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Original article

Expression of the neural cell adhesion molecule in the renal interstitium in different stages of fibrosis

Ana Mioljević1, Isidora Filipović1,2, Gorana Nikolić1,2, Aleksandar Janković1,4, Nikola Bogosavljević1,3, Petar Djurić1,4, Novica Boričić1,2, Maja Životić1,2
  • University of Belgrade, Faculty of Medicine, Belgrade, Serbia
  • University of Belgrade, Faculty of Medicine, Institute of Pathology, Belgrade, Serbia
  • Institute for Orthopedic Surgery "Banjica!, Belgrade, Serbia
  • “Zvezdara” University Medical Center, Belgrade, Serbia

ABSTRACT

Introduction: In healthy adult kidneys, differentiated tubular epithelial cells do not express the neural cell adhesion molecule (NCAM), while a small number of NCAM-expressing cells can be detected in the renal interstitium. The role and the significance of these cells have not yet been clarified, but it has been observed that the number of NCAM-expressing cells increases in the initial stage of interstitial fibrosis.

Aim: The aim of the study is to examine the significance of the expression of NCAM molecules in the renal interstitium, in etiologically different diseases, with varying degrees of interstitial fibrosis, as well as to define the pathohistological and clinical indicators (predictors) of impaired kidney function.

Materials and methods: The study included 69 patients who underwent needle biopsies of the kidneys in 2011 and 2012. Clinical and laboratory data were collected at the time of the biopsy and at the time of the latest follow-up examination. Pathohistological characteristics were defined optically-microscopically, while NCAM-expressing interstitial cells were detected with immunohistochemical staining, using the primary NCAM antibody (1:50, clone 123C3.D5).

Results: NCAM-expressing interstitial cells were detected in 59.4% of kidney biopsies, the presence of these cells was significantly more frequent in the initial stages of interstitial fibrosis than in the remaining stages (p < 0.001), and it did not depend on the pathohistological diagnosis (p = 0.995). Patients in whom NCAM cells were detected had significantly lower proteinuria levels at the time of biopsy, as compared to patients without NCAM interstitial cells (p = 0.024). The levels of serum creatinine (p < 0.001) and urea (p = 0.007) significantly influenced the probability of the deterioration of renal function.

Conclusion: The presence of NCAM cells in the kidney interstitium is a characteristic of the early stages of chronic kidney disease with incipient interstitial fibrosis and a lesser degree of proteinuria.


INTRODUCTION

Neural cell adhesion molecule (NCAM) is a sialoglycoprotein involved in cell-cell interactions and cell interactions with the extracellular matrix [1],[2].

This molecule plays a very important role in the embryonic development of the brain, the peripheral nerves, the muscles and the kidneys [3]. The cells of the metanephric mesenchyme abundantly express NCAM, but the expression of this molecule gradually disappears with the progression of the differentiation of the cells that will predominantly build the renal tubular epithelium [4]. In healthy adult kidneys, differentiated epithelial cells do not express NCAM [5]. However, a small number of NCAM-expressing cells can be detected in the interstitium of healthy kidneys, and they are thought to represent metanephric mesenchymal cells left behind after embryonic kidney development [3],[4]. The role and the importance of these cells have not as yet been clarified, but it has been observed that the number of NCAM-expressing cells increases in the initial stage of interstitial fibrosis, and there is increasing speculation about the importance of these cells in the early stage of renal parenchymal repair [4]. This hypothesis is supported by the results of other researchers who have indicated the importance of the NCAM molecule in the process of skeletal muscle and pancreatic fibrosis [6].

NCAM is also a specific marker of neuroectodermal and neuroendocrine cell differentiation [1],[2]. Given that it is assumed that the erythropoietin-producing cells in the kidneys originate from the neural crest, i.e., they are believed to have neuroectodermal origin [7],[8],[9], the possibility that NCAM-expressing interstitial cells actually represent erythropoietin-producing cells should not be excluded. Transcriptional induction of several NCAM isoforms was observed along with FGFR1, suggesting a mechanical link between NCAM/ FGFR1 signaling and fibrogenesis induction in the kidney [10].

