Diffuse Proliferative Glomerulonephritis

Diffuse proliferative glomerulonephritis (DPGN) is a histopathologic classification of glomerulonephritis (GN) characterized by an increased cellular proliferation affecting > 50% of the glomeruli. Mesangial, endothelial, and epithelial cells are notably increased. The most common causes are lupus nephritis class IV and IgA nephropathy. Individuals may present with symptoms related to the renal disease, such as fatigue, nausea, vomiting, hematuria, proteinuria, hypertension, and edema. Other manifestations related to the underlying disease can be present. Diagnosis is made by laboratory tests, renal imaging, and renal biopsy. Microscopic findings show hypercellularity of mesangial and endothelial cells, with capillary loop thickening. Early aggressive therapy is indicated and is based on the specific etiology.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Diffuse proliferative glomerulonephritis (DPGN), a histopathologic classification of glomerulonephritis (GN) commonly associated with autoimmune diseases, is characterized by an increased cellular proliferation affecting > 50% of the glomeruli.

  • Mesangial, epithelial, endothelial, and inflammatory cells are increased in the glomeruli.
  • Can progress to rapidly progressive GN

Etiology

  • Lupus nephritis class IV is the most common cause of DPGN.
  • IgA nephropathy
  • Anti–glomerular basement membrane (GBM) disease 
  • Granulomatosis with polyangiitis
  • Microscopic polyangiitis
  • Henoch-Schönlein purpura
  • Cryoglobulinemia
  • Vasculitis
  • Infectious causes:
    • Infective endocarditis
    • Hepatitis C
    • Hepatitis B

Epidemiology

  • Prevalence of lupus nephritis: around 40% of individuals with lupus in the United States
  • Incidence of end-stage renal disease (ESRD) attributed to lupus nephritis: 4.5 cases per 1 million cases in the general population
  • Women are more likely to develop DPGN.
  • Men are more likely to develop aggressive cases of DPGN.
Diffuse_proliferative_lupus_nephritis

“Flea-bitten” appearance of the cortical surface of a kidney in diffuse proliferative glomerulonephritis.

Image: “Diffuse Proliferative Lupus Nephritis class IV” by Ed Uthman. License: Public Domain

Pathophysiology

Mechanism of injury

  • Depends on the underlying cause of DPGN
  • Typically involves deposition on immune complexes, which in turn activates the complement pathway:
    • Immune complexes are aggregates of antigens and antibodies.
    • Deposition occurs in the mesangium, GBM, or subendothelial or subepithelial locations.
    • Results in recruitment of inflammatory cellular infiltrates, proliferation of mesangial and endothelial cells, and necrosis
    • Severe cases may have cellular crescents (epithelial cells, activated macrophages, and fibrin) and fibrin thrombi. 
  • Cytokine release leads to cellular injury.

Effects

  • Immunologic attack on the glomerulus → ↑ GBM permeability to protein, RBCs, and WBCs
  • Capillary loops become obliterated and sclerosis develops → hypertension and renal failure
  • Fibrinoid necrosis in the glomerular vasculature → vasculitis → ↓ renal filtration and function

Clinical Presentation

General manifestations

Presentations vary considerably, with most symptoms occurring because of the decrease in GFR caused by DPGN.

  • Nonspecific symptoms:
    • Nausea
    • Fatigue
    • Vomiting
    • Oliguria
  • Nephritic symptoms:
    • Proteinuria
    • Hypertension
    • Edema
    • Hematuria

Presentation in relation to underlying disease

Because DPGN is caused by another condition, the symptoms of the underlying cause are often present, such as in: 

  • Systemic lupus erythematosus (SLE):
    • Rash
    • Joint pains
    • Photosensitivity
    • Serositis
    • Oral ulcers
  • IgA nephropathy:
    • Preceding upper respiratory or GI infection
    • Flank pain
    • Gross hematuria
  • Anti-GBM disease:
    • Majority with renal disease
    • About 25%–60% with pulmonary manifestations:
      • Hemoptysis
      • Cough
      • Dyspnea
  • Granulomatosis with polyangiitis:
    • Pulmonary (hemoptysis, cough)
    • Head and neck (nosebleeds, hearing loss, nasal cartilage deformities)

Diagnosis

Renal biopsy

  • Gold standard for diagnosis 
  • Light microscopy:
    • Marked hypercellularity of endothelial and mesangial cells
    • Capillary loop thickening (wire loops)
    • Inflammatory cell infiltration
    • Severe forms: cellular crescents and necrosis
  • Immunofluorescence microscopy:
    • Absent (or mild) glomerular staining for Ig and/or complement in ANCA-associated GN (pauci-immune disease)
    • Granular deposition of Ig, complement, and fibrin along the GBM in most, except anti-GBM disease
    • Linear deposition in anti-GBM disease
  • Electron microscopy:
    • Electron-dense deposits noted in the mesangial, subendothelial  intramembranous, and subepithelial areas
    • In SLE: wire loop lesions in the mesangial and subendothelial areas
    • In anti-GBM disease: linear and intramembranous deposits 
    • In poststreptococcal GN: subepithelial deposits (humps) 
    • In ANCA-associated GN: few or no deposits
histology for diffuse proliferative glomerulonephritis

