1. Saddam Hassan
lecturer of Nephrology
Nephrology UNIT
Benha University
saddamnephro@yahoo.com

3. Metformin Lakes

4. “ From Bench to Bedside “
Glomerular or Tubuloglomerular?
“ Conventional Paradigm “
Does Benefit justify Risk ?
“ Opportunities or Challenges “
Multi-Pathway Signal Blockade ?

5. “ From Bench to Bedside “
Glomerular or Tubuloglomerular?

6. The 5-Staged model of DKD
A1 A2 A3
T1DM Natural History

7.  Albuminuria (A2)
“Micro”:
 Highly Variable:
(Ontarget)
Spontan.regression (30%).
 “Non-Proteinuric”
Phenotype (30%)/
RIACE (55%>>> F/CVD)
 Low Specificity:
Competing risk
(MACE & MAKE)
 Renal Endpoint?
(ME Molitch et al.
KI 2014)
 Albuminuria (A1)
“Normo”:
 High Normal UAER:
Increased risk of
MACE/MAKE!
(Babazono et al.
Diabetes Care 2009)
A1 A2 A3

8. A1 A2 A3
Cr-Based eGFR
U-shaped Mortality Curve
 Low eGFR:
 CVD + Renal Mortality(1)
 High eGFR
(Hyperfiltration):
 CVD Mortality(2)
Cyst.C-Based eGFR
Better predicts
 death & prog. to
ESRD(3)
(ME Molitch et al., KI 2014)
(Fox et al., Lancet 2012)
(de Boer et al.,
Diab Care 2009)

9. Biomarker?
Functional vs Structural
(RPS Classif.2010)

10. The 5-Staged model of DKD
Biomarker?
(RPS Classif.2010)
∆𝐴𝐸𝑅 ≠
∆Biopsy
∆GFR

11. A new player in the town
?
“Verifying Biopsy”

13. CRIC study

14. In search of new Biomarkers…
“Epigenetics”

15. “ From Bench to Bedside
“
Glomerular or Tubuloglomerular?

16. “Glomerulo”/centric
DKD
“TubuloGlomerular DKD”

17. Albuminuria: “The Holy Grail
“?

20. “ From Bench to Bedside
“
Glomerular or Tubuloglomerular?

22. SGLT2:
 S1 PCT
 low-affinity
 high-capacity
 90%
Gl.Absorb.
SGLT1:
 S2,3
PCT/GIT
 High-affinity
 Low-capacity
TubuloGlomerular Feddback:
“ Cross Talks “?
Tahrani et al. Lancet 2011

23. TubuloGlomerular Feddback:
“ Cross Talks“?

24. TubuloGlomerular Feddback:
“ Cross Talks“ ?

25. TubuloGlomerular Feddback:
“ Cross Talks“ ?

26. TubuloGlomerular Feddback:
“ Cross Talks“ ?

27. TubuloGlomerular Feddback:
“ Salt Paradox“?
Richard Gilbert KI 2013

29. “Tubulo”/centric DN
“Tubulopathic DKD ?”
Volker Vallon
Nephron Clin Pract
2014

30. “ From Bench to Bedside “
One-size-fits-all Approach?
“ Conventional Paradigm “
Number-tunneled vs Patient-centered?
“ Opportunities or
Challenges “
Multi-Pathway Signal Blockade

33. Conventional
wisdom:

35. RAAS Blockade:
The Mantra ?Target Dose?
Salt restriction
Dual Blockade
VDR
Analogues
Sara Roscioni Nature Nephrology 2013

36. RAAS Blockade:
“Challenging the Dogma?”
OnTarget:
Telmisartan
+ Ramipril
Va –Nephron:
Losartan+
Lisinopril
Altitude:
Aliskirin

37. You Are What You Eat ?
“Salt Paradox”
David Charytan &
John Forman
KI 2012

38. RAAS Blockade:
Optimizing the response
?

39. RAAS BLOCKADE:
The Holy Grail?
“Opposite View”
 “Imperfect ?”
 Breakthrough/Escape
“phenomenon”
 Non-proteinuric Progressors
 Ischemic Nephropathy (25-30%).
 “Deleterious ?” :
 Early: AKI ”s” !!
(Ontarget)/)(Roadmap)
 Late: SORO-ESRD !!
(Maculay Ongabli/Nahas)
Macaulay Onuigbo
Nephron Clin Pract
2011

41. BP Targets:
Less prescriptive & More Personalized!

42. Uric Acid ?

43. wisdom:
“Challenging the
Dogma?”

