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Management of Chronic Kidney Disease

Charlie Tomson, DM, FRCP; Pippa Bailey, MRCP, DTM&H

Management of chronic kidney disease (CKD) requires a systematic approach that includes all components of the chronic disease model. Some causes of CKD require specific additional management directed at the underlying cause.

Principles of Chronic Disease Management

Chronic kidney disease (CKD) is a prime example of a chronic disease requiring life­long management, involving the patient, the primary care team and specialists. Most people with CKD also have other long­term conditions (hypertension, cardiovascular disease, diabetes mellitus, atherosclerosis). Current disease­based clinical services (eg, nephrology clinics, hypertension clinics, diabetes clinics, heart failure clinics) seldom provide optimal care, with poor communication occurring between these ‘silos’ of care, and between hospital­based clinics, the primary care team, and the patient.

This lack of integration is harmful and can contribute to patients’ loss of control and to conflicting messages on what drug treatment the patient should be taking. The system is also wasteful, with much duplication of effort, tests, and wasted travel time. Research on systematic attempts to achieve improvement in the delivery of care for patients with chronic diseases has resulted in development of a framework, the ‘chronic care model’. Improvement is more likely if each component of the organization of care (self­management; decision support; delivery system design; clinical information systems) is addressed, and unlikely if, for instance, improvement efforts are confined to a hospital­based clinic. 1,2 Many of the components of the model, including national guidelines on identification, management and referral, are already in place for CKD. 3

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Early CKD is largely asymptomatic, so a balance has to be struck between ‘labelling’ patients as having ‘chronic kidney disease’ and ensuring that patients who are at increased risk of cardiovascular disease or progressive loss of kidney function are identified and offered the options of treatment that will reduce these risks.

Diagnosis of CKD

In this article, CKD will be defined according to the five­stage classification adopted in the UK. 3,4 This classification endorses the use of the four­variable Modification of Diet in Renal Disease (MDRD) equation to estimate normalized glomerular filtration rate (GFR) from serum creatinine, age, gender, and racial origin. The estimate provided by the laboratory should be used wherever possible, as this should include correction factors for the type of creatinine assay used. 4,5

Some patients will have other evidence of chronic kidney damage, such as:

• persistent microalbuminuria; • persistent proteinuria; • persistent haematuria (after exclusion of other causes, eg, urological disease); • structural abnormalities of the kidneys demonstrated on ultrasound scanning or other

radiological tests (eg, polycystic kidney disease, reflux nephropathy); or • biopsy­proven chronic glomerulonephritis (most of these patients will have

microalbuminuria or proteinuria, and/or haematuria).

In February 2007, a consensus conference in the UK 6 approved two enhancements to this five­ stage classification; dividing stage 3 CKD into stage 3A (estimated GFR [eGFR] 45–59) and stage 3B (eGFR 30–44), and adding the suffix ‘p’ to the GFR­based stage for patients with proteinuria (random urine protein to creatinine ratio > 100 mg/mmol).

These changes are endorsed by the National Institute for Health and Clinical Excellence (NICE), 4 the Scottish Intercollegiate Guidelines Network (SIGN) 7 and the American National Kidney Framework’s National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) guidelines. 8 Proteinuria should be assessed by measurement of either the urinary protein to creatinine or albumin to creatinine ratio. 9 Adoption of this enhanced classification system is likely to focus greater attention on those patients in stage 3 CKD, who are at greatest risk of complications of CKD and progressive loss of kidney function.

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Limitations of MDRD and the CKD­EPI Formula

There are many limitations to the use of the MDRD formula to estimate renal function. First, the formula is less accurate when the GFR is more than 60 mL/minute/1.73 m 2 . Second, its use has not been fully validated in the elderly, children or pregnant women, acute kidney injury (AKI), extremes of body size, or in ethnic groups other than Caucasians and African­Americans. There is therefore ongoing work to find a more accurate estimation of renal function than that offered by the MDRD; as a result, the CKD­EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was published in May 2009.

Preliminary work suggests that the CKD­EPI equation performs better (with less bias and greater accuracy) than the MDRD formula, especially at higher GFRs, but it has not been extensively validated in the elderly or in ethnic minorities. The formula is more complex to compute than the MDRD formula, and has not yet been adopted by UK laboratories for routine reporting of eGFR.

