Urology

Re: “An unusual cause of severe metabolic acidosis”, by John V Peter, Natasha Rogers, Shailesh Murty, Rosemarie Gerace, Richard Mackay and Sandra L Peake, in the 21 August issue of the Journal (Med J Aust 2006; 185: 223-225). During the production process, the drug name “timentin” was inadvertently changed to “timolol”. The sentence describing antibiotic therapy should read: “On Day 14, ceftriaxone and gentamicin were changed to empirical clavulanate/ticarcillin (Timentin, GlaxoSmithKline, Australia) and ciprofloxacin because of persistent fever and rising WCC.” The html and pdf versions of the article were corrected on 29 August 2006.

John V Peter MD, DNB, FRACP · Natasha Rogers MB BS · Shailesh Murty MB BS, MD · Rosemarie Gerace BSc · Richard Mackay FRACP · Sandra L Peake BM BS, FJFICM, PhD

To the Editor: The incidence of obesity is rising, and physicians are likely to face the problem of obesity-related glomerulopathy (ORG) recently illustrated by Tran.1 But how can the clinician distinguish ORG from primary (idiopathic) focal segmental glomerulosclerosis (FSGS)? Both may present with nephrotic-range proteinuria, but the prognosis and choice of treatment may differ. To date, the largest published study comparing ORG with primary FSGS is one by Kambham et al.2 In an analysis of 6818 renal biopsies, 71 patients with ORG were identified and compared with a control group of 50 patients with classic FSGS. The study showed that ORG less frequently progressed to end-stage kidney failure, with a 5-year renal survival rate of almost 90% (compared with about 50% in primary FSGS).2 While weight loss can reduce hyperfiltration and albuminuria in ORG,3 spontaneous remission is uncommon in primary FSGS.4,5 Does every obese patient with nephrotic-range proteinuria have ORG and an “indolent” course? The degree of weight loss reported in the case described by Tran may not be achievable or sustainable in most obese patients. Do we have the luxury of waiting to assess the impact of weight loss on proteinuria? In about 50% of patients with primary FSGS, the serum creatinine level doubles after an average of 39 months.2 Furthermore, patients with primary FSGS and nephrotic-range proteinuria who do not achieve remission have a 5-year renal survival of only 50%, compared with almost 100% for those who attain remission.4 In addition, patients treated with corticosteroids (with or without cyclosporin or cyclophosphamide) have higher remission rates (30%–63%) than untreated patients (11%–14%).4,5 Therefore, a delay in introduction of specific therapy is not ideal. There are some clinicopathological differences between ORG and primary FSGS that may help distinguish the two entities (Box). However, Kambham et al found that only two parameters were independently significant: serum albumin level and age.2 Although their study was based on a US population, it serves to demonstrate the principle that the major distinguishing feature between ORG and primary FSGS is the presence of full-blown nephrotic syndrome in primary FSGS (as demonstrated by the severity of hypoalbuminaemia). Obese patients have a similar risk of developing primary FSGS to people in the general population, and patients with nephrotic syndrome (particularly older adults) should not be presumed to have ORG and treated with weight loss alone. Certain pathological findings in a renal biopsy are helpful, but not definitive, in distinguishing ORG from primary FSGS. A biopsy would also exclude other treatable causes, such as minimal change disease. In addition to treatment with angiotensin-converting enzyme inhibitors, immunotherapy should be considered for obese, nephrotic patients, after discussing the potential risks and benefits with a nephrologist. Clinicopathological differences between ORG and primary FSGS* Parameter ORG Primary FSGS Mean age at presentation (years)† 42.9 32.6 Ethnicity White (%) 74 52 African American (%) 21 22 Nephrotic syndrome (%) 5.4 54 Mean 24-hour protein excretion (g) 4.1 6.9 Mean serum albumin level (g/L)† 39 29 Mean serum cholesterol level (mmol/L) 5.9 8.6 Presence of pedal oedema (%) 35 68 Mean degree of segmental sclerosis (%) 10 39 Proportion of cases with glomerulomegaly (%) 100 10 Mean arteriosclerosis score (range, 0–3) 1.34 0.98 Mean degree of glomerular podocyte foot process fusion (%) 40 75 ORG = obesity-related glomerulopathy. FSGS = focal segmental glomerulosclerosis. * Adapted from Kambham et al.2 † Independently significant.

Andy K H Lim

Re: “The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study)”, by Merlin C Thomas, Andrew J Weekes, Olivia J Broadley, Mark E Cooper and Tim H Mathew, in the 7 August issue of the Journal (Med J Aust 2006; 185: 140-144). In Box 2 on page 142, the figures for mean patient age in the first row were reversed. The correct figures are 63.3 years for patients with estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73m2 and 73.0 years for those with estimated GFR < 60 mL/min/1.73m2. The html and pdf versions of this article have been corrected.

Merlin C Thomas · Andrew J Weekes · Olivia J Broadley · Mark E Cooper · Tim H Mathew

Objective: To evaluate the outcomes of and barriers to implementing standard guidelines (Caring for Australasians with renal impairment [CARI]), using iron management in patients having dialysis as an example.Design and setting: On-site review of iron management processes at six Australian dialysis units varying in size and locality. Patients’ iron indices and haemoglobin levels were obtained from the Australian and New Zealand Dialysis and Transplant Registry.Participants: Patients with chronic kidney disease who were dependent on dialysis.Main outcome measures: Processes for assessing indices of iron stores and iron supplementation; comparison with target indices in the CARI guidelines.Results: There was considerable variability among the units in achievement of haemoglobin and iron targets, with 25%–32% of patients achieving haemoglobin targets of 110–120 g/L, 30%–68% achieving ferritin targets of 300–800 μg/L, and 65%–73% achieving transferrin saturation targets of 20%–50%. Implementation barriers included lack of knowledge, lack of awareness of or trust in the CARI guideline, inability to implement the guideline, and inability to agree on a uniform unit protocol. Factors associated with achieving the CARI guideline targets included nurse-driven iron management protocols, use of an iron management decision aid, fewer nephrologists per dialysis unit, and a “proactive” (actively keeping iron levels within target range) rather than “reactive” (only reacting if iron levels are out of the range) protocol.Conclusions: Variability in achievement of iron targets, despite the availability of a clinical practice guideline, may be explained by variability in processes of care for achieving and maintaining adequate iron parameters.

Michelle J Irving MHSciEd · Jonathan C Craig MMed, PhD, FRACP · Martin Gallagher MB BS, MMEpi, FRACP · Stephen McDonald MB BS(Hons), PhD, FRACP · Kevan R Polkinghorne MB ChB, FRACP, MClinEpi · Rowan G Walker MD, MB BS, FRACP · Simon D Roger MD, FRACP

CorrectionsRe: “The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study)”, by Merlin C Thomas, Andrew J Weekes, Olivia J Broadley, Mark E Cooper and Tim H Mathew, in the 7 August issue of the Journal (Med J Aust 2006; 185: 140-144). In the statement defining microalbuminuria, macroalbuminuria and normoalbuminuria on page 141, the sexes were transposed. The correct statement is: Albuminuria was stratified according to International Diabetes Federation guidelines12,13 as follows: Microalbuminuria — urinary albumin–creatinine ratio (ACR) of 3.5–35 mg/mmol (women) or 2.5–25 mg/mmol (men). Macroalbuminuria — urinary ACR > 35 mg/mmol (women) or > 25 mg/mmol (men). Normoalbuminuria — urinary ACR < 3.5 mg/mmol (women) or < 2.5 mg/mmol (men). The html and pdf versions of this article were corrected before publication.

Merlin C Thomas · Andrew J Weekes · Olivia J Broadley · Mark E Cooper · Tim H Mathew

