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Review Article
Drug-induced Kidney Diseases
NP Singh*, A Ganguli**, A Prakash***
Abstract
Drug-induced kidney disease constitutes an important cause of acute renal failure and chronic kidney
disease in present day clinical practice. Different classes of drugs, by virtue of immunological mechanisms
or direct toxicity initiate certain stereotyped renal responses. For most patients suffering from druginduced nephropathy common risk factors which precipitate the adverse effects include: old age, volume
-depleted state, pre-existing renal dysfunction and coexisting use of other nephrotoxins. Although it is
impossible to present all the drugs causing renal disease, a few prototype drugs are mentioned. In a case
of undiagnosed renal disease a possibility of drug-induced renal failure should be kept as the prompt
removal of the drug and supportive management can reverse the renal dysfunction to a large extent.
INTRODUCTION
demeclocycline, aminoglycosides, amphotericin B.
he incidence of drug-induced nephrotoxicity has been
increasing with the ever increasing number of drugs and
with easy availability of over-the-counter medication viz. nonasteroidal anti-inflammatory drugs (NSAIDs). Antibiotics,
NSAIDs, angiotensin converting enzyme inhibitors (ACEI)
and contrast agents are the major culprit drugs contributory
to kidney damage. Drug-induced acute renal failure (ARF)
accounted for 20% of all ARF in an Indian study;1 of which
aminoglycosides accounted for 40% of total cases.
A. Syndromes of drug-induced nephropathies
Table 1 delineates common syndromes associated with
drug-induced kidney diseases.
Other syndromes include-
The summary of management of drug-induced kidney
diseases is mentioned in Table 2. Table 3 outlines dose
adjustments for kidney disease patients.
B. Individual classes of drugs
T
•
Acute glomerulonephritis (rarely seen with drugs like
rifampicin)- Associated with generalized anasarca,
hypertension, oliguria; blood urea nitrogen (BUN) and
serum creatinine (SCr) elevated; urine microscopy reveals
proteinuria (> 2 g/24 hr) and RBC casts with > 80%
dysmorphic RBCs. Renal biopsy may be indicated to
assess the pathology and to gauge the severity of
inflammatory response.
Syndrome of inappropriate ADH secretion- seen with
phenothiazines, vincristine, chlorpropamide,
cyclophosphamide, tricyclic antidepressants,
vasopressin analogues.
Nephrogenic diabetes insipidus- seen with lithium,
•
•
*Professor; **Postgraduate Student; ***Senior Resident; Nephrology
Division, Department of Medicine, Maulana Azad Medical College
and Lok Nayak Hospital, New Delhi - 110 002.
Received : 3.4.2003; Revised : 22.5.2003; Accepted : 1.9.2003
970
1. Aminoglycosides (AMG)
AMG are prototype drugs having nephrotoxicity as major
side effect. Number of patients developing nephrotoxicity
increases with duration of therapy reaching 50% with 14 days2
or more of therapy.
Clinical features - Classically it presents as acute tubular
necrosis which is generally milder than oliguric ARF. Features
include: non-oliguric ARF, proximal tubular dysfunction,
enzymuria, proteinuria, glycosuria, hypokalemia,
hypocalcemia, hypomagnesemia. In over 50%, renal functions
decline after completion of therapy. Recovery is slow and
requires 4-6 weeks.
Recovery is incomplete3 if pre-existing renal insufficiency
exists. Some patients may progress to chronic interstitial
nephritis.
Mechanisms2 - The drug is actively concentrated in the
renal cortex and proximal tubular cells achieve maximum
concentration. After entering the cortical cells AMG bind to
lysosomes with formation of myeloid bodies/secondary
lysosomes. Thereafter mechanisms are unclear. It is believed
that the release of AMG into cytoplasm interferes with the
phosphatidyl-inositol pathway. The transport system is a
low affinity high capacity system that is not easily saturable.
Thus momentary high drug concentrations as achieved
immediately after intravenous injection result in saturation of
the uptake mechanism. Hence, multiple dosing is more
deleterious than single dosing bolus injection.
JAPI • VOL. 51 • OCTOBER 2003
Table 1: Syndromes of drug-induced kidney disease
Syndrome
Clinical features
Pre-renal
failure/
functional
renal failure
Caused by reduced blood delivery
NSAIDs, ACEOliguria, anasarca, acute fluid
inhibitors,
retention with or without
amphotericin-B,
hypotension. Investigations reveal
cyclosporine,
- BUN/Cr > 20:1
norepinephrine,
- decreased urinary volume
diuretics,
- FeNa < 1%
interleukin-2
- Urinary Na < 10 mMol/L
- Urine sediment is bland
Casts : RBCs or white blood cells
Seen with drugs secreted by kidneys. AMG,
Toxicity may be effect of the drug
cephalosporins
per se or the physiological conse(cephaloridine,
quence as in rhabdomyolysis or by
cephalothin)
the added toxicity of two drugs e.g.
Am-B,
cisplatin with AMG. Mostly nonrifampicin,
oliguric renal dysfunction detected
pentamidine,
biochemically first or with patients
NSAIDs,
developing overt signs of dehydration contrast media,
and electrolyte loss. Oliguria may
cyclosporine,
occur if drug is continued.
cisplatin, OKT3
• BUN/SCr=10 or 15
• Fractional excretion of Na (Fe Na) > 2%
• Urinary sodium content > 20 mmol/d
• Represents systemic manifestation
Methicillin,
of a hypersensitivity reaction with
ampicillins,
fever, rash and arthralgias
rifampicin,
• Onset after drug exposure variable NSAIDs,
• Systemic signs and symptoms
allopurinol,
dominate but associated with non- sulfonamides,
oliguric renal failure
thiazides.
