This document summarizes IgA nephropathy (IgAN), the most common primary glomerulonephritis globally. Key points include: IgAN is characterized by deposition of IgA in the mesangium. Clinical presentations range from asymptomatic hematuria to rapidly progressive glomerulonephritis. Prognosis depends on factors like proteinuria level and hypertension. Treatment involves renin-angiotensin system blockade, glucocorticoids, and immunosuppression. The Oxford classification uses pathological features to predict prognosis.

1. IgA Nephropathy
Dr. Ajay Kumar Yadav
PGY2,Internal Medicine
IOM-TUTH, Kathmandu
2074/8/19

2. Introduction
• The most common GN globally
• Described in the late 1960s by Berger and Hinglais
• Characterized by : deposition predominantly of IgA (and, to a
lesser extent, of other immunoglobulins) in the mesangium
with mesangial proliferation
Source : Brenner and Rector's The Kidney, 10th Edition

3. Introduction
• Clinical features : span from asymptomatic hematuria to
rapidly progressive glomerulonephritis
• 40% of patients may progress to ESRD
• Idiopathic form
• Associated with a variety of disease processes
Source : Brenner and Rector's The Kidney, 10th Edition

4. Introduction
• Age : all ages, most common in the second and third decades
of life, uncommon below 10 yrs of age
• Sex : M > F ( 2:1 to 6:1 )
• Geopraphical variation
o most common form of primary glomerular disease in Asia
o Asia : 30% to 40% of all biopsies ( cause ?)
o Europe : 20% of all biopsies
o North America : 10% of all biopsies
Source : Brenner and Rector's The Kidney, 10th Edition

5. Mukunda Prasad Kafle, Dibya Singh Shah, Shailendra
Shrestha, Mahesh Raj Sigdel, Kanak Bahadur Raut.
Prevalence of specific types of kidney disease in
patients undergoing kidney biopsy: a single centre
experience. Journal of Advances in Internal Medicine
2014;03(01):5-10.

6. Source : Brenner and Rector's The Kidney, 10th Edition

7. Classification
• Primary IgAN
• Secondary IgAN
o Infections : Toxoplasmosis , HIV , Leprosy
o Rheumatological : Seronegative RA , Ankylosing spondylitis ,
Reiter’s syndrome
o GIT : Celiac disease , Dermatitis herpetiformis , Crohn’s
disease , Liver disease , Alcoholic cirrhosis

8. o Neoplasia : Mycosis fungoides , Lung carcinoma , Mucin-
secreting carcinoma
o Hematological : Cyclic neutropenia , ITP
o Eye : Scleritis , Sicca syndrome
o HSP
o Pulmonary hemosiderosis
• Familial IgA Nephropathy
Source : Brenner and Rector's The Kidney, 10th Edition

9. Immuno-Pathogenesis

10. IgA
• Most produced antibody overall, but has lower serum
concentrations. Released into secretions (tears, saliva, mucus) and
breast milk.
• Mucosal defense.
• Monomer (in circulation) or dimer (with J chain when secreted).
• It has two subclasses, IgA1 and IgA2.

11. IgA
• Mucosal antigen challenge provokes polymeric IgA (pIgA) production by
plasma cells of the mucosa-associated lymphoid tissue.
• Crosses epithelial cells by transcytosis. Picks up secretory component from
epithelial cells, which protects the Fc portion from luminal proteases---
released as secretory IgA (sIgA).
• The function of circulating IgA is less clear . It is bone marrow derived and
mostly monomeric IgA1 (mIgA1) and is cleared from the circulation by the
liver .

12. Normal mechanism of IgA production
Source :Clinical Journal of the American Society
of Nephrology 2017

13. Abnormal immune mechanism in IgAN
Source :Clinical Journal of the American
Society of Nephrology 2017

14. Pathogenesis
• Susceptibility to IgAN and risk of disease progression :
influenced by a confluence of genetic and environmental
factors.
• Multi-“hit” process
• Central finding : presence of circulating and glomerular
immune complexes comprised of galactose-deficient IgA1, an
IgG autoantibody directed against the hinge region O-glycans,
and C3.
Source :Clinical Journal of the American Society of
Nephrology 2017

15. Pathogenesis
• Immune complexes : nephritogenic, contributing directly to
glomerular inflammation and mesangial proliferation.
• Activation of the local and systemic RAAS and complement
activation : glomerulosclerosis and tubulo-interstitial fibrosis,
leading to loss of renal function.
• Coexistent risk factors such as hypertension and smoking
contribute to disease progression, potentially through
microvascular injury .

