all type of xenobiotic that affect the kidney

1. Xenobiotic effect on
the kidney
Maysam nameer
Higher diploma in pharmacology and toxicology
Supervised by
Dr. Ammar ali hussein
Baghdad university college of pharmacy

2. overview
urine is the principal route by which most toxicants are excreted
the kidney has a high volume of blood flow, concentrates toxicants in the
filtrate, transports toxicants across the tubular cells, and bioactivates or
detoxifies certain toxicants. It is therefore a major target organ for adverse
effects.
The predominant structures in the kidney are the nephrons, Each nephron
consists of a glomerulus and a series of tubules . The glomerulus is supplied
with a high-pressure capillary system that produces an ultrafiltrate from the
plasma. The filtrate collected in the Bowman’s capsule flows through the
proximal convoluted tubule, the loop of Henle, and the distal convoluted
tubule, and then drains through a collecting tubule into the renal pelvis for
excretion as urine.

3. The major function of the kidney is to eliminate wastes resulting
from normal metabolism and to excrete xenobiotics and their
metabolites. These functions occur through the
production of urine, a process that also contributes to the
maintenance of the homeostatic status of the body. In addition, it has
several non excretory functions.

4. Anatomy
Each kidney contains approximately 1 million similar functional units called
nephrons. Each nephron consists of :
(1) an initial filtering component called the renal corpuscle and (2) a tubule
that extends from the renal corpuscle .
The renal tubule is a very narrow, fluid-filled cylinder made up of a single
layer of epithelial cells resting on a basement membrane. The epithelial cells
differ in structure and function along the length of the tubule, and at least
eight distinct segments are now recognized .
This filtrate then leaves the renal corpuscle and enters the tubule. As it flows
through the tubule, substances are added to or removed from it. Ultimately,
the fluid remaining at the end of each nephron combines in the collecting
ducts and exits the kidneys as urine.

7. Glomeruli
*puromycin
* the aminoglycoside antibiotics, (decrease the glomerular filtration)
* gold, mercury, and penicillamine, (glomerulonephritis )

8. Proximal Tubules
* Heavy metals, such as mercury, chromium, cadmium,and lead
*Various aminoglycoside antibiotics
*Chloroform
*Cisplatin

9. *Analgesic mixtures containing aspirin and phenacetin, a derivative of
acetaminophen, produce chronic renal failure .The effects might be a result of
vasoconstriction due to an inhibition of the synthesis of vasodilator
prostaglandin .
*Penicillins and sulfonamides were reported to produce inflammatory
interstitial nephritis .
*High concentrations of calcium may lead to calcification in the kidney and
subsequent renal failure

10. Reasons for the Susceptibility of the
Kidney to Toxicity
1-The unusual susceptibility of the mammalian kidney to the toxic effects of noxious
chemicals can be attributed in part to the unique physiologic and anatomic features of this
organ.
2-Although the kidneys constitute only 0.5% of total body mass, they receive about 20–
25% of the resting cardiac output. Consequently, any drug or chemical in the systemic
circulation will be delivered to these organs in relatively high amounts.
3-The processes involved in forming concentrated urine also serve to concentrate potential
toxicants in the tubular fluid.
4-As water and electrolytes are reabsorbed from the glomerular filtrate, chemicals in the
tubular fluid may be concentrated, thereby driving passive diffusion of toxicants into
tubular cells. Therefore, a nontoxic concentration of a chemical in the plasma may reach
toxic concentrațions in the kidney. Progressive concentration may result in intraluminal
precipitation of relatively insoluble compounds, causing Acute renal failure secondary
tubular obstruction.

11. 5- renal transport, accumulation, and metabolism of
xenobiotic contribute significantly to the susceptibility of the kidney
(and specific nephron segments) to toxic injury.
6-In addition to intrarenal factors, the incidence and/or severity of
chemically induced nephrotoxicity may be related to the sensitivity
of the kidney to circulating vasoactive substances. Under these
conditions, vasoconstrictors such as angiotensin II or vasopressin are
increased.

12. NEPHROTOXICANTS: SITE OF ACTION
the proximal tubule is the primary target for most nephrotoxic antibiotics,
antineoplastics , halogenated hydrocarbons , and heavy metals
whereas the glomerulus is the primary site for immune complexes,
the loop of Henle/collecting ducts for fluoride ions, and the medulla/papilla
for chronically consumed analgesic mixtures.
The reasons underlying this site-selective injury are complex but can be
attributed in part to site-specific differences in blood flow, transport, and
accumulation of chemicals, physicochemical properties of the epithelium,
reactivity of cellular/molecular targets, balance of bioactivation
/detoxification reactions, cellular energetics, and/ or regenerative/repair
mechanisms.

14. SPECIFIC NEPHROTOXICANTS
Heavy Metals
Mercury its high affinity for sulfhydryl groups, virtually all of the Hg+
found in blood is bound to cells-albumin, other sulfhydryl-containing
proteins, glutathione, and cysteine.
oRenal uptake of Hg²+ is very rapid with as much as 50% of a nontoxic
dose of Hg²+ found in the kidneys within a few hours of exposure.
oThe acute nephrotoxicity induced by HgCl , is characterized by
proximal tubular necrosis and Acute Kidney Injury within 24 to 48
hours after administration.
ooxidative stress and dysregulation of Ca2+ homeostasis plays an
important role in HgCl ,-induced renal injury.

