Clinical Topic A-Z Clinical Speciality

Chronic kidney disease - not diabetic

Chronic kidney disease - not diabetic
D051436Renal Insufficiency, Chronic
D007674Kidney Diseases
CardiovascularEndocrine and metabolicKidney disease and urology
2009-07-27Last revised in July 2009

Chronic kidney disease - not diabetic - Summary

Chronic kidney disease (CKD) is said to be present when there is persistent impairment of kidney function, or evidence of kidney damage (for example proteinuria, haematuria, biopsy-proven glomerulonephritis or a structural abnormality of the kidney).

The classification of CKD is as follows:

Stage 1: eGFR 90 or greater. Normal or increased eGFR, and kidney damage.

Stage 2: eGFR 60–89. Slight decrease in eGFR, and kidney damage.

Stage 3A: eGFR 45–59. Moderate decrease in eGFR, with or without other evidence of kidney disease.

Stage 3B: eGFR 30–44. Moderate decrease in eGFR, with or without other evidence of kidney disease.

Stage 4: eGFR 15–29. Severe decrease in eGFR, with or without other evidence of kidney disease.

Stage 5: eGFR less than 15. Established renal failure (end-stage renal disease).

A reduced eGFR is associated with hypertension, anaemia, renal bone disease, malnutrition, neuropathy, and lipid abnormalities.

The eGFR should be measured on a regular basis (frequency of testing depends on the stage).

A test for proteinuria should be done every 12 months regardless of stage of CKD.

For people with stage 4 and 5 CKD, the haemoglobin level (to exclude anaemia), and serum calcium, phosphate, vitamin D, and parathyroid hormone should also be measured. Frequency of subsequent monitoring will depend on the results and clinical circumstances.

People with CKD should be encouraged to:

Stop smoking (if appropriate).

Drink alcohol sensibly.

Take regular exercise, eat healthily and achieve a healthy weight.

Avoid using over-the-counter nonsteroidal anti-inflammatory drugs (except on medical advice).

The blood pressure which should ideally be aimed for in people with CKD is:

Systolic blood pressure less than 140 mmHg (target range 120–139 mmHg).

Diastolic blood pressure less than 90 mmHg.

The blood pressure which should ideally be aimed for in people with CKD and a urinary albumin creatinine ratio of 70 mg/mmol or more is:

Systolic blood pressure less than 130 mmHg (target range 120–129 mmHg).

Diastolic blood pressure less than 80 mmHg.

An angiotensin-converting enzyme (ACE) inhibitor should be offered to people with CKD if there is:

Hypertension and proteinuria with a urinary albumin:creatinine ratio of 30 mg/mmol or more, or

Proteinuria with a urinary albumin:creatinine ratio of 70 mg/mmol or more (irrespective of blood pressure).

Antiplatelet and statin treatment should be offered as for the rest of the population.

Referral is required (urgency dependent on clinical judgement) if there is:

Acute renal failure.

Heavy proteinuria (urinary albumin:creatinine ratio 70 mg/mmol or more).

Proteinuria (urinary albumin:creatinine ratio 30 mg/mmol or more) with haematuria.

Uncontrolled hypertension.

Suspected or known genetic cause of CKD.

Suspected renal artery stenosis.

Rapidly declining eGFR.

Complications such as anaemia or renal bone disease.

Stage 4 or 5 disease.

Have I got the right topic?

216months3060monthsBoth

This CKS topic is based on the National Institute for Health and Care Excellence guidance Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care [NICE, 2008].

This CKS topic covers the identification and management of chronic kidney disease in adults.

This CKS topic does not cover the management of people with diabetes and chronic kidney disease (see the CKS topic on Diabetes - type 2 for information).

This CKS topic does not cover the detailed management of the complications of chronic kidney disease (such as anaemia and bone osteodystrophy).

There are separate CKS topics on Anaemia - iron deficiency, and Lipid modification - CVD prevention.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in July 2009

December 2013 — minor update. Prescribing information has been updated in line with the Summary of Product Characteristics for perindopril [ABPI Medicines Compendium, 2013].

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic [BMA and NHS Employers, 2013].

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

March 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic [BMA and NHS Employers, 2012]. Issued in April 2012.

May 2011 — minor update. The 2011/2012 QOF indicators and the 2010/2011 QIPP options for local implementation have been added to this topic [BMA and NHS Employers, 2011; NPC, 2011]. Issued in June 2011.

March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

January to July 2009 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

Guidelines published since the last revision of this topic:

BTS (2010) Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax 65(6), 559-570. [Abstract]

Moyer, V.A. (2012) Screening for chronic kidney disease: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine 157(8), 567-570. [Abstract] [Free Full-text]

NICE (2013) Hyperphosphataemia in chronic kidney disease. Management of hyperphosphataemia in patients with stage 4 or 5 chronic kidney disease (NICE guideline). Clinical Guideline 157. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Qaseem, A., Hopkins, R.H., Sweet, D.E., et al. (2013) Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: a clinical practice guideline from the Clinical Guidelines Committee of the American College of Physicians. Annals of Internal Medicine 159(12), 835-847. [Abstract] [Free Full-text]

Stevens, P.E. and Levin, A. (2013) Evaluation and management of chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline. Annals of Internal Medicine 158(11), 825-830. [Abstract] [Free Full-text]

HTAs (Health Technology Assessments)

No new HTAs have been published since 1 October 2008.

Economic appraisals

A cost-effectiveness study has been published since the last revision of this topic:

Manns, B., Hemmelgarn, B., Tonelli, M., et al. (2010) Population based screening for chronic kidney disease: cost effectiveness study. BMJ 341, c5869. [Abstract] [Free Full-text]

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Bullo, M., Tschumi, S., Bucher, B.S., et al. (2012) Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 60(2), 444-450. [Abstract]

Caldeira, D., Alarcao, J., Vaz-Carneiro, A. and Costa, J. (2012) Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis. BMJ 345, e4260. [Abstract] [Free Full-text]

Chronic Kidney Disease Prognosis Consortium (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375(9731), 2073-2081. [Abstract]

Duranton, F., Rodriguez-Ortiz, M.E., Duny, Y., et al. (2013) Vitamin D treatment and mortality in chronic kidney disease: a systematic review and meta-analysis. American Journal of Nephrology 37(3), 239-248. [Abstract]

Etgan, T., Chonchol, M., Forstl, H., and Sander, D. (2012) Chronic kidney disease and cognitive impairment: a systematic review and meta-analysis. American Journal of Nephrology 35(5), 474-482. [Abstract]

Fink, H.A., Ishani, A., Taylor, B.C., et al. (2012) Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services task Force and for an American College of Physicians clinical practice guideline. Annals of Internal Medicine 156(8), 570-581. [Abstract] [Free Full-text]

Gallagher, H., de Lisignan, S., Harris, K. and Cates, C. (2010) Quality-improvement strategies for the management of hypertension in chronic kidney disease in primary care: a systematic review. British Journal of General Practice 60(575), 436-441. [Abstract] [Free Full-text]

He, Y.M., Feng, L., Huo, D.M., et al. (2013) Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis. Nephrology 18(9), 605-614. [Abstract]

Heiwe, S., and Jacobson, S.H. (2011) Exercise training for adults with chronic kidney disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Hou, W., Lv, J., Perkovic, V., et al. (2013) Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. European Heart Journal 34(24), 1807-1817. [Abstract]

Howden, E.J., Fassett, R.G., Isbel, N.M., and Coombes, J.S. (2012) Exercise training in chronic kidney disease patients. Sports Medicine 42(6), 473-488. [Abstract]

Jun, M., Venkataraman, V., Razavian, M., et al. (2012) Antioxidants for chronic kidney disease (Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Jun, M., Zhu, B., Tonelli, M., et al. (2012) Effects of fibrates in kidney disease: a systematic review and meta-analysis. Journal of the American College of Cardiology 60(20), 2061-2071. [Abstract]

Kandula, P., Dobra, A., Schold, J.D., et al. (2011) Vitamin D supplementation in chronic kidney disease: systematic review and meta-analysis of observational studies and randomized controlled trials. Clinical Journal of the American Society of Nephrology 6(1), 50-62. [Abstract] [Free Full-text]

Lafeuille, M.H., Bailey, R.A., Vekeman, F., et al. (2010) Drug utilization and cost for erythropoiesis-stimulating agents in a long-term care resident population with chronic kidney disease. Consultant Pharmacist 25(8), 493-500. [Abstract]

Lee, J.S., Park, D.A., Hong, Y., et al. (2013) Systematic review and meta-analysis of prophylactic antibiotics in COPD and/or chronic bronchitis. International Journal of Tuberculosis and Lung Disease 17(2), 153-162. [Abstract]

Lopez-Vargas, P.A., Tong, A., Sureshkumar, P., et al. (2013) Prevention, detection and management of early chronic kidney disease: a systematic review of clinical practice guidelines. Nephrology 18(9), 592-604. [Abstract]

Lv, J., Ehteshami, P., Sarhnak, M.J., et al. (2013) Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis. CMAJ 185(11), 949-957. [Abstract]

Navaneethan, S.D., Palmer, S.C., Vecchio, M., et al. (2011) Phosphate binders for preventing and treating bone disease in chronic kidney disease patients (Cochrane Review). The Cochrane Library. Issue 2. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Navaneethan, S.D., Vecchio, M., Johnson, D.W., et al. (2010) Prevalence and correlates of self-reported sexual dysfunction in CKD: a meta-analysis of observational studies. American Journal of Kidney Diseases 54(4), 670-685. [Abstract]

Navaneethan, S.D., Yehnert, H., Moustarah, F., et al. (2009) Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clinical Journal of the American Society of Nephrology 4(10), 1565-1574. [Abstract] [Free Full-text]

Nderitu, P., Doos, L., Jones, P.W., et al. (2013) Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Family Practice 30(3), 247-255. [Abstract]

Ni, Y., Shi, G., and Wan, H. (2012) Use of cardioselective beta-blockers in patients with chronic obstructive pulmonary disease: a meta-analysis of randomized, placebo-controlled, blind trials. Journal of International Medical Research 40(6), 2051-2065. [Abstract]

Palmer, S.C., Craig, J.C., Navaneetgan, S.D., et al. (2012) Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Annals of Internal Medicine 157(4), 263-275. [Abstract]

Palmer, S.C., Di Micco, L., Razavian, M., et al. (2013) Antiplatelet agents for chronic kidney disease (Cochrane Review). The Cochrane Library. Issue 2. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Palmer, S.C., Hayen, A., Macaskill, P., et al. (2011) Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 305(11), 1119-1127. [Abstract]

Palmer, S.C., McGregor, D.O., Craig, J.C., et al. (2009) Vitamin D compounds for people with chronic kidney disease not requiring dialysis (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Palmer, S.C., McGregor, D.O., Craig, J.C., et al. (2009) Vitamin D compounds for people with chronic kidney disease requiring dialysis (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Regeniter, A., Freidank, H., Dickenmann, M., et al. (2009) Evaluation of proteinuria and GFR to diagnose and classify kidney disease: systematic review and proof of concept. European Journal of Internal Medicine 20(6), 556-561. [Abstract]

Salgado, T.M., Moles, R., Benrimoj, S.I., et al. (2012) Pharmacists’ interventions in the management of patients with chronic kidney disease: a systematic review. Nephrology, Dialysis, Transplantation 27(1), 276-292. [Abstract]

Sharma, P., Blackburn, R.C., Parke, C.L., et al. (2011) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease(Cochrane Review). The Cochrane Library. Issue 10. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Sharma, P., McCullough, K., Scotland, G., et al. (2010) Does stage-3 chronic kidney disease matter? A systematic literature review. British Journal of General Practice 60(575), 442-448. [Free Full-text]

Susantitaphong, P., Sewaralthahab, K., Balk, E.M., et al. (2012) Short- and long-term effects of alkali therapy in chronic kidney disease: a systematic review. American Journal of Nephrology 35(6), 540-547. [Abstract]

Susantitaphong, P., Sewaralthahab, K., Balk, E.M., et al. (2013) Efficacy and safety of combined vs. single renin-angiotensin-aldosterone system blockade in chronic kidney disease: a meta-analysis. American Journal of Hypertension 26(3), 424-441. [Abstract]

Stoycheff, N., Pandya, K., Okparavero, A., et al. (2010) Early change in proteinuria as a surrogate outcome in kidney disease progression: a systematic review of previous analyses and creation of a patient-level pooled dataset. Nephrology, Dialysis, Transplantation 26(3), 848-857. [Abstract] [Free Full-text]

Upadhyay, A., Earley, A., Haynes, S., and Uhlig, K. (2011) Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Annals of Internal Medicine 154(8), 541-548. [Abstract] [Free Full-text]

Upadhyay, A., Earley, A., Lamont, J.L., et al. (2012) Lipid-lowering therapy in person with chronic kidney disease: a systematic review and meta-analysis. Annals of Internal Medicine 157(4), 251-262. [Abstract]

Vecchio, M., Navaneethan, S.D., Johnson, D.W., et al. (2010) Interventions for treating sexual dysfunction in patients with chronic kidney disease (Cochrane Review). The Cochrane Library. Issue 12. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Wali, R.K., Iyengar, M., Beck, G.J., et al. (2011) Efficacy and safety of carvedilol in treatment of heart failure in chronic kidney disease: a meta-analysis of randomized trials. Circulation: Heart Failure 4(1), 18-26. [Abstract] [Free Full-text]