Specific Causes of CKD

Some cases of CKD are attributable to specific diseases, for which specific treatments are sometimes available to reduce the risk of progressive kidney damage. However, most patients with these well­defined causes of CKD will also benefit from the non­specific interventions discussed below.

Non­specific Causes of CKD

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Many patients with reduced GFR do not have proteinuria, radiological abnormalities or other markers that suggest a specific underlying cause; in particular, elderly patients with reduced GFR commonly have no proteinuria. 10

There is controversy about the assessment of renal function in the elderly and how renal function changes as part of ‘normal ageing’. 11 The MDRD formula is not as well validated in the elderly, and any creatinine­based formula that incorporates assumptions about muscle mass at different ages will face the same problems. The apparent high prevalence of CKD in the elderly may occur because of:

• the presence of numerous risk factors for CKD, such as diabetes and hypertension; • an age­associated decline in kidney function that is not explained by other known risk

factors; or • inaccuracy of creatinine­based estimating equations in the elderly population.

The Baltimore Longitudinal Study of Aging (BLSA) suggested that on average kidney function tends to decline with age even without co­morbidities, but this decline did not appear to be inevitable. 12 The majority of CKD in the elderly is non­progressive, and research is needed to identify those at risk of developing established renal failure. The increased relative risk for death associated with lower GFR (mostly due to cardiovascular disease) is more evident in younger people than in older people, largely because of fewer competing risks in younger people; patients aged over 75 years with moderate eGFR 45–60 mL/minute/1.73 m 2 were at no higher risk of death over 1–3 years’ follow­up than their age peers with levels of eGFR above 60 mL/minute/1.73 m 2 . 13

Reducing the Risk of Progressive Loss of GFR

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In addition to specific therapy targeted at the underlying primary disease, recognition of the role of several modifiable secondary factors associated with progressive kidney damage is important clinically, as these can be treated effectively thereby minimizing renal injury. Most of these interventions also reduce the risk of cardiovascular disease.

Systemic Hypertension

The two main goals of antihypertensive therapy are cardiovascular disease risk modification and reduction of risk of progressive decline in GFR.

There is strong evidence that high blood pressure (BP) is associated with increased risk both of cardiovascular disease and of progressive kidney disease, and that these risks are higher amongst people with diabetes than in non­diabetic subjects at any given level of kidney function.

Several randomized controlled trials have shown that the risks of cardiovascular events and progressive kidney disease are reduced by BP­lowering treatment. However, studies comparing different intervention thresholds, different BP ‘targets’, and different strategies for patients with varying degrees of proteinuria, co­morbidity, and conduit artery compliance or pulse pressure are still required. Two important studies ‘targeted’ mean arterial pressure rather than systolic or diastolic, 14,15 in contrast to current clinical practice. Many of the existing guidelines, therefore, are based on post hoc analyses of randomized controlled trials and observational studies, and of ‘translation’ of mean arterial pressures into systolic and diastolic pressures. As a result, there is considerable confusion between the various guidelines and audit measures currently used in the UK. We suggest following the recommendations by the Renal Association and NICE (Figure 1).

According to British Hypertension Society guidelines and NICE guidance, the threshold BP for intervention is 140/90 mm Hg for patients with CKD without diabetes, and 130/80 mm Hg for patients with CKD and diabetes. The target BP to be achieved is determined by the degree of proteinuria present. In people with CKD and a urine protein to creatinine ratio of 100 mg/mmol or lower, the target BP is systolic blood pressure less than 140 mm Hg (target range 120–139 mm Hg) and the diastolic blood pressure below 90 mm Hg. In patients with CKD and a urine protein to creatinine ratio more than 100 mg/ mmol, and for all patients with CKD and diabetes, aim to keep the systolic blood pressure below 130 mm Hg (target range 120–129 mm Hg) and the diastolic blood pressure below 80 mm Hg. 4 Patients with proteinuria higher than 1 g/day may benefit from more rigorous BP control (< 125/75 mm Hg). Reduction of proteinuria is an additional therapeutic goal; dietary salt restriction amplifies the antiproteinuric effect of antihypertensive therapy. 16