Urine R/M → erythrocytes,
leucocyturia (mainly eosinophiluria),
WBC casts
• Urinary proteinuria usually < 2 g/day
but > 2/day seen with NSAIDs
• Fe Na > 1%
Proximal tubulopathy seen with
glycosuria, bicarbonaturia, phosphaturia,
aminoaciduria, proximal RTA
Distal tubulopathy
Hyperkalemia, Na+ washing, distal RTA
Medullary and interstitial defects
Na+ wasting, defect in urine
concentration (nephrogenic DI)
AIN usually has overlap of different
tubular dysfunctions.
Eosinophilia and eosinophiluria seen in
> 75% of AIN.
NSAIDs induced AIN is remarkable in
that eosinophiluria is usually absent and
associated with heavy proteinuria (> 2 g/d)
Renal biopsy required for diagnosis
Histology show evidence of tubular edema
with interstitial inflammation with or
without interstitial fibrosis or glomerular
involvement.
High degree of interstitial fibrosis is a
strong predictor of decline in GFR and
progression to chronic kidney disease.
Syndrome due to outflow tract
Sulfadiazine,
obstruction due to crystal
methotrexate,
Acute
tubular
necrosis
Acute
interstitial
nephritis
Druginduced
Drugs
Risk factors for AMG toxicity include Na+ and K+
depletion, renal ischemia, increasing age, liver disease, diuretic
use and concomitant use of nephrotoxic agents. Rising trough
JAPI • VOL. 51 • OCTOBER 2003
crystalluria
formation in tubules or ureter or
methoxyflurane,
• Due to retroperitoneal fibrosis as
acyclovir,
with methysergide
indinavir,
• Associated with volume depleted
nelfinavir,
states or bolus drug administration acetazolamide,
• Typical history of renal colic
triamterine
or lumbar pain followed by hematuria
and/or oligoanuria of sudden onset
Characteristic findings in urine microscopy
Showing gross hematuria with RBC
or crystals
Acyclovir → needle-shaped crystals
Indinavir → reactangular plates or rosettes
Hypersensit- • Rare
Penicillin G,
ivity angiitis • Associated with vasculitis of small
ampicillin,
vessels, can cause ARF
sulfonamides,
• Extrarenal manifestations present;
thiazides,
systemic complaints of vasculitis with metolazone
hematuria, hypertension, proteinuria
and modest elevation of SCr with
abdominal pain, joint involvement or
pulmonary changes
• Kidney biopsy - fibrinoid necrosis of
intima and media of small medium sized
renal vessels with cell infiltration
Thrombotic Rare syndrome
Mitomycin-C,
microangio- Associated with fever, hemolytic
cyclosporine,
pathy/
anaemia, thrombocytopenia and renal contraceptives,
hemolytic
dysfunction and CNS disease (diffuse) OKT3, 5-FU,
uraemic
Suspect drug as the cause in cases of quinine, cocaine,
syndrome Coomb's negative hemolytic anaemia ticlopidine,
with thrombocytopenia and renal
clopidogrel
failure with a known nephrotoxin.
Limited form of disease is the hemolytic
uraemic syndrome
Isolated
Associated with edema, proteinuria
Gold, heroine,
proteinuria (> 3.5 g/day) with hypoalbuminuria.
captopril,
with
Renal biopsy necessary to confirm
NSAIDs, IFNnephrotic pathology and prognosis, mostly
alpha, Dsyndrome membranous glomerulopathy or
penicillamine
minimal change disease (no light
microscope finding); rarely FSGS
Chronic
Symptoms of uraemia with occasional Heroine
glomerulo- fluid overload states and hypertension
pathy
Urine may show moderate proteinuria
(subnephrotic) or glomerular hematuria
Chronic
History suggestive of tubular defects NSAIDs,
tubulointer- in early stage with polyuria and
Thiazides,
stitial
nocturia
Lithium,
disease
Renal insufficiency develops slowly
Chinese herb
Glomerular dysfunction seen at late
nephropathy,
stage
germanium
Renal histology - Interstitial fibrosis,
Mononuclear cell infiltration, tubular
atrophy and glomerular sclerosis
Drugs implicated for AIN may cause
CIN if given longer.
Excessive consumption of calcium
carbonate and alkalis in antacids may
cause alkalosis, hypercalcemia and renal
tubular acidosis (Milk-alkali syndrome).
Retroperito- Unexplained uremia, polyuria,
Methysergide,
neal fibrosis Ultrasonography of the urinary tract hydralazine,
shows hydroureteronephrosis with
methyldopa
no apparent sign of calculi
levels may indicate impending nephrotoxicity.
Relative toxicites (in decreasing order)
Neomycin > Gentamycin > Tobramicin > Netilmicin >
Amikacin > Streptomycin
971
Table 2 : Summary of management of drug-induced
nephropathy
•
Drug-induced kidney disease may be immunological or nonimmunological toxic reaction
• Special risk groups include - Age (elderly), volume-depleted state,
concomitant use of other nephrotoxic drugs, Pre-existing renal
disease and risk factors specific to each drug class
• Patients need be monitored for - Symptoms, blood pressure, urine
volume, SCr, [GFR (predicted), urine Na+, FeNa] urine
microscopy, serum electrolytes, serum levels (trough) of certain
drugs (cyclosporine, aminoglycosides, vancomycin)
• Kidney biopsy in drug-induced renal disease; is indicated for* Suspected glomerular disease i.e. proteinuria > 2 g/day or
gomerular hematuria
* Drug-induced tubulopathies, to establish nature of
tubulointerstitial disease
* Post-renal transplant renal dysfunction to distinguish rejection
from CS-A toxicity.
* In patients of suspected microthrombotic angiopathies, to rule
out pre-renal cause.
• Treatment - Adequate fluid administration and treatment of
hypertension
Steroid use is controversial as long-term trials lacking, but may be
used for * Glomerular proteinuria with intake of NSAIDs, gold,
penicillamine not responding to cessation of drug
* All patients of hypersensitivity vasculitis due to drugs
* AIN unresponsive to drug cessation with granulomatous
reaction (biopsy proven)
* In patients of cisplatin toxicity
* Prednisolone in a dose of 1 mg/kg/day or methylprednisolone
has been used.
