High Prevalence of Hyperuricemia and Gout in North American Patients with IgA Nephropathy

Objectives: To determine the prevalence of hyperuricemia (HU) and gout in 153 adult IgAN patients in North America (NA) and to compare this with the prevalence in the USA general population and with IgAN patients in Asia and Europe. Methods: Serum creatinine and serum uric acid (SUA) concentrations were measured in a central laboratory. Estimated glomerular filtration rates (eGFR) were determined in 109 of the patients and the prevalence of HU (SUA>7 mg/dl in men; >5.7 mg/dl in women) was correlated with chronic kidney disease (CKD) Stages 1 (eGFR ≥ 90 ml/min/1.73m2), 2 (eGFR 60-89 ml/min/1.73m2), 3 (eGFR 30-59 ml/min/1.73m2), and 4 (eGFR<30ml/min/1.73m2). Results: Seven patients (all males with a median age 50 years, range 33-63 years), who had been diagnosed with gout, were receiving allopurinol. The SUA levels in these patients were not used in defining the prevalence of HU. They all had reduced eGFRs (30-90 ml/min/1.73m2). HU was detected in 96 (65.8%) of the other 146 patients. SUA was >9mg/dl in 30 of these patients. HU was present in 43.2% of CKD1 patients; 67.6% of CKD2 patients, 85.7% of CKD3 patients, and both of the two CKD4 patients. Conclusions: Persistent HU and gout occur more frequently in IgAN patients in NA compared with the general population and with IgAN patients in other parts of the world.


Subjects and Methods
Inclusion criteria for this post-hoc study 1

Laboratory Evaluations
SUA and serum creatinine (SCr) concentrations were measured on the Roche Modular Chemistry Analyzer in a central laboratory (Laboratory Corporation of America). eGFR was calculated using both the Cockcroft-Gault (CG) and CKD-EPI equations [32,33].

Definitions
There is no standard definition for HU in men or women. This is exemplified by published reports of HU in IgAN patients from around the world, wherein at least 9 different definitions have been used [7,9,10,[13][14][15][17][18][19]. We define HU as SUA>7 mg/dl in men, >5.7 mg/dl in women.

Statistics
Summary statistics are reported as count (%). Pearson correlation coefficients were calculated to estimate the linear relationship between Open Access continuous variables. The criterion for statistical significance was set at alpha=0.05, two-tailed. SPSS version 22 (IBM, Armonk, NY) was used for analyses.

Prevalence of HU in non-gout IgAN patients
The overall prevalence of HU in 146 non-gout IgAN patients aged 20-63 years was 65.8% (96/146). The prevalence of HU in the 145 nongout IgAN patients aged 20-59 years is compared with the general US population in Table 1 [34]. One non-gout patient was 63 years old and is not included here. The data are categorized according to a) sex and b) age group. Severe HU (>9 mg/dl) in both men and women was present in 30 (20.5%) of the patients. Evidence of the persistence of severe HU in 18 of these patients, who had 3-4 SUA levels at monthly intervals (but were not treated), is depicted in Figure 1. Figure 2 shows the relationship between eGFR (based on both the CG equation and the CKD-EPI equation) and SUA levels. The correlation was stronger when the eGFR was estimated using the CKD-EPI equation, which will therefore be used below to define the CKD categories. HU was present in 43.2% of the patients who were categorized as CKD1 (eGFR ≥ 90 ml/min/1.73m 2 ); 67.6% of the patients categorized as CKD2 (eGFR 60-89 ml/min/1.73m 2 ); and 85.7% of the patients categorized as CKD3 (eGFR 30-59 ml/min/1.73m 2 ). Both of the two CKD4 patients (eGFR<30 ml/min/1.73m 2 ) had HU.

Prevalence of gout in IgAN patients
Seven male gout patients, 33-63 years of age (10% of 70 males in this age range), had SUA levels ranging from 5.9 to 9.5 mg/dl despite receiving allopurinol for gout. Clinical features, laboratory results and medications in the 7 patients, and in a 26-year-old male patient who had a SUA 11.4 mg/dl and then developed gout 6 months later, are shown in (Table 2). The eGFR was below the normal range in all 8 patients. Although the 7 gout patients were receiving allopurinol, SUA levels had been reduced to the desired range (<6 mg/dl) in only one of them (5.9 mg/dl). Also shown in Table 2 are the body mass indices (BMI), which ranged from 24.9 to 30.6 kg/m 2 in all but one patient who had a BMI of 44 kg/m 2 . Most of the gout patients would therefore be classified as "overweight" or "mildly" obese (BMI >30 kg/m 2 ).

