FEBUXOSTATE UNTUK HYPERURICEMIA

PADA PASIEN PGK

Andri Budiman SpPD FINASIM

PIT V PAPDI JAMBI

 GOUT ARTHRITIS

Old disease,is the most well

understood arthritis……
5th centuries..
Gout is still poorly
managed
 Epidemiology Gout and CKD

ASIA
Hyperurisemia
Japan 0,51%, South Korea 0,4%,
Hongkong 5,1%, Taiwan 4,92%,
Singapore 4,1%
Aboriginal community 7,63%

GOUT AND CKD

USA 14%, 8-16% globally

Risk of developing gout in
CKD doubled compared to
subjects not having CKD
 Renal Problem in Gout
Acute Uric Acid Chronic urate
nephropathy Nephropathy

-Acute renal failure resulting from Chronic Hyperuricemia and

precipitation of large quantities of uric gout studies revealed
acid crystals in collecting duct and microtophi formation in renal
medula interstisial
ureters
-Rapid malignant Cell Turn Over

Nephrolithiasis
GOUT and CKD
 GOUT AND CKD

Hyperuricemia-
associated disease:
-Hypertension
-CKD
-Cardiovascular disease
GOUT, CKD, CVD
Kang DH, et al. Semin Nephrol 2005;25:43-9
GOUT IN CKD
Pathophysiological Relationship between uric
acid and Chronic Kidney Disease
Prasad Sah et al Nephrol Urol Mon.2015;7

Disease

Medication

Diet
Uric acid and comorbid condition
Johnson et al, Nephrol dial Transplant 2013;28:2221-2228

Disease

Medication

Diet
Serum uric acid and progression of CKD
Hisatome E et al. CircJ 2016;80:1710-1711
IDEAS
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CREATIVITY
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TEAM WORK
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MANAGEMENT
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Risk of ESKD: Control vs Uncontrolled Gout
Stack et al. Association of Gout control with reduced Risk of Kidney Failure in The UK Health system
 General goals of gout therapy

Terminate acute attacks Prevent recurrences of

as promptly and safely acute gout attacks
as possible

Prevent complication of
monosodium urate in the
joint, kidney, or at other side
(chronic gout).
 f

Richette P, et al. Ann Rheum Dis 2016;0:1-14

 Gout management in CKD

Urate lowering therapy

Acute Gout
Systemic corticosteroids
Allopurinol..dose
Local steroid injection
colchicine adjustment
AVOID NSAID Febuxostat

ALLOPURINOL URICOSURIC AGENT

-STARTING DOSE NO GREATER PROBENECID

100mg Not recommended as first line
-Start at 50 mg /day in stage 4 or Contraindication :
worst CKD CCT<50mL/min
-Gradually titrate Urolithiasis
-HLA-B5801 Elevated urine uric acid
Allopurinol lowers Uric Acid level and prevent decline in
Kidney function
Goicoechea et al: CJASN 2010
GOUT treatment
 Dossage of ALLOPURINOL shoud be
Adjusted in CKD
Hande KR.Am.J med 1984

CKD , higher risk for severe

allopurinol hypersensitivity

STARTING DOSE SHOULD

BE NO GREATER THAN 100
mg
GOUT

Doherty M, Hui M, Rees F; Nat. Rev. Rheumatol,10,271-283 (2014)

Pedoman dan Diagnosis Pengelolaan Gout ; Rekomendasi Perhimpunan Reumatologi Indonesia 2018
 Treatment of
Hyperuricemia
in Gout Patient

Pedoman dan Diagnosis Pengelolaan Gout ; Rekomendasi Perhimpunan Reumatologi Indonesia 2018
Goals of Pharmacology Treatment in Gout
 Gout Treatment Overview
• 4 Main types of Treatment:
1) Dietary Therapy/ Lifestyle changes
2) Symptom relief for acute gout attacks
3) Urate- lowering therapy (ULT)
 Only therapy that addresses the underlying factors driving
gout
 Aim is to “cure” by lowering SUA levels to below the
saturation point for urate
4) Acute gout prophylaxis

28
Khanna D et al. Arthritis Care Res (Hoboken) 2012; 64:1431-46.
Hypouricemic agents

Allopurinol Rasburicase
Febuxostat

Uricosuric
- Benzbromarone
- Probenecid
- Sulfinpyrazone

Sattui SE, et al. Ther Adv Musculoskelet Dis. 2016;8(4):145-59.

