prof. Ahmed Shokr Professor of kidney disease and director of kidney transplant program.- Saskatchewan University MNDU 8

1. RATE of KIDNEY FUNCTION
DECLINE (KFD) and
SUBSEQUENT ESRD
Ahmed Shoker

3. KFD
•Aim:
• Highlight SIGNIFICANCE of rate of
kidney function decline (KFD) as a
potential Predictive outcome
measure to manage and study CKD
progression to ESRD, and perhaps
for the study of CKD in Egypt
• as highlighted in the 2016 ISN Global kidney health Summit
outputs published in KI , volume 7, issue 2, October 2017 and
thereafter

4. Kidney function decline
•Background:
• ISN Global kidney health Summit
outputs published in KI , volume
7, issue 2, October 2017

5. KFD
•Background
• Output of summit included
suggested plans to :
• 1) determine and monitor prevalence of
CKD

6. KFD
•Background
• Output of summit included suggested plans to :
• 2) Genetic and environmental risk factors for CKD
• Heavy metals
• Agriculture chemicals
• Occupational exposure
• Traditional herbals
• Sugary beverages
• Salty foods
• Infections

7. Kidney function decline
•Background
• Output of summit included suggested
plans to :
• 3) Closing the gap between evidence and practice in
CKD
• 4) Systemic kidney disease and complications
associated with decline in kidney function
• 5) Establish and validate novel therapeutic targets
to retard progression of CKD
• 6) optimize design of clinical trials in CKD

8. Kidney Function decline
•Background
• Output of summit included suggested
plans to :
• 7) Strategies to improve
monitoring disease progression,
assessing CVD risk, and defining
prognostic biomarkers in CKD

9. KFD
•Aim:
• Highlight SIGNIFICANCE of rate of
kidney function decline (KFD) as a
potential predictive outcome
measure to study CKD
progression to ESRD, and perhaps
for the study of CKD in Egypt.

10. KFD
• GFR
TIME
Threshold for intervention
Rate of decline in kidney function=
delta change in GFR per time unit

11. KFD
•Aim:• highlight SIGNIFICANCE of rate of kidney function decline (KFD) as a potential predictive
outcome measure to study CKD progression to ESKD, and perhaps for the study of CKD in
Egypt.
•Q # 1
•Why is the focus on
Study of CKD?

12. KFD
•Quiz
• In population studies of kidney disease, what is
the percentage of CKD patients who will make it
to ESRD
• 1-2 %
• 10- 20 %
• 40- 60%
• 70- 80 %
• 90%

13. KFD
• Incidence/Prevalence of ESRD,
• 150/1800 per million= .0001%
• Incidence/ Prevalence of CKD= 3- 11%
• Ratio (Incidence/Prevalence) of ESRD/CKD=
• 1/500
• 1/1000
• eGFR< 60 ml/min is attributed to 4% of
deaths worldwide
• Thomas B, JASN, 2017

14. Risk of nephrectomy
• Study natural history of CKD in 27,998 with
eGFR below 90 ml/m
• 5 yrs follow up
• ESRD= 1.1% (stage 2) ****Mortality= 19.5%
• ESRD= 1.3% (stage 3) ****mortality= 24.3%
• ESRD= 19.9% (stage 4)****Mortality= 45.7%
• Conclusion” Only 2% will progress to ESRD”
• Keith D,et al
• Arch Intern Med 2004;164: 659

15. KFD
• Why is the focus on CKD?
• 1) 9 out of 10 will die before ESRD
• 2) Manage CKD differs by stage
• 3) High prevalence of CKD and it’s association
with modifiable causes and increased CVD
and mortality rates, long before dialysis
• 4) Early intervention and avoidance of
nephrotoxic exposure can be done

16. KFD
• Why is the focus on CKD?, because; Early intervention
before it’s to late
•Q #2
• Can we predict patients who progresses
to ESRD/ high risk mortality?
•Q # 3
• Can we develop Predictor outcome
measures ( ESRD, etc) for clinical studies
and patient management with CKD?

