Urology

Early detection and prevention of kidney disease reduces the risk of cardiovascular disease. This official World Kidney Day 2011 editorial is being published concurrently in many medical journals around the world. Protect your kidneys, save your heart 10 March 2011 will mark the celebration of the sixth World Kidney Day, an annual event jointly sponsored by the International Society of Nephrology and the International Federation of Kidney Foundations. Since its inception in 2006, World Kidney Day has grown dramatically to become the most widely celebrated event associated with kidney disease in the world and the most successful effort to raise awareness among both the general public and government health officials about the dangers of kidney disease, especially chronic kidney disease. In 2011, World Kidney Day will call attention to the large, and often unappreciated, role played by kidney dysfunction in increasing premature cardiovascular disease, the most common cause of morbidity and mortality worldwide. Can a focus on early detection and prevention of kidney disease really improve long-term cardiovascular health? We hope to convey the message that increased attention to the kidneys can indeed improve long-term health outcomes by reducing both kidney and cardiovascular disease. This should therefore be a central component of any global health strategy intended to reduce the enormous and growing burden of chronic non-communicable diseases. Cardiovascular disease (CVD) is the most common of the chronic non-communicable diseases that affect global mortality. About 30% of all deaths worldwide and 10% of all healthy life lost to disease are accounted for by CVD alone.1 Although there has been some decline in mortality from CVD in developed countries, no such decline has been reported in developing countries, ethnic and socially disadvantaged minority populations, or in people with accompanying chronic kidney disease (CKD).2,3 The presence of CKD significantly increases the risk of a cardiovascular event in patients with diabetes or hypertension.4,5 However, less well appreciated is that CKD alone is a strong risk factor for CVD, independent of diabetes, hypertension or any other conventional CVD risk factor.6,7 This is especially true when an increase in proteinuria, a major target of any CKD screening program, is present.6-9 The 20–30-fold increase in CVD in patients with end-stage renal disease (ESRD) has long been recognised. However, the association between lesser degrees of renal functional impairment and increased risk of CVD was definitively demonstrated only in 2004, when a community-based study of over 1000 individuals reported an independent and graded association between glomerular filtration rate (GFR) and risk of death, cardiovascular events and hospitalisations.6 Is this dramatic increase in CVD risk associated with CKD really due to CKD or does it just reflect the coexistent diabetes or hypertension present in a majority of these patients? The independent effect of CKD alone has now been well documented in many studies.7 The risk of cardiac death is increased by 46% in people with a GFR of 30–60 mL/min (stage 3 CKD) independent of traditional cardiovascular risk factors including diabetes and hypertension.10 The increased risk of cardiovascular events and mortality in people aged over 55 years with CKD alone is equivalent to, or even higher than, that seen in patients with diabetes or previous myocardial infarctions.11 Both general6,12 and high-risk populations13,14 exhibit an increased risk of CVD with CKD. This increased risk of CVD is not confined to the elderly — in volunteers with an average age of 45 years, the risk of myocardial infarction, stroke and all-cause mortality doubled in those with CKD.14 Proteinuria and cardiovascular riskIn considering the value of recommending screening for CKD along with screening for conventional CVD risk factors in selected individuals, data showing that the risk of CVD is better correlated with proteinuria (albuminuria) than with GFR alone are particularly relevant because proteinuria is virtually always a marker of kidney disease and is not a conventional CVD risk factor.6,8,9,15 Proteinuria has been shown to be a predictor of later CVD. The Prevention of Renal and Vascular Endstage Disease study showed a direct linear relationship between albuminuria and risk of cardiovascular death in the general population, even at levels of albumin excretion generally considered to be within the “normal” range (15–29 mg/day). The risk was increased more than sixfold when albumin excretion exceeded 300 mg/day.8 Recent data from the US National Health and Nutrition Examination Survey database as well as from Japan document an independent effect of albuminuria on risk of both CVD and all-cause mortality at any GFR.15,16 In patients with congestive heart failure but without diabetes, hypertension or reduced GFR, increased urinary albumin predicts both cardiovascular and all-cause mortality.17 In patients with coronary disease or previous myocardial infarctions, proteinuria confers a greater risk of mortality than reduced GFR, although both adversely influence outcomes.18 Not only the likelihood but also the time to development of a cardiovascular event is accelerated significantly by the presence of proteinuria at any GFR.19 About 78% of non-diabetic subjects with normal serum creatinine levels undergoing percutaneous coronary interventions have demonstrable CKD when screened more stringently for renal function (estimated GFR, urinary protein).20 As well as being a likely factor in accelerating development of coronary disease in these patients, the presence of CKD has been associated with an increase in other risks, including haemorrhagic complications, contrast nephropathy, re-stenosis, and death.10 Thus, multiple studies now confirm that proteinuria is a graded risk factor for CVD independent of GFR, hypertension and diabetes, and that this risk extends down into ranges of albumin excretion generally considered “normal”.21,22 Moreover, this increased cardiovascular risk has been well demonstrated in several studies where only dipsticks were used to screen for increased protein excretion.6,18,23 Although there has been concern that CKD diagnosed by reduced GFR alone identifies predominantly older adults at increased risk because of age alone,24 the connection between proteinuria as an independent risk factor for cardiovascular mortality has been confirmed by meta-analysis of 22 separate, general population, cohort studies and in both older (> 65 years of age) and younger (< 65 years of age) people of several nationalities and racial groups.23 Can treatment of CKD reduce CVD?Finally, and most importantly from a clinical perspective, there are provocative data to suggest that renal-targeted interventions designed to reduce proteinuria and slow progression of CKD can reduce CVD risk as well. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers are of documented benefit in slowing progression of established diabetic and non-diabetic CKD.25-29 The incidence of CVD in patients with CKD is significantly higher than in patients without CKD, with more rapid reduction of GFR independent of other risk factors, suggesting that interventions that slow progression of CKD may also reduce CVD.19 A 44% reduction in cardiovascular mortality over 4 years has been reported in patients from a general population who were screened and showed no cardiovascular risk factors except increased albumin in the urine, for which they were treated with renal-targeted ACE-inhibitor therapy.30 This effect was seen primarily in people with albumin excretion rates > 50 mg/day in a pilot study, and the intervention was shown to be cost-effective in that population.31 Cardiovascular endpoints were significantly reduced in direct proportion to the reduction of albuminuria with ACE-inhibitor therapy, and albuminuria proved to be the only predictor of cardiovascular outcome.32 Other studies have also demonstrated that changes in proteinuria in people with diabetes better predict cardiovascular outcomes than changes in blood pressure achieved with ACE-inhibitor therapy.33 The potential benefit of renal-targeted therapies has recently been highlighted by observations that doses of renin-angiotensin system blockers that are higher than those required for blood pressure control alone can further reduce proteinuria independent of their effects on blood pressure or GFR.34 Restricting salt intake and adding diuretics, both very inexpensive interventions, have also been found to further enhance the proteinuria-reducing effect of renin-angiotensin system blockade.35 Data are not yet available to establish whether screening for CKD and subsequent interventions will reduce cardiovascular mortality and be cost-effective in people younger than 55 years of age.36 However, it is now known that albuminuria is a better predictor of renal and cardiovascular events than blood pressure alone, that reducing proteinuria confers more renal and cardiovascular protection than lowering blood pressure alone, and that identification of CKD can improve cardiovascular outcomes. As celebrations of the sixth World Kidney Day approach, it is worth noting that before the past decade, kidney disease was seen by most government and public health authorities as largely confined to patients with ESRD — thankfully, a rare condition because the enormous cost of renal replacement therapy disproportionately consumes scarce health care resources and is well beyond the means of countries inhabited by over 80% of the world’s population.37,38 Much has changed. We now appreciate that kidney disease is not rare — some 10% of the population has evidence of renal dysfunction. And we know these individuals are not of concern just because a few will progress to ESRD, but more because they carry a greatly enhanced risk of premature death from CVD, the single largest and most expensive health care threat we confront at a global level.1 Just as progress is being made in treating most of the traditional cardiovascular risk factors, CKD has emerged as yet another one that independently causes substantial vascular toxicity. Fortunately, there is good news as well. Biomarkers of CKD (proteinuria, estimated GFR) are easy and relatively inexpensive to detect or estimate, and one of these, proteinuria, emerges early in the evolution of generalised vascular disease. Thus, kidney-targeted detection and prevention programs seem to offer a valuable opportunity to institute early preventive measures that go beyond traditional cardioprotective approaches. There is now compelling evidence that including selective screening for CKD in global health programs designed primarily to reduce CVD will significantly improve the outcomes of not only renal disease but especially the non-communicable diseases like diabetes and CVD that dominate future health care strategies. Roadmaps for accomplishing this have already been presented for both developed39,40 and emerging1,41 countries. However, effective implementation of such strategies will only come when both the general public and the renal community work together to convince health authorities that it is in the public interest to do this. It is our sincere hope that worldwide celebration of World Kidney Day 2011 will provide an opportunity to reinforce the message that kidney disease is indeed common, harmful and treatable, and that protecting your kidneys is an important health strategy that may save your heart.

for the Joint International Society of Nephrology and International Federation of Kidney Foundations World Kidney Day 2011 Steering Committee*

