Introduction

Chronic kidney disease (CKD) is a major public health problem, especially in developing countries [1]. A cross-sectional study in China showed that the prevalence of chronic kidney disease was 10.8% among adults aged 18 years and older [2]. Immunoglobulin A (IgA) nephropathy, one of the primary glomerulonephritis, is the most common cause of chronic renal failure [3]. IgA nephropathy is defined by the presence of IgA-dominant or co-dominant immune deposits within glomeruli [4]. The disease can present with a spectrum of clinical syndromes ranging from asymptomatic abnormalities noted on urinalysis to rapidly progressive glomerulonephritis, and there is a substantial variation in clinical course and outcomes [5]. In recent researches, the mucosal immune system and complement system play an important role in IgA nephropathy pathogenesis. Up to now, there is no ideal therapy to treat IgA nephropathy. Several risk factors have been identified for IgA nephropathy progression and need to be intervened as early as possible, which include proteinuria, high blood pressure, and estimated glomerular filtration rate (eGFR) at the time of renal biopsy [6,7,8]. However, there are still some patients at high risk of evolving into end-stage kidney disease (ESKD) even after 20 years [9]. Therefore, there is an urgent and pressing need to explore new predictive factors to prevent the progression of IgA nephropathy.

Recently, a meta-analysis of 12 cohort studies with 25,546 patients found every 1 mg/dL (0.32 mmol/L) increase in serum phosphorus level was associated independently with an increased risk of kidney failure [hazard ratio (HR) = 1.36, 95% confidence interval (CI) = 1.20–1.55] [10], and a prospective study in China showed that serum phosphorus was an independent risk factor for adverse renal outcomes in patients with CKD [11]. However, studies on the effect of serum phosphorus on adverse renal outcomes in IgA nephropathy are scarce, and the relationship between serum phosphorus and IgA nephropathy progression remains uncertain, especially normal-range serum phosphorus. Therefore, our study aims to explicit the relationship between the normal-range serum phosphorus and the progression of IgA nephropathy.

Materials and methods

Study population

We assessed the patients with primary IgA nephropathy who were diagnosed by percutaneous renal biopsy at the Department of Nephrology, Qilu Hospital of Shandong University, between January 1, 2017, and August 30, 2021. The inclusion criteria were that patients were ≥ 18 years old, baseline serum phosphorus was within the normal reference range for the laboratory at Qilu Hospital of Shandong University, and eGFR (according the chronic kidney disease epidemiology collaboration) was above 15 mL/min per 1.73m2 at baseline. The exclusion criteria included patients with secondary IgA nephropathy or other kidney diseases, such as IgA vasculitis, systemic lupus erythematosus, diabetes nephropathy, and hypertensive nephropathy. Patients who received phosphate binder or other drugs that affected serum phosphate levels therapy and with unavailable clinical data and follow-up time of fewer than three months were also excluded.

Data collection and definitions

All data were obtained from the database of Qilu Hospital of Shandong University. Clinical data at the time of renal biopsy were used as baseline data, including age, sex, height, weight, systolic and diastolic blood pressure, hemoglobin, urine albumin to creatinine ratio (UACR), plasma albumin, triglyceride, cholesterol, serum creatinine, serum uric acid, and serum phosphorus. Medications used during follow-up were also collected, including glucocorticoid or other immunosuppressants, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs).

The Chronic kidney disease epidemiology collaboration equation was used for reporting eGFR [12]. Baseline serum phosphorus levels at the time of renal biopsy were measured using an automatic biochemical analyzer (Hitachi AutoAnalyzer 7100, Hitachi, Japan) with a reference range of 0.60–1.60 mmol/L, and serum phosphorus levels above 1.6 mmol/L were considered hyperphosphatemia [13]. Patients were categorized into three groups according to tertiles of baseline serum phosphorus (first tertile: 0.73–1.04 mmol/L; second tertile: 1.04–1.21 mmol/L; third tertile: 1.21–1.60 mmol/L). The composite outcome was a decrease of at least 50% in the eGFR from baseline or ESKD (defined as eGFR < 15 mL/min/1.73 m2 or need for kidney replacement therapy).

Histopathologic parameters

All kidney tissue specimens were obtained by percutaneous renal biopsy in Qilu Hospital of Shandong University and were scored according to the Oxford Classification of IgA nephropathy [14], including mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and cellular/fibrocellular crescent (C). On immunofluorescence microscopy, the severity of mesangial deposition of IgA, immunoglobulin G (IgG), immunoglobulin M (IgM), complement component 3 (C3), and complement component 1q (C1q) was coded as five grades of 0 to 5 according to 0, ± , 1+ , 2+ , 3+ , and 4+ .

