Ueda2015 diabetic nephropathy dr.ashraf talaat
Transcript of Ueda2015 diabetic nephropathy dr.ashraf talaat
Diabetic Nephropathy:
Update
Ashraf Talaat,MD.Banha Faculty of Medicine
Nephrology&Diabetes, endocrinology units
Global Epidemic of Type 2
Diabetes
•Aging Population.
•Global Lifestyle (Westernization).
•Surging Obesity (children & adolescence).
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.
Russo E, et al. Diabetes Metab Syndr Obes. 2013; 6: 161–170.
*Per 100,000
http://www.worldlifeexpectancy.com/cause-of-
death/kidney-disease/by-country/ accessed 2012
Oct.
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 ofother kidney or urinary system diseases.
Why is Diabetic Nephropathy
Important?
What are Diabetics with Nephropathy Dying From?
Stroke MyocardialInfarction
HeartFailure
SuddenDeath
©2005. American College of Physicians. All Rights Reserved.
What is the Natural History of
Diabetic Nephropathy?
Stages of
Progression and
Natural History of diabetic nephropathy
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 ++ +++
0
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
G3aMildly to moderately
decreased45-59
G3bModerately to
severely decreased30-44
G4 Severely decreased 15-29
G5 Kidney failure <15
GF
R c
ate
go
rie
s (
ml/
min
/
1.7
3 m
²)
De
sc
rip
tio
n a
nd
ra
ng
e
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
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).
So How Big Is The Risk In Diabetes?
Avoiding AKI In Diabetes :
Pathophysiology of diabetic nephropathy
Factors involved in the pathophysiology of diabetic
nephropathy
Genetic susceptibility
Haemodynamic raised intraglomerular pressure
Biochemical
Growth factors
Vasoactive factors
glucose, protein kinase C, diacylglycerol, etc.
IGF-1, TGF-ß, connective tissue growth factor
VEGF, angiotensins, endothelin
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
Simple schema for the pathogenesis of diabetic nephropathy
Biochemical Hypothesis for diabetic
nephropathy
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.
Aldosterone
Sympathetic activation
Growthfactor stimulation↑TGF β, ECM↑CTGF,PAI-1
NA+ retention
H2O retention
K+ excretion
Mg+ excretion
Vascular smooth muscle constriction ↑GP↓RBF
Angiotensinconvertingenzyme(ACE)
Angiotensin II
Liver secretes angiotensinogen
Kidneys secreterenin
The Renin-Angiotensin-Aldosterone (RAA)
System activation and diabetic nephropathy
Angiotensinogen Angiotensin I
Adrenal cortex secretes aldosterone
Blood Renin
Non ACE
AT2 RVD↑NO↓ tissue proliferation
AT1 R
Angiotensin II stimulates release of growth factors
through NF-B activation
Wiecek et al. Nephrol Dial Transplant (2003) 18 [Suppl 5]: v16–v20
Role of angiotensin II in the progression of
diabetic nephropathy – 2
The renin–angiotensin system, angiotensin receptors and their action
Ca2+
ExtracellularAngiotensin II
AT1receptor
AT1receptor
Cell membrane
Intracellular
G protein Gq protein
Mitochondria
Aldosterone
production
Steroid
Synthesis
Ca2+
Myofilaments
Vaso-
constricton
Endoplasmic reticulum
Ca2+ storage
Secretory
Granules
Catecholaminerelease
PLA2 AA LysPC
PC
Prostaglandins
GeneTranscriptionTranslation
mRNA
AT1
A II
Cell growth
Protein
Synthesis
Growth
factor
Structural Proteins
Angiotensin II
PLC
PIP2
DAG
IP3
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
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
TGF
Collagen
Fibrosis
PAI-1
Vascular
occlusion
NF-B
Pro-inflammatory
gene-expression
NAD(P)H oxidases
Multiple
effects
ROS
Transforming growth factor ß and
diabetic nephropathy
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.
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.
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 .
Pathology of diabetic
nephropathy
Glomerulopathy Tubulopathy Vascular Interstitial
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 .
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
Clinical diagnosis of diabetic
nephropathy
– Albuminuria.
– Diabetic retinopathy.
– No evidence for another renal disease:
• HTN, renovascular disease, SLE,
vasculitis, paraproteinemia
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.
Renal functions assessment
• Urinary ACR: spot sample (mg/gm).
• 24 hour urine protein.
• Serum creatinine,creatinine clearance & 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 .
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
Primary prevention of nephropathy
• Tight blood glucose control: – <7% on insulin.
– <6.5% not on insulin.
• Tight blood pressure control: – <140/90 mm Hg for type 2.
• ?Non-smoking.
• ?Statin therapy.
What is the Proper Therapy of
Kidney Disease in patients with
Diabetes?
Stratton IM et al. BMJ. 2000;321:405-412.
Improved Glycemic Control Has Been
Shown to Reduce the
Risk of ComplicationsAccording to the United Kingdom Prospective Diabetes
Study (UKPDS) 35, Every 1% Decrease in A1C Resulted in:
Decrease in risk of
microvascularcomplications
(P<.0001)
Decrease in risk of any
diabetes-related end point
(P<.0001)
Decreasein risk of MI
(P<.0001)
Decrease in risk of stroke
(P=.04)
21% 14% 12%
37%
Targets for incipient and overt
Diabetic Nephropathy
Parameter
• Lower BP………………………
• Block RAAS……………………
• Improve glycemia …………….
• Lower LDL cholesterol………..
• Anemia management ………...
• Endothelial protection…………
• Smoking………………………..
Target
< 140/90 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
©2015. American College of Physicians. All Rights Reserved.
