uric acid

Kidney Stones (Nephrolithiasis): A Pain In My… Flank?

virtualmedstudent

Kidney stones, or nephrolithiasis, come in different types. There are calcium, struvite, uric acid, and cystine stones. They all form under different conditions with some being more common than others. In addition, when urine is analyzed under a microscope the crystals form unique shapes that help identify one type of stone from another.

Calcium Kidney Stone
Struvite Stone
Uric Acid Stones
Cystine Stones
Calcium stones are the most common. They are composed of either calcium phosphate or calcium oxalate. They form under conditions of hypercalciuria (ie: high calcium in the urine). There are many reasons why someone would have elevated urinary calcium levels. Some examples include hyperparathyroidism (an overactive parathyroid gland), vitamin D toxicity, cancer, and the milk alkali syndrome. In many patients the reason for the elevated urinary calcium is never discovered.

Calcium stones are also associated with hyperoxaluria (ie: too much oxalate in the urine), as well as hyperuricosuria (ie: too much uric acid in urine), and hypocitraturia (ie: too little citrate in the urine).

The second most common type of stone is a struvite stone. A struvite stone is composed of magnesium, ammonium, and phosphate. They form during kidney infections when the "bug" responsible for the infection is a urease spliting bacteria such as proteus vulgaris. These bacteria are capable of producing ammonium from urea. In large enough quantities the ammonium can combine with magnesium and phosphate to form a struvite stone. These stones can be large and in the shape of the draining system of the kidney (ie: calyces); when the have this appearance they are referred to as "staghorn calculi".

Uric acid stones are produced under conditions of high amounts of uric acid in the blood and urine (ie: gout or conditions where cell death is high such as in leukemias and other cancers). Some patients lack elevated levels of uric acid in the blood or urine. However, they are still capable of forming uric acid stones, especially if their urine is acidic. This is because urate precipitates in acidic environments.

Finally, cystine stones form because of certain genetic conditions. The cells that line the urinary tract are normally able to re-absorb amino acids like cysteine. However, certain genetic mutations cause abnormalities in the ability of these cells to transport cysteine from the urine back into the blood. The resultant increase in cysteine in the urine can cause cystine stones to form.

Signs and Symptoms

A fair number of kidney stones are asymptomatic. However, occasionally a stone will pass from the kidney to the bladder through a narrow tube called the ureter. This can produce excruciating pain that is located in the flank region. Sometimes the pain can be referred to the scrotum in males, or labia majora in women.

In addition, sometimes the urine will have blood in it from irritation of the urinary tract. If there is enough blood, the urine will turn pink; although, microscopic hematuria (ie: blood in the urine that can only be picked up by lab testing) can also occur.

Complications

There are several worrisome complications of kidney stones. They include hydronephrosis and pyelonephritis. Hydronephrosis refers to dilation of the urinary tract secondary to blocked urine and increased pressures. The increased pressure is reverberated all the way to the filtration unit of the kidney, the glomerulus. If high enough pressures are reached, irreversible kidney damage can occur leading to chronic kidney disease and renal failure.

Pyelonephritis is a fancy term for an infected kidney. The irritation caused by the stones provides a suitable environment for bacteria to proliferate. These infections can be life threatening, and like hydronephrosis, can lead to irreversible kidney damage and renal failure.

Diagnosis

Diagnosis of kidney stones is made by looking at urine under the microscope. This is known as urine microscopy. Different types of stones have different appearances (see images above), but more importantly also have different treatments.

In addition, a urine analysis is often performed in order to determine the pH. Urine electrolytes including calcium, magnesium, sodium, etc. are also sent, and can be helpful in determining the type of stone.

Imaging studies are also commonly done. The quickest, cheapest, and most readily available is an ultrasound of the kidney. If stones are present they can cast shadows (similar to the ones gallstones cast), which are picked up by the ultrasound machine. CT scans of the kidney can also show stones. Occasionally a procedure known as intravenous pyelography (IVP) is done. In IVP, radio-opaque dye is injected into the veins. It ultimately gets filtered and excreted by the kidneys, at which point an X-ray is taken; the X-ray can provide information about stones if they are present.

CT of Kidney Stones

Treatment

The treatment of kidney stones depends in part on the size of the stone, as well as the type. Stones that contain large amounts of calcium cannot be dissolved with current medicines available; uric acid and cysteine stones can. Medical therapy is designed to either (a) dissolve the stone, or (b) get it to pass with minimal amounts of discomfort.

Expulsive therapy involves using medications to relax the smooth muscles around the "tubes" (ie: ureter, urethra) of the urinary tract. Commonly used medications that do this include:

(1) Alpha-blockers (ie: tamsulosin, terazosin, etc.)
(2) Calcium channel blockers (ie: nifedipine)

These medications help stones pass, especially when they are larger than 3mm in size. In addition, medications for controlling pain associated with kidney stones are paramount to ensuring stone expulsion.

Stones that are larger than 8mm in diameter usually do not pass on their own, even with medical expulsive therapies. These stones must be managed through mechanical or surgical means.

The first approach is to break the stones into smaller fragments using a technology called extracorporeal shockwave lithotripsy. This is a non-invasive method that delivers powerful waves through the body designed to fragment the stone. The second, and more invasive, procedure is ureteroscopy. This refers to placing a tiny camera into the urethra, bladder, and ultimately into the ureter in order to directly visualize the stone. It is then removed with small forceps.

Staghorn calculi larger than 4 cm diameter require a procedure known as percutaneous nephrolithotomy. In essence, a tube is placed through the skin into the kidney. From there the stone can be directly visualized and removed.

Preventing stones from re-forming is also important. Adequate hydration is critical in preventing all stone types, and is probably the single most important preventative measure! Hydration ensures that urine output is high enough to prevent precipitation of minerals that commonly cause stones.

