This document provides an overview of glomerular causes of hematuria including definitions, diagnostic workup, differential diagnoses, and treatment approaches. Key points discussed include: - Definitions of gross and microscopic hematuria and their clinical significance. Dysmorphic red blood cells and red blood cell casts can indicate glomerular disease but have low sensitivity. - Diagnostic workup may include complement levels, ANCA, ANA, hepatitis and cryoglobulin serologies to identify underlying causes like ANCA-associated glomerulonephritis, lupus, or hepatitis. - Biopsy of the kidney has the highest diagnostic yield compared to other organs and should be considered for rapidly progressive or unexplained

1. Noon Conference
Di Yan
08/16/2018

2. © 2016 Virginia Mason Medical Center 2
Objectives
Glomerular causes of hematuria
• Definitions and initial approach
• Further workup and differential diagnosis
• ANCA associated GN
• Review illness script
• Discuss treatment

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Definition of hematuria
Gross (macroscopic) hematuria
-Visibly discolored urine due to blood
-Always pathologic
Microscopic hematuria
- ≥3 RBC’s/HPF
-Common incidental finding: 40.9% of US
adults have asymptomatic microscopic
hematuria on urinalysis (Halpern et al.,
2017)
Degree of hematuria does not correlate with
severity of inflammation
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Our patient

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-Vigorous exercise
-Viral illness
-Trauma
-Sexual activity
Causes of hematuria
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Clues to glomerular disease
- RBC casts
- Dysmorphic RBC’s (esp. acanthocytes)
- Proteinuria/Albuminuria
RBC cast
Acanthocyte

 Normal RBC
Gai et al., 2002
(Pohl, 2011; Gai et al., 2002,

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Sensitivity and specificity for
glomerular disease
Finding Sensitivity Specificity Source
RBC casts 24% 97% Saad, 1996
Dysmorphic RBC’s
>5% Ancanthocytes 50% 95% Hebert et al., 2013
≥ 25% dRBC’s 20.4% 96.3% Hamada et al., 2017
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20% of patients with biopsy-proven glomerulonephritis have hematuria alone
(Fassett et al., 1982)
Both RBC casts and dysmorphic RBC’s have poor sensitivity
Dysmorphic RBC’s are more common than RBC casts, which can
indicate more severe disease

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Further workup
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Complement (CH50, C3, C4)
ANCA
Our
patient
Madaio and Harrington, 2001
Percentages indicate the approximate frequencies of depressed C3 or hemolytic
complement levels.

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Further workup (cont’d)
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Test Associated cause of GN
ANA, Anti-DNA
antibodies
SLE
ANCA (PR3,
MPO)
ANCA vasculitides (GPA, pauci-
immune GN)
Cryoglobulins, RF Cryoglobulinemia
Hep B, C
serologies
Hep associated glomerulonephritis
(Membranoproliferative GN Type I is
most common), Polyarteritis nodosa
Bld Cx Endovascular or occult infection
Anti-GBM
antibodies
Goodpasture’s syndrome
Streptozyme PSGN
Don’t need every test on every patient- Use clinical judgment!
C-ANCA
P-ANCA
Madaio and Harrington, 2001
Hebert et al., 2013
Others: SPEP, D-Dimer, ADAMSTS-13, CXR

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Associated systemic findings
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Disease Hx/Pex findings
SLE Rash, athralgias, serositis/pleuritis/pericarditis,
oral/nasal ulcers
Cryoglobulinemia Purpura, arthralgias
Granulomatosis with
polyangiitis (GPA)
Chronic sinusitis, nasal ulcers, bloody nasal
discharge, saddle nose, cough, wheeze,
hemoptysis, dyspnea, arthralgias, orbit pain, rash
Goodpasture’s syndrome Pulmonary hemorrhage
Henoch-Schönlein
purpura/ IgA vasculitis
Nausea, vomiting, abdominal pain, purpura
Subacute bacterial
endocarditis
Fever, murmur, IV drug use, prosthetic valves
Post-Strep
glomerulonephritis
(PSGN)
7-14 days s/p group A strep pharyngeal infection,
14-21 days s/p skin infection
Richards, 1991; Madaio and Harrington, 2001

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Diagnostic algorithm
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Madaio and Harrington, 2001
Complement levels
NormalLow
ANA, Anti-DNA Ab
Cryoglobulins
RF
Hep B, C serologies
ANCA
Anti-GBM
Renal only:
-PSGN
-MPGN
Renal only
-IgG-IgA
nephropathySystemic disease:
-SLE
-Cryoglobulinemia
-Endocarditis
-Shunt nephritis
Systemic disease:
-PAN
-GPA
-Hypersensitivity
vasculitis
-Goodpasture’s
-H-S PurpuraRapidly progressive:
-Pauci-immune
-Renal limited anti-GBM disease







