1. Glomerulonephritis in Children
Dr. Hala Wannous
pediatric nephrologist
damascus university
faculty of medicine
children’s hospital 1

2. Glomerulonephritis
Glomeulonephritis is an immune-mediated renal disease induced by two mechanisms:
1- Antibody-mediated immunity:
In situ immune complexes: Antibodies (autoantibodies) that bind to planted (exogenous) antigens, or interact with intrinsic glomerular cell surface antigens, as a result of changes to the cell surface ( anti-GBM antibody nephritis, membranous glomerulonephritis).
Circulating immune complex: Pre-formed immune complexes from the circulation that trapped by glomerulous. Regardless of whether they are endogenous (lupus nephritis),
or exogenous (acute post streptococcal GN), the antigens are
not glomerular in origin. 2

3. Glomerulonephritis 3 2- Cell-mediated immunity :
Caused by sensitized T-cells, cytotoxic action of T cells which
may damage the intrinsic glomerular cells or alter glomerular
filtration barrier (e. In pauci-immune glomerular diseases, such as
ANCA-related crescentic glomerulonephritis).
Then, Activation of classical or alternative complement pathway,
followed by secretion of secondary inflammatory mediators,
including cytokines and chemical mediators, derived from
activated leukocytes. Following the initiation of immune-mediated
glomerular injury, various cytokines, chemokines, and growth
factors are significantly involved in the promotion of glomerular
injury as second messengers. 3

4. Complement Cascade:

5. Pathogenesis of glomerular damage

6. Terminology Glomerulonephritis : inflammation of the glomeruli
Glomerulopathy : disease of the glomeruli
All glomeruli are involved: Diffuse (generalized)
Some glomeruli are involved: Focal
In one glomerulus:
if the whole glomerulus is involved : Global
if only a part of the glomerulus is involved: Segmental
Other terminologies in common use:
Proliferative: increase in the number of cells
Sclerosing: Hardening of the tissue

7. Glomerular lesion The lesion Consists of: Infilteration of leucocytes.
Proliferation of endothelial, mesangial and epithelial cell.
Formation of deposits.
Also immunoglobulins and complements form deposits (granular deposits).
The formed deposits lie at three sites:
In the mesangium (mesangial deposits ).
Between the endothelial cells and glomerular basement
membrane (GBM ) (subendothelial deposits ).
Between the outside of GBM and podocytes (subepithelial deposits).

8. Glomerular injury
Glomerulonephritis arises from the responses of intrinsic glomerular cells to inflammatory reactions. Glomerular deposition, hypercellularity (intrinsic and inflammatory cells), and capillary destruction are typical features of glomerular injury.
Extensive inflammatory damage to glomeruli → Impairment of selective filtering properties of the kidney leading to a decreased GFR and eventually produce uremic symptoms with salt and water retention, leading to edema and hypertension.
Molecules normally not filtered such as constituents of the blood, pass into the urine and are excreted. 8

9. Glomerulonephritis: Classification
classification is difficult : a mix of clinical and pathological descriptions:
Clinical features : RPGN
Morphology- biopsy defined (eg: various histology patterns)
Pathogenetic mechanisms (eg anti GBM disease)
Etiology : post- infectious GN
Based on acuity : acute, RPGN, chronic
Glomerulonephritis can be primary or secondary:
- Primary : confined to the kidney (MPGN).
- Secondary : due to a systemic disease (SLE). 9

10. Anatomy:

11. Anatomy:

12. Anatomy:

14. Light micrograph of a normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke. 14

15. Electron microscopy
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin and no electron dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut Rennke, MD. 15

16. Possible Clinical Manifestations:
Proteinuria: asymptomatic
Haematuria: asymptomatic (especially dysmorphic red cells, red cell casts)
Hypertension
Nephrotic syndrome
Nephritic syndrome
Acute renal failure
Rapidly progressive renal failure
End stage renal failure 16

17. Dysmorphic erythrocytes in the scanning electron microscope

18. Red blood cell cast

19. Acute Nephritic Syndrome:
Syndrome characterised in typical cases by:
haematuria
oliguria
oedema
hypertension
reduced GFR
proteinuria
fluid overload
Phase contrast microscopy showing dysmorphic red cells in a patient with glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions (arrows). Courtesy of Hans Köhler, MD. 19

