Diabetic nephropathy, patho physiology update

first DNG meeting
Prof. Ashraf Talaat

1. Diabetic Nephropathy:
Update Pathophysiology
Ashraf Talaat,MD.
Banha Faculty of Medicine
Nephrology,Diabetes&Endocrinology Units

2. Global Epidemic of Type 2
Diabetes
•Aging Population
•Global Lifestyle “Westernization”
•Surging Obesity

3. The facts
•Almost one in three people with type 2
diabetes develops overt kidney disease.
•Diabetes is the single most common cause of
end stage renal failure.
•Kidney disease accounts for 21 per cent of
deaths in type 1 and 11 per cent of deaths in
type 2.

4. Russo E, et al. Diabetes Metab Syndr Obes. 2013; 6: 161–170.

5. *Per 100,000
http://www.worldlifeexpectancy.com/cause-of-death/kidney-disease/by-country/
accessed 2012 Oct.

6. Afkarian M et al., J Am Soc Nephrol. 2013
Feb;24(2):302-8

7. Definition of Diabetic Nephropathy
•Persistent albuminuria from 3 to 6 months in at
least two out of three consecutive urine
collections,with longstanding history of diabetes.
•With presence of Diabetic retinopathy
,hypertention & decreased eGFR.
•With absence of clinical or laboratory evidence of
other kidney or urinary system diseases.

8. Why is Diabetic Nephropathy
Important?

9. What are Diabetics with Nephropathy Dying From?
Stroke
Myocardial
Infarction
Heart
Failure
Sudden
Death
©2005. American College of Physicians. All Rights Reserved.

10. What is the Natural History of
Diabetic Nephropathy?

11. Stages of
Progression and
Natural History of diabetic nephropathy

13. Stages of Diabetic Nephropathy
Stage I II III IV V
GFR
H H H L L
uAER
N HN MIA MAA MAA
BP
N N HN H H
Hypertrophy
+ ++ +++ + +/-
BM thicken.
N + ++ +++ +++
Mesang. Expan.
N +/- ++ +++ +++
G.Closure & A. hyalinosis
N N N ++ +++

15. A1 A2 A3
Normal to
mildly
increased
Moderately
increased
Severely
increased
<30 mg/g
<3 mg/mmol
30-300 mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
•CKD is defined as abnormalities of kidney structure or function, present for >3 months, with
implications for health and CKD is classified based on cause, GFR category, and albuminuria
category (CGA).
KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3:136-150.
http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf Accessed February 26, 2013
G1 Normal or high ≥90
G2 Mildly decreased 60-89
G3a
Mildly to moderately
decreased
45-59
G3b
Moderately to
severely decreased
30-44
G4 Severely decreased 15-29
G5 Kidney failure <15
Persistent albuminuria categories
Description and range
Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk.
Prognosis of CKD by GFR
and Albuminuria Categories:
KDIGO 2012

16. Category
Spot collection (µg/mg
creatinine)
Normal <30
Increased urinary albumin
excretion* ≥30
ADA. VI. Prevention, Management of Complications. Diabetes Care 2014;37(suppl 1):S44; Table 11
*Historically, ratios between 30 and 299 have been called microalbuminuria and those 300
or greater have been called macroalbuminuria (or clinical albuminuria).

17. Prevalence of different stages of CKD
1st 2nd 3rd
4th 5th

18. So How Big Is The Risk In Diabetes?

19. Pathophysiology of
diabetic nephropathy

20. Factors involved in the pathophysiology of diabetic
nephropathy
Genetic susceptibility
Haemodynamic raised intraglomerular pressure
Biochemical
Growth factors
Vasoactive factors
glucose, protein kinase C, diacyl
glycerol, etc.
IGF-1, TGF-ß, connective tissue
growth factor
VEGF, angiotensins, endothelin

21. Genetic predisposition
•Genetic predisposition to or protection from diabetic
nephropathy appears to be the most important
determinant of diabetic nephropathy risk in both type 1
and type 2 diabetics.
•A polymorphism in the gene that encodes the ACE has
been associated with diabetic nephropathy
•Genes for pyrophosphatase/phosphodiesterase-1,
peroxisome proliferator-activated receptor-γ2 (PPAR-γ2),
glucose transporter 1, apolipoprotein E, and lipoprotein
lipase (HindIII) have been associated with diabetic
nephropathy risk.
•A1a12 allele of PPAR-γ2 may confer protection

22. Simple schema for the pathogenesis of diabetic nephropathy

23. Biochemical Hypothesis for diabetic
nephropathy

24. Hypertension
•In diabetics who have disordered autoregulation at the
level of the kidney, systemic hypertension can contribute to
endothelial injury.
•Systemic blood pressure levels are implicated in
progression and, as noted earlier, lack of normal
nocturnal blood pressure dipping may be implicated in
the genesis of diabetic nephropathy.
•Intensive blood pressure control has been associated with
decreased rates of progression of diabetic nephropathy in
both normotensive and hypertensive diabetics.

