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Atazanavir associated with significant risk of kidney stones and renal impairment

Studies presented at last week’s BHIVA conference found that kidney stones were four times more common in people taking the protease inhibitor atazanavir than in people taking other drugs. However they were still relatively uncommon – about one case in 50 patients who were being investigated for possible kidney stones turned out to have them.

A parallel study found a significant association between atazanavir and signs of renal failure, though it also found associations between impairment and other protease inhibitors too.

Atazanavir and kidney stones

In the first study Neesha Rockwood and colleagues from the Chelsea and Westminster Hospital in  west London did a retrospective case note review of patients attending the clinic between May 2006 and February 2010, singling out those who had had an abdominal X-ray or CT scan, a renal ultrasound scan, or an intravenous urogram (in which a contrast medium is injected and then x-rays are taken of it being excreted via the urinary system). These four procedures indicate that kidney stones are being investigated as a possible diagnosis.

She only included in this study patients who underwent one of the above investigations and were taking either the non-nucleoside drug (NNRTI) efavirenz (Sustiva, and in Atripla) or one of the protease inhibitors (PIs) atazanavir, lopinavir or darunavir (Reyataz, Kaletra, Prezista).

There have been case reports of kidney stones in patients taking atazanavir and analysis of these stones showed that they consisted of drug that has dissolved out of urine: atazanavir is less soluble in alkaline fluids, which is why it must also not be taken with antacids.

A sub-analysis excluded people with previous exposure to the PI indinavir (Crixivan), which is now hardly used because of its tendency to cause kidney stones. In all over 6,000 patients’ notes were reviewed. Of these 1206 people had taken atazanavir, 2803 efavirenz, 828 lopinavir and 818 darunavir, and 206 had previously taken indinavir.

Two per cent of patients taking atazanavir developed kidney stones, at an annual rate of 0.73% of patients per year (an annual event rate of one case per 137 patients). In contrast 0.54% of patients on the other three drugs developed kidney stones, an event rate of 0.19% or one event per 526 patients.

When patients with previous indinavir exposure were excluded, this brought the percentage of patients with kidney stones on atazanavir to 1.5%, with an annual event rate of 0.46% (one in 217 patients a year). The annual event rate in patients on the other three drugs who had not taken indinavir was 0.12% (one in 833 patients a year).

This meant that patients on atazanavir were 3.85 times as likely to get kidney stones as patients on the other drugs, and although excluding previous indinavir users brought the rates down, the relative difference remained the same.

Patients on darunavir were somewhat more likely to get kidney stones than patients on lopinavir or efavirenz (annual event rates 0.45%, 0.19% and 0.15% respectively).

Patients who had kidney stones were ten times more likely than others to have histories of chronic renal impairment and their levels of the liver waste product bilirubin (which causes jaundice, another side-effect associated with atazanavir) were on average twice as high.

Dr Rockwood said her study probably underestimated the prevalence of kidney stones in patients as some stones were transparent to X-rays and cases in patients who had transferred from other hospitals could have been missed. Atazanavir could have consequences after it was stopped: in one case, a kidney stone containing atazanavir was found in a patient who had stopped the drug 21 months previously.

Protease inhibitors and renal impairment

In a second study, this time of atazanavir’s effect on the kidneys’ ability to filter waste products, the same team found a 52% increased risk of this kind of chronic kidney disease in patients on atazanavir compared to the whole patient group. However this was lower than the risk associated with lopinavir (69% increased risk) and there was some association with darunavir use too, though this became statistically insignificant in multivariate analysis.

Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) of less than 60 millilitres per minute per 1.72m². EGFR is based on levels of the waste product creatinine in the blood and defines the amount of blood the kidneys are able to filter.

This study assessed the rate of kidney impairment in patients prescribed the same four drugs as in the previous study. Out of 2115 patients (78% male, 60% with an undetectable viral load) prescribed these therapies, 386 (18%) developed renal impairment as defined above.

