Diabetes and Kidney Disease - Baptist Health South Florida · 2018-03-14 · Diabetes and Kidney...

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Diabetes and Kidney Disease

Alessia Fornoni, MD PhDProfessor of Medicine

Chief, Katz Family Division of Nephrology and Hypertension

Director, Peggy and Harold Katz Family Drug Discovery Center

University of Miami School of Medicine

DisclosuresI am vice President and CSO of L&F Health LLC

L&F Health LLC and affiliated companies have apatent estate covering some of the topics beingpresented

L&F Health LLC has consulting agreements withand/or has received honoraria from Hoffman LaRoche, Genentech, Mesoblast, Bristol Myers Squibb,Abbvie, Jenssen, Boehringer Ingelheim, Astra Zeneca,Pfizer, Mallinkrodt, Chemocentryx, Dimerix, VariantPharmaceutical.

Variant Pharmaceuticals, Inc. has licensed worldwide rights to develop and commercialize hydroxypropylbeta cylodextrin for treatment of kidney disease from L&F Research

Objectives•Definition and screening for DKD

•2018 Treatment guidelines

•New approaches to patients risk stratification




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DKD yearly updates

Page S105: Microvascular complications

Diabetes Care, 2018, Supplement 1 USRDS 2010-2016

DKD remains the most common cause of ESRD

ESRD prevalence (per M) ESRD prevalence by cause 2014

2014

1992

Prevalence of Diabetic Kidney Disease (DKD)

deBoer JAMA 2011; 305: 2532

DKD and yearly risk of death

> 5000 Type 2 Diabetes patients

Yearly risk associated

Adler et al, Kidney International, 2003;63:225

CVD risk protection needs early implementation

3

Kidney disease is among the top causes of death

Murray et al NEJM 2013; 369: 5Copyright ©2004 BMJ Publishing Group Ltd.

Hovind, P. et al. BMJ 2004;328:1105

277 patientsType 1 DMf/u 18 yrs

Natural progression of DKD in T1D

75% ESRD at 20 years

Early Detection and Treatment are EssentialEarly biomarkers are missing

10,290 members of a managed care organization with HTN and T2D (Kayser Permanente)ACR at baseline and with at least 2 additional determinations over time, 7 1/2 years follow up

Vupputuri S et al, Diabetes Res Clin Pr, 91: 246, 2011

30%

12%

Natural progression of DKD in T2D Screening for DKD

yearly follow up, Level of evidence B

ADA recommendations, Diabetes Care, January 2017

At diagnosis if HTN

4

Definition of DKDDIABETES with:

Abnormal urine albumin excretion >30 mg/24 hours>30 mg/g creatinine (preferred)>20 µg/min

and/ordiabetic glomerular lesions

and/orloss of glomerular filtration rate (CKD-EPI

preferred)ADA recommendations, Diabetes Care, January 2018

ACR & Progression to ESKD

Babazono Diabetes Care 2009; 32: 1518

White: FBlack: M

Proteinuria and GFR: risk factors for ESRD

Shahinfar S et al, Kidney Int: S48-S51, RENAAL Baseline Characteristics

Albuminuria and kidney failure risk

Tangri N et al, JAMA. 2016 Jan 12;315(2):164-74

Risk calculator: kidneyfailurerisk.com

Chronic Kidney Disease Prognosis Consortium721357 participants30 countries

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Risk stratification

KDIGO 2012, Kidney International, Issue 1, 2013

1

1

1

1

1

2

2

2

2

3 3

3

3

3

4

44 4

Numbers indicate the suggested number of visits/year

Is testing for albuminuria enough?

Albuminuria and DKD progression in T1D: DCCT/EDIC >20 years follow up

Molitich et al, Diabetes Care, 2010; 33:1536-43, DCCT-EDIC f/u

11.4%Severe albuminuria was a strong predictor of risk of developing sustained eGFR <60 ml/min/1.73 m2

Screening with AER alone would have missed 24% of cases of sustained impaired eGFR

Normoalbuminuric DKD progression in T2D

Ravi Retnakaran et al. Diabetes 2006;55:1832-1839, UKPDS 74

5102 UKPDS patients with T2DNormal albuminuria and creatinine at baseline

51% NA

6

Normoalbuminuric DKDPrevalence of low GFR and normoalbuminuria

MacIsaac Kidney Int 2014; 86: 50 MacIsaac, Kidney Int 2014; 86: 50

Natural history of albuminuria

Nephrology referral and biopsy

Worsening proteinuria despite treatmentLoss of eGFR> 1cc/min/1.73m2/monthActive urine sedimentAbsence of retinopathy

