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EVALUATION OF
PROTEINURIA AND HEMATURIA
Melanie (Derman) Hoenig, M.DRenal Division
Beth Israel Deaconess Medical CenterHarvard Medical School
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• Nothing to disclose
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Q1. Which of the following patients
should have a routine UA at his/her
annual physical examination?
A. A 17 year old woman planning to play high
school basketball
B. A 34 year old man who is getting married
C. A 52 year old man who just obtained health
insurance
D. A 72 year old woman who returns for follow-up
E. None of the above
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Routine UA is not recommended by US
Preventative Task Force on the Periodic Health Examination
Annals Int Med 2012
In fact, the even annual health examination
has been debated. This is the recommended
interval for Well-Care visits
Interval in years.
Annals Int Med 2016
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Boulware, L. E. et al. JAMA 2003;290:3101-3114.
Cost-effectiveness of Screening vs Not Screening for Proteinuria at Different Frequencies and Different Ages
With HypertensionNo HTN or DM
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Normal urinary excretion of protein
• Low molecular weight proteins and a small amount of albumin are normally filtered
• Most is reabsorbed by the proximal tubules
• 30-50 mg of Tamm-Horsfall protein (now called uromodulin) is secreted by the loop
• Net result: <150mg total protein excreted
(40-80mg) –10mg is albumin
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Q 2. A patient presents to establish care. He
reports longstanding proteinuria. Which of
the following tests would you order? next?
A. Urinalysis (includes dipstick and
microscopy)
B. 24 hour urine collection
C. Spot urine for protein to creatinine ratio
D. Spot test for albuminuria
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Dipstick for measuring protein
• Stick impregnated with dye->> color change related to the protein concentration
• Most sensitive to albumin
• Detects other proteins poorly(i.e.-light chains and tubular proteins)
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Which patient has more urinary protein?
Patient A Patient B from Sieman’s Multistix® 10SG Reagent strips
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24 hour collection for urinary protein
is traditionally considered
the gold standard
• Begin with second void, include ALL urine
for day and night plus first void of am
• Order protein AND creatinine
• Provide jugs and hatsCOPYRIGHT
URINARY PROTEIN:CREATININE RATIO
• Aliquot of random specimen
• Uses reagent that detects ALL proteins
• In steady state, correlates with
24 hour urinary protein excretion
• Normal ratio is <0.2
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• Imagine a normal and average person
• Excretes creatinine throughout the day (≈1,000 mg/day per 1.73 m2)
• Excretes small amt of protein throughout day
• The ratio is relatively constant-example
4000 mg protein = 4 protein : creatinine1000 mg creatinine about 4 grams
100 mg protein = 0.1 protein : creatinine
1000 mg creatinine normal
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Schwab Arch Int Med 1987
Prot
ein
: cr
eat
inin
era
tio
24 hour urine
Protein:creatinine ratio
approximates protein in grams/day
Units= mg/mg or g/g
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Albuminuria: what’s in a name?• < 30 mcg alb/mg creatinine is normal
– (30 mg alb/g creat) note the units!
• 30-300 mcg alb/mg creatinine was called microalbuminuria (now “moderately increased albuminuria”)
• >300 mcg alb/mg creatinine is usually detectable by dipstick. This is OVERT proteinuria or “macroproteinuria” and now called “severely increased albuminuria”)
• Marker for early diabetic nephropathy
• Associated with cardiovascular disease in both diabetics and non diabetics
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< 30 mcg
mg
NORMAL
MICROALBUMINURIA
30-300 mcg
mg
OVERT PROTEINURIA
Nowcalled“moderately
increased”albuminuria
Nowcalled“severely
increased”albuminuria
Idonotagreewiththenew
recommendedterminology
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Levey A et al. KI 2011 80(1): 17-28.
ACR
>300
30-300
<30
But it is true that
greater proteinuria
confers more risk-
Stay tuned---
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Which protein should we measure?• In a diabetic-start with
albumin:creatinine ratio(ACR)
• In nondiabetics, consider urinary protein to creatinine ratio for overt and heavy proteinuria
• (measuring ACR in nondiabeticis not wrong but no clear data on outcomes for treating low levels of albuminuria)
Alice, I am a
fan of the
spot protein
to creat ratio
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INITIAL APPROACH TO PATIENT WITH PROTEINURIA
l UNDER WHAT CONDITION IS PROTEIN
EXCRETED?
l HOW MUCH PROTEIN?
l IS PROTEINURIA ISOLATED OR PART OF
SYSTEMIC DISORDER?
l IS PROTEINURIA ISOLATED ABNORMAL?
