1. Professor of Nephrology University of Florence
What’s new for IgA Nephropathy. Part 2: Clinical presentation, Diagnosis, Prognosis, Treatment
Professor of Nephrology
University of Florence
Professor of Nephrology
University of Florence

2. CLINICAL PRESENTATION
AGENDA
CLINICAL PRESENTATION
DIAGNOSIS
PROGNOSIS
TREATMENT

3. CLINICAL PRESENTATION
AGENDA
CLINICAL PRESENTATION
DIAGNOSIS
PROGNOSIS
TREATMENT

4. CLINICAL PRESENTATION
Patients diagnosed accidentally
Patients affected by recurrent macroscopic hematuria
Patients with rapidly progressive renal disease
Patients with IgAN recurrence after kidney transplantation
Patients with AKI due to macroscopic hematuria

5. Patients diagnosed accidentally
Often found while looking for clinical manifestations such as reduced GFR, hypertension or urinary abnormalities
THE SILENT MAJORITY

6. Patients affected by macroscopic hematuria
Patients with macroscopic recurrent hematuria strictly connected with acute infective disease occurring in the upper respiratory tract
TYPICAL IgAN PATIENTS

7. Patients with rapidly progressive renal disease
Atypical presentation, often occurring in patients with nephrotic syndrome and with presence of crescents on the renal biopsy

8. Patients with IgAN recurrence after renal transplantation
IgAN often recurs after renal transplantation as happens for any autoantibody-related glomerulonephritis. The prognosis is often benign

9. Patients with AKI due to macroscopic hematuria
Patients presenting with AKI accompanying macroscopic hematuria. AKI is related to the acute tubular necrosis
Good prognosis without disease progression

10. Factors influencing the disease evolution
Clinical presentation
Histological presentation
Time of diagnosis

11. expansion &proliferation
Typical courses of IgAN patients
Primary IgAN
recurrent
macroscopic
hematuria Hb
minimal
segmental
glom sclerosis
proteinuria
and Hb +++
asymptomatic
hematuria
hypertension
macroscopic
hematuria
initial mesangial
expansion &proliferation
followed by
mesangial sclerosis
diffuse
glomerular
& interstitial
sclerosis

12. HISTOLOGICAL PRESENTATION
A Glomerulus near normal
B Glomerulus with segmental
mesangial hypercellularity
C Endocapillary hypercellularity
D Segmental sclerosis and
extracapillary proliferation
E Sclerotic and atrophic changes
F Segmental glomerulosclerosis
and adhesion

13. Time at diagnosis
Geddes CC et al. NDT 2003; 18: 1541

14. Extreme variability in clinical presentation and in disease evolution
Most guidelines concerning IgAN are based
on low level of evidence and are often opinion
Need for research on histological, biological
and clinical markers able to predict the risk of
IgAN progression

15. CLINICAL PRESENTATION
AGENDA
CLINICAL PRESENTATION
DIAGNOSIS
PROGNOSIS
TREATMENT

16. Only renal biopsy observed on IF is diagnostic of IgA Nephropathy
DIAGNOSIS
Due to the variability of clinical presentation, clinical signs may only offer a diagnostic suspicion.
Similarly, renal biopsy on light microscopy is not diagnostic because of the different histologic patterns
Only renal biopsy observed on IF is diagnostic of IgA Nephropathy

17. TYPICAL IgA STAINING IN IgAN

18. CLINICAL PRESENTATION
AGENDA
CLINICAL PRESENTATION
DIAGNOSIS
PROGNOSIS
TREATMENT

19. PROGNOSIS
Due to the extreme variability of the disease evolution
Need of markers to predict the long time evolution

20. MARKERS FOR PROGNOSIS OF IgAN
HISTOLOGIC MARKERS
BIOLOGICAL MARKERS
CLINICAL MARKERS

21. RATIONALE FOR HISTOLOGICAL MARKERS
The glomerular histopathology in IgAN is extremely variable
Identification and reproducibility among different observers is essential to establish any relationship between renal pathology and disease evolution

22. HISTOLOGICAL CLASSIFICATIONS PROPOSED
Lee et al. Hum Pathol
Haas M. Am J Kidney Dis
Wakai et al. N.D.T
Oxford classification Kidney Int 2009

