1

New Directions in Diabetic Renal Disease:

Kamran Hasni, M.D.Professor of Medicine (Community based)

Department of Internal Medicine University of Kentucky

Screening for Diabetic Kidney Disease(DKD)

• Patients with diabetes should be screened annually for DKD commencing:

– After 5 years, then annually in Type 1

– At diagnosis, then annually in type 2

– Measurements should include:

– Urine albumin to creatinine ratio in a spot collection

– Estimate of GFR from MDRD formula and Cockgraft golt formula

Take Home Message

• Diabetic nephropathy is progressive kidney disease

• Most common cause of ESRD in the US

• More likely to die than progress to ESRD

• Multi-risk factor intervention is critical

• Lowering blood pressure with RAAS blockade is critical

• Combinations of ACEi + ARB or MRA sensible

• Prevent cardiovascular morbidity and mortality

2

Why is Diabetic Nephropathy Important?

Diabetes: The Most Common Cause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%

Other

10%

United States Renal Data System. Annual data report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r2=99.8%243,524

281,355520,240

No

. o

f d

ialy

sis

pa

tie

nts

(t

ho

usa

nd

s)

Cardiovascular Death is Major Cause of Mortality in ESRD

0.001

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 65-74 75-84 > 85

Age (years)

An

nu

al

Ca

rdio

va

sc

ula

r M

ort

alit

y (

%)

GP Male

GP Female

GP Black

GP White

Dialysis Male

Dialysis Female

Dialysis Black

Dialysis White

Sarnak MJ and Levey AS. Am J Kidney Dis. 2000;35(4)(suppl1):S117-S131.Foley RN. Am J Kidney Dis. 1998;32(S3):S112-119.

General Population

ESRD Population

3

What is the Natural History of Diabetic Nephropathy?

Definition of Diabetic Nephropathy

• Clinical diagnosis based on Hx, Exam and urine albumin/creatinine ratio in most cases

• Longstanding History of diabetes + retinopathy

• Macroalbuminuria (a.k.a “overt nephropathy”) defined as random urine albumin/creatinine ratio > 300 mg/g

• Hypertension (> 90%)

• Renal Biopsy confirmation is rare

Natural History of Diabetic Nephropathy

Declining GFR

Time

GF

R

ESRD

Hypertension

BP

TimeGlomerular Basement Membrane

PodocytesFoot process

DamagedEndothelium

Albumin-rich filtrate

Albuminuria

AlbuminLeak

GFR

CardiovascularDeath Risk

CV

Ris

k (f

old

) 20

15

10

5

1

0 20 40 60 80 100

4

Development of Macroalbuminuria Heralds Rapid Decline in Glomerular Filtration in Type II Diabetes

-50

-40

-30

-20

-10

0

1 1.5 2 2.5 3 3.5 4

Cha

nge

in G

FR m

l/min

Time years

Microalbuminuria Macroalbuminuria

Nelson RG. et al NEJM, 1996

Diabetics with Nephropathy (DM/CKD) are More Likely to Die than to Progress to ESRD

Status in the entry periodDM/CKDDM/Non-CKD NDM/CKDNDM/Non-CKD

19,335188,596 33,586N=1,045,263

0.070.31

2.255.85

Pe

rce

nt

of

Pa

tie

nts

Event Free

ESRD

All CauseDeath

5% Medicare sample , 1996-1997 cohort, 2 year follow-up

9.40 14.65

29.04

85.0473.18

65.12

24.57

90.53

0

20

40

60

80

100

Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRD

CV

DEATHElevated Serum Creatinine

19%

No albuminruia1.4%

2.0%

Microalbuminruia3.0%

2.8%

Macroalbuminruia4.6%

2.3%

The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics)Newly diagnosed, predominantly white, medically treated

Adler et al. Kid Int, 2003

5

What are Diabetics with Nephropathy Dying From?

Stroke MyocardialInfarction

HeartFailure

SuddenDeath

Improving Outcomes in Diabetic Nephropathy

Prevention of Cardiovascular Events

Prevention of End-Stage Renal Disease

Diabetic Nephropathy

Diabetic Nephropathy: Take Home Message 1

• Leading cause of end-stage kidney disease

• Characterized by hypertension, proteinuria and progressive loss of kidney function

• Cardiovascular complications excessive an increase with worsening kidney function

• More likely to die than progress to end-stage

6

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

The Renal Injury Triad

Angiotensin II

ProteinuriaHypertension

Definition of Abnormal Albuminuria in Diabetes Mellitus

Microalbuminuria Macroalbuminuria

(Nephropathy)

Detected by dipstick No Yes

Urine Albumin / Cr 30 - 299 mg Alb / g Cr > 300 mg Alb / g Cr

Renal Risk Marker of future nephropathy

in some

Marker progressive renal

disease

Cardiovascular Risk Increased Increased* Random (Spot) urine preferably A.M. recommended

7

ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)

ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)

19

- 40 –

- 20 –

0 –

- 20 –

- 40 –

- 60 –

% Reductionin

Proteinuria

P <.001

Lewis et al. N Engl J Med. 1993;329:1456-1462.

