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Keywords:

  • Immunoglobulin A nephropathy;
  • N-acetylgalactosamine;
  • proteinuria;
  • renal pathology

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Aim

Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis with various histological and clinical phenotypes. N-acetylgalactosamine (GalNAc) exposure plays a pivotal role in the pathogenesis of IgAN. The aim of the current study is to investigate whether GalNAc exposure of serum IgA1 was associated with clinical and pathological manifestation of IgAN.

Methods

Sera from 199 patients with biopsy proved IgAN were collected. Clinical and pathological manifestations were collected. Biotinylated Helix aspersa were used in ELISA to examine GalNAc exposure on IgA1 molecules. Patients were divided into two groups according to the GalNAc exposure rate less or more than 0.4.

Results

Age, gender, and serum creatinine were comparable between the two groups. Univariate analysis showed that significantly higher urinary protein excretion rate but less severe glomerular sclerosis and tubularinterstitial fibrosis were observed in the lower GalNAc exposure group. Multivariate regression analysis demonstrated that adjusted by age and gender, the GalNAc exposure rate more than 0.4 was a risk factor of glomerular sclerosis and tubularinterstitial fibrosis, OR*(95% CI) were 2.76 (1.19–6.37) and 2.49 (1.18–5.25), respectively.

Conclusion

Immunoglobulin A nephropathy patients with lower proteinuria had higher GalNAc exposure rates. The GalNAc exposure rate more than 0.4 was a risk factor of severe chronic renal tissue change.

Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis in the world. It was characterized by the mesangial deposition of polymeric IgA1 along with other immunoglobulins and complements, which could induce mesangial cell proliferation and extracellular matrix expansion.[1, 2] Proteiniuria, hypertension, glomerular sclerosis, tubular atrophy and interstitial fibrosis were recognized with poor prognosis.[3-6] It is well accepted that the glycosylation defect of serum IgA1 molecules play an important role in the pathogenesis of IgAN.[7-10]

Human serum IgA1 is one of the most exceptional human serum immunoglobulins, which is due to O-linked oligosaccharides in its hinge region besides the two N-linked carbohydrate chains in its structure.[11] N-acetylgalactosamine linked to the serine or threonine is the basic structure of O-glycans, and then it was expanded by galactose or sialic acid. Many studies have suggested that glycosylation deficiency of IgA1 molecules, usually with a reduced content of galactose (Gal) and sialic acid (SA) but increased exposing of GalNAc, was one of the clinical features of IgAN.[12-14]

Immunoglobulin A nephropathy was variable in clinical and histological manifestations. It is unclear whether there is any association between the GalNAc exposure and the clinical manifestation or pathological change. Our previous work first found that aberrantly glycosylated serum IgA1 of patients with IgAN was associated with renal pathological phenotypes and the altered glycosylation of IgA1 existed only in the IgA1-containing macromolecules. The glycans deficiency of IgA1 molecules in sera from patients with severe renal pathological damage were more prevalent than those found in the mild type.[15, 16] The renal survival rate was significantly lower in patients with more severe sialic acid deficiency and the lower alpha 2, 6 sialic acid level of IgA1 might be a predictor for poor prognosis in patients with IgAN.[17] The recently published Oxford Classification of IgAN identified four key pathologic consequences of IgA deposition that independently determine the risk of developing progressive renal disease: mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubulointerstitial scarring (T).[18, 19] However, little is known about the association of GalNAc exposure with these histological changes.

Based on above knowledge, in the current study, we investigated the GalNAc exposure of serum IgA1 in IgAN patients, and explored the associations between the GalNAc exposure of serum IgA1 and clinical parameters and histological manifestations, respectively.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients and sera

A total of 199 patients with renal biopsy proved IgAN between April 2008 to July 2010 were enrolled in the current study. None of these patients had been treated by immunosurpressive drugs. Patients who had secondary IgAN diseases, such as Henoch-Schonlein purpura nephritis or lupus nephritis were excluded. Sera from patients were obtained at the time of renal biopsy and stored at −40°C. Clinical data were collected at the time of renal biopsy. Estimated glomerular filtration rate (eGFR) was calculated by MDRD (modification of diet in renal disease) equation. The pathological characteristics of IgAN patients were evaluated by the level of mesangial cell proliferation (mild/moderate and severe), glomerulasclerosis or not (including glomerular and segmental), endocapillary hypercellularity or not, the area of tubular atrophy/interstitial fibrosis. The ethics committee of the Guangdong General Hospital approved the study and peripheral blood samples were obtained with the informed consent of all patients.

