drug-induced nephrotoxicity and its management...

International Bulletin of Drug Research., 2(3): 50-65

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DRUG-INDUCED NEPHROTOXICITY AND ITS

MANAGEMENT -AN OVERVIEW

*M. LEENA1, SUBASH VIJAYAKUMAR

2, A.Y. RAO

3

______________________________________________________________________________

ABSTRACT

Drug-induced renal failure is common and responsible for a variety of pathological effects on the

kidney. Many medications can lead to renal dysfunction through various mechanisms, which can

cause significant morbidity. Our review article mainly focused on drugs associated with

nephrotoxicity and its prevention strategies. We developed a search strategy to find publications

on drug induced nephrotoxicity and its management so; we searched Science Direct, Medline

and PubMed bibliographic databases, and renal texts to identify relevant articles. Our review

suggested that proper understanding the mechanisms involved, and recognizing the clinical

presentations of renal dysfunction arising from use of commonly prescribed medications are

important if injury is to be detected early and prevented. As it is impossible to list all drugs

associated with nephrotoxicity, this article will summarize the mechanism of injury associated

with particular common medications, discuss clinical presentations, renal markers, and evaluate

strategies that prevent or minimize renal injury.

KEY WORDS

Nephrotoxicity, Renal biomarkers, Renal toxicity, Renal injury and Medications.

AFFILIATION

1. *M. Leena, Assistant Professor, MGM Hospital, Vaagdevi college of pharmacy Ram

Nagar, Hanamkonda, Warangal, Mob:9908114422, Email id: [email protected]

2. Subash vijayakumar, Department of Pharmacy Practice, Vaagdevi College of Pharmacy,

MGM Hospital, Warangal,A.P, India.

3. A.Y. Rao, Department of Oncology, KMC/MGM Hospital, Warangal, A.P, India.

mailto:[email protected]


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INTRODUCTION

Medication-induced nephrotoxicity has been cited, a major cause for acute renal failure in

humans, and antibiotics especially aminoglycoside antibiotics, have been among the most

common offending agents.1 Drugs causes approximately 20 percent of community and hospital

acquired episodes of acute renal failure. Among older adults, the incidence of drug-induced

nephrotoxicity may be as high as 66 percent.2 Most episodes of renal dysfunction are reversible,

with function returning to baseline when the medication is discontinued. Chronic renal injury can

however be induced by some medications, leading to chronic tubulo-interstitial inflammation,

papillary necrosis or prolonged proteinuria.3

Incidence of acute renal failure in the newborn

Acute renal failure in the new born may be caused by a failure of renal perfusion (pre-renal

failure), damage to the renal parenchyma (intrinsic renal failure) or obstruction of the urinary

tract (post-renal failure). Most cases of intrinsic renal failure in the newborn are due to asphyxia,

often in combination with sepsis and nephrotoxic drugs.4

Exposure to nephrotoxic drugs

separately, or in combination precede most episodes of ARF in the newborn. Antibacterial-

induced nephrotoxicity is an important parameter to be considered when treating the newborn

and this is particularly true when use of a combination of different antibacterials and/or drugs

with a nephrotoxic potential is being considered.5

Epidemic Nephrotoxicity

Nephrotoxicity can also induced by 'atypical' or 'unconventional' agents, such as environmental

agents (metals, minerals & animals), food agents (mushrooms, medicinal traditional herbals,

dietary supplement & melamine), drugs, and other products (ethylene glycol). Nephrotoxicity

varies according to local background, dependent on different food and cultural customs, as well

as to differences in local fauna and flora.6

Recent outbreaks of nephrolithiasis and acute kidney

injury among children in China have been linked to ingestion of milk-based infant formula

contaminated with melamine. The USFDA has twice amended its assessment of melamine

toxicity for infants, and concluded that only foods with less than 1 p.p.m. of melamine are safe

for infants.7

Mechanism of toxicity

Toxicity is a relative phenomenon that depends on the inherent structure and properties of a

chemical and on its dose. Exogenous chemicals are absorbed after ingestion, inhalation, or skin

contact and then distributed to various organs. Chemicals are frequently metabolized, often by

multiple enzymatic pathways; to produce that may be more toxic, les toxic than the parent

chemical. One or more of these products then interacts with the target macro molecules, resulting

in a toxic effect.8


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Figure 1: Absorption and distribution of toxicities.

