IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide . Its incidence is particularly high in Asia compared with North America or Europe , , , , . During the past several decades, a number of studies using various therapeutic modalities have been conducted to prevent the progression of kidney disease in IgAN , . In addition, experimental studies have suggested potential candidates with promising results , , but most of these have not yet been proven in clinical practice. Currently, no confirmative treatment is available in IgAN and therapeutic options are limited to renin-angiotensin system blockers, low protein diet, corticosteroids, etc. Nevertheless, IgAN can progress to kidney failure and ~30% patients eventually require dialysis or transplantation in the end 20 years after diagnosis .
The pathogenesis of IgAN is a complicated multi-step process . First, IgA1 with a poorly O-galactosylated hinge region is produced and increased in the circulation , , . Then, IgG antibodies are generated against the misglycated IgA1 and they drive the formation of a large immune-complex . Subsequently, the pathogenic immune complexes are deposited within the mesangium via interaction with mesangial IgA receptors such as CD71 , . Upon binding to the receptors, the complement pathway is activated along with other sequential cascades that can damage mesangial cells and glomerular structures, such as tumor necrosis factor, transforming growth factor, and platelet-derived growth factor , , . These processes eventually lead to the activation of a terminal fibrotic process, followed by glomerulosclerosis and tubulointerstitial fibrosis , , .
To date, several IgA receptors and IgA-binding molecules have been identified . These include hepatic asialoglycoprotein receptor, polymeric Ig-receptor on mucosal epithelial cells, Fcα/γ-receptor on most B lymphocytes and macrophages, transferrin receptor (CD71), and myeloid FcαR1-receptor (CD89) , , , , . Among these, CD89 has been highlighted in light of its role in the pathogenesis of IgAN , , , , . CD89 is a type I receptor glycoprotein expressed on myeloid cells, and binds with high affinity to IgA , . It has been suggested that CD89 contributes to the formation of polymeric serum IgA  and facilitates the formation of the immune-complex. Launay et al.  demonstrated that circulating levels of soluble CD89 (sCD89)-IgA complexes were significantly higher in patients with IgAN than in those with other glomerular diseases. They further delineated the role of CD89 in an animal model of IgAN by showing that IgAN-like features spontaneously developed in the kidney of transgenic mice expressing human CD89 on macrophage/monocytes.
In spite of intriguing findings from several studies regarding the role of CD89 in the development of the immune-complex, clinical evidence supporting an association between the circulating levels of sCD89-IgA complex and disease progression are limited. Launay et al.  first identified this complex in the serum of IgAN patients and suggested its pathogenic role. Their findings were partly corroborated in a recent study by Berthelot et al.  In contrast, Vuong et al.  showed that circulating sCD89-IgA complex levels were decreased in progressive IgAN compared to stable levels in non-progressive IgAN. Of note, whether sCD89-IgA complex is superior to well-known clinical risk factors in predicting renal outcome has not been evaluated in detail. Furthermore, given the geographic variability and ethnic differences in the disease progression of IgAN , , it would be interesting to test the clinical implication of this complex in an Asian population. Thus, we evaluated whether the sCD89-IgA complex is of help for the risk stratification of IgAN and compared the predictability of this complex with conventional well-known risk factors for disease progression.
Materials and methods
A total of 344 patients with biopsy-proven IgAN between 2005 and 2014 were eligible for this study. Demographic and laboratory data were obtained from the Glomerulonephritis Registry of Yonsei University Health System (YUHS). A flow diagram depicting the process of participant selection is presented in Figure 1. We excluded 18 patients who met the following criteria: (1) age <18, (2) missing data during follow-up, (3) previous history of kidney transplantation, (4) diagnosed as end stage renal disease (ESRD), (5) estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, and (6) Henoch-Schonlein purpura nephritis. Thus, 326 patients with IgAN were included in the primary analysis. The study was approved by the Institutional Review Board of YUHS, and all participants gave written informed consent.
Clinical, biochemical and histologic data collection
Using the database from the Glomerulonephritis Registry of YUHS, demographic, clinical and biochemical data at the time of renal biopsy including age, sex, blood pressure and body mass index (BMI) were retrieved and considered as baseline data. BMI was calculated as weight/height (kg/m2). At the time of renal biopsy, sera from all patients were collected and stored at −80 °C freezer. The following biochemical laboratory data were also collected: blood urea nitrogen, serum creatinine, random urine protein-to-creatinine ratio (UPCR), serum IgA, hemoglobin, fasting blood glucose, serum albumin, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hs-CRP). The calculation of eGFR was performed by using the Modification of Diet in Renal Disease Study equation . Serum total cholesterol, HDL-C, LDL-C, and triglyceride were measured by enzymatic colorimetry using an autoanalyzer (Hitachi 7150; Hitachi Ltd., Tokyo, Japan), and hs-CRP levels were determined by a latex-enhanced immunonephelometric method using a BNII analyzer (Dade Behring, Newark, DE, USA). Follow-up data such as blood pressure, UPCR and eGFR were recorded at 3-month interval visits. All renal biopsy specimens were re-assessed by one pathologist blinded to the patients’ clinical data using the Oxford classification.