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Currently, there is no good evidence to suggest that lowering BP below standard targets reduces mortality or morbidity. 17,18 There is some evidence that intensive BP lowering is of benefit in those who are high risk for cerebrovascular events, but in other patient groups a lower target BP may be harmful because of impaired perfusion of vital organs; these include patients who are at high risk of falls, especially those with postural hypotension, and those with concomitant coronary artery and peripheral vascular disease. 19 Patients with multiple co­ morbidities are unlikely to have been included in most of the informative randomized controlled trials. It is clear that antihypertensive therapy should be individualized for patients, having assessed the risks and benefits of intensive versus standard BP control, and taken into account the patient’s attitude to risk and medication. Given that arterial blood pressure is just one of several risk factors for cardiovascular and kidney disease, it would be more logical to adopt a ‘risk­based’ approach rather than one based on separate thresholds for blood pressure, serum cholesterol, etc; using this approach, more intensive treatment to reduce blood pressure (and other risk factors) would be recommended for patients at higher risk. This transition to a risk­ based approach to risk factor modification is under way in many national and international guideline groups; it is likely to result in more coherent guidelines that will allow patients and their physicians to use the evidence base to come to shared decisions on which treatments to use. Such an approach is likely also to improve adherence to treatment.

Choice of Anti­hypertensive Agents

ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) afford significant renal protection, in addition to that attributable to blood pressure lowering, and should be used as

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firstline agents in all patients with diabetes (with or without evidence of albuminuria), 20 in non­ diabetic kidney disease with proteinuria (random urine protein to creatinine ratio > 100 mg/mmol) 21 and in those with heart failure. 22

The role of ACEIs and ARBs in non­diabetic kidney disease with less severe proteinuria is not as well established; although there is good evidence that these drugs reduce albumin excretion, 23 the benefits in terms of ‘hard’ clinical outcomes have not been established. In the absence of diabetes and/or albuminuria/proteinuria, the NICE Clinical Guideline 34 for hypertension should be consulted. Many patients need more than one agent to achieve target BP goals. Non­dihydropyridine calcium channel blockers, such as verapamil and diltiazem, have additional antiproteinuric effects and are preferred to the dihydropyridine agents, which may increase proteinuria. Many patients with CKD are fluid overloaded and may benefit from concomitant diuretic therapy, preferably a loop diuretic, as thiazide diuretics are less effective at GFR less than 30 mL/minute/1.73 m 2 .

β­Blockers, α­blockers and sympathetic antagonists may be needed in patients with resistant hypertension (ie, BP > 150/90 mm Hg despite three classes of antihypertensive agents).

Combination ACEI and ARB Therapy

There is some evidence that combination ACEI and ARB therapy offers a greater reduction in proteinuria compared with monotherapy. 24 However, the CO­OPERATE study, which appeared to support dual therapy, has now been withdrawn after the results of an academic investigation indicated serious concerns surrounding this publication. 25 The ONTARGET study suggests that combination therapy should be used with caution, especially in patients with vascular disease, owing to the greater risk of hypotensive symptoms, syncope and renal dysfunction. 26 An international, double­blinded, randomized, controlled trial is ongoing to assess the effect of combination reninangiotensin system blockade on CKD in diabetics. 27 Owing to the risks of serious adverse effects, dual blockade with an ACEI and an ARB should only be initiated under specialist supervision.

Patients commencing therapy with ACEIs or ARBs should have their serum creatinine and potassium checked within 2 weeks of initiation of therapy and after every increment in dosage. If the serum creatinine rises by more than 30% or the GFR falls by more than 25% from baseline, alternative causes of a deterioration in renal function should be investigated, dosage reduced to that previously tolerated or the agent withdrawn, and an alternative antihypertensive agent deployed. A significant fall in kidney function during ACEI/ARB inhibition can indicate haemodynamically significant renal artery narrowing, but the selection of patients who will benefit from revascularization remains problematic.

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Reduction of Intraglomerular Hypertension

Proteinuric CKD (including diabetic nephropathy) is typically characterized by intraglomerular hypertension, caused by alterations in the regulation of vascular tone in the afferent and efferent glomerular arterioles, permitting greater transmission of systemic pressure to the glomerulus.

This increase in intraglomerular pressure is thought to be a major cause of progressive glomerular damage.

