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AD_HTT_019_026___FEB02_07 31/1/07 11:52 AM Page 19 How to treat Pull-out section w w w. a u s t r a l i a n d o c t o r. c o m . a u Earn CPD points on page 26 Complete How to Treat quizzes online (www.australiandoctor.com.au/cpd) or in every issue. inside Definition, incidence and prevalence Classification Screening Management The authors DR COLIN McCLINTOCK renal unit, Royal Prince Alfred Hospital, Camperdown, NSW. DR ALAN CASS renal division, The George Institute for International Health, Camperdown, NSW. Chronic KIDNEY DISEASE ASSOCIATE PROFESSOR STEVE CHADBAN renal unit, Royal Prince Alfred Hospital, Camperdown, NSW. Background Definition of chronic kidney disease CHRONIC kidney disease (CKD) is defined as either kidney damage or decreased kidney function that has persisted for three or more months. Cardinal markers of kidney damage include proteinuria, haematuria, abnormalities on kidney imaging and decreased kidney function (glomerular filtration rate [GRF] <60mL/min/1.72m 2 [adjusted for surface area]).1, 2 Prediction equations are a practical way of estimating GFR. In 2005, following recommendations by Kidney Health Australia, pathology laboratories throughout Australia initiated the automatic reporting of estimated glomerular filtration rate (eGFR) from serum creatinine. Whenever eGFR is <60mL/min, this is reported to the clinician. As the prevalence of eGFR<60mL/min is about 10% among Australian adults, a rapid increase in the awareness of CKD in our community is anticipated. Assessing severity of CKD based on the above markers and eGFR allows allocation of individuals into the five stages of CKD according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) system (see Classification of chronic kidney disease, page www.australiandoctor.com.au 20). Identifying severity and stage of CKD, independent of the cause of kidney damage, improves patient management strategies. Incidence, prevalence and disease burden Recent cross-sectional studies have estimated the CKD prevalence in the adult population of Australia straticont’d next page 2 February 2007 | Australian Doctor | 19 AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 20 How to treat – chronic kidney disease from previous page fied by K/DOQI stage. In Australian adults aged over 25, the proportions with stage 1-5 CKD were 0.9%, 2.0%, 10.9%, 0.3% and 0.1%, respectively (table 1).1 These figures clearly delineate the burden of CKD in Australia, with more than 10% of the entire population having an eGFR <60mL/min. The bulk of these patients have an eGFR of 30-59mL/min — a population potentially at risk of further deterioration in kidney function. CKD is a significant burden in terms of ongoing health provision both in Australia and worldwide. Managing CKD and providing ongoing renal replacement therapy in those who progress to end-stage kidney disease (ESKD) is costly. Population-based studies in Australia and the US have addressed the prevalence and burden of disease. The AusDiab study1 suggests that 14% of the population have key manifestations of kidney damage, although those with ESKD considered in the AIHW report. It is important to identify population groups at high risk of developing CKD, so that we can undertake targeted, primary care-based opportunistic screening. This is especially important given that effective therapies are available to delay progression of CKD and because the ‘at risk’ population continues to grow as a result of population ageing and the rapid increase in the prevalence of type 2 diabetes. receiving renal replacement therapy account for significantly less than 1%. The Australian Institute of Health and Welfare (AIHW) estimated that total health expenditure on CKD in 2000-01 was $647 million, representing 1.3% of total recurrent health expenditure.2 Furthermore, CKD is now recognised as an independent risk factor for vascular disease, and the population and financial burden of vascular disease associated with CKD was not Because of the excess cardiovascular complications and other comorbidities seen in people with CKD, the health service burden relating to providing care to people with complex chronic disease will also continue to grow. Quality of life becomes a significant issue for patients approaching ESKD, when decisions need to be made about the use of renal replacement therapies, and an education and preparation process should begin. Classification of chronic kidney disease THERE are two distinct methods for classifying CKD: a classification system based on cause of kidney disease, and a system largely based on the degree of kidney damage independent of the cause. The latter system is simple, logical and pragmatic and will be discussed first. Table 1: K/DOQI classification of CKD3 (Prevalence from AusDiab and ANZDATA [Stage 5]) K/DOQI classification system according to degree of kidney damage A general lack of uniformity in diagnosis, definition and staging of CKD led to the emergence of the K/DOQI classification system in 2002 (table 1).3 The aim of this system is to produce a consistent framework on which diagnosis and management can be based, both for nephrologists and GPs. As suggested, K/DOQI is not a causal classification system; rather, it classifies according to degree of kidney damage, recognising the following key manifestations: ■ Reduced GFR. ■ Albuminuria/proteinuria. ■ Haematuria. ■ Abnormal kidney structure. Early detection and uniform staging of CKD using simple laboratory measurements should allow earlier treatment and slowing of progression. Delineation of stage is primarily based on estimation of GFR which can be CKD stage Definition Prevalence in Australian adults 1 Kidney damage (albuminuria, haematuria or abnormal kidney imaging), eGFR >90mL/min 0.9% (n = 112,000) 2 Kidney damage, eGFR 60-90mL/min 2.0% (n = 250,000) 3 Moderate kidney failure, GFR 30-59mL/min 10.9% (n = 1,400,000) 4 Severe kidney failure, GFR 15-29mL/min 0.3% (n = 40,000) 5 End-stage kidney failure requiring dialysis or transplant, GFR <15mL/min 0.1% (n = 14,000) CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; K/DOQI = Kidney Disease Outcomes Quality Initiative Table 2: Primary renal disease of new patients reaching ESKD, 4 01/01/2004-31/12/2004 (reproduced from ANZDATA Report, 2004 ). Cause assessed