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Drug induced kidney disease refers to the Kidney damage induced by the medication administered
for the purpose of diagnosing or treating another medical disorder.
Drug-induced kidney disease constitutes an important cause of acute renal failure (ARF) and
Chronic kidney disease (CKD) 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 drug induced 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.
ARF and CKD in itself complicate the drug therapy limiting the options available for the
treatment of a particular medical condition arising in the patient with acute or chronic renal failure
Potential nephrotoxic medications are constantly being released for use in clinical practise these
drugs are often not tested in the patient populations who subsequently receive them.
The 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. Non steroidal 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 (jha v et al) of
which amino glycosides accounted for 40% of total cases.
Acute kidney injury is an independent risk factor for patient mortality, even with small
decrements in kidney function. In addition, it increases length of stay in the hospital and increases
cost of treatment. Renal injury is often multi factorial, with drugs being only one of the factors in
its pathogenesis. Hence, it is often difficult to estimate involvement of drugs as a cause of acute
kidney injury. However, some data shows that in almost one quarter of cases of severe acute
kidney injury nephrotoxic drugs are significant contributors. Renal handling of drugs involves
glomerular filtration, excretion through trans cellular transport into tubular fluid and reabsorption
from the tubular fluid.
High renal blood flow and process of concentration of drugs and their metabolites during
formation of urine predisposes kidneys to toxic drug injury. From the pathogenic
(pathophysiologic) perspective drug-induced kidney injury can be divided into hemodynamic,
intrinsic (injury to renal tissue) and intra renal obstruction (obstruction of tubule fluid flow). From
didactical point of view kidney histology can be divided into four compartments: glomeruli,
tubules, interstitium and vasculature. Each of these compartments can be target of drug-induced
injury, with clinical and laboratory manifestations being dependent on which of them is
predominantly involved. It is important to appreciate that a single drug renal toxicity can involve
multiple path physiologic pathways and that predisposing factors are common to virtually all
causative agents mediating kidney injury. Dehydration, hypotension, pre existing kidney disease,
advanced age, diabetes and simultaneous use of multiple nephrotoxic drugs all greatly increase
risk for any nephrotoxic drug to exert its nephrotoxic effect. At an increased risk are particularly
patients in intensive care units.
In general drug induced kidney disease is reversible by the prompt intervention like withdrawal of
the causative drug that is inducing renal damage but subsequently observation of the signs and
symptoms and by haematological and biochemical evaluations. But given the high morbidity and
mortality associated with acute kidney injury and the frequent and necessary use of drugs in
critically ill patients clinicians should be aware of the potential nephrotoxicity and mechanisms.


Drugs can cause acute renal failure by causing pre-renal, intrinsic or post-renal toxicity.
Drugs cause pre-renal failure by impairing glomerular haemo filtration. Drugs can reduce the
renal blood perfusion by modulating the vasomotor tone of the afferent (pre-glomerular) or
efferent (post glomerular) arterioles and decrease glomerular filtration rate with subsequent renal
failure. Patients who already have compromised renal perfusion (heart failure or volume
depletion) are most at risk. Adequate intra glomerular pressure is maintained by prostaglandin
mediated afferent vasodilatation and angiotensin II-mediated efferent vasoconstriction.
Angiotensin-converting enzyme inhibitors (ACE-I and angiotensin-receptor blockers (ARBs)
decrease renal blood perfusion by inhibiting angiotensin II-mediated vasoconstriction at the
efferent arteriole. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin-induced
afferent arterial dilatation. As the renal parenchyma is normal, but the renal blood flow is
impaired, patients will present with low urine output, low sodium excretion and high osmolality.
The urea:creatinine ratio is usually more than 20 as the low urine flow facilitates a
disproportionate urea reabsorption relative to creatinine. The urine sediment is clear.
Tubular necrosis, interstitial nephritis or thrombotic angiopathy are common causes of
parenchymal drug-induced renal injury.
Aminoglycoside antibiotics and amphotericin B are commonly used drugs that cause dose-related
acute tubular necrosis. Acute tubular necrosis is usually caused by direct drug toxicity, but
prolonged impaired renal perfusion as described above may also cause tubular damage.
Microscopically, tubular necrosis is recognised by degenerative and regenerative tubular changes.
Patients present with a sudden rise in creatinine concentration, and develop oliguria if the
offending drug is continued. Urinary sodium excretion is increased and urinary sediment contains
granular casts and renal epithelial cells. The injury is dose dependent and generally resolves with
discontinuation of the causative drug.

