TOPIC: TOXIC RESPONSES OF KIDNEY

DATE: MAY 2024

SEMESTER: 9TH

SHIFT: MORNING

SUBMITTED TO: MA’aM IFFAT

PRESENTED BY: AAMNA MUJTABA

ANSA ASHRAF

ARUBA MUZAFFAR

BANEEN FATIMA

GULNAZ JABBAR
 TOPICS
I. Introduction

 Structure and functions of kidney

 Definition and significance of nephrotoxicity

II. Etiology of Nephrotoxicity

 Medications: NSAIDs, aminoglycosides, chemotherapeutic agents, contrast media

 Chemicals: Heavy metals, solvents, pesticides, industrial chemicals
 Toxins: Bacterial toxins, fungal toxins
 Medical Treatments: Radiation therapy, chemotherapeutic agents

III. Mechanisms of Nephrotoxicity

 Renal tubular damage

 Oxidative stress
 Inflammation
 Vascular effects
 Metabolic activation

IV. Clinical Manifestations of Nephrotoxicity

 Acute Kidney Injury (AKI)

 Urinary changes: Proteinuria, hematuria, oliguria, anuria
 Fluid and electrolyte imbalance
 Systemic effects: Hypertension, fluid overload, uremia

V. Diagnosis of Nephrotoxicity

 Laboratory tests: Serum creatinine, blood urea nitrogen (BUN), urinalysis, urine protein/creatinine ratio
 Imaging studies: Ultrasound, CT scans, MRI

VI. Management of Nephrotoxicity

 Discontinuation of offending agent

 Supportive care: Fluid and electrolyte management
 Specific antidotes or therapies: Chelation therapy, supportive medications

VII. Prevention of Nephrotoxicity

 Optimizing medication dosages

 Monitoring renal function
 Patient education on risk factors and preventive measures.
 TOXIC RESPONSES OF KIDNEY OR NEPHROTOXICITY

I. INTRODUCTION

The kidneys are bean-shaped organs located on either side of the spine, below the rib cage, and are
approximately the size of a fist. Each kidney is composed of three main regions: the renal cortex, renal medulla,
and renal pelvis.

Renal Cortex:
The outer region of the kidney is called the renal cortex. It contains structures such as the renal corpuscles
(glomerulus and Bowman's capsule), proximal and distal convoluted tubules, and cortical portions of the
collecting ducts. The renal cortex is where the initial filtration of blood occurs.

Renal Medulla:
The renal medulla is the inner region of the kidney, surrounding the renal cortex. It consists of renal pyramids,
which are triangular structures that contain tubules responsible for the concentration of urine. The loop of
Henle, a critical component for concentrating urine, extends into the renal medulla.

Renal Pelvis:
The renal pelvis is a funnel-shaped structure at the center of the kidney. It collects urine from the renal pyramids
and transports it to the ureter, which carries urine to the urinary bladder for storage and eventual excretion.

Functional Units - Nephrons:

The nephron is the functional unit of the kidney responsible for filtering blood and producing urine. Each
kidney contains millions of nephrons, and they work together to maintain fluid and electrolyte balance, regulate
blood pressure, and remove waste products from the body. Here's a detailed breakdown of the structure of a
nephron:

Renal Corpuscle:
Glomerulus: The glomerulus is a network of specialized capillaries where blood filtration occurs. It receives
blood from the afferent arteriole and drains it into the efferent arteriole. Blood pressure forces small molecules
and ions out of the blood into the Bowman's capsule.

Bowman's Capsule (Glomerular Capsule): Bowman's capsule surrounds the glomerulus and collects the
filtrate that is forced out of the blood. It consists of a parietal layer (simple squamous epithelium) and a visceral
layer (made of podocytes with filtration slits).

Renal Tubules:
Proximal Convoluted Tubule (PCT): The filtrate from Bowman's capsule enters the PCT. It is highly
convoluted to increase surface area for reabsorption of water, ions, glucose, amino acids, and other nutrients
back into the bloodstream.