The study endpoint was the onset of a 30% decline in eGFR during follow-up. This was defined as a sustained decrease in eGFR >30% for at least three consecutive measurements. The first of these consecutive measurements was retrospectively designated as the study endpoint. We also compared the decline rate of eGFR based on circulating CD89-IgA complex levels.
Indirect enzyme-linked immunosorbent assay for determination of sCD89-IgA complex in sera of IgAN patients
To determine the sCD89-IgA complex levels in patients with IgAN, we used the patients’ sera and performed an indirect sandwich enzyme-linked immunosorbent assay (ELISA). There are two isoforms of CD89 in humans: 50–70 kDa and 30 kDa isoforms , . The former is believed to play a key role in the formation of the immune complex , and thus was used in this study. Mouse monoclonal CD89 antibodies were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA). High binding 96-well microtiter plates (Costar, Corning, NY, USA) were coated with anti-CD89 antibody at a concentration of 0.26 μg/mL and incubated overnight at 4 °C. Serum complexes were isolated using polyethylene glycol precipitation. The samples were diluted to 1:1000 bovine serum albumin with 0.05% Tween 20 in phosphate-buffered saline (PBS) (pH 7.2) and added to the plates. A patient’s serum with median level of sCD89 was used as a reference. The plates were incubated at 37 °C for 2 h and incubated with rabbit anti-human IgA conjugated to alkaline phosphatase (AP, Dako, Glostrup, Denmark) in PBS-Tween-1% fish gelatin (1:1000) for 2 h. After adding AP substrate (Sigma-Aldrich, St. Louis, MO, USA), absorbance was measured as the optical density at 405 nm in a multiscan spectrophotometer. The complex levels were expressed as percent of the reference.
Western blot analysis
The band size of CD89 was confirmed by Western blot analysis. For this, sera from IgAN patients were diluted 50- to 100-fold in a standard detergent-containing buffer, and the proteins were resolved by 10% SDS-PAGE and transferred to nitrocellulose membranes. The membranes were incubated with the monoclonal anti-CD89 antibody. The bands were visualized by enhanced chemiluminescence (Western Lightning-ECL; Thermo Scientific, Waltham, MA, USA).
All statistical analyses were performed using SPSS for Windows version 21.0 (SPSS, Inc., Chicago, IL, USA) and SAS version 9.2 (SAS, Inc., Cary, NC, USA). Continuous variables were expressed as the mean±standard deviation, while categorical variables were expressed as absolute numbers with percentages. Each variable was tested for normality before statistical analysis. Comparisons between groups were conducted by analysis of variance or Student’s t-test for continuous variables and by the χ2 test or Fisher’s exact test for categorical variables. The Kolmogorov-Smirnov test was performed to determine the normality of the distribution of parameters. If data did not show a normal distribution, data were log-transformed and presented as median and interquartile range. For these data, the Mann-Whitney U test or Kruskal-Wallis test was used for multiple comparisons. Relationships between sCD89-IgA complex levels and eGFR were evaluated by Pearson’s correlation analysis. We further examined the independent association between the two parameters using multiple linear regression analysis. To assess the prognostic utility of sCD89-IgA complex levels for the progression of kidney disease, a multivariable Cox model was conducted to evaluate the association between eGFR reduction and baseline circulating CD89-IgA complex levels. Hazard ratios (HRs) for developing a 30% decrease in eGFR were compared among the three groups by tertiles of sCD89-IgA complex levels. Because proteinuria and blood pressure were highly variable during follow-up, these variables were modeled as time-varying covariates. The decline rates in eGFR between groups were further compared using mixed linear models. Furthermore, the predictive power of sCD89-IgA complex levels was assessed by C-statistics. For this, we calculated Harrell’s C index for a multivariable Cox model including conventional prognostic factors with and without sCD89-IgA complex. p-Values <0.05 were considered statistically significant.