Role of dialysis in drug nephrotoxicity
* Persistent azotemia after drug withdrawal. Indications are
same as usual CKD patients.
* Removal of certain drugs may be easily accomplished due to
their high sieving coefficient.
These are acyclovir, gentamicin, tobramicin, amikacin and
cyclosporine.
* Modalities like CAVH, CVVH and CVVHD are especially useful
in the ICU setting for hemodynamically unstable patients.
* Plasmapharesis may be of help in HUS, but prognosis is usually
poor.
* Drug removal by peritoneal dialysis may be effective for drugs
which are highly protein-bound e.g. Cisplatin, cyclosporine,
beta-lactams; but the disadvantage is the relatively slow
dialysate flow rate (7 ml/min) which is seen with CAPD.
In most cases renal function may return to normal. However in
patients already in chronic stages chances of recovery are less. In
such cases only renal replacement therapies (dialysis of transplant)
many help.
Prevention and management
• Use total dose as once daily dosing;3 and for shortest
possible time in empirical therapy
• Mostly subclinical toxicity and beyond detection as
electrolyte imbalances are subtle
• Routine monitoring of SCr daily with calculation of dose
on basis of GFR/creatinne clearance especially in elderly.
Daily monitoring of serum Na+ and K+.
• If SCr > 1.5 mg/dl stop the drug and consider alternate
therapy.
•
972
Monitor urine output and start adequate fluid and
electrolyte therapy with specific emphasis on K+ and
NaCl as well as Ca2+ and Mg2+ replacement.
2. b-Lactams and vancomycin
True nephrotoxicity is rare. Acute interstitial nephritis
(AIN) may be seen especially with methicillin. Early
formulations of vancomycin had substantial nephrotoxic
potential due to impurities4,5 but current preparations are free
from adverse effect. AMG + vancomycin combination may
have synergistic toxicity.
3. Sulfonamides
Use of sulfonamides has increased with advent of AIDS.
Sulfadoxine + pyrimethamine combination is used in malaria.
Spectrum of nephrotoxicity includes6
1.
2.
3.
Acute interstitial nephritis (not common)
Necrotizing arteritis
ARF due to massive haemolytic anaemia in G-6-PD
deficient patients
4. ARF due to crystalluria (seen only with long-acting
agents like sulphadiazine)
Sulfadiazine: prototype drug causing crystalluria and ARF.
The overall incidence is 6%. Renal dysfunction starts after
three weeks of commencing treatment in AIDS patients and
is related to the cumulative dose (> 84g), the acetylated byproduct is toxic. Sulphadiazine has low solubility in acidic
urine. Crystals of sulfadiazine and acetylsulfadiazine are
typically recognized by examining the urine sediment where
they resemble “sheaves of wheat”. As the crystals transmit
through tubular lumen they cause local abrasion and chemical
irritation of collecting duct epithelium followed by peritubular
haemorrhage, tubular necrosis and obstruction at any level
from collecting duct to bladder. Patient manifests with
asymptomatic crystalluria and microhematuria, gross
hematuria, oliguria to anuria and post-renal ARF.
Risk factors especially in AIDS patients are:
1.
2.
3.
Prolonged duration of therapy than in community
acquired pneumonia
Oral fluid intake may be prevented by toxoplasma
encephalitis for which it is used
Concurrent diarrhoea and volume depletion
4. Associated presence of HIV associated nephropathy
Prevention and treatment
• Maintain adequate hydration (~3L/day)
• Urinary alkalinization with 6-12 g/day of sodium
bicarbonate to ensure urine pH > 7.5.
•
•
•
•
•
Routine urine microscopy 2-3 times a week, to detect
gross/microscopic hematuria.
Perform ultrasonography in all patients of hematuria.
Treatment is reduction or omission of sulfadiazine dose;
stoppage causes resolution.
Maintain hydration and alkalinization.
Ureteral stents may be placed or dialysis may be resorted
JAPI • VOL. 51 • OCTOBER 2003
Table 3 : Dose adjustments for patients of renal
dysfunction
Drugs
Acetazolamide
Acetaminophen
Acyclovir
Allopurinol
Alprazolam
Aminoglycosides
Amiodarone
Amoxy/Ampicillin
Amphotericin B
Analgesics-NSAIDs
Analgesics-opioids
Antidepressants
Aspirin
Atenolol
Azathioprine
Azithromycin
Aztreonam
Benazepril
Benzylpenicillin
Beta-blockers
Bumetanide
Captopril
Carbamazepine
Carbenicillin
Carbenoxolone
Cefadroxil
Cefazolin
Cefixime
Cefoperazone
Cefotaxime
Cefpodoxime
Ceftazidime
Ceftizoxime
Ceftriazone
Cefuroxime
Cephalexin
Cetrizine
Chloramphenicol
Chlorpromazine
Cisapride
Cisplatin
Clarithromycin
Clofibrate
Clonidine
Colchicine
Co-trimoxazole
Cyclophosphamide
Cycloserine
Diazepam
Digoxin
Dipyridamole
Disopyramide
Domperidone
Doxazosin
Enalapril
Ergotamine
Ethambutol
Ethosuximide
GFR
(mL/min)
<
<
<
<
10
50
50
50
< 50
< 50
< 50
< 50
< 10
< 50
< 10
<
<
<
<
50
50
50
10
<
<
<
<
<
<
<
10
10
50
10
50
50
50
<
<
<
<
<
<
<
<
50
50
50
50
10
50
10
50
< 50
< 50
<
<
<
<
10
50
20
50
< 50
< 50
< 10
<
<
<
<
10
50
50
10
Dosage
recommendations
Avoid
Reduce dose frequency
Reduce dose frequency
Reduce dose
No change
Reduce dose frequency
No alteration, hepatic metabolism
Decrease frequency
Use only if no alternative
No alteration
Decrease dose