Allopurinol

 First indicated in gout patients in 1963.

 Dose adjustment required in renal impaired patients
 Purine-base structure and excreted mainly through
kidneys
 May induce severe allergic reactions that are life
threatening, like toxic epidermal necrolysis and
Stevens–Johnson Syndrome
 Risk factors: HLA-B*5801(+), renal impairment and
age>65yr drug-drug interaction：may play a role in
triggering allergic reactions, such as ampicillin, thiazide
or ACEI
Hung SI, et al. Proc Natl Acad Sci USA. 2005; 102:4134–9.
Tassaneeyakul W, et al. Pharmacogenet Genomics. 2009; 19:704–9.
 Risiko tinggi Allopurinol: Severe Allergic
Reactions (SJS, TEN and DRESS)

Risiko tinggi Severe Allergic Reactions (SJS, TEN and DRESS).

Faktor risiko:
• HLA-B*8501 (+) terutama pada suku Han Chinese, Thai, Koreans dengan CKD3 atau lebih
• Renal impairment
• Elderly (usia >65)
Dosis Allopurinol harus dimulai dari dosis rendah untuk meminimalkan flares dan hypersensitivity
Multiple drug-drug interactions (e.g. ampicillin, thiazide, ACE inhibitors) – dapat memicu reaksi alergi
36
TEN: Topic Epidermal necrolysis DRESS: Drug Reaction with Eosinophilia and Systemic symptom
HLA-B*5801: What the guidelines Say?
 Allopurinol dosing and pharmacogenetics
− Prior to initiation of allopurinol, HLA-B*5801 testing
should be considered in selected patients sub-
populations at elevated risk for AHS (Evidence A).
Those with HLA-B*5801 and of Korean descent with
stage 3 or worse CKD (HLA-B*5801 allele frequency
~12%), or of Han Chinese or Thai extraction
irrespective of renal function (HLA-B*5801 allele
frequency ~6–8%)

2012 American College of Rheumatology Guidelines for Management of Gout

 The New Non-purine XOI: Febuxostat 38
Bi-Pathway Elimination

Febuxostat Allopurinol

Liver metabolize Liver metabolize

Metabolites Metabolites

Feces Urine Urine

45% 49% 80%

febuxostat prescribing information.

Murrell GA et al. Clin Pharmacokinet 1986; 11:343-53.
 Febuxostat Has Been Extensively Studied in
a Number of Clinical Trials
Phase 2 studies
FOCUS2
Study 0041 Open-label extension study
153 patients 116 patients
5 years

Phase 3 studies

APEX3
1072 patients
6 months EXCEL4
Open-label extension study
FACT5 1086 patients
760 patients 3 years
1 year

CONFIRMS6
2269 patients
6 months

1. Becker MA, et al. Arthritis Rheum. 2005;52(3):916-923. 2. Schumacher HR Jr, et al. Rheumatology (Oxford). 2009;48(2):188-194.
3. Schumacher HR Jr, et al. Arthritis Rheum. 2008;59(11):1540-1548. 4. Becker MA, et al. J Rheumatol. 2009;36(6):1273-1282. 5.
Becker MA, et al. N Engl J Med. 2005;353(23):2450-2461. 6. Becker MA, et al. Arthritis Res Ther. 2010;12(2):R63.
 Checklist of Dietary Recommendation
comorbidities
ACR
recommendation
AVOID
Organ meat high in purine :
High fructose corn syrup-
Obesity, alcohol intake sweetened sodas
Alcohol
Metabolic syndrome, type 2 DM

Hypertension, hyperlipidemia LIMITED

beef , lamb, pork, seafood
Urolithiasis , CKD Sweetened dessert, salt

Genetic cause, malignancy ENCOURAGE

Low fat or non fat dairy product
vegetables.
Summary
1 Uric acid is a potensial causative agent of
worsening renal function

2 Reducing uric acid levels reduced the progression of

renal disease
3 Lifestyle, dietary modifications, and pharmacologic
treatment for gout are thr proven strategies for reducing the
risk of worsening CKD.

4 Spesial attention should be given to specific contraindication to

certain drugs.

5 Allopurinol, low starting dose and conservative dose

escalations..
Febuxostat can be used in patient with GFR >30 without
dose adjustment