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Goodpastures and gene associations

-high prevalence with certain HLA subtypes and haplotypes (HLADRB1) in RPGN patients
-genetic predisposition to autoimmunity


Tx for Goodpastures

-Plasmapheresis to remove pathogenic circulating Abs is part of Tx regimen which is effective in conjunction with immunosuppressive Tx


Type II vs Type III RPGN

-Type II immune complex deposition RPGN associated with acute proliferative GN, lupus nephritis and IgA nephropathy
--Type I=celluar proliferation within glomerular tufts occurs in addition to crescent formation; IF studies reveal GRANULAR pattern of immune complex deposition
-Type II pts DO NOT RESPOND to plasmapheresis

-Type III defined by lack of anti GBM Abs or immune complexes by IF or EM
-Most pts with type III (pauci immune) have circulating antineutrophil cytoplasmic Abs (ANCA)


Renal syndrome where basic defect is increased permeability of glomeruli to plasma proteins resulting in proteinuria

Nephrotic syndromes


Major clinical features of nephrotic syndrome

-Severe proteinuria (>3.5 gm/day)
-Edema; common to start with periorbital but becomes GENERALIZED
-Hyperlipiemia--elevated serum cholesterol & lipoproteins


Causes of Nephrotic syndrome in children vs adults

-Children usually Minimal change disease (children usually get it from PRIMARY glomerular disease 95% like minimal change disease)
-Adults usually FSGS and Membranous glomerulopathy (more often associated with systemic disease compared to children but 60% still from primary disease)


Massive increase in urinary protein in nephrotic syndrome is due to

diffuse changes in the majority of glomeruli
-GBM becomes diffusely leaky or porous to proteins especially albumin which is both a small protein and represents half the total protein in blood
-But in NS the generalized increase in GBM porosity to proteins does not allow RBCs to transmit into urinary space (size and charge selectivity)


Primary vs secondary renal disease in nephrotic syndrome

-Primary: only kidney is affected (renal etiology); MOST common cause of NEPHROTIC syndrome in children
-Secondary: systemic diseases causing nephrotic renal disease (DM, SLE) with alterations in renal histomorphology; more frequent in adults (40% of cases)


PURE protein disorders (rarely exhibit hematuria)

-Minimal Change disease
-Membranous Glomerulopathy
-Focal segmental Glomerulosclerosis (of the 3, this is most likely to have hematuria)


Acute Proliferative GN and RPGNs (I, II and III) are nephritic or nephrotic?



Leading etiologies of Nephrotic syndrome

-DM, and SLE most common
-Infections (malaria, syphillis, Hep B and C, HIV)--typically membranous glomerulopathies
-Malignant disease (carcinoma, lymphoma)--also membranous
Drugs (non steroidal anti-inflammatory, penicillamine)
-Miscallaneous (bee sting allergy, hereditary nephritis)


Membranous Glomerulopathy major characteristics

-75% of cases are primary
-Autoimmune disease linked to HLA-DQA1 and Abs to renal auto antigen PLA2 receptor with pathophysiologic involvement of complement (primarily MAC) and IgG4
-Remainder due to drugs, underlying malignancies, SLE, infections, other AI disease
-85% are NEPHROTIC! Hematuria and HTN CAN occur (15-35% of cases)
-NON-selective proteinuria!


Primary vs secondary membranous glomerulopathy response to steroid therapy

-primary responds POORLY to steroid therapy; high disease recurrence in transplant patients; in contrast Minimal change disease responds very well to steroids!
-some evidence that women may have more beingn course


Membranous glomerulopathy morphology

-Marked diffuse thickening of capillary walls without increase in cellularity; spikes of silver staining matrix project from basement membrane toward urinary space
-acellular sclerotic glomerulus
-Effaced Foot processes
-Thick basement membrane: 5-20 fold increased thickness
-subepithelial deposits: dense aggregates IgG (electron dense) along epithelial side of BM
-Obliterated foot processes overlying dark deposits
-Lumpy bumpy IgG deposits


The only disease where you see ONLY fusion of foot processes

Minimal Change disease


Membranous Glomerulopathy Clinical Course

-Proteinuria persists in 60% of patients
-40% develop renal insufficiency
-10% progress to end stage renal failure
-corticosteroids and immunosuppressive tx NOT efficacious (in contrast to Minimal change disease)


MCD clinical characterisitics

-NS presentation--Edema
-Biopsy--ONLY foot process fusion
-peak incidence bw 2-6 yrs
-MCC of NS in children and may follow a respiratory infection or immunization
-significant evidence that it has immunologic basis
-associated with Hodgkin lymphoma and other lymphoreticular diseases
-HTN is rare
-highly selective proteinuria (albumin mostly)
-Respond well to corticosteroids and no clinical recurrence--very good prognosis


Visceral Epithelial Cell (podocyte) injury

-Abs against epithelial cell Ags, certain toxins, cytokines or other factors cause injury, resulting in foot process effacement (fusion or simplification)
-can be Associated with detachment of epithelial cells and protein leakage through defective GBM and filtration slits


Nephritic or nephrotic
MPGN Type II (dense deposit)
IgA nephropathy

type 1: mixed
type 2: hematuria, renal failure
IgA nephropathy: recurrent hematuria


FSGS involves what part of kidney

not just bowman's capsule but has a sclerosing pattern that extends deep into the glomerular tufts as well


FSGS types/classifications

-other known conditions/associations
-often a secondary glomerular event!!
-adaptive response to loss of renal mass
-uncommon inherited forms/mutations in genes that encode proteins localized to podocyte slit diaphragms
-can be associated with HIV
-Often a SECONDARY event in contrast to membranous and minimal change disease
-adaptive response to glomerular injury--leads to FSGS


Idiopathic FSGS epidemiology and clinical course

-idiopathic accounts for 35% of adults with NS--10% NS in children
-Primary FSGS most common overall cause of NS syndrome now in US adults ; greater incidence among Hispanics and African Americans
-5-10% of MCD in children that does NOT respond to steroid tx exhibit FSGS upon biopsy (but children overall have better prognosis than adults in this disorder)
-FSGS also occurs in other disease settings and is generally a Dx that implies poor prognosis, as progressive renal disease occurs over time
-20% of pts follow unusually rapid course with massive proteinuria and renal failure within 2 years


FSGS different from MCD and other podocytopathies how?

-higher incidence of hematuria, reduced GFR, and HTN
-Proteinuria is nonselective (large serum proteins equally part of exhibited proteinuria, as well as smaller proteins, i.e. albumin)
-Poor response to steroids
-significant progression to CKD with at least 50% developing ESRD within 10 years


FSGS HIV associated Nephropathy

-HIV can directly and indirectly cause renal disease including acute renal failure and/or acute interstitial nephritis
-collapsing variant of FSGS
-occurs in 5-10% of pts, more frequently in African americans and caucasians