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

Abstract

A role for uric acid in the pathogenesis and progression of renal disease had been proposed almost a century ago, but, too hastily dismissed in the early eighties. A body of evidence, mostly accumulated during the last decade, has led to a reappraisal of the influence of uric acid on hypertension, cardiovascular, and renal disease. The focus of this review will be solely on the relationship between serum uric acid and renal function and disease. We will review experimental evidence derived from animal and human studies, evidence gathered from a number of epidemiological studies, and from the few (up to now) studies of uric-acid-lowering therapy. Some space will be also devoted to the effects of uric acid in special populations, such as diabetics and recipients of kidney allografts. Finally we will briefly discuss the challenges of a trial of uric-acid-lowering treatment, and the recent suggestions on how to conduct such a trial.

Key Words: Uric acid; Urate; Chronic kidney disease; Allopurinol; Febuxostat; Diabetes; Renal transplantation

Core tip: The evidence presented so far, derived from experimental, epidemiological, and a few, small, intervention studies, points towards a role for uric acid in the progression of chronic kidney disease and deterioration of renal function. However, conclusive proof, such as that coming from a randomized clinical trial, is lacking. Finally we will briefly discuss the challenges of a trial of uric-acid-lowering treatment, and the recent suggestions on how to conduct such a trial.

INTRODUCTION

Recent evidence, accumulated in the last decade, has led to a reappraisal of the role of uric acid (UA), in the deterioration of renal function and progression of chronic kidney disease (CKD). In this review, after providing a background concerning UA physiology, we will focus on evidence deriving from experimental, epidemiological and intervention studies linking UA to renal disease; we will also briefly review the role of UA in special populations, such as patients with diabetes and those with solid organ transplantation. In this review, we will use (although not completely correct) the terms urate and uric acid interchangeably.

PHYSIOLOGY OF UA

UA, an organic compound comprised of carbon, nitrogen, oxygen and hydrogen, is the oxidation end-product of purine metabolism in man and higher primates. Its elimination is urinary for approximately 70% and for the remaining part occurs through the gastroenteric tract. In most other mammals, with the exception of the Dalmatian dog, the enzyme uricase (urate oxidase) further oxidates UA into allantoin, a more soluble molecule. However, in man and higher primates, mutations in the uricase gene occurred during evolution and, making the enzyme non-functional, resulted in higher levels of serum UA in hominids than in other mammals[1]. The variability in serum UA levels is multifactorial and influenced by both environmental and genetic factors[2]. As already mentioned, renal elimination accounts for the disposal of the greatest part of UA daily load. Dietary factors, such as purine intake, may also be important determinants of serum UA levels. Serum UA can also rise due to high dietary fructose intake or reduced excretion by diseased kidneys[3]. Table 1 displays the principal causes of hyperuricemia in man.

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

Renal handling of UA is complex: in humans, only 5%-10% of the filtered UA is finally excreted, the largest part being reabsorbed at the tubular level, mostly by the proximal convoluted tubule. Earlier studies had suggested that UA is almost completely reabsorbed and that the amount excreted by the kidney results from active tubular secretion. However, recent evidence suggests that secretion plays a negligible role, and that excreted UA represents the amount filtered, escaping reabsorption[4]. Since UA is poorly soluble, it must be transported across cell membranes. Recently, four protein complexes that may act as UA transporters across the tubular cell membranes, have been identified: urate transporter/channel (UAT), two members of the family of organic anion transporters (OAT1 and OAT3) related to the tubular secretion, and urate transporter 1 (URAT1), which is the main protein responsible for tubular reabsorption, located at the apical membrane of the proximal tubular cells[5-14]. Although filtered UA is reabsorbed mainly via the URAT1 (coded by SLC22CA12), to a lesser extent it may be also secreted directly into the tubular lumen via the multidrug resistance peptide 4 pump[14]. Single nucleotide polymorphisms in URAT1, may be implicated in increased serum UA[15,16]. Accordingly, several mutations in SLC22A12 gene have been associated with primary gout[16,17]. It has also been reported that the mutation of 5-methylenetetrahydrofolate reductase C677T may contribute to increased levels of serum UA in both genders[18]. Although genetic factors affecting UA metabolism are mostly unknown, mutations in all of the proteins involved in the synthesis and secretion of urate, especially xanthine oxidase (XO) inhibitor, URAT1, MRP4, OAT1, and OAT3 could potentially be involved and may prove interesting targets for future drug development[14].