Women were over 50% more likely to develop renal failure, and older patients considerably more likely, as seen in other studies (kidney failure becomes more frequent with age). Patients taking atazanavir, darunavir or lopinavir were, respectively, 27%, 53% and 71% more likely to develop kidney failure. Other risk factors included a history of tenofovir use (68% more likely) and chronic hepatitis B infection (21% more likely).

The risk associated with current tenofovir use appeared to accumulate with time (9% raised risk for each year on tenofovir).

Viral load or CD4 count at baseline, ethnic origin and hepatitis C co-infection were not associated with kidney failure.

Patients currently taking efavirenz had a 40% reduced risk of renal impairment compared with the average patient, though this advantage disappeared if they stopped efavirenz.

In multivariate analysis, taking lopinavir was associated with a 69% higher risk of kidney impairment than taking efavirenz. Patients taknig atazanavir had a 52% higher risk of renal impairment than patients taking efavirenz.. The risk with darunavir (versus efavirenz) was raised 31% but this became statistically non-significant (i.e. the effect of other variables became more important).

There was some recovery after the protease inhibitors were withdrawn. Half the patients who reached an eGFR below 60ml/min/1.73m² had an eGFR above this figure a year after stopping. Patients who were on tenofovir had a 30% greater rate of renal recovery if they stopped this drug in addition to their protease inhibitors; however stopping tenofovir by itself was not associated with significant improvement.

Atazanavir side effects are likely to come under more scrutiny in the future as the London HIV Consortium has recently made an agreement with HIV clinicians that it will be the first PI of choice in patients who need to take this class of drugs, and some patients will be encouraged to switch to it.

There are several ways to treat kidney stones

Kidney stone (also known as nephrolithiasis) is one of the most painful urologic diseases. It is the migration of stone that forms at the level of the kidney through the different structures of the urinary system (the uretere, urinary bladder and urethra). 

Kidney stone disease was described by ancient civilizations (Mesopotamia, India, China, Persia, Greece and Rome). It was discovered in the pelvis of an Egyptian mummy (dated to 4800 BCE). Among the famous leaders that suffered from this disease were Napoleon Bonaparte, Napoleon III, Peter the Great, Louis XIV, George IV and former U.S. President Lyndon B. Johnson. 

Clinically, during the process of migration, the stone can cause severe pain that typically starts in the flank. As the stone progresses, the pain starts to localize to the groin and the genital area, causing blood in the urine, nausea and vomiting. In most cases, the stone continues its migration and is eliminated in the urine. Many stones are formed and passed without causing symptoms. In a small percentage of patients, the stone is big in size and will block the uretere causing blockage of the urine flow compromising the kidney’s function and increasing the risk of infection of the kidney

TYPES OF STONES
 
There are several types of kidney stones which are categorized by the type of crystal forming the stone. The most common stones contain calcium oxalate, which can be formed without any predefined risk factors. The calcium phosphate is mainly common for patients with genetic or acquired defect in excretion of acidic materials in the urine. 

Struvite stones are exclusively present in patients with recurrent urinary tract infections. Cystine stones result from an inherited condition that causes an increase in the amount of cystine (an amino acid) in the urine. Uric acid stones form only in acidic urine and cannot typically be seen by X-ray imaging. 

TREATMENT
 
The treatment includes two parts: The acute management of the stone and the prevention of recurrence. The management during the acute kidney stone crisis is conservative and consists mainly of hydration (usually oral hydration is enough unless the patient has continuous vomiting) and pain medication (NSAIDs and/or opioids). 

The need for immediate evaluation by a urologist is warranted if the patient has a fever, is not producing urine or has acute renal failure. Intervention is indicated urgently in these cases to remove the stone which is blocking the urine flow. 

Patients are instructed to strain the urine in order to collect the stone and bring it to the lab for analysis. The stone size will determine the likelihood of passage. Most stones that are 4 millimeters (mm) in diameter pass spontaneously. Stones that are 10 mm in diameter are unlikely to pass. 