Wang, H., Song, H., Yue, J., et al. (2012) Rheum officinale (a traditional Chinese medicine) for chronic kidney disease (Cochrane Review). The Cochrane Library. Issue 7. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Zheng, Z., Shi, H., Jia, J., et al. (2013) Vitamin D supplementation and mortality risk in chronic kidney disease: a meta-analysis of 20 observational studies. BMC Nephrology 14(1), 199. [Abstract] [Free Full-text]

A secondary analysis of a randomized controlled trial has been published since the last revision of this topic:

Bakris, G.L., Sarafidis, P.A., Weir, M.R., et al. (2010) Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet 375(9721), 1173-1181. [Abstract]

Primary evidence

Randomized controlled trials published since the last revision of this topic:

Appel, L.J., Wright, J.T., Greene, T., et al. (2010) Intensive blood-pressure control in hypertensive chronic kidney disease. New England Journal of Medicine 363(10), 918-929. [Abstract] [Free Full-text]

Baigent, C., Landray, M.J., Reither, C., et al. (2011) The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377(9784), 2181-2192 [Abstract] [Free Full-text]

Blood Pressure Lowering Treatment Trialists' Collaboration (2013) Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 347, f5680. [Abstract] [Free Full-text]

DeFronzo, R.A., Tripathy, D., Schwenke, D.C., et al. (2011) Pioglitazone for diabetes prevention in impaired glucose tolerance. New England Journal of Medicine 364(12), 1104-1115. [Abstract] [Free Full-text]

Goicoechea, M., Vinuesa, S.G., Verdalles, U., et al. (2010) Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clinical Journal of the American Society of Nephrology 5(8), 1388-1393. [Abstract] [Free Full-text]

Observational studies published since the last revision of this topic:

Di Angelantonio, E., Chowdhury, R., Sarwar, N., et al. (2010) Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. BMJ 341, c4986. [Abstract] [Free Full-text]

Peralta, C.A., Shlipak, M.G., Judd, S., et al. (2011) Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA 305(15), 1545-1552. [Abstract]

Tonelli, M., Munter, P., Lloyd, A., et al. (2011) Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease. A cohort study. Annals of Internal Medicine 154(1), 12-21. [Abstract]

Tonelli, M., Munter, P., Lloyd, A., et al.(2012) Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 380(9844), 807-814. [Abstract]

Weinberg, J.M., Appel, L.J., Bakris, G., et al (2009) Risk of hyperkalemia in nondiabetic patients with chronic kidney disease receiving antihypertensive therapy. Archives of Internal Medicine 169(17), 1587-1594. [Abstract] [Free Full-text]

New policies

No new national policies or guidelines since 1 October 2008.

New safety alerts

January 2012: The Medicines and Healthcare products Regulatory Agency (MHRA) has issued the following advice for healthcare professionals:

There is sufficient evidence to support an association between statin use and new onset diabetes.

The risk appears to be mainly in people already at increased risk of developing diabetes.

Raised fasting blood glucose at baseline is a key risk factor. Other risk factors include a history of hypertension, raised triglycerides, and a raised body mass index at baseline.

Patients at risk should be monitored both clinically and biochemically according to national guidelines.

The level of risk of new onset diabetes may vary between statins. However, there is insufficient evidence to confirm or exclude an increased risk for any particular statin.

The reduced vascular risk from statin therapy outweighs any risk of diabetes, including in people at increased risk of developing diabetes, and those with pre-existing diabetes at baseline: statin treatment should not be stopped.

Reference: MHRA (2012) Statins: risk of hyperglycaemia and diabetes. Drug Safety Update 5(6), A2. [Free Full-text (pdf)]

Changes in product availability

No changes in product availability since 1 October 2008.

Goals and outcome measures

Goals

To support primary health care professionals to:

Make a diagnosis of chronic kidney disease

Offer appropriate initial and subsequent management

Refer people with chronic kidney disease, when appropriate, to other healthcare professionals

NICE quality standards

NICE quality standards

People with risk factors for CKD are offered testing, and people with CKD are correctly identified.

People with CKD who may benefit from specialist care are referred for specialist assessment in accordance with NICE guidance.

People with CKD have a current agreed care plan appropriate to the stage and rate of progression of CKD.

People with CKD are assessed for cardiovascular risk.

People with higher levels of proteinuria, and people with diabetes and microalbuminuria, are enabled to safely maintain their systolic blood pressure within a target range 120–129 mmHg and their diastolic blood pressure below 80 mmHg.

People with CKD are assessed for disease progression.

People with CKD who become acutely unwell have their medication reviewed, and receive an assessment of volume status and renal function.

People with anaemia of CKD have access to and receive anaemia treatment in accordance with NICE guidance.

People with progressive CKD whose eGFR is less than 20 mL/min/1.73 m2, and/or who are likely to progress to established kidney failure within 12 months, receive unbiased personalised information on established kidney failure and renal replacement therapy options.

People with established renal failure have access to psychosocial support (which may include support with personal, family, financial, employment and/or social needs) appropriate to their circumstances.

People with CKD are supported to receive a pre-emptive kidney transplant before they need dialysis, if they are medically suitable.

People with CKD on dialysis are supported to receive a kidney transplant, if they are medically suitable.

People with established kidney failure start dialysis with a functioning arteriovenous fistula or peritoneal dialysis catheter in situ.

People on long-term dialysis receive the best possible therapy, incorporating regular and frequent application of dialysis and ideally home-based or self-care dialysis.

People with CKD receiving haemodialysis or training for home therapies who are eligible for transport, have access to an effective and efficient transport service.

[NICE, 2011b]

QOF indicators

Table 1 . Indicators related to chronic kidney disease in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.
Indicator Points Payment stages
CKD001 The contractor establishes and maintains a register of patients aged 18 or over with CKD (US National Kidney Foundation: Stage 3 to 5 CKD) 6
CKD002 The percentage of patients on the CKD register in whom the last blood pressure reading (measured in the preceding 12 months) is 140/85 mmHg or less 11 41–81%
CKD003 The percentage of patients on the CKD register with hypertension and proteinuria who are currently treated with an ACE-I or ARB 9 45–80%
CKD004 The percentage of patients on the CKD register whose notes have a record of a urine albumin:creatinine ratio (or protein:creatinine ratio) test in the preceding 12 months 6 45–80%
SMOK002 The percentage of patients with any or any combination of the following conditions: CHD, PAD, stroke or TIA, hypertension, diabetes, COPD, CKD, asthma, schizophrenia, bipolar affective disorder or other psychoses whose notes record smoking status in the preceding 12 months 25 50–90%
SMOK005 The percentage of patients with any or any combination of the following conditions: CHD, PAD, stroke or TIA, hypertension, diabetes, COPD, CKD, asthma, schizophrenia, bipolar affective disorder or other psychoses who are recorded as current smokers who have a record of an offer of support and treatment within the preceding 12 months 25 56–96%
Data from: [BMA and NHS Employers, 2013]

QIPP - Options for local implementation

QIPP - Options for local implementation

Renin-angiotensin system drugs

Review and, where appropriate, revise prescribing to ensure it is in line with NICE guidance.

[NICE, 2013]

Background information

Definition

What is it?

Chronic kidney disease is said to be present when there is persistent impairment of kidney function, or evidence of kidney damage or structural abnormality of the kidney.

Kidney damage causes leakage of protein and/or blood into the urine, resulting in proteinuria and haematuria.

Renal impairment can range from mild (with minimal or no symptoms) to end-stage renal disease (and the need for renal replacement therapy).

With increasing renal impairment, the function of the kidney deteriorates resulting in a worsening ability to regulate electrolyte-fluid balance and maintain normal calcium metabolism.

Classification

How is CKD classified?

The classification of chronic kidney disease is based on an assessment of renal function (glomerular filtration rate) and the presence of kidney damage (for example proteinuria, haematuria) or a structural abnormality of the kidney [National Collaborating Centre for Chronic Conditions, 2008].

Renal function:

The glomerular filtration rate is equal to the sum of the filtration rates in all of the functioning nephrons, and is the best index of overall kidney function.

Measuring glomerular filtration rate directly (for example by measuring a filtration marker such as inulin) is expensive and impractical. Therefore, prediction equations have been developed which combine serum creatinine level with age, gender, and ethnicity to give an estimated glomerular filtration rate (eGFR).

The National Institute for Health and Care Excellence (NICE) recommends the use of the Modification of Diet in Renal Disease (MDRD) equation to calculate eGFR.

Kidney damage:

NICE recommends that proteinuria be quantified by measuring the urinary albumin:creatinine ratio.

Significant proteinuria is present if the urinary albumin:creatinine ratio is 30 mg/mmol or more (approximately equivalent to a urinary protein:creatinine ratio of 50 mg/mmol or more, or urinary protein excretion of 0.5 g/24 hours or more).

NICE has adopted and updated the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) classification of chronic kidney disease, which describes five stages (see Table 1).

NICE also recommends using the suffix '(p)' to denote the presence of proteinuria and further sub-categorizing stage 3 into stages 3A and 3B (based on eGFR) to reflect the increased mortality and cardiovascular risk seen when eGFR is less than 45 mL/min/1.73 m2 or when proteinuria is present [NICE, 2008].

Stages 1 and 2 require the presence of persistent proteinuria, haematuria, or a structural abnormality of the kidney.

Table 1 . Classification of chronic kidney disease.
Stage Estimated glomerular filtration rate (mL/min/1.73 m2) Description
1 90 or greater Normal or increased eGFR, with evidence of kidney damage
2 60–89 Slight decrease in eGFR, with evidence of kidney damage
3A 45–59 Moderate decrease in eGFR, with or without other evidence of kidney disease
3B 30–44
4 15–29 Severe decrease in eGFR, with or without other evidence of kidney disease
5 Less than 15 Established renal failure (end-stage renal disease)
Note: kidney damage includes the presence of persistent proteinuria, albuminuria, or haematuria (after exclusion of other causes); structural abnormalities detected by ultrasound (such as polycystic kidney disease); or biopsy-proven glomerulonephritis.
Data from: [NICE, 2008]

Causes

What causes it?

Conditions associated with intrinsic kidney disease, such as:

Hypertension.

Diabetes mellitus.

Nephrotoxic drugs, such as:

Lithium.

Ciclosporin.

Calcineurin inhibitors (such as tacrolimus).

Aminoglycosides.

Mesalazine.

Conditions associated with obstructive kidney disease:

Bladder voiding dysfunction such as neurogenic bladder, benign prostatic hypertrophy.

Urinary diversion surgery.

Recurrent urinary stones.

Multi-system diseases that may involve the kidney, such as:

Systemic lupus erythematosus (SLE).

Vasculitis.

Myeloma.

Autosomal dominant polycystic kidney disease, Alport's syndrome, and familial glomerulonephritis.

[Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and Renal Association, 2006]

Prevalence

How common is it?

A large primary care study suggests the prevalence of chronic kidney disease stage 3–5 is 8.5% (10.6% in females and 5.8% in males) in UK adults. The study also found that the prevalence increased dramatically with age [National Collaborating Centre for Chronic Conditions, 2008].

A general practice with a list size of 10,000 will have at least 500 people with chronic kidney disease stage 3–5, including around 20 people with stage 4 and 10 people with stage 5 disease [NHS Employers and GP Committee of BMA, 2007].

Complications

What are the complications?

About 90% of people with chronic kidney disease stage 3–5 have hypertension and 40% have vascular disease [NHS Employers and GP Committee of BMA, 2007].

A reduced glomerular filtration rate is associated with a wide range of complications, such as hypertension, anaemia, renal bone disease, malnutrition, neuropathy, and lipid abnormalities [Feehally et al, 2008].

Observational studies have shown that cardiovascular events, frailty, and cognitive impairment increase significantly in people with a glomerular filtration rate less than 60 mL/min/1.73 m2 compared with those with an eGFR above this level [National Collaborating Centre for Chronic Conditions, 2008].

Prognosis

What is the prognosis?

People with chronic kidney disease are roughly twenty times more likely to die of cardiovascular disease than to progress to end-stage renal failure. The all-cause mortality rate for chronic kidney disease is 30–60 times higher than that of the general population [NHS Employers and GP Committee of BMA, 2007].

UK population studies have shown that the risk of cardiovascular death with chronic kidney disease far outweighs the risk of renal progression [National Collaborating Centre for Chronic Conditions, 2008].

A retrospective cohort study (n = 1076) found that only 4% of people with chronic kidney disease stage 3 progressed to end-stage kidney disease over a 5.5-year follow-up period. However, 69% of people had died at the end of follow up, and 46% of deaths were due to cardiovascular disease.

A prospective cohort study (n = 3240) of people with a median glomerular filtration rate of 28.5 mL/min/1.73 m2 found that mortality was 39.5% after a median follow-up period of 31.3 months, and 39.7% of deaths were due to cardiovascular disease. Only 8.3% of people had a decline in glomerular filtration rate greater than 5 mL/min/1.73 m2 per year during the period of follow up.

Management

Management

Scenario: Testing : covers who should be tested for chronic kidney disease and how they should be tested.

Scenario: Stage 1 and 2 CKD : covers the referral and monitoring of chronic kidney disease stages 1 and 2. This section also covers lifestyle advice, advice about blood pressure control, and provides information on when to start angiotensin-converting enzyme inhibitors, aspirin, and statins.

Scenario: Stage 3 CKD : covers the referral and monitoring of chronic kidney disease stage 3. This section also covers lifestyle advice, advice about blood pressure control, and provides information on when to start angiotensin-converting enzyme inhibitors, aspirin, and statins.