Bearing in mind that interstitial fibrosis is a pathomorphological substrate of impaired kidney function and that it occurs in many, etiologically diverse kidney diseases, significant effort is being made to investigate the molecular basis and the signaling pathways contributing to this process. Therefore, the aim of this study was to examine the significance of the expression of NCAM molecules in the kidney interstitium in etiologically diverse kidney diseases with different degrees of interstitial fibrosis, as well as to define the clinical characteristics of patients in whom these cells were detected. Also, this study was conducted with the aim of defining indicators (predictors) of impaired kidney function.

MATERIALS AND METHODS

Needle biopsies of kidneys of patients diagnosed during 2011 and 2012 at the Institute of Pathology of the Faculty of Medicine, University of Belgrade, were retrospectively analyzed optically and microscopically. Sixty-nine patients, who had enough tissue in paraffin-embedded biopsies to make slides for immunohistochemical staining, were selected. Also, by reviewing the medical histories of these 69 patients, relevant clinical and laboratory data recorded at the time of the biopsy, as well as data from the latest regular follow-up of the patients, were collected.

Plates with tissue cut to a thickness of 5 μm were made from paraffin blocks. After deparaffinization in xylene and hydration, the slides were placed in a citrate buffer (pH = 6.0) and exposed to microwaves for 20 minutes at 400 W. Peroxidase activity was blocked with 1% bovine serum albumin (BSA). After antigen unmasking, incubation with the primary NCAM antibody (1:50, clone 123C3.D5, LabVision, USA) was performed for 60 minutes. EnVisionTM (DAKO, Denmark) was used to visualize the antigen-antibody reaction with 3,3’-diaminobenzidine (DAB), upon which counterstaining with hematoxylin was performed. Negative controls were obtained by omitting the primary antibody, and fetal kidney tissue was used as a positive control. Plates were examined using a BX53 light microscope with a DP12CCD camera (Olympus, Germany). The number of NCAM-expressing cells was presented as the number of cells per field of view at ×400 magnification.

The degree of interstitial renal fibrosis (IRF) was determined semiquantitatively, using a score from 0 to 3, whereby the following applied: 0 – no interstitial fibrosis; 1 – less than 25% of tissue affected by interstitial fibrosis; 2 – between 25% and 50% of tissue affected by interstitial fibrosis; 3 – more than 50% of tissue affected by interstitial fibrosis. The best-known international guide was used to classify patients according to the stages of chronic kidney disease (CKD) [11].

Statistical analysis was performed using the IBM SPSS software, version 20.0. Depending on the nature of the observed variable and the number of investigated groups, the χ2 test, Student’s t test and Mann-Whitney U test were used to examine the difference between the groups. Kaplan-Meier univariate survival analysis was used to determine predictors of the deterioration of renal function, whereby p < 0.05 was considered statistically significant.

RESULTS

NCAM-expressing interstitial cells were detected in 59.4% of kidney biopsies, and the presence of these cells did not depend on pathohistological diagnosis (p = 0.995). However, the frequency of positive biopsy cases was found to be statistically significantly higher in patients who had incipient interstitial fibrosis (IRF1), as compared to patients in other IRF categories (p < 0.001; Table 1). Figure 1 shows NCAM-expressing interstitial cells in biopsy samples with interstitial fibrosis.

p361 1

Figure 1. Presence of NCAM-expressing interstitial cells in biopsy specimens with interstitial fibrosis: (A) Masson’s trichrome staining, ×200; (B) immunohistochemical staining with the NCAM antibody (1:50, clone 123C3.D5), ×200; (C) Masson’s trichrome staining, ×400; (D) immunohistochemical staining with the NCAM antibody (1:50, clone 123C3.D5), ×400

Table 1. Distribution of patients with NCAM-expressing interstitial cells in relation to pathohistological parameters

p361 2

The distribution of patients with NCAM-expressing interstitial cells in relation to CKD stage did not differ significantly, both at the time of biopsy (p = 0.954; Table 2) and at the time of the latest follow-up (p = 0.601; Table 3).

