Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins are substances displaying nephrotoxicity.
2. KIDNEY-
The kidney plays a principal role in
the excretion of metabolic wastes and
in the regulation of extracellular fluid
volume, electrolyte composition, and
acid–base balance. In addition, the kidney
synthesizes and releases hormones, such
as renin and erythropoietin, & metabolizes
vitamin D3 to the active 1,25-dihydroxy
vitamin D3 form.
3. FUNCTIONALANATOMY-
Gross examination of a sagittal section of the kidney reveals three
clearly demarcated anatomic areas:
I. Cortex
II. Medulla
III. Papilla
The cortex constitutes the major portion of the kidney and receives
higher percentage (90%) of blood flow compared to the medulla (∼6–
10%) or papilla (1– 2%).
4. The functional unit of the kidney, the nephron, may be considered in
three portions:
I. The vascular element
II. The glomerulus
III. The tubular element
5. Renal Vasculature and Glomerulus-
The renal artery branches successively
into interlobar, arcuate, and interlobular
arteries. The last of these give rise to the
afferent arterioles, which supply the
glomerulus; blood then leaves the
glomerular capillaries via the efferent
arteriole. Both the afferent and efferent
arterioles, arranged in a series before and
after the glomerular capillary,
respectively are ideally situated to control
glomerular capillary pressure and glomerular
plasma flow rate.
6. The glomerulus is a complex, specialized capillary bed composed primarily of
endothelial cells.
In general, the filtration of small molecules,
such as inulin (MW 5,500), are freely filtered,
whereas large molecules, such as albumin
(MW 56,000–70,000),are restricted.
7. Proximal Tubule-
The proximal tubule consists of three segments:
I. S1 (pars convoluta)- is Characteristic of Na+-transporting epithelia.
II. S2 (transition between pars convoluta and pars recta)- is the end of the convoluted segment
and the initial portion of the straight segment.
III. S3 (pars recta)- is the distal portion of proximal segments and extends to the junction of the outer
and inner stripe of the outer medulla.
Loop of Henle-
It is a long, U-shaped portion of nephron.
The thin ascending limb of loop of Henle Na+ & Cl– are reabsorbed by passive diffusion.
The thick ascending limb active transport of Na+ and Cl– is mediated by the Na+/K+ Cl– cotransport
mechanism.
Distal Tubule and Collecting Duct-
Distal tubule reabsorbs most of the remaining Na+, K+, and Cl– ions. The remaining Na+ is reabsorbed
in conjunction with K+ and H+ secretion in the late distal tubule & cortical collecting tubule.
8. PATHOPHYSIOLOGIC RESPONSES OF THE
KIDNEY -
●Acute Kidney Injury
One of the most common of nephrotoxic damage is acute renal failure. AKI is
defined as a complex disorder that responsible for a minimal elevation in serum
creatinine to an uric renal failure.
Any downfall in GFR may result from pre renal factors (renal vasoconstriction,
intravascular volume depletion, and insufficient cardiac output), post renal
factors (ureteral or bladder obstruction), and intra renal
factors(glomerulonephritis, tubular cell injury, death, and renal vasculature
damage, interstitial nephritis).
9. ●Mechanisms of reduction of the GFR -
A) GFR depends on four factors:
I. Suitable blood flow to the glomerulus.
II. Suitable glomerular capillary pressure.
III. Glomerular permeability.
IV. Low intra tubular pressure.
B)
Afferent arteriolar
constriction decrease
GFR
By reducing blood
flow
Decrease
capillary pressure
11. ●Mechanisms that contribute to decreased GFR in acute renal failure -
This picture illustrates after exposure to a nephrotoxicant, one or more mechanisms may
contribute to a reduction in the GFR.
These include renal vasoconstriction resulting
due to precipitation of a drug or endogenous
compound within the kidney. Intrarenal factors
include direct tubular obstruction & dysfunction,
with or without inflammation, resulting in tubular
back-leak and increased tubular pressure.
Vascular damage, with or without inflammation,
leading to hemodynamic changes. Alterations in
the levels of a variety of vasoactive mediators may
result in decreased renal perfusion pressure or
efferent arteriolar tone & increased afferent
arteriolar tone, leading to decreased glomerular hydrostatic pressure.
12. Adaptation Following Toxic Insult-
After a population of cells is exposed to a nephrotoxicant, the cells respond;
ultimately the nephron recovers function or, if cell death and loss are extensive,
nephron function stop. Terminally
injured cells undergo cell death through
oncosis or apoptosis. Injured cells undergo
repair.
