DRUGS AND TOXINS ASSOCIATED WITH KIDNEY

S.SOUNDARI I M.SC. BIOCHEMISTRY

DEDICATED TO

LATE Mr.RAVIKUMAR RAJENDRAN Ph.D

DRUGS AND TOXINS ASSOCIATED WITH KIDNEY

• INTRODUCTION: Kidney, an excretory organ which plays a

major role in homeostasis of the body. • By excreting water and electrolytes through

urine, kidney plays a major role in homeostatsis.

STRUCTURE OF KIDNEY

Kidneys are pair of excretory organ situated on the posterior abdominal wall behind the peritoneum.

Each kidney is a bean shaped and is surrounded by a fibrous fatty and a fascial capsule.

It has an outer cortex, inner medulla and renal sinus.

STRUCTURE OF KIDNEY

NEPHRON It is the structural and functional unit of kidney.Each kidney has 1 to 1.3 billion nephrons.It has 2 parts: renal corpuscle and renal tubule.Renal corpuscle consist of glomerulus and

bowman’s capsule.Renal tubule consist of proximal convoulted

tubule, loop of henle and distal convoultd tubule.

PARTS OF A NEPHRON

KIDNEY SYNDROME CAUSED BY THERAPEUTIC AGENTS

S.NO CLINICAL SYNDROME CAUSATIVE AGENTS

1. ACUTE RENAL FAILURE

Prerenal/ heomodynamic Cyclosporine, tarcolimus, ACE inhibitors, amphotericin B, NSAIDs

intrarenal

i. Acute tubular necrosis Aminoglycosides, amphotericin B, cisplatin, certain cephalosporins

ii. Acute interstitial nephritis Penicillin, cephalosporins, sulfonamides, rifampin, NSAIDs, interferon.

Postrenal/obstructive Acyclovir, methotrexate, indinavir, sulfadiazine.

2. CHRONIC KIDNEY DISEASE Lithium, cyclosporine, analgesic abuse, cisplatin.

3. NEPHROTIC SYNDROME Gold, NSAIDs, interferon, captopril, pencillamine

ACUTE RENAL FAILUREARF is a “sudden reduction in the Glomerular

Filtration Rate(GRF) that is expressed clinically as the retention of nitrogenous waste products (urea, creatinine) in the blood”.

The accumulation of these waste products is termed as azotemia.

ACUTE RENAL FAILURE

ARF is also clinically described as

Anuria – no urine output or less than 100ml/ 24 hours

Oliguria - <400ml urine output/ 24 hours Polyuria/ Non oliguria - >400ml urine output / 24

hours.Anuria is uncommon and suggests either

complete obstruction or a major vascular event such as renal infraction, high grade ischemic acute tubular necrosis (ATN).

Non oliguric ARF is common in intra renal ARF.

Oliguric more commonly characterizes obstruction and pre-renal azotemia.

PRE-RENAL ACUTE FAILURE• Pre-renal abnormalities are the physiologic

response that leads to decreased kidney function (i.e. GFR).

• Elevated blood urea nitrogen (BUN) & creatinine due decreased perfusion of the kidney. Decreased perfusion of kidney which may be due to ↓se

Consequence of inadequate volume bloodInadequate cardiac output due to impaired MIMarked vasodilation as may occur with

sepsis(severe infection).

INTRARENAL OR INTRINSIC ACUTE RENAL FAILURE

• Intrinsic ARF can be categorized anatomically by the area of the kidney parenchyma involved: vascular, glomerular, tubular or intersititial areas.

• The decrement in GRF is directly proportional to the kidney damage.

Acute tubular necrosis (ATN) is the death of tubular cells, which may result when tubular cells do not get enough oxygen (ischemic ATN) or when they have been exposed to a toxic drug.

CAUSES• Hypotension • Obstetric (birth-related) complications• Obstructive jaundice • Sepsis (infection in the blood or tissues)• Surgery Use of drugs such as Aminoglycosides, Amphotericin B, Cisplatin, Radioisotopes.

ACUTE INTERSTITIAL NEPHRITIS• The interstitium is the tissue that surrounds and imbeds the

glomeruli and tubules within the kidneys. • AIN is rapidly developing inflammation that occurs within

the interstitium which results in reduced GFR and renal flow.CAUSES Mainly due to antibiotics and NSAIDs such as Ibuprofen, Cephatholin, Cimetidine Cyclosporine, Methicillin, Penicillins.

