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Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Causative drugs. Prevention and management. Drug-induced hyperuricaemia and gout.
Ben Salem , C. Ben Salem. Oxford Academic. Raoudha Slim. Neila Fathallah. Houssem Hmouda. Revision received:. Cite Cite C. Select Format Select format. Permissions Icon Permissions.
Suggested mechanism. Open in new tab. Loop diuretics and thiazide diuretics interact with renal urate transporters. Like diuretics, many other drugs inducing hyperuricaemia and gout may also interfere with these renal urate transporters Fig. Loop diuretics and thiazide diuretics inhibited basolateral organic anion transporters OAT1 and OAT3, involved in the active uptake of plasma uric acid as a first step in its tubular secretion in renal proximal tubules.
These may include:. Return to list of Blood Test Abnormalities. Note: We strongly encourage you to talk with your health care professional about your specific medical condition and treatments.
The information contained in this website is meant to be helpful and educational, but is not a substitute for medical advice. For information about the 4th Angel Mentoring Program visit www. Toggle navigation. Spanish About Chemocare. Hyperuricemia High Uric Acid. What Is Hyperuricemia? What Causes Hyperuricemia? Causes of High Uric Acide Levels: Primary hyperuricemia Increased production of uric acid from purine Your kidneys cannot get rid of the uric acid in your blood, resulting in high levels Secondary hyperuricemia Certain cancers, or chemotherapy agents may cause an increased turnover rate of cell death.
This is usually due to chemotherapy, but high uric acid levels can occur before chemotherapy is administered. After chemotherapy, there is often a rapid amount of cellular destruction, and tumor lysis syndrome may occur. You may be at risk for tumor lysis syndrome if you receive chemotherapy for certain types of leukemia, lymphoma, or multiple myeloma, if there is a large amount of disease present. Kidney disease - this may cause you to not be able to clear the uric acid out of your system, thus causing hyperuricemia.
Medications - can cause increased levels of uric acid in the blood Endocrine or metabolic conditions -certain forms of diabetes, or acidosis can cause hyperuricemia Elevated uric acid levels may produce kidney problems, or none at all. People may live many years with elevated uric acid levels, and they do not develop gout or gouty arthritis arthritis means "joint inflammation". Symptoms of Hyperuricemia: You may not have any symptoms.
If your blood uric acid levels are significantly elevated, and you are undergoing chemotherapy for leukemia or lymphoma, you may have symptoms kidney problems, or gouty arthritis from high uric acid levels in your blood. You may have fever, chills, fatigue if you have certain forms of cancer, and your uric acid levels are elevated caused by tumor lysis syndrome You may notice an inflammation of a joint called "gout" , if the uric acid crystals deposit in one of your joints.
You may have kidney problems caused by formation of kidney stones , or problems with urination Things You Can Do About Hyperuricemia: Make sure you tell your doctor, as well as all healthcare providers, about any other medications you are taking including over-the-counter, vitamins, or herbal remedies. Since , various metabolic disturbances have been recognized in association with cancer therapy.
TLS is more severe when there is a high tumor growth fraction and rapid tumor growth rates, and the syndrome is sensitive to chemotherapy. A rare but highly malignant type of skin cancer usually found on sun-exposed body areas e. A polymorphic ventricular tachycardia characterized by phasic changes in the amplitude and polarity of the ventricular complexes; often associated with a prolonged QT interval. A measurement of the interval between the sum of 'routinely measured' cations and the sum of the 'routinely measured' anions in the blood; a high anion gap indicates metabolic acidosis.
A rare tumor of the thymus gland, which is located in the anterior mediastinum. The most common disease in people with thymoma is one in which the muscles are weak, called myasthenia gravis. Medulloblastoma is a highly malignant tumor representing the most common malignant posterior fossa tumor in the pediatric population.
This tumor is characterized by the tendency to seed along the neuraxis, following cerebrospinal fluid pathways, and represents one of the few brain tumors to metastasize to extraneural tissues. Originally classified as a glioma, medulloblastoma is now referred to as a primitive neuroectodermal tumor.
Rhabdomyosarcoma is a malignant soft tissue tumor found in children and it is believed to arise from a primitive muscle cell. The most common sites are the structures of the head and neck, the urogenital tract and the arms or legs.
