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1. Dr. Anass Ahmed Qasem

2.  History
 Pathogenesis
 Clinical Presentation
 Diagnosis
 Treatment
 Prognosis

3. Immunoglobulin A (IgA)
nephropathy was first
described by the pathologist
Jean Berger and thus is
sometimes called Berger’s
disease.
Jean Berger published his
description of glomerulo-
nephritis with mesangial IgA
deposition in winter 1968.

5.  History
 Pathogenesis
 Clinical Presentation
 Diagnosis
 Treatment
 Prognosis

6. Definition
Immunoglobulin A nephropathy is defined by the presence of
IgA-dominant or co-dominant mesangial immunoglobulin
deposits. Lupus glomerulonephritis, which may have IgA
dominant or co-dominant deposits, is excluded from this
diagnostic category.
Immunoglobulin A nephropathy occurs as :
1- primary (idiopathic) disease, as a component of Henoch- Schِ lein n
purpura small-vessel vasculitis,
2- secondary to liver disease (especially alcoholic cirrhosis), and
associated with a variety of inflammatory diseases including
ankylosing spondylitis, psoriasis, Reiter’s disease, uveitis, enteritis
(e.g., Yersinia enterocolitica infection), inflammatory bowel
disease, celiac disease, dermatitis herpetiformis, and HIV infection

7. The etiology of IgA nephropathy is unknown, but infections
and/or genetic characteristics may predispose to the development
of kidney disease.
It has also been suggested that IgA nephropathy results from
hypersensitivity to food antigens, in view of its association with
celiac disease. There is, however, no evidence for widespread
hypersensitivity to food antigens in IgA nephropathy .
IgA nephropathy results from dysregulation of mucosal-type
IgA immune responses. As a result, any mucosal infection or food
antigen may drive the production and release of pathogenic IgA
into the circulation where it has the propensity to deposit within
the mesangium and trigger glomerular injury.

8. Immunoglobulin A nephropathy probably can result from
multiple different etiologies and pathogenic processes, such as :
(1) Abnormal structure and function of IgA molecules.
(2) Reduced clearance of circulating IgA complexes.
(3) Increased affinity for or reduced clearance of IgA deposits
from the glomerular mesangium.
(4) Excessive IgA antibody production in response to mucosal
antigen exposure.
(5) Increased permeability of mucosa to antigen.
(6) Combinations of these factors.

9. Some secondary forms of IgA nephropathy appear
to be caused by either decreased clearance of IgA from
the circulation (e.g., reduced hepatic clearance caused
by cirrhosis) or increased entry of IgA complexes into
the circulation (e.g., caused by increased synthesis and
greater access to the circulation in inflammatory bowel
disease).
Impaired IgA clearance
Impaired systemic clearance of IgA promotes IgA
deposition in the mesangium. Persistent mesangial IgA
accumulation occurs by one or both of two
mechanisms: the rate of IgA deposition exceeds the
mesangial clearance capacity; or the deposited IgA is
resistant to mesangial clearance.

10. Systemic clearance
Alterations in systemic IgA and IgA-immune
complex clearance mechanisms will facilitate their
persistence in the serum. The liver play an important role in
IgA clearance from the circulation and radiolabeled IgA
clearance studies suggest reduced hepatic clearance in IgA
nephropathy. A second route of IgA clearance is through
CD89, which is the Fc receptor for IgA. IgA nephropathy is
associated with downregulated CD89 expression on
myeloid cells and decreased IgA binding to CD89.
Mesangial clearance
Mesangial IgA deposition is not always associated with
the development of glomerular inflammation. Furthermore,
mesangial IgA deposition may be reversible.

11. However, an important pathogenic mechanism in
many patients with IgA nephropathy appears to
derive from abnormally reduced galactosylation of the
O-linked glycans in the hinge region of IgA1
molecules.