Biotransformation of toxicants

Exposure

Absorption at portals of entry

Distribution to body

Metabolism

to more toxic

metabolites

Turnover

& repair

Metabolism

to more less

toxic

metabolites

Metabolism

to more

conjugate

products

Interaction with macromolecules

(Proteins, DNA, RNA, receptors)

Distribution

Toxic effects

(Genetic, carcinogenic, reproductive, immunotoxic)

Excretion

Toxicants

Phase I

reactions

Elimination in urine, bile, or feces

Secondary

metabolites

Phase II

reactions

Primary

metabolites


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Why the kidney is vulnerable to toxins

Kidney excretes many drugs, it is routinely exposed to high concentrations of drugs or their

metabolites or both. Furthermore, the kidney has several features that allow nephrotoxins to

accumulate. The proximal renal tubule presents a large area for nephrotoxin binding and

transport into the renal epithelium. Reabsorption of the glomerular filtrate progressively

increases intraluminal nephrotoxin concentrations, while specific transport pathways in the

kidney may engender site-specific toxicity.9

Pathogenic mechanism of drug induced nephrotoxicity

Most drugs found to cause nephrotoxicity by one or more common pathogenic mechanisms.

These include altered intraglomerular hemodynamics, tubular cell toxicity, inflammation, crystal

nephropathy, rhabdomyolysis, and thrombotic microangiopathy. 2

Tabble 1: Drug Induced Nephrotoxicity and its Mechanism.10-37

Nephrotoxic drugs Mechanisms

NSAIDs, Cyclosporins, Tacrolimus, ACE

Inhibitors.

Intraglomerular hemodynamics

Antimicrobials, Amphotericin B,

Betalactum antibiotics, s Rifampicin,

Adefovir, Cidofovir, Contrast dye,

Zoledronate.

Tubular Cell Toxicity

Foscornet, Methotrexate, Triamterene,

Ganciclovir.

Crystal nephropathy

Inflammation Acetaminophen, Aspirin, Acyclovir, Betalactum

antibiotics, Quinolones, Rifampicin, Sulfonamides,

Cisplatin, Allopurinol, Loops & thiazide diuretics,

Chinese medicines.

Rhabdomyolysis Amitryptiline, Diphenhydramine, Doxylamine,

Benzodiazepines, Statins, Methodone.

Thrombocytic Microangiopathy Cyclosporin, Clopidogrel, Mitomycin C, Quinine.


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Figure 2: General Nephrotoxic factors.10

Figure 3: Clinical Features of Drug Induced Nephrotoxicity. 11

Acute tubular

necrosis

Magnesium

wasting

oliguria

Nephrolithiasis

Renal colic

hematuria

Glomerulo nephritis

Foamy urine

Marked facial and lower

extremity pitting edema

Oliguria

Protenuria

Skin rash

General

Costo –vertebral

angle edema

Elevated serum

creatinine fever

hypertension,

malaise

rapid weight gain

Acute interstitial

nephritis

Arthralgia

Eosinophilia

Eosinophiluria

Pyuria

Skin rash


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ASSESSMENT OF RENAL FUNCTION TESTS

According to the ICH S7A Harmomized tripartite Guideline (Safety Pharmacology Studies for

Human Pharmaceuticals), most of the parameters suggested to asses renal function includes

urinary volume, specific gravity, Osmolality, pH, fluid/electrolyte balance, proteins, cytology,

blood urea nitrogen, plasma creatinine and plasma proteins.12

Renal function test is given in the figure: 4.13

Table 2: Normal Ranges of blood and urine biochemistry.