Cell destruction that occurs with aggressive treatment of malignant diseases causes a rise in excreted waste products and is accompanied by metabolic disturbance. Increased purine metabolism as a result of high tumor cell turnover leads to hyperuricemia. Cytolytic chemotherapy causes tumor cell breakdown and a rapid increase in plasma uric acid, potassium and phosphorus.
These events together with hypocalcemia, which occurs as a consequence of increased phosphorus, are the major components of TLS. Potassium, uric acid and phosphate are primarily excreted during renal clearance, and development of renal failure can further aggravate this electrolyte imbalance. Normally, the urate is filtered by the glomerulus, partial proximal tubular reabsorption and distal renal tubular secretion of the kidney.
The rate of urate clearance is highly dependent on the glomerular filtrate flow rate and may fall significantly if dehydration is present. Dehydration can occur as a consequence of tumor development or treatment, resulting in ureteral obstruction and other complications that further compound dehydration.
Urate nephropathy develops as a result of the acid conditions and urate crystal formation in the renal tubules and collecting ducts. This condition can cause complications leading to renal insufficiency and therapy-related death; acute urate nephropathy associated with TLS results from pathological urate crystal deposition in the distal renal tubules.
In certain patients, renal tumors may coexist with kidney pathology induced by TLS, which can manifest before the initiation of chemotherapy or up to 5 days after the chemotherapy, especially with tumors that are highly proliferative and sensitive to chemotherapy. TLS should be suspected in patients with tumor burden who develop ARF and have hyperuricemia, hyperphosphatemia and elevated lactate dehydrogenase. Specific clinical features of TLS are shown in Boxes 2 and 3.
A rise in serum potassium levels occurs 6—72 hours after the initiation of chemotherapy. The most common electrocardiogram abnormalities are peaked T waves in the precordial leads, prolongation of the PR interval, flattening or absence of the P wave, widening of the QRS complex, and a 'sine wave' appearance, which is associated with severe hyperkalemia. Nonspecific symptoms, such as nausea and vomiting, can result from hyperphosphatemia, hypocalcemia, hyperuricemia and especially renal failure.
These symptoms are often poorly managed with antiemetic treatments, which should be used with caution in the presence of renal or hepatic failure.
Hyperphosphatemia develops 24—48 hours following initiation of chemotherapy, and can cause many kinds of symptoms, including decreased mental status, weakness, cramps, hyperreflexia, tetany and renal failure. Hyperphosphatemia can also cause dysrhythmias, including polymorphic ventricular tachycardia and torsades de pointes Box 1 due to a prolonged QT interval on the electrocardiogram.
Hypocalcemia also causes dysrhythmias and cardiac arrest in extreme cases. Hyperuricemia can develop within 48—72 hours of chemotherapy. Uric acid is an end product of purine metabolism and is excreted by the kidneys. Hyperuricemia can cause a myriad of abnormal physical symptoms, including nausea, vomiting, lethargy, oliguria, anuria, anorexia, and hematuria.
Blood urea nitrogen and creatinine levels can rise, causing edema, acute acid nephropathy and renal failure Table 1. Occasionally, TLS is accompanied by a coagulopathy. The fractional excretion of uric acid can be calculated as the ratio between uric acid and creatinine clearances.
The fractional excretion is influenced by the extracellular volume, in that expansion increases whereas contraction decreases the urate excretion. This process is independent of urine flow rate.
The causes of ARF are multifactorial, and complications can result in multiple organ failure and death. ARF is defined as a sudden loss of renal function over several hours to several days , and perturbs extracellular fluid balance, acid—base balance, electrolytes levels, and divalent cation regulation.
An increased serum creatinine concentration, accumulation of other nitrogenous waste products, and often a decline in urinary output, are the hallmarks of this condition. Hyperuricemia, hyperkalemia, and hyperphosphatemia result from rapid destruction of malignant cells and release of intracellular ions, nucleic acids, proteins and their metabolites leading to ARF.
Determination of serum electrolytes offers valuable information, such as potassium levels, clues about volume status e. Arguably, the most important laboratory test for a patient with ARF is urinanalysis. Both the urinary sediment and urinary indices in combination with serum values can often be extremely helpful in determining the cause of ARF. These indices are designed to determine whether tubular function is intact. Hande and Garrow attempted to qualify the clinical and pathological characteristics of patients at risk of TLS.