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Urine dipstick (and the ACR) detects only albumin, the major
protein in blood, but can miss important other proteins
* Note: In setting of tubular toxicity (as with TDF formulation of tenofovir)-
ACR will also be considerably lower that Protein to creatinine ratio-
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UNDER WHAT CONDITIONS IS PROTEIN EXCRETED?
• TRANSIENT PROTEINURIA
• POSTURAL PROTEINURIA
• PERSISTENT PROTEINURIA
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TRANSIENT PROTEINURIA
• Acute illness (fever)
• Exercise
• Congestive heart failure
• Mild (<1 gram/day)
• Repeat evaluation with resolution
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ORTHOSTATIC PROTEINURIA
• Protein excretion is normal when recumbent
• Increased proteinuria in the upright position
• Occurs in children and young adults
• Document by separate collections
• Total usually < 1 gram
• Benign: Resolves > age 30
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PERSISTENT PROTEINURIA
• DOCUMENTED ON 2 OR MORE OCCASIONS
• SUGGESTS UNDERLYING RENAL PATHOLOGY EVEN IF RENAL FUNCTION IS NORMALCO
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EVALUATION OF PERSISTENT PROTEINURIA
• TAKE HISTORY OF SYSTEMIC DISEASE,
RENAL DISEASE, FAMILY HISTORY
• PHYSICAL EXAMINATION
• LOOK AT URINARY SEDIMENT (casts, WBC s, RBC s, lipid)
(is the proteinuria “isolated” or associated with hematuria?)
• QUANTIFY AMOUNT OF PROTEIN
• ASSESS RENAL FUNCTION
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HOW MUCH PROTEIN EXCRETED?
• >3 GRAMS/24 HRS: NEPHROTIC RANGE
PROTEINURIA
• 1-2 GRAMS/24 HRS- POTENTIALLY SERIOUS
RENAL DISEASE
• <1 GRAM/24 HRS- May be BENIGN
PROTEINURIA
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SYSTEMIC DISEASES ASSOCIATED WITH ISOLATED PROTEINURIA
• DIABETES MELLITUS• SLE• AMYLOIDOSIS• MULTIPLE MYELOMA• HIV/AIDS
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Case 1
A 37 year old man presents with several months of edema. He is a healthy, no medications.
BP 128/84, well appearing but bilateral lower
extremity edema.
Data:
serum creatinine of 1.1 mg/dL
Serum albumin of 2.8 mg/dL
total cholesterol of 375 mg/dL
Urine protein to creatinine ratio 6.9 mg/mg
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Fatty cast with polarized light
Melanie Hoenig’s iphone
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A. Membranous glomerulopathy
B. Post infectious glomerulonephritis
C. Diabetic nephropathy
D. IgA nephropathy
Q 3. What is the most likely
diagnosis? (37 year old man with nephrotic syndrome)
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The nephrotic syndrome• Proteinuria
• Hypoalbuminemia
• Edema
Hyperlipidemia
Fatty casts in urine Netter
triad
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PRIMARY RENAL CAUSES OF NEPHROSIS
• MINIMAL CHANGE DISEASE• FOCAL SEGMENTAL
GLOMERULOSCLEROSIS • MEMBRANOUS GLOMERULOPATHY
• MEMBRANOPROLIFERATIVE GN• IgA NEPHROPATHY
Nephrotic
syndrome
Also typically
have hematuria
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Minimal Change Disease
• Most common cause in
children; second peak in
older individuals
• Rapid response to
steroids (though relapse
is common)
• AKI can occur in setting
of heavy proteinuria
• Associated with NSAID s
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Focal and Segmental
Glomerulosclerosis• Increasingly common cause of
nephrosis in US—now #1 cause
• Confusing terminology
– Primary disease presents as idiopathic nephrotic syndrome
– Secondary disease is more indolent-response to old injury (reflux, AKI with incomplete recovery, prior GN)
• Treatment: – immunosuppressive therapy for
primary
– conservative for secondary
www2.Niddk.nih.gov/NIDDKLabs/GlomerularDiseases.htm#d
Segmental sclerosis
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Membranous Glomerulopathy• most common cause of
nephrotic syndrome in
Caucasian adults (previously #1)
• Benign initial course:
1/3 spontaneous remission
1/3 partial remission
• Idiopathic (70% associated with
antibody to phospholipase A2
receptor on podocyte)
• secondary causes:
hepatitis B, NSAIDS, SLE
malignancy Library.med.utah.edu
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Membranoproliferative GN
• Descriptive term--patients appear
to have thickened GBM AND
proliferative changes on biopsy
• Clinically, patients may have both
heavy proteinuria AND evidence
of nephritis
• Multiple patterns and causes.