Blood Chemistry Urine Biochemistry

Sodium 132–144 mmol/l

Potassium 3.5–5.5 mmol/l

Urea 3.5–7.4 mmol/l

Creatinine 44–80 μmol/l

Chloride 95–110 mmol/l

Plasma osmolality 275–295 m

osmol/kg

(HCO−3 + Cl−) 12–16 mmol/l

Sodium 100–200 mmol/24 h

Potassium 30–90 mmol/24 h

Protein < 0.15 g/24 h

Creatinine 9–17 mmol/24 h

Creatinine Clearance -120

ml/min

Urine Analysis

Urinalysis by definition refers only to the chemical analysis of urine. Routine urinalysis refers to

1. Macroscopic analysis which includes assessment of physical characteristics and chemical

analysis

2. Microscopic analysis for formed elements.15

Assessment of kidney function and identification of the site of injury within the nephron is the

best performed through the examination of urine. Injury can be assessed by examination of

cellular enzymes which are preferentially leaked into the urine.12

Renal function and glomerular filtration rate 14

Glomerular filtration rate (GFR) is the rate (volume per unit of time) at which ultrafiltrate is

formed by the glomerulus.16

and it is calculated by the clearance of specific substances.

Characteristics of an ideal marker for GFR Measurement17


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Constant rate of production (or for exogenous marker can be delivered intravenously at a

constant rate)

Freely filterable at the glomerulus (minimal protein binding)

No tubular reabsorption

No tubular secretion

No extra renal elimination or metabolism

Availability of an accurate and reliable assay

For exogenous marker: safe, convenient, readily available, inexpensive, and does not

influence GFR (physiologically inert)

Causes of interpatient variability include: 18

Body size: GFR conventionally factored by 1.73 m2

Sex: GFR approximately 8% higher in males

Race

Age: age-related decline in GFR, 0.75 to 1.0 mL/min/1.73 m2 (0.01 to 0.02 mL/s/ 1.73

m2) per year

Pregnancy: GFR elevated as much as 50% in first trimester and onward; returns

Toward normal by 4 to 8 weeks postpartum

Protein intake: GFR higher in patients on high-protein diet

Diurnal variation: values tend to be about 10% higher in afternoon than at night.

Normal range for GFR

The normal corrected GFR are

Male: 120±25 mL/min

Female: 95±20ml/min.19

Creatinine Clearance (C): creatinine concentration alone can be used to estimate GFR by a

number of mathematical models.

The commonly used are

Cockkroft-Gault equation,


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Modification of diet in renal disease (MDRD), and

Schwartz equation.14

Formulas to assess renal function.

and

Adjust Medication Dosages.

RENAL BIOMARKERS

Biochemical markers play an important role in accurate diagnosis and also for assessing risk and

adopting therapy that improves clinical outcome. According to the NIH working group, a

biomarker is a characteristic that is objectively measured as an indicator of normal biological

processes, pathogenic processes, or a pharmacological response to a therapeutic intervention

(Biomarkers Definitions Work Group, 2001).22

Ideal features of biomarkers used to detect drug-induced nephrotoxicity

Identifies kidney injury early (well before the renal reserve is dissipated and levels of

serum creatinine increase)

Reflects the degree of toxicity, in order to characterize dose dependencies

Displays similar reliability across multiple species, including humans

Localizes site of kidney injury

Tracks progression of injury and recovery from damage

Schwartz equation

eCrCl = (length [cm] × k) ÷ serum

creatinine (mg per dL)

k =0.55 (children one to 13 years of age)

0.70 (males 14 to 17 years of age)

0.55 (females 14 to 17 years of age). 20

MDRD equation

eGFR = 186 × serum creatinine (mg

per dL) −1.154

× age (years) −0.203

×

(0.742 if patient is female) × (1.210 if

patient is black).2

Cockcroft and Gault equation

Male: eCrCl = ([140 – age (years)]

× ideal body weight [kg]) ÷ (serum

creatinine [mg per dL] × 72).21


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Is well characterized with respect to limitations of its capacities

Is accessible in readily available body fluids or tissues.23

Existing biomarkers for detecting kidney injury

The current biomarkers, serum creatinine (SCr) and blood urea nitrogen (BUN), to monitor renal

safety are late and insensitive and show limited specificity with the serious consequences that

AKI can not be prevented or managed with appropriate tools. 24

Second-generation biomarkers for acute kidney injury

In the past decade, several efforts have been undertaken to identify better and earlier markers of

nephrotoxicity using genomics and proteomics approaches (Amin et al. 2004; Devarajan 2008;