This classification has several limitations. Clinical TLS requires one or more clinical manifestations i. Recently, Cairo and Bishop developed a new version of this classification, which incorporates laboratory and clinical TLS.
The clinical TLS manifestation i. TLS requires prompt diagnosis and staging before cancer treatment can be initiated. TLS can either be present prior to chemotherapy or develop during treatment. To prevent TLS, it is important to identify high-risk patients, such as those with a large tumor load in both rapidly growing lymphoproliferative malignancies and solid tumors with extensive metastases, and those with a rapid rise in serum lactate dehydrogenase levels Box 2.
Tumor and drug characteristics, including the drug dose and density, should be taken into account Box 3. Patients with TLS or who are at high risk of developing TLS should be evaluated with frequent clinical laboratory testing.
In addition, it is necessary to monitor carefully the patient's fluid intake and output, weight and blood pressure at frequent intervals.
Before cytotoxic chemotherapy begins, metabolic stability should be achieved, using methods such as those described below and summarized in Table 3. Diuretic therapy and urinary alkalization and hydration should also be given immediately after chemotherapy. Excluding patients who are at risk of volume overload, such as elderly patients or those with heart failure, aggressive fluid administration has been recommended in patients at risk of TLS.
Aggressive intravenous hydration increases intravascular volume and helps correct electrolyte disturbances by diluting extracellular fluid, thereby reducing serum potassium, uric acid and phosphate concentration.
Increased intravascular volume via hydration also enhances renal blood flow, glomerular filtration rate and urinary volume, thereby decreasing the solute concentration in the distal nephron and medullary microcirculation, and possibly avoiding the need for dialysis Figure 2.
In patients with gout an increase of serum level and a decrease of urate transport in the nephron is observed. Uric acid of both normal patients and those with gout is filtered freely at the glomerulus and nearly all of this acid is reabsorbed before entering the distal convoluted tubule. The majority of uric acid in the urine is the result of secretion. Secretion and post-secretory reabsorption are thought to occur in the proximal tubule. Diuresis may be assisted with mannitol, furosemide or acetazolamide if adequate fluids are administered.
Mannitol induces osmotic diuresis and is used when hydration alone is insufficient to maintain adequate diuresis. Diuretics can facilitate the renal excretion of potassium, but furosemide is not very effective if the renal tubules are affected by urate precipitation. In these instances, mannitol can be used. To induce alkaline diuresis, furosemide or acetazolamide can be used.
To avoid a further increase of this electrolyte, it is important that potassium is not added to intravenous fluids. Diuretic therapy is not recommended unless volume overload from overhydration is present, which would necessitate temporary termination of intravenous fluids, and would also help avoid hyperkalemia. To reduce the risk of uric acid crystallization, it is important to increase the urinary pH to prevent uric acid nephropathy. The pH alkalization can be obtained by adding sodium bicarbonate to a hydrating physiologic solution, via oral administration of bicarbonate tablets, or by giving oral acetazolamide, but these approaches are only successful in patients without risk of systemic acidosis.
The ways to achieve urinary alkalization are controversial. Conger and Falk reported that alkalization does not improve the abnormalities induced by hyperuricemia.
Moreover, urinary alkalization may decrease the solubility of xanthine and increase the risk of xanthine nephropathy. If alkalosis occurs, bicarbonate should be stopped and the patient managed according to the degree of alkalosis present. Severe alkalosis can be accompanied by hyperirritability or tetany, and these symptoms can be controlled by calcium gluconate.
An acidifying agent such as ammonium chloride might also be indicated in severe alkalosis. Allopurinol is a synthetic structural analog of hypoxanthine and competitively inhibits xanthine oxidase, thereby blocking the conversion of hypoxanthine and xanthine into uric acid. Since , allopurinol combined with alkaline hydration has represented the standard treatment for malignancy-associated hyperuricemia, 57 and allopurinol is also used in the management of patients at risk for TLS.