Discussion
The main conclusion that can be drawn from this study is that the prevalence of HU is very high in North American IgAN patients. This includes patients who have a relatively well preserved GFR (i.e. HU was present in 55% of patients with CKD stages 1 and 2 (eGFR ≥ 60 ml/ min/1.73m 2 ). Our study also suggests that severe HU (SUA >9 mg/dl) and gout are relatively common in NA males with IgAN, especially those over 39 years of age, and that management of elevated SUA levels in such patients is sub-optimal since none of the asymptomatic HU patients were being treated and the SUA was <6 mg/dl in only one of the gout patients.
The prognostic importance of HU in IgAN patients has been examined in previous reports by two major approaches: a) correlation with renal histopathology and b) correlation with progressive deterioration of renal function. At least 9 reports, from 5 countries, have shown more severe histologic lesions in adult IgAN patients with HU when compared to patients with normal SUA levels [10][11][12][14][15][16]22,23,25]. The first large study evaluating the relationship between SUA and renal pathology in IgAN patients was reported by Ohno et al. in 2001 [10]. They found that HU correlated positively with tubulo-interstitial damage in a study involving 748 IgAN patients. This correlation was confirmed by Myllymaki in 2005 [11]. In 2011, Ghani et al. found that higher SUA levels were associated with Hass classes III to V [16]. Cheng et al. [22] in 2013,     [24] reported that HU was associated with global sclerosis in patients with IgAN, specifically patients with CKD Stage 3A [25].
Ten studies over the past 15 years have shown that HU is an independent risk factor for progressive renal insufficiency in IgAN patients [7,9,10,[17][18][19][20]22,24,25]. Four of the studies from China, which involved a total of 2,868 patients, showed that HU was an independent risk factor by multivariate analysis [17,18,22,24]. Similar findings were reported in 2 studies from Japan that involved 1,238 patients [7,10]. Other reports from Finland, Hungary and Korea involved fewer patients [9,19,20], but came to the same conclusions.
The prevalence of HU and gout in our patients appears to be considerably higher than reported elsewhere-even when different definitions for HU are employed (Table 3). For example, in Japan, where HU is defined as SUA>7 mg/dl in both men and women, the average prevalence of HU was 25% of 561 patients [7,10] compared to 52% of our patients using the same definition. In China, where HU is defined as SUA >7 mg/dl in men and >6 mg/dl in women, the average prevalence of HU in 4 reports describing 1472 patients [15,18,22,23] was 41% compared to 67% of our patients using the same criteria.
Why is HU so prevalent in IgAN patients in NA? The answer to this question is probably multifactorial. It is clear that the prevalence of HU in the USA population as a whole is on the increase [34]. It is likely that changes in diet, which include a higher intake of fructose, may play a significant role in this phenomenon [35]. In addition to these dietary considerations, recent studies have raised the possibility that the association of HU with IgAN may have a genetic component. Gharavi et al. [36] demonstrated linkage of IgAN to chromosome 6q22-23 in 60% of 30 IgAN kindreds and Nath et al. [37] demonstrated that a major focus for control of SUA was also present in chromosome 6q22-23 in 644 participants in the San Antonio Family Heart Study. Nath et al. [37] suggested that one or more genes in this genetic region may influence SUA levels and be associated with IgAN.   Open Access

4
Our study has also documented a high prevalence of gout in NA patients with IgAN (10% of 70 males aged 30-63 years). The most striking statistic in our study was seen in men aged 41-63 years. Five (19.2%) of 26 men in this age group were receiving allopurinol for gout when IgAN was diagnosed. Surprisingly, the prevalence of gout in IgAN patients has only been addressed in 3 previous publications. Hosoya et al. [7] described gout in 2 of 357 patients; Shi et al. [18] in 2 of 353 patients, and Syrjanen et al. [9] in 2 of 223 patients. However, Syrjanen et al. [9] reported that gout developed subsequently in 11 of their patients during a prolonged follow-up (median 10 years). It is worth noting that the patient cohort reported by Syrjanen et al. [9] was older (median age 41 years at the time of renal biopsy) than most series in the literature.
The results of our post hoc analysis indicate that many adult IgAN patients in NA have persistent levels of SUA that have been shown to be associated with increased rates of cardiovascular events [26][27][28][29], as well as progressive CKD. The lack of specific guidelines regarding the management of HU in NA patients with IgAN, or other forms of CKD, has resulted in most patients with severe HU being untreated (as exemplified by patients with persistent levels of SUA ≥ 9 mg/dl in the present study). In contrast, recent Japanese guidelines, published by Yamanaka, recommend that drug therapy to reduce SUA levels should be considered in patients with asymptomatic HU when the SUA reaches 8 mg/dl if the patients have renal disease or hypertension [38]. If the Japanese guidelines were adopted for patients in this study, uric acid lowering therapies would be considered in at least 31% of the patients (40% of the male patients). Hopefully, future clinical trials will define the risk/benefit of therapeutic approaches designed to lower SUA levels in patients with IgAN and HU, especially those with SUA levels ≥ 9 mg/dl, despite the challenges associated with such a trial as detailed by Badve et al. [39].