Prevention includes:
(1) adequate hydration
(2) low sodium diet
(3) low protein diet
(4) low oxalate diet
(5) normal or high
       calcium diet
In addition, dietary modifications are also recommended. Paradoxically, excess restriction of calcium from the diet can actually lead to stone formation. This is believed to be due to oxalate being absorbed from the GI tract instead of calcium. The excess absorption of oxalate leads to increased calcium oxalate stone formation in the tubules of the kidneys. Therefore, people with calcium stones should eat a diet that is high in calcium (1 to 4 grams/day); however, supplementing the diet with calcium tablets is not recommended. Diets high in oxalate should be avoided. Avoidance of diets high in salt and protein are also generally recommended.

Treatment for specific types of stones are also given. To prevent the re-formation of uric acid stones, potassium citrate is commonly given to make the urine less acidic (more alkaline). This increases the solubility of urate and keeps it from precipitating into a stone.

Overview

Kidney stones come in different shapes and sizes. The most common type are calcium stones. Many patients are asymptomatic although flank pain that radiates into the scrotum and labia majora are common. Blood tinged urine may also be seen. Diagnosis is based on urine microscopy, kidney ultrasound, CT scan, and urinalysis. Treatment for all kidney stones consists of adequate hydration and analgesics. Stones larger than 8mm often need to be broken up or removed via mechanical means.

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References and Resources

Gout: Uric Acid, Negatively Birefringent, and My Big Toe

virtualmedstudent

Gout occurs when uric acid crystals form in joint spaces. Everyone has some level of uric acid in their blood stream. However, it is only when the level becomes high enough that uric acid leeches into the joint spaces and crystallizes. Once there, the crystals cause signifcant inflammationand the affected joint becomes painful, red, and swollen.

The causitive agent, uric acid, is a by product of purine catabolism. Purines are an important component of nucleotides, which are the building blocks of DNA and RNA. Purines are also seen in molecules like adenosine triphosphate, which serves as a source of cellular energy. The final product of the degradation of these molecules is, you guessed it, uric acid!

The degradation pathway for both adenine and guanine (and their constituent molecules) are shown below. The key enzymes involved in this degradation are shown in red.

Purine Catabolism

When uric acid is formed, the kidneys filter it, and then excrete it into the urine. Some people are predisposed to either under-secrete or over-produce uric acid. In either case it builds up in the blood stream. This is known as "hyperuricemia". In some people hyperuricemia can cause gout. However, it is important to note that not everyone with hyperuricemia develops gout.

Diagnosis

Gout Crystals

An official diagnosis of gout can only be made by tapping the joint (ie: sticking a needle into the joint and aspirating the contents) and looking at the fluid under a microscope.

If uric acid crystals are present, they will be "negatively birefringent", which means that they appear yellow under a parallel light source. Interestingly, if the light source is turned perpendicular the crystals turn blue (this is the exact opposite of pseudogout, which is discussed in another article).

Often times clinicians will order a blood uric acid test. In an acute attack, uric acid levels are meaningless because patients suffering from a gout flair may suprisingly have normal blood levels. However, in patients who are on medications to prevent gout, monitoring the blood uric acid levels can help guide treatment. In addition, hyperuricemia almost always precedes a gout attack.

Signs and Symptoms

As discussed above, the uric acid crystals cause inflammation in the joint space. This leads to a painful, swollen, and red joint. Gout attacks joints asymmetrically, meaning that it rarely affects the same joint on both sides of the body at that same time. Symmetric joint pain is more consistent with other rheumatological diseases.

Many joints can be affected by gout. The most common joint is the metatarsal phalangeal joint (MTP), which is a joint in the big toe. When this joint is involved the disease is referred to as "podagra".

Gout attacks usually occur quickly and unexpectedly with peaking of symptoms within 12 to 24 hours. Multiple repeated attacks of gout can lead to a chronic form of the disease known as "tophaceous gout". In chronic gout, not only are joints affected, but crystal formation can also occur in other areas of the body. For example, the achilles tendon and earlobes can be affected.

Tophaceous Gout

Patients with gout may also be at increased risk of developing uric acid kidney stones due to elevated uric acid in the urine.

Treatment

Acute treatment is aimed at controlling the inflammatory process within the joint. The most common drugs used to treat acute gout flairs are non-steroidal anti-inflammatory medications (NSAIDSs). Ibuprofen, naproxen, and indomethacin are the most common NSAIDs used to treat gout flairs. Steroids are also sometimes used, especially in people with contraindications to NSAIDs such as kidney failure.

An additional second line medication used to treat acute gout flairs is colchicine. It is typically used in people who cannot tolerate NSAIDs.

To prevent gout attacks from reoccurring, or to prevent tophaceous gout, there are several medicines that are used. The first medication is known as probenecid. It is most effective in people who "under-excrete" uric acid because it inhibits the re-absorption of uric acid in the kidney.

The second medication is known as allopurinol. It is most useful in people who "over-produce" uric acid because it inhibits the enzyme xanthine oxidase (see degradation pathway above) and reduces the amount of uric acid formed from the breakdown of purines.

Allopurinol and probenecid should not be used to treat acute gout flairs. Paradoxically, they can actually worsen an acute flair and should only be used to prevent recurrent attacks.

Overview

Gout is a disease of the joints caused by deposition of uric acid crystals. The joint becomes hot, swollen, red, and extremely painful. Diagnosis is made by aspiration of the crystals from the joint space. Treatment for acute flairs is usually with non-steroidal anti-inflammatories. Colchicine is occasionally used as well. Allopurinol and probenecid are used to prevent recurrent attacks.

References and Resources