Abstract
Introduction
Prognostic value of glomerular hematuria in primary membranous nephropathy (PMN) patients with nephrotic syndrome (NS) has not been well understood. We investigated the earlier improvement of hematuria in PMN patients with NS receiving immunosuppressive (IS) therapies to illuminate its prediction capacity for the treatment response and remission status at 12 months.
Methods
This is a single-center retrospective study. From 1 January 2021 to 30 June 2024, patients with biopsy-proven PMN and NS starting IS therapy after renal biopsy were recruited. The main exposures were baseline hematuria and hematuria disappearing at 6 months. The outcome was nephrotic remission status at 12 months. Binary logistic regression models were used to estimate the relationship between exposures and outcomes. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive performance of exposures.
Results
Overall, 127 patients met the eligibility criteria. Overall, 112 patients (88.2%) had glomerular hematuria at the renal biopsy. Patients with hematuria had higher ages (57.2 ± 12.4 vs. 47.9 ± 12.7, p = 0.007), higher serum h-CRP levels (1.14 [0.66, 2.11] vs. 0.41 [0, 0.91], p = 0.004), and lower remission rate at 12 months (66/112 [58.9%] vs. 13/15 [86.67%], p = 0.037). In the subgroup of patients with glomerular hematuria, baseline hematuria levels were 18 (8, 25) RBC/μL. No significant correlations were found between baseline hematuria levels and other clinical indexes. At 6 months, 31 out of 112 (27.7%) patients had negative conversion of hematuria, and they had lower baseline PLA2R Ab titer (43.6 [0, 78.2] vs. 67.5 [10.8, 191.4], p = 0.025) and higher nephrotic remission rates at 12 months (26/31 [83.9%] vs. 40/81 [49.4%], p = 0.037), compared with those without. There were no significant differences among IS agents between the groups. Binary logistic regression demonstrated that hematuria disappearance at 6 months was an independent predictor for nephrotic remission at 12 months (OR = 0.211, 95% CI: 0.070–0.635, p = 0.006). ROC curve analysis revealed that the area under the curve for forecasting nephrotic remission at 12 months was 0.643 (p = 0.010) independently by the hematuria disappearance at 6 months and 0.781 (p < 0.001) combined with PLA2R Ab titer and IS therapeutic programs.
Conclusions
Patients with PMN and NS have high prevalence of glomerular hematuria. Patients without hematuria or negative conversion of hematuria at 6 months after IS treatment have higher nephrotic remission rates at 12 months. For patients with hematuria, hematuria disappearance at 6 months was an independent predictor for nephrotic remission at 12 months.
Keywords: Hematuria, Primary membranous nephropathy, Prediction value, Treatment response
Introduction
Primary membranous nephropathy (PMN) is a major cause of nephrotic syndrome (NS) of nondiabetic origin in adults over 40 years of age [1]. A significant increase in the PMN incidence was observed in China, with an annual growth rate of 13% from 2004 to 2013 [2]. This places PMN as the second most prevalent diagnosis, following IgA nephropathy [3]. Despite variant supportive and/or immunosuppressive (IS) treatments, in PMN patients who continue to have NS, kidney failure develops in 40%–50% after several years [4–7], which is associated with poor therapeutic responses. There is usually a delay between the initiation of treatment and improvement, which often takes up to 12 months or even more [8, 9]. Therefore, it is important to identify the possible response to interventions in the earlier stage, such as 3–6 months, which will greatly help to optimize patients’ managements and decrease treatment-related excessive risks and medical expenses [10, 11]. Unfortunately, validated indicators or biomarkers beyond serum levels of PLA2R remain limited.
In the clinical practice, we noticed that many PMN patients had glomerular microhematuria. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal disease [12–14]. In immune-complex glomerulonephritis without cellular crescents, hematuria may result from small ruptures in glomerular basement membrane that may occur due to lysosomal digestion around deposited immune complexes, which implies the presence of active glomerular inflammation [13]. However, the prognostic value of hematuria in PMN patients with NS has not been well understood. Above all, the present retrospective study investigated the earlier improvement of glomerular microhematuria in PMN patients with NS receiving IS therapies to illuminate its prediction capacity for the treatment response and remission status at 12 months.