% with Doubling of

Baseline Creatinine

Baseline creatinine > 1.5 mg/dl

0

25

50

75

100

0 1 2 3 4

Captopril

Conventional therapy

- 2 –

0 –

- 2 –

- 4 –

- 6 –

- 8 –

Decrease inMean Blood

Pressure(mm Hg)

NS

ARB (losartan) Reduces Risk of ESRD in Diabetic Nephropathy

ESRD

Months

% w

ith

ev

en

t

0 12 24 36 48

0

10

20

30

p=0.002Risk Reduction: 28%

Placebo

Losartan

P (+ CT)

L (+ CT) 751 714 625 375 69762 715 610 347 42

Brenner et al. New Engl J. Med Sept 20 2001

BP 142 / 74

BP 140 / 74

Reduction in Endpoints in NIDDM with Angiotensin Antagonist Losartan (RENAAL) Trial: 1513 type 2 Diabetics with Nephropathy

• Avg: 3.5 BP drugs/pt• 90% in both groups

received a CCB

-40

-35

-30

-25

-20

-15

-10

-5

0

5

Per

cen

t R

edu

ctio

n

Change in Proteinuria

Irbesartan

Placebo

Irbesartan in Diabetic Nephropathy Trial:

Time to Doubling of Serum Creatinine, ESRD, or Death

Lewis EJ, et al. N Engl J Med. 2001;345:851-860.

Su

bje

cts

(%)

0 6 12 18 24 30 36 42 48 54

Follow-up (mo)

60

0

10

20

30

40

50

60

70

RRR 20%P=.02P=NS

RRR 23%P=.006

Irbesartan

Amlodipine

Placebo

1,715 Type 2 Diabetics with Nephropathy

-35

-30

-25

-20

-15

-10

-5

0

5

Pe

rce

nt

Re

du

cti

on

Change in Proteinuria

Irbesartan

Amlodipine

Placebo

BP 141/77

BP 144/80

BP 140/77

8

% w

ith

ES

RD

en

d p

oin

t

80

100

40

60

20

048362412

Month

≥3.0 g/g

≥1.5<3.0 g/g

<1.5 g/g

HR

8.10

3.23

1.0

0

Albuminuria at Baseline Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial (N=1513)

Baseline Albuminuria

de Zeeuw et al. Kid. Int. June 2004

Reduction in Proteinuria is Associated with Reduced Risk for End-Stage Renal Disease in Diabetic Nephropathy

0.5

1.0

3.5

4.0

2.5

3.0

1.5

2.0

0.0<-40 ≥10 ≥60≥-10≥-40 ≥40

<60<-10 <10 <40

Change in Albuminuria %

Re

lati

ve

Ris

k f

or

ES

RD

de Zeeuw et al. Kid. Int. June 2004

RENAAL; Proteinuria Reduction (<0% versus >30%) determines the cardiovascular outcome

CV Endpoint Heart Failure

0 12 24 36 48

Month

0

10

20

30

40

% w

ith C

V e

nd

po

int >30%

<0%

0 12 24 36 48

Month

0

10

20

30

40

% w

ith h

ea

rt f

ailu

re

<0%

>30%

De Zeeuw et al; Circulation, in press

9

Continuation of Losartan After Serum Creatinine Doubles Reduces Incidence of ESRD

25

Months

% w

ith E

SR

D e

ven

t

0 6 12 18 240

20

40

60

80p=0.013Risk Reduction: 30%

198 111 48 11 4P (+CT)

LP

L (+CT) 162 104 43 19 3

Combination Therapy for BP Control: Rule Rather Than Exception

1 2 3 4

Number of BP Medications

ALLHAT

IDNT

RENAAL

UKPDS

ABCD

MDRD

HOT

AASK

Trial/Systolic Blood Pressure Achieved (mm Hg)

Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646-661.

138

138

141

144

138

128

132

132

Q1

How I do get My Patient’s BP to the Goal of <130 / < 80 mmHg?