>30% reduction in eGFR after initiation of ACEi/ARBRefractory hypertension

eGFR<30 cc/min/1.73m2 at diagnosis

biopsy

CKD care and referral for renal replacement strateg ies

ADA recommendations, Diabetes Care, January 2018NKF QDOQI guidelines for diabetes, AJKD 2014

ADA

QDOQI

Gonzalez Suarez ML, Thomas DB, Barisoni L, Fornoni A., World J Diabetes, 2013

Often the diagnosis

In clinically indicated kidney biopsies differs

from DKD

Protocol kidney biopsies

are needed to understand the

disease

Limitation of clinically indicated kidney biopsies

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TYPICAL DIABETIC NEPHROPATHY (C2) – 30 %

NEAR NORMAL HISTOLOGY

(C1) – 30 %

NON-SPECIFIC FINDINGS

(C3) – 40 %

(a) Both normal and totally destroyedglomeruli

(b) Severe arteriolohyalinosis

(c) Tubulointerstitialfibrosis

Fioretto et al. Diabetologia 1998;41:233-236

Albuminuria and T2D: pathologic heterogeneity

Change in GFR (%) in patients with T2D and albuminuria

-20

-10

0

+10

∆ %

GF

R/y

ear C3

C1

C2

Nosadini et al. Diabetes 2000;49:476-484

* p<0.05, C2 vs C1 ja C3

*

(n=33, 4 year follow-up)

GBM thickening can predict decline in kidney function in T1D with NA

Caramori M L et al. JASN 2013;24:1175-1181Pagtalunan ME et al, JCI, 99: 342-348, 1997Meyer TW et al, Diabetologia, 42:1341-1344

Podocytopathy in early DKD in T2D

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Podocytopathy in DKD in T1D

White K E et al. Diabetes 2002;51:3083-3089

Podocyte detachment occurs in T1D correlates with AER and loss of GFR

Toyoda M et al, Diabetes, 2007, 56: 2155

Fraction of peripheral GBM covered by intact foot processes




Prevention and treatment of DKD

American Diabetes Association recommendations 2018

Level of evidence A:control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD)control glycemia (A1C about 7%, personalized)control dyslipidemia (LDL goal <70-100 mg/dl)counsel about smoking cessationeducation

Level of evidence B:protein intake to 0.8 mg/kg/day (more if dialysis)


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JNC7 versus ACC/AHA 2017

ACC/AHA recommendations Nov 13 2017

Recommendations for the treatment of hypertension in DKD


Metabolic and hemodynamic factors in DKD

Bakris, AJKD, 36:646, 2000

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Bakris GL, AJKD, 36:646, 2000

Role of BP in DKD Role of ACEi to treat DKD

The Collaborative Study Group, NEJM, 329:1456, 1993

Type I DM (207 captopril and 202 placebo)

Proteinuria>500 mg/24 h

Creat <2.5 mg/dl

Significant effect of captopril on blood pressure

0

10

20

30

40

50

%

1 2 3 4

Risk reduction of 51% P=0.006

Captopril 25mg x 3

Time (year)

Placebo

Captopril

% o

f patient

s with e

ndpoints

* dialysis, transplant, death

Role of ARB to treat DKD

IDNT trial, NEJM 345:851, 2001

1715 pt type 2 DM + HTN

Irb 300 mg vs amlo 10 mg vs placebo

End points:

doubling creatinine

ESRD

death

F/u 2.6 years

-3.3 mmHg mean BP in tx vs placebo

Placebo

Irbesartan 150 mg

Irbesartan 300 mg

20

15

10

5

0

0 3 6 12 18 22 24

Inc

idenc

e o

f diabetic

nephro

path

y (%

)

P<0.001

P=NS

Time (months)

IRMA-2. Parving et al. N Engl J Med 2001;345:870-8

ACEi vs CCB in primary prevention of DKD with mild hypertension

BENEDICT, NEJM, 251:1941, 2004

1204 patients, type 2 DM

Primary end point: persistent MA

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ARB vs placebo in primary prevention of DKD with normal BP

Bilius R et al, DIRECT, Annals of internal medicine, 2009; 151:11-20

3326/1905 (type 1/type2) patients.

