Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is a common glomerulonephritic disease that is one of the major causes of end-stage renal disease (ESRD) [1]. The prevalence of IgAN in male and female patients differs geographically. The ratios of male to female patients range from less than 2:1 in Asians to as high as 6:1 in Europe and the United States [2‐4]. Poor prognostic factors for renal progression in IgAN have been identified, including hypertension, heavy proteinuria, and severe histopathological abnormalities [5‐7]. However, the differences in renal progression between male and female IgAN patients are controversial. Several studies have found that renal progression occurs faster in males than in females [5, 8], whereas other studies have found either no gender differences [9, 10] or a greater risk of renal progression in females [11]. The impact of gender on the progression of IgAN remains uncertain. Meanwhile, few studies have specifically described the associations between gender and renal outcomes [8, 12]. To better understand these associations in IgAN patients, we conducted a retrospective study of a large number of Chinese patients with biopsy-diagnosed primary IgAN.

To date, only a few studies have evaluated differences in clinicopathologic features and the prognosis of IgAN between the different genders. In this study, we found that male IgAN patients presented with worse clinicopathological features than female patients. However, no significant difference was observed in long-term renal survival between male and female patients after frequency matching of baseline eGFR and SUA levels. In addition, we found that male and female patients shared similar risk factors, including low eGFR, heavy proteinuria and extensive segmental sclerosis, but the proportion of global glomerulosclerosis was a significant risk factor only in male patients.

According to our study, approximately 58.3% of the patients diagnosed with IgAN were females. The gender distribution of IgAN in China is similar to that in other nations in East Asia, with a male to female ratio of less than 2:1 [9, 15, 16], but it is different from that in Northern Europe and the United States, with a ratio as high as 6:1 [11, 17]. Variations in the gender distribution of IgAN may reflect differences in biopsy indications in different regions and could also be due to the diversity of genetic backgrounds.

In the clinicopathologic baseline data, we noticed the relatively worse condition of the male patients compared with the female patients, which is similar to previous reports. A study by Cattran DC et al. reported a higher mean arterial pressure (MAP) and lower corrected creatinine clearance (CrCl) in males than in females with IgAN [10]. In another study, Eiro et al. indicated that male gender was positively correlated with hypertension [18]. However, Tanaka K et al. more frequently observed a high level of urinary red blood cells (≥20/HPF) in female patients [19]. Our study not only confirmed these results but also found that male IgAN patients exhibited greater urinary protein excretion. In addition, we found that severe renal histological injury occurred even in male patients, including increased S, T and interstitial inflammation, which may be predictors of renal progression in IgAN. These findings suggest that male patients with IgAN disease, which was mainly mediated through worse clinicopathological characteristics, may have poorer renal outcomes.

However, the impact of gender on the progression of IgAN remains under debate. In a study by Goto M, male gender, rather than female gender, was associated with the risk of ESRD [5]. In addition, according to correlation analysis of the main prognostic risk factors affecting the progression of IgAN, Riispere Ž et al. concluded that IgA nephropathy progressed more rapidly in males compared with females [8]. The possible mechanisms underlying the renal protective role of female gender seem to be related to oestrogen [12]. However, other investigators have found either no gender-related differences or have observed women to be at a greater risk of a progressive loss of renal function. Donadio JV et al. reported contrary results for IgAN in female patients, pointing to worse disease outcomes [11]. Furthermore, a study performed by Cattran DC et al. showed no significant difference in long-term renal survival in IgAN between the different genders [10].

To our surprise, in our study, male gender predicted poorer outcomes in multivariable analysis, but male gender lost its prognostic value after frequency matching of baseline eGFR and SUA levels. The reason for this finding may be the possible confounding effects of baseline factors. Significant differences were observed in baseline eGFR and SUA levels between female and male patients. As shown in Table 1, a low eGFR and a high SUA level were more frequently observed in males than in females (P < 0.001). The major confounding factors in our study were imbalances in baseline eGFR and SUA levels. To control for the confounding effect of renal function on the association between gender and progression, eGFR- and Scr-matched and frequency matching analyses were performed. After frequency matching of clinically relevant factors, including eGFR and SUA levels, which are associated with renal outcomes, the gender difference lost its significance in multivariate analysis. Therefore, the potential risk effect of gender on renal outcomes may be due to these gender differences in the association between the eGFR and SUA levels and the progression of IgAN. The MDRD study showed slower renal disease progression in glomerular filtration rate (GFR) in women, as well as a significantly slower rate of GFR decline in women than in men [20, 21]. In general, women have lower average rates of creatinine generation, due to lower muscle mass and meat intake. Similarly, the SUA concentration increases with age and is physiologically higher in males than age-matched females [22]. The study by Nagasawa Y et al. indicated a gender difference with respect to the effects of uric acid on the progression of uric acid-induced kidney disease [23]. The mechanism of this gender difference in the association between the SUA level and the progression of IgAN remains unclear. Oestrogen suppresses the protein levels of the urate reabsorptive transporter (urate transporter1; URAT1) in the kidney, which results in an increase in uric acid excretion and a decrease in the uric acid level in the serum [24]. Moreover, Kolz et al. have found that the minor allele for rs734553 in SLC2A9 has a greater influence on reducing SUA levels in females and that the minor allele of rs2231142 in ABCG2 increases SUA levels more strongly in males compared with females [25].

Proteinuria, hypertension and renal function are important risk factors for IgAN [5, 7, 9, 16]. In addition, the proportions of glomerular glomerulosclerosis and S were critical predictors of poor prognosis of IgAN [14, 26, 27]. As expected, we confirmed that a low eGFR, heavy proteinuria and increased S were significantly associated with an increased risk in both male and female patients. Generally, no significant differences were observed in the associated risk factors or renal outcomes relative to gender in IgAN patients.

This study has several limitations. First, this was a single-centre retrospective study, with a median follow-up time of 48.6 (34.7, 62.7) months, therefore, we will continue to follow up with these patients. The current follow-up time was not long enough compared with the development of the disease. Second, treatment may play a role in the prognosis of IgAN, but the effects of therapeutic interventions could not be considered. Therapeutic regimes were flexible according to the physicians’ clinical decision making, and immunosuppression, in particular, was not standardized; thus, such unadjusted confounding impairs data interpretation. Therefore, further well-designed, multicentre, large cohort studies with longer, regular follow-ups are necessary to confirm these findings.

In summary, our findings suggested that male IgAN patients presented with worse clinicopathological changes than female patients, but when we controlled for the confounding effect of renal function by eGFR- and Scr-matching using frequency matching analyses, no significant difference in long-term renal survival was observed between male and female patients.