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Internal Medicine

Lupus nephritis (LN)

Form of glomerulonephritis that constitutes one of the most severe organ manifestations of the autoimmune disease systemic lupus erythematosus (SLE)

  • Occurs in 60% lupus cases
  • First clinical manifestation of SLE in 15-20% cases

Classification

International Society of Nephrology/Renal Pathology Society (ISN/RPS) histological classification:

  • Class I: Minimal mesangial LN (20%)
  • Class II: Mesangial proliferative LN
  • Class III: Focal LN (<50% glomeruli)
    • III(A): Active lesions
    • III(A/C): Active and chronic lesions
    • III(C): Chronic lesions
  • Class IV: Diffuse LN (>50% glomeruli) (M/C form)
    • Diffuse segmental (IV-S) or global (IV-G)
    • IV(A): Active lesions
    • IV(A/C): Active and chronic lesions
    • IV(C): Chronic lesions
  • Class V: Membranous LN
  • Class VI: Advanced sclerotic LN (≥90% globally sclerosed glomeruli without residual activity)

Pathophysiology

Glomerular immune complex accumulation, which leads to glomerular inflammation and, if unchecked, also involves the renal interstitium.

ar3378-1
Molecular pathogenesis of lupus nephritis and potential therapeutic targets: Multiple steps lead to the pathogenesis of systemic lupus erythematosus (SLE). Captioned are two key sets of events underlying lupus nephritis (LN): one that engenders systemic autoimmunity, and another that drives end-organ inflammation and damage, as discussed in the text. Many of the cells and molecules in these pathogenic cascades also serve as attractive therapeutic targets, as detailed below. (1), (2) Dendritic cell (DC):T-cell and T-cell:B-cell interactions involve multiple co-stimulatory molecules, including CD28/B7, ICOS/ICOSL, and CD40/CD40L; blockade of these co-stimulatory pathways is being tested as potential therapeutic strategies in lupus. (3) Blys/BAFF elaborated by myeloid cells binds to receptors on B cells, and drives autoantibody production in SLE. Blocking this axis is emerging as a promising therapeutic avenue, based on recent clinical trials. (4) CD20, CD22, and CD19 are receptors on B cells. Several trials are aimed at depleting B cells in SLE, using antibodies to these B-cell molecules. (5) The activation of autoreactive B cells (and other leukocytes) in SLE is mediated by several signaling axes; some of these have been therapeutically targeted with success in preclinical models of the disease, and in limited clinical trials. (6) Type 1 interferon-elicited gene signatures have emerged as a distinctive feature of SLE. Based on these exciting leads, therapeutics targeting this axis are currently in active trials. (7) Activated lymphocytes and myeloid cells utilize a variety of cell adhesion molecules in order to gain access to the target organs. Therapeutics targeting these adhesion molecules and/or vascular addressins have shown promise in preclinical models of lupus. (8) Clearance of immune complexes is mediated by complement (receptor) and Fc/FcR-mediated mechanisms; targeting these nodes has also shown promise in murine lupus. (9) Activated leukocytes (as well as resident renal cells) elaborate a large spectrum of disease mediators, including various cytokines and chemokines. Blockade of these mediators also hold promise in ameliorating LN, although we are in the infancy of these studies. CD40L, CD40 ligand; | ICOS, inducible T-cell costimulator; ICOSL, inducible T-cell costimulator ligand; TCR, T-cell receptor. | Saxena, R., Mahajan, T., & Mohan, C. (2011). Lupus nephritis: current update. Arthritis research & therapy, 13(5), 240. doi:10.1186/ar3378

Clinical features

  • Proteinuria (characteristic feature) (100%)
  • Nephrotic range proteinuria/nephrotic syndrome (45-65%)
  • Microscopic hematuria (80%), invariably associated with proteinuria
  • Macroscopic hematuria (rare, < 5%)
  • Urinary RBC casts (30%)
  • Other urinary cellular casts (30%)
  • Hypertension (30%)
  • Renal insufficiency (60%)
  • Acute kidney injury (uncommon, 15%)
  • Tubular abnormalities (70%)
  • Disturbed renal tubular function:

Diagnosis

24-hour urine collection:

  • Proteinuria (100%)
  • Microscopic hematuria (80%), invariably associated with proteinuria
  • Macroscopic hematuria (rare, < 5%)
  • Urinary RBC casts (30%)
  • Other urinary cellular casts (30%)
  • ↓ Glomerular filtration rate (GFR) (50%)
  • Disturbed tubular function: Tamm-Horsefall proteins, light chains and β2-microglobulin

Renal biopsy (GOLD STANDARD):

  • “Full house” staining pattern: Positive staining for immunoglobulin G, A, and M with C1q, C3, and C4
  • “Wire loop” structures: Circumferential thickening of the capillary wall

Management

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Current standard of care treatment protocols for LN induction therapy. Patients with proliferative forms of LN are treated with oral corticosteroids, typically prednisone starting at 1 mg/kg per day and tapered over weeks to months. In severe disease with rapid deterioration of kidney function, high-dose intravenous methylprednisolone (0.25–1 g/d) is often given for 1–3 days preceding oral corticosteroids. In addition to corticosteroids one of four immunosuppressive regimens using cyclophosphamide or MMF is generally used. The NIH high-dose regimen consists of monthly intravenous pulses of cyclophosphamide dosed at 0.5–1 g/m2 for 6 months. Oral cyclophosphamide dosed at 1–1.5 mg/kg per day for 2–4 months provides a cumulative cyclophosphamide burden similar to the NIH regimen. In both cases cyclophosphamide is dosed based on nonobese body weight. The Euro-Lupus (low-dose) intravenous cyclophosphamide regimen is dosed at 500 mg every 2 weeks for six total doses. Cumulative cyclophosphamide for the Euro-Lupus regimen is 3 g, which is at least 50% lower than the NIH regimen. MMF is given for 6 months and dosed at 2–3 g/d. | Parikh, S. V., & Rovin, B. H. (2016). Current and Emerging Therapies for Lupus Nephritis. Journal of the American Society of Nephrology : JASN, 27(10), 2929–2939. doi:10.1681/ASN.2016040415

Summary:

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Anders, H.-J., Saxena, R., Zhao, M., Parodis, I., Salmon, J. E., & Mohan, C. (2020). Lupus nephritis. Nature Reviews Disease Primers, 6(1), 7. https://doi.org/10.1038/s41572-019-0141-9

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