allopurinol use may decrease CKD

A recent data-mining study confirmed that high dose allopurinol seems to be actually beneficial to kidney function (see gout ckd allopur helps jamaintmed2018 in dropbox, or doi:10.1001/jamainternmed.2018.4463 0)

Details:

-- 4760 adults aged 18-89 with newly diagnosed gout were propensity score-matched with similar number of controls

-- patients were from The Health Improvement Network in the UK, which includes more than 11 million patients

-- mean age 57, 83% male, BMI 30, gout duration 1.2 years, hospitalizations in prior year 11%, allopurinol dose 300mg in 95%/400-500 mg in 4%, mean GFR 77 mL per minute, CKD stage II 71%/hypertension 47%/diabetes 8%/cardiovascular disease 11%/heart failure 4%

-- concomitant medications: diuretics 31%, ACE-I 26%, losartan 2%, colchicine 17%, NSAIDs 73%, low-dose aspirin 17%

-- propensity scoring covariates included gout duration, baseline serum uric acid level, baseline kidney function, baseline albuminuria, age, sex, BMI, comorbidities (cardiovascular, diabetes, heart failure, hypertension), hospitalization within one year prior to starting the study, number of visits to the general practitioner within the year prior to the study, medication use (ACE-I, low-dose aspirin, colchicine, diuretics, insulin, other diabetes drugs, losartan, non-losartan ARBs, NSAIDs)

-- all patients were on >= 300 mg of allopurinol  per day

-- exclusions included chronic kidney disease stage (CKD) III or higher

-- primary outcome: development of chronic kidney disease stage III or higher

-- follow-up of 4 to 5 years

Results:

-- development of CKD stage III or higher:

    -- allopurinol: 579 people

    -- control: 623 people

-- risk of developing CKD stage III or higher: 13% decreased with allopurinol, HR 0.87 (0.77-0.97)

    -- adjusting for propensity score covariates: 12% decreased with allopurinol, HR 0.88 (0.79-0.99)

-- in those on allopurinol <300mg: no association with renal function decline, HR 1.00 (0.91-1.09)

Commentary:

-- gout is really common, 3.9% of Americans, but only 1/3 are on urate lowering therapy (ULT)

-- 20% of patients with gout have CKD stage III or higher, as compared to 5% of those without gout

    -- it is likely that this high rate of CKD in patients with gout is related to potential deleterious effects of hyperuricemia, use of NSAIDs, prevalent comorbidities of hypertension and diabetes (and their associated medications)

    -- the reno-protective benefit of allopurinol may have to do with lowering the uric acid level itself, or otherwise reducing oxidative stress

-- many people haved use the results of the quite old Hande article as a means to dose allopurinol for those with renal disease (see AmJ Med.1984;76(1):47-56). This study looked at 78 patients with severe allopurinol toxicity, where the majority were on 200 to 400 mg of allopurinol per day. The study found an inverse relationship between allopurinol clearance and creatinine clearance, and that those taking allopurinol 300 mg per day had elevated levels of its metabolite, therefore suggesting reduced doses of allopurinol in the setting of renal insufficiency. However, as per the UK study above, “there are no data

demonstrating reductions in allopurinol hypersensitivity syndrome (AHS) risk with this approach" (ie, no data suggesting that keeping the allopurinol dose lower decreases AHS). And, the result of this Hande approach may lead to under-treatment of gout.

    -- More recent studies do suggest starting with lower doses of allopurinol, but then escalating to the appropriate uric acid target is safe and does not increase the risk of AHS (but slowly, see below)

    -- there is no evidence in the literature that allopurinol is nephrotoxic

-- most patients need more than 300 mg a day to lower their uric acid levels efficiently. So, most patients should benefit from its apparent renoprotective effect of >= 300mg/d, per the above UK study (see http://gmodestmedblogs.blogspot.com/2017/05/higher-allopurinol-dosages-for-gout.html  )

