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ARTICLE
Drugs and the kidney
S Naidoo,1 MB BCh, FCP (SA), Cert Nephrology (SA), MMed; A M Meyers,2 MB BCh, FCP (SA), Cert Nephrology (SA), FRCP (Lond)
1
S chool of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand; Charlotte Maxeke Johannesburg Academic Hospital; and Wits
Donald Gordon Medical Centre, Johannesburg, South Africa
2
Donald Gordon Medical Centre, Klerksdorp Hospital, and National Kidney Foundation of South Africa, Johannesburg, South Africa
This article on drug nephrotoxicity is detailed, as it is important to be fully aware of renal side-effects of drugs with regard to prevention and
early diagnosis in order to manage the condition correctly. Many therapeutic agents are nephrotoxic, particularly when the serum half-life is
prolonged and blood levels are raised because of decreased renal excretion. Distal nephrotoxicity is markedly enhanced when the glomerular
filtration rate (GFR) is reduced and is a particular threat in elderly patients with so-called ‘normal’ creatinine levels. In patients of 45 - 55 years of age the
GFR is reduced by about 1 mL/min/year, so that an otherwise healthy person of 80 may have an estimated GFR (eGFR) of <60 mL/min or <50 mL/min,
i.e. stage 2, 3 or 3b chronic kidney disease (CKD). Furthermore, other effects related to kidney dysfunction may be seen, e.g. worsening of hypertension
with the use of non-steroidal anti-inflammatory drugs, increased bruising or bleeding tendency with aspirin, and hyponatraemia hypertension
acidosis with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Digoxin is contraindicated in stage 3 CKD, even in
a reduced dosage. Other drugs can cause the direct formation of kidney stones, e.g. topiramate (used in the prophylaxis of resistant migraine).
Levofloxacin (Tavanic) can cause rupture of the Achilles tendon and other tendons.
Radiocontrast media must be used with care. Occasionally, strategies to prevent acute kidney insufficiency cause irreversible CKD,
especially in patients with diabetes and those with myeloma who have stage 4 - 5 CKD. Gadolinium in its many forms (even the newer
products) used as contrast medium for magnetic resonance imaging is best avoided in patients with stages 4 and 5 CKD.
S Afr Med J 2015;105(4):322. DOI:10.7196/SAMJ.9537
blood that has already passed through the at different segments of the renal tubular Spironolactone
glomerulus. system. Sometimes a combination of two Spironolactone as a class is a potassium-
The kidneys perform two major functions. diuretics is given as it can be significantly sparing diuretic. Its mode of action is
Firstly, they excrete most of the end-products more effective than either compound antagonising the effect of aldosterone at
of the bodily metabolism, and, secondly, alone, the reason being that one nephron levels of the mineralocorticoid receptor.
they control the concentration of most segment can compensate for altered sodium The aldosterone complex translocates to
of the constituents of the body fluids. In reabsorption at another nephron segment; the nucleus to effect gene transcription.
normal kidney function the counter current therefore, blocking multiple nephron sites Indications include the prevention of hypo
multiplier system, together with the renin- significantly enhances efficacy. kalaemia in patients on diuretics or digoxin.
angiotensin-aldosterone system (RAAS), It improves survival in advanced heart failure
involves extracellular fluid volume control, Overall conclusions (Randomised Aldactone Evaluation Study).[1]
electrolyte balance, waste product excretion, Cumulative event rates from the primary Spironolactone can be used as an anti
drug and hormone elimination/metabolism, outcome (fatal chronic heart disease hypertensive (adjunctive third-line therapy for
blood pressure (BP) and haematocrit (CHD) or non-fatal myocardial infarction hypertension) or as a first-line drug (patients
regulation, and calcium/phosphate balance (MI)) of the Antihypertensive and Lipid with Conn’s syndrome). Another indication is for
(vitamin D3 metabolism). Lowering Treatment to Prevent Heart Attack the treatment of ascites in patients with cirrhosis.
Therefore, the kidney is involved in Trial (ALLHAT) treatment group, have The side-effects of aldactone include anti-
absorption, distribution, metabolism, eli demonstrated that because of the superiority androgenic effects through the antagonism
mination, secretion and filtration, and the of thiazide-type diuretics in preventing of dihydrotestosterone at its binding site.
effects of drugs can be idiosyncratic or accu one or more major forms of cardiovascular Drug interactions occur with other
mulative (Table 1). disease (CVD) and their lower cost, they potassium-sparing drugs, e.g. angiotensin-
Many drugs and their metabolites are should be the drugs of choice for first-step converting enzyme (ACE) inhibitors/angio
excreted by the kidney by glomerular antihypertensive drug therapy. tensin II receptor blockers (ARBs) and
filtration, by tubular secretion, or in some In Table 2 the mechanism of action and potassium supplements.
cases by both. Renal impairment has a indications of diuretics are shown. (LoSalt may be used as an NaCl substitute
significant effect on clearance of these drugs, Table 3 lists the side-effects and half-life in cooking.)
with important clinical consequences. of diuretics. Table 5 lists diuretic adverse effects and
The glomerular filtration rate (GFR)/ Specific diuretics are listed in Table 4. drug interactions.
estimated GFR (eGFR) is an important tool
in staging chronic kidney disease (CKD).
