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
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