Normotensive with normoalbuminuria

Candesartan versus placebo (significant effect on BP)

4.7 years follow up

Primary end point: development of MA

Secondary: Change in UAER Barnett AH, NEJM, 351:1952, 2004

ACEi or ARB?

Prospective, multicentered, double-blind study250 patients with type 2 DM and DNTelmisartan 80 mg vs enalapril 20 mg.Five year follow-upPrimary end-point: change in iohexol GFRSecondary end-points: creat, UAE, BP

no difference!

ACEi or ARB?

ADA 2017:

Type 1 DM with HTN and albuminuria: ACEiType 2 DM with HTN and microalbuminuria: either ACEi or ARBsType 2 DM with HTN and overt nephropathy: ARBsWhen not tolerated, substitute one for the other


Combination not supported

Is there a role for ACEi/ARB combinationin DKD in type 2 DM? ON TARGET

Mann J et al, ONTARGET trial, The Lancet, 2008, 372: 547-562

25620 patients with CV disease or high risk diabetes Follow up for 5 yearsPrimary renal outcome: dialysis, x2 creat, death

BP -2.4/1.4 mmHg

BP -0.9/0.6 mmHg

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Aldosterone antagonism in DN

J Hyperten, 2006, 24:2285

Randomized trial59 patients with type 2 DM+ macroalbuminuriaOn ACEi or ARB25-50 mg spironolactone x 1 year

Epstein, M. et al. Clin J Am Soc Nephrol 2006;1:940-951

Figure 3. Percentage change in median UACR from baseline to we ek 12, by quartile of baseline estimated glomerular filtration rate (eGFR) and treatment group

Aldosterone antagonism in DKD

ARTS-DN Japan

Journal of Diabetes and Its Complications 2017 31, 758-765DO

Aldosterone antagonism in DKD:phase 2b with finerenone

ARTS-DN

JAMA 2015, 314:884






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Kovesdy CP et al, AJKD 2008, 52: 766Cohen RM et al, Diabetes Care. 2003 Jan;26(1):163-7McCarter RJ et al, Diabetes Care. 2004 Jun;27(6):1259-64

A1C: a real measure in CKD?

Falsely elevated A1C:

Uremic toxinsMetabolic acidosis

Falsely decreased A1C:

Decreased 1/2 life RBCsBlood transfusionsEPO treatment

May need to change to glycated fructosamine, glycated albumin, variation of A1C or glycosylation gap (based on A1C and fructosamine)

Intensive treatmentWith A1c 7.2

Standard treatment With A1c 9.1

-64

-54-51

-39

-56-61

-72-80

-70

-60

-50

-40

-30

-20

-10

0Retinopathy Severe DR Laser Rx Microalb Severe

MicroalbAlbuminuria Neuropathy

NEJM 1993; 329:977

DCCT: 1441 patients with type 1 DM

f/u 6.5 years

Insulin 3 x day or pump vs conventional (1 or 2 daily insulin injection)

Primary prevention/secondary prevention

Difference maintained after discontinuation of tx (7 yr follow up)

Role of glycemia in type 1 DM and DKD

Treatment with A1c 7.0

Diet with A1c 7.9

-12

-25-29

-24

-34-40

-35

-30

-25

-20

-15

-10

-5

0Any Diabetes

RelatedEndpoint

MicrovascularEndpoints

Laser Rx Cataract Albuminuria

UKPDS: 3867 type 2 DM

Median age 54

Intensive tx (sulpha or insulin) versus diet

End points: any DM related end-point, diabetes related death and all cause mortality

F/u 10 years (15 years f/u had no difference in diabetes related death)Lancet 1998; 352: 837-853

Role of glycemia in type 2 DM and DKD Role of glycemia in advanced DKD

Ricks et al., Diabetes 61(30): 708–715, 2012

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Regression of MA in type 1 DM

% Risk Reduction Perkins, NEJM, 2003;348:2285

386 patients with persistent MATotal f/u of 4 periods of 2 years eachRegression defined as 50% reduction in UAE from one period to the other

Regression of MA in type 2 DM

% Risk Reduction Araki, Diabetes, 2005;54:2983

216 Japanese patients with type 2 DMF/u 6 years, 3 periods of 2 years eachRegression: 50% reduction MARemission: back to NA

A1C: how low can we get?

