Abstract
Purpose
Whether different crescentic proportions determine the progression of IgA nephropathy (IgAN) with crescents in less than 50% of glomeruli remains controversial. We aimed to evaluate the relationship between different proportions of crescents and kidney outcomes in IgAN with partial crescent formation.
Methods
Patients diagnosed as IgAN, having at least two crescents and in less than 50% of glomeruli, were categorized into three groups: Group I (crescents in ≤10% of glomeruli), Group II (10%< crescents ≤25% of glomeruli) and Group III (crescents >25% of glomeruli). Baseline clinicopathological parameters were evaluated. The kidney endpoint was a composite of a ≥ 40% decline in the initial estimated glomerular filtration rate, end-stage kidney disease, and kidney disease-related death.
Results
Of 183 IgAN patients with crescents in less than 50% of glomeruli, baseline 24-hour urinary protein and immunosuppressive treatment varied among the three groups (p < 0.05). During a median follow-up of 57 months (interquartile range 28–86), 50 (27.3%) patients reached the composite outcome. Kaplan–Meier survival analysis revealed that kidney survival in Group II (p = 0.049) and Group III (p = 0.008) was significantly shorter than in Group I, with no significant difference between Group II and III (p = 0.2). After adjusting for clinical factors and MEST score based on the multivariate Cox regression analysis, a crescent proportion >10% (HR = 3.431, 95% CI 1.067–11.03, p = 0.039) was predictive of time to unfavorable kidney outcome, with model adjustments improving predictability (c-index: 0.817).
Conclusion
The proportion of crescents reaching 10% of glomeruli in IgAN was identified as an independent risk factor for kidney survival.
Introduction
IgA nephropathy (IgAN) remains the commonest primary glomerulonephritis worldwide and a dominant cause of kidney failure in East Asian countries, with approximately 20–40% of patients developing into kidney failure within 10 to 20 years after diagnosis [Citation1–3]. The variable clinical presentations of IgAN are reflected in pathological changes, visible under light microscopy, ranging from near normal to severe proliferative glomerulonephritis with crescents or a morphology analogous to primary focal segmental glomerulosclerosis (FSGS) [Citation4].
Crescent formation had been reported as one of the most important prognosticators in IgAN, occurring in approximately 20–50% of IgAN patients [Citation4,Citation5]. The presence of cellular/fibrocellular crescents, independently associated with a higher risk of adverse prognosis, was added to the Oxford classification scoring system for IgAN (MEST-C). Cellular crescents refer to two or more layers of proliferating cells in Bowman’s capsule, affecting at least 10% of the glomerular circumference [Citation6], whereas older crescents become fibrocellular [Citation7]. Biopsy specimens from patients diagnosed as IgAN are scored as C0 (no crescents), C1 (crescents in at least one but <25% of glomeruli), or C2 (crescents in at least 25% of glomeruli) [Citation8]. Crescents presenting in more than 50% of glomeruli in IgAN patients (crescentic IgAN) typically indicate rapid kidney deterioration [Citation9]. However, whether a small proportion of crescents in IgAN patients presenting with partial crescent formation (crescents in <50% of glomeruli) could predict unfavorable kidney survival is still debated. For most nephrologists, the value of cellular/fibrocellular crescents remains an unsolved conundrum, particularly when the relative rate of crescents is shown to be low by kidney biopsy. A consensus has not be reached regarding the treatment strategy, and its effect on prognosis is still controversial [Citation10,Citation11]. Therefore, the aim of this study was to verify the association between the proportion of cellular/fibrocellular crescents and the clinicopathological characteristics of patients, and to discuss the predictive value of the crescent ratio for kidney outcomes in IgAN patients with partial crescent formation.
