Uric acid and chronic kidney disease: A time to act?

Table 1 Causes of hyperuricemia

Drugs: Diuretics, salicylates, pirazinamide, cyclosporine, nicotinic acid

Diet: Excess intake of purine rich foods, such as animal internal organs, sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts, herring, mackerel, game meats, beer and alcoholic beverages

High dietary fructose intake

Ketogenic diet

Starvation

Reduced excretion due to chronic kidney disease

Malignancies, polycythaemia vera, haemolytic anaemias and other conditions with a rapid cellular turnover

Genetic causes: Mutations in enzymes involved in purine metabolism, such as xanthine oxidase, urate transporter/channel, organic anion transporters 1 and 3 and urate transporter 1, UMOD associated renal diseases, phosphofructokinase deficiency

Lead toxicity

Table 2 Epidemiological studies linking uric acid to chronic kidney disease

Ref.	Numerosity	Major findings
Madero et al[28]	840	CKD 3–4 and uric acid correlate with death but not with ESRD
Domronggkitchaiporn et al[29]	3499	Hyperuricemia (> 6.29 mg/dL) associated with increased odds (1.68) of reduced renal function
Iseki et al[30]	48177	Uric acid > 8 mg/dL increased CKD risk three-fold in men and 10-fold in women
Obermayr et al[31]	21475	Uric acid > 7 mg/dL increased risk of CKD 1.74-fold in men and 3.12-fold in women
Hsu et al[32]	177750	Higher uric acid quartile conferred 2.14-fold increased risk of ESRD over 25 years
Borges et al[33]	385	Elevated uric acid associated with 2.63-fold increased risk of CKD in hypertensive women
Chen et al[34]	5722	Uric acid associated with prevalent CKD in elderly
Sturm et al[35]	227	Uric acid predicted progression of CKD only in unadjusted sample
Weiner et al[36]	13338	Each 1 mg/dL increase in uric acid increased risk of CKD 7%–11%
Chonchol et al[37]	5808	Uric acid strongly associated with prevalent but weakly with incident CKD
Bellomo et al[38]	900	Each 1 mg increase in uric acid associated with 1.28 odds ratio of reduced e-GFR at 5 years
Ben-Dov et al[39]	2449	Uric acid > 6.5 mg/dL in men and > 5.3 mg/dL in women, associated with hazard ratios of 1.36 for all-cause mortality and 2.14 for incident CKD

CKD: Chronic kidney disease; ESRD: End stage renal disease; e-GFR: Estimated glomerular filtration rate.

Table 3 Studies investigating the association between serum uric acid and renal function/graft survival in patients with kidney transplantation

Ref.	Numerosity	Major findings
Gerhardt et al[48]	375	Hyperuricemia (> 8.0 mg/dL in men and > 6.2 mg/dL in women), associated with reduced graft survival
Armstrong et al[49]	90	UA independent predictor of follow-up e-GFR, but not of e-GFR change over time
Akgul et al[50]	133	No association found between serum UA and the development of chronic allograft nephropathy
Saglam et al[51]	34	Serum UA associated to development of cyclosporine A nephropathy (biopsy proven)
Akalin et al[52]	307	Hyperuricemia 6 mo after transplantation significantly associated with new cardiovascular events and graft dysfunction
Bandukwala et al[53]	405	Hyperuricemia associated with cardiovascular events, and, inversely with e-GFR
Karbowska et al[54]	78	Hyperuricemia associated with markers of endothelial dysfunction and inflammation
Meier-Kriesche et al[55]	1645	UA levels one month after transplantation not associated with follow-up e-GFR, after adjustment for baseline renal function
Haririan et al[56]	212	Serum UA during the first six months postransplant, is an independent predictor of graft survival
Boratyńska et al[57]	100	Serum UA not associated to graft survival during 30 mo of follow-up
Kim et al[58]	556	Serum UA levels affect graft function, even after adjustment for baseline e-GFR
Wang et al[59]	524	Retrospective study: UA significantly lower in patients with longer graft survival

e-GFR: Estimated glomerular filtration rate; UA: Uric acid.