in a number of ways; nuclear medicine scanning (cumbersome), 24-hour urine for creatinine clearance (inconvenient and inaccurate) and, most recently, eGFR derived from serum creatinine measurement using prediction equations. In stage 1 and 2 CKD, in which GFR is normal or increased, kidney dysfunction is defined by the presence of persistent albuminuria/proteinuria, haematuria (after exclusion of urological causes) or structural abnormalities on kidney imaging tests. Classification according to cause of kidney disease A more traditional way of classifying CKD relates to the actual pathological cause of the kidney disease; however, not uncommonly, the cause is difficult to determine. In Australia in 2004, diabetes (primarily type 2) was the most common cause of ESKD, closely followed by glomerulonephritis, then hypertension, polycystic kidney disease, reflux nephropathy and analgesic nephropathy (table 2). Australia New Zealand Number Per million Number Per million Glomerulonephritis 479 24 107 26 Analgesic nephropathy 46 2 2 <1 Polycystic renal disease 126 6 24 6 Reflux nephropathy 55 3 12 3 Hypertension 256 13 72 18 Diabetes 576 29 177 44 Type 1, insulin dependent 63 13 Type 2, not requiring insulin 260 82 Type 2, requiring insulin 253 Miscellaneous 247 12 30 7 Uncertain 127 6 23 6 Total 1912 95 447 110 Glomerulonephritis can be subclassified as to cause, with IgA disease being the most common form. Some diagnoses of renal disease will require specialist nephrological guidance for diagnosis and management 82 (see When to refer to a nephrologist, page 21), especially given the wide array of potential pathology. However, the K/DOQI stage classification, which unifies diagnosis and global management strategies, is a more important focus for primary care management. This is further emphasised by many aspects of treatment not being specific to cause, such as blood pressure control and anti-proteinuric therapies. Screening for chronic kidney disease Who is at risk of CKD? EVIDENCE does not support screening the entire Australian population for CKD. However, certain groups are known to have high risk for developing CKD. All people attending their primary care practitioner should be assessed, as part of routine primary health encounters, to determine whether they are at increased risk for developing CKD on the basis of clinical and demographic factors (table 3). Among high-risk individuals, a targeted opportunistic screening program should be adopted to identify those with CKD. The most significant risk factors for CKD include age over 50, diabetes, hypertension, smoking and, 20 | Australian Doctor | 2 February 2007 to a lesser degree, obesity and raised cholesterol and triglyceride levels. There would also appear to be genetic risks for kidney disease, with evidence of familial clustering of CKD and ESKD. Up to 20% of new ESKD patients report a firstor second-degree relative with ESKD, with a positive family history more common in patients with diabetes or glomerulonephritis. It may also be useful to ask patients if there is personal or family history of UTI, renal calculi or analgesic use. Certain ethnic groups within Australia deserve a special mention with regard to CKD risk. Indigenous Australians experience ESKD at a rate about nine times higher than the general population. How- Table 3: CDK high-risk groups* Modifiable risk factors ■ Smoking ■ Diabetes ■ High blood pressure Non-modifiable risk factors ■ Age >50 ■ Family history of kidney disease ■ Aboriginal or Torres Strait Islander heritage *From Kidney Health Australia www.australiandoctor.com.au ever, this is thought to rise to up to 30 times the national incidence in remote areas. Reasons for this are complex, with a much higher incidence of proteinuria among remote Aboriginal populations — 50% of those in their 20s have some degree of proteinuria and 50% in their mid50s have heavy proteinuria. General risk factors for both proteinuria and ESKD among Indigenous Australians include: ■ Rural or remote area of residence. ■ Low birth weight. ■ Recurrent skin infections. ■ Post-streptococcal glomerulonephritis. ■ Family history of ESKD. ■ Obesity. Hypertension. Uncontrolled blood sugar levels. ■ Poverty. New Zealand Maori and Pacific Islanders living in Australia are also at increased risk for ESKD. ■ ■ Targeted opportunistic screening In view of the burden of CKD in Australia, people at high risk should be identified to allow opportunistic screening and intervention to prevent disease progression. This is particularly important when the prevalence of diabetes and hypertension, two cardinal risk factors for CKD, is unlikely to diminish. Within primary health care, targeted opportunistic screening of AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 21 people with clear risk factors (table 3) should be carried out, for example, at routine health checks. Simple strategies involving blood pressure checks, urine dipstick and eGFR can be used for those at risk. Mass population screening for CKD has not been proven to be cost-effective. However, given that advancing age is the strongest predictor of CKD, population screening in the over-50 age group is likely to be costeffective and also in people with hypertension over age 30. There is evidence that screening of other high-risk groups within the population is cost-effective. The diabetic population is one such group where anti-proteinuric therapies (see Antiproteinuric therapy, page 22), blood pressure control and glycaemic control have been shown to alter outcomes: screening for early detection of modifiable risk is worthwhile. Screening concepts Estimated glomerular filtration rate GFR is the best measure of overall kidney function in health and in disease. Normal GFR varies with age, sex and body size. The normal value for GFR in young adults is 120140mL/min and declines from age 30 at an annual rate of about 1mL/min. It is clear that a significant number of elderly Australians will have an eGFR of 3060mL/min. This is an important finding, as it identifies a group at increased long-term risk of both cardiovascular disease and ESKD. This population should be screened for other markers of CKD, such as proteinuria/haematuria, hypertension and diabetes. There are several ways to measure or estimate GFR. However, prediction equations based on