Scenario: Stage 4 and 5 CKD : covers the referral and monitoring of chronic kidney disease stages 4 and 5. This section also covers lifestyle advice, advice about blood pressure control, and provides information on when to start angiotensin-converting enzyme inhibitors, aspirin, and statins.

Scenario: Testing

Scenario: Testing for chronic kidney disease

216months3060monthsBoth

Who to test

Who should I test for chronic kidney disease?

Test people with risk factors for chronic kidney disease:

Diabetes (Types 1 and 2).

Hypertension.

Cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease, cerebrovascular disease).

Structural renal tract disease, renal calculi, or benign prostatic hypertrophy.

Multi-system diseases with potential kidney involvement, such as systemic lupus erythematosus.

Family history of chronic kidney disease stage 5 or hereditary kidney disease.

Those taking nephrotoxic drugs such as lithium, ciclosporin, diuretics, and long-term nonsteroidal anti-inflammatory drugs.

Test people with an incidental finding of:

Proteinuria or haematuria on a urinary dipstick.

A low estimated glomerular filtration rate. For example, less than 60 mL/min/1.73 m2.

Do not use obesity (in the absence of diabetes or hypertension), or age, gender, and ethnicity alone as a risk factor for chronic kidney disease.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The aim of early identification and treatment of chronic kidney disease is to decrease the risk of cardiovascular disease and progression to end-stage renal disease.

Basis for testing people with risk factors for chronic kidney disease

General population screening is not cost effective, but targeted screening directed at high-risk groups is cost effective.

The NICE guideline development group reviewed the evidence (three cohort, and 16 observational or cross sectional, studies) on risk factors for chronic kidney disease and agreed that the risk factors shown, and the presence of proteinuria or haematuria, indicated a high risk of chronic kidney disease.

Basis for testing people with incidental haematuria for chronic kidney disease

Causes of haematuria can be both renal and urological (for example malignancy, renal stone). People who present with persistent haematuria (after excluding a urinary tract infection) should be tested for chronic kidney disease, as this will determine whether referral should be to a urologist (see the CKS topic on Urological cancer - suspected) or renal physician.

Basis for not using age alone when deciding whether to test for chronic kidney disease

The effects of ageing on renal function are controversial. The prevalence of chronic kidney disease increases markedly with age, although the exact level of reduction in renal function is still uncertain.

Data from studies suggest that the decline in glomerular filtration rate with ageing may be largely due to comorbidities (such as hypertension and heart failure) and that loss of renal function may not be an inevitable consequence of ageing.

This has been further supported by longitudinal studies showing no decline, or very little decline, in glomerular filtration rate in the older population.

Basis for not using lifestyle factors, obesity, or ethnicity as indications for testing for chronic kidney disease

The guideline development group concluded that the evidence was not strong enough to recommend routinely testing for chronic kidney disease in people who smoke, have a high alcohol intake, have abnormal lipids, are obese (in the absence of metabolic syndrome), are from a lower socioeconomic group, or who come from any particular ethnic group.

Tests for diagnosis

How should I test for chronic kidney disease?

For people at risk of chronic kidney disease, measure serum creatinine (to calculate estimated glomerular filtration rate [eGFR]) and urinary albumin:creatinine ratio, and check urine for haematuria by dipstick.

If eGFR is less than 60 mL/min/1.73 m2, repeat within 2 weeks (unless previous values show the eGFR is stable):

If the eGFR remains less than 60 mL/min/1.73 m2 with no evidence of acute deterioration, repeat within 3 months to confirm the diagnosis of chronic kidney disease.

If the eGFR is deteriorating (a decrease of more than 25% of the initial value), consider a diagnosis of acute kidney injury and seek specialist advice.

If the urinary albumin:creatinine ratio is 30 mg/mmol or more:

Repeat on an early morning urine sample (if it is 70 mg/mmol or more, there is no need to repeat the test).

If dipstick test shows 1+ or more of blood:

Exclude a urinary tract infection (UTI).

Persistent haematuria is considered to be present if two out of three dipstick tests show 1+ or more of blood (after exclusion of a UTI).

For more information on measuring serum creatinine and eGFR, and testing for proteinuria, see Additional information.

If the eGFR is 60 mL/min/1.73 m2 or more, the urinary albumin:creatinine ratio is less than 30 mg/mmol, and there is no haematuria, reassure the person that they do not have chronic kidney disease. However, if the person is in a high risk group continue to monitor eGFR annually.

If the person has confirmed chronic kidney disease (eGFR is persistently less than 60 mL/min/1.73 m2, or there is persistent proteinuria or haematuria, or there is a structural kidney abnormality) assess for possible causes and grade severity (based on classification system).

Additional information

Additional information

Measuring serum creatinine and eGFR

Advise the person not to eat any meat for at least 12 hours before measuring eGFR (for most people this will mean avoiding a cooked breakfast).

Allow for biological variation (creatinine +/– 5%) if the eGFR has decreased.

Multiply the eGFR by 1.21 if a person is of African–Caribbean or African ethnicity to correct for differences in muscle mass.

Interpret the eGFR with caution if the person has extremes of muscle mass, or in people who are pregnant, oedematous, or malnourished, or if the person is Asian or Chinese in origin (eGFR is less well validated in these ethnic groups).

Testing for proteinuria

Do not use a dipstick to test for proteinuria unless it is capable of measuring albumin at low levels and expressing the result as an albumin:creatinine ratio.

A urinary albumin:creatinine ratio of 30 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 50 mg/mmol or more, or a urinary protein excretion of 0.5 g/24 hours or more.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or a urinary protein excretion of 1.0 g/24 hours or more.

Dipstick tests can give false positive results (for example due to dehydration, exercise, or infection) and false negative results (for example due to excessive hydration or the presence of proteins other than albumin).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for measuring eGFR

Serum creatinine levels alone are insensitive for detecting impaired renal function; it is possible to lose up to 50% of renal function before serum creatinine increases, especially in the elderly.

The eGFR, calculated by applying the Modification of Diet in Renal Disease (MDRD) equation, is more sensitive than serum creatinine at detecting chronic kidney disease.

Basis for not eating meat in the 12 hours prior to having eGFR measured

The cooking process converts creatine in meat to creatinine, which is subsequently absorbed into the bloodstream.

Small studies have shown that ingestion of cooked meat causes a significant increase in serum creatinine concentration (up to 50% higher).

Basis for testing for proteinuria

Epidemiological studies show that proteinuria is a cardinal sign of kidney disease and that significant proteinuria is an independent risk factor for progression of chronic kidney disease and the development of cardiovascular disease (CVD).

Proteinuria is associated with a doubling of CVD risk and mortality at all levels of glomerular filtration rate.

Evidence from longitudinal population studies and meta-analyses suggests that a urinary albumin:creatinine ratio greater than 30 mg/mmol should be used as a marker of increased risk.

Basis for measuring urinary albumin:creatinine ratio rather than protein:creatinine ratio when first testing for chronic kidney disease

The urinary albumin:creatinine ratio has greater sensitivity than protein:creatinine for the detection of low levels of proteinuria.

The NICE guideline development group was divided over the use of albumin:creatinine versus protein:creatinine to measure proteinuria. A consensus statement recommended the albumin:creatinine ratio, but they agreed that the protein:creatinine ratio could be used subsequently for monitoring proteinuria.

Basis for testing a morning urine sample

A morning urine sample is more reliable, as false positive proteinuria (due to the presence of orthostatic proteinuria, which is not clinically significant) is less likely to be detected.

Basis for testing for haematuria

The prevalence of asymptomatic invisible haematuria in the UK adult male population is high (around 2.5%, increasing to 22% in men older than 60 years of age).

After consultation with NICE, an expert from the guideline development group confirmed that all people at risk of CKD should have their urine tested for haematuria. However, people with isolated haematuria (after exclusion of a urological cause) would not usually require referral to a renal specialist because a renal biopsy would only be recommended if, in addition to persistent haematuria, there was also evidence of a low eGFR or proteinuria.

Scenario: Stage 1 and 2 CKD

Scenario: Management of stage 1 and 2 chronic kidney disease

216months3060monthsBoth

Referral

When is referral recommended in stage 1 or 2 CKD?

Refer according to local guidelines, where available. The urgency of referral should be based on clinical judgement. Consider discussing management with a specialist (by letter, e-mail, or telephone) even if it is thought that it may not be necessary for the person to be seen by the specialist.

Referral to a nephrology specialist is usually required for people with:

Heavy proteinuria (urinary albumin:creatinine ratio 70 mg/mmol or more), unless this is known to be due to diabetes and already appropriately treated.

Proteinuria (urinary albumin:creatinine ratio 30 mg/mmol or more) with haematuria.

Uncontrolled hypertension (despite four antihypertensive drugs at therapeutic doses — see the CKS topic on Hypertension - not diabetic).

A rare or genetic cause of chronic kidney disease, or the suspicion of one (such as polycystic kidney disease).

Suspected renal artery stenosis (such as refractory hypertension, recurrent pulmonary oedema with normal left ventricular function, or an increase in serum creatinine of 20% or more when started on an angiotensin-converting enzyme inhibitor).

Once a referral has been made and a plan jointly agreed, it may be possible for follow up to take place in primary care.

When the laboratory reports only that the eGFR is greater than 60 mL/min/1.73 m2, suspect a significant deterioration in renal function (such as acute renal failure) if serum creatinine increases greater than 1.5-fold.

If the person has urinary tract obstruction (for example the bladder is palpable), refer to a urologist — unless urgent medical intervention is needed for problems such as hyperkalaemia (potassium greater than 6 mmol/L) or fluid overload.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group noted that there was no evidence to guide recommendations on referral. Therefore, they based their recommendations on other guidelines and their own professional judgement.

Basis for referring people with a significant deterioration in estimated glomerular filtration rate (eGFR)

There is evidence that late referral leads to increased morbidity and mortality in people with advanced chronic kidney disease.

Basis for referring people with complications, proteinuria with haematuria, or risk factors for progression of chronic kidney disease

A specialist may carry out a renal biopsy or imaging (ultrasound, computed tomography) to identify causes of chronic kidney disease, especially if there is heavy proteinuria, or proteinuria with haematuria.

A specialist team will also help manage risk factors for chronic kidney disease progression (for example uncontrolled hypertension) and identify complications which need further intervention (such as anaemia, renal bone disease).

Tests to monitor

What tests should be monitored in CKD stage 1 and 2

Use clinical judgement; if in doubt, seek specialist advice.

The following should be measured routinely:

Estimated glomerular filtration rate (eGFR) every 12 months.

A test for proteinuria every 12 months:

If the person is not already known to have proteinuria, measure the urinary albumin:creatinine ratio.

If the person is known to have proteinuria, monitoring can be with urinary albumin:creatinine or protein:creatinine ratios.

If there is haematuria (with no urological cause), carry out a dipstick test for haematuria every 12 months or until it is no longer persistent.

Do not routinely measure full blood count to exclude anaemia unless it is clinically indicated (symptoms such as tiredness, shortness of breath, lethargy, palpitations).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for monitoring estimated glomerular filtration rate (eGFR)

Many people with chronic kidney disease do not progress to end-stage renal disease. In those that do progress, the subsequent risks of mortality and morbidity rise exponentially (see eGFR deterioration).

Basis for monitoring proteinuria

Proteinuria is associated with renal progression and cardiovascular disease.

If proteinuria develops (a urinary albumin:creatinine ratio of 30 mg/mmol or more) and the person has hypertension, an angiotensin-converting enzyme inhibitor (or angiotensin-II receptor antagonist) is indicated (see ACE inhibitors or AIIRAs).

If heavy proteinuria develops (urinary albumin:creatinine ratio of 70 mg/mmol or more, or urinary protein:creatinine ratio of 100 mg/mmol or more), an angiotensin-converting enzyme inhibitor (or angiotensin-II receptor antagonist) is indicated irrespective of blood pressure (see ACE inhibitors or AIIRAs), and blood pressure should be controlled more aggressively (see Blood pressure). In addition, a specialist nephrology opinion should usually be sought.

Basis for monitoring isolated haematuria

The NICE guideline development group noted that the commonest abnormality identified in people with isolated invisible haematuria was IgA nephropathy, and that this condition has the propensity to progress. However, it was agreed that if haematuria disappeared there was a low or non-existent risk of developing progressive chronic kidney disease.

eGFR deterioration

How do I know if the eGFR has deteriorated significantly?

If a decline in estimated glomerular filtration rate (eGFR) is seen, repeat three times over a period of at least 90 days.

A significant eGFR decline is indicated if there is more than a:

5 mL/min/1.73 m2 decrease within 1 year, or

10 mL/min/1.73 m2 decrease within 5 years.

If a large decline in eGFR is seen (25% or more), repeat within 2 weeks to exclude acute kidney injury.

Consider the person's baseline eGFR and the lifetime likelihood, if they continued the same rate of decline, that they would eventually reach an eGFR level that would require renal replacement therapy.

For example, a rate of decline of 3 mL/min/1.73 m2 per year would be of greater concern in a person of 40 years of age with a baseline eGFR of 30 mL/min/1.73 m2 than in a person of 70 years of age with a baseline eGFR of 60 mL/min/1.73 m2.

