Chronic kidney disease

Contributed by Dr Timothy Doulton, specialist registrar, and Dr Simon Steddon, consultant nephrologist at Guy's & St Thomas' NHS Foundation Trust.

Section 1: Epidemiology and classification
Chronic kidney disease (CKD) encompasses abnormalities of both kidney structure and function. It is an important condition associated with excess cardiovascular mortality, decreased quality of life and considerable healthcare expenditure.

It is also very common - the age standardised prevalence of stages 3-5 within a UK primary care population has been estimated at 8.5 per cent (5.8 per cent in men, 10.6 per cent in women).1 A comparison of the National Health and Nutritional Survey data from 1988-1994 to 1999-2004 showed an increase in prevalence from 10 to 13 per cent.2

It frequently coexists with other conditions, particularly diabetes and cardiovascular disease (CVD).

Treatment
Treatment at early stages can prevent progression through to eventual kidney failure; complications such as anaemia and abnormalities of mineral and bone metabolism can be prevented. The small number who progress to kidney failure will require timely preparation for renal replacement therapy (RRT); including transplantation, dialysis or, where appropriate, conservative management and palliative care.

At least 30 per cent of patients with advanced CKD are still referred late from both primary and secondary care.

Stages of CKD
Serum creatinine (SCr) often overestimates kidney function, mainly because it is derived from muscle, and muscle bulk varies appreciably between individuals.

An SCr of 150 micromol/l in a muscular 25-year-old African man represents much better renal function than it does in a 75-year-old Caucasian woman.

Whenever an SCr is requested, laboratories should report an estimated glomerular filtration rate (eGFR), calculated using the Modification of Diet in Renal Disease (MDRD) equation.

The MDRD formula takes into account sex and gender (although a correction factor of x1.21 is still required for patients of African-Caribbean ethnicity) and provides a more sensitive measure of kidney function than SCr alone.

eGFR approximates roughly to percentage kidney function, which can help with patient understanding and involvement, and also facilitates the division of CKD into five stages. eGFR becomes less reliable as true GFR increases and many laboratories only report a numerical value if it is [s39] 60ml/min/1.73m2.

Higher values may not actually indicate impaired kidney function and should be interpreted with this in mind. After the age of 40, there is a progressive loss of GFR, particularly in those with cardiovascular co-morbidities.

Whether this should be regarded as 'physiological' remains a matter for debate, but it should not influence treatment.

CKD: Key facts

  • CKD is common and its prevalence is increasing.
  • eGFR facilitates earlier identification, classification and stage-specific interventions.
  • It is closely associated with diabetes, hypertension and CVD.
  • Patients with CKD are at far higher risk (approx 20-fold) of cardiovascular morbidity and mortality than they are of kidney failure.
  • Proteinuria confers an increased risk of both CVD and progressive CKD.
  • ACE inhibitors and ARBs are the antihypertensive agents of choice in CKD and should be prescribed in proteinuric patients (urine ACR[s40]30mg/mmol) regardless of BP.
  • The majority of patients can be managed in primary care.

Section 2: Screening
CKD is usually asymptomatic and often unrecognised. There is no evidence that screening entire populations for CKD is beneficial and it is recommended that certain groups at higher risk are targeted (see box).

Once discovered, an abnormal eGFR should be confirmed after a two-to-four week interval unless acute renal failure is suspected, when it should be repeated as soon as possible (within five days). If eGFR is reduced, a urinary albumin: creatinine ratio (ACR) or protein:creatinine ratio (PCR) should be determined, preferably on an early morning sample.

Urine samples
These simple investigations have replaced the collection of 24-hour urine samples for quantification of proteinuria. In those without diabetes, significant proteinuria is present when the ACR exceeds 30mg/mmol (PCR>50mg/mmol) whereas in diabetic patients, ACR [s40]2.5mg/mmol in men and [s40]3.5mg/mmol in women are considered significant. Once a management plan is agreed, follow up in a specialist centre is often unnecessary (see box).

Information needed for specialist referral
Essential
Helpful
  • Current and historical eGFRs (or serum creatinine) if available.
  • Past medical history.
  • Drug history (past and present).
  • BP.
  • Urine ACR or PCR (+/- dipstick and MSU) result.
  • Renal tract ultrasound scan especially if haematuria, lower urinary tract symptoms, rapid fall in eGFR, family history of polycystic kidney disease.
  • Haemoglobin, ferritin and iron studies.
  • Serum calcium, phosphate.

 

Patient groups that should be screened for CKD
Patient Group Examples
Conditions associated with high risk of development of silent CKDHypertension; diabetes mellitus; heart failure; atherosclerotic coronary, cerebral or peripheral vascular disease
Conditions associated with high risk of obstructive nephropathyKnown or suspected bladder outslow obstruction; neurogenic bladder (spina bifida, cord injury); renal stone disease
Long-term treatment with potentially nephrotoxic drugsACE inhibitors and ARBs; NSAIDs and COX2 inhibitors; lithium carbonate; ciclosporin
and tacrolimus; sulfasalazine and mesalazine
Previously diagnosed CKDPolycystic kidney disease; reflux nephropathy; persistent proteinuria or urologically unexplained haematuria; biopsy-proven glomerulonephritis
or other renal disease.
Multisystem diseases that may involve the kidney myelomaSLE; rheumatoid arthritis; myeloma
Family history of stage 5 CKD or hereditary kidney disease

Section 3: Management
The majority of patients identified with CKD will be in stages 1-3 and are likely to have very stable kidney function over time.3 Most of these, as well as many stable stage 4 patients, can be looked after in primary care, with secondary care involvement.