only one labbased measure (serum creatinine) allow automatic estimation of GFR and rapid classification of CKD stage when GFR is reduced to <60mL/min. The Modification of Diet in Renal Disease (MDRD) 5 Study prediction equation has been in existence since 1999 and has many advantages. It is more accurate at predicting GFRs <90mL/min, is reasonably well validated and does not require knowledge of patient weight or height. The eGFR now provided automatically with every serum creatinine measured in Australia to help identify CKD stage and at-risk populations (eGFR <60mL/min) is calculated from the MDRD equation. It is important to remember that MDRD-based eGFR has not been validated in Kidney disease in Australia: the Titanic/iceberg model Adults aged over 25 Stage 5 — kidney failure 14,000 Stage 4 — GFR <30mL/min 40,000 1.7 million Stage 1-3 Hypertension or diabetes >4.5 million at risk Derived from AusDiab data. Table 4: Urinary albumin:creatinine ratio ■ <3mg/mmol Normal ■ 3-30mg/mmol Microalbuminuria range ■ >30mg/mmol Macroalbuminuria It is rational to screen for proteinuria among patients at risk of CKD, except for those with diabetes, who should be screened for microalbuminuria instead. certain population groups within Australia (Aboriginal and Torres Strait Islander people, Asian populations [including Japanese, Chinese and Vietnamese], Maori and Pacific Islander people). In addition, MDRD has not been proven for calculating drug dose reductions in CKD (although it is likely to be acceptable in this regard). In these situations other methods of evaluating GFR may be necessary. Screening for proteinuria Proteinuria is a cardinal marker of kidney damage. Albumin, present in normal urine in small amounts, contributes about 25% of the total protein content of urine. With the development and progression of CKD, the proportion of albumin to total protein in urine increases. In early CKD, despite total protein excretion remaining within the normal range, albumin content may become abnormal. This is usually termed microalbuminuria, while higher rates of albumin excretion are termed macroalbuminuria (table 4). In such cases, tests for (total) proteinuria will usually be abnormal. The AusDiab study showed that 2.4% of the Australian population had proteinuria, most of which was found among those with hypertension and/or dia1 betes. The AusDiab study also suggests albuminuria (a term that includes both microand macroalbuminuria) is present in just over 6% of Australian adults, much of that being in the microalbuminuria range and in people with diabetes. Like proteinuria, microalbuminuria is a marker of kidney damage, and testing for proteinuria should form the basis of any screening for CKD. In non-diabetic CKD, anti-proteinuric therapies have been shown to reduce risk of disease progression. However, in patients with diabetes anti-proteinuric treatment has only been proven to be of benefit for people with microalbuminuria. Thus it is rational to screen for proteinuria among patients at risk of CKD, except for those with diabetes, who should be screened for microalbuminuria instead. There are several ways to detect proteinuria — standard dipstick, protein:creatinine ratio (spot urine) and formal 24-hour urine for protein excretion. In our opinion dipstick testing for proteinuria is a useful ‘first round’ screening test for proteinuria in the non-diabetic population, to be followed by confirmatory testing with a spot urine protein:creatinine ratio in those positive on dipstick testing. In the AusDiab survey, dipstick testing at a threshold of 1+ or greater was highly sensitive: dipstick testing was highly successful in identifying people with significant proteinuria. However, among those who tested positive, secondround testing with spot urine protein:creatinine ratio confirmed significant proteinuria in only half of the cases (unpublished data, S. Chadban). Dipstick testing had a negative predictive value of more than 99%: those who tested negative were extremely unlikely to have significant proteinuria. Twenty four-hour urine collection for protein excretion is not required as part of screening for CKD. Patients with diabetes should be screened annually for microalbuminuria by spot urinary albumin:creatinine ratio (ACR), ideally using a morning specimen. If they test positive for microalbuminuria, two further samples should be sent www.australiandoctor.com.au for ACR within two months, given that only 63% of patients persistently test positive. Microalbuminuria, and hence early-stage diabetic nephropathy, can be diagnosed if at least two samples are positive. Although an early morning sample is ideal, a spot urine for ACR can be collected at any time, which makes it a very versatile test and significantly easier than a timed urine collection for albumin excretion rate. ACR is also achieving widespread use in quantification of macroalbuminuria for diagnosis, follow-up and response to treatment. In our opinion, and in accordance with the position statement of the Australian Diabetes Society, screening for microalbuminuria may be performed on spot urine specimens. Again, when screening for kidney damage in diabetes, timed urine collection is not required. We suggest annual dipstick screening for proteinuria for those at risk of CKD (table 3) and annual testing for microalbuminuria by spot urine ACR for all patients with diabetes, in addition to serum creatinine (and so eGFR) and blood pressure. urgent referral to a nephrologist for investigation and management. Among people aged over 40 or at higher risk (eg, smokers or people with a history of compound analgesic use), further investigation is warranted to exclude significant urological pathology, such as malignancy, prostatic disease or stones. Haematuria When to refer to a nephrologist Microscopic haematuria is common and was detected in 4.6% of Australian adults 1 in the AusDiab study. A standard urine dipstick is highly sensitive for haematuria. In most people, haematuria is related to menstruation or UTI and is transient and not a marker of kidney disease. However, persistent haematuria, or haematuria found in conjunction with other markers of kidney damage, necessitates follow-up. Among people with persistent haematuria, key issues for GPs include when to consider referral to a nephrologist and/or