Treat-to-target allopurinol titration in CKD

CKD Managementmedium

A 68-year-old man with CKD stage 3b, hypertension, and type 2 diabetes is seen 3 months after his third episode within a year of acute pain and swelling of the right first metatarsophalangeal joint. He was treated with colchicine and then maintenance allopurinol, and symptoms resolved. Medications are allopurinol 50 mg, lisinopril 10 mg, amlodipine 5 mg, and furosemide 40 mg. Examination is unremarkable. K 4.9 mEq/L; creatinine 1.9 mg/dL; uric acid 6.9 mg/dL (reference 3–7); AST 32 and ALT 25 U/L. What is the most appropriate next step?

  1. A.Increase allopurinol doseCorrect
  2. B.Change allopurinol to probenecid
  3. C.Continue to monitor
  4. D.Change allopurinol to pegloticase

Explanation

The most appropriate next step is to increase the allopurinol dose. He has recurrent gout, with three flares in a year, and CKD stage 3b, both clear indications for urate-lowering therapy. The 2020 American College of Rheumatology guideline recommends a treat-to-target strategy with a serum urate goal below 6 mg/dL, achieved by starting allopurinol at a low dose (no more than 50 mg daily in stage 3 or worse CKD) and titrating upward every 2 to 5 weeks. His urate of 6.9 mg/dL is within the laboratory reference range but above the therapeutic target, so continued crystal deposition and further flares are likely. The traditional practice of capping allopurinol by creatinine clearance led to chronic underdosing. Allopurinol hypersensitivity syndrome is related mainly to a high starting dose and to HLA-B*58:01, not to the final maintenance dose, and gradual titration above creatinine clearance-based doses is safe and effective in CKD. HLA-B*58:01 testing is recommended before starting allopurinol in patients of Southeast Asian or African descent. Flare prophylaxis with low-dose colchicine, adjusted for kidney function, or another anti-inflammatory should continue for 3 to 6 months during titration. Furosemide raises urate and may be reconsidered if not essential. Pegloticase, a recombinant uricase given intravenously, is reserved for refractory tophaceous gout after failure of maximally titrated oral xanthine oxidase inhibitors. It is costly, carries infusion reaction risk, and is not indicated before allopurinol has been optimized. Probenecid is a uricosuric that works poorly when the GFR falls below about 50 mL/min, increases the risk of uric acid nephrolithiasis, and is not preferred as monotherapy in CKD. Continued monitoring alone accepts a urate above target in a patient with frequent flares, ignoring the treat-to-target recommendation and leaving him at risk of further attacks and tophi.

Why each option

A.
Correct. Treat-to-target therapy requires titrating allopurinol upward from 50 mg until serum urate is below 6 mg/dL, which is safe in CKD.
B.
Probenecid loses efficacy below a GFR of about 50 mL/min, raises uric acid stone risk, and is not preferred monotherapy in CKD 3b.
C.
Monitoring alone accepts a urate of 6.9 mg/dL, above the treat-to-target goal of below 6 mg/dL, in a patient with frequent flares.
D.
Pegloticase is reserved for refractory tophaceous gout after maximally titrated xanthine oxidase inhibitors fail, and allopurinol has not been optimized here.

Reference: FitzGerald JD, Arthritis Care Res 2020 (2020 American College of Rheumatology Guideline for the Management of Gout); Stamp LK, Arthritis Rheum 2012 (Starting dose is a risk factor for allopurinol hypersensitivity syndrome)

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