GLOMERULONEPHRITIS PATHOPHYSIOLOGY DIAGNOSIS AND MANAGEMENT

1. Glomerulonephritis
1
Dr Manzoor Ahmad Parry
Assistant Professor Nephrology SKIMS

2. Normal Glomerulus
• The structural and functional unit of the kidney – ‘Nephron‘
• Consists of renal corpuscle (glomerulus surrounded by a Bowman
capsule) and a renal tubule.
• Each kidney has 1 million nephrons
• Glomerulus:
• Fenestrated endothelium, inner glomerular layer
• Glomerular basement membrane: layer composed of various extracellular proteins
forming a meshwork
• The outer layer has visceral epithelial cells, podocytes, and mesangial cells

3. 3

4. 4

5. Glomerulonephritis means 'inflammation of
glomeruli’
• Subset of renal diseases with immune-mediated damage to the basement
membrane, the mesangium, or the capillary endothelium
• Characterized by intraglomerular inflammation and cellular proliferation
• Results in hematuria, proteinuria, and azotemia.

6. Mechanisms of glomerular
inflammation
 Both humoral and cell-mediated immune mechanisms play a part in
the pathogenesis of glomerular inflammation
 Two basic mechanisms of antibody-mediated glomerular injury have
been identified:
• Antibodies can bind either to a structural component of the glomerulus or to
material that is not intrinsic to the glomerulus

7. Mechanism..cont’d
• Circulating antigen–antibody complexes form, escape clearance by the
reticuloendothelial system, and are deposited in the glomerulus
• Activation of cell-mediated immunity can also induce glomerular injury
• Complement activation, influx of circulating leukocytes, cytokine synthesis,
release of proteolytic enzymes, activation of the coagulation cascade, and
generation of proinflammatory lipid mediators

9. Mechanisms of Glomerulonephritis

10. Structural Changes of GN
• Cellular proliferation causes an increase in the cellularity of the glomerular tuft due to the excess
of endothelial, mesangial, and epithelial cells
• Endocapillary - within the glomerular capillary tufts
• Extracapillary - in the Bowman space, including the epithelial cells
• Thickening of glomerular basement membrane
• Electron-dense deposits corresponding to an area of immune complex deposition, such as
subendothelial, subepithelial, intramembranous, and mesangial
• Features of irreversible injury include hyalinization or sclerosis

11. Terminology
 Glomerulonephritis: inflammation of the kidney (glomerulos)
 Diffuse: process that involve all glomeruli,>50%
 Focal: involvement of some glomeruli NOT all,<50%
 Global: if the whole glomerular tuft is involved,
 Segmental: only part of the tuft involved

12. Functional Changes
Include the following:
• Proteinuria
• Hematuria
• typified by the presence of dysmorphic red cells or red-cell casts in the urine
• Reduction in creatinine clearance, oliguria, or anuria
• Active urine sediments, such as RBCs and RBC casts
This leads to intravascular volume expansion, edema, and systemic
hypertension

14. Patients with glomerulonephritis present with one of five clinical
syndromes:
1. Asymptomatic urinary abnormality
2. Acute glomerulonephritis
3. Rapidly progressive glomerulonephritis
4. Nephrotic syndrome
5. Chronic glomerulonephritis

15. Asymptomatic Urinary Abnormality
(AUA)
 Hematuria or subnephrotic proteinuria without HT, renal insufficiency,
edema
 U/A abnormality : persistent or recurrent
Hematuria with or without
proteinuria
Isolated non-nephrotic
proteinuria
 IgA Nephropathy
 Thin basement membrane
disease
 Alport syndrome
 Orthostatic proteinuria
 MN, FSGS, DM,
amyloidosis

17. IgA Nephropathy

18. Most common GN worldwide (10-40%)
Etiology : most cases are idiopathic
Clinical spectrum with Henoch-Schonlein Purpura
Secondary IgA N due to liver cirrhosis, Crohn’s disease
IgA Nephropathy
Epidemiology : between 16 and 35 years, male>female
Initial manifestation
Recurrent gross hematuria, often 24 to 48h after pharyngitis,
GI infection (“synpharyngitic”)
Or, microscopic hematuria during routine examination
HT, nephrotic proteinuria rare at initial presentation