urologist. Accurate phase contrast microscopy (on a fresh urine sample) can identify ‘glomerular haematuria’ by the red cell morphology; however, this requires the urine to be sent for pathology testing. It is prudent to refer individuals with haematuria found in conjunction with reduced eGFR, proteinuria or elevated blood pressure to a nephrologist, as this may signify treatable glomerular disease. Nephritic syndrome — characterised by sudden onset of haematuria (which may be macroscopic and thus reported by a patient as abnormally dark-coloured urine), elevated blood pressure and progressive reduction in urine output and eGFR — is an uncommon diagnosis that necessitates Imaging Classification of CKD stage (especially 1 and 2) also relies on knowledge of structural kidney abnormalities. Baseline renal imaging is not only of use for classification purposes but also constitutes an essential part of diagnostic workup and should be done in patients with cardinal signs of kidney damage, such as proteinuria, low eGFR or glomerular haematuria. Standard ultrasonography of the renal tract is appropriate and can be used to assess kidney size, cortical thickness, presence of scarring, presence of cysts (simple or otherwise) or obstruction. For example, bilateral decrease in kidney size with cortical thinning is likely to suggest a chronic process with associated risk of further disease progression. Guidelines outlining what to do with the results of clinical and laboratory screening are needed. AusDiab data suggest that 14% of the Australian population have CKD, but that most are elderly women with isolated reduced eGFR in the 30-60mL/min range (stage 3 CKD). Referring all such patients to a nephrologist is impractical and unlikely to be cost-effective. Therefore the bulk of initial management and also decision making about referral will fall to the GP. Kidney Health Australia has formulated the following guidelines on when specialist referral is indicated: ■ eGFR <30mL/min. ■ Rapidly declining kidney function (>15% reduction in eGFR over three months, irrespective of baseline level). ■ Proteinuria >1g/24 hours. ■ Glomerular haematuria (especially when associated with decreased eGFR, proteinuria or hypertension). ■ Kidney disease and/or hypertension that is difficult to control. ■ Diabetes and eGFR <60mL/min. Following these guidelines would require knowledge of screening tests and CKD clinical risk factors, and implementing them would establish primary care as the appropriate arena for managing CKD. 2 February 2007 | Australian Doctor | 21 AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 22 How to treat – chronic kidney disease Management of chronic kidney disease THE aims of management are to prevent disease progression and deterioration of kidney function to the level of ESKD requiring renal replacement therapy, and to manage the elevated cardiovascular risk associated with CKD. This involves the following strategies: ■ Anti-progression therapy — blood pressure control, antiproteinuric therapy. ■ Specific therapy based on the defined aetiology of CKD (generally guided by a nephrologist). ■ Preventing cardiovascular disease. ■ Managing specific complications of CKD, including preparation for renal replacement therapy. ■ Appropriate drug dosing (table 5). 50 20 Obesity is a risk factor for CKD. Although people can often lose weight, sustaining the weight loss is particularly difficult. If sustained, weight loss is expected to be beneficial for CKD long term, but also a generally effective secondary prevention goal. 10 Correction of renal anaemia Dialysis/Tx 40 N = 27,988 over 66 months Event (%) 30 0 89-60 89-60 (prot) 30-59 GFR (mL/min) 29-15 Risk of dying from CVD events 20 times greater than requiring dialysis/transplant Keith, et al. Archives of Internal Medicine 2004; 164:659-63. Table 5: The eGFR action plan (Kidney Health Australia) eGFR (mL/min) ≥60 Maintaining tight blood pressure control is a central management goal in delaying progression of CKD (<130/85mmHg for proteinuria <1g/day; <125/75mmHg for proteinuria >1g/day or patients with diabetes). In the patient with proteinuria, ACE inhibitors or angiotensin-II-receptor antagonists should be considered as first-line agents. Combination therapy using both classes may be the optimal strategy, although multiple agents are frequently required to achieve targets. The choice of agent should be tailored to the individual. 30-59 15-29 Anti-proteinuric therapy 22 Weight reduction Death Blood pressure control Proteinuria is a strong marker of the risk of progressive renal injury in CKD. The extent of decline in proteinuria that occurs in response to therapy is also a useful guide to the likelihood that therapy will delay progression. Although most classes of antihypertensive agents can decrease proteinuria (by decreasing systemic blood pressure and hence intraglomerular pressures), ACE inhibitors and angiotensin IIreceptor antagonists have consistently been shown to be the most effective agents in decreasing proteinuria and delaying progression of proteinuric CKD. This has recently been shown to be true even in cases of advanced disease (stage 4 CKD). Combination therapy with these two classes of drug may produce further benefits. Detecting CKD early and prescribing ACE inhibitors might not only slow progression of kidney disease but also reduce the high risk of cardiovascular disease. The potential side effects of these two classes of antihypertensive deserve mention: ■ Intractable dry cough. ■ Angioneurotic oedema/anaphylaxis. ■ Hypotension (elderly). tigation in SHARP). Outcomes in patients with CKD <15 Description Clinical action plan No kidney damage or Stage 1 CKD (kidney damage* with normal kidney function) or Stage 2 CKD (kidney damage* with mild kidney function) Stage 3 CKD (moderate kidney function) Further investigation for CKD may be indicated in those at increased risk: ■ Assessment of proteinuria ■ Urinalysis ■ Blood pressure Cardiovascular risk reduction (blood pressure, lipids, blood glucose, smoking, obesity, physical activity) As above, plus: ■ Monitor eGFR three monthly ■ Avoid nephrotoxic drugs ■ Prescribe antiproteinuric drugs (angiotensin converting enzyme inhibitors and/or angiotensin-II-receptor blockers) if appropriate ■ Address anaemia, acidosis and hyperparathyroidism ■ Ensure drug dosages appropriate for level of kidney function Consider referral to nephrologist As above plus referral to nephrologist is usually indicated for preparation for dialysis (including access surgery, education) or transplantation As above plus referral to nephrologist Stage 4 CKD (severe kidney function) Stage 5 CKD (end-stage kidney failure) *Imaging or biopsy abnormalities or proteinuria/haematuria Acute minor deterioration in renal function (usually stabilises). ■ Acute continued deterioration in renal function (bilateral renal artery stenosis or intra-renal small-vessel disease). ■ Hyperkalaemia. For these reasons patients often require closer clinical and laboratory monitoring on starting these drugs, especially elderly patients, those with diabetes (hyperkalaemia) or significantly impaired kidney function. Serum creatinine should be checked at least once 3-5 days after starting an ACE inhibitor or angiotensin-II-receptor antagonist. If any rise in creatinine level is seen, therapy is safe to continue provided that the rise is <30% of baseline, and the creatinine test is repeated within a month. If a greater rise is observed, treatment should be suspended and a search for renovascular disease may be advisable. While the choice of screening test depends on local availability and expertise, appropriate screening tests include renal artery Doppler ■ | Australian Doctor | 2 February 2007 ultrasonography, CT angiography and MRI angiography. (The gold standard test and approach to confirm the diagnosis of renal arterial disease remains referral to a nephrologist to arrange DSA renal arteriography.) Hyperkalaemia is frequent among elderly people and those with diabetes after starting an ACE inhibitor or angiotensin-II-receptor antagonist. In the latter this may be predisposed to by the presence of hyperkalaemic-type renal tubular acidosis (type 4). Provided that hyperkalaemia is modest (potassium level ≤6.0mmol/L) and stable on repeat testing, therapy should be continued because of the beneficial effects of ACE inhibitors in such populations. Advice on a low potassium diet is often particularly useful. Glycaemic control Optimal glycaemic control helps prevent CKD progression in patients with nephropathy due to type 1 or type 2 diabetes. HbA1c levels <7.0% should be targeted by use of diet, oral hypogly- caemics and/or insulin, taking care to avoid metformin and sulfonylureas that are renally excreted in patients with eGFR<30mL/min. Smoking cessation Current smoking has been shown to be a significant risk factor for CKD in the general population and increases the risk of progression for those with known kidney disease. Smoking cessation is therefore of paramount importance, decreasing the risk of progression and also cardiovascular events. Lipid lowering Raised serum cholesterol and triglyceride levels may be an independent risk factor for CKD. The evidence that lowering cholesterol with statin therapy slows progression of CKD is lacking, but is currently under investigation in the Study of Heart and Renal Protection (SHARP) study. It seems likely that cholesterol lowering will also decrease the risk of cardiovascular events for those with CKD (this is also under inves- www.australiandoctor.com.au Renal anaemia is caused by reduced erythropoietin production by loss of renal parenchymal mass in progressive CKD. It can be corrected by supplements of erythropoietin subcutaneously or intravenously, guided by a nephrologist. Two trials of erythropoietin therapy in people with CKD, published in November 2006 in the New England Journal of Medicine (the CHOIR and CREATE trials), showed no benefit and possible harm in correcting anaemia to a normal haemoglobin (>130g/L). Correcting anaemia has not been convincingly shown to slow CKD progression; however, improved quality of life and reduced transfusion requirements support therapy for people with haemoglobin levels <100g/L. Control of hyperphosphataemia Phosphate retention is universal in CKD and is a strong risk factor for cardiac death. Correction of serum phosphate through the use of binders such as calcium carbonate is likely to decrease the risk of vascular events. Protein restriction A small amount of evidence suggests protein restriction will slow CKD progression. However, this approach is unlikely to be of benefit given the significant risk of protein energy malnutrition. Australian guidelines recommend a normal dietary protein intake. Cardiovascular risk CKD is an independent risk factor for cardiovascular disease, with elevated risk arising even at mild to moderate stages of CKD. Large-scale cohort studies have shown that people with CKD have a much higher risk of premature death (largely due to cardiovascular disease) than of progressing to ESKD requiring dialysis or a transplant.6 Among people who do progress to ESKD, cardiovascular mortality rates are at least 10 times higher than the age- and sex-matched healthy population. The reasons for this increased risk are complex. Cardiovascular risk factors cluster in CKD; for example, people with diabetes causing significant kidney damage will usually also have hypertension and lipid abnormalities. In addition, CKD alters calcium/phosphate regulation, leading to increased coronary artery calcification and increased cardiovascular risk. Altered salt and water homeostasis and renal anaemia lead to chronic cardiac overload, hypertension and so left ventricular hypertrophy. Chronic overload and/or cardiac ischaemia leads to congestive cardiac failure. Left ventricular hypertrophy from chronic fluid overload is a marker of risk for sudden death in the ESKD population. In view of this excess burden of cardiovascular disease, primary care physicians need to be aware of the potential for cardiac complications in any person with CKD and have a lower threshold for investigation. Modifiable risk factors for cardiovascular disease should be managed aggressively. Bone disease Renal bone disease can be split into two major groups: disease associated with high bone turnover stimulated by high parathyroid hormone (PTH) levels (osteitis fibrosa); and low bone-turnover states with low or normal serum PTH levels (adynamic bone disease or osteomalacia). Secondary hyperparathyroidism is a common complication of CKD. With GFR <60mL/min, phosphate retention, loss