Urology

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Paul D Lawton MB BS, FRACP · Joan Cunningham ScD, ALM, AB · Nicholas A Gray MB BS, FRACP · Mark D Chatfield MSc, MA · Peter D Baade BAppSc(Hons), MMedSc, PhD · Karumathil Murali FRACP · Matthew D Jose FRACP, PhD, FASN

Given the link between high sodium intake and hypertension, gathering information on salt consumption among Indigenous Australians should be a public health priority.

Christopher G Lawrence*

The publication of the Australasian Creatinine Consensus Working Group’s position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. ...

Australasian Creatinine Consensus Working Group

To the Editor: Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor that is used in Australia as first-line antiviral treatment for HIV infection.1,2 Tenofovir may be nephrotoxic, particularly affecting proximal tubular function.3 We report a case of tenofovir-associated Fanconi syndrome, which demonstrates the need for vigilance in patients taking tenofovir. A 17-year-old rurally residing boy with perinatally acquired HIV infection presented to a tertiary referral hospital with renal impairment. His serum creatinine level had been normal 4 years previously. He had had severe leg pain and weakness for over a year, and was unable to mobilise without a walking frame. Because of his illness, he had stopped studying. He had commenced antiretroviral therapy in 1996, when he was 3 years old, and at presentation was taking tenofovir plus emtricitabine and lopinavir plus ritonavir. Follow-up with his local clinician was intermittent. The patient’s HIV viral load was undetectable, and he had a CD4 count of 0.62 × 109 cells/L. His serum creatinine level was 150 μmol/L (reference interval, 60–110 μmol/L) and his estimated glomerular filtration rate (eGFR) was 52 mL/min/1.73 m2 (normal value, > 90 mL/min/1.73 m2). He had all the features of Fanconi syndrome — hypophosphataemia with renal phosphate wasting, glycosuria, aminoaciduria, a reduced serum uric acid level and proteinuria (1.93 g/day). He also had hypokalaemia and acidosis, and his urine tested positive for β2-microglobulin. Histological analysis of a renal biopsy specimen showed proximal tubular abnormalities (Box). In addition, he had severely reduced bone mineral density, elevated bone turnover markers and vitamin D deficiency. The patient’s tenofovir therapy was ceased, he was started on an alternative antiretroviral regimen, and he was given phosphate, potassium, bicarbonate and calcium supplementation plus vitamin D and calcitriol therapy. Two months later, his serum creatinine level was 130 μmol/L, his eGFR was > 60 mL/min/1.73 m2, and his proteinuria, glycosuria and aminoaciduria had resolved. His leg pain and weakness resolved within another month. He has since been able to recommence full-time study. The persistent biochemical and renal abnormalities in this patient may have been a result of delayed recognition of Fanconi syndrome leading to prolonged illness. Risk factors for tenofovir-associated nephrotoxicity include a GFR of less than 90 mL/min/1.73 m2, use of nephrotoxic medications, comorbidities (eg, diabetes and hypertension) and use of some protease inhibitors. Patients on tenofovir should be screened at least 6-monthly for eGFR, serum phosphate levels, proteinuria and glycosuria.4 Three-monthly testing is also suggested in the initial year, due to the occurrence of tenofovir-associated nephrotoxicity without risk factors.5 Urinary protein to creatinine ratio is usually increased in tenofovir-associated nephrotoxicity, and tests for some urinary proteins may be useful in subtle cases of the condition.3 Testing for albuminuria (a marker of glomerular disease) and sole reliance on eGFR are insufficient for detecting tenofovir-associated tubular dysfunction.3 Due to potential renal toxicity, optimal outcomes for patients on tenofovir require careful monitoring of patients and close liaison between treating practitioners. Renal biopsy specimens showing proximal tubular abnormalities in a patient with tenofovir-associated Fanconi syndrome A: Prominent changes of acute tubular necrosis (haematoxylin and eosin stain; original magnification, × 4). B: Acute tubular necrosis with proximal tubular eosinophillic inclusions (arrows) representing giant mitochondria visible by light microscopy (haematoxylin and eosin stain; original magnification, × 10).