When the laboratory reports only that the person's eGFR exceeds their reference range (for example, they only report an eGFR as greater than 60 mL/min/1.73 m2), suspect a significant deterioration in renal function (such as acute kidney injury) if the person's serum creatinine increases greater than 1.5-fold.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for identifying a sudden decline in estimated glomerular filtration rate (eGFR)

A decline in eGFR of greater than 25% suggests acute kidney injury, which requires an urgent assessment and specialist intervention (see Referral).

Basis for the definition of a significant gradual decline in eGFR

The NICE guideline development group based their recommendations on a consideration of biological and assay variability in serum creatinine concentrations, and evidence (from two cross-sectional studies) that a decline in eGFR of more than 2 mL/min/1.73 m2 per year is more than can be explained by ageing alone.

Basis for identifying people with a declining eGFR

People with a declining eGFR have a worse prognosis (in terms of adverse outcomes) and require early intervention (to prevent further renal deterioration) compared with people with a stable eGFR.

Lifestyle advice

What lifestyle advice is recommended?

Encourage people with chronic kidney disease to:

Stop smoking (if appropriate) and drink sensible amounts of alcohol (see the CKS topics on Smoking cessation and Alcohol - problem drinking).

Take regular exercise, and achieve a healthy body weight (see the CKS topic on Obesity).

Eat a healthy diet.

Avoid using over-the-counter nonsteroidal anti-inflammatory drugs (except on medical advice).

Provide information appropriate to the stage and cause of chronic kidney disease.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group investigated the effect of lifestyle habits on the progression of chronic kidney disease. There were very few interventional lifestyle studies, so observational studies were included, all of which were limited by small sample sizes.

Basis for advising regular exercise, eating a healthy diet, and obtaining a healthy weight

The guideline development group recognized that weight control, healthy eating, and taking regular exercise are of particular benefit to people with cardiovascular disease (CVD). There was no direct evidence that lifestyle changes had any additional benefit in people with chronic kidney disease. However as people with chronic kidney disease are at increased risk of CVD, the guideline development group agreed that exercise and weight control should be encouraged.

Basis for stopping smoking

Stopping smoking reduces the risk of CVD. In addition, smoking has been shown to be associated with an increased risk of chronic kidney disease progression.

Basis for a reduced alcohol intake

There is no evidence on specific adverse effects of alcohol consumption in people with chronic kidney disease. However, sensible drinking will reduce the risk of hypertension and CVD.

Basis for healthy eating

People with advanced chronic kidney disease commonly have a poor appetite, making them vulnerable to malnutrition, disease, and infection. Specialist input should be sought to give advice about the risks and benefits of protein restriction in advanced stages of disease (slowing down renal progression versus protein-calorie malnutrition).

Basis for avoiding over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs)

Short-term use of NSAIDs can lead to a sudden decrease in glomerular filtration rate. Long-term use, even at therapeutic doses, can be associated with progression of chronic kidney disease. The guideline development group recommended that if NSAIDs are clinically necessary, their effect on glomerular filtration rate should be monitored and they should be stopped if there is evidence of renal progression (see eGFR deterioration).

Blood pressure

What blood pressure is recommended?

In people with chronic kidney disease, ideally aim for:

Systolic blood pressure less than 140 mmHg (target range 120–139 mmHg).

Diastolic blood pressure less than 90 mmHg.

In people with chronic kidney disease and a urinary albumin:creatinine ratio of 70 mg/mmol or more, ideally aim for:

Systolic blood pressure less than 130 mmHg (target range 120–129 mmHg).

Diastolic blood pressure less than 80 mmHg.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or urinary protein excretion of 1.0 g/24 hours or more.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group reviewed evidence (meta-analyses, randomized controlled trials [RCTs], longitudinal cohort studies) that investigated diastolic and systolic blood pressure control in people with chronic kidney disease in relation to cardiovascular and renal outcomes.

Basis for blood pressure control in chronic kidney disease

There is strong evidence that reducing blood pressure reduces cardiovascular risk and renal progression.

Basis for an optimal range for systolic and diastolic blood pressure control in chronic kidney disease

The evidence suggests that there are optimal ranges, with increased risk of adverse outcomes both above and below the optimal range, for both systolic and diastolic blood pressures.

Systolic blood pressure:

Less than 120 mmHg is associated with an increase in mortality, cardiovascular mortality, stroke, and congestive heart failure.

More than 140 mmHg is associated with increased risk of end-stage renal disease, doubling of serum creatinine concentration, and death.

Diastolic blood pressure:

Less than 60 mmHg is associated with an increased risk of death, myocardial infarction, and decline in estimated glomerular filtration rate.

More than 80 mmHg is associated with an increased risk of end-stage renal disease, doubling of serum creatinine concentration, and death.

The guideline development group noted that adverse outcomes seen with lower blood pressure may have been subject to reverse causality (the adverse outcome resulted in the low blood pressure reading rather than vice versa).

Basis for a diastolic blood pressure threshold rather than an optimal range

Although diastolic blood pressure less than 60 mmHg has been associated with adverse outcomes, the guideline development group agreed that, in practice, when treatment is given to maintain systolic blood pressure in the optimal range, this can result in diastolic blood pressure falling below its optimal range.

Basis for a lower blood pressure target in people with a urinary albumin:creatinine ratio of 70 mg/mmol or more

The guideline development group noted there was some evidence (from a meta-analysis of 11 RCTs) that a systolic blood pressure target of 130–139 mmHg (compared with 110–119 mmHg) results in a significantly increased risk of renal disease progression in people with higher levels of proteinuria.

ACE inhibitors or AIIRAs

When are ACE inhibitors or AIIRAs recommended?

Offer an angiotensin-converting enzyme (ACE) inhibitor to people with chronic kidney disease if there is:

Hypertension and proteinuria with a urinary albumin:creatinine ratio of 30 mg/mmol or more, or

Proteinuria with a urinary albumin:creatinine ratio of 70 mg/mmol or more (irrespective of blood pressure).

A urinary albumin:creatinine ratio of 30 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 50 mg/mmol or more, or a urinary protein excretion of 0.5 g/24 hours or more.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or a urinary protein excretion of 1 g/24 hours or more.

Start with a low dose and titrate up to the maximum tolerated therapeutic dose (within the maximum licensed dose), by doubling the dose every 1–2 weeks. After each upward titration, monitor the person's renal function, serum potassium level, and blood pressure.

If the person cannot tolerate an ACE inhibitor (due to non-renal adverse effects), offer an angiotensin-II receptor antagonist (AIIRA) as an alternative (see prescribing ACE inhibitors and AIIRAs).

For people with hypertension and no proteinuria (urinary albumin:creatinine ratio less than 30 mg/mmol), treat in line with current guidance on hypertension management (see the CKS topic on Hypertension - not diabetic).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group reviewed the evidence (six systematic reviews and 10 randomized controlled trials [RCTs]) which compared the use of ACE inhibitors or angiotensin-II receptor antagonists (AIIRAs) with placebo or other antihypertensive drugs (such as alpha- or beta-blockers, calcium-channel blockers, thiazide diuretics) in people with chronic kidney disease. Most trials used antihypertensives (non-ACE inhibitors or non-AIIRAs) in both arms to achieve blood pressure control.

Basis for an ACE inhibitor or AIIRA in people with chronic kidney disease and proteinuria

The guideline development group noted that the beneficial effects of ACE inhibitors and AIIRAs appeared to be more closely related to the presence or absence of proteinuria rather than blood pressure control. For example, when used for blood pressure control in people with chronic kidney disease and proteinuria, ACE inhibitors and AIIRAs resulted in a significant reduction in cardiovascular outcomes, proteinuria, and renal progression compared with control treatment.

Basis for offering a choice of antihypertensive medication in people with chronic kidney disease and no evidence of proteinuria

A number of trials of antihypertensive treatment have shown that a reduction in blood pressure reduces the risk of end-stage kidney disease and of cardiovascular disease regardless of the class of drug used. Although ACE inhibitors and AIIRAs may also be beneficial in people with chronic kidney disease with lower levels of proteinuria, there is no evidence that they are more beneficial than other antihypertensive drugs for the same level of blood pressure reduction.

Basis for offering any ACE inhibitor first-line

The guideline development group agreed that there was no evidence to suggest an advantage of one ACE inhibitor over any other.

Basis for offering an ACE inhibitor first-line compared with an AIIRA

The guideline development group agreed that there was no evidence to suggest an advantage of ACE inhibitor over an AIIRA. However, health economic analysis based on RCTs (only three RCTs were UK-based) suggested an increased cost-effectiveness for ACE inhibitors compared with AIIRAs when used in people with chronic kidney disease for blood pressure control.

Basis for not combining an ACE inhibitor and an AIIRA

There was no evidence to suggest increased effectiveness of combining an ACE inhibitor with an AIIRA over the maximum recommended dose of each individual drug.

Combining drugs could result in a deterioration in renal function (see Adverse effects of ACE inhibitors or AIIRAs). However, combination treatment may be initiated by a specialist under certain circumstances to control blood pressure and worsening proteinuria.

Statins or aspirin

When are statins or aspirin recommended?

People with chronic kidney disease should be offered antiplatelet and statin treatment as for the rest of the population.

For primary prevention of cardiovascular disease (CVD), calculate the CVD risk based on existing risk tables (see the CKS topic on CVD risk assessment and management).

For secondary prevention of CVD, see the CKS topics on Antiplatelet treatment and Lipid modification - CVD prevention.

Additional information

Additional information

Dyslipidaemia

Dyslipidaemia in chronic kidney disease is distinct from the general population. The key changes appear to be hypertriglyceridaemia, increased remnant lipoproteins, reduced high-density lipoprotein (HDL) cholesterol, and increased atherogenic sub-types of low-density lipoprotein (LDL) cholesterol.

When calculating cardiovascular disease (CVD) risk, remember that the Framingham risk tables significantly underestimate the risk of CVD in people with chronic kidney disease.

Bleeding and thrombosis

People with chronic kidney disease paradoxically have both thrombotic and bleeding tendencies.

Increased bleeding is due to prolonged bleeding times, which become more prevalent with increasing severity of chronic kidney disease.

Increased thrombosis is due to higher levels of procoagulant activity.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for prescribing statins based on existing cardiovascular disease (CVD) risk tables

Epidemiological studies suggest that dyslipidaemia is a risk factor for chronic kidney disease. The NICE guideline development group discussed whether chronic kidney disease itself should influence the use of statins in the primary prevention of CVD. They agreed that currently there is no evidence to support chronic kidney disease as a causal risk factor for CVD. Therefore, people with chronic kidney disease should have their CVD risk assessed using current risk tables for CVD.

The guideline development group reviewed three meta-analyses (mainly including people with CVD, or at high risk of CVD) which investigated the role of statins compared with placebo on progression of chronic kidney disease. Due to significant heterogeneity in the studies, the guideline development group concluded that there was insufficient evidence to recommend the use of statins to reduce proteinuria or renal progression in chronic kidney disease.

Basis for prescribing antiplatelet drugs based on existing CVD risk tables

Chronic kidney disease is an independent risk factor for atherosclerosis. Large trials in the general population have shown that antiplatelet drugs reduce the risk of cardiovascular events. However:

There is no trial evidence to support the use of aspirin in people with chronic kidney disease without CVD or an estimated CVD risk greater than 20%.

Observational studies suggest that people with chronic kidney disease receiving aspirin are at increased risk of minor bleeding, but the evidence does not show a significant increase in the incidence of major bleeding.

Basis for prescribing statins in people with chronic kidney disease and CVD

The benefits of statins in CVD are clear. Although people with chronic kidney disease are at increased risk of CVD and might be expected to benefit from statins, the published evidence on statin use in CVD has largely excluded people with chronic kidney disease.

The guideline development group reviewed a systematic review investigating cardiovascular outcomes in people with chronic kidney disease and CVD randomized to statins or placebo or no treatment. Compared with placebo, statins significantly reduced the risk of all-cause mortality, cardiovascular mortality, non-fatal cardiovascular events, and major coronary events in all people (not just those with raised lipid concentrations).

Basis for prescribing aspirin in people with chronic kidney disease and CVD

The guideline development group reviewed observational studies and concluded that there was no reason to believe that antiplatelet drugs were less effective for secondary prevention of cardiovascular events in people with chronic kidney disease.

Observational studies have suggested worsening progression of chronic kidney disease with aspirin use. However, these results should be interpreted with caution, as the participants had existing CVD, a known risk factor for progression of chronic kidney disease.

Scenario: Stage 3 CKD

Scenario: Management of stage 3 chronic kidney disease

216months3060monthsBoth

Referral

When is referral recommended in stage 3 CKD?

Refer according to local guidelines, where available. The urgency of referral should be based on clinical judgement. Consider discussing management with a specialist (by letter, e-mail, or telephone) even if it is thought that it may not be necessary for the person to be seen by the specialist.

Referral to a nephrology specialist is usually required for people with:

Acute renal failure, suggested by a rapid decrease in the estimated glomerular filtration rate (eGFR) of more than 25% of the initial value.

Heavy proteinuria (urinary albumin:creatinine ratio 70 mg/mmol or more), unless this is known to be due to diabetes and already appropriately treated.

Proteinuria (urinary albumin:creatinine ratio 30 mg/mmol or more) with haematuria.

Rapidly declining eGFR, defined as more than 5 mL/min/1.73 m2 in 1 year, or more than 10 mL/min/1.73 m2 within 5 years.

Uncontrolled hypertension (despite four antihypertensive drugs at therapeutic doses — see the CKS topic on Hypertension - not diabetic).

A rare or genetic cause of chronic kidney disease, or the suspicion of one (such as polycystic kidney disease).

