Prognosis of IgA Nephropathy with Stages 3b-5 CKD

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, especially in the Asia-Pacific region [1]. In China, it accounts for approximately 40% of all primary glomerular diseases [2]. It has been reported that 30–40% of patients with IgAN will progress to end-stage renal disease (ESRD) within 20 years [3‒5]. Massive proteinuria, uncontrolled hypertension, impaired renal function at the time of renal biopsy, and severe histological damage are commonly recognized as risk factors for renal endpoints in IgAN [6, 7].

Recently, several studies have comprehensively evaluated the efficacy and safety of immunosuppressive therapy in IgAN. The TESTING study [8, 9] reported that steroid therapy significantly reduced the frequency of primary kidney outcomes, albeit with increased adverse events. Immunosuppressant treatment is frequently recommended for IgAN patients who are at high risk for chronic kidney disease (CKD) progression. There are conflicting opinions regarding the use of immunosuppressant treatment in IgAN patients with an estimated glomerular filtration rate (eGFR) of less than 50 mL/min/1.73 m² and persistent proteinuria with a daily excretion of ≥1.0 g. The controversy stems from uncertainties about the therapy’s benefits and risks, particularly in those with severe renal insufficiency.

Therefore, in this study, we aimed to analyze the prognosis of IgAN with stages 3b-5 CKD. Additionally, we sought to evaluate the impact of immunosuppressive therapy on the progression of the disease in this specific group of IgAN patients.

This was a retrospective cohort study at the Tianjin Medical University General Hospital, focusing on patients with IgAN. The study comprised a total of 110 participants who met specific inclusion criteria: (1) the diagnosis of IgAN was based on renal biopsy; (2) eGFR less than 45 mL/min/1.73 m². Data for the study were collected from January 2010 to December 2020. A total of 110 patients were initially included in the baseline data analysis (Fig. 1). Afterward, 20 patients who lacked follow-up data were excluded from the subsequent analysis. Consequently, a final cohort of 90 patients was formed and included in the follow-up analysis (Fig. 1). Informed written consent was provided from all patients.

Patient’s demographics and clinical data including sex, age, systolic blood pressure (SBP), diastolic blood pressure, serum hemoglobin, platelet, erythrocyte sedimentation rate, prothrombin time, activated partial thromboplastin time, fibrinogen (FIB), D-dimer, serum albumin, serum globulin, serum creatinine, eGFR, serum uric acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum IgG, serum IgA, serum IgE, Complement 3, Complement 4, C-reactive protein, and proteinuria and hematuria levels were collected at the time of renal biopsy. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [10]. For the evaluation of pathologic injuries in IgAN, the Oxford classification was utilized (MEST-C: M, mesangial hypercellularity; E, endocapillary hypercellularity; S, segmental glomerulosclerosis; T, tubular atrophy/interstitial fibrosis; and C, crescent) [11].

Immunosuppressive therapy was defined as the administration of steroids and/or immunosuppressive agents, such as cyclophosphamide, cyclosporine, tacrolimus, or mycophenolate mofetil, after renal biopsy.

The composite kidney endpoint was the composite of a doubling of the baseline serum creatinine, 50% reduction in eGFR, or ESRD (eGFR <15 mL/min per 1.73 m²).

Normally distributed continuous variables were described using the mean value along with the standard deviation and nonnormally distributed data were described using the median value and the interquartile range (IQR). Student’s t test was used for normally distributed continuous data and the Mann-Whitney U test was used for nonnormally distributed data. Categorical variables were expressed as numbers and percentages and compared using the χ² inspection. Kaplan-Meier (K-M) survival analysis and Cox regression analysis were used to evaluate the potential impact of the factor on the endpoint events in IgAN patient. A two-tailed p < 0.05 was statistically significant. The analysis was performed using SPSS 27.0 software.

This study comprised a total of 110 patients diagnosed with IgAN and having an eGFR less than 45 mL/min/1.73 m². Within this patient cohort, there were 52 males and 58 females. The mean age at the time of renal biopsy was 45.2 ± 13.5 years, while the mean eGFR for the participants was 32.0 ± 10.2 mL/min/1.73 m² per year. The average follow-up duration was 46.1 ± 37.9 months. The mean rate of decline in eGFR was 3.6 mL/min/1.73 m². There were 43 (47.8%) composite kidney endpoints occurred in these patients. Other characteristics are shown in Table 1.