David M Gracey · Mangalee Fernando · John Ziegler · Christopher P White · Jeffrey J Post

A 10-year-old boy from Papua New Guinea with multidrug-resistant tuberculosis and multibacillary leprosy developed acute glomerulonephritis while being treated as an inpatient at Thursday Island Hospital in the Torres Strait, Queensland. This is the first such case to be reported in Australia, where these diseases are uncommon and the combination is extremely rare, and it outlines important learning points regarding the aetiology of renal disease among patients with tuberculosis and leprosy. (MJA 2011; 195: 150-152) Clinical recordA 10-year-old boy from a remote village in Western Province, Papua New Guinea (PNG), presented to Saibai Island Primary Health Centre in the northern Torres Strait, Queensland, with a 4-year history of intermittent malaise, fevers, night sweats, recurrent skin sores and a cough productive of green sputum. He had received treatment for leprosy for 1 month the previous year at Daru Hospital (Western Province, PNG). There was a strong family history of leprosy and tuberculosis among both first- and second-degree relatives. On initial examination, the patient appeared cachectic. There was evidence of recent impetigo on both lower limbs and depigmented areas on his upper and lower limbs. He had thickened ulnar and posterior tibial nerves bilaterally, with normal sensation and motor function on repeated clinical assessments. His lungfields were clear to auscultation, but he had an ejection systolic murmur; he was also found to have hepatomegaly and enlarged inguinal, anterior and posterior cervical lymph nodes. He was transferred to Thursday Island Hospital for inpatient management. Slit skin smears were performed; phenotypic analysis of the right earlobe smear was positive for Mycobacterium leprae, confirming the diagnosis of multibacillary leprosy.1 An initial chest x-ray showed left upper lobe changes consistent with pulmonary tuberculosis; subsequent sputum samples and an aspirate of an anterior cervical lymph node cultured Mycobacterium tuberculosis resistant to rifampicin, isoniazid, streptomycin and ethionamide, in keeping with a diagnosis of disseminated multidrug-resistant tuberculosis (MDR-TB).2 HIV and hepatitis serological tests were negative. On admission, his serum creatinine level was 30 μmol/L (reference range [RR], 46–81 μmol/L). The patient was given intravenous amikacin and oral moxifloxacin, isoniazid, pyrazinamide, ethambutol, pyridoxine and rifampicin; cycloserine, aminosalicylic acid (mesalazine), dapsone and clofazimine were later added. One week after admission, the patient developed acute glomerulonephritis, which manifested as fluid retention (pulmonary oedema, peripheral oedema and ascites), hypertension (maximum blood pressure, 160/112 mmHg), haematuria, proteinuria (up to 9700 mg/L [RR, < 100 mg/L]) and impaired kidney function (serum creatinine level peaked at 69 μmol/L). He was treated with frusemide, nifedipine and prednisolone. There was serological evidence of recent infection with Streptococcus pyogenes (elevated antistreptolysin O and anti-DNAse B titres) and hypocomplementaemia (decreased complement component 3 [C3] concentration with normal complement component 4 [C4] concentration). The nephritic illness resolved slowly over the next few weeks. During this period, the patient developed painful, erythematous nodules over his upper torso and limbs (Box 1). His mother reported that he had experienced several such episodes in the past. The lesions measured 5–10 mm in diameter and were tender to palpation; in association with the cardiac murmur and elevated streptococcal serology there was some initial concern about the possibility of acute rheumatic fever and the patient was commenced on penicillin prophylaxis. However, expert consensus was that the lesions more likely represented erythema nodosum leprosum (ENL) — an immune complex-mediated inflammatory reaction that can occur in both acute and chronic relapsing forms among leprosy patients with a high mycobacterial load. Treatment options for this condition have historically included simple analgesics, steroids, non-steroidal anti-inflammatory drugs, clofazimine and thalidomide. A recent Cochrane review found a paucity of evidence for most treatments of ENL, and only a modest benefit from clofazimine and thalidomide.3 As the patient was already taking clofazimine, thalidomide was not considered to be a practical or necessary option in his case (given its significant side effects, the need for monitoring and the patient’s planned return to PNG); his several subsequent bouts of ENL were treated successfully with oral prednisolone. His renal function remained stable throughout these episodes, and an inpatient echocardiogram was normal. After three negative sputum smears, the patient was removed from isolation and continued treatment with intravenous amikacin. He was discharged home on oral therapy for both MDR-TB and leprosy, with follow-up planned at Saibai Island Primary Health Centre. Unfortunately, at the time of writing, due to unknown patient factors and unforeseen circumstances (such as the closure of the border and cancellation of outreach clinics), the patient has not been seen, nor his medications collected, for almost 6 months. DiscussionThe area encompassed by the Torres Strait and Northern Peninsula Area Health Service District in Queensland includes some of the most remote and isolated communities in Australia, and incorporates the porous maritime border with PNG. Thursday Island Hospital is the main referral hospital for the region and many PNG patients are seen in outer