Diabetic

Nephropathy Rachel Brock, DO

Nephrology Assoc of MI

No financial

disclosures

Overview of Slides

Intro to Diabetic Nephropathy (DN)

Understanding albuminuria/Proteinuria

Screening

Recognizing AKI and CKD

Progression

Risk Factors

Associated symptoms/conditions

Treatment

Clues against DN

When to refer

Take home message

Works cited

Abbreviations

Diabetic Nephropathy (DN)

Leading cause of ESRD in the USA (over 50%

of pts on HD)

Of the pts with DM on HD, over 80% of them

are type II diabetics

Annual cost >10 BILLION dollars

High mortality, marked increase in

cardiovascular risk

Once overt proteinuria is present, ESRD can

possibly be postponed, but in most

instances not prevented

CKD definition

Nomenclature

CKD 5 pts are not yet on permanent dialysis.

ESRD means the pt is undergoing chronic RRT

– these people are no longer being monitored

for improvement.

Someone on HD who is being monitored for

renal recovery is “acute” and is therefore

NOT ESRD.

USRDS

United States Renal Data System

Annual Data Report on ESRD & Chronic Kidney Disease (CKD) in the United States

Goals:

Characterize the ESRD population

Describe the prevalence and incidence of ESRD along with trends in mortality and disease rates

Investigate relationships among patient demographics, treatment modalities, and morbidity

Report the costs of ESRD treatments and total burden of ESRD program in the United States

Identify new areas for special renal studies and support investigator-initiated research

Provide data sets and samples of national data to support research by the Special Studies Centers

USRDS 2013 ADR

Distribution of markers of CKD in NHANES participants with diabetes & hypertension, 2005–2010 Figure 1.11 (Volume 1)

NHANES 1988–1994 & 2005–2010 participants age 20 & older; single sample estimates of eGFR & ACR.

eGFR calculated using the CKD-EPI equation.

USRDS 2013 ADR

Prevalent counts & adjusted rates of ESRD, by primary diagnosis Figure 1.15 (Volume 2)

December 31 point prevalent ESRD patients.

Adj: age/gender/race; ref: 2010 ESRD patients.

USRDS 2013 ADR

Prevalence (%) of CKD in the NHANES population within age, gender, race/ethnicity, & risk factor categories Table 1.a (Volume 1)

NHANES 1988–1994 & 2005–2010 participants age 20 & older; single-sample

estimates of eGFR & ACR. eGFR calculated using the CKD-EPI equation. eGFR

calculated using the CKD-EPI equation.

USRDS 2013 ADR

Incident counts & adjusted rates of ESRD, by primary diagnosis Figure 1.7 (Volume 2)

Incident ESRD patients.

Adj: age/gender/race; ref: 2010 ESRD patients.

Proteinuria Matters Worsening proteinuria is the most

significant risk factor for progressive kidney disease/worsening of eGFR

Compared with normoalbuminuria, pts with proteinuria have a 3-4x increased risk of progression to ESRD

Risk for renal failure doubles with doubling of baseline level of proteinuria

The worse the proteinuria, the worse the renal prognosis

Lowering proteinuria lowers risk of progression to ESRD

Misnomers

“Microalbuminuria” is NOT small albumin

“Macroalbuminuria” is NOT big albumin

Normal urine albumin level = A1

Microalbuminuria is being replaced by A2

proteinuria or “moderate proteinuria”

Macroalbuminuria is being replaced by A3

proteinuria or “overt proteinuria”

Albuminuria

A1 “Normo”albuminuria: < 30 (µg/mg or mg/g)

Diagnose with a random albumin to creatinine ratio (ACR)

Technically, ACR and not a spot albumin alone correlates with 24hr urine studies.

2/3 tests over 6 months needed for “positivity”

Spot albumins fluctuate and AM checks are most accurate.

Albuminuria

Microalbuminuria = A2

ACR 30-300

Indicative of some degree of DN

Macroalbuminuria = A3

ACR >300

“Overt” nephropathy

Protein dipstick positive

Can start checking Urine Protein Creatinine Ratio instead

UPC >0.15 is abnormal

Watch the units!

proteinuria

= 30-300 mg/g

= 30-300 µg/mg

= 30-300 mg/L

= 30-300 mg/24hrs

Example:

U prot 60mg/L

U Cr 125mg/dL

Referred for proteinuria 0.5g/d

But 60mg/L = 6mg/dL

UPC is 0.05g/d

Screening

DM1

Starting 5 years after diagnosis

Screen annually for albuminuria

and renal function

MDRD or CKD-epi generally used to

calculate GFR

Screening

DM2

Screen for proteinuria and renal

dysfunction immediately, and then

annually

Proteinuria is less predictive of

progression of disease

Average time of progression, from A3 to

ESRD, with no intervention: 6-7yrs

MDRD or CKD-epi generally used to

calculate GFR

“False-Positive” Proteinuria

Remember to recheck!