Blood pressure control
• A sustained reduction in BP appears to be the most important single intervention to prevent progressive nephropathy in T1DM and T2 DM.
• In the UKPDS, a reduction in BP from 154 to 144 mm Hg was associated with a 30% reduction in microalbuminuria.
How I do get My Patient’s BP to the Goal
of <140 / < 90 mmHg?
• First line drugs: ACE Inhibitor / ARBs (maximum dose) + Low ( 2 gram ) Sodium Diet
• Second line drugs
Diuretic
o eGFR > 50 ml/min, thiazide
o eGFR < 50 ml/min, loop diuretic, Metolazone
Long-Acting CCB or -blocker
Long-acting a-blocker vs clonidine
Minoxidil
RAAS blockade
• ACE inhibitors, ARBs reduces microalbuminuria and rate of progression to ESRD & have renoprotective actions beyond their antihypertensive effects .
• Patients placed on an ACE inhibitor or an ARB should have their serum creatinine and potassium checked within 2 weeks of initiation of therapy and periodically thereafter.
RAAS blockade
Adverse effects of ACEI
• Cough : 0-39%, F>M, class effect.
• Angioedema: 0.1-0.2 %: 1hr to <1 wk.
• Metallic taste: captopril.
• Hyperkalemia.
• Worsening renal failure.
• 30-35 % increase in creatinine may occur : in proteinuric patients with creatinine values >1.4 mg/dl.
Who are prone for hyperkalemia?
Rates of ACEI discontinuation due to hyperkalemia
is extremely low in clinical trials
• Higher levels of creatinine.
• Associated drugs: Spironolactone, triamterene, trimethoprim, cyclosporine.
• Interstitial disease.
• Type 4 renal tubular acidosis.
• Renal artery stenosis.
• Left ventricular dysfunction.
• Poor volume status: high dose diuretics, low filling pressures.
Who are prone for worsening renal
function ?
Aldosterone blocking agents
• Aldosterone receptor antagonists
(eplerenone) decrease proteinuria further in
patients with diabetes on ACEIs.
• It is similar to spironolactone but lacks the sex
steroid side effects, such as impotence and
gynecomastia.
Is Combination Therapy With
An ACE Inhibitor And An ARB
Safe And Effective For Patients
With Diabetic Renal Disease?
©2005. American College of Physicians. All Rights Reserved.
Ang I
Ang II
Progressive Diabetic Nephropathy
ACE
Renal Injury
and Proteinuria
ACEI
AT1 Receptor
Non-ACEPathways
ARB
Can Dual Blockade of the RAAS Improve Renal
Outcomes in Diabetic Nephropathy?
+
+
©2005. American College of Physicians. All Rights Reserved.
ACEI- or ARB-Based Regimens for Diabetic
Nephropathy Do Not Go Far Enough!
ACEi or ARB
DGFR = - 6 ml/min/yr
Time to ESRD 6.6 yrs
Time (yrs)
ESRD
50
2 4 6 8 10
No ACEi/ARB
or BP control
DGFR = - 10 ml/min/yr
Time to ESRD 4 yrs
40
30
20
10
ACEi + ARB
DGFR = - ? ml/min/yr
Time to ESRD ?
RAAS blockade + Other?
What is beyond the RAAS
blockade?
Calcium channel blockers
• Non-dihydropyridine CCBs (diltiazem,
verapamil) slow renal disease progression
and proteinuria in proteinuric hypertensive
patients with type 2 DM.
• Avoid initial therapy with a dihydropyridine
CCBs.
Bakris GL et al. Kidney Int. 2004. In press.
NDHP-CCBs show greater reductions in proteinuria in hypertensive adults with proteinuria, with or without diabetes.
DHP-CCB NDHP-CCB
Ch
an
ge (%
)
P=0.01
-35
-30
-25
-20
-15
-10
-5
0
5
ProteinuriaN=510
Systolic Blood PressureN=1,338
NS
2%
-30%
-13%
-18.5%
Renal Effects of CCBs: Comparison
Systematic Review of 28 Studies 17
©2005. American College of Physicians. All Rights Reserved.
Low protein diet
• Low-protein diets (0.75 g/kg per day) retard the progression of renal disease although the data are not totally convincing for diabetic nephropathy per se.
• A meta-analysis of five studies in type 1 diabetic subjects supported a minor renoprotective role for these diets, but this has not been a universal finding.
• There are even fewer data in type 2 diabetic subjects with overt nephropathy.
• Target Hb 11-12 gm/dl
• Treatment of anemia with agents such as erythropoietin ,darbepoeitein
• The role of these agents as renoprotective drugs remains to be clarified.
• The potential benefits on general patient well-being and in reducing left ventricular hypertrophy provide a rationale for using such agents judiciously in diabetic patients.
Treatment of anemia
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.
Lipid lowering agents
• The role of lipid-lowering agents as renoprotective drugs remains controversial.
• There are already recommendations for tight lipid control in diabetics because of the high cardiac risk in these patients.
• Statins may have additional unique benefits, independent of lipid lowering ( found to block intracellular signaling and decreases the mRNA expression of TGF-β, beneficial effects on NO, and ET-1 )
Some Novel Therapies of
diabetic nephropathy
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
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.
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.
Polyol pathway inhibitors
Protein Kinase C (PKC) Beta-1 antagonistRobuxistaurin
Transforming growth factor ß inhibitors
• 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
• 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
• 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
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.
Hemodialysis Renal Transplantation
Peritoneal Dialysis
Treatment of End-Stage Renal
Disease (ESRD)
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.
Thank You
6/21/2015
,
.DCDC I7th,6-8 April,2016,Ras Elbarr,Domyat
6/21/20
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