1. Dr. Paula Blanco & Dr. Peter Magner
Glomerular Diseases
Dr. Paula Blanco
&
Dr. Peter Magner
April 27th, 2015

2. Objectives
1491 List and describe the clinical syndromes with which patients with
glomerular disease may present and name actual diseases for
each syndrome.
1492 Explain the effect of glomerular changes on normal glomerular
function, i.e. how the changes in the glomerulus affect the
following: proteinuria, hypoalbuminemia, edema, hematuria,
hypertension, hyperlipidemia and glomerular filtration rate.
1494 Describe an immunopathogenic mechanism involved in one of the
various forms of glomerulonephritis and how it affects glomerular
morphology.
1913 Propose a diagnostic approach for a patient with hematuria, and
differentiate glomerular from non glomerular hematuria. 
2879 Define nephrotic syndrome.

3. Manifestations of Glomerular Disease
Proteinuria
Hematuria
Hypertension
Decreased GFR
Rapid/acute
Slow/chronic

4. Proteinuria 3+ protein on dipstick: What protein(s)? How much?
Where from?
What diseases?

5. What proteins? Small plasma proteins (freely filtered)
enzymes
light chains
etc.
Albumin (should not be filtered)
Immunoglobulins (IgG) (should not be filtered)

6. Normal Renal Handling of Protein
Albumin: < 15 mg / 24 hr
other small proteins: < 100 mg / 24 hr
So 24 hour urine protein < 150 mg
* more small proteins are filtered, but most is reabsorbed

7. Quantifying Proteinuria
Traditional to use 24 hour urine protein
Inconvenient, expensive, innaccurate
Should factor for body size
(but many do not in adults)
Random urine:
Protein:creatinine ratio “PCR” or
Albumin:creatinine ratio “ACR”

8. Proteinuria Tubular proteinuria Glomerular proteinuria
up to 1 gm/ 24 hr mixed small proteins
PCR 30 – 100 mg/mmol but ACR low
Glomerular proteinuria
Albumin is the majority
normal glomeruli can leak albumin transiently with fever, exercise, severe CHF 8

9. Urine dipstick for protein 24-hour urine collection for albumin*
Stages of Diabetic renal involvement according to the urinary albumin  
Stage of nephropathy
Urine dipstick for protein
Urine ACR
(mg/mmol)
24-hour urine collection for albumin*
Normal
Negative
<~ 30 mg/day
Mild
(“Microalbuminuria”)
~ 30–300 mg/day
Overt nephropathy
(“macroalbuminuria” )
+, ++, +++
++, +++, +++
+++, ++++
>~ 300 mg/day
>~ 1000 mg/day
>~ 3000 mg/day
< 3
3 - 30
30 – 60
>60
> 200

10. Nephrotic Syndrome proteinuria (mostly albumin) hypoalbuminemia edema
ACR > 200 or PCR > 300
(traditional threshold is > 3 gm /24 hr)
hypoalbuminemia
edema
hyperlipidemia (mostly LDL)
lipiduria
THIS MEANS GLOMERULAR DISEASE

11. Manifestations of Glomerular Disease
Proteinuria (albuminuria)
If severe may have other features of nephrotic syndrome
Hematuria
Hypertension
Decreased GFR
Rapid/acute
Slow/chronic

12. Glomeruli
Anatomy
Mechanisms of injury
Pathological changes

18. Normal Glomerulus

19. Capillary lumen

20. Immune Mechanisms in Glomerular diseases
Circulating immune complex deposition
most common mechanism (~ 70% of all glomerulonephritis)
many different diseases have a similar pathogenesis in terms of immune complexes activating complement
antigens may be endogenous or exogenous

21. GBM
Circulating immune
complex deposition

22. Immune Complex Deposition
Sites of deposition may be:
subendothelial
mesangial
subepithelial
Immune complexes may be detected by immunofluorescence or by electron microscopy