23. STRENGHT OF OXFORD CLASSIFICATION
Made up by an international working group of over 40 pathologists and nephrologists
Evidence based and reproducible classification for IgAN
Distinction between markers of acute and chronic activity
Four histological variables identified
Mesangial hypercellularity (M), segmental glomerulosclerosis (S), endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T)

24. WEAKNESS OF THE OXFORD CLASSIFICATION
Retrospective
Materials coming from different countries and different centers
Few histologic samples with crescents
NEED FOR VALIDATION STUDIES

25. VALIDATION STUDIES OF OXFORD CLASSIFICATION
Study
Patients (n)
End Point
Univariate analysis
Multivariate analysis
Coppo et al
206 A, 59 C
Rate of eGFR decline
M,E,S,T
Herzenberg et al
143 A, 44 C
Not done
E, S, T
Katafuchi et al
702 A
ESRD
S, T
Zeng et al
1026 A
M,S,T
M,T
Shi et al
410 A
S,T
Halling et al
99 C
GFR reduction >50%,ESRD
M,E,T E
Shima et al
161 C
eGFR<60% mL/min per m2
973 A, 174 C
Alamartine et al
183 A
Doubling of sCr or ESRD
E,S,T
None
El Karoui et al
128 A T
Lee et al
69 A
GFR reduction>50%,ESRD
E,T
Kang et al
197 A
Le et al
218 C
eGFR reduction>50%,ESRD
T,S

26. POTENTIAL BIOMARKERS FOR IgAN
Biologics
Source
Rationale
Galactose deficient IgA1
serum
Core antigen of the pathogenic IgA1 immune complex: activate mesangial cells
Glycan-specific IgG
Form glycan dependent complex with calactose-deficient IgA1; alanine to serine substitution (88% specificity, 95% sensitivity)
Activated complement C3
Up-regulated level in 30% of patients; correlates with detreriorating renal function
FGF 23
Significantly associated with IgAN progression
Soluble CD89
Low level in patients with disease progression
Mannose-binding lectin
urine
Assiciated with severe histological lesion
EGF and MCP-1
An EGF/MCP-1 ratio greater than extends renal survival
Proteomic pattern
High throughput characterization of 2000 polypeptide
MicroRNA profile
Sequencing identified microRNA profiling that is specific to IgA nephropathy

27. CLINICAL PROGNOSTIC MARKERS
Impaired GFR at diagnosis or higher reduction of GFR over time
Sustained hypertension
Proteinuria
Combination of clinical markers

28. OUTCOME AND AVERAGE FOLLOW-UP PROTEINURIA IN IgA NEPHROPATHY

29. HYPERTENSION AT DIAGNOSIS

30. GFR DECLINE

31. COMBINATION OF DIFFERENT PROGNOSTIC TOOLS

32. PROGNOSTIC FACTORS (SUMMARY)

33. CLINICAL PRESENTATION
AGENDA
CLINICAL PRESENTATION
DIAGNOSIS
PROGNOSIS
TREATMENT

34. GENERAL CRITERIA
Only a fraction of patients with IgAN requires treatment in order to prevent or reduce progressive loss of GFR
Proteinuria, hypertension and any evidence of established renal damage enable a relatively reliable estimation of patient risk
The “low-risk” patient with minor urinary abnormalities, normal GFR and normotension requires regular follow-up only
The “intermediate-risk” patient with “significant” proteinuria, hypertension and/or a slow reduction in GFR will benefit from comprehensive supportive care
Several ongoing studies will re-evaluate the role of systemic or enteric corticosteroids in “intermediate-risk” patients
The “high-risk” patient with a rapid loss of GFR may require more aggressive immunosuppression

35. CLINICAL PRACTICE GUIDELINE FOR GLOMERULONEPHRITIS
KI Supplements (2): 1-274
CLINICAL PRACTICE GUIDELINE FOR GLOMERULONEPHRITIS