EXPERIMENTAL STUDIES

Using a rat animal model in which hyperuricemia was induced by the administration of the uricase inhibitor oxonic acid, a renal vascular disease that includes cortical vasoconstriction, afferent arteriolar swelling, and glomerular hypertension has been induced[19,20]. These physiological abnormalities were at least partially reversible by the administration of the XO inhibitor febuxostat[21]. Several mechanisms have been postulated and are under investigation for explaining these perceived endothelial abnormalities induced by elevated serum UA. Incubation of vascular smooth muscle cells with uric acid has been found to stimulate proliferation, angiotensin II production, and oxidative stress. These changes were reversed by the addition of captopril or losartan, which suggested an effect mediated through the renin-angiotensin system[22]. Hemodynamic abnormalities found in the hyperuricemic rat model were reversed by the administration of a superoxide scavenger, lending additional support to a link between elevated urate levels and damage induced by reactive-oxygen species (oxidative stress)[23]. Alterations in the expression of endothelin-1[24], which has been consistently associated with cardiovascular disease, have also been postulated as a potential mechanism of an association between hyperuricemia and cardiovascular conditions.

Endothelin-1 exerts a powerful vasoconstrictive effect by binding to the receptors ET-A and ET-B in human vascular cells[24]. How urate, known as an extracellular molecule, gains entry into vascular endothelial cells is still unknown but is possibly related to the demonstrated capacity of afferent renal arterioles to express URAT1[25]. This molecule is a urate-anion exchange transporter, expression of which had been previously described only in the renal tubular epithelium. The presence of URAT1 in endothelial cells may allow for explanations of intracellular effects of urate.

From a pathological standpoint, in hyperuricemic rats, light microscopy (PAS staining) of the kidney shows minor, non specific, changes consisting of tubular dilatation and atrophy in the renal cortex[19] and some glomerular sclerosis. However, on careful examination, one can also observe thickening of the afferent arterioles and some interlobular arteries, with sparing of the larger vessels.

In humans, besides crystal deposition nephropathy, which is rare, chronic hyperuricemia is characterized by crystal-independent renal damage. As early as in 1928, Gudzent described the association between gouty arthritis and renal disease. The histological lesion, “gouty nephropathy”, was found in autopsies of 79%-99% of patients with gout[26]. This lesion consists of interstitial fibrosis, glomerulosclerosis and renal arteriolosclerosis and arterial wall thickening, caused by intimal fibrosis, which resembles the lesion observed in hyperuricemic rats. Similar, non-specific, alterations also occur in patients with familial juvenile hyperuricemic nephropathy type 1 (FJHN-1), clinically characterized by the early onset of hyperuricemia, and sometimes gout, leading to end stage renal disease (ESRD) by the 4^th and 7^th decade of life[27]; FJHN-1 is associated with mutations in the uromodulin gene, and is inherited in an autosomal dominant manner.

EPIDEMIOLOGY

Table 2 summarizes the most relevant studies investigating the relationship between serum UA levels and renal function, incidence and/or progression of renal disease[28-39], which generally support a significant role of UA, although not all the studies are concordant in this respect[28,37]. A recently published study has clarified the contribution of urate as an independent risk factor in the development of incident stage 3 CKD, defined as a calculated glomerular filtration rate ≤ 60 mL/min[31]. The study divided the participants (n = 21475 healthy volunteers followed for a median period of time of 7 years) into three categories of serum urate levels: < 7.0 mg/dL, 7.0 to 9.0 mg/dL, and > 9.0 mg/dL. After adjustment for identified confounders, both higher categories of serum urate were associated with significant risks of developing stage 3 CKD [odds ratio = 1.74 (95%CI: 1.45-2.09) for the intermediate category of serum urate, odds ratio = 3.12 (95%CI: 2.29-4.25) for the higher category of serum urate]. Additional data showed that the adjusted odds ratio increased linearly up to a level of serum urate approaching 7 mg/dL, after which the slope of the curve increased. This implied considerably greater risk for developing the outcome at serum urate levels > 7 mg/dL. A large study including 177570 individuals for a total of 5275957 person-years of follow-up, showed UA to be associated with an increased hazard ratio for incident ESRD[32]. Our group, also showed, in 900 healthy normotensive subjects, an inverse relation between serum UA and epidermal growth factor receptor (e-GFR) at 5 years, and an increased risk of e-GFR reduction at follow-up, in hyperuricemic subjects[38]. Finally, in the recently published Jerusalem Lipid Research Clinic Cohort Study[39], the authors demonstrated an association between serum UA and long-term all-cause mortality, incident chronic and acute renal failure. Finally, on the other side, a recent study by Madero et al[28], performed in patients with advanced CKD, found a significant association between serum UA and mortality, but no independent association with the risk of progression to ESRD.