Detection of glycans of serum IgA1 by sandwich-ELISA

The O-glycans in the hinge region of IgA1 were detected by specific lectin binding enzyme linked immunosorbent assay (ELISA) as previously reported.[15] Rabbit anti-human IgA (Dako, Denmark) diluted to 5.5 μg/mL in 0.05 M bicarbonate buffer PH 9.6 and were coated to the wells of one-half of a polystyrene microtiter plates (Costar, NY, USA). The wells in the other half were coated with bicarbonate buffer alone to act as antigen-free wells. The volumes of each well for this step and for subsequent steps were 100 μL, all incubations were carried out at 37°C for 1 h and the plate was washed by 0.01 M phosphate-buffered saline containing 0.1% Tween20 (PBST) three times. Then the plate was blocked with PBST containing 2% bovine serum albumin (PBST/BSA), the test sera diluted 1:200 in PBST/BSA were added in duplication to both antigen-coated and antigen-free wells. IgA1 purified by jacalin affinity chromatography and then digested by neuraminidase and β-galactosidase was used as a positive control. Every plate contained blank control (PBST/BSA) and positive control. After incubation and washing, the 1:250 diluted biotinylated helix aspersa (HAA) PBST/BSA were added to detect GalNAc. The wells were then incubated with 1:10 000 diluted avidin-HRP (Sigma, St. Louis, MO, USA). The results were revealed with 0.1 M citrate phosphate buffer PH 5.0 containing 0.4% o-phenylenediamine (OPD) and 0.1% H2O2 (V/V), then the reaction was stopped with 1 M H2SO4. The absorbance at 490 nm (A) was recorded in an ELISA reader (Thermo multiscan MK3, Thermo Votta, Finland).

The relative levels of GalNAc were calculated as follows: the A value of the blank control was regarded as 0, and the A value of the known control was regarded as 100%, the A value of each sample was calculated by log transformed data.

Statistical analysis

Data entry and management were performed on Microsoft Office Excel 2007. All analyses and calculations were performed using statistical analysis software SAS 9.3 (SAS Institute, Cary, NC, USA). Data are presented as the mean ± standard deviation (SD) for continuous variables and as proportions for categorical variables. Based on the mean, GalNAc exposure rate was 0.4 ± 0.2, the prevalence and mean values of selected IgAN parameters were compared between GalNAc exposure levels (<0.4 and ≥0.4) by using χ2 statistics for categorical variables and the Student t-test for continuous values. The unadjusted odds ratio (OR) between IgAN traits and GalNAc exposure level (≥0.4) was determined by univariate logistic regress models and then adjustments were made for age and gender, as well as other IgAN traits by multivariate logistic regression models. All statistical tests were two-sided, and P < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patient's demographics and clinical characteristics

Table 1 summarizes patient demographics and the clinical characteristics of 199 IgAN patients. There were 90 males and 109 females in the study. The mean age was 34.5 ± 11.0 years. The proteinuria of 24 h was 1.77 ± 1.84 g/24 h and about 53.8% of patients had proteinuria excretion more than 1 g/24 h. Serum creatinines of these patients were about 159.9 ± 184.8 μmol/L. The mean GalNAc exposure rate was 0.4 ± 0.2. It was shown that, the proteinuria excretion was a light negative correlation with GalNAc exposure rate (R = −0.184, P = 0.011; see Fig. 1).

figure

Figure 1. The proteinuria excretion had a light negative correlation with N-acetylgalactosamine (GalNAc) exposure rate (R = −0.184, P = 0.011).

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Table 1. General traits of patients with immunoglobulin A nephropathy (IgAN)
Variables Total (n = 199) GalNAcP-value
<0.4 (n = 87) ≥0.4 (n = 112)
  1. eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein.

Age (years)34.5 ± 11.034.3 ± 11.534.6 ± 10.60.85
Male, n (%)90 (45.2)42 (48.3)48 (42.9)0.45
Alb32.1 ± 7.031.4 ± 8.132.6 ± 5.90.26
Proteinuria (g/24 h)1.77 ± 1.842.14 ± 1.911.47 ± 1.730.01
Proteinuria >1 g/24 h107 (53.8)55 (63.2)52 (46.4)0.02
Scr (μmol/L)159.9 ± 184.8155.3 ± 171.4163.4 ± 195.30.75
Uric acid (μmol/L)409.8 ± 107.1410.8 ± 117.4409.0 ± 99.00.91
Cholesterol (mmol/L)5.2 ± 2.05.6 ± 2.74.9 ± 1.30.03
LDL (mmol/L)2.9 ± 1.53.2 ± 2.02.7 ± 0.80.02
Serum IgA (g/L)3.1 ± 1.03.2 ± 1.13.0 ± 1.00.15
Serum IgG (g/L)10.7 ± 3.010.0 ± 3.011.3 ± 2.90.002
C3 (mg/L)919.3 ± 189.6949.6 ± 199.1895.7 ± 79.20.046
eGFR (mL/min)69.5 ± 36.771.4 ± 37.368.0 ± 36.40.52