island clinics and treated as inpatients at Thursday Island Hospital. These include a significant number of patients with tuberculosis. Although accurate figures on the epidemiology of infectious diseases in PNG are difficult to obtain, it is likely that the rates of mycobacterial infections such as tuberculosis and leprosy in PNG are both underreported and among the highest in the world. The World Health Organization recently reported an annual incidence of 6.5 per 100 000 for leprosy in PNG,4 with historical prevalence of up to 3% recorded in some remote villages.5 For tuberculosis, PNG has reported an incidence of 233 per 100 000, of which about 25% may be MDR-TB.6 A recent literature review described only isolated case reports and small case series studies of concomitant infection with leprosy and tuberculosis over the past few decades.7 Most of these reported cases were from India, with documented co-infection rates (ie, the proportion of leprosy patients found to also have tuberculosis) in the order of 2.5%–7.7% in India and up to 13.4% in South Africa.8,9 Despite the relative dearth of published accounts of co-infection, it seems plausible that simultaneous infection with M. tuberculosis and M. leprae occurs more frequently than is described in published reports in regions with relatively high rates of both diseases (including countries in sub-Saharan Africa, South America, the Indian Subcontinent, and South-East Asia). Some postulated reasons for why rates of co-infection may nevertheless be lower than expected in high prevalence regions include improvements in the detection rate and treatment for both infections; the WHO’s initiative of providing free leprosy treatment in an effort to eliminate the disease; the effects of BCG immunisation; and the complex, possibly antagonistic interaction between the two strains of mycobacteria.7 Our patient developed acute glomerulonephritis as an inpatient receiving treatment for MDR-TB and leprosy; hence, a number of possible causes of his renal dysfunction were considered. Renal abnormalities occur among most patients with leprosy, particularly those with multibacillary disease (“borderline” or “lepromatous” disease using the Ridley–Jopling Classification of Leprosy), and renal failure is a frequent cause of death in patients with leprosy.10,11 Glomerulonephritis, nephrosclerosis, tubulointerstitial nephritis, amyloidosis and granulomas are the most common renal pathologies found on biopsy or autopsy of leprosy patients.12 Of the glomerulonephropathies, the proliferative glomerulonephritides are the most frequently described lesion among patients with leprosy.11,12 Hypocomplementaemia is a recognised association of renal disease in this setting, particularly among patients with multibacillary leprosy and ENL.12 Typical serum protein profiles seen among patients with renal disease associated with some selected infections are presented in Box 2. The pattern of hypocomplementaemia varies somewhat between the different forms of glomerular disease; low C3 with normal C4 (as in our patient’s case) tends to suggest either poststreptococcal or membranoproliferative glomerulonephritis.13 Evidence of streptococcal infection was found on biopsy from five leprosy patients with renal disease in India; the same case series reported two patients with microfilariae in peripheral blood samples, indicating the possibility of a range of concomitant infections contributing to renal disease in patients with leprosy.14 With respect to drug-induced nephrotoxicity, rifampicin (a common component of the pharmacological regimen for treatment of both leprosy and tuberculosis) has been implicated in acute renal failure, often associated with thrombocytopenia, immune haemolytic anaemia and intravascular coagulation.15 In our patient, however, the combination of oedema, hypertension, haematuria, hypocomplementaemia (in the pattern described), elevated streptococcal serological results and a history suggestive of recent skin infections is strongly supportive of a diagnosis of poststreptococcal glomerulonephritis, which is an uncommon form of renal disease in patients with leprosy. The patient did not undergo kidney biopsy as his condition was clinically improving and it was felt that this highly invasive procedure would not have yielded sufficient additional diagnostic information to make it worthwhile. It is also a moot point whether, given his nationality, this procedure would have been available to him. In summary, our patient had the misfortune to suffer simultaneous infection with multibacillary leprosy and MDR-TB (and may be the first such reported case in Australia), which was complicated by ENL and an acute glomerulonephritis that was probably poststreptococcal glomerulonephritis — a rare form of renal disease in a subset of patients among whom renal impairment is commonly due to other causes. 1 Erythema nodosum leprosum reaction, indicated by red patches 2 Serum protein profiles seen in renal disease associated with specific infections* Serum protein profile Group A streptococcus infection Acute glomerulonephritis Classic diffuse proliferative Decreased C3 Focal proliferative (IgA disease) Increased IgA Mycobacterium leprae infection Acute glomerulonephritis Proliferative forms Decreased C3 Cryoglobulinaemia (ENL) Decreased C3 and C4 Nephrotic syndrome Amyloid Increased AA Mycobacterium tuberculosis infection Nephrotic syndrome Amyloid Increased AA AA = amyloid A. C3 = complement component 3. C4 = complement component 4. ENL = erythema nodosum leprosum. IgA = immunoglobulin A. * The serum concentrations of certain proteins are altered in these conditions.