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Question 1
Which of the following patterns of complement
abnormalities is most consistent with post-
streptococcal glomerulonephritis?
A) Low C3, Low C4
B) Low C3, Normal C4
C) Normal C3, Low C4
D) Normal C3, Normal C4
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Answer 1
Correct answer is B
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GN C3 levels C4 levels
Systemic lupus
erythematous,
endocarditis
Low Low
Cryoglobulinemia
(Type I, II)
Normal Low
Post-strep GN Very low Normal
Membranoproliferative
GN Type I, HUS
Low Normal
(Hebert et al., 2013)

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When to biopsy?
Potential contraindications
-Anticoagulation or bleeding diathesis
-Small kidney size
-Anatomic abnormalities- single kidney
Horseshoe kidney
-Active infection- UTI/Pyelonephritis/Abscess
-Hydronephrosis
Helpful when:
-Rapidly progressive, clinically deteriorating
-Unexplained renal failure
-Need to assess disease activity or damage reversibility to guide
management
Not helpful:
- Patient asymptomatic with normal GFR
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Madaio and Harrington, 2001
Hogan et al., 2016
Our patient has not
had a renal biopsy

13. © 2016 Virginia Mason Medical Center
Question 2
Which of the following organs, if affected,
has the highest diagnostic yield on biopsy?
A) Lung
B) Nasal sinus
C) Skin
D) Kidney
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Answer: D
Diagnostic yield for kidney biopsies in
GPA with renal involvement is as high
as 91.5%
In contrast, lung biopsies have a
sensitivity of only 12% for GPA.
Affected ENT areas are positive for
inflammatory changes in 68.2% of
biopsies.
(Yates et al., 2017)

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ANCA associated GN
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Most common histologic pattern
(kidneys): focal segmental
necrotizing glomerulonephritis +/-
crescents
(Smith, 2017; Schulte-Pelkum, 2014)

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Illness Scripts
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Granulomatosis with polyangiitis
Post-streptococcal
glomerulonephritis
Pathophysiology
ANCA directed against neutrophil and monocyte
granules-> tissue damage
Immune complex deposition in glomeruli->
complement +inflammatory cascade activation
Epidemiology
40-65 yo
M = F
HLA DPB1 gene
Infection leading to granulomas
5-12yo or >60
2M:1F
7-14 days after pharyngitis, 14-21 days after
skin infection
Time course subacute/chronic acute
Clinical
presentation
hematuria, hemoptysis, sinusitis, wheezing,
cough, malaise, purpuric rash
hematuria, edema, HTN, oliguria
Diagnostics
Labs: leukocytosis and anemia; elevated
ESR, CRP, Cr, BUN
Serologic testing: PR3/c-ANCA
Specimen: hematuria, subnephrotic
proteinuria, dysmorphic RBC &/or RBC casts
Renal biopsy: necrotizing GN with crescents
CXR: large nodular densities, infiltrates
Labs: low complement (C3), elevated Crt,
proteinuria, hypoalbuminemia
Serologic testing: streptozyme (DNase B,
Streptolysin O, hyaluronidase and
streptokinase)
Specimen: hematuria, subnephrotic
proteinuria, dysmorphic RBC &/or RBC casts
Renal biopsy: subepithelial electron dense
deposits +C3, +IgG +/-IgM
Therapeutics
high-dose corticosteroids, cyclophosphamide,
rituximab , MTX, AZA, MM
Treat infection if present, HTN management,
diuresis

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Management of GPA
Acute non-organ
threatening flare
- GC’s + Methotrexate
or mycophenolate
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(Yates et al., 2017)
Remission maintenance
(at least 24 mos)
- Low-dose GC’s +:
- Azathioprine
- Rituximab
- Methotrexate
- Micophenolate mofetilAcute organ or life
threatening flare
- Methylprednisolone
- Cyclophosphamide
- Rituximab
- PLEX can be
considered if Crt >5.7
New onset organ
or life-threatening
disease
- High dose GC’s +
Cyclophosphamide
OR rituximab
Remission induction

17. © 2016 Virginia Mason Medical Center
Acknowledgements
Thank you Dr. Cyrus Cryst!
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18. © 2016 Virginia Mason Medical Center
Literature cited
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pathology & laboratory medicine. 2017;141(2):223-231.
13. Tesser Poloni JA, Bosan IB, Garigali G, Fogazzi GB. Urinary red blood cells: not only glomerular or nonglomerular.
Nephron Clinical practice. 2012;120(1):c36-41; discussion c41.
14. van der Molen AJ, Hovius MC. Hematuria: a problem-based imaging algorithm illustrating the recent Dutch guidelines
on hematuria. AJR American journal of roentgenology. 2012;198(6):1256-1265.
15. Yates M, Watts R, Bajema I, et al. Validation of the EULAR/ERA-EDTA recommendations for the management of
ANCA-associated vasculitis by disease content experts. RMD open. 2017;3(1):e000449.
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