POST RENAL ACUTE RENAL FAILURE

Post renal ARF is caused by an acute obstruction that affects the normal flow of urine out of both kidneys. The blockage causes pressure to build in all of the renal nephrons.

The excessive fluid pressure ultimately causes the nephrons to shut down.

The degree of renal failure corresponds directly with the degree of obstruction.

CAUSES

Drugs that cause Post renal ARF areAcyclovir, Methotrexate,Indinavir, Sulfadiazine.

CLASSIFICATION OF ARF

CHRONIC KIDNEY DISEASE

• Chronic renal failure (CRF) or kidney failure is the progressive loss of kidney function.

• CKD caused by drugs is usually manifested tubulointerstitial injury.

• The kidneys attempt to compensate for renal damage by hyperfiltration (excessive straining of the blood) within the remaining functional nephrons. Over time, hyperfiltration causes further loss of function.

CAUSES

DiabetesHigh blood pressure Drugs such as CyclosporineAnalgesic abuseCisplatinNitrosureas

NEPHROTIC SYNDROME

Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema.

Nephrotic-range proteinuria is 3 grams per day or more.

It is usually caused due to damage of cluster of small blood vessels in the kidney.

CAUSES• There are many specific causes of nephrotic syndrome.

These include kidney diseases such as minimal-change nephropathy, and membranous nephropathy.

• Nephrotic syndrome can also result from systemic diseases that affect other organs in addition to the kidneys, such as diabetes, amyloidosis, and lupus erythematosus.

• Infection is a major concern in nephrotic syndrome; patients have an increased susceptibility to infection with Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and other gram-negative organisms.

EFFECT OF DRUGS ON KIDNEY

NSAIDS

• NSAIDs are non-steroidal anti-inflammatory drugs, also known as NAIDs, non-steroidal anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal anti-inflammatory medicines (NSAIMs).

• They are medications with analgesic (pain reducing), antipyretic (fever reducing) effects. In higher doses they also have anti-inflammatory effects - they reduce inflammation (swelling).

NSAIDS DRUGS

The most common NSAIDs are Aspirin IbuprofenNaproxen DiclofenacMelaoxicam

RENAL ADVERSE REACTION REPORTS

ACTION OF NSAIDS

• Prostaglandins - These are hormone-like substances that participate in a wide range of body functions, one of which causes pain and inflammation.

• NSAIDs prevent the COX enzymes from releasing the prostaglandin chemicals responsible for inflammation and pain.

• COX-2 enzymes cause inflammation and pain in the body. NSAID medications were created that inhibited the COX-2 enzyme.

SIDE EFECTSCardiovascular system Blood pressure may rise with use of NSAIDs. Control

of treated hypertension may be adversely affected by the addition of either selective or nonselective NSAIDs.

Gastrointestinal system Short-term use of NSAIDs can cause stomach upset

(dyspepsia). Long-term use of NSAIDs, especially at high doses, can lead to peptic ulcer disease and bleeding from the stomach.

Liver toxicity Long-term use of NSAIDs, especially at high doses,

can rarely harm the liver. Monitoring the liver function with blood tests may be recommended in some cases.

SIDE EFFECTS

Kidney toxicity Use of NSAIDs, even for a short period

of time, can harm the kidneys. This is especially true in people with underlying kidney disease. The blood pressure and kidney function should be monitored at least once per year but may need to be checked more often, depending on a person’s medical conditions.

EFFECT ON KIDNEY

• All non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with the development of acute kidney injury.

• NSAIDs and Acute Kidney Injury • NSAIDs can cause two different forms of acute

kidney injury.• Haemodynamically mediated (eg, pre-renal injury

and/or acute tubular necrosis). • Immune mediated (eg, acute interstitial nephritis).

NSAID INDUCED ARF• NSAIDs reversibly inhibit the production of renal

prostaglandins via their inhibition of COX-1 and COX-2. Maximal inhibition occurs at steady state plasma concentrations (usually 3–7 days).

• Renal prostaglandins cause dilatation of the renal afferent arteriole. This mechanism is important for maintaining GFR when renal blood flow is reduced (ie, not in young, healthy people).

• Therefore, NSAID use is likely to have a greater effect on renal function in patients with other risk factors.

• It is unclear how NSAIDs induce acute interstitial nephritis.

AMPHOTERICIN B

Amphotericin B is an antifungal drug often used intravenously for systemic fungal infections.

It is the only effective treatment for some fungal infections.

