Case: patient history
Mr. F has a 5-year history of hypertension, for which he has been receiving hydrochlorothiazide. He was on a low-sodium diet. He has also suffered from nephrolithiasis with several calcium oxalate renal calculi in the last five years. Mr. F has no history of kidney disease. His father and two uncles also suffered from gout but they did not have kidney disease.
Discussion: comorbidities affecting hyperuricemia
The medical history has revealed several conditions associated with gout. An association between hypertension and gout has long been documented. The use of hydrochlorothiazide increases distal tubular sodium excretion, which leads to a secondary increase in proximal tubular sodium reabsorption. The increased proximal tubular sodium reabsorption secondarily leads to increased urate reabsorption and hyperuricemia.4
Nephrolithiasis is also highly associated with gout. Patients who experience urate overproduction excrete increased levels of urate in the urine. While a high urinary urate excretion is a risk factor for uric acid calculi, an even more important determinant is urinary pH owing to the solubility of urate vs. uric acid and the pKA of uric acid. There is a significant difference in the solubility of urate vs uric acid, with urate having a solubility of 158 mg/dL, and uric acid having a solubility of only 8 mg/dL. The pKA of uric acid is 5.7. This means that at a pH of 7, 95% is present as urate (very soluble), and at a pH of 5, about 80% is present as uric acid (very insoluble).
Shifting pH can change uric acid solubility by almost a factor of 20.5 Dietary factors such as excess meat in the diet will not only increase uric acid production but will also decrease urinary pH, resulting in an increased potential for uric acid calculi.5,6
In addition, there is an increased risk of calcium oxalate calculi in patients with hyperuricosuria, as uric acid acts as a promoter for calcium oxalate stone formation, with approximately 20% of patients with calcium oxalate nephrolithiasis having urinary urate excretions of >800 mg/d (men) and >750 mg/d (women).5 Excess consumption of meat causes increased uric acid production as well as increased urinary acidity, thereby increasing the risk of calcium oxalate calculi.
In a double-blind randomized study,6 60 patients suffering from recurrent calcium oxalate calculi, hyperuricosuria, and normocalciuria were randomized to allopurinol (300 mg/d) vs. placebo. In this study, the mean rate of subsequent calculous events was 0.26 per patient-year in the placebo group and 0.12 in the allopurinol group (P<0.02). While allopurinol is currently only indicated in the treatment of symptomatic gout, one needs to consider this possible benefit in patients with the disease.
While 24-hour urine collections are not necessary in the management of most patients with gout, in difficult cases such as this, it is important to understand the pathophysiology of urate excretion. Random spot urine uric acid:creatinine ratios have been found to be unreliable in predicting 24-hour urinary uric acid excretion due to diurnal variation. For this reason, one must consider obtaining a 24-hour collection for uric acid and creatinine with a simultaneous measurement of uric acid excretion. A 24-hour excretion of greater than 700 mg of uric acid is the diagnostic threshold for urate overproduction.7
Case: identifying urate overproduction
In 24 hours, the patient produces one liter of urine containing 800 mg of uric acid and 1500 mg of creatinine. The serum uric acid level is 9.5 mg/dL, and the serum creatinine is 0.9 mg/dL.
Discussion: understanding high serum urate levels
The results indicate that the patient has a high daily uric acid excretion of 800 mg. As he is in a relatively steady state, the amount produced will be equal to the amount excreted. The fractional excretion of uric acid in this patient is (800/9.5)/ (1500/0.9) = 0.05%, which is low.
Thus, there are two factors that are contributing to the high serum uric acid levels observed in this patient. He produces excessive uric acid (800 mg/dL; at the same time, he reabsorbs more uric acid than normal, leading to a low fractional excretion of urate.
Uric acid excretion is very high in infancy and about 8% to 20% during childhood. With puberty, there is a decline in the fractional excretion of uric acid in men, but not in women, resulting in an increase in serum uric acid relative to women.
After menopause, the fractional excretion of uric acid is similar between men and women. The low fractional excretion of uric acid, in addition to the relative increased dietary protein intake in men, results in an increased incidence of gout in men vs. women. In an observational study of 100 patients with gout vs. 72 controls,7 the mean fractional excretion of urate was 4.6 ± 1.2 mg/dL in gout patients and 7.6 ± 1.9% in controls.
