Author Archives: Alila Medical Media

Antibiotics – Mechanisms of Action, with Animation

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Antibiotics are medications used to fight bacterial infections. Originally, the term “antibiotics” referred to natural compounds produced by certain microorganisms for the purpose of fending off others; for example, penicillin is produced by the fungus Penicillium. Nowadays, this term includes all antibacterial products, most of which are semi-synthetic, meaning they are modifications of natural products. Antibiotics are just one type of antimicrobials. They target bacteria, and are usually not effective against other types of organisms. Antibiotics cannot treat viral infections such as common cold or flu.
Antibiotics can be bactericidal, meaning they destroy bacterial cells; or bacteriostatic, meaning they inhibit bacterial growth.
Some antibiotics are broad-spectrum – they are effective against a wide range of bacteria, including both Gram-positive and Gram-negative; while others are narrow-spectrum – they are more specific, affecting a smaller group of bacteria.
Antibiotics can be classified by their mechanisms of action:
– Inhibitors of cell wall synthesis. Bacterial cells are surrounded by cell walls made of peptidoglycan. Antibiotics that affect bacterial cell wall act at different stages of peptidoglycan synthesis and cell wall assembly. Because mammalian cells do not have cell walls, this class of antibiotics is highly selective – they target bacteria and have minimal effects on mammalian host cells.
– Disruptors of cell membrane. Some antibiotics disrupt the integrity of cell membrane by binding to membrane phospholipids. Because cell membrane is also found in mammalian cells, these antibiotics are also toxic to host cells if administered systemically. Their clinical use is therefore limited to topical applications.
– Inhibitors of protein synthesis. Antibiotics that interfere with bacterial protein synthesis may act at different steps of this process, including: formation of the 30S initiation complex, assembly of the 50S ribosome subunit, formation of the 70S ribosome from the 30S and 50S complexes, and elongation process. Some of these antibiotics also inhibit the eukaryotic mammalian counterparts, but their effect on bacterial ribosomes is significantly greater.
– Inhibitors of nucleic acid synthesis. Some antibiotics interfere with DNA synthesis by binding to bacterial topoisomerase II – the enzyme that relaxes the supercoil DNA before its replication. Some others interfere with RNA synthesis by inhibiting RNA polymerase. Some antibiotics of this class are selective – they do not interact with mammalian counterparts of these enzymes, while others do affect mammalian host cells. The latter are used for cancer treatment instead. Because cancer cells grow faster than normal cells, they are more affected by the action of these agents.
– Inhibitors of folic acid synthesis. Bacteria synthesize their own folic acid, unlike humans who get the vitamin from food. Because of this, antibiotics that inhibit enzymes involved in folic acid synthesis only harm bacterial cells, and not human cells.

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How Vaccines Work, Herd Immunity, Types of Vaccines, with Animation