25. Aldosterone
Sympathetic
activation
Growth
factor
stimulation
↑TGF β, ECM
↑CTGF,PAI-1
NA
+
retention
H
2
O retention
K
+
excretion
Mg
+
excretion
Vascular
smooth muscle
constriction
↑GP
↓RBF
Angiotensin
converting
enzyme
(ACE)
Angiotensin II
Liver secretes
angiotensinogen
Kidneys secrete
renin
The Renin-Angiotensin-Aldosterone (RAA)
System activation and diabetic nephropathy
Angiotensinogen Angiotensin I
Adrenal cortex
secretes aldosterone
Blood Renin
Non ACE
AT2 R
VD
↑NO
↓ tissue
proliferation
AT1 R

26. Angiotensin II stimulates release of growth factors
through NF-B activation
Wiecek et al. Nephrol Dial Transplant (2003)
18 [Suppl 5]: v16–v20

27. Role of angiotensin II in the progression of
diabetic nephropathy – 2
The renin–angiotensin system, angiotensin receptors and their action

28. Glomerulosclerosis
Interstitial Fibrosis
Proteinuria
Renal Failure
Ventricular Hypertrophy
Cardiac Fibrosis
Contractile Dysfunction
Heart Failure

Endothelial dysfunction
Inflammation
Oxidative Stress
Aldosterone
©2005. American College of Physicians. All Rights Reserved.
Aldosterone and of Diabetic
Nephropathy

29. Protein Kinase C (PKC) and diabetic
nephropathy
Brownlee M. Nature 414: 813-820, 2001
Hyperglycaemia
DAG
Protein kinase C
eNOS↑ ET-1↑
Blood-flow
abnormalities
VEGF­
Permeability
angiogenesis
TGFb­
¯
Collagen
Fibrosis
PAI-1¯
Vascular
occlusion
NF-kB­
Pro-inflammatory
gene-expression
NAD(P)H oxidases
Multiple
effects
ROS

30. Transforming growth factor ß and
diabetic nephropathy

31. CV mortality and systolic pressure in diabetics and nondiabetic
SYSTOLIC BP
C
V

m
o
r
t
a
lit
y

r
a
t
e

p
e
r

1
0

0
0
0

p
e
r
s
o
n
-
y
r
s
Adapted from Stamler J et al Diabetes Care 1993;16(2):435-444

32. Klotho-FGF23 axis
•CKD patients sarting from stage G1 onwards have increased
vascular stiffness.
•This stiffness is related to vascular calcification.
•V.C. in CKD pts affects both intima and tunica media.
•Intimal calcification is related to atherosclerosis.
•Medial calcification is related to Klotho-FGF23 axis.

34. Górriz JL ,et al., Clin J Am Soc Nephrol. Apr 7;10(4):654-66, 2015.
Nasrallah MM, et al., Nephrol Dial Transplant, Aug; 25(8): 2679-85, 2010.

35. Chang Hu M, et al., Nephrol. Dial. Transplant.
(2012) 27 (7): 2650-2657

37. Normal Control Vs FGF23 -/- mice

38. So,
•CKD inflammation Klotho gene  decrease
in Klotho FGF23 resistance increase in FGF23 &
phosphate retension transformation of VSMC to
osteoblasts calcification of vessel wall.

39. Inflammation
•Chronic inflammation is one of the hallmarks of DKD.
–Increased secretion of MCP1 in urine
–It is triggered by the uremic status itself
–periodontal disease
–infection of vascular access for hemodialysis
–Diabetic foot
–cholecystitis

41. Klotho
•Possible strategies that can be used to increase
endogenous Klotho include:
–Control of hyperphosphatemia .
–Angiotensin II blockade.
–Vitamin D repletion .
Komaba H and Fukagawa K , Kidney International (2012) 82, 1248–1250

42. Results Valsartan/hydrochlorothiazide treatment significantly increased mean soluble
Klotho (from 432.76179 to 506.46226.8 pg/ml; P=0.01) and reduced serum phosphate
compared with amlodipine. Attained BP was similar in the two groups.
Conclusions Treatment with a RAS blocker, valsartan, is associated with an increase
in soluble Klotho, which may contribute to the BP-independent cardiorenal benefits of
these drugs in DKD.
Effect of Renin-Angiotensin System Blockade on Soluble Klotho in
Patients with Type 2 Diabetes, Systolic Hypertension, and
Albuminuria
Karalliedde J., et al., CJASN

November

07, 2013 vol. 8 no. 11 1899-1905

43. Chang Hu M, et al., Nephrol. Dial. Transplant.
(2012) 27 (7): 2650-2657

44. Other mechanisms possibly associated
with diabetic nephropathy
•ROS.
•abnormalities of the endothelin and prostaglandin
pathways .
•↓glycosaminoglycan content in basement membranes.
•Insulin resistance gene polymorphisms.
•↑Plasma levels of ICAM-1.
•↑ expression of human mesangial cell MCP-1 mRNA and
downregulation of MCP-1 receptor mRNA expression.
•↑ Plasma and urinary MCP-1 levels and fluorescent
products of lipid peroxidation and malondialdehyde
content.