Statistical analysis

For continuous variables, data with normal distributions were described as means with standard deviations and compared using a one-way analysis of variance (ANOVA) test. Skewed data were expressed as the median (lower quartile, upper quartile), and the Kruskal–Wallis test was used to identify differences among the three groups. Categorical data were expressed as numbers (percentages) and assessed using the chi-squared test. The Kaplan–Meier survival curve with the log-rank test, restricted cubic splines, and Cox regression model were used to analyze the association of serum phosphorus with IgA nephropathy progression. All tests were two-tailed, and p values < 0.05 were considered statistically significant. The data analysis was performed using IBM SPSS Statistics 22.0 [IBM Corp. (2013) IBM SPSS Statistics for Windows, Version 22.0. IBM Corp, Armonk, NY].

Results

Baseline characteristics of the study population

A total of 162 IgA nephropathy patients were included in our study, and males were predominant, accounting for 61.7% of the cohort. The mean age of the whole cohort was 37 ± 11 years, and the baseline serum phosphorus was 1.13 ± 0.18 mmol/L. The median (lower quartile, upper quartile) baseline eGFR was 66.43 (48.37–93.40) mL/min/1.73 m2. The proportion of patients with CKD stage 1–4 was 25.9%, 30.2%, 37.7%, and 6.2%, respectively.

According to tertiles of serum phosphorus, the clinical data and pathological characteristics of patients were shown in Tables 1 and 2. Comparing with men, women’s serum phosphorus levels were higher. In the high tertile of serum phosphorus group, patients’ serum hemoglobin and serum albumin were lower than in the low tertile group (all P < 0.05). Next, we assessed the correlation between serum phosphorus and pathological characteristics among 162 IgA nephropathy patients. There was no statistically significant difference among the three groups in the Oxford classification and the severity of mesangial deposition of IgA, IgG, IgM, complement C3, and C1q on immunofluorescence microscopy (all P > 0.05).

Table 1 Clinical characteristics of study population
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Table 2 Pathological characteristics of study population
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Serum phosphorus and renal outcomes

During a median 16 month follow-up, 15 patients reached the composite outcome. There were statistically significant different among the three groups (log-rank test P = 0.005) by Kaplan–Meier survival analysis (shown in Fig. 1). Patients of the high tertile of serum phosphorus group was with a poor renal prognosis compared with the low tertile group patients (log-rank test P = 0.003).

Fig. 1
figure 1

Kaplan–Meier survival analysis among three tertiles of serum phosphorus groups

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The restricted cubic splines showed that there was a positive correlation between baseline serum phosphorus and hazard ratio of adverse renal outcomes, which meant higher serum phosphorus levels may result in poor renal outcomes (shown in Fig. 2).

Fig. 2
figure 2

Restricted cubic spline curve of hazard ratio (HR) of serum phosphorus for IgA nephropathy progression. The solid line represents the estimated HR, the shaded area represents the 95% confidence interval (CI), and the dashed lines on it are the upper and lower limits of the 95% CI, the horizontal dashed line represents HR equal to 1

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In an unadjusted Cox proportional hazard model (shown in Table 3), baseline serum phosphorus as a continuous variable was associated with increased risk for adverse renal outcomes (HR = 63.510, 95% CI = 3.953–1020.284, P = 0.003), and the high tertile of serum phosphorus group had an increased risk of the composite outcome by using the low tertile group as the reference (HR = 11.895, 95% CI = 1.522–92.993, P = 0.018). In addition, mean arterial pressure, hemoglobin, eGFR and tubular atrophy/interstitial fibrosis ≥ 25% were also associated with poor renal prognosis. After adjustment for initial mean arterial pressure, hemoglobin, eGFR, tubular atrophy/interstitial fibrosis ≥ 25% and other traditional risk factors such as age, sex, and UACR, the high tertile of serum phosphorus group significantly related to IgA nephropathy progression compared with the low tertile group (HR = 9.424, 95%CI = 1.019–87.165; P = 0.048) (shown in Table 4).

Table 3 Unadjusted Cox regression analysis affecting the prognosis of patients with IgA nephropathy
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Table 4 Hazard ratio of serum phosphorus for IgA nephropathy progression with Cox proportional hazard models
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Discussion

Disorders of calcium and phosphorus metabolism are common complications in patients with ESKD. An increasing body of evidence suggested that higher serum phosphorus levels were strongly associated with increased mortality in patients with CKD [10, 15]. Serum phosphorus is also a risk factor associated with increased cardiovascular events in the general population [16]. Several studies have explored the association of serum phosphorus with kidney disease outcomes in patients with CKD. However, the association of serum phosphorus with IgA nephropathy progression is still uncertain.