of activated vitamin D and decreased serum calcium drive abnormal secretion of PTH. Hyperparathyroidism leads to abnormal bone turnover, which in turn leads to decreased bone strength and fracture. Laboratory tests typically show raised serum phosphate, low or low normal serum calcium, and raised PTH and alkaline phosphatase levels. Treatment primarily depends on reducing serum phosphate with phosphate binders such as calcium carbonate taken with meals. Use of ‘activated’ 1,25 vitamin D in the form of calcitriol (generally 0.25g/day) also directly inhibits PTH secretion, but may cause hypercalcaemia and raised calcium/ phosphate product, potentially increasing cardiac risk. Low bone-turnover states result in adynamic bone disease and osteomalacia, both characterised by reduced osteoclast and osteoblast number and function. Adynamic bone disease may be at least as common as hyperparathyroid bone disease and probably relates to oversuppression of PTH. Bone pain and increased fracture risk are seen in low turnover states. AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 23 Other clinical problems THERE are several other clinically important effects of CKD, usually seen with significantly reduced GFR. 16 Glucose metabolism The kidneys play an important role in the metabolism of insulin. Severe CKD leads not only to increased serum levels of both endogenous and exogenous insulin, but also to increased tissue resistance to insulin. Note that renally excreted sulfonylureas should be avoided (especially in the elderly) in CKD — gliclazide and glimepiride are the best options. Metformin should be avoided in all patients with diabetes and eGFR <30mL/min, because of the risk of lactic acidosis. Fertility Abnormal sex hormone levels and cyclical changes are commonly seen as CKD advances, leading to reduced fertility with oligomenorrhoea or amenorrhoea. Impotence and decreased spermatogenesis is commonly seen in men. Neurological effects Central, peripheral and autonomic Cumulative incidence of ESKD % Urate retention is common in CKD and often exacerbated by diuretic use. NSAIDs are generally contraindicated, leaving colchicines for use in acute attacks and allopurinol for prevention (dose reduction required in line with decreased GFR). CKD is a common problem and frequently goes undetected. ■ The K/DOQI classification of CKD into five stages of increasing severity, independent of cause, provides a practical framework for diagnosis and management ■ Within general practice, clinical and sociodemographic risk factors for CKD can identify an ‘at risk’ population appropriate for targeted opportunistic screening. ■ The cardinal markers of CKD are reduced eGFR, proteinuria, haematuria and kidney-imaging abnormalities. ■ eGFR is now automatically provided by most labs when serum creatinine is measured. ■ Guidelines are available that indicate when referral to a nephrologist is appropriate. ■ Simple strategies can prevent CKD progression: blood pressure control, anti-proteinuric therapies, smoking cessation and tight glycaemic control. ■ CKD is an independent risk factor for cardiovascular death. ■ Prescribing practices may need to be altered for patients with CKD. ■ Risk of ESKD related to baseline proteinuria over 18-year period Metabolic/endocrine effects Gout Summary N = 106,000 14 12 10 8 Progression to ESKD 6 4 2 0 Proteinuria Number of screened Number of ESKD NSAIDs, iodine contrast) unless absolutely necessary. Many drugs require dose adjustment in line with progressive decline in GFR (eg, digoxin, sotalol, allopurinol), generally when predominant clearance is via renal excretion. Very occasionally doses for drugs which are dependent on GFR for renal delivery (such as loop diruetics) need to be increased. 86,253 185 ± 10,000 38 + 4007 55 2+ 1072 76 ≥3+ 357 55 Iseki, et al. Kidney International 2003; 63:1468-76. neuropathy as well as abnormalities in muscle composition and function are complications in CKD. protein restriction has been used to delay the need for this therapy. However, this should not be at the risk of protein energy malnutrition. Gastrointestinal and nutritional problems Prescribing for patients with CKD With advanced CKD, risk of gastritis and peptic ulcer disease is increased. In addition, diverticulosis and also pancreatitis are more common, particularly in individuals with polycystic kidney disease. Clinically patients suffer nausea, vomiting, anorexia and hiccups late in the course of their CKD. These symptoms should respond to introduction of renal replacement therapy, although A comprehensive discussion of renal prescribing is beyond the scope of this review (see also How to treat: Kidney complications of commonly used drugs part 1 and 2, 7 April and 14 April, 2006). It is always important to consider a person’s degree of renal impairment when modifying pharmacological treatment. Consideration must be given to avoiding renotoxic drugs (eg, The aim of this review has been to provide knowledge and improve understanding of CKD to enable GPs to identify CKD among their patients, particularly through opportunistic targeted screening. The suggested classification, management and referral strategy should help GPs to manage this growing health problem. This is important for two reasons: best-practice CKD management will reduce the risk of premature mortality due to associated cardiovascular disease; and it will reduce the number of people progressing to ESKD. More than 15,000 Australians with ESKD are receiving dialysis or living with a functioning kidney transplant. In addition, significant numbers of patients are managed conservatively and die as a consequence of their kidney disease. CKD causes or contributes to about 9% of all deaths in Australia. Hopefully, early detection and appropriate management in general practice will help reduce this disease burden. Authors’ case study Proteinuria with hypertension and significant CKD A 73-YEAR-old Caucasian woman attends her local GP for a health checkup, admitting she has avoided doctors over the years. There is very little in her past history beyond hypertension, and she has refused medication for blood pressure on three previous visits. There is no family history of kidney disease. She smoked a packet of cigarettes/day for 30 years but “gave them away” 10 years ago because of cost. She