Methods
Patient Cohort
From 1 January 2021 to 30 June 2024, patients with biopsy-proven PMN from Nephrotic Department of Beijing Friendship Hospital Affiliated to Capital Medical University participated in this retrospective cohort. The inclusion criteria were (1) age 18–75 years; (2) NS at the time of renal biopsy; (3) a baseline (established at the time of renal biopsy) eGFR ≥60 mL/min/1.73 m2, calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation [15]; (4) starting IS therapy after renal biopsy; (5) at least 12 months of follow-up with complete clinical data available for investigation. Patients with secondary membranous nephropathy, atypical membranous nephropathy, other concomitant glomerular diseases or IS agents before renal biopsy were excluded. The study protocol was reviewed and approved by the Ethics Committee of Beijing Friendship Hospital, with approval number 2021-P2-269-01. Written informed consent was not required.
Data Collection
Patients attended regular visits at intervals of 1–3 months. Urine sediment, 24-h urinary protein (UTP), serum albumin (ALB), and serum creatinine (Cr) were tested at each visit and recorded prospectively. Skilled clinical examiners performed microscopic analyses of urine sediments. Each urine sample was strictly analyzed within 2 h of collection and reported as red blood cell (RBC)/high-power field and RBC/μL. Other demographic and clinical information, including age, sex, white blood cells (WBC), hemoglobin (Hb), platelets (PLT), hypersensitive C-reactive protein (h-CPR), and immunofluorescence staining, for complement C3 in renal biopsies was collected from the initial medical records at the renal biopsy. PLA2R antibody titers were determined using a validated quantitative ELISA test kit (EUROIMMUN, Lübeck, Germany).
Definitions and Outcomes
Glomerular hematuria was characterized by the presence of dysmorphic RBCs in the urine under microscopic examination with >3RBCs/high-power field [16]. Glomerular hematuria levels were expressed as RBC/μL. Complete remission was defined as UTP <0.3 g and ALB ≥35 g/L, with a stable eGFR [17, 18]. Stable eGFR referred to no change or a decrease of <40% [19]. Partial remission was proteinuria >0.3 but <3.5 g/d plus a ≥50% reduction from baseline level, with ALB ≥35 g/L and stable kidney function [17, 18]. No remission was defined as proteinuria ≥3.5 g/d, a <50% decline in proteinuria, ALB <35 g/L, or a ≥40% decline in eGFR prior to achieving proteinuria reduction [19].
Statistical Analysis
Skewness and Kurtosis tests were used to conduct normality analyses. Quantitative variables were expressed as the mean ± SD for normally distributed data or median (interquartile range) for non-normally distributed data, and categorical data were represented as absolute frequencies or percentages. Continuous data for two groups were compared by the independent-samples t test or the Mann-Whitney U test when appropriate, while the chi-square test was performed for categorical data. The correlation between baseline hematuria and other clinical indexes was determined by Spearman rank correlation analysis. Binary logistic regression models were used to estimate the relationship between the measures and treatment responses. Receiver operating characteristic (ROC) curves were generated to evaluate the power of the measures to predict NS remission at 12 months. Statistical analysis was performed by SPSS software (version 22.0; SPSS, Chicago, IL, USA). For single variant regression analysis of nephrotic remission, a variable was enrolled when a two-sided p value was less than 0.10. In other conditions, a two-sided p value <0.05 was considered statistically significant. Forest plot of binary logistic regression was prepared by GraphPad Prism 9.0 software for Windows (San Diego, CA, USA).