Lachlan J McIver MB BS, MPHTM, FACRRM · Shaun T Parish MB BS, DTMH, FACRRM · Samuel P Jones MB ChB, DTMH, JCPTGP · Alexander N Kippin MB BS, MPHTM · Timothy J Furlong MB BS, PhD, FRACP

To the Editor: Weight fluctuations may lead to significant changes in a patient’s treatment, so it is vital that hospital scales are accurate. A literature review revealed that calibration,1 accuracy2 and centralised hospital quality control3 of hospital scales were issues that are being recognised and addressed around the world. We audited all scales at the Royal Melbourne Hospital, city campus, to assess their accuracy and identify the types of scales that are likely to be most accurate. A preliminary survey identified all scales on the wards and in outpatient departments. On a single survey day, each scale was categorised and photographed. Scales were “zeroed” and standard weights of 5 kg, 10 kg, 15 kg and 20 kg, and a person whose weight had been established elsewhere as 106 kg, were then weighed on each scale. Our primary measure of accuracy was the difference between 106 kg and the recorded weight of the person, as this most closely approximated the weight of an average patient (rather than using the 5, 10, 15 and 20 kg weights). Forty-three of 50 scales identified in the hospital were tested. Scales that were excluded were either not working or not able to be tested with the weights we used. All scales in the outpatients department were digital (22). On the wards, there was a mix of sit-on (6) and stand-on (15), and digital (9) and analogue (12) scales. The digital scales had an accuracy (range around the standard weight) of − 1 kg to +1.5 kg, compared with an accuracy of − 3.5 kg to +1 kg for the analogue scales (P = 0.006; Wilcoxon signed rank test). Interquartile ranges were − 0.45 kg to +0.07 kg for digital scales and − 2 kg to +0.5 kg for analogue scales. The mean deviation from the correct weight was 0.06 kg for digital scales and 0.55 kg for analog scales. The most accurate scales were in the renal wards, used by dialysis outpatients and inpatients. Some areas had scales that were unusable by patients, such as sit-on scales in the geriatric ward (Box 1) that were difficult to mount. A haematology ward, where decisions are often made on the basis of changes in weight, had five sets of scales, with significant inaccuracies and differences between them. In one ward, no scales could be located, and five out of 23 outpatient rooms had no scales. The digital scales were more accurate than the analogue scales (Box 2). In areas where treatment decisions are made on the basis of changes in weight, scales should regularly be checked for accuracy, and patients should be weighed on the same scales each time they are weighed. For greater accuracy and consistency in measuring patient weights, we recommend that all scales be upgraded to digital scales throughout the hospital. 1 Sit-on analogue scale at Royal Melbourne Hospital, unusable for some patients 2 Weight variations in 43 digital and analogue scales at Royal Melbourne Hospital * As measured using standard weights of 5 kg, 10 kg, 15 kg, 20 kg and a 106 kg person.