Clinical record A previously well 43-year-old Australian lawyer was hiking the Kokoda Track in Papua New Guinea in August 2008. She awoke with a headache on the second day and, suspecting dehydration, consumed about 7 L of fluid while hiking. By late afternoon she complained of increased headache and nausea, which was exacerbated by her lying supine. She developed seizures several hours after profuse vomiting. Temazepam and metoclopramide were administered rectally due to limited medical resources. Three doctors present provisionally diagnosed dilutional hyponatraemia but had no facilities for intravenous therapy. Arrangements were made for urgent repatriation by helicopter to Port Moresby but this was later abandoned due to bad weather. She deteriorated overnight, becoming unresponsive to painful stimuli and lapsing into coma. Her vomiting and convulsions continued. With no rescue imminent, salt solution approximating normal saline was administered rectally. There was some improvement in eye-opening and verbal responses on the Glasgow Coma Scale. Fortuitously, an American naval hospital ship anchored outside Port Moresby retrieved her via helicopter the following afternoon. Her plasma sodium on arrival to intensive care was 114 mmol/L. After she was intubated and treated with intravenous hypertonic saline, the patient made a good recovery. Exercise-associated hyponatraemia (EAH) is a modern, life-threatening condition first described in 19851 after introduction of guidelines promoting excessive fluid intake during exercise.2 EAH is defined as hyponatraemia occurring during or up to 24 hours after prolonged exercise (generally > 4 hours duration).3 This “conditioned overhydration” — drinking beyond thirst, variously influenced by misunderstanding of exercise physiology, media including sports-drink advertising,4 and forced rehydration protocols5 — has been reported among hikers,6 military personnel5 and long-distance sports participants.7 Despite being well documented in scientific literature, those most at risk are unaware of this preventable condition. EAH is common, with reported incidences of hyponatraemia (serum sodium concentration, < 135 mmol/L) and critical hyponatraemia (serum sodium concentration, < 120 mmol/L) during the 2002 Boston Marathon of 13% and 0.6%, respectively.7 At least eight fatalities have been documented8 — likely an underestimation given difficulties with postmortem diagnosis.9 The unexplained deaths in 2009 of four previously well hikers on the Kokoda Track in similar conditions provide urgency to the need to raise awareness of the association between overhydration and EAH. Extensive research confirms EAH is primarily dilutional secondary to overhydration,10 manifest as weight gain during exercise. That only a small proportion of individuals exposed to overhydration develop hyponatraemia suggests a role for associated underlying defects in free water excretion. These include exercise-induced non-osmotic antidiuretic hormone secretion,11 while the recent description of an activating mutation of the arginine vasopressin receptor 212 may explain the undetectable antidiuretic hormone levels found in other cases.13 Excessive-sweat sodium losses associated with subclinical cystic fibrosis have also been described.14 Identified risk factors for EAH8 include excessive drinking behaviour, weight gain during exercise, female sex, slow performance pace, high availability of drinking fluids, > 4 hours’ exercise duration and hot environmental conditions consistent with our scenario. Female sex hormones inhibit cellular sodium–potassium–ATPase function, which may explain the observed higher risk of EAH and cerebral oedema among women.8 Slow performance pace may reflect insufficient physical training and provides the opportunity for overhydration. Lessons from practice Military personnel, hikers and endurance sports participants are at risk due to overhydration during prolonged exercise. Non-specific symptoms are commonly mistaken for dehydration. Diagnosis requires a high degree of suspicion, and biochemical testing. Water should be consumed according to thirst and guided by weight comparison before and after exercise. Weight gain should be avoided, aiming for a 1%–2% weight loss during prolonged exercise. Education of at-risk groups is essential for prevention. Symptoms include lethargy, dizziness, headache, nausea and vomiting, with progression to confusion, ataxia, seizures and coma.3 Importantly, EAH cannot be easily distinguished clinically from heat exhaustion, with subsequent mistaken “rehydration” exacerbating the condition. EAH requires a high index of suspicion to facilitate timely evacuation for biochemical diagnosis and treatment. Specific clinical features include euvolaemia and polyuria. A recent review of 145 United States military cases identified that the training cadre often mistook EAH for dehydration, and treatment by aggressive water rehydration had fatal consequences in three cases.15 Overhydration was encouraged by well-meaning guides and colleagues in another near fatal case on the Kokoda Track reported in 2008.5 In this context, a prominent tour operator’s media assertion that “dehydration” in “the death zone”16 caused the recent deaths among young healthy Kokoda Track hikers may perpetuate a dangerous culture of conditioned overhydration. It is of grave concern that, in 2009, a second fatality occurred shortly after media speculation that dehydration was the cause of the first. Available evidence suggests that, in an environment of excess water (most trekkers carry > 4 L water per day), hikers on the Kokoda Track should be more concerned with severe EAH secondary to overhydration, rather than with dehydration. Initial treatment of EAH is fluid restriction to avoid exacerbation of hyponatraemia. Those with critical hyponatraemia or symptomatic, biochemically confirmed EAH require treatment with intravenous hypertonic saline (100 mL of 3% saline solution over 10 minutes) in a supervised environment. This is based on the assumption that the hyponatraemia is acute (< 48 hours) and that no cases of osmotic demyelination syndrome have been reported in treating EAH.3 No single preventive fluid intake regimen can be recommended to cover all activities. The Second International EAH Consensus Development Conference statement3 recommends drinking to thirst instead of a predetermined protocol. The aim should be never to gain weight during endurance exercise and to expect a small percentage weight loss (1%–2%) due to substrate use.3 Fluid intake requirements could be estimated for guided treks by comparison to baseline weight. Point-of-care electrolyte testing could be used. There is insufficient evidence to recommend salt tablet use.3 Importantly, there is no evidence that commercial sports drinks prevent hyponatraemia3 — in fact, given their sodium hypotonicity relative to normal saline (10–20 mmol/L v 145 mmol/L), excessive consumption could worsen hyponatraemia. At a public health level, education of those leading and participating in high-risk activities is critical. The number of EAH casualties at a New Zealand ultradistance event was reduced by spacing the distance between, and volume of fluid available at, drinking stations.17 EAH is a modern, life-threatening condition which is preventable through adherence to sensible fluid intake during prolonged exercise. Although American sports and military bodies have revised their guidelines, researchers have been critical of the sports-drink industry’s role in perpetuating a culture of overhydration.18 As medical practitioners, it is our responsibility to ensure the wider community is aware of the risks of conditioned overhydration during exercise in the face of lay misinformation and commercial interests.

David A Pattison MB BS · Tomos E Walters MB BS, BMedSci · Eric Seal MB BS, FRACP, PhD

Clinical record We report the case of a 20-year-old man who suffered an artefactual elevation of creatinine after consuming a creatine water supplement. Before this event, the patient was regularly seen in our clinic to monitor progression of a secondary paroxysmal nocturnal haemoglobinuria clone complicating childhood aplastic anaemia, for which he was previously treated with immunosuppression. Aside from his asymptomatic, stable, moderate thrombocytopenia (platelet count, 50–60 × 109/L), there had never been evidence of haemolysis or thrombosis. The patient took no regular prescription medications and had previously documented normal renal function (Table). Blood tests performed 1 day before the patient’s admission to hospital showed a significantly elevated creatinine level of 196 μmol/L (reference range, 40–120 μmol/L), with an estimated glomerular filtration rate of 38 mL/min, calculated using the MDRD (modification of diet in renal disease) formula.1 The patient reported no recent systemic illnesses or symptoms. However, on specific questioning, he reported using a creatine water supplement at 1.0–2.5 L/day for the previous 2–3 months — an intake greater than that recommended in the product packaging information (3 g creatine in 500 mL of water daily). Physical examination was unremarkable and fluid status was clinically euvolaemic. The patient was admitted to hospital for investigation of apparent acute renal dysfunction. Repeat blood tests confirmed a disproportionately elevated creatinine level of 206 μmol/L relative to the urea level, which was normal (6.9 mmol/L; reference range, 2.1–7.1 mmol/L). All electrolyte levels were within normal limits, including a potassium level of 4.1 mmol/L. A full blood count examination demonstrated stable thrombocytopenia with a platelet count of 58 × 109/L. Other parameters, including glycated haemoglobin level, white cell count and neutrophil count, fell within their reference ranges. Results of further directed investigations did not show any significant abnormalities to account for the apparent renal impairment. These included a total protein level of 82 g/L, an albumin level of 47 g/L, and a creatine kinase level of 331 U/L. Although above the reference range, at this level the creatine kinase would not be associated with elevated creatinine. Also within reference range were the patient’s levels of negative antinuclear antibodies, extractable nuclear antigens, anti-double-stranded DNA, antinuclear cytoplasmic antibodies, antiglomerular basement membrane antibody, antistreptolysin serology, HIV, and hepatitis B and C serology. Midstream urine analysis was unremarkable, being within the reference range for cells, casts, protein and myoglobin. Renal tract ultrasound with Doppler studies showed normal-sized kidneys with no evidence of renal artery or vein thrombosis, or obstruction. The patient was initially treated with intravenous normal saline and cessation of the creatine water supplement. Further blood tests performed 2.5 hours later showed a reduction in his creatinine level to 152 μmol/L; and those performed 17 hours later showed that the level had normalised to 81 μmol/L. In view of the rapid return to a normal creatinine level, a renal biopsy was not performed. The patient was clinically well throughout his hospital stay and, since discharge, has experienced normal renal function. Patient’s renal function tests Time of test Creatinine (μmol/L)* eGFR (mL/min)† Urea (mmol/L)‡ 1 month before supplement use 79 > 90 8.1 At admission to hospital 206 36 6.9 2.5 hours after admission to hospital 152 51 7.1 17 hours after admission to hospital 81 > 90 4.3 1 week after ending supplement use 96 87 7.1 eFGR = estimated glomerular filtration rate, calculated using the MDRD (modification of diet in renal disease) formula. * Reference range (RR), 73–108 μmol/L. † RR, > 60 mL/min. ‡ RR, 2.1–7.1 mmol/L. Creatine supplements are commonly used by professional and amateur athletes to help enhance their sporting performance.2 Creatine is typically sold in powder form to limit spontaneous hydrolysis to creatinine. Recently, creatine monohydrate suspended in water (Creatine Water AsthNon3000, Immuno-Biological Laboratories Co, Takasaki-Shi, Gunma, Japan) has become commercially available in Australia. The manufacturing process attempts to stabilise creatine in liquid for prolonged periods of time. Our patient’s disproportionately elevated creatinine level compared with a urea level within reference range, lack of evidence for organic renal abnormality, and rapid normalisation of creatinine level once he stopped using the creatine supplement suggest that artefactual elevation of creatinine secondary to consumption of creatine water was responsible for the abnormal biochemical test results seen. We investigated this hypothesis further by analysing a previously unopened bottle of the creatine water product that the patient had been using. The product information stated that a 500 mL bottle contains water, sorbitol 5 g, creatine monohydrate 3 g and sodium 0.27 mg. We analysed the fluid on the hospital’s laboratory analyser (UniCel DxC-800 Synchron, Beckman-Coulter, Brea, Calif, USA) using the Jaffé method and obtained a creatinine concentration of 21 000 μmol/L. To determine whether the drink actually contained creatinine or if this concentration was an artefact of the creatine present in the supplement, we then analysed it using high-performance liquid chromatography. This analysis showed a creatine concentration of 46.5 mmol/L, which was about the same as that stated on the product label, and a creatinine concentration of 20 000 μmol/L, which was similar to that from the hospital’s laboratory analyser. Further testing also found that creatine itself caused minimal cross-reactivity; a separately produced creatine solution with a concentration of 55.6 mmol/L recorded a creatinine concentration of only 80 μmol/L (Jaffé method). Given the creatine level we found in the supplement was consistent with that reported in the manufacturer’s product information, it appears that the creatine was not spontaneously converting to creatinine after bottling. This suggests that a substantial amount of creatinine was produced during the manufacturing process. When our patient consumed the creatine water, he would have directly absorbed this creatinine, which was subsequently measured in blood tests as an artefactually elevated creatinine level in the absence of renal abnormality.3 There are many case reports describing renal impairment attributed to creatine supplements. Pritchard and Kalra4 reported a 25-year-old man with focal segmental glomerulosclerosis and deteriorating renal function attributed to creatine supplements. Thorsteindottir et al2 and Koshy et al5 described cases of acute interstitial nephritis in previously healthy young men taking creatine supplements. In contrast to our case, both these patients were symptomatic, had proteinuria, and had renal biopsies that confirmed organic abnormality. Willis and colleagues6 reported a series of four patients with HIV referred for investigation of elevated creatinine level, in whom no kidney disease was identified, and whose creatinine levels improved when they stopped consuming creatine or protein supplements. Willis and colleagues proposed that the elevated creatinine level may have been the result of endogenous metabolism of creatine to creatinine. Several prospective studies have demonstrated that creatine supplements may produce mild elevations of creatinine in the absence of kidney injury in healthy patients as well as those with pre-existing renal impairment;3,7,8 this is generally attributed to conversion of creatine to creatinine in vivo. Our case is novel in that the creatinine appears to have been consumed directly, rather than being the result of increased endogenous production from creatine. In relatively asymptomatic patients with elevated creatinine levels for whom investigations do not identify evidence of organic renal disease, a full nutritional supplement history should be obtained. Our case provides evidence that creatine monohydrate water supplements may contain creatinine contamination that can cause artefactual elevation of creatinine levels on routine laboratory testing. Lessons from practice History of non-prescription medication and supplement use is important in assessing patients with acute renal impairment. Creatine water supplements may contain significant quantities of creatinine that can cause an artificial elevation of blood creatinine levels on routine laboratory analysis. Disproportionately elevated creatinine levels compared with urea levels should raise suspicion of artefactual elevation.