Protein levels vary during the day

UTI, heavy exercise, very high

protein intake, febrile illness, heart

failure, menstruation, vaginal

discharge can confound results

USRDS 2013 ADR

Probability of urine albumin & creatinine testing in Medicare patients at risk for CKD Figure 2.5 (Volume 1)

Medicare patients from the 5

percent sample, age 20 &

older, with Parts A & B

coverage in the prior year;

patients diagnosed with CKD

or ESRD during prior year

are excluded. Tests tracked

during each year.

How do we do with screening?

Recognizing CKD

SCr 1.2, 60yo pt

What’s the eGFR ?

AAM = 70ml/min

WM = 66

AAF = 59

WF = 49

Age Appropriate GFR

Loss of 1ml/min per year over the age of 40 (some

would argue age 30)

This means that a normal GFR for a:

70yo is about 70ml/min

80yo is about 60ml/min

90yo is about 50ml/min

Whether or not this should “qualify as true CKD” remains

controversial

AKI

An increase in SCr by 0.3 is AKI

– if baseline is 0.6, then 0.9 is AKI whether or not it “flags” as abnormal!

USRDS 2013 ADR

Life expectancy of NHANES participants with or without CKD, 1999–2004 Figure 1.16 (Volume 1)

NHANES 1999–2004 participants age 20 & older; single sample estimates of eGFR & ACR. eGFR calculated

using the CKD-EPI equation.

Proteinuria vs. eGFR – what matters more?

Ultrasound as appropriate

screening

Eval for kidney size, which is usually

normal to increased in the initial stages

If CKD is advanced, kidneys may begin to

atrophy

Rule out obstruction/reversible causes

Degree of echogenicity can help

determine presence of chronic renal

disease

Risk Factors

Family history of diabetic nephropathy

Other genetic risk factors

HTN

Loss of nocturnal dip

Poor glycemic control

Race: African Americans, Mexican, Pima Indians

Obesity

Smoking

Hyperfiltration as a risk factor

GFR appears good, but this is

compensatory, and can be an early

indicator of damage, especially if

proteinuria is present

Afferent arteriolar vasodilation as seen

in patients with diabetes

Efferent arteriolar vasoconstriction

owing to activation of the RAAS

Leads to glomerular hypertension and

ultimately renal injury (drop in eGFR)

Linking Retinopathy and DN In DM1, if overt DN is present, then it should

have been proceeded by retinopathy.

However, the presence of retinopathy in

DM1 does NOT mean that DN is present, nor

that it will develop.

In DM2, retinopathy has a very high positive

predictive value when combined with

proteinuria:

If DM2, retinopathy, and proteinuria are

present, then DN is likely.

If DM2 and proteinuria are present and

retinopathy is NOT, then nothing can be

said about likelihood of DN.

Hematuria in DN

Hematuria CAN be present in DN,

and is glomerular in origin

Hematuria should be evaluated for

alternative etiologies

Including cytology and potentially

with urologic eval

RBC casts are very rare in DN: urine

sediment should generally be bland

Nephrotic Syndrome

Hypoalbuminemia,

Hyperlipidemia, Edema,

>3g/day (nephrotic range)

proteinuria

Nephrotic syndrome CAN be

seen in DN

Should be evaluated by nephro

Histopath of Diabetic Nephropathy:

Mesangial expansion

GBM thickening

Sclerosis

Nodularity

Normal Glom

Progression

5 stages of Diabetic Nephropathy (not CKD)

STAGE 1

Duration 0-3-5yrs: renal hypertrophy, increased

GFR

STAGE 2

Duration 3-5yrs: Histologic changes

STAGE 3

Duration 7-15yrs: A2 proteinuria, HTN

STAGE 4

Duration 15-20yrs: Proteinuria, HTN, reduced

GFR

STAGE 5

Duration >15yrs: ESRD

DM1: Progression Pts with normoalbuminuria at 25yrs post

diagnosis will likely never develop significant

DN

20-30% of pts have A2 proteinuria at 15yrs after

diagnosis (similar to DM2)

Less than 50% of pts with A2 will progress to A3

BUT, the majority of the A3 population will

progress to ESRD

Onset of A3 proteinuria is generally 10-15yrs

post-diagnosis of DM1.