Rimma Goldberg · Geoffrey Hebbard

To the Editor: We read with interest the article by Ng and colleagues on life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis,1 and wish to present our own experience of four patients presenting to our hospital over a year (Box). The patients all presented with biochemical signs of renal tubular acidosis with severe hypokalaemia and a normal anion gap metabolic acidosis from long-standing misuse of ibuprofen taken in combination with codeine from over-the-counter (OTC) medications. Patients 1 and 2 presented acutely with deliberate misuse that included an ibuprofen–codeine combination product. Both patients subsequently admitted to long-standing misuse of ibuprofen and codeine taken in combination. Patients 3 and 4 presented with constitutional symptoms and generalised weakness with a history of taking large amounts of an ibuprofen–codeine combination product. Both these patients required intensive care unit admission for central venous access and potassium replacement. As in the case series by Ng and colleagues, there was no history to suggest gastrointestinal loss of potassium, and medication histories were negative for drugs known to cause intracellular potassium movement or potassium wasting (eg, diuretics). Ibuprofen cessation, potassium replacement and supportive care resulted in biochemical recovery in all four patients. Opioid addiction appears to be the common thread reported by Ng et al and in our case series. Other case reports support this.2,3 Paracetamol taken in supratherapeutic doses is known to cause hepatotoxicity, and it appears that patients with opioid addiction may now be turning to ibuprofen–codeine combination products. More evidence of the danger of these products comes from a case series reporting 27 patients with ibuprofen–codeine misuse that resulted in significant morbidity, including presentations for opioid dependence, gastrointestinal haemorrhage, hypokalaemia, anaemia and/or renal failure.4 In Australia, ibuprofen–codeine combination products are available OTC, albeit in restricted amounts due to problems related to codeine misuse.1 Further restrictions may need to be considered in light of the significant morbidity related to the ibuprofen component. Baseline laboratory investigations and other characteristics of four patients with ibuprofen-induced renal tubular acidosis* RR Patient 1 Patient 2 Patient 3 Patient 4 Sex, age in years Female, 35 Male, 55 Male, 41 Female, 39 Ibuprofen dose† Unclear, years’ duration 9.0–18.0 g/day 5.0 g/day 8.0 g/day Other medications Amitriptyline 50 mg at night Esomeprazole 40 mg daily Multiple medications Nil Serum pH 7.35–7.45 7.29 7.13 7.26 7.32 Pco2, mmHg 35–45 45 42 30 28 HCO3-, mmol/L 22–32 21 13 13 14 Anion gap, mmol/L 7–17 3 9 12 11 Na+, mmol/L 136–146 137 139 142 135 Cl-, mmol/L 98–106 116 120 120 111 Urea, mmol/L 3.0–8.0 4.7 4.4 3.0 6.9 Creatinine, μmol/L 60–120 70 123 125 99 K+ on presentation, mmol/L 3.5–5.0 2.8 2.9 2.5 1.4 K+ on discharge, mmol/L 3.5–5.0 3.5 3.8 3.7 4.5 RR = reference range. Pco2 = partial pressure of carbon dioxide. HCO3- = bicarbonate ion. Na+ = sodium ion. Cl- = chloride ion. K+ = potassium ion. * Same format as used in Ng et al case series1 to allow direct comparison. † Maximum recommended: 3.2 g/day.

Colin B Page · Paul A Wilson · Aidan Foy · Michael A Downes · Ian M Whyte · Geoffrey K Isbister