Results
Patient Characteristics
Of the 301 screened patients, 175 patients received IS treatment. Among them, 127 patients had at least 12 months of follow-up with complete clinical data (Fig. 1). The 127 enrolled patients showed comparable demographic and clinical features with those of the 48 excluded patients (Table 1). Among the enrolled patients, the average age was 56.1 ± 12.7 years at the time of renal biopsy, 86 (67.7%) were male, and 41 (32.3%) were female. Overall, 112 patients (88.2%) had glomerular hematuria at the renal biopsy. Baseline serum ALB was 24.2 ± 6.3 g/L, serum Cr was 75.7 (62.5, 90.5) μmol/L, 24-h UTP was 3.76 (2.14, 5.89) g, and hematuria was 11 (6, 23) RBC/μL. A total of 82 (64.6%) patients presented with positive serum PLA2R Ab, whose median titer was 52.0 (2.5, 130.6) RU/mL. IS therapy comprised corticosteroids (n = 13), corticosteroids + cyclophosphamide (n = 55), corticosteroids + cyclosporine A (CsA) (n = 8), CsA only (n = 1), corticosteroids + mycophenolate mofetil (n = 7), corticosteroids + CsA + mycophenolate mofetil (n = 6), and rituximab (RTX) (n = 37). At 12 months, 52 patients and 27 patients achieved complete remission and partial remission , respectively. Pooled remission rate was 62.2%.
Fig. 1.
Flow diagram of the study population selection.
Table 1.
Comparison of the included and excluded patients with PMN
| Characteristic | PMN patients (n = 175) | Included (n = 127) | Excluded (n = 48) | p value |
|---|---|---|---|---|
| Gender (male (%)) | 119 (68.0) | 86 (67.7) | 33 (68.8) | 0.896 |
| Age, years | 55.3±13.0 | 56.1±12.7 | 53.2±13.6 | 0.189 |
| Baseline UTP, g/24 h | 3.50 (2.10, 5.62) | 3.76 (2.14, 5.89) | 3.17 (1.98, 5.21) | 0.322 |
| Baseline hematuria, RBC/μL | 11 (6, 23) | 12 (6, 22) | 11 (5, 25) | 0.984 |
| Baseline ALB, g/L | 23.7±5.9 | 24.2±6.3 | 22.3±4.6 | 0.056 |
| Baseline Cr, µmol/L | 74.1 (62.5, 89.8) | 75.7 (62.5, 90.5) | 73.6 (62.4, 85.5) | 0.507 |
| Baseline h-CRP, mg/L | 1.03 (0.52, 2.11) | 1.08 (0.62, 2.02) | 0.82 (0.49, 2.32) | 0.701 |
| PLA2R-Ab titer, RU/mL | 59.1 (5.0, 176.2) | 52.0 (2.5, 130.6) | 105.3 (11.6, 276.0) | 0.053 |
| PLA2R-Ab (+/−) | 116/59 | 82/45 | 34/14 | 0.434 |
PMN, primary membranous nephropathy; UTP, 24-h urinary protein; RBC, red blood cell; ALB, plasma albumin; Cr, serum creatinine; h-CRP, high-sensitivity C-reactive protein; PLA2R-Ab, anti-phospholipase A2 receptor antibody.
Comparison of Patients with Glomerular Hematuria and Those without
The differences between the patients with hematuria and those without were analyzed first. The results showed that the patients with hematuria had higher ages, higher serum h-CRP levels, lower remission rate at 12 months, and trended to have higher baseline serum Cr levels (Table 2). There was no significant difference in IS agents between the groups (Table 2).
Table 2.