17. Kidney function decline
•The story of
potential outcome
measures in CKD

18. KFD
• Outcome measures in nephrology clinical studies
• Differs between CKD/ HD/ PD/TX
• Different priorities of Pts, clinicians, researchers,
caregivers
• Outcome: is something that can be measured, and
can arise or change because of a health condition or
treatment
• Core outcome set: is an agreed standardized set of
outcomes that should be measured and reported,
as a minimum, in all clinical trials in specific areas of
health or health care. Researchers may add other
outcomes to the core outcome set
• Nistor, NDT, 2017

19. KFD
• Standardized Outcomes In Nephrology (SONG)
• Initiative to establish set of outcome measures
• SONG- Tx
• SONG- Kids
• SONG-PD
• SONG-CKD
• SONG- PCKD
• SONG handbook,2017
• Transplant, 2017
• Tong, A. NDT, 2017

20. Kidney function decline
•The story of rate of kidney
function decline (KFD) as a
potential predictive
outcome measure for
subsequent ESRD

22. Kidney Function Decline
• Mean rates ( ml/min/yr) of eGFR decline ( is variable, but
constantin individual pts)
• DM .0 - 12.6
• IGA 1.4 - 9.5
• MN 4.6 - 9.5
• Chronic GN 2 - 10.4
• TID 2 - 5.4
• PCKD 3.8- 5.4
•Q # 4
• Can we grade rates of kidney function
declines into slow/ fast? to use as
outcome measure in the study CKD?

23. KFD
• Meta-analysis of 1.7 million pts
• Adjusted HR for ESRD, mortality were
higher for larger decline in eGFR over 1-
3 yrs
• JAMA, 2014,, Coresh et al

24. KFD
• AHR of ESRD for Pts with eGFR
decline over 2 yrs of
• > 57% = ESRD of 32.1
• > 30% = ESRD of 6.9
• < 30% = ESRD of 5.4
• AHR for patient mortality adjusted
for 10 yrs were similar

25. KFD
• 1) Decline in EGFR smaller than doubling SCr
occurs more commonly
• And strongly associate with risk for ESRD
• 30% reduction in eGFR over 2 years is
alternative end point for CKD progression in
10 yrs.
• JAMA, 2014,, Coresh et al
• Inker, Am j Kid Dis, 2014
• Badve,NDT,2015
• PLoS One, Tsai,2017

26. KFD
•Definition of rapid
progression as rate of
eGFR > 5 ml/min/yr.
• KI,91,issue6, june2017

27. KFD
• FDA accepts 30%- 40% decline in eGFR over
2- 3yrs in eGFR as an end point in clinical
studies
• Acceptable, shorter duration, smaller
population and simple and cheap target
• Coresh, JAMA, 2014
Coresh, JASN 2016: 27;2447
• Badve, NDT,,2016
• Carlesson CJASN, 2017. vol12
•

28. KFD
•The story of rate of kidney
function decline (KFD) as a potential
predictive outcome measure for
subsequent ESRD Continues

30. Patterns of progression of chronic
kidney disease at later stages
Fernando Caravaca-Fontán Lilia Azevedo Enrique
Luna Francisco Caravaca
Clinical Kidney Journal,
sfx083, https://doi.org/10.1093/ckj/sfx083
Published:
28 July 2017
Conclusions: A majority of patients with advanced CKD show patterns of renal function
decline different from linear, and several of the main determinants of CKD progression
are potentially modifiable.

31. From: Patterns of progression of chronic kidney disease at later stages
Clin Kidney J. Published online July 28, 2017. doi:10.1093/ckj/sfx083
Clin Kidney J | © The Author 2017.

32. From: Patterns of progression of chronic kidney disease at later stages
Clin Kidney J. Published online July 28, 2017. doi:10.1093/ckj/sfx083
Clin Kidney J | © The Author 2017.

33. Fast renal decline to end-stage renal
disease: an unrecognized feature of
nephropathy in diabetes.
Krolewski AS1, Skupien J2, Rossing P3, Warram JH4.
Kidney Int. 2017 Jun;91(6):1300-1311. doi:
10.1016/j.kint.2016.10.046. Epub 2017 Mar 31.