Loop of Henle:

Descending Limb: The descending limb of the loop of Henle descends into the renal medulla. It is permeable
to water but not ions, allowing water to passively move out of the tubule into the surrounding interstitial fluid,
concentrating the filtrate.
Ascending Limb: The ascending limb ascends back towards the renal cortex. It is impermeable to water but
permeable to ions. Active transport mechanisms in the thick ascending limb reabsorb sodium, chloride, and
other ions, but not water, leading to dilution of the filtrate.

Distal Convoluted Tubule (DCT): The filtrate from the ascending limb enters the DCT. Here, further selective
reabsorption of ions and water occurs, under the influence of hormones like aldosterone and antidiuretic
hormone (ADH).

Collecting Duct: Multiple DCTs drain into a collecting duct. The collecting ducts pass through the medulla,
where they merge and ultimately empty into the renal pelvis. The collecting duct is responsible for the final
concentration or dilution of urine based on the body's hydration status.

Blood Supply:
Afferent Arteriole: Branches off the renal artery and delivers blood to the glomerulus for filtration.

Efferent Arteriole: Carries blood away from the glomerulus. It may form a capillary network around the renal
tubules (peritubular capillaries) or vasa recta around the loop of Henle, facilitating exchange of substances with
the renal tubules.

The nephron's intricate structure and function enable it to filter blood, reabsorb essential substances, and
produce urine, playing a critical role in maintaining homeostasis in the body.

Functions of the Kidney:

1. Filtration:
The kidneys filter waste products, toxins, and excess substances from the blood to form urine. Filtration occurs
in the renal corpuscles.

2. Reabsorption:
Essential substances, such as glucose, amino acids, and electrolytes, are reabsorbed from the renal tubules back
into the bloodstream to maintain homeostasis.
3. Secretion:
Certain substances, including drugs, toxins, and excess ions, are actively secreted from the blood into the renal
tubules for excretion in the urine.

4. Regulation of Blood Pressure:

The kidneys help regulate blood pressure by controlling blood volume and secreting hormones such as renin,
which regulates blood pressure and electrolyte balance.

5. Regulation of Electrolyte Balance:

The kidneys maintain the balance of electrolytes, such as sodium, potassium, calcium, and phosphate, in the
body, which is essential for various physiological processes.

6. Acid-Base Balance:
The kidneys help regulate the pH of the blood by excreting hydrogen ions and reabsorbing bicarbonate ions,
thereby maintaining acid-base balance.

7. Erythropoiesis Regulation:
The kidneys produce and release erythropoietin, a hormone that stimulates the production of red blood cells in
the bone marrow.

8. Metabolism of Vitamin D:
The kidneys play a role in activating vitamin D, which is essential for calcium absorption in the intestines and
for maintaining bone health.

Overall, the kidneys play crucial roles in maintaining fluid and electrolyte balance, blood pressure regulation,
and waste elimination, thus supporting the body's overall homeostasis.

Nephrotoxicity
Nephrotoxicity refers to the ability of certain substances or medications to cause damage to the kidneys, leading
to impaired kidney function. These substances are known as nephrotoxins. Nephrotoxicity can manifest as acute
kidney injury (AKI) or chronic kidney disease (CKD), depending on the duration and severity of exposure to
the nephrotoxic agent.

II. ETIOLOGY OF NEPHROTOXICITY:

Nephrotoxicity can arise from various sources, including medications, chemicals, toxins, and medical
treatments. Understanding the diverse etiological factors is essential for pharmacists to identify potential
nephrotoxic agents and mitigate risks for patients.