Comparison of patients with and without glomerular hematuria
| Characteristics | Positive hematuria (n = 112) | Negative hematuria (n = 15) | p value |
|---|---|---|---|
| Gender (male (%)) | 79 (70.5) | 7 (46.7) | 0.118 |
| Age, years | 57.2±12.4 | 47.9±12.7 | 0.007a |
| Baseline UTP, g/24 h | 3.61 (2.08, 5.85) | 4.22 (3.03, 6.13) | 0.494 |
| Baseline ALB, g/L | 24.1±6.4 | 25.2±5.7 | 0.519 |
| Baseline Cr, µmol/L | 78.6 (63.6, 90.5) | 59.8 (55.4, 88.5) | 0.058 |
| Baseline h-CRP, mg/L | 1.14 (0.66, 2.11) | 0.41 (0, 0.91) | 0.004a |
| PLA2R-Ab titer, RU/mL | 57.4 (5.4, 130.6) | 33.1 (0, 71.6) | 0.233 |
| PLA2R-Ab (+/−) | 74/38 | 8/7 | 0.333 |
| C3 IFA (0/1/2/3) | 5/48/37/22 | 2/7/5/1 | 0.166 |
| Remission rate at 12 months, n (%) | 66 (58.9) | 13 (86.67) | 0.037b |
| IS therapy | | | 0.089 |
| Corticosteroids | 11 | 2 | |
| Corticosteroids + CTX | 51 | 4 | |
| Corticosteroids + CsA | 6 | 2 | |
| CsA | 1 | 0 | |
| Corticosteroids + MMF | 7 | 3 | |
| Corticosteroids + CsA + MMF | 6 | 1 | |
| RTX | 37 | 3 | |
UTP, 24-h urinary protein; ALB, plasma albumin; Cr, serum creatinine; h-CRP, high-sensitivity C-reactive protein; PLA2R-Ab, anti-phospholipase A2 receptor antibody; C3, complement 3; IFA, semiquantitative direct immunofluorescence analysis of renal biopsy samples; 0, negative; 1, +; 2, ++; 3, +++; IS, immunosuppressive; CTX, cyclophosphamide; CsA, cyclosporine A; MMF, mycophenolate mofetil; RTX, rituximab.
a p < 0.01.
b p < 0.05.
Subgroup Analysis of Patients with Glomerular Hematuria
Baseline Hematuria
The median baseline hematuria value was 18 (8, 25) RBC/μL. No significant correlations were found between baseline hematuria levels and other clinical indexes, including serum ALB, Cr, and 24-h UTP at different time points (baseline, at 6 and 12 months), baseline h-CRP and PLA2R Ab, C3 staining in renal biopsies, and remission rates at 12 months (Table 3).
Table 3.
Correlation between baseline hematuria and other clinical indices
| Variables | Baseline hematuria levels | |
|---|---|---|
| R | p value | |
| Gender | −0.003 | 0.975 |
| Age | 0.011 | 0.905 |
| Baseline UTP | −0.066 | 0.492 |
| Baseline ALB | −0.050 | 0.598 |
| Baseline Cr | −0.068 | 0.474 |
| Baseline h-CRP | −0.059 | 0.539 |
| PLA2R Ab titer | 0.013 | 0.896 |
| PLA2R Ab (+/−) | 0.043 | 0.651 |
| C3 IFA | −0.053 | 0.578 |
| UTP at 6 months | −0.095 | 0.320 |
| ALB at 6 months | −0.031 | 0.746 |
| Cr at 6 months | −0.088 | 0.354 |
| UTP at 12 months | −0.082 | 0.390 |
| ALB at 12 months | 0.034 | 0.721 |
| Cr at 12 months | −0.100 | 0.296 |
| Remission status at 12 months | −0.108 | 0.255 |
UTP, 24-h urinary protein; ALB, plasma albumin; Cr, serum creatinine; h-CRP, high-sensitivity C-reactive protein; PLA2R-Ab, anti-phospholipase A2 receptor antibody; C3, complement 3; IFA, semiquantitative direct immunofluorescence analysis of renal biopsy samples.
Negative Conversion of Hematuria at 6 Months
At 6 months, 31/112 (27.7%) patients had negative conversion of hematuria, and they had lower baseline PLA2R Ab titer, higher serum ALB levels, less 24-h UTP at both 6 and 12 months, and higher nephrotic remission rates at 12 months, compared with those without (Table 4). There were no significant differences among IS agents between the groups (Table 4).
Table 4.
