Membranous Nephropathy: Key Concepts

• Part 2 of Primary Glomerular Diseases, by Axel Baez Torres, M.D.
• Describes common clinical disorders associated with Nephrotic Syndrome.
• Describes etiology, mechanisms of injury, clinical course, and the prognoses of membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis.
• Describes systemic causes of Nephrotic Syndrome.
• Describes characteristics of chronic glomerulonephritis.

Nephrotic syndrone

• Glomerular syndrome is marked by heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria.
• Characterized by having over 3.5 g of protein / 24 hours.
• The primary glomerular diseases causing nephrotic syndrome in adults include:
  • Membranous glomerulopathy occurs in 30% of cases.
  • Focal segmental glomerulosclerosis occurs 35% of cases.
  • Other proliferative glomerulonephritis (focal, "pure mesangial," IgA nephropathy) happens in 15% of cases
• The primary glomerular diseases causing nephrotic syndrome in children include:
  • Minimal change disease occurs in 65% of cases. - Membranoproliferative glomerulonephritides and membranous glomerulopathy occur in 10% of cases.
• Systemic conditions causing nephrotic syndrome include:
  • Diabetes mellitus
  • Amyloidosis
  • Systemic lupus erythematosus
  • Drug use (nonsteroidal anti-inflammatory, penicillamine, or "street heroin")
  • infections (malaria, syphilis, hepatitis B and C, or acquired immunodeficiency syndrome)
  • Malignant disease (carcinoma, lymphoma)
  • Miscellaneous factors (bee-sting allergy, hereditary nephritis)

Membranous nephropathy

• Common cause of nephrotic syndrome in adults due to primary glomerular disease.
• 80-90% of cases are idiopathic.
• The nephropathy may occur in association with systemic lupus erythematosus, malignant neoplasms, exposure to gold and mercury, or hepatitis B.
• Most idiopathic cases are caused by autoantibodies against the phospholipase A2 receptor (PLA2R), which is expressed on the podocyte.
• Infectious agents, parasitic drugs and other planted antigens cause the secondary form.

Membranous nephropathy and microscopy

• Light Microscopy:
  • The glomeruli may appear normal in the early disease, due to small deposits.
  • Capillary walls are thickened with sub-epithelial spikes on a silver stain.
• Immunofluorescence Microscopy:
  • Shows bright granular staining of the capillary loops with IgG and C3.
• Electron Microscopy:
  • Subepithelial electron dense deposits with intervening basement membrane spikes.
  • The disease stage correlates with incorporation of deposits into the glomerular basement membrane.

Membranous nephropathy clinical features

• Treatment: Does not respond to steroid therapy.
• Prognosis: Indolent clinical course in the majority of patients.
• Approximately 30-40% of patients eventually develop renal insufficiency.
• About 10% die or progress to chronic renal failure within 10 years.

Minimal Changes Disease

• The most common cause of nephrotic syndrome in children.
• Associated disorder of T lymphocytes, possibly including production by T cells that increases glomerular permeability.
• Clinical Features:
  • Mild periorbital edema prior to the rapid onset of the nephrotic syndrome.
  • Proteinuria is "selective" or composed primarily of albumin.
• Other clinical features:
  • Hematuria is rare
  • Hypertension is unusual

Minimal Changes Disease and Microscopy

• Light Microscopy:
  • The glomeruli, tubules, and interstitium appears normal
• Immunofluorescence Microscopy:
  • Usually negative.
• Electron Microscopy:
  • Diffuse effacement of the epithelial cell (podocyte) foot processes

Minimal Change Disease and Prognosis

• Over 90% of patients achieve complete remission with corticosteroid therapy.
• Intermittent relapses frequently present after withdrawal of steroids.

Focal Segmental Glomerulosclerosis

• The most common cause of nephrotic syndrome in adults, due to primary glomerular disease.
• The glomerulopathy may be primary (idiopathic) or secondary to unilateral renal agenesis, renal ablation, sickle cell disease, reflux nephropathy, or HIV infection.
• Pathogenesis:
  • Secondary to injury to, or dysfunction of podocytes.
• Conditions are characterized by functional overwork over nephrons inducing glomerular hypertrophy.
• Primary FSGS: Resulting from an undefined circulating factor or factors, which mediate abnormal glomerular permeability and ultimately sclerosis.