-- small studies have confirmed the renoprotective benefit of ULT, one comparing patients on allopurinol plus colchicine, vs colchicine alone, another with high-dose febuxostat of 120 mg per day

--​ this UK article brings up a particularly confusing issue: guidelines overall suggest uric acid lowering to <5 or <6 mg/dL, but a recent Am College of Physicians guideline questioned the whole approach of uric acid targets, commenting that there was insufficient evidence that the benefits of reaching a specifc target outweighed the harms of repeated monitoring and adverse effects of the meds, and the lack of data that find one target is better than another, though they do note that observational studies seem to consistently find that those with lower uric acid levels have fewer gout flares (see gout management guidelines AIM2016 in dropbox, or doi:10.7326/M16-0570). see http://gmodestmedblogs.blogspot.com/2016/12/new-gout-management-guidelines.html  

    ​--a recent AHRQ Comparative Effectiveness Review noted that there are high-strength data that urate lowering therapy does not affect the risk of gout flares in the first 6 months, and that colchicine (low-dose) should be used for at least 2-3 months, but also that  there is only low-strength evidence that treating urate levels to a specific target is beneficial (see https://effectivehealthcare.ahrq.gov/sites/default/files/related_files/gout_executive.pdf ), or http://gmodestmedblogs.blogspot.com/2016/03/gout-management-ahrq-report.html 

    -- it probably makes sense to check the HLA-B*5801 allele to see if increased frequency of AHS, especially in those of asian ancestry) prior to starting allopurinol, or use febuxostat (though there are reports of increased cardiovascular events with that)

    --and, all that being said, current practice is to titrate uric-acid lowering to achieve a target of <6 mg/dL in general, and <5 mg/dL in those with tophaceous gout

    --and, it is best to lower the uric acid level slowly (eg <0.6 mg/dL per month for first 6 months), which seems to be associated with fewer gout flares (lowering uric acid levels itself can induce flares, hence the benefit also of concommitant colchicine)

-- urate-lowering therapy may have other benefits:

    --see http://gmodestmedblogs.blogspot.com/2016/03/hyperuricemia-allopurinol-decreases.html  for Taiwanese study finding dramatic decrease in cardiovascular disease with ULT

    --see http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html  for a really intersting blog on an evolutionary perspective suggesting that eating fructose (which increases uric acid levels) leads to fat depositiion, which provides an evolutionary advantage in times of starvation (and that a high fructose diet in animals, along with allopurinol, blocks many of the features of the metabolic syndrome)

--also, as a related item given the high frequency of hypertension overall and esp in patients with hyperuricemia, there are antihypertensives which help lower uric acid levels, specifically losartan (but NOT other ARBs), nifedipine and amlodipine (see htn and uric acid losartan ccbs bmj 2012 in dropbox, or doi:10.1136/bmj.d8190)

so, given the above and even without rock-solid evidence to support this, i really do embrace a pretty aggressive approach to uric acid lowering in those with gout, sometimes going to quite high levels of allopurinol. and also non-pharmacologic interventions to decrease uric acid levels (though a recent BMJ article found that genetics were significantly more decisive than diet, but will leave this to another blog). and, it does make sense to start low, go slow, and titrate up to a uric acid level of <6 mg/dL (<5 mg/dL with tophaceous gout). and this leads to a few ancillary issues:

--changing anti-hypertensives to losartan (1st choice), then amlodipine/nifedipine

--reinforcing low fructose diet (soda often being the major culprit with high-fructose corn syrup), decrease alcohol, decrease organ meats/high purine diets, dec alcohol, and do healthy lifestyle things to decrease cardiometabolic effects associated often with hyperuricemia (exercise, weight management...)

--continuing colchicine at least for 3 months after starting ULT

--try really hard to avoid NSAIDs, including steroid joint injections in those with 1-2 joints involved

geoff

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https://blogs.bmj.com/bmjebmspotlight/2016/12/01/primary-care-corner-with-geoffrey-modest-md-new-gout-management-guidelines/

gout management AHRQ2016,

gout management guidelines AIM2016