Comparison of patients with and without hematuria remission 6 months after IS therapy
| Characteristics | Negative conversion (n = 31) | No negative conversion (n = 81) | p value |
|---|---|---|---|
| Gender (male (%)) | 21 (67.7) | 58 (71.6) | 0.688 |
| Age, years | 55.0±13.5 | 58.1±11.9 | 0.243 |
| Baseline UTP, g/24 h | 3.84 (2.88, 6.29) | 3.36 (1.89, 5.65) | 0.286 |
| Baseline ALB, g/L | 23.5±7.5 | 24.3±6.0 | 0.547 |
| Baseline Cr, µmol/L | 83.6 (67.1, 100.9) | 73.1 (63.5, 89.0) | 0.224 |
| Baseline h-CRP, mg/L | 1.40 (0.71, 2.80) | 1.11 (0.64, 2.07) | 0.385 |
| PLA2R Ab titer, RU/mL | 43.6 (0, 78.2) | 67.5 (10.8, 191.4) | 0.025b |
| PLA2R Ab (+/−) | 14/17 | 24/57 | 0.120 |
| C3 IFA (0/1/2/3) | 2/15/7/7 | 3/33/30/15 | 0.471 |
| UTP at 6 months, g/24 h | 0.70 (0.23, 1.54) | 3.11 (1.52, 6.25) | <0.001c |
| ALB at 6 months, g/L | 37.4±4.7 | 30.2±7.0 | <0.001c |
| Cr at 6 months, µmol/L | 78.8 (67.9, 93.0) | 74.9 (65.2, 88.9) | 0.346 |
| UTP at 12 months, g/24h | 0.36 (0.15, 1.46) | 1.48 (0.26, 4.62) | 0.001a |
| ALB at 12 months, g/L | 40.4±4.6 | 35.2±8.6 | <0.001c |
| Cr at 12 months, µmol/L | 78.0 (63.1–100.7) | 78.0 (69.1–95.1) | 0.480 |
| Remission rate at 12 months, n (%) | 26 (83.9%) | 40 (49.4%) | 0.001a |
| IS therapy | | | 0.157 |
| Corticosteroids | 5 | 6 | |
| Corticosteroids + CTX | 18 | 33 | |
| Corticosteroids + CsA | 2 | 4 | |
| CsA | 0 | 1 | |
| Corticosteroids + MMF | 1 | 3 | |
| Corticosteroids + CsA + MMF | 0 | 5 | |
| RTX | 5 | 29 | |
UTP, 24-hour urinary protein; ALB, plasma albumin; Cr, serum creatinine; h-CRP, high-sensitivity C-reactive protein; PLA2R-Ab, anti-phospholipase A2 receptor antibody; C3, complement 3; IFA, semiquantitative direct immunofluorescence analysis of renal biopsy samples; 0, negative; 1, +; 2, ++; 3, +++; IS, immunosuppressive; CTX, cyclophosphamide; CsA, cyclosporine A; MMF, mycophenolate mofetil; RTX, rituximab.
a p < 0.01.
b p < 0.05.
c p <0.001.
Single variant regression analysis showed that hematuria disappearance at 6 months, PLA2R Ab titer, and IS therapeutic protocol were more significantly correlated with nephrotic remission at 12 months (Table 5). Binary logistic regression demonstrated that hematuria disappearance at 6 months was an independent predictor for nephrotic remission at 12 months (OR = 0.211, 95% CI: 0.070–0.635, p = 0.006) (Fig. 2). ROC curve analysis revealed that the area under the curve for predicting nephrotic remission at 12 months was 0.643 (95% CI: 0.541–0.744, p = 0.010) for hematuria disappearance at 6 months, 0.592 (95% CI: 0.479–0.705, p = 0.098) for PLA2R Ab titer, 0.593 (95% CI: 0.486–0.700, p = 0.095) for IS therapy, and 0.781 (95% CI: 0.695–0.866, p < 0.001) for the combination of all three predictive factors (Fig. 3).
Table 5.
Correlation analysis between nephrotic remission at 12 months and other clinical data and treatment response
| Variables | Nephrotic remission at 12 months | |
|---|---|---|
| R | p value | |
| Gender | −0.062 | 0.517 |
| Age | 0.001 | 0.995 |
| Baseline hematuria | −0.108 | 0.255 |
| Baseline UTP | −0.118 | 0.215 |
| Baseline ALB | 0.127 | 0.181 |
| Baseline Cr | −0.008 | 0.932 |
| Baseline h-CRP | −0.020 | 0.832 |
| PLA2R Ab titer | 0.157 | 0.097a |
| PLA2R Ab (+/−) | −0.015 | 0.875 |
| C3 IFA | −0.057 | 0.551 |
| Hematuria disappearance at 6 months | 0.341 | 0.001b |
| IS therapy | 0.169 | 0.075a |
Baseline hematuria: RBC/μL.