19. Lab : Elevated serum IgA level in 50% cases, circulating IgG or IgA
Immune complex
Prognosis: 20 to 50% progress to ESRD over 20 years
Poor prognosis group :
- Male sex
- Older age at onset
- Absence of gross hematuria
- heavy proteinuria
- Hypertension
- azotemia at initial diagnosis
IgAN

20. mesangial expansion with increased matrix and cellularity
LM
IgAN

21. Mesangial deposits of IgA
Subendothelial and subepithelial
deposits are rarely seen.
IgAN

22. AUA : Isolated Non-nephrotic Proteinuria
of Glomerular Origin
Dx : separate urine collection(7A-
11P, 11P-7A)
Prognosis : excellent
Etiology : smoldering GN (mild mes.
Prolif. GN, FSGS, focal or diffuse
prolif. GN),
interstitial nephritis
Prognosis : slowly progressive azotemia
Orthostatic Proteinuria Persistent Proteinuria

23. Acute Glomerulonephritis or
Acute Nephritic Syndrome (AGN)

24. AGN
Acute glomerular inflammation
Sudden onset of acute renal failure and oliguria
Obstruction of glomerular capillary lumen
FFR falls Na and water retention
ECF volume expansion, Edema, Hypertension
U/A : RBC cast, dysmorphic RBC, leukocytes,
subnephrotic proteinuria
Often gross hematuria
Azotemia
General pathologic feature :
proliferative GN (capillary endothelial cell, mesangial cell)

26. AGN - PSGN
Acute post-streptococcal GN
Etiology : Pharyngeal or cutaneous infection with group A beta-hemolytic
streptococcus, nephritogenic strain
Epidemiology : common in children, male > female
Latent period : 6-15 days (“post-pharyngitic”)
Hematuria (gross or microscopic),
Edema, mild HT,
Oliguria,
Nausea, mild fever,
Flank pain
ARF of variable degrees

27. Lab finding & Pathology
U/A : hematuria, mild proteinuria
GFR reduced
Elevated ASO, anti-hyaluronidase, elevated anti-DNase B
Culture: Streptococcus in throat or skin
Complement level :
C3, CH50 markedly reduced, normalized in 8 weeks, C4 mildly reduced
LM : Diffuse endocapillary proliferation
PMN cell and monocyte infiltration
EM : hump (large subepithelial deposit: characteristic)
IF : IgG, C3 deposit

28. LM IF

29. EM

30. Treatment & prognosis
Benign course in children
Acute symptom : relieved in 1-2 wks
U/A abnormality esp. hematuria persists for 2 years
Treatment : symptomatic
Rest, salt water restriction, diuretics, protein restriction
Antibiotics (PCN, EM) needed in limited cases
- i.e. incomplete treatment, elevated CRP

31. Crescent
Normal
glomerulus
Rapidly Progressive
Glomerulonephritis (RPGN)

32. RPGN
Subacute glomerular inflammation
Patient develop renal failure over weeks to months
Nephritic urinary sediment, subnephrotic proteinuria, oliguria,
HT, hypervolemia, edema
Renal biopsy almost invariably shows crescents (=Crescentic
GN)

33. Crescentic GN
Pathology : diffuse crescent formation > 50% glomeruli
Clinically : progression to renal failure over weeks to
months, clinical features of GN (proteinuria, hematuria,
active urinary sediment)
If not properly treated, end stage renal disease ensues in 80-
90%

34. Classification of Crescentic GN
Type I : anti-GBM disease without pulmonary
hemorrhage
Type II : Immune complex deposition
Type III : pauci-immune
(no immunoglobulin deposition)
ANCA (anti-neutrophil cytoplasm antibody) positive

35. C-ANCA on ethanol fixed slide
P-ANCA on ethanol fixed slide
C-ANCA is identified as a positive result when there is intense positive granular staining of the cytoplasm
that extends to the border of the human granulocyte substrate displaying a 1+ or greater fluorescence
and there is absence of nuclear staining
P-ANCA exhibits intense positive perinuclear staining of the multi-lobed nucleus with a poorly defined cell
border.
A 1+ or greater fluorescence is considered a positive result
RPGN

36. LM
RPGN

37. IF with antibody to fibrinogen.
There is a linear pattern of staining along the
glomerular basement membrane with IgG.
IF RPGN