For unclear reasons, patients with increased urinary uric acid excretion frequently have low fractional excretions of uric acid as well.7
An interesting note in this patient is the low urinary output. This low urinary excretion places the patient at increased risk of kidney stones, as decreased urinary output has consistently been associated with an increased risk of renal calculi. In addition, increased water intake has been associated with a decreased risk of development of gouty attacks.
There are two important conditions that the nephrologist should consider in patients with chronic kidney disease, hyperuricemia, and decreased fractional excretion of uric acid. First, lead poisoning has been well associated with both gout and chronic kidney disease. Lead poisoning can be due to lead exposure to paint that was produced many years ago or from occupational exposure. This is less common today.
Another important consideration is mutation in the UMOD gene encoding uromodulin (Tamm-Horsfall protein) as a cause of gout and chronic kidney disease.8 In this condition, production of abnormal uromodulin in the thick ascending limb results in defective function of the thick ascending limb and impaired sodium reabsorption.
The impaired sodium reabsorption leads to increased proximal tubular sodium (and secondarily urate) reabsorption. Patients usually present with gout in the teenage years, but attacks can begin at any age.
Chronic kidney disease with a bland urinary sediment and absence of proteinuria occurs during the third through seventh decades of life. Clues to the diagnosis include a very strong family history of gout and kidney disease. Mutational analysis is available in many clinical genetics laboratories.
At this point, the clinician had a good understanding of the pathophysiology of the patient’s gout and initiated prolonged discussion with the patient about potential treatments.–pagebreak–
Case: chronic debility
Mr. F stated that he had suffered from gout for about 10 years. Over the last five years, he has become increasingly debilitated with the development of tophi on the feet and both hands. Mr. F, an accountant, has acknowledged that the pain from the tophi now substantially hinders his job performance. The patient was tearful in his discussion about how the progressive gout has not only affected his professional life, but decreased his ability to do many things outside of the home.
Discussion: indications and options for treatment
Indications for the treatment of chronic gout are based on attack frequency and severity, uric acid burden, and prognosis. Gout attacks occurring less than once per year may respond well to symptomatic care. Many patients would opt for symptomatic treatment of acute events together with lifestyle modification rather than chronic medication. On the other hand, individuals who are very active may find even infrequent gout attacks a burden and desire preventive treatment.
Patients with more frequent attacks are more likely to favor preventive care; the decision is a personal one that must be discussed between the patient and clinician. The risk of developing another gout attack is also associated with higher serum urate levels; this should be taken into account when discussing therapy. For a patient with mild gout and a mildly elevated serum urate level, preventive therapy may not be required.
In this patient with severe tophaceous gout, it is likely that the uric acid burden will increase over time and that attacks will become more frequent. Prevention with attempts to significantly lower serum urate levels are required in this case, since an increased body burden of uric acid will result in an increased risk of gout in the future.
Mr. F has been treated chronically with colchicine and prednisone. These two medications decrease inflammation and prevent gout attacks; in the meantime, however, the body’s uric acid burden will increase, and tophi can increase in size.
Prednisone is an unacceptable agent for long-term gout management, because of the potential for toxicities over time. Colchicine, which is no longer generic, is now quite expensive, and chronic therapy with this agent may result in myopathy and other adverse effects. For this reason, treatment should focus on decreasing the body’s burden of urate.
In patients whose hyperuricemia is solely due to underexcretion of urate, probenecid is a possible alternative to lower serum urate levels. This agent is not used as frequently in the United States as in other countries. A 24-hour urine collection should be obtained prior to usage to rule out uric acid overproduction.
Urine output must remain high, and urine pH should be monitored to prevent the development of uric acid stones. For this patient, probenecid would not be a good choice because he is overproducing uric acid, has renal calculi, and produces low urinary volume.
There are three agents that are of potential benefit in the treatment of this patient’s gout: allopurinol, febuxostat, and pegloticase.
Allopurinol and febuxostat are both xanthine oxidase inhibitors. They prevent hypoxanthine and xanthine metabolism to uric acid, and as such function to decrease serum uric acid levels.
