KHA‐CARI Guideline: Early chronic kidney disease: Detection, prevention and management

This guideline addresses issues relevant to the detection, primary prevention and management of early chronic kidney disease. Chronic kidney disease (CKD) is a major public health problem in Australia and throughout the world. Based on data from the Ausdiab study,1 it is estimated that over 1.7 million Australian adults have at least moderately severe kidney failure, defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m2. This pernicious condition is often not associated with significant symptoms or urinary abnormalities and is unrecognized in 80–90% of cases.1-3 CKD progresses at a rate that requires approximately 2300 individuals each year in Australia to commence either dialysis or kidney transplantation.4 Furthermore, the presence of CKD is one of the most potent known risk factors for cardiovascular disease (CVD), such that individuals with CKD have a 2- to 3-fold greater risk of cardiac death than age- and sex-matched controls without CKD.5-7 According to death certificate data, CKD directly or indirectly contributes to the deaths of approximately 10% of Australians and is one of the few diseases in which mortality rates are worsening over time.8 However, timely identification and treatment of CKD can reduce the risks of CVD and CKD progression by up to 50%.9 Early detection of CKD may therefore have value, although criteria for a screening programme to detect the disease must be met to balance the aggregate benefits with the risks and costs of the screening tests. General practitioners, in particular, play a crucial role in CKD early detection and management. All people attending their general practitioner should be assessed for CKD risk factors as part of routine primary health encounters. A number of studies10-20 have further demonstrated that early referral of patients with more serious CKD to a multidisciplinary renal unit is associated with reduced rates of kidney failure decline, decreased need for and duration of hospitalization, increased likelihood of permanent dialysis access created prior to dialysis onset, reduced initial costs of care following the commencement of dialysis, increased likelihood of kidney transplantation, and decreased patient morbidity and mortality. Nevertheless, approximately one-quarter of CKD patients in Australia are referred ‘late’ to nephrologists (i.e. within 3 months of needing to commence kidney replacement therapy).4 Such ‘late referred’ patients have markedly reduced survival rates on dialysis and are much less likely to receive a kidney transplant.21 The objective of this guideline is to identify what risk factors, present in an appreciable portion (>5%) of the community, are associated with the development of CKD and which are remediable or potentially modifiable, in order to detect early CKD and intervene at the earliest possible stage. Also, evidence regarding outcomes and complications of CKD is evaluated with particular emphasis on outcomes and symptoms that are likely to be deemed significant by people diagnosed with early stage of CKD. The role and cost-effectiveness of screening for CKD, the target population, setting and screening strategies are also addressed. Recommended screening algorithm for detection of CKD (chronic kidney disease). Sources: The Royal Australian College of General Practitioners (RACGP) ‘Red Book’ Taskforce.22 National Aboriginal Community Controlled Health Organisation (NACCHO/RACGP).23 ACR, albumin : creatinine ratio; eGFR, estimated glomerular filtration rate. *It is important to note that intra-individual variation in eGFR readings can be as high as 15–20% between consecutive eGFR measurements, such that a number of readings are required before one can be confident that a decrease in eGFR of >5 ml/min per 1.73 m2 in 6 months is real. Chronic kidney disease is associated with considerable morbidity and increased mortality risk. Biochemical evidence of CKD (reduced estimated GFR, elevated serum creatinine) usually indicates the presence of tubulointerstitial fibrosis within the kidney. Such pathology is irreversible, therefore the aim of treatment in many patients with CKD is to delay progression of disease rather than achieve a cure. In light of this it is clear that implementation of primary prevention measures to avoid development of CKD is a preferable strategy. While much information is available about risk factors for development of CKD (refer to Early CKD CARI Guideline Part I) it is less clear whether risk factor modification prevents development of CKD. In addition to primary prevention strategies, the needs of patients and their families to access CKD education and information tailored to the stage and cause of CKD, has been highlighted by some studies. White et al.25 conducted a cross sectional survey of participants of the AusDiab study to assess the level of awareness of the causes of kidney disease. The results indicated an overall low level of awareness of risk factors for kidney disease and low level of recall of kidney function testing even among subgroups of the cohort who were at greatest risk of CKD.25 A study by Ormandy et al.26 found that CKD patients had clear information needs, which changed according to their CKD stage. Moreover, Nunes et al.27 reported disparity between perceived knowledge and objective knowledge in patients with CKD. Although information is crucial to knowledgeable decision-making by patients, how it is provided is also very important. Successful contemporary educational interventions for people with a chronic disease typically incorporate psychological methods to empower patients and change behaviour.28 The aim of this guideline was to evaluate currently available clinical evidence of interventions relevant to lifestyle modification, patient education, elevated blood pressure, diabetes mellitus, referral to multidisciplinary care and the effect of