|Year : 2020 | Volume
| Issue : 5 | Page : 1014-1024
|The Comparison Spondin 2 Levels in Primary Glomerular Diseases
Serdar Kahvecioglu1, Alparslan Ersoy2, Yasemin Üstundag3, Yavuz Ayar4, Cuma Bülent Gül1, Abdülmecit Yildiz2, Selin Akturk Esen5, Ibrahim Dogan6, Aysegul Oruc2
1 Department of Nephrology, Health Science University Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
2 Department of Nephrology, Uludag University Faculty of Medicine, Bursa, Turkey
3 Department of Biochemistry, Health Science University Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
4 Department of Nephrology, Bursa City Hospital, Bursa, Turkey
5 Department of Internal Medicine, Gürsu Cüneyt Yildiz State Hospital, Bursa, Turkey
6 Department of Nephrology, Hitit University Erol Olçok Training and Research Hospital, Çorum, Turkey
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|Date of Web Publication||21-Nov-2020|
| Abstract|| |
Spondin 2 (SPON2) plays an important role in multiple processes and is a member of the Spondin 2/F-spondin family of extracellular matrix proteins. We investigated serum SPON2 levels and its correlation with renal functions and urine protein excretion in different glomerular diseases. The cohort included 97 consecutive adults with persistant proteinuria (>300 mg/day) with the diagnosis of focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MN), IgA nephropathy (IgAN), membranoproliferative glomerulonephritis (MPGN), and AA amyloidosis and the control groups with 15 polycystic kidney disease (PKD) and 32 healthy people. Serum SPON2 levels in MN (64.6 ng/mL), FSGS (47.8 ng/mL), IgAN (52.6 ng/mL), MPGN (54.6 ng/mL), and AA amyloidosis (60.7 ng/mL) groups were higher than those of the control (26.4 ng/mL) and nonglomerular disease groups (PKD) (15.3 ng/mL). Only serum SPON2 levels were correlated with serum uric acid and triglyceride levels in patients with glomerular disease. This is the first study to show that serum SPON2 levels are similar in different glomerular diseases and that there is no correlation between SPON2 and proteinuria grade.
|How to cite this article:|
Kahvecioglu S, Ersoy A, Üstundag Y, Ayar Y, Gül CB, Yildiz A, Esen SA, Dogan I, Oruc A. The Comparison Spondin 2 Levels in Primary Glomerular Diseases. Saudi J Kidney Dis Transpl 2020;31:1014-24
|How to cite this URL:|
Kahvecioglu S, Ersoy A, Üstundag Y, Ayar Y, Gül CB, Yildiz A, Esen SA, Dogan I, Oruc A. The Comparison Spondin 2 Levels in Primary Glomerular Diseases. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Aug 1];31:1014-24. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1014/301166
| Introduction|| |
Defects in any of the components of glomerular capillary wall can lead to proteinuria. Proteinuria is not only a marker of kidney damage but also a prognostic risk factor for progression of chronic kidney disease (CKD). Further, greater early reductions in proteinuria are associated with slower progression of CKD, especially when baseline proteinuria was higher. The injury or loss of podocytes by immunologic and nonimmunologic mechanisms contributes to the development of glomerulosclerosis in proteinuric glomerular diseases, such as diabetic nephropathy (DN), focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), and active lupus nephritis, but typically not in minimal change disease (MCD). Proteinuria is a nonspecific marker for kidney diseases, and podocyte dysfunction remains silent until proteinuria is detected., As microalbuminuria in DN, sensitive and specific noninvasive biomarkers needed for early diagnosis of podocyte dysfunction. Measurement of podocyte-derived biomarkers such as protein, mRNA, microRNA, and exosomes detect, and they can provide an information about the activity or progression of glomerular diseases such as IgAN and lupus nephritis.,,
Spondin 2 (SPON2, mindin), a member of the F-spondin family of extracellular matrix proteins, plays an important role in multiple processes such as involvement in the immune response and inflammatory processes, inhibition of the development of obesity, hepatic steatosis, inflammation, and insulin resistance. Integrin can be a key molecule for podocyte injury. Transmembrane receptors such as α3β1-integrin and α-/β-dystroglycans link extracellular glomerular basement membrane (GBM) proteins to the intracellular cytoskeleton. Hence, they mediates attachment of podocytes to the GBM. Impairment of this attachment is one of the mechanisms in the development of podocyte injury., In α3β1-integrin-deficient mice, the GBM is disorganized and podocytes are unable to form mature foot processes. Expression of the dystroglycan complex is negatively correlated with disease activity in proteinuria in animal models and with MCD in humans., SPON2 regulates cytoskeletal changes via integrin and serves as a novel ligand for integrins and mindin–integrin interactions which are critical for in vivo inflammatory cell recruitment. Urinary SPON2 excretion in type 2 diabetic patients with DN may be related to podocyte injury. Our previous study revealed a positive correlation between SPON2 levels and stage of DN inpatients with type 2 diabetes mellitus. In this study, we aimed to compare SPON2 level in patients with nondiabetic glomerular diseases and its correlation with renal functions and proteinuria.
