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Management developments in chronic renal failure

Dr Brett Cullis outlines the latest thinking on the treatment of chronic renal failure

Chronic renal failure describes a vast spectrum of diseases that result in the irreversible destruction of nephrons. There are few other conditions where teamwork between GPs, nephrologists, home care nurses, district nurses and dietitians is of such vital importance. Creatinine clearance (CrCl) is a surrogate marker of glomerular filtration rate (GFR) and is more accurate at assessing renal function than plasma creatinine.

The poor correlation of plasma creatinine with GFR is due to a linear decline in creatinine generation with age and loss of muscle mass.

In clinical practice calculations using serum creatinine, age and weight are at least as reliable as physical measurements of creatinine clearance. The most commonly used formula is that described by Cockroft and Gault1 (see above).

Cockroft-Gault formula

------- K x body weight x (140 - age)

CrCl = -----------------------------

------- Serum creatinine

Nb: K = 1.04 (female) or 1.23 (male)

Example: 80-year-old, 45kg woman with a creatinine of 150 has a creatinine clearance of 18ml per minute

Once a patient has chronic renal failure there is an irreversible decline in renal function, the rate of which is dependent on the potentially modifiable factors mentioned below. It is imperative that all is done to slow the rate of progression and delay the initiation of dialysis, indefinitely if possible.

The first step is early referral to a nephrologist. This places the patient in a system designed to slow the rate of progression of CRF and co-ordinate an uncomplicated transition to dialysis if necessary.

It is very frustrating for nephrologists to manage patients who have had worsening renal function for years and are referred in imminent need of dialysis, often with a host of potentially preventable complications.

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Once the diagnosis is confirmed it is useful to plot a creatinine clearance to time graph for the patient. Most will have a linear deterioration in their renal function and therefore one can differentiate whether there has been a sudden deterioration due to an insult, such as infection, or whether the decline is just 'normal' disease progression.

The graph is also useful to help motivate those patients whose progression has been slowed by good blood pressure control and other factors

(see figure below).

Modifiable factors

The rate of progression of chronic renal failure is very variable and is often related to the cause. There are, however, a number of modifiable risk factors, which, if treated may markedly slow disease progression.

 · Proteinuria

This is the most important prognostic marker for the progression of renal disease. For every 1g/day of protein, there is a three times relative risk of doubling creatinine or progressing to end-stage renal failure2. ACE inhibitors and angiotensin receptor blockers reduce proteinuria and slow the rate of progression of CRF independently of their blood pressure reduction2-5.

Lowering blood pressure reduces proteinuria by decreasing intra-glomerular pressure. Low-protein diets reduce proteinuria and slow progression of renal failure.

This carries a risk of undernutrition and patients should rather just avoid high-protein diets. This is especially important with the fashionable weight loss diets available at present.

 · Hypertension

If there is one message in this article it is the importance of aggressive blood pressure lowering in patients with chronic renal failure.

With diabetic nephropathy aggressive blood pressure control can reduce the rate of decline in GFR from 8ml/minute/year to 4ml/minute/ year. This potentially means starting dialysis in 22 years as opposed to 11.

The Kidney Disease Outcomes Quality Initiative (K/DOQI) and the UK Renal Association guidelines state:

 · All patients with progressive chronic renal failure who have proteinuria of less than

1g/day should have a blood pressure of less

than 135/85mmHg.

 · Those with proteinuria more than1g/day should maintain a blood pressure of less than 125/75mmHg6,7.

Controversy has arisen as the NICE guidelines for diabetic nephropathy suggest a blood pressure of less than 135/75 for all patients, but the above guidelines suggest this level is too high.

One has to be pragmatic when prescribing antihypertensives. In the elderly and patients with other co-morbid conditions, it is often not possible to reduce the blood pressure due to symptoms of hypotension. In these patients one has to weigh up longevity versus quality of life

(see above).

 · Glycaemia

In patients with diabetic nephropathy good glycaemic control can slow the rate of progression of disease. One should aim for an HbA1C of 7.0 and lower if possible8.

 · Lipids

Lipid-lowering therapy has been shown to significantly slow the rate of decline in GFR9.

 · Smoking

Smoking increases the risk of developing end-stage renal failure by 10 times in men with proteinuric chronic renal failure10.

 · Salt and water

Salt restriction is only important in hypertension or oedema. Patients should be advised to have a 'no salt added' diet. If patients are oedematous they should be fluid restricted to 1,500ml/day.

