Dr Mark MacGregor discusses the recommendations on diagnosis and management of CKD, which highlight greater monitoring and reduction of associated cardiovascular risk

Kidney disease has traditionally been considered to be rare and complex, and has been managed in secondary care. The chronic kidney disease (CKD) paradigm has transformed that approach, with the understanding that reduced kidney function is common and primarily associated with increased cardiovascular risk. The CKD concept was only published in 2002,1 and yet by 2006 CKD was accepted as treatable in primary care by its inclusion in the quality and outcomes framework.2 This rapid transition has been understandably challenging, and the Scottish Intercollegiate Guidelines Network (SIGN) has therefore produced its guideline on Diagnosis and management of chronic kidney disease3 to support practitioners looking after these patients.

What is chronic kidney disease?

Chronic disease of the kidneys had no precise definition, until the CKD concept was introduced by the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI™).1 This staging system is based on three pieces of information:

  • glomerular filtration rate (GFR)
  • presence of kidney damage, such as proteinuria, haematuria, or structural abnormalities—if the GFR is
    ?60 ml/min/1.73m2 then kidney damage must also be present to fulfil the definition
  • time-course—in order to confirm chronic disease, the reduced GFR and/or kidney damage must be present for >90 days.
  • The SIGN guideline has modified the KDOQI classification by dividing CKD3 into two categories, A and B (see Table 1), recognising that CKD3B carries a substantially increased risk of cardiovascular disease and death compared to CKD3A,3,4 and is more likely to be accompanied by complications. These include:

    • renal anaemia
    • high blood pressure
    • renal mineral and bone disorder.

    Stage CKD3A may require little action other than annual monitoring, particularly in the elderly.

    Addition of the suffix p to the CKD stage has been introduced to denote significant proteinuria (protein–creatinine ratio ?100 mg/mmol, equivalent to ?1 g/day proteinuria). This group are at even greater risk of cardiovascular events, and are also at high risk of deteriorating kidney function: CKD1p indicates greater risk than CKD3A.

    Table 1: The US National Kidney Foundation’s KDOQI classification,1 as modified by SIGN3

    Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood, urine tests, or imaging studies. Note that with a normal or mildly impaired GFR (stages 1 and 2), kidney damage must be present to diagnose CKD, whereas stages 3 to 5 require only a reduced GFR. Reduced GFR and/or kidney damage must be present for >90 days to make the diagnosis of CKD.
    Stage
    Description
    GFR (ml/min/1.73m2)
    1* Kidney damage with normal or raised GFR ?90
    2* Kidney damage with mild decrease in GFR 60–89
    3A Moderately lowered GFR 45–59
    3A

    30–44

    4 Severely lowered GFR 15–29
    5 Kidney failure (end-stage renal disease) <15
    *In order to diagnose stages 1 and 2 CKD, additional evidence of kidney damage must be present, e.g. proteinuria
    If proteinuria (?1 g per day or ?100 mg/mmol) is present, the suffix p should be added)
    Patients on dialysis are classified as stage 5D
    The suffix T indicates patients with a functioning renal transplant (can be stages 1-5)
    KDOQI=Kidney Disease Outcomes Quality Initiative; GFR=glomerular filtration rate; CKD=chronic kidney disease
    Adapted from the National Kidney Foundation, with permission. NKF KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. www.kidney.org/Professionals/Kdoqi/guidelines_ckd/p4_class_g1.htm

    Detection

    Chronic kidney disease is more common with increasing age and is also associated with hypertension, vascular disease, smoking, and lower socio-economic status. Diabetes mellitus can also cause progressive renal failure. Epidemiological studies of CKD are of relatively poor quality, and there is little evidence to support implementation of widespread screening programmes (apart from for patients with diabetes mellitus). Most patients will be identified when kidney function is measured for a clinical indication. Annual monitoring of renal function (serum creatinine and urine albumin–creatinine ratio) is recommended in patients with diabetes mellitus5 and in patients receiving antihypertensive drugs or lipid-lowering agents.6 The Joint British Societies’ guideline on prevention of cardiovascular disease also recommends measuring serum creatinine and urine albumin–creatinine ratio in all hypertensive patients.7

    Implications

    Patients are usually asymptomatic until reaching CKD4. The large majority will never progress beyond CKD3 and so will be unaware of symptoms. So why does CKD matter to the patient? The main consequence of CKD is an increased risk of cardiovascular events, hospitalisation, and death, with a mortality rate of 24% in one CKD3 cohort after 5 years.8 This increased risk remains even after adjustment for numerous other risk factors such as age, presence of diabetes mellitus, and hypertension. The risk appears to increase when the GFR drops below ~75 ml/min/1.73m2, and increases markedly with reducing GFR.9 Longitudinal studies are relatively sparse, but only 1.3% of patients with CKD3 progressed to dialysis over 5 years.8 It is, however, of major importance to identify those with progressive disease early.

