Proteinuria

A common problem

by
Dr/ khalid s ramadan
Internist
Zagazig University Hospitals , Egypt
Mouwasat Hospital Dammam, KSA
TAKE HOME MESSAGE

DON’T LET
PERSISTENT
PROTEINURIA GO
UNQUANTIFIED OR
UNEVALUATED!
Definition
Proteinuria is defined as excess serum protein excreted in
the urine.
Normal protein excretion
< 150 mg total protein/d and ~30 mg albumin/d
Microalbuminuria
30–300 mg albumin/d
Also defined as 30–300 μg albumin/mg creatinine
It is not detectable by dipstick analysis.
Albuminuria and moderate proteinuria
300–3500 mg albumin/d
Nephrotic-range proteinuria
>3500 mg albumin/d
Isolated proteinuria
Proteinuria in the presence of an otherwise normal
urinary sediment, a radiologically normal urinary
tract, and absence of known renal disease
Physiology/Pathophysiol
ogy
• Protein flow through renal arteries =
121,000 g/day
• Protein filtered through glomerulus = 1-2
g/day (< 0.001%)
• Protein excreted in urine < 150 mg/day
(<1% of filtered)
• Composition of normal urine: Tamm-
Horsfall protein 60-80%, albumin 10-20%.
 Magnitude of proteinuria and protein
composition depends on the
mechanism of renal injury

Glomerular proteinuria results from glomerular

disorders, which typically involve increased
glomerular permeability; this permeability
allows increased amounts of plasma proteins
(sometimes very large amounts) to pass into
the filtrate.
EXAMPLES
Primary glomerular disorders (eg, membranous
nephropathy, minimal change disease, focal
segmental glomerulosclerosis)
Secondary glomerular disorders (eg, diabetic
nephropathy, preeclampsia, postinfectious
glomerulonephritis, lupus nephritis,
amyloidosis)
Tubular proteinuria results from renal
tubulointerstitial disorders that
impair reabsorption of protein by the
proximal tubule, causing proteinuria
(mostly from smaller proteins such
as immunoglobulin light chains
rather than albumin). Causative
disorders are often accompanied by
other defects of tubular function (eg,
HCO3 wasting, glycosuria,
aminoaciduria) and sometimes by
glomerular pathology (which also
contributes to the proteinuria).
EXAMPLES
Fanconi syndrome
Acute tubular necrosis
Tubulointerstitial nephritis
Polycystic kidney disease
Overflow proteinuria occurs when
excessive amounts of small
plasma proteins (eg,
immunoglobulin light chains
produced in multiple myeloma)
exceed the reabsorptive
capacity of the proximal
tubules.
EXAMPLES
Acute monocytic leukemia with
lysozymuria
Monoclonal gammopathy
Multiple myeloma
Myelodysplastic syndromes
Functional proteinuria occurs when
increased renal blood flow (eg, due
to exercise, fever, high-output heart
failure) delivers increased amounts
of protein to the nephron, resulting in
increased protein in the urine
(usually < 1 g/day). Functional
proteinuria reverses when renal
blood flow returns to normal.
EXAMPLES
Fever
Heart failure
Intense exercise or activity
sizures
• Orthostatic proteinuria is a
benign condition that most
commonly occurs in children and
adolescents in which proteinuria
occurs mainly when the patient is
upright. Thus, urine typically
contains more protein during waking
hours (when people are more often
upright) than during sleep. It has a
very good prognosis and requires no
special intervention
Subnephrotic Proteinuria
• Transient or orthostatic proteinuria
• Hypertensive nephrosclerosis
• Ischemic renal disease/renal artery
stenosis
• Interstitial nephritis
• All causes of nephrotic-range
proteinuria
Nephrotic Syndrome

• Def: nephrotic-range proteinuria,

lipiduria, edema, hypoalbuminemia,
hyperlipidemia.
• Implies glomerular origin of
proteinuria.
• Clinical manifestations: edema,
hypercoagulability,
immunosuppression, malnutrition, +/−
hypertension, +/− renal failure.
Nephrotic Syndrome (cont.)