The patients were divided into two groups based on whether they received immunosuppressive therapy. Out of 110 patients, 87 received immunosuppressive therapy, while 23 did not. Table 2 shows the clinical and pathological manifestations, as well as the renal prognosis, in both groups. The creatinine level of the treatment group was lower than that of the untreated group (206.5 ± 84.9 µmol/L vs. 236.9 ± 162.6 µmol/L, p = 0.008). Additionally, the eGFR level of the treatment group was higher than that of the untreated group (32.3 ± 9.6 mL/min/1.73 m² vs. 30.6 ± 12.4 mL/min/1.73 m²), although the difference was not statistically significant (p = 0.061). It was observed that the level of proteinuria in the treated group was higher than that in the untreated group (2,940.0 [IQR, 1,679.2–5,066.3] mg/24 h vs. 1,690.0 [IQR, 756.0–3,605.0] mg/24 h, p = 0.011). There were no significant differences in other clinical features and pathological parameters between the two groups (Table 2).

As shown in Table 2, the proportion of renal endpoint events in the treated group (32/71, 45.1%) was slightly lower than that in the untreated group (11/19, 57.9%), but the difference did not demonstrate statistically significant (p = 0.320). K-M survival analysis did not find a statistically significant association between the use of immunosuppressive therapy and renal survival in these groups of IgAN patients (Fig. 2).

Furthermore, we compared the clinicopathological features and renal prognosis of patients with stage 3b CKD (68, 61.2%) and patients with stages 4–5 CKD (42, 38.8%). Comparisons of clinical manifestations, pathological changes, or treatment options were shown in Table 3. Patients with stage CKD 3b had higher hemoglobin levels (114.1 ± 23.7 g/L vs. 106.1 ± 15.3 g/L, p = 0.002), lower levels of proteinuria (2,171.4 [IQR, 1,180.0–4,275.0] mg/24 h vs. 3,877.5 [IQR, 2,089.5–5,070.0] mg/24 h, p < 0.001), and lower levels of hematuria (236.0 ± 332.3/µL vs. 647.2 ± 1,829.9/µL, p = 0.005) than those with stage CKD4 and 5. Additionally, patients with stage 3b CKD had a higher prevalence of M1 lesions (98.5% vs. 85.7%, p = 0.007).

At the end of follow-up, the incidence of endpoint events in stage 3b CKD patients was lower than patients with stage CKD4 and 5 patients (36.8% vs. 66.7%, p = 0.006). K-M survival analysis showed that CKD stage was associated with renal survival in IgAN patients (Fig. 3). The analysis revealed that patients with more severe renal dysfunction experienced a worse prognosis in terms of renal outcomes.

To elucidate the relationship between proteinuria and the clinical-pathological features and renal prognosis of IgAN patients, we categorized the patients into two groups based on proteinuria levels: the low proteinuria group (<1,000 mg/24 h) and the high proteinuria group (≥1,000 mg/24 h). Table 4 shows clinical and pathological findings, treatment, and renal outcomes in both groups. The hemoglobin levels in the low proteinuria group were found to be lower than those in the high proteinuria group (96.7 ± 11.8 g/L vs. 113.6 ± 21.6 g/L, p = 0.008). Additionally, the eGFR level in the low proteinuria group was higher than that in the high proteinuria group (36.7 ± 5.3 mL/min/1.73 m² vs. 31.1 ± 10.6 mL/min/1.73 m², p = 0.001). Also, the Complement 4 levels in the low proteinuria group were higher than those in the high proteinuria group (24.9 ± 16.9 mg/dL vs. 24.6 ± 5.8 mg/dL, p = 0.011). Furthermore, 82.8% of patients in the high proteinuria group received immunosuppressive treatment, while only 52.9% of patients in the low proteinuria group underwent this form of treatment (p = 0.006).

The incidence of kidney endpoint events in the high proteinuria group was higher than that in the low proteinuria group, although the difference was not statistically significant (51.9% vs. 23.1%, p = 0.054, Table 4). K-M survival analysis showed that proteinuria was associated with renal survival in IgAN patients (p = 0.023, Fig. 4).

To further investigate the relationship between clinical-pathological characteristics and kidney outcome and crescent proportions, we divided the patients into two groups according to the crescent proportions: the low crescent proportions group (<50%) and the high crescent proportions group (≥50%). Table 5 shows the clinical and pathological findings, treatment, and renal outcomes in both groups. The high crescent proportions group had higher levels of FIB (7.9 ± 12.3 g/L vs. 3.6 ± 0.8 g/L, p < 0.001), D-dimer (1,200.9 ± 2,174.8 ng/mL vs. 687.7 ± 933.0 ng/mL, p = 0.004), and IgE (651.7 ± 1,712.3 mg/dL vs. 268.1 ± 440.6 mg/dL, p < 0.001) compared to the low crescent proportions group. The prevalence of E1 lesions was higher in the group of high crescent proportions (69.2% vs. 39.2%, p = 0.040), whereas the prevalence of S1 lesions was lower in the same group (69.2% vs. 89.7%, p = 0.038).