Table 2. Distribution of patients with NCAM-expressing interstitial cells in relation to clinical and laboratory parameters at the time of biopsy

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Table 3. Distribution of patients with NCAM-expressing interstitial cells in relation to clinical and laboratory parameters at the last follow-up examination

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However, it was observed that the average levels of serum creatinine (sCr) and creatinine clearance (CCr), in the group of patients in whom NCAM-expressing cells were detected in the interstitium (sCr: 200.1 ± 239.4; CCr: 104.3 ± 70.2) were higher, as compared to the group of patients without NCAM-expressing cells in the interstitium (sCr: 146.6 ± 136.3; CCr: 77.6 ± 39.5). A similar trend was observed at the latest follow-up; however, the differences were not statistically significant. Also, the average levels of eGFR, urea and glucose, as well as the frequency of erythrocyturia, did not differ statistically significantly between the compared groups (Table 2; Table 3).

Patients in whom NCAM-expressing interstitial cells were detected had statistically significantly lower proteinuria levels at the time of biopsy, as compared to patients whose biopsy samples did not have NCAM-positive cells in the interstitium (3.97 g/24 h vs. 8.41 g/24 h; p = 0.024), (Table 2).

The erythrocyte count, hemoglobin level, hematocrit level, and the mean corpuscular volume (MCV) did not differ significantly between the compared groups (Table 2; Table 3). Patients were followed up for an average of 16 months. Pathohistological and clinical features were observed as potential predictors of CKD progression to the advanced stages. We observed that none of the patients with minimal changes progressed to advanced stages of CKD during the follow-up period, while all patients with rapidly progressive glomerulonephritis (GN) had a rapid deterioration of renal function. However, due to the large number of different pathohistological diagnoses and the relatively small number of patients in these groups, statistical analysis was not performed.

It was also observed that patients without interstitial fibrosis, during the three years of follow-up, preserved renal function in 90% of cases, while in other stages, renal function progressively declined over time. Renal function declined the slowest in patients with incipient interstitial fibrosis, more rapidly in the second stage, while in the third stage, kidney function declined the fastest. However, due to the small number of patients included in the survival study and the degree of fibrosis (graded into four stages), statistical analysis was not performed.

The probability of renal function deterioration was significantly dependent on the serum creatinine level (p < 0.001) and the urea level (p = 0.007). Renal function was preserved for a significantly longer period of time with normal levels of serum creatinine (< 104 μmol/l, reference value of the laboratory of the University Clinical Center of Serbia), (Figure 2. A) and normal levels of urea (< 7.5 mmol/l, reference value of the laboratory of the University Clinical Center of Serbia), (Figure 2. B), as opposed to patients who had elevated levels of sCr and urea, in whom there was a rapid deterioration of renal function. We observed that patients who had proteinuria below 3 g/24 h maintained kidney function significantly longer, as compared to patients who had proteinuria above 3 g/24 h. However, proteinuria was not a significant predictor of poor patient outcome (p = 0.231), as shown in Figure 2. C.

p364

Figure 2. Probability of renal function deterioration depending on (A) serum creatinine level, (B) urea level, and (C) proteinuriae

DISCUSSION

Interstitial fibrosis occurs in etiologically different kidney diseases. Progression of interstitial fibrosis leads to progressive loss of renal function (kidney failure), leading to patients requiring dialysis and kidney transplantation [12]. There is an increasing number of studies examining the molecular basis of fibrosis, and among the most important are those focused on examining early indicators of potential disease progression.

Fibrosis is an abnormal accumulation of extracellular matrix. It is believed that different cells can contribute to the production of extracellular matrix, but that the main cells in this process are activated fibroblasts, i.e., myofibroblasts [12],[13]. It is known that the activation and mobilization of fibroblasts is the result of the stimulation of fibroblast growth factor receptor 1 (FGFR-1). FGFR-1 can be stimulated by different ligands including NCAM [14],[15],[16], which has led us to examine in more detail the expression of NCAM molecules in interstitial cells, in different stages of interstitial fibrosis.