Kathryn A Jackson MB BS(Hons), BSc · Kacey M O’Rourke MB BS(Hons), BAppSc · Adrian Kark MB ChB, FRACP · Glen A Kennedy MB BS(Hons), FRACP, FRCPA

To the Editor: The article on home haemodialysis by Agar and colleagues describes a changing pattern of practice that has seen many patients enjoy the freedom of dialysing at night in their home environment.1 One consideration not mentioned is the need for appropriate vascular access. For a patient to engage in self-cannulation, a fistula needs to be created for ease of use. This requires a few imperatives in fistula design to be met. In my practice, an attempt is made to create an autogenous fistula for vascular access whenever possible. It is well documented that an autogenous arteriovenous fistula (AVF) is superior to prosthetic graft or catheter access in terms of access longevity and patient-related complications.2-4 In the past 11 years, I have found it necessary to create a new AVF with prosthetic material in no more than 1% of cases. For some patients, however, a fistula may be positioned where it is accessible to renal nursing staff but not for self-cannulation. This would make nocturnal home dialysis difficult and underpins the importance of surgical access design to facilitate it. For self-cannulating patients, great effort is made to create vascular access in the non-dominant arm, in the forearm rather than the upper arm, and with cephalic rather than basilic vein run-off. The cephalic vein lies on the upper outer aspect of the forearm with the limb in a neutral position, and a needle in it remains fairly secure when a patient is asleep. Guidelines on surgical placement of an AVF from the Society for Vascular Surgery, while not specifically prescriptive for patients wanting to self-cannulate, include the same recommendations.5 Use of a long saphenous vein loop fistula in the forearm, positioned appropriately, also provides ready access for a patient who may otherwise struggle with the dexterity required for venepuncture. A thigh loop is an alternative but less desirable option, as patients with chronic renal disease are likely to have lower-extremity occlusive disease, an increased incidence of groin infection, and a greater likelihood of vascular steal.5 I applaud efforts to facilitate nocturnal home dialysis, and enjoy the challenge of surgically creating vascular access to make this endeavour successful.

David N McClure

A 66-year-old woman on peritoneal dialysis for end-stage renal disease secondary to diabetic nephropathy was admitted on Christmas Day with suspected osteomyelitis of her left third toe. During admission, she complained of constipation and mild abdominal pain. There were no focal abdominal findings on examination. Of note, she was prescribed 750 mg three times daily of the rare metal lanthanum carbonate hydrate for hyperphosphataemia of renal failure. An abdominal x-ray was taken after the second dose of the day (Figure). Lanthanum has been shown to be radio-opaque on x-ray1,2 and computed tomography,3 and this is briefly mentioned in the full product information. The radiology report in this case suggested alternative diagnoses of residual contrast from a barium study, sclerosing peritonitis, tuberculosis or lead ingestion, none of which were consistent with the clinical history. The use of lanthanum as a phosphate binder is likely to increase since it was listed on the Pharmaceutical Benefits Schedule in 2009. Awareness of its radio-opaque features will prevent unnecessary investigations.

Yohan Chacko · Carolyn J Clark

In the mid 1970s, home haemodialysis accounted for nearly half of all patients on dialysis, both in Australia and elsewhere. The advent of both peritoneal dialysis (itself a home therapy) and satellite haemodialysis resulted in a gradual attrition in the use of home haemodialysis. Since 2000, the introduction of nocturnal home haemodialysis has begun to change this pattern in Australia, with a sharp growth in the uptake of home haemodialysis. Home haemodialysis, which enables longer hours and more frequent treatments than facility-based (hospital or satellite centre) dialysis, appears to offer improved patient outcomes in observational studies; randomised studies are necessary to confirm these findings. Home haemodialysis is also a cheaper form of therapy than facility-based dialysis. As newer, simpler and more user-friendly equipment is emerging that will make home haemodialysis even more accessible and attractive to the consumer, we believe that this trend toward a greater uptake of home haemodialysis should and will continue.

John W M Agar MB BS, FRACP, FRCP(Lond) · Carmel M Hawley MB BS, MMedSci, FRACP · Charles R P George MB BS, PhD, FRACP · Timothy H Mathew MB BS, FRACP · Stephen P McDonald MB BS(Hons), PhD, FRACP · Peter G Kerr MB BS, PhD, FRACP

The 21st century has the most diabetogenic environment in human history with the number of people with diabetes worldwide increasing to 380 million by 2025. The fastest rate of increase will be in developing countries. Diabetes is now the major cause of end-stage kidney disease globally; 20%–40% of people on dialysis are diabetic. In Australia, the number of people with type 2 diabetes starting dialysis increased fivefold between 1993 and 2007. We must act now at local, national and international levels to prevent type 2 diabetes; screen for early diabetic kidney disease; increase public awareness of kidney disease; treat with medications proven to reduce kidney disease progression; and promote research into and trialling of new therapies. The problem is global yet requires local action. World Kidney Day on 11 March 2010 is a time to intensify action on diabetic kidney disease and to continue to do so until this huge but largely preventable health burden is controlled.

Robert C Atkins MSc, DSc, FRACP · Paul Z Zimmet PhD, MD, FRACP

Falling numbers of deceased organ donors and longer kidney transplant waiting lists have increased the emphasis on live kidney donation to meet demand for kidney transplantation. Several new strategies have been introduced to expand live donation beyond the classic direct donation. These include: altruistic donation; paired kidney exchange (PKE); and altruistic donor chains programs. Using incompatible donor–recipient pairs and altruistic donors, the Western Australian PKE program achieved nine successful kidney transplantations between October 2007 and November 2008. If PKE were performed routinely in Australia, the rate of kidney transplants could increase by 7%–10%.

Paolo Ferrari MD, FRACP, FASN · Claudia Woodroffe BAppSc · Frank T Christiansen MD, FRCPA

