The Codex of Business Writing Software for Real-World Solutions 2.pptx
Proteinuria
1. Proteinuria
SIMON E. PRINCE, D.O., F.A.C.P., F.A.S.N.
Clinical Assistant Professor of Medicine
NYU School of Medicine
Thursday, March 12, 2009
2. Huge range in clinically significant
proteinuria
the upper limit of urinary protein is
250-300 mg of protein a day
proteinuria a log unit lower (25-30 mg) is
clinically significant
proteinuria a log unit higher (2,500 to 3,000 mg)
are commonly encountered
Thursday, March 12, 2009
3. The normal amount of protein was
defined by the detection limits of a
dip-stick U/A.
Trace proteinuria on a dip, usually
corresponds to 300 mg of protein on a
24-hour collection.
Thursday, March 12, 2009
4. this lecture will
trace proteinuria
from the tiniest
microscopic
albuminuria through
normal up to tens
of grams found in
nephrotic syndrome.
Thursday, March 12, 2009
5. cells and large proteins
play the peas
Plasma is filtered freely
Peas in the
urine (e.g. proteinuria,
hematuria) indicate a tear
in the colander (damaged
glomerulus)
Thursday, March 12, 2009
6. urinary space
epithelial cell
(podocyte) foot
process
basement membrain
endothelial cell
capillary lumen
Thursday, March 12, 2009
7. the glomerulus is remarkably
efficient at preventing the loss of
protein in the urine
normal 24-hour urine albumin is less
than 300 mg/day
normal albumin level 4.0 g/dL
normal renal plasma flow is 600 mg/min
Thursday, March 12, 2009
9. 4g 600 mL plasma 1 dL 1440 min
dL plasma min 100 mL 24 hrs
Thursday, March 12, 2009
10. 4g 600 mL plasma 1 dL 1440 min
dL plasma min 100 mL 24 hrs
Thursday, March 12, 2009
11. 4g 600 mL plasma 1 dL 1440 min
dL plasma min 100 mL 24 hrs
Thursday, March 12, 2009
12. 4g 600 mL plasma 1 dL 1440 min
dL plasma min 100 mL 24 hrs
Thursday, March 12, 2009
13. 4g 600 mL plasma 1 dL 1440 min
dL plasma min 100 mL 24 hrs
Thursday, March 12, 2009
14. 4g 600 mL plasma 1 dL 1440 min
dL plasma min 100 mL 24 hrs
34,560 g of Albumin flow
through the kidney each day
Thursday, March 12, 2009
15. less than 0.3 g of albumin
ends up in the urine, or
0.3
x 100 = 0.0008%
34,560
Thursday, March 12, 2009
16. More than 0.0008% of
the albumin actually
passes the glomerular
barrier BUT it is
absorbed by the
proximal tubule cells
and metabolized
Thursday, March 12, 2009
17. Urine
Dipstick
Most common method of testing for
proteinuria
It is a plastic strip impregnated
with a pH indicator which changes
color in presence of proteins, due
to a pH change
Intensity of the color correlates
with the concentration of protein
Mainly albumin detected
Thursday, March 12, 2009
18. False Positive
Dipstick
Very alkaline urine (some UTIs)
Pigmented urine (hematuria)
Very concentrated urine (Usg >1.030)
Drug interference (chlorhexidine)
Contamination
Thursday, March 12, 2009
19. False Negative
Dipstick
The protein is not albumin
(i.e. Multiple Myeloma)
Urine is too dilute (Usg <1.005)
Thursday, March 12, 2009
20. Classification of Proteinuria
Tubular Proteinuria
Overflow Proteinuria
Glomerular Proteinuria
Microalbuminuria
Selective Proteinuria
Non-selective proteinuria
Thursday, March 12, 2009
21. Tubular
Proteinuria
Tubular dysfunction leads
to small MW proteins
(beta2 MG, lysozyme,
light chains, AAs) freely
filtered but not able to
be reabsorbed.