15. Cadmium Chronic exposure of nonsmoking humans and to
cadmium is primarily through food , in the workplace, inhalation
of cadmium-containing dust and fumes is the major route of exposure.
Cadmium has a half-life of greater than 10 years in humans
and thus accumulates in the body over time.
Approximately 50% of the body burden of cadmium can be found in
the kidney and nephrotoxicity can be observed when cadmium
concentrations exceed 50 µg/g kidney wet weight .
Cadmium produces proximal tubule dysfunction (S, and S, segments)
and injury
This may progress to a chronic interstitial nephritis.

16. Therapeutic Agents
Nonsteroidal Anti-Inflammatory Drugs NSAIDS
• three different types of nephrotoxicity have been associated with NSAID
administration .
• Acute kidney injury may occur within hours of a large dose of an NSAID, is
usually reversible, and is characterized by decreased renal blood flow and
GFR and by oliguria. When the prostaglandins is inhibited by NSAIDS,
vasoconstriction induced by circulating catecholamines and angiotensin II is
lead to ischemia.
• A number of risk factors (e.g., renal insufficiency, congestive heart failure,
hepatic cirrhosis, hemorrhage, hypertension, sepsis, and diabetes) are
known to facilitate the development of AKI after NSAIDS consumption.
• chronic consumption of combinations of NSAIDS (more than 3 years)
results in an often irreversible form of nephrotoxicity known as analgesic
nephropathy .

17. The third type of nephrotoxicity
associated with NSAIDS is an interstitial
nephritis with a mean time of NSAID
exposure to development of
approximately 5 months.
This nephrotoxicity is characterized by a
diffuse interstitial edema with mild-to-
moderate infiltration of inflammatory
cells.

18. Aminoglycosides
• affect the proximal tubular cells.. They exert their main toxic effect
within the tubular cell by altering phospholipid metabolism . also
cause renal vasoconstriction.
• The 2 critical factors in the development of acute kidney injury (AKI)
secondary to aminoglycoside nephrotoxicity are dosing and duration
of therapy.
• the lysosomes become progressively distended until they rupture,
releasing lysosomal enzymes and high concentrations of
aminoglycosides into the cytoplasm.
• Another mechanism is decrease glomerular filtration rate

19. calcineurin inhibitor (CNI)
Cyclosporine
Is an important immunosuppressive drug and is widely used to prevent
graft rejection in organ Transplantation..
calcineurin inhibitor (CNI)-induced nephrotoxicity may manifest as
(1) acute reversible renal dysfunction,(acute kidney injury)
(2) acute vasculopathy
(3) persistent injury lead to interstitial fibrosis.
These effects are decrease by reducing the dosage or by cessation of
therapy
Long-term treatment with cyclosporine can result in chronic nephropathy
& tubular atrophy.

20. Cisplatin
Cisplatin is a valuable drug in the treatment of solid tumors, with
nephrotoxicity limiting its clinical use.
usually affects the proximal tubules primarily, with some secondary
effect on the glomeruli and distal tubules. Cisplatin is excreted primarily
in the urine, resulting in concentrated drug levels, which encourage
uptake into the cells by passive diffusion or active uptake
The nephrotoxicity of cisplatin canbe grouped as
(1) tubular toxicity, (2) vascular damage,
(3) glomerularinjury, and (4) interstitial injury.

21. Radiocontrast Agents
The nephrotoxicity of these agents is due to both hemodynamic alterations
(vasoconstriction) and proximal tubular injury.
Iodinated contrast media are used for the imaging of tissues,
with two major classes of compounds
1/The ionic compounds, diatrizoate derivatives, potentially nephrotoxic,
particularly in patients with existing renal impairment, diabetes, or heart failure or
who are receiving other nephrotoxic drugs
2/The newer agents (e.g., iotrol and iopamidol) are nonionic, with lower osmolality,
and less nephrotoxicity.
Some non-therapeutic xenobiotics may be potentially toxic
in patients with kidney impairment while being relatively benign in patients with
normal GFR. This is the case for
gadolinium-based contrast used for magnetic resonance imaging, which carries the
risk of nephrogenic systemic fibrosis

22. refers to the breakdown of skeletal muscle fibers, which leads to the
release of potentially nephrotoxic intracellular contents into the
circulation.
Acute kidney injury (AKI) develops in this setting via the following 3
mechanisms:
• Renal vasoconstriction
• Heme-mediated proximal tubular cell toxicity
• Intra-tubular cast formation
Rhabdomyolysis

24. common nephrotoxicants , and mechanisms
of injury.
• Thrombotic microangiopathy / Calcineurin inihibitors ,
Clopidogrel Cocaine, Mitomycin, Quinine .
• Hemodynamic alteration / ACE - L , ARB , Amphotericin B ,
Calcineurin inhibitors , Diuretics , NSAIDs , Radiocontrast agents.
• Distal tubule injury / Amphotericin B , Calcineurin inhibitors ,
Lithium , Sulfadiazine

25. common nephrotoxicants , and mechanisms
of injury.
• Proximal tubule injury / Acylovir ,Aminoglycosides ,Cadmium ,
Cidofovir , Cisplatin, lead , Mercuric chloride.
• Interstitial nephritis/ Allopurinol , Aristolochic acid ,
Cephalosperins ,Ciprofloxacin, Diuretics, Macrolides NSAIDs ,
Pencillins , Phenytoin
• Tubular obstruction / Acylovir , Indinavir , Methotrexate
,Sulfonamides

26. Reference:
• Casarett and Doull’s TOXICOLOGY
The Basic Science of Poisons/9 th edition.
• Vanders human physiology/ fifteenth edition .