Mechanisms of renal tubulo-interstitial fibrosis prepared for the CKD Nephrology Online Course (NOC) of 2013

1. Sheffield Kidney Institute
Global Kidney Academy
CKD NOC 2013
CKD Scarring Mechanisms
3. Inflammation
Professor Meguid El Nahas, PhD, FRCP
Chairman, Global Kidney Academy
Sheffield, UK
Nephrology Online Courses

2. Sheffield Kidney Institute
CKD & Scarring
4. Inflammation
Learning Objectives
1.Learn about Cellular Meditors of Scarring
2.2. Appreciate the role of Monocytes/macrophages
3.Learn about the heterogeneity of Macrophages
4.Learn their roles in Scarring and Healing
Nephrology Online Courses

3. Sheffield Kidney Institute
CKD
Nephrology Online Courses

4. Sheffield Kidney Institute
FIBROSIS
Kidney
Liver
Lung Aorta
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5. Sheffield Kidney Institute
El Nahas, 2001
Glomerulosclerosis
Atherosclerosis
Myocardial Fibrosis
Jugdutt, 2009
Nephrology Online Courses

6. Sheffield Kidney Institute
CKD1 & 2 CKD3 CKD4 CKD5
Stages of Kidney Scarring
INJURY INFLAMMATION FIBROSIS

7. Sheffield Kidney Institute
Nephrology Online Courses

8. Sheffield Kidney Institute
Nephrology Online Courses

9. Sheffield Kidney Institute
Nephrology Online Courses

10. Sheffield Kidney Institute
Alikhan & Ricardo, 2013
Nephrology Online Courses

11. Sheffield Kidney Institute
Alikhan & Ricardo, 2013
Nephrology Online Courses

12. Sheffield Kidney Institute
Figure 3. Subpopulations of inflammatory macrophages in vivo
Schematic showing three different types of inflammatory macrophage, and factors that
regulate their activation/differentiation in sterile inflammation in vivo. Although cell-derived
and tissue-derived factors can regulate recruited monocytes to differentiate into different
macrophage subtypes, regulatory macrophages also differentiate from M1 and M2/wound
healing activated macrophages, triggered by mechanisms that are poorly understood.
Duffield Page 22
NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-P
Duffield, 2010
Nephrology Online Courses

13. Sheffield Kidney Institute
M1 M2
Nephrology Online Courses

14. Sheffield Kidney Institute
Duffield, 2010
Nephrology Online Courses

15. Sheffield Kidney Institute
Guerrot et al, 2012
Nephrology Online Courses

16. Sheffield Kidney Institute
Nephrology Online Courses

17. Sheffield Kidney Institute
Nephrology Online Courses

18. Sheffield Kidney Institute
Nephrology Online Courses

19. Sheffield Kidney Institute
Duffield, 2010
Nephrology Online Courses

20. Sheffield Kidney Institute
Kanazaki et al, 2013
Nephrology Online Courses

21. Sheffield Kidney Institute
Desmouliere et al, 2009
Nephrology Online Courses

22. Sheffield Kidney Institute
Myofibroblasts Activation
Nephrology Online Courses

23. Sheffield Kidney Institute
Tubulo-Interstitial Diseases
Nephrology Online Courses

24. Sheffield Kidney Institute
Figure 3. Subpopulations of inflammatory macrophages in vivo
Schematic showing three different types of inflammatory macrophage, and factors that
regulate their activation/differentiation in sterile inflammation in vivo. Although cell-derived
and tissue-derived factors can regulate recruited monocytes to differentiate into different
macrophage subtypes, regulatory macrophages also differentiate from M1 and M2/wound
Duffield Page 22
NIH-PAAuthorManuscriptNIH-PAAuthorManuscript
Duffield, 2010
Nephrology Online Courses