Allopurinol should be given primary consideration in the treatment of gout because it is inexpensive and has been used for many years. Dosage usually starts at 100 mg/d and is titrated up to 300 mg/d. The initial lowering of serum urate levels that accompanies the administration of allopurinol and febuxostat has been associated with the development of acute gout attacks. Patients are at risk for these attacks after allopurinol or febuxostat initiation for up to 6 months. Educating the patient about the potential for acute attacks and the prescribing of a glucocorticoid dose pack may be indicated.
Prophylaxis with colchicine or non-steroidal agents may also be considered, though these agents may not be appropriate in patients with a decreased glomerular filtration rate. Prophylaxis with prednisone is not recommended but in an extreme case such as this patient’s, it may be considered for a short period of time.
At usual doses, allopurinol does not lower serum uric acid levels as much as febuxostat. Some physicians, especially rheumatologists, are more comfortable prescribing doses of allopurinol up to 800 mg/d in individuals with “normal” kidney function.9 It is unclear if this places patients at increased risk of toxicity or the severe allergic reactions that have been documented with allopurinol.
Febuxostat appears to be more potent and at routine doses has been found to be more effective than allopurinol. Febuxostat is not a purine analogue; as such, patients may not be at risk of developing the severe hypersensitivity reactions that have been seen with allopurinol. In a study of 762 hyperuricemic patients10 assigned to febuxostat (80 mg or 120 mg) or allopurinol (300 mg) daily for one year, the primary end point of a serum urate level less than 6 mg/dL was reached in 53% of patients receiving 80 mg of febuxostat, 62% of patients receiving 120 mg of febuxostat, and in 21% of individuals receiving
300 mg of allopurinol (P<.001).
Pegloticase is a pegylated uric acid- specific enzyme that is indicated for chronic gout in adult patients who are refractory to conventional therapy. Most animal species have the enzyme uricase, which converts uric acid to allantoin, which is benign and soluble. Humans do not produce this enzyme.11
Administering uricase to humans is immunogenic and results in the rapid production of antibody. Therefore, investigators developed a porcine uricase enzyme that was surrounded by methoxy polyethylene-glycol.
Due to the need for intravenous administration every two weeks and the rate of anaphylactic reactions, pegloticase is reserved for more severe, refractory cases of gout or in individuals who cannot tolerate other treatments. When antibodies do not render pegloticase inactive, it dramatically lowers serum urate levels and is extremely effective in tophaceous gout in patients in whom allopurinol or febuxostat cannot be given.12
Two replicated randomized prospective studies have been done with pegloticase.13 These studies enrolled 225 patients with serum urate levels ≥8 mg/dL with chronic gout refractory to other medications. Patients were randomized to placebo, a pegloticase dose of 8 mg every two weeks, or a pegloticase dose of 8 mg every four weeks. All patients received colchicine or nonsteroidal prophylaxis and received fexofenadine on the night prior and the morning of infusion, as well as 200 mg of hydrocortisone immediately before treatment.
Serum uric acid levels fell to less than 6 mg/dL in 42%, 35%, and 0% of individuals in the two-week, monthly, and placebo groups. Serum uric acid levels fell precipitously within 24 hours of the first infusion. Resolution of at least one tophus occurred in 40% of those receiving pegloticase every two weeks. Unfortunately, antibodies developed in nearly 90% of those receiving active drug, and 41% developed an inability to respond to pegloticase.
The patients who sustained a loss of the urate-lowering effect of pegloticase were especially at high risk of developing infusion reactions. The loss of response to pegloticase usually occurred within the first four months of therapy.
Thus, pegloticase represents a new therapeutic agent that can be dramatically effective in reducing tophus size and treating gout; however, development of antibodies may reduce its efficacy in a substantial proportion of patients. Instead of prescribing this medication infrequently, it is probably better to refer patients to a physician with expertise in its use.
Case: patient summary
As Mr. F had previously been on allopurinol and developed a questionable rash, he opted to receive febuxostat. In conjunction, he is changing his diet and has been placed on losartan (which decreases proximal tubular reabsorption of urate) instead of hydrochlorothiazide for gout. He is considering starting pegloticase if he does not notice a decrease in the size of his tophi.
Due to the severe nature of his gout and the risk of future gout attacks, Mr. F was also referred to a rheumatologist for help in management of his arthritis and the potential use of pegloticase.
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