| Materials and Methods|| |
The cohort included stable consecutive adults with persistant proteinuria (>300 mg/day) who were older than 18 years at a six-month period and the control groups. Proteinuria of the control groups was negative with urine dipstick test (<10 mg/dL). We used the following exclusion criteria; presence of CKD stage 4 and 5, diabetes mellitus, evidence of acute infection, cardiovascular, hepatic or respiratory diseases, nonsteroidal anti-inflammatory drug usage, active inflammatory conditions, AL amyloidosis, multiple myeloma, malignancy, a history of burn, prostatic disease, surgery, or severe trauma during the preceding one month. We evaluated the medical data and charts of patients in our center. Informed written consent was taken from all patients before they entered the study. The study was approved by the Bursa Regional Ethical Committee (No. 2013/19/6) in accordance with the Second Declaration of Helsinki. Same nephropathologist studied the renal biopsy specimens by light microscopy (hematoxylin and eosin, Masson's trichrome, periodic acid–Schiff, periodic acid–silver methenamine, Congo red, and immunohistochemical AA amyloid stains) and immunofluorescence microscopy (staining for IgG, IgA, IgM, C3, C1q).
The etiologies of diseases were FSGS (n: 27), membranous glomerulonephritis (MN, n: 27), IgAN (n: 19), membranoproliferative glomerulonephritis [(MPGN), n: 8], and AA amyloidosis (n: 16). The causes of AA amyloidosis were familial Mediterranean fever in six patients, chronic infection in four patients, spondyloarthritis in one patient, and unknown etiology in five patients [Figure 1]. Among patients with primary glomerular disease, 43 patients were newly diagnosed (12 FSGS, 12 MN, 5 IgAN, 3 MPGN, and 11 AA amyloidosis). Fifty-four patients on regular outpatient clinic follow-ups were treated previously (15 FSGS, 15 MN, 14 IgAN, 5 MPGN, and 5 AA amyloidosis) and no remission was achieved. The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) was made by the ultrasonographic criteria described by Pei and Watnick.  The control groups were consisted of 15 patients with ADPKD and 32 participant from hospital staff.
The optimal treatments for many of the specific glomerulonephritis were applied according to the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for glomerulonephritis. The treatment of patients with ADPKD included nonspecific measures, such as maintaining strict blood pressure control, increasing fluid intake, and a low-salt diet. We empirically treated all AA amyloidosis patients with colchicine and control of the underlying inflammatory disease. The distribution of other drugs used in patients are shown in [Table 1]. Nephrotic proteinuria was defined as 24-h urinary protein ≥3 g/day. Complete remission was defined as 24-h urinary protein <500 mg/day and partial remission as 24-h urinary protein <3 g/day with a reduction in proteinuria by at least 50% from the baseline.
In the patients treated previously, the measurements before the diagnosis were taken into consideration. Venous blood samples were collected after an overnight fast. Serum was immediately prepared and stored in aliquots at −80°C before analysis. The levels of fasting glucose, blood urea nitrogen, creatinine, uric acid, total protein, albumin, triglyceride, total cholesterol, and high-density lipoprotein cholesterol were determined using commercially available assay kits (Abbott Diagnostics, Abbott Park, Illinois, USA) with a Architect c16000 auto-analyzer (Abbott Diagnostics, Abbott Park, Illinois, USA). 24-h urinary protein excretion (UPE) was measured by immunoassay (DCA 2000 system, Siemens AG, Munich, Germany). High-sensitivity C-reactive protein (hs-CRP) was measured on an Abbott Architect i1000 analyzer. We calculated estimated glomerular filtration rate (eGFR) using 2009 the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation. Serum SPON2 levels were measured using a commercial sandwich enzyme-linked immunosorbent assay kit from Cloud-Clone Corp (Houston, TX, USA).
