kidney disease due to diabetes disclosures · 2017. 11. 22. · gonzalez suarez ml, thomas db,...

Kidney Disease due to DiabetesAlessia Fornoni, MD PhD

Professor of MedicineChief, Katz Family Division of Nephrology and Hypertension

Director, Peggy and Harold Katz Family Drug Discovery CenterUniversity of Miami School of Medicine

Jessica W. Tsai Science 2015;350:1434

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

Case

JD is a 30 year old male with a 15 yearhistory of type 1 DM and establishedretinopathy. A urine dipstick is negative forprotein, but spot urine for albumin shows aconcentration of 10 mg/dl (“normal” values0-15 mg/dl) in two of three urine collections.Urine creatinine is 40 mg/dl: ratio is 0.25 =250 mg/24 hours.

Is JD affected by DKD?

Objectives•Definition and screening for DKD

•2017 Treatment guidelines



DKD yearly updates

Page 88: Microvascular complications

Diabetes Care, 2017, 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

Kidney disease is among the top causes of death

Murray et al NEJM 2013; 369: 5

Screening for DKD

yearly follow up, Level of evidence B

ADA recommendations, Diabetes Care, January 2017

At diagnosis if HTN

Copyright ©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

Definition of DKDDIABETES with:

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

and/ordiabetic glomerular lesions

and/orloss of glomerular filtration rate (CKD-EPI

preferred)ADA recommendations, Diabetes Care, January 2017

Proteinuria and GFR: risk factors for ESRD

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

Risk stratification

KDIGO 2012, Kidney International, Issue 1, 2013

11

1

1

1

2

2

2

2

3 3

333

4

44 4

Numbers indicate the suggested number of visits/year

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

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 biopsiesObjectives

•Definition and screening for DKD


Prevention and treatment of DKD

American Diabetes Association recommendations 2017

Level of evidence A:control BP with appropriate agents (goal

Recommendations for the treatment of hypertension in DKD

Ian H. de Boer et al. Dia Care 2017;40:1273-1284©2017 by American Diabetes Association

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 hCreat

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

ADA recommendations, Diabetes Care, January 2017

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

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 week 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




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 DMf/u 6.5 yearsInsulin 3 x day or pump vs conventional (1 or 2 daily insulin injection)Primary prevention/secondary preventionDifference 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 DMMedian age 54Intensive tx (sulpha or insulin) versus dietEnd points: any DM related end-point, diabetes related death and all cause mortalityF/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

Regression of MA in type 1 DM

% Risk Reduction Perkins, NEJM, 2003;348:2285386 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?

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) Inhibitor.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 outcome: doubling of the serum creatinine initiation of renal-replacement therapy death from renal disease

46%

Worsening Nephropathy:eGFR300 mg/g

39%

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?

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%




Cigarette smoking and DKD (T1D)

normo→micro mild→moder moder→ESRD

NCE

E

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




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!

Acknowledgments

Nephrotic Syndrome Study Network

Questions?



•Novel biomarkers

DKD: Ongoing trials on new targets

Adapted from Fineberg, D. et al. (2013) Nat. Rev. Endocrinol. doi:10.1038/nrendo.2013.184

pyridoxamine

Allopurinol PentoxifyllineNox1-4CXC-140JAK-STAT

SGLT2 inhibitors

finerenone

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/u

Uric acid measured 3 years after onset of diabetes

All patients NA at enrollment (23 with macroalbuminuria at f/u)

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

DKD: role of Vitamin D

168 consecutive patients in a CKD clinic (28% with DN)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

DKD: role of Vitamin D

AgeGenderRaceseason

AgeGenderRaceSeasonHTNDMBMIHDLeGFRAlbVitD suppCRP

Melamed M et al, J Am Soc Nephrol 20: 2631-2639, 2009

Role of dyslipidemia in DKD

Sacks F M et al. Circulation. 2014;129:999-1008

TNF Receptors: new biomarkers

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.

MultivariateBaseline variables Univariate TNFR1 TNFR2TNFR1 (per

IQR) 2.5 (2.1, 3.1) 1.6 (1.1, 2.2) —TNFR2 (per

IQR) 2.5 (2.1, 3.0) — 1.7 (1.2, 2.3)

T1DM T2DM

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 QuizMr BN is a 38 yo male with a 15 years history of type 1 diabetes. His A1C is7% and his blood pressure is 130/80. He comes to you for an upper respiratoryinfection that started 10 days prior. His Strep throat test is positive. You screenfor DKD and find no albuminuria and normal eGFR. His complement is normal.He has microhematuria. A renal U/S demonstrates a complex mass that isconfirmed by biopsy to be a renal cell carcinoma. When the patient undergoesnephrectomy, the pathologist reports thickening of the glomerular basementmembrane in the non-tumoral portion of the parenchima and no deposits.