Confirmation of CD89 size
First, we sought to confirm the size of CD89. Western blot analysis detected the band at ~55 kDa (Supplemental Figure 1). Interestingly, there was a smear of 50–70 kDa in some patients. Presumably, the smear shape can be seen when heavily glycosylated CD89 is captured. It is also possible that circulating form of CD89 is less glycosylated than membrane form, thus resulting in a single band on Western blot analysis. In addition, we further tested an antibody capturing different isotype of CD89 (30 kDa), and a band image of Western blot corresponding to 30 kDa size is shown in Supplemental Figure 2.
Baseline characteristics between three groups by tertiles of circulating CD89-IgA complex levels
Among 344 patients who were diagnosed with biopsy-proven IgAN between 2005 and 2014, 326 were included in the final analysis. Figure 1 represents a flow diagram of depicting the process of participant selection. The baseline characteristics of study subjects are shown in Table 1. The mean age of the study subjects was 38.8±12.8 years, and 138 (42.3%) patients were male. Patients were categorized into three groups by tertiles of circulating CD89-IgA complex levels. There were no significant differences in baseline eGFR among three groups (92.8±27.9 mL/min/1.73 m2 in lowest tertile, 89.3±25.9 mL/min/1.73m2 in middle tertile, and 85.8±26.5 mL/min/1.73 m2 in highest tertile, p=0.15).
Factors associated with sCD89-IgA complex levels
Pearson’s correlation analysis was performed to evaluate the association between sCD89-IgA complex levels and baseline parameters at the time of biopsy (Table 2). sCD89-IgA complex levels positively correlated with serum IgA levels, and negatively correlated with eGFR (Figure 2A). However, sCD89-IgA complex levels did not differ among chronic kidney disease (CKD) stages (Figure 2B). Multivariable linear regression analysis also showed that eGFR was not significantly associated with the sCD89-IgA complex (ß=0.35, p=0.75, Table 3).
In addition, sCD89-IgA complex levels did not correlate with proteinuria. When we analyzed among patients with UPCR of >1.0 g/g, there was no correlation between UPCR and sCD89-IgA complex levels. Furthermore, we additionally analyzed the correlation between pathologic lesions and sCD89-IgA complex levels. There was no significant difference in mesangial proliferation, endocapillary proliferation, segmental sclerosis, or tubular atrophy/interstitial fibrosis by the Oxford classification or crescentic lesions according to the tertiles of sCD89-IgA complex levels (data not shown). In aggregates, sCD89-IgA complex levels did not correlate with any clinical important parameters in IgAN.
sCD89-IgA complex does not predict adverse kidney outcome
Next, we further evaluated the clinical utility of the sCD89-IgA complex in predicting the progression of kidney disease. During a median follow-up of 48.4 months, 20 (18.7%), 14 (12.7%), and 14 (14.7%) patients in the lowest, middle, and highest tertiles reached a 30% decline in eGFR, respectively (p=0.37). Unadjusted HRs for reaching the endpoint in the highest and middle tertiles were 0.68 (95% CI, 0.34–1.35; p=0.27) and 0.64 (95% CI, 0.32–1.26; p=0.19) as compared to the lowest tertile. In the multivariable Cox model adjusted for age, sex, mean arterial pressure (MAP), eGFR, UPCR, and presence of hypertension (HTN) with MAP and UPCR being treated as time-varying covariates, the highest (HR, 0.75; 95% CI, 0.35–1.61; p=0.45) and middle (HR, 0.93; 95% CI, 0.46–1.89; p=0.84) tertiles of sCD89-IgA complex levels were not associated with an increased risk of developing a 30% decrease in eGFR (Table 4). When the log value of sCD89-IgA complex levels was treated as a continuous variable, the results remained unaltered (HR, 0.99; 95% CI, 0.55–1.79, p=0.99). Because a different isotype of CD89 (30 kDa) was used in other studies, we also measured sCD89-IgA levels using 30 kDa CD89 antibody and performed a multivariable-adjusted Cox model. The result consistently showed that sCD89-IgA levels measured by 30 kDa isoform were not associated with the study endpoint (Supplemental Table 2).
We also calculated the slopes of eGFR decline by using a linear mixed model. The decline rates in eGFR did not differ between the three tertile groups (Supplemental Table 1 and Supplemental Figure 3). To substantiate our results, we calculated Harrell’s C indexes for the two Cox models with and without sCD89-IgA complex levels (Table 5). C-statistics of a model including conventional factors only such as age, sex, presence of HTN, blood pressure, UPCR, eGFR and the Oxford-T score was 0.69 (95% CI, 0.57–0.81). Adding the sCD89-IgA complex levels to this model did not improve the predictive ability of the model including clinical factors only (C-statistics, 0.70; 95% CI, 0.58–0.82). Receiver operating characteristics analysis revealed that the areas under the curves were comparable between the two models (0.74 [95% CI, 0.64–0.84] vs. 0.75 [95% CI, 0.65–0.85]; p=0.69), suggesting a lack of predictive power of sCD89-IgA levels (Figure 3).