Allopurinol administration reduces renal uric acid load, preventing its further production, but it does not affect existing uric acid. Allopurinol has a half-life of 60— minutes; the active metabolite of this agent, oxypurinol, is also an effective inhibitor of xanthine oxidase and remains active for 18—30 hours.
Since oxypurinol is cleared in the kidney, its half-life can be prolonged in patients with renal insufficiency. Skin rashes and hypersensitivity are the most frequent side effects of allopurinol, which is a less potent inhibitor of xanthine than oxypurinol, and in rare instances these symptoms can be life threatening. Because high uric acid can exist before allopurinol treatment is initiated, a period of 2—3 days is generally necessary for uric acid levels to decrease after initiation of allopurinol treatment.
Although allopurinol is effective in the reduction of hyperuricemia, it has some disadvantages, including the need to delay chemotherapy, unfavorable drug interactions, the need for dose reduction in patients with impaired renal function, allergic side effects, and induction of xanthine nephropathy.
If cellular lysis persists, xanthine and hypoxanthine cannot be converted into uric acid, and high quantities of these agents enter the renal tubules, where they can crystallize and produce xanthine nephropathy. Urate oxidase also known as uricase , a proteolytic enzyme not present in humans and other primates, oxidizes uric acid in water-soluble allantoin.
Since allantoin is readily water soluble, its elimination by urinary excretion is less problematic than seen with xanthine or uric acid.
In fact, the kidneys readily excrete allantoin, and its reactive by-product, hydrogen peroxide, is neutralized by catalase to oxygen and water. Hydrogen peroxide, produced as a result of uric acid breakdown, caused kidney complications such as ARF in patients with leukemia and lymphoma.
The primary advantage of recombinant urate oxidase is its rapid onset of action. Urate oxidase can rapidly decrease serum levels of uric acid with associated diuresis.
The efficacy and safety of rasburicase is currently being tested and compared with that of allopurinol in a phase III clinical trial.
Moreover, a retrospective comparison of rasburicase and allopurinol showed that the former was significantly more effective at reducing uric acid levels, and also improved renal function as demonstrated by lower blood urea nitrogen and creatinine levels.
The pegylated form of urate oxidase, PEG-uricase, reduces plasma uric acid levels without antigenicity. Two groups detected antibodies to rasburicase in 17 of patients and in 7 of 97 patients using an enzyme-linked immunosorbent assay. A significant advantage of rasburicase is that chemotherapy can be promptly initiated with a significant reduction in the risk of renal dysfunction requiring dialysis.
Although rasburicase prevents renal uric acid accumulation, it causes phosphate reabsorption, and calcium phosphate deposition remains a concern. Rasburicase may also be used to spare the costs and complications of cytoreductive procedures. Other treatment modalities for severe hyperkalemia with or without electrocardiographic changes include hypertonic glucose and insulin, loop diuretics, and bicarbonate.
There is evidence that bicarbonate will not result in lowering of serum potassium unless there is a severe metabolic acidosis. Treatment of hyperphosphatemia should take into consideration the underlying biological alterations e.
A mild asymptomatic hyperphosphatemia in patients with chronic renal failure can be corrected with a reduced dietary phosphate intake; phosphate binders such as aluminum hydroxide or aluminum carbonate 30 ml taken four times daily will decrease the absorption of phosphate in the gout. A severe hyperphosphatemia in patients with end-stage renal failure can be corrected by hemodialysis or peritoneal dialysis.
Usually, treatment of hyperphosphatemia will also correct any related hypocalcemia. If calcium gluconate is injected, however, severe arrhythmias can occur. Data comparing the various dialytic modalities hemodialysis, peritoneal dialysis and continuous dialysis hemofiltration are lacking.
Furthermore, initiation of hemodialysis before severe pathophysiologic deterioration occurs has been suggested to benefit patients with multiorgan failure and ARF. Dialysis every 12—24 hours may also be necessary in patients presenting with a large phosphate burden. Peritoneal dialysis is much less efficient than hemodialysis in correcting metabolic abnormalities, and hemodialysis affords much higher clearance of both uric acid and phosphorus.
TLS is an oncologic emergency, and as more-aggressive and more-highly-targeted therapies, high doses of cytotoxic agents and biologic response modifiers have become a standard therapy, TLS will be more frequently encountered.
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