There are several other mechanisms by which drugs can lead to nephrotoxicity. Table 1 lists these
mechanisms along with prototypical drugs that may induce nephrotoxicity.

Mechanisms Drugs Clinical Findings
Hemodynamic Radiocontrast agents,
calcineurin inhibitors,
angiotensin inhibitors,
angiotensin receptor blockers,
NSAIDs, interleukin 2
Benign urine sediment, FENa <1%,
UOsm >500
Acute tubular
Aminoglycosides, amphotericin,
cisplatin, radiocontrast agents,
methoxyflurane, outdated
tetracyclines, cephalosporins,
mithramycin, calcineurin inhibitors,
pentamidine, IVIG, ifosfamide,
zoledronate, cidofovir, adefovir,
FENa>2%, UOsm <350, urinary
sediment contains granular casts,
renal epithelial cells
Acute tubular
Lovastatin (statins), ethanol,
barbiturates, diazepam Elevated CPK, granular casts

Acute tubular

Quinine, quinidine,
sulfonamides, hydralazine,
triamterene, nitrofurantoin

Elevated LDH, decrease haptoglobin
Allergic interstitial Penicillins, rifampin,
sulfonamides, thiazides,
cimetidine,phenytoin, allopurinol,
furosemide, NSAIDS,
ciprofloxacin, pantoprazole,
omeprazole, atazanavir,

Rash, fever, eosinophilia,
eosinophiluria, pyuria
Osmotic nephrosis Mannitol, immune globulin, Urine sediment shows vacuole
dextrans, hetastarch containing cells

Papillary necrosis NSAIDs Hematuria, renal tissue

Obstruction Acyclovir, methotrexate, sulfonamides, sediment might be benign des
(intratubular triametrene, indinavir, foscarnet, -pite obstruction.
precipitation) gancyclovir.

Table 1 : Common drugs associated with nephrotoxicity in the ICU.

Complex factors maintain constancy of renal blood flow and glomerular filtration despite
widely varying arterial pressures. Such factors such as the renal nervous system,
prostaglandins, angiotensin II, adenosine, tubuloglomerular feedback as well as other factors
participate in regulating glomerular filtration rate. Normally drugs that affect renal
hemodynamics are unlikely to precipitate AKI alone unless patients have underlying
concomitant predisposing factors.

Volume contraction from any cause or other forms of prerenal AKI (cirrhosis, congestive
heart failure) will increase the incidence of and severity of nephrotoxicity due to nonsteroidal
anti-inflammatory drugs (NSAIDs). Conditions such as congestive heart failure, hypotension,
volume depletion, 3rd spacing, decrease effective arterial volume are conditions that
predispose to NSAID-induced nephrotoxicity. Prostaglandins under these conditions have an
important effect to maintain renal blood flow and glomerular filtration rate. Similarly
compensatory vasconstriction due to synthesis of angiotensin II, norepinephrine, vasopressin,
and endothelin are balanced by vasodilatory prostaglandins. The use of other drugs that
increase renin such as diuretics, angiotensin converting enzyme inhibitors (ACEI) or
angiotensin receptor blockers (ARBs) when used concomitantly with NSAIDs leads to a
reduced prostaglandin synthesis, renal vasoconstriction and AKI. Because the kidney medulla
is relatively hypoxic, a decrease in medullary blood flow may exacerbate the already hypoxic
medulla leading to AKI. Radiocontrast agents in addition to being a direct tubule toxin
induces vasoconstriction and when administered in patients using NSAIDS may lead to AKI.
Vasopressors, often used in the ICUs, as well as amphotericin can precipitate AKI when
NSAIDs are concomitantly used. Similarly, acute nephrotoxicity due to calcineurin inhibitors,
and vasopressors contributes to toxicity especially when used with NSAIDs. The renal effects
of NSAIDS are dose, drug and duration related. Aspirin is the least likely to cause AKI but
nonselective and selective NSAIDS were associated with AKI.