Methods
Study population
This is a retrospective study investigating IgAN patients who underwent kidney biopsy at the China-Japan Friendship Hospital from January 2010 to December 2020. The inclusion criteria were as follows: (1) biopsy-proven IgAN in kidney tissue with at least 2 crescents and a minimum of 20 glomeruli; (2) IgAN patients with cellular/fibrocellular crescents in <50% of glomeruli; and (3) patients who were 14–75 years old with complete data and follow-up for at least 12 months. Patients with kidney biopsies showing less than 2 crescents or 20 glomeruli were excluded from this study because a sufficient number of glomeruli could ensure accuracy and avoid the influence of bias. Patients with secondary causes of glomerulonephropathy such as IgA vasculitis, systemic lupus erythematosus, IgAN superimposed on ANCA-associated necrotizing/crescentic glomerulonephritis, diabetes, severe chronic liver disease, or malignant tumors, were excluded. Patients with other active pathological lesions such as fibrinoid necrosis, and initial estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2 were also excluded. The eligible patients were divided into Group I (crescents in ≤10% of glomeruli), Group II (10%<crescents ≤ 25% of glomeruli), and Group III (crescents in >25% of glomeruli). IgAN patients without crescent formation was served as controls.
Clinical and pathological data
Clinical data at the time of kidney biopsy were extracted from electronic medical records, including age, gender, duration before biopsy, blood pressure, urinary erythrocytes at high magnification, and urinary protein excretion (UPE) levels over 24 h. Data on hemoglobin, serum levels of albumin and creatinine, and uric acid were also collected. Mean arterial pressure (MAP) was calculated as diastolic blood pressure +1/3 (systolic pressure - diastolic pressure), and the eGFR was calculated via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [Citation12]. Hypertension was defined as a systolic pressure ≥140 mmHg, a diastolic pressure ≥90 mmHg, or the need for antihypertensive medications.
The kidney biopsy data were reviewed by two pathologists who were blinded to the original clinical and pathological data and scored using the Oxford Classification of IgAN (MEST-C score). The MEST-C score includes mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C) [Citation8,Citation13]. The proportion of crescents was calculated as the number of glomeruli with large crescents (cellular and fibrocellular) divided by the total number of glomeruli without glomerulosclerosis (global and ischemic). Large crescents mean the volume of each crescent exceeded 50% of the bowman’s capsule. Global glomerulosclerosis means the entire glomerular tuft involved with sclerosis; Collapsed/ischemic glomerulosclerosis means a glomerulus showing collapse of the capillary tuft with or without thickening of Bowman’s capsule and fibrosis in the Bowman’s space.
Therapeutic regimen and follow-up
The use of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), was recorded. In addition, data on the use of immunosuppressive medications, including a full dose of oral prednisone (starting from 0.8–1 mg/kg per day and regularly reduced) in conjunction with or without glucocorticoid pulse therapy (e.g., intravenous methylprednisolone 500 mg for 1 to 3 times), and immunosuppressants (including cyclophosphamide, mycophenolate mofetil, leflunomide, and cyclosporine), were also collected. The kidney endpoint was a composite of ≥40% decline in the initial eGFR [Citation14], end-stage kidney disease (ESKD), and death due to kidney disease. ESKD was defined as the initiation of kidney replacement therapy including maintenance dialysis or kidney transplantation. Survival time was defined as the interval from the time of kidney biopsy to one of the three endpoints: kidney endpoint, loss to follow-up, or the study end date (September 2022).
Statistical analysis
Statistical analyses were performed using R 4.1.3 (the R Foundation for Statistical Computing, Vienna, Austria). Normally distributed quantitative variables are expressed as mean ± standard deviation (SD), and the median and interquartile range (IQR) are shown for nonnormally distributed quantitative variables. Categorical variables are summarized as numbers (percentages). Normally distributed continuous variables were compared using one-way analysis of variance (ANOVA), and skewed variables were analyzed using the Kruskal–Wallis H test or Mann–Whitney U test as applicable. The χ2 test or Fisher’s exact test was used to compare the categorical variables. Correlation coefficients between variables were computed using Spearman rank correlation analysis. The Kaplan–Meier survival curve and log-rank test were utilized to perform the survival analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk factors related to the composite outcome were calculated using the Cox proportional hazard model. A univariate analysis to estimate the association of baseline variables with the composite outcome was performed first; clinically significant variables and those with a P value <0.1 in the univariate analysis were added individually to the multivariate models. Differences were considered statistically significant if p < 0.05.