In 2006, with outstanding cooperation from Department of Corrective Services staff at Cessnock Correctional Centre, two Justice Health staff made a huge step in walking together in the constant fight for Aboriginal health. In a mere six and a half hours, 88 Aboriginal offenders — 100% of the Aboriginal population in that centre — were screened for markers of kidney disease. We had been fighting for years to get renal screening into the jails. Finally it happened! A special renal screening research project funded by the Hunter New England Area Health Service was to be carried out in three facilities in the Hunter Valley and northern New South Wales: Cessnock, St Heliers (Muswellbrook) and Tamworth. We were offered five days to do three jails. If anyone could pull it off, I reckoned I could. I’ve been an Aboriginal Health Worker in the system since 1985, longer than most of the “lifers” — but they let me out from time to time, I like to remind everyone. I did some serious thinking and strategic planning on just how to pull this off at the Cessnock site. I had 66 Aboriginal patients spread over five wings and various other locations, and no nurse or place to do the screening. A well-meaning officer jokingly said to me on hearing about it, “How many you wanting to do?” “Sixty-six, officer — the lot”, I answered. He laughed and retorted, “Impossible, you’ll never do it . . . I’d say 30, tops . . . and three days. It’s a bet”. They were fighting words. “You’re on.” That was how this story started. What I first needed was a nurse and a place to do it. I fronted the clinic and did some passionate Aboriginal-kidney-health-at-an-all-time-low talking to the Justice Health Nursing Unit Manager. She was already four nurses down that day, but after some drastic roster raping and creative roster placing, I got my Aboriginal male nurse for the project. We needed a toilet for collection of specimens. Urine testing is not the easiest thing to do in a hurry. Next we needed to give the patients-to-be an incentive. I headed into the prison-yards — “Calling all Kooris!” I’d kick that Koori grapevine into gear fast to get the word out. The bait was a Koori-coloured red, yellow and black water bottle. One each. It wasn’t much, but then most of these guys have almost nothing. To make sure everyone knew what was happening and how important it was to get 66 permission forms signed beforehand, we arranged afternoon tea for the next day. Hot buttered damper with syrup and billy tea were promised. That hit the spot. Full turn-up next day and 66 names and forms were signed and collected, with spares kept at the ready for any new arrivals. The officer’s challenge was taken by all offenders with wry grins and much laughing as hot buttered damper with syrup was consumed with lots of lip-smacking and licking of fingers and enthusiastic agreement as we planned D-Day down to the minute. The jobs of rounding everyone up and getting them from point A to point B were allocated. Twelve patients at a time was agreed — ready to roll out, bladders brimming, as others returned. They were ready — all they needed was complete cooperation from all officers concerned on the day. D-Day arrived. By 7.30 am I was already in the yards as the wings were emptying for breakfast. We rallied the Kooris to win the bet as soon as methadone parade was over. We had 66 for sure, and others signing on, as the transports arrived with more offenders. It was shaping up well. By mid morning, the Aboriginal Delegate (the community leader of all Aboriginal offenders of the centre) had 22 more signed permissions: 100% of the Aboriginal population in the Cessnock facility, now 88 in total. All in. “Bring it on Aunt, we’re ready for them!” The war cry went up. Something was about to break the boredom that day. Everybody knew it and was ready to play a part — not just the Kooris. The operation was fully planned for speed. As each patient arrived in the allotted clinic area, I would give him a specimen cup to write his name and ID number on; record his height and weight; then send him on to the nurse to have his specimen tested and blood pressure taken. Each patient was warned — any abnormality and he would be listed to see the doctor. After receiving their water bottles, each group returned to the yards to spread the word of encouragement and help rally the rest. When the queue got down to five, the Aboriginal Delegate and I would take off down the “avenue” to gather the next 12. This is where the story gets humorous. Some of the old laggers who were taking it easy, sitting in the sun on the walls along the avenue and generally bored silly with the monotonous routine of their surroundings, started to take a keen interest in the comings and goings and the unusual enthusiasm of the Koori lads that morning. At this point they decided to get in on the act too. As they spied them striding fast (you don’t run inside jails) towards the avenue gates, the laggers would call out, “Come on you Koori lads, Aunt is coming for you, boots and all”. Fact is, Kooris never hurry for anyone or anything, it’s kind of a principle — but when they heard that call, “there was movement in the yards, for the word had passed around, that Aunt was coming fast and the boots were gaining ground”, they were gathering and forming up already in lines. The old laggers sitting on the walls were well into the game by now and sent out a new call to the avenue rover: “Hey chief, they’re on their way back now . . . big bunch of ’em coming up fast”. This alerted the rover to open up each of the three security gates promptly for us to pass through. On the third trip down, the old laggers called out in jovial fashion, “Go Aunt, go! We’re taking book on this, you know”. That called for some laughter and cheering as the patients passed each time. The applause and calls of encouragement from the crowd, which had now swelled considerably, added a definite flavour to the day. Our project had become a talking point. Some officers remarked later that the Aboriginal health exercise lifted morale that week for the whole jail. It had been all good. By lunchtime, we were out of resources. Hunter Area Health had only sent 50 packs. We’d ordered more, but were still waiting for them. I phoned again — they were on their way. We still had two wings and the work crews to get through. Cuppa was in order, but then word came — “The parcels are here and on their way down!” Yes! The officers were met halfway. They had two big bags of water bottles and the testing gear. Cheers rang out from the avenue throng and the officers were heroes for a minute or so. Because of the tight security in the next areas (Maximum), it took a little longer, but we finished by 2.30 pm, still with time to catch the Aboriginal lads returning from work in their assigned prison duties for the day. Because of prison staff shortages, early lockdown in Maximum meant they had to be escorted individually down two flights of stairs to take part. With great officer cooperation, it happened. We needed to complete the project before total jail lockdown at 4.00 pm, and we did. Hoping we’d managed to test everyone, the pair of us wearily trudged back through the long jail yards past all five wings to the clinic. Our step lightened as we heard the inmates calling to us, “Good on you fellas, did you get them all? . . . Deadly job you two, a great day!” Everyone wanted to know if they had reached the goal, headed by the officer who’d bet we couldn’t do it. With a grin on his face he asked if we’d done all 66 prisoners, looking very confident we hadn’t. I was happy to bring him up to date. Count done: 100% of current Aboriginal offenders had participated and all had been tested. By the clock, we had done 88 patients in six and a half hours! The officer was astounded: “That was some feat you two pulled off . . . I can’t believe it . . . glad I didn’t put money on it!” The serious side of the screening research project showed itself in the results. Of the 88 Aboriginal offenders, 14 screened positive for microalbuminuria and many more were positive for other high-risk chronic illnesses such as hypertension and diabetes. The next two jails visited were St Heliers and Tamworth. At St Heliers, all 37 Aboriginal offenders were screened. Of these, 13 tested positive, and again many were referred for other high-risk illnesses. At Tamworth, 42 Aboriginal people were screened (one refusing), with 14 being positive and one dangerously positive. In all, over the three sites, 167 renal screenings were carried out, resulting in 42 abnormal kidney readings. As a result of this successful renal screening project, one new Aboriginal position has been created for the area: the Coordinator Aboriginal Renal/Health Promotion will be working with the Aboriginal Health team for two years within the existing 16 Aboriginal Chronic Care Program sites. The Program gives us vital information on the cardiovascular health of Aboriginal offenders well in advance of onset of cardiovascular disease. The renal health component is a nice addition to the Program. Aboriginal people normally don’t access the mainstream Justice Health centres in the jails because Aboriginal staff from many external Aboriginal Medical Services can’t regularly visit the centres any more due to a lack of staff and funding. This is why we need Aboriginal Health Workers in every jail, especially in those with a high percentage of identified Aboriginal offenders. Change — stalled a decade ago — is slowly starting to happen again. Twenty per cent of the male client base and 31% of the female client base in NSW prisons are Aboriginal people, with levels as high as 50% in younger offenders. Despite the Royal Commission into Aboriginal Deaths in Custody1 20 years ago, which recommended that culturally appropriate medical care be provided to offenders, with access to Aboriginal Health Workers wherever possible, and despite what you read in annual reports since then, Justice Health 10 years ago adopted an unofficial policy of mainstreamed take-it-or-leave-it medical service to Aboriginal offenders. It is now slowly moving away from this stance by employing its own Aboriginal Health Workers as part of the health centre staffing profile, beginning with one of the newer facilities at Wellington in midwestern NSW. Visiting Aboriginal Medical Services staff should be welcome to work with members of their community who are in jail, but clearly, Aboriginal Health Workers are needed within the system itself, trained to go into the yards with the Aboriginal Delegates to encourage the brothers to access and be tested at the Health Centre. The hardest part of the process is moving the prisoners within the jail. Locked gates, classification, segregation, non-association, constant lockdowns, inter-jail transfers without notice, request forms denied or simply lost — all add to the burden of self-destructive thinking that offenders bring into jail with them. Even knowing of a serious medical problem, they will often give up and cease to care. Aboriginal people in general, and prisoners in particular, are also dealing (or not dealing, as the case may be) with the blight of long-term systemic racism. A popular notion (unfortunately given scientific credibility by Charles Darwin) is that they are the lowest form of human life — one step above the apes: [H]ow little can the hard-worked wife of a degraded Australian savage, who uses hardly any abstract words and cannot count above four, exert her self-consciousness, or reflect on the nature of her own existence? [quoting Büchner] . . . At some future period . . . the civilised races of man will almost certainly exterminate and replace throughout the world the savage races.2 I commend you instead to the words of Kevin Gilbert — a self-educated Wiradjuri man and former offender — writing 100 years later, after doing 15 years for murder: As Aborigines began to sicken physically and psychologically, they were hit by the full blight of an alien way of thinking. They were hit by the intolerance and uncomprehending barbarism of a people intent only on progress in material terms, a people who never comprehended there could be cathedrals of the spirit as well as of stone. Their view of Aborigines as the most miserable people on earth was seared into Aboriginal thinking because they now controlled the provisions that allowed blacks to continue to exist at all. Independence from them was not possible. White people’s devaluation of Aboriginal life, religion, culture, and personality caused the thinking about self and race that I believe is the key to modern Aboriginal thinking. As Robert Kantilla said, “Suffering is that the white people class them as the lowest person on earth”. My thesis is that Aboriginal Australia underwent a rape of the soul so profound that the blight continues in the minds of most blacks today. This psychological blight, more than anything else, causes the conditions we see in reserves and missions today and is repeated down the generations . . . [T]hey have been patterned into that stereotype, and they do live it.3 No more is needed to explain the present and ongoing over-representation of Aboriginal people in the prison population, or their generally poor health. And the solution? Kevin Gilbert goes on to say that it starts with your education, and I agree. But it’s a special education. It’s a pity I don’t have room to quote him more, because he just blows Charles Darwin away. And healthwise, whether you’ve been injured by a truck or by generations of white racism, it’s the same solution, believe it or not — education. Kooris, Gooris, Murris and all Aboriginal people, your health education can start right here, with you learning these principles: Recovery and ongoing maintenance of your good health starts, first and foremost, with a free decision by you to take primary personal responsibility for it. Yes, you can do it, and yes, you are worth it. You need education — information, strategies, and especially role models. Find them, and stick with the strength, or else . . . For the many Aboriginal people locked in prison — especially those also locked in their self-destructive rituals of negativity, resentment and blame — experience shows that the process of health education in prison is only likely to start when they are targeted, brought together and encouraged into the caring hands of Justice Health’s wonderful Health Centres, with their specially trained and enthusiastic Aboriginal Health Workers.

Beverley F Spiers BEd(Aboriginal Adult Ed), GradDipAdultEd

Objective: To describe the natural history and risk of early chronic kidney disease (CKD) in Indigenous Australian populations.Design, setting and participants: A prospective cohort of 2266 Aboriginal and non-Aboriginal children enrolled from primary schools throughout New South Wales from February 2002 to June 2004 and followed for 4 years.Main outcome measures: Urinalysis, height, weight, blood pressure, birthweight and sociodemographic status at baseline and 2- and 4-year follow-up; CKD risk factors: haematuria, albuminuria, obesity, and systolic and diastolic hypertension.Results: 2266 children (55% Aboriginal; 51% male; mean age, 8.9 years [SD, 2.0 years]) were enrolled at baseline. 1432 children (63%) were retested at 2-year follow-up, and 1506 children (67%) at 4-year follow-up. Prevalence of baseline CKD risk factors was frequent (2%–7%), but most abnormalities were transient. Besides persistent obesity (5.0%), persistence of CKD risk factors at final follow-up was low: haematuria (1.9%), albuminuria (2.4%), systolic hypertension (1.5%) and diastolic hypertension (0.2%). There was no difference in prevalence of persistent CKD risk factors between Aboriginal and non-Aboriginal children.Conclusions: Over 4 years of follow-up, Indigenous Australian children had no increased risk for early evidence of CKD. More than 70% of baseline risk factors were transient, and persistent risk factors were uncommon. Our findings suggest the increased risk for end-stage kidney disease seen in Indigenous adults is not yet manifest in these schoolchildren, and may be potentially preventable.

Leigh Haysom MB BS, MClinEpi, FRACP · Rita Williams BA · Elisabeth M Hodson MB BS, FRACP · Pamela A Lopez-Vargas BN, BSc, BHSc(TCM) · Leslie P Roy MB BS, MD, FRACP · David M Lyle MB BS, PhD, FAFPHM · Jonathan C Craig MB BS, PhD, FRACP

To the Editor: Critics of the proposal to legalise trade in kidneys have pointed out the low rates of renal transplantation in Australia compared with the United States,1 where the trade in organs is also illegal. However, it is unclear if the lower rate of renal transplantation in Australia is a result of a shortfall in transplants from living or deceased donors. First, I ranked renal transplantation rates in 2005 in US states and from Australia using the numbers of transplants from deceased and living donors from the United States Renal Data System (Beth Forrest, Coordinating Center, US Renal Data System, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md, personal communication), the Australia and New Zealand Dialysis and Transplant Registry,2 and populations from the US Census Bureau.3 In 2005, there were 12.1 per million population renal transplants from living donors in Australia. All of the states of the US except Oklahoma had higher rates of renal transplantation from the living, and the rate in Minnesota was four times higher. In contrast, the rate of renal transplantation from deceased donors in Australia was 18.6 per million population, which was higher than 24 American states and lower that 26 states and the District of Columbia. Some US states had twice the Australian rate of kidney donation from the deceased. I then used multiple linear regression to examine associations between rates of renal transplants from the deceased and rates of homicide, suicide and motor vehicle accident deaths in US states.4 Rates of renal transplantation from living donors were included as a covariable to control for differing degrees of development in US state transplant services. Homicide rates were associated with rates of transplants from the deceased (R = 0.607, R2 = 0.386; Box), but deaths from suicide and motor vehicle accidents were not. Hence, the higher rate of renal transplantation from deceased donors in the US appears to be the result of greater availability of organs from homicide victims. The high mortality and morbidity associated with endstage renal failure, despite renal dialysis treatment, suggests a need for new approaches to increasing the availability of donor kidneys. Assumed consent for organ donation might increase donation rates from the deceased, but this has been resisted in both Australia and the US on the grounds that failure to opt out might only indicate lack of forethought and not consent. While Australia continues with an opt-in system for deceased donation, measures to encourage live donation might have more realistic prospects of success than attempts to increase the rate of renal transplantation from the deceased.

Matthew M Large

The estimated glomerular filtration rate (eGFR) algorithm has some advantages over serum creatinine concentration for estimating GFR. There are a number of caveats around the use of eGFR, predominantly because it assumes subjects are of average body size and similar lean body weight. eGFR has not been validated as a safe method of adjusting drug dosing, nor as a screening test for impaired renal function in the general population. eGFR has not been validated as a robust measure of kidney function in many groups (eg, older people, inpatients, differing racial groups, obese people). eGFR is inaccurate in many settings, such as in high, low or rapidly changing GFRs. Until evidence of safety and efficacy is provided, eGFR should not be used for calculating drug doses, and use of the Cockcroft–Gault formula or other validated methods should continue.