ACEI and ARBs are commonly prescribed drugs used for hypertension, congestive heart
failure and in chronic kidney disease. These drugs affect renal hemodynamics through an
decrease in efferent arteriolar tone and intraglomerular capillary pressure. The use of these
drugs under normal circumstances when renal perfusion is adequate poses very little problem.
However when these drugs are used in states of prerenal azotemia, renal artery stenosis or
concomitantly with other drugs such as NSAIDs, renal failure may ensue. In general AKI
under these circumstances is reversible following their discontinuation.

Drugs such as cyclosporine and tacrolimus, belong to a class of commonly used
immunsuppressants for organ transplantation referred to as calcineurin inhibitors. Calcineurin
inhibitors are associated with early prerenal azotemia and oliguria (<50 mL/h urine output)
due to vasoconstriction. Calcineurin inhibitor-induced vasoconstriction is thought to bedue to:
1) effects on the endothelium, 2) an increase in sympathetic activity, 3) an increase in
adenosine 4) a relative decrease of nitric oxide and transforming growth factor-beta 1, and 4)
an increase in endothelin-1, reactive oxygen and nitrogen species. Other factors that may lead
to renal vasoconstriction are drugs such as NSAIDs and ACEI/ARBs. In addition, drugs
that may increase blood levels of calcineurin inhibitors such as ketoconazole are likely to lead
to an increase in nephrotoxicity. Cyclosporine metabolism occurs in the liver via hepatic
cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, inhibits the
cytochrome P-450 enzyme system leading to an increase in cyclosporine levels and potential
toxicity. The early AKI from calcineurin inhibitors associated with prerenal indices is rapidly
reversible upon discontinuation of the drug.

Direct tubule injury occurs with different classes of drugs and is commonly associated with
antibiotics, chemotherapeutic agents, bisophosphonates, immunosuppressive agents and
contrast agents (Table 1).
Cidofovir or tenovir, antiviral nucleotide analogues with activity against DNA viruses are
associated with dose dependent AKI in 12-24% of patients with urinary abnormalities that
resemble Fanconis syndrome (proteinuria, glucosuria, and bicarbonate wasting. The
predilection for proximal tubule injury is due to its uptake in this segment across the
basolateral membrane by the human organic anion transporter(hOAT). Probenecid blocks this
transporter and reduces the cytotoxicity by reducing intracellular accumulation of these drugs.
Renal function usually improves upon discontinuing antiviral nucleotide analogues however
they can lead to end stage renal disease.
Aminoglycosides including gentamicin, tobramycin amikacin, streptomycin, neomycin,
kanamycin, paromomycin, netilmicin, and spectinomycin are approved by the Food and Drug
Administration (FDA) for clinical use in the United States. Gentamicin, tobramycin, and
amikacin are the most frequently prescribed for use intravenously although tobramycin has
been prescribed for inhaled use especially in patients with cystic fibrosis. All forms have been
associated with AKI (7-9%) including inhaled tobramycin. The renal toxicity was reported to
be 3.9%,in the first week,30% during the second week and after 2 weeks of therapy,
respectively. Aminoglycosides are organic bases that are freely filtered and taken up by
megalin located on the apical membrane of the S1/S2 segments of the proximal tubule and
collecting duct. Aminoglycosides rapidly traffick retrogradely through the Golgi complex and
to the ER and are finally released into the cytosol. Renal toxicity is frequently reversible. Risk
factors for aminoglycoside-induced nephrotoxicity include sepsis, preexisting renal disease,
age, diabetes, liver disease, hypovolemia, concurrent use of other drugs or exposure to
contrast and the use of diuretics.