NOT detected on dipstick
Thursday, March 12, 2009
22. Overflow
Proteinuria
Occurs when the
concentration of one of
the small MW proteins is
so high that the filtered
load exceeds the tubular
reabsorptive capacity
Thursday, March 12, 2009
23. Causes of Overflow
Proteinuria
Multiple Myeloma
Amyoidosis
Light Chain Disease
Hemoglobinuria
Myoglobinuria
Thursday, March 12, 2009
24. Glomerular
Proteinuria
Glomerular dysfunction at
the level of the GBM
Most common and
clinically significant
form of proteinuria
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25. Microalbuminuria
persistent trace proteinuria which is
invisible on conventional urinalysis
(dipstick detects urine albumin >300 mg/day)
Microalbuminuria is defined as
urinary albumin excretion:
30-300 mg/day
20-200 mcg/min
Thursday, March 12, 2009
26. Why is
Microalbuminuria
important?
Predicts the
development of
nephropathy in
Diabetes
Correlates with
mortality in
diabetics and
hypertensives
Thursday, March 12, 2009
27. How to treat
Microalbuminuria
Strict blood pressure control
goal at least <130/80 mmHg with
ACE-inhibitors and/or Angiotensin
Receptor Blockers (or Renin
Inhibitors)
Strict Glycemic control in Diabetics
Thursday, March 12, 2009
28. Types of Glomerular
Proteinuria
SELECTIVE NON-SELECTIVE
PROTEINURIA PROTEINURIA
Only intermediate- Range of different
sized (<100kDa) protein sized
proteins (albumin, proteins leak
transferrin) leaks through including
through the larger proteins
glomerulus (Immunoglobulins)
Thursday, March 12, 2009
29. Edema
The palpable swelling
produced by an expansion of
the interstitial fluid volume
Thursday, March 12, 2009
30. Pathophysiology
Alteration in the capillary
hemodynamics that favors the movement
of fluid from the vascular space into
the interstitium
Retention of dietary or intravenous
Na+ and H2O by the kidneys
Thursday, March 12, 2009
31. Edema requires change in
Starling’s Forces
Elevated capillary hydraulic pressure
Increased capillary permeability
Increased interstitial oncotic
pressure
Reduction in plasma oncotic pressure
Thursday, March 12, 2009
34. Increased capillary blood pressure
blood
↑capillary
pressure
Causes:
•Elevated plasma volume
driving fluid into
↑force •Increased venous pressure
interstitium - Increased general venous
pressure
- Increased local venous
↑formation of
pressure
interstitial fluid
•Arteriolar dilation
When greater than
lymphatic
compensatory return
edema
Thursday, March 12, 2009
35. Decreased plasma colloid osmotic pressure
↓ plasma colloid Causes of Hypoproteinemia:
osmotic pressure
―Decrease of protein production
↓force drawing water
back into capillary from
interstitium ―Excessive loss of protein
↑formation of ―Elevated catabolism of protein
interstitial fluid
edema
Thursday, March 12, 2009
36. Increased capillary permeability
permeability
↑capillary
Causes:
Filtration of more protein from •Inflammation
capillary to interstitium
•Infection
•Burn
↓Plasma colloid osmotic pressure
•Allergic response
•Trauma
↑formation of interstitial fluid
•Anoxia
•Acidosis
edema
Thursday, March 12, 2009
37. The three great edematous
states
Congestive Heart Failure
Cirrhosis
Nephrotic Syndrome
Thursday, March 12, 2009
39. Congestive Heart
Failure
SYSTOLIC
DIASTOLIC
Thursday, March 12, 2009
40. Systolic Dysfunction
Decreased
myocardial
contractility
Thursday, March 12, 2009
41. Systolic Failure
Cardiac Output (Q) = SV x HR
Decreased stroke volume leads to
decreased cardiac output and
increased LVEDP
Increasing the capillary hydraulic
pressure
Decreased CO triggers renal Na+ and
H2O retention further increasing end-
diastolic pressure and volume
Thursday, March 12, 2009
42. Diastolic Dysfunction
Stroke Volume is preserved
Increased LV diastolic pressure at
any volume caused by a decrease in LV
compliance
Thursday, March 12, 2009
45. question
• Why can congestive heart failure make
edema?
Thursday, March 12, 2009
46. question
• Why can congestive heart failure make
edema?