• ACE Inhibitor / AII Receptor Antagonist (maximum dose)

• Low ( 2 gram ) Sodium Diet

• Diuretic : thiazide, loop diuretic

• Long-Acting CCB or b-blocker

• Long-acting a-blocker vs clonidine

• Minoxidil

Slide 26

Q1 M54_1803_Sec IIQ050240, 2/11/2005

10

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

Combination ACEi and Non-Dihydropyridine CCB Reduces Proteinuria Further in Type 2 Diabetics With Nephropathy

0

-20

-40

-60

Trandolapril5.5 mg/d

Verapamil SR314 mg/d

Trandolapril (2.9 mg/d) +Verapamil SR (219 mg/d)

Pe

rce

nt

red

uct

ion

fro

m b

ase

line

Proteinuria

Blood Pressure

Bakris, et al. Kid Int. 1998;54:1283.

NKF Kidney Disease Outcomes Quality Initiative: Pharmacologic Treatment

Type of CKD BP Goal Preferred Agents for CKD, + HTN

Diabetic < 130/80 ACEi or ARB

Non-Diabetic with Spot Urine Total Prot-to-Cr ratio > 200 mg/g

< 130/80 ACEi or ARB

Non-diabetic with Spot Urine Total Prot-to-Cr ratio < 200 mg/g

< 130/80 None Preferred30KDOQI BP guidelines for CKD Am. J. Kid. Dis. Suppl. May 2004

11

Steno-2: Multiple Risk Factor Intervention Improves Outcomes in Type 2 diabetics with Microalbuminuria

• Randomized, open-label, target driven, long-term intensified intervention trial aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria

– BP < 130/80, (all treated with an ACEi or ARB)

– A1c < 6.5%

– Total Cholesterol < 175 mg/dl

– Total Triglyceride 150 mg/dl

– Aspirin 81 mg daily

– Exercise program

– Smoking Cessation

Gaede et al N.Engl.Med. 3448:383. 2003

Pri

ma

ry C

om

po

site

En

d P

oin

t (%

)

10

20

50

60

30

40

00 96842412 4836 7260

P=0.007

Conventional therapy

Intensive therapy

Months of Follow-upNo. at Risk

Intensivetherapy

Conventionaltherapy

80 72 70 63 59 50 44 41 13

80 78 74 71 66 63 61 59 19

Intensive Multi-risk Factor Intervention Improves Outcomes in Type 2 Diabetes

Gaede et al N.Engl.Med. 3448:383. 2003

Composite outcome: CV death, MI, coronary or peripheral revascularization, CVA, amputation

33

Risk of Death after AMI is Reduced across all Levels of Kidney Function with Recommended Interventions

0.400.45

0.52

0.61 0.62 0.580.52

0.41 0.44

0.200.300.400.500.600.700.800.901.001.101.20

< 1.5 1.5-2.4 2.5-3.9

Ha

zard

rat

io

Serum creatinine (mg/dl)

Aspirin

Beta Blocker

ACE-I

Shlipak et al., Ann Int Med 2002;137:555-62

12

Diabetic Nephropathy: Take Home Message 2

• Lower blood pressure < 130 / 80 mmHg

• Reducing Proteinuria

• Inhibition of Renin-Angiotensin System

• Multiple risk factor intervention

– Glycemia

– Dyslipidemia

– Physical activity

– Aspirin

– Smoking cessation

Is Combination Therapy With An ACE Inhibitor And An ARB Safe And Effective For Patients With Diabetic Renal

Disease?

Diabetic Nephropathy: Take Home Message 3

• VA NEPHRON and ONTARGET trials suggest combinations of ACEi and ARB reduce proteinuria synergistically but increases complications like hyperkalemia , mortality and incidence of ESRD, although greater reductions in proteinuria

13

Is There a Role for Spironolactone (or Eplerenone) in Combination with Other Drugs in Patients with Diabetic

Nephropathy?

Adverse Renal and Cardiovascular Effects of Aldosterone

GlomerulosclerosisInterstitial FibrosisProteinuriaRenal Failure

Ventricular HypertrophyCardiac FibrosisContractile DysfunctionHeart Failure

Endothelial dysfunctionInflammationOxidative Stress

Aldosterone

Ang I

Ang II

Progressive Diabetic Nephropathy

ACE

Renal Injury and Proteinuria

ACEi

AT1 Receptor

Non-ACEPathways

Aldosterone

MRA

ARB

Can Dual Blockade of the RAAS Improve Renal Outcomes in Diabetic Nephropathy?