Drugs may produce an idiosyncratic or allergic reaction leading to inflammation and
infiltration of immune cells such as lymphocytes, monocytes, plasma cells and eosinophils
leading to injury to the renal tubules and interstitium. Renal dysfunction in druginduced AIN
is believed to be the cause of AKI in 3-15% of all cases and 27% of undiagnosed cases with
normal size kidneys by ultrasound. Most cases of AIN in the ICU stem from antibiotics due to
the frequency of sepsis encountered requiring multiple antibiotics. A number of drugs have
been associated with AIN including beta-lactams, quinolones, rifampin, macrolides,
sulfonamides, NSAIDS, diuretics, cimetidine, randitine and proton-pump inhibitors (Table 1).
Recently bevacizumab, a recombinant humanized monoclonal immunoglobulin G antibody to
vascular endothelial growth factor (VEGF) used in clinical trials to treat cancer, has been
reported to cause interstitial nephritis. In addition there are other causes of interstitial
nephritis including infections, immune mediated diseases, glomerular diseases and other
idiopathic causes. The onset may range from 3 days to 20 days and maybe accelerated
following rechallenge. In general the clinical presentation includes, fever, rash and
eosinophilia. However this triad only occurs in one third of the patient who actually have the
disease. In addition AIN is often accompanied by low grade proteinuria and biopsy findings
consistent with interstitial infiltration of immune cells.

Bisphoshonates are used for treatment of hypercalcemia, fracture prevention and in patients
with metastatic cancer. This class of drugs reduce morbidity from hypercalcemia is
increasingly recognized to cause nephrotoxicity. Both pamidronate and zoledronate have been
associated with nephrotoxicity that features nephrotic syndrome with a collapsing glomerular
sclerosis. The mechanism is unkown and the return of renal function is slow.

Drug crystallization and deposition in kidneys cause AKI. The main cause of injury is due to
the relative insolubility of drugs in urine leading to precipitation within the tubule lumen that
in most instances are pH dependent. Drugs such as acyclovir, sulfonamides, methotrexate,
indinavir, and triamterene may lead to crystal deposition. Tumor lysis syndrome leading to
uric acid and calcium phosphate crystals may occur in the setting of malignancies. Acyclovir
commonly used to treat VZV and HSV infections is associated with AKI particularly in those
receiving high doses (500 mg/m2) over a relatively short period of time. The incidence is
thought to be 12-48% and in approximately 50% of the cases, the renal insufficiency is
reversible. Indinivar, a protease inhibitor used in the treatment of HIV induces crystal
formation and deposition in the kidney due to its relative insolubility in urine.

Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes
involved in drug disposition (e.g., absorption, drug distribution, nonrenal clearance
[metabolism]). Drug dosing errors are common in patients with renal impairment and can
cause adverse effects and poor outcomes. Dosages of drugs cleared renally should be adjusted
according to creatinine clearance or glomerular filtration rate and should be calculated using
online or electronic calculators.
Loading doses usually do not need to be adjusted in patients with chronic kidney disease.
Published guidelines suggest methods for maintenance dosing adjustments: dose reduction,
lengthening the dosing interval, or both. Dose reduction involves reducing each dose while
maintaining the normal dosing interval. This approach maintains more constant drug
concentrations, but it is associated with a higher risk of toxicities if the dosing interval is
inadequate to allow for drug elimination. Normal doses are maintained with the extended
interval method, but the dosing interval is lengthened to allow time for drug elimination
before redosing. Lengthening the dosing interval has been associated with a lower risk of
toxicities but a higher risk of subtherapeutic drug concentrations, especially toward the end of
the dosing interval. Dosing recommendations for individual drugs can be found in Drug
Prescribing in Renal Failure: Dosing Guidelines for Adults. The guidelines are divided into
three broad GFR categories (less than 10 mL per minute per 1.73 m
, 10 to 50 mL per minute
per 1.73 m
, and more than 50 mL per minute per 1.73 m
), encompassing an up to 10-fold
range in renal function. The guidelines do not correspond with the K/DOQI staging system;
therefore, although they can be used for initial dosages, regimens must be individualized
further based on patient response and serum drug concentrations.