14.  History
 Pathogenesis
 Clinical Presentation
 Diagnosis
 Treatment
 Prognosis

15. Epidemiology :
 Occur at any age but more common in children and
young adult.
 Male > female ( 2 folds )
 Genetic predisposition : IGAN1, on 6q22-q23.
Susceptibility to IgA nephropathy has been associated
with single-nucleotide polymorphisms (SNPs) in the E-
selectin and L-selectin genes, as well as in the Polymeric
Immunoglobulin Receptor (PIGR )gene.
Polymorphism in the ACE and AGT genes has been
associated with progression to chronic renal failure in
patients with IgA nephropathy

17. A- Gross Hematuria : (40-50% )
 Occur cocurrent with upper respiratory tract
infection
 Occur 1-2 days after onset of infectious
symptoms so called synpharyngitic heamaturia
 Loin pain , malaise , and fever are found
 Hypertension and peripheral oedema are rare
 Rare to occur after age of 40 yrs.

18. B- Asymptomatic haematuria (30-40%):
 Accidentally discovered on routine examinaion
 Protenuria is variable but less than 1gm/day
C- Nephrotic syndrome (10%):
Presented with advanced glomerular disease and
hypertension
Maybe presented with normal kidney function and
normal blood pressure where protenuria is selective
(albumin)

19. D- Rapidly progressive gromerulonephritis:
 Occur in case of cresent IgA nephropahy
 Maybe due to heavy glomerular hematuria which leads
o tubular occlusion ( reversible phenomenon)
 In elderly patients , chronic IgA nephropathy
E- Chronic renal failure with hypertension

20. F- In case of HSP :
Seasonal variation more on spring and autumn
Joint : Joint swelling which is non migratory and
non damaging
Intestinal Tract : Sever abdominal pain , vomiting
and melena
Skin : Purpuric eruption on lower trunk and legs

23.  History
 Pathogenesis
 Clinical Presentation
 Diagnosis
 Treatment
 Prognosis

24. The diagnosis of IgA nephropathy is often
suspected on the basis of the clinical history,
but can be confirmed only by kidney biopsy.
A kidney biopsy is usually performed for the
evaluation of suspected IgA nephropathy only
if there are signs suggestive of more severe or
progressive disease such as protein excretion
above 0.5 to 1 g/day, elevated serum creatinine
concentration, or hypertension.

25. Light Microscopy:
Immunoglobulin A nephropathy and Henoch-Schِ lein purpura nephritis
n
can have any of the histologic phenotypes of immune complex–mediated
glomerulonephritis other than pure membranous glomerulopathy, including”
1- No lesion by light microscopy with immune deposits by immunohistology,
2- Mesangioproliferative glomerulonephritis with mesangial but no
endocapillary hypercellularity.
3- Focal or diffuse proliferative glomerulonephritis with endocapillary
hypercellularity (with or without crescents).
4- Overt crescentic glomerulonephritis with 50% or more crescents.
5- Type I membranoproliferative (mesangiocapillary) glomerulonephritis .
6- Focal or diffuse sclerosing glomerulonephritis

29. Light Microscopy:
A variety of classification systems have been used to
categorize the light microscopic phenotypes of IgA
nephropathy, such as those proposed by Kurt Lee et
al(1982) and by Mark Haas (1997). Another approach is
to use the same descriptive terminology that is in the
World Health Organization (WHO) lupus classification
system to categorize IgA nephropathy as well as other
forms of immune complex glomerulonephritis.

32. Immunofluorescence Microscopy
The sine qua non for a diagnosis of IgA
nephropathy is immunohistologic detection of
dominant or co-dominant staining for IgA in the
glomerular mesangium.
A caveat to this is that the staining for IgA
should at least be 1+ on a scale of 0 to 4+ or 0 to 3+.
Trace amounts of IgA are not definitive evidence
for IgA nephropathy. The IgA is predominantly
IgA1 rather than IgA2.

34. Rare patients have IgA nephropathy concurrent with
membranous glomerulopathy, and thus their specimens
show granular capillary wall IgG staining and mesangial
IgA dominant staining .
Staining for IgA essentially always is accompanied by
staining for other immunoglobulins and complement
components (properdin , factor H and membrane attack
complex). Staining for IgG and IgM often is present, but at
low intensity compared to IgA.

