Transcript Proteinuria - Shantou University

Proteinuria
November, 2004
Objectives
1. Define proteinuria.
2. Discuss relationship of proteinuria to
disease.
3. Briefly review recognition of Nephrotic
Syndrome.
4. Discuss evidence for screening for
microalbuminuria in diabetic patients.
Introduction
When is Proteinuria Disease?
 ESRD/Dialysis = Disease
 GFR < 90 ml/min = Stage I Chronic Kidney Disease
 1+ Proteinuria = disease
 Microalbuminuria = ? disease
Defining Evidence Terms
 POEMs (e.g., prevents ESRD, stroke, death)
 SMOREs: surrogate markers of reliable evidence
(e.g., prevents ↓GFR, ↑ proteinuria)
 DOEs: disease oriented evidence (e.g., prevents
microalbuminuria)
Pathophysiology
 Proteinuria represents disruption of glomerulo-basement
membrane by hypertension, protein deposits, glucose, or
inflammation.
 Controlling blood pressure reduces damage to glomeruli.
 Controlling glucose prevents small vessel disease in kidney
and glomeruli damage.
 ACE Inhibitors and ARBs, independent of B.P. control,
reduce hydrostatic pressures in afferrent arterioles to prevent
glomeruli damage.
Defining Proteinuria
Degree of Proteinuria
24 Hour Urine
Urine Dipstick
Normal
<30 mg albumin
/day
None
Microalbuminuria
30 – 300 mg/day
None
Macroalbuminuria
300 – 3500 mg/day
>15 mg/dl (trace)
>3.5 g /day
>300 mg/dl (3+)
Nephrotic Range
Office Urine Dipstick
Trace
1+
2+
3+
4+
15 mg/dl
30 mg/dl
100 mg/dl
300 mg/dl
2000 mg/dl
Microalbuminuria
 Timed Urine (24 hour urine)
(30 – 300 mg/day
or 20-200 ug/min)
 Urine albumin/creatinine ratio
(>30 ug/mg creatinine)
 Spot microalbumin tests
(detects >2 ug/ml)
Case #1
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54 yo heroin addict with new onset 2+ bilateral
edema and 3+ proteinuria.
DDx includes CHF (valve damage), cirrhosis,
nephrotic syndrome, infection (HIV, Hep B,…,)
nephritis.
Initial workup:
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CXR, murmurs, echo
PT, LFTs, liver span, splenomegally
24 hour urine, albumin, lipids.
HIV, Hep B & C
Case # 2
 8 year old with strep. throat 2 weeks ago
with fatigue & dark urine & 2+ protein on
dipstick. 24 hour urine 3.7 g/ 24hrs.
Nephrotic Syndrome
 > 3.5 g/day albuminuria
 ↓ serum albumin
 Edema
 ↑ Lipids
 Our job is mainly to diagnose and refer for
renal biopsy.
Nephrotic Syndromes
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Membranous Nephropathy (adults, drugs)
Minimal Change Disease (80% of pediatric)
Focal Glomerulosclerosis
Membranoproliferative GN (post strep)
Rapidly Progressing GN
Systemic Diseases That Cause
Nephrotic Syndrome
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Neoplasm
Heavy Metals
Post Strep
Infection
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Hep B & C
HIV
Endocarditis
Syphillis
Schistosomiasis
Malaria
Filaria
 Vasculitis
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Lupus
HSP
Polyarteritis Nodosa
Wegner’s
 Amyloid
 Diabetes
 Drugs
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Heroin
NSAIDS
Penicillamine
Gold
Case 3
 36 yo woman who is asymptomatic but 1 day
late for menses comes in for a pregnancy test
(negative). The nurse also dips the urine and
finds 1+ proteinuria. The result ends up in
your box. Should patient make a follow up
appointment?