Medications
● Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs, commonly used for pain relief and anti-
inflammatory purposes, are known to cause nephrotoxicity, particularly when used at high doses or for
 prolonged durations. Mechanisms of NSAID-induced nephrotoxicity include inhibition of prostaglandin
synthesis, leading to renal vasoconstriction and reduced renal blood flow, as well as direct tubular
damage.
● Aminoglycoside and Beta Lactamase Antibiotics: Aminoglycoside antibiotics, such as gentamicin
and amikacin, are effective against severe bacterial infections but are associated with nephrotoxicity,
especially when administered at high doses or for extended periods. Aminoglycosides accumulate in
renal tubular cells, leading to mitochondrial dysfunction, oxidative stress, and apoptosis.
● Chemotherapeutic Agents: Certain chemotherapeutic agents, including cisplatin and methotrexate, can
induce nephrotoxicity as a dose-limiting adverse effect. Cisplatin, a platinum-based chemotherapy drug,
causes renal tubular injury through the formation of reactive oxygen species and DNA damage, while
methotrexate can lead to acute kidney injury due to crystalluria and tubular obstruction.
● Contrast Media: Iodinated contrast media, used in medical imaging procedures such as computed
tomography (CT) scans and angiography, are associated with contrast-induced nephropathy, particularly
in patients with pre-existing renal impairment or other risk factors. The exact mechanisms of contrast-
induced nephropathy involve renal vasoconstriction, medullary ischemia, oxidative stress, and direct
tubular toxicity.

Chemicals
● Heavy Metals: Heavy metals, including lead, mercury, and cadmium, are environmental pollutants that
can exert nephrotoxic effects upon exposure. These metals accumulate in the kidneys, leading to
oxidative stress, inflammation, and direct tubular damage, ultimately impairing renal function.
● Solvents: Certain organic solvents, such as toluene and trichloroethylene, used in industrial processes
and consumer products, have been implicated in nephrotoxicity. Solvent exposure can result in tubular
dysfunction, glomerular injury, and interstitial nephritis, often observed in occupational settings.
● Pesticides: Exposure to pesticides, including organophosphates and paraquat, poses a risk of
nephrotoxicity, particularly among agricultural workers and individuals living in pesticide-contaminated
areas. Pesticide-induced nephrotoxicity may manifest as acute kidney injury, tubulointerstitial nephritis,
or chronic kidney disease, mediated by oxidative stress, inflammation, and direct cellular damage.
● Industrial Chemicals: Various industrial chemicals, such as benzene, styrene, and chloroform, are
nephrotoxic and can cause renal injury through diverse mechanisms, including oxidative stress,
mitochondrial dysfunction, and disruption of cellular signaling pathways. Occupational exposure to
industrial chemicals requires careful monitoring to prevent nephrotoxic effects.

Toxins
● Bacterial Toxins: Bacterial toxins, produced by pathogens such as Escherichia coli and Staphylococcus
aureus, can cause nephrotoxicity by inducing inflammation, endothelial dysfunction, and tubular injury.
Certain bacterial toxins, such as Shiga toxin produced by E. coli strains, can lead to hemolytic uremic
syndrome, characterized by acute kidney injury and thrombotic microangiopathy.
● Fungal Toxins: Mycotoxins, produced by molds such as Aspergillus and Fusarium species, are
nephrotoxic compounds found in contaminated food and agricultural products. Mycotoxin exposure can
result in renal tubular necrosis, interstitial fibrosis, and glomerular damage, contributing to chronic
kidney disease and renal dysfunction.

III. MECHANISMS OF NEPHROTOXICITY

Renal Tubular Damage
● Direct Toxicity: Involves nephrotoxic agents like aminoglycosides entering renal cells and inducing
oxidative stress, mitochondrial dysfunction, and cell death.
● Ischemia: Caused by NSAIDs and other drugs that inhibit prostaglandin production, reducing kidney
blood flow and leading to tubular injury.
● Crystalluria: Happens when certain drugs, such as sulfonamides and triamterene, form crystals within
the tubules, blocking and damaging them.
● Inflammatory Damage: Results from nephrotoxins initiating inflammatory responses in the tubules,
worsening damage through immune cell recruitment and cytokine release.

