Nephrotoxic drugs can damage the kidneys by several mechanisms. Certain patient characteristics like older age, pre-existing kidney disease, and volume depletion increase risk. Common nephrotoxic drug classes include antibiotics, chemotherapy drugs, antivirals, NSAIDs, and statins. Drugs may cause acute kidney injury through effects on hemodynamics, tubular toxicity, inflammation, crystal formation, or rhabdomyolysis. Early recognition of rising creatinine and discontinuing the offending drug is important to reverse damage. Preventing nephrotoxicity requires assessing risks, monitoring for injury, and avoiding unnecessary nephrotoxic medications.

1. Nephrotoxic Drugs
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Kidney and Drugs
The kidney maintains the vital functions of clearing excess body
fluid and removing metabolic and exogenous toxins from blood.
The heart pumps approximately 25% of blood into the
kidneys.
If the drug is primarily cleared by the kidney, the drug will
become increasingly concentrated as it is moves from the renal
artery into the smaller vasculature of the kidney.
The drug may be filtered or secreted into the lumen of the
renal tubules.
The concentrated drug exposes the kidney tissue to far greater
drug concentration per surface area.
The kidney is particularly vulnerable to drugs and other agents
that cause renal damage.

3. Nephrotoxicity
Drugs are a common source of acute kidney injury.
Drug-induced kidney failure is a major adverse event
associated with multiple medication classes .
Compared to a few decades earlier , the average patient
today is:
older,
has more comorbidities, and
is exposed to more diagnostic and therapeutic
procedures with the potential to harm kidney function.

4. Nephrotoxicity
Although renal impairment is
often reversible if the offending drug is
discontinued, the condition can be costly and
may require multiple interventions, including
hospitalization.

5. Drug-induced nephrotoxicity tends to be more
common among certain patients and in specific clinical
situations.
Therefore, successful prevention requires knowledge of
•pathogenic mechanisms of renal injury,
•patient related risk factors,
•drug-related risk factors, and
•coupled with vigilance and
•early intervention.
Nephrotoxicity

6. Causes of Renal Failure in Hospitalized patients:
l
Diagnostic procedures (IV contrast agents)
Sudden decrease in blood pressure (gastrointestinal
bleed, sepsis, variceal bleeding)
The use of nephrotoxic drugs (aminoglycosides,
amphotericin, chemotherapy)

7. List of Drugs causing
Nephrotoxicity
NSAIDs-
Celecoxib, Rofecoxib
ACE Inhibitors-
Enalapril, Captopril, Lisinopril
Angiotensin Receptor Blockers
Indinavir
Methotrexate
Amphotericin B
Cisplatin
Atorvastatin, Rosuvastatin

8. Mechanisms for Renal Toxicity
Altered IntraGlomerular Hemodynamics
Tubular Cell Toxicity
Inflammation

Acute interstitial nephritis

Chronic interstitial nephritis
Crystal Nephropathy
Rhabdomyolysis
Thrombotic Microangiopathy

9. Altered IntraGlomerular
Hemodynamics
The amount of plasma cleared by the kidneys per minute is
120 ml, which corresponds to the GFR.
Kidney is known to auto-regulate the intraglomerular
pressure by changing the afferent and efferent arterial tone
to preserve GFR and urine output.
In case of volume depletion, following changes occur:

circulating prostaglandins vasodilate the afferent arterioles,
allowing more blood to flow through the glomerulus;

while angiotensin-II causes vasoconstriction of the efferent
arterioles

10. Altered IntraGlomerular
Hemodynamics
l
Some drug classes are known to interfere with kidneys
ability to autoregulate glomerular pressures and thereby
decrease GFR.
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NSAIDs with antiprostaglandin activity
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Drugs with anti-angiotensin-II activity (ACEIs &
ARBs)
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Similarly, Calcineurin inhibitors Eg, cyclosporine,
tacrolimus, cause dose dependent vasoconstriction of
the afferent arterioles, leading to renal impairment in at-
risk patients.

11. Tubular Cell Toxicity
l
Renal tubular cells, in particular proximal tubule
cells, are vulnerable to the toxic effects of drugs
because their role in concentrating and
reabsorbing glomerular filtrate exposes them to
high levels of circulating toxins.
l
Drugs that cause tubular cell toxicity do so by:

impairing mitochondrial function,

interfering with tubular transport,

increasing oxidative stress, or

forming free radicals.

12. Tubular Cell Toxicity
l
Drugs associated with tubular cell toxicity
include:
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aminoglycosides,
l
amphotericin B,
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antiretrovirals (adefovir, cidofovir, tenofovir),
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cisplatin,
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contrast dye,
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foscarnet , and
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zoledronate

13. Inflammation
l
Drugs can cause inflammatory changes in the
glomerulus, renal tubular cells, and the surrounding
interstitium, leading to fibrosis and renal scarring.
l
Glomerulonephritis is an inflammatory condition
caused primarily by immune mechanisms and is
often associated with proteinuria in the nephrotic
range.

