CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Diabetologist Physician, Director – Diabetes and Heart Research Centre (DHRC), Dhanbad, Chairman – RSSDI Jharkhand, Editor – CME INDIA.

This Scenario is Confusing

• 60-year-old man.
• Diabetic for 9 years, on Glimepiride 2mg/Sitagliptin 50mg and Metformin 1/day.
• CAD, Post PTC so on Nitrates, aspirin and statin.
• History of Gout 8 year back.
• CKD with recent eGFR 38 mL/min.
• Uric Acid 9.5 mg.
• Cardiologist started Allopurinol 100mg mg/day.
• Nephrologist stopped it and started Febuxostat 40 mg/day.
• Do you want to modify it?

Hyperuricemia is toxic to Kidneys

• Experimental studies of hyperuricemic models show.
• Both soluble and crystalline uric acid can cause significant kidney damage.
• It leads to ischemia, tubulointerstitial fibrosis, and inflammation.
• Most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD.
• Clinical trials have had variable results. 

Hyperuricemia is common in chronic kidney disease (CKD)

• If someone suffers from gout or symptomatic hyperuricemia lowering the SUA below the target of 6 mg/dL is recommended.
• It is to prevent acute flares, quality of life deficit.
• Many patients presenting for dialysis may have hyperuricemia.
  • 40% to 60% of patients with CKD stages 1 to 3.
  • 70% of patients with CKD stage 4 or 5.
• Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR).
• Hyperuricemia can also precede the development of kidney disease and predict incident CKDL.
• Lowering uric acid presents a critical strategy in the management and prevention of renal disease progression among patients with CKD.

The management of gout   

We want to:

1. Lower SUA (i.e., manage the hyperuricemia).
2. Provide prophylaxis while initiating ULT.
3. Treat gout flares.
4. Optimize dietary and lifestyle factors as appropriate.

Issues with Allopurinol in CKD

• Allopurinol retains a core role in gout treatment.
• Allopurinol is not contraindicated in patients with coexisting chronic kidney disease.
• It is at present considered safer than Febuxostat if coexisting cardiovascular conditions.
• But it must be appreciated that chronic kidney disease is a risk factor for allopurinol hypersensitivity, a low starting dose and gradual adjustment of the dose of allopurinol are safe.
• Siu et al (2006) reported that Allopurinol inhibits the progression of renal dysfunction by lowering the UA level and decreasing s-Cr in CKD patients with hyperuricemia.
• Conclusion: Allopurinol therapy significantly decreases serum uric acid levels in hyperuricemic patients with mild to moderate chronic kidney disease. Its use is safe and helps preserve kidney function during 12 months of therapy compared with controls.
• Allopurinol has long been regarded as a first-line drug for the treatment of hyperuricemia.
• Adverse reactions with Allopurinol such as renal dysfunction, hepatic dysfunction, Stevens-Johnson syndrome, and hypersensitivity vasculitis, have been reported.
• Allopurinol efficacy is insufficient in some cases.
• Allopurinol has low lipid solubility and is excreted via the kidneys; impaired renal excretion can lead to adverse reactions.
• Allopurinol carries a life-threatening risk of HLA-B*58:01–mediated cutaneous adverse drug reactions in some Asian populations.
• CKD increases additional risk for allopurinol side effects.
• Genotyping screening before allopurinol initiation and starting at a lower dose then slowly titrating the dose upward to achieve the SUA target are recommended in practice.

Febuxostat in CKD Preferred

• Febuxostat suppresses uric acid (UA) production by inhibiting xanthine oxidase. Unlike allopurinol, febuxostat does not inhibit nucleic acid metabolizing enzymes other than xanthine oxidase, so it is also called a “selective xanthine oxidase inhibitor.”
• Febuxostat has a high lipid solubility and a different carboxyl group from allopurinol, so it is also excreted in the bile. Therefore, it is considered that febuxostat can be given to patients with renal disease.

Why Febuxostat is preferred in CKD?

Important trials are leading the Path

The NU-FLASH trial 2015

• Febuxostat was more effective for hyperuricemia than allopurinol.
• In the NU-FLASH trial, 141 cardiac surgery patients with hyperuricemia were randomized to a febuxostat group or an allopurinol group.
• This study analyzed 109 patients with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m², and also analyzed 87 patients with stage 3 CKD.
• Febuxostat reduced serum UA more markedly than allopurinol.
• Febuxostat had a renoprotective effect based on the levels of urinary albumin and cystatin-C, as well as inhibiting oxidative stress, based on the O-LDL.
• Authors concluded: In cardiac surgery patients with renal dysfunction, febuxostat reduced uric acid earlier than allopurinol, had a stronger reno-protective effect than allopurinol, and also had superior antioxidant and anti-inflammatory effects.

