LAB 3: Glomerular Diseases (nephritic syndrome)
Case 1: (Answer: Post-infectious glomerulonephritis or PIGN)
A 12-year-old Costa Rican boy is brought into clinic by his parents because of dark brownish-red urine over the last 24
hours. The family has been visiting friends in Indianapolis for two-weeks. While touring the Children’s Museum two days
ago they noticed their son had puffiness around his eyes. The week prior to leaving home, the child had a febrile illness
associated with a sore throat but he improved within five days while taking children’s Tylenol. On exam the boy has a
blood pressure of 132/92 mmHg as well as periorbital and ankle edema bilaterally. A Monospot test was negative. No
family history of kidney disease.
Questions:
A. What would you expect the urinalysis to show? Blood & protein in urine by reagent dipstick; dysmorphic RBCs
or red cell casts by urine microscopy. Proteinuria is usually not nephrotic-range.
B. What blood tests would you order and what would you expect them to show? Do any of these tests help you to
determine if a renal biopsy is necessary?
1. Serum creatinine, BUN, electrolytes, and serum albumin
2. Serum complements. In PIGN (including poststreptococcal GN), serum complement C3 is usually low (C3
is also low in MPGN type I & II, lupus nephritis) and C4 is usually normal (C4 is usually low in MPGN type I
and lupus nephritis). Low C3 and normal C4 indicate alternative pathway of complement activation.
Serum C3 is normal in 10-20% of kids with PIGN.
3. Stretococcal enzyme antibody detection to evaluate for previous Strep infection, including (A) antistreptolysin O antibody (ASO) titer, (B) Streptozyme or (C) Strep Enzyme Ab by Passive Hemagglutination
(last test is offered by IU Health). The last two tests assay for 5 enzymes: anti-streptolysin O, antihyaluronidase, anti-NADase, anti-deoxyribonuclease, and anti-streptokinaseococcal antibodies). Strep
skin infections might not generate an elevated anti-streptolysin O titer and can be missed by testing for
ASO only. ASO & Streptozyme are each positive in approx. 16% to 18% of healthy children (i.e., kids
without GN). Therefore, in a child with hypocomplementemic glomerulonephritis, a positive Streptozyme
does not confirm the nephritis as truly streptococcal. However, negative Streptozyme suggests an
alternative diagnosis (and perhaps the need for a renal biopsy).
4. Other helpful serology: ANA (lupus), ANCA (vasculitis), hepatitis B & C antigens and antibodies (usually
drawn as a “hepatitis panel”) and anti-GBM (Goodpasture syndrome, although rare in kids).
C. Is this an example of nephrotic or nephritic syndrome? Why?
D. Which portion of the nephron would you expect to be abnormal? Glomerulus (source of blood in urine)
E. Would you biopsy the patient’s kidney and how might that change clinical management?
Renal biopsy specimen shows the following:
1. Light Microscopy: Glomerulonephritis (GN) means too many cells in glomerulus:
A. Resident cells are proliferating: mesangial and/or endothelial
B. Non-resident leukocytes are infiltrating glomeruli: monocytes/macrophages, lymphocytes, and
neutrophils (acute/exudative).
Glomerulonephritis of postinfectious GN is usually endocapillary [meaning hypercellularity of
mesangium and within capillary loops (intracapillary hypercellularity)]. May see crescents.
2. Immunofluorescence: coarse granular IgG and complement C3 along capillary loops. Detecting
complement in serum is different from detecting complement in glomeruli.
3. Electron Microscopy: electron dense subepithelial immune deposits (humps)
Case 2: (Answer: Lupus glomerulonephritis, also called nephritis in the setting of systemic lupus erythematosus)
A 29-year-old Country-Western singer (67 kg Caucasian female) presents with complaints of facial rash, generalized
malaise, pleuritic chest pain, and diffuse joint pain that has gradually worsened over the last week. On exam she has a
blood pressure of 160/98 mmHg, a palpable malar rash in a butterfly distribution over her face, and a pleural rub. Negative
family history. She smokes unfiltered cigarettes, drinks two 6-packs of Lone Star Pilsner each week, recently lost her
boyfriend and her Bluetick Coon dog ran away.
Questions:
A. What is the reason for the edema and hypertension? The patient has nephritic syndrome. The GFR may decrease
due to glomerulonephritis (glomerular hypercellularity may decrease renal blood flow and/or alter vascular
permeability). This decreases one’s ability to handle fluid and salt loads, predisposing to edema and
hypertension. In addition, the juxtaglomerular apparatus (JGA) detects the decrease in filtration (low filtrate
flow), and this activates renin-angiotensin-aldosterone system (angiotensin II is a potent vasoconstrictor).
B. What is the clinical syndrome? nephritic syndrome Why? Renal failure, glomerular hematuria, hypertension
C. What simple “bedside” (point-of-case) test could you do to support your clinical diagnosis? urine dipstick (confirmed
by urine microscopy)
D. What blood tests would provide further support for your diagnosis? +anti-dsDNA, +ANA, low serum complements
E. Would you biopsy the patient’s kidney and how might that change clinical management?
Renal biopsy specimen shows the following:
1. Light Microscopy: there may be a variety of findings with SLE but this biopsy shows: diffuse
proliferative glomerulonephritis (polys, karyorrhexis, wire loops, +/- crescents and fibrin) +/interstitial nephritis
2. Immunofluorescence: intense granular immune deposition in glomeruli (capillary loop & mesangial)
and perhaps TBM, of many immune reactants: “fullhouse” (IgG, IgA, IgM, C3, C1q)
3. Electron Microscopy: many granular electron dense deposits throughout glomeruli including large
subendothelial, mesangial, and subepithelial electron dense deposits. On occasion, the deposits can
aggregate in a ‘thumbprint” or “fingerprint” pattern. Sometimes endothelial cells contain
tubuloreticular inclusions (also found in viral diseases like HIV).