Drug GFR(mL/min) Recommendations
Acetazolamide < 10 Avoid

Acetaminophen < 50 Reduce dose frequency
Acyclovir < 50 Reduce dose frequency
Allopurinol < 50 Reduce dose
Alprazolam No change
Aminoglycosides < 50 Reduce dose frequency
Amiodarone No alteration, hepatic metabolism
Amoxy/Ampicillin < 50 Decrease frequency
Amphotericin B < 50 Use only if no alternative
Analgesics-NSAIDs No alteration
Analgesics-opioids < 50 Decrease dose
Antidepressants Mainly hepatic excretion
Aspirin < 10 Avoid
Atenolol < 50 Decrease dose
Azathioprine < 10 Reduce dose
Azithromycin No change
Aztreonam < 50 Reduce dose
Benazepril < 50 Reduce dose
Benzylpenicillin < 50 Reduce dose
Beta-blockers < 10 Reduce dose


< 10
No dose alteration; at low GFR
may require high doses
Reduce dose
Carbamazepine < 10 Reduce dose to 75%
Carbenicillin < 50 Reduce dose
Carbenoxolone < 10 Avoid
Cefadroxil < 50 Reduce dose frequency
Cefazolin < 50 Reduce dose frequency
Cefixime < 50 Reduce dose
Cefoperazone No alteration
Cefotaxime < 50 Reduce dose frequency
Cefpodoxime < 50 Reduce dose frequency
Ceftazidime < 50 Reduce dose frequency
Ceftizoxime < 50 Reduce dose frequency
Ceftriazone < 10 Reduce dose frequency
Cefuroxime < 50 Reduce dose frequency
Cephalexin < 10 Reduce dose frequency
Cetrizine < 50 Reduce dose
Chloramphenicol No dose alteration
Chlorpromazine No change
Cisapride No alteration
Cisplatin < 50 Avoid
Clarithromycin No change
Clofibrate < 50 Reduce dose frequency
Clonidine No change
Colchicine < 10 Reduce dose by half
Co-trimoxazole < 50 Reduce dose frequency
Cyclophosphamide < 20 Reduce dose
Cycloserine < 50 Avoid
Diazepam No change
Digoxin < 50 Reduce dose frequency
Dipyridamole No change

Domperidone < 10 Reduce dose by half
Doxazosin No change
Enalapril < 10 Reduce dose hy half
Ergotamine < 50 Avoid

Domperidone < 10 Reduce dose by half
Doxazosin No change
Enalapril < 10 Reduce dose hy half
Ergotamine < 50 Avoid
Ethambutol < 50 Reduce dose frequency
Ethosuximide < 10 Reduce dose to 75%

Erythromycin No change
Famotidine < 10 Reduce dose by half
Finasteride No change
Fluconazole < 50 Reduce dose
Flucytosine < 50 Reduce dose frequency
Foscarnet < 50 Reduce dose
Furosemide No change
Ganciclovir < 50 Reduce dose frequency
Gemfibrozil < 50 Reduce dose
Glibenclamide No changes; but increased risk of hypoglycemia
Gliclazide No changes; but increased risk of hypoglycemia
Glipizide No change but hypoglycemia may occur
Glucorticoids No change
Gold salts < 50 Avoid
Haloperidol No change
Heparin No change
Hydralazine < 10 Reduce dose frequency
Hydroxy-chloroquine Reduce dose
Imipenem < 50 Reduce dose
Indapamide No change
Insulin < 10 May need dose reduction as insulin requirement falls
Isoniazid No change
Itraconazole < 10 Reduce dose by half