Table 3. Side-effects and half-life of diuretics
Pathophysiology
of drug-induced Diuretic Side-effect Half-life
nephropathy Loop • Electrolyte imbalance Oral bioavailability between
Multiple drugs can affect the same site, • Hypokalaemia 10% and 90%
e.g. acute tubular necrosis, which is the • Volume depletion (prerenal uraemia) Acts at luminal side of the
commonest cause of renal failure in • Tinnitus (acts within the cochlea – can synergise thick ascending limb (NaK2Cl
adults, can be caused by aminoglycosides, with aminoglycoside antibiotics transporter)
radiocontrast dyes and many other drugs. Highly protein bound
A single drug can affect different sites Rebound after single dose
in the kidney, e.g. non-steroidal anti- T½: 4 hours
inflammatory drugs (NSAIDs) can cause Thiazide Metabolic T½: 3 - 5 hours
acute renal failure, interstitial nephritis and • Hyperuricaemia, impaired glucose tolerance
glomerulonephritis (Table 1). and electrolyte disturbances (hypokalaemia and
hyponatraemia)
The nephron and • Volume depletion
electrolyte balance
The different diuretics include the loop
diuretics, thiazide diuretics, aldactone and Filter plasma
osmotic agents. They can by their effect on Adjust Na, K, H
Reabsorb good stuff
the nephron significantly alter electrolyte
balance.
The indications for diuretic use include
Reabsorb water as needed
Nephrotoxic drugs
Table 4. Specific diuretics Nephrotoxic drugs may have a dose-dependent
Class Drug Comments effect and/or cause idiosyncratic renal damage.
Dose-dependent nephrotoxic drugs include
Thiazide Chlorothiazide
NSAIDs, such as cyclo-oxygenase-2 (COX-2)
Chlorthalidone Thiazide-like in action, not in structure inhibitors, aminoglycosides and radio-opaque
Hydrochlorothiazide Prototypical drug contrast materials. Idiosyncratic renal damage
Hydroflumethiazide may be secondary to NSAIDs, penicillins, gold
and penicillamine.
Indapamide Thiazide-like in action, not in structure
Methyclothiazide NSAIDs
Metolazone Thiazide-like in action, not in structure The NSAIDs are commonly used and have a
Polythiazide
wide range of pathological and physiological
effects. They interfere with prostaglandin
Loop Bumetanide
production, disrupt regulation of renal
Ethacrynic acid medullary blood flow and salt water balance.
Furosemide With habitual use they can cause chronic renal
impairment. Their effect can be exacerbated
Torsemide
by other drugs (antihypertensives, ACE
K+-sparing Amioloride Distal tubule Na+-channel inhibitor inhibitors). They have typical radiological
Eplerenone Aldosterone receptor antagonist; fewer side-effects than features with advanced renal dysfunction.
spironolactone The pharmacology of the NSAIDs
Spironolactone Aldosterone receptor antagonist; side-effect: includes good absorption and hepatic
gynaecomastia metabolism, they are highly protein bound
and are excreted by both enterohepatic and
Triamterene Distal tubule Na+-channel inhibitor
renal routes. Their half-lives vary. They have
Carbonic Acetazolamide Prototypical drug; not used for treating hypertension or common therapeutic indications and adverse
anhydrase heart failure effects. Even though their pharmacokinetics
inhibitors and potencies differ and they are from
Dichlorphenamide Not used for treating hypertension or heart failure different chemical families, their mechanism
Methazolamide Not used for treating hypertension or heart failure of action is similar. NSAIDs are cyclo-
oxygenase inhibitors with different levels of
selectivity for COX-1 and COX-2 enzymes.
Their similarities are more striking than
their differences.
Table 5. Adverse effects and drug interactions of diuretics
The role of prostaglandins is described
Class Adverse side-effects Drug interactions in Table 6.
Thiazide Hypokalaemia Hypokalaemia potentiates Table 7 lists the functions of COX-1 and
Metabolic alkalosis digitalis toxicity COX-2 enzymes.