In the patients with elevated serum creatinine, the GalNAc exposure rate was comparable to that in patients with normal serum creatinine (0.44 ± 0.19 vs. 0.43 ± 0.15). There is no relation between the GalNAc exposure rate and serum creatinine. It was also demonstrated that the serum IgA concentration (R = 0.297, P < 0.001; Fig. 2) and the GalNAc exposure rate (R = 0.24, P = 0.001; Fig. 3) were positively correlated with serum IgG concentration.

figure

Figure 2. The serum Immunoglobulin A (IgA) concentration had a positive correlation with IgG concentration (R = 0.297, P < 0.001).

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figure

Figure 3. The N-acetylgalactosamine (GalNAc) exposure rate had a positive correlation with serum immunoglobulin G (IgG) concentration (R = 0.24, P = 0.001).

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Patients were divided into two groups according the GalNAc exposure rate more or less than 0.4. The mean ages for the low and high exposure groups were 34.3 ± 11.5 and 34.6 ± 10.6 years, respectively. There were no significant differences in age or gender. The serum creatinine, uric acid, and serum IgA concentration were comparable for the two groups. However, the 24 h urine protein excretion was significantly heavier in the low exposure group than that in the high exposure group (2.14 ± 1.91 g/24 h vs. 1.47 ± 1.73 g/24 h, P = 0.01). Simultaneously, the total cholesterol, low density lipoproteins and complement C3 level was significantly higher in the low GalNAc exposure group (P < 0.05 for all parameters). However, the IgG concentration had the same trend with GalNAc exposure rate, 10.0 ± 3.0 mg/L in the low exposure group and 11.3 ± 2.9 mg/L in the high exposure rate group (P = 0.002). See Table 1.

Pathological characteristics

Patients with IgA nephropathy were divided into two groups, with (n = 160) and without (n = 39) glomerulosclerosis in the renal specimen. The level of GalNAc was 0.38 ± 0.16 in patients had no sclerosis but 0.44 ± 0.17 in patients had sclerosis. Although the GalNAc exposure of serum IgA1 was a little higher in the sclerosing group, but the difference had no significance (P = 0.06).

The associations between the tubular atrophy and the GalNAc exposure rate were also evaluated. The tubular atrophy was divided into four groups; grade 1 has no atrophy (n = 17), the GalNAc exposure rate was 0.37 ± 0.15, less than 25% tubular atrophy was regarded as grade 2 (n = 111), the GalNAc exposure rate was 0.43 ± 0.16, about 25–50% tubular atrophy was grade 3 (n = 54), the GalNAc exposure rate was 0.44 ± 0.18, and more than 50% was grade 4 (n = 17), the GalNAc exposure rate was 0.47 ± 0.17. Although the GalNAc exposure rate was increasing along with the tubular atrophy, the difference has no significance.

Table 2 shows the difference of the mesangial proliferation, endocapillary hypercellularity, glomerular sclerosis and tubular atrophy/interstitial fibrosis (more or less than 25%) in the two groups. As we can see, there were no significant differences in the two parameters mesangial proliferation and endocapillary hypercellularity between the two groups. But when it come to glomerular sclerosis and tubular atrophy/interstitial fibrosis, the percentages of patients with glomerular sclerosis or tubular atrophy/interstitial fibrosis were significantly higher in the high GalNAc exposure group (P-values, 0.004 and 0.04, respectively).

Table 2. General pathological character of patients with immunoglobulin A nephropathy (IgAN)
Variables Total (n = 199) GalNAcP-value
<0.4 (n = 87) ≥0.4 (n = 112)
Glomerular Sclerosis (yes/no)160 (80.4)62 (71.3)98 (87.5)0.004
T/I fibrosis ≥25%71 (35.7)24 (27.6)47 (42.0)0.04
Endothelial hypercellularity (yes/no)28 (14.1)15 (17.2)13 (11.6)0.26
Mesangial proliferation (moderate and severe)52 (26.1)22 (25.3)30 (26.8)0.81
mild14262 (71.3)80 (71.4)0.75

Association between GalNAc exposure rate and clinical or pathological parameters of IgA nephropathy