38. Nephrotic Syndrome
• Proteinuria > 3.5 g/d in adults and > 40mg/m2/hr in children
• Edema
• Hyperlipidemia/oval fat bodies
• Hypoalbuminemia

39. Complications of nephrotic syndrome
Increased risk of atherosclerosis
Elevated levels of
• Total and low density lipoprotein cholesterol
• Lipoprotein (a)
Low or normal high density lipoprotein cholesterol
It is related to the hypoproteinemia and low serum oncotic pressure
of nephrotic syndrome, which then leads to reactive hepatic protein
synthesis, including of lipoproteins

40. Complications of nephrotic
syndrome…cont’d
• Increase risk of thrombosis- DVT,PE… due to urinary anti-thrombin III
loss
• Increase risk of infections due to urinary Ig loss.

41. Minimal Change Disease (MCD)
• Synonyms : Nil disease, Lipoid nephrosis
Foot process disease
• Incidence : male>female
80% of NS in children
20-40 % of NS in adults
• Cause : Idiopathic, Drug (NSAIDs, rifampin, interferon a),
Hodgkin’s disease, HIV infection
• Pathology : normal in LM, IF
epithelial foot process effacement in EM

42. LM EM
MCD

44. Treatment
• Highly steroid responsive, excellent prognosis to glucocorticoid therapy
90% (children) and 50% (adult) : remission after
8weeks of high dose steroid therapy
• Sometimes relapse upon tapering (50-70%)
• Alkylating agents are reserved for frequent relapsers, cyclosporine for
steroid resistant MCNS

45. 10% of idiopathic NS
Cause: idiopathic, heroin abuse, VUR, AIDS, solitary kidney
Clinical features: Most typical nephrotic syndrome (nonselective)
Hypertension, hematuria, decreased renal function
Pathology: nonproliferative, sclerotic changes (focal, segmental)
Immunofluorescence findings are non-specific
Treatment: long-term steroid treatment, less effective on steroids
Prognosis: 50% of patients progress to ESRD in 7-10 years,
Recurrence common after renal transplantation
Focal Segmental Glomerulosclerosis

46. LM
FSGS

48. 1. Most common idiopathic NS in adults (40%)
Rare in children
Peak incidence between 30 and 50
2. Clinical manifestation
Mostly nephrotic (80%), Nonselective proteinuria
Microhematuria (50%)
HT : less than 30% at initial manifestation
but common later with renal progression
Membranous Nephropathy

49. Membranous Nephropathy

50. Idiopathic (majority)
Systemic disease or drugs
1. Infection : hepatitis B, hepatitis C
2. Autoimmune disease : SLE, RA, MCTD
3. Malignancy : carcinoma
4. Drugs : gold, penicillamine, NSAID, captopril
5. Miscellaneous : sarcoidosis, DM,
Etiology

51. ① Mean onset age: 30 ∼ 50 age (male: female = 2:1)
② Older age: correlate with malignancy 20% (>60 age)
③ Massive proteinuria (80%), edema
④ RVT*: 50% - high incidence
Clinical Sx

52. LM : diffuse thickening of the GBM (PAS staining)
spike pattern (Silver staining)
IF : granular deposit of IgG, IgM, C3
EM : subepithelial electron dense deposit
stage I, II, III, IV
Pathology

53. LM
MGN

54. IF with antibody to IgG. deposition of electron dense material and
interposition of lighter GBM material-
subepithelial deposition
EM
IF
MGN

55. 40% : spontaneous remission
30-40% : repeated relapse and remission
10-20% : persistent NS and progressive azotemia
(ESRD in 20 to 30 years)
Risk factors of renal progression :
male, older age at onset, heavy proteinuria,
hypertension, stage IV lesion, azotemia at initial Bx
Tx : no therapeutic effect with steroid alone
cyclophosphamide, chlorambucil, cyclosporine, Rituximab
Treatment & Prognosis

56. Membranous Proliferative
Glomerulonephropathy

57. Variable combination of nephritic or nephrotic features
Common in ages between 5-30
Decline in GFR, active urine sediment,
Proteinuria often in nephrotic range (50%)
Type I MPGN : Immune complex disease
C3 usually depressed
C1q, C4, properdin, factor B : borderline or low
Primary MPGN
Secondary MPGN : associated with infection, rheumatolgival (SLE), malignancy
MPGN Clinical Manifestation

