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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