Complications

Once the GFR falls below 50ml/minute patients begin to get complications of renal failure.

 · Hyperparathyroidism

When the creatinine clearance falls below 50ml/min the 1-alpha hydroxylation of vitamin D diminishes. This reduces the absorption of calcium and increases secretion of parathyroid hormone (PTH). This is later exacerbated by rising phosphate, which is an even stronger stimulus for PTH release. The result is leaching of bones and the development of renal bone disease.

Treatment involves the use of 1-alpha hydroxylated vitamin D and phosphate binders given with meals. Calcium should be kept in the normal range and phosphate less than 1.8.

 · Anaemia

Anaemia of renal failure is secondary to decreased erythropoietin production by the kidney and is exacerbated by decreased absorption of oral iron.

Treatment is by subcutaneous injection of recombinant erythropoietin, with or without intravenous iron. This has decreased the need for transfusions making transplantation easier, reducing iron overload and most importantly patients feel better.

A number of the so-called uraemic symptoms are improved by erythropoietin ­ sleep patterns, cognitive function, sexual dysfunction and so on.

 · Itching

This is one of the most disabling complications of CRF. The reversible cause is

hyperphosphataemia and is treated with phosphate binders taken with meals. In other cases patients need to be treated symptomatically and are advised to bath with baby oil, use emollients and so on. The use of antihistamines such as clorpheniramine may be helpful.

 · Medication The list of medications to be avoided or require dosage adjustment in renal failure is exhaustive and all should be checked in the British National Formulary appendix 3. Alternatively use the EdRen website (see below).

Commonly used drugs that require special mention are:

 · NSAIDs

Avoid until patients are established on dialysis.

 · ACE-I or ATRAs

Check potassium and creatinine after one week. Need to stop if creatinine rises greater than 30 per cent. Contraindicated in renovascular disease.

 · Metformin

Stop if creatinine clearance is less than 50ml/minute.

 · Diuretics

These need to be increased as renal function worsens, up to 500mg bd of frusemide may be needed if oedematous.

Routine screening

tests for CRF

 · ANA/autoimmune profile

 · ANCA

 · Protein electrophoresis

 · Bence Jones protein

 · Immunoglobulins

 · Calcium/phosphate

 · Complement

 · 24-hour urine protein

 · Renal ultrasound

Antihypertensives in proteinuric renal disease

First-line / Second-line

ACE inhibitors (ACE-I) / Diuretics

Angiotensin receptor antagonists (ATRA) / ?-blockers

Non-dihydropyridine calcium channel blockers (for example verapamil or diltiazem) / Dihydropyridine calcium channel blockers (for example amlodipine, nifedipine LA)

Key points

 · Calculate creatinine clearance

 · Treat blood pressure very aggressively:

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<135 5="" for=""><1g ay="">

 · Proteinuria ­ use ACE inhibitors first, followed by ATRAs

 · Control blood glucose and treat hyperlipidaemia

 · Stop smoking

 · Beware of drug doses if creatinine clearance <>

 · Most complications are preventable

Key websites

For doctors:

www.EdRen.org

Edinburgh Royal Infirmary website which has excellent guidelines for GPs, information on different diseases and useful links.

www.nephron.com/cgi-bin/CGSI.cgi

A direct link to the Cockroft-Gault calculator.

For patients

www.kidney.org.uk

National Kidney Federation website which has excellent information on all aspects of kidney disease and will supply printed information. There is a telephone helpline: 0845 6010209.

www.renal.org/Patients/patients.html

The Renal Association website has numerous resources for patients and links to other websites.

References

01.Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-4

02.Jafar TH et al. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease. Kidney Int 2001;60:1131-40

03.The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857-63

04.Parving HH et al. The effect of Irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-7

05.Brenner BM et al. Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9

06.National Kidney Federation. DOQI kidney disease outcome quality initiative. Am J Kidney Dis 2002;39(suppl 1):51-5266

07.Renal Association. Treatment of adults and children with renal failure: standards and audit measures. Third Edition. London: Royal College of Physicians of London and the Renal Association, 2002

08.Stratton IM et al. UKPDS 35 Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes: prospective observational study. BMJ 2000;321:405-12

09.Fried LF et al. Effect of lipid reduction on the progression of renal disease:

A meta-analysis. Kidney Int 2001;59:260-69

10.Orth SR et al. Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int 1998;54:926-31

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