16. Familial IgAN
• Familial IgA nephropathy has been reported in multiple ethnic
groups around the world, including in Africa and Central
America.
• Some studies suggest that 4% to 14% of patients with IgA
nephropathy may have a family history of renal disease.
• Inheritance : Autosomal dominant transmission with
incomplete penetrance .

17. Characteristics of Pathogenic IgA
• Abnormal mucosal antigen handling.
o pIgA1 production is downregulated in the mucosa and upregulated
in the bone marrow.
• Poor 0-glycosylation of IgA1
o Increased tendency to both self-aggregate and form antigen-
antibody complexes with IgG antibodies directed against an N-
acetylgalactosamine residue in the IgA1 hinge region.
• Impaired systemic clearance of IgA by liver

19. Clinical features

20. • Macroscopic hematuria : 40% to 50%
o Close temporal relationship to upper respiratory tract
infection(tonsillo-pharyngitis) : Syn-pharyngitic nephritis .
o May also be a/w infection of the urinary tract or
gastroenteritis
o Systemic symptoms frequent , including nonspecific
symptoms such as malaise, fatigue, myalgia, and fever.

21. o More often in children than in young adults.
o When it occurs in older individuals, it should raise the
possibility of the more common causes of urinary tract
bleeding, such as stones or malignancy .
• Asymptomatic microscopic hematuria with/out proteinuria :
30% to 40%
• Hematuria with HTN : IgA nephropathy is the most common
cause

22. o Intermittent macroscopic hematuria occurs in 25% of
these patients.
o Microscopic hematuria and proteinuria persist between
episodes of macroscopic hematuria.
• Malignant hypertension : < 5%
• AKI : 5-10%

23. • Nephrotic syndrome : widespread proliferative GN or
coexisting IgAN and MCD .
• ESRD

24. Natural history of IgAN
• Measured from the time of diagnosis, 1% to 2% of all patients
with IgAN develop ESRD each year
• Overall, about 25% of patients develop ESRD within 10 to 25
years from diagnosis, depending on the initial severity of
disease

25. Presentations
IgAN may have any presentation
o Hematuria (macroscopic / microscopic ) with/out HTN
o AKI
o RPGN
o Nephrotic syndrome
o ESRD

26. Favourable prognostic markers
• The proliferative forms of IgAN seem to be associated with
better outcomes in children than in adults.
• Patients with episodes of gross (macroscopic) hematuria
generally have a more favorable prognosis than those with
persisting microhematuria
Source : Brenner and Rector's The Kidney, 10th Edition

27. Poor prognostic markers
• Sustained hypertension
• Persistent proteinuria ( 24UTP > 1 g/d )
• Impaired renal function
• Nephrotic syndrome
• Older age at onset
• M > F
• Individuals with protein excretion of less than 500 mg/dL/24
hr had no renal failure within 7 years, whereas those with
over 3 g had an approximately 60% chance of ESRD within 7
yrs .
Source : Brenner and Rector's The Kidney, 10th Edition

28. Prediction of prognosis
• Many formulas have been advanced
• Toronto formula
o based on average mean arterial pressure and proteinuria
during the first 2 years of observation
o best-validated in white American and European subjects
o Limitation : large fraction of the variation in progression
remains unexplained by these two factors
Source : Brenner and Rector's The Kidney, 10th Edition

29. Pathology

30. Immunofluorescence Microscopy
• Prominent, globular deposits of IgA (often accompanied by
C3 and IgG) in the mesangium and, to a lesser degree, along
the glomerular capillary wall.
• This deposited IgA is predominantly J chain containing
polymeric IgA1.