In this study, we examined the clinical implication of sCD89-IgA complex in patients with IgAN. We showed that sCD89-IgA complex levels were not significantly associated with eGFR at the time of the biopsy. Furthermore, the sCD89-IgA complex was not associated with an increased risk of developing a 30% decline in eGFR and showed a lack of predictive power for the progression of kidney disease compared to conventional clinical factors. These findings suggest that sCD89-IgA complex has limited clinical utility as a biomarker for predicting adverse outcomes in IgAN.
It has been suggested that CD89 can contribute to the generation of the immune complex and plays a role in the pathogenesis and progression of IgAN . CD89, which is normally expressed on the cell surface of monocytes , is shed upon binding to polymeric IgA, making the immune complex in the circulation. This phenomenon was first demonstrated in a previous study by Launay et al. . They found increased sCD89 levels in the serum of the immune complex of patients with IgAN by using a sandwich ELISA, while the levels were significantly lower in patients with other glomerular diseases. To explore the role of CD89, they generated transgenic mice expressing human CD89 on macrophage/monocytes and found IgAN-like features such as massive IgA deposition within the mesangium and development of hematuria and albuminuria. Several years later, however, their findings were contradicted in a study by van der Boog et al. . In their study, sCD89-IgA complexes did not correlate with any clinical parameters and circulating levels of the complex were similar in patients with IgAN and controls. Furthermore, Vuong et al.  found that sCD89-IgA complex levels did not differ among IgAN patients, healthy controls, and patients with non-IgA glomerulonephritis. Notably, in contrast to the previous findings by Launay et al. , the circulating complex levels were decreased in progressive IgAN, while the levels remained stable and were elevated in non-progressive IgAN. They suggested a consumption theory such as that observed in lupus nephritis, where complement levels are decreased in flare disease . It can be speculated that sCD89-IgA complexes become “sticky”, and thus preferentially deposit within the glomerulus, resulting in the disappearance of the complex from the circulation in IgAN, particularly in severe disease. Interestingly, a recent study by Berthelot et al.  analyzed sCD89-IgA complex levels in patients who underwent transplantation due to IgAN and found that the complex levels were significantly increased in both recurrence and non-recurrence recipients compared to healthy controls. However, the levels were significantly lower in the recurrence group than in the non-recurrence group. As such, previous studies regarding the sCD89-IgA complex have yielded conflicting results, and thus the clinical implication of the circulating complex levels is not conclusive.
In this study, we found a weak but significantly negative association between sCD89-IgA complex levels and kidney function assessed by eGFR in a correlation study using variables obtained at the time of biopsy. This led us to presume two possibilities: (1) a potential role of this complex in the progression of kidney disease or (2) a simple reflection of decreased clearance of the complex due to kidney failure. However, both are unlikely, as multivariate linear regression analysis failed to find an independent association between the two factors and combining sCD89-IgA complex with conventional clinical factors was not superior to clinical factors alone in predicting renal adverse outcomes. Several previous studies showed elevated levels of this complex in IgAN, but did not compare its predictability with other well-known clinical factors such as proteinuria . Our findings are in agreement with assumption by Vuong et al. . In their negative study of sCD89-IgA complex, they speculated that the circulating complexes itself are not pathogenic and may not play an important role in kidney disease progression. Presumably, although sCD89 can facilitate the IgA1 recognition by IgG autoantibodies, IgG autoantibodies independently form complexes with poorly galactosylated IgA1 without the help of sCD89 . Of note, Tissandie et al.  showed that patients with alcoholic liver cirrhosis had elevated sCD89-IgA complex levels, which were comparable to those with primary IgAN. However, no glomerular abnormalities could be found in patients with liver cirrhosis. This finding supports our results that sCD89-IgA complex does not contribute to the pathogenesis of IgAN.