Mainly hepatic excretion
Avoid
Decrease dose
Reduce dose
No change
Reduce dose
Reduce dose
Reduce dose
Reduce dose
No dose alteration; at low GFR
may require high doses
Reduce dose
Reduce dose to 75%
Reduce dose
Avoid
Reduce dose frequency
Reduce dose frequency
Reduce dose
No alteration
Reduce dose frequency
Reduce dose frequency
Reduce dose frequency
Reduce dose frequency
Reduce dose frequency
Reduce dose frequency
Reduce dose frequency
Reduce dose
No dose alteration
No change
No alteration
Avoid
No change
Reduce dose frequency
No change
Reduce dose by half
Reduce dose frequency
Reduce dose
Avoid
No change
Reduce dose frequency
No change
Reduce dose
Reduce dose by half
No change
Reduce dose hy half
Avoid
Reduce dose frequency
Reduce dose to 75%
JAPI • VOL. 51 • OCTOBER 2003
Erythromycin
Famotidine
Finasteride
Fluconazole
Flucytosine
Foscarnet
Furosemide
Ganciclovir
Gemfibrozil
Glibenclamide
< 10
< 50
< 50
< 50
< 50
< 50
Gliclazide
Glipizide
Glucorticoids
Gold salts
Haloperidol
Heparin
Hydralazine
Hydroxy-chloroquine
Imipenem
Indapamide
Insulin
Isoniazid
Itraconazole
Ketoconazole
Labetolol
Lisinopril
Lithium
Lovastatin
Magnesium salts
Melphalan
Mercaptopurine
Metformin
Methocarbomol
Methotrexate
Methyldopa
Metoclopramide
Metolazone
Metoprolol
Metronidazole
Mezlocillin
Miconazole
Misoprostol
Morphine
Nicardipine
Nifedipine
Nitrates
Nitrofurantoin
Nitroprusside
Omeprazole
Penicillamine
Pentamidine
Pentoxiphylline
Phenobarbitone
Phenytoin
Piperacillin
Potassium salts
Pravastatin
Prazosin
Primidone
Probenecid
< 50
< 10
< 50
< 10
< 10
< 50
< 50
< 20
< 20
< 20
< 50
< 50
20-50
< 20
< 50
< 50
< 10
< 50
< 50
< 50
< 50
< 10
< 10
< 50
< 20
< 10
< 50
< 10
No change
Reduce dose by half
No change
Reduce dose
Reduce dose frequency
Reduce dose
No change
Reduce dose frequency
Reduce dose
No changes; but increased risk of
hypoglycemia
No changes; but increased risk of
hypoglycemia
No change but hypoglycemia may
occur, although it is short-acting
No change
Avoid
No change
No change
Reduce dose frequency
Reduce dose
Reduce dose
No change
May need dose reduction as
insulin requirement falls.
No change
Reduce dose by half
No change
No change
Reduce dose
Reduce dose
No change
Avoid or reduce dose
Reduce dose
Reduce dose
Avoid
Avoid
Reduce dose
Avoid
Reduce dose frequency
Reduce dose frequency
No change
No change
Reduce dose by half
Reduce dose frequency
No change
No change
Reduce dose frequency
No change
No change
No change
Avoid
No change
No change
Avoid if possible, or reduce dose
Dosing interval 24-48 hrly
No change
Reduce dose frequency
No change
Reduce dose frequency
Avoid routine use
Reduce dose to half
No change
Reduce dose frequency
Avoid
973
Procainamide
Propranolol
Propylthiouracil
Pyrazinamide
Quinolones
Ramipril
Ranitidine
Rifampicin
Simvastatin
Spironolactone
Sucralfate
Sulphadiazine
Sulphasalazine
Terazosin
Theophylline
Thiazide diuretics
Ticlopidine
Tolbutamide
Trimethoprim
Tubocurarine
Valproic acid
Vancomycin
Warfarin
Zidovudine
< 50
<
<
<
<
<
50
10
50
50
50
< 10
10-50
< 10
< 10
< 10
< 10
<
<
<
<
50
20
10
50
Reduce dose frequency
No change
Reduce dose
Reduce dose by half
Reduce dose frequency
Reduce dose
Reduce dose frequency
No change
Reduce dose to half
Reduce dose frequency
Avoid
No change
Avoid
Ensure high fluid intake
No change
No change
Avoid
No change
No change
Reduce dose frequency
Reduce dose
Reduce dose to 75%
Reduce dose frequency
No change
No change
“Reduce dose frequency” means that the frequency of
administration that is the dosing intervals have to be increased;
“Reduce dose” means that the dose being administered to the
patient has to be decreased by half if the GFR is between 10-50 ml/
min, and to one-fourth when the GFR is 10-50 ml/min
to, if surgical option not available.
Cotrimoxazole - The trimethoprim component achieves
more concentration in renal cortex than in serum and in the
process impairs the tubular secretion of creatinine resulting
in increase in its serum concentration with decline in creatinine
rate (CCR) calculated from Cockroft-Gault equation but GFR
measured by radio-labeled isotope is normal.7 It is important
as it may cause false diagnosis of renal failure in a case of
AIDS. Sulfamethoxazole as good urinary solubility compared
to sulfadiazine but rare reports of crystalluria8 can be eliminated
with adequate hydration. AIN due to the sulfa component is
far more common. Hyperkalemia due to trimethoprim
inhibition of the apical sodium channels of distal tubule is
known and is a dose-related side effect.9
4. Acyclovir
Doses > 500 mg/m2 given i.v. leads to nephrotoxicity.10 Its
low solubility leads to intratubular precipitation with
symptoms of obstructive uropathy and hematuria. Urine
analysis reveals birefringent needle-shaped crystals.
Interstitial inflammation is seen adjacent to areas of
intratubular obstruction. Oliguria is very rare. Risk factors
include: volume depletion, pre-existing renal insufficiency
and rapid bolus infusion. Treatment is prompt withdrawal of
therapy, which restores near normal renal function within 1014 days. However severe renal failure may occur necessitating
hemodialysis.
