This document discusses chronic kidney disease (CKD) mechanisms and future therapies. It provides global statistics on the prevalence and incidence of CKD, end-stage renal disease (ESRD), and renal replacement therapy. It examines CKD detection programs worldwide and the stages of kidney scarring. The role of transforming growth factor beta 1 (TGFβ1) in fibrosis is discussed, along with potential therapies targeting TGFβ1 signaling pathways. Pre-clinical studies in animal models are summarized. The challenges of translating experimental therapies to clinical trials are also reviewed.
1. Sheffield Kidney Institute
CKD Mechanisms
and
Future Therapies
PROFESSOR MEGUID EL NAHAS, PhD, FRCP
CHAIRMAN, GLOBAL KIDNEY ACADEMY
UNIVERSITY OF SHEFFIELD
SHEFFIELD, UK
6. Sheffield Kidney Institute
Global Prevalence Distribution
0
200
400
600
800
1000
1200
1400
1600
1800
Japan USA
Europe
Developing
World
Prevalence pmp
8. Sheffield Kidney Institute
GLOBAL CKD Programmes
Canada
USA
Mexico
Cuba
Morocco Egypt
RSA
Iceland
Holland
Germany
UK
Spain
Belgium
China
Hong Kong
Japan
Korea
Singapore
Malaysia
Thailand
Australia
Argentina
Venezuela
Brasil
Chile
Peru
Bolivia
Paraguay
Italy
Switzerland
Norway
Denmark
Finland
Iran
Nigeria
10. Sheffield Kidney Institute
Prevalence of CKD in USA
NHANESIII
0%
5%
10%
15%
20%
25%
30%
35%
40%
Prevalenc
e (%)
20-39 40-59 60-69 70+
Age Group (years)
<2%
>30%
34. Sheffield Kidney Institute
by centrifugation and fixed to a slide using a
SP-1 antibody over night and revealed with anti-
re before being counterstained with Carazzi’s
an Olympus (Cell F™ imaging software) BX-61
6.12: Urine cytospin from patient’s SKI 17 stained for FSP-1 positive cells
200 X
Eltemtam, PhD Thesis 2012
35. Sheffield Kidney Institute
S t a g e 0 3 S t a g e 0 4
0
N
P r o g r e s s o r s N o n - P r o g r e s s o r s
0
2 0
4 0
6 0
8 0
P = 0 . 0 0 4
%ofpositiveFSP-1cells
(A) The number of urine positive FSP-1 cells per patient was determined according to the
stage of DKD. (B) The percentage of urine positive FSP-1 cells in progressors and non-
B
Eltemtam, PhD Thesis 2012
36. Sheffield Kidney Institute
Figure 6.17: ROC curve analysis of urine FSP-1/Podocytes positive cells as predictors of
progressive DKD
The AUC was calculated; the fraction of true positive results (sensitivity) and false positive
results (1-specificity) of urine FSP-1 positive cells as predictors of DKD. A value of 0.5 is no
better than that expected by chance (the null hypothesis), and a value of 1.0 reflects a perfect
predictor.
Eltemtam, PhD Thesis 2012
80. Sheffield Kidney Institute
upon activation, normal upon expression normal T cell expressed
and secreted (RANTES) [18,19,20]. This proinflammatory
microenvironment promotes renal scarring [14,15]. In the kidney,
tubular epithelial cells are considered to be a prominent source of
chemokines [21]. MCP-1 and RANTES are two key chemokines
that recruit monocytes/ macrophages to the kidney [22,23].
Many mediators, including transformation growth factor-beta1
(TGF-beta1), epidermal growth factor (EGF), and platelet-derived
whether suramin is able to interfere with those signaling pathway
and inactivation of NF-kappaB in the remnant kidney.