UTP, 24-hour urinary protein; ALB, plasma albumin; Cr, serum creatinine; h-CRP, high-sensitivity C-reactive protein; PLA2R-Ab, anti-phospholipase A2 receptor antibody; C3, complement 3; IFA, semiquantitative direct immunofluorescence analysis of renal biopsy samples; IS, immunosuppressive.
a p <0.10.
b p <0.01.
Fig. 2.
Forest plot of binary logistic regression for remission of NS.
Fig. 3.
The ROC curve analysis revealed the area under the curve (AUC) for predicting nephrotic remission.
Discussion
In the present study, we found a high prevalence of glomerular hematuria in PMN patients with NS and revealed that the negative conversion of hematuria at the first 6 months of IS therapy was an independent predictor for nephrotic remission at 12 months.
As is well known, not all PMN patients have NS presentation [20, 21]. Only patients with NS were enrolled in this study because these patients are more likely to develop end-stage renal disease, especially those with poor response to treatments and persistent NS [22]. PMN patients with NS often need IS treatment and subsequently face more drug-associated adverse effects and economic loads [23–25]. However, many early-stage indicators predicting therapeutic effects are limited to anti-PLA2R antibody titers [26]. In our clinical practices, we noticed that many PMN patients had glomerular microhematuria. Therefore, we executed the retrospective study to evaluate the association of early hematuria disappearance with IS therapy efficacy and nephrotic remission and its predictive value as well.
First, we compared 127 patients with at least 12 months of complete clinical data with 48 patients without and found that there were no statistically significant differences in the demographic and clinical features between them. The results suggested selective bias seemed to be negligible.
Second, hematuria prevalence was investigated, and 82 out of 127 (64.6%) patients were found to have microscopic hematuria at the renal biopsy. Actually, hematuria is frequently present in podocytopathies [27]. Previous studies reported that microscopic hematuria could be seen in 50%–66.9% of patients with membranous nephropathy [27–29]. In our group, the prevalence seemed to be higher. This is very likely related to the characteristics of our participants whose clinical manifestations were all NS. Marchel et al. [27] analyzed combined data of a large cohort of patients with podocytopathies from the Nephrotic Syndrome Study Network (NEPTUNE) and Cure Glomerulonephropathy (CureGN) studies. They reported that in the three podocytopathies (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy), participants with hematuria compared to those without were more likely to have an underlying diagnosis of membranous nephropathy and had a higher mean urine protein-creatinine ratio (3.8 [1.4–8.0] vs. 0.9 [0.1–3.1] g/g). These results partly verified our findings, and heavier proteinuria may mean more severe damages of glomerular filtration membrane and/or active inflammation or immune reaction (disease activity) in glomerular regions, which would contribute to the presence and magnitude of glomerular hematuria [30]. Furthermore, the comparison between the groups suggested the patients with hematuria were older (p = 0.007) and have higher serum h-CRP concentrations (p = 0.004) and more poor remission rates at 12 months (p = 0.037) but showed no difference in C3 staining in the biopsy sample or IS therapeutic options. Given that aging is associated with chronic low-grade inflammation [31], such results can be largely expected. The older patients may have more poor context conditions of their kidneys and more susceptibilities to nephrotoxic factors, resulting in more severe glomerular inflammations, easily seen microhematuria, and consequently poorer outcomes, which are consistent with those reports of Marchel et al. [27]. Normally, the standardized renal pathology utilizes the antibodies against C3c in the immunofluorescence staining [32]. C3c is the degradation product of C3b and may not always be parallel to real-time glomerular active inflammations [10, 33].