36. SUPPORTIVE THERAPY Level 1
Control blood pressure (sitting systolic BP in the 120s)
ACE inhibitor or ARB therapy with up-titration of dosage or combination ACE inhibitor and ARB therapy
Level 2
Control protein intake
Restrict NaCl intake/institute diuretic therapy
Control each component of the metabolic syndrome
Aldostrerone antagonist therapy
Beta-blocker therapy
Smoking cessation
Other measures
Allopurinol therapy
Empiric NaHCO3 therapy
Avoid NSAIDs altogether, or no more than once or twice weekly at most
Avoid severe prolonged hypokalemia
Avoid phosphate cathartics
Ergocalciferol therapy to correct vitamin D deficiency
Control hyperphosphatemia and hyperparathyroidism

37. OTHER CONTROVERSIAL NON-IMMUNOSUPPRESIVE TREATMENTS
Fish oil supplementation (discordant results)
Dillon JJ  Fish oil therapy for IgA nephropathy: efficacy and interstudy variability. JASN 1997;8:
Donadio JV et al. The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. JASN1999;10:1772-7
 Hogg RJ et al. Efficacy of omega-3 fatty acids in children and adults with IgA nephropathy is dosage- and size-dependent. CJASN 2006 ;1:
Antiplatelet and anticoagulant therapy (only in Asia, studies not controlled)
Statins (small study, not controlled)

38. Reid S et al. Non-immunosuppressive treatment for IgA nephropathy Cochrane Database
The only documented beneficial effect of the different non-immunosuppressive treatment is exerted by the antihypertensive drugs, mainly mediated by the proteinuria reduction

39. TONSILLECTOMY (Discordant results) across different studies

40. Logistic regression analysis of the impact of tonsillectomy, renal function, blood pressure and urinary protein excretion at baseline and after disappearance of proteinuria, hematuria or both at study completion

41. AS A CONSEQUENCE THE KDIGO SUGGESTS THAT TONSILLECTOMY SHOULD NOT BE PERFORMED TO TREAT IgAN

42. CORTICOSTEROIDS IN IgAN
Effects of corticosteroids on ESRD or doubling of creatinine

43. OPEN QUESTIONS CONCERNING STEROID TREATMENT
Are steroids also effective for patients with a low GFR at diagnosis?
Which are the best steroid dosage and regimen to avoid side effects?
When steroids should be added to treatment in the therapy flow-chart?
Answer from the STOP IgAN and the TESTING trials

44. Other Immunosuppressants: Azathioprine

45. Other Immunosuppressants: MMF
Country
MMF
Placebo
S Creat
Proteinuria
Outcome
Belgium
Maes et al Kidney Int 2004
N=21
N=12
1.5
1.4
1.9
1.3
No MMF benefit
USA
Frisch G et al
NDT 2005
N=17
N=15
2.6
2.2
2.7
China
Tang S et al
Kidney Int 2010
N=20
1.7
1.8
Proteinuria reduced
GFR strable
Hogg R et al
Am J Kidney Dis 2015
N=27
N=25
eGFR
105
UP/Cr
1.8 g/g
Chen X et al
N=31 ?
Proteinuria ↓
Creat Stable

46. KDIGO POSITION Intervention Recommendation Grade
Other immunosuppressive agents
Patients with crescentic IgAN involving > 50% of glomeruli and rapidly course should be treated with steroids and cyclophosphamide
2 D
Not treating with corticosteroids combined with cyclophosphamide or azathiprine (unless crescentic forms wirh rapidly progressive course)
Not using immunosuppressive therapy in patients with GFR <30mL/min (unless crescentic forms with rapidly progressive course)
2 C
Not using MMF

47. SUGGESTED THERAPEUTIC APPROACH TO IgAN

48. ONGOING CLINICAL TRIALS 1
Identifier
Country
Interventions
Primary
Outcomes
NCT
China
Prednisone
MMF
Prednisone + MMF
Remission of proteinuria
NCT
ARB
Doubling of sCr/ESRD
NCT
Prednisone at different dosing
NCT
TOPplus-IgAN
Prednisone + Cyc
NCT
USA
ACTH (gel)
Disease remission

49. ONGOING CLINICAL TRIALS 2
Identifier
Country
Interventions
Primary Outcomes
NCT
USA
ACTH (gel)
UP/Cr ratio
NCT
CCX168
Safety
NCT BRIGHT-SC
Blisibimod
PLACEBO
Decrease in proteinuria
NCT
Bortezomib
Proteinuria
NCT
Fosfamatinib
Placebo
Decrease of proteinuria

50. THANK YOU FOR YOUR ATTENTION !!!