44. You Are What You Eat ?
“ Sweet Debate ”

45. Dysglycemia
?
 AKI.
 CKD.

46. Glycemic Control:
“Monitoring= eAG”
 Glycated Haemoglobin?
 Longer duration
 Surrogate used in major Trials
 Glycated Albumin?
 Fructosamine (AlbF)?
Contin. Gluc. Monitoring(CGM)
(Marijn Speeckaert et al., ERPB, NDT, 2014)

47. Glycemic Control:
“Monitoring”
 HBA1c!!

49. 90 day mortality: IIT:(27.5%), CIT: (24.9%)
Absolute mortality difference: 2.6%
Odds ratio for death with IIT was 1.14 .
Glycemic Control:
in AKI: “ NICE SUGAR ”

50. Short-term
HYPERGLYCEMIA:
“ DYSGLYCEMIC PEAKS“?

51. Glycemic Control:
CKD
“Act Now or Pay Later”
Mortality & HbA1c
 U-shaped curve
HbA1c ( ) 6.5% -- 9 %
 CKD-ND
(Arch Intern Med 2011)
 CKD5-HD
(Diabetes care 2012)
 CKD5-PD
DOPPS (JASN 2011) & (KI 2012)
 HbA1c > 8% pretransplant
Tx ??
(Molnar et al. Diabetes Care 2011)
Observational
studies

52. All-cause mortality
23,618 DM on Hd

53. Glycemic Control:
“Act Now >> T1DM:
DCCT/EDIC”

54. Glycemic Control:
“Act Now >> T2DM: UKPDS”
Holman NEJM 2008

55. Posthoc
Subgroup
Analysis
“Intensive Glycemic Control”:
Do the Benefits justify the Risks
?
Excess
ALL-Cause/
CVD mortality
Munehro et al., WJD,2014
Soft
Surrogates

56. Act Now !
 Metabolic Memory?
 (UKPDS)
 Legacy effect?
 (DCCT/EDIC)
 microRNAs?
Pay Later !
 Burnt out DKD ?
 (ACCORD).
 (ADVANCE/ON).
 (VADT).
Glycemic Control:
“Act Now or Pay Later”

57.  Age
 B.W
 Complication
 Duration
 Expectancy
ADA/AHA position statement 2014:
Skyler (Diabetes Care 2009)

58. You Are What You Lose
?
 “Weight Reduction”

59. NODAT

60. NODAT
Adnan Sharif and Keshwar Baboolal 2012, Nature reviews

61. NODAT

62. Metformin:
Reappraisal
SGLT2i:
New Promises
“Crescedence”0

63. wisdom:
“Challenging the
Dogma?”

64. (1 B) : CKD-ND & RTx : Statin +/- Ezetimibe.
Posthoc
Subgroup
Analysis
MACE
reduction
Not
Renal
endpoints
Negative outcomes:
4D
AURORA
SHARP
CKD-D: Non-Start Non-Stop Policy
“Not to initiate” (1B) !

65. KDOKI 2012 :
(1 B) : CKD-ND & CKD-RTx : Statin +/- Ezetimibe.
(1B) : CKD-D: Non-Start Non-Stop Policy
“Not to initiate” !
Posthoc
Subgroup
Analysis
MACE
reduction
Not
Renal
endpoints

66. CKD-D: Non-Start Non-Stop Policy
“Not to initiate” (1B) !
Low
“signal to noise”
phenemenon

67. Lipid management:
Diabetogenicity of
Statins

68. “ From Bench to Bedside “
One-size-fits-all Approach?
“ Conventional Paradigm “
Number-tunneled vs Patient-centered?
“ Opportunities or
Challenges “
Multi-Pathway Signal Blockade

69. MSPB ?
Multiple Signal Pathway
Blockade?
Pleiotropic?
context -
specific
limited?

70. Beatriz et al., Nature Reviews 2014
Novel Approaches to DKD

71. Pleiotropic?
context -
specific
limited?
Novel Approaches to DKD

72. In Summary….
 Care
for
Glomerulus
but
Mind the
Tubules !