Diabetic Nephropathy: Update Pathophysiology

Ashraf Talaat,MD. Banha Faculty of Medicine

Nephrology,Diabetes&Endocrinology Units

Global Epidemic of Type 2 Diabetes

•Aging Population

•Global Lifestyle “Westernization”

•Surging Obesity

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 100,000http://www.worldlifeexpectancy.com/cause-of-death/kidney-disease/by-country/

accessed 2012 Oct.

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

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.

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 ofProgression 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

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).

Prevalence of different stages of CKD

1st 2nd 3rd

4th 5th

So How Big Is The Risk In Diabetes?

Pathophysiology of diabetic nephropathy

Factors involved in the pathophysiology of diabetic nephropathy

Genetic susceptibil i ty

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

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+ retentionH2O retentionK+ excretionMg+ 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

GlomerulosclerosisInterstitial FibrosisProteinuriaRenal Failure

Ventricular HypertrophyCardiac FibrosisContractile DysfunctionHeart Failure

Endothelial dysfunctionInflammationOxidative 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-flowabnormalities

VEGF↑

Permeabilityangiogenesis

TGFβ↑↓

Collagen

Fibrosis

PAI-1↓

Vascularocclusion

NF-κB↑

Pro-inflammatorygene-expression

NAD(P)H oxidases

Multipleeffects

ROS

Transforming growth factor ß and diabetic nephropathy

CV mortality and systolic pressure in diabetics and nondiabetic

SYSTOLIC BP

CV

mor

talit

y ra

te p

er 1

0 00

0 pe

rson

-yrs

Adapted from Stamler J et al Diabetes Care 1993;16(2):435-444

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.

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.

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

Normal Control Vs FGF23 -/- mice

So,

• CKD inflammation Klotho gene decrease

in Klotho FGF23 resistance increase in FGF23 &

phosphate retension transformation of VSMC to

osteoblasts calcification of vessel wall.

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

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

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

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

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 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 .

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: – <7.5% on insulin.– <6.5% not on insulin.

• Tight blood pressure control: – <140/80 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 Complications

According to the United Kingdom Prospective DiabetesStudy (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< 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.

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.

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

Chemokines Functions • Chemokines promote chemotaxis in the direction of highest

concentration

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.

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.

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

• 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.

08/30/15

,

.DCDC I7th,5-8 April,2016,Ras Elbarr,Domyat

08/30/15