25. Sheffield Kidney Institute
Nephrology Online Courses

26. Sheffield Kidney Institute
Figure 3. Subpopulations of inflammatory macrophages in vivo
Schematic showing three different types of inflammatory macrophage, and factors that
regulate their activation/differentiation in sterile inflammation in vivo. Although cell-derived
and tissue-derived factors can regulate recruited monocytes to differentiate into different
macrophage subtypes, regulatory macrophages also differentiate from M1 and M2/wound
healing activated macrophages, triggered by mechanisms that are poorly understood.
Duffield Page 22
NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH
Nephrology Online Courses

27. Sheffield Kidney Institute
M1 M2
Nephrology Online Courses

28. Sheffield Kidney Institute
Nephrology Online Courses

29. Sheffield Kidney Institute
Figure 3. Subpopulations of inflammatory macrophages in vivo
Schematic showing three different types of inflammatory macrophage, and factors that
regulate their activation/differentiation in sterile inflammation in vivo. Although cell-derived
and tissue-derived factors can regulate recruited monocytes to differentiate into different
macrophage subtypes, regulatory macrophages also differentiate from M1 and M2/wound
Duffield Page 22
NIH-PAAuthorManuscriptNIH-PAAuthorManuscript
Nephrology Online Courses

30. Sheffield Kidney Institute
Nephrology Online Courses

31. Sheffield Kidney Institute
Wang et al, 2010
AN M0 M1 M2
Nephrology Online Courses

32. Sheffield Kidney Institute
Figure 3. Subpopulations of inflammatory macrophages in vivo
Schematic showing three different types of inflammatory macrophage, and factors that
regulate their activation/differentiation in sterile inflammation in vivo. Although cell-derived
and tissue-derived factors can regulate recruited monocytes to differentiate into different
macrophage subtypes, regulatory macrophages also differentiate from M1 and M2/wound
Duffield Page 22
NIH-PAAuthorManuscriptNIH-PAAuthorManuscript
Nephrology Online Courses

33. Sheffield Kidney Institute
Nephrology Online Courses

34. Sheffield Kidney Institute
Fate of inflammation
• Resolution: HEALING
• Chronicity
• Fibrosis: SCARRING
Nephrology Online Courses

35. Sheffield Kidney Institute
Nephrology Online Courses

36. Sheffield Kidney Institute
Mechanism of chronic inflammation
• Persistent of Antigen/Stimulus
–Immune
–PAMPs
–DAMPs
• Continuous Tissue injury: DAMPs
• Defective anti-Inflammatory cascade
Nephrology Online Courses

37. Sheffield Kidney Institute
Inflammation Resolvers
Borgeson & Godson, 2012
Nephrology Online Courses

38. Sheffield Kidney Institute
AKI
PIGN
ATIN
Hypertension
DM
CVD
CKD
Nephrology Online Courses

39. Sheffield Kidney Institute
Tubulo-Interstitial Fibrosis
Nephrology Online Courses

40. Sheffield Kidney Institute
Renal Scarring
Recommended Reading
1. http://www.ncbi.nlm.nih.gov/pubmed/23255577
2. http://www.ncbi.nlm.nih.gov/pubmed/23722183
3. http://www.ncbi.nlm.nih.gov/pubmed/23259697
4. http://www.ncbi.nlm.nih.gov/pubmed/22105921
5. http://www.ncbi.nlm.nih.gov/pubmed/21554437
6. http://www.ncbi.nlm.nih.gov/pubmed/21422927
7. http://www.ncbi.nlm.nih.gov/pubmed/23114895
Nephrology Online Courses

41. Sheffield Kidney Institute
CKD & Scarring
4. Inflammation
MCQ1
The following cells are involved in the kidney repair
process
1.Lymphocytes
2.Neutrophils
3.Macrophages (M1)
4.Macrophages (M2) (T)
Nephrology Online Courses

42. Sheffield Kidney Institute
CKD & Scarring
4. Inflammation
MCQ2
The following lymphocyte has a key role in renal
fibrosis:
1.C4d
2.CD8
3.CD4 (T)
4.CD25
Nephrology Online Courses

43. Sheffield Kidney Institute
CKD & Scarring
4. Inflammation
MCQ3
The following growth factor may reverse kidney
fibrosis:
1.PDGF
2. IL-2
3. IL-1
BMP7 (T)
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