To facilitate stone passage several medications can be used. The most common medication is tamsulosin. For large stones, patients are referred for nonurgent urology evaluation. Current therapy options for stones that fail to pass include: 

*Shock wave lithotripsy, in which a doctor uses a machine to send shock waves directly to the kidney stone and break it into smaller stones that can pass in the urine. 

*Ureteroscopic lithotripsy with electrohydraulic or laser probes, which utilizes specialized probes to remove or fragment the stone. 

*Percutaneous nephrolithotomy, also known as tunnel surgery, in which a doctor makes a small cut into the patient’s back and makes a narrow tunnel through the skin to the stone inside the kidney. Using a special instrument that goes through the tunnel, the doctor can find the stone and remove it. 

*Laparoscopic stone removal, which uses small scopes inserted through the skin to remove the stone. 

Open surgical stone removal is rarely needed. The choice of therapy depends again on the size of the stone and the composition. 

PREVENTION 
    
Preventing a recurrence of kidney stones depends on the type of stones, but here are some general measures applicable for all types of kidney stones. 

*Increase fluid intake. Patients should increase their fluid intake to produce at least two liters of urine per day. However, be careful about the choice of fluid. Grapefruit juice may be associated with an increased risk of stones. Patients should avoid cranberry juice and calorie-containing beverages. Coffee, tea and alcohol have a lower risk of causing stones. 

*Reduce animal protein intake. 

*Increase fruit and vegetable intake (high in citrate an inhibitor of stone formation). 

*Limit dietary oxalate intake, such as spinach, rhubarb, peanuts, cashews and almonds. 

*Limit salt, sucrose, fructose, high dose vitamin C intake. 

*Weight control may be helpful in preventing stone recurrence. 

*Drug therapy is indicated if the stones are recurrent. Therapy is dependant on the type of stone. 
    

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Kidney Stones - Treatment Overview

Your first diagnosis of kidney stones often occurs when you see your doctor or go to an emergency room because you are in great pain. Your doctor may suggest that you wait for the stone to pass and take pain medicine or have a procedure to remove the stone.

Most small stones [less than 5mm] move out of the body (pass) without the need for any treatment other than taking pain medicine and drinking enough fluids.

• The smaller a stone is, the more likely it is to pass on its own. About 9 out of every 10 stones smaller than 5mm and about 5 out of every 10 stones 5mm to 10mm pass on their own. Only 1 or 2 out of every 10 kidney stones need more than home treatment.¹
• The average time a stone takes to pass ranges between 1 and 3 weeks, and two-thirds of stones that pass on their own pass within 4 weeks of when the symptoms appeared.²

Not all kidney stones are diagnosed because of immediate symptoms. Your stone may not be causing you pain, and your doctor may find it during a routine exam or an exam for another condition or disease. In this case, you have the same treatment options as noted below.

Treatment for your first stone

If your doctor thinks the stone can pass on its own, and you feel you can deal with the pain, he or she may suggest home treatment, including:

• Using pain medicine. Nonprescription medicine, such as nonsteroidal anti-inflammatories (NSAIDs), may relieve your pain. Your doctor can prescribe stronger pain medicine if needed.
• Drinking enough fluids. You'll need to keep drinking water and other fluids when you are passing a kidney stone. If you don't get enough fluids, you could getdehydrated. Drink enough fluids to keep your urine clear, about 8 to 10 glasses a day. If you have kidney, heart, or liver disease and are on fluid restrictions, talk with your doctor before increasing your fluid intake.

Your doctor may prescribe medicine to help your body pass the stone. Alpha-blockers have been shown to help kidney stones pass more quickly with very few side effects.⁵ Ask your doctor if these medicines can help you.