– ↑General venous pressure
– ↓Plasma colloid osmotic pressure because of dilution of
blood
– Dysfunction of lymphatic return because of increased
venous pressure
– ↓GFR
– ↑Activation of the Renin-Angiotensin-Aldosterone axis
– ↑ADH
Thursday, March 12, 2009
49. Cirrhosis
Increased capillary
permeability
(vasodilitation)
leading to RAS
activation and renal
Na+ and H2O retention
Increased plasma
volume and hydraulic
pressure
Decreased oncotic
pressure
(hypoalbuminemia)
Thursday, March 12, 2009
52. Nephrotic Syndrome
Heavy urinary loss of albumin, leads
to hypoalbuminemia
Reduced intravascular albumin results
in decreased oncotic pressure
Loss of fluid from intravascular
compartment activates the RAS (under-
filling hypothesis)
Thursday, March 12, 2009
55. Why the
Hyperlipidemia?
Increased hepatic
synthesis cannot fully
compensate for the severe
urinary loss of most
proteins... Except for
lipoproteins which are
retained.
Thursday, March 12, 2009
56. Hypercoagulable state
Loss of proteins which are
anti-coagulants such as
anti-thrombin III, Protein
C and S... can lead to a
hypercoaguable state.
Classically renal vein
thrombosis (most often
associated with Membranous
Nephropathy)
Thursday, March 12, 2009
57. Causes of
Nephrotic
Syndrome
PRIMARY
(Idiopathic)
Thursday, March 12, 2009
59. How to Differentiate types
of Nephrotic Syndrome
History
PMHx, Family Hx,
Medications
Physical
Labs
Renal Biopsy
Thursday, March 12, 2009
60. What tests to order?
Comprehensive Metabolic
Lipid Panel
CBC
HbA1c
Serology based on clues
ANA, dsDNA, anti-Sm
ANCAs, anti-GBM Ab
Complements
HIV testing
Hepatitis Serologies
Serum protein and urine
electrophoresis
Thursday, March 12, 2009
61. Renal
Sonogram
Helps with structure not
function
Thursday, March 12, 2009
64. NEPHROTIC
Urinary Sediment: “bland”
Heavy proteinuria
Possible lipuria
Rare-few cells/ casts
HTN less frequent
Relatively preserved renal function
Thursday, March 12, 2009
65. Common causes of
Primary Nephrotic Syndrome
Minimal Change Disease
Focal Segmental Glomerulosclerosis
Membranous Nephropathy
Thursday, March 12, 2009
67. Minimal Change
Disease
Named because no changes seen on
Light Microscopy (AKA Nil disease or
lipoid nephropathy)
Thursday, March 12, 2009
68. Minimal Change
Disease
Most common cause
of NS in children
90% in children
<10 years old
>50% cases in
older children
10-15% adult cases
Thursday, March 12, 2009
69. Causes of MCD
Primary or Idiopathic (most common)
Secondary
Drugs: NSAIDs, rifampin, PCN, Lithium
Heme Malignancy: Hodgkins (most common),
NHL, Leukemia
Toxins: Mercury, lead, bee stings
Infectious: Mononucleosis, HIV
Obesity
Thursday, March 12, 2009
70. Signs and Symptoms
of MCD
Massive edema
Ascites
Pleural and Pericardial effusions
HTN uncommon
Hematuria uncommon
Renal function impairment uncommon
Thursday, March 12, 2009
73. Treatment of
MCD
Steroids are mainstay of
therapy
Complete Remission ~90%
Children remit more rapidly-
50% within 2 wks; nearly all by
8 weeks
Adults can take 12-16 wks
DOSE: 1 mg/kg/d Prednisone or
2mg/kg/qod
DURATION: 8-16 weeks (continue
1-2 wks after remission) then
taper
Thursday, March 12, 2009
74. COMPLETE REMISSION:
<300 mg/d proteinuria
PARTIAL REMISSION:
decrease >50% proteinuria
RELAPSE: return to >3.5 g/d in pt who
was in complete or partial remission
STEROID DEPENDENCE: need to cont. Tx
to maintain remission
STEROID RESISTANCE: little or no
reduction after 12-16 wks of steroid
therapy
Thursday, March 12, 2009
75. Alternative Therapies
for MCD
Alkylating agents
(Cyclophosphamide,
Chlorambucil)
CellCept (MMF)
Azathioprine (Imuran)
Cyclosporin (Neoral)
FK506 (Prograf)
Levamisole
Thursday, March 12, 2009
77. FSGS
Most common cause of nephrotic
syndrome in adults especially in AA
