Serum Phosphorus Might Be a Predictor of Kidney Disease Progression in IgA Nephropathy

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is defined by the predominant deposition of IgA in the glomerular mesangium [1, 2]. The clinical manifestations of IgAN are diverse, ranging from isolated hematuria, subnephrotic proteinuria, nephrotic proteinuria to rapidly progressive renal failure [3]. Approximately 30–40% of patients could slowly progress to end-stage kidney disease (ESKD) for 20–30 years [1]. Previous studies have indicated that impaired renal function, sustained hypertension, persistent proteinuria, and severe renal lesions at initial biopsy were risk factors for the long-term outcome of patients with IgAN [4‒8]. However, a substantial proportion of IgAN patients continue to progress even with well-controlled proteinuria and blood pressure. The factors responsible for IgAN progression are incompletely understood. Thus, new prognostic biomarkers were needed to improve the prediction of renal outcomes in patients with IgAN.

High levels of serum phosphorus are frequently observed in advanced chronic kidney disease (CKD) and associated with cardiovascular and all-cause mortality in dialysis patients [9‒11]. Recent studies have also demonstrated that phosphorus played a vital role in the progression of CKD and higher serum phosphate levels were associated with increased risk for progression to ESKD even within the reference range [12, 13], whereas the role of phosphorus in IgAN, which is the most common cause of CKD, has not been well established yet. This study aimed to evaluate the association between serum phosphorus and renal progression in patients with IgAN.

Patients diagnosed with IgAN from 2016.11 to 2019.12 at the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively selected for this study. The diagnosis of IgAN was based on the dominant deposition of IgA in the mesangial area as observed with immunofluorescence. Patients with secondary IgAN, such as IgA vasculitis, systemic lupus erythematosis and rheumatic disease, acute kidney injury, and missing serum phosphorus at the time of biopsy, were excluded. All enrolled patients had been followed up for a minimum of 12 months. A total of 247 IgAN patients were eligible for further analysis (shown in online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000535608). The study was conducted according to the Declaration of Helsinki and approved by the Human Research Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University. Written informed consent was obtained from all participants in this study.

We collected the clinical data, including age, gender, blood pressure, serum creatinine level, 24-h urine protein excretion, hemoglobin, albumin, serum calcium, and phosphorus at the time of kidney biopsy. Information was obtained from medical records about medications used during the follow-up, including renin-angiotensin system inhibitors (RASI), steroids, and other immunosuppressants. Pathologic lesions were evaluated according to the Oxford classification. The estimated glomerular filtration rate (eGFR) was estimated according to the Chronic Kidney Disease Epidemiology Collaboration equation. Mean arterial pressure (MAP) was calculated as the sum of one-third of pulse pressure and the diastolic blood pressure. Baseline was defined as the time of kidney biopsy. Patients were divided into three groups according to the tertiles of baseline serum phosphorus levels for the analysis of the association between serum phosphorus and the kidney disease progression. End-stage kidney disease (ESKD) was defined as an eGFR <15 mL/min/1.73 m² or the need for KRT (including hemodialysis, peritoneal dialysis, or kidney transplantation). During the follow-up, the composite endpoint was defined as a 30% decrease in the eGFR or ESKD.

Non-normally distributed and normally distributed quantitative parameters were expressed as medians (IQRs) and means ± standard deviations, respectively. Comparisons between study groups were performed with one-way analysis of variance or Kruskall-Wallis test for continuous variables and Pearson’s χ² test or Fisher’s exact test for categorical variables. Serum phosphorus was tested both as a continuous variable and a 3-level categorical variable (low, middle, and high) defined by tertiles of levels. We compared the cumulative incidence of kidney disease progression events across tertiles of phosphorus using Kaplan-Meier survival analysis and log-rank tests. The association between serum phosphorus and IgAN progression was examined by both a uni- and multivariable Cox proportional hazard model. Parameters significantly associated with composite endpoints by univariate analysis were included in the multivariate models. We built a reference Cox proportional hazard model for IgAN progression and tested whether incorporating serum phosphorus levels further improved the risk prediction. C statistic was calculated for the survival outcome. Interaction terms were used to investigate whether the association between serum phosphorus and kidney disease progression differed according to the use of immunosuppression. A two-sided p value <0.05 was considered statistically significant. All statistical tests were performed using SPSS version 20.0.