Suspected renal artery stenosis (such as refractory hypertension, recurrent pulmonary oedema with normal left ventricular function, or an increase in serum creatinine of 20% or more when started on an angiotensin-converting enzyme inhibitor).

Complications of chronic kidney disease, such as anaemia (haemoglobin less than 11 g/dL) and renal bone disease (for example abnormal serum calcium or phosphate).

Once a referral has been made and a plan jointly agreed, it may be possible for follow up to take place in primary care.

When the laboratory reports only that the eGFR is greater than 60 mL/min/1.73 m2, suspect a significant deterioration in renal function (such as acute renal failure) if serum creatinine increases greater than 1.5-fold.

If the person has urinary tract obstruction (for example the bladder is palpable), refer to a urologist — unless urgent medical intervention is needed for problems such as hyperkalaemia (potassium greater than 6 mmol/L), uraemia, acidosis, or fluid overload.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group noted that there was no evidence to guide recommendations on referral. Therefore, they based their recommendations on other guidelines and their own professional judgement.

Basis for referring people with a significant deterioration in estimated glomerular filtration rate (eGFR)

There is evidence that late referral leads to increased morbidity and mortality in people with advanced chronic kidney disease.

Basis for referring people with complications, proteinuria with haematuria, or risk factors for progression of chronic kidney disease

A specialist may carry out a renal biopsy or imaging (ultrasound, computed tomography) to identify causes of chronic kidney disease, especially if there is heavy proteinuria, or proteinuria with haematuria.

A specialist team will also help manage risk factors for chronic kidney disease progression (for example uncontrolled hypertension) and identify complications which need further intervention (such as anaemia, renal bone disease).

Tests to monitor

What tests should be monitored in CKD stage 3

Use clinical judgement; if in doubt, seek specialist advice.

In chronic kidney disease stage 3A (estimated glomerular filtration rate [eGFR] 45–59 mL/min/1.73 m2):

Measure eGFR every 6 months.

Do not routinely measure full blood count to exclude anaemia unless it is clinically indicated (symptoms such as tiredness, shortness of breath, lethargy, palpitations).

In chronic kidney disease stage 3B (eGFR 30–44 mL/min/1.73 m2):

Measure eGFR every 6 months.

Do a full blood count to exclude anaemia (haemoglobin 11 g/dL or less). The frequency of subsequent monitoring depends on whether there is evidence of a downward trend.

Do not routinely measure serum parathyroid hormone or vitamin D unless this is clinically indicated (such as in the presence of an abnormal calcium level).

Test for proteinuria every 12 months:

If the person is not already known to have proteinuria, measure the urinary albumin:creatinine ratio.

If the person is known to have proteinuria, monitoring can be with urinary albumin:creatinine or protein:creatinine ratios.

If the person has haematuria (with no urological cause), carry out a dipstick test for haematuria every 12 months or until it is no longer persistent.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for monitoring estimated glomerular filtration rate (eGFR)

Many people with chronic kidney disease do not progress to end-stage renal disease. In those that do progress, the subsequent risks of mortality and morbidity rise exponentially (see eGFR deterioration).

Basis for monitoring proteinuria

Proteinuria is associated with renal progression and cardiovascular disease.

If proteinuria develops (a urinary albumin:creatinine ratio of 30 mg/mmol or more) and the person has hypertension, an angiotensin-converting enzyme inhibitor (or angiotensin-II receptor antagonist) is indicated (see ACE inhibitors or AIIRAs).

If heavy proteinuria develops (urinary albumin:creatinine ratio of 70 mg/mmol or more, or urinary protein:creatinine ratio of 100 mg/mmol or more), an angiotensin-converting enzyme inhibitor (or angiotensin-II receptor antagonist) is indicated irrespective of blood pressure (see ACE inhibitors or AIIRAs), and blood pressure should be controlled more aggressively (see Blood pressure). In addition, a specialist nephrology opinion should usually be sought.

Basis for monitoring isolated haematuria

The NICE guideline development group noted that the commonest abnormality identified in people with isolated invisible haematuria was IgA nephropathy, and that this condition has the propensity to progress. However, it was agreed that if haematuria disappeared there was a low or non-existent risk of developing progressive chronic kidney disease.

Basis for screening for anaemia in stages 3B, 4, and 5

UK primary care data demonstrate that the prevalence of anaemia rises sharply if the glomerular filtration rate is less than 45 mL/min/1.73 m2 (the prevalence of anaemia is 10% in stage 4 disease compared with 2.9% in stage 3).

The recommendation that anaemia should be investigated if haemoglobin is 11 g/dL or less, or if the person has symptoms suggesting possible anaemia is based on the NICE clinical guideline Anaemia management in people with chronic kidney disease [NICE, 2011a].

Basis for measuring calcium, phosphate, parathyroid hormone, and vitamin D in stages 3B, 4, and 5

Metabolic bone disease is often asymptomatic, with symptoms appearing only late in its course. Problems can be identified early by decreasing serum calcium, phosphate, and vitamin D concentrations and increasing serum parathyroid hormone concentrations.

The guideline development group reviewed five cross-sectional studies and one observational study. They concluded that although abnormal levels of calcium, phosphate, parathyroid hormone and vitamin D were noted in some people with chronic kidney disease stage 1, 2, or 3, the clinical significance of these levels was uncertain.

eGFR deterioration

How do I know if the eGFR has deteriorated significantly?

If a decline in estimated glomerular filtration rate (eGFR) is seen, repeat three times over a period of at least 90 days.

A significant eGFR decline is indicated if there is more than a:

5 mL/min/1.73 m2 decrease within 1 year, or

10 mL/min/1.73 m2 decrease within 5 years.

If a large decline in eGFR is seen (25% or more), repeat within 2 weeks to exclude acute kidney injury.

Consider the person's baseline eGFR and the lifetime likelihood, if they continued the same rate of decline, that they would eventually reach an eGFR level that would require renal replacement therapy.

For example, a rate of decline of 3 mL/min/1.73 m2 per year would be of greater concern in a person of 40 years of age with a baseline eGFR of 30 mL/min/1.73 m2 than in a person of 70 years of age with a baseline eGFR of 60 mL/min/1.73 m2.

When the laboratory reports only that the person's eGFR exceeds their reference range (for example, they only report an eGFR as greater than 60 mL/min/1.73 m2), suspect a significant deterioration in renal function (such as acute kidney injury) if the person's serum creatinine increases greater than 1.5-fold.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for identifying a sudden decline in estimated glomerular filtration rate (eGFR)

A decline in eGFR of greater than 25% suggests acute kidney injury, which requires an urgent assessment and specialist intervention (see Referral).

Basis for the definition of a significant gradual decline in eGFR

The NICE guideline development group based their recommendations on a consideration of biological and assay variability in serum creatinine concentrations, and evidence (from two cross-sectional studies) that a decline in eGFR of more than 2 mL/min/1.73 m2 per year is more than can be explained by ageing alone.

Basis for identifying people with a declining eGFR

People with a declining eGFR have a worse prognosis (in terms of adverse outcomes) and require early intervention (to prevent further renal deterioration) compared with people with a stable eGFR.

Lifestyle advice

What lifestyle advice is recommended?

Encourage people with chronic kidney disease to:

Stop smoking (if appropriate) and drink sensible amounts of alcohol (see the CKS topics on Smoking cessation and Alcohol - problem drinking).

Take regular exercise, and achieve a healthy body weight (see the CKS topic on Obesity).

Eat a healthy diet.

Avoid using over-the-counter nonsteroidal anti-inflammatory drugs (except on medical advice).

Provide information appropriate to the stage and cause of chronic kidney disease.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group investigated the effect of lifestyle habits on the progression of chronic kidney disease. There were very few interventional lifestyle studies, so observational studies were included, all of which were limited by small sample sizes.

Basis for advising regular exercise, eating a healthy diet, and obtaining a healthy weight

The guideline development group recognized that weight control, healthy eating, and taking regular exercise are of particular benefit to people with cardiovascular disease (CVD). There was no direct evidence that lifestyle changes had any additional benefit in people with chronic kidney disease. However as people with chronic kidney disease are at increased risk of CVD, the guideline development group agreed that exercise and weight control should be encouraged.

Basis for stopping smoking

Stopping smoking reduces the risk of CVD. In addition, smoking has been shown to be associated with an increased risk of chronic kidney disease progression.

Basis for a reduced alcohol intake

There is no evidence on specific adverse effects of alcohol consumption in people with chronic kidney disease. However, sensible drinking will reduce the risk of hypertension and CVD.

Basis for healthy eating

People with advanced chronic kidney disease commonly have a poor appetite, making them vulnerable to malnutrition, disease, and infection. Specialist input should be sought to give advice about the risks and benefits of protein restriction in advanced stages of disease (slowing down renal progression versus protein-calorie malnutrition).

Basis for avoiding over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs)

Short-term use of NSAIDs can lead to a sudden decrease in glomerular filtration rate. Long-term use, even at therapeutic doses, can be associated with progression of chronic kidney disease. The guideline development group recommended that if NSAIDs are clinically necessary, their effect on glomerular filtration rate should be monitored and they should be stopped if there is evidence of renal progression (see eGFR deterioration).

Blood pressure

What blood pressure is recommended?

In people with chronic kidney disease, ideally aim for:

Systolic blood pressure less than 140 mmHg (target range 120–139 mmHg).

Diastolic blood pressure less than 90 mmHg.

In people with chronic kidney disease and a urinary albumin:creatinine ratio of 70 mg/mmol or more, ideally aim for:

Systolic blood pressure less than 130 mmHg (target range 120–129 mmHg).

Diastolic blood pressure less than 80 mmHg.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or urinary protein excretion of 1.0 g/24 hours or more.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group reviewed evidence (meta-analyses, randomized controlled trials [RCTs], longitudinal cohort studies) that investigated diastolic and systolic blood pressure control in people with chronic kidney disease in relation to cardiovascular and renal outcomes.

Basis for blood pressure control in chronic kidney disease

There is strong evidence that reducing blood pressure reduces cardiovascular risk and renal progression.

Basis for an optimal range for systolic and diastolic blood pressure control in chronic kidney disease

The evidence suggests that there are optimal ranges, with increased risk of adverse outcomes both above and below the optimal range, for both systolic and diastolic blood pressures.

Systolic blood pressure:

Less than 120 mmHg is associated with an increase in mortality, cardiovascular mortality, stroke, and congestive heart failure.

More than 140 mmHg is associated with increased risk of end-stage renal disease, doubling of serum creatinine concentration, and death.

Diastolic blood pressure:

Less than 60 mmHg is associated with an increased risk of death, myocardial infarction, and decline in estimated glomerular filtration rate.

More than 80 mmHg is associated with an increased risk of end-stage renal disease, doubling of serum creatinine concentration, and death.

The guideline development group noted that adverse outcomes seen with lower blood pressure may have been subject to reverse causality (the adverse outcome resulted in the low blood pressure reading rather than vice versa).

Basis for a diastolic blood pressure threshold rather than an optimal range

Although diastolic blood pressure less than 60 mmHg has been associated with adverse outcomes, the guideline development group agreed that, in practice, when treatment is given to maintain systolic blood pressure in the optimal range, this can result in diastolic blood pressure falling below its optimal range.

Basis for a lower blood pressure target in people with a urinary albumin:creatinine ratio of 70 mg/mmol or more

The guideline development group noted there was some evidence (from a meta-analysis of 11 RCTs) that a systolic blood pressure target of 130–139 mmHg (compared with 110–119 mmHg) results in a significantly increased risk of renal disease progression in people with higher levels of proteinuria.

ACE inhibitors or AIIRAs

When are ACE inhibitors or AIIRAs recommended?

Offer an angiotensin-converting enzyme (ACE) inhibitor to people with chronic kidney disease if there is:

Hypertension and proteinuria with a urinary albumin:creatinine ratio of 30 mg/mmol or more, or

Proteinuria with a urinary albumin:creatinine ratio of 70 mg/mmol or more (irrespective of blood pressure).

A urinary albumin:creatinine ratio of 30 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 50 mg/mmol or more, or a urinary protein excretion of 0.5 g/24 hours or more.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or a urinary protein excretion of 1 g/24 hours or more.

Start with a low dose and titrate up to the maximum tolerated therapeutic dose (within the maximum licensed dose), by doubling the dose every 1–2 weeks. After each upward titration, monitor the person's renal function, serum potassium level, and blood pressure.

If the person cannot tolerate an ACE inhibitor (due to non-renal adverse effects), offer an angiotensin-II receptor antagonist (AIIRA) as an alternative (see prescribing ACE inhibitors and AIIRAs).

For people with hypertension and no proteinuria (urinary albumin:creatinine ratio less than 30 mg/mmol), treat in line with current guidance on hypertension management (see the CKS topic on Hypertension - not diabetic).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group reviewed the evidence (six systematic reviews and 10 randomized controlled trials [RCTs]) which compared the use of ACE inhibitors or angiotensin-II receptor antagonists (AIIRAs) with placebo or other antihypertensive drugs (such as alpha- or beta-blockers, calcium-channel blockers, thiazide diuretics) in people with chronic kidney disease. Most trials used antihypertensives (non-ACE inhibitors or non-AIIRAs) in both arms to achieve blood pressure control.

