Mediators of Immune Injury

Cells

– Neutrophils and monocytes – Macrophages, T lymphocytes, and NK, platele

ts – Resident glomerular cells, mesangial cells

• Generation of C5a and the recruitment of neutrophils and monocytes.

• Release proteases- GBM degradation; ROS-cell damage and AA metabolites- reduction in GFR.

Mediators of Immune Injury

• The membrane attack complex, C5b-C9: causes cell lysis

• Eicosanoids, NO, angiotensin, and endothelin : involve in hemodynamic changes

• Cytokines, particularly IL-1 and TNF

• Chemokines such as MCP-1 and RANTES promote monocyte and lymphocyte influx.

• Growth factors: PDGF, TGF-β etc seem to be critical in the ECM deposition and hyalinization leading to glomerulosclerosis in chronic injury.

• The coagulation protein: fibrin stimulate crescent formation in crescentic GN

The Nephrotic Syndrome

• Non-immune complex– MCD– FSGS, collapsing glomerulopathy– C1q nephropathy, congenital NS(Finnish type)

• Immune complex– Membranous glomerulopathy– MPGN type 1– Dense Deposit Disease– Fibrillary GN– Immunotactoid GN

The Nephrotic Syndrome

• Nephrotic syndrome refers to a clinical complex that includes the following:

– Massive proteinuria, with the daily loss of 3.5 gm or more of protein 

– Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL 

– Generalized edema – Hyperlipidemia and lipiduria

• The initial event is a derangement in the capillary walls of the glomeruli, resulting in increased permeability to plasma proteins

Causes

• The primary glomerular lesions:– Minimal-change disease (MCD)– Membranous glomerulopathy– Focal segmental glomerulosclerosis (FSGS)

• Systemic causes: DM, amyloidosis, and SLE. • The MCD- most common in children• Membranous glomerulopathy- common in older

adults• FSGS- occurs at all ages. • The MPGN, frequently present as a mixed syndr

ome with nephrotic and nephritic features.

Minimal Change Disease (Lipoid Nephrosis)

• The most frequent cause of nephrotic syndrome in children.

• It is characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes) in glomeruli that appear virtually normal by light microscopy.

• The peak incidence is between 2 and 6 years of age. The disease sometimes follows a respiratory infection or routine prophylactic immunization.

• Its most characteristic feature is its usually dramatic response to corticosteroid therapy

Etiology and pathogenesis

• Associated with respiratory infections, immunizations, lead or mercury ingestion, allergies, Hodgkin’s lymphoma

• In elderly, associated with NSAIDs

• Increased prevalence of certain HLA haplotypes

Morphology

• LM: glomeruli appear normal

• Cells of the proximal convoluted tubules - heavily laden with protein droplets and lipids (lipoid nephrosis).

• IF: no immune deposits

• EM: uniform and diffuse effacement of the foot processes of the podocytes

Clinical Feature

• Massive selective proteinuria, most of the protein being albumin.

• Most children (>90%) respond rapidly to corticosteroid therapy.

• MCD in adults can be associated with Hodgkin lymphoma

• Prognosis - good

• < 5% develop CRF after 25 years

Focal segmental glomerulosclerosis (FSGS)

• Characterized by sclerosis of some (focal ) but not all glomeruli and involving only segments of each affected glomerulus

• FSGS can be: – Primary (or idiopathic)– Secondary to heroin abuse, HIV infection, sick

le cell disease, HTN, adaptive process to loss of kidney or another primary glomerular disease (IgA nephropathy) or mutation in podocin, actin or nephrin

FSGS

• Most common cause of nephrotic syndrome in USA

• differs from minimal change disease• i) higher incidence of hematuria,

reduced GFR, and hypertension• ii) poor response to corticosteroids• iii) proteinuria is non selective• iv) progression to chronic

glomerulosclerosis• v) IgM and C3 trapping on sclerotic

segments

Pathogenesis

• whether this is a specific disease or is an evolution of minimal change disease is unresolved !!

• Damage of visceral epithelial cells-hallmark of FSGS

• Genetic basis• - NPHS1 gene encodes nephrin• - several mutations of this gene give rise t

o congenital nephrotic syndrome .