Compared with the group prescribed low GalNAc exposure rate, the unadjusted odds ratio of urinary protein excretion more than 1 g/24 h for those high GalNAc exposure rate patients was 0.54 (95% confidence interval [CI] 0.28 to 0.89, Table 3). Analysis by the pathological manifestation indicated that patients with high GalNAc exposure rate were at higher risk of glomerulosclerosis and tubular atrophy/interstitial fibrosis (OR = 2.82, 95% CI 1.36 to 5.84, OR = 1.90, 95% CI 1.04 to 3.46 respectively). Adjusted by age, gender, creatinine, cholesterol, IgG concentration, C3 concentration, the results of multivariate logistic regression also showed that patients with high GalNAc exposure rate had lower odds ratio of urinary protein excretion of 24 h (OR = 0.39 95% CI 0.19 to 0.81) but higher glomerulosclerosis (OR = 2.76 95% CI 1.19 to 6.37) and tubular atrophy/interstitial fibrosis (OR = 2.49 95% CI 1.18 to 5.25). Although in the univariate analysis, patients with high GalNAc exposure had a higher serum IgG concentration and lower C3 concentration; however, adjusted by multivariate, the odds ratio had no significance.

Table 3. Odds ratios (ORs) of N-acetylgalactosamine (GalNAc) (≥0.4) by individual immunoglobulin A nephropathy (IgAN) trait
IgAN traitUnadjustedAge and Gender adjustedMultivariate-adjusted
OR (95% CI)OR (95% CI)OR* (95% CI)
  1. *Adjusted for age, gender, Alb, serum IgA, serum IgG, serum creatinine and estimated glomerular filtration (eGFR). CI, confidence interval; LDL, low-density lipoprotein.

Proteinuria >1 g/24 h0.54 (0.28–0.89)0.51 (0.29–0.91)0.39 (0.19–0.81)
Cholesterol (>5.2 mmol/L)0.49 (0.23–1.01)0.50 (0.24–1.05)0.95 (0.38–2.36)
LDL (>2.9 mmol/L)0.56 (0.31–1.01)0.58 (0.32–1.05)0.69 (0.34–1.41)
IgG (>10.7 g/L)1.86 (1.03–3.34)1.82 (1.00–3.34)1.51 (0.76–2.98)
C3 (>920 mg/L)0.55 (0.31–0.97)0.54 (0.30–0.95)0.60 (0.32–1.13)
Sclerosis (yes/no)2.82 (1.36–5.84)2.98 (1.41–6.29)2.76 (1.19–6.37)
T/I fibrosis1.90 (1.04–3.46)2.10 (1.10–3.62)2.49 (1.18–5.25)

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Immunoglobulin A nephropathy has diverse clinical manifestations, reflecting a wide range of histological changes, from near normal appearance on light microscopy to severe glomerulosclerosis and tubular interstitial fibrosis. The Oxford classification of IgA nephropathy found that four histological changes, including mesangial proliferation, endocapillary hypercellularity, segmental sclerosis and tubular atrophy/interstitial fibrosis were predictors of disease prognosis.[18] Conversely, glomerulosclerosis and tubulointerstitial fibrosis may be advanced lesions that are irreversible.[20, 21] The exact pathogenesis of IgAN has not been elucidated to date. Aberrant glycosylation in the hinge region of IgA1 molecular is deemed generally to be a crucial and initial factor for the development and pathogenic characteristics of IgAN.[7, 8, 10, 11] In the present study, we first investigate GalNAc exposure rate with the pathological change evaluated by mesangial proliferation, endocapillary hypercellularity, glomerulosclerosis and tubular atrophy/interstitial fibrosis of IgAN. Our result showed that the GalNAc exposure rate of IgA1 more than 0.4 was a risk factor of glomerular sclerosis and tubular atrophy/interstitial fibrosis in patients with IgAN independent of proteinuria. But there is no relation between the GalNAc exposure with mesangial cells proliferation and endocapillary hypercellularity.