ADVANCE trial, NEJM, 358:24, 2008

11140 patients, standard vs intensive (sulfa + other drugs to achieve A1C less than 6.5).Macro: CV death, MI, strokeMicro: development of alb, x 2 creat, ESRD

21% relative reductionin nephropathy

ACCORD, NEJM, 358:24, 2008

10,251 patients, standard vs intensive (mainly insulin and TZDs).1/3 patients had prior CV eventEnd point: CV death, MI, strokeDiscontinued after 3.5 years f/u for high mortality in intensive arm.

A1C: how low can we get?

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Are all anti-diabetic drugs alike?

Legend: MET=Metformin, GLP1 RA= incretins, SGLT2i= glycosuric a, DPP4-i= incretins, AGi=alpha-gluc inhib, TZD=glytazones, Su= sulphanilurea, GLN= glucosaminog, COLSVL= bile acid, BCR=bromocriptin, PRAM=pramlintide

www.AACE.com Hattersley AT, Thorens B. N Engl J Med 2015;373:974-976

Renal Absorption of Glucose and Glucagon Secretion According to the Presence or Absence of a Sodium-

Coupled Glucose Transporter Type 2 (SGLT2) Inhibito r.Glycemia and DKD: drug class effect

SGLT2 inhibition: is sweet urine the solution?

Wanner C et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1515920

K–Meier Analysis of Two Key Renal Outcomes.SGLT2 inhibitors and DKD: EMPA-REG

Composite outcomeComposite outcomeComposite outcomeComposite outcome: doubling of the serum creatinine initiation of renal-replacement therapy death from renal disease

46%

Worsening NephropathyWorsening NephropathyWorsening NephropathyWorsening Nephropathy:eGFR<60 ml/min and/or ACR>300 mg/g

39%

Neal et al, et al. N Engl J Med 2017. 377:644-657

K–Meier Analysis of Two Key Renal Outcomes.SGLT2 inhibitors and DKD: CANVAS trial

With better A1C and BP control

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K–Meier Analysis of Two Key Renal Outcomes.ARB versus SGLT2 inhibitors

Doubling of serum creatinine

ESRD

All cause mortality

0.1 0.4 0.7 1.0 1.4

0.67

0.92

0.77

Hospitalisation for heart failure

0.78

Doubling of serum creatinine

ESRD

All cause mortality

0.1 0.4 0.7 1.0 1.4

0.56

0.68

Hospitalisation for heart failure

0.65

0.45

IDNT EMPA-REG

Courtesy of Dr Per-Henrik Groop % Risk Reduction

SGLT2 inhibitors and TG feedback

Cherney D et al, CirculationAHA 2013

No difference in incident albuminuria!

Other effects?

DN: the gut to kidney connection

Muskiet et al, Nature Review, 10:88-103, 2014

K–Meier Analysis of Two Key Renal Outcomes.Liraglutide and DKD: LEADER trialTime to first renal event: ACR>300, x2 creat, ESRD, renal death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

Mann J et al, NEJM 2017, 377:839-848, 2017l

9340 T2DM patients3.8 yrs f/uCKD1 35%, CKD2 42%, CKD3 20%

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K–Meier Analysis of Two Key Renal Outcomes.DPP4 inhibition and DKD: linagliptin

5466 T2D pt13 trialsSec EP: new onset A50% eGFR loss (CKD-EPI)S creat >250 umol/L






Statins do not prevent GFR loss

CARDS study group, Am J Kidney Dis. 2009 Nov;54(5):810-9

Haynes R et al. JASN 2014, 25:1825-1833






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Cigarette smoking and DKD (T1D)

normo→micro mild→moder moder→ESRD

NC

EE

N

C

E

N

C

HR=2.39* for current smokers HR=ns* for current smokers HR=ns* for current smokers *Adjusted for duration of diabetes, HbA1c and hypertension

N=non-smokers, C= current smokers, E=Ex-smokers

Feodoroff et al Acta Diabetol 2016






Multifactorial intervention in type 1 DM

Hovind, P, Diabetes Care, 26: 1258, 2003

600 patients20 years follow up

ACEi

SmokingA1CMAP

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Multifactorial intervention in type 2 DM

Gaede, P, NEJM, 358: 580, 2008Diabetic Nephropathy Remission and Regression Team Triial (DNETT-Japan)