Jennifer H Martin MB ChB, FRACP, PhD · Michael F Fay MB ChB, FRACP, FRACR · Jacobus P Ungerer MB ChB, MMed, FRCPA

Estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula has been shown to provide unbiased and acceptably accurate estimates of measured GFR across a broad range of individuals with impaired kidney function. eGFR is superior to measuring serum creatinine (SCr) concentration alone, more accurate than other prediction formulas (such as Cockcroft–Gault) in the setting of reduced kidney function, and more practical and reliable under most circumstances than measuring urinary creatinine clearance. Routine eGFR reporting with requests for SCr, in concert with clinician education, has been shown to enhance the detection of chronic kidney disease (CKD), resulting in improved cardiac and renal outcomes for patients. eGFR has been shown to effectively identify individuals at increased risk of adverse drug reactions (even when SCr concentration is in the normal range). For most drugs prescribed in primary care and for most patients of average age and body size, drug dosage adjustments based on eGFR should be similar to those based on Cockcroft–Gault. eGFR should not replace Cockcroft–Gault for determining dosage adjustments for critical-dose drugs that have a narrow therapeutic index. eGFR has resulted in important spin-off benefits, such as standardisation of laboratory creatinine assays and enhanced public and clinician awareness of CKD. Clinicians should be aware of the strengths, weaknesses and appropriate use of eGFR. Considerable research effort is being directed towards further refinement of eGFR.

David W Johnson MB BS(Hons), FRACP, PhD · Graham R D Jones MB BS, DPhil, FRCPA · Gavin J Becker MB BS, MD, FRACP · Timothy H Mathew MB BS, MRACP, FRACP

Like most children, I had heroes, and the heroes I chose have in certain ways shaped my life. The first was fighter pilot Douglas Bader, who lost both legs in an aircraft crash but talked his way back into the Royal Air Force and became one of its most decorated pilots in World War II. I knew his life story by heart because, as a small child, I had polio and spent much of my childhood unable to walk, so I read instead. My second hero was cricketer Don Bradman. Being flat on my back in splints over a period of years, I spent a lot of time listening to the wireless and grew very fond of cricket. Bradman retired very shortly after I was born, so I never saw him play. What was important to me was that not only was Bradman the best, he was Australian. My other great hero just happened to be a woman, the scientist Marie Curie. But she was a hero not because she was a woman, wife and mother, but rather, because she triumphed over poverty and adversity to become one of the world’s greatest scientists. So, from quite early on, I was fiercely Australian, fascinated by the notion of research, determined that handicap was a challenge rather than an impediment, and very familiar with the inside of hospitals. And so I studied medicine at the University of Melbourne (Box 1). HospitalsMy residency at the Royal Melbourne Hospital (RMH) shaped the rest of my career. I worked at the RMH with some outstanding physicians, including Jock Frew, Ken Fairley, Tom Hurley and Margaret Henderson. But the most important influence was a term spent in the Clinical Research Unit affiliated with the Walter and Eliza Hall Institute of Medical Research and headed by Ian Mackay, who encouraged me to think about research. At this time (1968–1971), the RMH Residency (the living quarters for resident medical officers) was a lot of fun and the work ethic and sense of responsibility for patients extraordinarily strong. If you had a problem, you simply rang the Residency and a resident would come and help, whether he or she was on duty or not. None of us ever had enough sleep. Life outside work and study presumably went on (I do remember watching the landing on the moon), but those junior years were when I most enjoyed medicine. My membership exam for the Royal Australasian College of Physicians (RACP) was held in Adelaide. At the party afterwards, Jim Lawrence suggested that, as I was thinking of becoming a nephrologist, I spend a year at the Queen Elizabeth Hospital (QEH), where he was Head of the Renal Unit (Box 2). At the time, the QEH had the only renal unit in Adelaide, and we looked after all nephrology patients in South Australia and the Northern Territory, as well as Broken Hill in New South Wales. I have a vivid memory of a young man with post-obstructive polyuria who passed 50 L of urine daily (thought to be a world record!) and our efforts to keep him hydrated and in electrolyte balance. He made the sleepless nights worthwhile. Thanks to an RACP scholarship, I then spent a year in France at Hôpital Tenon from 1973 to 1974 (Box 3) working with Liliane Morel-Maroger, a renal immunopathologist. While there, I became enamoured of French language and culture, particularly cinema and opera — Placido Domingo was the tenor-in-residence at the Paris Opera that year. My stay in Paris was followed by a year in London at Guy’s Hospital (Box 4) with Stewart Cameron, again working in immunopathology. I took full advantage of the theatre, ballet and opera, Glyndebourne, the Chelsea Flower Show and the tennis at Wimbledon, and came back to Australia with great reluctance. By then, in the mid 70s, feeling I was well trained in renal medicine but less so in medical science, I decided to pursue a doctorate at the Howard Florey Institute (directly opposite the RMH), opting to work on blood pressure — particularly on mechanisms of adrenocorticotropic hormone (ACTH) hypertension in sheep. My PhD supervisor John Coghlan was a splendid mentor who encouraged me to become involved with the Australian Society for Medical Research. Eventually I became the Society’s first woman president. It was the beginning of a lifelong interest in research policy. A couple of years later, I was back at the RMH as an outpatient physician (with Ken Fairley) and nephrologist (with Priscilla Kincaid-Smith).1 The unit Priscilla had built from scratch was rightly regarded as a leading international centre, with a huge and very varied clinical load. I continued to do research at the Florey, while at the same time developing a rat model of ACTH hypertension at the hospital and, more importantly, beginning work on glucocorticoid hypertension in humans. Over the years, we were able to disprove the perceived wisdom that glucocorticoids raise blood pressure through salt and water retention and to show that the mechanism actually relates to nitric oxide deficiency and excess reactive oxygen species. This had major implications for the design of synthetic glucocorticoids for clinical practice. Further, we assembled evidence implicating glucocorticoid abnormalities in some forms of essential and renal hypertension, suggesting a broader role for steroids in raising blood pressure. This work was recognised by the Smith Kline & French Award of the International Society of Hypertension in 1984. I rarely found my gender to be a problem in medicine. My peers judged people on whether they were good doctors rather than other criteria, and I was lucky in that my own professional colleagues tended to be generous about giving women a go. One example stands out. When I was pregnant with my daughter Emma (now making movies in Hollywood), the Medical Officers Award did not contain any provision for maternity leave and so all I had was a couple of weeks of annual leave. This was balanced by the fact that my male colleagues at the RMH Renal Unit were all very supportive, both during and after my pregnancy. When I returned as a new mother, they took turns, over a period of 6 months or more, to do all my night and weekend work. One highlight of these years was a short sabbatical at the Medical Research Council Blood Pressure Unit at the Western Infirmary in Glasgow. It was a highly productive few months that set up a number of lifelong friendships and collaborations. I did physiological studies on glucocorticoid effects in normal subjects (or more correctly, staff of the Unit). This involved putting in cannulae and starting infusions around midnight. I used to rug up against the Glasgow sleet and snow and follow the blood stains into Casualty, the rest of the place presumably being closed for security reasons. After putting in the drips, I would doze for a few hours on a trolley until the experiment proper began, around 4:00 am. The Scots were enormously hospitable and I managed to road-test a variety of single malts. The only downside was the rugby. Watching Scotland v Ireland in January at Murrayfield, with all the excitement of kicking for touch in the mud, made me wish I was back in sunny Australia watching Mark Ella. My view of the dismal game was shared by my host, who kept standing up and yelling futilely at both sides to “run the ball”. University of New South WalesIn 1991, I joined the University of NSW (UNSW) as Professor of Medicine at St George Hospital in Sydney. It turned out that I was the first woman to be appointed Head of a department of medicine in Australia. I started out thinking that the main task was to recruit good people, and finished by thinking it was almost the only task — if you get that right, other things follow. These were very enjoyable years in which we worked to promote a research culture in the hospital. One particular highlight was the establishment of a successful renal transplant program. At this time, again with strong support from my male colleagues at UNSW and St George Hospital, I became the first woman to chair the Medical Research Committee of the National Health and Medical Research Council (NHMRC). I enjoyed enormously the chance to help shape the nature and extent of the national research agenda and my first glimpses of how policies were formulated in practice. Funding for research was increased and the biomedical and public health efforts were reintegrated. We instituted a variety of changes to better match research funding schemes to the overall national research strategy. A particular highlight was the development of partnerships with other funding bodies, notably Juvenile Diabetes International and the Wellcome Trust. Australians gained about 20 years’ life expectancy in the course of the 20th century, and about half of that is estimated to be a consequence of research.2 Research is absolutely fundamental to health care and, in an ideal world, would be fundamental to health policy. Department of HealthWhile chairing the Medical Research Committee of the NHMRC (1994–1997), I spent a considerable amount of time in Canberra, and when I stepped down from that position I was approached about another role, as Commonwealth Chief Medical Officer (CMO). I became the first woman to be CMO. In the event, I very much enjoyed the job and enjoyed living in Canberra. The Australian Capital Territory combines all the advantages of city and bush life and is very different from the mythical location regularly featured in the media in the eastern states. Having signed the “Official Secrets Act”, I am not at liberty to reveal the really interesting bits about my time in the Department of Health, but I did learn very quickly to admire the professionalism and work ethic of the Australian Public Service. In all my jobs I have worked with smart people, and certainly doctors work hard, but the quality that sets a good bureaucrat apart is not just intelligence and hard work, but also excellent judgement. Certainly, in stark contrast to the perceived wisdom outside Canberra, the work ethic was strong and the workload immense. One morning early on in my term, the Department of Health Secretary, Andrew Podger, drove me to our Senate Estimates hearings. On the way I chatted about my plans for the afternoon. He seemed to think my afternoon would be spent in Estimates, so I showed him my program where it said “Senate Estimates 9–11”. He smiled slightly and explained that the finishing time was 11:00 pm, not am! The particular barrow I chose to push during my term as CMO was evidence-informed policy, a counterpoint for the bureaucratic interest in evidence-based medicine. The work was extremely varied. As CMO I had executive responsibility for two divisions (the Office of NHMRC and the Public Health Division) and for all medical professional matters. I was one of the three members of the Vos Committee, commissioned by the Treasurer to determine how the Goods and Services Tax (GST) would apply to health, education, religion and, surprisingly, used cars. I was later publicly reviled for determining that tampons were a sanitary product (thus attracting the GST), not a medical device, and people doing feminist studies still send me angry letters. I chaired a committee for Defence and Veterans’ Affairs on the health effects of the deseal/reseal program in F-111 aircraft, which meant climbing over one at the Royal Australian Air Force (RAAF) base at Amberley to see for myself and left me with a great respect for the RAAF. I chaired an interdepartmental committee on quarantine and another on biotechnology. A tangible outcome from the former was the blending of two forms (customs and immigration) into one, to the delight of many arriving travellers. We promoted a reform agenda at the World Health Assembly and contributed to major policy initiatives relating to the National Health Priorities, quality and safety, and medical research. The theme for me was promoting consistent use of research and evidence to assist policy development. The Pharmaceutical Benefits Advisory Committee had long been regarded as a world leader in the use of evidence for rational prescribing, and the Medical Services Advisory Committee was set up to introduce a similar evidence base into provision of medical services. However, it was less clear that the same rigour was being applied to developing new policies in other areas. Health policy questions are influenced by the political context, particularly health system financing, local culture, community values, and history and geography. Realistically, the best we can hope for is that policy is informed by research and evidence. Policymakers often look for evidence to justify policies developed on other grounds, rather than using evidence to develop policy. As one former state Chief Health Officer put it, “we want evidence-informed policy, but what politicians want is policy-informed evidence”. Some years ago, the satirical magazine Punch (now sadly extinct) ran a competition for the most misleading advice to foreigners. A number of entries, as you might expect, gave misleading advice on how to behave at the cricket, most of which unhappily has come to pass, but the winning entry said “Try the famous echo in the British Museum reading room”. Misleading advice has even more serious consequences in health care and health policy. An example is the advice to parents, from Dr Spock and others, to sleep babies on their stomachs, on the basis of zero evidence, when this in fact increased sudden infant death syndrome. Not all health policy development requires systematic review of the available evidence: for example, equity of access and universal health coverage are self-evidently desirable policies. The difficulty, of course, is that we all want access, quality and affordability. In practice, we can pick any two. John Curtin School of Medical Research (JCSMR)I was very ambivalent about leaving the Department of Health, having thoroughly enjoyed my time there, but, given my background and interests, the Directorship of JCSMR was an offer I could not refuse. It had an outstanding reputation for medical science. The old JCSMR building was very extensive. I spent my first week wandering around meeting people and then discovered I had entirely missed one wing. Armed with directions, I made my way into the previously undiscovered lab and held out my hand to a woman in a white coat, saying “Hello, Judith Whitworth”. “No”, she said, and went back to work. At my interview, I was clear that the School needed to join the national competitive grant scheme, to engage further with the Australian medical research community, to design and build contemporary laboratories, to re-engage with clinicians, and to attract a medical school to Canberra. Before I took up the job as JCSMR’s first female director, I was given a copy of Machiavelli’s The prince. His 15th century view may be politically incorrect, but it contains insights that are as true now as then. The one maxim that stood out for me was that, in trying to effect change, you will have lukewarm support, at best, from those who will benefit and vigorous opposition from those who will not. Another aphorism I took to heart was variously ascribed to Edith Cavell and Harry Truman: you can do anything as long as you don’t care who gets the credit. In the event, these things have come to pass and, more importantly, the School has continued to make cutting-edge and important discoveries. International HealthDuring my stint as CMO in the Department of Health, one of my tasks was to take the Australian delegation to the World Health Assembly in Geneva (Box 5). On the first occasion, I had only recently joined the Department of Health and was still very “wet behind the ears”. Happily, the team (from Health, AusAID and Foreign Affairs) were all highly skilled, and my main tasks were sitting behind the flag, making interventions from prepared briefs and eating and drinking for Australia. At one point in the debate, a question came up about quarantine. I was hazy on our position and so, in the best bureaucratic tradition, I tried to pass the buck, asking our people who was in charge of human quarantine. “You are!”, they said in unison. Weakly I asked what it meant and one junior officer helped me out, explaining that I had the power to close the borders but I couldn’t pat the sniffer dogs, because they belonged to another department. We used the vehicle of the annual Australian speech to the World Health Assembly to advocate for research on health practice and health policy. At that time, despite some very notable World Health Organization research successes, there was little evidence of a strong research culture within the organisation, or of a valuing of research by member states at the Assembly. Perhaps as a consequence of these interventions, I was invited to chair a consultation on the role of the WHO’s Advisory Committee on Health Research (ACHR) and then to join the Committee. I am now in my second term as Chair, the first woman and first Australian to hold that position. The role of the Committee is to provide the Director-General with advice in relation to research. The ACHR is committed to a leadership role for WHO in the use of evidence from research to inform decisions about prevention, practice or policy in health and to bridge the “know–do gap” (ie, turn knowledge into action). The research culture in the WHO has changed substantially in the past decade. Established programs such as TDR (Tropical Diseases Research) and HRP (the Human Reproduction Programme) continue to perform strongly, but strength has also been built in health systems research (Alliance for Health Policy and Systems Research). One very promising initiative is EVIPNet (the Evidence-Informed Policy Network), which seeks to promote the systematic use of health research evidence in policy making, focusing on low-and middle-income countries and promoting partnerships at country level between researchers, policymakers and civil society. Also in the present decade, WHO ethics and guidelines review committees have been instituted and a clinical trials registry established. A code of conduct for research is being developed. Most excitingly, WHO is developing a research strategy that looks both to position the organisation as a standard setter and to use its stewardship role and convening power to promote and foster research relevant to the needs of low- and middle-income countries. Currently, I also co-chair the WHO/International Society of Hypertension Liaison Committee. The 1999 guidelines on hypertension3 have been cited over 2000 times, and the 2003 statement updating those guidelines in key areas4 has been cited over 400 times. ConclusionMy life in medicine has been fortunate. I have moved from a focus on individual patients to populations and policy, and from medical research to research for health. Medicine has been good to me. And my philosophy: today’s research is tomorrow’s prevention, practice and policy. 1 Graduation, University of Melbourne, 1967 2 Queen Elizabeth Hospital Renal Unit, Adelaide, 1972 Back row (L–R): Graham Rowe, David Miller, Napier Thomson, Bim Biswas. Front row (L–R): Judith Whitworth, Jim Lawrence, Geoff Burfield. 3 Hôpital Tenon, Paris, 1973 4 Guy’s Hospital, London, 1975 5 Addressing the World Health Assembly, Geneva, 1998