    CKD in the elderly

    A substantial proportion of patients with CKD3 are elderly, with 30% of white men over 80 years of age affected.10 Whether this represents normal ageing or pathology remains controversial, but the majority of the elderly have a GFR ?60 ml/min/1.73m2, and in those with no co-morbidity there is very little reduction in GFR. What is perhaps more important is the question whether reduced GFR is associated with increased risk in the elderly. In patients over 75 years old CKD3A may carry little if any additional mortality risk,11 so interventions specifically for CKD should be used with caution, if at all. It is still debated whether intervention improves outcomes in the elderly with CKD.

    Assessment

    Patients may be identified as having CKD for various reasons including abnormal estimated GFR (eGFR), proteinuria, haematuria, or structural kidney disease found on imaging. A baseline assessment is required to estimate the cardiovascular and renal risk, and to identify those needing further investigation and referral. This includes a targeted history to identify risk factors and causes of renal disease, with a particular focus on:

    • medication
    • blood pressure measurement
    • eGFR
    • urine dipstick for blood
    • urine protein–creatinine ratio.

    Serum creatinine leads to under-recognition of renal disease in women and the elderly, because of their reduced muscle mass. The Modification of Diet in Renal Disease (MDRD) study group’s equation allows laboratories to estimate GFR from a serum creatinine without requesting additional information, and although MDRD eGFR is not perfect, it gives a more accurate estimate of GFR in CKD3–5 than serum creatinine or creatinine clearance. It is less accurate in patients with unusually low or high muscle mass. In those patients, 24-hour urinary creatinine clearance may still be of value.

    If an eGFR <60 ml/min/1.73m2 is found for the first time, then a repeat sample should be measured within a week to exclude acute kidney injury. Subsequent samples are required to establish the rate of change of the eGFR. There is no evidence to support specific recommendations, but sampling frequency should be based on clinical judgement of risk, and the measured rate of change. It is recommended that confirmatory samples for staging of CKD are performed on fasting (water allowed) patients to minimise the impact of dietary meat, which falsely reduces eGFR.3

    Dipstick urinalysis does not reliably exclude or confirm a diagnosis of proteinuria. Formal laboratory assessment with protein–creatinine ratio (albumin–creatinine ratio in diabetes mellitus) should be undertaken.3 In asymptomatic patients, there is no need to exclude urine infection. Repeated dipstick urinalysis is still required to assess the presence of non-visible (microscopic) haematuria, as a single dipstick test is not sufficient to indicate pathology.3 This does not need to be confirmed by microscopy.12

    There is no evidence to support routine ultrasound in CKD3, but it is reasonable to use this if renal function is deteriorating or in patients with urinary tract symptoms.

    Referral

    The SIGN guideline makes no recommendations on referral, as this is dependent on local health service structure, but referral should be considered in case of:

    • CKD4–5
    • deteriorating renal function
    • protein–creatinine ratio ?100 mg/mmol
    • the presence of persistent non-visible haematuria.

    Reducing cardiovascular risk

    The core aspect of treating CKD3 is reduction of cardiovascular risk, and the treatments are essentially the same as for the general population. The evidence base is weak, consisting of re-analysis of large studies in other populations at vascular risk, and tends to focus on patients with mild CKD3, who happened to be included in the studies. With those caveats, anti-hypertensive drugs (particularly angiotensin-converting enzyme [ACE] inhibitors) and statins seem to be effective in reducing cardiovascular risk in CKD.

    While microalbuminuria and reduced GFR are both associated with increased cardiovascular risk, it should be remembered that they are not accounted for in cardiovascular risk scores.

    Limiting progression of renal disease

    In patients with significant proteinuria (protein–creatinine ratio ?100 mg/mmol), reducing systolic blood pressure to ?130 mmHg reduces the risk of progression to dialysis. Angiotensin-converting enzyme inhibitors are especially effective at reducing renal risk in type 1 diabetes mellitus with microalbuminuria. Both ACE inhibitors and angiotensin II receptor blockers are effective at reducing renal risk in type 2 diabetes mellitus with microalbuminuria, and also in non-diabetic CKD with proteinuria (protein–creatinine ratio ?50 mg/mmol).3 Statins may reduce renal risk, but the evidence is weak.

    There is no evidence to support interventions to reduce renal risk in non-proteinuric CKD, so cardiovascular risk reduction should remain the focus.

    Complications of CKD

    There is still debate over whether the complications of CKD should be managed in primary or secondary care. Local services should establish their own approach, but joint working between GPs and nephrologists is likely to be necessary.