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Vaccines prepare the immune system, getting it ready to fight disease-causing organisms, called pathogens. To understand how vaccines work, we must first learn how our immune system responds to invading pathogens.
When a new pathogen enters the body, it meets with the body’s first-line defense, the innate division of the immune system. The innate response is immediate, but non-specific, meaning it destroys all foreign invaders without discrimination. Fever is one of the signs that the body is fighting the disease at this stage. If this fails to contain the infection, the adaptive immune system comes into play. The adaptive response is more effective, but it may take many days to activate, during which time the person is being sick. The adaptive response produces the so-called antibodies, which specifically bind to a component on the surface of the pathogen, labeling it for destruction. This component is called an antigen and is the one that has triggered the production of antibodies against it.
Remarkably, the adaptive response also leaves the body with a “memory” of the pathogen, so it can react faster the next time the same pathogen attacks. In fact, pathogen-specific antibodies are produced so fast upon reexposure to the pathogen, that no signs of illness are visible. This is called immunity, and it explains why most people get diseases such as chickenpox only once, even though they may be exposed multiple times in their lifetime.
A vaccine is basically an altered form of a pathogen, or part of it that acts like an antigen. It is introduced to the body to trigger production of antibodies, mimicking the first infection, but without causing the illness. The immune system now has the antibodies, and is ready for a fast response whenever it is exposed to the real pathogen.
When enough people in a community are vaccinated, the whole community, including the individuals that were not vaccinated, is protected against the disease. This phenomenon is known as herd immunity. Herd immunity is possible because a pathogen cannot spread without a sufficient number of vulnerable hosts. An analogy is the spread of wildfires. A wildfire only spreads where there is vegetation, or fuel, for it to burn; it would stop at a river, or a large open space. These are called firebreaks. Vaccinated individuals essentially serve as firebreaks, preventing spread of infections caused by pathogens. Herd immunity is important because not everyone can be vaccinated. Often, the very young, very old, and immunocompromised people must rely on vaccinated individuals to stop disease outbreaks. To note, however, that the number of vaccinated individuals must be great enough for community protection to occur, just like a firebreak must be large enough to stop a fire.
There are several types of vaccines:
– Live, attenuated vaccines are live pathogens that have been weakened so they don’t cause disease in people with healthy immune systems. Being the closest thing to a natural infection, they are most effective and can provide life-long immunity with a single dose. However, weakened pathogens can still be strong enough to cause illness in people with compromised immune systems, and therefore cannot be used for this group of people.
– Inactivated vaccines are pathogens that have been completely inactivated by heat or chemicals. They are safer than attenuated vaccines but less effective, and multiple doses may be required to achieve and maintain immunity.
– Subunit vaccines use only part of a pathogen, usually a peptide. These vaccines are very safe as they cannot cause disease, but to make such a vaccine, scientists must first identify the part of the pathogen that can elicit a good immune response, and this can be a difficult task.
– Toxoid vaccines: Some bacteria cause illness by releasing toxins. These toxins are inactivated and used as vaccines. Inactivated toxins do not cause disease, but can induce production of antibodies against the natural toxins.
– Conjugate vaccines: Some bacteria have a protective coat that helps them evade the immune system. This is because the coat is a weak antigen, it does not provoke a strong production of antibodies. Vaccines based on weak antigens will not protect the person effectively. To overcome this problem, the weak antigen is combined with a strong antigen from another source as a carrier, in a conjugate vaccine, to boost the immune response.

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Long QT Syndrome and Torsades de Pointes, with Animation

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Long QT syndrome, LQTS, is a condition that affects the heart’s electrical activities. LQTS is largely a genetic disorder: children inherit mutations from their parents that either cause the disease since birth, or make them more susceptible to develop it later in life when triggered by certain medications or metabolic imbalances.

LQTS itself is not the problem, many people with the syndrome don’t have any symptoms and may not even be aware of it. However, it predisposes the patient to a life-threatening type of abnormal heart rhythm, known as torsades de pointes, which may lead to fainting, seizures, or sudden cardiac arrest. This complication is usually triggered when heart rate accelerates by adrenergic stimulation, such as during exercise, stress or strong emotions. LQTS can cause sudden death in seemingly healthy young people.

On an electrocardiogram that records electrical activities of the heart, P wave represents atrial depolarization, QRS complex is produced by ventricular depolarization, and T wave corresponds to ventricular repolarization. The QT interval, measured from the start of Q wave to the end of T wave, reflects the time taken for ventricular depolarization and repolarization, which is basically the duration of action potentials in the cells of the ventricles.

An action potential is essentially a brief reversal of electric polarity of the cell membrane. It is made possible by the flow of ions in and out of the cell, through specific ion channels. Basically, the depolarizing phase is caused by sodium influx; early re-polarization is due to initial outflow of potassium; plateau phase occurs when potassium efflux is balanced by calcium influx, and repolarization is when potassium efflux dominates calcium influx. The duration of repolarization is determined by the balance of current flow through these ion channels.

The rate of repolarization is slightly different for the 3 layers of the heart wall: the epicardium, mid-myocardium or M-cells, and endocardium. Because M-cells have less potassium channels and more sodium channels, they repolarize more slowly. On an ECG, the peak of T wave reflects repolarization of epicardial cells, while the end of T wave corresponds with repolarization of M-cells.