Renal tubular acidosis is an underreported complication of ibuprofen misuse, and can result in life-threatening hypokalaemia. We describe four patients who presented with profound hypokalaemia and muscle weakness associated with excessive ibuprofen ingestion. Ibuprofen cessation and supportive management resulted in complete biochemical resolution within a few days. These cases remind practitioners about potential complications of unmonitored use of over-the-counter analgesics, including those with potential for misuse due to their codeine content. (MJA 2011; 194: 313-316) Clinical recordsPatient 1A 32-year-old woman presented to the emergency department with a 2-day history of evolving paralysis associated with profound hypokalaemia (potassium, 1 mmol/L; reference range [RR], 3–5 mmol/L). She also had epigastric pain without diarrhoea or vomiting and a past medical history of depression, iron deficiency anaemia, chronic constipation, migraines, cigarette smoking and previous intravenous drug use. Family history was unremarkable. Her only medications were citalopram 20 mg daily and a combination of ibuprofen (200 mg) and codeine phosphate (12.8 mg) for migraines. She denied taking laxatives, diuretics, alcohol or illicit drugs. On examination, the patient weighed 38 kg (body mass index, 14 kg/m2), her blood pressure was 90/55 mmHg, and other vital signs were normal. There was generalised flaccid weakness (graded 3/5) with normal sensation. She also had epigastric tenderness. Results of initial laboratory investigations (Box 1) were consistent with distal renal tubular acidosis (dRTA). An electrocardiogram (ECG) demonstrated features of hypokalaemia, including widespread ST-segment depression and U waves. Endoscopy revealed oesophageal erosions and a benign gastric ulcer. An abdominal computed tomography scan demonstrated enlarged, oedematous kidneys without nephrocalcinosis. The patient’s husband revealed she had been consuming the combination ibuprofen–codeine over a prolonged period — at least 25 tablets (5.0 g of ibuprofen) per week and up to 20 tablets in 1 day. Ibuprofen toxicity explained both the gastrointestinal symptoms and the biochemical manifestations of dRTA. No alternate explanation for dRTA was found. The ibuprofen–codeine combination was ceased, and intravenous potassium chloride (KCl) was administered (610 mmol at 5–10 mmol/h over 5 days), with concurrent oral replacement of 64 mmol potassium/day. No signs of opioid withdrawal were detected. Within 5 days, her serum potassium level stabilised at 4 mmol/L and bicarbonate levels normalised without bicarbonate supplementation. She was discharged 3 weeks later on a regimen of 16 mmol of potassium daily; her serum potassium level at discharge was 5 mmol/L. Patient 2A 37-year-old man presented with 3 days of progressive muscle weakness. He had been taking ibuprofen–codeine for several years, with a daily dose of 24 tablets (4.8 g ibuprofen). He was a smoker and denied taking any other medications. There was no history of diarrhoea or vomiting, and family history was unremarkable. He had proximal muscle weakness (graded 3/5) with hyporeflexia and muscle tenderness, but sensation was preserved. Initial investigation revealed a very low serum potassium level (2 mmol/L) and biochemical features consistent with dRTA (Box 1). The ibuprofen–codeine was ceased, and intravenous KCl was administered for 4 days (10–30 mmol/h) with 112 mmol of oral potassium/day. The weakness resolved after 2 days. Oral sodium bicarbonate supplementation (2520 mg/day for 9 days) contributed to normalisation of serum bicarbonate levels. Symptoms of overt opioid withdrawal developed on Day 3 and buprenorphine treatment was commenced. He was discharged on Day 9 after cessation of potassium and bicarbonate supplements, with a serum potassium level of 4 mmol/L. Patient 3A 45-year-old woman, with a remote history of intravenous drug use, presented after 7 days of lethargy and anorexia. She had multiple dental caries, and for several months had ingested 9.6–14.4 g/day of ibuprofen (about 50 tablets per day). She took no other medications and had an unremarkable family history and physical examination. Initial investigations revealed hypokalaemia (potassium, 2 mmol/L) with acute kidney injury, renal potassium wasting and biochemistry consistent with dRTA (Box 1). Gastroscopic investigation of microcytic anaemia found gastric antral ulceration with a peptic oesophageal stricture. No cause for RTA other than ibuprofen overdose was found. Ibuprofen was ceased, and intravenous sodium bicarbonate and KCl (220 mmol over 3 days at a maximum rate of 10 mmol/h) were administered. Concurrent oral potassium replacement occurred at 60 mmol/day. On discharge, 5 days later, renal function was normal and the serum potassium level was 3 mmol/L. Patient 4A 40-year-old man presented with a 2-day history of profound generalised weakness associated