35. A very distinctive feature of IgA nephropathy
compared to other immune complex diseases is the
predominance of staining for lambda over kappa light
chains in many specimens
C3 staining is almost always present and usually
relatively bright. However, staining for C1q is
uncommon and when present is typically of low
intensity. The presence of substantial C1q should raise
the possibility of lupus nephritis with conspicuous IgA
deposition. This suspicion would be supported further
by finding endothelial tubuloreticular inclusions by
electron microscopy and antinuclear antibodies
serologically

36. Immunofluorescence Microscopy:
In case of HSP :
Skin biopsy of the purpuric skin shows a
leukocytoclastic vascultitis with IgA and C3 in the wall
of dermal capillaries.
Occasional found in clinically unaffected skin of
patients with IgA nephropathy.

38. Electron Microscopy
The typical ultrastructural finding is immune complex–
type electron-dense deposits in the mesangium.
Dense deposits most often are found immediately
beneath the paramesangial glomerular basement membrane.
The amount of deposits varies substantially, with occasional
specimens having massive replacement of the matrix by the
dense material.
Capillary wall subepithelial, subendothelial, and
intramembranous deposits are identified in approximately a
quarter to a third of specimens with IgA nephropathy, and
are more frequent in patients with Henoch-Schِ lein n
purpura nephritis. Capillary wall deposits are least frequent
in histologically mild disease and most frequent in
histologically severe disease, especially when crescents are
present.

42.  History
 Pathogenesis
 Clinical Presentation
 Diagnosis
 Treatment
 Prognosis

43. The optimal approach to the treatment of IgA nephropathy is
uncertain. The slow rate of loss of GFR (1 to 3 mL/min per year) seen
in many patients hinders the ability to perform adequate studies.
There are two separate approaches to the therapy of IgA nephropathy:
 General interventions to slow progression that are not specific to IgA
nephropathy, include blood pressure control, angiotensin converting
enzyme (ACE) inhibitors and/or angiotensin II receptor blockers
(ARBs) in patients with proteinuria.
 Therapy with glucocorticoids with or without other
immunosuppressive agents to treat the underlying inflammatory
disease

44. Patient selection :
 Patients with isolated hematuria, no or minimal
proteinuria, and a normal GFR are typically not treated
(and often not biopsied and identified), unless they have
evidence of progressive disease such as increasing
proteinuria, blood pressure, and/or serum creatinine.
 Patients with persistent proteinuria (above 500 to 1000
mg/day), normal or only slightly reduced GFR that is
not declining rapidly, and only mild to moderate
histologic findings on renal biopsy are managed with
general interventions to slow progression and perhaps
with fish oil.

45. Patient selection :
 Patients with more severe or rapidly progressive
disease (eg, nephrotic range proteinuria or proteinuria
persisting despite ACE inhibitor/ARB therapy, rising
serum creatinine, and/or renal biopsy with more
severe histologic findings, but no significant chronic
changes) may benefit from immunosuppressive
therapy in addition to nonimmunosuppressive
interventions to slow disease progression

46.  patients with isolated hematuria, no or minimal
proteinuria, and a normal GFR (Grade 2C). Such patients
should be periodically monitored at 6 to 12 month
intervals to assess for disease progression that might
warrant therapy.
 patients with persistent proteinuria (>500 or >1000
mg/day), we recommend angiotensin inhibition with an
ACE inhibitor or ARB (Grade 1A). We initiate
monotherapy and target a minimum reduction in protein
excretion of at least 50 to 60 percent from baseline values
and a goal protein excretion of less than 500 or less than
1000 mg/day.

47.  patients with acute onset of nephrotic syndrome and
minimal change disease as well as mesangial IgA
deposits on renal biopsy, we recommend
glucocorticoid therapy as in other patients with
minimal change disease (Grade 1A).
 patients with persistent nephrotic syndrome and/or
chronic kidney disease who have dyslipidemia be
treated with a statin, primarily for cardiovascular
protection (Grade 2B).