In this study, we examined the effect of suramin on glomerula
and vascular sclerosis, and inflammatory cell infiltration in th
remnant kidney model. Further, we investigated the effect o
suramin on the expression of MCP-1 and RANTES and th
activation of growth factor receptors/ intracellular signaling path
ways associated with the development of progressive renal injury
Figure 1. Effect of suramin on glomerular sclerosis in rat remnant kidney. (A) Photomicrographs Photomicrographys (4006 ) illustratin
periodic acid-Schiff-stained sections of kidney tissue on week 4 after various treatments as indicated. (B) Photomicrographs (4006 ) illustratin
trichrome stained kidney tissue on week 4 after various treatments. RK, remnant kidney.
doi:10.1371/journal.pone.0036194.g001
Suramin
Liu et al, 2012
86. Sheffield Kidney Institute
Transglutaminase stabilisation of collagen
Extract
Collagen I
Radio label
Fibril
assembly
Transglutaminase
MMP1
MMP1
Count released
(Collagen degradation)
Johnson et al, JCI 1999
87. Sheffield Kidney Institute
TG2 Crosslink product
Johnson et al, 1997, 2003
Epsilon (γ-glutamyl)-Lysine dipeptide bonds
Diabetic nephropathy
96. Sheffield Kidney Institute
Human Pharmacology (Phase 1)
• First human doses – usually healthy volunteers
• Estimation of initial safety and tolerability
– Dose range
– Single and multiple doses
• Pharmacokinetics (PK)
• Pharmacodynamics (PD)
99. Sheffield Kidney Institute
Therapeutic Exploratory (Phase 2)
• “Proof of concept” (POC)
• Early testing of efficacy
• Narrow inclusion and exclusion criteria
• Small number of patients
• Dose and dose regimen for phase 3
• Multiple endpoints
105. Sheffield Kidney Institute
Therapeutic Confirmatory (Phase 3)
• To demonstrate therapeutic benefit
• To demonstrate safety in a large cohort
• Extended exposure
• To provide adequate basis for marketing
approval
• Typically RCT design
– Multicentre
– Multinational
And when we look at the so-called CKD “epidemic” in the US; those with CKD are older people and again 35% of those over 70 have CKD.
NOTES FOR PRESENTERS:
Key points to raise:
The graph above illustrates a rise in recorded prevalence of CKD stages 3–5 arising from the inclusion of a CKD indicator set within the primary care quality and outcomes framework from April 2006.
In preparation for the inclusion of CKD within the QOF, from April 2005 laboratories began to provide estimated glomerular filtration rates (eGFR) (an indication of CKD) alongside routine serum creatinine testing results.
The five-stage classification system for CKD was introduced into the UK in 2001.
In the year to March 2007 approximately 1.5 million people in England were diagnosed with CKD (Department of Health 2007).
It is estimated that there are approximately 2 million unrecorded cases of CKD in England (Information Centre analysis of a sample of anonymised GP patient records using IMS Disease Analyzer).
Additional information:
Between April 2001 and 2004 facilities for identifying CKD using eGFR were not freely available.
Related NICE guidance includes:
Type 2 diabetes: the management of type 2 diabetes (update). NICE clinical guideline 66 (2008).
Anaemia management in people with chronic kidney disease. NICE clinical guideline 39 (2006).
Hypertension: management of hypertension in adults in primary care. NICE clinical guideline 34 (partial update of NICE clinical guideline 18) (2006).
This guidance sits within the following policy context:
Department of Health (2007) Vascular disease – briefing pack for strategic health authorities
Department of Health (2007) The national service framework for renal services: second progress report
Department of Health (2006) Supporting people with long-term conditions to self-care: a guide to developing local strategies and good practice
Department of Health (2005) Renal services information strategy: supporting part two of the national service framework for renal services
Department of Health (2005) National service framework for renal services - Part two: chronic kidney disease, acute renal failure and end of life care
Department of Health (2005) Supporting people with long term conditions: an NHS and social care model to support local innovation and integration
Department of Health (2001) National service framework for diabetes: standards
Same prevalence in the UK as shown by the Neoerica study; hardly anybody suffering from CKD under the age of 55 but up to 40-50% of those over 75 have “CKD”