Clinical record A 29-year-old man presented with a history of increasing lethargy and malaise for 3 months. He had lost 3 kg in weight and noticed mild ankle oedema. His previous medical history was unremarkable, and he had no relevant family history. He had been a professional body builder for 10 years, previously competing at high levels. He attended a gymnasium daily for weight-lifting. His dietary protein intake was very high (3.5 g/kg daily) and he took 5 g/day creatine powder supplement. Although he was not taking any regular medication, he admitted to extensive use of anabolic steroids (including testosterone and nandrolone) over a 10-year period. On examination, he weighed 103 kg and was 175 cm tall (body surface area, 2.24 m2) and his blood pressure was 195/110 mmHg. His chest was clear, and cardiovascular examination showed no abnormalities except for mild peripheral oedema. Investigations revealed a serum creatinine level of 1346 μmol/L (reference range [RR], 30–120 μmol/L) and a urea level of 63.5 mmol/L (RR, 2.5–7.5 mmol/L). Values obtained in other investigations included: haemoglobin, 112 g/L (RR, 125–175 g/L); albumin, 35 g/L (RR, 34–50 g/L); potassium, 3.8 mmol/L (RR, 3.5–5.0 mmol/L); corrected calcium 1.98 mmol/L (RR, 2.10–2.55 mmol/L); phosphate, 2.95 mmol/L (RR, 0.81–1.45 mmol/L); and parathyroid hormone, 31.8 pmol/L (RR, 1.3–6.8 pmol/L). Results of a mid-stream urine test were unremarkable except for protein 3+, and a 24-hour urine collection revealed 10.7 g/day proteinuria. An ultrasound examination of the renal tract showed two normal-sized kidneys without hydronephrosis, but with diffusely increased parenchymal echogenicity. A renal biopsy confirmed a diagnosis of focal segmental glomerulosclerosis, with marked tubulointerstitial damage. Counselling was provided, with information about dialysis and kidney transplantation options. The patient was prescribed amlodipine, which gave good blood pressure control, and calcium carbonate as a phosphate binder. He was also given dietary advice. As he had only mild symptoms, and to avoid using a tunnelled dialysis catheter, haemodialysis was not immediately initiated. Calculations of overall renal function gave varying results (Box 1). Calculated from the serum creatinine level at presentation, the estimated glomerular filtration rate (eGFR) (based on the abbreviated MDRD [modification of diet in renal disease]) was 5.18 mL/min/1.73 m2. The full MDRD equation (6-variable) gave a GFR of 4.96 mL/min/1.73 m2. However, the Cockcroft–Gault formula, weight included, gave a GFR of 8.05 mL/min/1.73 m2, and 24-hour urine collection gave results for creatinine clearance of 12.97 mL/min/1.73 m2. A radioisotope nuclear renal scan (DTPA [diethylenetriaminepentaacetate]) to better clarify the degree of renal impairment showed equal function of both kidneys and a GFR of 13.51 mL/min/1.73 m2. Over the following few weeks, with changes in diet and cessation of creatine supplements, serum creatinine and urea levels decreased slightly, and arrangements for an early living-related renal transplant were formulated. However, because of worsening uraemic symptoms, dialysis was eventually commenced and was required for 3 months before successful transplantation with a kidney donated by the patient’s mother. Serum creatinine level, the most commonly used measure of kidney function in clinical practice, varies with factors other than kidney function. These include age, sex, muscle mass, and dietary protein intake. Glomerular filtration rate (GFR) is therefore widely accepted as a better marker. Numerous equations using the serum creatinine level have been developed to calculate estimated GFR (eGFR) (Box 2). Recently, automated reporting of eGFR using the MDRD (modification of diet in renal disease) formula has been introduced, but limitations exist, especially with extremes of body size. Our patient illustrates the difficulties of calculating GFR for a person with a large muscle mass, with different methods giving widely varying results. The recently published CARI (Caring for Australasians with renal impairment) guidelines recommend that serum creatinine level alone should not be used to measure kidney function, because of the multitude of factors other than renal function that can affect this marker.1,2 Serum creatinine is derived from the metabolism of creatine in muscle and the generation of creatinine tends to be proportional to muscle mass. In adults, the abbreviated (4-variable) MDRD, the 6-variable MDRD, and the Cockcroft–Gault equations generally provide reliable eGFRs. The Cockcroft–Gault formula is probably the most widely recognised formula for conversion of serum creatinine level, although with reductions below 60 mL/min it becomes increasingly inaccurate compared with the MDRD formula. Recently, the abbreviated MDRD formula has been used in the automated laboratory reporting of eGFR in Australia, given extensive validation with no correction needed for body surface area. It is important to note that the different units for GFR measurements (mL/min for Cockcroft–Gault versus mL/min/1.73 m2 for MDRD) can create some discrepancy in their comparison (see Box 1). MDRD and Cockcroft–Gault equations are essentially rescaled serum creatinine levels with the same pitfalls as using the serum creatinine level itself. They are based on statistical models predicting averages, and our patient was not average. Therefore, clinical judgement is always required with eGFR, and the clinician has the advantage of being able to consider dietary history and physical examination — factors not considered in these equations. Lessons from practice Estimated glomerular filtration rate (eGFR) may be inaccurate in patients whose body size and muscle mass, or dietary intake (eg, high protein diets and creatine supplements), are at the extremes of the normal range. In such patients, formal measurement of GFR by radioisotope nuclear renal scan should be undertaken. eGFR should not be relied on as the sole determinant in making decisions about the commencement of dialysis; investigations should be interpreted in conjunction with the overall clinical picture. Previously, 24-hour urine collections to assess creatinine clearance were commonly used. These are inconvenient, inaccurate because of inadequate collection techniques, and, with severe renal impairment, creatinine clearance overestimates GFR. With worsening impairment there is an increase in tubular creatinine secretion, ranging from 10% to 50%, and therefore variations may alter the relationship between serum creatinine level and GFR.3 Nuclear medicine scans provide validated direct measures of GFR and are useful in circumstances of extremes of body size or age, high or low dietary intake of creatinine or creatine supplements, and patients with muscle disease or atrophy. They determine renal clearance of exogenous filtration markers, most commonly DTPA (diethylenetriaminepentaacetate), and provide acceptably accurate measurements, although it is recognised that they may overestimate GFR.1,2 The disadvantages of radionucleotide GFR measurement relate to safety with the use of radiolabelled compounds and the cost. In our patient, different methods of GFR measurement provided a range from 4.96 to 13.51 mL/min/1.73 m2, depending on the equation or the investigation used. The CARI guidelines suggest that dialysis should be commenced when GFR falls below 10 mL/min/1.73 m2, if associated with symptomatic uraemia or malnutrition, or below 6 mL/min/1.73 m2, if asymptomatic.4 Initiation of dialysis in our patient, with risks of temporary dialysis access, was weighed against the decision to wait for a renal transplant, given that the patient was initially relatively asymptomatic. The best option for renal replacement therapy is kidney transplantation where appropriate, and the patient’s mother had volunteered as a potential donor. The commencement of dialysis is sometimes a difficult decision and clinicians need to recognise the inaccuracies with eGFR measurement. Symptoms, treatment options and rate of GFR decline are among a multitude of factors that must be taken into account in the decision to initiate dialysis. Having illustrated some of the limitations in determining renal function using eGFR, we strongly advocate routine automated reporting in clinical practice. eGFR is extremely useful for identifying patients at risk of progressive chronic kidney disease and correlates well with complications, including an increased risk of cardiovascular morbidity and mortality. An educational program is underway, involving distributed written material and short courses organised by Kidney Health Australia, to ensure that information is available to help health professionals interpret eGFR values. It should be appreciated that there are specific clinical settings in which eGFR is not appropriate and GFR should be measured directly through other methods. 1 Variations in estimated and measured glomerular filtration rate (GFR) for the same patient (serum creatinine level, 1346 μmol/L; body surface area, 2.24 m2) Method of calculation GFR (mL/min) GFR (mL/min/1.73 m2) MDRD 6.42 4.96 MDRD (abbreviated) 6.71 5.18 Reciprocal serum creatinine 7.33 5.66 Cockcroft–Gault 10.43 8.05 Creatinine clearance (24-h urine) 16.80 12.97 Radioisotope scan (DTPA) 17.50 13.51 MDRD = Modification of diet in renal disease. DTPA = diethylenetriaminepentaacetate. 2 Equations for calculating estimated glomerular filtration rate (eGFR) Body surface area (BSA): BSA (m2) = 0.007184 × (height [cm])0.725 × (weight [kg])0.425 Cockcroft–Gault formula: GFR (mL/min) = (140 − age) × weight × 1.228/SCr × (0.85, if female) Reciprocal serum creatinine: GFR (mL/min) = 100/SCr × 100 MDRD (6-variable): GFR (mL/min/1.73 m2) = 170 × (SCr/88.4)−0.999 × age−0.176 × (SU × 2.78)−0.17 × albumin0.318 × (0.762, if female) × (1.18, if African American) Abbreviated MDRD (4-variable): GFR (mL/min/1.73 m2) = 186 × (SCr/88.4)−1.154 × age−0.203 × (0.742, if female) × (1.210, if African American) GFR = glomerular filtration rate. SCr = serum creatinine level (μmol/L). SU = serum urea level (mmol/L). MDRD = Modification of diet in renal disease.

Nigel D Toussaint MB BS, FRACP · John W M Agar MB BS, FRACP · Vincent D'Intini MB BS, FRACP

A 50-year-old man was transferred to the intensive care unit with high anion gap metabolic acidosis. Investigations suggested a diagnosis of pyroglutamic acidaemia. Factors contributing to the acidosis were medications (paracetamol and flucloxacillin), sepsis and renal failure. The acidosis resolved with supportive therapy and withdrawal of the drugs. It is important to recognise this treatable aetiology of metabolic acidosis. Clinical recordA 50-year-old man with cerebral palsy, intellectual impairment and epilepsy was referred to hospital with a 1-week history of fever, chills, rigors, haematuria and loin pain. His usual medications included phenytoin 300 mg/day, phenobarbitone 30 mg/day and carbamazepine 1200 mg/day. There was no history of prior renal disease. At hospital admission (Day 1), he was conscious, in no obvious distress, and afebrile. He was dehydrated and tachypnoeic (respiratory rate, 22 breaths/minute), but haemodynamically stable. There was no pallor, jaundice or cyanosis. Cardiorespiratory examination was unremarkable. Abdominal examination revealed tenderness in the left renal angle, left loin and right upper quadrant with no features of peritonism. Key initial (and subsequent) screening investigations are summarised in Box 1. Of note was neutrophilia and significant renal impairment (glomerular filtration rate, 28 mL/min by MDRD 4-variable equation). Urinalysis showed sterile pyuria, haematuria (dysmorphic red blood cells on microscopy) and proteinuria (3.46 g following 24-hour collection). A chest x-ray (CXR) showed mild generalised bronchial wall thickening, with no focal parenchymal opacity. Treatment with empirical broad-spectrum intravenous antibiotics (ceftriaxone and gentamicin) was initiated for suspected urinary tract infection following blood and urine cultures. A computed tomography (CT) scan on Day 1 revealed a 2.3 cm simple cyst in the upper pole of the right kidney, multiple nodules in the lung bases and a small left pleural effusion. A vasculitic work-up, including assessment of antinuclear antibody, extractable nuclear antigen, antibodies to double-stranded DNA, antineutrophil cytoplasmic antibodies and complement levels, did not assist in diagnosis. Urine culture was negative, so a renal biopsy was performed to establish the aetiology of the acute nephritic syndrome, consistent with IgA nephropathy with mild activity (segmental crescents/necrotising lesions in two of 14 glomeruli), but without scarring. No treatment was indicated. In view of the persistent fever on Day 3, a repeat CXR was performed. A small left-sided effusion was noted and pleural fluid aspirate was consistent with an exudate (pleural fluid white cell count [WCC], 16.6 × 109/L; 85% neutrophils; total protein, 37 g/L; lactate dehydrogenase [LDH], 420 U/L), which was presumed secondary to an underlying pneumonic process. Intravenous flucloxacillin was commenced at 2 g/day to broaden the gram-positive antibiotic cover and continued for 11 days. Blood, urine and pleural fluid cultures were negative. Despite initial clinical and laboratory improvement, the fever recurred on Day 7 with a radiographically visible increase in the pleural effusion size. Repeat pleural aspirate confirmed an empyema (pleural fluid pH 6.4; LDH, 833 U/L; glucose, 0.2 mmol/L) requiring intercostal catheter insertion. However, there was minimal further drainage, despite intrapleural streptokinase administration. On Day 14, ceftriaxone and gentamicin were changed to empirical timentin and ciprofloxacin because of persistent fever and rising WCC. Flucloxacillin was increased to 4 g/day. Oral paracetamol (1 g every 6 hours as required) and subcutaneous fentanyl were administered for pain relief. On Day 18, deteriorating renal function and conscious state necessitated transfer to the intensive care unit (ICU). Investigations at ICU admission (Box 1) revealed a severe high anion gap (42 mmol/L) metabolic acidosis. Arterial blood gas analysis (on 100% inspired oxygen) showed a pH of 7.31, PaO2 242 mmHg, PaCO2 12 mmHg, and HCO3 5.6 mmol/L. Flucloxacillin and paracetamol were ceased, and intravenous vancomycin was commenced. Intravenous bicarbonate infusion (25 mL/hour), commenced in the ward for the acidosis, was continued. With supportive therapy (fluids, oxygen, antibiotics), the patient improved over the next 36 hours and the metabolic acidosis resolved. Following stabilisation, the patient underwent decortication of the left pleura. Histopathology was consistent with an organising fibrinous pleuritis. No bacteria were seen. Decortication was complicated by significant bleeding, requiring massive transfusion. After surgery, the patient’s renal function, respiratory function and conscious state steadily improved; he was extubated 5 days after decortication. Recovery was complicated by protracted vomiting. Endoscopy confirmed a Barrett’s oesophagus and small hiatus hernia; he improved with a proton-pump inhibitor. In the absence of further respiratory compromise, he was discharged home. DiagnosisThe cause of the high anion gap metabolic acidosis at ICU admission was not immediately apparent. Serial evaluation of biochemical markers showed worsening renal function. However, even with a creatinine level of 0.541 mmol/L, the expected level of unmeasured anions was only 10–19 mmol/L and was insufficient to explain an anion gap of 42 mmol/L and the severity of the metabolic acidosis. Lactate (0.7 mmol/L) and blood glucose levels (6.1 mmol/L) were not elevated, and urinalysis was negative for ketones, suggesting that lactic or keto-acidosis were unlikely causes (blood ketones were not measured). There was no history of salicylate administration or ethylene glycol, ethanol or methyl alcohol consumption. Case-note review indicated that the patient had received a total of 8 g of paracetamol and 16 g of flucloxacillin in the 4 days before ICU admission. Ongoing sepsis and worsening renal failure, in combination with these drugs, suggested a possible diagnosis of pyroglutamic acidaemia (PGA). Urine pyroglutamic acid levels, highly elevated 36 hours after ICU admission (Box 1) remained elevated 10 days later, although the values had decreased significantly. Plasma pyroglutamic acid levels were also markedly elevated 36 hours after ICU admission (Box 1). The very high urine and plasma pyroglutamic acid levels supported our diagnosis of PGA. Red cell glutathione synthetase activity was normal (5.6 μmol/g haemoglobin; reference range, 4.2–9.8 μmol/g haemoglobin), suggesting that it was unlikely that this patient had a hereditary disorder of the γ-glutamyl cycle. DiscussionHigh anion gap metabolic acidosis is frequently encountered in critical care practice. Recently, there have been several reports of high anion gap acidosis resulting from excess production of 5-oxoproline, and termed “pyroglutamic acidaemia”.1-5 This acidaemia is most frequently reported with paracetamol therapy,1 but has also been associated with flucloxacillin2 and vigabatrin,3 particularly in the setting of severe sepsis, renal or hepatic dysfunction.4 The reported inciting dose of paracetamol has been variable: 8 g of paracetamol daily for 3 weeks in one study,6 and a cumulative dose of 20.8 g of paracetamol over 2 weeks in another.7 In a series of 11 patients with transient oxoprolinuria, all patients were taking paracetamol, with most receiving therapeutic dosages.8 A serum paracetamol level of > 200 μmol/L was seen in only one of the eight patients in whom paracetamol levels were checked. Our patient received a cumulative dose of 8 g of paracetamol over 4 days, and it is likely that PGA was precipitated by a combination of factors, including sepsis, renal dysfunction, and co-administration of flucloxacillin. PGA also occurs with genetic deficiency of either glutathione synthetase or 5-oxoprolinase.5 However, not all causes of 5-oxoprolinuria are necessarily associated with acidaemia. The mechanism of non-hereditary PGA is probably multifactorial. Suppression of glutathione levels because of sepsis, as seen in animal models of polymicrobial sepsis,9 may have contributed to the development of PGA in our patient. Flucloxacillin could have further compounded this acidosis by inhibiting the breakdown of pyroglutamic acid by 5-oxoprolinase.2 The role of paracetamol in PGA is more complex. The metabolite of paracetamol, N-acetyl benzoquinoneimine, reacts irreversibly with glutathione. Under normal circumstances, glutathione depletion leads to increased γ-glutamyl cysteine synthetase activity and excessive production of γ-glutamyl cysteine (Box 2). However, under altered conditions, glutathione synthetase activity becomes rate-limiting, leading to the conversion of γ-glutamyl cysteine to 5-oxoproline by γ-glutamyl cyclotransferase.5 Our patient’s antiepileptic medications, which are known hepatic enzyme inducers and metabolised via CYP2E1, may have further compromised glutathione availability by decreasing glutathione stores and competing with paracetamol for metabolism. Renal impairment may also be important. Renal tubular epithelial dysfunction may impair intracellular glutathione re-formation (a high ATP-requiring state), leading to accumulation of 5-oxoproline and prompt excretion (because of its small molecular size) into the urine, peritubular capillaries and systemic circulation. The use of N-acetyl cysteine to treat PGA has been advocated to replenish glutathione stores by supplying cysteine for glutathione synthesis. Another theoretical treatment option is the use of cysteamine, which increases cytosolic cysteine and restores substrate availability for the glutamate pathway, normalising pyroglutamic acid levels. As PGA can be easily missed in a critically ill patient, where several factors may contribute to a metabolic acidosis, a high index of suspicion is required to diagnose this condition. PGA should be considered in the differential diagnosis of high anion gap acidosis, especially when the levels of organic acids do not sufficiently account for the degree of anion gap and when there is co-administration of drugs such as paracetamol and flucloxacillin. Where PGA is suspected, the offending drugs should be withdrawn and treatment with N-acetyl cysteine considered. 1 Investigations* Day 1 Hospital admission Day 18 ICU admission Day 63 On recovery Reference range Haematology Haemoglobin (g/L) 125 115 120 135–175 White cell count (× 109/L) 13.6 24.7 7.82 4–11 Neutrophil count (× 109/L) 11.1 22.75 6.09 1.8–7.5 International normalised ratio 1.2 7.6 1.0 0.8–1.2 APTT (s) 27 65 26 24–37 Fibrinogen level — 5.7 — 1.5–4.0 D-dimer FDP — 2.15 — < 2.0 Biochemistry Sodium (mmol/L) 134 138 137 137–145 Potassium (mmol/L) 3.9 2.8 4.1 3.5–4.9 Chloride (mmol/L) 97 93 99 100–109 Bicarbonate (mmol/L) 23 6 29 22–32 Urea (mmol/L) 9.1 18.6 2.7 2.7–8.0 Creatinine (mmol/L) 0.210 0.541 0.100 0.05–0.12 Gamma GT (U/L) 152 92 116 0–60 Albumin (g/L) 25 17 23 34–48 Lactate dehydrogenase (U/L) 252 293 210 110–230 Serum amylase (U/L) — 119 — 20–100 C-reactive protein (mg/L) 290 160 47 < 10 Anion gap (mmol/L) 18 42 13 7–17 Lactate level (mmol/L) — 0.7 — 0.2–2.0 Serum pyroglutamic acid level† (μmol/L) — 11 010 — 15–215 Urine pyroglutamic acid level† (μmol/mmol creatinine) — 20 495 13 103 < 100 * Platelet count, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and creatinine kinase were normal when measured. † Initial serum and urine pyroglutamic acid levels were measured 36 hours after admission to the intensive care unit, and repeat urine test was performed on Day 10. Serum and urine pyroglutamic acid levels not measured at discharge. — = Not measured. Bold indicates highly abnormal results. APTT = activated partial thromboplastin time. FDP = fibrinogen degradation products. GT = glutamyl transpeptidase. ICU = intensive care unit. 2 The γ-glutamyl cycle: mechanism of oxoprolinuria Sepsis and paracetamol reduce glutathione levels, lifting feedback inhibition of γ-glutamyl cysteine synthetase. Excess γ-glutamyl cysteine is converted by γ-glutamyl cyclotransferase to 5-oxoproline, the build-up of which leads to acidaemia and oxoprolinuria. Flucloxacillin may inhibit further the rate-limiting enzyme 5-oxoprolinase.