Focal segmental glomerulosclerosis pathogenesis

• Some cases have a genetic basis involving mutations of components of the slit diaphragm.
• Familial forms of FSGS include:
  • Congenital nephrotic syndrome of Finnish type: Autosomal recessive inheritance; mutated NPHS1 gene produces abnormal nephrin protein.
  • Corticosteroid-resistant nephrotic syndrome: Autosomal recessive inheritance; mutated NPHS2 gene produces abnormal podocin protein.
  • Familial FSGS: Autosomal dominant inheritance; mutations in Alpha-actinin 4 and Transient receptor potential cation channel-6.

Focal Segmental Glomerulosclerosis and Microscopy

• Light Microscopy:
  • Focal (including some glomeruli) and segmental (involving part of a single glomerulus) sclerosis of the glomeruli with capillary loop collapse, hyaline and lipid deposition, and often adhesion to Bowman's capsule.
• Immunofluorescence Microscopy:
  • May show nonspecific entrapment of IgM or C3 in areas of sclerosis or may be negative.
• Electron Microscopy:
  • Effacement of podyte foot processes.
  • Podocyte denudation may be present focally as an early lesion.

Focal Segmental Glomerulosclerosis prognosis

• Not all patients improve with corticosteroid therapy
• Most people show persistent proteinuria and progressive decline in renal function
• Many patients progress to end-stage renal disease after 5 to 20 years
• FSG recurs in half of transplanted kidneys

Membranoproliferative Glomerulonephritis

• Chronic progressive glomerulonephritis, most frequent in older children and young adults.
• Three types have been described, type I is the most common form.
• Patients may present with nephrotic syndrome, non-nephrotic proteinuria, or the acute nephritic syndrome.
• Type I is most commonly idiopathic: It may be associated with systemic disorders - subacute bacterial endocarditis, infected ventriculo-atrial shunts, hepatitis C virus infection, and malignancy.
• Type II is an autoimmune disorder.
• Pathogenesis:
  • Type I is caused by deposition of immune complexes.
  • Type II is caused by the deposition of complement.
  • Type II etiology is proposed to be prolonged C3 convertase activity induced by a circulating IgG autoantibody ("C3 nephritic factor").

Membranoproliferative Glomerulonephritis and Pathology

• Type I and Type II MPGN are characterized by glomerular hypercellularity and capillary wall thickening.
• Type I MPGN electron microscopy: Subendothelial and mesangial deposits containing C3, IgG, and IgM by IF.
• Type II MPGN electron microscopy: Intramembranous deposits containing C3 (dense deposit disease); immunoglobulin deposits are not detected by IF.
• Prognosis:
  • Type I is usually a persistent but slowly progressive disease.
  • Half of patients reach end-stage renal disease after 10 years.
  • Type II and recurrence of MPGN after renal transplantation have worse prognoses.

IgA Nephropathy aka Berger Disease

• The most common form of primary glomerulonephritis in the world.
• Displays geographic variability.
• Related to a genetic or an acquired abnormality of immune regulation, yielding increased mucosal IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents.
• Occurs with increased frequency in patients with celiac disease, dermatitis herpetiformis, and liver disease
• Patients usually present with one of these syndromes:
  • Macroscopic hematuria concurrent with an upper respiratory infection
  • Asymptomatic hematuria and variable proteinuria.
  • Henoch-Schonlein purpura is more common in children.
• Pathology:
  • Light microscopy is variable
  • Immunofluorescence microscopy shows mesangial deposits of IgA

IgA Prognosis

• Disease most often tends to be mild, but recurrent.
• 25-50% of the patients develop chronic renal failure within 20 years.
• Older patients tend to have a worse prognosis.

Chronic Gloerulonephritis features

• End-stage pool of glomerular diseases fed by a number of different glomerulonephritides.
• Some cases arise with no antecedent history of any of the well recognized forms of acute glomerulonephritis.
• Disease is manifested by chronic renal failure and related uremic complication:     - Pericarditis     - Secondary hyperparathyroidism     - Anemia, etc.
• Some causes of Chronic Glomerulonephritis include - Poststreptococcal
  • Rapidly progressive GN
  • Membranous GN
  • Focal glomerulosclerosis
  • Membranoproliferative GN
  • IgA
• Others
• Gross Morphology: -Symmetrically contracted kidneys -Diffusely granular cortical surfaces -Thin cortex -Increased peripelvic fat

Chronic Glomerulonephritis microscopy

• Glomeruli may still show evidence of primary disease or may show hyaline obliteration. -Arterial/arteriolar sclerosis -Tubular atrophy -Interstitial fibrosis and chronic inflammation
• Prognosis is relentlessly progressive.
• The outcome is invariably death if patients are not maintained with continued dialysis or if they do not receive a renal transplant.