Results
Baseline demographic, clinical and pathological characteristics
describes a flow diagram of the selection of the study participants. This study ultimately included 183 IgAN patients with cellular/fibrocellular crescents in <50% of glomeruli, and 104 IgAN patients with no crescent formation included in the control group. The clinical and pathological characteristics of the 183 patients with partial crescent formation and 104 patients without crescent formation are presented in . In the group of enrolled patients, at the time of kidney biopsy, the median age was 37.0 ± 13.2 years, and 95 (51.9%) patients were male. The median serum creatinine level was 101.0 μmol/L (IQR 74.7–139.9 μmol/L), and the median eGFR was 69.5 mL/min/1.73m2 (IQR 49.0–102.0 mL/min/1.73m2). The mean serum albumin level was 39.3 ± 5.7 g/L, and the 24-h (24-h) UPE level was 1.74 g/d (IQR 0.88–3.36 g/d).
Figure 1. Flow chart of the study participants. IgAN, IgA nephropathy; eGFR, estimated glomerular filtration rate; ANCA, anti-neutrophil cytoplasmic antibodies.
Table 1. Baseline clinicopathological characteristics of IgAN with crescents in <50% glomeruli and those without crescent formation.
Among the 44 (24.0%) patients in Group I, 84 (45.9%) patients in Group II, and 55 (30.1%) patients in Group III, hypertension occurred in 10 (22.7%), 23 (27.4%) and 21 (38.2%) patients, respectively. In addition, 3 (6.8%), 15 (17.9%) and 22 (40%) patients exhibited proteinuria at the level of nephrotic syndrome. Baseline 24-h UPE levels and prescriptions of immunosuppressive drugs differed significantly among the three groups compared in pairs (p < 0.05).
Association of the crescent proportion with clinical data
As shown in , the crescent proportion was positively correlated with serum creatinine (, R = 0.267, p < 0.001) and 24-h UPE levels (, R = 0.322, p < 0.001) and negatively correlated with the eGFR (, R=–0.275, p < 0.001) and serum albumin level (, R=–0.273, p < 0.001).
Figure 2. Correlations between serum creatinine (a), eGFR (b), serum albumin (c) and 24-h UPE (d), and different proportions of crescents. eGFR, estimated glomerular filtration rate; 24-h UPE, 24-h urinary protein excretion.
Crescent formation and kidney outcomes
In the study group, patients were followed up for a median of 57.0 months (IQR 28.0-86.0 months), of which 50 (27.3%) reached the endpoint. Among these three groups, 4 (Group I), 23 (Group II), and 23 (Group III) patients reached the endpoint. No individual died during the follow-up. Kaplan–Meier curves showed that the event-free kidney survival of patients in Group I was significantly longer than that of patients in Group II (p = 0.049) and Group III (p = 0.008), whereas the event-free survival probability of patients in Group II and Group III showed no significant difference (p = 0.2) ().
Figure 3. Kaplan–Meier curves for a composite of ≥40% decline in initial eGFR, end-stage kidney disease, and death in IgA nephropathy patients presenting crescents less than 50% of glomeruli (a), and in patients comparing the study group and the control group (B). Group I, crescents ≤10% of glomeruli; Group II, 10%<crescents ≤ 25% of glomeruli; Group III, crescents > 25% of glomeruli.
In the control group, patients were followed up for a median of 68.5 months (IQR 50.25–90.0 months), of which 13 (12.5%) reached the kidney endpoint. There was no difference in prognosis between patients without crescent and patients with crescents in ≤10% of glomeruli (p = 0.87).