John V Peter MD, DNB, FRACP · Natasha Rogers MB BS · Shailesh Murty MB BS, MD · Rosemarie Gerace BSc · Richard Mackay FRACP · Sandra L Peake BM BS, FJFICM, PhD

Objective: To estimate the frequency of chronic kidney disease (CKD) in a clinic-based sample of patients with type 2 diabetes in the setting of Australian primary care.Design, setting and participants: Expressions of interest were invited from all registered general practitioners in Australia: 500 GP investigators were randomly selected from each stratum (state and urban versus rural location), proportional to the census population, and asked to recruit and provide data for 10–15 consecutively presenting adults with type 2 diabetes between April and September 2005.Main outcome measures: Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 and evidence of kidney damage on urinalysis (eg, microalbuminuria).Results: 348 GP investigators submitted data for 3893 individuals with type 2 diabetes (52% men; median age, 66 years). Almost one in every four patients consulting their GPs had an eGFR < 60 mL/min/1.73 m2 (23.1%; 95% CI, 21.8%–24.5%). More than one in three had an elevated urinary albumin–creatinine ratio (ACR) (34.6%; 95% CI, 33.3%–35.9%). There was an overlap of 10.4% of patients with both an eGFR < 60 mL/min/1.73 m2 and an elevated urinary ACR, meaning that almost one in two patients with type 2 diabetes consulting their GPs (47.1%; 95% CI, 45.8%–48.4%) had CKD. CKD was significantly more common in women, in older people, and in individuals with established macrovascular disease.Conclusion: CKD is a common complication of type 2 diabetes, found in about half of all patients with type 2 diabetes consulting their GPs. Efforts to increase the recognition of CKD will lead to improved care, and possibly survival, of patients with type 2 diabetes.

Merlin C Thomas PhD, FRACP · Andrew J Weekes MD · Olivia J Broadley BSc, BCA · Mark E Cooper MB BS, PhD · Tim H Mathew PhD, FRACP

A 40-year-old Indigenous woman with type 2 diabetes presented with a 6-month history of intermittent left flank pain. She reported worsening pain of 2 days’ duration associated with fever, nausea, vomiting and reduced urine output. Clinical examination revealed tenderness over the left loin. An x-ray (not shown) and computed tomogram of the abdomen (Box) suggested a diagnosis of emphysematous pyelonephritis. Over the next few hours, the patient developed septic shock. In view of the severity of the emphysematous pyelonephritis, as evidenced by the extent of gas in the renal system on imaging and the development of septic shock, an urgent laparotomy and left nephrectomy were performed. Escherichia coli was isolated from blood cultures and from tissue of the necrotic kidney. After surgery and with antibiotic treatment, the woman made a slow recovery. Emphysematous pyelonephritis is a rare, severe gas-forming infection of the renal parenchyma, typically seen in people with diabetes. Radiologically, four classes of emphysematous pyelonephritis are described on computed tomography:1 in Class 1 and 2, the gas is localised to the collecting system and the renal parenchyma, respectively, without extension to the extrarenal space; in Class 3A, as seen in this case, there is extension of gas or abscess into the perinephric space, and in Class 3B, to the pararenal space; bilateral emphysematous pyelonephritis or emphysematous pyelonephritis of a solitary kidney represents the most severe form of the disease (Class 4). Emphysematous pyelonephritis is associated with a high mortality rate (40%) when treated with antibiotics alone.1 Although milder forms of the disease (Class 1 and 2) have been successfully treated with a combination of percutaneous drainage and antibiotics, these modalities alone may not be sufficient in more severe presentations of the disease or in patients presenting with septic shock. In such patients, early nephrectomy is recommended.1,2 Computed tomography scan There is necrosis within the renal parenchyma, with mottled gas radiating from the medulla to the cortex. Gas locules and a crescent of subcapsular gas are present in the perinephric space.

John V Peter MD, DNB, FRACP · Vishwanath Biradar MB BS, DNB · Sandra L Peake BM BS, FJFICM, PhD

To the Editor: I agree with Jones1 that the body surface area (BSA) formula printed in the position statement on reporting of estimated glomerular filtration rate (eGFR)2 is wrong, even though the authors say that he is mistaken.3 As stated by Jones, the correct formula4 for BSA in m2, for a body weight W kg and height H cm is: (i) BSA = W0.425 × H0.725 × 0.007184. However, the position statement2 gave the following formulas: (ii) BSA = W0.425 × H0.725 × 0.007184/1.73; and (iii) Uncorrected eGFR = GFR estimate (mL/min/1.73m2) × BSA. It appears that the denominator “1.73” has migrated from formula (iii) to formula (ii), so in fact both of these formulas are incorrect. This is potentially misleading for doctors and others who may want to calculate the eGFR for someone who is unusually big or small. Formula (iii) should in fact be: (iii) Uncorrected eGFR = GFR estimate (mL/min/1.73m2) × BSA/1.73. It is interesting that the same two errors in BSA calculations are present on the US National Kidney Disease Education Program website,5 which was presumably the source of the formulas used by the Australian Creatinine Consensus Working Group.

Alan McNeil PhD, FRACP, FRCPA

In reply: McNeil draws attention to the detail in the correction factor we published in an attempt to assist users to “uncorrect” the eGFR derived from the MDRD (Modification of Diet in Renal Disease) equation used in calculating GFR from a serum creatinine concentration. Recalculating the eGFR to remove the adjustment for body surface area (BSA) in an individual is unnecessary except at extremes of body size.1 Readers can be reassured that the formulas published in the position statement,2 if used as directed, will not lead to any error. However, it would have been clearer if we had labelled the “BSA” equation as “correction factor” instead of “BSA”. In the position statement2 it can be misinterpreted that the BSA formula has a denominator, whereas, when used primarily to calculate BSA, it of course does not. Both versions of the formulas (ours in the position statement and McNeil’s) therefore lead to identical answers. The reader can choose which one to use.