There was no significant difference in the incidence of endpoint events between the two groups (48.7% vs. 41.7%, p = 0.649, Table 5). K-M survival analysis also showed that the prevalence of C1-2 lesions was not associated with renal survival in IgAN patients (Fig. 5).

During the median follow-up of 38.5 months (range 16.0–66.5 months), both univariate and multivariate cox analyses were conducted to investigate potential risk factors affecting eGFR decline in IgAN patients. The results showed that SBP, FIB, and CKD stage were identified as risk factors for eGFR decline in IgAN patients, even after adjusting for multiple covariates (Table 6).

Given the diversity of clinical course of IgAN, our study specifically focused on patients with eGFR <45 mL/min/1.73 m². This subgroup of patients exhibited a poor prognosis, with 47.8% experiencing progression to renal endpoints within a 46-month period. Despite this challenging scenario, we found that immunosuppressive treatment did not demonstrate significant efficacy in reducing the composite kidney endpoint. Our study revealed that patients with more severe renal dysfunction and heavy proteinuria had a poorer prognosis in terms of renal outcomes in IgAN. The prevalence of C1-2 lesions was not found to be associated with renal survival in IgAN patients. Moreover, the results indicated that SBP, FIB levels, and CKD stage were identified as risk factors for a decline in eGFR decline in IgAN patients. Overall, our findings suggest that immunosuppressive therapy does not confer any advantages over supportive care therapeutic regimens in managing this particular cohort of IgAN patients. Therefore, addressing the identified risk factors and focusing on new therapy may be more beneficial in improving the renal prognosis for these patients.

In the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline, it is recommended 6 months of glucocorticoid therapy for IgAN patients with proteinuria >0.75–1 g/day despite 3–6 months of optimized supportive therapy [12]. However, the design limitations of these available RCTs explain the assignment of a low level of evidence (2B) to support the suggestion for the use of glucocorticoid made in the KDIGO guidelines. Whether the benefits of this treatment extend to patients with severe renal insufficiency remains unknown. Observational studies have indicated that immunosuppressive therapy could be beneficial when eGFR falls below 50 mL/min/1.73 m², particularly in cases where there are high levels of proteinuria. However, the exact point at which therapeutic effectiveness diminishes has not been definitively established [13]. Recent randomized controlled trials, including the STOP-IgAN and TESTING trials, conducted subgroup analyses in IgAN patients with renal insufficiency. They found no evidence of any benefit from immunosuppressive therapy in patients with an eGFR ranging from 30 to 60 mL/min/1.73 m² in the STOP-IgAN trial and those with an eGFR of 20–50 mL/min/1.73 m² in the TESTING trial [3, 8, 14, 15]. In this study, we observed that patients who underwent immunosuppression therapy had comparable kidney survival rates when compared to patients who did not receive such treatment. Multiple Cox analyses did not demonstrate that immunosuppression therapy was associated with a beneficial effect in improving the renal prognosis for these patients. This suggests that immunosuppressive therapy did not provide a significant advantage in terms of kidney survival in these populations under study.

Impaired renal function at renal biopsy has been recognized as an independent risk factor for the progression to ESRD of IgAN [16]. Lv et al. found that the risk of ESRD increased by 4% for every 1 mL/min/1.73 m² reduction of basal eGFR [17]. Research indicates that IgAN patients at stage 3b of CKD have a 5-year renal survival rate of 23%. However, their 10-year renal survival rate drops drastically to less than 1% [18]. Our results showed that the incidence of renal endpoint events was lower in stage 3b CKD patients compared to patients with stages 4 and 5 CKD. This observation suggests that patients with severe renal insufficiency (stages 4 and 5 CKD) experienced a poorer prognosis. Furthermore, the multivariate Cox regression analysis yielded consistent results, confirming that CKD stage remained a significant risk factor for the decline in eGFR in IgAN patients. This analysis supported the previous findings and strengthened the evidence that CKD stage plays a crucial role in predicting the progression of renal function decline in IgAN patients. Early recognition of CKD stage is crucial for identifying patients at higher risk and implementing appropriate interventions to mitigate the decline in renal function and improve their long-term prognosis. Timely management and close monitoring of patients with decreased renal function can potentially lead to better outcomes and improved quality of life for individuals affected by IgAN.