| Statistical Analysis|| |
The data were analyzed using IBM SPSS Statistics, version 23.0 (IBM Corp, Armonk, NY, USA). Shapiro–Wilk test was used for assessing the normal distribution of variables. Categorical variables were given as frequency with related percentages. Continuous variables were expressed as median (minimum:maximum). Fisher-Freeman-Halton, Pearson's Chi-square, or Fisher's Exact test was used to test the differences in proportion of the categorical variables. Comparisons between the groups were made using Kruskal–Wallis test. The two-group comparisons were carried out using Mann–Whitney test. Relationships between SPON2 and other parameters were investigated with Pearson's or Spearman's correlation analysis and multiple linear regression analyses. Statistical significance was defined as a two-sided P <0.05.
| Results|| |
The gender distribution, body mass index, blood pressures, eGFR, serum creatinine, glucose and lipid values of the groups were similar. The median known disease durations of patients treated previously were comparable in FSGS (29 months), MN (42 months), IgAN (70.5 months), MPGN (64 months) and AA amyloidosis (90 months) groups (P = 0.577). The mean ages of FSGS group were higher than those of MN (0.002), AA amyloidosis (P = 0.006), ADPKD (P = 0.002), and control (P = 0.048) groups. Hemoglobin levels of AA amyloidosis group were lower than those of FSGS (P = 0.002), MPGN (P = 0.025), and ADPKD (P = 0.018) groups, while that of MN group was higher than AA amyloidosis group (P = 0.039). The uric acid levels of ADPKD and AA amyloidosis groups were lower than those of FSGS (P = 0.003 and P = 0.016, respectively) and IgAN (P = 0.008 and P = 0.017, respectively) groups. The uric acid levels of MN group were higher than that of ADPKD group (P = 0.037). Serum total protein level in ADPKD group was higher than FSGS (P = 0.043), MN (P = 0.01) and AA amyloidosis (P = 0.001) groups. Serum total protein level of AA amyloidosis group was lower than those of FSGS (P = 0.003), IgAN (P = 0.006), and MPGN (P = 0.004) groups. Serum albumin level in AA amyloidosis groups were lower than FSGS, IgAN, MPGN, and ADPKD groups (P <0.001) and that of ADPKD group was higher than FSGS (P = 0.03), MN (P = 0.003), and IgAN (P = 0.047) groups. Serum albumin level of MN group was lower than MPGN group (P = 0.045) and higher than AA amyloidosis group (P = 0.005). UPE in AA amyloidosis group was higher than FSGS (P = 0.037), IgAN (P = 0.04), and MPGN (P = 0.002) groups. hs-CRP level of ADPKD group was lower than FSGS (P <0.001), MN (P = 0.002), IgAN (P <0.001), and AA amyloidosis (P <0.001) groups and that of IgAN group was higher than MN (P = 0.01) and MPGN (P = 0.025) groups [Table 2].
Serum SPON2 levels of glomerular disease groups are given in [Figure 2]. Serum SPON2 levels in MN (P = 0.001 and P <0.001), FSGS (P = 0.003 and P = 0.002), IgAN (P = 0.001 and P <0.001), MPGN (P = 0.013 and P = 0.008), and AA amyloidosis (P = 0.003 and P = 0.002) groups were higher than those of ADPKD and control groups, respectively. There was no significantly difference between serum SPON2 levels in MN, FSGS, IgAN, MPGN, and AA amyloidosis groups (P >0.05). The SPON2 levels of ADPKD and control groups were comparable (P >0.05) [Table 2].
Serum SPON2 levels of the patients with glomerular disease who had newly diagnosed (n = 43, 67.5 ng/mL) or treated previously (n = 54, 52.1 ng/mL) were similar (P = 0.435) [Figure 3]. Further, serum SPON2 levels of the groups who had proteinuria in nephrotic (n = 31, 51 ng/mL) or nephritic (n = 66, 53.3 ng/ mL) ranges did not differ (P = 0.645). When the same analysis was made for MN, FSGS, IgAN, MPGN, and AA amyloidosis groups, separately, serum SPON2 levels in patients who were newly diagnosed or treated previously and having nephrotic (9 FSGS, 7 MN, 6 IgAN, and 9 AA amyloidosis) or nephritic (18 FSGS, 20 MN, 13 IgAN, 8 MPGN, and 7 AA amyloidosis) proteinuria were comparable among these groups (P >0.05, [Table 3]).
|Figure 3: Serum SPON2 levels of the patients with glomerular disease who had newly diagnosed or treated previously.|
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|Table 3: The comparison of the intra- and inter-group of serum spondin 2 levels according to new diagnosis or treatment status and proteinuria ranges.|
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Among MN, FSGS, IgAN, MPGN, and AA amyloidosis groups, serum SPON2 levels in 87 patients who were using ACE inhibitors or angiotensin receptor blockers were lower than those of 10 patients who were not using these medications, but the difference was insignificant (median 51 ng/mL, 62.2 ng/mL, respectively, P = 0.240).