45. Biomarkers of onset and progression of DN
1121 titles and abestracts screened

15 articles on 27 different biomarkers included

•Beacause of the heterogeneous quality of biomarker
studies in this field, in serum, plasma and urine, a more
rigorous evaluation of these biomarkers and validation
in larger trials are advocated.

46. New urinary biomarkers for diabetic kidney disease
•Transferrin.

•IgG.
•IgM.
•Cystanic C.

•Podocytes.
•Type IV collagen.
•Cerulospasmin.
•MAP-1.
•8-oxo-7,8 dihydro-2-
deoxyguanosine .

47. Pathology of diabetic
nephropathy
GlomerulopathyTubulopathyVascular Interstitial

48. Diabetic Glomerulopathy
•Mesangial expansion, Glomerular hypertension.
•Diffuse thickening of GBM.
•Broading of foot process, Loss of podocytes.
•Reduced slit pore proteins.
•Glomerulomegally.
•Kimmelstiel- Wilson lesion.
•Adhesion to bowman
,
s capsule.
•Neovascularization.
•Diffuse and nodular glomerosclerosis.
•Arteriolar hyalinosis .

49. Diabetic Tubulopathy
•Tubuloepithelial cell hypertrophy,
•Tubular BM thickening and reduced tubular brush border.
•Epithelial-mesenchymal transition,and the accumulation
of glycogen.
•Expansion of the interstitial space with infiltration of
various cell types, including myofibroblasts and
macrophages.
•Abnormal tubuloglomerular feedback mechanisms
•Abnormal lysosomal processin.
•Increases tubular salt reabsorption & Impaired tubular
acidification

51. Clinical diagnosis of diabetic
nephropathy
–Albuminuria.
–Diabetic retinopathy.
–No evidence for another renal disease:
•HTN, renovascular disease, SLE,
vasculitis, paraproteinemia

52. When to suspect non diabetic
nephropathy?
•Significant proteinuria with short term DM .
•Absence of retinopathy.
•Progresssive renal insufficiency occurs without
concomitant proteinuria.
•Micro/ macroscopic hematuria with dysmorphic RBCs.
•Active sediments.
•Shrunken kidneys on ultrasound .
•Coexisting illness : SLE, Hepatitis C.

53. Renal function assessment
•Urinary ACR: spot sample (mg/gm).
•24 hour urine protein.
•Serum creatinine & electrolytes.
•GFR calculated by equations ( MDRD/Cockroft-Gault)
• Renal ultrasound and Doppler .
•Serum creatinine levels should be measured and
creatinine clearance estimated annually in those patients
with diabetes without albuminuria and at least every 6
months in those with albuminuria .

54. Increases AER Decreases AER
 Strenuous exercise
 Poorly controlled DM
 Heart failure
 UTI
 Acute febrile illness
 Uncontrolled HPT
 Haematuria
 Menstruation
 Pregnancy
 NSAIDs
 ACE inhibitors
Factors affecting urinary albumin excretion

55. Primary prevention of nephropathy
•Tight blood glucose control:
–<7.5% on insulin.
–<6.5% not on insulin.
•Tight blood pressure control:
–<140/80 mm Hg for type 2.
•?Non-smoking.
•?Statin therapy.

56. What is the Proper Therapy of
Kidney Disease in patients with
Diabetes?

57. Stratton IM et al. BMJ. 2000;321:405-412.
Improved Glycemic Control Has Been
Shown to Reduce the
Risk of Complications
According to the United Kingdom Prospective Diabetes
Study (UKPDS) 35, Every 1% Decrease in A1C Resulted in:
Decrease
in risk of
microvascular
complications
(P<.0001)
Decrease
in risk of any
diabetes-related end
point
(P<.0001)
Decrease
in risk of MI
(P<.0001)
Decrease
in risk of stroke
(P=.04)
21%
14%
12%
37%

58. Targets for incipient and overt
Diabetic Nephropathy
Parameter
•Lower BP………………………
•Block RAAS……………………
•Improve glycemia …………….
•Lower LDL cholesterol………..
•Anemia management ………...
•Endothelial protection…………
•Smoking………………………..
Target
< 130/80 mmHg
ACEI or ARB to max tolerated
A1c < 6.5% (Insulin)
< 100 (70) mg/dl statin + other
Hb 11-12 g/dl (Epo + iron)
Aspirin daily
Cessation
©2005. American College of Physicians. All Rights Reserved.