20. Clinical Features of the Acute Nephritic Syndrome:
haematuria is usually macroscopic with smoky brown urine (like coca cola)
oliguria may be overlooked or absent in milder cases
oedema is usually mild and is often just peri-orbital, weight gain may be detected
hypertension common and associated with raised urea and creatinine
proteinuria is variable but usually less than in the nephrotic syndrome 20

21. Etiology of the Nephritic Syndrome
Most common cause is Acute Poststreptococcal Glomerulonephritis
Subacute Bacterial Endocarditis
Lupus Nephritis (SLE)
Anti-glomerular Basement Membrane Disease
IgA Nephropathy
ANCA-related glomerulonephritis(Wegener's granulomatosis)
Henoch-Schonlein purpura
Membranoproliferative Glomerulonephritis
Crescentic glomerulonephritis 21

22. Management issues in the nephritic syndrome
Appropriate investigations: skin and throat swabs,strep serology, complement, urea, creatinine, electrolytes, urinalysis and CXR
BP, urine output and daily weight
Fluid and diet management
Treat hypertension and fluid overload
Treat infection 22

23. Complications of the Nephritic Syndrome
Hypertensive encephalopathy (seizures, coma)
Heart Failure (pulmonary oedema)
Uraemia requiring dialysis 23

24. Prognosis in the Nephritic Syndrome
More than 95% of children make a complete recovery.
Chronic renal impairment in the longer term is uncommon in children.
Bad prognostic features include severe renal impairment at presentation and continuing heavy proteinuria and hypertension.
Adults more likely to have long term sequelae than children. 24

25. Acute Post-Streptococcal Glomerulonephritis(APSGN)
Post-streptococcal glomerulonephritis is an immune-
mediated disease involving:
- Streptococcal antigens (endostreptosin)
- Circulating (and in situ) immune complexes
- Activation of complement, and glomerular
infiltration of lymphocytes and macrophages in
association with cell-mediated immunity .
Poststreptococcal glomerulonephritis is prototypical
for acute endocapillary proliferative
glomerulonephritis. 25

26. APSGN: Pathogenesis
It is caused by an exogenous antigen (endostreptosin)
following infection of the pharynx or skin with strain
of group A β-hemolytic streptococcus.
Specific M proteins in group A streptococci were
initially considered “nephritogenic,”
Host susceptibility factors (HLA-DR) 26

27. APSGN: Pathogenesis
Studies in epidemics revealed that APSGN was associated with pyodermitis due to Group A streptococci of M types 47, 49, 55, 57 and 60,
and with upper respiratory infections due to streptococci of M types 1, 2, 4, 12, 18 and 25.
Immune complexes formed against nephritogenic streptococcal antigen(s) may be formed in circulation, and deposited in the glomeruli, or formed in situ against antigenic fractions planted in the glomeruli. 27

28. APSGN: Clinical Characteristics
Children from 4 to 14 years are more frequently
affected by APSGN, It is rare below the age of 2
and above the age of 20.
Twice more frequent in males than in females.
The latent period between infection and nephritis
is longer after skin infections (3–5 weeks) than
after upper respiratory infections (1–2 weeks). 28

29. APSGN: Clinical Characteristics
The classic presentation is an acute nephritic syndrome with hematuria (usually gross and the urine looks smoky brown), pyuria, red blood cell casts, edema, hypertension, and oliguric renal failure, which may, exceptionally, be severe enough to appear as RPGN (crescentic GN). and more rarely with heavy proteinuria (nephrotic).
Systemic symptoms of slight fever, headache, nausea, malaise, anorexia, and flank pain (due to swelling of the renal capsule) are reported in as many as 50% of cases.
Subclinical disease is characterized by a reduction of serum complement, microscopic hematuria and normal or increased blood pressure in asymptomatic patients. 29

30. APSGN: Serological Findings
The most constant serological finding is the reduction in serum complement levels that occurs in more than 90% of the cases. The activation of the complement system is usually via the alternative complement pathway and reduced C3 with normal C1 and C4.
IgG and IgM serum levels are elevated in 80–90% of the patients with APSGN.
Rising antistreptococcal antibody titers are the usual clinical indication of a preceding streptococcal infection since positive cultures are obtained in only 20–25% of the cases. 30

31. APSGN: Serological Findings
Antistreptolysin O titers and anti-DNAse B titers
are the most frequently elevated antibody titers
after streptococcal throat infections and after streptococcal skin infection, respectively.
Throat cultures are usually negative by the time patient presents with GN, but ASLO, anti-DNAse B should be high along with low complements. 31