Judith A Whitworth FTSE, DSc, MD, PhD, BS, FRACP

To the Editor: Urinary stones are very common, with a cumulative lifetime incidence of 5%–15% and a recurrence rate of about 50%.1 Many new treatment techniques have been developed, but availability, particularly in public hospitals, is variable. The Greater Metropolitan Clinical Taskforce2 assessed patterns of treatment in patients requiring urological consultation who presented to the emergency departments (EDs) of 12 New South Wales public teaching hospitals in major centres that had a specialty urology registrar. Between February and September 2007, the urology registrar or specialist completed a survey on consecutive patients presenting with urolithiasis who agreed to participate. The survey contained questions on patient demographics, the position and size of the stone, and the preferred treatment option. One of us (J W H M) conducted a telephone interview with each patient to obtain details of treatment, and follow-up interviews at 3-monthly intervals (until treatment was completed or the study ended) to determine the outcome. Ninety-two patients entered the study: 64 men (mean age, 50.4 years) and 26 women (mean age, 47.8 years) (sex was not reported for two patients). Thirty-seven patients were subsequently treated in the public system, and the remainder in the private system, either using private health insurance or at their own expense. The preferred treatment option of the treating medical officer, usually the urology registrar, was nominated: non-operative (spontaneous stone expulsion) with or without calcium-channel blockers, 13 patients (received by 6); rigid ureteroscopy with grasper or lithoclast, 21 patients (18); rigid ureteroscopy with laser, 4 patients (4); flexible ureteroscopy with laser, 17 patients (2); percutaneous nephrolithotomy, 3 patients (3); extracorporeal shock wave lithotripsy, 6 patients (2); or “other”, 28 patients — of whom stent was specified in 24 (23). The preferred treatment option was not used for 34% of patients because it was not available at the hospital. The mean duration of treatment (defined as the period between initial ED presentation and final treatment episode) for patients with pelvi-ureteric or upper ureteric stones requiring more than one treatment episode is shown in the Box. Thirty-nine patients had stents inserted in the ED, of whom four did not reach definitive management by the end of the study. Of the remaining 35, 20 were public patients and 15 were private patients. Fourteen had stents in situ for more than 3 months and required a change of stent before initiation of definitive treatment to avoid encrustation; 12 of these patients had treatment in the public system. Despite the relatively small number of participants in this study, its findings on access to timely treatment for public patients should not be ignored. Management of kidney stones was heavily influenced by insurance status. Ureteric stents are intended to be temporary, but patients treated in the public system who had a stent inserted at initial presentation had a 60% (12/20) chance of still having it 3 months later, thus requiring a change of stent before definitive intervention — an unnecessary procedure that increases hospital re-admissions. Patients would be treated more efficiently and effectively with more timely access to appropriate resources. This is an unacceptable burden of morbidity for patients. Urgent action is required to improve the current state of care for public patients with kidney stones in NSW. Duration of treatment of public and private patients with a pelvi-ureteric junction or upper ureteric stone who required more than one treatment episode* Public patients (n = 18) Private patients (n = 18) Mean duration of treatment in weeks (95% CI) 18.3 (12.9–23.7) 6.2 (3.0–9.4) Range (weeks) 3.0–49.5 0.6–25 Difference in weeks (95% CI) 12.1 (5.5–18.7) P < 0.001 * Up to four treatment episodes.

Finlay Macneil · James W H Macneil · Kylie L Fraser · Andrew J Brooks

Handbook of dialysis therapy. 4th ed. Allen R Nissenson, Richard N Fine, editors. Philadelphia: Saunders, 2008 (1632 pp). ISBN 978 1 4160 4197 9. Renal replacement therapy for end-stage renal disease continues to be a complex area requiring integrated care by physicians, surgeons, nursing staff, technical staff and allied health staff. There is a continued need for well written books in this area, providing useful overviews and guides to formulating diagnostic and management plans. This handbook fulfils many of these criteria. Handbook of dialysis therapy is problem-oriented and clinically relevant, covering many areas of day-to-day management and long-term issues relating to the patient undergoing chronic dialysis. The standard medical topics in dialysis therapy are covered, as well as many other key areas for optimising patient management (such as the technical aspects of dialysis, setting up a dialysis unit, and nutritional, psychological, social, and pharmacological considerations). It includes topics relating to the adult and paediatric dialysis population, and a range of dialysis modalities available to patients. As a handbook in a very specialised area, it assumes a base level of knowledge by the reader, yet provides an easy-to-read overview for professional staff dedicated to the area of dialysis, including nephrology trainees. It is well referenced for further in-depth reading. Throughout the book, there are numerous summary tables and diagrams, making it reader friendly. If there are criticisms to be mentioned, they mainly relate to the brief nature of some chapters; however, the intention of the authors was always the provision of a wide coverage of topics in a concise style. Considering the extent of the areas covered, the authors have done well to balance breadth and detail. Chapters are written by a number of prominent individuals in the area of nephrology. I am impressed with the practical daily considerations that are covered — one of the book’s strengths. In addition, this handbook would appeal to both medical and allied health staff, particularly to those at an early stage in their careers involving the management of patients undergoing dialysis therapy.