58. Pathology
Diffuse proliferation of mesangial cells
Increased mesangial matrix
Thickening and reduplication of GBM
(Double contour, Tram-tract)
Type I and type II MPGN
Prognosis
Poor, slow progression to ESRD
Worse in type II MPGN
MPGN

59. LM
Normal kidney
MPGN

60. Type I: Subendothelial Deposits Type II: Dense Deposit Disease
EM
MPGN

61. EM IF
MPGN

62. Crescent
Normal
glomerulus
Rapidly Progressive
Glomerulonephritis (RPGN)

63. RPGN
Subacute glomerular inflammation
Patient develop renal failure over weeks to months
Nephritic urinary sediment, subnephrotic proteinuria, oliguria, HT,
hypervolemia, edema
Renal biopsy almost invariably shows crescents (=Crescentic GN)

64. Crescentic GN
Pathology : diffuse crescent formation > 50% glomeruli
Clinically : progression to renal failure over weeks to months, clinical
features of GN (proteinuria, hematuria, active urinary sediment)
If not properly treated, end stage renal disease ensues in 80-90%

65. Classification of Crescentic GN
Type I : anti-GBM disease without pulmonary
hemorrhage
Type II : Immune complex deposition
Type III : pauci-immune
(no immunoglobulin deposition)
ANCA (anti-neutrophil cytoplasm antibody) positive
RPGN

66. C-ANCA on ethanol fixed slide
P-ANCA on ethanol fixed slide
C-ANCA is identified as a positive result when there is intense positive granular staining of the cytoplasm
that extends to the border of the human granulocyte substrate displaying a 1+ or greater fluorescence
and there is absence of nuclear staining
P-ANCA exhibits intense positive perinuclear staining of the multi-lobed nucleus with a poorly defined cell
border.
A 1+ or greater fluorescence is considered a positive result
RPGN

67. LM
RPGN

68. IF with antibody to fibrinogen.
There is a linear pattern of staining along the
glomerular basement membrane with IgG.
IF RPGN

69. Alport’s Syndrome
Genetic defect in type IV collagen
Alpha 5 chain
X-linked dominant
Ant. lenticonus
Sensorineural hearing loss
Recurrent hematuria
Slowly progress to ESRD
EM : thickenend GBM with
lamellation, splitting

70. Thin Basement Membrane Disease
(= Benign familial hematuria)

71. Chronic Glomerulonephritis (CGN)
 Persistent proteinuria/hematuria/HT
 Insiduous onset, slowly progressive renal insufficiency over years
 Can be a manifestation of virtually all of the major GNs
 Pathology : renal atrophy, cortical thinning, glomerulosclerosis
irrespective of causative GN

72. Lupus Nephritis
Systemic Vasculitis
Amyloidosis
Cast Nephropathy
Secondary GN

73. Lupus Nephritis -- Diffuse Proliferative
Lupus Nephritis

74. Amyloidosis
Nodular pattern apple green on polarized light

75. Randomly oriented thin fibrils
(EM: x 51,250)

76. Cast Nephropathy
T-H protein(cast)

77. Diagnostic Approach to GN

78. DIAGNOSIS
• History .
• Physical exam.
• Investigations:
Labs.
Imaging.
Renal biopsy.

79. History
• Onset ( sudden or gradual).
• Symptoms: edema,hematuria,proteinuria,etc.
• Family history.
• Drug history.
• Past history of infections or malignancy.

80. LAB work up
• Antinuclear and anti-DNA antibodies for lupus,
• Cryoglobulins and rheumatoid factor suggesting cryoglobulinemia.
• Anti–glomerular basement membrane (anti-GBM) antibodies for Goodpasture
disease, antineutrophil cytoplasmic autoantibody (ANCA) for vasculitis,
• Antistreptolysin O titer or streptozyme test for poststreptococcal
glomerulonephritis

81. • Hepatitis profile.
• ASO titer.
• Serum and urine electrophoresis( MM,LCD,HCD)
• Measurement of systemic complement pathway activation by testing for serum
C3, C4, and CH50 (50% hemolyzing dose of complement) is often helpful in
limiting the differential diagnosis.

82. Imaging
• You need to make sure you have both kidneys.
• Size :normally 10-13 cm in adults.
• No anatomical or structural abnormalities.
• Presence of hydronephrosis.

