NEPHROTOXIN

Presented by
VAISHNAVI SAHU

Under the Supervision of

DR. DHARAMVEER
Professor and Head
Department of Pharmacology

Hygia Institute of
Pharmaceutical Education &
Research, Lucknow
NEPHROTOXICITY
Nephrotoxicity can be defined as the adverse effect of substances on renal
function .
These substances can include molds and fungi, cancer therapeutics such as
cisplatin, antibiotics such as aminoglycosides, metals such as mercury,
arsenic and lead, and drugs of abuse such as cocaine.
 TYPE OF NEPHROTOXICITY
Acute Renal Failure (ARF)
Acute renal failure (ARF) is a syndrome characterised by rapid onset of renal
dysfunction, chiefly oliguria or anuria, and sudden increase in metabolic
waste-products (urea and creatinine) in the blood with consequent development
of Uraemia

Chronic Renal Failure (CRF)

Chronic renal failure is a syndrome characterised by progressive and irreversible
deterioration of renal function due to slow destruction of renal parenchyma,
eventually terminating in death when sufficient number of nephrons have been
damaged.
 MECHANISMS INVOLVED IN
NEPHROTOXICITY
Impaired Blood Flow to the Kidneys
•Blood or fluid loss.
•Use of Aspirin, Ibuprofen and Naproxen.

Damage to the Kidneys

•Blood clots in the veins and arteries in and around the kidneys.
•Cholesterol deposits that block blood flow in the kidneys.
•Glomerulonephritis, inflammation of the tiny filters in the kidneys
(glomeruli).

Urine Blockage in the Kidneys

•Kidney stones
•Nerve damage involving the nerves that control the bladde
•Prostate cancer.
Inflammation
Nephrotoxic drugs often induce inflammation in glomerulus, proximal tubules, and
surrounding cellular matrix, and then fiberize the kidney tissue. Inflammation that
disturb normal kidney functions and induce toxicity includes glomerulonephritis,
acute and chronic interstitial nephritis. Glomerulonephritis has been shown to be
closely related to proteinuria.

Tubular cell toxicity

Because renal tubules, especially proximal tubule cells, are exposed to drugs in the
process of concentration and reabsorption through the glomerulus, they are infl
uenced greatly by drug toxicity .

Oxidative damage
Leading to peroxidation of lipids, changes in the structure of when
proteins, represents an important cause of kidney damage that must be addressed
attempting to treat AKI.
SYMPTOMS OF NEPHROTOXICITY

•Hypertension
•Alteration in urination frequency and volume.
•Dysuria and haematuria
•Swelling of different body parts including hands,
ankles, feet etc.
•Burning sensation, fatigue
•Anemia
VARIOUS DRUGS ASSOCIATED WITH
NEPHROTOXICITY
Several drugs induced nephrotoxicity such as anticancer
drug cisplatin, aminoglycosides antibiotics, antiviral drug
cidofovir, immune-suppressant drug tacrolimus and some
contrast reagents.
Drug class/drug(s) Pathophysiologic mechanism
Aminoglycosides Tubular cell toxicity (renal proximal
Eg,Gentamicin convoluted tubules) by induce the apoptosis and
necrosis ,
Inflammation caused by increasing the level of pro
. inflammatory cytokines
eg. TNF-α, IL-1β, and IL-6
Oxidative stress

Analgesics Chronic interstitial nephritis,

Eg. Acetaminophen,aspirin Acute interstitial nephritis ,
hymodynamic mediated kidney injury

Cytotoxic agents Chronic interstitial nephritis,

Eg .Cisplitin, Methotrexate Crystal nephropathy
Mitomycin C
KIDNEY FUNCTION TEST
1. URINE ANALYSIS

i) Physical examination
(output, colour, specific gravity, pH, osmolality)

ii) Chemical constituents

(protein, glucose, red cells, haemoglobin)

iii) Bacteriologic examination

iv) Microscopy

2. CONCENTRATION AND DILUTION TESTS:

i)Concentration test (fluid deprivation test)

ii) Dilution test (excess fluid intake test)

3. BLOOD CHEMISTRY:
i) Urea

ii) Blood urea nitrogen (BUN)

iii) Creatinine

iv) β2-microglobulin

4. RENAL CLEARANCE TEST:

i) Inulin or mannitol clearance test

ii) Creatinine clearance

ii) Urea clearance

iv) Para-aminohippuric acid (PAH) clearance

PREVENTIVE STRATEGIES
Gentamicin
•Use the lowest dose and shortest possible course of therapy;
•Avoid combination with other potential nephrotoxins.