Basis for an ACE inhibitor or AIIRA in people with chronic kidney disease and proteinuria

The guideline development group noted that the beneficial effects of ACE inhibitors and AIIRAs appeared to be more closely related to the presence or absence of proteinuria rather than blood pressure control. For example, when used for blood pressure control in people with chronic kidney disease and proteinuria, ACE inhibitors and AIIRAs resulted in a significant reduction in cardiovascular outcomes, proteinuria, and renal progression compared with control treatment.

Basis for offering a choice of antihypertensive medication in people with chronic kidney disease and no evidence of proteinuria

A number of trials of antihypertensive treatment have shown that a reduction in blood pressure reduces the risk of end-stage kidney disease and of cardiovascular disease regardless of the class of drug used. Although ACE inhibitors and AIIRAs may also be beneficial in people with chronic kidney disease with lower levels of proteinuria, there is no evidence that they are more beneficial than other antihypertensive drugs for the same level of blood pressure reduction.

Basis for offering any ACE inhibitor first-line

The guideline development group agreed that there was no evidence to suggest an advantage of one ACE inhibitor over any other.

Basis for offering an ACE inhibitor first-line compared with an AIIRA

The guideline development group agreed that there was no evidence to suggest an advantage of ACE inhibitor over an AIIRA. However, health economic analysis based on RCTs (only three RCTs were UK-based) suggested an increased cost-effectiveness for ACE inhibitors compared with AIIRAs when used in people with chronic kidney disease for blood pressure control.

Basis for not combining an ACE inhibitor and an AIIRA

There was no evidence to suggest increased effectiveness of combining an ACE inhibitor with an AIIRA over the maximum recommended dose of each individual drug.

Combining drugs could result in a deterioration in renal function (see Adverse effects of ACE inhibitors or AIIRAs). However, combination treatment may be initiated by a specialist under certain circumstances to control blood pressure and worsening proteinuria.

Statins or aspirin

When are statins or aspirin recommended?

People with chronic kidney disease should be offered antiplatelet and statin treatment as for the rest of the population.

For primary prevention of cardiovascular disease (CVD), calculate the CVD risk based on existing risk tables (see the CKS topic on CVD risk assessment and management).

For secondary prevention of CVD, see the CKS topics on Antiplatelet treatment and Lipid modification - CVD prevention.

Additional information

Additional information

Dyslipidaemia

Dyslipidaemia in chronic kidney disease is distinct from the general population. The key changes appear to be hypertriglyceridaemia, increased remnant lipoproteins, reduced high-density lipoprotein (HDL) cholesterol, and increased atherogenic sub-types of low-density lipoprotein (LDL) cholesterol.

When calculating cardiovascular disease (CVD) risk, remember that the Framingham risk tables significantly underestimate the risk of CVD in people with chronic kidney disease.

Bleeding and thrombosis

People with chronic kidney disease paradoxically have both thrombotic and bleeding tendencies.

Increased bleeding is due to prolonged bleeding times, which become more prevalent with increasing severity of chronic kidney disease.

Increased thrombosis is due to higher levels of procoagulant activity.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for prescribing statins based on existing cardiovascular disease (CVD) risk tables

Epidemiological studies suggest that dyslipidaemia is a risk factor for chronic kidney disease. The NICE guideline development group discussed whether chronic kidney disease itself should influence the use of statins in the primary prevention of CVD. They agreed that currently there is no evidence to support chronic kidney disease as a causal risk factor for CVD. Therefore, people with chronic kidney disease should have their CVD risk assessed using current risk tables for CVD.

The guideline development group reviewed three meta-analyses (mainly including people with CVD, or at high risk of CVD) which investigated the role of statins compared with placebo on progression of chronic kidney disease. Due to significant heterogeneity in the studies, the guideline development group concluded that there was insufficient evidence to recommend the use of statins to reduce proteinuria or renal progression in chronic kidney disease.

Basis for prescribing antiplatelet drugs based on existing CVD risk tables

Chronic kidney disease is an independent risk factor for atherosclerosis. Large trials in the general population have shown that antiplatelet drugs reduce the risk of cardiovascular events. However:

There is no trial evidence to support the use of aspirin in people with chronic kidney disease without CVD or an estimated CVD risk greater than 20%.

Observational studies suggest that people with chronic kidney disease receiving aspirin are at increased risk of minor bleeding, but the evidence does not show a significant increase in the incidence of major bleeding.

Basis for prescribing statins in people with chronic kidney disease and CVD

The benefits of statins in CVD are clear. Although people with chronic kidney disease are at increased risk of CVD and might be expected to benefit from statins, the published evidence on statin use in CVD has largely excluded people with chronic kidney disease.

The guideline development group reviewed a systematic review investigating cardiovascular outcomes in people with chronic kidney disease and CVD randomized to statins or placebo or no treatment. Compared with placebo, statins significantly reduced the risk of all-cause mortality, cardiovascular mortality, non-fatal cardiovascular events, and major coronary events in all people (not just those with raised lipid concentrations).

Basis for prescribing aspirin in people with chronic kidney disease and CVD

The guideline development group reviewed observational studies and concluded that there was no reason to believe that antiplatelet drugs were less effective for secondary prevention of cardiovascular events in people with chronic kidney disease.

Observational studies have suggested worsening progression of chronic kidney disease with aspirin use. However, these results should be interpreted with caution, as the participants had existing CVD, a known risk factor for progression of chronic kidney disease.

Scenario: Stage 4 and 5 CKD

Scenario: Management of stage 4 and 5 chronic kidney disease

216months3060monthsBoth

Referral

When is referral recommended in stage 4 or 5 CKD?

Refer according to local guidelines, where available. The urgency of referral should be based on clinical judgement.

People with chronic kidney disease stage 4 or 5 should usually be referred to a nephrology specialist.

Once a referral has been made and a plan jointly agreed, it may be possible for follow up to take place in primary care.

When the laboratory reports only that the eGFR is greater than 60 mL/min/1.73 m2, suspect a significant deterioration in renal function (such as acute renal failure) if serum creatinine increases greater than 1.5-fold.

People with urinary tract obstruction (for example the bladder is palpable) should be referred to a urologist — unless urgent medical intervention is needed for problems such as hyperkalaemia (potassium greater than 6 mmol/L), uraemia, acidosis, or fluid overload.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group noted that there was no evidence to guide recommendations on referral. Therefore, they based their recommendations on other guidelines and their own professional judgement.

Basis for referring people with a significant deterioration in estimated glomerular filtration rate (eGFR) or with chronic kidney disease stage 4 or 5

An early referral for people with stage 4 or 5 disease will allow time to prepare for renal replacement therapy. There is evidence that late referral leads to increased morbidity and mortality in people with advanced chronic kidney disease.

Basis for referring people with complications, proteinuria with haematuria, or risk factors for progression of chronic kidney disease

A specialist may carry out a renal biopsy or imaging (ultrasound, computed tomography) to identify causes of chronic kidney disease, especially if there is heavy proteinuria, or proteinuria with haematuria.

A specialist team will also help manage risk factors for chronic kidney disease progression (for example uncontrolled hypertension) and identify complications which need further intervention (such as anaemia, renal bone disease).

Tests to monitor

What tests should be monitored in CKD stage 4 and 5

People with chronic kidney disease stage 4 or 5 should usually be under specialist care, but monitoring of blood tests may take place in primary care as part of shared care arrangements.

Measure estimated glomerular filtration rate (eGFR) every 3 months in stage 4 disease and every 6 weeks in stage 5 disease.

Check haemoglobin level to exclude anaemia (haemoglobin 11 g/dL or less), as well as serum calcium, phosphate, vitamin D, and parathyroid hormone. Frequency of subsequent monitoring will depend on the results and clinical circumstances.

Test for proteinuria every 12 months:

If the person is not already known to have proteinuria, measure the urinary albumin:creatinine ratio.

If the person is known to have proteinuria, monitoring can be with urinary albumin:creatinine or protein:creatinine ratios.

If the person has haematuria (with no urological cause), carry out a dipstick test for haematuria every 12 months or until it is no longer persistent.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for monitoring estimated glomerular filtration rate (eGFR)

Many people with chronic kidney disease do not progress to end-stage renal disease. In those that do progress, the subsequent risks of mortality and morbidity rise exponentially (see eGFR deterioration).

Basis for monitoring proteinuria

Proteinuria is associated with renal progression and cardiovascular disease.

If proteinuria develops (a urinary albumin:creatinine ratio of 30 mg/mmol or more) and the person has hypertension, an angiotensin-converting enzyme inhibitor (or angiotensin-II receptor antagonist) is indicated (see ACE inhibitors or AIIRAs).

If heavy proteinuria develops (urinary albumin:creatinine ratio of 70 mg/mmol or more, or urinary protein:creatinine ratio of 100 mg/mmol or more), an angiotensin-converting enzyme inhibitor (or angiotensin-II receptor antagonist) is indicated irrespective of blood pressure (see ACE inhibitors or AIIRAs), and blood pressure should be controlled more aggressively (see Blood pressure). In addition, a specialist nephrology opinion should usually be sought.

Basis for monitoring isolated haematuria

The NICE guideline development group noted that the commonest abnormality identified in people with isolated invisible haematuria was IgA nephropathy, and that this condition has the propensity to progress. However, it was agreed that if haematuria disappeared there was a low or non-existent risk of developing progressive chronic kidney disease.

Basis for screening for anaemia in stages 3B, 4, and 5

UK primary care data demonstrate that the prevalence of anaemia rises sharply if the glomerular filtration rate is less than 45 mL/min/1.73 m2 (the prevalence of anaemia is 10% in stage 4 disease compared with 2.9% in stage 3).

The recommendation that anaemia should be investigated if haemoglobin is 11 g/dL or less, or if the person has symptoms suggesting possible anaemia is based on the NICE clinical guideline Anaemia management in people with chronic kidney disease [NICE, 2011a].

Basis for measuring calcium, phosphate, parathyroid hormone, and vitamin D in stages 3B, 4, and 5

Metabolic bone disease is often asymptomatic, with symptoms appearing only late in its course. Problems can be identified early by decreasing serum calcium, phosphate, and vitamin D concentrations and increasing serum parathyroid hormone concentrations.

The guideline development group reviewed five cross-sectional studies and one observational study. They concluded that although abnormal levels of calcium, phosphate, parathyroid hormone and vitamin D were noted in some people with chronic kidney disease stage 1, 2, or 3, the clinical significance of these levels was uncertain.

eGFR deterioration

How do I know if the eGFR has deteriorated significantly?

If a decline in estimated glomerular filtration rate (eGFR) is seen, repeat three times over a period of at least 90 days.

A significant eGFR decline is indicated if there is more than a:

5 mL/min/1.73 m2 decrease within 1 year, or

10 mL/min/1.73 m2 decrease within 5 years.

If a large decline in eGFR is seen (25% or more), repeat within 2 weeks to exclude acute kidney injury.

Consider the person's baseline eGFR and the lifetime likelihood, if they continued the same rate of decline, that they would eventually reach an eGFR level that would require renal replacement therapy.

For example, a rate of decline of 3 mL/min/1.73 m2 per year would be of greater concern in a person of 40 years of age with a baseline eGFR of 30 mL/min/1.73 m2 than in a person of 70 years of age with a baseline eGFR of 60 mL/min/1.73 m2.

When the laboratory reports only that the person's eGFR exceeds their reference range (for example, they only report an eGFR as greater than 60 mL/min/1.73 m2), suspect a significant deterioration in renal function (such as acute kidney injury) if the person's serum creatinine increases greater than 1.5-fold.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for identifying a sudden decline in estimated glomerular filtration rate (eGFR)

A decline in eGFR of greater than 25% suggests acute kidney injury, which requires an urgent assessment and specialist intervention (see Referral).

Basis for the definition of a significant gradual decline in eGFR

The NICE guideline development group based their recommendations on a consideration of biological and assay variability in serum creatinine concentrations, and evidence (from two cross-sectional studies) that a decline in eGFR of more than 2 mL/min/1.73 m2 per year is more than can be explained by ageing alone.

Basis for identifying people with a declining eGFR

People with a declining eGFR have a worse prognosis (in terms of adverse outcomes) and require early intervention (to prevent further renal deterioration) compared with people with a stable eGFR.

Lifestyle advice

What lifestyle advice is recommended?

Encourage people with chronic kidney disease to:

Stop smoking (if appropriate) and drink sensible amounts of alcohol (see the CKS topics on Smoking cessation and Alcohol - problem drinking).

Take regular exercise, and achieve a healthy body weight (see the CKS topic on Obesity).

Eat a healthy diet.

Avoid using over-the-counter nonsteroidal anti-inflammatory drugs (except on medical advice).

Provide information appropriate to the stage and cause of chronic kidney disease.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group investigated the effect of lifestyle habits on the progression of chronic kidney disease. There were very few interventional lifestyle studies, so observational studies were included, all of which were limited by small sample sizes.

Basis for advising regular exercise, eating a healthy diet, and obtaining a healthy weight

The guideline development group recognized that weight control, healthy eating, and taking regular exercise are of particular benefit to people with cardiovascular disease (CVD). There was no direct evidence that lifestyle changes had any additional benefit in people with chronic kidney disease. However as people with chronic kidney disease are at increased risk of CVD, the guideline development group agreed that exercise and weight control should be encouraged.

Basis for stopping smoking

Stopping smoking reduces the risk of CVD. In addition, smoking has been shown to be associated with an increased risk of chronic kidney disease progression.

Basis for a reduced alcohol intake

There is no evidence on specific adverse effects of alcohol consumption in people with chronic kidney disease. However, sensible drinking will reduce the risk of hypertension and CVD.