Less than 10% incidence of ESRD at 20-30yrs

post-diagnosis of DM1.

DM2: Progression

Approximately 5-10% of newly

diagnosed patients with type 2 DM

have overt nephropathy at the time of

diagnosis.

At 10yrs post-diagnosis of DM2, 25% of

pts will be A2, and 5% A3

Once A3, then progression rates similar

to DM1, but much more prevalent

Treatment

Can’t cure it, so endure it?

Goal is to SLOW rate of progression,

not to STOP progression

There is little agreement about

targets/goals for sugar control and

glycemic control

Glycemic control

Theory:

Improves hyperfiltration and

glomerular hypertrophy

Delay onset of proteinuria

Stabilize already existing

proteinuria

Slow decline in GFR

But is this true???

Glycemic Control

In DM1, tighter glycemic

control does improve incidence

of A2 proteinuria

Effect on renal disease is

controversial in DM2

Glycemic Control

ACCORD study

Intense vs. standard glycemic control

HbA1c 6.4-6.9 vs 7.3-8.4

Intense group:

Increase in hypoglycemia

No change in doubling of SCr or

need for RRT

Take home: No renal benefit from A1c <7

Metformin

FDA renal impairment contraindication

Males: Contraindicated if serum creatinine >1.5 mg/dL

Females: Contraindicated if serum creatinine >1.4 mg/dL

There is no systematic evidence that metformin increases risk of lactic acidosis in CKD

Off the record recommendations:

For eGFR <45, decrease dose by 50% and avoid initiation of metformin

Stop once eGFR <30

“My doctors days my diabetes medicines are hurting my

kidneys”

Insulin in CKD Increased incidence of hypoglycemia in CKD, whether

or not DM is present.

At low eGFR:

Insulin, which renally cleared, is not

metabolized as fast

Degradation of insulin in peripheral tissue is

reduced

Uremia poor appetite lower caloric intake

Renal mass is lower therefore renal

gluconeogenesis is reduced

Decreased metabolism of other oral anti-

hyperglycemics

As GFR worsens, you may need to be actively

reducing diabetes medications in your patients.

BP and Diabetic Nephropathy

Does BP control help renal

outcomes?

With ACE/ARB/CCBs, its often hard

to separate out if benefit is from

the antihypertensive vs

antiproteinuric effect of the

medicine.

Type of DM may matter.

Treatment: BP control

ACCORD study

Intense vs. standard BP control

Intense BP <120, standard <140

Intense group:

Improvement in proteinuria

Increased bradycardia, hypotension

Increase in SCr (worse eGFR)

No change in ESRD rate

Take home: No renal benefit to aggressive

BP management

Angiotensin Inhibition

ACEi and ARBs are more renoprotective than other non-angiotensin inhibiting meds

Antiproteinuric and antihypertensive properties

In general ACEi = ARB in terms of renoprotection in CKD

ACEi > ARB in terms of overall mortality in DM

Efficacy in both primary prevention of DN and in pts with overt DN

ACEi in DM1 - Proteinuria Moderate benefit in moderate proteinuria

Pronounced benefit in overt proteinuria

Benefit regardless of presence of HTN

However…

At SCr >1.5

Slower rate of SCr increase and lesser likelihood of ESRD are limited to pts with SCr >1.5

At SCr <1.5

no improvement in SCr rise or progression to ESRD

Not quite clear if benefit is from antihypertensive or antiproteinuric effect (likely both)

ARB and DM2 - BP

IDNT trial (Irbesartan Diabetic Nephropathy Trial)

Irbesartan vs amlodipine vs placebo

SBP control to 120

improved risk of CV death and CHF

Decreased doubling of SCr and progression to

ESRD

SBP control to <120

Increase in all-cause mortality and CV death

Results may have been skewed by diff

proportions of CVD in the 2 groups

ARB and DM2 -

renoprotection

RENAAL

Losartan vs placebo (both in addition to conventional therapy except ACEi)

Most significant risk factor for worsening of eGFR was degree of proteinuria

Baseline retinopathy was associated with poor renal outcomes

Correcting for BP control, the antiproteinuric effect was estimated to be about ½ of the improvement in incidence of ESRD

Both INDT and RENAAL show lower risk of doubling of SCr, development of ESRD in DM2 with ARB