• One of most common is an
Immune complex
glomerulonephritis associated with
hepatitis C +/-cryoglobulins
PAS
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IgA nephropathy
• Most common cause of
glomerulonephritis world-wide
• Dx based on IgA predominance
on IF of biopsy but several
histological patterns and clinical
patterns
– Recurrent gross hematuria + URI
– Microscopic hematuria and
proteinuria
– proteinuria
• Worse prognosis with presence
of proteinuria
PAS
IgA
IgA
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ISOLATED PROTEINURIAWITH LESS THAN 1.5 GRAMS
• CHECK URINARY SEDIMENT• RULE OUT SYSTEMIC DISEASES• URINE PROT/CREAT; 24 HOUR URINE• RENAL ULTRASOUND(r/o PKD, chronic pyelo, obstruction)• RULE OUT POSTURAL PROTEINURIA
(if under 30 years old)
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REFER FOR POSSIBLE RENAL BIOPSY
• Patients with 1-2 grams protein and reduced
renal function
• Patients with nephrotic range protein
– (>3 g/24)
• Proteinuria and an active urinary sediment
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FOLLOW-UP FORBENIGN PROTEINURIA
• Repeat urine protein: creatinine q 6 months
• Repeat serum creatinine (assess renal function)
q 6 months
• Vigilance for the development of a systemic
disorder
• Nonspecific treatments for proteinuria
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NONSPECIFIC TREATMENT OF PROTEINURIA
• ACE Inhibitors or ARB s (or renin inhibitor?)
• Treat hyperlipidemia and encourage healthy
lifestyle choices
• Aggressive control of blood pressure
with goal of <130/80 (or ? <125/75)
• Smoking cessation
X
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Check list for the Evaluation of Proteinuria
Quantify proteinuria _____________________
If proteinuria is mild,
Consider transient proteinuria and repeat after resolution
acute illness CHF exercise
Or orthostatic proteinuria (in a young patient with <1gram/day)
split 24-hour urine collection
Is there nephrotic syndrome?
low serum albumin edema >3.5 grams/day of urinary protein
Is proteinuria in the context of another disorder?
Diabetes mellitus Hypertension Other ______________
Is there an active urine sediment? _________________Refer to nephrology
Is there reduced renal function? _________________Refer to nephrology
Nonspecific treatment for patients with proteinuria
ACE inhibitor or ARB strict control of blood pressuretreatment of hyperlipidemia no tobacco
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EVALUATION OF HEMATURIA
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Case 2
• A 40 year old woman was referred for
hematuria. The week before, she had sudden visible hematuria but no urgency or dysuria. It
recurred the following day and she was seen at
a local ED and given ciprofloxacin for
hemorrhagic cystitis. COPYRIGHT
• She followed up with her PCP’s office the
following week and was found to have new hypertension and was referred for possible
glomerulonephritis
• Medications: none
• ROS 3: lb unintentional weight loss. COPYRIGHT
• BP 180/90, weight 109 lb
• Completely normal exam
• Urine dipstick: large blood, no protein
• Urine protein to creatinine ratio 0.2 (nl < 0.2)
• Serum creatinine 0.8 mg/dLCOPYRIGHT
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Q4. This patient most likely has
A. Glomerulonephritis
B. Urinary tract infection
C. Another cause of hematuria
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CAUSES OF HEMATURIA
• MALIGNANCY (BLADDER, KIDNEY)• GLOMERULAR DISEASE• POLYCYSTIC KIDNEY DISEASE• NEPHROLITHIASIS• URINARY TRACT INFECTION (BLADDER,PROSTATE)• VASCULAR (RENAL INFARCT, AVM, MALIGNANT HTN)• METABOLIC (CALCIUM, URIC ACID)• TRAUMA (CONTUSION, EXERCISE)• PAPILLARY NECROSIS (SICKLE DZ, TRAIT, DM, MEDS)• SICKLE TRAIT
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VISIBLE HEMATURIA
• Visible (GROSS) Hematuria
Urine appears visibly red
(only 1cc/L required)
Smoky urine
May suggest upper tract
(glomerular) bleeding
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DEFINITION OF HEMATURIA
MICROSCOPICHEMATURIA:>3RBC/HPF
WBC
RBC
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Positive urine dipstick for blood does always = hematuria. Sensitive but not specificDetects myoglobin and hemoglobin
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FALSE POSITIVE (SUPERNATANT RED/NO
HEME)
• PORPHYRIA
• BEETS (GENETICALLY SUSCEPTIBLE)
• MEDICATIONS
– (Phenazopyridine and Rifampin)COPYRIGHT
EVALUATION OF HEMATURIA
• ELICIT HISTORICAL CLUES
• EXCLUDE TRANSIENT HEMATURIA
• CONFIRM WITH MICROSCOPIC UA
• DETERMINE GLOMERULAR VS.