Uninjured cells not under go
dedifferentiation, migration or spreading,
and differentiation.
Uninjured cells may also undergo
compensatory hypertrophy in response to
the cell loss and injury. Finally the uninjured cells also may undergo adaptation
& proliferation in response to a nephrotoxicant exposure.
13. ●Chronic Renal Failure-
Progressive degradation of renal function may occur with long term exposure to a
variety of chemicals(e.g., analgesics, lithium, and cyclosporine).
In CRF, following nephron loss, mechanism of action -
Increases in glomerular
pressures
Mechanical damage to the
capillaries
Damage to the glomerular
capillary wall
Altered permeabilityAltered renal function
Increased shear stress on
the endothelium
14. SITE-SELECTIVE INJURY-
Many nephrotoxicant have their primary effects on
separated regions of the nephron.
●Glomerular Injury-
Cyclosporine, Amphotericin B are examples of
chemicals that impair glomerular ultrafiltration without
loss of structural injury and decrease GFR.
Amphotericin B decreases GFR by causing renal
vasoconstriction and decreasing the glomerular capillary
ultrafiltration coefficient (Kf).
15. ●Proximal Tubular Injury-
The proximal tubule is the most common site of toxicant-induced renal injury..
Cytochrome P450 and cysteine conjugate β-lyase activity are enhanced
activation of the proximal tubule. Nephrotoxicity requiring P450 and β-lyase-
mediated bioactivation will most certainly be localized in the proximal tubule.
Finally, interfere with RBF and mitochondrial function.
●Loop of Henle/Distal Tubule/Collecting Duct Injury-
Chemically induced injury is more distal tubular structures, than proximal
tubule by different mechanism mechanisms.
The first phase of mechanisms is responsive for vasopressin and inhibitors of
prostaglandin synthesis.
And the second phase is not responsive to vasopressin or prostaglandin
synthesis inhibitors but is associated with decreased papillary solute content.
16. ASSESSMENT OF RENAL FUNCTION-
Done by both in-vivo and in-vitro method.
nephrotoxicity can be evaluated by serum and urine concentration.
● Test include measurement of –
i. Urine volume
ii. Osmolality
iii. pH
iv. Urinary composition (e.g., electrolytes, glucose, and protein).
For example, In case for RF, Glucosuria may reflect chemically induced
defects in proximal tubular reabsorption of sugars. Glucose Test.
● GFR can be measured –
i. Insulin clearance determine.
ii. Creatinine clearance determine.
In normal condition both should be excreted 100%.
● If any reabsorption of creatinine/insulin Indicate RF abnormality.
●Creatinine or inulin clearance is determined by the following formula:
17. BIOCHEMICAL MECHANISMS/MEDIATORS OF
RENAL CELL INJURY -
●Cell Death-
In many cases, renal cell injury may culminate
in cell death. In general, cell death is occur
through either oncosis or apoptosis. The
morphologic and biochemical characteristics
of oncosis (“necrotic cell death”) & apoptosis
are very different.
In general, nephrotoxicants produce cell death
through apoptosis and oncosis, that both forms
of cell death contribute to AKI.
For many toxicants, low concentrations primarily
cause apoptosis and oncosis occurs principally at higher concentrations. When the
primary mechanism of action of the nephrotoxicant is ATP depletion, oncosis may be the
predominant cause of cell death, with limited apoptosis occurring.
18. ●Mediators of Toxicity-
A chemical can initiate cell injury by a variety of mechanisms .In some cases the
chemical may initiate toxicity due to its reactivity with cellular macro molecules.
The covalent binding of the reactive intermediate to critical cellular macro
molecules is thought to interfere with the normal biological activity of the macro
molecule and there by initiate cellular injury.
Finally, chemicals may initiate injury indirectly by inducing oxidative stress via
increased production of Reactive Oxygen Species(ROS), such as superoxide
anion, hydrogen peroxide, and hydroxyl radicals.
Oxidative stress has been proposed to contribute, at least in part, to the
nephrotoxicity associated with ischemia/reperfusion injury, gentamicin,
cyclosporine, cisplatin, and halo alkene conjugates. In the presence of oxidative
stress, nitric oxide can be converted into reactive nitrogen species that contribute
to cellular injury and death.
19. Nephrotoxicants are generally thought to produce cell injury and death through many
mechanisms, either alone or in combination.
In some cases the toxicant may have a high affinity
for a specific macromolecule or class of macro
molecules that results in altered activity(increase or
decrease) of these molecules and cell injury.