1+ Proteinuria
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UTI
Diabetes
HTN
NSAIDS
ATN/Nephritis
Polycystic kidney
Renal stone
Multiple myeloma
Sickle cell
Renal tublar defects
Renal tumors
Paraneoplastic syndromes
Heavy metals
HIV
Hep B & C
Endocarditis
Syphillis
Glomerulonephritis
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CHF
Orthostatic Proteinuria
Fever
Exercise
Emotional stress
Idiopathic
Lupus
Henoch schloein pupura
Polyarteritis nodosa
Wegener’s
Amyloid
Schistosomiasis
Malaria
Filaria
Heroin
Penicillamine
Gold
Captopril
1+ Proteinuria
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UTI
Diabetes
HTN
NSAIDS
ATN/Nephritis
Polycystic kidney
Renal stone
Multiple myeloma
Sickle cell
Renal tublar defects
Renal tumors
Paraneoplastic syndromes
Heavy metals
HIV
Hep B & C
Endocarditis
Syphillis
Glomerulonephritis
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CHF
Orthostatic Proteinuria
Fever
Exercise
Emotional stress
Idiopathic
Lupus
Henoch schloein pupura
Polyarteritis nodosa
Wegener’s
Amyloid
Schistosomiasis
Malaria
Filaria
Heroin
Penicillamine
Gold
Captopril
Persistent
Macroalbuminuria merits
workup and explanation.
Microalbuminuria
Should Diabetic (I & II) Patients Be Screened for
Microalbuminuria and Started on ACE Inhibitors?
Microalbuminuria
 58 yr old ♀with DM II, HTN, Obesity and ↑Lipids
comes in for routine Diabetic Checkup. B.P 128/80.
HgA1c 10.4. Cr 1.2
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Meds: ASA, HCTZ 25, Glucophage 500 BID, Lipitor 40
mg.
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Screen for Microalbuminuria?
What’s the best way to keep this patient from needing
dialysis?
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Microalbuminuria
 22 yo type I diabetic (5 years) on insulin and
no other meds comes in for routing checkup.
 Screen for microalbuminuria?
 What’s the best way to keep this patient from
needing dialysis?
Do you ever believe in DOEs?
Harm
Unknown
Theoretical
Improves
Outcomes
that Matter
ADA Guidelines:
Diabetic Nephropathy
 A-Level Evidence (well done RCTs)
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To reduce the risk and/or slow the progression of
nephropathy, optimize glucose control.
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To reduce the risk and/or slow the progression of
nephropathy, optimize blood pressure control.
ADA: Screening Guidelines
 Expert Consensus
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Perform an annual test for the presence of microalbuminuria
in (1) type 1 diabetic patients who have had diabetes >5 years
and (2) all type 2 diabetic patients starting at diagnosis.
Acceptable samples to test for increased urinary albumin
excretion are timed (e.g., 12 or 24 h) collections for
measurement of albumin concentration and timed or untimed
samples for measurement of the albumin:creatinine ratio. For
screening, an untimed sample for albumin measurement
(without creatinine) may be considered if a concentration
cutoff is used that allows high sensitivity for detection of an
increased albumin excretion rate. Level of evidence: E
ADA: Treatment Guidelines
 A-Level Evidence (well done trials)
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In the treatment of albuminuria/nephropathy both angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) can be used:
In hypertensive and nonhypertensive type 1 diabetic patients with
any degree of albuminuria, ACE inhibitors have been shown to delay
the progression of nephropathy. (1a)
In hypertensive and non hypertensive type 2 diabetic patients with
microalbuminuria, ACE inhibitors and ARBs have been shown to
delay the progression to macroalbuminuria. (Cochrane 1a DOE)
In patients with type 2 diabetes, hypertension, macroalbuminuria,
and renal insufficiency (serum creatinine >1.5 mg/dL), ARBs have
been shown to delay the progression of nephropathy.
If one class is not tolerated, the other should be substituted.
ADA: Treatment
 B-Level Evidence (well done cohort
studies)
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With the onset of overt nephropathy, initiate
protein restriction to <0.8 g • kg-1 body weight •
day-1 (approximately 10% of daily calories), the
current adult recommended daily allowance for
protein. Further restriction may be useful in
slowing the decline of glomerular filtration rate
in selected patients.
ADA: Treatment
 Expert Consensus
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If ACE inhibitors or ARBs are used, monitor serum
potassium levels for the development of hyperkalemia.
Consider referral to a physician experienced in the care
of diabetic renal disease when the glomerular filtration
rate has fallen to either <60 mL • min-1 • 173 m-2 or
difficulties have occurred in the management of
hypertension or hyperkalemia.
Consider the use of non-dihydropyridine calcium channel
blockers or beta-blockers in patients unable to tolerate
ACE inhibitors or ARBs.
Microalbuminuria (MA) Predicts
Death and Cardiovascular Events
But Not Nephropathy
(Diabetes Care 2001: LOE 4 Casecontrol).
Microalbuminuria (MA) Predicts
Death and Cardiovascular Events
But Not Nephropathy
df
(Diabetes Care 2001: LOE 4 Case-control).