5. Amphotericin-B (Am-B)
It contains hydrophilic as well as lipophilic regions;
974
allowing it to easily mingle with cellular membranes, disrupting
them and increasing their permeability.11 Disruption of cell
membranes leads to endothelial damage with vasoconstriction
of afferent and efferent arterioles, causing an acute fall in
GFR and an initial oliguric ARF in some patients. Tubular
toxicity is related to direct effect on cellular membrane and
also medullary ischaemia caused by sudden vasoconstriction.
Recent studies show protective effect of pentoxiphylline
which is a vascular decongestant and antagonist to TNF-α,
IL-1α.12 Am-B typically causes distal tubular dysfunction.
Clinical spectrum of amphotericin nephrotoxicity
1.
Azotemia : It is almost universal with Am-B. GFR falls to
40% in first 2-3 weeks and stabilizes at 20-60% of normal
throughout course of treatment; normalizing on cessation
of therapy. Cumulative doses of 3-4g have greater risk;
implying a greater incidence with longer duration of
therapy and greater chances of irreversibility as well.
2. Inability to concentrate urine occurs universally within
1-2 weeks of therapy even in absence of decrease in GFR
and is not related to occurrence of azotemia. It occurs
due to failure of arginine-vasopression (AVP) response
on medullary collecting tubule.
3. Electrolyte disturbance occurs as a consequence of
distal tubulopathy with predominantly- Mg2+ and K+ loss
is important as it may cause worsening of renal function
with impairment of concentration ability, urinary
acidification, renal insufficiency.
4. Renal tubular acidosis can occur at cumulative doses
of 0.5-1 g but is reversible.
Management of a case of amphotericin toxicity
Prevention is the key with risk factors for Am-B toxicity
remain the same as for any toxic nephropathy but sodium
deficiency is important especially in patients on diuretics.
Novel measures to reduce amphotericin nephrotoxicity• Dopamine agonists - may exert protective role.13
• Salt supplementation - is the most effective measure in
reducing incidence.14 A titre of normal saline infused
prior and post Am-B significantly lowers incidence of
nephrotoxicity.
• Liposomal amphotericin-B15 - Liposomal compounds
and lipid complexes reduce Am-B toxicity. The lipid
complex is rapidly taken up by the reticuloendothelial
system thereby significantly increasing the tissue
concentration in the liver, spleen and lymphoid tissues.
A higher total dose of 5 mg/kg/day compared to a
maximum of 0.5 to 1.5 mg/kg/day with Am-B can be
achieved without risking the renal tissue; and the efficacy
is similar. High cost is the disadvantage. Liposomal
preparations should be used in patients with pretreatment renal dysfunction (SCr > 3 mg/dl) and where
use of alternative antifungals is not feasible.
• Age - important risk factor and careful use of CCR for
dose titration is necessary for elderly.
•
Frequency of dosing - alternate day administration
JAPI • VOL. 51 • OCTOBER 2003
reduces incidence of nephrotoxicity.
6. Rifampicin
Incidence of rifampicin nephrotoxicity varies from 1.8% to
16% of all ARF. Most cases of rifampicin-related renal failure
are secondary to drug-induced haemolytic anaemia. However,
AIN, rapidly progressive glomerulonephritis presenting as
proteinuria with acute onset deterioration of renal functions
and light-chain proteinuria constitute the remaining. Duration
of therapy seems important and cases have been reported
after two months of therapy; although reactions as early as
13 days have also been seen. Intermittent regimens carry
greater risk. The possibility of toxic interaction between
isoniazid and pyrazinamide also exists. In most cases prompt
withdrawal of therapy and supportive management leads to
recovery within three weeks.16-18
Poor prognostic factors19 are- longer duration of anuric
phase, severity of immunological abnormalities on renal
biopsy; associated hemolysis, leucocytosis and
hyperglobulinemia.
The Indian experience is less known.16,20 Overall incidence
of rifampicin-induced ARF was 1.8% and mortality was 18%.
AIN was the most common pathology followed by ATN.
Higher incidence of ARF was observed with intermittent
therapy.
7. NSAID-induced renal diseases
Overall incidence is 3%; but over-the-counter availability
of these drugs puts a large population at risk.
Conditions causing NSAID-induced hemodynamic
deterioration of renal function - Higher than usual dose,
volume depletion due to flow loss diarrhoea, congestive heart
failure, nephrotic syndrome, cirrhosis particularly with ascites,
preexisting renal disease, third space fluid sequestration,
diuretic therapy, age > 65 years.
Syndromes of NSAID nephrotoxicity
Acute effects
1. ARF - usually oliguric
2. Acute interstitial nephritis (AIN) - Associated with heavy
proteinuria (> 3 g/24 hr); usually non-oliguric; rarely
without proteinuria; takes weeks or months to resolve
3.
4.
5.
Hyperkalemia
Sodium and water retention
Hypertension
Effects of NSAIDs on blood pressure21-23 - Modest increase
of mean arterial pressure (~6-8 mmHg) in all patients with
increase more in patients already hypertensive. Most
vulnerable are patients on diuretics and/or β-blocker
especially patients on propanolol; but less vulnerability seen
with calcium channel blockers, direct vasodilators and
clonidine. Effects in combinatin with ACE inhibitors are
controversial and may cause deterioration of renal function.
Most vulnerable are patients with low renin hypertension i.e.
elderly and blacks.
JAPI • VOL. 51 • OCTOBER 2003
NSAID-induced tubulointerstitial nephritis- clinical
features
• Usually subacute to chronic course
• Mostly seen with fenoprofen but all NSAIDs till date
observed to cause
• Mean period of development 5.4 months
•
•
•
•
Associated with heavy proteinuria (> 3.0 g/d) in 83% of
cases
Fever, rash, eosinophilia rare (<19%)
Renal biopsy characteristically shows tubulo-interstitial
infiltrate with some fibrosis. Immunofluorescence shows
variable staining for IgA, IgM and C3.