32. APSGN: Pathology
Renal biopsy is usually not done in patients with APSGN.
If the clinical presentation is atypical or resolution of the
disease delayed, then renal biopsy is mandatory:
1- The serum complement is normal
2- The serum complement remains low after 8 weeks
3- Proteinuria in the nephrotic range
4- Depressed GFR > 3 – 4 weeks
5- Gross hematuria > weeks.
6- Persistent proteinuria > months
7- Hypertension > 2 – 3 weeks
8- Severe anuria and rapid progressive course 32

33. APSGN: Pathology
Biopsy findings in APSGN are those of endocapillary proliferative glomerulonephritis. glomeuli enlarged due to swelling and hypercellularity ( mesangial and endothelial cell proliferation). Glomerular basement membrane is normal. Macrophages and lymphocytes can be found in increased numbers in the glomeruli and in tubulointerstitial areas.
the more remarkable histologic characteristics are found in the glomeruli that present a diffuse increment in cellularity.
The immunofluorescent appearance: Glomerular granular subendothelial immune deposits C3, IgG and IgM are usually present and they may be demonstrated in the mesangium and in the glomerular basement membrane. 33

34. APSGN: Pathology
The hallmark of APSGN is the electron microscopy findings
of large subepithelial deposits ( humps ), believed to be
immune complexes formed in situ against antigenic fractions
planted in the glomeruli.
Follow-up studies performed several years after the initial
episode of acute poststreptococcal glomerulonephritis,have
revealed immune deposits and a variable degree of mesangial
sclerosis and obliteration, even in the absence of clinical
manifestations of renal disease. 34

35. APSGN: Pathology

36. APSGN: Pathology

37. APSGN: Diagnosis
The clinical presentation is that of a child of 4–15 years
who suddenly develops dark and scanty urine and
swelling of the face and legs.
History and physical examination determines a high blood
pressure and the absence of a systemic illness.
A history of a precedent upper respiratory infection and/or
skin infections suggests a post-streptococcal etiology that
maybe confirmed by a positive culture or rising anti-
streptococcal antibody titers.
The serum complement C3 is low. 37

38. APSGN: Differential Diagnosis
The complement is a first line diagnostic test that permits
consideration of acute glomerulonephritis that present low (C3):
APSGN
Lupus nephritis
shunt nephritis
endocarditis
cryoglobulinemia
membranoproliferative glomerulonephritis
The reduction of C1, C4 and C3 levels, indicating activation
of the classic pathway of complement, is characteristic of
lupus erythematosus. 38

39. APSGN: Treatment
Antibiotic treatment for streptococcus: Even without infection
(penicillin or, in allergic individuals, erythromycin) should be
given to all patients and their cohabitants.
Antibiotic treatment after the onset of APSGN does not alter
the course of the disease. Antibiotic prophylaxis given to
family members may reduce the risk of spread of APSGN.
Treatment of the Acute Nephritic Syndrome: Supportive
Restrictions of fluid and sodium intake are the cornerstones
of the treatment.
Cases that present significant edema, hypertension and
circulatory congestion benefit from the administration of
loop diuretics. 39

40. APSGN: Treatment
Antihypertensive treatment in cases of severe hypertension: Nifedipine, Parenteral hydralazine may be required with close observation. Angiotensin converting enzyme inhibitors carry the risk of hyperkalemia.
Hemodialysis or peritoneal dialysis may be required
occasionally in children for the treatment of hyperkalemia,
uremia or severe circulatory congestion.
Steroids are not generally indicated but are used in patients who have renal failure or rapidly progressive GN, which is usually associated with crescentic APSGN.
There are reports of beneficial effects of pulse methyprednisolone therapy. 40

41. APSGN: Prognosis
Majority of children with APSGN are believed to make a full
recovery without significant long-term consequences.
Recurrences of APSGN are rare.
Progression to chronic kidney disease (CKD) and end-stage
renal disease (ESRD) may occur in exceptionally severe
cases of APSGN.
Complete resolution of the hematuria and proteinuria in
children occurs within 3–6 weeks of the onset of nephritis. 41