Long QT syndrome is due to prolongation of underlying action potential durations, and is most commonly caused by mutations in various ion channels that affect the balance of ion flow. Specifically, a reduced outward current caused by loss of function of potassium channels, or an increased inward current caused by gain of function of sodium or calcium channels, would increase the duration of repolarization. If inward currents exceed outward currents during the plateau phase, early after-de-polarizations and consequently extra heartbeats can be triggered. Mutations in ion channels also disproportionately lengthen action potentials in M-cells, increasing the difference in refractoriness of the different layers.  This can cause electrical impulses to travel around in loops, known as re-entrant pathways, producing the characteristic wave pattern of torsades de pointes.

For diagnosis, patient’s QT interval is measured. But because QT interval varies with heart rate, a corrected QT interval, QTc, is calculated after measurement. Diagnosis, however, cannot rely on QTc values alone.  Asymptomatic patients can have longer than normal QTc and develop no arrhythmias, while patients with established long QT syndrome may have normal QT intervals at rest. Diagnosis must therefore also include genetic testing, personal history of fainting, and family history of sudden death.

Treatment aims to prevent a long QT heart from developing dangerous arrhythmias. Most patients are treated with beta-blockers, which blunt the heart’s response to adrenaline produced during exercise and stress, making the heart beat slower, thus reducing the risks for torsades de pointes. Medications that shorten QT interval may also be prescribed. On the other hand, medications that prolong QT interval or precipitate development of torsades de pointes must be avoided. Patients are also advised to seek immediate treatments for conditions that may result in low potassium in the blood.

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Understanding the Virus that Causes COVID-19, with Animation

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Coronaviruses are a large family of enveloped, RNA viruses. There are 4 groups of coronaviruses: alpha and beta, originated from bats and rodents; and gamma and delta, originated from avian species. Coronaviruses are responsible for a wide range of diseases in many animals, including livestock and pets. In humans, they were thought to cause mild, self-limiting respiratory infections until 2002, when a beta-coronavirus crossed species barriers from bats to a mammalian host, before jumping to humans, causing the Severe Acute Respiratory Syndrome, SARS, epidemic. More recently, another beta-coronavirus is responsible for the serious Middle East Respiratory Syndrome, MERS, started in 2012. The novel coronavirus responsible for the Coronavirus Disease 2019 pandemic, COVID-19, is also a beta-coronavirus. The genome of the virus is fully sequenced and appears to be most similar to a strain in bats, suggesting that it also originated from bats. The virus is also very similar to the SARS-coronavirus and is therefore named SARS-coronavirus 2, SARS-CoV 2. At the moment, it’s not yet clear if the virus jumped directly from bats to humans, or if there is a mammalian intermediate host.

Coronavirus genome is a large, single-stranded, positive-sense RNA molecule that contains all information necessary for the making of viral components. The RNA is coated with structural proteins, forming a complex known as nucleocapsid. The nucleocapsid is enclosed in an envelope, which is basically a LIPID membrane with embedded proteins. From the envelope, club-like spikes emanate, giving the appearance of a crown. This is where the “corona” name came from.

The integrity of the envelope is essential for viral infection, and is the Achilles’ heel of the virus, because the lipid membrane can easily be destroyed by lipid solvents such as detergents, alcohol and some disinfectants. In fact, enveloped viruses are the easiest to inactivate when they are outside a host.

In order to infect a host cell, the spikes of the virus must BIND to a molecule on the cell surface, called a receptor. The specificity of this binding explains why viruses are usually species specific – they have receptors in certain species, and not others. Host jumping is usually triggered by mutations in spike proteins which change them in a way that they now can bind to a receptor in a new species.

The novel coronavirus appears to use the same receptor as SARS-coronavirus for entry to human cells, and that receptor is the angiotensin-converting enzyme 2, ACE2. Infection usually starts with cells of the respiratory mucosa, then spreads to epithelial cells of alveoli in the lungs.

Receptor binding is followed by fusion of the viral membrane with host cell membrane, and the release of nucleocapsid into the cell. The virus then uses the host machinery to replicate, producing viral RNAs and proteins. These are then assembled into new viral particles, called virions, by budding into intracellular membranes. The new virions are released and the host cell dies.