FOCAL: <50 % glomeruli effected
SEGMENTAL: sclerosis with hyalinosis
involving portions of the glomerulus
Primary- Idiopathic most common
Thursday, March 12, 2009
78. Secondary FSGS
Obesity
OSA
Sickle Cell
HIV/AIDS
Hematologic malignancies
Decreased nephron number
Chronic vesicoureteral reflux
DRUGS: Lithium, Heroin, alpha-IF
Thursday, March 12, 2009
79. Clinical Features of
FSGS
Proteinuria- often nephrotic
Can range from 1 gram to 20-30 g/d
HTN common: ~45-65%
Microscopic Hematuria 30-50%
Decreased GFR at presentation 35-50%
Normocomplementemia
Thursday, March 12, 2009
81. Renal Biopsy in FSGS
LM: Sclerosis in segments (focal) of
the glomeruli (especially
juxtaglomerular)
Tubulointerstitial fibrosis
IF: non-specific “trapping”
EM: diffuse loss of podocyte foot
processes
Thursday, March 12, 2009
82. Treatment of FSGS
Immunosuppressive Tx for Primary FSGS
CORTICOSTEROIDS
Similar to MCD but longer duration
required with longer tapering
Second line: Cyclosporin or
Cyclophosphamide
Third line: CellCept or Prograf
Thursday, March 12, 2009
84. Characteristics of MN
Among most common causes of NS
especially white males >40 yo
Nephrotic Syndrome: 60-70%
others subnephrotic
Majority normal CrCl
10-20% decreased CrCl
HTN uncommon at presentation
Urine sediment often bland
30-40% microscopic hematuria
Renal Vein Thrombosis
seen in up to 20% cases
Thursday, March 12, 2009
86. Light Microscopy in MN
Early MN appears normal
Later increased size and
# of immune complexes in
subEPIthelial space
produces thickened GBMs
Thursday, March 12, 2009
87. Special
Stain
Classic “spikes” can be
seen as complexes
accumulate and disrupt
the GBM
Thursday, March 12, 2009
88. IF MN
Stains positive for
IgG and C3 in a
typical “beaded
appearance”
Thursday, March 12, 2009
89. EM MN
SUBEPITHELIAL DEPOSITS
Stage I
deposits subepi GBM
Stage II
deposits partially
surrouned by new BM
Stage III
deposits fully
surrounded
Stage IV
deposits lucent
Thursday, March 12, 2009
90. Therapy in
MN
Non-specific
vs.
Immunosuppression
Thursday, March 12, 2009
92. Blood Pressure and
Proteinuria
Goal BP:
< 130/80 mmHg
or
<125/75 mmHg if
>1 gram/d proteinuria
Preferred medications:
ACE inhibitors
Angiotensin Receptor Blockers
Renin Inhibitors
Aldosterone Antagonists
Non-Dihydropyridine CCBs
Thursday, March 12, 2009
93. Other non-specific
therapy for proteinuria
Tight glycemic control in DM
Goal HbA1c < 7
Dietary protein restriction
0.6 g / kg/ day
Statin based lipid therapy
Goal LDL at least <100
Thursday, March 12, 2009
94. Immunosupression in
MN
More intensive than
in MCD or FSGS
Who should we treat?
Thursday, March 12, 2009
95. Rule of Thirds
1/3 Spontaneously
Remit
1/3 Partially
Remit
1/3 Progress
towards ESRD
Thursday, March 12, 2009
96. Who’s at Risk for Progression?
LOW RISK
Normal Serum Creatinine
Proteinuria <4grams/d over 6 month observation
MEDIUM RISK
Near normal Creatinine / CrCl
Proteinuria 4-8 grams/d
HIGH RISK
Elevated Serum creatinine
Persitently high grade proteinuria >8 grams/d
Poor prognositic signs on renal biopsy
Thursday, March 12, 2009
97. LOW AND HIGH RISK
No immunosuppression
Non-specific anti-proteinuric
strategy is most prudent
Both groups: Risk > Benefit
MEDIUM RISK
Receive immunosuppression to
attempt to achieve remission
Thursday, March 12, 2009
98. Immunosuppression in MN
Steroids alone are NOT recommended
FIRST LINE: Corticosteroids +
Cytotoxic agent (Cyclophosphamide or
chlorambucil)
SECOND LINE: Cyclosporin
ALTERNATIVES: CellCept, Prograf,
Azathioprine, Rituxan, IvIg
Thursday, March 12, 2009
100. Diabetic Nephropathy
Most common type of Secondary NS
Can occur in both Type I and II DM
Prognosis can be improved with
aggressive monitoring and therapy
Thursday, March 12, 2009
101. Which diabetics are
at risk for DN?