Oxidative Stress
● Lipid Peroxidation: ROS can cause peroxidation of lipids in the cell membranes of renal cells, leading
to loss of cellular integrity and function.
● Protein Oxidation: Oxidative modifications to proteins can alter their function and degradation,
impairing cellular operations and signaling.
● DNA Damage: ROS can induce mutations and other damages to DNA, which may lead to cell death or
malfunction, and potentially oncogenic transformations.
● Mitochondrial Dysfunction: The mitochondria are particularly susceptible to oxidative damage due to
their role in energy production, which involves electron transport and oxygen consumption. Damage to
mitochondria can lead to reduced ATP production and release of pro-apoptotic factors.

Inflammation
Inflammatory triggers can include bacterial infections, exposure to toxins, autoimmune reactions, and systemic
inflammatory diseases.
● Immune Cell Recruitment: In response to injury or infection, immune cells such as neutrophils,
macrophages, and lymphocytes are recruited to the site of damage. These cells release various cytokines
and chemokines, which further amplify the inflammatory response.
● Cytokine and Chemokine Release: These signaling molecules increase vascular permeability, allowing
more immune cells to infiltrate the kidney and exacerbate tissue damage. Cytokines can directly injure
renal cells and also promote fibrosis, which can impair renal function.
● Activation of Complement System: The complement system can be activated by pathogens or
damaged cells, leading to the formation of membrane attack complexes that can lyse cells and increase
inflammation.

Vascular Effects
Vascular effects in nephrotoxicity involve alterations to the renal blood vessels, impacting kidney function
significantly.
● Vasoconstriction: Certain drugs and toxins can induce vasoconstriction of renal arteries and arterioles,
reducing blood flow to the kidney. This reduction in blood supply can lead to ischemic damage to renal
tissues. Common culprits include drugs like cyclosporine and radiocontrast agents, which can cause
afferent arteriole constriction.
 ● Endothelial Dysfunction: Toxins can directly damage the endothelial cells lining the renal vasculature,
leading to impaired vasodilation and increased susceptibility to thrombosis. This dysfunction can be
exacerbated by factors such as oxidative stress and inflammation.
● Thrombosis: Some nephrotoxic agents promote the formation of blood clots within the renal
vasculature, blocking blood flow and leading to ischemic injury. This can occur due to endothelial
damage or changes in blood coagulability.
● Structural Changes: Chronic exposure to nephrotoxic agents can lead to structural alterations in the
renal vessels, such as hyalinosis and fibrosis, which permanently reduce renal blood flow and impair
kidney function.

Metabolic Activation
Metabolic activation in nephrotoxicity refers to the biochemical processes by which certain substances are
transformed into metabolites that can be more harmful than their parent compounds.
● Bioactivation: Many drugs and toxins are initially non-toxic but become harmful when metabolized by
enzymes such as the cytochrome P450 system. This metabolic conversion can generate reactive
intermediates, such as free radicals or electrophiles, which can damage renal cells.
● Proximate and Ultimate Toxins: Some substances undergo several metabolic transformations. The
intermediate products (proximate toxins) may be slightly harmful or inactive but are eventually
metabolized into highly toxic compounds (ultimate toxins). These ultimate toxins can covalently bind to
cellular macromolecules in the kidneys, leading to cellular dysfunction and death.
● Mitochondrial Toxicity: Some metabolites specifically target renal mitochondria, disrupting energy
production and inducing oxidative stress, which further damages kidney cells.

IV. CLINICAL MANIFESTATIONS OF NEPHROTOXICITY

Acute Kidney Injury (AKI): AKI is a rapid decline in renal function over hours to days, leading to the
accumulation of waste products in the blood, reflected by a rise in serum creatinine and a reduction in urine
output. Nephrotoxic AKI is often caused by direct renal injury from toxins, ischemia, or an inflammatory
response.