24. Subepithelial deposits

25. IgG

26. Expansion of mesangial areas

27. IgA 27

28. IgA 28

29. Anti-GBM Autoantibodies
antigen is part of collagen IV in the GBM
antigen also in alveolar basement membranes, hence lung + kidney syndrome
autoantibody (IgG class) fixes to GBM forming an in situ immune complex, activates complement
antibody can be detected in kidney and in serum

30. IgG

31. Clinical- Pathological relationships
3 cases as examples

32. Case 1
22 year old woman complaining of swelling of the legs and a 9 kg weight gain
no shortness of breath
B.P. 120/70, weight 69 kg
serum albumin 20 gm /L
serum creatinine 80 umol/L

33. Case 1 Urinalysis findings: random urine ACR 450 mg/mmol (PCR 600)
4+ protein
0-2 RBC’s/HPF
random urine ACR 450 mg/mmol
(PCR 600)

34. Why do a renal biopsy? Prognosis:
many different diseases present in similar ways
some are relatively “benign”, others progressive to chronic renal failure
some diseases (e.g.. SLE) have different degrees of severity
Treatment
some are treatable and some are not
some diseases require immediate treatment with potentially toxic drugs

35. How is a renal biopsy done?
done with biopsy gun under U/S guidance
tissue divided up for examining by:
light microscopy
immunofluorescence
electron microscopy
complications rare, most important is bleeding requiring transfusion, or embolization

36. Light microscopy

37. Immunofluorescence
                                                                    

38. Electron Microscopy

40. Normal glomerulus

41. Thickened basement membranes

42. “Spikes” along GBM

43. IgG - Granular GBM pattern

44. Subepithelial dense deposits
Lumen

45. Case 1 “Pure” Nephrotic Syndrome
Clinical Differential diagnosis
(before we did the biopsy) includes:
minimal change glomerulopathy
focal glomerulosclerosis (FSGS)
Membranous glomerulopathy
IgA nephropathy (usually hematuria too)
Diabetes (should be able to diagnose this without a biopsy!)
Amyloidosis (rare)

46. Case 1 “Pure” Nephrotic Syndrome
Pathology Diagnosis:
Membranous Glomerulopathy
Usually ”primary”
Sometimes “secondary”
(we’ll come to this later)

47. Nephrotic Proteinuria - Points to remember
High ACR implies glomerular pathology
glomerular changes in all causes of nephrotic syndrome include
visceral epithelial cell “foot process fusion”
features such as immune complex deposition point to specific disorders
Permeability changes in GBM that permit heavy proteinuria may or may not be associated with breaks large enough for hematuria

48. What about lesser degrees of proteinuria. eg. PCR < 150 ( < 1
What about lesser degrees of proteinuria? eg. PCR < 150 ( < 1.5 gm/24 hr )
Tubular proteinuria? (< 50 % albumin)
Normal glomeruli (transient albuminuria)
Non-nephrotic glomerular diseases
Suspect if other clues that point to glomerular disease
Hematuria (especially with RBC casts)
hypertension
decreased GFR
Systemic illness that may be associated with secondary glomerular involvement

49. Case 2
27 year old east asian man complaining of recent onset of dark colored urine
had flu-like illness with sore throat 3 days ago
no frequency or dysuria (pain on urination)
feels well

50. Case 2 Physical Examination
BP 130/80
no skin rashes
no edema
rest of exam normal

51. Case 2 Laboratory findings
Urinalysis:
1+ proteinuria
20-30 RBC’s / HPF
urine ACR 50 mg/mmol (~750 mg/24hr)
serum creatinine = 116 umol/L
Hb = 126 gm/L

52. Case 2 Special Laboratory Studies
ANA - negative
Complement levels normal
Streptococcal serology negative

53. Increased mesangial matrix - Mesangial proliferation

54. Increased mesangial matrix - Mesangial proliferation

55. IgA 55

56. Lumen
Mesangial dense deposits
RBC

57. Mesangial dense deposits

58. Case 2 Clinical presentation: “Nephritic” syndrome: some or all of
Hematuria,
mild proteinuria,
reduced GFR
high BP
Pathology Diagnosis:
IgA Nephropathy
Mesangial proliferation on LM
IgA deposits on IF
dense deposits EM