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.

SPECIAL POPULATIONS-DIABETES

In diabetes, the effect of serum UA levels on both the initiation and progression of diabetic nephropathy has recently been evaluated by several prospective observational studies. In a study from the Steno Diabetes Center, where a cohort of patients with type-1 diabetes was followed up from onset of diabetes and for a median of 18 years, serum UA was measured 3 years after onset of diabetes before any patient developed microalbuminuria[40]. At that time, all patients had serum UA levels within the normal range, however, the mean level of serum UA was significantly higher in those who eventually progressed to overt diabetic nephropathy, that is, persistent macroalbuminuria, compared to those who remained normoalbuminuric or who later progressed to microalbuminuria only. When segregating the patients according to quartiles of UA measured close to onset of diabetes and before development of micro- or macroalbuminuria, there was a significantly higher proportion of patients who developed overt nephropathy among those with serum UA levels in the highest quartile (4.2 mg/dL, still within the normal range) and with cumulative incidence of persistent macroalbuminuria of 22.3% as compared with the 9.5% among patients with uric acid in the three lower quartiles. In a Cox proportional hazard model including gender and age as fixed covariates, UA was independently associated with subsequent development of persistent macroalbuminuria (hazard ratio, 2.37 per each 1.7 mg/dL increase in UA level). Adjustment for confounders did not change the estimate significantly. In a recent study, Jalal et al[41] confirmed these findings by showing that serum UA was a strong predictor of the development of albuminuria in a prospective follow-up study of 324 patients with type-1 diabetes who were followed up for 6 years. The risk of micro- or macroalbuminuria was found to increase by 1.8-fold per each 1 mg/dL increase in serum UA. In this study, no separate analysis of patients either remaining in the microalbuminuric range or progressing further to macroalbuminuria was performed, because these groups were pooled together in the analysis. These two studies performed early in the course of type-1 diabetes, concurrently found serum UA to be significantly, after adjustment for confounders, associated with later development of persistent macroalbuminuria, thereby supporting the hypothesis that UA may be involved in the pathogenesis of microvascular complications in diabetes. However, a clear association with development of persistent microalbuminuria only, has not yet been established. In their study, Jalal et al[41] reported micro- and macroalbuminuria as a combined endpoint, whereas Hovind et al[40] were not able to find an association, which may be explained by the observation that patients progressing to microalbuminuria may be a more heterogeneous group than previously assumed, as not all patients progress to nephropathy. In an observational, cross-sectional study, Rosolowsky et al[42] found serum UA in the high-normal range to be associated with impaired renal function, in patients with type-1 diabetes and normo- or microalbuminuria. A recently published follow-up of a selected subgroup of the patients (excluding 183 patients with very low urinary albumin excretion rate), confirmed the results, extending them to show a clear dose-response relationship between serum UA and early decline in renal function evaluated by the serum concentration of cystatin C in 355 patients followed up for 4 to 6 years[43]. However, the study did not find any association between serum UA and progression or regression of urinary albumin excretion rate. Quite surprisingly, the significant decline in kidney function observed before proteinuria developed in 79 of 355 patients. These findings are discordant with those from a Japanese population study[44], where no association between UA and progression of diabetic kidney disease in 1622 Japanese patients with diabetes and chronic kidney disease was found. In the latter study, however, the patients had more advanced kidney disease.