160 patients from Steno27.8 years tx + 5.5 yrs f/u

Primary end point: deathSec end point: ESRD

INTENSIVE:StatinASAACEi/ARBExercisediet



Level of evidence A:control BP with appropriate agents (goal <140/90mmHg, <130/80 only for younger patients)control glycemia (A1C about 7%, personalized)control dyslipidemia (LDL goal <70-100 mg/dl)counsel about smoking cessationeducation

Level of evidence B:protein intake to 0.8 g/kg/day (more if dialysis)


Dietary protein intake in DKD

Hansen HP et al, Kidney International, 62:220, 2002

Careful protein restriction in CKD 3 and above

Case

SmokerObeseBP150/90A1c 11%LDL 150High protein diet

Mr JD comes to you with GFR 50 cc/min/1.73m2

Non smokerExercise TIWBP130/80A1c 6.9%LDL 70Low protein diet

GFR loss 20 cc/min/year GFR loss 2 cc/min/year

ESRD in 2 year ESRD in 20 year

IT’’’’S UP TO MR JD AND TO YOU!

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Is hyperuricemia a predictor of outcome?

355 patients with DM and MABaseline uric acid determination6 years f/uEnd points: GFR Cystatin decline albuminuria

Ficociello et al, Diabetes Care. 2010 Jun;33(6):1337-43.

263 patients with type 1 diabetes, 18.1 years f/uUric acid measured 3 years after onset of diabetesAll patients NA at enrollment (23 with macroalbuminuria at f/u)

Hovind P et al, Diabetes, 2009 Jul;58(7):1668-71

Awaiting the results of the preventing early renal function loss

(PERL) allopurinol study

DKD: role of Vitamin D

168 consecutive patients in a CKD clinic (28% with DKD)6 years follow upBaseline Vitamin D adjusted for age, sex, smoking, CRP, albumin, ACE/ARB usage, eGFR

Ravani P et al, Kidney International (2009) 75, 88–95

TNF Receptors 1 and 2 in DKD

Cumulative risk for CKD>3 in patients with T1D during 12 years of follow-up according to quartile (Q1–Q4) of circulating TNFR2 at baseline.

Gohda T and Niewczas M et al, JASN, 23:516-524, 2012

(Caucasian Americans, 410 patients) Adapted from

Niewczas MA et al., JASN, 2012.(PIMA Native Americans, 193 patients) Adapted from

Pavkov ME et al. KI, 2014.

T1DM T2DM

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Soluble Urokinase Receptor (suPAR)

Hayek SS et al. N Engl J Med 2015;373:1916-1925.

2292 patientsQ1: eGFR loss of 0.9 cc/minQ4: eGFR loss of 4.2 cc/min

suPAR levels in patients with T1D and DKD

(A)

0 2 4 6 82500

3000

3500

4000

4500

time (years)

suP

AR

(pg

/ml)

Normo-normo(n=10)

Normo-micro(n=10)

##

(B)

0 2 4 6 82500

5000

7500

10000

time (years)

suP

AR

(pg

/ml) Micro-micro

(n=10)

Micro-macro(n=10)

##

**

Normo Micro Macro

0

5000

10000

15000

suP

AR

(pg

/ml)

**

**

**

Normal GFR

(C)

Yoo T, Pedigo C.Fornoni et al., JASN, 2014

(D)

BA

SE

LIN

E

Role of dyslipidemia in DKD

Sacks F M et al. Circulation. 2014;129:999-1008 Anne J Overgaard et al, Proteome Sci. 2010; 8: 4

Plasma proteome analysis of patients with type 1 DM and DKD

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Serum Amyloid A and DKD

Dieter BP et al, J Diabetes Complications. 2016 Nov - Dec;30(8):1467-1472

135 T2D patientsDKD stage 3a and severe albuminuria3.5 years of follow upOutcomes: death and ESRD

Plasma metabolomic analysis of patients with type 2 DM and DKD

Red circles: Common and stable metabolitesRed empty circles: Common metabolites that are not stableBlue: essential amino acids

Niewczas et al, Kidney International, 2014, 85:1214

DKD: next generation biomarkers DKD: system biology

Fornoni et al, Brenner Rector 11th Edition, In pressHeinzel et al,Frontiers in Cell and Developmental Biology, 2014

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Acknowledgments

Nephrotic Syndrome Study Network

Questions?

Diabetes and Kidney Disease - Baptist Health South Florida · 2018-03-14 · Diabetes and Kidney...

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