83. Hypocomplementemia in glomerular disease DDX
• Classical pathway activation ( low C3,low C4,low CH50):
• Lupus nephritis (especially Class IV), Cryoglobulinemia, Membranoproliferative GN type 1.
• Alternative pathwayactivation (C3 ↓, C4 normal, CH50 L):
• Poststreptococcal GN, GN associated with other infection* (e.g., endocarditis, shunt
nephritis),HUS, Atheroembolic renal disease.

84. Renal biopsy
• Aid in diagnosis.
• Help to expect prognosis.
• WHEN TO DO IT??
this is debatable sometimes between nephrologist.

85. Indications
• For diagnosis of ?primary GN.
• Unexplained AKI.
• First presentation of CKD in young adult.
• When kidney disease is part of systemic illness and the kidney is the easiest to
access for Dx.
• Evaluation of RPGN.

86. NOT indicated
• Isolated glomerular hematuria.
• Isolated non-nephrotic proteinuria (1gram per day).
• Nephrotic syndrome: when one of the following is present:
DM
 history and presence of extrarenal involvement( eg: amyloidosis)
Children under the age of six years with the acute onset of nephrotic syndrome.
Malignancy, massive obesity.

87. • THANK YOU

88. General Principles of Management
• Conservative treatment
• Decrease Proteinuria
• Treatment of hypertension
• Therapy to address complications
• Edema
• Hypoproteinemia
• Infection
• Hypercoagulability
• Hyperlipidemia
• Disease specific therapies
• Immunosuppression

89. Proteinuria
• Proteinuria represents the key modifiable factor to preserve GFR in patients with
glomerular disease
• “dose dependent effect” (25x prot >3g/d comp to <1 g/d)
• Progressive loss of renal function in glomerular diseases can be decreased if
proteinuria is reduced < 0.5 g/day

90. Treatment of Proteinuria
• The antiproteinuric agents of choice are ACE inhibitors and
ARBs
• Block efferent arteriolar constriction, ↓ glom Htn
• Reduce the increased glomerular capillary wall permeability
• Reduce proteinuria by an average of 40% to 50%
• Nondihydropyridine CCB Therapy
• Diltiazem and verapamil
• Antiproteinuric and may be renoprotective.
• Protein Intake
• 0.7 to 0.8 g/kg ideal body weight per day
• Decreases proteiuria & GFR fall
• Risk of malnutrition & PEW

91. Treatment of HTN
• Hypertension is very common in pr. Glomerular diseases
• Sodium and water overload is an important part of the
pathogenetic process
• BP control not only protect against the cardiovascular diseases
but also delay progression of the renal disease
• In the MDRD study, patients with prot. >1g/day, had a better outcome if
their blood pressure was reduced to 125/75 mm Hg rather than 140/80
N Engl J Med. 1994;330: 877-884.

92. Treatment of HTN
• KDIGO recommends a BP <130/80 mm Hg in proteinuric patients
• ACE inhibitors and ARBs are the first-choice of therapy
• Nondihydropyridine CCBs have a beneficial effect on proteinuria as well
as on blood pressure
• Dihydropyridine CCBs can exacerbate proteinuria
• Dilate the afferent arteriole, increase glom htn
• Safe to use if the patient is receiving either an ACE inhibitor or an ARB
• Lifestyle modification is integral part of therapy
• salt restriction, weight normalization, regular exercise, and smoking
cessation

93. Treatment of complications

94. • Edema
• Diuretic therapy
• Loop diuretics, can be combined with Thiazides, K sparing diuretics
• Dietary sodium restriction `(2 to 3 g of sod.)
• Hyperlipidemia
• Treatment should usually follow the guidelines that apply to the general
population to prevent CVD
• statin or statin/ezetimibe combination
• Side effects , such as rhabdomyolysis occur more frequently with
decrease GFR

95. • Correction of Hypoproteinemia
• Dietary protein intake (0.8 to 1 g/kg/day) with high carbohydrate
• With heavy proteinuria, the amount of urinary protein loss should be
added to dietary protein intake.
• Hypercoagulability
• Risk of thrombotic events increases < 2.5 g/dl
• Immobility d/t edema aggravates the risk
• Anticoagulation (Heparin or warfarin) if sr albumin < 2 g/dl
• Infection
• Loss of IgG, complement, steroid
• varicella, peritonitis by encapsulated bacteria