+

+

14

• Role for spironolactone or eplerenone in diabetics with nephropathy not established

• Small, short-term studies suggest adding on is efficacious for lowering proteinuria

• Not clear if combinations are safe in larger population

• No long-term trials with cardiovascular or renal endpoints

Diabetic Nephropathy: Take Home Message 4

Beyond RAAS Blockade

©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

15

Hb < 11.3*

Hb > 13.8

Hb 12.5-13.8*

Hb 11.4-12.5*

Time, years

4321

En

d-s

tag

e r

en

al

dis

ea

se

, %

10

20

50

60

30

40

0

Baseline Hemoglobin Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial (N=1513)

Mohanram et al. Kid. Int. Sept 2004

-1.00> 13.8

0.0021.8512.5-13.8

0.021.6111.3-12.5

0.0011.99< 11.3

P value

Adjusted HR*

Hb g/dl

* Age, gender, GFR, Race, Proteinuria,CV disease, A1c, lipids, BP, Ca, P, albumin

Diabetic Nephropathy: Some Novel Therapies Under Investigation

• Pirfenidone –antifibrotic agent• Aliskerin anti-renin agent• Robuxistaurin- Protein Kinase C Beta-1

antagonist• Advanced Glycation Endproduct antagonists• Others

How Should I Manage My Patient With Diabetic Nephropathy Today?

16

Diabetic Nephropathy Management

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/TZD)

< 100 (70) mg/dl statin + other

Hb 11-12 g/dl (Epo + iron)

Aspirin daily

Cessation

Dose adjustment for Insulin Sensitizers, Exenatide and Pramlintide in CKD

Drug CKD Stages 3-4 Dialysis

Metformin Avoid Avoid

Pioglitazone No Adjustment No Adjustment

Rosiglitazone No Adjustment No Adjustment

Exenatide No Adjustment Avoid

Pramlintide No Adjustment Avoid

Dose Adjustments for Insulin Secretagogues and alpha glucosidase Inhibitors in CKD

Drugs CKD Stages 3-4 Dialysis

Glipizide No Adjustment No Adjustment

Glyburide Avoid Avoid

Glimepiride lower dose Avoid

Repaglinide No Adjustment No Adjustment

Nateglinide Lower dose Avoid

Acarbose Avoid Avoid

Sitagliptin Lower dose Lower dose

Invokana Noadjustment Avoid

17

Special Note:

Metformin is contraindicated in females with Cr 1.4 and males with Cr 1.5

Invokana causes hyperkalemia if combined with ACEi/ARB, also can cause Acute kidney injury

Diabetic Nephropathy: What about proteinuria?

• Lower BP to goal with max dose ACEi or ARB

• Consider Adding: ACEi or ARB, mineralocorticoid receptor antagonist

• Calcium Channel Blockers

– Non-dihydropyridine

– Dihydropyridine

Discussion

18

What is mentorship?

A relationship in which a more experienced or more knowledgeable person helps to guide a less experienced or less knowledgeable person. The mentor may be older or younger than the person being mentored, but he or she must have a certain area of expertise.

Different types of mentors

Senior professional mentor

● When people think of mentor, often they think of the senior professional mentor, the successful VP with over 20 years of career experience. The Senior Professional mentor is a fantastically helpful mentor and can give you a much-needed long-term perspective on your career.

19

Peer mentor

● Peer mentors, sadly, get overlooked and underappreciated too frequently. The Peer mentor is someone who is close to your age and only a step or two above you, if at all, in the workplace. A less prestigious mentor-type, the peer mentor knows the lay of the land and is with you in the trenches at your company or in your industry. There advice is often the most helpful day-to-day advice you will find.

The supervisor mentor ● Supervisors can be tremendous mentors. As a

coach, a supervisor gets to see you in action first hand. He or she has the chance to know your best talents and fundamental flaws in the workplace. Not everyone has a boss focused on mentorship, but those who do have a valuable opportunity for real-time feedback and growth. Colleagues too can share important information about the office or industry.

Benefits of mentoringThere are several benefits when mentoring. You can get many advantages and great ideas from mentoring.

● Exposure to new ideas and ways of thinking● Advice on developing strengths and

overcoming weaknesses● Guidance on professional development and

advancement● Increased visibility and recognition within the

20

outcomes

● Increasing the engagement of employees through interactions with a mentor,

● Assisting employees in developing a mentoring relationship for career development in an effort to increase knowledge, skills, and competencies that may be needed for current job duties or future career advancement.

● Provide an avenue to access available

Final thoughts

Having a mentor or being a mentor could be really beneficial to many people. And have several different positive outcomes.

Sources

https://hr.maricopa.edu/professional-development/mentoring/mcccd-mentor-program/outcomes-impacts-and-benefits

https://www.michaelpage.co.in/advice/management-advice/leadership/what-are-benefits-mentoring

https://bossedup.org/3-types-of-mentors-you-need-to-succeed/