Kidney nontumor / medical renal

• Immunoglobulin A (IgA) nephropathy: dominant or codominant mesangial IgA deposits in the absence of systemic diseases
• Variable light microscopic and clinical features

• Increased serum levels of poorly galactosylated IgA1 (galactose deficient IgA1; GD-IgA1)
• Overproduction of GD-IgA1 in response to immune challenges in mucosal sites (upper respiratory and GI tract infections)
• GD-IgA1 binds to CD71 on mesangial cells; it also triggers autoimmune response with autoantibody production against GD-IgA1 GalNAc epitopes (Colvin: Diagnostic Pathology - Kidney Diseases, 3rd Edition, 2019)
• Disease progression (Colvin: Diagnostic Pathology - Kidney Diseases, 3rd Edition, 2019):
  • Mesangial cell proliferation
  • IgA / anti-IgA complex deposition in mesangium
  • Cytokine release by mesangial cells leading to podocyte injury
• 25 - 50% of patients will progress to renal failure at 20 years; recurs in 20 - 60% of allografts (average 30%)

• 40 - 50%: at least one episode of visible hematuria associated to upper respiratory tract infection (synpharyngitic hematuria) (UptoDate: Clinical Presentation and Diagnosis of IgA Nephropathy [Accessed 6 April 2020])
• 30 - 50%: microscopic hematuria
• < 10%: nephrotic syndrome or rapidly progressive glomerulonephritis
• Rare: acute kidney injury (due to either rapidly progressive glomerulonephritis or red cell cast nephropathy)
• Secondary IgA nephropathy: associated with chronic liver disease, celiac disease and HIV

• Aims at slowing progression of renal damage (nonimmunosuppresive measures: control of blood pressure and proteinuria) and dampening inflammatory activity (immunosuppression: steroids) (UptoDate: Treatment and Prognosis of IgA Nephropathy [Accessed 6 April 2020])
  • If hematuria, normal eGFR with or without proteinuria < 0.5 g/day: watchful monitoring at 6 to 12 month intervals
  • If proteinuria > 500 mg/day over 6 months and or mildly reduced eGFR and mild to moderate histologic findings on renal biopsy: nonimmunosuppressive therapies (ACE-I / ARB)
  • If rising creatinine, active lesions on renal biopsy (E1, C1/2) or nephrotic range proteinuria or proteinuria after 3 - 6 months of nonimmunosuppressive: consider association of immunosuppressive therapy in addition
• There is some evidence that patients with E1, podocytopathic S1 lesions and C1 and C2 have a markedly lower rate of decline in eGFR when immunosuppressed (J Am Soc Nephrol 2017;28:691)
• Fish oil: low quality evidence; tonsillectomy: evidence from randomized controlled trials missing

• Oxford classification: first evidence based glomerular disease classification (Semin Nephrol 2018;38:477)
• Variable light microscopic patterns; in the original classification 4 lesions were reproducible and predictive of outcome (Kidney Int 2017;91:1014):
  • Mesangial hypercellularity (M0 ≤ 50% of glomeruli; M1 > 50% of glomeruli): > 3 mesangial cell nuclei / peripheral mesangial area, not adjacent to vascular pole, in 2 - 3 μm thick PAS stained section
  • Endocapillary hypercellularity (E0 absent; E1 present): CD68 count > 6 in most affected glomerulus of the sample is associated with E1
  • Segmental glomerulosclerosis / adhesions / synechiae (S0 absent; S1 present): due to hyperfiltration, healed necrotizing lesions or podocytopathy
  • Tubular atrophy / interstitial fibrosis (T0 absent to involving ≤ 25% of the cortex; T1 26 - 50% of the cortex; T2 > 50% of the cortex)
  • Crescents: added to the classification in 2016 (C0 absent; C1 1 - 24% of glomeruli with cellular / fibrocellular crescents; C2 ≥ 25% of glomeruli with cellular / fibrocellular crescents)
• Other lesions: fibrinoid necrosis (10% of biopsies), glomerular basement membrane duplication (< 10% of biopsies), thrombotic microangiopathy changes (5 - 50% of biopsies; usually associated with malignant hypertension) (Colvin: Diagnostic Pathology - Kidney Diseases, 3rd Edition, 2019)

Contributed by Maria Fernanda Soares, M.D., Ph.D.



Contributed by Arkana

Images hosted on other servers:

• Dominant IgA mesangial deposits (100%) - only defining and consistent feature of the disease
• Predominance of J chain containing IgA1 and lambda light chains
• Other mesangial deposits: C3 (90%), IgG (20 - 30%), IgM (50%), C1q (< 10% - almost always absent, indicating lack of activation of classical pathway) (Colvin: Diagnostic Pathology - Kidney Diseases, 3rd Edition, 2019)
• Occasional capillary loop subendothelial deposits

• Henoch-Schönlein purpura nephritis:
  • Morphologically indistinguishable
  • Clinical information is important for differential diagnosis (e.g. history of purpuric rash, abdominal pain, arthritis)
• IgA dominant infection associated glomerulonephritis (in general, Staphylococcus associated):
  • Electron microscopy contains hump shaped deposits
• Mesangial IgA deposits in chronic liver disease:
  • Present in 60% of autopsies of cirrhotic patients
  • Rarely associated with active glomerular disease (UptoDate: Clinical Presentation and Diagnosis of IgA Nephropathy [Accessed 6 April 2020])

A 32 year old man presents with mild reduction in eGFR, proteinuria and microscopic hematuria. Urine protein / creatinine ratio in nephrotic range. Immunofluorescence microscopy of a renal biopsy core showed mesangial deposition of IgA (strong - see image), C3, kappa and lambda (moderate) and IgG (weak and focal). IgM and C1q were negative. Based on these findings, what is the best diagnosis?

1. Accurate diagnosis of a renal biopsy cannot be assigned on the basis of the immunofluorescence findings only
2. Alport syndrome
3. Immunoglobulin A nephropathy
4. Lupus nephritis
5. Membranous glomerulonephritis

C. Immunoglobulin A nephropathy

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Reference: IgA nephropathy

Indicate the correct association in the Oxford classification of IgA nephropathy

1. Absence of necrosis / karyorrhexis - NO
2. Crescents in 10% of glomeruli - C2
3. Interstitial fibrosis / tubular atrophy in 25 - 50% of the cortex - T2
4. Presence of endocapillary hypercellularity - E1
5. Presence of segmental sclerosis in > 50% of glomeruli - S2

D. Presence of endocapillary hypercellularity - E1

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Reference: IgA nephropathy