Timothy H Mathew MB BS, MRACP, FRACP · Graham Jones MB BS, DPhil, FRCPA · David Johnson MB BS, FRACP, PhD

To the Editor: Obesity-related glomerulopathy (ORG) is a condition that is partially reversible by weight loss. A 48-year-old morbidly obese man presented with massive proteinuria (8.4 g/day; reference range[RR], < 0.03 g/day). His medical history included hypertension of 4 years, morbid obesity, gout and impaired fasting glycaemia. His hypertension had been relatively well controlled, with no known end-organ complication until the current review. His urinary protein excretion rate measured 6 months earlier had been 0.13 g/day. Longstanding medications included aspirin, lisinopril and allopurinol. The patient weighed 125 kg and was 1.77 m in height (body mass index, 40 kg/m2 [class III obesity]). His blood pressure was 130/70 mmHg, with no postural hypotension. The fundi were normal, with no evidence of hypertensive retinopathy. There was no peripheral pitting oedema and there were no tendon xanthomata. A repeat urinary protein measurement showed an excretion rate of 7.9 g/day, confirming the earlier result. Renal and liver function tests were normal. Other laboratory tests produced the following results: fasting cholesterol, 5.5 mmol/L (RR, < 4.0 mmol/L); triglycerides, 2.4 mmol/L (RR, < 1.8 mmol/L); serum creatinine, 92 μmol/L (RR, 60–110 μmol/L); albumin, 38 g/L (RR, 35–45 g/L); fasting glucose, 6.8 mmol/L (RR, < 5.5 mmol/L); serum insulin, 66 mU/L (RR, 5–25 mU/L); and C-peptide, 6.8 nmol/L (RR, 0.2–0.6 nmol/L). All relevant tests for glomerulonephritis, including serum antinuclear antibodies, antinuclear cytoplasmic antibodies, C3 and C4 levels, protein electrophoretic studies, and hepatitis B and C serology were negative, making a diagnosis of glomerulonephritis unlikely. While awaiting the renal biopsy, the patient decided to attempt rapid weight loss. He began consuming mostly one meal a day of about 5000 kJ (which included about 2000 kJ of protein). Six weeks later, his weight had fallen to 118 kg and his blood pressure was 130/80, with no oedema. His urinary protein excretion rate was 7.6 g/day. After 18 weeks, the patient weighed 110 kg and his urinary protein excretion rate had fallen to 2.1 g/day. At 6 months, his weight loss had plateaued at 102 kg and urinary protein excretion was 0.85 g/day. The renal biopsy showed features consistent with ORG1 (Box). No other abnormality was detected. A concomitant minimal change lesion with spontaneous remission would be a possible explanation, but such a lesion is exceedingly rare and difficult to exclude in the absence of electron microscopy. It is also unlikely given the patient’s age and abnormal light microscopy finding. It is apparent that class III obesity, through unknown mechanisms,2 is a major contributing factor in causing ORG and massive proteinuria — conditions that can be readily improved by weight loss. It remains to be seen in this case whether further weight reduction will further reduce the proteinuria, which, on the other hand, may also be confounded by the hypertension. Impaired fasting glycaemia is not a cause of proteinuria.3 This clinical vignette reinforces the need to check vigilantly for proteinuria and rigorously advise obese patients to attempt weight reduction, especially now that obesity has been confirmed to be an independent risk factor for end-stage renal disease.4 Histopathology of a representative glomerulus There is prominent vascular pole/perihilar sclerosis (broken circular line) and mild fibrosis of the Bowman capsule (arrow) (haematoxylin–eosin stain; original magnification, 3 40). No evidence of hypertensive diabetic nephropathy or tubular disease was detected. Other histological findings (not shown here) included glomerulomegaly, peripheral hyalinosis and mild basement membrane thickening.1 Morphologically, obesity-related glomerulopathy can be difficult to separate from idiopathic focal and segmental glomerulosclerosis.1

Huy A Tran FRACP, FRCPA

A recent position statement issued by the Australasian Creatinine Consensus Working Group sparked a lively response from our readers (Med J Aust 2005; 183: 138-141)

Christopher M Florkowski · Wolf W Woltersdorf · Peter M George · Mohammed Saleem

Clinical records Patient 1 A 30-year-old woman presented to hospital with bilateral hand paraesthesia and a serum potassium level of 2.9 mmol/L (reference range [RR], 3.5–5.0 mmol/L). She denied taking medications and had no significant past medical history. However, 3 months before admission, she had presented to her general practitioner complaining of anorexia, nausea, lethargy, fevers and aches. An erythrocyte sedimentation rate (ESR) of 91 mm/h (RR, 7–18 mm/h) and a serum creatinine level of 0.106 mmol/L (RR, 0.030–0.110 mmol/L) were noted. (Twelve months previously, her serum creatinine level had been 0.073 mmol/L.) Then, 1 month before admission, she had developed blurred vision due to anterior uveitis, diagnosed by an ophthalmologist, and was treated with topical steroids. In the intervening period, she had lost 12 kg in weight. A normochromic, normocytic anaemia was now present (haemoglobin level, 103 g/L; RR, 115–165 g/L), and her serum creatinine level was 0.230 mmol/L. The hypokalaemia was corrected, and she was discharged with a referral to the renal outpatient clinic. In clinic, her blood pressure was 140/85 mmHg, but the physical examination was otherwise normal. Repeat laboratory tests showed: creatinine, 0.250 mmol/L; potassium, 3.1 mmol/L; bicarbonate, 17 mmol/L (RR, 23–31 mmol/L); and phosphate, 0.64 mmol/L (RR, 0.60–1.40 mmol/L). Urine microscopy showed no leukocytes, erythrocytes or casts. Urine pH was 7.0, with glucosuria on dipstick. Protein excretion was 0.9 g/day (RR, < 0.15 g/day). Autoimmune markers were negative, including antinuclear antibody, antineutrophil cytoplasmic antibody, antidouble-stranded DNA antibody, and antibodies to extractable nuclear antigens. Serum calcium and angiotensin-converting enzyme (ACE) levels were normal. A chest x-ray and renal ultrasound were unremarkable. A renal biopsy showed acute interstitial nephritis and chronic renal damage (Figure A). After taking prednisolone 60 mg/day and concurrent phosphate, bicarbonate and potassium supplements for 4 weeks, her serum creatinine level fell to 0.130 mmol/L. The dose of steroids was reduced gradually over 4 months and renal function remained stable. Shortly after stopping prednisolone, her eye symptoms recurred. Ophthalmological examination revealed a bilateral visual acuity of 6/4, keratic precipitates, posterior synechiae and perilimbal injection, consistent with anterior uveitis (Figure B). This responded to topical steroids. Patient 2 A 34-year-old woman was referred to the renal clinic by her general practitioner, with a creatinine level of 0.190 mmol/L, normochromic, normocytic anaemia (haemoglobin level, 110 g/L), and an elevated ESR (120 mm/h). She gave a 1-month history of weight loss (15 kg), with anorexia, nausea, arthralgias, myalgias, fatigue and fevers. She had mild asthma, which was being treated with salbutamol, and took no other medications. Physical examination was unremarkable. Repeat laboratory tests 1 week later showed a serum creatinine level of 0.250 mmol/L. Urine microscopy showed no leukocytes, erythrocytes or casts. Proteinuria was absent and a renal ultrasound gave normal results. A renal biopsy revealed granulomatous acute interstitial nephritis with multinucleated giant cells (Figure C). Her serum calcium and ACE levels were normal, and a chest x-ray was unremarkable. Oral prednisolone 60 mg/day was commenced. One week later, her constitutional symptoms and renal function markedly improved. Repeat tests showed: creatinine, 0.120 mmol/L; potassium, 2.9 mmol/L; and phosphate, 0.40 mmol/L. Glucosuria was detected on urine dipstick analysis. All autoimmune markers and HLA-B27 were negative. Potassium supplementation was commenced. After the prednisolone dose was reduced to 2.5 mg/day over 2 months, she developed bilateral red and painful eyes, photophobia and watery discharge. Ophthalmological examination showed bilateral anterior uveitis, with a visual acuity of 6/9 bilaterally, perilimbal injection, keratic precipitates, anterior chamber cells 3+, and posterior synechiae. The uveitis resolved with topical steroids and cycloplegic agents. Her serum creatinine level remained stable without steroid dose adjustment. A: Renal biopsy specimen (Patient 1) showing an interstitial infiltrate of lymphocytes, plasma cells, histiocytes and eosinophils, without granulomas. There is prominent tubular atrophy and wide separation of tubular structures due to interstitial fibrosis (haematoxylin–eosin stain, original magnification x 200). B: Photograph of the right eye of Patient 1, with the thick arrow showing pupil irregularity and posterior synechiae, and thin arrows showing inflammatory perilimbal injection. Keratic precipitates and anterior chamber cells are best appreciated on slit lamp examination. C: Renal biopsy specimen (Patient 2) showing tubulointerstitial mononuclear infiltrate with non-caseating granulomas and multinucleated giant cells (large arrows) (haematoxylin–eosin stain, original magnification x 200). Inset: Small arrows highlight eosinophils with typical bilobed nuclei (x 400). Tubulointerstitial nephritis and uveitis syndrome (TINU) was first reported in 1975.1 Diagnosis of TINU requires identification of acute interstitial nephritis and uveitis, in the absence of systemic diseases associated with either condition. TINU occurs more frequently in females (3 : 1), with the median age of onset being 15 years, and has no racial association.2 At least 50% of cases are probably idiopathic based on the absence of risk factors for acute interstitial nephritis.2 Associations that have been reported include: drugs (antibiotics, non-steroidal anti-inflammatory drugs), infections (herpes zoster, Epstein–Barr virus, toxoplasmosis), and systemic diseases (hyperthyroidism, hypoparathyroidism, rheumatoid arthritis).2 The main differential diagnosis is sarcoidosis. Although uveitis associated with sarcoidosis is typically granulomatous, uveitis associated with TINU is mostly non-granulomatous. Sarcoidosis rarely causes acute interstitial nephritis and frequently affects the lungs, whereas lung involvement has not been reported with TINU. Sjögren’s syndrome is not a differential diagnosis because patients with Sjögren’s syndrome do not develop uveitis despite having sore eyes (sicca). Neither patient was taking medications known to cause acute interstitial nephritis. There is often a time interval between the diagnosis of uveitis and that of acute interstitial nephritis, making the diagnosis of TINU difficult. In 35% of patients with TINU, ocular findings precede or develop concurrently with acute interstitial nephritis. In 65% of patients, ocular symptoms follow acute interstitial nephritis by a median time of 1 month, but can occur up to 14 months later.2 The most common systemic features are fever, weight loss, fatigue and malaise (50%); and eye pain and redness are the most usual ocular symptoms (77%).2 Acute anterior uveitis is the typical finding (80%) and is usually bilateral. About 20% of patients develop ocular complications, such as posterior synechiae (most common), cataracts and glaucoma. Patient 1 developed recurrence of uveitis despite quiescent renal disease, showing that the course of ocular disease can be independent of renal disease.2,3 Uveitis recurs or becomes chronic in about 50% of patients. It is commonly treated with topical or systemic steroids, and cycloplegic agents. Methotrexate, cyclosporin or azathioprine may prevent relapses in steroid-resistant, recurrent or persistent uveitis, but randomised trials are lacking.2,4 Both patients demonstrated features of proximal tubular dysfunction consistent with Fanconi’s syndrome. This syndrome causes aminoaciduria, glucosuria, metabolic acidosis (bicarbonate wasting), hypophosphataemia, natriuresis, kaliuresis, polyuria and proteinuria. It has been reported in idiopathic interstitial nephritis,3 drug-related interstitial nephritis,5 and TINU.6,7 Incomplete Fanconi’s syndrome and distal tubular defects with hyperkalaemia have also been reported.8 Urinary electrolyte losses can be significant and symptomatic, as in Patient 1. Lessons from practice Beware of red eyes — check for interstitial nephritis and renal failure. In patients with uveitis, acute interstitial nephritis may not develop concurrently and may be asymptomatic. In tubulointerstitial nephritis and uveitis syndrome, complications of proximal tubular dysfunction (leading to metabolic acidosis and serious electrolyte disorders) and chronic renal damage can occur. Potassium, bicarbonate and phosphate supplementation may be needed. Steroid treatment may prevent chronic renal damage. Another complication that has been found is chronic renal damage. Some authors consider renal disease in TINU to be benign,9 but the renal biopsy from Patient 1 suggests that TINU produces chronic damage. Renal failure may resolve spontan-eously and almost always responds to steroids.2 Persistent renal dysfunction occurs in about 10% of patients, with few needing dialysis. Renal biopsy findings are typical of acute interstitial nephritis, with eosinophils seen in 34% and non-caseating granulomas in 13%.2 Granulomas have been described in lymph nodes and bone marrow.1 Despite its propensity to affect the young, TINU is not limited to paediatric patients, as these cases demonstrate. TINU may be underreported, given the frequent temporal dissociation between uveitis and acute interstitial nephritis. Chronic renal damage and electrolyte abnormalities do occur; hence, patients with uveitis should be evaluated for renal involvement. If any abnormalities are detected, a renal biopsy may be indicated. Early detection and steroid treatment may prevent renal complications.