14. Inflammation
Acute interstitial nephritis, which can result from an allergic
response to a suspected drug, develops in an idiosyncratic,
non–dose-dependent fashion.
Numerous drugs have been implicated, including:
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Allopurinol,
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Antibiotics (beta lactams, quinolones, rifampin, sulfonamides, and
vancomycin)
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Antivirals (acyclovir and indinavir)
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Diuretics (loops, thiazides);
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NSAIDs;
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Phenytoin;
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Proton pump inhibitors (omeprazole, pantoprazole, and
lansoprazole), and
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Ranitidine.

15. Inflammation
l
Chronic interstitial nephritis has been reported with
analgesics such as acetaminophen, aspirin, and
NSAIDs when used chronically in high dosages (i.e.,
more than 1 gram daily for more than two years) or in
patients with pre-existing kidney disease.
l
Early recognition is important because chronic
interstitial nephritis has been known to progress to
end-stage renal disease.

16. Inflammation
l
Medications --causative agents of CIN:
l gold therapy,
l hydralazine ,
l Interferon-alfa,
l lithium,
l NSAIDs,
l propylthiouracil, and
l pamidronate

17. Crystal Nephropathy

Renal impairment may result from the use of drugs that produce
crystals that are insoluble in human urine.

The crystals precipitate, usually within the distal tubular lumen,
obstructing urine flow and eliciting an interstitial reaction.

Commonly prescribed drugs associated with production of crystals
include:

Antibiotics (e.g., ampicillin, ciprofloxacin, sulfonamides);

Antivirals (e.g., acyclovir, foscarnet, ganciclovir, indinavir)

Methotrexate

Patients most at risk of crystal nephropathy are those with volume
depletion and underlying renal insufficiency.

18. l
Rhabdomyolysis
Rhabdomyolysis is a syndrome in which skeletal muscle injury
leads to lysis of the myocyte, releasing intracellular contents
including myoglobin and creatine kinase into the plasma.
Myoglobin induces renal injury secondary to direct toxicity, tubular
obstruction, and alterations in GFR.
Drugs may induce rhabdomyolysis directly secondary to a toxic
effect on myocyte function.
l
Statins are the most recognizable agents associated with
rhabdomyolysis
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Many drugs of abuse, such as cocaine, heroin, ketamine,
methadone, and methamphetamine, have been reported to
cause rhabdomyolysis.

19. Thrombotic Microangiopathy

In thrombotic microangiopathy, organ damage is caused by
platelet thrombi in the microcirculation, as in thrombotic
thrombocytopenic purpura.

Mechanisms of renal injury secondary to drug-induced
thrombotic microangiopathy include
 an immune-mediated reaction or
 direct endothelial toxicity.

Eg, antiplatelet agents (e.g., clopidogrel, ticlopidine),
 cyclosporine, mitomycin-C (Mutamycin), and
 quinine

20. -Nephrotoxicity-
Clinical presentations
Patients who experience acute-onset renal failure often
complain of:
 increased shortness of breath,
 ankle swelling and weight gain
The reduced ability of the kidney to clear extra fluid from
the body.
Stopping the medication may allow the kidney to recover
If the kidney has extensive damage, the kidney may
reduce or even stop producing urine
Hemodialysis may be necessary for a short-term bridge
until the kidney can recover
In some cases, the damage is irreversible and the patient
will require life-long dialysis or a kidney transplant.

21. DRUG INDUCED
RENAL FAILURE

22. ARF-Causes-Drugs Involved

23. Patient-Related Risk Factors
Age older than 60 years,
underlying renal insufficiency (e.g., GFR of
less than 60 mL per minute per 1.73 m2 ),
intravascular volume depletion,
exposure to multiple nephrotoxins,
diabetes,
heart failure, and
sepsis

24. Patient-Related Risk Factors
l
The risk of acute renal failure increases with the
presence of each additional risk factor.
l
Patients with any of these risk factors, especially
those who have more than one risk factor (e.g., a
patient with diabetes and heart failure), should be
closely monitored for changes in renal function
when a medication is added or a dosage is
increased.

25. Patient-Related Risk Factors
l
Both “absolute” and “effective” intravascular volume depletion are
risk factors for drug-induced renal impairment.
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Absolute intravascular volume depletion may occur in patients
who have gastroenteritis, chronic diarrhea, aggressive
diuresis, or poor oral intake.
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Effective intravascular volume is the volume of blood
perceived by baroreceptors located in the right atrium and the
kidney.
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Decreased effective circulating blood volume results from
sequestration of fluid into third-space compartments and is
associated with sepsis, heart failure, ascites, or pancreatitis.

