular acidosis, where the basic defect is impaired excretion of hydrogen ions; type 2 or proximal renal tubular acidosis, where the basic defect is a failure in bicarbonate reabsorption; and type 4 renal tubular acidosis, which is caused by apparent or real aldosterone deficiency or resistance and is most commonly associated with diabetes or interstitial nephritis. Hyperchloraemic metabolic acidosis with a normal anion gap, with or without associated defects in potassium homeostasis, and a urine pH greater than 5.5 in the presence of acidaemia are the hallmark features of renal tubular acidosis.

Kidneys respond to acidosis by increasing ammonium excretion in the urine. Failure of the kidney to increase ammonium output in the setting of acidosis indicates that a defect in renal acidification may be primarily responsible for the acidosis.1 Because renal ammonium excretion is not measured directly in most laboratories, urine anion gap provides an estimate of renal ammonium excretion. Urine anion gap should be negative in the presence of excess acidosis because of excess ammonium excretion. A positive urine anion gap indicates impairment of the urinary acidification process.

Distal renal tubular acidosis is an important cause of nephrolithiasis, nephrocalcinosis, osteodystrophy, and growth retardation in children.2 In one study of more than 300 patients with nephrocalcinosis, 20% had underlying distal renal tubular acidosis.3 Hypercalciuria and low urinary excretion of citrate are important factors in the development of nephrocalcinosis. In distal renal tubular acidosis, systemic acidosis leads to increased citrate reabsorption in the proximal tubule and thus to reduced urinary citrate excretion. Kidney stones and nephrocalcinosis are less common in proximal renal tubular acidosis because citrate reabsorption is often reduced and urinary citrate excretion increased.4

Our patient presented with profound hypokalaemia, non-anion gap metabolic acidosis, and a urine pH of 7.0 despite metabolic acidosis. A positive urine anion gap of 8.2 (urine sodium+urine potassium−urine chloride) meant impaired excretion of ammonia, thus confirming a diagnosis of an impaired renal acidification mechanism. Laing and Unwin provide a detailed discussion of the molecular pathophysiology of renal tubular acidosis.5

Short answer

Primary Sjögren’s syndrome.

Long answer

Acquired distal renal tubular acidosis can be associated with several underlying diseases including sickle cell disease, Sjögren’s syndrome, systemic lupus erythematosus, and drugs such as amphotericin B and lithium. Sjögren’s syndrome is defined as an autoimmune epithelitis characterised by lymphocytic infiltration of exocrine glands and epithelia. The lacrimal and salivary glands are commonly affected, resulting in dry eyes and xerostomia. A third of patients, however, present with systemic extraglandular manifestations.6 Renal tubular problems are common in primary Sjögren’s syndrome. In one study of 130 patients with primary Sjögren’s syndrome, 95 patients (73%) developed renal tubular acidosis, with 91 of them having distal renal tubular acidosis.7 Serological markers have a higher predictive value in the diagnosis of Sjögren’s syndrome than clinical symptoms and signs.8 Anti-Ro/SSA and anti-La/SSB antibodies are highly specific for Sjögren’s syndrome. Anti-Ro/SSA are the most prevalent antibodies in many autoimmune diseases, such as systemic lupus erythematosus, Sjögren’s syndrome/systemic lupus erythematosus overlap syndrome, subacute cutaneous lupus erythematosus, neonatal lupus, and primary biliary cirrhosis. Anti-La/SSB antibodies have the highest specificity (97%) for predicting Sjögren’s syndrome, however, and their presence is associated with internal organ manifestations or haematological abnormalities. Our patient did not have ocular or oral symptoms and did not undergo salivary gland biopsy so does not fulfil the diagnostic criteria for primary Sjögren’s syndrome. However, symptomatology has been challenged as a classification criterion and although sicca syndrome and dysfunction of the parotid and salivary glands are traditional hallmarks of Sjögren’s syndrome, these are not necessary for severe life threatening renal tubular acidosis and paralysis from Sjögren’s syndrome.6 9 Moreover, antibodies appear early in primary Sjögren’s syndrome, sometimes years before the first symptoms manifest.6 10

Short answer

Oral potassium and bicarbonate replacement.

Long answer

In distal renal tubular acidosis, adequate base should be provided to balance hydrogen ion production, usually 1-2 mmol/kg given as a mixture of sodium and potassium salts. Children require a higher dose because hydrogen ions are released from bone during the process of skeletal growth, so the required dose decreases progressively with age. Potassium citrate can also be used, and a dose of 4 mmol/kg per 24 hours is recommended in children. An appropriate dosage should correct most of the metabolic abnormalities, including hypercalciuria. It is important that hypercalciuria is prevented to avoid long term complications of nephrolithiasis and dystrophy. It is useful to monitor the urinary calcium to creatinine ratio and citrate to creatinine ratio so that the appropriate amount of alkali supplementation can be calculated. Treatment should be maintained throughout life.11