Kramer et al. 2004; Thukral et al. 2005). Those new markers are more sensitive and can detect

damage earlier than BUN and creatinine levels.25

Table 3: List of biomarkers of nephrotoxicity. 26

Urinary protein with

enymatic activity

Filtered low- molecular

proteins

Heart -type fatty acid

binding protein

Liver type fatty acid

binding protein

Alanine amino peptidase

α-Glutathione-S-tranferase

γ-Glutamyl transpeptidase

п- Glutathione-S-tranferase

N-Acetyl-β-D-

glucosaminidase

α1

-Microglobulin

β2-

Microglobulin

Cystatin-C

Retinol binding protein

Interleukin-18

Kidney injury molecule-1

Microalbumin

Neutrophil gelatinase-

associated lipocalin

MANAGEMENT OF NEPHROTOXICITY.

Most patients with ARF recover with conservative management which includes

Fluid monitoring,

Protein restriction,

Drug adjustments,

Dietary or potassium control, and

Dialysis (usually temporary).27


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Main metabolic abnormalities in patients with renal failure.28

Anorexia – reduced oral nutrient intake

Gastrointestinal consequences of uraemia

Restrictive diets

Uremic toxicity – inadequate dialysis prescription

Metabolic acidosis

Endocrine factors (PTH, insulin resistance etc.)

Peripheral insulin resistance

Impairment of lipolysis

Low grade inflammatory state _activation of protein catabolism

Augmented catabolic response to intercurrent disease

Metabolic acidosis

Hyperparathyroidisms, uremic bone disease

Impairment of vitamin D3 activation

Conservative management

Fluid balance

Adequate hydration is important to maintain renal perfusion and avoid drug-induced renal

impairment. Whenever possible, volume status should be assessed and corrected, if necessary,

before initiation of nephrotoxic agents. This is particularly true when prescribing medications

such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and NSAIDs,

which induce alterations in renal hemodynamics in patients who are significantly volume

depleted. 29

Nutrition

Nutrition is an important consideration in ARF Adequate energy must be provided in order to

promote anabolism and prevent catabolism, which potentiates hyperkalemia, hyperphosphatemia

and acidosis. The purpose of nutritional management is to prevent or treat malnutrition, to reduce

accumulation of waste products, potassium and phosphorus, and to prevent complications of

uremia 30


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Table 4: Vitamin supplementation in acute renal failure. 31

Vitamins Dose

Vitamin K 4mg/wk

Vitamin E 10iu/d

Thiamine Hcl (B1) 2mg/dl

Vitamin E 10iu/d

Riboflavin (B2) 2mg/d

Pantothenic acid 10mg/d

Ascorbic acid (C) 70-100mg/d

Biotin 200mg/d

Folic acid 1mg/d

Vitamin B12 4µg/d

Folic acid 1mg/d

Vitamin B12 4µg/d

Renal replacement therapy.

Renal replacement therapy is indicated in a patient with ARF when kidney function is so poor

that life is at risk.The common types of renal replacement therapy includes

Haemodialysis

Haemofiltration

Haemodiafiltration

Peritoneal dialysis.27

Common indications for dialysis in acute renal failure.30

Hyperkalemia

Severe metabolic acidosis

Hyperphosphatemia/hypocalcemia

To make space for nutrition and drug administration

Failure to improve with conservative management

Specific Prevention Strategies for Selected Agents


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Table 5: Drugs altering intraglomerular hemodynamics.

Medications Prevention strategies

Angiotensin converting enzyme

inhibitors

Angiotensin receptor blockers , NSAIDs

Tacrolimus

Use analgesic with less prostaglandin activity

Correct volume depletion before initiation of drug

especially if used on chronic basis.

Monitor renal function and vital signs, following

initiation or dose escalation especially if used in- at

risk patient

Use low effective dose.

Drugs associated with tubular cell toxicity


Aminoglycosides

Amphotericin B

Contrast dye

Use extended-interval dosing ,administer during active period of day,

limit duration of therapy, monitor serum drug levels and renal function

2-3 times /week, maintain trough levels ≤1mcg/ml.