F. Is this an example of: (1) in situ immune complex deposition or (2) circulating immune complexes with antigen of
endogenous origin (DNA) or (3) circulating immune complex deposition with antigen of exogenous origin?
Case 3: (Answer: Anti-GBM glomerulonephritis)
A 55-year-old pharmaceutical representative (102 kg African American man) presents with complaints of increasing
shortness of breath over the last week. Yesterday he coughed up blood but reports no fever or chills. He usually smokes
a pack of cigarettes a day and one cigar per week but he quit 3 weeks ago. No alcohol. His territory includes Indiana,
Michigan, Kentucky and Ohio so he spends many hours sitting in his car. On exam he has a blood pressure of 178/100
mmHg, bilateral crackles on auscultation of the chest and 1+ edema of the lower extremities. The patient has no rashes.
CXR reveals bilateral infiltrates and serum creatinine is 8.9 mg/dl. His creatinine was 0.9 mg/dl six months ago when he
had a work-related physical exam. PPD at that time was negative. No family history of renal disease.
Questions:
A. What clinical syndrome does this man have? What are the potential causes for this syndrome? (1) rapidly
progressive glomerulonephritis (2) pulmonary-renal syndrome (pulmonary hemorrhage + decline in renal fct)
R/O Goodpasture's. (Why is this not nephrotic syndrome?)
B. What simple test could you do in the office to provide support for your clinical diagnosis? Urine dipstick and micro
(UA) - look for blood and protein in urine
C. What other clinical and laboratory tests would be helpful in sorting out this problem? What would you expect them to
show? CXR, lung function tests, renal function tests, ANCA (vasculitis), anti-GBM antibody titers (anti-GBM
ds. Or Goodpasture’s), ANA (lupus), ASO/streptozyme (poststreptococcal).
D. What is the significance of the previous serum creatinine and urinalysis? Establishes baseline for previously
normal renal function
E. Would you do a tissue biopsy on this patient? If so, would you biopsy the lung or the kidney: A renal biopsy might
not be indicated if the patient’s presentation (positive anti-GBM titers) is consistent with anti-GBM disease.
However, in some hospitals it may take 1-2 weeks to receive results of anti-GBM labs. However, a renal
biopsy interpretation may be obtained within hours (<24 hours). If pulmonary symptoms are more severe, a
lung biopsy may be indicated (although the complication of bleeding is potentially more life threatening in
lung than kidney).
Pathologist shows images from biopsy specimen:
1. Light Microscopy: crescents (extracapillary hypercellularity with macrophages and parietal epithelial cells).
Crescents are preceded by fibrinoid necrosis (rupture of GBM with bleeding from capillary loop into
Bowman’s space, followed by fibrin clot, then influx of macrophages, all of which trigger crescents)
2. Immunofluorescence: linear IgG along glomerular capillary loops (anti-GBM)
3. Electron Microscopy: no distinctive immune-type deposits (can’t see IgG by EM). +/- fibrin and crescents.
F. Is this an example of: (1) in situ immune complex deposition or (2) circulating immune complexes with antigen of
endogenous origin or (3) circulating immune complex deposition with antigen of exogenous origin?
RPGN is a clinical syndrome in which glomerular damage is accompanied by rapid and progressive decline in
renal function. Can be irreversible in weeks or months. Pathology lesion is a crescent. RPGN may be
postinfectious, idiopathic, or systemic: Goodpasture's syndrome, SLE, vasculitis, Wegener's, HSP, and
essential cryoglobulinemia. RPGN associated with Goodpasture syndrome is a classic presentation of antiglomerular basement membrane disease.
From Mayo Lab website: Antineutrophil cytoplasmic antibodies (ANCA) occur in patients with autoimmune
vasculitis including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), or organ-limited variants
thereof such as pauci-immune necrotizing glomerulonephritis. ANCA react with enzymes in the cytoplasmic
granules of human neutrophils including proteinase 3 (PR3), myeloperoxidase (MPO), elastase, and cathepsin G.
Normal glomerular structure
References:
ANCA vasculitis
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Am J Kidney Dis. 1990 Jun;15(6):517-29.
Am J Kidney Dis. 2003 Mar;41(3):539-49.
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Complement
Arch Immunol Ther Exp (Warsz). 2014 Feb;62(1):47-57
Immunobiology. 2012 Feb;217(2):195-203.
Autoimmun Rev. 2013 Apr;12(6):657-60.
Goodpasture Disease
Clin Rev Allergy Immunol. 2011 Oct;41(2):151-62
Pediatr Nephrol. 2011 Jan;26(1):85-91.
Pulmonary-renal syndrome
Postgrad Med J. 2013 May;89(1051):274-83.
Rapidly progressive glomerulonephritis
Autoimmun Rev. 2013 Apr;12(6):657-60.
Semin Nephrol. 2011 Jul;31(4):361-8.
SLE – lupus nephritis
Semin Immunopathol. 2014 Jan 9
Clin Nephrol. 2012 Jan;77(1):18-24.
Clin J Am Soc Nephrol. 2013 Jan;8(1):138-45.