drinks no alcohol. On close questioning she informs her GP of a mild ache in her chest when walking up hills, although she still keeps pretty active. There is little to find on clinical examination beyond persistent hypertension of 160/90mmHg and obesity (BMI 32). In view of her age and hypertension, urine dipstick is performed, which shows 1+ protein and no blood. Serum for routine blood count, fasting biochemistry and also morning urine for ACR are sent for testing. These tests show haemoglobin 108g/L, creatinine 178µmolL, urea 15.4mmol/L, fasting glucose 4.8mmol/L, cholesterol 6.8mmol/L and triglycerides 2.6mmol/L. The urine ACR result is 45mg/mmol, consistent with mild proteinuria. An automated eGFR of 28mL/min, consistent with CKD stage 4, is provided with the creatinine result. Following these results her GP arranges a baseline ultrasound scan of the renal tract, which documents bilateral reduced kidney size of 9.4cm (normal 11-14cm), with mild parenchymal thinning and a simple cyst in the left kidney. Although the patient is clinically well, her GP is concerned about the degree of renal impairment and risk of progression and also cardiovascular disease risk, especially given her symptom of mild exertional chest ache. The main consideration is to achieve blood pressure control and, given the mild proteinuria, first-line treatment with an ACE inhibitor (perindopril 4mg daily) is started. With her degree of renal dysfunction, creatinine and potassium are checked five days later as a safeguard against bilateral renal artery stenosis. The repeat creatinine is 191µmolL, which is felt to be acceptable, and the potassium is 5.0mmol/L. A statin is added in view of the cholesterol level, and weight loss initiatives are diswww.australiandoctor.com.au cussed with the patient. At the same time, given the stage of CKD and hypertension, the GP refers her to a nephrologist, but also a cardiologist for investigation and risk-factor modulation for CVD. On nephrologist review a diagnosis of hypertensive nephrosclerosis is made. Given the symmetrical reduction in kidney size and the stable creatinine level with ACE inhibition, investigation for renal artery stenosis is not deemed necessary at this stage. Blood pressure is now 145/85mmHg and the nephrologist increases the perindopril dose to 8mg daily with a view to adding atenolol if required at a later date. The patient is deemed moderate to high risk for CKD progression and the nephrologist opts to see her in three months, with monthly creatinine, potassium and blood pressure checks by her GP. Repeat ACR at three months has dropped to 30mg/mmol, blood pressure is now 125/70mmHg and renal function is stable. A plan is made to see the patient every 6-12 months to monitor for CKD progression and further modulate risk if possible. Coronary angiography with prehydration and n-acetylcysteine protection is booked. References and Further reading Available on request from julian.mcallan@ reedbusiness.com.au Online resources ANZDATA: www.anzdata.org.au ■ Caring for Australasians with Renal Impairment: www.cari.org.au/ guideline.php ■ Australian Diabetes Society: www.racp.edu.au/ads/ posstate.htm ■ K/DOQI: www.kidney.org/ professionals/KDOQI/ guidelines.cfm ■ Kidney Health Australia: www.kidney.org.au ■ 2 February 2007 | Australian Doctor | 23 AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 26 How to treat – chronic kidney disease GP’s contribution DR CAROLYN BLOCK Double Bay, NSW Case study MRS D is 75 and surprisingly spritely for her age. She looks after herself and her many grandchildren well. She has no medical problems apart from a long history of hypertension and hypercholesterolaemia, for which she is being treated, nor any significant family history. She regularly sees an ophthalmologist and has had no microor macrovascular effects from her conditions. On her routine yearly blood test her serum creatinine was 114µmol/L, eGFR 43mL/min, cholesterol 5.0mol/L and LDLcholesterol 2.7mmol/L. Her creatine kinase was 197U/L. Her blood pressure was 140/80mmHg and her weight was 57kg. She had no symptoms of the renal insufficiency on her test results. Comprehensive blood tests, including an immunological screen and urine analysis, including a Bence-Jones protein were normal. Ultrasound of the renal tract and renal artery Dopplers was also normal. The dosages of her antihypertensive (an angiotensin-IIreceptor antagonist) and lipidlowering agent were doubled and on review she was tolerating the increases well. Questions for the authors If Mrs D had been unable to tolerate these increases in medication doses, what options would there be for treatment? Although Mrs D is an active 75-year-old, as an elderly person with high blood pressure, hypercholesterolaemia and chronic kidney disease, she has very high absolute risk of cardiovascular disease. In this setting, increasing her medication dosages was appropriate. If she had been unable to tolerate a doubling of her angiotensin-II-receptor antagonist, other options would include: combination with a low dose of another class of antihypertensive (ACE inhibitor, diuretic, beta blocker or calcium-channel blocker), or investigating changes to diet (particularly to explore whether she has high salt intake or low intake of fruit and vegetables). If she had been unable to tolerate a doubling of her lipid-lowering agent, other options would be: combination with a low dose of another class of lipid-lowering agent (for example, combining a statin with ezetimibe), provision of tailored dietary advice with a possible focus on the beneficial role of plant-sterols and omega-3 fatty acids (fish oils). What parameters should we aim for when measuring her LDL and total cholesterol and blood pressure? Emphasis is now being placed on LDL levels rather than total cholesterol. For Mrs D, who has high absolute risk, but has not had a previous major CV event and does not have proteinuria, appropriate targets are an LDL-C level of <2.5mmol/L and a blood pressure of <130/80mmHg. Nevertheless, the key is to provide effective therapy to reduce her overall cardiovascular disease risk, which will involve broader assessment regarding appropriate dietary and lifestyle change. If I had used the CockcroftGault calculation instead of the eGFR, the result would have been 34 instead of 43. Which is the more accurate calculation and should it affect my treatment? There has been significant debate regarding which calculation provides the most accurate estimate of eGFR. One clear advantage of MDRD is that the equation does not require the persons’ weight; eGFR can be calculated using the serum creatinine, age and sex. Both the MDRD and Cockcroft-Gault estimating equations have been found to be accurate when compared with measured GFR in studies How to Treat Quiz INSTRUCTIONS Chronic kidney disease — 2 February 2007 FAX BACK Photocopy form and fax to (02) 9422 2844 1. Which THREE findings are cardinal markers of kidney damage or reduced kidney function? 