Pathogenesis

• Permeability-increasing factors produced by lymphocytes have been proposed.

• Deposition of hyaline masses in the glomeruli represents the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops.

• Circulating mediator is the cause of the damage to podocytes.

Morphology

• First affects only some of the glomeruli • With progression, eventually all levels of the cort

ex are affected.

• LM: Segmental glomerular sclerosis, more pronounced at vascular pole near afferent arterioles.

• – Affected glomeruli exhibit increased mesangi

al matrix, obliterated capillary lumens, and deposition of hyaline masses (hyalinosis) and lipid droplets.

• IF: IgM and C3 staining

• EM: effacement of foot processes.

• With progression- global sclerosis of the glomeruli with pronounced tubular atrophy and interstitial fibrosis.

• Variant of FSGS: Collapsing glomerulopathy : collapse of the entire glomerular tuft and podocyte hyperplasia.

– more severe manifestation of FSGS that may be idiopathic or associated with HIV infection or drug-induced toxicities.

– EM: Tubuloreticular bodies +

Prognosis

• Little tendency for spontaneous remission

• Responses to corticosteroid therapy- poor.

• 50% of individuals: renal failure after 10 years.

• The recurrence of proteinuria in some persons with FSGS after transplantation

IgA Nephropathy (Berger Disease)

• Usually affects children and young adults

• One of the most common causes of recurrent microscopic or gross hematuria

• The pathogenic hallmark is the deposition of IgA in the mesangium.

• Localized variant of Henoch-Schönlein purpura

• is a systemic syndrome involving the skin (purpuric rash), GIT (abdominal pain), joints and kidneys.

Pathogenesis

• Associated with an abnormality in IgA production and clearance.

• IgA is low in normal serum but increased in 50% of patients with IgA nephropathy.

• Circulating IgA-containing immune complexes are present in some individuals.

• An abnormality in glycosylation of the IgA - reduce plasma clearance of IgA

• Entrapment of IgA immune complexes in the mesangium, and activation of the alternative complement pathway.

Morphology

• Glomeruli may be normal or may show mesangial widening and segmental inflammation confined to some glomeruli

• Diffuse mesangial proliferation

• IF: mesangial deposition of IgA, often with C3 and properdin and smaller amounts of IgG or IgM

• EM: electron-dense deposits in the mesangium.

Clinical Features

• Affects people of any age, but older children and young adults are most commonly affected.

• Gross hematuria

• 30% to 40% have only microscopic hematuria, with or without proteinuria; and 5% to 10% develop a typical acute nephritic syndrome.

• Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years.

• Recurrence of IgA deposits in transplanted kidneys is frequent.

Nephritic Syndromes

• Diffuse intracapillary proliferative GNDiffuse intracapillary proliferative GN– Post streptococcal

• Diffuse extracapillar proliferative GN (Crescentic GN)Diffuse extracapillar proliferative GN (Crescentic GN)

– Goodpasture’s syndrome

• Focal proliferative GNFocal proliferative GN:: Berger disease (IgA Nephropathy)

Acute Post Streptococcal GN

• Associated with nephritogenic strains of Streptococcus pyogenes (beta hemolytic Strep group A) infection of the pharynx or skin

• Children age 6-10: – Hematuria, oliguria, fever, malaise and nausea 1-4

weeks after strep infection of pharynx or skin (impetigo); RBC casts, proteinuria, periorbital edema, hypertension

• Adults: may have atypical presentation with sudden hypertension, edema, elevated BUN; 60% recover, others develop RPGN

Etiology and Pathogenesis

• Is an immunologically mediated disease.

• Only certain strains of group A β-hemolytic streptococci are nephritogenic

• > 90% of cases- types 12, 4, and 1

• Identified by typing of M protein of the cell wall

• The latent period between infection and onset of nephritis is compatible with the time required for the production of antibodies and the formation of immune complexes.

Laboratory value

• High ASO titers, low C3

Morphology

• LM: The classic diagnostic picture is enlarged, hypercellular glomeruli.