Uncontrolled growth of the virus destroys respiratory tissues, producing symptoms. Infection triggers the body’s inflammatory response, which brings immune cells to the site to fight the virus. While inflammation is an important defense mechanism, it may become excessive and cause damage to the body’s own tissues, contributing to the severity of the disease. In an otherwise healthy person, there is a good chance that the virus is eventually eliminated and the patient recovers, although some may require supportive treatments. On the other hand, people with weakened immune system or underlying chronic diseases may progress to severe pneumonia or acute respiratory distress syndrome, which can be fatal.

 

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Angina: Stable, Unstable, Microvascular and Prinzmetal, with Animation

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Angina pectoris, or simply angina, refers to chest pain or discomfort caused by reduced blood flow to the heart, in a condition known as myocardial ischemia. Angina is described as a squeezing pain or heaviness in the chest, which may also spread to the neck, arms, shoulders and back; or in the stomach area, particularly after meals. Women are more likely to experience a burning sensation or tenderness instead of squeezing pain. Angina is not the same as heart attack. It is associated with transient ischemia of the heart without permanent damage, while heart attack is when a patch of the heart muscle dies from lack of oxygen. But having angina significantly increases the risks for heart attacks, especially when left untreated.
Angina is most commonly caused by the narrowing of one or more coronary arteries that supply the heart. This can result from a fixed obstruction by cholesterol plaques, or a temporary constriction due to blood vessel spasms. Angina can also be caused by anemia, when the flow is adequate, but the blood does not have enough red blood cells to carry oxygen.
There are several types of angina.
Stable angina, the most common form, is usually caused by a fixed obstruction, a plaque. Stable angina is predictable, with familiar pain patterns, and typically prompted by physical exertion, when the heart requires more oxygen than it can get from narrowed vessels. Factors that constrict blood vessels or increase blood pressure, such as emotional stress, cold temperatures or heavy meals, may also induce angina. Stable angina does not happen at rest, when the reduced flow is sufficient for the low demand of the heart. It usually subsides when the inducer is removed and responds well to medications.
Unstable angina, on the other hand, may occur unexpectedly, even at rest, with a changed pattern from the usual stable angina. It is more severe, lasts longer, does not respond to rest or medications, and is often the sign that a plaque has ruptured or a clot has formed. Unstable angina is a medical emergency as it often precedes a heart attack.
Electrocardiograms of patients with obstructive angina commonly show ST-segment depression during attacks. Diagnosis is confirmed with stress test, where patients are monitored while exercising. The site of obstruction can be detected with imaging techniques, such as angiography.
It appears, however, that a significant number of patients with stable angina symptoms have more or less normal coronary arteries on angiograms. These cases are now recognized as microvascular angina (Cardiac syndrome X), where the problem lies not in the large coronary arteries, but their tiny branches, and is therefore undetectable by angiography. Microvascular angina is much more common in women than in men.
Variant angina (Prinzmetal angina), a less common type, is caused by vascular spasms of coronary arteries. Variant angina can occur during rest, usually at certain times of the day, often at night. Emotional stress, smoking and use of cocaine are known triggers. Variant angina is often severe, but responds well to medications. Diagnosis is by presence of ST-segment elevation during attacks, and provocative testing with drugs that induce coronary artery spasms (ergonovine, acetylcholine).
Treatment of angina aims to relieve symptoms, reduce frequency of future anginas, but most importantly, reduce risks of heart attacks. Apart from lifestyle changes to modify risk factors, treatment options include a number of medications and surgical procedures.
Nitroglycerin, a potent vasodilator, is most effective for acute anginal attacks. Long-lasting nitrates, antiplatelet drugs (aspirin…), beta-blockers, and calcium channel blockers can be prescribed to prevent future anginas.
Several revascularization procedures are available to restore normal blood supply to the heart. Coronary angioplasty makes use of a balloon, and sometimes a stent, to widen the affected artery. Coronary bypass uses a graft to create an alternative route for blood to flow beyond the site of blockage.