NONGLOMERULAR?
• Visible HEMATURIA VS. MICROSCOPIC
HEMATURIA
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HISTORICALCLUES• Symptoms c/w urinary tract infection• Renal colic• Blood clots -> heavy nonglomerular bleeding• Family Hx (PKD, hereditary nephritis, Sickle)• ROS: Smoking Hx, Occupational Hx• Recent URI (IgA)• Use of anticoagulants does not explain
hematuria• Past medical history/Systemic Disorder• Exposure to cyclophosphamide• Recent trauma or vigorous exercise
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TRANSIENT HEMATURIA
• CAUSES• VIGOROUS EXERCISE
• SEXUAL INTERCOURSE
• MENSTRUATION
• MILD TRAUMA
• URINARY TRACT INFECTION
• REPEAT EVALUATION AFTER RESOLUTION
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Step 1: Confirm hematuria-
ideally, 2nd UA and microscopic confirmation
If no blood, consider myoglobin, free hemoglobin
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Urinalysis performed by the laboratory (on a
fresh specimen) is excellent for cell count
http://www.irisdiagnostics.com/clinical-info/urinalysis-basics
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Cohen R and Brown R. N Engl J Med 2003;348:2330-2338
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Melanie Hoenig’s phone
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Images courtesy of Elizabeth Houssman, MD
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Findingssuggestiveof
GLOMERULARHEMATURIA
• DYSMORPHIC RBC S
• RBC CASTS, OTHER CASTS
• PROTEINURIA(>300MG/DAY)
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Proteinuria and hematuria
increases risk of ESRD
Iseki et al. Kidney Int 1996
Mass screening of
about 100,000
Okinawa Japan
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LABORATORY INVESTIGATION IF URINARY SEDIMENT IS NEPRHITIC
• COMPLEMENT ê in Immune complex GN (except anti-GBM dz)
• Streptozyme POST-STREP GN
(includes ASO, anti-DNAse B, AHase and anti-NAD)
• BlOOD CULTURES subacute bacterial endocarditis
• ANA SLE
• HEPATITIS B & C membranoproliferative glomerulonephritis
• CRYOGLOBULINS CRYOGLOBULINEMIA
• ANCA pauci-immune glomerulonephritis
• Anti-GBM Ab s ANTI-GBM DZ/GOODPASTURE S DZ
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Back to Case 2
Although the hypertension was new,
•renal function was normal
•Nondysmorphic RBC’s (normal appearing)
•No proteinuria
Q5. The next appropriate step is
A.Urine culture
B.Complement levels
C.Urine cytology
D.Imaging of the upper tract
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Urinary Tract Cancer rate in patients with
hematuria in comparison to age
0-2 RBC/hpf
3-5 RBC/hpf
6-10 RBC/hpf
11-25 RBC/hpf
25-50RBC/hpf
50-100 RBC/hpf
Jung H Journal of Urology 2011 1698
age
13 Kaiser centers, 309,000 members with UA (2004-5) but no UTI, pregnancy or prior malignancy
156,000 had hematuria followed for urinary cancer over next 3 years
Urinary tract cancer
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Q6.IfthiswasmypatientIwouldorder:
A. INTRAVENOUSPYELOGRAM
B. RENALULTRASOUND
C. COMPUTERIZEDTOMOGRAPHY(CT)
D. MAGNETICRESONANCEIMAGING(MRI)
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IVP
• May miss small or
posterior mass
• Contrast
• Can detect medullary
sponge kidney
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Ultrasound
• May miss small
nonobstructing
stone or masses
• No contrast
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CT scan can detect all types of stones
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September 18, 2014
• US less radiation
• No sig difference in Dx of high risk cx,
total serious or related serious adverse events
• No difference: pain scores, hospital admit or ED
revisits
This paper
was not
about the
evaluation
of hematuria
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Maher et al. Korean J Radiology
2004 March; 5(1):55-67
CT scan with 3D reconstruction
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CT urogram
Sudakoff G J Urology 2008; 179: 862
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MRI
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ACR Appropriateness Guidelines for hematuria
Acr.org
* Separate guidelines for renal parenchymal disease or when assoc with benign conditions