32. Light Microscopy
• Mesangial proliferation and matrix expansion : diffuse > focal
• Focal segmental or global glomerular sclerosis : disease has
been ongoing for some time.
• Segmental crescents : relatively common, although they may
be missed by sampling error if only a few glomeruli are
obtained

34. Light Microscopy
• long-standing disease : tubulointerstitial inflammation : interstitial fibrosis
and tubular atrophy (IFTA )
• Occasionaly IgAN and MCD coincide : light microscopy is normal with
mesangial IgA deposits.
• Two distinct patterns of injury in AKI.
o Tubular occlusion by RBCs : a/w gross hematuria : toxic ATN-AKI.
o Necrotizing GN and cellular crescent formation.

35. Electron Microscopy
• Electron-dense deposits : primarily limited to the mesangium
but may also occur in the subendothelial and subepithelial
spaces.

38. Clinical-Pathologic Correlation in IgAN
• Four key pathologic features were consistently independently-
associated with renal outcome including mesangial
hypercellularity (M), endocapillary hypercellularity (E),
segmental glomerulosclerosis (S), and tubular atrophy and
interstitial fibrosis (T) now known collectively as the MEST or
Oxford score

39. Oxford classification scheme
• The absence/presence of 50% of glomeruli showing
mesangial hypercellularity is denoted M0/M1, respectively
• E1 indicates any endocapillary hypercellularity
• S1 denotes any segmental glomerulosclerosis
• T0, T1, and T2 reflect fibrosis involving 1%–25%, 26%–50%, or
50% of the cortical area

40. Oxford classification
• 265 patients- followed for a median of five years.
• Patients included : ≥ 0.5 g/d of proteinuria, eGFR ≥ 30 ml/min per
1.73 m2 at renal biopsy
• Variables correlated with renal outcomes:
o rate of kidney function decline,
o survival from a 50% decline in kidney function or ESKD, and
o proteinuria during follow-up.

41. Oxford classification
• Mesangial hypercellularity was significantly associated with ESKD or 50%
reduction in GFR.
• Segmental sclerosis was associated with the rate of decline in kidney
function.
• IFTA was statistically associated with both the rate of decline and ESKD or
50% decline in kidney function.
• Endocapillary (or extracapillary) hypercellularity : are responsive to
immunosuppressive therapy.

42. • Biopsies with < 8 glomeruli should be considered of uncertain
value for prognosis.
• Weakness : does not include crescents or necrotizing lesions.

43. • VALIGA cohort
o largest validation study , included 1147 pts.
o Unlike the original Oxford study entry criteria were less restrictive;
patients at both ends of the spectrum of disease severity were
included. The cohort was predominantly white (97.5%)
o The combined end point of ESRD or decrease in eGFR by 50%
occurred in 26% of patients at 10 years.
o Most of the histologic variables remained independently associated
with outcome, when adjusted for baseline and longitudinal clinical
variables.

44. • Working group in 2014 : First Oxford Conference on IgA
Nephropathy : association of crescents with renal outcomes in
3096 patients combined from four published studies: the
original Oxford cohort, the VALIGA study cohort, and two
large Asian cohorts, one from China and the other from Japan.
• The presence of any such crescents was a significant,
independent predictor of the likelihood of developing a
combined event of ESRD or a ≥ 50% reduction in eGFR.

45. • The authors proposed adding crescent scores to the Oxford
(MEST) classification as follows:
o C0 : no cellular or fibrocellular crescents
o C1 : cellular/fibrocellular crescents in 25% of glomeruli :
increased risk of a poor outcome (compared with C0) among
those not given immunosuppressive therapy
o C2 : crescents in ≥ 25% of glomeruli : increased risk of a poor
outcome even if given immunosuppression

46. Treatment Strategies:
Current Evidence and Novel Therapies

47. • When to treat ?: proteinuria of more than 0.5 g per day.
• Three major approaches have emerged and are supported by
substantial direct evidence
o RAAS blockade
o Oral and/or intravenous glucocorticoids
o Combined immunosuppressive (cytotoxic) therapy.
• Combinations of these approaches are under intense evaluation,
including in the Supportive versus Immunosuppressive Therapy of
Progressive IgA Nephropathy (STOP-IgAN) trial