Urinary Changes:
● Proteinuria: The presence of abnormally high levels of protein in the urine, often indicating damage to
the glomeruli or tubules.
● Hematuria: Blood in the urine can be a sign of damage to any part of the renal system, including the
glomeruli, tubules, or interstitium.
● Oliguria: Decreased urine output (typically less than 400 mL per day), which may indicate significantly
reduced kidney function.
● Anuria: A severe form of oliguria where the kidneys produce no urine, often a sign of kidney failure or
severe damage.

Fluid and Electrolyte Imbalance:

● Hyperkalemia: Elevated potassium levels, which can be life-threatening if severe.
● Hyponatremia or Hypernatremia: Abnormal sodium levels, which can affect cellular function and
fluid balance.
 ● Acidosis: Accumulation of acids or loss of bicarbonate, leading to a decrease in blood pH.

Systemic Effects:
● Hypertension: High blood pressure can both cause and result from kidney damage. Nephrotoxic
substances may cause renal artery constriction or damage that impairs pressure regulation.
● Fluid Overload: Impaired kidney function can lead to an inability to excrete water, resulting in edema
and fluid accumulation in the lungs and other tissues.
● Uremia: A build-up of urea and other waste products in the blood, which can cause symptoms such as
nausea, fatigue, confusion, and, if severe, uremic encephalopathy or pericarditis.

V. DIAGNOSIS OF NEPHROTOXICITY
Accurate diagnosis of nephrotoxicity relies on a comprehensive evaluation of clinical history, physical
examination findings, laboratory tests, and imaging studies. Pharmacists play a crucial role in interpreting
diagnostic data and collaborating with healthcare providers to optimize patient care.

Laboratory Tests
Lab tests help diagnose nephrotoxicity by measuring various biomarkers in the blood or urine. Here are some
common lab tests and their explanations:
● Serum Creatinine: Measures the level of creatinine in the blood, which increases when kidney function
● declines.
● Blood Urea Nitrogen (BUN): Measures the level of urea nitrogen in the blood, which also increases
when kidney function declines.
● Urinalysis: Examines the urine for abnormalities like protein, blood, or casts (tiny tube-shaped
structures) that can indicate kidney damage.
● Creatinine Clearance: Estimates the kidney's filtration rate by measuring creatinine levels in both
blood and urine.
● Cystatin C: Measures the level of cystatin C, a protein that increases in blood when kidney function
declines.
● Kidney Injury Molecule-1 (KIM-1): Detects the presence of KIM-1, a protein released by damaged
kidney cells.
● Neutrophil Gelatinase-Associated Lipocalin (NGAL): Measures the level of NGAL, a protein that
increases in response to kidney damage.
These lab tests help healthcare providers diagnose and monitor nephrotoxicity, enabling timely interventions to
prevent further kidney damage.

Urinalysis
Urinalysis for diagnosing nephrotoxicity involves examining the urine for abnormalities. Here are some simple
explanations of what urinalysis can detect:
 ● Proteinuria: Excess protein in the urine, indicating damaged kidney filters.
● Hematuria: Blood in the urine, suggesting kidney damage or inflammation.
● Pyuria: White blood cells in the urine, indicating infection or inflammation.
● Casts: Tiny tube-shaped structures in the urine, indicating kidney damage or inflammation.
● Specific Gravity: Abnormal urine concentration, indicating kidney function issues.
● Ph: Abnormal urine pH, indicating kidney function issues or infection.
● Urine Osmolality: Abnormal urine concentration, indicating kidney function issues.
● Micro Albuminuria: Small amounts of albumin (a protein) in the urine, indicating early kidney
damage.
● Nag (N-Acetyl-Β-D-Glucosaminidase): An enzyme that increases in urine when kidney tubules are
damaged.
● Urinary Biomarkers: Urinalysis helps diagnose nephrotoxicity by detecting these abnormalities,
enabling healthcare providers to take prompt action to prevent further kidney damage.