Alternatively, the parent nephrotoxicant may
not be toxic until it is bio transformed into a reactive
Intermediate that binds covalently to macro molecules
and, in turn, alters their activity, resulting in cell
injury.
Finally, the toxicant may increase ROS in the
cells directly, after being bio transformed into are
active intermediate or through redox cycling.
The resulting increase in ROS results in oxidative damage and cell injury.
20. ●Cell Volume and Ion Homeostasis-
Cell volume and ion homeostasis are tightly regulated and are critical for the
reabsorptive properties of the tubular epithelial cells. Toxicants generally disrupt cell
volume and ion homeostasis by interacting with the plasma membrane and increasing
ion permeability or by inhibiting energy production. The loss of ATP, results in the
inhibition of membrane transporters that maintain the internal ion balance and
transmembrane ion movement. Following ATP depletion, Na+, K +-ATPase activity
decreases, resulting in cell swelling, and ultimately cell membrane rupture.
●Mitochondria-
Whether toxicants target mitochondria directly or indirectly, it is clear that
mitochondria play a critical role in determining whether cells die by apoptosis or
oncosis. The mitochondrial permeability transition (MPT) is characterized by the
opening of a high conductance pore that allows solutes of <1500 molecular weight to
pass. It is thought that the MPT occurs during cell injury and ultimately progresses to
apoptosis if sufficient ATP is available or oncosis if ATP is depleted.
Further, the release of apoptotic proteins such as apoptosis inducing factor (AIF),
cytochrome and Endonuclease G following MPT play a key role in activating
downstream caspases and executing apoptosis.
21. ●Ca2+ Homeostasis-
Ca2+ is a second messenger and plays a critical role in a variety of cellular
functions, binding to anionic site on macromolecules.
For example, an increase in cytosolic free Ca2+ can activate a number of
degradative Ca2+-dependent enzymes, such as phospholipases and
proteinases(e.g., Calpains), and can produce change in the structure and
function of cytoskeletal elements.
Prior depletion of ER Ca2+ stores protects renal proximal tubules from
extracellular Ca2+ influx and cell death produced by mitochondrial
inhibition & Hypoxia.
Further, the release of ER Ca2+ activates calpains which leads to further
disruption of ion homeostasis, cleavage of cytoskeleton proteins, cell
swelling, and ultimately oncosis.
22. ●Phospholipase-
Phospholipase A2 (PLA2) consists of a family of enzymes that hydrolyze the acyl
bond of phospholipids, resulting in the release of arachidonic acid and
lysophospholipid.
Cell membranes are rich with poly unsaturated fatty acids susceptible to lipid
peroxidation, degradation by PLA2; resulting in increased PLA2 activity and
formation of peroxidized arachidonic acid metabolites and lysophospholipid.
Lysophospholipid can be toxic to cells and change membrane permeability and
uncouple mitochondrial respiration.
Arachidonic metabolism are chemotactic for neutrophils, which also may cause
tissue damage.
23. ●Endonucleases-
Endonucleases have been suggested to play a role in renal cell oncosis and
apoptosis. Endonuclease activation with associated DNA cleavage produces a
“ladder” pattern by gel electrophoresis and late event in apoptosis.
With respect oncosis reported DNA damage and the activation of an endonuclease
G by ceramide in rat renal proximal tubules or NRK-52E cells subjected to
hypoxia/ reoxygenation.
●Proteinases-
Calpains responsible for cell death because they are cysteine proteinases; they are
activated by calcium.
For example, calpain activity increased in rat proximal tubules subjected to
hypoxia, and calpain inhibitors were cytoprotective.
24. SPECIFIC NEPHROTOXICANTS-
●Heavy Metals-
Many metals, including cadmium, chromium, lead, mercury, platinum, and uranium, are
nephrotoxic. It is important to recognize that the nature of metal nephrotoxicity varies
with respect to its form.
1.Cadmium-
Cadmium is primarily through food and results in nephrotoxicity. Cadmium produces
proximal tubule dysfunction (S1 and S2 segments) and injury by increases in urinary
excretion of glucose, amino acids, calcium, and cellular enzymes. This injury may
progress to a chronic interstitial nephritis.
2. Mercury-
Inorganic mercury has a very high affinity for protein sulfhydryl groups, and this
interaction play an important role in the toxicity of mercury at the cellular level.
Due to this changes in mitochondrial morphology and that mitochondrial
dysfunction is a nearly and important contributor to inorganic mercury-induced
cell death along the proximal tubule.
The kidneys are the primary target organs for accumulation of Hg2+, and the S3
segment of the proximal tubule is the initial site of toxicity.