In the interstitium of healthy kidneys, NCAM-expressing cells are very rare, but during the course of certain pathological conditions their number can increase [17]. The results of our study showed that a greater number of NCAM-expressing cells almost exclusively appears in the initial stages of interstitial fibrosis, in etiologically different kidney diseases, while in advanced stages the expression is significantly lower. The results of other researchers suggested that the extent of NCAM expression in the interstitium is closely related to the degree of interstitial damage, both in humans and animals [4],[18]. Thus, a sudden increase of NCAM cells was observed in the early phase of the regeneration process after ischemic tubule damage in rats [19]. Also, Luo et al proved a significant presence of NCAM in advanced stages of liver fibrosis, in patients with non-alcoholic steatosis of the liver [20]. In an in vitro model of kidney interstitial fibrosis, a strong induction of the expression of NCAM isoforms together with FGFR1 was observed, 24 hours after stimulation of the fibrogenesis process under the influence of transforming growth factor beta 1 (TGF-β1), although, at that moment, morphological changes were not visible. After 48 hours, a decrease in NCAM and FGFR1 mRNA levels was observed, indicating the key role of these molecules in the initiation of the fibrogenesis process. Also, by blocking the FGFR1 signaling pathway after exposure to TGF-β1, morphological reversion of the fibrogenesis process was observed, thus confirming the significant role of NCAM/FGFR1 in the initial stage of kidney fibrosis [10]. The discovery of molecular mechanisms of fibrogenesis, important in the initial phase of fibrosis, is significant due to the application of new, targeted therapeutic modalities, which would reduce the need for dialysis and kidney transplantation in patients suffering from various, etiologically heterogeneous, non-tumor kidney diseases.

The expression of NCAM, as a pathological substrate, apart from kidney fibrosis, has also been found in the heart, the lungs, and the hepatobiliary system. Studies also indicate the potential development of new therapeutic modalities in order to slow down the progression of fibrosis and suggest the possibility of reversing the process of fibrogenesis [21],[22],[23],[24],[25].

Our study was the only one to examine the clinical significance of the detection of NCAM cells in the kidney interstitium of nephrological patients, and it was established that patients with NCAM-expressing cells in the interstitium had significantly lower average proteinuria levels. Because of the assumption that there is a possibility that NCAM-expressing interstitial cells actually represent erythropoietin producing cells [7], we examined the relationship between the distribution of patients expressing NCAM cells and the erythrocyte count, the hemoglobin level, the hematocrit level, and the mean corpuscular volume (MCV). However, we did not observe any association.

Studies focused on determining clinical and pathological predictors of renal function deterioration are of great practical importance. Among the clinical parameters, significant predictors of the deterioration of kidney function are elevated levels of creatinine and urea in the serum of patients, as well as high levels of proteinuria, especially those in the nephrotic range [19],[26],[27]. Among the examined clinical parameters in our study, elevated levels of serum creatinine and urea also stood out as predictors of renal function deterioration. In previous studies, it has been observed that proteinuria is a predictor of poor outcome [26],[28],[29]. We observed that patients who had proteinuria below 3 g/24 h maintained normal renal function longer, however, proteinuria did not stand out as a significant predictor of declining renal function. It is also known that the probability of kidney disease progression to advanced CKD stages significantly depends on the pathohistological diagnosis and stage of interstitial fibrosis [30], which was not statistically investigated due to the small number of patients in our study.

CONCLUSION

The presence of NCAM cells in the renal interstitium is characteristic of the early stages of chronic kidney disease with incipient interstitial fibrosis and mild proteinuria. The levels of serum creatinine and urea significantly affected the probability of kidney function deterioration, which is why they represent important clinical predictors of patients progressing to advanced stages of CKD.

  • Conflict of interest:
    None declared.

Informations

Volume 4 No 4

December 2023

Pages 360-369
  • Keywords:
    NCAM-expressing renal interstitial cells, interstitial fibrosis, renal impairment, predictors
  • Received:
    13 August 2023
  • Revised:
    06 October 2023
  • Accepted:
    13 October 2023
  • Online first:
    25 December 2023
  • DOI:
  • Cite this article:
    Mioljević A, Filipović I, Nikolić G, Janković A, Bogosavljević N, Đurić P, et al. Expression of the neural cell adhesion molecule in the renal interstitium in different stages of fibrosis. Serbian Journal of the Medical Chamber. 2023;4(4):358-67. doi: 10.5937/smclk4-46516
Corresponding author

Ana Mioljević
Institute of Pathology, Faculty of Medicine, University of Belgrade
1 Dr Subotića starijeg Street, 11129 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


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    2. Gordis C, Brunet JF. NCAM: structural diversity, function and regulation of expression. Semin Cell Biol 1992 Jun;3(3):189-97. doi: 10.1016/s1043- 4682(10)80015-7. [CROSSREF]