Imaging Studies
Imaging studies help diagnose nephrotoxicity by visualizing the kidneys and detecting damage or abnormalities.
Here are some simple explanations of common imaging studies:
● Ultrasound: Uses high-frequency sound waves to produce images of the kidneys, detecting: kidney size
and shape, fluid accumulation (hydronephrosis), and kidney stones
● Computed Tomography (CT) Scan: Uses X-rays and computer technology to produce detailed images
of the kidneys, detecting kidney damage or inflammation, kidney stones, tumors or masses.
● Magnetic Resonance Imaging (MRI): Uses magnetic fields and radio waves to produce detailed
images of the kidneys, detecting kidney damage or inflammation, kidney function, blood flow.
● Radionuclide Imaging: Uses small amounts of radioactive material to visualize kidney function and
detect kidney damage or inflammation, kidney function decline, urinary tract obstruction.
● Angiography: Uses X-rays and contrast agents to visualize blood vessels, detecting blood clots or
blockages kidney artery stenosis (narrowing).
Imaging studies help healthcare providers:
● Diagnose nephrotoxicity
● Monitor kidney damage
● -Guide treatment decisions
● Detect complications
Imaging studies may not always detect early kidney damage, so lab tests and urinalysis are also important
for diagnosis and monitoring.
VI. MANAGEMENT OF NEPHROTOXICITY
Effective management of nephrotoxicity involves recognition of renal injury, discontinuation of the offending
agent, supportive care to improve renal function.
● Discontinuation Of Offending Agent: The first step in managing nephrotoxicity is to identify and
discontinue the causative agent responsible for renal injury.
● Fluid Management: Maintain adequate hydration and manage fluid balance to prevent dehydration or
overhydration.
● Electrolyte Management: Monitor and correct electrolyte imbalance such as potassium, sodium and
phosphorus.
● Supportive Care: Manage symptoms like nausea, vomiting and pain with appropriate medication.

Medications
● Diuretics: Diuretic help increase in urine production, promote the elimination of excess fluid and waste
products from the body.
● ACE Inhibitors: These are commonly used to manage high blood pressure and protect the kidney.
● NSAIDs: They help to reduce inflammation and pain.
● Dialysis: In severe cases when kidney function impaired dialysis may be necessary, help to remove
waste product and excessive fluid from the blood.

Specific Antidotes Or Therapies:

In certain cases of nephrotoxicity, specific antidotes or therapies may be indicated to counteract the toxic effects
of the offending agent. Examples include chelation therapy for heavy metal toxicity, alkalinization of urine to
enhance drug elimination.
Chelation therapy is a treatment used to remove toxic metal or mineral such as lead , mercury from the body .It
involve the administration of chelating agent which are substances that bind to toxic metal and help to
eliminate through urine .
Different toxins may required different antidotes for example , if nephrotoxicity is caused by an overdose of
acetaminophen (Tylenol ) then the antidote N- acetylcysteine is used.

VII. PREVENTION OF NEPHROTOXICITY:

Preventing nephrotoxicity involves strategies to minimize the risk of kidney damage from toxic
substances, certain drugs and other harmful agents.
● Avoid Nephrotoxic Substances: Limit the exposure to known nephrotoxin such as heavy metals ,
certain drugs etc
● Hydration: Adequate hydration helps flush out toxins and reduce kidney damage .
● Monitor Kidney Function: Regularly assess kidney function especially in high risk individual (e.g
those with pre – existing
● kidney disease).
● Balanced Diet: A healthy diet low in sodium and high in fruits and vegetables can help support kidney
function.
● Manage Underlying Condition: Control underlying condition like diabetes , hypertension and. obesity
which can increase the risk of kidney damage
● Regular Exercise: Engage in regular physical activity can help to maintain kidney health.