Norris et al. [17] found that serum phosphorus was directly associated with adverse renal events in African American Study of Hypertension and Kidney Disease. In the prospective Ramipril Efficacy In Nephropathy (REIN) trial, Zoccali et al. [18] found that serum phosphate levels could aggravate CKD progression and attenuate the renoprotective effect of ACEI. In a Spanish study, they found that time-averaged serum phosphorus levels (serum phosphorus levels averaged over the follow-up time) were independently associated with a more rapid decline of renal function in patients with advanced CKD [19]. This effect does not seem to be limited to hyperphosphatemia. Chang et al. [20] used propensity score analysis to evaluate the causal effects of the normal range serum phosphorus on the incidence of ESKD, and they discovered that the relative higher baseline phosphorus levels were associated with clinical parameters consistent with the advancement of CKD, and the patients with the higher time-averaged phosphorus showed significantly higher HRs for ESKD. Furthermore, in prospective studies of the general population, serum phosphorus levels in the upper-normal range were associated with a doubling in the risk of developing incident CKD and ESKD [21]. More controversially, the largest cohort study of early CKD failed to validate the independent association of serum phosphorus with risk of death or progression to ESKD [22], and the possible explanations were that serum phosphorus levels were measured only once and the follow-up period years were relatively short in this study.

There are few pieces of research regarding the relationship between serum phosphorus and the progression of IgA nephropathy, and the relationship between normal-range serum phosphorus and poor renal outcomes in IgA nephropathy has not been explored. In our study, we included 162 primary IgA nephropathy patients with normal serum phosphorus levels at the renal biopsy, and focused on the effects of normal-range serum phosphorus on IgA nephropathy progression. We found relative higher serum phosphorus as a categorical variable was significantly associated with poor renal survival, whether in crude analysis or multivariable Cox proportional hazard model. This was consistent with previous reports that the higher serum phosphorus within the normal range may be a risk factor for the progression of CKD [11, 20, 21]. Yu et al. [23] first indicated disorders of phosphorus metabolism were associated with IgA nephropathy progression in patients without dialysis and found the fourth phosphorus quartile (1.33–2.24 mmol/L) had higher risk for renal progression (HR = 2.62, 95%CI = 1.44–4.77, P < 0.002) compared with those in the bottom quartile (0.35–1.07 mmol/L), serum phosphorus levels (1.33–2.24 mmol/L) of the top quartile were mostly within the normal range, while the adverse effect on the renal outcome was observed. Our study was conducted in patients with normal-range serum phosphorus and excluded those with hyperphosphatemia, therefore, the mean serum phosphorus levels at baseline were relatively low. These results suggested that we should pay attention not only to the harm of hyperphosphatemia but also to the potential adverse effects of the relative higher serum phosphorus even in normal range. In addition, according to analysis of pathology types and serum phosphorus levels, there was no correlation between the two factors.

However, our study is only an observational study and cannot elucidate the causality. We should be aware that a slight tubular dysfunction may be represented as relatively higher serum phosphorous level, leading to the worse prognosis in the high tertile group. Namely, serum phosphorous may not affect kidney function but reversely, less healthy kidney may exhibit as high serum phosphorous. Our patients' serum phosphorus levels were within the normal range, however, normal-range serum phosphorous may less likely to cause vascular calcification. Animal models showed that overload phosphate induced podocyte injury via type III Na-dependent phosphate transporter [24]. Furthermore, several studies showed that fibroblast growth factor 23 (FGF23) was closely associated with CKD progression [25, 26]. FGF23 is elevated prior to the appearance of high phosphorus levels and maintains serum phosphorus within the normal range by increasing the rate of phosphate excretion per nephron [27], potentially causing calciprotein particle formation in the tubular lumen, interstitial fibrosis, and tubular injury [28], these seem to indirectly suggest that higher serum phosphorus levels within the normal range can lead to an unfavorable renal prognosis, however, the hypothesis of causality still needs to be tested by high-quality randomized controlled studies.

Currently, phosphorus-lowering treatment focuses on patients with overt hyperphosphatemia in clinical practice, and normophosphatemia may not be an indication to start phosphate-lowering treatment due to concerns about the efficacy and safety of phosphate binders in the Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines [29]. Although our study suggests that normal range serum phosphorus is associated with poor renal outcomes in patients with IgA nephropathy, whether appropriate phosphorous management is important in IgA nephropathy needs additional study.

Study limitation

This research was a retrospective study with small sample size and a short follow-up period. In this study, we only explored the relationship between baseline serum phosphorus levels and renal outcomes in patients with IgA nephropathy by multifactorial regression analysis, despite unavoidable confounding factors were remained. The relationship between time-averaged phosphorus and renal outcomes was not considered in the analysis. Large-scale prospective studies are still needed to explore this in the future.

Conclusion

In summary, our study showed that relatively higher serum phosphorus levels within the normal range were significantly associated with the progression of IgA nephropathy.