    3. Klein G, Langegger M, Goridis C, Ekblom P. Neural cell adhesion molecules during embryonic induction and development of the kidney. Development. 1988 Apr;102(4):749-61. doi: 10.1242/dev.102.4.749. [CROSSREF]

    4. Marković-Lipkovski J, Müller CA, Klein G, Flad T, Klatt T, Blaschke S, et al. Neural cell adhesion molecule expression on renal interstitial cells. Nephrol Dial Transplant. 2007 Jun;22(6):1558-66. doi: 10.1093/ndt/gfm006. [CROSSREF]

    5. Meran S, Steadman R. Fibroblasts and myiofibroblasts in renal fibrosis. Int J Exp Path. 2011 Jun;92(3):158-67. doi: 10.1111/j.1365-2613.2011.00764.x. [CROSSREF]

    6. Gollon A, Sheard P. Elderly mouse skeletal muscle fibres have a diminished capacity to upregulate NCAM production in response to denervation. Biogerontology. 2015 Dec;16(6):811-23. doi: 10.1007/s10522-015-9608-6. [CROSSREF]

    7. Zeisberg M, Kalluri R. Physiology of the renal interstitium. Clin J Am Soc Nephrol. 2015 Oct 7;10(10):1831-40. doi: 10.2215/CJN.00640114. [CROSSREF]

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REFERENCES

1. Rutishauser U, Acheson A, Hall AK, Mann DM, Sunshine J. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 1988 Apr 1;240(4848):53-7. doi: 10.1126/science.3281256. [CROSSREF]

2. Gordis C, Brunet JF. NCAM: structural diversity, function and regulation of expression. Semin Cell Biol 1992 Jun;3(3):189-97. doi: 10.1016/s1043- 4682(10)80015-7. [CROSSREF]

3. Klein G, Langegger M, Goridis C, Ekblom P. Neural cell adhesion molecules during embryonic induction and development of the kidney. Development. 1988 Apr;102(4):749-61. doi: 10.1242/dev.102.4.749. [CROSSREF]

4. Marković-Lipkovski J, Müller CA, Klein G, Flad T, Klatt T, Blaschke S, et al. Neural cell adhesion molecule expression on renal interstitial cells. Nephrol Dial Transplant. 2007 Jun;22(6):1558-66. doi: 10.1093/ndt/gfm006. [CROSSREF]

5. Meran S, Steadman R. Fibroblasts and myiofibroblasts in renal fibrosis. Int J Exp Path. 2011 Jun;92(3):158-67. doi: 10.1111/j.1365-2613.2011.00764.x. [CROSSREF]

6. Gollon A, Sheard P. Elderly mouse skeletal muscle fibres have a diminished capacity to upregulate NCAM production in response to denervation. Biogerontology. 2015 Dec;16(6):811-23. doi: 10.1007/s10522-015-9608-6. [CROSSREF]

7. Zeisberg M, Kalluri R. Physiology of the renal interstitium. Clin J Am Soc Nephrol. 2015 Oct 7;10(10):1831-40. doi: 10.2215/CJN.00640114. [CROSSREF]

8. Bahlmann FH, Kielstein JT, Haller H, Fliser D. Erythropoietin and progression of CKD. Kidney Int Suppl. 2007 Nov;(107):S21-5. doi: 10.1038/sj.ki.5002484. [CROSSREF]

9. Tanaka T, Nangaku M. Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents. Exp Cell Res. 2012 May 15;318(9):1068-73. doi: 10.1016/j.yexcr.2012.02.035. [CROSSREF]

10. Životić M, Tampe B, Müller G, Müller C, Lipkovski A, Xu X, et al. Modulation of NCAM/FGFR1 signaling suppresses EMT program in human proximal tubular epithelial cells. PLoS One. 2018 Nov 1;13(11) doi: 10.1371/journal. pone.0206786. [CROSSREF]

11. National Kidney Foundation. Definition and classification of stages of chronic kidney disease. In: KDOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266.