Andy K H Lim MB BS · Vicki Levidiotis MB BS, FRACP, PhD · Matthew A Roberts MB BS, FRACP · Troy Lim Joon MB BS, FRANZCO, FRACS

Estimating glomerular filtration rate using a simplified formula will lead to a vast increase in detection of chronic kidney disease in Australia In patients with chronic kidney disease (CKD), the degree of reduction in the glomerular filtration rate (GFR) is closely linked to the development of complications of CKD, and GFR is the best index for classifying the severity of the disease. In 2002, a US working party produced a five-stage classification of CKD, with guidelines for management according to stage, based largely upon GFR (Box).1 The classification is logical and simple and has enjoyed worldwide endorsement. However, one problem has impeded widespread usage of the classification — most clinicians do not measure or calculate GFR. Why estimate GFR?The gold standard for measurement of GFR is kidney clearance of inulin, but this method is a research tool and not practical for clinical practice. GFR may be accurately measured by determining the clearance rate of exogenous radioisotopes, such as radiolabelled Cr51-EDTA. Alternatively, the measurement of 24-hour creatinine clearance provides a reasonable, though less accurate, approximation. Both methods are inconvenient, time-consuming and costly. Serum creatinine concentration is widely used as a surrogate marker of GFR, but is crude and insensitive. For example, among the nationally representative AusDiab cohort of 11 247 Australian adults, 1.1% had elevated serum creatinine levels whereas 11.2% had a calculated GFR < 60mL/min.2 Because of these anomalies, much effort has been directed at deriving formulas that use serum creatinine level together with other clinical variables, such as age, sex and weight, to yield an accurate estimated GFR (eGFR). The abbreviated MDRD (Modification of Diet in Renal Disease) formula for deriving eGFR has been extensively validated in US populations and is endorsed for the classification of CKD.1 The inputs required for the (predominantly white) Australian population are serum creatinine level, age and sex (the performance of the formula is less satisfactory among people of Chinese origin,3 and thus possibly others of Asian ethnicity, and is untested among Indigenous Australians). Thus, all data required for calculating eGFR using the abbreviated MDRD formula are currently provided on the typical pathology request form, making automated reporting of eGFR potentially feasible. The growing burden of CKDThe burden of CKD has long been underappreciated. Stage 5 CKD (end-stage kidney disease [ESKD]), which requires dialysis or transplantation to prevent death from kidney failure, provides the most obvious burden of CKD, as dialysis and transplantation are highly visible and enormously costly health problems. Earlier stages of CKD are more prevalent and may be even more costly than ESKD. Projections based on data from the AusDiab survey suggest that 1.4 million Australian adults (11.4% of the non-institutionalised population) had CKD stages 3–5 in 2000.2 Of these, 11 660 (< 1%) were living on dialysis or a functioning kidney transplant.4 For the 99% with CKD who were not receiving dialysis or had not had a transplant, two major consequences have become apparent: increased risk of developing ESKD and increased cardiovascular risk compared with the normal population. Both of these risks are associated with a progressive increase in mortality rate through successive stages of CKD, as was demonstrated in a longitudinal study of subjects in a large health maintenance organisation in the United States (figures represent 5-year mortality rates): no CKD, 10.2% ± 0.5%; stage 2, 19.5% ± 1.9%; stage 3, 24.3% ± 0.8%; stage 4, 45.7% ± 3.5%.5 Indeed, overwhelming evidence now shows that CKD is an independent risk factor for cardiovascular disease and should be added to the list of “traditional” risk factors.6 The need to identify CKDIdentifying cases of CKD may help to prevent ESKD and the attending increase in cardiovascular morbidity and mortality. There is clear evidence that intervention may slow the rate of decline in GFR for people with CKD, particularly if identified at an early stage. Blood pressure control, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists for patients with proteinuric nephropathies, blood sugar control and regular clinical follow-up are all proven to be of benefit.7 Reduction in the cardiovascular burden associated with CKD through aggressive management of traditional and non-traditional (eg, elevated calcium phosphate product) cardiovascular risk factors appears likely to be effective, although definitive studies are awaited. CKD is generally asymptomatic. Subject awareness at all stages other than stage 5 is almost non-existent, and clinician awareness is similarly low.8 Thus, detecting CKD requires GFR measurement or estimation. In this issue of the Journal (page 138), a working group representing the peak bodies of Australian nephrology, pathology and biochemistry plus Kidney Health Australia has proposed that eGFR be automatically calculated whenever a serum creatinine measurement is requested through any pathology service in Australia. The eGFR will be reported whenever the value is < 60 mL/min, enabling classification of the patient within CKD stages 3–5. Values above 60 mL/min will not be reported, because of inaccuracies in eGFR in that range and because the complications of CKD are mainly seen at GFR < 60 mL/min. The program will include a comprehensive, ongoing strategy for quality control of laboratory serum creatinine measurements, as this is critical to the accuracy of eGFR, and a major education campaign designed to provide clinicians with guidance on interpreting eGFR and managing CKD. This initiative may prove to be incredibly important if Australia is to limit the current escalation in the burden of CKD. One crucial aspect will be to determine whether automated reporting of eGFR and early detection of CKD result in better health outcomes for the general population, by formally assessing the impact on the health system and individuals before and after the recommended change in eGFR reporting. As with any bold undertaking, there are certain risks and limitations. Firstly, an enormous number of patients will be identified, particularly among elderly Australians. The AusDiab study suggests the majority of patients with stage 3 CKD will be elderly women.2 The natural history of CKD in older people is poorly understood, as is the difference between the impact of normal ageing versus disease on GFR. The potential for increased costs to the health care system through an increase in tests, prescriptions and referrals to nephrologists may be significant, and the potential benefits are uncertain. The increase in workload for nephrologists, in particular, may be unsustainable. Education of clinicians will be crucial here, as will further research into the natural history of CKD in older people. Secondly, although eGFR is well validated for adult whites, caution will be required in applying eGFR to other patient groups such as Indigenous Australians and people of Asian origin.3 Finally, clinicians must not fall into the trap of interpreting an eGFR of > 60mL/min as indicative of healthy kidney function. While GFR is the best overall measure of kidney function and therefore the dominant determinant of the stage of CKD, for people at risk of kidney disease, testing for other markers of kidney damage — such as hypertension, haematuria, abnormal structure and, most importantly, albuminuria/proteinuria — must not be forgotten. K/DOQI classification of chronic kidney disease1 CKD stage Definition Prevalence in Australian adults2 1 Kidney damage (albuminuria, haematuria or abnormal kidney imaging), eGFR > 90 mL/min 0.9% (n = 112 000) 2 Kidney damage, eGFR 60–90 mL/min 2.0% (n = 250 000) 3 Moderate kidney failure, GFR 30–59 mL/min 10.9% (n = 1 400 000) 4 Severe kidney failure, GFR 15–29 mL/min 0.3% (n = 40 000) 5 End stage kidney disease requiring dialysis or transplant, GFR < 15mL/min 0.1% (n = 13 000) CKD = chronic kidney disease. eGFR = estimated glomerular filtration rate. K/DOQI = Kidney Disease Outcomes Quality Initiative.

Steven J Chadban PhD, FRACP · Francesco L Ierino PhD, FRACP

The systematic staging of chronic kidney disease (CKD) by glomerular filtration measurement and proteinuria has allowed the development of rational and appropriate management plans. One of the barriers to early detection of CKD is the lack of a precise, reliable and consistent measure of kidney function. The most common measure of kidney function is currently serum creatinine concentration. It varies with age, sex, muscle mass and diet, and interlaboratory variation between measurements is as high as 20%. The reference interval for serum creatinine concentration includes up to 25% of people (particularly thin, elderly women) who have an estimated glomerular filtration rate (eGFR) that is significantly reduced (< 60 mL/min/1.73m2). The recent publication of a validated formula (MDRD) to estimate GFR from age, sex, race and serum creatinine concentration, without any requirement for measures of body mass, allows pathology laboratories to “automatically” generate eGFR from data already acquired. Automatic laboratory reporting of eGFR calculated from serum creatinine measurements would help to identify asymptomatic kidney dysfunction at an earlier stage. eGFR correlates well with complications of CKD and an increased risk of adverse outcomes such as cardiovascular morbidity and mortality. We recommend that pathology laboratories automatically report eGFR each time a serum creatinine test is ordered in adults. As the accuracy of eGFR is suboptimal in patients with normal or near-normal renal function, we recommend that calculated eGFRs above 60 mL/min/1.73m2 be reported by laboratories as “> 60 mL/min/1.73m2”, rather than as a precise figure.