with hypokalaemia (potassium, 1 mmol/L). He had consumed 1.4–2.0 g/day of ibuprofen for 3 months for degenerative back pain. There was no history of diarrhoea or vomiting, he took no other medications and had no significant family history, and he was a smoker. The patient had normal vital signs apart from bradycardia (50 beats/min), with generalised flaccid weakness (graded 1–2/5) with preserved reflexes and sensation. An ECG demonstrated sinus bradycardia with prolonged QTc interval and U waves. Initial biochemistry results (Box 1) were consistent with RTA. Although the urine pH of 6.5 was higher than expected for the low serum bicarbonate level (11 mmol/L), proximal RTA (pRTA) was diagnosed in view of the negative urine anion gap and findings suggesting proximal tubular dysfunction. These included hypouricaemia (0.18 mmol/L; RR, 0.20–0.42 mmol/L), hypophosphataemia (0.40 mmol/L; RR, 0.8–1.5 mmol/L) and mild proteinuria. As there were no features suggesting alternative causes for pRTA, ibuprofen was considered the most likely causative factor, and was discontinued. Intravenous potassium (1010 mmol over 3 days at a maximum rate of 20 mmol/h), bicarbonate (total dose, 500 mmol) and phosphate (total dose, 50 mmol) were administered under electrocardiographic monitoring. The patient’s muscle strength improved within 24 hours and he was discharged 4 days later with a serum potassium level of 3 mmol/L. Potassium supplementation was ceased on discharge. DiscussionIbuprofen, a non-steroidal anti-inflammatory drug (NSAID), is widely used and readily available over the counter (OTC). Excessive ingestion of ibuprofen, in combination with codeine or alone, can result in ibuprofen toxicity, including RTA. In Australia, the maximum quantity of ibuprofen–codeine available OTC has recently been reduced from 72 to 28 tablets due to problems related to codeine misuse. We have described four patients with profound hypokalaemia due to ibuprofen-induced RTA. This is an underreported complication, which may present with hypokalaemic paralysis. Three of the patients were admitted to the same tertiary care hospital within 3 months of each other. The remaining patient was admitted to a peripheral hospital the previous year. In each case, the differential diagnosis of hypokalaemia initially included transcellular potassium shift, renal potassium wasting and gastrointestinal losses. Medication histories were uniformly negative for drugs known to cause intracellular potassium movement. Thyroid function was normal and there was no family history of hypokalaemic periodic paralysis. Urinary potassium wasting was documented in all cases by excessive urine potassium excretion (> 20 mmol/day or spot urine potassium > 20 mmol/L) in the presence of hypokalaemia.1 This was not explained by diuretic use or magnesium deficiency. The hyperchloraemic metabolic acidosis and non-acidified urine pH were in keeping with RTA. Gastrointestinal potassium and bicarbonate loss was unlikely in the absence of diarrhoea or laxative use. In two cases, gastric ulceration provided corroborative evidence for ibuprofen toxicity. Investigations found no alternative aetiology for RTA (Box 2). Ibuprofen cessation and supportive therapy allowed complete biochemical resolution within days. Unfortunately, no follow-up information could be obtained to ascertain whether the RTA was recurrent, or whether a previously unrecognised aetiology for RTA had become apparent. Characteristics of RTA are summarised in Box 3. Renal acidification is impaired, resulting in a hyperchloraemic metabolic acidosis.2 Hypokalaemia due to kaluresis is a feature of both proximal and distal RTA. Multiple factors contribute to hypokalaemia. Metabolic acidosis impairs proximal sodium reabsorption, leading to increased distal sodium delivery, secondary hyperaldosteronism and increased potassium secretion.3 In distal RTA, impaired hydrogen ion excretion promotes potassium loss in exchange for sodium to maintain electroneutrality. Reduced H–K-ATPase pump activity results in reduced distal potassium reabsorption.4 Four previously published case reports5-8 have described similar clinical presentations occurring with ibuprofen use of 4.8 to 28 g per day. However, one of our patients (Patient 4) developed RTA at a dose below the maximum recommended. No other NSAID has yet been implicated with this complication. The mechanism by which ibuprofen induces RTA is unknown. Other nephrotoxic effects of NSAIDs, including acute and chronic kidney injury, interstitial nephritis and nephrotic syndrome, result from impaired synthesis of cytoprotective prostaglandins, a consequence of cyclo-oxygenase-1 (COX-1) inhibition. It is hypothesised that the pathogenesis of ibuprofen-induced RTA may involve carbonic anhydrase (CA) inhibition. CA catalyses the interconversion between carbon dioxide and bicarbonate and is crucial to renal acid–base regulation. It is