Among patients treated previously, the ratios of subjects with refractory nephrotic proteinuria or partial remission were 5/11 in FSGS, 1/14 in MN, 2/12 in IgAN, 0/5 in MPGN, and 2/3 in AA amyloidosis groups. There was no significant difference between serum SPON2 levels of the patients with refractory nephrotic proteinuria (median 37.1 ng/mL) and partial remission (median 54.2 ng/mL) (P = 0.180). In these patients, serum SPON2 levels did not correlate with the mean percentage changes in serum creatinine, eGFR, and UPE values after treatment according to the baseline values.
All patients with glomerular disease were divided into three groups according to the eGFR values except ADPKD and control groups. There was no statistically significant difference in the serum SPON2 levels between patients with CKD stage I (n = 44, median eGFR: 115.5 mL/min, median SPON2: 63.6 ng/mL), stage II (n = 26, eGFR: 76.5 mL/min, SPON2: 54.2 ng/mL), and stage III (n = 27, eGFR: 48 mL/min, SPON2: 44.7 ng/mL) (P = 0.390).
Serum SPON2 levels were positively correlated with triglyceride levels (r = 0.277, P = 0.004) but negatively correlated with total protein levels (r = −0.220, P = 0.025) in 112 patients with all kidney disease. Only serum SPON2 levels were correlated with serum uric acid (r = −0.251, P = 0.013) and triglyceride (r = 0.267, P = 0.008) levels in 97 patients with glomerular disease. No correlations were found between serum SPON2 levels and clinical, demographic, and other laboratory parameters of patients in the both analysis [Table 4]. In the regression analysis of patients with all kidney diseases, statistical significance was not obtained in a model including SPON2 and other parameters (P = 0.632). The correlation analysis was performed for each group. In FSGS group, serum SPON2 was inversely correlated with duration of disease (r = −0.432, P = 0.024, [Figure 4]) and positively with hs-CRP (r = 0.435, P = 0.023), total cholesterol (r = 0.390, P = 0.045), and triglyceride (r = 0.399, P = 0.04). In MN group, serum SPON2 was inversely correlated with serum creatinine (r = −0.426, P = 0.027) and positively correlated with eGFR (r = 0.545, P = 0.003). In AA amyloidosis group, serum SPON2 was positively correlated with age (r = 0.489, P = 0.049). In ADPKD group, it was positively correlated with age (r = 0.519, P = 0.047) and uric acid (r = 0.630, P = 0.012). There was no significant correlation between SPON2 and other studied parameters in MPGN and IgAN groups.
|Figure 4: Correlation between serum SPON2 levels (ng/mL) with duration of disease (month) in 27 patients with focal segmental glomerulosclerosis (P = 0.024).|
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|Table 4: Analysis of the correlation between some parameters and spondin 2.|
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| Discussion|| |
SPON2 may be related to podocyte injury (including foot-process effacement, podocytopenia and podocyte hypertrophy) in the pathogenesis of diabetic and nondiabetic glomerular diseases. In the present study, serum SPON2 levels in patients with MN, FSGS, IgAN, MPGN, and secondary amyloidosis were higher than those of the control group and patients with ADPKD. Our observation results suggested that SPON2 was produced by damaged podocytes in glomerular diseases. However, there was no significant difference in the serum SPON2 levels between these diseases. For this reason, our study did not provide any additional benefit in the differential diagnosis of nondiabetic glomerular diseases. It has been shown that hyperglycemia increases the expression of SPON2 in podocytes. Murakoshi et al reported that urinary SPON2 expression was higher in 17 patients with type 2 diabetes mellitus than in four healthy volunteers, and its urinary levels increased gradually with the progression of DN. The levels of urinary SPON2 in diabetic patients were higher than those of five patients with IgAN, despite a similar degree of proteinuria. In the present study, serum SPON2 levels in patients with IgAN were as high as in the other glomerular diseases. The results of Murakoshi’ study are consistent with our previous study in diabetic patients., In contrast to Murakoshi’ study, we measured serum SPON levels in both of our studies, but not urinary SPON2 levels.