Histology for diffuse proliferative glomerulonephritis with leukocytic infiltration

Image: “Diffuse proliferative glomerulonephritis with leukocytic infiltration” by Cannata-Ortiz P. License: CC BY 4.0

Other diagnostic tests

  • CBC findings (depending on underlying disease) can include:
    • Anemia 
    • Leukopenia
    • Lymphopenia 
    • Thrombocytopenia
  • Renal function tests: 
    • ↑ Serum creatinine due to kidney damage
    • ↑ BUN due to kidney damage
  • Urinalysis may show any of the following:
    • RBCs and casts
    • WBCs 
    • Granular casts
    • Proteinuria
  • Serologic tests to evaluate for the primary etiology of DPGN:
    • Positive ANAs: nonspecific, but positive in majority of cases of SLE
    • Positive anti–double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies: SLE
    • Low C3, C4, and CH50: SLE, postinfectious GN, poststreptococcal GN, cryoglobulinemia
    • Positive ANCA: granulomatosis with polyangiitis
    • Positive anti-GBM antibodies: anti-GBM disease
    • High titers of anti–streptolysin O: poststreptococcal GN
    • Elevated serum IgA levels: IgA nephropathy
  • Renal ultrasonography:
    • Confirm that 2 kidneys are present and obtain renal size.
    • Evaluate for obstruction or structural lesions that may cause azotemia.

Management

Treatment approach

  • Depends on severity of disease
  • Generally, should be aggressively treated in a timely manner to minimize the risk of ESRD
  • Mild disease:
    • Characteristics:
      • Normal serum creatinine levels
      • Non–nephrotic-range proteinuria
      • Normal estimated GFR (eGFR)
    •  May be managed with an ACEi, a statin (↓ atherosclerosis), and regular follow-up
  • Individuals with significant disease (e.g., hypertension, ↓ GFR, ↑ creatinine): a course of steroids for up to 6 months
  • Additional therapy (including immunosuppressants) is used depending on response and etiology of DPGN.
  • In ESRD → renal replacement therapy:
    • Dialysis 
    • Kidney transplantation

Underlying disease

To reduce progression of renal disease, management will vary depending on the underlying condition. Options are as follows:

  • Lupus nephritis:
    • Pulse methylprednisolone + mycophenolate mofetil (MMF) or cyclophosphamide
    • Other treatments:
      • Biologic therapies (e.g., belimumab)
      • Calcineurin inhibitors (e.g., tacrolimus)
  • IgA nephropathy:
    • Glucocorticoids
    • For rapidly progressive disease: consider glucocorticoids + cyclophosphamide then azathioprine
  • Anti-GBM disease:
    • Initial treatment with high-dose corticosteroids
    • Cyclophosphamide
    • Plasmapheresis (removal of antibodies)
  • Granulomatosis with polyangiitis:
    • Corticosteroids
    • Add other immunosuppressants (e.g., cyclophosphamide, rituximab, azathioprine)

Differential Diagnosis

  • Rapidly progressive glomerulonephritis (RPGN): nephritic syndrome accompanied by features of glomerular disease, microscopic glomerular crescent formation and progression to renal failure within weeks to months. Glomerular injury in RPGN can be from anti-GBM disease, immune complex–mediated injury, pauci-immune necrotizing and crescentic GN, or idiopathic causes. Diagnosis is by history, urinalysis, serology, and renal biopsy. Treatment is with immunosuppressants, with specific therapy depending on the underlying mechanism of renal disease. 
  • Poststreptococcal glomerulonephritis (PSGN): occurs after infection with a group A beta-hemolytic streptococcus. Diagnosis of PSGN is by history, laboratory tests (including urinalysis), and serology testing. Treatment is supportive, and the prognosis is usually excellent, with the majority of individuals recovering without long-term complications.  
  • Membranoproliferative glomerulonephritis (MPGN): histologic renal lesion characterized by glomerular injury with GBM thickening and mesangial proliferation. The pathogenic process of MPGN can be either immune complex–mediated or complement-mediated. Individuals can present with nephritic syndrome, variable proteinuria, and renal function. Renal biopsy shows the pathologic renal lesion, and further investigation (e.g., laboratory tests) will point to the underlying cause (infections, autoimmune disease). Treatment is based on the etiologic disease.

References

  1. Bomback A.S., et al. (2021). Lupus nephritis: diagnosis and classification. UpToDate. Retrieved August 13, 2021, from https://www.uptodate.com/contents/lupus-nephritis-diagnosis-and-classification
  2. Falk R.J., et al. (2021). Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis. UpToDate. Retrieved August 13, 2021, from https://www.uptodate.com/contents/lupus-nephritis-initial-and-subsequent-therapy-for-focal-or-diffuse-lupus-nephritis
  3. Ikhlas M., Anjum, F. (2021). Diffuse proliferative glomerulonephritis. StatPearls. Retrieved August 13, 2021, from https://pubmed.ncbi.nlm.nih.gov/32644412/
  4. Ikhlas M, Anjum F. (2021). Diffuse proliferative glomerulonephritis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK558986/

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details