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Saddam Hassan
lecturer of Nephrology
Nephrology UNIT
Benha University
saddamnephro@yahoo.com
Metformin Lakes
“ From Bench to Bedside “
Glomerular or Tubuloglomerular?
“ Conventional Paradigm “
Does Benefit justify Risk ?
“ Opportun...
“ From Bench to Bedside “
Glomerular or Tubuloglomerular?
The 5-Staged model of DKD
A1 A2 A3
T1DM Natural History
 Albuminuria (A2)
“Micro”:
 Highly Variable:
(Ontarget)
Spontan.regression (30%).
 “Non-Proteinuric”
Phenotype (30%)/
R...
A1 A2 A3
Cr-Based eGFR
U-shaped Mortality Curve
 Low eGFR:
 CVD + Renal Mortality(1)
 High eGFR
(Hyperfiltration):
 CV...
Biomarker?
Functional vs Structural
(RPS Classif.2010)
The 5-Staged model of DKD
Biomarker?
(RPS Classif.2010)
∆𝐴𝐸𝑅 ≠
∆Biopsy
∆GFR
A new player in the town
?
“Verifying Biopsy”
CRIC study
In search of new Biomarkers…
“Epigenetics”
“ From Bench to Bedside
“
Glomerular or Tubuloglomerular?
“Glomerulo”/centric
DKD
“TubuloGlomerular DKD”
Albuminuria: “The Holy Grail
“?
“ From Bench to Bedside
“
Glomerular or Tubuloglomerular?
SGLT2:
 S1 PCT
 low-affinity
 high-capacity
 90%
Gl.Absorb.
SGLT1:
 S2,3
PCT/GIT
 High-affinity
 Low-capacity
TubuloGlo...
TubuloGlomerular Feddback:
“ Cross Talks“?
TubuloGlomerular Feddback:
“ Cross Talks“ ?
TubuloGlomerular Feddback:
“ Cross Talks“ ?
TubuloGlomerular Feddback:
“ Cross Talks“ ?
TubuloGlomerular Feddback:
“ Salt Paradox“?
Richard Gilbert KI 2013
“Tubulo”/centric DN
“Tubulopathic DKD ?”
Volker Vallon
Nephron Clin Pract
2014
“ From Bench to Bedside “
One-size-fits-all Approach?
“ Conventional Paradigm “
Number-tunneled vs Patient-centered?
“ Opp...
Conventional
wisdom:
RAAS Blockade:
The Mantra ?Target Dose?
Salt restriction
Dual Blockade
VDR
Analogues
Sara Roscioni Nature Nephrology 2...
RAAS Blockade:
“Challenging the Dogma?”
OnTarget:
Telmisartan
+ Ramipril
Va –Nephron:
Losartan+
Lisinopril
Altitude:
Alisk...
You Are What You Eat ?
“Salt Paradox”
David Charytan &
John Forman
KI 2012
RAAS Blockade:
Optimizing the response
?
RAAS BLOCKADE:
The Holy Grail?
“Opposite View”
 “Imperfect ?”
 Breakthrough/Escape
“phenomenon”
 Non-proteinuric Progre...
BP Targets:
Less prescriptive & More Personalized!
Uric Acid ?
wisdom:
“Challenging the
Dogma?”
You Are What You Eat ?
“ Sweet Debate ”
Dysglycemia
?
 AKI.
 CKD.
Glycemic Control:
“Monitoring= eAG”
 Glycated Haemoglobin?
 Longer duration
 Surrogate used in major Trials
 Glycated ...
Glycemic Control:
“Monitoring”
 HBA1c!!
90 day mortality: IIT:(27.5%), CIT: (24.9%)
Absolute mortality difference: 2.6%
Odds ratio for death with IIT was 1.14 .
G...
Short-term
HYPERGLYCEMIA:
“ DYSGLYCEMIC PEAKS“?
