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Primary gradient defect distal renal tubular acidosis presenting as hypokalaemic periodic paralysis
  1. P A Koul,
  2. A Wahid,
  3. F A Bhat
  1. Department of Internal Medicine, SheriKashmir Institute of Medical Sciences, Srinagar, Kashmir, India
  1. Correspondence to:
 Dr Parvaiz A Koul
 Department of Internal Medicine, SheriKashmir Institute of Medical Sciences, Soura, Srinagar 190 011, Kashmir, India;


A 45 year old man presented with recurrent hypokalaemic paralysis. Laboratory investigations revealed renal tubular acidosis as the cause of the hypokalaemia, and dynamic tubular studies suggested a gradient defect as the underlying cause. The patient had associated dextrocardia. To our knowledge, this is the first report of this condition

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One of the important presentations of distal renal tubular acidosis (DRTA) is recurrent hypokalaemic weakness, which can be life threatening.1,2 DRTA has been reported to cause periodic hypokalaemic paralysis, and the defect is usually secretory, characterised by an inability of the tubular cells to secrete H+ ions, resulting in acidosis and alkaline urine.1–4 However, amphotericin B has been known to cause DRTA due to a permeability defect, where the inability to lower urinary pH despite unimpaired H+ secretion is attributable to H+ leakback, which is more evident when the tubular urine is acidic.5,6 One study reported an infant with a spontaneous metabolic acidosis induced by a gradient defect;7 however, to our knowledge, no case of hypokalaemic periodic paralysis caused by a gradient defect DRTA has been reported previously. We report a case of hypokalaemic periodic paralysis in which the renal tubular defect was subsequently found to be due to an underlying gradient defect.


A 45 year old man was admitted with a 1-day history of lower limb weakness that had progressed slowly to involve his upper limbs over a period of 12 hours. He had received an insect bite on his right thigh 4 days previously, which had resulted in local cellulitis for which he was receiving cefuroxime and nimuselide. There was no history of intake of any diuretics, excessive sweating, gastrointestinal illness, or exposure to excessive cold or heat. The patient denied any tingling, paresthesias, weakness of the cranial nerves or respiratory muscles, or any sphincteric disturbance. He had experienced three similar episodes in the past, each being managed in the hospital by oral potassium chloride.

Clinical examination revealed a pulse rate of 96 beats/min, a blood pressure of 130/80 mmHg, a respiratory rate of 23 breaths/min, and temperature of 37.5°C, with grade 3 motor weakness of the upper limbs and grade 0–1 weakness of the lower limbs. Reflex, sensation, and sphincter responses were normal. The patient had non-localisation of the cardiac impulse, cardiac dullness from the right third space in the midclavicular line to the midsternal line, but stronger heart sounds on the right side of the chest (findings consistent with dextrocardia). He had resolving cellulitis of the left inguinal region, and the rest of the general and systemic examination was normal.

Haemoglobin was 132 g/l, leucocytes 5.3 × 109/l with a normal differential, platelet count 157 × 109/l, serum urea nitrogen 6.33 mmol/l, creatinine 70.7 mmol/l, glucose 4.77 mmol/l, proteins 78 g/l, and albumin 40 g/l. Serum alanine transferase was 86 IU/l (normal 0–40), aspartate transferase 75 IU/l (normal 0–35), creatinine kinase 1941 U/l (normal 50–195), lactate dehydrogenase 555 U/l (normal 250–450), sodium 130 mmol/l (normal 135–145), potassium 2.9 mmol/l (normal 3.5–5.5), and chloride 112 mmol/l (normal 98–108). Arterial pH was 7.41 (normal 7.38–7.44), pCO2 26.5 mmHg (normal 35–45), and bicarbonate 15.3 mmol/l (normal 22–28). Chest radiograph and electrocardiogram were consistent with dextrocardia. The patient was started on potassium chloride and recovered over a period of 24 hours.

Dynamic tubular function testing

Urinary pH was 7.0. In order to test renal acidification after induced academia, ammonium chloride (0.1 g/kg body weight) was administered, during which the blood pH increased to 7.30 but the urinary pH continued alkaline (pH>6.5), suggesting a defect in distal tubular acidification. Serum osmolality was 286 mOsmol/kg and urinary osmolality 379 mOsmol/kg; the osmolality did not change after administration of pitressin, suggesting hyposthenuria.