42. APSGN: Follow-up
Follow-up of APSGN is important to document full recovery.
Proteinuria usually resolves by 6–8 weeks. Prolonged
proteinuria for more than 3 months may indicate irreversible renal injury.
Gross hematuria usually improves within 1–3 weeks.
Microscopic hematuria can persist for up to 1 year and is not an indicator of poor prognosis.
Recovery of serum complement C3 to normal usually takes 6–8 weeks. Persistent hypocomplementemia beyond 8 weeks requires a careful search for other diagnoses, such as MPGN and SLE nephritis. 42

43. Other acute post-infectious GN
Acute GN follows other infections:
Bacterial sepsis
Acute or subacute bacterial endocarditis
Visceral abscess
Infected ventriculoperitoneal shunt
Osteomyelitis
Treatment is aimed at eradicating the primary
disease. 43

44. IgA Nephropathy (Berger’s Disease)
IgA nephropathy (IgA N) is the most frequent type of chronic
glomerulonephritis in children.
Pathogenesis:
IgA N is generally considered to be an immune complex-
mediated or aggregated IgA - mediated glomerulonephritis.
Genetic factors have been suggested as important in
the development of IgA Nephropathy.
Because of the frequent association between upper respiratory
tract or gastrointestinal infection and the onset of macroscopic
hematuria, It has been suggested that certain viral or bacterial
infections may lead to IgA nephropathy. 44

45. IgA Nephropathy: Pathogenesis
Many antigens, including herpes simplex virus, cytomegalovirus,
Epstein-Barr virus, adenovirus and milk antigen, have been
Identified.
Circulating IgA immune complexes have been detected, often
associated with IgG immune complex.
Serum levels of IgA are increased in 50–70% of patients with IgA
nephropathy,
IgA production is T cell-dependent, and the increased production
in IgA nephropathy may indicate altered T cell function. 45

46. IgA Nephropathy: Pathogenesis
The mesangial deposits in IgA nephropathy is consistent with
antigen-polymeric IgA complexes predominantly of IgA1 subclass.
Proposed potential mechanisms:
Decreased IgA response to mucosal antigens may promote
Increased production of polymeric IgA1 by the bone marrow,
leading to increased serum levels of IgA1.
Defective galactosylation of IgA1 may decrease hepatic
clearance of IgA1 and promote binding of IgA1complexes to
glomerular mesangial cells. 46

47. IgA Nephropathy: Pathology
Light microscopic findings: are quite variable, often
mild to moderate mesangial cell proliferation.
The most characteristic abnormality is mesangial
enlargement, caused by various combinations of
hypercellularity and increase in matrix.
Progression of IgA nephropathy leads to gradual
resolution of mesangial hypercellularity and an
increase of matrix associated with The development
of sclerosis. 47

48. IgA Nephropathy: Pathology
Immunofluorescence (IF):
- The diagnostic immunopathological pattern of IgAN
is the presence of IgA in the glomerular mesangium
as the sole or predominant Ig (IgA1 deposits).
- There are also deposits of IgG and/or IgM with the
same staining pattern as IgA but with lesser intensity
and frequency.
- C3 deposits were observed in a similar distribution
pattern in 64% of cases. 48

49. IgA Nephropathy: Clinical Features
IgA N occurs at all ages but is most common during the second
and third decades of life.
Male > Females 2 to 1
The clinical presentation varies:
Some patients have asymptomatic persistent microscopic hematuria with or without proteinuria.
Another classic presentation is recurrent episodes of macroscopic haematuria typically occur during a URI (less frequently, in association with other infections) and clearing after a period of 2–4 days. The interval between the precipitating infection and the appearance of hematuria ranges from 1 to 2 days compared with 1 or 2 weeks in acute postinfectious glomerulonephritis. 49

50. IgA Nephropathy: Clinical Features
The blood pressure and renal function at onset are normal.
Hypertension is infrequent and usually mild to moderate.
Some patients present with acute nephritic syndrome or nephrotic syndrome.
Renal function is usually normal but occasionally a patient will present with acute renal failure due to acute tubular necrosis secondary to the gross haematuria.
Less than 5% have chronic renal insufficiency (CRI) at diagnosis
Some patients develop extensive crescents and arapidly progressive course. 50

51. IgA Nephropathy: Diagnosis
There is no specific serologic marker for IgA Nephropathy.
Diagnosis depends on IF examination:
The presence of IgA as the sole or predominant Ig in the glomerular mesangium.
Serum concentrations of C3 and C4 are normal.
Although serum IgA level is usually above the mean and often significantly elevated,
the sensitivity and specificity are too low for its use
as a diagnostic test. 51