Glycemic Control:
CKD
“Act Now or Pay Later”
Mortality & HbA1c
 U-shaped curve
HbA1c ( ) 6.5% -- 9 %
 CKD-ND
(Arch Inte...
All-cause mortality
23,618 DM on Hd
Glycemic Control:
“Act Now >> T1DM:
DCCT/EDIC”
Glycemic Control:
“Act Now >> T2DM: UKPDS”
Holman NEJM 2008
Posthoc
Subgroup
Analysis
“Intensive Glycemic Control”:
Do the Benefits justify the Risks
?
Excess
ALL-Cause/
CVD mortalit...
Act Now !
 Metabolic Memory?
 (UKPDS)
 Legacy effect?
 (DCCT/EDIC)
 microRNAs?
Pay Later !
 Burnt out DKD ?
 (ACC...
 Age
 B.W
 Complication
 Duration
 Expectancy
ADA/AHA position statement 2014:
Skyler (Diabetes Care 2009)
You Are What You Lose
?
 “Weight Reduction”
NODAT
NODAT
Adnan Sharif and Keshwar Baboolal 2012, Nature reviews
NODAT
Metformin:
Reappraisal
SGLT2i:
New Promises
“Crescedence”0
wisdom:
“Challenging the
Dogma?”
(1 B) : CKD-ND & RTx : Statin +/- Ezetimibe.
Posthoc
Subgroup
Analysis
MACE
reduction
Not
Renal
endpoints
Negative outcome...
KDOKI 2012 :
(1 B) : CKD-ND & CKD-RTx : Statin +/- Ezetimibe.
(1B) : CKD-D: Non-Start Non-Stop Policy
“Not to initiate” !
...
CKD-D: Non-Start Non-Stop Policy
“Not to initiate” (1B) !
Low
“signal to noise”
phenemenon
Lipid management:
Diabetogenicity of
Statins
“ From Bench to Bedside “
One-size-fits-all Approach?
“ Conventional Paradigm “
Number-tunneled vs Patient-centered?
“ Opp...
MSPB ?
Multiple Signal Pathway
Blockade?
Pleiotropic?
context -
specific
limited?
Beatriz et al., Nature Reviews 2014
Novel Approaches to DKD
Pleiotropic?
context -
specific
limited?
Novel Approaches to DKD
In Summary….
 Care
for
Glomerulus
but
Mind the
Tubules !
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
Diabetic kidney disease " Challenging the Dogma"
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Diabetic kidney disease " Challenging the Dogma"

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Diabetic kidney disease " Challenging the Dogma"

  1. 1. Saddam Hassan lecturer of Nephrology Nephrology UNIT Benha University saddamnephro@yahoo.com
  2. 2. Metformin Lakes
  3. 3. “ From Bench to Bedside “ Glomerular or Tubuloglomerular? “ Conventional Paradigm “ Does Benefit justify Risk ? “ Opportunities or Challenges “ Multi-Pathway Signal Blockade ?
  4. 4. “ From Bench to Bedside “ Glomerular or Tubuloglomerular?
  5. 5. The 5-Staged model of DKD A1 A2 A3 T1DM Natural History
  6. 6.  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
  7. 7. 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)
  8. 8. Biomarker? Functional vs Structural (RPS Classif.2010)
  9. 9. The 5-Staged model of DKD Biomarker? (RPS Classif.2010) ∆𝐴𝐸𝑅 ≠ ∆Biopsy ∆GFR
  10. 10. A new player in the town ? “Verifying Biopsy”
  11. 11. CRIC study
  12. 12. In search of new Biomarkers… “Epigenetics”
  13. 13. “ From Bench to Bedside “ Glomerular or Tubuloglomerular?
  14. 14. “Glomerulo”/centric DKD “TubuloGlomerular DKD”
  15. 15. Albuminuria: “The Holy Grail “?
  16. 16. “ From Bench to Bedside “ Glomerular or Tubuloglomerular?