Saline hydration before and after dose administration, consider

administering as a continuous infusion over 24hours, use liposomal

formulation, limit duration of therapy.

Use low-osmolar contrast in the lowest dose possible and avoid

multiple procedures in 24 to 48 hours, 0.9% saline or sodium

bicarbonate (154mEq/L) infusion before and after procedure, with hold

NSAIDs and diuretics at least 24 hours before and after procedure,

monitor renal function 24 to 48 hours post-procedure, consider

acetylcysteine pre-procedure.

Drugs associated with chronic interstitial nephropathy


Acetaminophen , aspirin,

NSAIDs

Lithium

Avoid long-term use, particularly of more than one analgesic, use

alternate agents in patients with chronic pain.

Maintain drug levels within the therapeutic range, avoid volume

depletion.


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Drugs associated with crystal nephropathy


Acyclovir, methotrexate, sulfa

antibiotics, triamterene.

Discontinue or reduce ensure adequate hydration, establish

high urine flow. Administer orally

General Goals to Prevent Drug-Induced Nephrotoxicity.

1. Avoid simultaneous use of two or more different nephrotoxic drugs

2. Be careful with the use of angiotensin-converting enzyme inhibitors or angiotensin

receptor blockers in patient who are taking dugs that induce afferent arteriole vaso

constriction (e.g., contrast agents, calcineurin blockers).32

3. Adjust medication dosages using the Cockcroft-Gault formula (in adults) or Schwartz

formula (in children).

4. Assess baseline renal function using the MDRD equation, and consider patient's renal

function when prescribing a new drug.

5. Correct risk factors for nephrotoxicity before initiation of drug therapy.

6. Ensure adequate hydration before and during therapy with potential nephrotoxins

7. Use equally effective non-nephrotoxic drugs whenever possible. 2

Role of antioxidants in the prevention of drug nephrotoxicity

Reactive oxygen species play a significant role in the pathogenesis of many chronic diseases

such as diabetes mellitus, cancer, chronic renal failure etc. The primary event leading to renal

failure is a free radical mediated injury to the endothelial cells in the outer meddula.33

Antioxidants are first line defense against free radical damage and are critical for maintaining

optimum health and well being. The administration of various natural or synthetic antioxidants

has been shown to be of benefit in prevention and attenuation of renal scaring in numerous

animal models of kidney diseases. These include vitamins, N-acetylcysteine, -lipoic acid,

melatonin, dietary flavonoids and phytoestrogens, and many others. Supplementation of

antioxidant vitamin C and vitamin E (500mg/day during 6 months) corrects plasma antioxidant

status and attenuating the cardiovascular disease that accompanies kidney failure. 34

Administration of superoxide dismutase provides a marked protection against gentamicin-

induced impairment of renal function.35


63

Table 6: List of Antioxidants that ameliorate the nephrotoxicity of platinum compounds.36

Antioxidants Dose Route Duration Species Reference

Vitamin C or

E

100mg/kg Intraperitoneal Once Rats Kadikoylu et al.

(2004)

Xanthorrzhiol 200/kg Per oral 4 days Rats Kim et al. (2005)

Lycopene 4mg/kg Per oral 10 days Rats Atessahin et al.

(2005)

Tomato juice

+dried black

grapes

Supplement

to diet

– 6 days Rats Cetin et al.(2006)

Capsaicin 10mg/kg Per oral 6 days Rats Shimeda et al.

(2005)

Quercitin 50mg/kg Per oral 20 days Rats Francescato et

al.(2004)

Desferrioxami

ne

250mg/kg Intraperitoneal Once Rats Kadikoylu et al.

(2004)

Glutamine 300mg/kg Per oral Once Rats Mora et al. (2003)

CONCLUSION

Drug-induced kidney injury is a common condition associated with considerable morbidity and

mortality. Successful prevention requires assessing base line renal function before the initiation

of the therapy, followed by adjusting the dosage, monitoring renal function and vital signs during

therapy and avoiding nephrotoxic drug combinations. Additional characterization and validation

of individual biomarkers and biomarkers panels will ultimately result in earlier diagnosis of

kidney injury and improved prognosis of outcome.

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