Neither study found significant CV mortality reduction

Both underpowered, both short study duration

ACEi vs ARB in DM2 –

renoprotection DETAIL

Enalapril vs Telmisartan in pts with moderate or overt proteinuria

Similar decline in GFR

Similar SCr, albumin excretion, progression to ESRD, CV events, mortality

VA NEPHRON-D

ACE + ARB

Good proteinuria reduction

No improvement in progression of renal disease

Increase adverse events

Trial halted early

ONTARGET

Ramipril + Telmisartan vs. Ramipril alone

Combo therapy

higher incidence of progression to ESRD and doubling of SCr

Higher incidence of hyperK, AKI requiring RRT, and hypotension

Angiotensin Inhibition – use in

who?

Any patient with CKD/proteinuria

Normotensive diabetics with A2 and

A3 proteinuria should be started on an

ACEi or ARB!

Ace + NSAID + poor PO intake

Complications of ACE/ARB

therapy

Hyperkalemia

Most likely in patients with

high-normal or high levels

prior to therapy

Levels up the mid 5’s are

generally acceptable

Complications of ACE/ARB

therapy Elevation of Creatinine

Efferent Arteriole Vasodilation reduction in

glomerular pressure fall in GFR

This fall in GFR is important and expected, it

reflects that the ACEi/ARB is doing its job!

A less than 30% elevation in creatinine is tolerable

if stable after 2-4months of therapy

Elevation in creatinine over 30% is concerning,

and should likely lead to cessation of the med.

Measure Creatinine and Potassium within 7 days of

initiation of ACEi or ARB

Antihypertensives

Even antihypertensives with no anti-proteinuric

effects are better than nothing

Lower BP is NOT always better

Additional reductions in BP may increase

mortality

In general avoid SBP <120 and DBP <75

Other antihypertensives

Aliskiren + ACEi/ARB not recommended

Spironolactone

Good antiproteinuric

No info available yet about effect on GFR in DN

Hyperkalemia

Need for diuretics is common

Volume status often contributes to degree of HTN

Discuss risk vs benefit! We don’t avoid diuretics to “save renal function” in the setting of CHF.

Remember CardioRenal Syndrome

Calcium Channel Blockers

Nondihydropyridines: Diltiazem and

Verapamil

Generally believed to show some

reduction in protein excretion

Verapamil and ACEi – additive effect?

Dihydropyridines: Nifedipine, Amlodipine

Variable effect on proteinuria

BP Guidelines in DM

KDIGO

In pts with CKD, regardless of

presence of DM:

Urine albumin <30mg/24hr (or

equivalent): goal BP < 140/90

Urine albumin >30mg/24hr (or

equivalent): goal BP <130/80

Initial choice of therapy should

be ACE/ARB if urine albumin >30.

USRDS 2013 ADR

NHANES participants at target blood pressure Figure 1.12 (Volume 1)

NHANES 1988–1994 & 2005–2010 participants age 20 & older; single sample estimates of eGFR & ACR; dialysis

patients excluded from NHANES 2005–2010. eGFR calculated using the CKD-EPI equation. This figure cannot be

directly compared to values in Table 1.b. The table represents NHANES participants who are classified as

hypertensive (measured/treated) but some of those are at target blood pressure. Represents all hypertensives plus

those hypertensives who are at target blood pressure probably due to medication.

How do we do with BP targets?

Other treatments - Sodium

Low sodium (2g/d) diet

Recommended for HTN control

Helps antiproteinuric effect of ACEi/ARBs

A true low salt diet is not the same as a No Added Salt diet!

Other treatments - Protein

Restriction

Controversial

Theory: reduction in protein intake should

reduce the intraglomerular pressure

At this time we are NOT recommending

dietary protein restriction

No long term data available

Small prospective studies show reduction

in progression to ESRD

Other treatments - Lipid

Management

Hyperlipidemia is common in DM

Cardiovascular disease is the number one

cause of death in CKD patients

In addition to systemic atherosclerosis,

glomerulosclerosis is possible

Unclear effects of lipid control alone on

DN (preventative effect not proven)

Take home message re: BP

ACEi with proven benefit in DM1 pts

with at least moderate proteinuria

ARB benefit not “proven” in DM1

ARB with proven benefit in DM2

Its likely that ARB = ACEi in DM 2 (in

particular if overt proteinuria)

Take home message re: BP

Combo therapy is best (sugar control, low Na,

BP control, ACEi/ARB)

Decreased proteinuria = SLOWING of rise in

SCr and decreased risk of ESRD

If pt has OVERT proteinuria, there is no study

which proves that improvement in proteinuria

will lead to better long-term outcomes

Dose-response relationship

Greater reduction in moderate proteinuria

= greater reduction in risk of renal disease

Any type of antihypertensive control is better

than none

What are proteinuria goals?