Following that, we investigated the clinical value of baseline hematuria and its negative conversion at 6 months in the subgroup of the patients with hematuria, respectively. No significant correlations were observed between baseline hematuria and other clinical indexes, which were somewhat different from previous studies. Marchel et al. [27] reported that the initial hematuria is independently associated with worse kidney-related outcomes, including both progressive loss of kidney function and remission of proteinuria. In their study, three types of podocytopathies were measured simultaneously, not only membranous nephropathy. He et al. [19] retrospectively followed a cohort of 639 patients with biopsy-proven PMN from two Chinese centers for a median of 40 months. The relapse rather than remission rate was their focus, and a higher level of initial hematuria was believed as a predictor of relapse. Although hematuria worsening or diminution were analyzed and then remission of hematuria was confirmed to be independently associated with reduced risk for renal progression (37%), the response of IS therapy was not evaluated, which was not only one of the most important determinants of renal outcomes but also often was associated with adverse events, such as infection, myelosuppression, metabolic disorders, even cardiovascular risks, and so on [34]. In our study, the patients with hematuria disappearance at 6 months were compared with those without, and the results illustrated that the former had lower PLA2R Ab titers (p = 0.025) and higher remission rate at 12 months compared with the latter (p = 0.001). The negative conversion at 6 months was significantly associated with nephrotic remission at 12 months (p = 0.001). These findings highly indicated the predictive value of the early improvement of hematuria for therapeutic responses. Therefore, logistics regression analysis was subsequently performed, which demonstrated that the negative conversion of hematuria at 6 months was a significant and independent predictor for nephrotic remission at 12 months in PMN patients with NS receiving IS therapy. Our findings provided very important clues with optimized and individualized managements of PMN patients with NS. For the patients with persistent glomerular hematuria after more than 6-month IS treatment, proteinuria remission might be difficult thereafter. Reevaluation of clinical conditions needed to be done, underlying factors influencing effects needed to be established, and IS therapy conversion or tapering were worthy being thought about ,especially for some weak and/or elderly patients.
Finally, ROC curve was employed to assess the independent and combined predicting power of the negative conversion of hematuria at 6 months, respectively. Area under the curve for forecasting nephrotic remission at 12 months was 0.643 (p = 0.010) independently and 0.781 (p < 0.001) combined with PLA2R Ab titer and IS therapeutic programs. The result strongly suggests the importance of incorporating the early improvement of glomerular hematuria into a therapeutic effect assessment of PMN patients with NS. Barbour et al. [35] reported the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R Ab levels combined with albumin levels after 3 months of treatment. However, that was a trial targeting RTX, and as is well known, there are many factors that could influence the response of RTX, such as serum RTX concentrations, urinary loss, anti-RTX antibody, and so on [36–40]. Our participants received varied IS treatments, not only RTX.
Our study has several limitations. First, the generalizability of our findings may be limited as the study was conducted in only one center. Second, a prospective study would provide more in-depth results compared with a retrospective study.
In conclusion, patients with PMN and NS have high prevalence of glomerular hematuria. Patients without hematuria or negative conversion of hematuria at 6 months after IS treatment have higher nephrotic remission rates at 12 months. For patients with hematuria, hematuria disappearance at 6 months was an independent predictor for nephrotic remission at 12 months.
Acknowledgment
We thank Jane Charbonneau, DVM, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.
Statement of Ethics
The study protocol was reviewed and approved by the Ethics Committee of Beijing Friendship Hospital, with approval No. 2021-P2-269-01. This study has been approved by the Ethics Committee of Beijing Friendship Hospital to proceed without written informed consent.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Qing-lian Hu contributed to the first draft of the manuscript and data collection and analysis. Gang Wang, Wen-na Song, Xu Liu, and Qi-dong Zhang also performed data collection. Hong-dong Huang was responsible for revising the article. Ai-hua Zhang performed the research design, article revision, and final draft determination.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
The data underlying this article were provided by Capital Medical University Affiliated Beijing Friendship Hospital under license. Further inquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data underlying this article were provided by Capital Medical University Affiliated Beijing Friendship Hospital under license. Further inquiries can be directed to the corresponding author.