  17. 17. 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
  18. 18. TubuloGlomerular Feddback: “ Cross Talks“?
  19. 19. TubuloGlomerular Feddback: “ Cross Talks“ ?
  20. 20. TubuloGlomerular Feddback: “ Cross Talks“ ?
  21. 21. TubuloGlomerular Feddback: “ Cross Talks“ ?
  22. 22. TubuloGlomerular Feddback: “ Salt Paradox“? Richard Gilbert KI 2013
  23. 23. “Tubulo”/centric DN “Tubulopathic DKD ?” Volker Vallon Nephron Clin Pract 2014
  24. 24. “ From Bench to Bedside “ One-size-fits-all Approach? “ Conventional Paradigm “ Number-tunneled vs Patient-centered? “ Opportunities or Challenges “ Multi-Pathway Signal Blockade
  25. 25. Conventional wisdom:
  26. 26. RAAS Blockade: The Mantra ?Target Dose? Salt restriction Dual Blockade VDR Analogues Sara Roscioni Nature Nephrology 2013
  27. 27. RAAS Blockade: “Challenging the Dogma?” OnTarget: Telmisartan + Ramipril Va –Nephron: Losartan+ Lisinopril Altitude: Aliskirin
  28. 28. You Are What You Eat ? “Salt Paradox” David Charytan & John Forman KI 2012
  29. 29. RAAS Blockade: Optimizing the response ?
  30. 30. 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
  31. 31. BP Targets: Less prescriptive & More Personalized!
  32. 32. Uric Acid ?
  33. 33. wisdom: “Challenging the Dogma?”
  34. 34. You Are What You Eat ? “ Sweet Debate ”
  35. 35. Dysglycemia ?  AKI.  CKD.
  36. 36. 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)
  37. 37. Glycemic Control: “Monitoring”  HBA1c!!
  38. 38. 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 ”
  39. 39. Short-term HYPERGLYCEMIA: “ DYSGLYCEMIC PEAKS“?
  40. 40. 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
  41. 41. All-cause mortality 23,618 DM on Hd
  42. 42. Glycemic Control: “Act Now >> T1DM: DCCT/EDIC”
  43. 43. Glycemic Control: “Act Now >> T2DM: UKPDS” Holman NEJM 2008
  44. 44. Posthoc Subgroup Analysis “Intensive Glycemic Control”: Do the Benefits justify the Risks ? Excess ALL-Cause/ CVD mortality Munehro et al., WJD,2014 Soft Surrogates
  45. 45. 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”
  46. 46.  Age  B.W  Complication  Duration  Expectancy ADA/AHA position statement 2014: Skyler (Diabetes Care 2009)
  47. 47. You Are What You Lose ?  “Weight Reduction”
  48. 48. NODAT
  49. 49. NODAT Adnan Sharif and Keshwar Baboolal 2012, Nature reviews
  50. 50. NODAT
  51. 51. Metformin: Reappraisal SGLT2i: New Promises “Crescedence”0
  52. 52. wisdom: “Challenging the Dogma?”
  53. 53. (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) !
  54. 54. 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
  55. 55. CKD-D: Non-Start Non-Stop Policy “Not to initiate” (1B) ! Low “signal to noise” phenemenon
  56. 56. Lipid management: Diabetogenicity of Statins
  57. 57. “ From Bench to Bedside “ One-size-fits-all Approach? “ Conventional Paradigm “ Number-tunneled vs Patient-centered? “ Opportunities or Challenges “ Multi-Pathway Signal Blockade
  58. 58. MSPB ? Multiple Signal Pathway Blockade? Pleiotropic? context - specific limited?
  59. 59. Beatriz et al., Nature Reviews 2014 Novel Approaches to DKD
  60. 60. Pleiotropic? context - specific limited? Novel Approaches to DKD
  61. 61. In Summary….  Care for Glomerulus but Mind the Tubules !

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