48.  Patients with progressive active disease (eg, hematuria with
increasing proteinuria and/or increasing serum creatinine
concentration) despite the use of ACE inhibitors or ARBs, we
suggest initiating therapy with Glucocorticoids alone (Grade 2B).
Two regimens we use are:
Intravenous methylprednisolone (500 to 1000 mg per dose or, in
children, 7 to 15 mg/kg in children per dose to a maximum of
1000 mg) for three consecutive days at the beginning of months
one, three and five, and alternate day oral prednisone (0.5 mg/kg,
approximately 30 to 40 mg) for six months, then tapered to
discontinuation.
An alternative regimen that avoids pulse therapy can also be
used, such as 2 mg/kg of prednisone (maximum 100 to 120 mg)
every other day for two months, with a rapid taper to a dose of 0.5
mg/kg (approximately 30 to 40 mg) every other day for an
additional four months. Prednisone is then tapered to
discontinuation

49.  For patients with severe disease at baseline (defined as initial
serum creatinine >1.5 mg/dL or progressive disease with
glucocorticoids alone (eg, increasing serum creatinine and/or
protein excretion) who do not have significant chronic damage on
kidney biopsy, we suggest therapy with oral prednisone and
cyclophosphamide (Grade 2B).
 One regimen we use is:
Prednisone (1 mg/kg to a maximum 60 to 80 mg/day) for
two to three months followed by a slow taper to a maintenance
dose of 10 mg/day for one to two years.
Cyclophosphamide (1.5 mg/kg per day) orally for three
months, followed, if the serum creatinine has stabilized and
protein excretion has fallen, by either azathioprine (1.5 mg/kg per
day) or mycophenolate mofetil (starting with 1000 mg twice a day
and tapering over time to 500 mg twice a day) for a period of one
to two years as maintenance therapy.

50.  patients with crescentic glomerulonephritis and a rapidly
progressive clinical course, we suggest therapy with intravenous
pulse glucocorticoids and cyclophosphamide (Grade 2B).
One regimen we use is:
Intravenous methylprednisolone for three consecutive days
(500 to 1000 mg per dose or, in children, 7 to 15 mg/kg in children
per dose to a maximum of 1000 mg) followed by oral prednisone
(1 mg/kg per day, maximum dose 60 to 80 mg) for two to three
months, then a slow taper to a maintenance dose of 10 mg/day for
one to two years.
Intravenous cyclophosphamide (0.5 g/m2) monthly for at least
three months followed, if the serum creatinine has stabilized and
protein excretion has fallen, by either azathioprine (1.5 mg/kg per
day) or mycophenolate mofetil (starting with 1000 mg twice a day
and tapering over time to 500 mg twice a day) for a period of one
to two years as maintenance therapy, provided the creatinine
stabilized and proteinuria was reduced.

51. If the serum creatinine or degree of proteinuria have
not improved after the initial course of
cyclophosphamide, we suggest a repeat biopsy to
estimate the activity of the disease (eg, potential for
reversal) and the amount of tubulointerstitial damage
(the irreversible component) before deciding to
continue immunosuppressive therapy.
Other lines of treatment :
1. Tonsillectomy
2. Low antigen diet
3. Intravenous immune globulin
4. Vitamin D

54.  History
 Pathogenesis
 Clinical Presentation
 Diagnosis
 Treatment
 Prognosis

55. Factors affecting the prognosis:
A- Clinical :
 Hypertension
 Absence of history of macroscopic hematuria
 Persistent microscopic hematuria
 Older age at onset of the disease
B- Laboratory:
 Renal dysfunction at diagnosis in absence of acute
tubular damage
 Proteinuria , non selective more than 0.5gm/day

56. C- Renal Histology
 Glomerular sclerosis
 Segmental glomerular necrotizing lesion or
extensive cresent (>20% of glomeruli)
 Arteriolosclerosis
 Tubulointerstitial fibrosis
 IgG deposits in the mesangium
 IgA deposits in he peripheral capillary wall

58. Thank