59. Hypothesis: Anemia is an Important CV Risk Factor
in Chronic Kidney Disease
Chronic Kidney
Disease
Cardiovascular disease
Anemia
©2005. American College of Physicians. All Rights Reserved.

60. Some Novel Therapies of
diabetic nephropathy

61. Novel therapies for diabetic nephropathy
•Inhibitors of growth factors and
vasopeptides:
– Insulin-like growth factor-1.
– Growth hormone.
– Transforming growth factor-ß.
– Vascular endothelial growth factor
neutralising antibodies.
– Endothelin-1 antagonis

62. Other novel therapies
•Pirfenidone –antifibrotic agent
•Sulodexide, an agent postulated to restore
the glomerular charge by repleting the loss of
glycosaminoglycans.
•Histone deacetylase inhibitors
•Raloxifene, a selective estrogen receptor
modulator.

63. Endothelin antagonists
•Endothelin antagonists have antifibrotic, anti-
inflammatory, and antiproteinuric effects in
experimental studies.
•Wenzel et al conducted a study on the effect of
the endothelin-A antagonist avosentan on UAER
in 286 patients with diabetic nephropathy.
•Avosentan, treatment, were found
to reduce the mean relative urinary albumin
excretion rate (-16.3% to -29.9%, relative to
baseline) in the study's patients.

64. Polyol pathway inhibitors

65. Protein Kinase C (PKC) Beta-1 antagonist
Robuxistaurin

66. Transforming growth factor ß inhibitors

67. Chemokines Functions
•Chemokines promote chemotaxis in the direction of highest
concentration

68. Emapticap Pegol
•Pegol means: pegylated monoclonal antibodies
•Emapticap pegol is a Spiegelmer
•Binds and neutralizes CCL2/MCP-1 (C-C
Chemokine Ligand / Monocyte Chemoattractant
Protein-1), a pro-inflammatory chemokine that plays
an important role in diabetic kidney disease.

69. Emapticap Pegol
•Treatment was for 12 weeks with twice-weekly subcutaneous
emapticap pegol or placebo.
•This treatment period was followed by a 12 week
observational period to study the long-term effect of
emapticap pegol treatment on albuminuria.
•Emapticap pegol was found to be safe and well tolerated.
•For the primary efficacy analysis, patients with major protocol
violations, on dual RAS blockade, or with concomitant
hematuria and leukocyturia were excluded.

70. Emapticap Pegol
•Results showed relevant, statistically significant reductions in
urinary albumin excretion and improved glycemic control.
•Importantly, these effects were independent of hemodynamic
changes and maintained after cessation of treatment,
suggesting that emapticap pegol interferes with the
underlying pathophysiology of diabetic nephropathy.
•Long-lasting effects on urinary albumin after cessation of
treatment are not seen with agents currently approved to
treat diabetic nephropathy

71. •Rapamycin (sirolimus): m-TOR inhibitor
–systemic administration of rapamycin, a systemic and
potent inhibitor of mTOR, markedly ameliorated
pathological changes and renal dysfunction in Diabetic
db/db mice as a model of ESRD associated with DN
–Sirolimus lowered the expression and activity of
glomerular TGF-β and VEGF

72. •Pentoxifylline
–Pentoxifylline administration has prevented Renal
expression of proinflammatory cytokines, such as tumor
necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6
–Pentoxifylline treatment caused regression and
prevented the progression of renal damage

73. •Advanced glycation end-products inhibitor
–1) AGE formation inhibitor: ARBs, R-147176, aminoguanidine,
benfotiamine, pyridoxamine
–2) AGE cross-link breaker (alagebrium)
–3) RAGE antagonist (PPAR-γ antagonists)
–4) AGE binder (Kremezin)
–5) hypoxia-inducible factor (HIF) activator

74. Management of DM with Failing Kidney
.Early referral to a nephrologist (Scr >2 mg/L ).
•Structured physical and psychological
preparation for RRT.
•Younger patients will usually be offered
transplantation .
•Before transplantation, full cardiovascular
assessment is essential.
•PTCA or even CABG may be required before
transplantation.

75. Hemodialysis
Renal Transplantation
Peritoneal Dialysis
Treatment of End-Stage Renal
Disease (ESRD)

76. Summary
•Identifying nephropathy by screening for
albuminuria.
•Multiple risk factors intervention for preventing
DN progression.
•RAAS blockade is the key to prevent
progression.
•Manage acute deterioration of renal function in
DN.

77. 08/30/15
,
.DCDC I7th,5-8 April,2016,Ras Elbarr,Domyat

78. 08/30/15