pregnancy in the primary prevention of CKD. In this guideline prevention of CKD is defined as a normal serum creatinine, eGFR above 60 mL/min and absence of urinary albumin, protein or haematuria. *SI units recommended as per The International HbA1c Consensus Committee.29, 30 Patients with diabetes should be referred to other professionals specializing in diabetes (e.g. diabetologist, diabetes educator and dietician) as soon as practicable. Note: Chronic kidney disease is a significant contributor to morbidity and mortality, and represents a major expense to the healthcare system. Early intervention with appropriate medical therapies is essential to address this public health burden and may reduce the progression of CKD and cardiovascular risk by up to 50%.9 Important risk factors for CKD include diabetes mellitus, hypertension, obesity and smoking. Modification of lifestyle habits (e.g. healthy diet, physical exercise, smoking cessation, moderate alcohol consumption and weight loss in obese people) may therefore be of value in retarding the progression of CKD. In addition, restriction of dietary protein31 and augmentation of fluid intake32 have been recommended as a treatment for retarding CKD progression for over 50 years. While the National Health and Medical Research Council (NHMRC) Dietary Guidelines for Australian Adults (http://www.nhmrc.gov.au/guidelines/publications/n29-n30-n31-n32-n33-n34) provide useful generalized, evidence-based information about healthy food choices, patients with CKD often require individualized diet prescription by an appropriately qualified dietitian. Diabetes mellitus, particularly type 2, is increasing in prevalence and associated with significant cardiovascular morbidity and mortality. It also represents the leading cause of CKD worldwide. Evidence from large, prospective trials indicates that tight glycaemic control in type 133 and, to a lesser extent, type 234, 35 diabetic patients results in clinically significant preservation of renal function. The optimal level to which glycosylated haemoglobin (HbA1c) should be targeted (<7.0%) is largely based on the Diabetes Control and Complications Trial (DCCT) and UKPDS trials33-35 but the threshold below which the benefit is lost or at which the incidence of side-effects becomes unacceptable is not clear. Chronic kidney disease is also a well-established independent cardiovascular risk factor. Evidence36, 37 for anti-platelet therapy suggests that low-dose aspirin reduces the risk of CVD by 25–33%, particularly in patients with established CVD (secondary prevention) or those at high risk (primary prevention). However, these potential benefits need to be weighed against an increased risk of bleeding in CKD.38 With regard to blood pressure management new evidence reviewed in this updated guideline has led to an upward revision of the recommended BP targets. These new targets are in line with those recommended by the NHMRC.39 There are a number of epidemiological studies40, 41 which have established that asymptomatic hyperuricaemia is associated with both CKD and ESKD. However, hyperuricaemia is a ubiquitous finding in CKD42 and could be a consequence of reduced excretion, diuretic therapy, or oxidative stress. Although it is not clear whether urate plays a causative role or is an indirect marker of kidney function, uric acid lowering therapy has emerged as a potentially novel therapeutic treatment for slowing the progression of CKD.41 In the CKD population, both vitamin D deficiency and insufficiency are common. As GFR falls, hydroxylation/activation of vitamin D is impaired leading to hyperparathyroidism and CKD mineral and bone disorder (CKD-MBD). Retention of phosphate may begin to occur when renal function falls below 80% of normal. Changes in any of these laboratory values may begin in stage CKD 3, although the presence, rate of change and severity of these abnormal parameters are highly variable among individuals. In a study of 168 consecutive new referrals of patients with stages 2–5 CKD to a CKD clinic, Ravani et al.43 observed that both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin-D levels were significantly, inversely associated with eGFR. Consequently, the prevalence rates of vitamin D insufficiency and deficiency increased from 62% and 25% in stage 2 CKD to 88% and 56% in stage 5 CKD. Similarly, a cross-sectional study of 15 068 adults participating in the Third National Health and Nutrition Examination Survey (NHANES) reported a strong, inverse association between albuminuria and serum 25-hydroxyvitamin D concentrations.44 The objective of this guideline is to review currently available evidence with regards to medical therapies for the management of: hypertension, hypercholesterolaemia, diabetes mellitus, CVD, hyperuricaemia and vitamin D insufficiency and deficiency in patients with stage 1–3 CKD. Evidence for lifestyle modification and nutrition is also reviewed. *SI units recommended as per The International HbA1c Consensus.29, 30 Note: Few foods contain significant amounts of vitamin D, the major sources being fatty fish (salmon, sardine, herring and mackerel), liver, eggs and fortified foods, such as margarine and some varieties of low-fat milk. There are limited data on vitamin D content of local foods. It is exceedingly difficult to obtain sufficient vitamin D from the diet alone. Emelia Atai, Graeme Turner, Kate Wiggins, Maria Chan, Tim Usherwood, Clodagh Scott and Nigel Toussaint have no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by KHA-CARI. Richard Phoon has a level II b. conflict of interest for receiving speaker fees and honoraria from several companies related to anaemia, CKD-MBD and cardiovascular disease between 2008 and 2010. David Johnson has a level II b. conflict of interest for receiving speaker honoraria and advisor's fees from several companies related to anaemia, CKD-MBD, hypertension and cardiovascular disease between 2008 and 2012.