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Renal Replacement Therapy: Hemodialysis vs Peritoneal Dialysis, with Animation

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Dialysis is a therapy that artificially removes wastes from the blood of patients whose kidneys can no longer perform this function adequately. There are two main types of dialysis: hemodialysis and peritoneal dialysis.
In hemodialysis, blood is filtered outside the body, in a dialysis machine. The patient’s blood is pumped to the machine, cleansed, then returned to the body. To prepare for regular hemodialysis treatments, a one-time minor surgery is performed to create a vascular access, which is essentially a large and strong vein, enough to sustain the high flow rate through the machine. This can be accomplished by fusing an artery to a vein, forming a so-called fistula; or by adding a synthetic tube – a graft. For emergency treatment, a catheter can be used for temporary access.
Once inside the machine, blood flows within tiny tubes surrounded by a dialysis solution, called dialysate. The walls of the tubes act as semipermeable membranes that allow only small molecules, such as water, nitrogenous wastes and electrolytes, to pass through. The filtration occurs by osmosis and diffusion, where water and solutes move from higher to lower concentration. The dialysis fluid contains solutes at the levels similar to those in healthy blood. Urea, potassium and other solutes that are present at higher levels in patient’s blood, move out to the dialysate, which is constantly replaced and discarded. At the same time, other substances can be added to the dialysis fluid to be administered to the patient. These may include: bicarbonate, to adjust the patient’s blood pH; erythropoietin, to compensate for its low production by the failing kidneys; and certain medications. Because of the increased risks of blood clotting associated with its contact with foreign surfaces, an anticoagulant such as heparin is usually added. The composition of dialysis fluid is typically prescribed by a nephrologist based on the patient’s needs.
Hemodialysis is normally performed as 4-hour treatments, 3 times a week, in a dialysis center. Complications include risks of blood infection, thrombosis, and internal bleeding due to the added anticoagulant.
In peritoneal dialysis, the dialysis fluid is introduced into the patient’s abdominal cavity via a catheter. The lining of the abdomen, the peritoneum, serves as the natural filtering membrane. The fluid remains in the body for several hours, allowing exchange and equilibrium with the blood running in the underlying vessels, before being discarded. The therapy can also be done automatically at night during sleep.
Peritoneal dialysis is less effective than hemodialysis, but because it can be performed for longer periods of time, the result is comparable. Peritoneal dialysis offers more flexibility, is better tolerated by patients, and less expensive, but is more often complicated with abdominal infections.

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Jugular Venous Pressure, with Animation

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Jugular venous pressure, JVP, also known as jugular venous pulse, is the pressure within the jugular vein. Because the right internal jugular vein communicates directly with the right atrium via the superior vena cava, JVP essentially reflects the central venous pressure; and its cyclic changes with each heartbeat accurately mirror the dynamics of blood flow to the right atrium.

JVP can be recorded precisely by inserting a central line; or assessed, non-invasively, by observing the pulsation of the vein on the right side of the patient’s neck.

The mean JVP, measured at the highest point of jugular pulsation, serves as an indicator of fluid status. A higher than normal JVP indicates hypervolemia, while lower values are associated with hypovolemia. Generally, fluid overload is diagnosed when the jugular vein is distended to the jaw in upright position.

Understanding JVP waveforms:

A normal JVP waveform has 3 positive waves: A, C and V, of which only A and V can be seen by looking at the vein; and their corresponding descents.

Reminder: blood flows from higher to lower pressure; contraction increases the pressure within a chamber, while relaxation lowers the pressure.

The A wave represents atrial contraction, which actively pushes blood into the right ventricle. Contraction increases pressure inside the atrium, pushing blood both downward and upward, creating a distension in the jugular vein.

The X descent is generated by the subsequent relaxation of the right atrium. The resulting reduced pressure pulls the blood down from the jugular vein.

As the right ventricle starts to contract, blood pushes against the closed tricuspid valve, causing it to bulge into the right atrium. This slightly raises right atrial pressure, producing the small positive C wave in the middle of the X descent.

V wave reflects the passive rise in pressure and volume of the right atrium as it fills, reaching the peak right before the tricuspid valve reopens.

