DRUGS

&
NEPHROTOXICITY

Dr. Sunil Kale

 Overview
• Background
• Functions of Kidney
• Drug-induced Renal Disease/Injury
- Mechanisms of Renal Injury
- Mechanisms of renal susceptibility to drug toxicity
- Important Drug Induced Syndromes
• Prescribing In Renal Disease/Injury
- Risk factors for Renal Injury
- Measures to Prevent Drug-Induced Nephrotoxicity
• Summary

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 Background
• Drug-induced renal injury contributes up to 25% of
all cases of acute renal failure

• The kidneys comprise only 0.5% of body weight, yet

they receive 25% of the cardiac output

• Hardly surprising that drugs can damage the kidney

and that disease of the kidney affects responses to
drugs.
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 Function of the kidneys
• A vital role in regulating
extracellular fluid and excreting
soluble wastes by:
1. Filtration of blood
2. Tubular Reabsorption
3. Tubular Secretion
4. Elimination
• To accomplish these vital
functions, nephrons have
vascular, glomerular and tubular
components
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Mechanisms of Drug-induced Renal Injury

Renal Injury

Cumulative dose-
Idiosyncratic dose-
dependent toxicity
independent toxicity

• Predictable/anticipated
• Unpredictable
• Dose dependent
• Dose independent
• Can be prevented
• Can not be prevented

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 Mechanisms of Drug-induced Renal Injury

Renal Injury

Immune- mediated Non-immunologic

Direct Effect
glomerulonephritis and allergic Anticoagulants may cause
interstitial nephritis due to circulating hemorrhage into the kidney
immune mediators and intrinsic
immune function of glomerular
mesangial cells and renal cytokine Indirect Effect
activation Antimicrobials (aminoglycosides)

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Non-immunologic Mechanisms of Renal
Susceptibility to Drug Toxicity
 Auto-regulation of Renal Blood Flow
•Interplay of various vaso-active agents at afferent and
efferent arteriole

E.g. NSAIDS (Aspirin) inhibit Prostaglandin synthesis there by decrease renal

blood flow and ACE Inhibitors (Captopril) mainly dilate efferent arterioles to cause
to cause alterations in GFR and subsequent renal damage
(ACE Inhibitor: Angiotensin Converting Enzyme Inhibitors)
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 Intra-renal Drug Metabolism
Kidney Enzymes
CYP 450 & ALDH

Promote toxicity
Protect from toxicity
(formation of a
(metabolism)
nephrotoxic metabolite)

Example : Metabolism of the

chemotherapeutic agent cisplatin via
CYP 450 located in the proximal tubule
leads to the development of reactive
oxygen intermediates which are
responsible for cisplatin induced
nephrotoxicity

Cytochrome P450 (CYP 450) and aldehyde dehydrogenase (ALDH) 9

 Tubular Transport Processes

Tubular Active
Transport

Organic Acid P – glycoprotein (Pgp)

Transporter

e.g. Aspirin, Serves as a

Penicillin, transporter
Probenecid, to many drugs
Furosemide etc.

Usually protective

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Mechanisms of Renal Susceptibility to
Drug Toxicity: Overview

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 Important Drug Induced
Lesions/Syndromes

• Analgesic Nephropathy e.g. NSAIDs (Aspirin, Ibuprofen etc.)

• Acute renal failure, e.g. aminoglycosides, cisplatin etc.

• Chronic renal failure, e.g. NSAIDs etc.

• Nephrotic syndrome, e.g. ACE Inhibitor (captopril) etc.

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 Analgesic nephropathy
• Due to prolonged ingestion of analgesisc e.g. NSAIDs
(acetaminophen, aspirin, combination of analgesics etc.)