Based on the results of the log-rank test, Group II and Group III were combined together (crescents in >10% of glomeruli), and were compared to Group I (crescents in ≤10% of glomeruli). Three multivariate analysis models were constructed to adjust for clinical and pathological variables, mitigating potential bias and improving prognostic accuracy. In Model 1, adjusting for M, E, S, and T, higher T scores (HR = 1.955, 95% CI 1.268–3.014, p = 0.002) and crescents in >10% of glomeruli (HR = 3.370, 95% CI 1.195–9.500, p = 0.022) were significantly associated with poor kidney outcomes (c-index: 0.73). Model 2 included age, gender, MAP, duration before biopsy, hemoglobin, 24h-UPE, serum uric acid, and serum creatinine. Elevated serum creatinine (HR = 1.016, 95% CI 1.008–1.024, p < 0.001) and crescents >10% of glomeruli (HR = 3.176, 95% CI 1.030–9.787, p = 0.044) were significant risk factors (c-index: 0.815). Model 3 incorporated adjustments from both models, with higher serum creatinine (HR = 1.017, 95% CI 1.008–1.026, p < 0.001) and crescents > 10% of glomeruli (HR = 3.431, 95% CI 1.067–11.03, p = 0.039) as significant risk factors (c-index: 0.817) ().
Table 2. Cox Regression for the composite endpoint in IgAN with crescents <50%.
Discussion
This study focuses on the association between different crescentic proportions and the composite outcome in IgAN patients with crescents in less than 50% of the glomeruli, as the threshold at which the crescent ratio predicts IgAN prognosis has previously been uncertain. Finally, a total of 183 IgAN patients with partial crescent formation and 104 without, were included in the present study. The median follow-up time for patients with and without partial crescent formation were 57.0 and 68.5 months, respectively. As such, we found that crescents above 10% of glomeruli in these patients were associated with unfavorable kidney outcomes.
Among the various histological manifestations of IgAN biopsies, crescents are present in 20-50%. In contrast with what occurs in other glomerular diseases, monocytes and macrophages may not play a critical role in the crescent pathogenesis of IgAN [Citation6]. It is generally believed that crescent formation in IgAN initially begins due to damage to the endothelium of the glomerular filtration barrier, where podocytes and parietal cells interact within and outside of the surrounding glomerulus. The development of crescents is a consequence of this interaction involving many molecules associated with endothelial cell proliferation and complement activation. Cellular and fibrocellular crescents are special manifestations indicating that IgAN is in an active state, which is related to various clinical manifestations including proteinuria and kidney function damage [Citation15]. Similar to the results of other cohort studies, baseline clinical and pathological factors (an increase of 24h-UPE and serum creatinine, and a decrease of serum albumin and eGFR) were more severe with an increase in the proportion of crescents [Citation16–18]. In this study, the 24-h UPE at the time of kidney biopsy was significantly different among the three groups, and individuals in Group III had the highest baseline 24-h UPE level. Compared with Group I, Group II and Group III had lower baseline serum albumin levels. Group III had a lower eGFR than the other two groups, while Group I and Group II had similar kidney function. Spearman correlation analysis further showed that the crescent proportion was positively correlated with 24-h UPE and serum creatinine levels, and negatively correlated with the serum albumin level and eGFR.
Based on previous research, crescent scores were added to the Oxford classification to evaluate the prognosis of IgAN [Citation8]. As a meta-analysis of 3893 patients with IgA nephropathy showed, crescents were associated with the increasing of kidney failure events [Citation19]. Furthermore, Haas et al. found that cellular/fibrocellular crescents are a prognostic indicator of poor outcomes in IgAN patients [Citation20]. A study from Iran showed that the presence of crescents in ≥30% of glomeruli was an independent risk factor associated with ESKD [Citation21]. In this study, we observed a significant difference in prognosis between Group II and Group I (p = 0.049). Interestingly, IgAN patients with crescents affecting 10–25% of glomeruli exhibited a comparable prognosis to those with crescents affecting 25–50% of glomeruli (p = 0.2), while patients without crescent formation displayed a similar prognosis to patients with crescents less than 10% (p = 0.87). Consequently, Group II and Group III, which consisted of patients with crescents in more than 10% of glomeruli, were combined and compared to Group I.