Opening of tricuspid valve allows blood to flow down the ventricle, emptying the right atrium, reducing its pressure, and resulting in the Y descent.

Abnormalities in JVP waveforms can help with diagnosis of a number of cardiac and pulmonary diseases:

– Absence of proper atrial contraction, such as in atrial fibrillation, leads to absence of A waves.

– Abnormally large A waves occur when the right atrium contracts against a higher-than-usual resistance. Examples include right ventricular hypertrophy, tricuspid valve stenosis, and obstruction of right ventricular outflow. These conditions produce giant A waves that are uniform and occur on every beat.

– Cannon A waves, on the other hand, are also large, but occur intermittently, and usually of various height. Cannon A waves typically result from cardiac arrhythmias, when there is a disconnection between atrial and ventricular activation, and the right atrium contracts against a closed tricuspid valve, in some but not all beats. Examples include premature beats, complete atrioventricular block, and ventricular tachycardia.

– A large V wave occurs when there is increased atrial filling during ventricular contraction. The most common cause is tricuspid regurgitation. Because regurgitation begins during C wave (when the ventricle starts to contract), the large V wave is commonly FUSED with C wave, forming a so-called CV wave.

Atrial septal defects may also result in larger V waves.

– Unusually steep X and Y descents can be observed as abrupt collapse of the neck vein, in conditions such as constrictive pericarditis. The reduced elasticity of the pericardial sac raises atrial pressure while also limiting ventricular filling to early diastole.

– Cardiac tamponade, on the other hand, attenuates the Y descent as it impedes ventricular filling.

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Chronic kidney disease, with animation

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Chronic kidney disease, CKD, is a gradual loss of renal function, typically developing over the course of months or years. Many conditions, both within and outside the kidneys, can cause progressive damage to the kidneys over time, leading to CKD. Of these, most common are diabetes and hypertension, both of which directly damage blood vessels within the kidney, destroying renal tissue. An acute kidney injury, if not completely resolved, may also become chronic kidney disease.
The severity of renal disease is evaluated based on glomerular filtration rate, GFR, an indicator of how well the blood is filtered by the kidneys. GFR is calculated as a function of serum creatinine, a waste product that accumulates in blood plasma when renal function declines. The calculation takes into account the patient’s age, gender and race.
Symptoms develop slowly over time, progressing from renal insufficiency to end-stage renal failure. Often, initial loss of renal tissue does not produce any symptoms, because the remaining healthy tissue becomes more active and can temporarily compensate for the loss, a phenomenon known as renal adaptation. Symptoms appear when a significant portion of kidney function is already lost. The ability to concentrate urine is usually the first to be impaired, resulting in frequent trips to the bathroom, especially at night. Other early signs include fatigue, loss of appetite, and decreased mental ability.
Because the kidneys remove metabolic wastes, control blood pH and fluid/electrolyte balance, as well as produce several hormones, loss of kidney function may result in a number of complications:
– Accumulation of toxic nitrogenous wastes can cause a range of symptoms, from nausea, vomiting to confusion and seizures.
– Reduced excretion of hydrogen ions leads to increased blood acidity, or metabolic acidosis.
– Reduced excretion of potassium results in potassium overload in the blood, or hyperkalemia, which may cause cardiac arrhythmias. Hyperkalemia usually occurs only in advanced stage, but excessive potassium intake or use of drugs that prevent potassium excretion, may precipitate the condition in earlier stages.
– Decreased excretion of phosphate results in hyperphosphatemia.
– Reduced renal production of calcitriol, an active form of vitamin D, contributes to low blood calcium level, or hypocalcemia. Low blood calcium stimulates production of parathyroid hormone, PTH, by the parathyroid gland. PTH promotes calcium release from bones in an attempt to raise blood calcium. This sequence eventually leads to an overactive parathyroid gland, or secondary hyperparathyroidism, which can develop before hypocalcemia occurs. As the bones continuously lose calcium to the blood, they become thin and weakened, a condition known as renal osteodystrophy. Symptoms include bone and joint pain, and increased risks of fractures.
– Reduced renal secretion of erythropoietin, a stimulating factor for red blood cell formation, can lead to anemia.
Diagnosis is based on renal function tests, which include blood and urine analysis. Ultrasound is performed to detect renal obstruction. It may also help in distinguishing chronic kidney disease from acute kidney injury based on kidney size.
Treatments aim to control the underlying condition, address the complications, and involve certain nutrition supplements and restrictions. End-stage kidney disease requires dialysis or kidney transplantation.