GalNAc exposure, which can be called Tn antigen, will induce the anti-GalNAc antibody production. Anti-GalNAc antibodies of the IgG isotype are present in sera of all IgAN patients.[8, 22] The binding of the glycan-specific IgG from patients with IgAN to GalNAc exposure IgA1 greatly favoured the formation of immune complexes. Undergalactosylated IgA-contained immune complexes, including IgA-IgG and IgA self aggregation were hard to clear by liver and they could bind more to mesangial cells and trigger mesangial cell activation. Mesangial cells activation, the pivotal event in driving glomerular injury in IgAN, could induce production of more extracellular matrix (ECM) and cytokines.[23-25] Mesangial cell-derived mediators will injure the podocytes by local effect (mesangial-podocyte crosstalk). Continued immune complex deposition and mesangial cell activation lead to progressive glomerulosclerosis through excessive ECM deposition and irreversible podocyte loss.[26, 27] At the same time, proinflammatory cytokines and angiotensin II are released by mesangial cells are also filtered into the urine, which will activate proximal tubular epithelial cells (PTECs). This procedure initiates and amplifies an inflammatory cascade through increased local release of chemotactic mediators, which attract further proinflammatory immunocompetent cells. A positive feedback loop of activation is then established leading to increased matrix formation, tubulointerstitial fibrosis and ultimately renal failure (glomerulotubular crosstalk).[28] There is increasing evidence about the histological change of IgAN that glomerular sclerosis (glomerular or segmental or both) and tubular atrophy/interstitial fibrosis which are likely to be irreversible with the treatments currently available appear to be the strongest independent predictors of a progressive course.[29-31] GalNAc exposure may induce the injury of podocyte and PTECs by mesangial-podocyte crosstalk and glomerulotubular crosstalk, respectively.

Recently, Roberta et al. found that oxidative stress and galactose deficient IgA1 were markers of progression in IgA nephropathy.[32] Moldoveanu et al. using HAA to detect the GalNAc of serum IgA1, the sensitivity as a diagnostic test of IgAN was 76.5%, with specificity 94%.[12] Furthermore, cells secreting antibodies specific for Gal-deficient IgA1 can be easily detected and enumerated in peripheral blood from IgAN patients.[33] It was also shown in our data that serum IgG concentration was higher in the GalNAc exposure more than the 40% group. Using a lectin-binding assay to detect GalNAc exposure of IgA1 in serum might have potential as a non-invasive predictive test for IgAN prognosis. However, whether the immunosuppressive treatment will change the GalNAc exposure level needs to be confirmed in further prospective therapeutic trials.

Proteinuria has a particularly strong association with poor kidney prognosis in IgA nephropathy.[3, 34-36] Remission of proteinuria is an important predictor of renal survival. The correlation of proteinuria with GalNAc exposure is not well established yet. Recently, Hastings et al. found that GalNAc exposure was not associated with the proteinuria at presentation of paediatric IgAN.[37] However, in a research carried out by Camilla et al., it was suggested that some weak correlations were indeed found between proteinuria and IgA galactose deficiency.[32] The proteinurias of both studies were detected once at the diagnosis of IgA nephropathy. Xie et al. demonstrated that proteinuria was strongly associated with the risk of end-stage renal disease in univariate analysis; however, it did not independently contribute to the risk in multivariate models.[35] Although proteinuria at presentation is an important consideration, increasing evidence suggests that proteinuria overtime more closely correlates with disease outcome. Several studies suggest that regardless of the peak level of proteinuria, partial remission to protein excretion <1/g will improve the renal progression.[38, 39] Repeated measurements of proteinuria averaged over time have been shown to predict GFR loss better than proteinuria at presentation in several studies. Expanded proteinuria evaluation beyond 1-time cross-sectional assessments at the time of diagnosis to include longitudinal measurements of proteinuria for improved quantification of disease activity and risks of progression are very important.[40, 41] The therapy of steroid and angiotensin converting enzyme inhibitor/ angiotensin receptor blocker (antagonist) (ACEI/ARB) could drastically improve the clinical parameters but could not affect the HAA-IgA levels.[42, 43]

This phenomenon supports the notion that HAA-IgA levels perhaps better predict disease activity and risks of progression than proteinuria at presentation. In the present study, interestingly, we found that the proteinuria level was not consistent with GalNAc exposure. The level of proteinuria is higher in the less GalNAc exposure group. It is tempting to speculate that patients with lower GalNAc exposure will reach a remission of disease not long after immunosupressive treatment even with heavy proteinuria.

For the first time, we herein investigated the GalNAc exposure of serum IgA1 in IgAN patients, and explored its associations with clinical parameters and histological manifestations. Our results indicated that patients of IgAN with higher GalNAc exposure rate have lower proteinuria. However, the GalNAc exposure rate of more than 40% was a risk factor of glomerular sclerosis and tubulointerstitial injury. The GalNAc exposure rate may be used to predict prognosis of IgA nephropathy. Our study had several limitations that should be noted. First, it is only a cross-section study. Second, Chinese patients were the only ethnic group to be studied and finally, it was a single-centre study. Therefore, further prospective and multicenter studies are needed to confirm our results. Meanwhile, whether GalNAc exposure will change along with prognosis of disease will also need further clarification.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This work was supported by the fund of National Nature Science Foundation of China (81100511) and the NSFC of Guangdong province (845100800400162). We are deeply grateful to all the patients who donated blood.

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  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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