The Australasian Creatinine Consensus Working Group

Two patients with anorexia nervosa and raised serum creatinine levels were found to have nephrocalcinosis on renal biopsy, an association not previously described. Clinical records Patient 1 A 26-year-old woman was referred with a serum creatinine level of 0.21 mmol/L (reference range [RR], 0.03–0.11 mmol/L). She had a 5-year history of anorexia nervosa, laxative misuse, and unexplained intermittent hypercalcaemia requiring hospital admissions (calcium, > 3.0 mmol/L). During one admission, she disclosed taking a vitamin preparation containing vitamin D3 200 IU and calcium phosphate 40 mg. Investigations for hypercalcaemia included assays of parathyroid hormone, parathyroid hormone-related peptide, vitamin D, 1,25-hydroxy vitamin D, osteocalcin, serum cortisol, serum angiotensin-converting enzyme, and 24-hour urinary calcium; thyroid function tests; and serum and urine protein electrophoresis. These were all in the normal range. A urine diuretic screen was negative on two occasions. Bone mineral density measurement was normal. On examination, the patient was thin, weighing 40 kg (height, 160 cm; body mass index, 15.6 kg/m2). Her blood pressure was 110/80 mmHg. Estimated glomerular filtration rate (GFR) was 29 mL/min per 1.73 m2 (normal mean value in young women is 125 mL/min per 1.73 m2). Urinalysis showed 18 000 erythrocytes/mL (RR, < 10 000/mL) and 0.17 g/day of proteinuria (RR, < 0.1 g/day). Autoimmune, hepatitis B and C serology were negative. C3 was 0.68 g/L (RR, 0.81–1.66 g/L) and C4 was 0.17 g/L (RR, 0.12–0.42 g/L). Her serum electrolytes at presentation are shown in Box 1. Ultrasound showed kidneys 9.5 cm and 9.3 cm in length, with possible calcification of the pyramids adjacent to the upper pole calyces. There was no calcification on plain abdominal x-ray. Her renal biopsy showed calcification in degenerate tubular basement membranes within the interstitium, and in three of 36 glomeruli. There was widespread interstitial fibrosis indicating chronic damage. One glomerulus showed basement membrane reduplication, but immunoperoxidase staining was negative. Eighteen months later, her renal function has remained unchanged. Patient 2 A 31-year-old woman was referred by her general practitioner because of a rise in serum creatinine level from 0.16 to 0.41 mmol/L. An eating disorder had been diagnosed 8 years earlier. Two years previously, diarrhoea and abdominal pain were investigated. A malabsorption screen, upper endoscopy, and small bowel biopsy were all normal. Colonoscopy showed melanosis coli, consistent with laxative misuse. One year before the current admission, she had been hospitalised with hypokalaemia and renal failure (Box 1). Her potassium was corrected with intravenous replacement. She discharged herself the following day. She reported having 30 bowel actions a day, and was taking spironolactone 25 mg daily, effervescent potassium chloride (14 mmol K+) 6 tablets/day, diazepam 2 mg as required, and diclofenac 50 mg as required. Her blood pressure was 100/60 mmHg, and she weighed 43.6 kg (height, 162.5 cm; body mass index, 16.5 kg/m2). Electrolytes on admission are shown in Box 1. Her serum calcium levels were high on two occasions, but normal on others. Mid-stream urine had no erythrocytes or pyuria, and 24-hour urine protein was 0.44 g/day. Ultrasound showed echogenic kidneys without calcification. Serum complement and autoimmune serology were negative. Twenty-four-hour urine biochemistry showed potassium 17 mmol/day (RR, 25–100 mmol/day); sodium 21.0 mmol/day (RR, 40–210 mmol/day), calcium 0.6 mmol/day (RR, 2.5–7.5 mmol/day); oxalate 0.23 mmol/day (RR, 0.04–0.34 mmol/day); and phosphate 18.0 mmol/day (RR, 10–40 mmol/day). Bone mineral density measurement was normal. Her creatinine level reduced to 0.23 mmol/L (estimated GFR, 26 mL/min per 1.73 m2) before she underwent a renal biopsy (Box 2). She subsequently had multiple episodes of hypokalaemia (potassium 2.0 mmol/L) despite large quantities of potassium supplements being supplied, with a positive urine laxative screen on two occasions. Serum calcium was intermittently high, the highest being 3.0 mmol/L (corrected for albumin). One year after her renal biopsy, nasogastric feeding increased her weight from 30 kg to 38 kg after 5 weeks. A year later, she developed pneumonia and septic shock, and died. A key clinical feature of anorexia nervosa is “the relentless pursuit of thinness”1 and a “desperate need to grow thinner”.2 People with this disorder often engage in behaviour that affects fluid and electrolyte balance, including vomiting, laxative or diuretic misuse, fluid restriction, and the injudicious use of health supplements. Anorexia nervosa can cause significant renal problems, some of which may have contributed to the development of nephrocalcinosis in our patients. Electrolyte disturbances include hypokalaemia, hyponatraemia, hypercalcaemia, hypomagnesaemia and hypophosphataemia.3,4 Hypokalaemia with metabolic alkalosis indicates either vomiting or diuretic misuse, whereas metabolic acidosis indicates laxative misuse.4 Hypokalaemia is rare in the absence of these behaviours.5 Body phosphate stores can be depleted, and refeeding can exacerbate hypophosphataemia, with serious consequences such as seizures and myocardial dysfunction.6 Renal function may also be affected by volume depletion. Nephrolithiasis has been reported in patients with anorexia nervosa,7-11 but, to our knowledge, nephrocalcinosis has not. Nephrocalcinosis results from excessive calcium deposition in the kidney, and renal failure may result from tubular cell injury, tubular obstruction by calcified debris, and atrophy of nephrons. Chronic inflammation and interstitial fibrosis accompany these changes.12 In a series of 350 patients with nephrocalcinosis, the commonest causes were primary hyperparathyroidism (34.1%), distal renal tubular acidosis (20.9%), and medullary sponge kidney (11.7%).13 Medullary calcification is typical in most of these conditions, but neither of our patients had computed tomography to demonstrate medullary calcification. Both patients had hyperphosphataemia secondary to reduced glomerular filtration rate (GFR), causing an elevated calcium-phosphate product, which predisposed them to tissue calcification. However, an alternative cause for impaired GFR was not found in either patient. Both the amount of calcification and its presence in glomerular and tubular basement membranes disclosed by renal biopsy argue against calcification secondary to other renal disease. Hypercalcaemia is the most likely cause of the nephrocalcinosis in Patient 1, probably due to use of a vitamin D preparation. However, vitamin D was not elevated on the occasion it was measured. In Patient 2, diclofenac use may have contributed to fluctuations in renal function, but does not explain the biopsy findings. Chronic severe hypokalaemia and laxative misuse characterised Patient 2, and in her case, diarrhoea and laxative misuse were the most prominent potential causes for hypokalaemia. However, her metabolic alkalosis is more consistent with diuretic misuse or vomiting (or both) than diarrhoea. Her low urinary potassium excretion does not disprove diuretic misuse, because she was taking a potassium-sparing diuretic (spironolactone), and her diuretic misuse may have been intermittent. Indeed, chronic use of frusemide for weight control has been associated with nephrocalcinosis in patients without anorexia nervosa.14,15 Chronic diarrhoea may contribute to nephrocalcinosis by causing volume depletion. Nephrocalcinosis associated with acute renal failure has been reported in relation to an oral sodium phosphate preparation used for bowel preparation for colonoscopy.16 Prolonged hypokalaemia can cause tubular atrophy, damage to tubular cells, interstitial lymphocyte infiltration, interstitial fibrosis and juxtaglomerular apparatus hyperplasia.17 Chronic tubulo-interstitial nephritis due to hypokalaemia has been described as a cause of end-stage renal disease in anorexia nervosa patients18 and may explain some of the chronic damage observed in Patient 2. ConclusionPatients with anorexia nervosa have potential risk factors that may predispose them to nephrocalcinosis, and this should be considered in the differential diagnosis of patients with eating disorders and abnormal renal function. 1 Electrolyte results for the two patients Patient 1 Patient 2 Reference range Admission 1 year prior Admission Sodium (mmol/L) 134 136 131 135–145 Potassium (mmol/L) 4.1 2.0 2.6 3.5–5.0 Chloride (mmol/L) 100 76 77 95–107 Bicarbonate (mmol/L) 25 41 36 23–31 Urea (mmol/L) 7.2 15.3 15.0 2.5–7.7 Creatinine (mmol/L) 0.214 0.285 0.410 0.03–0.11 Calcium* (mmol/L) 2.70 2.79 2.41 2.10–2.60 Albumin (g/L) 38 27 26 36–48 Phosphate (mmol/L) 2.02 2.07 3.35 0.60–1.40 Ca x P product (mg2/dL2) 5.5 Not measured 8.1 < 5.8† Magnesium (mmol/L) 0.87 Not measured 1.81 0.70–1.00 * Calcium value has been corrected for albumin. †Recommended by the Caring for Australians with Renal Impairment draft guidelines (http://www.kidney.org.au/cari/CARI_guidelines.php). 2 Renal biopsy from Patient 2 Six of 27 glomeruli were totally sclerosed and there was widespread interstitial fibrosis with tubular atrophy and interstitial lymphocytosis (a). Calcification was seen in glomerular basement membranes (b, arrow), within tubule lumens (c) and in tubular basement membranes (d, arrow). There was also intimal thickening of interlobular arteries, indicating arteriosclerosis and there were no significant abnormalities on immunofluorescence or electron microscopy. (Haematoxylin and eosin stain; original magnifications (a) × 40, (b) and (d) × 100, (c) × 200.)

Matthew A Roberts FRACP · Duncan P MacGregor FRCPA, PhD · Nick Paoletti FRANZCP · Francesco L Ierino PhD · Campbell R Thorpe FRANZCP, MPsych

Deborah J Verran Senior Transplant Surgeon, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050. deborahATemail.cs.nsw.gov.au To the Editor: A recent editorial by Mathew et al1 and an article by Kennedy et al2 tackle the issue of commercial kidney transplantation. In their editorial, Mathew and colleagues conclude that if the nationwide Australian deceased donor organ donation rate approached South Australian levels, dialysis patients would not travel overseas to purchase renal allografts.1 I believe that this statement oversimplifies the situation with respect to organ trafficking and the motives behind patients’ acceptance of this option. Organ trafficking is illegal under all state and territory laws within Australia and hence cannot occur. In a number of other countries around the world this is not the case. Although laws have been introduced in India, this has not necessarily led to cessation of trafficking in kidneys.3 Compounding this, the option of purchasing an organ is becoming more readily accessible by means of an increasing number of Internet sites.4,5 What motivates patients to go through with purchasing an organ overseas is not explored either in the editorial by Mathew et al1 or the article by Kennedy et al.2 Kennedy et al do not state whether any of the patients who travelled overseas for a kidney had been deemed not fit to be on the renal transplant waiting list in New South Wales. They also do not give the waiting time on dialysis for each patient before he or she decided to travel overseas. What is clear is that only patients who can afford to pay the US$70 000 or more currently quoted for a renal allograft will be the ones who end up travelling overseas. It would be nice to think that, with an increased organ donor rate in Australia, patients will no longer travel overseas to purchase organs. However, the ready availability of the commodity in not-too-distant countries and the increasing ease of access to this organ trade, combined with sufficient cash, will mean that there is no major barrier to some individuals.

Deborah J Verran

Sean E Kennedy,* Yvonne Shen,* John A Charlesworth,† James D Mackie,‡ John D Mahony,§ John J P Kelly,¶ Bruce A Pussell** * Renal Registrar, † Professor of Renal Medicine, Prince of Wales Hospital, Sydney, NSW. ‡ Renal Physician, Prince of Wales Hospital, Sydney, and Illawarra Regional Hospital, Wollongong, NSW. § Renal Physician, Royal North Shore Hospital, Sydney, NSW. ¶ Renal Physician, St George Hospital, Sydney, NSW. ** Professor of Medicine, Department of Nephrology, Prince of Wales Hospital, Sydney NSW 2031. b.pussellATunsw.edu.au In reply: We agree that the motives for organ trafficking are complex. The reasons that people choose to travel overseas to obtain an organ was not addressed in our article on this occasion, but some possible reasons may be self evident given the long waiting time, especially in New South Wales. Our aim was to alert our colleagues to the increased risks associated with overseas commercial transplant procedures so that they could ensure that their patients were fully informed when making a decision. Most of our patients were on the waiting list, and the time on dialysis was detailed in Box 2 in our article.1 However, two were not on the waiting list — one had a pre-emptive transplant and another was not on the list because of age-related medical problems.

Sean E Kennedy · Yvonne Shen · John A Charlesworth · James D Mackie · John D Mahony · John J P Kelly · Bruce A Pussell

Laurelle J Burrell,* Elizabeth A Grabsch,† Alexander A Padiglione,‡ M Lindsay Grayson§ * Infectious Diseases Research Nurse, † Infection Control Scientist, § Director of Infectious Diseases, Austin Hospital, Studley Road, Heidelberg, VIC 3084; ‡ Infectious Diseases Physician, Department of Epidemiology and Preventive Medicine, Monash University (Alfred Hospital), Melbourne, VIC. Lindsay. GraysonATaustin.org.au To the Editor: Patients with end-stage renal failure are a key risk group for colonisation and infection with vancomycin-resistant enterococcus (VRE). Consequently, many renal units in Australia screen these patients regularly for VRE colonisation, to assist with infection control and treatment.1-3 Screening protocols are usually applied equally to inpatients and outpatients, even though the risk of VRE colonisation among outpatients (and therefore the cost–benefit of such screening) has not been clearly defined. To assess the prevalence of faecal VRE colonisation among haemodialysis outpatients, we conducted a cross-sectional survey of outpatients attending 12 Victorian in-centre haemodialysis units — Austin Health (four units), Southern Health (three units) and five regional haemodialysis units (Bendigo, West Gippsland, La Trobe Valley, Central Gippsland and Bairnsdale). Patients attending these units represent about a third of the state’s in-centre haemodialysis population. The study was approved by the ethics committee at each hospital, and written informed consent was obtained from all participants. All patients who attended the units between 1 October 2001 and 3 April 2002 were invited to participate. VRE faecal carriage was assessed by three rectal swabs and one faecal specimen taken on at least three separate occasions. Specimens were inoculated onto Enterococcosel agar (BBL, Sparks, USA) containing 6 μg/mL vancomycin. All cultures were processed by standard methods for VRE identification, as described previously.2,3 Of 345 available haemodialysis patients, 269 (78%) consented to participate in the study (205 [76%] metropolitan, and 64 [86%] regional; participation rate per centre, 70%–91%). The 269 patients represented approximately 30% of Victorian in-centre haemodialysis patients. Overall, 74% of participants had assessment of all three rectal swabs and a faecal specimen. VRE faecal colonisation was found in three of the 269 participants (1.1%) — two were from separate metropolitan hospitals, and one from a regional centre. All isolates were Enterococcus faecium vanB (the most common type of VRE in Australia).3 None of these three patients were known to be previously colonised. This 1.1% prevalence was substantially lower than the 3.0%–4.6% prevalence previously described in renal inpatients in Melbourne,2,3 and the 10% rate reported in the United States (where 33% of dialysis centres have one or more VRE-positive patients).1,4 Statistical comparisons of this study with our previous two Australian studies2,3 should be undertaken cautiously, as screening methods differed in specimen frequency, type and number. Bearing in mind this caveat, the rate of faecal VRE carriage was significantly lower among the haemodialysis outpatients in our current study compared with renal inpatients in a 1997 study by Grayson et al2 (3/269 v 9/194; P = 0.02 by χ2 test), but less definitely so when compared with renal inpatients in the 1998–1999 study of Padiglione et al3 (3/269 v 22/739; P = 0.09, by χ2 test). Since the outpatient study, screening surveys at our hospital have shown intermittent high rates of colonisation in renal inpatients and environmental contamination (unpublished data). Given our findings in outpatients, we believe future VRE screening protocols in Australian hospitals should focus primarily on inpatients, rather than faecally continent outpatients, who have both a low rate of colonisation and low potential risk for VRE transmission or acquisition. Good compliance with practical infection control guidelines remains important to avoid widespread dissemination of VRE in our haemodialysis centres.5