48. Angiotensin II Inhibition
• Ist line of treatment for patients of any age with IgAN and
proteinuria of more than 500 mg of protein per day – target
24UTP < 1 g/day.
• Associated with
o slower rate of loss of renal function
o higher frequency of remission of proteinuria
compared with either no therapy or the use of β-blockers
• Antiproteinuric effects of the ACE inhibitor appear to be more
profound in patients with the ACE gene DD genotype

49. Angiotensin II Inhibition
• Randomized controlled : 207 patients
• High-dose ARB (losartan 200 mg/day) Vs ARB given at the
usual dose (losartan 100 mg/day) as well as with a usual-
dose ACE inhibitor (enalapril 20 mg/day ) Vs low-dose ACE (
enaapril 10 mg/day )
• High-dose ARB therapy was most efficacious in reducing
proteinuria and slowing the rate of decline in estimated GFR.

50. • Statin therapy for lipid lowering in selected patients with
elevated LDL cholesterol to lower cardiovascular risk.
o No evidence is available to show that such therapy slows the
rate of progression of renal disease

51. Fish oil
• anti-inflammatory property .
• A Cochrane meta-analysis of four trials
o In the largest and best quality trial from the Mayo Clinic
o 106 patients - mean baseline Crcl of 82 mL/min
o protein excretion- 2.5 to 3.2 g/day
o either 12 g of fish oil or a similar amount of olive oil for 2 years
o There was no difference in blood pressure control and no
significant effect on protein excretion during the study.

52. Fish oil
• At four years, patients receiving fish oil had a lower incidence of a
≥50 % increase in the serum creatinine concentration (6 vs 33 %)
• lower incidence of death or ESRD at four years (10 vs 40 %).
• More than six years, the benefits of continuous fish oil therapy
persisted (15 vs 37 % incidence of ESRD).
• Benefit from fish oil has not been clearly established.
Source : Donadio JV Jr, Bergstralh EJ, Offord KP, et al. A controlled trial of fish oil in IgA
nephropathy. Mayo Nephrology Collaborative Group. N Engl J Med 1994; 331:1194.

53. Glucocorticoids as sole immunosuppressive
• Indication
o well-preserved renal function (GFR >60 mL/min/1.73m2)
o who remain proteinuric despite a 3- to 6-month trial of
angiotensin II inhibitors
o Morphologic evidence of active disease based upon kidney
biopsy (eg, proliferative or necrotizing glomerular changes)
Source : Brenner and Rector's The Kidney, 10th Edition

54. Glucocorticoids as sole immunosuppressive
6-month course of corticosteroid therapy to pts with persistent proteinuria >1 g/d,
despite 3–6 months of optimized supportive care, and GFR >50 ml/min per 1.73 m2,

55. Mycophenolate
• Systematic reviews and meta-analyses of the randomized
trials of MMF suggest mixed results .

56. Rituximab
• Although evidence for rituximab in other glomerular diseases
is promising, early results in IgAN are not encouraging.
• A pilot trial evaluated the outcome of 34 patients with
proteinuria >1 g/d and eGFR < 90 ml/min per 1.73 m2
randomized to rituximab versus conservative management.
• No effects on proteinuria or renal function were seen .
Source : Clinical Journal of the American Society of Nephrology 2017

57. Combination immunosuppresive therapy
• More severe disease :
o rapidly progressive clinical course and/or histologic evidence
of severe active inflammation (eg, crescent formation).

58. Prednisone and cyclosphosphamide/azathioprine as
compared with no immunotherapy
• A single-center, prospective, randomized, controlled trial of 38
patients with “high-risk” IgAN (hypertension,15% rise in
creatinine in prior year) demonstrated improved renal
survival after 2 years .
Source : Clinical Journal of the American Society of Nephrology 2017

59. • A multicenter, open-label, trial of 207 patients with creatinine < 2.0
mg/dl and proteinuria ≥ 1.0 g/d for at least 3 months randomized
patients to corticosteroids alone (1 g intravenously for three
consecutive days at months 1, 3, and 5, and then continued at 0.5
mg/kg) or corticosteroids in addition to azathioprine 1.5 mg/kg.
• There was no difference in primary outcome of time to 50%
increase in creatinine or secondary outcome of change in
proteinuria
Source : Clinical Journal of the American Society of Nephrology 2017