A total of 247 patients with IgAN were enrolled in this study. The baseline characteristics of these patients are presented in Table 1. At baseline, there were 135 (54.7%) men and mean age was 36.0 ± 12.4 years. The mean eGFR was 86.2 ± 38.7 mL/min/1.73 m², median protein excretion was 1.76 (IQR, 1.10–3.03) g/d, and MAP was 114.8 ± 18.0 mm Hg. The serum phosphorus and calcium levels were 1.30 ± 0.43 and 2.15 ± 0.41 mmol/L, respectively. The distributions of M1, E1, S1, T1/2, and C1/2 were 92.3%, 18.2%, 64.0%, 30.4%, and 31.6%, respectively. 168 (68.0%) patients were treated with RASI and 136 (55.1%) patients received immunosuppression (steroids and/or other immunosuppressive agents). The mean follow-up time was 35.8 ± 18.8 months. Overall, 55 (22.3%) patients reached the composite endpoint.

The patients were divided into three groups according to the tertiles of serum phosphorus levels: Group 1: 0.89 ± 0.14 mmol/L; Group 2: 1.23 ± 0.07 mmol/L; Group 3: 1.78 ± 0.34 mmol/L. The baseline characteristics of the cohort stratified by tertiles of serum phosphorus are summarized in online supplementary Table S1. Patients with higher serum phosphorus levels had greater daily proteinuria, lower serum calcium, and hemoglobin levels. The eGFR, follow-up time, use of RASI, and immunosuppression were similar among the three groups.

Baseline serum phosphorus level was first analyzed as a continuous variable in survival analysis. By using univariate Cox proportional hazards models, we found that baseline urine protein, eGFR, MAP, hemoglobin, albumin, serum phosphorus, Oxford S and T score were associated with the composite outcome. In the multivariate Cox proportional hazards models, after adjusting for age, gender, urine protein, MAP, eGFR, hemoglobin, Oxford S and T score, serum phosphorus remained an independent risk factor for poor renal outcome (HR, 2.586; 95% CI, 1.238–5.400, p = 0.011) (Table 2). The model containing clinical data at biopsy (age, gender, urine protein, eGFR, MAP, hemoglobin) and pathological variables (Oxford S and T score) was defined as the reference model. The addition of serum phosphorus to the reference model significantly improved the risk prediction of IgAN progression (C statistic, 0.836; 95% CI, 0.783–0.889) as compared with the reference model (C statistic, 0.821; 95% CI, 0.756–0.886) (online suppl. Table S2). In Kaplan-Meier survival analysis, the rate for the composite endpoint was 12.2%, 23.2%, and 31.3% in low, middle and high tertile, respectively (log-rank test, p = 0.016) (shown in Fig. 1).

We also evaluated the role of baseline serum phosphorus in kidney disease progression according to use of RASI and immunosuppression. The results showed the use of RASI did not significantly modify the association of serum phosphorus level with IgAN progression (P for interaction > 0.05). However, the ability of serum phosphorus level to predict progression was much stronger in IgAN patients without the use of immunosuppression (P for interaction = 0.017). In the subgroup without use of immunosuppression, after adjusting for age, gender, eGFR, proteinuria, hemoglobin, MAP, and Oxford S and T score, higher serum phosphorus level was independently associated with IgAN progression (HR 5.173; 95% CI, 1.791–14.944; p = 0.002). Whereas, in patients with use of immunosuppression, serum phosphorus level was no longer significantly associated with the composite endpoint (Table 3).

Abnormal phosphorus homeostasis is typical in patients with CKD and serum phosphorus level has been reported to be an important risk factor for kidney disease progression to ESKD and all-cause mortality in patients undergoing maintenance dialysis [9, 14‒17]. Whereas the association between the serum phosphorus level and disease progression in IgAN which is one of the leading causes of CKD still remains uncertain. In this study, we found that serum phosphorus level was an independent and strong predictor of disease progression defined as a 30% decline in eGFR or kidney failure in patients with IgAN, especially in those without use of immunosuppression. 1-mmol/L increment in serum phosphorus level was associated with a 2.59-fold higher risk for IgAN progression in adjusted analyses. The addition of serum phosphorus level significantly improved the performance of risk prediction over the clinical model that incorporated major clinical risk factors (eGFR, MAP, and proteinuria) and pathological characteristics at biopsy. These observations suggested that phosphorus-lowering therapy might be renoprotective in non-dialysis-dependent IgAN patients.