Laurelle J Burrell · Elizabeth A Grabsch · Alexander A Padiglione · M Lindsay Grayson

Basic clinical dialysis. David C Harris, Grahame Elder, Lukas K Kairaitis, Gopala K Rangan (eds). Sydney: McGraw Hill, 2005 (xxiv + 264 pp). ISBN 007471501 1. Many clinicians will have unpleasant memories of their first visit to their hospital’s haemodialysis unit. Unfortunately, this situation hasn’t improved much over the years, where the evening RMO is called to check Mr Jones’ “dry weight” pre-haemodialysis. This can be a difficult task for a nephrologist, so it was refreshing to review this handbook which states, after a series of helpful instructions, “In practice, initial determination of the dry weight of the patient is trial and error using the signs above and frequent assessment”. This is a handbook in every sense of the word, of use to its target population of students, RMOs, advanced trainees, nurses and paramedical staff. Information on haemodialysis and peritoneal dialysis as well as acute dialysis and plasmapheresis is backed up by protocols developed within the dialysis units of the Western Sydney Renal Service. While some protocols may be of little use in established units, they could easily be incorporated into the structure of any new department with benefit. Because many dialysis units have become the domain of the nursing profession over the past few decades, doctors’ dialysis knowledge and skills are often limited. Nevertheless, it is the RMO and rotating registrar that should benefit most from this book. Each section is well referenced with up to date reviews including Australian (CARI) and United States (K/DOQ1) guidelines. Basic clinical dialysis covers more than dialysis, with sections detailing normal renal function, chronic kidney disease stages, pre-dialysis management and transplantation. In my view, this additional coverage is the book’s main weakness. Excluding these ancillary areas may have allowed space to better cover emerging issues such as nocturnal dialysis. A more detailed guide to dosing of commonly prescribed drugs as found in The Oxford handbook of dialysis (Oxford University Press, 2001) would have been helpful. In handbooks such as this, it can be difficult to get the correct balance and cover all relevant areas without too much detail. This one gets it right most of the time and would complement the library of any dialysis unit. Shane L Carney Nephrologist John Hunter Hospital, New Lambton, NSW

Shane L Carney

Desperate people seek desperate remedies The treatment alternatives available to Australians with endstage kidney failure are dialysis, transplantation or no active treatment. The last of these options allows kidney failure to progress spontaneously to uraemia and death. Over the past decade the number of Australians on dialysis has grown by 6% per annum, adding an additional $25 million yearly to healthcare expenditure.1 This growth is caused by both increasing numbers of people entering dialysis programs and a low rate of transplantation because of a shortage of donor kidneys. Kidney availability in Australia remains low and, if anything, is worsening, with only 6.8% of those on dialysis receiving transplants in 2002, compared with 11.7% a decade earlier.1 It is remarkable that Australia has been so slow to fully examine and take up systems that appear to work Dialysis is the only initial treatment option for most patients with endstage kidney failure. Transplantation without prior dialysis is increasingly popular, but requires a live donor available at the right time; currently, only 3% of patients undergoing transplantation have not been on dialysis beforehand. Of those on dialysis, only 23% overall and 39% of those aged under 65 years are on the waiting list for a deceased-donor transplant.2 Those not on the list are either not interested in undergoing transplantation, have medical barriers to safe transplantation, or are deemed too frail to tolerate the procedure and subsequent immunosuppression. Both patients and healthcare professionals believe that transplantation, when feasible, is the preferred therapeutic option. The scientific justification for this belief appears well founded. In particular, there is strong evidence that patients who receive transplants have a significant survival advantage. The annual mortality rate of an age-matched population maintained by transplantation is reduced about 80% beyond the first year compared with those remaining on dialysis on the waiting list.3 The major difference is an up to 30-fold increase in relative risk of cardiovascular events and death experienced by those on long-term dialysis.4 In most Australian states, the average wait for a kidney from a deceased donor is about 4 years, and some patients wait much longer. The prospect of an extended wait on dialysis, as well as the possibility that a suitable kidney may never become available, drives some patients to consider more drastic options. One pathway that is illegal in Australia, but open to those able to afford it, is to travel overseas to purchase a kidney transplant. It is not known how often Australians are choosing this option. The report by Kennedy et al in this issue of the Journal (page 224) describes the outcomes for 16 Sydney-based patients who travelled overseas for kidney transplantation over the past 14 years. The risk of going down this path is evident, with an increased risk of serious infection being a major hazard. The annual rate of deceased-donor kidney transplants in Australia for 2004 was a low 11 donors per million population.5 In 2003, the rate in Australia was 9.0 per million population, compared with 33.8 in Spain, 23.9 in Austria, 24.8 in Belgium, 18.3 in France and 22.1 in the United States. 6 Thus, the rate of organ donation in this country is low compared with other developed countries, and remains so despite the publicity campaign promoting organ donation following the untimely death following a brain injury of Australian cricket icon David Hookes. One response to the shortage in deceased-donor organs has been an increase in live kidney donation, and the proportion of live donations in 2003 was 40% of total transplants. The source of live kidney donors, previously restricted to close blood relatives, has broadened in recent years to allow unrelated and poorly matched emotionally connected donors. In the past 12 months, there have been several kidney transplants from altruistic strangers donating to the pool of waiting dialysis patients (so-called non-directed donations). We can now add overseas commercial sources as another contributor to live kidney donation for Australian residents. The real reasons for Australia’s poor performance in deceased-donor organ procurement have not been fully established. Clearly, there is no lack of public support, which has exceeded 80% in repeated surveys over many years.7 One outstanding observation that has received little prominence and no systematic study is the high and internationally competitive organ donor rate achieved in South Australia. Over the last decade, South Australia has consistently doubled the rate in all other Australian states.5 A similar variation in performance is seen in the teaching hospitals in capital cities, with some having double the rate of others. This marked variation in the donation rates between states and hospitals points to the probability that the barriers to increased organ donation are within the hospital system. The situation in Australia appears ripe for a collaborative approach, such as one reported from the United States that sought to “identify, learn, adapt, replicate and celebrate ‘breakthrough’ practices associated with higher donation rates”.8 It is remarkable that Australia has been so slow to fully examine and take up systems that appear to work in some regions or hospitals. Positive moves are being made. A special working group of the Australian Health Ministers’ Council has recently made 11 recommendations for change in the arrangements and process for organ donation. The most fundamental recommendation is for intensive care staff to routinely interrogate the Australian Organ Donor Registry to ascertain the recorded intent of all suitable patients with severe brain injury after the first set of brain death tests. Relatives will then be informed of the intent recorded on the Registry and be asked only if they are aware of any change. Importantly, in this approach, the family will not need to be asked for consent. If Australia’s organ donation rate could match that of its best-performing hospitals and states, the embarrassing situation driving dialysis patients to take the risks involved with travelling overseas for kidney transplantation would not exist. Much remains to be accomplished, but there are grounds for optimism in believing Australia’s deceased-donor organ donation rate could double if the barriers existing in the hospital system could be removed.

Timothy Mathew FRACP · Randall Faull PhD, FRACP · Paul Snelling FRACP

Lack of donors has led to a worldwide increase in commercial kidney transplantation programs where recipients acquire kidneys either from executed prisoners or live non-related donors. Commercial transplantation is prohibited by legislation in Australia. Our centres have had 16 patients who have travelled overseas to receive a commercial kidney transplant; five have subsequently died. As has been found previously, patients who received commercial transplants were more likely to develop infections such as HIV, hepatitis B virus, cytomegalovirus and fungal infections. Previous reports have found that patient and graft survival were comparable to local results, whereas we found that patient and graft survival were worse than transplantation within Australia. Patients considering the option of overseas commercial donation should be advised that heightened risks to life and graft survival exist.

Sean E Kennedy FRACP · Yvonne Shen FRACP · John A Charlesworth MD, FRACP · James D Mackie FRACP · John D Mahony FRACP · John J P Kelly MD, FRACP · Bruce A Pussell PhD, FRACP