52. IgA Nephropathy: Management
There is no clear guidelines for the treatment of pediatric IgA N.
Aggressive control of blood pressure and proteinuria with
ACEI’s or AR2B’s.
Combination therapy with ACEI and AR2B has an additive
dose-dependent antiproteinuric effect compared to
monotherapies.
Corticosteroid therapy is indicated for pediatric patients with IgA N who have the nephrotic syndrome.
Rapidly progressive or severe crescentic IgA N are usually
treated with high-dose intravenous methylprednisolone pulses
followed by oral corticosteroids and sometimes other
immunosuppressive agents such as cyclophosphamide. 52

53. IgA Nephropathy: Prognosis
The outcome for pediatric patients with IgA N ranges from complete resolution of all clinical signs of disease to ESRD.
Slowly progressive.
By 20 years, 50% have end stage kidney disease.
Clinical markers at diagnosis that associate with worse
prognosis and progression to CRI and/or ESRD are:
1- proteinuria >1g/day
2- severe histologic features such as the presence of
crescents and/or segmental sclerosis, glomerular fibrosis.
3- hypertension.
4- increased creatinine. 53

54. Rapidly Progressive GN (RPGN)
Rapidly progressive glomerulonephritis (RPGN), or crescentic
glomerulonephritis, is a clinicopathologic condition that is
characterized by a rapid deterioration of renal function and
demonstration of ‘crescents’ affecting at least 50% of the
glomeruli in an adequate biopsy specimen.
Severely affected glomeruli may eventually progress to global
sclerosis.
The crescents are believed to be the result of severe non-
specific glomerular injury, with numerous underlying causes. 54

55. RPGN: Classification
Current classification of RPGN is based on the nature of
immune deposits seen in the renal biopsy. It is categorized as:
Immune complex-mediated: MPGN, IgA nephropathy, SLE
nephritis, Henoch–Schönlein purpura nephritis, APSGN.
Anti-glomerular basement membrane (anti-GBM) antibody
mediated: Binding of circulating autoantibodies to the GBM.
Pauci-immune: Extensive glomerular crescent formation
without evidence of immune complex or anti-GBM antibody
deposition, such as Wegener’s granulomatosis ( ANCA related).
Anti-GBM antibody mediated RPGN is the most aggressive form of
RPGN, and accounts for approximately 12% of pediatric cases. 55

56. RPGN: Clinical manifestations
The manifestations of RPGN can vary from asymptomatic
proteinuria and hematuria, or increased serum creatinine, to life-
threatening renal failure or hypertensive crisis.
Nephritic features such as hypertension, oliguria, hematuria, or
nephrotic syndrome are also frequently present.
Renal failure, requiring dialysis, may be present at the time of
initial diagnosis, or develop subsequently over days to weeks.
Even in asymptomatic cases, progressive renal disease and
declining kidney function is common.
Indicators of poor renal prognosis are: impaired renal function at
onset, and large percentage fibrous crescents on renal biopsy. 56

57. RPGN: Diagnosis
Nephritic urinary sediment : red cells, white cells, red cell casts, white cell casts, hyaline casts.
Serology: depends on underlying disease.
Immediate hospitalisation and biopsy:
Crescentic GN : Proliferation of epithelial cells surrounding the glomerulus, but within Bowman’s space.
If IgG present in linear stain along the GBM, consistent with anti GBM antibiodies, which is a marker of Goodpasture’s syndrome.
Presence of IgG and complement in a granular staining on the capillary wall suggests an immune complex associated disease such as lupus, IgA nephropathy or APSGN.
Absence of immune deposition suggests a vasculitic process such as Wegener’s granulomatosis or microscopic polyangiitis. 57

58. RPGN: Treatment
The standard treatment of RPGN consists of glucocorticoids and
cytotoxic drugs.
Intravenous methylprednisolone pulses: 20 mg/kg on alternate
days for six doses. followed by oral prednisone: 2 mg/kg/day
gradually tapered over 1 year .
Monthly intravenous cyclophosphamide infusions at a dose of
mg/m2/dose for 6 months.
Maintenance therapy with azathioprine (2 mg/kg/day) was
recommended for 12 months after remission.
The combination of high-dose steroids and cyclophosphamide is
effective in inducing remission in up to 90% of adult patients with
RPGN. 58