Table 4 Urate lowering drugs

Pharmacologic options for the treatment of hyperuricemia

Xanthine-oxidase inhibitors: Allopurinol, febuxostat

Uricosuric agents: Probenecid, sulfinpyrazone, benzbromarone

Uricase: Rasburicase, pegloticase

Drugs and contrast media with hypouricemic properties, not primarily intended for the treatment of hyperuricemia

Acetohexamide, azauridine, chlorprothixene, dicumarol, estrogens, fenofibrate, glyceryl guaiacolate, iopanoic acid, losartan,meglumine iodapamide, phenylbutazone, salicylates and other NSAIDs, sodium diatrizoate, trimetoprim-sulfamethoxazole

NSAIDs: Nonsteroidal anti-inflammatory drugs.

Table 5 Studies of uric-acid-lowering therapy in patients with chronic kidney disease

Ref.	Study population	Intervention	Study findings	Limitations
Neal et al[61], 2001	18 liver transplant recipients with gout (n = 8) and hyperuricemia (n = 10)	Allopurinol (dose not stated)	Mean serum creatinine decreased from 2.0 to 1.8 mg/dL over a median period of 3 mo	Retrospective study; indication bias; small sample size
Fairbanks et al[62], 2002	27 patients with FJHN	Allopurinol (dose not stated)	Early treatment associated with slower decline of renal function	Case series, single center, partially inadequate controls
Siu et al[63], 2006	54 CKD patients with proteinuria > 0.5 g per day, serum creatinine > 1.4 mg/dL and serum uric acid > 7.6 mg/dL	Allopurinol 100-200 mg daily or their usual therapy for 12 mo	Lower serum creatinine in the allopurinol arm than the control arm (2.0 ± 0.9 vs 2.9 ± 0.9 mg/dL; P = 0.08) and no differences in effect on proteinuria (2.53 ± 4.85 g per day vs 2.16 ± 1.93 g per day; P = NS)	Small sample size, open-label design, short duration of follow-up
Shelmadine et al[64], 2009	12 prevalent adult hemodialysis patients	Allopurinol 300 mg twice daily for 3 mo	Reduction in LDL cholesterol by 0.36 μmol/L (14 mg/dL) (P = 0.04)	No control arm; small sample size; no safety data; no data on hemodynamic parameters; dose of allopurinol higher than recommended
Goicoechea et al[65], 2010	113 CKD patients with eGFR < 60 mL/min per 1.73 m2	Allopurinol 100 mg daily or no study medication for 24 mo	Allopurinol slowed the decline in eGFR (1.3 ± 1.3 mL/min per 1.73 m2vs–3.3 ± 1.2 mL/min per 1.73 m2); no effect on BP	Small sample size; open label and single-center study; allocation concealment unclear; assessor blinding unclear
Kao et al[66], 2011	53 stage 3 CKD patients with LVH	Allopurinol 300 mg daily or placebo for 9 mo	Allopurinol reduced LVMI (–1.42 ± 4.67 g/m2vs 1.28 ± 4.45 g/m2) and improved brachial artery FMD (1.26% ± 3.06% vs -1.05% ± 2.84%); improved augmentation index (P = 0.015)	Surrogate end-points only
Momeni et al[67], 2010	40 patients with type 2 diabetes and overt nephropathy (proteinuria > 500 mg/24 h, and serum creatinine < 3.0 mg/dL)	Allopurinol 100 mg or placebo	Treated patients had lower serum UA and 24 h proteinuria after 4 mo of follow-up	Small sample size, single-center, short follow-up, blinding unclear
Kanbay et al[68], 2011	30 hyperuricemic subjects vs 37 hyperuricemic and 30 normouricemic controls	4 mo treatment with allopurinol, 300 mg vs no study medication	Allopurinol treated patients had increased e-GFR with respect to baseline	Small sample size, short duration, blinding unclear

FJHN: Familial juvenile hyperuricemic nephropathy; CKD: Chronic kidney disease; e-GFR: Estimated glomerular filtration rate; LDL: Low-density lipoprotein; LVH: Left ventricular hypertrophy; FMD: Flow-mediated dilation; LVMI: Left ventricular mass index; UA: Uric acid.