60. Novel Agents
• Oral budesonide (Nefecon)
o Proposed to act locally at the MALT in the distal ileum and proximal
large intestine to modulate IgA production .
o Phase 2 double-blind, placebo controlled trial : results were recently
presented. After a 6-month run-in phase, patients with proteinuria > 0.5
g/d or 0.75 g/d and eGFR ≥ 45 ml/min per 1.73 m2 were randomized to
receive placebo and 8 or 16 mg/d of budesonide.
o There was a significantly greater reduction in proteinuria in patients
treated with the budesonide—up to 27% reduction with a 3% rise in
proteinuria in the placebo group .
Source :Clinical Journal of the American Society of Nephrology 2017

61. • An open-label efficacy/safety study is currently recruiting patients with
eGFR >30 ml/min per 1.73 m2 with IgAN and nephrotic syndrome who
failed previous immunosuppression to treatment with Acthar gel, a
purified form of adrenocorticotropic hormone (ClinicalTrials.gov
NCT02382523)
• Another open-label pilot study is currently recruiting for efficacy/safety in
patients with >1 g/d of proteinuria and no eGFR restriction of bortezomib,
a proteasome inhibitor (ClinicalTrials.gov NCT01103778).
• Both studies examine proteinuria at 12 months as the primary outcome
with varying requirements for RAS blockade.
Source :Clinical Journal of the American Society of Nephrology 2017

62. • A double-blind safety/efficacy study in patients with > 0.5 g/d
of proteinuria and eGFR > 30 ml/min per 1.73 m2 randomized
patients to either fostamatinib, an oral spleen tyrosine
kinase inhibitor, or placebo with the primary outcome of
proteinuria at 24 weeks (ClinicalTrials.gov NCT02112838)
Source :Clinical Journal of the American Society of Nephrology 2017

63. IgA Nephropathy and Kidney Transplantation
• Recurrence of IgA deposits after renal transplant : common, the rate may
reach 75% to 80% with long term (>20 yrs) survival of the patient and the
graft.
• Fortunately, most of these recurrences are clinically mild or are
discovered incidentally at the time of an allograft biopsy to assess for
possible rejection.
• Although graft loss due to recurrent IgAN is quite uncommon (<5%), a
recurrence of IgAN does worsen the overall prognosis for long term
survival of an allograft, especially if crescentic disease is present.

64. IgA Nephropathy and Kidney Transplantation
• Risk factors for recurrent IgAN after transplantation:
o Rapid course of the original disease due to crescentic GN
o Younger age
o IgA deposits in the donor kidney at the time of grafting
o Living related or zero mismatched kidney donor.
• Induction therapy with ATG appears to decrease the incidence of recurrent
disease.

66. KDIGO 2012 Recommendations for IgAN
• Initial evaluation including assessment of risk of progressive kidney
disease
o Assess all patients with biopsy proven IgAN for secondary causes of IgAN.
(Not Graded)
o Assess the risk of progression in all cases by evaluation of proteinuria,
blood pressure, and eGFR at the time of diagnosis and during follow-up.
(Not Graded)
o Pathological features may be used to assess prognosis. (Not Graded)

67. KDIGO 2012 Recommendations for IgAN
• Antiproteinuric and antihypertensive therapy
o We recommend long term ACE-I or ARB treatment when proteinuria is
>1g/d, with up-titration of the drug depending on blood pressure. (1B)
o We suggest ACE-I or ARB treatment if proteinuria is between 0.5g/d to
1g/d (in children, between 0.5 to 1 g/d per 1.73 m2). (2D)
o We suggest the ACE-I or ARB be titrated upwards as far as tolerated to
achieve proteinuria <1g/d. (2C)
o In IgAN, use blood pressure treatment goals of <130/80 mm Hg in
patients with proteinuria <1g/d and <125/75 mm Hg when initial
proteinuria is >1g/d.(not graded)

68. KDIGO 2012 Recommendations for IgAN
• Corticosteriods
o We suggest that patients with persistent proteinuria ≥1g/d,
despite 3-6 months of optimized supportive care (including
ACE-I or ARBs and blood pressure control) and GFR >
50ml/min per 1,73m2, receive a 6 month course of
corticosteroid therapy. (2C)