Cisplatin
•Treat with mannitol for diuresis or antioxidant drugs for renoprotection;
Monitor renal function for early detection of nephrotoxicity.
•Use the lowest dose and shortest possible course of therapy;
•Avoid combination with other potential nephrotoxins.

NSAIDs
•Avoid habitual use of NSAIDs
•avoid combination of analgesics
• Early intervention and stop NSAIDs if patients have any evidence of
renal insufficiency
CURRENT FOCUSES OF NEPHROTOXICITY
Biomarkers
Focused on microRNA in the urine, and assessment of exosomes and other
extracellular vesicles.
Mechanism
Significant effort has gone into studying the mechanisms of nephrotoxicant-
induced cell death. All 3 major types of cell death occur in renal cells
including apoptosis, autophagy and necrosis.
Transportes
The variation in expression of transporters between species and cell lines
results in some uncertainty in assessing the risk of nephrotoxicity to
humans
REFERENCES

Barnett, Lillie MA, and Brian S. Cummings. "Nephrotoxicity and renal

pathophysiology: a contemporary perspective." Toxicological
Sciences 164, no. 2 (2018): 379-390.

Wu, Huizi, and Jiaguo Huang. "Drug-induced nephrotoxicity: pathogenic

mechanisms, biomarkers and prevention strategies." Current drug
metabolism 19, no. 7 (2018): 559-567.

Randjelovic, Pavle, Slavimir Veljkovic, Nenad Stojiljkovic, Dušan

Sokolovic, and Ivan Ilic. "Gentamicin nephrotoxicity in animals: current
knowledge and future perspectives." EXCLI journal 16 (2017): 388.
Title: Nephrotoxicity and Renal Pathophysiology:
A Contemporary Perspective .

Author(s): Lillie M.A. Barnett* and Brian S. Cummings

JournalName: TOXICOLOGICAL SCIENCES
Volume: ……2….Issue: …… year: 2018………Page Number: 379-390
Publisher: OXFORD PUBLISHER

Aim of review
This review summarizes the current state of the field of nephrotoxicity

Type of review - Disease & Mechanism oriented

Conclusion-The field of nephrotoxicity is alive and well. Despite a perceived

decrease in the funding of studies focusing on toxicant-induced kidney injury, it
should be noted that funding for pathologicalinduced kidney injury, such as that
induced by diabetes or heart disease, remains strong.
Title: …Drug-Induced Nephrotoxicity: Pathogenic Mechanisms, Biomarkers and
Prevention Strategies.
Author(s): Huizi Wu and Jiaguo Huang
JournalName: … Current Drug Metabolism
Volume: ……19…………….Issue: ………… year:2018Page Number: …559-567
Publisher: …… Bentham Science

Aim of review This review summarized the mechanisms and prevention

strategies for some drugs that were commonly used clinically and had the
possibility of inducing acute and chronic kidney injuries.

Type of review ( Disease & Mechanism oriented)

Conclusion
Drug-induced nephrotoxicity is closely associated with AKI and CKD various
classes of drugs-induced nephrotoxicity are discussed
The mechanisms of drug-induced nephrotoxicity summarized here, supported by
specific examples of the nephrotoxicity of commonly used drugs in clinic, are
available to provide us relevant information to newer pharmacotherapies and
similar drug classes.
Title: GENTAMICIN NEPHROTOXICITY IN ANIMALS: CURRENT KNOWLEDGE
AND FUTURE PERSPECTIVES
Author(s): Pavle Randjelović1*, Slavimir Veljković1 , Nenad Stojiljković1 , Du
Journal: EXCLI Journal
Volume: ……16…………….Issue: ………… year: 2017……………Page Number: ……
1611-2156

Aim of review Aim can only be achieved through better understanding of

kidney metabolism of gentamicin.

Type of review ( Disease & Mechanism oriented)

Conclusion
Gentamicin induced nephrotoxicity has been extensively studied in the past
and has become one of the established models of drug induced
nephrotoxicityThis review can be used as a guide for everyone trying to
understand and further investigate every aspect of gentamicin nephrotoxicity.