Proposed mechanism is occurrence of delayed
hypersensitivity response with shunting of arachidonic
acid metabolites to lipoxygenase pathway. Leukotrienes
mediate chemotaxis for WBCs leading to cellular
infiltrates (T-cell and eosinophils).
Isolated proteinuria - Isolated reports of proteinuria in
absence of tubulointerstitial damage occur; proteinuria
reaching nephrotic range; and minimal change disease on
biopsy.24
Concept of renal sparing NSAIDs
Sulindac was previously considered as reno-protective
since its hepatic metabolite sulindacsulfoxide has shown to
be least affecting the renal cyclooxygenase system whereas
the sulfide metabolite is active as a vasoconstrictor. Present
views suggest that kidney can activate the prodrug and lead
to vasoconstrictive renal failure usually after days or weeks.
Chronic kidney disease (CKD) and NSAIDs - also known
as “analgesic nephropathy”. It is chiefly a chronic interstitial
nephritis associated with capillary sclerosis of the vessels of
renal pelvis and renal papillary necrosis followed by
calcification. It is due to medullary ischaemia induced by loss
of vasodilatory effects of prostaglandins on vasa recta. Long
term toxicity of individual drugs are unknown and so are
incidence and prevalence in view of most drugs available
over-the-counter. Classically seen with consumption of any
NSAID for over 20 years. The potential of CKD exists with
use of analgesic mixture and is most well studied with aspirincodeine. Incidence is higher in females and in patients
suffering from rheumatic disorders and migraine. Diagnosis
is difficult as there is lack of a simple non-invasive test that
reliably implicates analgesics as a cause of renal injury.
Clinico-radiological criteria25 - History of analgesic
abuse (i.e. daily use of mixture of analgesic drugs for a period
not less than five years) with non-contrast CT scan of
abdomen showing the following
1.
2.
3.
Bumpy contour of the kidneys
Decreased length of both the kidneys
Papillary calcification
1 or 2 with 3 carries maximum specificity (100%) and
sensitivity (94%) in diagnosis.
975
Prevention and management: It is one of the few CKDs
which can be prevented and early intervention can prevent
its progression. Stop NSAIDs if patients develop any
evidence of renal insufficiency. Appropriate legislation to
limit accessibility of all analgesics is required.
COX-2 selective inhibitors - the final answer to
nephrotoxicity?26
COX-2 selective inhibitors were designed to counteract
the gastrointestinal toxicity considering COX-1 as a
constitutive enzyme and COX-2, an inducible enzyme
(induced by inflammatory and mitogenic stimuli). COX-2 is
now known to exist constitutively in renal tissue especially
the cells of the thick ascending loop of Henle and macula
dense in humans as well as in renal medulla interstitial cells
and medullary collecting duct cells. Prostaglandins generated
by COX-2 are involved in tubuloglomerular feedback
mechanism leading to afferent arteriolar vasoconstriction. In
medulla COX-2 promotes diuresis and natriuresis. Expression
of COX-2 is enhanced in low salt diet in the cortex while it is
increased in medulla with high salt diet. The former preserves
renal function in volume depletion whereas the latter promotes
natriuretic and diuretic response during volume expansion.
Given the role of COX-2 in renal function; same precautions
need to be taken with COX-2 inhibitors; as is necessary for
non-selective NSAIDs. In patients with chronically salt
depleted state e.g. hypertensive or CHF on diuretics the risk
of ARF is the same as with conventional NSAIDs. However,
further studies are necessary to assess long-term outcomes.
8. Gold and D-penicillamine
Penicillamine - 7% develop nephrotic syndrome with
kidney biopsy demonstrating membranous nephropathy.
Proteinuria may occur at six months to six years.
Gold - Proteinuria occurs in 30% of patient with renal
pathology in most being membranous glomerulopathy and
minimal change disease in few cases. Proteinuria is usually
less than 3.5 g/d. Parenteral gold is more likely to cause
proteinuria.
At present, genetic predisposition to development of
proteinuria both with gold and penicillamine is shown to be
in HLA-B8 and HLD-DRW3 patients. Cases of rapidly
progressive renal failure due to crescentic GN have been
seen otherwise KFTs are maintained. Proteinuria stops on
cessation of the drug.
Treatment is supportive with withdrawal of the drug.
9. Anti-neoplastic agents
Cisplatin - Major side effects is nephrotoxicity and is
irreversible in most cases.
• Toxicity is cumulative and dose-related (> 25-33 mg/m2/
wk predisposes to nephrotoxicity).
• Nephrotoxicity is by acute tubular necrosis or
tubulointerstitial process with symptoms of azotemia and
fluid loss.
• Biochemical tests usually show tubular proteinuria with
prominent tubular casts. High BUN and SCr and low
976
serum Na+, K+, Mg2+, Ca2+, PO43- occur due to proximal
tubular damage. Hypomagnesemia is severe. Damage
typically occurs at the S3 portion of proximal tubule.
Free radicals may play an important role. Prevention of
toxicity is by avoidance of other nephrotoxic drugs like
AMG.
• Begin diuresis after drug administration; maintaining
urine output of 100 mL/hr can decrease nephrotoxicity.
Mannitol may also be helpful.
• Administration is better tolerated if given by hypertonic
saline which is also be given 12 hours prior and 12 hours
post-cisplatin dose.
• Sodium-thiosulfate i.v. has been tried with some success.
It should be added if > 200 mg/m2 of cisplatin is used.
• Some other measures to reduce nephrotoxicity are
methylprednisolone, N-acetylcysteine and antioxidants.