69. KDIGO 2012 Recommendations for IgAN
• Immunosuppressive agents ( cyclophosphamide, azathioprine, MMF,
cyclosporine)
o We suggest not treating with corticosteroids combined with
cyclophosphamide or azathioprine in IgAN patients (unless there is
cresentic IgAN with rapidly deteriorating kidney function. (2D)
o We suggest not using immunosuppressive therapy in patients with
GFR<30ml/min per 1.73m2 unless there is cresentic IgAN with rapidly
deteriorating kidney function. (2C)
o We suggest not using MMF in IgAN.

70. KDIGO 2012 Recommendations for IgAN
 Other treatments
• Fish oil treatment
o We suggest using fish oil in the treatment of IgAN with persistent
proteinuria ≥ 1g/d, despite 3-6 months of optimized supportive care
(including ACE-I or ARBs and blood pressure control). (2D)
• Antiplatelet agents
o We suggest not using antiplatelet agents to treat IgAN. (2C)
• Tonsillectomy
o We suggest that tonsillectomy not be performed for IgAN. (2C)

71. KDIGO 2012 Recommendations for IgAN
 Atypical forms of IgAN
• MCD with mesangial IgA deposits
o We recommend treatment as for MCD in nephrotic patients
showing pathological findings of MCD with mesangial IgA
deposits on kidney biopsy. (2B)

72. KDIGO 2012 Recommendations for IgAN
• AKI associated with macroscopic hematuria
o Perform a repeat kidney biopsy in IgAN patients with AKI
associated with macroscopic hematuria if, after 5 days from
the onset of kidney function worsening, there is no
improvement. (not graded)
o We suggest general supportive care for AKI in IgAN, with
kidney biopsy performed during an episode of macroscopic
hematuria showing only ATN and intratubular erythrocyte
casts.(2C)

73. KDIGO 2012 Recommendations for IgAN
• Crescentic IgAN
o Define crescentic IgAN as IgAN with crescents in more than
50% of glomeruli in the renal biopsy with rapidly progressive
renal deterioration.(not graded)
o We suggest the use of steroids and cyclophosphamide in
patients with IgAN and rapidly progressive crescentic IgAN,
analogus to the treatment of ANCA vasculitis. (2)

74. STOP IgAN NEJM,2015
• prospective, open-label, randomized, controlled clinical trial
with a two-group, parallel, group-sequential design.
• February 2008 - October 2011
• 379 patients with IgA nephropathy at 32 nephrology centers
in Germany.

75. 6-month run-in phase,
Blood pressure < 125/75
mm Hg.
Target proteinuria < 0.75
g per day
Total cholesterol levels <
200 mg/dl
INCLUSION CRITERIA
Age -18 to 70 years
Proteinuria > 0.75
g/day plus
BP ≥140/90 mm Hg
or
eGFR <90 ml/min or
both
EXCLUSION CRITERIA
eGFR <30 ml/min,
secondary and RPGN,
prior immunosuppressive
therapy.
Proteinuria > 0.75 g
/day, but lower than
3.5 g per day

76. Study End-points
• Two primary end points
o Full clinical remission (defined as proteinuria with a PCR of
<0.2 and stable renal function with a decrease in the eGFR of
<5 ml/min from the baseline eGFR at the end of the 3-year
trial phase)
o Decrease in the eGFR of at least 15 ml/min from the baseline
eGFR.

77. Study End-points
• Secondary end points
o absolute decrease in the eGFR
o decrease in the eGFR of at least 30 ml /min from the baseline eGFR
o need for dialysis (onset of end-stage renal disease)
o mean annual change in the slope of the reciprocal of serum creatinine concentration,
proteinuria at 12 and 36 months, and disappearance of microhematuria as determined
by means of a dipstick or urinary sediment test.

80. Conclusion of STOP-IgA trial
• Addition of immunosuppression to ongoing comprehensive
supportive care was not beneficial in patients with IgA
nephropathy that was characterized by moderate proteinuria
and chronic kidney disease stages 1 through 3.