Gout, Tophi and the Kidneys (PRA 2011 Presentation Part 3)

A serum uric acid (SUA) level <6mg/dl is the recommended target when treating patients with uncomplicated gout. At this level, below the limit of solubility of monosodium urate, crystal dissolution is promoted leading to less attacks of gout, reduction in tophus size and, in one old study, retards the decline of glomerular filtration rate. But so far, only tophi reduction has been shown in studies to be achievable as far as reversal of complications is concerned.
One observational study of 63 patients with chronic tophaceous gout showed that achieving a serum uric acid level <4mg/dl results in 2x faster reduction in tophus size compared to merely achieving a serum uric acid <6mg/dl. It was interesting to note that the reduction in tophus size didn’t depend on what medication (allopurinol, benzbromarone, or both) was used but rather on the SUA level achieved.
Therefore, in patients with complicated gout, several authors recommend a SUA level of 3-5mg/dl to promote tophus reduction. But why stop at SUA 3mg/dl and not push the patient to hypouricemia (SUA <2mg/dl). This is an interesting area of research right now. Recent epidemiologic studies show an association between elevated SUA and gout, kidney disease, cardiovascular disease and hypertension. And trials evaluating the benefits of lowering SUA to reduce risks associated with these diseases are well on their way. On the other hand, hypouricemia has also been associated with certain neurodegenerative diseases (multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and optic neuritis) and trials evaluating the impact of increasing SUA to prevent these diseases are also being evaluated. For now, at least, maintaining SUA within the “normal” range of 3-5mg/dl would appear most prudent.
Urate lowering therapies (ULT) should be started after the second attack of gout, in the presence of complications (tophi, arthropathy and nephrolithiases) and in settings for potentially difficult to treat gout (i.e. heart failure and chronic kidney disease stage 3). Uricosuric drugs which enhance urate excretion were previously preferred as first line drugs for gout given that 85-90% of gout patients underexcrete urate. However, probenecid and sulfinpyrazone essentially lose efficacy when serum creatinine >1.5mg/dl or creatinine clearance <50ml/min. Benzbromarone is the only uricosuric shown to retain its efficacy in patients with moderate renal insufficiency (CKD stage 3). Unfortunately, the drug was withdrawn from many markets over concerns of hepatotoxicity (rate 1/2500 compared to 1/4000 observed for allopurinol hypersensitivity syndrome).
Allopurinol, a xanthine oxidase inhibitor, is the most prescribed urate lowering agent following cost-effectivity analyses comparing XOIs and uricosurics. However there are concerns regarding dosing in patients with renal insufficiency. As early as 1984, dosing guidelines for allopurinol adjusted to the level of renal function were circulated. The authors had believed that the reduction of renal function increases the half life of allopurinol and reduces the excretion of oxypurinol thereby increasing the risks of adverse events. However, the widely circulated guidelines have never been validated.  In fact, several studies have shown that giving allopurinol in higher than the recommended doses for creatinine clearance does not increase the risk of adverse events. Likewise, studies have also shown that following these guidelines result in sub-optimal control of hyperuricemia. Now, there is a growing move to Treat-to-Target (TTT) – that is, to administer urate lowering agents to achieve a specified target SUA – instead of merely administering until the maximum allopurinol dose is achieved. The EMA allows allopurinol doses up to 900 mg/day while the US FDA recommends giving up to 800 mg/day. The Philippine CPG for uncomplicated gout recommends doses up to 600 mg/day.
However, observational data support the need to reduce Allopurinol doses in patients with kidney disease. But despite being available over the last 40 years, no studies have been made to determine the specific dose reductions in Allopurinol given the level of renal function. Likewise, no studies have been made to evaluate the safety of giving Allopurinol in doses of >300mg/day for prolonged periods of time. For now, it would be best to follow the guidelines (EULAR, BSR and Phil CPG) to start at 50-100 mg/day then gradually titrate up the dose by 50-100mg/day every 2-4 weeks while monitoring renal and liver function.


References

  1. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Ann Rheum Dis 2006; 65: 1312-1324.
  2. Jordan K, Cameron J, Snaith M, et al. British Society of Rheumatology and British Health Professionals in Rheumatology Guideline for Management of Gout. Rheumatology 2007; 46: 1372-74.
  3. Hershfield M. Reassessing SUA targets in the management of refractory gout. Curr Opin Rheum 2009; 21 (2): 138-42.
  4. Perez Ruiz F, Liote F. Lowering SUA levels: what is the optimal target for improving clinical outcomes in gout. Arth Rheum 2007; 57: 1324-28.
  5. Gibson T, Rodgers V, Potter C and Simmonds H. Allopurinol treatment and its effect on renal function in gout: a controlled study. Ann Rheum Dis 1982; 41:59-65.
  6. Kutzing M, Firestein B. Altered uric acid and disease states. J Pharm Exp Ther 2008; 324:1-7.
  7. El-Zawawy H, Mandell B. Managing gout: How is it different in patients with chronic kidney disease. Cleveland Clinic J Med 2010; 77: 919-28.
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