Francesco L Ierino

To the Editor: The revised recommendations of the Australasian Creatinine Consensus Working Group1 are improved with the recognition of an age-related reduction in glomerular filtration rate (GFR), but don’t deal with a number of other significant problems associated with an estimated GFR (eGFR). When a plasma creatinine measurement is requested, an eGFR is commonly provided, increasing the sensitivity but reducing the specificity of diagnosis of kidney disease. The eGFR remains a substantially flawed estimate of GFR. It is associated with significant predictive error (up to 30% of individual eGFRs differ by more than 30% from the measured GFR at 60–90 mL/min)2 and with substantial false positive and false negative outcomes. The flaws in the eGFR are, firstly, the limitations of creatinine clearance rate as a measure of GFR, and secondly (and more importantly), the use of age, sex and race as surrogates for muscle mass (the determining factor in creatinine production and, together with creatinine clearance, plasma creatinine level). Age, sex and race are imperfect predictors of muscle mass, and this leads to underestimation of GFR in people who are fit and well muscled and overestimation in those who are wasted and disabled. While reporting eGFR values represents a worthwhile advance on using plasma creatinine levels to detect kidney disease, it could be considered, at best, the “least bad” readily available measure of GFR. When no better test is readily available, how should we handle a suboptimal measure of GFR? Educating the medical profession about the limitations of eGFR is important, but, based on personal experience and anecdotal evidence, I believe that using conventional methods of informing doctors has not been uniformly effective. Providing “just in time” information support is likely to assist this process. Thus, I support the recommendation that laboratories routinely report eGFRs, but suggest that, when they do so, they add a product warning along the following lines: The eGFR is calculated assuming a normal muscle mass for age, sex and race. It will underestimate GFR in well muscled individuals and overestimate GFR in patients with muscle wasting. A creatinine clearance test or formal GFR measurement may be helpful in patients whose muscle mass differs from the average for their age and sex. Proteinuria and haematuria are other useful indicators of kidney disease. In patients over 70 years of age, an additional product warning, consistent with the Australasian Creatinine Consensus Working Group’s revised recommendations,1 could be as follows: GFR declines with age, and, in patients over 70 years of age, an eGFR of 45–59 mL/min/1.73m2, if stable over time and unaccompanied by proteinuria or haematuria, is unlikely to have specific renal prognostic or therapeutic implications.

William R Adam

To the Editor: The revised recommendations for the use of the estimated glomerular filration rate (eGFR) in the clinical setting use the Modification of Diet in Renal Disease (MDRD) formula to adjust drug dosing in people with renal impairment (Recommendation 6).1 Although the utility of the MDRD-based eGFR as a screening tool to identify people with chronic kidney disease represents an important clinical opportunity, we, and others,2,3 remain concerned about this recommendation. Certainly, adjusting the dose of renally excreted medicines based on a patient’s serum creatinine concentration alone is not appropriate. Accordingly, many drug monographs provide explicit dosing recommendations based on the estimated creatinine clearance (calculated using the Cockcroft–Gault formula) as a rational basis for dose adjustment using sound pharmacological principles. This assumes a significant correlation between the estimated creatinine clearance and the actual clearance of a drug (or metabolite). But such a correlation has not been established for the MDRD formula. Indeed, an empirical study comparing the use of the Cockcroft–Gault formula to the MDRD formula in 1067 elderly patients found that the MDRD formula significantly overestimated renal function and would, if used, lead to significantly higher doses of two drugs in question (enoxaparin and gentamicin) being administered.2 This highlights the need for further research to rigorously characterise the relationship between MDRD estimates of renal function and drug clearance before this formula can be recommended to guide dose adjustment in the clinical setting. Recommendation 6, that the MDRD-based eGFR should be used for dosing after considering body size,1 requires further clinical information about the patient — the same information needed to use the Cockcroft–Gault formula. Even limiting Recommendation 6 to drugs that are not “critical-dose drugs”1 is confusing. Many drugs would be considered critical-dose drugs when used in frail older people with some degree of renal impairment. We reaffirm the statement, from the 2008 Australian medicines handbook, that “there is no evidence that [automatically reported eGFR] is suitable for adjusting drug doses in people with renal impairment”.4

on behalf of the Editorial Advisory Board, Australian medicines handbook

In reply: We agree with Adam’s points that: The estimated glomerular filtration rate (eGFR) represents a worthwhile advance on the plasma creatinine level for detecting kidney disease, and is currently the best readily available measure of GFR; Educating the medical profession on the limitations of eGFR is important; and Further refinements of eGFR accuracy are highly desirable. Since the advent of automated laboratory reporting of eGFR, there has been a concerted effort by the Kidney Check Australia Taskforce to educate medical professionals and other clinicians about the strengths and limitations of eGFR and about how best to approach the patient with a significantly reduced eGFR. Education has been via printed office materials, accredited workshops, medical journal articles, online education, and decision-support systems embedded in medical software. Adding statements to laboratory reports has also been considered by the Australasian Creatinine Consensus Working Group, and some laboratories do provide explanatory eGFR statements. However, many have not embarked on this because of the difficulty of providing adequately informative explanatory remarks in very limited space. Individual laboratories balance the need for such supporting information against the space requirements on reports and the diminishing effect of excessive repetition. Given that routine reports are already complex, often containing over 20 result items, and that many millions of reports with serum creatinine results are produced annually in Australia, the value of any repetitive comment needs careful consideration. The response of clinicians to the introduction of automatic reporting of eGFR together with the linked educational campaign has been strongly positive, with outcomes that have included easier identification of chronic kidney disease, better decision making for affected patients, and more appropriate referral patterns, both in Australia and overseas. Nevertheless, we agree with Adam that eGFR is only an approximation of actual GFR and is subject to error. There are ongoing attempts to further improve the accuracy and clinical utility of eGFR through such ventures as the universal standardisation of creatinine calibration (which has already taken place in Australia and New Zealand) and the Chronic Kidney Disease Epidemiology Collaboration.1 McLachlan, on behalf of the Editorial Advisory Board of the Australian medicines handbook, reaffirms the Board’s position that eGFR is not appropriate for use in dosage calculations. However, for the reasons stated in the consensus document,2 we remain convinced that eGFR is a useful tool for most drug dosing decisions. We note with interest the recent change in the position taken by the British National Formulary (BNF 54) to one of support for the Modification of Diet in Renal Disease (MDRD)-based eGFR1 being used in place of creatinine clearance rate “for most drugs and for most patients of average build and height”3 — a stance similar to ours. In particular, we re-emphasise that eGFR, because of its ready availability, increases the rate of identification of renal failure. We agree with McLachlan that prescribers should continue to follow specific published recommendations for drugs such as enoxaparin and gentamicin (these are good examples of “critical-dose drugs” in the hospital setting). We note additionally that there is increasing acceptance of the eGFR in the drug literature. In the case of enoxaparin, the MDRD equation for eGFR has been used to assess the effect of renal function on bleeding in elderly patients4 and has been found to provide the best relationship with enoxaparin clearance in this setting.5 The eGFR is now an established feature of pathology reports in Australia, and we believe it is important to integrate this information into routine practice for drug dosing decisions. We therefore offer to work with the authors of the Australian medicines handbook and other interested parties to develop guidelines for drug dosing decisions using all available information.

on behalf of the Australasian Creatinine Consensus Working Group

Objective: To assess the outcomes for chronic dialysis patients requiring admission to an intensive care unit (ICU) or high dependency unit (HDU).Design: Retrospective audit of prospectively collected data from local and national databases.Setting: The ICU and HDU at a tertiary referral hospital.Participants: 70 chronic dialysis patients admitted between 2001 and 2006.Main outcome measures: Unit and hospital mortality, recurrent admission patterns and median survival after discharge from hospital.Results: For patients’ last admissions, mortality in the ICU or HDU was 17% and in hospital was 29%. The 12 deaths in the ICU or HDU occurred a median of 18 hours (range, 3–203 hours) after admission, reflecting the severity of their underlying illness. The independent predictors of death in hospital were age and the number of non-renal organ systems failing. Patients with pulmonary oedema had a lower risk of death than patients admitted for other reasons. Although 21 patients accounted for 55 of 104 admissions (53%), recurrent admissions to the ICU or HDU generally occurred during different hospital admissions. They were not associated with a higher risk of death in hospital. Patients discharged home had a median survival of 2.25 years, and a median survival of 3.5 years from starting dialysis. The median survival for patients on dialysis in Australia in general is 4.5 years (Australia and New Zealand Dialysis and Transplant Registry).Conclusion: Dialysis patients discharged home after an ICU or HDU admission have survival similar to that of Australian dialysis patients generally.

Sivagnanavel Senthuran FRCA, FJFICM · Hiran Bandeshe BSc, BEng(Biomed) · Dwarakanathan Ranganathan FRCP, FRACP · Robert Boots PhD, FRACP, FJFICM

Objectives: To explore awareness of the causes of kidney disease and recollection of kidney function testing in a cohort of Australian adults.Design, setting and participants: An interviewer-administered cross-sectional survey, conducted from October to December 2004 as a nested study within the 5-year follow-up phase of the Australian Diabetes, Obesity and Lifestyle Study (AusDiab); 852 subjects who attended a testing site in New South Wales were interviewed.Main outcome measures: Responses to the questions “What sort of things do you think may lead to a person developing kidney disease?” and “Has a doctor or health care worker ever tested your kidney function, outside of the AusDiab study?”Results: Respondents most commonly believed that kidney disease was caused by alcohol misuse or poor diet, with few identifying diabetes or high blood pressure. Awareness of risk factors was no greater in respondents identified as having chronic kidney disease (CKD). A third of respondents with CKD recalled having undergone a test of kidney function within the previous 2 years, while another third replied they had never had their kidney function tested. Of participants with previously diagnosed diabetes or treated hypertension, 54.1% and 32.0%, respectively, reported having their kidney function tested within the previous 2 years.Conclusions: Knowledge of risk factors for kidney disease and recall of kidney function testing were both limited, even among subgroups of the cohort who were at greatest risk of CKD. Prevention efforts may benefit from public and patient education to improve recognition of risk factors for CKD.

Sarah L White MPH · Kevan R Polkinghorne FRACP, MClinEpi · Alan Cass FRACP, PhD · Jonathan Shaw FRACP, MD · Robert C Atkins FRACP, DSc · Steven J Chadban FRACP, PhD

Since publication of the Australasian Creatinine Consensus Working Group’s position statement in 2005, most Australasian laboratories now automatically report an estimated glomerular filtration rate (eGFR) (based on the Modification of Diet in Renal Disease [MDRD] formula) with results of serum creatinine tests in adults. Anecdotal evidence suggests that automatic reporting of eGFR helps to identify asymptomatic kidney dysfunction at an earlier stage and to develop rational and appropriate management plans. Changes to the measurement and calibration of serum creatinine assays and issues regarding implementation of eGFR in clinical practice led the Australasian Creatinine Consensus Working Group to reconvene in 2007. The recommendations contained here build on the original 2005 position statement and consolidate the role of eGFR in clinical practice. The Working Group recommends that the eGFR upper reporting limit be extended to 90 mL/min/1.73 m2, with eGFR values above this amount being reported as “> 90 mL/min/1.73 m2”, rather than as a precise figure. The Working Group has concluded that it is currently premature to recommend age-related decision points for eGFR. However, it is appropriate to advise medical practitioners that, in people aged ≥ 70 years, an eGFR in the range 45–59 mL/min/1.73 m2, if stable over time and unaccompanied by other evidence of kidney damage, may be interpreted as consistent with a typical eGFR for this age group and is unlikely to be associated with chronic kidney disease-related complications. Pending publication of validation studies, the Working Group recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples and other ethnic groups. The Working Group supports the use of eGFR to assist drug dosing decision making in general practice.