Previous studies exploring the relationship between serum phosphorus and CKD progression yielded inconsistent results. However, a meta-analysis study which included 12 cohort studies with 25,546 CKD patients indicated that higher serum phosphorus level is an independent risk factor for kidney disease progression and mortality among non-dialysis-dependent patients with CKD [12]. Regarding the heterogeneity of disease progression in different subgroups of CKD, the etiologies of CKD should be taken into consideration when assessing the prognostic biomarkers of CKD progression. To date, whether serum phosphorus was significantly associated with poor renal outcome in IgAN has not been well established. In a Chinese cohort of 957 IgAN patients with a median follow-up of 83 months, univariate Cox regression indicated that higher serum phosphorus levels were associated with disease progression, whereas the risk was attenuated after adjusting for other risk factors [18]. In contrast, our results showed higher levels of serum phosphorus were associated with greater risk of progression after adjustment for potential confounders including age, gender, eGFR, proteinuria, MAP, hemoglobin, Oxford S and T score, which was consistent with another large Chinese cohort study including 2,567 IgAN patients with a median follow-up of 31.90 months [19].

In addition, we incorporated the use of RASI and immunosuppression in the analysis and evaluated whether the medications modified this association. The results revealed that in patients without use of immunosuppression, serum phosphorus level was a stronger predictor of IgAN progression after adjusting for clinical and histologic risk factors. Nevertheless, this association was not observed in patients with immunosuppression. The TESTING study revealed that among patients with IgAN at high risk of progression, treatment with oral methylprednisolone for 6–9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease [20]. Furthermore, previous studies also suggested other immunosuppressants (combined MMF and corticosteroid therapy) appeared to be beneficial in reducing proteinuria and preserving renal function [21]. Therefore, IS treatment including steroids or immunosuppressants served as a potential protective factor for IgAN progression [7] and might counteract the detrimental effect of phosphorus. Therapy-targeting serum phosphorus might be more imperative in patients without immunosuppression. Additional studies are warranted to assess whether reducing phosphorus exposure by restricted dietary intake and/or concomitant treatment with phosphate-binding agents could slow the progression in IgAN. Furthermore, these findings might help to screen high-risk patients for future therapeutic clinical trials.

Previous studies have reported that there existed interaction between the renoprotective effect of ACE inhibition and phosphorus. REIN study suggested that high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors [13]. Possible mechanism involve phosphate could increase the production of the converting enzyme and activate the RAS by stimulating FGF-23 secretion and the FGF receptor to all members of the FGF family [22]. However, the ANSWER study found that 3 months of treatment with sevelamer did not reduce proteinuria in patients with CKD on optimal dual RAS blockade but achieved amelioration of inflammation and dyslipidemia [23]. In the current study, use of RASI did not significantly modify the association of serum phosphorus with IgAN progression and the problem still needs further investigation to be elucidated.

This study has several limitations. First, this is a single-center study and the sample size was relatively small. Second, few patients had repeated measurements of serum phosphorus, and only single baseline serum phosphorus measurement was involved in the analysis. Third, biomarkers relevant to phosphate metabolization, such as phosphate excretion, FGF-23, or 1.25 vitamin D, were not measured routinely which precluded further analysis.

This study indicated that higher serum phosphorus levels were independently associated with kidney disease progression in patients with IgAN, especially in those without immunosuppression. Serum phosphorus level should be evaluated and included in risk prediction at the time of diagnosis for IgAN patients. Lowering-phosphorus therapy might provide potential benefit for slowing disease progression for IgAN patients.

We are grateful to all the patients for their participation in this study.

The study was conducted according to the Declaration of Helsinki. This study protocol was reviewed and approved by the Human Research Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University, approval number (XJTU1AF2017LSL-018). Written informed consent was obtained from all the participants in this study.

The authors have no conflicts of interest to declare.

This study was supported by the Natural Science Basic Research Program of Shaanxi (Program No. 2023-JC-QN-1001).

H.L. and H.J. conceived of the presented idea and developed the study. H.L., Y.W., and X.D. assisted the data collection. H.L. and X.X. performed the analysis. H.L. and W.L. drafted the manuscript and assembled the Figure. J.S. and H.J. revised the manuscript. All authors discussed the results and commented on the manuscript.

Huixian Li and Wanhong Lu contributed equally to the manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.