Podocytes are commonly detected in the urinary sediment of patients with glomerular diseases, including IgAN, Henoch–Schonlein purpura, lupus nephritis, FSGS, and diabetes mellitus. The human and animal studies consisted of patients with FSGS and MCD and their rat models showed that urinary angiotensinogen to UPE ratio represents a novel specific marker for podocyte injury. Exosomes are small vesicles released from the majority of epithelial cells that contain integral and peripheral membrane proteins, intracellular components, and cytosolic and nuclear proteins. Among urinary exosomes, novel studies associated with cytoplasmic contents including protein, mRNA, miRNA and lipids give promising results for the diagnosis and monitoring of renal and genitourinary abnormalities. A recent study reported that urine podocin to nephrin mRNA ratio could serve as a useful progression biomarker in heterozygous human diphtheria toxin receptor transgenic rats model of progression. Urinary mRNA expression of podocyte constituents such as nephrin and podocin are detected in the sediment of patients with proteinuric diseases. Besides, it is known that urine nephrin and podocin mRNA levels correlate with the rate of deterioration in renal function. In our study, serum SPON2 of patients with CKD stage I, II, and III were similar, but we did not recruit CKD patients with stage IV and V. Proteinuria is widely used as a clinical marker for podocyte injury, and it is well established to be a powerful marker of progression for glomerular diseases in human. In addition, serum SPON2 levels did not correlate with UPE in glomerular disease groups. Serum SPON2 measurement in these patients may not be an alternative biomarker in reflecting nephropathy. Furthermore, our study did not investigate the potential pathogenetic role of serum SPON2 in glomerular diseases.
In our study, the negative correlation between serum SPON2 levels and duration of disease in FSGS group may be explained by the fact that long-lasting FSGS is likely to be secondary form (not inflamed), while FSGS with a shorter disease duration includes idiopathic, genetic, and secondary forms. Decreased level of SPON2 with time in FSGS may be related with podocytopenia. Serum SPON2 levels of patients with glomerular disease who were diagnosed newly or treated previously (but not in complete remission) and in proteinuric patients with nephrotic or nephritic ranges were similar. This observation was same for all groups, separately. In addition, our patients who were under treatment were not in complete remission. Therefore, we could not compare serum SPON2 levels of patients who were in complete or partial remission. However, we only can assume that serum SPON2 levels in patients who are not in remission still remain high. In our study, serum SPON2 levels in the ADPKD group were lower than those of glomerular disease groups, and it was comparable with that of control group. The mechanisms by which cysts form in ADPKD are not fully understood, but our findings can support the fact that prominent podocyte injury is not present in this disease.
It has been reported that SPON2 plays an inhibitory role in the development of obesity, hepatic steatosis, inflammation, and insulin resistance via its regulation of lipid metabolism, largely mediated by peroxisome proliferators-activated receptor a signaling. In a mice study, circulating and hepatic levels of inflammatory factors such as adipokines and cytokines increased in high-fat diet-fed SPON2-knockout mice. In our study, there was no significant relationship between hs-CRP and SPON2 levels in patients with glomerular diseases.
Our study had cross-sectional design and relatively small sample size in some groups. Furtherm the glomerulopathy population was heterogeneous, and about half of the patients were new diagnosis. UPE levels are very high in patients with AA amyloidosis, and FSGS includes both idiopathic (bad) and secondary forms; none of the patients achieved complete remission (very unlikely in MN and IgAN).
| Conclusion|| |
SPON2 may be produced by damaged podocytes in various glomerular diseases that podocyte injury plays a role in their pathogenesis. Therefore, in the current preliminary study, we thought that serum SPON2 level could be increased in nephropathies associated with podocyte injury. However, we showed no significant differences in the serum SPON2 levels between different glomerular diseases and AA amyloidosis and concluded that serum SPON2 cannot serve as a useful biomarker in the differential diagnosis instead of kidney histopathology and UPE in patients who had new diagnosis. We also thought that proteinuria levels and SPON2 levels could be correlated and thus SPON2 could be an important biomarker in monitoring disease progression. However, SPON2 levels were not correlated with the degree of proteinuria in this study. Further investigations are required to prove its potential pathogenetic role in kidney injury or inflammation and to evaluate the role of SPON2 in the monitoring of progression of diseases.
Conflict of interest: None declared
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Selin Akturk Esen
Department of Internal Medicine, Gürsu Cüneyt Yildiz State Hospital, Bursa
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
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