34. Distribution of categories of progressive renal decline during 6–10 years of
follow-up in patients with type 1 diabetes and type 2 diabetes in the Joslin
Kidney Studies according to category of albuminuria at entry into follow-up

35. Distribution of categories of progressive renal decline during 6–10 years of
follow-up in patients with type 1 diabetes and type 2 diabetes in the Joslin
Kidney Studies according to category of albuminuria at entry into follow-up

36. Figure 3
Kidney International 2017 91, 1300-1311DOI: (10.1016/j.kint.2016.10.046)
Copyright © 2017 International Society of Nephrology

37. Kidney function decline
• Definition of rapid progression as
rate of eGFR > 5 ml/min/yr.
• Newer definitions; very fast, fast,
moderate and slow
• KI,91,issue6, june2017

38. KFD
Suggested outcomes in measuring kidney disease
status in randomized studies
• eGFR > 45 ml/min ( Stages G1- G3a) :
• slope of eGFR or surrogate biomarkers
• Rapid progression = 30- 40 % decline over 2yrs
• Later stages.
• Slow progression = 30%- 40% decline in eGFR
• Rapid progression = > than 40% decline in GFR
• Baigent. KI, 92, 297

39. KFD
• Limitations of rate of KFD as an outcome
measure
• 1) Is the rate of decline in eGFR linear?
• 22-18% Non linear in PCKD
• 20% in DM
• 30% in GN
•Q # 5
• Can we improve on rate of KFD as
outcome measure?

40. KFD
• Limitations of rate of KFD as an outcome
• 1) Is the rate of decline in eGFR linear?
• 22-18% Non linear in PCKD
• 20% in DM
• 30% in GN
•Q # 6
• Can we further, improve on rate
of KFD as measure of progressive
CKD?

41. KFD
• Contribution of past decline VS current eGFR
and subsequent risk of ESKD
• eGFR decline of 18 ml/min /3 yrs
• AHR of 2.28
• Current eGFR of 30 ml VS 50 ml= AHR of 19.9
• Conclusion; Current eGFR and rate of decline
contribute to risk of ESRD
• Kovesdy, JASN. 2017

42. KFD
•Q # 7
• To what extend proteinuria predicts
progressive decline in eGFR???
• Remains controversial
• Proteinuria course may not be linear
• Need for improved outcome measures using
biomarkers

43. Distribution of GFR slope/ yr. and
proteinuria in the AASK study

44. Mild albuminuria is a risk factor for GFR decline in nondiabetic
normal population. Melsom,KI,2018
Optimum
ACR< 3.4
mg/mmol is
too high
ACR of .11-
.12
mg/mmol
has a .28
ml/min/yr.
steeper rate
of FGR
decline than
< .1
mg/mmol

45. Cardiovascular Disease Biomarkers
and suPAR in Predicting Decline in
Renal Function: A Prospective
Cohort Study
Salim S.Hayek1Yi
AnKo12MosaabAwad1HinaAhmed1BrandonGray1Kareem
MohammedHosny1HiroshiAida1Melissa
J.Tracy3ChangliWei3SanjaSever4JochenReiser3Arshed A.
Discussion
hs-CRP, FDP, HSP-70, and hs-TnI were not associated with eGFR decline. The
specific association of suPAR with eGFR decline supported its involvement in
pathways specific to the pathogenesis of kidney disease.

46. Figure 5
Kidney International 2017 91, 1300-1311DOI: (10.1016/j.kint.2016.10.046)
Copyright © 2017 International Society of Nephrology

47. KFD
• Plasma high- sensitive troponin T
predicts ESRD and CVD and All
Cause mortality in DM
• Desai. AM J Kidney disease
• Galsgaard. KI, 2017

48. Saulnier, diabetes care, 2017

49. Prospective study of association of circulating biomarkers (
Adrenomodulin, sTNFR1, and N- terminal prohormone brain naturetic
peptide) with renal function decline in DM type 2
1,135 pts,
GFR 76
ml/min
RFL= > 40%
decline in
GFR
Rapid
decline=
slope < -5
ml/min/yr.
diabetes
care, 2017

50. KFD Conclusions
• CKD has Variable course
• 9 out of 10 will die before reaching ESRD
• eGFR and albumin/Cr ratio slopes are
good outcome measures to study kidney
disease progression
• Surrogate biomarkers can be added to
study protocols on disease progression

51. KFD
•Conclusions
• Rates of decline in eGFR,
albumin/creatinine ratio and
biomarkers can be implemented
in National Egyptian studies as a
priority over isolated
biochemical/ molecular studies