As far as type 2 diabetes is concerned, despite its increasing worldwide prevalence, and its leading role as a cause of end stage renal disease, few studies of the effect of UA on the progression of renal dysfunction in this population of patients have been conducted. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan Trial[45], Zoppini et al[46] estimated that 22% (95%CI: 6-35) of the renoprotective effect of losartan was attributable to its urate-lowering effect. In another study, including 1449 patients with type 2 diabetes and preserved baseline renal function, followed for 5 years, hyperuricemia was associated with an adjusted odds ratio of 2.1 (95%CI: 1.16-3.76) for developing incident CKD. Finally, a recent study conducted on 1213 type 2 diabetics in Japan[47], after a 12-mo follow-up showed an increased incidence of incident nephropathy (odds ratio = 2.79, 95%CI: 1.90-4.12).

UA AND RENAL TRANSPLANTATION

The relationship between serum UA and renal function and graft survival in kidney transplant recipient is complex and controversial. Hyperuricemia is a common complication in organ transplant recipients, and frequently associated with chronic cyclosporine immunosuppressive therapy. Risk factors for hyperuricemia include decreased GFR, diuretic use, and preexistent history of hyperuricemia. The influence of hyperuricemia in patient and graft survival is unclear because uric acid is not usually considered a common risk factor for cardiovascular disease that affects graft and patient survival. Table 3 summarizes the most relevant studies exploring this relationship[48-59]. Although most studies tend to favour an influence of UA on graft function and survival, there are notable exceptions: for instance, Meier-Kriesche et al[55], reviewing their data from the SYMPHONY Study, in which a cohort of 1645 was followed-up for 3 years, found that the association of baseline UA with follow-up e-GFR, disappeared when adjusting for baseline e-GFR. Conversely, in the study by Haririan et al[56], after a mean 68 mo follow-up, hyperuricemia was associated with a 1.26 (95%CI: 1.03-1.53) hazard ratio of graft loss. Kim et al[58] recently reported their review of patients transplanted between 1990 and 2009, and they observed that hyperuricemia conferred an 1.45 (P < 0.001)hazard ratio of graft loss. Other studies have yielded conflicting results, although those with a longer follow-up, and those assessing graft survival (rather than e-GFR) as an end-point, tend to favour an adverse effect of hyperuricemia. The reason for the discrepancies among studies are not completely clear, however differences in the definition of hyperuricemia, duration of follow-up, end-points evaluated, and in adjustment for confounders and comorbidity may have played a role.

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.

URATE LOWERING THERAPY AND RENAL FUNCTION

Among drugs capable of lowering serum UA levels (Table 4)[60], uricosuric agents, with the possible exception of losartan, are mostly not indicated, or ineffective, in patients with CKD and/or kidney stones, uricase and its analogues are expensive, must be administered parenterally, and have important side effects; thus, long-term treatment of hyperuricemia relies mainly on xantine-oxidase inhibitors.

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.

Only a few studies evaluating the effects of urate lowering therapy in patients with CKD, or its influence on renal function, have been published (Table 5)[61-68]. Short-term studies suggest that lowering serum UA levels with allopurinol may have beneficial effects on renal function. In a retrospective study of 134 liver transplant recipients, Neal et al[61] evaluated eight patients with gout and 10 patients with asymptomatic hyperuricemia who received allopurinol. Over a median follow-up period of 3 mo, mean serum creatinine concentration decreased from 2.0 ± 0.2 to 1.8 ± 0.2 mg/dL (P = 0.01). Although these results are encouraging, the effect size is small, and the study has limitations (Table 4).

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.

Although limited by its uncontrolled and non-randomized design, the study by Fairbanks et al[62], involving patients with FJHN, is important, for its long duration of follow-up, and for evaluating a chronic disease, characterized by hyperuricemia since childhood, and almost invariably evolving to ESRD later in life.