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Acute Kidney Injury, aka Acute Renal Failure, with Animation

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Acute kidney injury, AKI, also known as acute renal failure, is a sudden, rapid loss of kidney function, typically within days or weeks.
The function of the kidneys is to filter blood plasma, removing metabolic wastes in urine, while also adjusting urine composition to maintain balance of various blood parameters. In AKI, metabolic wastes accumulate; and fluid, electrolyte and acid-base disorders may develop quickly. Of the many possible complications, most serious are potassium overload – hyperkalemia, and excess of fluid volume, or hypervolemia. Usually, both kidneys must fail for AKI to be diagnosed.
While AKI can be caused by a rapidly progressing intrinsic kidney disease, it is most commonly a consequence of an underlying condition outside the kidney.
Causes are classified as prerenal, renal and postrenal, with prerenal being most common.
Urine formation occurs in the functional units of kidneys, called the nephrons. Blood enters the nephrons via the afferent arteriole, passes through a ball of capillaries called the glomerulus, where filtration takes place, then leaves via the efferent arteriole. Blood pressure inside the glomerulus must be high enough to enable filtration. This is achieved by having the afferent arteriole significantly larger than the efferent arteriole, creating a blood flow with a large inlet and small outlet.
Prerenal AKI is usually due to an inadequate blood flow to the kidneys. Major causes include extracellular fluid volume depletion and decreased blood pressure, both of which reduce the glomerular filtration rate. Normally, autoregulatory mechanisms within the kidney, which dilate the afferent arteriole in response to volume loss, can compensate for a certain degree of low blood flow. AKI develops when hypoperfusion is severe, or when these mechanisms are compromised in patients with preexisting chronic kidney disease. Medications that cause dilation of the efferent arteriole or constriction of the afferent arteriole, reduce the pressure inside the glomerulus, and may contribute to development of AKI.
In patients with prerenal AKI but otherwise healthy kidneys, renal function typically returns to normal after the underlying condition is resolved, or the offending drug is discontinued.
Renal causes refer to intrinsic problems within the kidney, such as inflammation or necrosis of any of its components: the glomeruli, renal tubules, and interstitium.
Postrenal causes include various types of obstruction in the storage or voiding parts of the urinary system. These range from microscopic obstruction within renal tubules, to blockage of ureters by kidney stones, to urethral obstruction due to enlarged prostate in men.
Some AKI may involve problems at MORE than one level. For example, renal hypoperfusion, a prerenal cause, may sometimes be severe enough to induce ischemia of renal tubule cells, leading to intrinsic kidney disease. As the cells die, cellular debris may clog the tubules, becoming a postrenal cause.
Initially, symptoms of AKI are commonly masked by those of the underlying condition. In a later stage, symptoms are due to accumulation of nitrogenous wastes and disturbances of fluid and electrolyte balance. Urine output may or may not be reduced.
Diagnosis is based on renal function tests, such as serum creatinine and urea, serum electrolytes, urinary sediment, urine output and urinalysis.
Cause must be determined. Prerenal causes are usually apparent. Ultrasound is commonly performed to detect postrenal blockage.
Treatments aim to address the underlying cause, although some patients may also require fluid and electrolyte management, or dialysis.