If your pain is too severe, if the stones are blocking the urinary tract , or if you also have an infection, your doctor will probably suggest medical or surgical treatment. Your options are:

• Extracorporeal shock wave lithotripsy (ESWL). ESWL uses shock waves that pass easily through the body but are strong enough to break up a kidney stone. This is the most commonly used medical treatment for kidney stones. See a picture of ESWL .
• Ureteroscopy. The surgeon passes a very thin telescope tube (ureteroscope) up the urinary tract to the stone's location, where he or she uses instruments to remove the stone or break it up for easier removal. Occasionally, you may need a small hollow tube (ureteral stent) placed in the ureter for a short time to keep it open and drain urine and any stone pieces. Ureteroscopy is often used for stones that have moved from the kidney to the ureter. See a picture of ureteroscopy .
• Percutaneous nephrolithotomy or nephrolithotripsy. The surgeon puts a narrow telescope into the kidney through a cut in your back. He or she then removes the stone (lithotomy) or breaks it up and removes it (lithotripsy). This procedure may be used if ESWL does not work or if you have a very large stone. See a picture ofnephrolithotomy .
• Open surgery. The surgeon makes a cut in the side or the belly to reach the kidneys and remove the stone. This treatment is rarely used.

Should I use extracorporeal shock wave lithotripsy (ESWL) for my kidney stones?

Kidney Stones - Medications

Medicine you can buy without a prescription, such as nonsteroidal anti-inflammatories (NSAIDs), may relieve your pain. Your doctor can give you stronger pain medicine if needed. NSAIDs include aspirinand ibuprofen (such as Motrin and Advil).

Your doctor may prescribe medicine to help your body pass the stone. Alpha-blockers have been shown to help kidney stones pass more quickly with very few side effects. Ask your doctor if these medicines can help you.

If you get more kidney stones despite drinking more fluids and making changes to your diet, your doctor may give you medicine to help dissolve your stones or to prevent new ones from forming. You may also receive prescription medicine if you have a disease that increases your risk of forming kidney stones. Which medicine you take depends on the type of stones you have.

Medication Choices

Medicine to prevent calcium stones

About 80% of kidney stones are calcium stones.¹ Calcium stones cannot be dissolved by changing your diet or taking medicines. These medicines may keep calcium stones from getting bigger or may prevent new calcium stones from forming:

• Thiazides (such as hydrochlorothiazide, chlorthalidone) and potassium citrate(Urocit-K) are commonly used to prevent calcium stones.
• Orthophosphate (Neutra-Phos) is sometimes used. It has more side effects than thiazides or potassium citrate.

Medicine to prevent uric acid stones

About 5% to 10% of kidney stones are made of uric acid, a waste product that normally exits the body in the urine.¹ Uric acid stones can sometimes be dissolved with medicine.

• Potassium citrate (Urocit-K) and sodium bicarbonate (baking soda) prevent the urine from becoming too acidic, which helps prevent uric acid stones.
• Allopurinol (Lopurin, Zyloprim) makes it more difficult for your body to make uric acid.

Medicine to prevent cystine stones

Less than 1% of kidney stones are made of a chemical called cystine.¹ Cystine stones are more likely to occur in families with a disease that results in too much cystine in the urine (cystinuria).

• Potassium citrate (Urocit-K) prevents the urine from becoming too acidic, which helps prevent cystine kidney stones from forming.
• Penicillamine (Cuprimine, Depen), tiopronin, and captopril (Capoten) all help keep cystine dissolved in the urine, which makes cystine-type kidney stones less likely to form.

Medicine to prevent struvite stones

About 10% to 15% of kidney stones are struvite stones.¹ They can also be called infection stones if they occur with kidney or urinary tract infections (UTIs). These types of kidney stones sometimes are also called staghorn calculi if they grow large enough.

• Urease inhibitors (Lithostat) are rarely used because of their side effects and poor results.

What To Think About

If you have uric acid stones or cystine stones and are taking medicine to prevent more stones from forming, you will most likely have to continue taking that medicine for the rest of your life.

Some struvite stones (staghorn calculi) form because of frequent kidney infections. If you have a struvite stone, you will most likely need antibiotics to cure the infection and help prevent new stones from forming, and you will most likely need surgery to remove the stone.