Cyclophosphamide - Although primarily a myelotoxic
drug, nephrotoxicity is known. At daily doses of more than
50 mg/kg hyponatremia is seen. Hyponatremia occurs due to
impaired water excretion by antidiuretic effect on distal
nephron. The effect is transient and dissipates after 24 hrs of
discontinuation of therapy. Hemorrhagic cystitis is a more
common side effect of cyclophosphamide and occurs in 9%
of cases.
Methotrexate - Effective chemotherapeutic agent
• Nephrotoxicity seen at doses greater than 1.5 g/m2/week.
•
Mainly due to intratubular deposition of 7hydroxymethotrexate leading to crystalluria and features
of non-oliguric renal failure. Element of direct tubular
toxicity are ameliorated with folinic acid. High doses of
methotrexate need routine monitoring of KFT for casturia
and tubular dysfunction. Rapid discontinuation reverses
the abnormality.
• In patients with overt nephrotoxicity, anion binding resin
and hemoperfusion therapy have been tried with some
success. High dose folinic acid at 200-400 mg i.v. four
hourly has been shown also to revert nephrotoxicity.
10. Antihypertensives
ACE inhibitors - Most common syndrome is reversible
ARF seen in cases of hypertension and congestive heart
failure and is related to action of angiotensin II on efferent
arterioles for maintenance of GFR at time of low perfusion
pressure with increasing filtration fraction. Hence ACEI cause
a sudden decline in GFR due to loss of efferent arteriolar
tone. In bilateral obstruction of renal arteries (> 70%); efferent
arteriolar tone is necessary for maintaining GFR. Therefore,
ACEI in such cases can cause renal failure.
Clinical features are associated with a sudden onset of
oliguria with fluid retention, deranged renal functions and
decreased FeNa (< 1%). Membranous nephropathy was
earlier seen with captopril; characterized by isolated glomerular
proteinuria without derangement of renal functions. Acute
tubular necrosis and interstitial nephritis have also been
reported.
JAPI • VOL. 51 • OCTOBER 2003
Approach to ACE inhibitors should therefore be careful.
Recognition of risk factor, vigilant monitoring and volume
management is necessary. A drug holiday of agents as
furosemide may be necessary before starting the therapy.
Serial SCr measurements are recommended especially if higher
than 1.6 mg%. Transient deterioration in SCr may be seen on
the 3rd day in most patients but derangement persisting
beyond the 7th day of therapy needs active intervention to
rule out sub-clinical renal stenosis.
Angiotensin receptor blockers (ARBs) - ARBs reduce BP
to a degree comparable to ACE inhibitors but propensity to
cause renal disease is believed to be less, especially with
regard to functional renal failure. However, the issue is largely
unresolved.
11. Immunosuppressants
Cyclosporine A (CS-A) - Two forms of cytotoxicity are
known (a) acute reversible nephrotoxicity (b) chronic
irreversible nephrotoxicity
Acute form : Most transplant recipients manifest one or
more episodes of acute renal failure.
• Usually due to vasoconstriction induced in systemic
circulation; secondary to vasospastic products of
arachidonate metabolism specially thromboxane-A2.
• Manifests as sudden onset hypertension occurring
within weeks of transplant.
• Preoperative conditions may have a role in nephrotoxicity
as prolonged cold ischemia time, donor hypotension and
advanced age of the donor may increase the risk.
• Manifests with preserved urine volume and Na+ excretion
but GFR and renal plasma flow are decreased with no
change in the filtration fraction along with hypertension.
Rapid improvement upon reduction of cyclosporine dose
is seen. GFR progressively rises to baseline as blood
levels of CS-A fall to trough levels.
• Ideal dose: 9-20 mg/kg/day; ideal trough levels of CS-A
150-400 ng/ml
•
Renal biopsy: shows vacuolization in proximal tubules
and microcalcification with or without interstitial fibrosis.
• Treatment: Calcium channel blockers provide protection
and ameliorate early cyclosporine toxicity in humans.
Large prospective studies now show that they can
decrease long-term cyclosporine toxicity and improve
graft survival.27 Prostaglandin analogue misoprostol has
shown some benefit in reversal of vasoconstrictive
effects.
Chronic CS-A nephrotoxicity - Typically manifests after
one year; mimics chronic rejection.
•
•
Presents as hypertension, mild proteinuria, rarely
hematuria, with marked decline in GFR.
Renal biopsy : shows CS-A associated obliterative
arteriolopathy, tubular atrophy and interstitial fibrosis;
may be seen as early as six months after therapy. Tubular
atrophy with diffuse fibrosis may appear as stripes
JAPI • VOL. 51 • OCTOBER 2003
(striped interstitial fibrosis- characteristic of CS-A).
•
Progression of interstitial fibrosis is dose-dependent with
more several lesions in patients with cumulative dose of
more than 1.8 g/kg over six months.
Hemolytic uraemia syndrome is a rare arteriopathy with
severe renal impairment associated with thrombosis in renal
microcirculation along with thrombocytopenia and hemolytic
anaemia. Prognosis for patients is poor. Plasmapheresis may
be of some benefit.
Prevention of CS-A toxicity
• Start CS-A on 5th day post-surgery as lowest dose with
upward titration to reach ideal trough concentration in
1-2 months.
• Meticulous SCr and BP monitoring.
• Calcium channel blockers are beneficial in initial stages
of acute hypertension.
• Avoid drugs which raise CS-A levels and hence cause
nephrotoxicity. These include cimetidine, ranitidine,
diltiazem, verapamil, erythromycin, metoclopramide,
anabolic steroids and oral contraceptives.
•
Micronized forms of CS-A are beneficial as total dose is
less and lower nephrotoxicity also.
In cases of proven CS-A toxicity strategies available
include the “Triple therapy” Prednisolone+CS-A (at lowest
dose) + azathioprine. Newer therapies using non-calcineurin
inhibitors like the mycophenolate mofetil (MMF) +
azathioprine regime or MMF + micronized CS-A have shown
some benefit in avoiding nephrotoxicity and ensuring graft
survival.
12. Diurectics
These cause reduction in GFR by extracellular fluid volume
contraction.