59. RPGN: Goodpasture’s Syndrome
Autoimmune
Commonly 2nd-3rd decade and second peak in
60 years age group.
Some present with renal involvement
(Goodpasture’s disease).
Some present with pulmonary haemorrhage
and nephritis (Goodpasture’s syndrome).
Rarely some present with only pulmonary
involvement. 59

60. Goodpasture’s Syndrome60

61. RPGN: Goodpasture’s Syndrome
Classic : haemoptysis after upper respiratory infection and have nephritic urinary sediment.
History of smoking or hydrocarbon exposure is common.
CXR: pulmonary haemorrhage.
Lab: iron deficiency anaemia and renal dysfunction, circulating anti-GBM antibodies.
Kidney biopsy: crescentic GN with linear staining IgG and C3 along the glomerular basement membrane. 61

62. RPGN: Goodpasture’s Syndrome
Treatment:
High dose IV methylprednisolone pulses:
(20 mg/kg daily for 3 days) followed by oral prednisolone and cyclophosphamide.
Plasma exchange every other day until anti- GBM Ab titer is negative. 62

63. Membranous nephropathy
Membranous nephropathy (MN) is the most common cause of
nephrotic syndrome in older adults, and although more common
in the adult population, has been described in children, and even
in the newborn.
The disease is defined by the presence of subepithelial immune
deposits (between the GBM and the podocyte).
In childhood: Idiopathic MN is a relatively rare cause of nephrotic
syndrome. By contrast, MN in children is more often due to
secondary causes such as SLE, hepatitis B, drugs and toxins. 63

64. MN: Pathogenesis
The presence of immune complexes in the subepithelial space
suggests in situ formation of immune complexes involving
podocyte antigens, or planted exogenous antigens, because the
layer of endothelial cells and the GBM provide an effective barrier
to the passage of pre-formed circulating immune complexes.
In idiopathic MN: the autoantibodies react to an endogenous
antigen on the podocyte foot process.
In secondary MN: reaction of antibody to an exogenous antigen
which has trapped in the subepithelial space (planted antigen). 64

65. MN: Pathogenesis 65 Common secondary causes of MN:
Infections: Hepatitis B, rarely Hepatitis C, syphilis.
Drugs: Penicillamine, gold, captopril, NSAID’s.
Autoimmune diseases : SLE
Malignancies
MN is an example of Immune-mediated podocyte injury,
which results from complement activation (alternate pathway).
The podocyte and GBM abnormalities can largely explain the
marked proteinuria that typically develops in MN. 65

66. MN: Pathology 66 Light Microscopy:
Diffuse thickening of the GBM. Glomerular cellularity is typically
normal. The presence of mesangial hypercellularity or leukocyte
infiltration suggests a secondary form of MN.
Immunofluorescence:
Finely granular deposits of IgG in a subepithelial distribution on
the outer surface of the GBM.
Complement C3 is present in about 50% of adult patients.
Electron Microscopy:
Effacement of podocyte foot processes overlying the areas of
electron dense deposits, new layers of GBM are laid down over
this electron-dense deposits. 66

67. MN: Clinical manifestations
Age at presentation can vary from neonatal to young
adulthood, but the mean age is typically 8–10 years.
MN in childhood affects males and females fairly equally.
Typically presents with either asymptomatic proteinuria, or
with features of nephrotic syndrome.
Proteinuria is typically within the nephrotic range (90%).
Microhematuria is common (80%).
Gross hematuria occurs in approximately 40%.
Hypertension at onset is uncommon.
Renal function is typically normal at presentation. 67

68. Treatment of Idiopathic MN
Exclusion of secondary causes of the disease.
Non-Immunosuppressive Therapy :
Angiotensin converting enzyme (ACE) inhibitor or angiotensin
receptor blocker (ARB) therapy are renoprotective.
Blood pressure should be controlled.
Lipid lowering therapy (statins) for hypercholesterolaemia.
Low dose aspirin therapy may be used, if increased risk of
venous thrombosis.
Immunosuppressive therapy:
Usually reserved for those with risk factors for disease
progression. Steroid therapy in children with nephrotic syndrome.
If steroid resistant: addition of cyclophosphamide or cyclosporin. 68

69. MN: Prognosis
The prognosis in children is much better than in adults,
however, overall about 25% progress to chronic kidney disease.
The most important prognostic indicator in children is the
presence of nephrotic syndrome.
Other adverse risk factors:
The renal biopsy findings: degree of glomerular sclerosis and
Interstitial fibrosis.
Age: older than 10 years.
Hypertension at onset.
The presence of renal vein thrombosis. 69

