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
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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/
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