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EVALUATION OF LOWER TRACT: CYSTOSCOPY
Age >35* and/or
RISKS FOR TCC:
• Smoking
• Occupational exposure
• Cyclophosphamide or other alkalating
agents or analgesic abuse
• Pelvic irradiation
• Chronic UTI’s or indwelling foreign body
• Visible hematuria
• Irritative voiding symptoms
*Age of >35 is from new guidelines from AUA-developed 2012, confirmed 2016
Level of evidence is Grade C whereas if risk factors, this is a clinical principle
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EVALUATION OF LOWER TRACT: Urine cytology is not recommended as part
of the routine evaluation algorithm(except if evaluation is negative and microscopic
hematuria persists and there are risk factors or other symptoms-GRADE C-low level evidence)
• INSENSITIVE FOR LOW GRADE TCC• DETECTS MOST HIGH GRADE TUMORSCO
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Bladder tumor markers and assays? STILL Not ready for screening
• Urine immunocytochemistry
• NMP22 (nuclear matrix protein 22)
• BTA-stat (bladder tumor antigen)
• UroVysion FISH
• Virtual Cystoscopy
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Smith MR Urology 2019 in press
In a retrospective series of evaluation for microscopic hematuria 2138 patients had US and
at least 3 years FU; 99.4% had no malignancy, 12 patients had upper tract malignancy (9
RCC 3 UTUC) and another 4 more than 4 years later (1.6 cases/10,000 person years)
The GOLD standard has been CT urogram but US
may be a reasonable alternative
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Rha S E et al. Radiographics 2004;24:S117-S131
Case 2 continued
• CT urogram demonstrated a mass in the renal pelvis
• Urine cytology c/w transitional cell carcinoma
• She underwent nephroureterectomy
• She is well at >10 years of follow up.
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UNEXPLAINED HEMATURIA• CONSIDER ALTERNATIVE DIAGNOSES
– Prostatic disease
– 24 hour urine for calcium and uric acid (and creatinine to assure complete collection)
– Hemoglobin electrophoresis
• AGGRESSIVE/REPEAT EVALUATION IF VISIBLE HEMATURIA DEVELOPS
• IF hematuria resolves after negative evaluation and remains negative for two annual urinalyses, no further evaluation is required.
• If hematuria persists, consider repeat evaluation in 3-5 years (Expert Opinion)
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UTI
BPH
4414 patients
Referred for hematuria
Evaluated per AUA 2009-2011
104 cases
Adapted from Loo et al. Mayo Clin Proc 2013
neoplasm
glomerular
2.6%
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Evaluation of Visible Hematuria
BPH
No diagnosis
64%
(n=372)
Bladder Cancer
85 (14.7%)
Renal cancer
14 (2.4%)
Stone + UTI
Adapted from Mishriki SF J of Urology 2009 182(4)
587 with
visible hematuria
Prostate CA
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Follow up of patients with - w/u for Visible Hematuria at 6 years
BPH
No
diagnosis
Adapted from Mishriki SF J of Urology 2009 182(4)
41 with recurrent hematuria
81 died (1 RCC, 4 prostate)Stone + UTI
Prostate CA
Renal CA Bladder CA
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Step 2
• If suspect glomerular
hematuria
(dysmorphic RBC, proteinuria)
Pursue additional sx/clues
(i.e. consider serology
i.e.. ANA, ANCA)
Consider referral to nephrologist
• If suspect nonglomerular
hematuria
• Pursue symptoms/clues
(ie Rx UTI, if colic,
pursue nephrolithiasis)
• Evaluate upper tract
• Evaluate lower tract
More involved algorithm at AUA website:
http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm#2
Recall: step 1
Confirm hematuria
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Check list for the Evaluation of Hematuria
Is there evidence of glomerular bleeding? Consider nephrology evaluation
New decline in renal function? ________________
Proteinuria ___________________________
Pursue historical clues
Urinary tract infection à Treat and repeat urinalysis
Kidney stones
Family history
Systemic illness
Sickle cell disease/trait
Vigorous exercise/trauma
Is hematuria visible? Refer to urology_________________
Evaluation of the upper tract
CT urogram if preserved GFR
Evaluation of the lower tract
Risk factors for bladder cancerà cystoscopy
age > 40? Or 35 ? (AUA guidelines)
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