DRUGS The common amphotericin b drugs areo Fungilino Fungizoneo Abelceto AmBisomeo Fungisomeo Amphocilo Amphotec

AMPHOTERICIN B

SIDE EFFECTS

Common side effects may include: a reaction which may include feverheadaches and low blood pressure kidney problemsAllergic symptoms including anaphylaxis may

occur.

EFFECT ON KIDNEY

This drug causes disturbances in both glomerular and tubular function.

The drug binds to the membrane sterol in the renal epithelial cells and altering its membrane permeability.

This also causes enhanced cell death, calcium channel blockage, etc.

AMINOGLYCOSIDES

• Aminoglycosides have long been important in the treatment of serious gram negative infections.

• They have bactericidal activity against most gram negative bacteria including Acinetobacter, Enterobacter, Escherichia coli, Klebsiella, Proteus and Shigella.

• They also act synergistically against gram positive organisms such as Staphylococcus aureus and Staphylococcus epidermidis.

EFFECT ON KIDNEY

The drug after entering the luminal fluid of proximal convoluted tubule, a small but toxicologically important portion of the drug is resorbed and stored in the cells.

This reacts with the negatively charged phospoholipids binding site in the brush border.

This forms apical cytoplasmic vesicles called endocytotic vesicles, which fuses with the lysosomes.

EFFECT ON KIDNEY

The overall result is the accumulation of polar phospholipids as “myleiod bodies”.

This leads to damage of cell organelle and finally leads to cell death.

ACE INHIBITORS• An angiotensin-converting-enzyme inhibitor (ACE

inhibitor) is a pharmaceutical drug used primarily for the treatment of hypertension (elevated blood pressure) and congestive heart failure.

• This group of drugs cause relaxation of blood vessels, as well as a decreased blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

• They inhibit the angiotensin-converting enzyme, an important component of the renin-angiotensin-aldosterone system.

ACE INHIBITORS DRUGS

Frequently prescribed ACE inhibitors include

PerindoprilCaptoprilEnalapril Lisinopril Ramipril.

SIDE EFFECTS

HypotensionCoughHyperkalemiaHeadacheDizzinessFatigueNauseaRenal impairment.

ACTION OF ACE INHIBITORS

• Angiotensin II is a very potent chemical produced by the body that primarily circulates in the blood. It causes the muscles surrounding blood vessels to contract, thereby narrowing vessels.

• The narrowing of the vessels increases the pressure within the vessels causing increases in blood pressure (hypertension).

• Angiotensin II is formed from angiotensin I in the blood by the enzyme angiotensin converting enzyme (ACE). (Angiotensin I in the blood is itself formed from angiotensinogen, a protein produced by the liver and released into the body.)

• ACE inhibitors block ACE enzyme thereby decrease the normal GFR rate.

EFFECT ON KIDNEY

Inhibition of ACE kinase –II results in atleast two important effects:

a. Depletion of angiotensin IIb. Accumulation of bradykinin

LITHIUM MEDIATED acute RENAL FAILURE

Lithium is currently a drug of choice for treating persons with bipolar depression and is widely used in this population.

• Lithium is completely absorbed by the GI tract. The drug is not protein bound and is completely filtered at the glomerulus. The majority of the filtered load is reabsorbed by the proximal tubule, but significant amounts are also absorbed in the loop of Henle and the early distal nephron.

SIDE EFFECTS• Confusion, poor memory, or lack of awareness• Fainting• Fast or slow heartbeat• Frequent urination• Increased thirst• Irregular pulse• Stiffness of the arms or legs• Troubled breathing (especially during hard work or

exercise)• Unusual tiredness or weakness

EFFECT ON KIDNEY

Lithium can affect renal function in several ways.

Acutely and chronically, lithium salts produce a natriuresis that is associated with an impaired regulation of the expression of the epithelial sodium channel in the cortical collecting tubule.

The most common complication of chronic lithium therapy is nephrogenic diabetes insipidus.

PREVENTION

• Limiting accessibility to highly toxic substances.

• Avoid culprit drugs• Educate those prescribing and taking

medication about its side effects.

CONCLUSION

“ PREVENTION IS BETTER THAN CURE”. Therefore one should take care of their health in order to lead a health and a contended life.

REFERENCE

Arthur Greenberg, Alfred K. Cheung-Primer on kidney disease.

WikipediaMarc E. De Broe - Acute renal failure

THANK YOU