Dehydration (hypovolaemia), leading to hypotension NSAIDs: reduce diuretic NSAIDs such as ibuprofen, diclofenac
Hyponatraemia efficacy and indomethacin have short half-lives,
Hyperglycaemia in diabetics Beta-blockers: potentiate with a more rapid effect and clearance.
Hypercholesterolaemia, hypertriglyceridaemia hyperglycaemia, The following NSAIDs have a longer half-
Increased low-density lipoproteins hyperlipidaemias life and slower onset and clearance: e.g.
Hyperuricaemia (at low doses) Corticosteroids: enhance naprosyn, celecoxib, rofecoxib, nabumetone
Azotaemia (in renal disease) hypokalaemia and piroxicam.
Loop Hypokalaemia Hypokalaemia potentiates NSAID toxicity is wide and variable on
Metabolic alkalosis digitalis toxicity the gastrointestinal, renal, haematological,
Hypomagnesaemia NSAIDs: reduce diuretic central nervous and hepatic systems, as well
Hyperuricaemia efficacy as on the skin, and causes allergies.
Dehydration (hypovolaemia), leading to Corticosteroids: enhance
hypotension hypokalaemia Table 6. Role of prostaglandins
Dose-related hearing loss (ototoxicity) Aminoglycosides: enhance
Pathological Physiological
ototoxicity, nephrotoxicity
• Asthma • Temperature control
K+-sparing Hyperkalaemia ACE inhibitors: potentiate
• Ulcers • Bronchial tone
Metabolic acidosis hyperkalaemia
• Diarrhoea • Cytoprotection
Gynaecomastia (aldosterone antagonists) NSAIDs: reduce diuretic
• Dysmenorrhoea • Intestinal mobility
Gastric problems, including peptic ulcer efficacy
• Inflammation • Myometrial tone
Carbonic Hypokalaemia • Bone erosion • Semen viability
anhydrase Metabolic acidosis • Pain
inhibitors • Fever
Tissue injury
Phospholipids
Leukotrienes
Arachidonic acid
• Bronchoconstriction
Inhibitors Inducers
• NSAIDs (non-COX-2) • Cytokines
• Aspirin • Growth factors
COX-1 COX-2
(constitutional) (inducible)
Inhibitors
• COX-2 inhibitors
• NSAIDs (non-COX-2)
• Aspirin
Diagnosis high peak concentration-enhancing efficacy interval may have to be adjusted. The half-
• Reversal of renal failure after discontinuing with a long postdose effect. A single daily dose life is often prolonged. Therefore, reduce
the drug. is less nephrotoxic. The dose depends on size the dose or increase the dosing interval.
• Renal biopsy (if the cause of acute renal failure and renal function. It is important to measure Some drugs have active metabolites that are
is uncertain, or known but a biopsy is taken to aminoglycoside levels. excreted renally, e.g. warfarin and diazepam.
ascertain that there are no other causes).
Intravenous contrast Amphotericin
Treatment It is commonly used for computed tomo Amphotericin is an antifungal agent for
• Withdrawal of the drug. graphy scanning, intravenous urography and topical and systemic use. It is a lipid-soluble
• Corticosteroid (30 - 60 mg/day). angiography. It is unsafe in patients with pre- drug that binds steroid alcohols (ergosterol)
• Supportive dialysis if needed (temporarily existing renal impairment. The risk increases in the fungal cell membrane, causing
in acute renal failure). in diabetic nephropathy, heart failure and leakage of cellular content and death. It is
dehydration. Contrast can precipitate ESRF. effective against Candida species and is both
Drug-induced chronic interstitial There is a cumulative effect with repeated fungistatic and fungicidal, depending on the
nephritis administration. The risk can be reduced by concentration. It has a broad spectrum of
Features using acetylcysteine.[2] activity (Candida, Cryptosporidium).
• Renal impairment that leads to end-stage It is administered intravenously for
renal disease (ESRD). Prescribing in kidney systemic invasive fungal infections and can
• Small-size kidneys, with proteinuria <2 g/day. disease be used orally for gastrointestinal mycosis.
• Tubular function defect. Patients include those: Side-effects include local/systemic
• Occurs within months or year. • with renal impairment effects with infusion (fever). It can cause
• Not reversible, so if left untreated it will • on dialysis chronic kidney dysfunction, with a decline
lead to ESRD. • with renal transplants. in GFR with prolonged use. Other effects
• Pathology. include tubular dysfunction (membrane
• Tubular atrophy and interstitial fibrosis Principles permeability), hypokalaemia, renal tubular
(there is no eosinophilia). It is important to establish the type of kidney acidosis (bicarbonate wasting type 1/distal),
disease. Most patients with kidney failure diabetes insipidus, and hypomagnesaemia.