 7 year case-control study showed association between MA and death and
cardiovascular events, but not nephropathy.
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Of diabetics with microalbuminuria:
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56% regressed to normal urine protein.
6% progressed to nephropathy.
Of diabetics without microalbuminuria:
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16% remained normal.
17% progressed to nephropathy.
 We don’t know whether treating the MA makes a difference in
preventing death or cardiovascular events.
 We don’t know whether treating MA prevents nephropathy over a longer
time period.
ACE Inhibitors slow progression of
albuminuria and nephropathy in Type I and II
Diabetics with hypertension.
(Arch. Int. Med. 1996. LOE 2c: small cohort-control trial)
(Am. J. of Kidney Dis. 2000 (LOE 1a: meta analysis)
ACE Inhibitors slow progression of
albuminuria and nephropathy in Type I and II
with hypertension.
Diabetics
(Arch. Int. Med. 1996. LOE 2c: small cohort-control trial)
(Am. J. of Kidney Dis. 2000 (LOE 1a: meta analysis)
 So ACEI is first line antihypertensive for diabetics.
 We still don’t know whether to screen for MA, but we want
our diabetics on ACE Inhibitors because we believe they
protect renal function.
 We don’t really know whether renal protection is from B.P.
control alone or if there is a separate renal protective effect.
ACE Inhibitors reduce albumin excretion
rate. Unclear evidence for a separate
renal protective effect beyond B.P control.
of
(Cochrane 2004 LOE 1a:systematic review)
Angiotenstin converting enzyme inhibitors in
normotensive patients with microalbuminuria.
(Cochrane 2004 LOE 1a:systematic review)
 Is any B.P. medicine as good as another?
ACE Inhibitors Prevent Progression
to Nephropathy in Normotensive
Type-I Diabetics with
Microalbuminuria (MA).
(Annals Int. Medicine 2001 (LOE 1a)
t
ACE Inhibitors Prevent Progression to Nephropathy in
Normotensive Type-I Diabetics with Microalbuminuria
(MA).
(Annals Int. Medicine 2001 (LOE 1a)
 Suddenly screening for MA looks better.
 Both hypertensive and non-hypertensive +
any proteinuria (including MA) should be on
an ACEI.
Diuretics are Superior to ACEI in
Treating Hypertension, Stroke
Prevention, and Overall Mortality in
All Subgroups, Including Diabetics.
(ALLHAT Trial, 2002: LOE 1b: large
RCT)
T
Diuretics are Superior to ACEI in Treating Hypertension,
Stroke Prevention, and Overall Mortality in All Subgroups,
Including Diabetics.
(ALLHAT Trial, 2002: LOE 1b: large RCT)
 Now we’re putting hypertensive diabetics on
HCTZ. ACEI is second agent of choice.
 What do we do with the non-hypertensive
diabetics?
 What do we do with the well controlled
hypertensive diabetics on HCTZ only?
To Prevent ESRD, I Recommend
 Treat HTN >130/80 in Diabetics (Lifestyle modification
then Diuretics 1st and ACEI 2nd) LOE 1b
 Screen type I diabetics not already on ACEI or ARB for
microalbuminuria yearly. (DOE 1a)
 Screen type II diabetics not already on ACEI or ARB for
microalbuminuria yearly (LOE 5)
 Use albumin/creatinine ratio or spot tests and confirm with
24 hour urine. (LOE 4)
 Tell patients there is no evidence that screening and treating
prevents ESRD and that lisinopril costs $70 for 90 days.
 Screen for proteinuria (1+) and any overt nephropathy and
consider protein restriction and renal consult.
Big Picture in Type II DM
 Control BP to prevent death, stroke, heart attack,
ESRD, (1a)
 Smoking cessation (same reasons) (1a)
 Aspirin 81 mg to prevent MI, stroke (1a)
 Lipid Control to prevent stroke, MI (1a)
 Metformin if obese. (1a)
 Glucose control to prevent retinopathy (2a), ESRD
(5)
 Screen/treat microalbuminuria to prevent ESRD (5)
Why Do I Believe in this DOE?
 I believe …
 microalbuminuria → macroalbumiuria → Chronic Kidney Disease
→ ESRD
 We can’t detect impact of ACEI with relatively short term studies
compared to length of time to develop ESRD.
 ESRD is epidemic and I’d rather err on the side of over treating.
 I’m prepared to change my mind if there is evidence that
either screening for MA or using ACEI is not cost effective,
harmful or long term data shows no benefit.