Gout: an animated, cited guide

This page needs JavaScript for its animations. The outline and key answers are below, and every claim in the full version carries a numbered citation.

Not medical advice. Gout Companion is an educational synthesis of published literature. It does not replace a clinician.

What is in it

What gout is Who gets it, the numbers, and the four stages from high urate to tophi.
Where urate comes from Purines, xanthine oxidase, and how the kidney and gut handle urate.
Crystals vs serum urate Why crystals form above about 6.8 mg/dL and dissolve below the target.
A flare, hour by hour From a shed crystal to the NLRP3 inflammasome, interleukin-1β and neutrophils, then resolution.
Colchicine inside the cell From the pill to the neutrophil to the microtubule.
Treating a flare Colchicine, NSAIDs, glucocorticoids, IL-1 blockers and ice.
Colchicine dosing and safety Published doses, kidney function and drug interactions.
How urate-lowering drugs work Allopurinol, febuxostat, uricosurics and pegloticase.
Treat to target Titrating to below 6 mg/dL, and why flares rise in the first months.
Safety of urate-lowering drugs HLA-B*58:01, the CARES and FAST trials, interactions.
Diagnosis and the ACR/EULAR score Crystals under polarised light, imaging, and the 2015 classification calculator.
The differential Calcium pyrophosphate crystal arthritis, septic arthritis, cellulitis and others.
Gout, kidneys and heart Chronic kidney disease, stones, blood pressure and cardiovascular risk.
Living with gout Diet, alcohol, weight, other medicines and a flare plan.
Nursing care Assessment, giving the medicines, teaching and documentation.
Toward a cure Dissolving crystals for good, and the research pipeline.
History and people From podagra to polarised light and allopurinol.
Flashcards, quiz and glossary Revision for students.
Sources Every reference behind the app.

Part 4 · Diagnosis & complications

Gout, kidneys & heart

Gout rarely travels alone: kidney disease, kidney stones, high blood pressure and heart disease are all more common in people with gout. Each link in the network carries its number, its source and a label for whether urate is shown to cause it. Press play for four scenes, or pick any link to read it.

Each link shows

Scenes

Established urate (or the named factor) shown to cause itEarly evidence consistent signals, not provenHypothesis association only; Mendelian randomisation or trials do not support causation

Node positions are schematic; the numbers are not. Each link's measure comes from a different study design and population, so they cannot be compared or multiplied. ^{48,49,59,61,184,189,218,230,341}

How often gout comes with company

Show

US national survey data. NHANES 2007–2008 (5,707 adults, self-reported physician diagnosis): every proportion was substantially higher than in people without gout, and at a serum urate of 10 mg/dL [595 µmol/L] or more the prevalence was 3 to 33 times that at below 4 mg/dL [238 µmol/L]; kidney stones were not reported for that group. Metabolic syndrome comes from NHANES III (1988–1994), revised NCEP/ATP III definition, age- and sex-adjusted OR 3.05. ^49,454

Comorbidity arrives sooner

In UK primary care, 39,111 people with new gout were compared with 39,111 matched controls. Gout was linked to a Charlson comorbidity index of 5 or more at diagnosis (adjusted OR 2.51). The median time to a first new comorbidity was 43 months, against 111 months in controls. After adjusting for comorbidities, all-cause mortality was modestly higher (HR 1.13). ²²⁴

Weight and diabetes

In 47,150 men followed for 12 years, gout risk rose with body mass index: RR 1.95 at 25–29.9, 2.33 at 30–34.9 and 2.97 at 35 or more. Losing at least 10 lb gave RR 0.61. ⁴⁸ A meta-analysis of 10 prospective studies found RR 1.55 per 5 BMI units. ¹⁰ In high-risk men, gout at baseline carried RR 1.34 for new type 2 diabetes Early evidence ⁵⁴

Does treating help? The trials

The associations are strong. The question trials ask is different: does lowering urate, or calming inflammation, change kidney or heart outcomes? Urate-lowering therapy treats gout. It has not been shown to protect the kidney or heart in people who do not have gout. ^11,40,96,242