For stages 1-3, general advice on healthy living and reduction of cardiovascular risk is desirable, whereas in stages 4 and 5 the focus should be more detailed information about kidney failure and its treatments.

CKD targets
All patients should be encouraged to undertake regular exercise, attain a healthy weight, stop smoking and, if relevant, improve their diabetic control. Patients with an ACR [s40]30mg/mmol (PCR [s40]50mg/mmol) should be treated with an ACE inhibitor or angiotensin receptor blocker (ARB) regardless of whether they are hypertensive, as there is good evidence this can reduce proteinuria and retard progression.

BP targets in CKD are 130/80mmHg, or 120/75mmHg if the patient has significant proteinuria (ACR [s40]70mg/mmol or PCR [s40]100mg/mmol).4

The difficulties involved in achieving these targets are acknowledged in the CKD quality framework, where the target is 140/85mmHg. Changes in the 2008 framework recognise the importance of proteinuria and the added benefit proteinuric patients will obtain from an ACE inhibitor/ARB.

There is evidence to support the dual blockade of the renin-angiotensin system with both an ACE inhibitor and ARB if significant proteinuria persists.5

Further antihypertensive drugs should be added according to guidelines, although thiazide diuretics are usually less effective in more advanced CKD and loop diuretics are preferred.

Statins are generally safe and effective in CKD. However, muscular side-effects, including myositis are more common as GFR falls, so careful introduction and dose titration is necessary. A recent meta-analysis has suggested that statin treatment can reduce proteinuria as well as modestly slow decline in eGFR,6 so they should be prescribed for those with an ACR [s40]30mg/mmol (PCR [s40]50mg/mmol).

Anti-platelet agents should be offered as secondary prevention for CVD, although patients should be warned of a small increased risk of bleeding in more advanced CKD.

Complications of CKD

The most frequent complication of CKD in primary care is anaemia, which becomes more common as GFR decreases. Other causes of anaemia should always be considered and excluded. Treatment is with iron and erythropoiesis stimulating agents.

Disorders of bone and mineral metabolism are virtually ubiquitous in more advanced CKD. However, there is no requirement to routinely measure calcium, phosphate, vitamin D or parathyroid hormone in stages 1-3.

Osteoporosis
If osteoporosis is discovered in a patient with stage 1-3 CKD then standard treatments, including bisphosphonates may be considered.

It is recommended that all patients with CKD are immunised against influenza and pneumoccocus.

Initiating an ACEI/ARB in CKD

  • Measure serum K+ and eGFR pre- and within two weeks post-treatment.
  • Do not start if serum K+ is above the normal reference range; review medications and offer dietary advice.
  • Measure serum K+ and eGFR within two weeks of every dosage increase.
  • Stop if serum K+ >6.0mmol/l; review other medications and offer dietary advice.
  • Allow a fall in eGFR of 20% without stopping or changing dosage (but recheck within one month).
  • If eGFR falls more than 20%, stop (or return to previous dosage) and consider specialist advice.
  • Measure serum K+ and eGFR during intercurrent illnesses.

Section 4: Prognosis
The outcome data for a large number of patients within the Kaiser Permanente system in Southern California have been published.7

In stage 3 CKD, only 1 per cent of patients developed kidney failure, while nearly 25 per cent died over a five-year period. Even in stage 4, which represents advanced kidney disease, only one in five reached kidney failure whereas nearly half died.

Dialysis in stage 5
Although the numbers reaching stage 5 are comparatively small, these patients carry a huge CVD burden. Compared with the non-dialysis population, the risk of death is 50-fold higher for someone receiving dialysis at age 30 and remains 50-fold at age 60.

The current UK acceptance rate for RRT is around 110 per million population and is expected to continue rising for at least a decade.

CKD increase
There has been a significant change in the way patients with impaired kidney function are identified and managed. A rising burden of hypertension, diabetes and circulatory disease, as well as an ageing population, has contributed to a rising prevalence of CKD with its attendant devastating cardiovascular consequences.

Public awareness remains low and new programmes aimed at educating both healthcare professionals and the public are required as a priority.

Resources

Further reading

References

  • Stevens P, O'Donoghue D, de Lusignan S et al. Chronic kidney disease management in the United Kingdom: NEOERICA project results. Kidney Int 2007; 72: 92-9.
  • Coresh J, Selvin E, Stevens L et al. Prevalence of chronic kidney disease in the United States. JAMA 2007; 298: 2,038-47.
  • John R, Webb M, Young A, Stevens P. Unreferred chronic kidney disease: a longitudinal study. Am J Kidney Dis 2004; 43: 825-35.
  • Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and the Renal Association. Chronic kidney disease in adults: UK guidelines for identification, management and referral. London: Royal College of Physicians, 2006.
  • Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117-24.
  • Sandhu S, Wiebe N, Fried L, Tonelli M. Statins for improving renal outcomes: A meta-analysis. J Am Soc Nephrol 2006; 17: 2, 006-16.
  • Keith D, Nichols G, Gullion C, Brown J, Smith D. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004; 164: 659-63.

Contributed by Dr Timothy Doulton, specialist registrar, and Dr Simon Steddon, consultant nephrologist at Guy's & St Thomas' NHS Foundation Trust.

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