The likely diagnosis is:-IgA nephropathy-Post-infectious GN-Diabetic kidney disease-Alport syndrome

QuizMs AF is a 48 yo female comes to you with uncontrolled type 1 diabetes, heartfailure and new onset of severe albuminuria despite maximal dose of ramipril.She does not have diabetic retinopathy. Her urinary sediment is unremarkableand her urine ACR is 1600 mg/g. She has a normocytic anemia and normalplatelet count. Her PCP send the patient to you for evaluation of DKD. Her labwork demonstrated a creatinine of 1.3 mg/dl. Which test is most likely to revealthe appropriate diagnosis?

-HbA1C-A peripheral blood smear-A Congo red staining on a kidney biopsy-the presence of 2/3 urine collections with an ACR>30 mg/g

QuizMr RN is a 35 yo male with type 1 diabetes and established DKD. He comes toyou with concerns about his DKD progression. He does have establisheddiabetic retinopathy. He is not a smoker and blood pressure and HbA1C are attarget. His urinary sediment is unremarkable and his urine ACR is 400 mg/g.You test for uric acid and the value is 8 mg/dl. At this point you tell the patientthat:

1- he should absolutely start allopurinol now2- high uric acid is not a biomarker for DKD progression3- the benefits of treating patients with DKD and high uric acid withallopurinol is being studied4- he is at high risk to develop gout

Quiz

Which one of the following statements is true?

1. Nodular glomerulosclerosis is pathognomonic for DKD2. Interstitial fibrosis and tubular atrophy is an early finding and starts before

diabetic glomerulopathy becomes established3. DKD lesions are more homogeneous in type 2 compared to type 1

diabetic patients4. Podocytopenia correlates with albuminuria

QUIZMr BN is 53yo male with type 2 DM and CKD 4A2 who comes to your clinic to discuss how best to slow the progression of DKD. His BP is controlled, he exercises, he quit smoking, his Vitamin D is being replaced, his metabolic acidosis is corrected. However,his HbA1C is still 8.5% and he was advised to discontinue metformin. He is asking if there is any advantage to be on one hypoglycemic agent versus another.

You suggest the following:A. There is no advantage of one hypoglycemic agent versus

anotherB. He should definitely be on a SGLT2 inhibitor given the results

of the EMPA-REG trialC.At an earlier stage of CKD, either liraglutide or empagliflozin

may have additional benefits on DKD progressionD.He should stay on metformin

QUIZMr PG is a 62 yo male who is receiving chronic hemodialysis because of kidney failure attributed to type 2 diabetes. He is new to your practice. His blood pressure is 150/82 mmHg, Hgb is 11.5 g/dl, and HbA1c is 9.5%. He is not being treated with any hypoglycemic medicines. The patient previously took metformin and never experienced a severe hypoglycemic episode, but his PCP took him off this medicine when his eGFRdropped below 45 ml/min/1.73 m2 because of the increased risk of lactic acidosis. When Mr PG went on dialysis, his nephrologist did not start any hypoglycemic medicines. The patient takes a statin daily and erythropoietin to maintain his Hgbwithin the recommended range. He has good nutritional status. Which of the following statements is true?A. The apparent hyperglycemia should not be treated because HbA1c is not a reliable indicator

of ambient glucose in the setting of kidney failure and the patient is otherwise in good condition.

B. The use of erythropoietin and the reduced RBC lifespan seen in kidney failure causes the HbA1c to overestimate ambient glucose, so the patient is in good glycemic control and should not be treated with a hypoglycemic drug because it would increase the risk of severe hypoglycemia.

C. Treatment with insulin should be considered to achieve a modest reduction in HbA1c and reduce mortality risk.

D. Measure glycated albumin instead of HbA1c to assess glycemic control, as it provides a measure of intermediate term glycemic control and is not confounded by anemia and shortened red cell survival, and decide how to treat the patient after results of this test become available.

QUIZ

Ms AF is a 28 yo female with T1D and severe albuminuria and an eGFR >60 cc/min/1.73m2 who comes to see you for uncontrolled hypertension (160/95 mmHg). Her A1C is currently at target and she exercise regularly. She is also on a low salt diet. She recently got married and is planning to have a baby before her disease progresses. She has not been taking any blood pressure medication. You discuss with her the risk of experiencing progressive DKD should she become pregnant.

Which of the following advise is correct

A. She should immediately start RAS blockadeB. Blood pressure targeting will affect the chance to develop major cardiovascular

events but will not affect DKD progressionC. Blood pressure should be targeted at 130/80 with appropriate safe agentsD. A combination of ACEi and ARB would be most beneficial

QUIZ

Ms OL is a 46 yo male with T1D that comes to you with a 30 years history of diabetes. He is normoalbuminuric and normotensive. He is concerned that one day he may develop DKD.

Which one of this is the correct advise?

A. He should be placed on RAS blockade to present DKD developmentB. You advise the patient to undergo a kidney biopsyC. You tell the patient that his chance to develop DKD after so many years

from the diagnosis of diabetes is unlikelyD. you tell the patient that insulin treatment is protecting his kidneys

kidney disease due to diabetes disclosures · 2017. 11. 22. · gonzalez suarez ml, thomas db,...

Documents