INTRODUCTION

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

conditions.

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.

MECHANISMS THROUGH WHICH DRUGS CAUSES ACUTE RENAL

FAILURE

Drugs can cause acute renal failure by causing pre-renal, intrinsic or post-renal toxicity.

PRE –RENAL FAILURE:

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.

INTRINSIC RENAL FAILURE:

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 necrosis(exogenous toxins)

Aminoglycosides, amphotericin, cisplatin, radiocontrast agents, methoxyflurane, outdated tetracyclines, cephalosporins, mithramycin, calcineurin inhibitors, pentamidine, IVIG, ifosfamide, zoledronate, cidofovir, adefovir, tenofovir

FENa>2%, UOsm <350, urinary sediment contains granular casts, renal epithelial cells

Acute tubular necrosis (endogenous toxins- rhabodmyolysis

Lovastatin (statins), ethanol,

barbiturates, diazepam Elevated CPK, granular casts

Acute tubular necrosis(hemoglobin)

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, bevacizumab

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.

HEMODYNAMICALLY MEDIATED NEPHROTOXICITY:

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.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS:

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 ICU’s, 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/ARBS:

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.

OTHER DRUGS THAT CAUSE ALTERED GLOMERULAR HEMODYNAMICS:

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.

ACUTE TUBULAR NECROSIS:

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 Fanconi’s 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.

ALLERGIC INTERSTITIAL NEPHRITIS (AIN):

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.

NEPHROTIC SYNDROME:

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.

CRYSTAL DEPOSITION:

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.

DRUG DOSING ADJUSTMENTS IN PATIENTS WITH RENAL

FAILURE

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 m2, 10 to 50 mL per minute

per 1.73 m2, and more than 50 mL per minute per 1.73 m2), 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) RecommendationsAcetazolamide < 10 AvoidAcetaminophen < 50 Reduce dose frequencyAcyclovir < 50 Reduce dose frequencyAllopurinol < 50 Reduce doseAlprazolam No changeAminoglycosides < 50 Reduce dose frequencyAmiodarone No alteration, hepatic metabolismAmoxy/Ampicillin < 50 Decrease frequencyAmphotericin B < 50 Use only if no alternativeAnalgesics-NSAIDs No alterationAnalgesics-opioids < 50 Decrease doseAntidepressants Mainly hepatic excretionAspirin < 10 AvoidAtenolol < 50 Decrease doseAzathioprine < 10 Reduce doseAzithromycin No changeAztreonam < 50 Reduce doseBenazepril < 50 Reduce doseBenzylpenicillin < 50 Reduce doseBeta-blockers < 10 Reduce doseBumetanide No dose alteration; at low

may require high dosesCarbamazepine < 10 Reduce dose to 75%Carbenicillin < 50 Reduce doseCarbenoxolone < 10 AvoidCefadroxil < 50 Reduce dose frequencyCefazolin < 50 Reduce dose frequencyCefixime < 50 Reduce doseCefoperazone No alterationCefotaxime < 50 Reduce dose frequencyCefpodoxime < 50 Reduce dose frequencyCeftazidime < 50 Reduce dose frequencyCeftizoxime < 50 Reduce dose frequencyCeftriazone < 10 Reduce dose frequencyCefuroxime < 50 Reduce dose frequencyCephalexin < 10 Reduce dose frequencyCetrizine < 50 Reduce doseChloramphenicol No dose alterationChlorpromazine No changeCisapride No alterationCisplatin < 50 AvoidClarithromycin No changeClofibrate < 50 Reduce dose frequencyClonidine No changeColchicine < 10 Reduce dose by halfCo-trimoxazole < 50 Reduce dose frequencyCyclophosphamide < 20 Reduce doseCycloserine < 50 AvoidDiazepam No changeDigoxin < 50 Reduce dose frequencyDipyridamole No change

DOSAGE ADJUSTMENTS OF DRUGS ON PATIENTS WITH RENAL FAILURE

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 AvoidHaloperidol 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

Procainamide

Propranolol

Propylthiouracil Pyrazinamide

Quinolones

Ramipril

Ranitidine

Rifampicin

< 50

< 50

< 10

< 50

< 50

< 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

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.

CLASSES OF DRUGS ASSOCIATED WITH NEPHROTOXICITY AND

THEIR MECHANISMS:

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 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

weeks.

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.

SULFONAMIDES:

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.

AMPHOTERICIN-B (Am-B):

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-α, IL-1α. 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

4

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

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

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

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 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.

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. 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

survival.

ACYCLOVIR:

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.

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. 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.

SUMMARY OF MANAGEMENT AND PREVENTION OF DRUG INDUCED

KIDNEY DISEASE

• Drug-induced kidney disease may be immunological or non- immunological 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.

•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.

REFERENCES