Because nearly all sCD89s are tightly bound to IgA within the CD89-IgA complexes and only a minor portion of the sCD89 is exposed for antibody recognition, it is very difficult to capture sCD89 in the serum. To overcome this limitation, several authors established a sandwich ELISA to detect sCD89-IgA complexes rather than free sCD89. There are two isoforms of CD89 in human: 50–70 kDa and 30 kDa isoforms , . It is possible that the discrepant findings between studies regarding sCD89-IgA complex levels are attributed to the use of the different isoforms. Interestingly, a 50–70 kDa isoform is thought to be more involved in the generation of immune complex, while the 30 kDa isoform may be protective against binding to IgG autoantibodies . In fact, in a study by Launay et al.  favoring the pathogenic role of sCD89, the 50–70 kDa isoform was detected exclusively in the patients’ sera. In contrast, Voung et al. captured the 30 kDa isoform and found no difference in sCD89-IgA complex levels between IgA patients, healthy controls and patients with other glomerulonephritis . However, this assumption regarding the discrepant role of two isoforms has not yet been verified. We also measured sCD89-IgA complex using an antibody capturing 30 kDa isoform. However, both methods failed to provide a significant prognostic value of the sCD89-IgA complex. Furthermore, previous studies did not provide the clinical characteristics of subjects in detail and did not explore whether the sCD89-IgA complex was as useful as a clinical factor in predicting kidney disease progression. Using sandwich ELISA as described in the previous studies , , , , we thoroughly evaluated the clinical utility of the sCD89-IgA complex. Nevertheless, we found no significant role of this complex as a biomarker of IgAN.
This study has several limitations. First, sCD89-IgA complex levels were measured once at the time of biopsy and patients with advanced IgAN were excluded. Therefore, it is uncertain whether the sCD89-IgA complex plays a role in later stages. In this study, only 13 patients had eGFR <30 mL/min/1.73 m2 at baseline. Although these patients were included in the analysis, the results remained similar. If the sCD89-IgA complex comes into play long after the onset of IgAN, serial measurements would be helpful for monitoring disease activity, particularly when the disease activity is highly variable. This hypothesis fits well with the consumption theory as suggested by Voung et al. . However, the null findings of our study in less advanced CKD further indicate the limited role of this complex as an early biomarker for predicting adverse outcomes. Second, we did not examine whether the sCD89-IgA complex can be deposited within the mesangium. It is well-known that mesangial cells do not express CD89 , , . Therefore, if the sCD89-IgA complex plays an important role in the pathogenesis of IgAN, identification of sCD89 within the mesangium at the protein level is mandatory irrespective of its circulating levels. A recent study by Lechner et al.  showed mesangial sCD89 deposition along with IgA1 by immunohistochemistry in an α1KI-CD89Tg mouse model of IgAN. However, there is lack of clinical evidence for mesangial sCD89 deposition in human IgAN. To date, only one study demonstrated the presence of IgA1-sCD89 complex in the graft kidney with recurrent IgAN. Interestingly, Moresco et al.  reported that lower urinary sCD89-IgA levels significantly associated with disease progression. They presumed that urinary excretion of the complex is decreased due to deposition of the complex within the mesangium. However, we could not analyze this in depth as urine samples were not collected at baseline. This needs to be confirmed through the future studies . Third, we defined the primary outcome as a 30% decline in eGFR because the follow-up duration was relatively short. In this study, ESRD occurred only in 12 patients and there was no difference in the development of ESRD between tertile groups (data not shown). No patients developed ESRD before reaching a 30% decline in eGFR. Given the slow progressive nature of IgAN, further long-term studies are required. Fourth, a recent study by Berthelot et al.  showed that immunosuppressive drugs modified sCD89-IgA levels. However, patient samples were obtained only at the time of biopsy, thus evaluation of changes of sCD89-IgA levels by immunosuppression was not feasible. Finally, this is a single center study involving one ethnic group; hence, our findings should be interpreted with caution. Notably, this is the first study to evaluate the clinical implication of the sCD89-IgA complex in an Asian population. In fact, the prevalence, biopsy practice pattern, treatment, and renal survival rate vary depending on regions , , . Given such geographic variability and ethnic differences, the role of sCD89-IgA complex may differ among different ethnic population. Further studies are needed to validate the role of sCD89-IgA complex in various ethnic populations.
In conclusion, this study found that sCD89-IgA complex levels were not significantly associated with an increased risk of kidney disease progression. Although sCD89 can contribute to the formation of the immune complex, our findings suggest that the sCD89-IgA level in the circulation is not a good predictor of adverse outcomes and has limited clinical utility as a biomarker for risk stratification in IgAN.
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About the article
Published Online: 2017-06-16
Published in Print: 2017-11-27
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Financial support: This study was supported by a faculty research grant of Yonsei University College of Medicine for 2015; Dr. Wu M is supported by China Scholarship Council.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.