Siu et al[63] studied the effect of the lowering of serum UA level on progression of CKD in an open-label randomized, controlled trial of allopurinol (100-200 mg daily) for 12 mo in 54 patients with proteinuria > 0.5 g per day and creatinine > 1.4 mg/d. At baseline, mean serum creatinine concentrations in the allopurinol and control group were 1.65 ± 0.6 and 1.85 ± 0.7 mg/dL, respectively. After 12 mo, mean serum creatinine increased in the control arm, but remained unchanged in the allopurinol arm (Table 5). Allopurinol had no effect on proteinuria. Overall, 12% of patients in the allopurinol arm experienced worsening of kidney function, compared with 42% in the controls. This trial was also limited by inadequate power and its open-label study design.

In a very intriguing study, Goicoechea et al[65] randomized 113 patients with CKD (e-GFR < 60 mL/min per 1.73 m²) to allopurinol 100 mg daily or no study medication. After 24 mo, e-GFR decreased by 3.3 ± 1.2 mL/min per 1.73 m² in the control group and increased by 1.3 ± 1.3 mL/min per 1.73 m² in the allopurinol group (P = 0.018). No differences in blood pressure between groups were reported. Fifteen of 56 patients in the control and seven of 57 patients in the allopurinol arm experienced a cardiovascular event (hazard ratio = 0.29, 95%CI: 0.09-0.86). Allopurinol was withdrawn in two patients as a result of gastrointestinal symptoms. No other serious adverse events were reported. Kao et al[66] assessed the effects of allopurinol 300 mg daily on cardiovascular surrogate measures over 9 mo in 53 patients with stage 3 CKD and left ventricular hypertrophy in a double-blind, placebo-controlled RCT. Compared with placebo, treatment with allopurinol was associated with a reduction in left ventricular mass index, and an improvement of the central Augmentation index, an indirect measure of arterial rigidity. In a small controlled study of forty type 2 diabetics with overt nephropathy, Momeni et al[67] observed a reduction of 24-h proteinuria, following 4-mo treatment with allopurinol (100 mg/d). Finally, Kanbay et al[68] in a small controlled trial, along a 4-mo observation period, found that healthy hyperuricemic subjects treated with allopurinol 300 mg, at the end of follow-up, had increased e-GFR, improved endothelial function, and decreased systolic BP with respect to baseline, whereas no change was observed in hyperuricemic and normouricemic controls.

PRACTICAL CONSIDERATIONS

While there exists a general consensus on treating hyperuricemia in patients with gout, in order to keep serum UA levels below 6.0 mg/dL[69], the dilemma whether to treat or not, asymptomatic hyperuricemia remains unresolved. The matter is further complicated by the use of different definitions for hyperuricemia in the various studies, and thus, it is difficult to identify a threshold for serum UA at which treatment should be initiated. In addition, the risk of developing CKD appears to rise as a continuum with increasing serum UA, rather than displaying a threshold effect. Nonetheless, based on the available epidemiologic studies, it seems reasonable to treat UA levels above 7.0 mg/dL in men, and above 6.0 mg/dL in women, with possibly, a lower threshold in people of Asian descent.

CONCLUSION

The evidence presented so far, derived from experimental, epidemiological, and a few, small, intervention studies, points towards a role for UA in the progression of CKD and deterioration of renal function. However, conclusive proof, such as that coming from a randomized clinical trial, is lacking.

Such a trial presents considerable challenges, nonetheless, it is feasible, as recently indicated by Badve et al[70], who have proposed a design for such a trial of uric-acid-lowering therapy (with either allopurinol or febuxostat, which has a better safety profile) for slowing the progression of CKD; briefly, they suggest a two-phase trial, with, first, a pilot study, evaluating surrogate end-points (change in UA level, GFR, proteinuria, systolic and diastolic BP, pulse wave velocity), including a limited number of patients (a few hundredths) and duration of follow-up (24 mo). The results of this pilot studies would help lay out the background (feasibility, power, design) for a subsequent outcome trial, using hard end-points, such as decrease in e-GFR of 50% (or > 25 mL/min per m²), ESRD requiring renal replacement therapy, and incident cardiovascular events as a secondary outcome. We fully endorse the suggestions of Badve, and heartily hope such a trial will be funded and performed, so that one more effective tool for halting or slowing the progression of renal disease might be supplied to our patients.