Kidney · no slowing

CKD-FIX

363 people with stage 3–4 CKD, no gout and a high risk of progression (mean eGFR 31.7 mL/min/1.73 m², mean urate 8.2 mg/dL [≈ 488 µmol/L]) took allopurinol 100–300 mg/day or placebo for 104 weeks. eGFR fell by 3.33 vs 3.23 mL/min/1.73 m² a year, a difference of −0.10 (P = 0.85). Serious adverse events were 46% vs 44%. Enrolment stopped early, at 369 of 620 planned. ¹¹

Kidney · no slowing

PERL

530 people with type 1 diabetes and early-to-moderate kidney disease took allopurinol or placebo for 3 years. Urate fell from 6.1 to 3.9 mg/dL [≈ 363 to 232 µmol/L] on allopurinol. Measured GFR after washout did not differ (difference 0.001 mL/min/1.73 m², P = 0.99), and albumin excretion was 40% higher with allopurinol. ⁹⁶

Kidney · missed its endpoint

FEATHER

441 Japanese people with stage 3 CKD and asymptomatic hyperuricaemia took febuxostat or placebo for 108 weeks. The eGFR slope was 0.23 vs −0.47 mL/min/1.73 m² a year, a difference of 0.70 (P = 0.1). A benefit appeared in the subgroup without proteinuria (P = 0.005), and gouty arthritis was rarer (0.91% vs 5.86%). ²⁰⁶

Kidney · open label

FREED Early evidence

1,070 older Japanese people with urate above 7.0 and up to 9.0 mg/dL [> 416 to ≤ 535 µmol/L] and cardiovascular or kidney risk were randomised, open label. Febuxostat cut a composite endpoint (HR 0.750), driven mainly by "renal impairment" (16.2% vs 20.5%), a laboratory endpoint. ²¹⁵

Heart · no benefit

ALL-HEART

5,721 people aged 60 or over with ischaemic heart disease and no gout were randomised to allopurinol up to 600 mg/day or usual care for a mean 4.8 years. MACE was 11.0% vs 11.3% (HR 1.04, 0.89–1.21), and all-cause death 10.1% vs 10.6%. ²⁴²

Pooled · no hard-outcome benefit

28 trials together

In 28 randomised trials (6,458 people, at least 6 months), urate lowering did not reduce kidney failure (RR 0.97), MACE (RR 0.93) or death (RR 1.04). It slowed the fall in GFR slope by 1.18 mL/min/1.73 m² a year and lowered systolic pressure by 3.45 mm Hg. The authors judged the evidence insufficient to lower urate to protect the kidney or heart. ⁴⁰

Heart · benefit

COLCOT

4,745 people within 30 days of a heart attack took colchicine 0.5 mg daily or placebo for a median 22.6 months. The primary endpoint fell from 7.1% to 5.5% (HR 0.77, 0.61–0.96), with stroke HR 0.26. Serious pneumonia was 0.9% vs 0.4%. ³⁹⁷

Heart · benefit

LoDoCo2

5,522 people with chronic coronary disease took colchicine 0.5 mg daily or placebo for a median 28.6 months. The primary endpoint was 6.8% vs 9.6% (HR 0.69, 0.57–0.83). Non-cardiovascular death was 0.7 vs 0.5 per 100 person-years (HR 1.51, 0.99–2.31). ²⁹⁴

Heart · neutral

CLEAR SYNERGY

7,062 people in 14 countries started colchicine or placebo soon after a heart attack and were followed for a median 3 years. The primary outcome was 9.1% vs 9.3% (HR 0.99, 0.85–1.16; P = 0.93), even though CRP fell by 1.28 mg/L at 3 months. Diarrhoea was 10.2% vs 6.6%. ¹⁸⁷

Approved · June 2023

LODOCO

The FDA approved LODOCO (colchicine 0.5 mg once daily) on 16 June 2023 to reduce the risk of heart attack, stroke, coronary revascularisation and cardiovascular death in adults with established atherosclerotic disease or multiple risk factors. Its efficacy evidence is LoDoCo2. The label contraindicates it with strong CYP3A4 or P-gp inhibitors, in CrCl < 15 mL/min and in severe hepatic impairment. ¹²³