12. Strutz F, Müller GA. Renal fibrosis and the origin of the renal fibroblast. Nephrol Dial Transplant. 2006 Dec;21(12):3368-70. doi: 10.1093/ndt/gfl199. [CROSSREF]

13. Strutz F, Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol. 2006 Nov;17(11):2992-8. doi: 10.1681/ ASN.2006050420. [CROSSREF]

14. Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N, Soroka V, et al. Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure. 2003 Jun;11(6):691-701. doi: 10.1016/s0969-2126(03)00096-0. [CROSSREF]

15. Francavilla C, Cattaneo P, Berezin V, Bock E, Ami D, de Marco A, et al. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking. J Cell Biol. 2009 Dec 28;187(7):1101-16. doi: 10.1083/ jcb.200903030. [CROSSREF]

16. Zeisberg M, Kalluri R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol. 2013 Feb 1;304(3):C216-25. doi: 10.1152/ajpcell.00328.2012. [CROSSREF]

17. Abbate M, Brown D, Bonventre JV. Expression of NCAM recapitulates tubulogenic development in kidneys recovering from acute ischemia. AJP – Renal Physiol. Am J Physiol. 1999 Sep;277(3):F454-63. doi: 10.1152/ajprenal.1999.277.3.F454. [CROSSREF]

18. Vansterthem D, Gossiaux A, Decleves AE, Caron N, Nonclercq D, Legrand A, et al. Expression of nestin,vimentin and NCAM by renal interstitial cells after ischemic tubular injury. J Biomed Biotechnol. 2010; 2010: 193259. doi: 10.1155/2010/193259. [CROSSREF]

19. Anderson S, Halter JB, Hazzard WR, Himmelfarb J, Horne FM, Kaysen GA, et al. Prediction, progression, and outcomes of chronic kidney disease in older adults. J Am Soc Nephrol 2009 Jun;20(6):1199-209. doi: 10.1681/ ASN.2008080860. [CROSSREF]

20. Luo Y, Wadhawan S, Greenfield A, Decato BE, Oseini AM, Collen R, et al. SOMAscan proteomics identifies serum biomarkers associated with liver fibrosis in patients with NASH. Hepatol Commun. 2021 Jan 20;5(5):760-73. doi: 10.1002/hep4.1670. [CROSSREF]

21. Ramos KS, Pool L, van Schie MS, Wijdeveld LFJM, van der Does WFB, Baks L, et al. Degree of fibrosis in human atrial tissue is not the hallmark driving AF. Cells. 2022 Jan 26;11(3):427. doi: 10.3390/cells11030427. [CROSSREF]

22. Serezani APM, Pascoalino BD, Bazzano JMR, Vowell KN, Tanjore H, Taylor CJ, et al. Multiplatform single-cell analysis identifies immune cell types enhanced in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2022 Jul;67(1):50-60. doi: 10.1165/rcmb.2021-0418OC. [CROSSREF]

23. Lasagni A, Cadamuro M, Morana G, Fabris L, Strazzabosco M. Fibrocystic liver disease: novel concepts and translational perspectives. Transl Gastroenterol Hepatol. 2021 Apr 5;6:26. doi: 10.21037/tgh-2020-04. [CROSSREF]

24. Wang W, Shui L, Liu Y, Zheng M. C-kit, a double-edged sword in liver regeneration and diseases. Front Genet. 2021 Feb 2;12:598855. doi: 10.3389/fgene.2021.598855. [CROSSREF]

25. Chen Y, Gao WK, Shu YY, Ye J. Mechanisms of ductular reaction in non-alcoholic steatohepatitis. World J Gastroenterol. 2022 May 21;28(19):2088-99. doi:10.3748/wjg.v28.i19.2088. [CROSSREF]

26. Plantinga LC, Boulware LE, Coresh J, Stevens LA, Miller ER, Saran R, et al. Patient awareness of chronic kidney disease:trends and predictors. Arch Intern Med. 2008; 168(20):2268-75. doi: 10.1001/archinte.168.20.2268. [CROSSREF]

27. Couchoud C, Pozet N, Labeeuw M. Screening early renal failure: cut-off values for serum creatinine as an indicator of renal impairment. Kidney Int. 1999 May;55(5):1878-84. doi: 10.1046/j.1523-1755.1999.00411.x. [CROSSREF]

28. Blakeman T, Protheroe J, Chew-Graham C, Rogers A, Kennedy A. Understanding the management of early-stage chronic kidney disease in primary care: a qualitative study. Br J Gen Pract. 2012 Apr; 62(597):e233-42. doi: 10.3399/ bjgp12X636056. [CROSSREF]