Possible causes are taking a number of drugs. Therefore, Caution should be taken with prehydration/
Analgesics, NSAIDs, cisplatin, cyclosporine. interactions are common and care needs saline loading to avoid problems. Toxicity can
to be taken to avoid drug toxicity. Patients be further reduced substantially by liposomal
Aminoglycosides with renal impairment and renal failure are packaging of amphotericin.
The aminoglycosides are highly effective often also taking antihypertensive drugs and
antimicrobials that are bactericidal, but phosphate binders. Lithium
nephrotoxic and ototoxic, with a narrow thera Lithium carbonate is used for the treatment
peutic range. When prescribing aminogly Dosing in renal impairment of bipolar mood disorder. Its toxicity is
cosides, a once-daily regimen is recommended The loading dose does not usually need to be closely related to serum levels. Symptoms
in patients with normal kidneys. There is a changed. Maintenance doses or the dosing and signs include cardiovascular arrhythmias
(especially junctional dysarrhythmias) and central nervous system Although 10 mg/kg/day has been used at these levels of GFR, cases
tremor, confusion, coma and neprhrogenic diabetes insipidus. of optic atrophy have been reported. Ethambutol is not dialysed to
Treatment is supportive and includes haemodialysis and any significant extent. Pyrazinamide should be given at a reduced
colonic irrigation for very high levels. There is inadvertent dose (10 - 15 mg/kg). Capreomycin is a second-line drug, which
toxicity from interactions with ACE inhibitors, and loop and can be used in isoniazid or streptomycin resistance. It is, however,
thiazide diuretics. Carbamazepine and other anti-epileptics nephrotoxic and ototoxic, but can be administered in a single
increase neurotoxicity. dose of 500 mg. In patients receiving multiple transplants, and
who are on cyclosporine, rifampicin cannot be used as it reduces
Digoxin the concentration of cyclosporine very substantially as a result of
Digoxin toxicity (high levels) is demonstrated in 10% of patients and toxicity hepatic enzyme induction. The necessity to use more than three
has been reported in 4% of a series of 4 000 digoxin samples assayed. agents will be dictated by the nature and severity of the infection.
The pharmacokinetics include a large volume of distribution Treatment may need to be prolonged (9 - 12 months) in uraemic or
(reservoir is skeletal muscle). About 30% of stores are excreted in immunosuppressed patients, in contrast to the shorter courses that
urine per day. are preferred in patients with normal renal function.
Treatment of digoxin toxicity includes supportive correction
of electrolyte imbalance. Atropine should be administered Antiretroviral therapy (ART)
for bradycardia, and stimulants should be avoided because of Renal toxicity of antiviral therapy is shown in Table 11.
arrhythmogenicity. Absorption can be limited with the use of Refer also to the Table on dose adjustments for ART in CKD and
charcoal (or cholestyramine) within 8 hours. Specific measures ESRD in the HIV and CKD section of the article ‘Important causes of
include the use of digoxin immune fab (Digibind and DigiFab) CKD in South Africa’.[3]
(digoxin-specific antibodies), which binds plasma digoxin, and the
complex is eliminated by the kidney. These antibodies are used when Other drugs
serum drug values approach those of an overdose or are near arrest Intravenous iodinated radiocontrast agents labelled with gadolinium
levels. Furthermore, digoxin elimination can be enhanced by using are used as contrast media in patients undergoing MRI scans.
charcoal/cholestyramine to interrupt enterohepatic cycling. Dialysis Gadolinium is contraindicated in patients with stages 4 and 5 CKD,
is ineffective. as it can result in a diffuse systemic fibrosis (sclerosis-like syndrome
with quadriplegia and eventual death). It is perfectly acceptable to
Antituberculosis drugs perform an MRI without contrast if indicated.
Tuberculosis can be a difficult therapeutic problem in patients with
renal failure. Rifampicin and isoniazid may be given in the normal
References
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should be given with isoniazid to prevent peripheral neuropathy. with severe heart failure. New Engl J Med 1999;341(10):709-717.
2. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of
The plasma half-life of ethambutol is prolonged in renal impairment. radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J
If the GFR is <30 mL/min, the dose should be 10 - 15 mg/kg/day, Med 2000;343(3):180-184.
3. Moosa MR, Van der Walt I, Naicker S, Meyers AM. Important causes of chronic kidney disease in
with a further reduction to 4 mg/kg/day if the GFR is <10 mL/min. South Africa. S Afr Med J 2015;105(4):320. [http://dx.doi.org/10.7196/SAMJ.9535]