Gout · observational

Colchicine in people with gout Early evidence

The colchicine heart trials enrolled people with coronary disease, not gout. ^187,294,397 In 99,800 people starting urate-lowering therapy in UK primary care, those also given colchicine prophylaxis had fewer heart attacks and strokes within 180 days (28.8 vs 35.3 per 1000 person-years; HR 0.82). ⁶⁰ In CANTOS, canakinumab cut gout flares at every urate level without changing urate. ³⁷⁵

Medicines for the other conditions

Lower urate and gout risk

SGLT2 inhibitors Early evidence

Across 62 trials in type 2 diabetes they lowered urate by about 0.63 mg/dL [−37.73 µmol/L], with the effect lost in CKD subgroups. ⁴⁵³ New gout was less common than on GLP-1 agonists (4.9 vs 7.8 per 1000 person-years; HR 0.64), and a meta-analysis of 5 trials gave HR 0.55. ^13,137 In people who already had gout, recurrent flares fell (RR 0.66 vs DPP-4 inhibitors), and recurrent stones fell too (rate ratio 0.67). ^257,258

Lowers urate a little

Losartan

Among people with hypertension, losartan carried RR 0.81 for new gout and calcium-channel blockers RR 0.87, while diuretics carried 2.36, β-blockers 1.48, ACE inhibitors 1.24 and other ARBs 1.29. ⁵⁷ In 13 people with gout, losartan 50 mg lowered urate from 538 to 491 µmol/L [≈ 9.0 to 8.3 mg/dL]; irbesartan did not. ⁴³⁵ ACR 2020 conditionally recommends choosing losartan when feasible. ¹³⁵

Raise gout risk

Diuretics

In 91,530 UK cases, the adjusted OR for gout with current use was 2.64 for loop diuretics, 1.70 for thiazides, 2.30 for thiazide-like diuretics and 4.65 for a loop plus a thiazide; potassium-sparing diuretics were neutral (1.06). ³⁰ ACR 2020 conditionally recommends switching hydrochlorothiazide to another antihypertensive when feasible. ¹³⁵

A safety signal

Febuxostat and the heart

In CARES (people with gout and cardiovascular disease), febuxostat was noninferior to allopurinol for MACE but cardiovascular death was higher (HR 1.34). ⁴³¹ FAST found no excess (HR 0.85). ²⁴¹ The US label carries a boxed warning and restricts febuxostat to second line, and ACR 2020 conditionally recommends switching away from it after cardiovascular disease or a new event. ^127,135

What the guidelines do with all this. KDIGO 2024 says people with CKD and gout should be offered urate-lowering treatment (1C), preferring xanthine oxidase inhibitors, and suggests not lowering urate in CKD without gout just to slow the kidney's decline (2D). ¹⁹⁷ ACR 2020 recommends against urate-lowering therapy for asymptomatic hyperuricaemia, including in people with CKD, cardiovascular disease, stones or hypertension; only 20% of people with asymptomatic urate above 9 mg/dL developed gout within 5 years. It does favour starting at a first flare when CKD stage ≥ 3, urate > 9 mg/dL [535 µmol/L] or stones are present. ¹³⁵ The Hong Kong consensus asks that everyone with gout be screened for kidney disease and cardiovascular risk factors. ⁴⁴⁰ EULAR 2016 adjusts the allopurinol dose to kidney function. ³³¹

Exam hookAssociation is not causation. About 1 in 4 people with gout has CKD ≥ 3, and about 1 in 4 with CKD has gout. Allopurinol did not slow CKD in CKD-FIX or PERL, or prevent MACE in ALL-HEART. Urate causes only gout and stones convincingly. After a flare, CV event odds roughly double for 60 days (OR 1.93).

In plain wordsGout often comes with kidney, blood pressure and heart problems, so checks for those are part of gout care. Doctors know these conditions are linked, but not that high urate itself harms the heart or kidneys. Lowering urate is for the gout. Some blood pressure and diabetes medicines help urate a little, and water pills can raise it, so it is worth asking before any change.