This study showed that after adjusting for either or both clinical and pathological indicators, crescents in >10% of glomeruli had a predictive effect on prognosis. This suggests that in patients with partial crescent formation, the proportion of crescents exceeding 10% should be noted. Notably, our study diverged from some previous studies, as we did not find a significant correlation between tubular atrophy/interstitial fibrosis and the composite outcome after adjusting both clinical and pathological variables. This may be due to tubular atrophy and interstitial fibrosis affecting the clinical markers, such as serum creatinine and urinary protein excretion. In other words, there is a certain degree of collinearity between these clinical indicators and renal interstitial fibrosis. Therefore, when adjusting for clinical and pathological indicators, respectively, T had a predictive effect on prognosis. This is consistent with previous studies [Citation22,Citation23]. In addition, elevated serum creatinine levels at baseline were identified as an independent risk factor in the present study. To some extent, this also suggests possible tubular and interstitial lesions.
Remarkably, IgAN with diffuse crescent formation is a rare yet severe pathological manifestation that often progresses rapidly to kidney failure. In such cases, more aggressive treatment options are recommended [Citation24], including adequate glucocorticoids combined with immunosuppressive agents, even monoclonal antibodies and plasma exchange, whereas patients may still suffer a poor prognosis and soon progress to chronic disease [Citation9,Citation25–28]. However, crescent formation in less than 50% of glomeruli is more commonly observed in clinical practice. The treatment and prognosis of these patients remain uncertain due to a lack of consensus in the research findings, especially regarding immunosuppression decisions [Citation29,Citation30]. A few studies have reported a decrease in crescents after receiving immunosuppressive treatment among IgAN patients with active glomerular lesions who underwent repeat biopsies [Citation31,Citation32]. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines highlights that the Oxford MEST-C score does not serve the purpose of guiding treatment or predicting treatment response, and the existing evidence is inadequate to establish whether the usage of immunosuppressive agents should be determined by histological parameters [Citation33]. In the present study, the effect of the crescent proportion on prognosis after the addition of immunosuppressive medications had no significant difference. Nonetheless, the potential interaction between a higher percentage of crescents and more aggressive treatment should be noted, which may obscure the relationship between crescents and disease severity. Whether immunosuppression is beneficial to kidney outcomes in this group of IgAN with partial crescent formation is modified by the proportion of glomeruli with crescents needs to be addressed in further studies [Citation20,Citation30].
This study had several limitations. Firstly, this is a descriptive, retrospective study, and information is limited. Secondly, there was variation in the use of immunosuppressive agents and differences in the duration of follow-up. Thirdly, due to the retrospective nature of the data collection, detailed and reliable information may be lacking. Finally, our choice of a 10% cutoff for crescent proportion differs from the current Oxford classification (15% for treated patients and 25% for both treated and untreated patients). We also examined the subgroup of untreated patients in our research, but the sample size was small (6 patients in Group I, 6 patients in Group II, and 2 patients in Group III), and no significant differences were observed among the three groups. Consequently, the evaluation of the untreated subgroup may be affected by potential bias and confounding factors.
In conclusion, crescent formation in more than 10% of glomeruli indicates poor prognosis in IgAN patients, and baseline serum creatinine levels significantly affect the prognosis of these patients. However, it should be noted that IgAN patients with crescentic lesions in 10–25% of glomeruli are likely to have normal clinical manifestations, which can be easily ignored by patients. Whether immunosuppression benefits kidney outcomes in this group of IgAN patients should be further investigated.
Author contributions
Dingxin Di conceived the idea and was a major contributor to manuscript writing. Lin Liu and Ying Wang conducted the data collection. Yue Yang and Shimin Jiang performed all statistical analyses and were involved in writing the manuscript. Shimin Jiang and Wenge Li critically revised the manuscript. All authors have read and approved the final manuscript.
Ethics approval
This study was approved by the institutional ethics committee of China-Japan Friendship Hospital.
Patient consent
Written informed consent for renal puncture was obtained from all the patients preoperatively. All patient data were deidentified for this study. The need for written informed consent was waived by the ethics committee of China-Japan Friendship Hospital due to retrospective nature of the study.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All data generated or analyzed during this study are included in this published article.
Additional information
Funding
References
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