Controversial

ACR <300?

UPC less than 0.5g/d?

60% reduction from baseline?

Clues hinting against DN Refer

Onset of proteinuria less than 5yrs

from onset of DM1

AKI or fast decline in eGFR

Active urine sediment (RBC and

casts)

Absence of retinopathy in DM1

Systemic symptoms (derm, pulm)

When to refer con’t…

If the patient has significant renal dysfunction, CKD

4 (GFR <30) or worse

Any patient with nephrotic range proteinuria

(>3g/d)

If an ACEi or ARB initiation caused a creatinine

increase of over 30%

Electrolytes abnormalities

If it’s not DN, then what is it?

Most common Non-diabetic

Glomerular diseases include:

Membranous

IgA nephropathy

FSGS

Post-infectious

Minimal Change

Arteriosclerotic vascular disease

(nephrosclerosis)

USRDS 2013 ADR

Cumulative probability of a physician visit by month 12 after CKD diagnosis in 2010, by demographic characteristics, physician specialty, & dataset Table 2.g (Volume 1)

Patients alive & eligible all of 2010. CKD diagnosis represents date of first CKD

claim during 2010; physician claims searched during 12 months following that date.

USRDS 2013 ADR

Pre-ESRD nephrologist care (row %), 2011 Table 1.f (Volume 2)

Incident ESRD patients, 2011. eGFR calculated using

the CKD–EPI equation.

How do we do on referrals to nephro?

DN: Take Home Messages If you don’t screen for it, you won’t find it.

A SCr of <1.3 may not “flag” as abnormal, but may signify significant reduction in eGFR.

A change in SCr of 0.3 is AKI by definition

Not all proteinuria and renal dysfunction in a patient with DM is due to DN.

DN is slowly progressive over years, and rapid loss of GFR should prompt nephrology referral.

Unless you are actively managing PTH/Vit D, anemia… then your CKD 4 pts should have a nephrologist.

If you can use an ACEi, do so, but don’t use it in combo with an ARB

Believe in low sodium diets

In general, ACEi are well studied in DM1 and ARBs in DM2

Goals for proteinuria reduction are controversial, but in general attempts at lowering proteinuria are considered beneficial

Most pts need combination therapy to achieve reduction in proteinuria

Control sugar and BP, but watch for low sugars and avoid BP <120.

Up to a 30% increase in creatinine should be expected and tolerated when starting an ACEi or ARB.

A potassium of 5.5 is not a catastrophe.

Don’t give NSAIDs to anyone, ever. Just kidding. Kind of.

PLEASE let your patients know why they are referred.

Since I still have you

captive…

Just because a catheter is sitting in the chest wall, it is not a subclavian!

Permacaths are almost always IJ catheters

An AV graft is a type of AV fistula

but a fistula is not necessarily a graft

A permacath is a tunneled, cuffed, semi-permanent line

Vs. an acute line (“Quinton or Trialysis”) which is neither tunneled nor cuffed

R IJ Tunneled Catheter

R SC Catheter

THANK YOU!

Contact:

Rachel.Brock@stjoeshealth.org

Works Cited

Primer on Kidney Disease, 5th edition

Up to Date

AACE Guidelines

NKF KDOQI/KDIGO Guideline

NKF

ASN

Medscape

JNC guidelines

AAFP

Harrisons

Comprehensive Clinical Nephrology

Abbreviations Used ACEi: Angiotensin Converting Enzyme Inhibitor

ARB: Angiotensin Receptor Blocker

AKI: Acute Kidney Injury

BP: Blood Pressure

CCB: calcium channel blocker

CKD: Chronic kidney disease

CV: cardiovascular

DM1: Diabetes Mellitus Type 1

DM2: Diabetes Mellitus Type 2

DN: Diabetic Nephropathy

eGFR: estimated GFR

ESRD: end stage renal disease

FSGS: Focal segmental glomerulosclerosis

GBM: Glomerular Basement Membrane

GFR: Glomerular Filtration Rate

HTN: Hypertension

IJ: Internal jugular

ESRD: End stage renal disease

RAAS: Renin Angiotension Aldosterone System

RBC: Red blood cell

RRT: Renal replacement therapy

SCr: serum creatinine

SC: subclavian