Lee 2019  

• It was done in patients with hyperuricemia and CKD stage 3.
• Febuxostat reduced serum uric acid level and delayed CKD progression more effectively than allopurinol.

Two newer Trials (2020)

• Two studies, were published in which significant progression did occur in the control groups but for which no benefit in treatment of uric acid levels were noted.
• Neither study targeted the population at risk, that being participants with hyperuricemia with or without gout.
• Conclusions on treating hyperuricemia in CKD are still unclear.
• Preventing Early Renal Loss in Diabetes (PERL): The PERL trial, which did not show a benefit with allopurinol. The trial was of limited generalizability because the participants had long-standing type 1 diabetes with mild chronic kidney disease, minimal proteinuria, controlled blood pressure, and normal serum uric acid levels.
• Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX)- CKD-FIX was limited by inadequate power. There was inclusion of participants with normal serum uric acid levels. There was no targeting of therapeutic levels of uric acid. High percentage of participants discontinued the trial regimen (25 to 30%).

FREED Trial (2019)

• Febuxostat lowers uric acid and delays the progression of renal dysfunction.

Renal risk associated with febuxostat and allopurinol

• Rey and colleagues conducted a disproportionality analysis of acute renal failure with both drugs.
• Method-WHO’s VigiBase pharmacovigilance database.
• Duration-Individual case safety reports of suspected adverse drug interaction within the database between Jan. 1, 2008, and Dec. 31, 2018.
• It was 5.7 times more frequently among patients treated with Febuxostat.
• It was 3.3 times more often with Allopurinol.

CME INDIA Learning Points

• There are clear guidelines concerning management of symptomatic hyperuricemia in acute conditions such as gout, urolithiasis or acute urate nephropathy.
• There is ongoing debate on the role of UA in the pathogenesis of chronic kidney disease, hypertension, cardiovascular disease and heart failure.
• The management of asymptomatic hyperuricemia in such patients is still mainly up to physicians’ judgement.
• Individual considerations should always be taken into account when prescribing urate-lowering therapy.
• Hyperuricemia per se is not an indication for specific ULT.
• Hyperuricemia is a risk factor for CKD, and there is strong evidence that it can cause kidney disease by either crystal-dependent or -independent mechanisms.
• Trials examining the effects of uric acid lowering interventions in CKD have been inconsistent.

Comment on the Case Scenario

• CAD and CKD both coexist in this case. With new network meta-analysis in 2021, Feboxostat has not been found detrimental for cardiovascular system. (https://cmeindia.in/is-febuxostat-safe-in-hyperuricemia-with-history-of-cardiovascular-disease/)
• These days Febuxostat is clearly the drug of choice in presence of CKD. So Nephrologist can opt for Febuxostat in presence of CVD.
• Also, there is no harm in continuing Allopurinol in reduced doses if CAD and CKD coexist.
• If you disagree, please do comment.

References:

1. Sezai, Akira & Soma, Masayoshi & Nakata, Kin-Ichi & Hata, Mitsumasa & Yoshitake, Isamu & Wakui, Shinji & Hiroaki, Hata & Shiono, Motomi. (2013). Comparison of Febuxostat and Allopurinol for Hyperuricemia in Cardiac Surgery Patients (NU-FLASH Trial). Circulation journal: official journal of the Japanese Circulation Society. 77. 10.1253/circj.CJ-13-0082.
2. Burns CM, Wortmann RL. Gout therapeutics: New drugs for an old disease. Lancet 2011; 377: 165–177.
3. Halpern, R., Fuldeore, M. J., Mody, R. R., Patel, P. A. & Mikuls, T. R. The effect of serum urate on gout flares and their associated costs: an administrative claims analysis. J Clin Rheumatol 15(1), 3–7 (2009).
4. Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008; 58: 25–32.
5. Siu Y, Leung, K, Tong MK, Kwan T. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006; 47: 51–59.
6. Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020 Jun;382(26):2493-503.
7. Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020 Jun;382(26):2504-13.
8. Lee JW, Lee KH. Comparison of renoprotective effects of febuxostat and allopurinol in hyperuricemic patients with chronic kidney disease. Int Urol Nephrol. 2019 Mar;51(3):467-73
9. Kojima S, Matsui K, Hiramitsu S, Hisatome I, Waki M, Uchiyama K, Yokota N, Tokutake E, Wakasa Y, Jinnouchi H, Kakuda H, Hayashi T, Kawai N, Mori H, Sugawara M, Ohya Y, Kimura K, Saito Y, Ogawa H. Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy. Eur Heart J. 2019 Jun 7;40(22):1778-1786. doi: 10.1093/eurheartj/ehz119. PMID: 30844048; PMCID: PMC6554652.
10. Rey A, et al. Arthritis Res Ther. 2019;doi:10.1186/s13075-019-2011-y.

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