Basis for healthy eating

People with advanced chronic kidney disease commonly have a poor appetite, making them vulnerable to malnutrition, disease, and infection. Specialist input should be sought to give advice about the risks and benefits of protein restriction in advanced stages of disease (slowing down renal progression versus protein-calorie malnutrition).

Basis for avoiding over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs)

Short-term use of NSAIDs can lead to a sudden decrease in glomerular filtration rate. Long-term use, even at therapeutic doses, can be associated with progression of chronic kidney disease. The guideline development group recommended that if NSAIDs are clinically necessary, their effect on glomerular filtration rate should be monitored and they should be stopped if there is evidence of renal progression (see eGFR deterioration).

Blood pressure

What blood pressure is recommended?

In people with chronic kidney disease, ideally aim for:

Systolic blood pressure less than 140 mmHg (target range 120–139 mmHg).

Diastolic blood pressure less than 90 mmHg.

In people with chronic kidney disease and a urinary albumin:creatinine ratio of 70 mg/mmol or more, ideally aim for:

Systolic blood pressure less than 130 mmHg (target range 120–129 mmHg).

Diastolic blood pressure less than 80 mmHg.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or urinary protein excretion of 1.0 g/24 hours or more.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group reviewed evidence (meta-analyses, randomized controlled trials [RCTs], longitudinal cohort studies) that investigated diastolic and systolic blood pressure control in people with chronic kidney disease in relation to cardiovascular and renal outcomes.

Basis for blood pressure control in chronic kidney disease

There is strong evidence that reducing blood pressure reduces cardiovascular risk and renal progression.

Basis for an optimal range for systolic and diastolic blood pressure control in chronic kidney disease

The evidence suggests that there are optimal ranges, with increased risk of adverse outcomes both above and below the optimal range, for both systolic and diastolic blood pressures.

Systolic blood pressure:

Less than 120 mmHg is associated with an increase in mortality, cardiovascular mortality, stroke, and congestive heart failure.

More than 140 mmHg is associated with increased risk of end-stage renal disease, doubling of serum creatinine concentration, and death.

Diastolic blood pressure:

Less than 60 mmHg is associated with an increased risk of death, myocardial infarction, and decline in estimated glomerular filtration rate.

More than 80 mmHg is associated with an increased risk of end-stage renal disease, doubling of serum creatinine concentration, and death.

The guideline development group noted that adverse outcomes seen with lower blood pressure may have been subject to reverse causality (the adverse outcome resulted in the low blood pressure reading rather than vice versa).

Basis for a diastolic blood pressure threshold rather than an optimal range

Although diastolic blood pressure less than 60 mmHg has been associated with adverse outcomes, the guideline development group agreed that, in practice, when treatment is given to maintain systolic blood pressure in the optimal range, this can result in diastolic blood pressure falling below its optimal range.

Basis for a lower blood pressure target in people with a urinary albumin:creatinine ratio of 70 mg/mmol or more

The guideline development group noted there was some evidence (from a meta-analysis of 11 RCTs) that a systolic blood pressure target of 130–139 mmHg (compared with 110–119 mmHg) results in a significantly increased risk of renal disease progression in people with higher levels of proteinuria.

ACE inhibitors or AIIRAs

When are ACE inhibitors or AIIRAs recommended?

Offer an angiotensin-converting enzyme (ACE) inhibitor to people with chronic kidney disease if there is:

Hypertension and proteinuria with a urinary albumin:creatinine ratio of 30 mg/mmol or more, or

Proteinuria with a urinary albumin:creatinine ratio of 70 mg/mmol or more (irrespective of blood pressure).

A urinary albumin:creatinine ratio of 30 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 50 mg/mmol or more, or a urinary protein excretion of 0.5 g/24 hours or more.

A urinary albumin:creatinine ratio of 70 mg/mmol or more is approximately equivalent to a urinary protein:creatinine ratio of 100 mg/mmol or more, or a urinary protein excretion of 1 g/24 hours or more.

Start with a low dose and titrate up to the maximum tolerated therapeutic dose (within the maximum licensed dose), by doubling the dose every 1–2 weeks. After each upward titration, monitor the person's renal function, serum potassium level, and blood pressure.

If the person cannot tolerate an ACE inhibitor (due to non-renal adverse effects), offer an angiotensin-II receptor antagonist (AIIRA) as an alternative (see prescribing ACE inhibitors and AIIRAs).

For people with hypertension and no proteinuria (urinary albumin:creatinine ratio less than 30 mg/mmol), treat in line with current guidance on hypertension management (see the CKS topic on Hypertension - not diabetic).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

The NICE guideline development group reviewed the evidence (six systematic reviews and 10 randomized controlled trials [RCTs]) which compared the use of ACE inhibitors or angiotensin-II receptor antagonists (AIIRAs) with placebo or other antihypertensive drugs (such as alpha- or beta-blockers, calcium-channel blockers, thiazide diuretics) in people with chronic kidney disease. Most trials used antihypertensives (non-ACE inhibitors or non-AIIRAs) in both arms to achieve blood pressure control.

Basis for an ACE inhibitor or AIIRA in people with chronic kidney disease and proteinuria

The guideline development group noted that the beneficial effects of ACE inhibitors and AIIRAs appeared to be more closely related to the presence or absence of proteinuria rather than blood pressure control. For example, when used for blood pressure control in people with chronic kidney disease and proteinuria, ACE inhibitors and AIIRAs resulted in a significant reduction in cardiovascular outcomes, proteinuria, and renal progression compared with control treatment.

Basis for offering a choice of antihypertensive medication in people with chronic kidney disease and no evidence of proteinuria

A number of trials of antihypertensive treatment have shown that a reduction in blood pressure reduces the risk of end-stage kidney disease and of cardiovascular disease regardless of the class of drug used. Although ACE inhibitors and AIIRAs may also be beneficial in people with chronic kidney disease with lower levels of proteinuria, there is no evidence that they are more beneficial than other antihypertensive drugs for the same level of blood pressure reduction.

Basis for offering any ACE inhibitor first-line

The guideline development group agreed that there was no evidence to suggest an advantage of one ACE inhibitor over any other.

Basis for offering an ACE inhibitor first-line compared with an AIIRA

The guideline development group agreed that there was no evidence to suggest an advantage of ACE inhibitor over an AIIRA. However, health economic analysis based on RCTs (only three RCTs were UK-based) suggested an increased cost-effectiveness for ACE inhibitors compared with AIIRAs when used in people with chronic kidney disease for blood pressure control.

Basis for not combining an ACE inhibitor and an AIIRA

There was no evidence to suggest increased effectiveness of combining an ACE inhibitor with an AIIRA over the maximum recommended dose of each individual drug.

Combining drugs could result in a deterioration in renal function (see Adverse effects of ACE inhibitors or AIIRAs). However, combination treatment may be initiated by a specialist under certain circumstances to control blood pressure and worsening proteinuria.

Statins or aspirin

When are statins or aspirin recommended?

People with chronic kidney disease should be offered antiplatelet and statin treatment as for the rest of the population.

For primary prevention of cardiovascular disease (CVD), calculate the CVD risk based on existing risk tables (see the CKS topic on CVD risk assessment and management).

For secondary prevention of CVD, see the CKS topics on Antiplatelet treatment and Lipid modification - CVD prevention.

Additional information

Additional information

Dyslipidaemia

Dyslipidaemia in chronic kidney disease is distinct from the general population. The key changes appear to be hypertriglyceridaemia, increased remnant lipoproteins, reduced high-density lipoprotein (HDL) cholesterol, and increased atherogenic sub-types of low-density lipoprotein (LDL) cholesterol.

When calculating cardiovascular disease (CVD) risk, remember that the Framingham risk tables significantly underestimate the risk of CVD in people with chronic kidney disease.

Bleeding and thrombosis

People with chronic kidney disease paradoxically have both thrombotic and bleeding tendencies.

Increased bleeding is due to prolonged bleeding times, which become more prevalent with increasing severity of chronic kidney disease.

Increased thrombosis is due to higher levels of procoagulant activity.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008; NICE, 2008].

Basis for prescribing statins based on existing cardiovascular disease (CVD) risk tables

Epidemiological studies suggest that dyslipidaemia is a risk factor for chronic kidney disease. The NICE guideline development group discussed whether chronic kidney disease itself should influence the use of statins in the primary prevention of CVD. They agreed that currently there is no evidence to support chronic kidney disease as a causal risk factor for CVD. Therefore, people with chronic kidney disease should have their CVD risk assessed using current risk tables for CVD.

The guideline development group reviewed three meta-analyses (mainly including people with CVD, or at high risk of CVD) which investigated the role of statins compared with placebo on progression of chronic kidney disease. Due to significant heterogeneity in the studies, the guideline development group concluded that there was insufficient evidence to recommend the use of statins to reduce proteinuria or renal progression in chronic kidney disease.

Basis for prescribing antiplatelet drugs based on existing CVD risk tables

Chronic kidney disease is an independent risk factor for atherosclerosis. Large trials in the general population have shown that antiplatelet drugs reduce the risk of cardiovascular events. However:

There is no trial evidence to support the use of aspirin in people with chronic kidney disease without CVD or an estimated CVD risk greater than 20%.

Observational studies suggest that people with chronic kidney disease receiving aspirin are at increased risk of minor bleeding, but the evidence does not show a significant increase in the incidence of major bleeding.

Basis for prescribing statins in people with chronic kidney disease and CVD

The benefits of statins in CVD are clear. Although people with chronic kidney disease are at increased risk of CVD and might be expected to benefit from statins, the published evidence on statin use in CVD has largely excluded people with chronic kidney disease.

The guideline development group reviewed a systematic review investigating cardiovascular outcomes in people with chronic kidney disease and CVD randomized to statins or placebo or no treatment. Compared with placebo, statins significantly reduced the risk of all-cause mortality, cardiovascular mortality, non-fatal cardiovascular events, and major coronary events in all people (not just those with raised lipid concentrations).

Basis for prescribing aspirin in people with chronic kidney disease and CVD

The guideline development group reviewed observational studies and concluded that there was no reason to believe that antiplatelet drugs were less effective for secondary prevention of cardiovascular events in people with chronic kidney disease.

Observational studies have suggested worsening progression of chronic kidney disease with aspirin use. However, these results should be interpreted with caution, as the participants had existing CVD, a known risk factor for progression of chronic kidney disease.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Choice of ACE inhibitor/AIIRA

Which ACE inhibitor/AIIRA is recommended?

CKS recommends enalapril, lisinopril, or ramipril (ACE inhibitors) first line.

CKS recommends irbesartan or losartan (AIIRAs) if an ACE inhibitor is not tolerated because of non-renal adverse effects (for example persistent, troublesome cough).

Basis for recommendation

There is no evidence to suggest that any particular angiotensin-converting enzyme (ACE) inhibitor is more effective than another in the management of chronic kidney disease [NICE, 2008].

However, there is evidence from randomized controlled trials to support the use of enalapril, lisinopril, ramipril, irbesartan, and losartan in people with diabetic nephropathy. For supporting evidence, see the CKS topic on Diabetes - type 2.

There is no evidence to suggest any advantage of an ACE inhibitor over an angiotensin-II receptor antagonist (AIIRA); however, economic evidence suggests increased cost-effectiveness for ACE inhibitors compared with AIIRAs [NICE, 2008].

Contraindications and cautions

Who should avoid taking ACE inhibitors or AIIRAs?

Contraindications to angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II antagonists (AIIRAs) include:

History of angioedema associated with previous exposure to an ACE inhibitor, or hereditary or idiopathic angioedema.

Severe bilateral renal artery stenosis (or severe unilateral renal artery stenosis in people with only one functioning kidney).

Severe hepatic impairment.

Pregnancy:

ACE inhibitors are contraindicated during the second and third trimesters of pregnancy. Exposure to an ACE inhibitor during the second and third trimester is known to induce human fetal toxicity (decreased renal function, oligohydramnios, delay in skull ossification, and neonatal toxicity) [MHRA, 2007; Schaefer et al, 2007; ABPI Medicines Compendium, 2008; ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2009c].

ACE inhibitors are not recommended during the first trimester of pregnancy. Evidence on the risk of teratogenicity after exposure to ACE inhibitors during the first trimester of pregnancy is conflicting, and an increase in the risk of congenital malformation (particularly of the cardiovascular system and central nervous system) cannot be excluded [MHRA, 2007; NTIS, 2007].

Unless continued treatment with an ACE inhibitor is considered essential, women who are planning a pregnancy should be switched to an alternative treatment with an established safety profile for use in pregnancy. The balance of risks and benefits of continued treatment with an ACE inhibitor versus the potential risk of congenital anomaly should be discussed with the woman. When pregnancy is confirmed, treatment with an ACE inhibitor should be stopped as soon as possible and, if appropriate, alternative treatment should be started [MHRA, 2007].

Breastfeeding:

ACE inhibitors are not recommended for use by women who are breastfeeding [MHRA, 2009b].

During the first few weeks after delivery ACE inhibitors can cause profound neonatal hypotension; preterm babies may be at particular risk [MHRA, 2009a].

In women who are breastfeeding older infants, the use of captopril, enalapril, or quinapril may be considered if the use of an ACE inhibitor is necessary [MHRA, 2009a]. If used, the infant should be carefully followed up for possible signs of hypotension [MHRA, 2009b].