on behalf of the Australasian Creatinine Consensus Working Group

We report a successful kidney transplant (A1 donor to an O recipient), with antibody removal pre- and post-transplant, and pre-transplant administration of anti-CD20 monoclonal antibody (rituximab), intravenous immunoglobulin, and conventional transplant immunosuppression. The transplant, which was performed without splenectomy, is the first such transplant in Australia. At 20 months, the patient’s creatinine level was 110–130 μmol/L, with no evidence of rejection and no complications. ABO-incompatible transplantation should increase “live donor” kidney transplantation, reduce waiting times, and improve patient outcomes. Clinical recordA 24-year-old white man with an antineutrophil cytoplasmic autoantibody (ANCA)-positive crescentic glomerulonephritis remained dialysis-dependent despite several months of immunosuppression. He was placed on the deceased-donor transplant waiting list, and potential live donors were evaluated. His mother (ABO blood group-compatible) was medically unsuitable. His father was blood group A1, while the patient was blood group O. The patient’s anti-A antibody titre, although moderately high at 1 : 256 (measured by conventional tube agglutination testing), was considered potentially amenable to lowering by systematic antibody removal to a preoperative target of between 1 : 8 and 1 : 16. A protocol for an ABO-incompatible transplant was established, reviewed and approved by the institutional ethics committee, and carefully discussed with the patient and his family. A month before surgery, the patient received the anti-B-cell (anti-CD20) monoclonal antibody, rituximab (375 mg/m2). Before infusion, his anti-A antibody titre was 1 : 1024 (the rise in titre was attributed to cessation of cyclophosphamide 6 months earlier). Two weeks before surgery, the antiproliferative immunosuppressant mycophenolate mofetil (MMF; 1000 mg orally, twice a day) was commenced, as was antibody removal using immunoadsorption treatments with Glycosorb ABO Columns (Glycorex Transplantation, Lund, Sweden). The antibody titre reduced to 1 : 64, but rebounded, and antibody removal was continued using plasma exchange. The patient eventually underwent transplantation at a stable antibody titre of 1 : 32 (5 weeks after commencing rituximab, and after 14 antibody removal treatments [five immunoadsorption; nine plasma exchange]). Intravenous immunoglobulin, 0.5 g/kg (12 hours before surgery), and daclizumab, an interleukin-2 receptor blocker (immediately before surgery) were administered. After surgery, tacrolimus, an oral calcineurin inhibitor (target trough blood levels, 8–12 ng/mL), and oral prednisolone (25 mg/24 h) were commenced. Splenectomy was not performed. The transplanted kidney functioned immediately, and the serum creatinine level fell from > 700 μmol/L to 110 μmol/L (reference range [RR], < 110 μmol/L) within 72 hours. Three postoperative antibody removal treatments were performed (one immunoadsorption, two plasma exchange) on postoperative Day 2, 4 and 6. By 1 month, immunosuppression consisted of 15 mg prednisolone, MMF, 750 mg twice daily, and tacrolimus (dosed to trough whole blood levels, 5–8 ng/mL) The serum creatinine level was 110 μmol/L (estimated glomerular filtration rate [eGFR], 75 mL/min [RR > 60 mL/min]). The anti-A antibody titre remained between 1 : 16 and 1 : 32. At Week 6, the creatinine level rose to 140 μmol/L. A transplant biopsy showed no rejection, no recurrent disease and no drug toxicity. At 3 months, the patient resumed work (not having worked for the previous year). At 20 months, the creatinine level ranged between 110 and 130 μmol/L; there was no evidence of rejection (on protocol biopsy), no opportunistic infections, and the patient had had no unscheduled admissions to hospital. Maintenance immunosuppression at this time was MMF 500 mg twice daily, tacrolimus (trough levels, 3–6 ng/mL), and prednisolone 5 mg/24 h. DiscussionRenal transplant recipients have an 80% lower mortality rate compared with those remaining on the transplant waiting list, largely due to the increased cardiovascular mortality rate in dialysis patients.1 In the 20–39-year age group, kidney transplant recipients are estimated to gain, on average, more than 17 years of life.2 The increase in deceased-donor transplant waiting times (which adversely affect the patient and transplant survival) has encouraged more transplantation from living donors (Australian average in 2004, > 37%3). However, around 30% of potential live donors are thwarted by blood group incompatibility, where there is a high risk of immediate, rapid graft loss due to (hyperacute) antibody-mediated rejection. As early as the 1950s, transplantation across the ABO barrier resulted in rapid loss of most kidneys due to hyperacute rejection.4 Sporadic attempts at blood group incompatible transplantation have occurred with limited success, employing plasma exchange for antibody removal. A small uncontrolled series in the mid 1980s reported improved results, and concluded that splenectomy was essential for transplant success.5 Japanese centres (without deceased-donor transplant programs) performed over 400 blood group incompatible kidney transplants between 1989 and 2001, all patients undergoing splenectomy, plasma exchange and intense immunosuppression.6 While the Japanese cohort had inferior early graft survival, the 9-year transplant survival (around 60%) was comparable with that of the concurrent blood group compatible transplant population in Japan (and in Australia) over that period. These results, as well as greater attention to measuring and monitoring of anti-blood group antibody titres, and the concurrent development of diagnostic tools and therapies for antibody-mediated rejection, revived interest in ABO-incompatible transplantation. Small series with excellent results have been reported from the United States and Sweden using MMF-based immunosuppression, pre-transplant antibody removal and, in some cases, anti-T-cell antibody (thymoglobulin) therapy, and splenectomy and/or administration of rituximab.7-10 The vast majority of the 300 ABO-incompatible transplants performed globally over the past 4 years have been performed without splenectomy; the collective 1-year graft survival is over 95% (First International Workshop on ABO-incompatible Kidney Transplantation, Stockholm, March 2007). Ten years ago, under the heading “ABO incompatible renal transplantation: a chance to re-examine?”, Mackie and Tiller reported an inadvertent ABO-incompatible transplant performed in Australia,11 with a fortuitously good outcome attributable to a very low antibody titre (1 : 8), and an A2 donor kidney (A2 is associated with lower antigen expression than A1, but is found in only 20% of the Australian population). The importance of antibody titres as a predictor of risk in ABO-incompatible transplantation has caused some centres to avoid transplanting patients with pre-treatment titres exceeding 1 : 128.8 Gloor and colleagues reported a cohort of 18 patients where the risk of antibody-mediated rejection and graft loss correlated strongly with pre-treatment antibody titres regardless of whether the kidneys were from A1 or A2 donors.9 In this, the first intentional ABO-incompatible kidney transplant undertaken in Australia (performed without splenectomy or anti-T cell antibody), the pretreatment titre was 1 : 1024, and yet no antibody-mediated rejection occurred. An important factor in the avoidance of rejection may have been the “incorporation” of post-transplant antibody removal into the protocol, a practice adopted by most centres currently undertaking ABO-incompatible transplantation.10-13 Our patient received rituximab, but its significance in ABO-incompatible regimens remains unclear.12 Although rituximab effectively eliminates B cells, it does not target the antibody-producing plasma cells (these express negligible amounts of CD20, the target antigen of rituximab). Segev et al have reported successful ABO-incompatible transplantation without splenectomy or rituximab,12 even in the presence of relatively high-titre anti-ABO blood group antibody, and again identified post-transplant plasma exchanges as a key factor. Both plasma exchange and immunoadsorbent columns are effective in removing antibodies. The latter are a safer alternative, as they specifically remove only the relevant anti-blood-group antibodies. Plasma exchange removes all antibodies, and other proteins; this includes clotting factors, which creates difficulties in the perioperative period and if diagnostic renal biopsies are required. Additional problems associated with plasma exchange are reactions to the replacement fluid and exposure to blood products. No complications have been reported to date with the use of the immunoadsorbent columns (but they are expensive). The essential components of protocols for ABO-incompatible transplantation are yet to be determined, and significant questions remain. The use of tacrolimus and MMF is common to almost all centres, while significant numbers of patients have been transplanted without splenectomy or rituximab. What is the highest anti-ABO titre that can be successfully overcome, and the highest titre that is acceptable at the time of transplantation? Regardless of these unknowns, blood group-incompatible transplantation has become an acceptable procedure in selected individuals, and selected centres, and provides a transplant option where sometimes none existed previously. While the 9-year data from Japan is reassuring, longer-term outcomes in patients receiving transplants under present protocols are awaited. An increase in transplantation from live donors by using ABO-incompatible donors should significantly reduce transplant waiting times, increase survival of patients with end-stage kidney disease, and improve the quality of the lives of patients and their families. The direct economic benefit of transplantation compared with maintenance dialysis is estimated to be between $40 000 and $60 000 per patient per year.14 Significant indirect benefits also arise from greater participation in the workforce and reduced reliance on welfare or social services. Safe, successful ABO-incompatible transplantation represents an important advance in the management of end-stage kidney disease in Australia.

Shlomo J Cohney PhD, MRCP, FRACP · Rowan G Walker MB BS, MD, FRACP · Michael N Haeusler BSc, FAIMS · David M Francis MS, MD, FRACS · Chris J Hogan MB BS, FRCPA

Organ donation after cardiac death increases organ availability, but raises several legal and ethical issues, including consent. Medical interventions for people who are unconscious usually require guardian consent and must meet patients’ best-interests standards. Antemortem procedures can improve the success of organ transplant after cardiac death, but do not serve the patient’s medical interests, and it is contentious whether consent for antemortem interventions is legal under current Australian guardianship legislation. We argue that consent decisions should take patients’ wishes as well as their medical interests into account. Antemortem interventions are ethically and legally justified if the interventions are not harmful and the person concerned wished to be an organ donor.

Bernadette Richards BA, DipEd, LLB(Hons) · Wendy A Rogers BM BS, FRACGP, PhD

To the Editor: The National Health and Medical Research Council’s National statement on ethical conduct in research involving humans1 recognises that prisoners can participate in research, but categorises them as “persons in dependent or unequal relationships”. They have limited capacity to provide informed consent. Responding to the high levels of transmission of bloodborne viruses in Australian prisons,2 the Australian Red Cross Blood Service excludes prisoners from donating blood and ex-prisoners are excluded for 12 months after they have been released from prison.3 The New South Wales Human Tissue Act 1983 is silent on whether prisoners can donate organs. We report here the case of a prisoner organ donor, highlighting the administrative, legal and operational hurdles that needed to be overcome. A 53-year-old male prisoner was a suitable living kidney donor for his first cousin. He provided consent willingly and without coercion. At initial assessment, the prisoner’s classification required that he be escorted to hospital and that constant surveillance by prison officers be maintained — at a cost of $1000 per day, for at least 7 days. These costs would have been borne by the family. Furthermore, as Australian prisoners are ineligible for Medicare under the Australian Constitution, the donor, as an uninsured patient, and his family would have been required to pay for all pre-, peri- and postoperative care. The donation was deferred for 14 months while these two administrative hurdles were overcome to permit the donation to proceed: 1. The Commissioner for the Department of Corrective Services gave approval for the prisoner to be reclassified to the lowest security classification, thus removing the need for surveillance while in hospital; and 2. A rarely used provision within the NSW Crimes (Administration of Sentences) Act 1999 was applied. Section 26(1) of the Act allows the Commissioner to issue a permit allowing an inmate to be absent from a correctional centre: (a) on such conditions and for such period as may be specified in the permit, and (b) for such purpose as the Commissioner considers appropriate. This allowed the prisoner to be temporarily reinstated to receive Medicare entitlements. The nephrectomy and transplantation were successfully performed. The donor returned to prison on the seventh postoperative day. The donor organ is functioning 4 months after the operation. Prisoners have a right to participate in organ donor programs; however, their precarious position to provide informed consent needs to be protected.

Elizabeth Magee · Michael H Levy