Drug Prescribing in Renal Impairment

Renal impairment may be the result of a variety of renal or systemic diseases, such as diabetic nephropathy or systemic lupus erythematosus. Normal ageing results in a decline in renal function due to loss of nephrons. Elderly patients should therefore be assumed to have some degree of renal impairment when prescribing. If even mild renal impairment is considered likely, renal function should be checked before prescribing any drug which requires dose modification. Reasons for problems with medications in renal failure include:

• Failure to excrete a drug or its metabolites.
• Many side-effects are tolerated poorly by patients in renal failure.
• Some drugs cease to be effective when renal function is reduced.

See separate article - Assessing Kidney Function - includes a calculator for estimating creatinine clearance from the plasma creatinine.

• eGFR is estimated Glomerular Filtration Rate.
• It is usually based on serum creatinine level, age, sex, and race.
• Normal GFR is approximately 100ml/min/1.73m.²
• Since April 2006 in the UK, most local laboratories calculate eGFR on all samples sent for creatinine measurement.

• Drugs that are renally excreted may need to have their doses reduced in patients with renal insufficiency or end-stage renal disease:
  • For prescribing purposes renal impairment is usually divided into 3 grades:
    • Mild: GFR 20-50 ml/minute; serum creatinine approximately 150-300 micromol/l.
    • Moderate: GFR 10-20 ml/minute; serum creatinine approximately 300-700 micromol/l.
    • Severe: GFR less than 10 ml/minute; serum creatinine > 700 micromol/l.
    • Patients with a GFR above 50ml/min do not usually require any dosage adjustment.
    • Nephrotoxic drugs should, if possible, be avoided in patients with renal disease because the consequences of nephrotoxicity are likely to be more serious when the renal reserve is already reduced.
  • The situation may change if a patient begins dialysis, since some drugs will be removed by the dialysis. Dialysis may lead to the loss of therapeutic effect for some drugs.
  • Drugs to which particular attention must be given include many antibiotics, H₂ blockers, digoxin, anticonvulsants and non-steroidal anti-inflammatory drugs
• For many drugs with only minor or no dose-related side-effects very precise modification of the dose regimen is unnecessary and a simple scheme for dose reduction is sufficient. For more toxic drugs with a small safety margin dose regimens based on glomerular filtration rate should be used.
• The total daily maintenance dose of a drug can be reduced either by reducing the size of the individual doses or by increasing the interval between doses. For some drugs, if the size of the maintenance dose is reduced it will be important to give a loading dose if an immediate effect is required. The loading dose should usually be the same size as the initial dose for a patient with normal renal function.

Drugs causing biochemical changes

• Prescribing any drug that increases potassium levels is potentially very dangerous, e.g. potassium supplements and potassium-sparing diuretics. Other products that contain potassium include ispaghula husk laxatives.
• Products with a high sodium content, e.g. some antacids, may cause sodium and water retention in patients with renal impairment.
• Excessive vitamin D replacement therapy can cause hypercalcaemia that may precipitate or exacerbate renal impairment. Many patients with chronic renal failure are prescribed alfacalcidol, and therapy should therefore be closely monitored.

Drugs causing prerenal damage

• Drugs that cause excessive GI losses, either through diarrhoea or vomiting, also cause volume depletion and may precipitate acute renal failure.
• NSAIDs, even in short courses, can cause acute renal failure as a result of renal underperfusion.
• ACE inhibitors can also cause a deterioration in renal function. However, this is a problem only in patients with compromised renal perfusion, particularly those with renal artery stenosis.
• Care should be taken when an ACE inhibitor and NSAID are prescribed together as this combination may precipitate an acute deterioration in renal function.

Drugs causing intrarenal damage

• Intrarenal damage may result a direct toxic effect on the kidneys or hypersensitivity reactions.
• Most drugs that cause damage within the kidneys do so as a result of hypersensitivity reactions, which involve either glomerular or interstitial damage.
• Drugs that have been reported to cause glomerulonephritis include penicillamine, gold, captopril, phenytoin and some antibiotics, including penicillins, sulphonamides and rifampicin.
• Drugs that may cause interstitial nephritis include penicillins, cephalosporins, sulphonamides, thiazide diuretics, furosemide, NSAIDs and rifampicin.
• There are a number of drugs that cause direct toxicity to the renal tubules (acute tubular necrosis), e.g. aminoglycosides, amphotericin and cyclosporin.

Drugs causing postrenal damage (urinary tract obstruction)

• High-dose sulphonamides, acetazolamide or methotrexate may cause crystalluria and could therefore cause obstruction.
• Anticholinergics, e.g. tricyclic antidepressants, and alcohol may cause urinary tract obstruction due to retention of urine in the bladder.

Other nephrotoxic drugs

• Cephalosporins: cephaloridine, one of the first cephalosporins introduced, has been associated with direct renal toxicity and is no longer in clinical use. Other cephalosporins are much less likely to produce renal damage but third generation cephalosporins, e.g. cefixime, have very rarely been reported to cause nephrotoxicity.
• Analgesics:
  • NSAIDs may cause acute renal failure due to hypoperfusion and interstitial nephritis, as well as analgesic nephropathy (chronic interstitial nephritis and papillary necrosis).
  • Analgesic nephropathy has been most commonly seen with combination analgesic products that contain aspirin and/or paracetamol.
  • Analgesic nephropathy is one of the few preventable causes of chronic renal failure. Discontinuation of the abused drugs often results in stabilisation or even improvement in renal function but continued abuse leads to further renal damage.
• Lithium: serum levels of lithium consistently above the therapeutic range have been associated with development of a nephrogenic diabetes insipidus

Dose recommendations are based on the severity of renal impairment. This is expressed in terms of glomerular filtration rate. The serum creatinine concentration is sometimes used instead as a measure of renal function but is only a rough guide even when corrected for age, weight, and sex. Nomograms should be used where accuracy is important.