• Chronic interstitial nephritis, papillary necrosis and altered

intraglomerular hemodynamics (auto-regulation of blood flow)
• Patients present with hematuria, renal colic, urinary infection,
and later with hypertension and renal failure (RF)

• The lesions are reversible if detected early and the drug

stopped
Note: Reduced risk by limiting the total dose, avoiding combined use of two or
more analgesics, and maintaining good hydration to prevent renal ischemia
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 Acute Renal failure (ARF)

Pre-renal
Haemodynamic :NSAIDs , ACE Inhibitors (captopril)

Intrinsic Renal Toxicity

• Acute interstitial nephritis (AIN): cephalosporins, penicillins,
sulphonamides etc.
• Acute Tubular necrosis (ATN) : gentamicin, amphotericin,
cisplatin etc

Post-renal
Obstructive Nephropathy :Cytotoxic drug cisplatin etc.
 Chronic renal failure (CRF)
• Slow progressive elevation of creatinine concentration

• Analgesic nephropathy seen as nephritis (from inflammatory

and immunologic mechanisms) and papillary necrosis
(through ischemia or cellular injury)

• E.g. NSAIDs

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 Prescribing in Renal Disease
What is the concern ?
• Safety concern in patients with impaired renal function who
must be treated with drugs that are potentially toxic and that
are wholly or largely eliminated by the kidney
What can go wrong ?
• Worsen renal disease
• Drug can be potentiated by accumulation due to failure of
renal excretion
• Drug can be ineffective, e.g. thiazide diuretics in moderate or
severe renal failure

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 Patient-Related Risk Factors
for Drug-Induced Nephrotoxicity

• Underlying renal disease

• Intravascular volume depletion
• Age older than 60 years
• Exposure to multiple nephrotoxins
• Diabetes
• Heart failure
• Sepsis

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 General Measures to Prevent
Drug-Induced Nephrotoxicity

• Adjust medication dosages using the Prescribing information

and appropriate formula
• Assess baseline renal function and need of monitoring renal
function (Serum creatinine and Blood Urea Nitrogen)
• Avoid nephrotoxic drug combinations
• Correct risk factors for nephrotoxicity before initiation of
drug therapy.
• Ensure adequate hydration before and during therapy with
potential nephrotoxins.
• Use equally effective non-nephrotoxic drugs whenever
possible

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 How to minimize drug-induced renal
injury ?
• Identify patients at risk

• Take precautions

• Frequently monitor renal function

 Dose adjustment for patients
with renal impairment
• Loading Dose :generally unnecessary, for the volume into
which the drug has to distribute should be the same in
patients with renal impairment and healthy subject.

• Maintenance Dose : either reducing each dose given or

increasing the time between doses

• Highly protein bound drugs need special caution when the

patient is hypoproteinaemic

Note : Most drugs that are eliminated by kidneys do not require dosage
adjustment until the creatinine clearance falls below 60 mL per minute
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 How to administer correct dose ?
• Take into account
- the extent to which the drug normally relies on renal
elimination
- the degree of renal impairment
• Study the prescribing information or use appropriate formula
to calculate the dose

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How renal impairment can affect kinetics
of drugs… a glimpse

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 Examples to remember
Commonly used drugs causing Nephrotoxicity

Class Drug (s)

Antimicrobials Penicillins, Aminoglycosides
(Gentamicin), Sulphonamides
Antitubercular Agents Isoniazid, Rifampicin

Analgesics (NSAIDS) Aspirin, Paracetamol, Ibuprofen etc.

Anticancer (Cytotoxic Agents) Cisplatin etc.

Antihypertensive Agents (ACEI) Captopril, Enalapril etc.

Antiepileptic Agents Phenytoin etc.

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 Take Home Message

• Exercise caution in patients with renal impairment

• Avoid combination of nephrotoxic drugs

• Prevention is better than cure: Therapeutic Drug Monitoring

(TDM), S. creatinine and Blood Urea Nitrogen (BUN) are
commonly used tools to monitor drug induced renal toxicity

• Most drugs that are eliminated renally do not require

dosage adjustment until the creatinine clearance falls below
60 mL per minute

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 Thank you…

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 BACK UP SLIDES

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Creatinine clearance
•Clearance is often measured as milliliters/minute (ml/min). Normal values are:
– •Male: 97 to 137 ml/min.
– •Female: 88 to 128 ml/min.
•The examples above are common measurements for results of these tests. Normal value ranges
serum creatinine
•A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women.
•Females usually have a lower creatinine than males, because they usually have less muscle
mass.may vary slightly among different laboratories

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