Ketoconazole No change
Labetolol No change
Lisinopril < 50 Reduce dose
Lithium < 50 Reduce dose
Lovastatin No change
Magnesium salts < 20 Avoid or reduce dose
Melphalan < 20 Reduce dose
Mercaptopurine < 20 Reduce dose
Metformin < 50 Avoid
Methocarbomol < 50 Avoid
Methotrexate 2 0 - 5 0 Reduce dose
Methyldopa < 50 Reduce dose frequency
Metoclopramide < 50 Reduce dose frequency
Metolazone No change
Metoprolol No change
Metronidazole < 10 Reduce dose by half
Mezlocillin < 50 Reduce dose frequency
Miconazole No change
Misoprostol No change
Morphine < 50 Reduce dose frequency
Nicardipine No change
Nifedipine No change
Nitrates No change
Nitrofurantoin < 50 Avoid
Nitroprusside No change
Omeprazole No change
Penicillamine < 50 Avoid if possible, or reduce dose
Pentamidine < 10 Dosing interval 24-48 hrly
Pentoxiphylline No change
Phenobarbitone < 10 Reduce dose frequency
Phenytoin No change
Piperacillin < 50 Reduce dose frequency
Potassium salts < 20 Avoid routine use
Pravastatin < 10 Reduce dose to half
Prazosin No change
Primidone < 50 Reduce dose frequency
Probenecid < 10 Avoid
Simvastatin Spironolactone
< 50

< 50
< 10
< 50
< 50
< 50

< 10
1 0 - 5 0
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 spiranolactone < 10 Avoid
Sucralfate No change
Sulphadiazine < 10 Avoid
Sulphasalazine < 10 Ensure high fluid intake
Terazosin No change
Theophylline No change
Thiazide diuretics < 10 Avoid
Ticlopidine No change
Tolbutamide No change
Trimethoprim < 50 Reduce dose frequency
Tubocurarine < 20 Reduce dose
Valproic acid < 10 Reduce dose to 75%
Vancomycin < 50 Reduce dose frequency
Warfarin No change
Zidovudine 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.


AMI NOGLYCOSI DES (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 days 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
Recovery is incomplete3 if pre-existing renal insufficiency exists. Some patients may
progress to chronic interstitial nephritis.
Mechanisms - 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.
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 levels
may indicate impending nephrotoxicity.
Relative toxicites (in decreasing order): Neomycin > Gentamycin > Tobramicin > Netilmicin
> Amikacin > Streptomycin.
Use of sulfonamides has increased with advent of AIDS. Sulfadoxine + pyrimethamine
combination is used in malaria.
Spectrum of nephrotoxicity includes
1. Acute interstitial nephritis (not common)
2. Necrotizing arteritis
3. 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 by- product 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. Prolonged duration of therapy than in community acquired pneumonia
2. Oral fluid intake may be prevented by toxoplasma encephalitis for which it is used
3. 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.
It contains hydrophilic and lipophylic regions allowing it to easily mingle with cellular
membranes, disrupting them and increasing their permeability. 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-, IL-1. Am-B typically causes distal tubular
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
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.
Salt supplementation - is the most effective measure in reducing incidence. A titre of
normal saline infused prior and post Am-B significantly lowers incidence of nephrotoxicity.
Liposomal amphotericin-B - 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 pre- treatment 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 reduces incidence of nephrotoxicity
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
serum Na+, K+, Mg2+, Ca2+, PO 3- 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
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 7- hydroxymethotrexate 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.
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. Prostaglandin analogue misoprostol has
shown some benefit in reversal of vasoconstrictiveeffects.
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 (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
Doses >500 mg/m2 given i.v. leads to nephrotoxicity. 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 10-14 days. However severe renal
failure may occur necessitating hemodialysis.
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. Hyperkalemia
4. Sodium and water retention
5. Hypertension.
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.

Drug-induced kidney disease may be immunological or non- immunological toxic
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
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
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.
Use total dose as once daily dosing; 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.
Monitor urine output and start adequate fluid and electrolyte therapy with specific emphasis
on K+ and NaCl as well as Ca2+ and Mg2+ replacement.