25. ●Chemically Induced α2u-Globulin Nephropathy-
A group of chemicals, including unleaded gasoline, 1,4-dichlorobenzene,
tetrachloroethylene, cause α2u-globulin nephropathy or hyaline droplet
nephropathy. This nephropathy occurring in male rats, by the accumulation of
protein droplets in the S2 segment of the proximal tubule, and results in single-
cell necrosis, the formation of granular casts at the junction of the proximal tubule
and the thin loop of Henle, and cellular regeneration.
●Halogenated Hydrocarbons-
Halogenated hydrocarbon are used extensively as chemical intermediates,
solvents, and pesticides.
1.Chloroform-
Chloroform produces nephrotoxicity in a variety of species. The primary cellular
target is the proximal tubule, with no primary damage to the glomerulus or the
distal tubule. Proteinuria, glucosuria, and increased BUN levels are all
characteristic of chloroform induced nephrotoxicity.
26. 2.Tetrafluoroethylene-
Tetrafluoroethylene is metabolized in the liver by GSH-S-transferases to S-(1,1,2,2-
tetrafluoroethyl) glutathione. The glutathione(GSH) conjugate is secreted into the bile and
small intestine where it is degraded to the cysteine
S-conjugate (TFEC), reabsorbed, and transported
to the kidney. The mercapturic acid may also be
formed in the small intestine and reabsorbed.
Alternatively, the glutathione conjugate can be
transported to the kidney and bio transformed to
the cysteine conjugate by γ-GT and a dipeptidase
located on the brush border.
27. ●Therapeutic Agents -
1.Acetaminophen-
Large doses of the antipyretic and analgesic acetaminophen (APAP) are commonly associated
with hepatoxicity. Large doses of APAP can also cause nephrotoxicity in humans and animals.
APAP nephrotoxicity is characterized by proximal tubular necrosis with increases in BUN and
plasma creatinine; decreases in GFR and clearance of para aminohippurate; increases in the
fractional excretion of water, sodium, and potassium; and increases in urinary glucose, protein,
and brush-border enzymes.
2. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)-
Different types of nephrotoxicity have been associated with NSAID administration. ARF may
occur within hours of a large dose of a NSAID and is characterized by decreased RBF and
GFR. A number of risk factors (e.g., congestive heart failure, hepatic cirrhosis, hemorrhage,
hypertension, sepsis, diabetes) are known to facilitate the development of ARF following
NSAIDs consumption.
28. ● Aminoglycosides-
Renal dysfunction by aminoglycosides is characterized by a nonoliguric renal failure (renal
failure with urine output > 1 ml/kg per hour after the 1st day) with reduced GFR and an
increase in serum creatinine and BUN.
Renal handling of aminoglycosides-
1) Glomerular Filtration.
2) Binding to the brush-border
membranes of the proximal
tubule.
3) Pinocytosis.
4) Storage in the lysosomes.
29. 1.Amphotericin B-
Amphotericin B is a very effective antifungal agent whose clinical utility is limited by its
nephrotoxicity.
Amphotericin B administration is associated with decreases in RBF and GFR secondary to renal
arteriolar vasoconstriction or activation of transforming growth factor(TGF).
Amphotericin B nephrotoxicity is characterized by ADH-resistant polyuria, renal tubular acidosis,
hypokalaemia, and either acute or chronic renal failure.
Amphotericin B nephrotoxicity is unusual in that it impairs the functional integrity of the
glomerulus and of the proximal and distal portions of the nephron.
2.Cisplatin-
Cisplatin is a valuable drug in the treatment of solid tumors, with nephrotoxicity limiting its
clinical use.
Early effects of cisplatin are decreases in RBF and GFR produced by vasoconstriction and is
followed by tubular injury with enzymuria.
Although the primary cellular target associated with ARF is the proximal tubule S3 segment in the
rat, in humans the S1 and S2 segments, distal tubule, and collecting ducts can also be affected.
The chronic renal failure observed with cisplatin is due to prolonged exposure and is
characterized by focal necrosis in numerous segments of the nephron.
30. 3.Radiocontrast Agents-
The nephrotoxicity of these agents is due to both hemodynamic alterations (vasoconstriction)
and proximal tubular injury. The vasoconstriction is prolonged and is probably produced by
more than one mediator while ROS are thought to play a role in the proximal tubular injury.
These agents have a very high osmolality (>1200 mOsm/L) and are potentially nephrotoxic,
particularly in patients with existing renal impairment, diabetes, or heart failure or who are
receiving other nephrotoxic drugs.