Guest Lecture Series by Dr. Karlene Hewan-Lowe.
A 63-year-old female was referred by her PCP and Dermatologist for evaluation of proteinuria and hematuria found during her assessment for a rash which was clinically diagnosed to be leukocytoclastic vasculitis, involving lower extremities up to mid-thigh. Her rash resolved, following treatment with steroids. PMH significant for hx of sinusitis and nosebleeds, hx of DM, fibromyalgia, asthma, OSA, CAD, glaucoma. Normal renal function with BUN of 19 and serum creatinine of 0.79mg/dL Urinalysis with +3 protein, 5-10 RBC, 15-20 WBC, LE positive.
Autoimmune testing: ANA<40, C3 138, C4 37, c-and p-ANCA negative, anti-GBM negative, HBV and HCV negative
Renal Biopsy Findings:
Light: 18 gloms, 1 glom with a fibrocellular crescent. focal activation of endothelial cells with one glom with segmental endocapillary proliferation, one with mesangial proliferation. Global sclerosisi of ischemic-type present in 4 gloms. Tubulointerstitial scarring 1%
IF: codominant IgA and IgM staining with accompanying C3, kappa, and lambda light chain staining
EM: 80% foot process effacement with microvillous transformation, sparse paramesangial and rare subendothelial, electron dense immune-complex deposits, segmental thickening of GM
Oxford Classification: IgA Nephropathy, Classification: M1, S1, E1, T0
Haas Classification: IgA Nephropathy, Class III with focal proliferative glomerulonephritis
Clinical presentations of IgAN
Acute HSP vasculitis with characteristic LE rash of palpable purpura, joint or GI symptoms, along with evidence of renal involvement including any of the following: microscopic or gross hematuria, proteinuria, elevation of serum creatinine, hypertension
IgAN presenting as painless gross hematuria within a few days following URI/gastroenteritis or infection with streptococcal bacterial species or bartonella
IgAN in young adult presenting with malignant hypertension and found to have renal failure
IgAN presenting with findings of nephritic syndrome: hypertension with microscopic hematuria and proteinuria with or without renal dysfunction
IgAN presenting with nephrotic syndrome
We reviewed clinicopathologic classifications:
In its “classic” presentation, IgAN is characterized by a mesangiopathic process with expansion of the mesangial matrix, immunofluorescent staining for IgA, and proliferation of mesangial cells (Tumlin et al)
Class I: mild mesangial hypercellularity and matrix expansion. No segmental sclerosis or crescents
Class II: mesangial hypercellularity with focal segmental glomerulosclerosis. No extracellular proliferation or crescents
Class III: focal proliferative GN: Endocapillary or mesangial hypercellularity involving 40% globally sclerosed glomeruli; >40% cortical tubular atrophy or loss
Developed based on clinicopathologic examination of 265 cases of IgAN with median 5 yr f/u, 70% adults, 30% children
Uses MSET scoring system:
– M-Mesangial hypercellularity score
– S-Segmental glomerulosclerosis
– E-Endocapillary hypercellularity
– T-Tubular atrophy/interstitial fibrosis
Prognosticators of disease progression:
Clinical: poor renal function, persistent high grade proteinuria of 1gm/24 hr or greater, poor hypertension control
Pathological: higher percentage of tubulointerstitial atrophy;50% crescents
Issues with Oxford Classification:
It includes multinational patients even though it is often felt that the IgAN presenting in Asian/Japanese patients may be a distinct entity from that seen in US/Western Europe. No difference in prognostic factors was found with respect to race, but a higher percentage of Asian patients were on immunosuppressive therapy
The Oxford study found no difference between prognostic factors and age, however Adult patients are over-representated, pediatric patients under-represented although this is a predominant pediatric-young adult disease.
It is known that over 10-20 years there may be further progression of disease with IgAN, however the patient base for Oxford classification included cases with 5-years average follow-up
Points of agreement:
1. We all agree on benefit of ACEi/ARB therapy and BP control
2. In patients with mild mesangial hypercellularity and 1gm proteinuria, persistent microscopic hematuria even with good serum creatinine and no biopsy evidence of disease activity Omega3 and Fish Oil therapy should be considered
3. In patients with rapidly progressive clinical renal disease with >50% crescents steroids +/- alkylating agents should be pursued
4. In patients with rapidly progressive clinical renal disease with renal biopsy evidence of disease activity with >10% crescents, or evidence of severe proliferative disease with fibrinoid necrosis even if <50% crescents; immunosuppressive therapy with steroids plus or minus alkylating agents should be considered
6. In patients with moderate to severe chronic lesions (global glomerulosclerosis, tubular atrophy, interstitial fibrosis), with little signs of disease activity, <10% crescents immunosuppressive therapy is unlikely to make a difference in poor renal prognosis
Areas of Doubt:
1. What is the optimal therapy in patients with active lesions: necrosis, inflammation, proliferation – potentially reversible lesions that meet criteria for crescentic IgAN?
2. What is the optimal therapy in patients with active lesions: necrosis, inflammation, proliferation – potentially reversible lesions that do not meet criteria for crescentic IgAN?
3. If patients persist with >1gm of proteinuria?