• The hypercellularity is caused by – infiltration by leukocytes, both neutrophils an

d monocytes– proliferation of endothelial and mesangial cell

s– and in severe cases by crescent formation

Morphology contd

• The proliferation and leukocyte infiltration are diffuse involving all lobules of all glomeruli.

• There is also swelling of endothelial cells, and the combination of proliferation, swelling, and leukocyte infiltration obliterates the capillary lumens.

• There may be interstitial edema and inflammation, and the tubules often contain red cell casts.

Morphology contd

• IF: Granular deposits of IgG, IgM, and C3 in the mesangium and along the GBM. Although immune complex deposits are almost universally present, they are often focal and sparse.

• EM: Discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of “humps”.

• Subendothelial and intramembranous deposits are also commonly seen.

• Mesangial deposits may be present

NormalPost Strepto GN

InflammationProliferationSwelling.Narrow capillary↓GFR-Renin-BP

Post Streptococcal GN

Enlarged hypercellular glomeruli.Cell Swelling.Inflammatory cells.Collapsed capillaries. Obstruction to blood flow.

Clinical Course

• Young child – Sudden malaise, fever, nausea, oliguria, and hemat

uria 1 to 2 weeks after recovery from a sore throat.

• O/E: RBC casts in the urine, mild proteinuria (usually < 1 gm/day), periorbital edema, and mild to moderate hypertension.

• • In adults: sudden appearance of HTN or edema, elevation

of BUN. • Elevations of ASO titers and a decline in the serum C3 and

other components of the complement cascade.

Clinical Course

• More than 95% of affected children recover totally with conservative therapy.

• In adults: about 60% of patients recover promptly. • In the remainder the glomerular lesions fail to resol

ve quickly, as manifested by persistent proteinuria, hematuria, and hypertension.

• May develop chronic GN or a syndrome of RPGN.• (1% develop RPGN, 1-2% develop chronic GN; 2-

5% die from pulmonary edema, hypertensive encephalopathy, crescentic glomerulonephritis)

Nonstreptococcal Acute GN (Postinfectious GN)

• A similar form of GN occurs sporadically in association with other infections– staphylococcal endocarditis, pneumococcal p

neumonia, and meningococcemia– hepatitis B, hepatitis C, mumps, HIV infection,

varicella, and infectious mononucleosis– malaria, toxoplasmosis

• IF: Granular deposits and subepithelial humps are present.

RPGN

• Syndrome associated with severe glomerular injury.

• Characterized clinically by rapid and progresive loss of renal function associated with severe oliguria and renal failure within weeks to months (if untreated).

• Regardless of cause, classic histologic pattern is presence of crescents in most of the glomeruli

Rapidly progressive GN (RPGN)

• Also called extracapillary proliferative GN, because cell proliferation is primarily in Bowman’s space

• Crescents are end result of damage to glomerular BM or Bowman's capsule; due to deposition of fibrin, epithelial cells and inflammatory cells

• Crescents affect at least in 50% of glomeruli• Rapid, usually irreversible loss of renal function ass

ociated with severe oliguria and hematuria, unresponsive to steroids

• Symptoms of nephritic syndrome, nephrotic syndrome and renal failure

• Causes death within weeks if untreated.

Chronic GN

• It represents the end stage of a variety of entities, prominent among which are the CrGNs, FSGS, MN, IgA nephropathy, and MPGN.

• 20% of cases arise with no history of symptomatic renal disease.

Morphology• Kidneys are symmetrically contracted.• Microscopically, the feature common to all cases is advanced scarri

ng of the glomeruli, sometimes to in the point of complete sclerosis

• Obliteration of the glomeruli is the end point

• Marked interstitial fibrosis- atrophy and dropout of many of the tubules in the cortex, and diminution and loss of portions of the peritubular capillary network.

• The small and medium-sized arteries are frequently thick walled, with narrowed lumina, secondary to hypertension.

• Lymphocytic infiltrates are present in the fibrotic interstitial tissue.

Clinical Course

• Often discovered only late in its course

• Proteinuria, HTN, or azotemia- routine medical examination.

• In some individuals - nephritic or the nephrotic syndrome.

• Without treatment, the prognosis is poor

• Renal dialysis and kidney transplantation