Although reduction of systemic BP helps to limit damage, some antihypertensive drugs (including ACEIs, ARBs, and non­dihydropyridine calcium channel blockers) directly reduce intraglomerular pressure by selective vasodilatation of the efferent arterioles, whereas others (including dihydropyridine calcium channel blockers) may increase intraglomerular pressure and worsen proteinuria. The benefits of ACEI/ARB treatment are, therefore, more evident if systemic blood pressure remains higher than optimal. 28

Inhibition of Renal Fibrosis

ACEIs and ARBs may have additional beneficial effects in progressive CKD, by inhibiting the actions of angiotensin II on glomerular permeability and tubulo­interstitial fibrosis. Several targets for anti­fibrotic agents have been validated in cellular and animal studies, but progress in translating these results to clinical practice has been disappointing. Nevertheless, drugs targeting the pathways of TGF­β, connective tissue growth factor, platelet­derived growth factor, Ki­Ras and NF­KB are all possible future therapeutic agents. 29

Smoking Cessation

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Population­based studies have shown an association between tobacco smoking and increased incidence of CKD. Smoking has also been shown to increase the risk of progression of CKD to end­stage renal disease (ESRD), an effect independent of the primary renal disease. There is evidence that cessation of smoking reduces loss of kidney function amongst patients with progressive CKD.

Correction of Obesity

Weight loss has been shown to ameliorate obesity­induced glomerular hyperfiltration, and to decrease proteinuria in patients with chronic proteinuric nephropathies. Weight loss also reduces blood pressure, and the reductions are larger in patients taking antihypertensive treatment. Lastly, weight loss can improve glycaemic control amongst people with diabetes mellitus. 30

Glycaemic Control

The Diabetes Control and Complications Trial (DCCT) and the UKPDS trial provided evidence that improved glycaemic control prevents the development of microalbuminuria as well as other microvascular complications in patients with type 1 and 2 diabetes mellitus; long­term follow­up suggests that improved glycaemic control may have long­term beneficial effects on macrovascular disease as well. 31 It is less clear whether improved glycaemic control slows down progressive renal injury once overt proteinuria has developed.

The target HbA1c for patients with CKD and diabetes continues to be debated. Although two large trials have found that intensive glucose control (target HbA1c < 6.5%; < 47 mmol/mol) compared with standard glucose control is associated with a reduction in new­onset microalbuminuria and macroalbuminuria, 32,33 and a reduction in the development of new or worsening nephropathy, 32 in neither trial did intensive control have an effect on the doubling of serum creatinine. Intensive control is also associated with an increased risk of hypoglycaemia, 33 which is associated with an increased risk of death. 34 We would advise that clinicians individualize therapy after discussion with patients, taking into account life expectancy, overall cardiovascular and renal risk, aiming for a target HbA1c of less than 7.5% (< 58 mmol/mol) for most.

Treatment of Dyslipidaemia

Dyslipidaemia is a risk marker for progressive kidney injury and a risk factor for cardiovascular disease. Current evidence that treatment of dyslipidaemia reduces CKD progression is mostly restricted to post hoc subgroup analyses from large cardiovascular clinical trials, such as the Heart Protection study and the Cholesterol and Recurrent Events (CARE) study, where renal function was not the primary outcome studied. Results from the Study of Heart and Renal Protection trial (SHARP) have recently provided evidence that reducing serum LDL cholesterol (using a combination of simvastatin and ezetimibe) significantly reduced the incidence of ‘major atherosclerotic events’ (myocardial infarction, stroke and revascularization), with no adverse effects. 35 The size of the risk reduction was similar in patients with CKD and in patients on dialysis. Previous trials of cholesterollowering therapies in patients with kidney disease 36,37 were not able to demonstrate benefit, possibly because they lacked power or included a large number of non­atherosclerotic cardiovascular events, such as sudden cardiac death and haemorrhagic stroke—particularly common in patients with established renal failure. The SHARP study

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showed no significant difference in the number of patients with CKD reaching established renal failure.

Pharmacological Management

Many water­soluble drugs are cleared by the kidney and accumulate in CKD as a result of impaired excretion. For drugs with a high therapeutic index, reduced excretion is seldom a problem in stage 3 CKD, but can become important in stages 4 and 5. When using an estimate of GFR to decide on drug dosage adjustments in patients at the extremes of body size, it is also important to remember that the MDRD formula gives a normalized estimate of GFR (ie, what the GFR would be if the patient had a ‘normal’ body surface area of 1.73 m 2 ; this is the best overall measure of the adequacy of renal excretory function, because metabolic rate—thus the need for excretion of waste products—varies with body size).

Actual GFR (which determines drug clearance) may be significantly lower than normalized GFR in small patients, and vice versa. Formula­based estimates of GFR should not, therefore, be used to adjust the dose of renally excreted drugs with a low therapeutic index.