    Renal anaemia

    Renal anaemia becomes increasingly common as the GFR drops below 30 ml/min/1.73m2. It may occur earlier in patients with diabetes mellitus. Epoetins are effective at correcting renal anaemia, and improve quality of life, but have not been shown to reduce mortality. There are concerns about increased mortality if anaemia is completely corrected, so haemoglobin should be maintained at 100–120 g/l.3 SIGN recommends that epoetins should be considered for all patients with renal anaemia, to improve their quality of life.

    Renal mineral and bone disorder

    This complex disorder involves abnormalities of calcium and phosphate balance, vitamin D, and parathyroid hormone levels. It is known to cause musculoskeletal problems, with pain, muscle weakness, and fractures, but increasingly is thought to contribute to the increased cardiovascular risk of CKD, perhaps mediated by vascular calcification. Abnormalities of serum phosphate and calcium occur relatively late in CKD3B–4, but are preceded by reduced levels of activated vitamin D and rising levels of parathyroid hormone.13 Although drug therapies and other interventions are available, there is little evidence to guide their use.

    Metabolic acidosis

    Metabolic acidosis is uncommon in CKD3, but becomes increasingly common in CKD4 onwards. It causes protein catabolism, bone demineralisation, and may accelerate loss of renal function.3 Treatment is straightforward, with oral bicarbonate administration aiming to normalise the serum venous bicarbonate, but outcome studies are lacking.

    Conclusion

    The SIGN guideline on Diagnosis and management of chronic kidney disease has made relatively few recommendations, reflecting a general lack of evidence—a clear challenge for researchers. However it has taken a clear step towards defining patients who are most at risk from their CKD, and who potentially have most to gain from increased monitoring and more vigorous cardiovascular risk reduction. People with proteinuria are the main focus of importance, and routine monitoring of urine protein–creatinine ratio is now required. Stage CKD3B represents only 20–25% of CKD3 but requires closer and more thorough monitoring. Thinking in terms of lifetime risk should also focus attention on younger adults with CKD3A.

    In the future, more refined estimates of both renal and cardiovascular risk will be required to target interventions effectively.

    References

    1. Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39 (2 Suppl 1): S1–S266. Available online at www.kidney.org/Professionals/Kdoqi/guidelines_ckd/toc.htm
    2. British Medical Association. Revisions to the GMS contract 2006/2007: Delivering investment in general practice. London: BMA, 2006.
    3. Scottish Intercollegiate Guidelines Network. Diagnosis and management of chronic kidney disease. A national clinical guideline. SIGN 103. Edinburgh: SIGN, 2008.
    4. Go A, Chertow G, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351 (13): 1296–1305.
    5. Scottish Intercollegiate Guidelines Network. Management of diabetes. A national clinical guideline. SIGN 55. Edinburgh: SIGN, 2001.
    6. Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease. A national clinical guideline. SIGN 97. Edinburgh: SIGN, 2007.
    7. JBS2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (suppl 5): v1–52.
    8. Keith D, Nichols G, Gullion C et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004; 164 (6): 659–663.
    9. Tonelli M, Wiebe N, Culleton B et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 2006; 17 (7): 2034–2047.
    10. Clase C, Garg A, Kiberd A. Estimating the prevalence of low glomerular filtration rate requires attention to the creatinine assay calibration: Reply from the authors. J Am Soc Nephrol 2002;13: 2812–2816.
    11. Raymond N, Zehnder D, Smith S et al. Elevated relative mortality risk with mild-to-moderate chronic kidney disease decreases with age. Nephrol Dial Transplant 2007; 22: 3214–3220.
    12. Prepared on behalf of the Renal Association and British Association of Urological Surgeons. Joint consensus statement on the initial assessment of haematuria. RA, BAUS, 2008.
    13. Vassalotti J, Uribarri J, Chen S et al; Kidney Early Evaluation Program Investigators. Trends in mineral metabolism: Kidney Early Evaluation Program (KEEP) and the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Kidney Dis 2008; 51 (4 Suppl 2): S56–68. G
    Click here for CPD questions on this article and the SIGN guideline on the diagnosis and management of chronic kidney disease
    • This guideline identifies cohorts of patients with CKD who are at higher risk of complications
    • Targets in the QOF do not reflect the detail of this guidance
    • Referral thresholds are not proscribed—PBC groups should consider agreeing local referral guidelines and pathways with local nephrologists
    • For those at higher risk—consider employing community specialist renal nurses to ensure they are treated to target (this could save referral costs)
    • The main costs in treating CKD to this guideline are the costs of primary care staffing and antihypertensive drugs (available generically except angiotensin II receptor blockers). Epoetins also represent a significant cost
    • Tariff costs nephrology outpatient = £194 (new), £96 (follow up)