A bicarbonate infusion was administered at the rate of 3 ml/min/kg. At an induced blood pH of 7.76, urinary (U) pCO2 was 71.2 mm Hg, and blood (B) pCO2 was 30.4 mm Hg, giving a U−B pCO2 of 40.8 mm Hg (a normal response against a low value of <20 in DRTA). Urinary sodium was 188 mmol/l and chloride 124 mmol/l. Fractional excretion of bicarbonate was 3.2%. In order to test the proton secretory ability of the distal nephron, acetazolamide (15 mg/kg) was administered to induce maximum urinary alkalinisation. Two hours after administration, urinary pH increased to 7.65, urinary bicarbonate was 190 mmol/l, urinary pCO2 was 56.8, and U−B pCO2 was 29.7, indicating an intact proton secretory ability in the distal nephron. The dynamic studies suggested a gradient type of distal acidification defect.

Furosemide 60 mg was given in order to test the acidification at an increased sodium delivery. Urinary pH decreased to 4.2, suggesting an intact ability of the nephron to acidify urine after furosemide, arguing strongly in favour of a "gradient defect".

Ultrasound examination of the abdomen and intravenous urogram was normal. Serum antibodies to nuclear antigen, latex agglutination test, and antibodies to smooth muscle, parietal cell, and mitochondrial antigen were not detected. Serum levels of copper, caeruloplasmin, rennin, and aldosterone were normal, as was urinary excretion of calcium, phosphate, urate, protein, and aminoacids. An upper gastrointestinal tract endoscopy for dyspeptic symptoms revealed anatomy consistent with situs inversus. All family members of the patient denied a similar history and tested negative for any urinary acidification defect.


Gradient defect was for many years postulated to be the primary mechanism underlying DRTA.7 However, an inability to increase urinary pCO2 was subsequently demonstrated, implying a defect in proton secretion.8,9 A reliable measure of this was found to be the difference in urinary and blood pCO2 (urine minus blood levels); in DRTA the value is low. However, in DRTA induced by amphotericin B, there is a typical gradient defect, characterised by the ability of the tubule to increase urinary pCO2 after maximum alkalinisation.6,7

The diagnosis of DRTA in our patient was made from his inability to acidify urine in the face of metabolic acidosis. Various mechanisms underlying the common forms of DRTA are shown in fig 1. Ability to increase urinary pCO2 after maximum alkalinisation and to decrease urinary pH after giving furosemide strongly argue in favour of a gradient defect in our patient, rather than a primary H+ ion defect, where there is a inability to increase urinary pCO2 following alkalinisation of urine. Such a gradient defect is similar to that induced by amphotericin B. Associated hypokalaemia in our case suggested a generalised permeability defect involving both intercalated and principal cells, as is typically seen with patients receiving amphotericin B. One previously described case of gradient DRTA did not have accompanying hypokalaemia, but hypokalaemia induced paralysis was the primary presentation in our case. We are unaware of a similar report in the literature.

Figure 1

 Mechanisms underlying the main types of defects in distal renal tubular acidosis. In the secretory defect there is a failure of H+ ion secretion even when conditions are favourable for its secretion. In the "voltage defect", the nephron is unable to generate and maintain a negative intratubular potential difference as a result of defective sodium delivery or transport, resulting in a reduced secretion of both H+ and K+ ions. In the gradient defect there is an inability to create a steep H+ ion gradient across the tubule owing to leakback of secreted H+ ions.

Recent insights into the molecular understanding of DRTA have unravelled certain genetic mutations associated with the condition, including mutations in the chloride–bicarbonate anion exchanger 1 (AE1) seen in autosomal dominantly transmitted DRTA,10 ATPB1 in autosomal recessive DRTA associated with sensorineural deafness,11 and H-ATPase in patients with autosomal disease without sensorineural deafness.12 An increase in U–B pCO2 has also been postulated to arise from a misdirection of AE1 to the apical membrane of type A intercalated cells in a patient with Southeast Asian ovalocytosis who presented with hypokalaemia, but on dynamic tubular testing was found to have high urinary CO2 tension with an inability to lower pH with furosemide.13

Our patient illustrates that a gradient defect might be the underlying defect in patients with DRTA. Investigating patients with RTA with dynamic tubular studies could unravel the defect in more cases.


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  • Competing interests: there are no competing interests

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