70. Membranoproliferative Glomerulonephritis(MPGN)
MPGN is uncommon histologic lesion associated with the
childhood nephrotic syndrome.
While primary (idiopathic) MPGN is more common, MPGN has
also been described as a consequence of other disorders.
Pathogenesis: MPGN I: Circulating immune complexes composed of [IgG (antibody)-unknown antigen-C3] which deposit in the subendothelial glomerular space, giving rise
to a response that includes marked mesangial proliferation.
MPGN II (Dense Deposit Disease: DDD): Circulating IgG autoantibody (nephritic factor) that activates complement via the alternative pathway. Excessive activation of C3 by unregulated C3 convertase (mutations in factor H?)
MPGN III: Uncertain 70

71. MPGN: Classification 71 MPGN type I:
Idiopathic ( primary): familial
Secondary: - Malignancy (B-cell lymphoma, Non-Hodgkin’s lymphoma)
- Immunologic (Cryoglobulinemia, SLE, Complement
deficiencies)
- Infectious (Hepatitis C, rarely Hepatitis B, HIV)
- Other (Heroin abuse, Partial lipodystrophy )
MPGN type II (Dense Deposit Disease: DDD):
Idiopathic( primary): familial
Complement deficiencies
Partial lipodystrophy
MPGN type III: 71

72. MPGN: Pathology
On light microscopy: all forms of MPGN are characterized by
an increased mesangial matrix and cellularity, capillary wall
thickening, a splitting of the GBM (double contour called tram-
tracking), and a characteristic lobular appearance of the glomeruli.
Immunofluorescence: IF staining is positive for C3 and IgG in
MPGN types I and III, and C3 alone are seen in dense deposit
disease (MPGN type II).
Electron microscopy: Based on the nature and location of the
electron-dense deposits, MPGN is classified into three subtypes.
Subendothelial deposits are seen in MPGN type I, whereas
intramembranous electron-dense deposits characterize dense
deposit disease or MPGN type II . 72

73. Light micrograph in membranoproliferative glomerulonephritis showing a lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls (small arrows). Courtesy of Helmut Rennke, MD. 73

74. MPGN: Clinical Manifestation
Characteristic clinical features included an older age at
presentation, a slight female predominance.
The presentation of MPGN generally falls into three
categories:
Asymptomatic micro-hematuria and proteinuria:
50% of patients.
Nephrotic syndrome: 1/3 of patients.
Acute nephritic syndrome with gross hematuria :
25% of patients. 74

75. MPGN: Clinical Manifestation
Systolic hypertension in approximately 50%.
Nearly 60% had microscopic hematuria at onset.
75% had persistently low serum complement C3.
50% had azotemia, relatively preserved renal
function.
Rare patients may develop rapidly progressive
glomerulonephritis.
Antecedent constitutional complaints, including
fatigue, lassitude, and weight loss, characterize the
onset in about 25% of patients with MPGN type I. 75

76. MPGN: Treatment
Manage hypertension, ACEI/AR2B, salt restriction, diuretics,
treat HCV.
Steroids (high dose): 2 mg/Kg (to a maximum of 80 mg),
alternate day prednisone for a minimum of 2 years.
Dose reduction thereafter is based on improvement of clinical
parameters (urinalysis, serum albumin, serum C3 level),
and glomerular morphology (degree of mesangial proliferation,
number of open capillary lumens).
Long-term, prednisone dose is slowly reduced if there is no
evidence for disease reactivation (increase in proteinuria,
and/or hematuria and/or decrease in serum C3 level). 76

77. MPGN: Treatment
Most patients will continue with at least some degree of proteinuria as a result of chronic glomerular damage.
Absence of microhematuria appears to be the best clinical indicator of disease remission.
Most patients have continued on alternate day steroids for at least 5 years and many for much longer periods.
In the most recent report using the same alternate day prednisone regimen, renal survival was 80% at 10 years in those with MPGN type I.
Other therapies (in patients resistant to steroids):
Cyclosporine, tacrolimus, mycophenolate. 77

78. Conclusions Take a history. Do a urine test.
If haematuria with (proteinuria,
dysmorphic RBCs, RBC casts) → GN ?
Exclude secondary causes.
Biopsy is the definitive way to diagnose. 78