Clinical records Patient 1 In 2004, a 63-year-old woman presented to the emergency department with a 1-month history of nausea and intermittent vomiting. Three weeks before presentation she was empirically prescribed esomeprazole for management of dyspepsia. A week before presentation, she stopped taking this medication, as she suspected it was exacerbating the malaise, nausea and vomiting. On presentation, she was pale, with blood pressure of 160/60 mmHg and no signs of fluid overload. Dipstick urinalysis showed blood +, protein ++, and leukocytes. Serum creatinine level was 1878 μmol/L (reference range [RR], 60–125 μmol/L), and serum urea level, 42 mmol/L (RR, 2.5–6.5 mmol/L). A normochromic, normocytic anaemia was present (haemoglobin level, 87 g/L; RR, 130–180g/L), with no eosinophilia. Urine microscopy revealed isomorphic red blood cells, some white blood cells, but no casts. Urine culture showed no growth. On admission, the patient’s remaining medications (irbesartan [150 mg daily] and atorvastatin [40 mg at night]) were also withdrawn as a precautionary measure. As acute interstitial nephritis was suspected, she was treated with methylprednisolone (500 mg daily for 3 days) followed by oral prednisone (50 mg daily). Supportive haemodialysis was begun. On Day 4 of admission, a renal biopsy was performed; results were consistent with acute interstitial nephritis. Prednisolone therapy was continued for a total of 4 weeks on a tapering dose. Supportive dialysis was required for 4 days, by which time renal function had improved. However, at follow-up 8 months later, serum creatinine level remained abnormal at 187 μmol/L (Box 1). Patient 2 In the same year, a 63-year-old man presented to the emergency department with a 3-week history of nausea, vomiting, weight loss and oliguria. Five weeks before presentation, he was prescribed rabeprazole by his family physician as empirical treatment for nausea and dyspepsia. This was replaced by esomeprazole a week later, as symptoms had not resolved. The patient discontinued the latter after 2 weeks’ therapy (12 days before presentation), as he had still gained no relief of symptoms. Medications on presentation were irbesartan/hydrochlorothiazide (300/12.5 mg daily), amlodipine (10 mg daily) and rofecoxib (12.5 mg daily) as required. He had been taking these medications for the previous 3 years, but used rofecoxib infrequently. On presentation, the patient was pale, with no signs of fluid retention. Dipstick urinalysis showed blood ++, protein +, and trace leukocytes. Serum creatinine and urea levels were 1110 μmol/L and 31 mmol/L, respectively. Six months previously, serum creatinine level had been 109 μmol/L. The patient also had normochromic, normocytic anaemia (haemoglobin level, 90 g/L), with no eosinophilia. Urine microscopy revealed isomorphic red blood cells, granular casts, hyaline casts, some white blood cell casts, but no red blood cell casts. Urine culture showed no growth. A clinical diagnosis was made of acute interstitial nephritis induced by a proton-pump inhibitor (PPI). The patient was admitted to hospital and treated with prednisolone (60 mg daily). Renal biopsy 2 days later confirmed acute interstitial nephritis (Box 2). Renal function improved after admission, and serum creatinine level was 600 μmol/L on discharge 5 days after presentation. Subsequently, renal function declined slowly, and, 9 months after presentation, long-term peritoneal dialysis was begun. In these two cases of acute interstitial nephritis, esomeprazole was implicated as the likely causative agent (although Patient 2 was also briefly exposed to rabeprazole). In both cases, renal function improved after esomeprazole was withdrawn and corticosteroid treatment begun, although Patient 2 went on to require long-term dialysis. Omeprazole was first implicated as a cause of acute interstitial nephritis in 1992.1 Since then, 22 case reports of omeprazole-induced acute interstitial nephritis have been referenced in Medline. 2-7 Recently, pantoprazole and lansoprazole have also been implicated as causes of acute interstitial nephritis, 3,8 along with rabeprazole (unpublished data from our centre). Before the cases reported here, the Adverse Drug Reactions Advisory Committee (ADRAC) had been notified of four cases of acute interstitial nephritis induced by esomeprazole, along with six cases of acute renal failure and two of renal impairment. In October 2004, the manufacturer of esomeprazole, AstraZeneca, reported being aware of at least 15 cases worldwide of acute interstitial nephritis possibly induced by esomeprazole, and at least 200 cases worldwide induced by omeprazole (data on file, Astra-Zeneca). Two of these esomeprazole cases and 20 of the omeprazole cases were from Australia (it is unclear whether these two esomeprazole cases were included in those notified to ADRAC). MIMS online lists acute interstitial nephritis as a complication of omeprazole but not esomeprazole.9 A recent hospital series reported drug-induced acute interstitial nephritis as the cause of biopsy-proven acute renal failure in 8% of cases, with PPIs accounting for eight of the 14 cases. 2 The diagnosis of acute interstitial nephritis is most common when renal biopsy is performed for unexplained renal impairment, with a reported prevalence in this setting of 27%.10 PPI-induced acute interstitial nephritis poses a particularly difficult diagnostic challenge, as symptoms are non-specific and may mimic the original indications for which the PPI was prescribed. Most patients diagnosed with PPI-induced acute interstitial nephritis recover renal function, but some fail to recover fully and, in extreme cases, require long-term renal replacement therapy, 2 as in Patient 2. Little is known about the relationship between the risk of PPI-induced acute interstitial nephritis and duration and dosage of PPI therapy, delay in diagnosis, or other factors. In addition, it is not clear whether the prognosis differs between acute interstitial nephritis induced by PPIs and that induced by other drugs. Although both our patients were treated with corticosteroids, evidence for their use remains anecdotal and is not derived from randomised controlled trials. A recent report of the largest retrospective series published to date found no statistically significant difference in outcome, as determined by serum creatinine level, between patients who received corticosteroid therapy and those who did not at 1, 6 and 12 months after presentation.11 PPIs are now the third most commonly prescribed drug in Australia. Although acute interstitial nephritis is a rare complication, it is a potentially catastrophic cause of acute and chronic renal failure. All medical practitioners need to be aware of this potential class reaction. Early recognition may prevent the development of irreversible renal injury. Lessons from practice Acute interstitial nephritis is a rare but serious adverse effect of proton-pump inhibitor (PPI) therapy, which may potentially lead to chronic kidney failure. Acute interstitial nephritis has now been described in association with all PPIs currently marketed in Australia. The initial symptoms of PPI-induced acute interstitial nephritis are usually non-specific, often mimicking the symptoms of dyspepsia for which the PPI was initially prescribed. A high index of suspicion is needed, and serum creatinine level should be checked promptly if the diagnosis is suspected. 1 Serum creatinine level over time after presentation in Patient 1 Shaded area indicates the reference range, 60–125 μmol/L. 2 Renal biopsy specimen in Patient 2 Biopsy specimen from the renal cortex taken 2 days after presentation, showing an interstitial inflammatory infiltrate composed of lymphocytes and eosinophils (I), with mild acute tubular necrosis and a cellular cast (C). (Original magnification × 40; haematoxylin–eosin stain.)

Nimeshan Geevasinga BSc · Lukas Kairaitis FRACP · Gopala K Rangan FRACP · Patrick L Coleman MRCI, FRACP

QuestionIn patients without diabetes, but with impaired renal function and proteinuria, does combination treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril and the angiotensin-receptor blocker (ARB) losartan prevent deterioration of renal function more effectively than treatment with either agent used alone? Trial details Design: Randomised controlled trial. Setting: Outpatient clinics in Kisarazu, Kimitsu and Futtsu (Japan). Participants: 263 patients (mean age about 45 years; 54% men) with non-diabetic biopsy-proven renal disease, impaired renal function (creatinine clearance rate, 20–70 mL/min), persistent proteinuria > 0.3 g/24 h, and hypertension. Patients with proteinuria > 10 g/24 h, renovascular or malignant hypertension, urinary tract infection, heart failure or myocardial infarction, connective tissue disease, chronic hepatic or pulmonary disease, cancer and those pregnant or breastfeeding were excluded. Duration: 36 months. Main outcome measures: Combined endpoint of end-stage kidney disease (ESRD) or doubling of serum creatinine level, death and proteinuria. Main results: At 3 years’ follow-up, 10 (11%) of 85 patients receiving combination treatment reached the combined primary endpoint, compared with 20 (23%) of 85 taking trandolapril alone (hazard ratio, 0.38; 95% CI, 0.18–0.63) and 20 (23%) of 86 taking losartan alone (hazard ratio, 0.40; 95% CI, 0.17–0.69). Proteinuria decreased significantly in all treatment groups, but the effect was greatest with combination teatment; the maximum median change in daily urinary protein excretion was –42.1% with losartan, –44.3% with trandolapril and –75.6% with the combination treatment (P = 0.01). There was no significant difference in the mean fall in systolic blood pressure (losartan, – 5.1 mmHg [standard deviation, 1.6]; trandolapril, – 5.2 mmHg [SD, 1.3] mmHg; combination, – 5.3 mmHg [SD, 1.4]) and diastolic blood pressure (losartan, – 2.9 mmHg [SD, 0.9]; trandolapril, 22.9 mmHg [SD, 0.8]; combination, 23.0 mmHg [SD, 0.7]) among the three groups. Conclusion: Combining ACE inhibitors and ARBs reduces the incidence of the combined end-point of ESRD or doubling of serum creatinine in non-diabetic chronic kidney disease, with moderate reduction of renal function and moderate proteinuria by at least 30% compared with treatment with either drug alone. CommentaryRationale for the trialThe renin–angiotensin system has been implicated in the progression of non-diabetic renal disease, and ACE inhibitors and ARBs have independently been shown in randomised controlled trials to reduce proteinuria and the risk of end-stage kidney disease (ESRD) and doubling of the serum creatinine level. Proteinuria lies in the causal pathway to ESRD; therefore, the antiproteinuric effect of these agents is a component of renoprotection.1-6 What needed further exploration was whether the combination of ACE inhibitor and ARB was better than treatment with either agent alone. The COOPERATE triallists postulated an advantage of complete inhibition of the renin–angiotensin system with combination treatment of ACE inhibitor and ARB at maximum dosage.7 Trial methodsAfter an 18-week active run-in period, participants were randomly allocated to ACE inhibitor (trandolapril, 1–3 mg/day plus a lactose placebo), ARB (losartan, 12.5–100 mg/day plus a lactose placebo) or ACE inhibitor (trandolapril, 0.5–3 mg/day) plus ARB (losartan, 12.5–100 mg/day). Run-in was performed to establish safety, adherence and the maximum tolerable dose of ACE inhibitor. There was no run-in period for the ARB, and the maximum tolerable dose was chosen on the basis of a previous study.8 Information essential for assessing the quality of the trial was missing from the methods section. The triallists detailed their randomisation technique, but the methods by which the randomised intervention was allocated to the patients — such as use of sequentially labelled, sealed, opaque envelopes, or a central or pharmacy randomisation, which would guarantee concealment — was not specified. Patients and investigators were blinded by the drugs being dispensed in identical containers, but there was no mention of whether the capsules themselves were similar. There was also no indication of blinding of the outcome assessors. Analysis was reported as intention-to-treat, but six of 263 patients (who could have had outcomes measured) were actually excluded from the trial because of “protocol invalidation” or “discontinuation”, and so analysis was “per-protocol” and not intention-to-treat. Overall, seven of 301 (2.3%) patients were lost to follow-up, a small number which was unlikely to cause any differences in the final results of the trial. The authors performed a subgroup analysis to assess whether the effect of combination treatment compared with single therapy with ACE inhibitor or ARB was affected by the degree of baseline proteinuria. Their methods for this subgroup analysis and reporting of results were incorrect and misleading, although common. They analysed the three groups separately, and showed no statistically significant benefit of combination treatment in patients with low grade (< 1 g/24 h) proteinuria (hazard ratio, 0.69; 95% CI, 0.22–2.28), and statistically significant benefit in patients with moderate (1–3 g/24 h) proteinuria (hazard ratio, 0.33; 95% CI, 0.19–0.74) and heavy (> 3 g/24 h) proteinuria (hazard ratio, 0.40; 95% CI, 0.21–0.84). What they should have done was a formal test of interaction (a statistical assessment of differences in the proportion of an outcome [eg, ESRD] in the three treatment groups across patients with low-grade, moderate or heavy proteinuria).9 Given the overlapping confidence intervals in their separate analyses, it is very likely that the test of interaction would have been negative. The absence of demonstrable effect in the lowest-risk stratum is explainable on the basis of lower event rates in this group, and therefore lack of power to detect an effect in this group separately. Urinary protein excretion on a continuous scale in grams per 24 hours (rather than groups) could also have been used as the explanatory variable. This study may also have been relatively underpowered to detect the harms of treatments because of the relatively small sample size (263) and because of the active run-in phase, which would tend to exclude patients at risk of adverse effects from the intervention. Run-in periods are common and very useful for improving the efficiency of trials by selecting patients most likely to comply with treatment and fulfil follow-up requirements. However, if there is an active run-in when patients with adverse effects are not randomised, there may be a systematic underestimation of the true harms of an intervention. Also, only the dose of ACE inhibitor, but not ARB, was established by an active run-in, and the dose of ARB in the combination treatment was not reported clearly. The potential variability of doses makes it possible that outcome differences are related to dose rather than greater efficacy. However, blood pressure — probably the most important confounder — was equalised across the two groups. Finally, in this study, no account was taken of how the effect of ACE inhibitors, ARB, or their combination, may be influenced by histological types of renal disease with different rates of progression. New informationIt is likely that there is an advantage of complete inhibition of the renin–angiotensin system with combined ACE inhibitor and ARB treatment compared with therapy with either drug alone, at maximum doses, in patients without diabetes, but with moderate (1–3 g/24 h) and heavy (> 3 g/24 h) proteinuria and moderate to severe renal impairment (creatinine clearance rate, 20–70 mL/min). These findings of the COOPERATE trial are promising, but need to be further explored in light of some of the study’s limitations, and the fact that comparative findings in patients with cardiovascular disease are conflicting. In chronic heart failure, combined treatment has proven to be advantageous compared with individual treatment with ACE inhibitors or ARBs.10,11 This has not been confirmed in studies of post-myocardial infarction.12 Implications for clinical practiceIn patients without diabetes who have renal impairment (creatinine clearance rate, 20–70 mL/min; proteinuria, > 0.3 g/24 h), combination treatment with ACE inhibitors and ARBs at their maximum dose appears to be effective and well tolerated. Further studies are awaited to confirm the findings of the COOPERATE trial. In the meantime, combination therapy may prove a useful strategy in patients who continue to have high-grade proteinuria despite maximal doses of ACE inhibitor or ARB.

Giovanni FM Strippoli MD, MPH, MM(Epi) · Craig C Jonathan MB ChB, PhD