Other renal diseases induced by the duretics
Hypokalemia nephropathy : all the diuretics expect the
potassium sparing diuretics.
Polyuria and abnormal concentrating ability : All
diuretics (except potassium-sparing) due to chronic
hypokalemia.
Interstitial nephritis : thiazides and furosemide
Vasculitis : Thiazides
Nephrolithiasis : Acetazolamide at low pH can precipitate
in urine leading to renal colic and obstructive uropathy.
Hyperuricemia induced by thiazides by inhibition of urate
excretion and the ECF volume contraction which enhances
proximal tubule uptake induced increase in serum urate levels.
Hyperuricaemia predisposes to uric acid nephrolithiasis.
Treatment is withdrawal of the offending agent and volume
and electrolyte support. Conditions which are immunologicalmediated may respond to steroids. Alkalinization of urine
normally used in prophylaxis of obstructive uropathy may be
detrimental in case of acetazolamide as it enhances calcium
phosphate stones.
977
13. Contrast-induced nephropathy
It is a condition with impairment in renal function defined
as an increase in SCr by more than 25% within three days
following intravenous administration of a contrast medium in
the absence of an alternative etiology. Incidence varies from
5-12% of those undergoing contrast administration.
Risk factors include renal failure, diabetic nephropathy,
severe congestive heart failure, amount of contrast media
(> 150 ml) and volume depletion.
Clinical features - Characteristically acute and progressive
rise in SCr within 24 hours of i.v. contrast administration is
seen. Oliguria is present in 95% of cases and pre-renal failure
is typically seen with FeNa < 1%.
Outcome of patients varies with the presentation. Three
syndromes have been identified28- oliguria with decreased
GFR (77%), reduced GFR without oliguria (12%) and normal
GFR without oliguria (11%). It was observed that 32% had
permanent renal damage with one out of every five dying of
uraemia or requiring renal replacement therapy. The residual
renal impairment is maximum with the acute oliguric renal
failure group.
Prevention and management
•
•
High risk patient must be identified
Monitor SCr on 2nd and 4th day post-procedure in all
high-risk patients.
• Adequate hydration with 0.45% saline at (1.5 ml/kg/hr)
starting 12 hours prior to the procedure and after the
procedure.
• Patient should be hemodynamically stable
• Minimize amount of contrast administered (< 2 ml/kg or
max of 150 mL)
• Use of non-ionic contrast iso-osmolar solution for high
risk patients is recommended. In a recent meta-analysis
of 31 trials over last 20 years, it was concluded that low
osmolar contrast media like ioversal is less nephrotoxic
than high osmolar/ionic contrast in existing renal failure
but no significant benefit in patients with normal renal
functions.29
• No benefit of mannitol and furosemide in preventing ARF
but may increase risk of ARF.
• Calcium blockers prevent renal ischemia during initial
renal vasoconstrictor phase.
Gadolinium30 is also nephrotoxic; more nephrotoxic than
iodinated contrast medium dose to dose and hence to be
avoided in patients at risk for contrast-induced nephropathy.
Doses of < 0.3 mmol/mg/BW of gadolinium is recommended.
If patient develops ARF, manage on conservative lines.
Most of the times it is reversible but in irreversible cases not
improving on hydration, temporary dialysis may be required.
14. Drugs causing hemolysis and myoglobinuria
Characteristic drugs are sulfonamides, dapsone, rifampicin
which have been already discussed. The mechanism of renal
damage resulting in acute tubular necrosis has been
978
mentioned in Table 1. Other agents include methyldopa,
phenacetin, quinidine, procainamide, melphalan, isoniazid,
penicillins and cephalosporins. Hemolysis may result in
genetically predisposed patients with G-6-PD deficiency.
Aminosalicylic acid, antimalarials e.g. primaquine, aspirin,
chloramphenicol, co-trimoxazole, dapsone, nalidixic acid,
nitrofuration, probenecid, phenacetin, sulfonamides,
procainamide and quinidine can cause hemolysis in these
patients, and possibly renal failure too.
15. Poisons masquerading as drugs
Various contaminants may find their way in drugs viz.
ethylene glycol, heavy metals (especially in bhasmas and
bhabhutis given by quacks). Ethylene glycol contamination
is recognized by a picture of ethanol-like intoxication, elevated
serum osmolality followed by increased anion-gap metabolic
acidosis and oxalate crystals in urine. Acute tubular necrosis
manifested by proteinuria, oliguria and anuria becomes
evident in 12 to 24 hours following ingestion. Heavy metals
like lead, cadmium, mercury and arsenic are constituents of
medicines given by quacks; and are selectively retained by
bone, liver and kidneys for years together. Besides, the
kidneys are the major route of their elimination. Chronic
administration of these medicines results in subclinical
exposure to these toxic agents resulting in interstitial nephritis,
tubular damage, decline in GFR and chronic kidney failure.
Nephrotic syndrome is another manifestation of heavy metal
poisonings and arsenic exposure may result in cancer of the
bladder and kidneys.
CONCLUSION
Given the large armamentarium of drugs available today
judicious use of such drugs is required to prevent untoward
side effects especially on such a vital organ as the kidney.
Identifying high risk patients and quick recognition of druginduced injury-related syndrome with prompt cessation of
the offending drug are the key to managing such a case before
the injury causes permanent damage to the renal tissue.
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25. Elseviers MM, De Schepper A, Corthouts R, et al. High
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Announcement
Following are the office bearers of API-Hisar, Haryana Chapter elected for the year 2003-2004.
Chairman
Secretary
:
:
AK Singh
A Mahajan
Vice Chairman
Treasurer
Joint Secretary
Executive Members
:
:
:
:
:
:
:
:
B Bhushan
S Singh
K Kishore
MP Kamboj
BS Jain
AK Gupta
S Suri
A Bhatia
Sd/A Mahajan
Hon. Secretary,
JAPI • VOL. 51 • OCTOBER 2003
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