• 75% have primary glomerular disease

• 25% have secondary glomerular disease
• Medications: NSAIDs, heavy metals,
“street” heroin, lithium, penicillamine,
α-INF
• Infections: post-strep, HIV, hepatitis
B/C, malaria, schistosomiasis
• Neoplasms: solid tumors, leukemias,
lymphomas, multiple myeloma
• Systemic diseases: diabetes mellitus,
SLE, amyloidosis
Diabetic Nephropathy

• #1 cause of ESRD in the U.S. (~35%

of all ESRD).
• ~ 40% of all diabetics (type I and II)
will develop nephropathy.
• Microalbuminuria (> 30 mg/day)
develops after ~ 5 years. Proteinuria
after 11-20 years. Progression to
ESRD ~15-30 years.
EVALUATION OF THE
PATIENT WITH
PROTEINURIA
Clinical Evaluation
History

• Diabetic history if applicable,

esp. h/o retinopathy/neuropathy
• Known renal disorders
• recent serious illness
(particularly with fever)
• intense physical activity .
• pregnancy
Clinical Evaluation
History (cont.)
• sickle cell disease
• cancer (particularly myeloma and
related disorders).
• Medications and toxins
• SLE
• red or brown urine
(glomerulonephritis)
• bone pain (myeloma).
Clinical Evaluation
Physical Examination

• BP and weight
• Fundoscopic exam
• Cardiopulmonary exam
• Rashes
• Edema
Clinical Evaluation
Urine dipstick
• Urine dipstick primarily detects albumin
• positive urine dipstick test usually
suggests overt proteinuria.
• Dipstick testing is also unlikely to detect
excretion of smaller proteins
characteristic of tubular and overflow
proteinuria
• Persistent proteinuria is a sign of a
glomerular disorder and requires further
testing
Clinical Evaluation
Sulfosalicylic Acid (SSA)
Assay

• Turbidimetric assay based on

precipitation of proteins.
• Measures all proteins.
Test sample
Clinical Evaluation
Urine Sediment

• Red cell casts or dysmorphic

RBCs suggest
glomerulonephritis.
• WBCs suggest interstitial
nephritis or infection.
• Lipid bodies suggest
hyperlipidemia and possible
nephrotic syndrome.
Clinical Evaluation
Quantitation of Proteinuria

• 24-hr urine is gold standard,

however is often not easily
obtained.
• Spot urine protein/creatinine
ratio is easier to get, nearly as
accurate.
• ALWAYS GET A CREATININE
WITH ANY QUANTITATIVE
MEASURE OF URINE!
Clinical Evaluation
other tests
• ultrasonography or CT to detect size of
kidneys.
• lipid profile .
• complement levels .
• cryoglobulins
• hepatitis B and C serology
• antinuclear antibody testing
• urine and serum protein electrophoresis
• renal biopsy
Clinical Evaluation
Who To Biopsy
• Non-diabetic nephrotic syndrome
• SLE for classification
• Planned use of immunosuppressive agents
in primary GNs (renal insufficiency, severe
edema, hypertension)
• Diagnosis of plasma cell dyscrasias
• < 2 gms proteinuria without other signs:
conservative therapy (biopsy resulted in
management change in only 3/24 patients
in prospective trial)
 E v a lu a t io n o f P r o t e in u r ia

A s s e s s m e n t o f
P r o t e i n u r ia

D ip s t ic k p o s it iv e S S A p o s it iv e
S S A n e g a t iv e b u t d ip s t ic k n e g a t iv e
o r d is p r o p o r t i o n a t e ly
s m a ll

T r a n s ie n t o r O v e r f lo w
p e r s is t e n t? p ro te i n u r ia
( C o n fir m o n ( L ig h t c h a in s ,
2 4 h r u r i n e o r s p o t r a t io ly s o z y m u r ia , e tc

T r a n s ie n t: P e r s is t e n t
P e r i o d ic
re a s s e s s m e n t

O r t h o s t a t ic F ix e d

R e a s s u ra n c e , F u r t h e r e v a lu a t io n
P e r i o d ic ( R e n a l u lt r a s o u n d ,
R e a s s e s s m e n t N e p r h o lo g y
R e f e r r a l)
MANAGEMENT OF
PROTEINURIA
Management
broad lines
• Blood pressure control
• Diabetic control
• ACEI ,, calcium channel
blockers
• Lipid control
• Dietary protein restriction
Management
ACE Inhibitors
• Have benefit over and above blood
pressure control.
• Type I Diabetes: Captopril use associated
with slower progression, less proteinuria
with or without co-existing HTN (Lewis et
al, 1993, Viberti et al, 1994)
• Type II Diabetes: Enalapril use associated
with slower progression, less proteinuria.
(Ravid et al, 1993, 1996).
Management
ACE Inhibitors
• Nondiabetic disease: use of
benazepril vs. placebo reduced by
38% the 3-yr progression of renal
failure in various diseases.
Reduction greater with higher
proteinuria (Maschio et al, 1996).
• Similar data emerging for
angiotensin II receptor antagonists.
Screening of proteinuria in
diabetic patient
Prognosis
• Diabetic nephropathy: progression to ESRD
over 10-20 years after onset of proteinuria.

• Isolated non-nephrotic proteinuria: 20-yr

follow-up shows incidence ~40% renal
insufficiency, ~50% HTN.

• Nephrotic syndrome: variable but poorer

overall prognosis.
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