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Pharmacology of Diuretics, with Animation

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Diuretics are substances that increase production of urine. Most diuretics act to increase excretion of sodium, which is followed by water. Because increased urine production results in reduced blood volume, diuretics are commonly used to treat primary hypertension and edema. Changes in body fluid and electrolytes induced by diuretics can also be therapeutic for some other conditions.
Sodium and water are filtered in the glomerular capsule of nephrons, then reabsorbed back to the blood at various sites along the renal tubule. Different classes of diuretics prevent sodium reabsorption, and thus increase sodium loss, at different sites, by different mechanisms.
Carbonic anhydrase inhibitors inhibit the enzyme carbonic anhydrase, which is required for reabsorption of bicarbonate in the proximal tubule. This leads to greater sodium loss, in the form of sodium bicarbonate, and subsequently greater water loss in the urine. These inhibitors have the weakest diuretic effect because most of sodium lost at this early stage is reclaimed further down the renal tubule. Increased delivery of sodium to the collecting duct increases its reabsorption at this site through epithelial sodium channels, in exchange for a greater potassium loss, and may cause hypokalemia. Loss of bicarbonate also affects acid-base balance, producing metabolic acidosis. Carbonic anhydrase inhibitors are rarely prescribed for cardiovascular diseases; they are mainly used in the treatment of glaucoma.
Osmotic diuretics, such as mannitol, promote water loss directly through osmosis. Being filtered without subsequent reabsorption, mannitol stays in the renal tubule, creating a higher osmolality which attracts water by osmosis. It produces a greater loss of water compared to sodium and potassium. Mannitol is not usually used to treat edema because its initial presence in the circulation may actually further increase fluid volume to a dangerous level. It is however effective in lowering intracranial pressure in patients with head injury, as well as lowering intraocular pressure in acute glaucoma. Osmotic diuretics act on the entire renal tubule, with predominant effect on the proximal tubule and the descending loop of Henle.
Loop diuretics inhibit the sodium/potassium/chloride cotransporter in the thick ascending limb of the loop of Henle. These are very powerful diuretics because this transporter not only reabsorbs a large share of sodium, but is also responsible for the osmolarity gradient in the medulla that enables the collecting duct to concentrate urine. As the loop diuretics cause the salinity gradient to diminish, the collecting duct loses less water, more water is excreted in urine.
Because the sodium/potassium/chloride cotransporter acts in conjunction with back diffusion of potassium to create a positive lumen potential that drives reabsorption of other positive ions, its inhibition by loop diuretics also induces a greater loss of these ions. Side effects include electrolyte imbalances, metabolic alkalosis, hypovolemia due to excessive loss of water, loss of hearing due to inhibition of a similar transporter in the inner ear, and gout due to interference with transporters involved in urate secretion.
Thiazide diuretics inhibit the sodium/chloride cotransporter in the distal tubule, which reabsorbs about 5% of the sodium load, and are not as powerful as loop diuretics. However, thiazides also have a vasodilation effect by a still poorly understood mechanism. Thiazides are first-line drugs for uncomplicated hypertension and most effective for heart failure prevention.
Unlike loop diuretics, thiazides reduce calcium loss in urine and can be used to prevent formation of new calcium kidney stones. This is because lower intracellular sodium induced by thiazides leads to higher calcium reabsorption mediated by sodium/calcium exchanger located on the basolateral membrane. Other side effects are similar to those of loop diuretics and include hypokalemia, metabolic alkalosis and hyperuricemia.
Potassium-sparing diuretics act mainly in the collecting duct. Here, sodium reabsorbs through epithelial sodium channels, ENaC, then sodium/potassium pump, in exchange for potassium loss. Sodium influx into cells creates a negative lumen potential, which drives reabsorption of chloride and excretion of potassium and hydrogen. Both ENaC and sodium/potassium pump are induced by aldosterone.
Potassium-sparing diuretics include aldosterone receptor antagonists and direct ENaC inhibitors. They are called potassium-sparing because they do not increase potassium loss, unlike all other diuretics acting upstream. Instead, they reduce potassium loss because reduced sodium reabsorption decreases the electrogenic exchange for potassium. Aldosterone antagonists also directly inhibit the sodium/potassium pump, reducing potassium loss.
Because the collecting duct reabsorbs only a small amount of sodium, this class of drugs has only a mild diuretic effect. They are commonly used in conjunction with thiazide or loop diuretics to prevent hypokalemia. Side effects include hyperkalemia, metabolic acidosis, and effects associated with inhibition of aldosterone.

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