2 ❏ a) GFR of >60mL/min/1.72m ❏ b) Haematuria ❏ c) Abnormalities on kidney imaging ❏ d) Proteinuria 2. Jim, 63, is a new patient. He has an Anglo-Saxon background, is obese and has had type 2 diabetes and hypertension for 10 years. He rarely attends the doctor. He requests a script for metformin and perindopril. Which THREE aspects of Jim’s history indicate he is at particular risk of renal impairment? ❏ a) Diabetes ❏ b) Treatment with perindopril ❏ c) Age over 50 ❏ d) Hypertension 3. Which THREE findings on examination and office testing are consistent with Jim having chronic kidney disease (CKD)? ❏ a) Pallor ❏ b) Blood pressure of 180/105mmHg ❏ c) +2 protein on dipstick testing ❏ d) Spider naevi 4. If Jim has evidence of CKD, appropriate investigations would include which THREE tests? ❏ a) Serum creatinine and eGFR ❏ b) Plasma aldosterone ❏ c) Spot urine albumin:creatinine ratio (ACR) ❏ d) Renal ultrasound 5. Jim is found to have reduced renal function and a urinary ACR of 20mg/mmol. Which THREE strategies are important in preventing progression of his kidney disease? ❏ a) Blood pressure control with a target of <130/85mmHg ❏ b) Decrease proteinuria with an ACE inhibitor or angiotensin-II-receptor antagonist ❏ c) Weight reduction ❏ d) Optimal glycaemic control 6. Despite working with Jim to put a number of kidney protective strategies in place, his renal function slowly deteriorates. Which THREE other among people with CKD. MDRD appears to be more accurate among elderly and obese people. In general, biological and measurement variability of GFR is greater at higher GFR levels and, for this patient, the MDRD eGFR would provide a reliable estimate of kidney function. General questions for the authors eGFR is now routinely reported. If it is low but the patient is optimally managed, is a diagnosis of chronic renal failure required? Mrs D would be classified as having stage 3 CKD. Even if optimally managed, a diagnosis of CKD is potentially beneficial in her management for the following reasons: ■ CKD is associated with increased CV risk. ■ Concomitant metabolic abnormalities need to be considered, including anaemia, bone disease and acidosis. ■ Priority should be given to avoiding agents with potential kidney toxicity. ■ Progression of disease should be monitored so that if Mrs D’s kidney function deteriorated further she would have adequate time to explore ESKD treatment options with her family, GP and nephrology team. What are the implications of these abnormal eGFRs in the light of insurance medicals? Will they result in excessive unnecessary investigations? Reporting of abnormal eGFRs is unlikely to constitute a major problem in terms of unnecessary investigations relating to insurance medicals. In population terms, advanced age is the strongest predictor of reduced kidney function. For elderly people, insurance medicals are not normally a concern. Young and middle-aged adults might have an unexpected finding of reduced eGFR reported as a result of an insurance medical. For these people, a finding of an eGFR of <60mL/min necessitates further investigation starting with screening for elevated blood pressure, diabetes, protein and blood in the urine. Decisions regarding further investigation can be shaped by these simple tests; however, a finding of significantly reduced kidney function in a younger adult cannot be ignored. Complete this quiz to earn 2 CPD points and/or 1 PDP point by marking the correct answer(s) with an X on this form. Fill in your contact details and return to us by fax or free post. FREE POST How to Treat quiz Reply Paid 60416 Chatswood DC NSW 2067 health problems is he most likely to encounter? ❏ a) Osteoporosis ❏ b) Peptic ulcer ❏ c) Peripheral neuropathy ❏ d) Congestive cardiac failure 7. In which TWO situations would Jim benefit from referral to a nephrologist? ❏ a) An eGFR of 50mL/min ❏ b) eGFR that has declined 12% over a 12-month period ❏ c) Proteinuria 0.5g/24 hours ❏ d) Kidney disease and/or hypertension that proves difficult to control 8. ACE inhibitors and angiotensin-II-receptor antagonists have been associated with which TWO effects? ❏ a) An immediate reduction in serum creatinine ❏ b) Angioneurotic oedema and anaphylaxis ❏ c) Polycythaemia ❏ d) Hypotension 9. When screening for proteinuria, which TWO statements are correct? ❏ a) It is appropriate to screen all Australian ONLINE www.australiandoctor.com.au/cpd/ for immediate feedback adults aged 25 years for proteinuria using dipstick testing ❏ b) People with diabetes should be screened annually for microalbuminuria by spot urinary ACR, ideally using a morning specimen ❏ c) A urinary ACR of 50mg/mmol is classified as microalbuminuria ❏ d) If a spot urinary ACR in a patient with diabetes is elevated, two further specimens should be sent within the next two months to confirm persistent microalbuminuria 10. Which TWO statements about CKD in Australia are true? ❏ a) More than 15,000 Australians with end-stage kidney disease are receiving dialysis or living with a functioning kidney transplant ❏ b) Indigenous Australians living in remote areas are at lower risk of end-stage kidney disease than those in urban areas ❏ c) CKD causes or contributes to about 9% of all deaths in Australia ❏ d) The ‘at risk’ population for CKD is reducing CONTACT DETAILS Dr: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phone: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E-mail: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RACGP QA & CPD No: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .and /or ACRRM membership No: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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