26. ANTIBIOTICS
AIN is hypersensitivity or allergic reaction to drug
Up to 71% of all cases of acute interstitial nephritis
(AIN) are drug-induced
The most common antibiotic classes associated with AIN
are
 Penicillins/cephalosporins and sulfonamides
 Ciprofloxacin & Rifampin (Rifampicin)
Features
Acute renal failure, Skin rash, Increased eosinophils

27. ANTIBIOTICS
Aminoglycosides (tobramycin, gentamicin, amikacin) and
amphotericin B can cause ATN
Risk of aminoglycoside toxicity is associated with increased
dose, duration of therapy, dehydration and concurrent use of
nephrotoxic drugs, such as NSAIDs
Amphotericin B renal toxicity is related to cumulative dose,
concurrent use of nephrotoxic drugs, baseline abnormal creatinine
and concurrent use of diuretics
80% of patients receiving amphotericin B experiencing some
decrease of renal function
Saline hydration can decrease the toxicity

28. CHEMOTHERAPY DRUGS
Nephrotoxicity is the major dose-limiting toxicity for
Cisplatin
Both acute and late-onset toxicities occur
Aggressive replacement of magnesium (lost when the
proximal tubule is damaged), saline hydration or
mannitol infusion is required.
High dose Methotrexate : postrenal obstruction by
precipitating in the tubules of the nephron
Also known to cause direct toxicity

29. ANTIVIRALS &
IMMUNOSUPPRESSANT
ANTIVIRALS
Acyclovir, foscarnet, and interferons can cause ATN
Acyclovir can precipitate within the renal tubules
IMMUNOSUPPRESSANT
Cyclosporine and tacrolimus
Acute, dose-dependent reduction in renal
blood flow and chronic structural changes in the
kidney

30. NSAIDs
Long-term use can cause chronic renal insufficiency
Patients who experience ARF with NSAIDs have
underlying risk factors
Prolonged NSAID use can cause chronic kidney disease,
especially in the elderly
1-5 % of all end-stage renal disease (ESRD) patients
have analgesic-associated nephropathy
Risk factors for this nephropathy include
 gender (women>men),
 age (>50 years old) and
 prolonged use of the analgesic

31. NSAIDs
Selective cyclooxygenase (COX-2) inhibitors cause
similar renal dysfunction -(Celecoxib, Rofecoxib)
COX-2 exists as a constitutive enzyme in the thick part
of the ascending loop of Henle and in the renal medulla
COX-2 causes natriuresis and diuresis
Inhibition of COX-2 by selective COX-2 inhibitors, such
as celecoxib and rofecoxib causes renal dysfunction
particularly in patients who are volume-depleted or
haemodynamically unstable.

32. STATINS
The lipid lowering drugs (Atorvastatin,
Rosuvastatin)
Rare but serious cases of rhabdomyolysis
Acute tubular necrosis
Muscle pain, dark urine, electrolyte
abnormalities and renal failure
Recognizing the process as drug-induced renal
failure and stopping the drug is essential

33. DRUGS OF ABUSE
Cocaine and heroin
Cocaine use can cause renal artery thrombosis
(clotting), severe hypertension and interstitial
nephritis
Long-term cocaine use can lead to chronic
renal failure
Long-term tobacco use also increases the risk
of kidney cancer

34. General preventive measures
General preventive measures include:
using alternative non-nephrotoxic drugs whenever
possible;
correcting risk factors,
If possible; assessing baseline renal function before
initiation of therapy,
adjusting the dosage;
monitoring renal function and vital signs during
therapy; and
avoiding nephrotoxic drug combinations.

35. Recognition and Early
Intervention
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Most episodes of drug-induced renal
impairment are reversible.
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Renal function generally returns to baseline
provided the impairment is recognized early
and the offending medication is discontinued.

36. Recognition and Early
Intervention
A decrease in renal function as evidenced by a rise
in serum creatinine levels following the initiation of a
drug signals the possibility of drug-induced renal
injury.
An exception to this is an increase in serum
creatinine following the initiation of cimetidine or
trimethoprim, because they compete with creatinine
for tubular secretion and are not associated with
kidney damage or urine abnormalities.

37. Recognition and Early
Intervention
Serum creatinine levels- Acute renal failure
A 50 percent rise from baseline, an increase
of 0.5 mg per dL or more when baseline
serum creatinine is less than 2 mg per dL or
an increase of 1 mg per dL or more if
baseline creatinine is greater than 2 mg per
dL have been used as biochemical criteria of
acute renal failure.

38. Recognition and Early
Intervention
At the first sign of renal dysfunction, the patient’s
medication list should be reviewed to identify offending
agents.
If multiple medications are present and the patient is
clinically stable, physicians should start by discontinuing
the drug most recently added to the patient’s medication
regimen.
Attention should then be directed at avoiding further renal
insults by:

supporting blood pressure,

maintaining adequate hydration, and

temporarily discontinuing all other possible nephrotoxins.

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