Currently, the commencement of treatment for patients with IgAN is determined by proteinuria levels and eGFR, which are late indicators of kidney damage. As a result, research efforts are being focused on identifying biomarkers for IgAN to better monitor patients at higher risk of disease progression. These include Gd-IgA1, IL-6, B-cell activating factor, proliferation-inducing ligand (APRIL), endothelin-1, and complement-associated proteins [19‒23]. Consequently, the exploration of new drugs, such as B-cell activation inhibitors, endothelin receptor antagonists, or complement inhibitors, may hold promise. Endothelin-1 plays a role in renal inflammation and fibrosis by activating endothelin-A receptors and angiotensin II [24]. Sparsentan, a dual-action antagonist targeting both the endothelin type A and angiotensin II subtype 1 receptors, has received approval from the US Food and Drug Administration for use in adults with IgAN at risk of rapid disease progression [25]. It offers benefits for IgAN patients by mitigating renal fibrosis and diminishing proteinuria. Several clinical trials are currently underway or being initiated to evaluate the potential benefits of targeting APRIL alone, both APRIL and B-cell activating factor, or the complement system in the treatment of IgAN.

Previous studies have consistently confirmed that proteinuria is a significant prognostic factor in IgAN [26, 27]. Le et al. [28] suggested that in Chinese patients, the primary objective of anti-proteinuria therapy is to achieve a proteinuria level below 1.0 g/day. In the current study, we specifically assessed the influence of baseline proteinuria on the overall prognosis in the context of our study population. The results showed that baseline proteinuria of less than 1.0 g/day was associated with a better renal survival. However, after adjusting for eGFR, the renal protective effect of baseline proteinuria of less than 1.0 g/day was no longer observed in this particular group of patients. This suggests that while proteinuria may serve as an important prognostic factor for renal outcomes, its significance may be influenced by other factors, such as eGFR. Further investigations are warranted to better elucidate the complex interplay between proteinuria, eGFR, and renal prognosis in this patient population.

The formation of crescent was seen in the pathology of IgA nephropathy, and the prognostic value of crescent was not previously recognized. A cohort study conducted in 2017 found that a glomerular ratio of crescents ≥25% independently predicted the progression to complex endpoint events in IgAN patients, regardless of whether they received glucocorticoid or immunosuppressive therapy [29]. These findings led to the inclusion of crescents as an important histological feature in the Oxford classification of IgAN. In the present study, no significant difference was observed in the incidence of endpoint events between the C0 group (crescents absent) and the C1-2 group (crescents present). Furthermore, K-M survival analysis demonstrated that the presence of C1-2 lesions was not associated with renal survival in IgAN patients. These findings suggest that the presence of crescents in the renal pathology may not be a reliable predictor of renal prognosis in this particular cohort of IgAN patients.

Furthermore, we investigated the risk factors for a decline in eGFR in patients with IgAN. The results suggest that SBP, FIB levels, and CKD stage are associated with a higher likelihood of experiencing a decline in eGFR in these patients. This information can help us identify patients who might need more intensive monitoring and interventions to slow down the progression of kidney damage.

There are several limitations to this study. First, it was a single-center retrospective cohort study, which makes it challenging to control for all potential factors that could influence kidney survival. Second, the study's findings may have been impacted by the lack of positive results in patients treated with immunosuppression compared to those receiving supportive care. The lower number of patients in the supportive care group and the strong bias stemming from the selection of therapeutic protocols at our institutions could have influenced the outcomes; moreover, the presence of higher baseline plasma creatinine levels and lower eGFR among patients in the supportive care group, compared to those receiving immunosuppressive therapy, could have impacted the study outcomes. Third, as a retrospective study, the analysis of adverse events associated with either immunosuppression or supportive care was not compared directly. The absence of a direct comparison might limit the ability to fully understand and assess the safety profile of the different treatment approaches. Future prospective studies with larger cohorts and comprehensive patient management are needed to provide stronger evidence of the benefit of immunosuppressive therapy in IgAN patients with decreased initial renal function.

IgAN patients with stages 3b-5 CKD exhibited a poor prognosis. It appears that in this specific cohort of IgAN patients, immunosuppressive therapy may not provide significant advantages over supportive care therapeutic regimens in terms of disease management. SBP, FIB levels, and CKD stage were identified as risk factors for the decline in eGFR decline in IgAN patients.

The authors thank all the study subjects for their participation.

This study protocol was reviewed and approved by Medical Ethics Committee of the Tianjin Medical University General Hospital, (approval number: IRB2024-YX-046-01). Informed written consent was provided from all patients.

The authors declare that they have no competing interests.

This study is supported by Tianjin Health Science and Technology Project (TJWJ2022MS005), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-071C), Kidney Medical development research Fund (SO.20220718TJ), and the National Key Research and Development Program of China (2019YFF0216502).

Y.L. conceived the study, and Y.L., J.J., and T.Y. participated in its design and coordination. Z.W., H.L., F.W., Y.X., and W.L. collected the clinical data. Z.W. analyzed the data and contributed to the writing of the manuscript. Y.L. revised the manuscript. All authors have read and approved the final manuscript for submission.

Due to privacy policy, the datasets analyzed in this study are not publicly available, but they are available from the corresponding author upon reasonable request.