Poor glycemic control (inc HbA1c)
Suboptimal BP control
Genetic factors (Family h/o ESRD)
Race (African Americans higher risk)
Age
Smoking
?OCP
Thursday, March 12, 2009
102. Stages of DN
STAGE 1
Hyperfiltration
Elevated CrCl
Glomerular Hypertrophy
Thursday, March 12, 2009
103. Stage II DN
Microalbuminuria
UAE 30-300 mg/d
Typically begins >5 yrs after overt
DM diagnosed
compared with normoalbuminuric
patients, those with microalbuminuria
are at 300-400% increased risk of
ESRD
Thursday, March 12, 2009
104. Stage III DM
Overt proteinuria
UAE >300 mg/day
Starts about 10-20 yrs after DM onset
BP elevated
Glomerular lesion worsens
Thursday, March 12, 2009
105. Stage IV DM
Progressive nephropathy
After 15-25 yrs of DM
Dipstick positive proteinuria
HTN 75%
Reduced GFR
Hyperlipidemia
Retinopathy and autonomic neuropathy
Thursday, March 12, 2009
106. Stage V DN
ESRD
Progression to
ESRD 5-15 yrs
after the
development of
overt proteinuria
Thursday, March 12, 2009
107. Pathogenesis of the
structural injury in DN
Hyperglycemia
Accumulation of glycosylation
products
increased advanced glycation end-products
(AGE) stimulate synthesis of various growth
factors as well as causing cytokine mediated
damage and oxidative stress
Intraglomerular HTN
Systemic HTN
Thursday, March 12, 2009
113. Case Presentation
70 yr old affluent
white male
CC: Swelling in Legs
Thursday, March 12, 2009
114. What do you want
next?
Past Medical History
Family History
Social History
Medications
Physical Exam
Anything Else?
Thursday, March 12, 2009
115. History
PMHx: HTN, GERD,
Hyperlipidemia, OA
Social Hx: Married, worked
in finance, Denies tobacco
or illicit drug use, Social
EtOH
Family Hx: No Kidney
Disease, ESRD
Medications: Amlodipine,
Prilosec, Lipitor, Motrin
Thursday, March 12, 2009
116. Physical Exam
VS: BP 134/76 mmHg P 96 R 14
HEENT: NCAT OP Clear
Neck: Supple no JVD no bruits
Chest: CTA B/L
Cor: S1 S2 RRR no M/R/G
Abd: Soft NT ND +BS, no HSM
Ext: +2 pitting edema B/L
mild Right > Left
Anything else?
Thursday, March 12, 2009
117. Labs
What do you want to
order?
Thursday, March 12, 2009
118. Lab Values
CBC: WBC 7.6 Hb 11.9 PLT 195
CMP: Na 138 K 4.3 Cl 108 HCO3 23
BUN 11 Creat 1.4 TBili 0.6 AST 22
ALT 25 AlkP 106 TP 6.2 Alb 3.0
Cholesterol: Chol 222 HDL 29 LDL 168
UA: +3 protein, trace blood, no
casts, no LE or nitrates
Want anything else?
Thursday, March 12, 2009
119. Other Lab Tests
to consider
SPEP/ IEP / UPEP
Hepatitis Panel
Compliments, Serology
24 Hour urine Creatinine Clearance
and total proteinuria (U TP/Creat)
Thursday, March 12, 2009
120. 24 Hour urine
collection
Creatinine Clearance
69 ml/min
Total proteinuria:
3,890 mg
Thursday, March 12, 2009
126. Membranous
Nephropathy
Thursday, March 12, 2009
127. What Should We do Next?
How Should we Treat?
What is the prognosis?
Thursday, March 12, 2009
128. FIN
Simon Prince, DO, FACP, FASN
Assistant Professor of Medicine;
NYU School of Medicine
email: sprince@nsneph.com
www.nsneph.blogspot.com
Thursday, March 12, 2009
Editor's Notes
it would be great to start the lecture with:
http://www.hulu.com/watch/17417/juno-pregnancy-test
Probably the best U/A ever in a movie.
Point is (and I do have one) a normal value defined by detection limits is a bad way to define normal