The use of metformin presents particular problems, given the frequency with which CKD is found amongst people with type 2 diabetes. Metformin can cause type 2 lactic acidosis, and the risk of this very rare complication is probably greater amongst patients with reduced GFR. For this reason, the summary of product characteristics suggests that the drug is avoided in patients whose serum creatinine concentration is >150 μmol/L. However, this corresponds to an eGFR of 67 mL/ minute/1.73 m 2 in a young black man, but to an eGFR of 33 mL/minute/ 1.73 m 2 in an elderly white female.

This illustrates the dangers of using serum creatinine concentration as the basis for drug dosage adjustment. It would be preferable to reach a decision that balances risk and benefit for each patient, based on the best available estimate of that patient’s actual GFR.

Nephrotoxic drugs are more likely to cause a clinically important reduction in GFR if GFR is already significantly reduced.

Avoiding Haemodynamic Insults

The ‘classical’ model of progressive, proteinuric CKD (for which diabetic nephropathy is the exemplar) does not fully explain the epidemiology of CKD; in particular, it is inconsistent with the frequency of stable stage 3 and 4 CKD.

The existence of so many patients with stable but significant kidney damage suggests an alternative model, in which kidney function deteriorates as a result of a series of step­wise ‘hits’ caused by episodes of nephrotoxicity, renal underperfusion, or renal atheromatous embolism. Clinical management of patients with CKD should, therefore, include precautions to minimize the risk of such insults. Patients taking ACEIs or ARBs should be advised to stop these temporarily during episodes of diarrhoea and/or vomiting, and during severe sepsis. Even more care should be taken in patients taking combinations of ARBs and ACEIs, as these agents significantly reduce the autoregulation of renal blood flow during episodes of renal underperfusion.

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Treatment of Acidosis

There is increasing evidence from a number of small trials that alkali therapy in the form of sodium bicarbonate or sodium citrate slows the rate of progression of renal failure, delays the development of established renal failure and improves nutritional status. 38–40 Although larger, randomized, controlled trials are required to support this, alkali therapy appears to be of benefit at all stages of CKD regardless of the presence or absence of metabolic acidosis. 40 Supplementation with sodium bicarbonate (typically 1.5–3.0 g/day) is reasonable.

An approach to common ‘uraemic’ symptoms is outlined in Table 1.

Follow­up and Preparation for Renal Replacement Therapy

Patients with CKD should be offered life­long follow­up to ensure optimal management (as set out above) and to monitor changes in kidney function.

Suggested frequency of follow­up is given in Table 2.

The great majority of patients with CKD stage 3 will not progress to established renal failure and, even among CKD stage 4 patients, death from cardiovascular disease is more frequent than progression to established renal failure. However, there is evidence that patients who require renal replacement therapy have increased morbidity and reduced survival, and are more expensive to manage if they present to a nephrologist late in their illness. 41,42 It is essential that those who are at risk of progressive decline in renal function are identified early and referred to secondary care. NICE recommends that the following patients should be referred to a consultant nephrologist 4 :

• stage 4 or 5 CKD; • heavy proteinuria (urine albumin to creatinine ratio ≥ 70 mg/mmol; urine protein to

creatinine ratio ≥ 100 mg/mmol) unless known to result from diabetes and already appropriately treated;

• proteinuria (urine albumin to creatinine ratio ≥ 30 mg/mmol; urine protein to creatinine ratio ≥ 50 mg/ mmol) if accompanied by haematuria;

• rapidly declining eGFR (> 5 mL/ minute/1.73 m 2 in 1 year, or > 10 mL/ minute/1.73 m 2 within 5 years);

• hypertension that remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic dosage;

• people with or suspected of having rare or genetic causes of CKD; • suspected renal artery stenosis.

Declaration of Interests

None.

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About the Author

Charlie Tomson is a Consultant Nephrologist at North Bristol NHS Trust, UK. As Chair of the Joint Specialty Committee on Renal Medicine of the Royal College of Physicians of London and the Renal Association, he led the development of UK guidelines for the Identification, Management, and Referral of Adults with Chronic Kidney Disease. His research interests include the causes of premature cardiovascular disease in patients with kidney disease, and quality improvement in healthcare. He is currently President of the Renal Association. Pippa Bailey is an Academic Clinical Fellow in Nephrology at Southmead Hospital, Bristol, UK.