29. Abrantes MM, Cardoso LSB, Lima EM, Penido Silva JM, Diniz JS, Bambirra EA, et al. Predictive factors of chronic kidney disease in primary focal segmental glomerulosclerosis. Pediatr Nephrol. 2006 Jul;21(7):1003-12. doi: 10.1007/ s00467-006-0138-y. [CROSSREF]

30. Životić M, Bogdanović R, Peco-Antić A, Paripović D, Stajić N, Vještica J, et al. Glomerular nestin expression: possible predictor of outcome of focal segmental glomerulosclerosis in children. Pediatr Nephrol. 2015; 30(1):79-90. doi: 10.1007/s00467-014-2893-5. [CROSSREF]

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20. Luo Y, Wadhawan S, Greenfield A, Decato BE, Oseini AM, Collen R, et al. SOMAscan proteomics identifies serum biomarkers associated with liver fibrosis in patients with NASH. Hepatol Commun. 2021 Jan 20;5(5):760-73. doi: 10.1002/hep4.1670. [CROSSREF]

21. Ramos KS, Pool L, van Schie MS, Wijdeveld LFJM, van der Does WFB, Baks L, et al. Degree of fibrosis in human atrial tissue is not the hallmark driving AF. Cells. 2022 Jan 26;11(3):427. doi: 10.3390/cells11030427. [CROSSREF]

22. Serezani APM, Pascoalino BD, Bazzano JMR, Vowell KN, Tanjore H, Taylor CJ, et al. Multiplatform single-cell analysis identifies immune cell types enhanced in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2022 Jul;67(1):50-60. doi: 10.1165/rcmb.2021-0418OC. [CROSSREF]

23. Lasagni A, Cadamuro M, Morana G, Fabris L, Strazzabosco M. Fibrocystic liver disease: novel concepts and translational perspectives. Transl Gastroenterol Hepatol. 2021 Apr 5;6:26. doi: 10.21037/tgh-2020-04. [CROSSREF]

24. Wang W, Shui L, Liu Y, Zheng M. C-kit, a double-edged sword in liver regeneration and diseases. Front Genet. 2021 Feb 2;12:598855. doi: 10.3389/fgene.2021.598855. [CROSSREF]

25. Chen Y, Gao WK, Shu YY, Ye J. Mechanisms of ductular reaction in non-alcoholic steatohepatitis. World J Gastroenterol. 2022 May 21;28(19):2088-99. doi:10.3748/wjg.v28.i19.2088. [CROSSREF]

26. Plantinga LC, Boulware LE, Coresh J, Stevens LA, Miller ER, Saran R, et al. Patient awareness of chronic kidney disease:trends and predictors. Arch Intern Med. 2008; 168(20):2268-75. doi: 10.1001/archinte.168.20.2268. [CROSSREF]

27. Couchoud C, Pozet N, Labeeuw M. Screening early renal failure: cut-off values for serum creatinine as an indicator of renal impairment. Kidney Int. 1999 May;55(5):1878-84. doi: 10.1046/j.1523-1755.1999.00411.x. [CROSSREF]

28. Blakeman T, Protheroe J, Chew-Graham C, Rogers A, Kennedy A. Understanding the management of early-stage chronic kidney disease in primary care: a qualitative study. Br J Gen Pract. 2012 Apr; 62(597):e233-42. doi: 10.3399/ bjgp12X636056. [CROSSREF]

29. Abrantes MM, Cardoso LSB, Lima EM, Penido Silva JM, Diniz JS, Bambirra EA, et al. Predictive factors of chronic kidney disease in primary focal segmental glomerulosclerosis. Pediatr Nephrol. 2006 Jul;21(7):1003-12. doi: 10.1007/ s00467-006-0138-y. [CROSSREF]

30. Životić M, Bogdanović R, Peco-Antić A, Paripović D, Stajić N, Vještica J, et al. Glomerular nestin expression: possible predictor of outcome of focal segmental glomerulosclerosis in children. Pediatr Nephrol. 2015; 30(1):79-90. doi: 10.1007/s00467-014-2893-5. [CROSSREF]


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