Concomitant use of perindopril with aliskiren (a renin inhibitor) is contraindicated in people with renal impairment (estimated glomerular filtration rate [eGFR] less than 60mL/min/1.73m2), as there is a risk of hyperkalaemia, worsening renal function, and cardiovascular morbidity and mortality [ABPI Medicines Compendium, 2013].

Close supervision of start dose

Who should start an ACE inhibitor or AIIRA under outpatient supervision?

People at high risk of first-dose hypotension, hyperkalaemia, or renal failure should start treatment under close supervision (if in doubt, discuss this with a specialist). This includes people with the following features:

Renal impairment, with an estimated glomerular filtration rate (eGFR) of less than 30 mL/minute/1.73 m2.

A previous decrease in eGFR of more than than 15% after taking an angiotensin-converting enzyme (ACE) inhibitor.

A strong clinical suspicion of renal artery stenosis.

Baseline serum potassium of 5.0 mmol/L or greater.

Hyponatraemia (sodium less than 130 mmol/L).

Hypovolaemia.

Unstable heart failure.

Receiving high-dose diuretic treatment (for example more than furosemide 80 mg per day) who cannot tolerate withdrawal of this prior to starting an ACE inhibitor.

Receiving high-dose vasodilator treatment.

[NICE, 2003; NICE, 2008; BNF 57, 2009]

Starting and titrating ACE inhibitors or AIIRAs

What dose of an ACE inhibitor or AIIRA should I prescribe and how should the dose be titrated?

Consider whether the ACE inhibitor or angiotensin-II receptor antagonist (AIIRA) should be started under specialist supervision.

Start with a low dose and titrate up to the maximum tolerated therapeutic dose (within the maximum licensed dose), by doubling the dose every 1–2 weeks. After each upward titration, monitor the person's renal function, serum potassium level, and blood pressure.

Do not increase the dose further if there is worsening renal function or hyperkalaemia.

The following tables show the recommended doses of ACE inhibitors and AIIRAs for hypertension and diabetic nephropathy.

Table 1 . Recommended doses of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists (AIIRAs) for hypertension.
Drug Usual starting dose Lower starting dose Maximum licensed dose (per day)
ACE inhibitors
Enalapril 5–10 mg daily 5 mg daily 40 mg
Lisinopril 10 mg daily 2.5–5 mg daily 80 mg
Perindopril erbumine 4 mg daily 2 mg daily 8 mg
Perindopril arginine 5 mg daily 2.5 mg daily 10 mg
Ramipril 1.25 mg daily 10 mg
Trandolapril 0.5 mg daily 4 mg
AIIRAs
Candesartan 8 mg daily 2–4 mg 32 mg
Irbesartan 150 mg daily 75 mg daily 300 mg
Losartan 50 mg daily 25 mg daily 100 mg
Valsartan 80 mg daily 40 mg daily 320 mg
Data from: BNF, Summaries of Product Characteristics
Table 2 . Recommended doses of ACE inhibitors and AIIRAs for diabetic nephropathy.
Drug Usual starting dose Lower starting dose Maximum recommended dose (per day)
ACE inhibitors
Enalapril 5–10 mg daily 5 mg daily 40 mg
Lisinopril 10 mg daily 5 mg daily 20 mg
Ramipril 2.5 mg daily 10 mg
AIIRAs
Irbesartan 150 mg daily 75 mg daily 300 mg
Losartan 50 mg daily 25 mg daily 100 mg
† Products not specifically licensed for the management of diabetic nephropathy. Data from: BNF, Summaries of Product Characteristics

[NICE, 2003; NICE, 2008; BNF 57, 2009]

Monitoring ACE inhibitors or AIIRAs

How should I monitor someone taking ACE inhibitors or angiotensin-II receptor antagonists?

Measure serum creatinine and electrolytes, and estimated glomerular filtration rate (eGFR):

Before starting therapy.

1–2 weeks after starting treatment.

1–2 weeks after subsequent dose increases.

Once the target blood pressure has been achieved and is stable, it is usual to monitor:

Blood pressure every 3–6 months.

Urea and electrolytes, and eGFR, every 12 months (unless required more frequently because of impaired renal function).

[Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and Renal Association, 2006; NICE, 2008; BNF 57, 2009]

Abnormal potassium or eGFR results

How should I manage abnormal potassium or eGFR results?

Some increase in serum creatinine and potassium is expected after starting or increasing the dose of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-II receptor antagonist (AIIRA).

If estimated glomerular filtration rate (eGFR) decreases by 24%, or serum creatinine increases by up to 29%:

Do not modify the ACE inhibitor/AIIRA dose and recheck levels in a further 1–2 weeks.

If eGFR decreases by 25% or more, or serum creatinine increases by 30% or more:

Investigate other causes of deteriorating renal function, such as volume depletion.

Stop or reduce the dose of the following drugs (where appropriate) if the person is taking them:

Nephrotoxic drugs (such as nonsteroidal anti-inflammatory drugs).

Vasodilators (such as calcium-channel blockers, nitrates).

Potassium supplements or potassium-sparing diuretics.

Diuretics (consider dose reduction if the person is hypovolaemic).

If the decrease in eGFR or the increase in serum creatinine persists despite these measures:

Stop the ACE inhibitor or AIIRA therapy, or

Reduce the dose to a previously tolerated lower dose and recheck levels in 5–7 days (add an alternative antihypertensive medication if required).

If serum potassium is 5.0 mmol/L or above:

Investigate other causes of hyperkalaemia and treat accordingly.

Stop or reduce the dose of potassium-sparing diuretics (amiloride, triamterene, spironolactone) or nephrotoxic drugs (such as nonsteroidal anti-inflammatory drugs).

If serum potassium persists between 5.0 and 5.9 mmol/L despite these measures, reduce the dose of ACE inhibitors or AIIRA to a previously tolerated lower dose and recheck levels in 5–7 days.

Stop ACE inhibitors or AIIRAs if serum potassium persists above 6 mmol/L despite these measures.

Consider referral to a dietician: a low-potassium diet (up to 2 g/day), or dietary advice may help resolve hyperkalaemia.

[NICE, 2008]

Adverse effects of ACE inhibitors or AIIRAs

What adverse effects of ACE inhibitors or angiotensin-II receptor antagonists should I be aware of?

Angiotensin-converting enzyme (ACE) inhibitors are generally well tolerated, but occasionally adverse effects can occur. Adverse effects with angiotensin-II antagonists (AIIRAs) are similar, although they tend to be milder.

Deterioration in renal function

Monitor renal function after starting an ACE inhibitor or an AIIRA, after each increase in dose, and regularly throughout treatment.

Hyperkalaemia

Monitor serum electrolytes after starting an ACE inhibitor or an AIIRA, after each increase in dose, and regularly throughout treatment.

Orthostatic hypotension is a common adverse effect of ACE inhibitors or AIIRAs and may cause dizziness, light-headedness, and confusion.

If hypotension is asymptomatic, there is no need to change treatment.

If hypotension is symptomatic:

If there are no signs or symptoms of congestion, consider reducing the dose of any concomitant diuretic.

Consider seeking specialist advice.

Cough occurs in 0–15% of people taking an ACE inhibitor, although it rarely necessitates stopping treatment (less than 5% of people) [Micromedex, 2009].

Cough is common in people with heart failure, or it can be due to smoking-related lung disease or pulmonary oedema.

If the cough is troublesome (for example it prevents the person from sleeping) and other causes have been ruled out, consider switching to an AIIRA.

AIIRAs do not cause cough.

[McMurray et al, 2005; European Society of Cardiology, 2008]

Advice for patients

What advice should I give to someone taking an ACE inhibitor or an AIIRA?

Explain the importance of:

Achieving the maximum tolerated dose of ACE inhibitor or angiotensin-II receptor antagonist.

Regular monitoring of eGFR and serum potassium to achieve this safely.

Advise the person:

That they may experience adverse effects, but that these rarely necessitate stopping treatment.

To report symptoms of hypotension to their healthcare professional.

To avoid nonsteroidal anti-inflammatory drugs (these may be present in over-the-counter products) and salt substitutes that are high in potassium.

The initial dose should be taken late at night or at bedtime to mitigate the hypotensive effects that can occur.

If the drug is well tolerated, subsequent doses should be taken in the morning.

If symptoms of hypotension occur, advise the person to go to bed and take no further doses until they have been reviewed.

[NICE, 2008]

Evidence

Evidence

Supporting evidence

ACE inhibitors and AIIRAs

Evidence on ACE inhibitors and AIIRAs for chronic kidney disease

The NICE guideline development group reviewed six systematic reviews and ten randomized controlled trials which compared the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists (AIIRAs) with placebo or other antihypertensive drugs in people with chronic kidney disease. The guideline development group noted that the beneficial effects of ACE inhibitors and AIIRAs seemed to be more closely related to the presence or absence of proteinuria rather than blood pressure control. ACE inhibitors and AIIRAs resulted in a significant reduction in cardiovascular outcomes, proteinuria, and renal progression compared with control treatment in people with chronic kidney disease and proteinuria [National Collaborating Centre for Chronic Conditions, 2008]:

End-stage renal disease:

There was a significant reduction in the risk of end-stage renal disease with ACE inhibitors (10 studies; n = 6819, RR 0.60, 95% CI 0.39 to 0.93) or AIIRAs (three studies; n = 3251, RR 0.78, 95% CI 0.67 to 0.91) compared with placebo or no treatment.

Proteinuria:

There was a significant reduction in albuminuria with ACE inhibitors or AIIRAs (eight trials; n = 414, mean difference –32.30, 95% CI –49.18 to –15.42) compared with other antihypertensive treatments in people with chronic kidney disease and no evidence of diabetes.

Search strategy

Scope of search

A full literature search was not requested as this CKS topic is primarily based on the National Institute for Health and Care Excellence (NICE) guideline Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care [NICE, 2008].

Search dates

Dates not restricted – October 2008

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSH subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

References

ABPI Medicines Compendium (2008) Summary of product characteristics for Carace 2.5mg, 5mg, 10mg and 20mg tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk

ABPI Medicines Compendium (2009a) Summary of product characteristics for Innovace. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2009b) Summary of product characteristics for Tritace tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk

ABPI Medicines Compendium (2009c) Summary of product characteristics for Zestril 2.5mg, 5mg, 10mg, and 20mg tablets. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013) Summary of product characteristics for Coversyl Arginine. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

BMA and NHS Employers (2011) Summary of 2011/12 QOF indicator changes, points and thresholds. BMA and NHS Employers. www.nhsemployers.org [Free Full-text]

BMA and NHS Employers (2012) Quality and outcomes framework for 2012/13. Guidance for PCOs and practices. BMA and NHS Employers. www.bma.org.uk [Free Full-text]

BMA and NHS Employers (2013) Summary of QOF changes for 2013/14 in England. British Medical Association and NHS Employers. www.nhsemployers.org [Free Full-text]

BNF 57 (2009) British National Formulary. 57th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain.

European Society of Cardiology (2008) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. European Heart Journal 29(19), 2388-2442. [Free Full-text]

Feehally, J., Griffith, K.E., Lamb, E.J. et al. (2008) Early detection of chronic kidney disease. British Medical Journal 337(7674), 845-847.

Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and Renal Association (2006) Chronic kidney disease in adults: UK guidelines for identification, management and referral. Royal College of Physicians. www.renal.org

McMurray, J., Cohen-Solal, A., Dietz, R. et al. (2005) Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice. European Journal of Heart Failure 7(5), 710-721. [Abstract] [Free Full-text]

MHRA (2007) ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy. Drug Safety Update 1(5), 8-9. [Free Full-text]

MHRA (2009a) ACE inhibitors and angiotensin II receptor antagonists: recommendations on use during breastfeeding. Drug Safety Update 2(10), 3-4. [Free Full-text]

MHRA (2009b) Clarification: ACE inhibitors and angiotensin II receptor antagonists: use during breastfeeding. Drug Safety Update 2(12), 10. [Free Full-text]

Micromedex (2009) MICROMEDEX [CD-ROM]. (Vol 135, 1st quarter 2009). Thomson Healthcare.

National Collaborating Centre for Chronic Conditions (2008) Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care (full NICE guideline). Clinical guideline 73Royal College of Physicians. www.nice.org.uk [Free Full-text]

NHS Employers and GP Committee of BMA (2007) Chronic kidney disease frequently asked questions. BMA and NHS Employers. www.bma.org.uk

NICE (2003) Chronic heart failure: management of chronic heart failure in adults in primary and secondary care (NICE guideline) [Replaced by NICE guideline 108]. . Clinical guideline 5. National Institute for Health and Care Excellence. www.nice.org.uk

NICE (2008) Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care (NICE guideline). Clinical guidance 73National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2011a) Anaemia management in people with chronic kidney disease. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2011b) Quality standards programme - chronic kidney disease in adults. Quality Standard advice to the Secretary of State for Health. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2013) Key therapeutic topics - medicines management options for local implementation. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NPC (2011) Key therapeutic topics 2010/11 - Medicines management options for local implementation. National Prescribing Centre. www.npc.nhs.uk [Free Full-text]

NPC (2012) Key therapeutic topics - medicines management options for local implementation. National Prescribing Centre. www.npc.nhs.uk [Free Full-text]

NTIS (2007) Use of angiotensin-converting enzyme inhibitors (ACEI) in pregnancy. TOXBASENational Teratology Information Service. www.toxbase.org

Schaefer, C., Peters, P. and Miller, R.K. (Eds.) (2007) Drugs during pregnancy and lactation: treatment options and risk assessment. 2nd edn. Oxford: Academic Press.