59. How can we classify glomerular diseases?
Clinical presentation (but lots of overlap)
Nephrotic
Nephritic
rapidly progressive (~ bad nephritic)
Etiology
Primary vs. Secondary
Pathology

60. Pathologic Classification of GN
Usually Nephrotic
Minimal change
Focal segmental glomerulosclerosis (FSGS)
Membranous
Usually Nephritic
Mesangial proliferative (IgA)
Diffuse proliferative +/- crescents
Others
diabetes, amyloid
Etc…

61. Secondary Causes of GN Infections Drugs- NSAIDs
Viruses: HBV, HCV, HIV,
malaria, bacterial endocarditis
post-streptococcal
Drugs- NSAIDs
Neoplasia (a “paraneoplastic syndrome”)
SLE & vasculitis
Diabetes
Amyloidosis (may be associated with myeloma)

62. Case 3
72 year old woman admitted to hospital with recent history of increasing fatigue, weakness and swelling of legs
no joint pains, skin rashes or shortness of breath
serum creatinine one year ago was 160 umol/L

63. Case 3 Physical Examination
BP 160/88, pulse 78/min & regular, afebrile
peripheral edema to knees
rest of exam normal

64. Case Studies - 3 Laboratory Findings Hemoglobin 91 gm/L
Serum Creatinine 364 umol/L
Urinalysis -
3+ protein
30-40 RBC’s/HPF and RBC casts
Urine ACR 100

65. RBC cast

67. Normal glomerulus

68. Crescent formation 68

69. Crescent 69

70. Crescent 70

71. IgG

72. Crescentic Glomerulonephritis
Pathologic manifestation of many different diseases
Three groups by immunofluorescence
Linear antibody deposits along the GBM:
Anti-GBM (+/- lungs involved)
Immune complexes (esp. SLE, infections)
No (or very few) immune deposits: “Pauci-immune”
Vasculitis

73. Rapidly Progressive GN
the clinical correlate of crescentic GN
proteinuria (usually PCR < 150 )
active urine sediment
RBC’s, casts (granular casts, RBC casts)
decreased GFR (days to weeks)
usually feel “sick”

74. Case 3 Clinical presentation: RPGN (rapidly Progressive GN)
- Nephritic syndrome with rapidly worsening GFR
Pathology Diagnosis:
Anti GBM syndrome with
inflammation & crescents on LM
Linear IgG along GBM on IF
often not much on EM

75. Clinical- Pathological relationships
3 cases as examples of
Nephrotic presentation
Nephritic presentation
RPGN

76. Summary

77. Manifestations of Glomerular Disease
Proteinuria
Mostly albuminuria
+/- edema, hypoalbuminemia, hyperlipidemia
(“nephrotic syndrome”)
Hematuria (usually microscopic +/- casts)
Hypertension
Decreased GFR
acute: consider “RPGN” (with crescents on biopsy)
chronic 77

78. Syndromes (presentations) of Glomerular Disease
Nephrotic Syndrome
Lots of proteinuria (ACR>200)
+/- edema, hypoalbuminemia, hyperlipidemia
Nephritic Syndrome
hematuria (usually microscopic +/- casts)
Proteinuria: ACR usually ;
High BP (usually)
Declining GFR (usually)
RPGN
Severe Nephritic syndrome with rapid decline in GFR 78

79. Hematuria Urologic (plumbing) Nephrologic (interesting diseases)
Think anatomically from glomerulus down to urethra
Then think about aetiology, investigations/referral
Urologic
(plumbing)
Microscopic or Gross
Clots very suggestive
Often pain or other plumbing symptoms
Occasionally “initial” or “terminal”
Nephrologic (interesting diseases)
Usually microscopic
Casts are very specific (but not sensitive)
Proteinuria is very suggestive
Consider if systemic illness (eg. Lupus)