present in renal proximal tubules and collecting ducts as well as a variety of other tissues, including bone, brain and gut.9 Congenital CA deficiency is characterised by proximal and distal RTA, osteopetrosis and cerebral calcification.10 High titres of an auto-antibody directed against CA II have been noted in some patients with dRTA associated with Sjögren syndrome.11 Induction of these auto-antibodies has resulted in the development of RTA in a mouse model of Sjögren syndrome.12 Other NSAIDs including aspirin13 and flurbiprofen14 have been shown to have CA-inhibitory activity in vitro. More recently, celecoxib and valdecoxib, which are COX-2 selective NSAIDs, have been demonstrated to be potent inhibitors of CA due to binding of their sulfonamide moiety to its zinc (Zn2+) ion.15 Although ibuprofen lacks a sulfonamide moiety, it can inhibit human and bovine erythrocyte CA II.14 CA inhibition would be consistent with our observations of both proximal and distal RTA. In conclusion, profound hypokalaemia due to RTA is a potentially fatal complication of ibuprofen use. Although it usually occurs with excessive doses, it can occur at doses below the maximum recommended. The pathogenesis is unknown but may involve CA inhibition. Opioid addiction with deliberate misuse of ibuprofen–codeine analgesics is common.16 Therefore, ibuprofen toxicity should be considered in the differential diagnosis of patients presenting with severe hypokalaemia or hypokalaemic paralysis. 1 Baseline laboratory investigations and other characteristics of four patients with ibuprofen-induced renal tubular acidosis Reference range Patient 1 Patient 2 Patient 3 Patient 4 Sex, age in years Female, 32 Male, 37 Female, 45 Male, 40 Ibuprofen dose* 0.6–4.0 g/day 4.8 g/day 9.6–14.4 g/day 1.4–2.0 g/day Other medications Citalopram 20 mg/day; no complementary medicines, laxatives, diuretics or illicit drugs No prescription medicines, laxatives, diuretics or illicit drugs No other prescribed or over-the-counter medicines No other prescribed, over-the-counter or complementary medicines, diuretics or laxatives Serum pH 7.32–7.43 7.26 7.28 7.16 (venous) 7.27 Pco2, mmHg 37–50 21 32 22 27 HCO3-, mmol/L 22–32 10 14 8 11 Anion gap 7–17 10 8 16 15 Na+, mmol/L 134–146 141 140 134 141 Cl-, mmol/L 98–108 122 120 112 116 Urea, mmol/L 3.8 3.9 5.4 18.0 6.0 Creatinine, μmol/L 60–110 106 83 222 83 K+, mmol/L at presentation 3–5 1 2 2 1 K+, mmol/L on discharge 3–5 5 4 3 3 Urine pH 6.5 6.9 6.5 6.5 Na+, mmol/L 63 49 35 42 K+, mmol/L 25 25 22 25 Cl-, mmol/L 85 69 32 78 Anion gap 3 5 25 − 11 Pco2 = partial pressure of carbon dioxide. HCO3- = bicarbonate ion. Na+ = sodium ion. Cl- = chloride ion. K+ = potassium ion. * Maximum recommended: 3.2 g/day. 2 Causes of renal tubular acidosis (RTA)1 Causes of proximal RTA Primary Secondary With Fanconi syndrome (eg, multiple myeloma, light chain disease) Drugs and toxins (acetazolamide, outdated tetracycline, aminoglycosides, sodium valproate, 6-mercaptopurine, streptozotocin, iphosphamide, lead, cadmium, mercury) Associated with other clinical entities (vitamin D deficiency, hyperparathyroidism, chronic hypocapnia, cyanotic congenital heart disease, medullary cystic kidney disease, Alport syndrome, corticoresistant nephrotic syndrome, renal transplantation, amyloidosis, recurrent nephrolithiasis) Causes of distal RTA Primary Secondary Autoimmune diseases (eg, systemic lupus erythematosus, Sjögren syndrome, chronic active hepatitis, primary biliary cirrhosis, thyroiditis, fibrosing alveolitis, rheumatoid arthritis) Drugs and toxins (amphotericin B, lithium, toluene, amiloride, trimethoprim, pentamidine, vanadium) Calcium disorders (eg, primary hyperparathyroidism, vitamin D intoxication, idiopathic hypercalciuria with nephrocalcinosis) Dysproteinemic syndromes (hypergammaglobulinemia, amyloidosis, cryoglobulinemia) Renal diseases (eg, renal transplant rejection, medullary sponge kidney, obstructive and reflux nephropathy) Liver disease (hepatic cirrhosis) Genetic diseases (eg, osteopetrosis, sickle cell disease, Ehlers–Danlos syndrome) 3 Characteristics of renal tubular acidosis (RTA)1 Distal RTA (type 1) Proximal RTA (type 2) RTA type 4 Primary defect Impaired distal H+ excretion Impaired proximal HCO3 2 reabsorption Decreased aldosterone secretion or effect Plasma potassium Usually reduced (hyperkalaemic forms exist) Reduced Increased Urine pH > 5.5 Variable: usually > 5.5 if plasma HCO3- > 16mmol/L; < 5.5 if plasma HCO3- < 16 mmol/L < 5.5 Urine anion gap Positive Negative Positive Nephrocalcinosis Common Rare Rare Other tubular defects Rare Common (generalised proximal tubular dysfunction) Rare H+ = hydrogen ion. HCO3 - = bicarbonate ion.

Jennifer L Ng MB BS(Hons) · David J R Morgan MB BS, DCH, DRANZCOG · Nelson K M Loh MB BS, BMedSci, FRACP · Seng K Gan MB BS(Hons), FRACP, PhD · Patrick L Coleman MB, MRCPI, FRACP · Gregory S Y Ong MB BS · David Prentice MB BS, FRACP