Glomerular Disease Flashcards
Causes of Glomerular damage
-Immunological injury
-Inherited diseases such as Alport syndrome
-Metabolic diseases such as diabetes mellitus
-Deposition of abnormal proteins such as amyloid in the glomeruli
Target cell types in various insults
-Circulating immune complexes
=Cryoglobulinemia
=Serum sickness
=Endocarditis
-Endothelium
=Small vessel vasculitis (ANCA)
-GBM
=Goodpasture’s disease (anti-GBM antibody)
-Mesangium
=IgA nephropathy (IgA)
-Podocyte
=Membranous nephropathy (anti-phospholipase A2 receptor 1)
-Planted antigens
=SLE (ANA, dsDNA)
=Post-infectious glomerulonephritis
Poor prognostic indicators in glomerular disease
-Male sex
-Hypertension
-Persistent and severe proteinuria
-Elevated creatinine at time of presentation
-Rapid rate of decline in renal function
-Tubulo-interstitial fibrosis observed on renal biopsy
Terminology used in light microscopy in glomerulonephritis
- Focal : affecting some but not all glomeruli
- Diffuse : affecting >50% of glomeruli
- Segmental : affecting a portion of a glomerulus
- Global : affecting all of the glomerulus
- Necrotising : severe injury leading to an area of necrosis, usually associated with vasculitis
- Crescentic : a crescent-shaped area of inflammatory cells responding to severe glomerular injury
Terminology used in electron microscopy in glomerulonephritis
- Subendothelial immune deposits : found between the endothelial cell and the GBM – often found in nephritic presentations
- Intramembranous immune deposits : found within the GBM – found in the dense deposit variant of mesangiocapillary glomerulonephritis
- Subepithelial immune deposits : found between the epithelial cell and the GBM – often found in nephrotic presentations, including membranous presentation of lupus
What is nephrotic syndrome?
-Nephrotic syndrome is not a diagnosis, but a pattern of presentation
-Injury is focused on the podocyte and there is little histological evidence of inflammation or cell proliferation in the glomerulus
=Minimal change and primary focal segmental glomerulosclerosis (FSGS) typically present with fulminant nephrotic syndrome, whereas in membranous nephropathy and secondary FSGS, the nephrosis tends to be more indolent.
-Other causes of nephrotic syndrome due to systemic disease are discussed elsewhere, including diabetic nephropathy and amyloid
Describe glomerulonephritis
-If there is blood as well as protein, then a glomerulonephritis may be present.
-Hypertension is usually present and the renal function may deteriorate, often quite rapidly (rapidly progressive glomerulonephritis or RPGN).
-Glomerulonephritis may be due to primary renal diseases such as IgA nephropathy or anti-glomerular basement membrane disease, but is also observed with systemic diseases such as vasculitis or lupus or during or following infections.
Overview of nephrotic syndrome
-Presentation: If there is very heavy proteinuria, with little or no blood, this is a nephrotic presentation. Heavy proteinuria (3g/24hr) leads to low serum albumin (hypoalbuminaemia (<30g/L)) and the loss of oncotic pressure results in oedema, but the renal function often remain normal
-Complications; increased risk of VTE (loss of antithrombin 3 and plasminogen in urine)- renal vein thrombosis and DVT, PE/ hyperlipidaemia (acute coronary syndrome, stroke), CKD, Infection (urinary immunoglobulin loss), hypocalcaemia (vitamin D and binding protein lost in urine)
Overview of minimal change disease
-Can occur at all ages but accounts for most cases of nephrotic syndrome in children (75%) and 25% adult
-Reversible dysfunction of podocytes
-P: acute and severe nephrotic, associated with atopy, NSAIDs, rifampicin, IM, haematological malignancies (Hodgkin’s lymphoma, thyoma), infectious mononucleosis (most idiopathic), normotension, highly selective proteinuria (only intermediate proteins such as albumin and transferrin leak)
-I: light microscopy (normal glomeruli)< electron (fusion of podocytes and effacement of foot processes)
M: High-dose glucocorticoid therapy (1 mg/kg prednisolone for 6 weeks)- poor response older, cyclophosphamide if resistance
=Some patients who respond incompletely (glucocorticoid-resistant) or relapse frequently need maintenance glucocorticoids (glucocorticoid dependence) or additional agents such as cytotoxics or calcineurin inhibitors.
=Glucocorticoid resistance in children warrants a biopsy to exclude an alternative diagnosis, but if minimal change is confirmed, a genetic cause should be considered.
-C: Minimal change disease typically does not progress to CKD but can present with problems related to the nephrotic syndrome and complications of treatment.
Overview of Focal segmental glomerulosclerosis
-Can occur all ages, maybe due to undiscovered circulating factor
-West African descent, APOL1 gene variants
-Can be secondary to HIV, morbid obesity, chronic hypertension, scarring from HUS, cholesterol embolism, vasculitis, heroin, Alport’s, sickle-cell, other renal pathology
-P: abrupt onset severe nephrotic syndrome
-I: sclerosis initially limited to segments of the glomeruli, which may also show positive staining for deposits of C3 and IgM on immunofluorescence
=abnormal glomeruli may not be detected on renal biopsy if only a few are sampled, leading to an initial diagnosis of minimal change nephropathy. focal and segmental sclerosis and hyalinosis on light microscopy, effacement of foot processes on electron microscopy
-Secondary more modest proteinuria
-M: high-dose glucocorticoid therapy (0.5–2.0 mg/kg/day) but the response is rarely as rapid as in minimal change disease, immunosuppressants. secondary FSGS is focused on treating the underlying cause and reducing proteinuria by inhibiting the renin–angiotensin system
-C: Progression to CKD is common in patients who do not respond to glucocorticoids and the disease frequently recurs after renal transplantation.
Overview of membranous nephropathy
-Most common cause of nephrotic syndrome/glomerulonephritis in European descent
-Autoantibodies targeting podocytes (Phospholipase receptor)
-Associated with heavy metal poisoning, drugs (gold, penicillamine, NSAIDs), infections (hep B, malaria, syphilis), lupus, tumours (prostate, lung, lymphoma, leukaemia), thyroiditis, rheumatoid
P: nephrotic syndrome, proteinuria
I: thickening of basement membrane on light microscopy, granular sub epithelial IgG. sub epithelial electron dense deposits. This creates a ‘spike and dome’ appearance. Anti-phospholipase A2 antibodies.
M: tight BP control, immunosuppression, steroids with either cyclophosphamide or rituximab when severe/ deteriorating renal function, anticoagulation for high-risk patients.
C: 33% idiopathic spontaneous remission, 33% remain nephrotic, 33% progressive CKD
Overview of IgA nephropathy
-Most common type worldwide, liver (alcoholic cirrhosis) and coeliac disease, Henoch-Schonlein purpura.
P: non-visible haematuria, hypertension, detected at routine screening, proteinuria later feature
=in young adults acute self-limiting exacerbations, often with visible haematuria, in association with minor respiratory infections.
=This may be so acute as to resemble acute post-infectious glomerulonephritis, with fluid retention, hypertension and oliguria with dark or red urine.
=Characteristically, the latency from clinical infection to nephritis is short, in contrast to post-infectious glomerulonephritis, which typically occurs after the infection has resolved.
=Asymptomatic presentations dominate in older adults, with non-visible haematuria, hypertension and reduced GFR
I:Occasionally, IgA nephropathy progresses rapidly in association with crescent formation on biopsy
M:control of blood pressure, with renin–angiotensin system inhibitors preferable in those with proteinuria. There is some evidence for additional benefit from several months of high-dose glucocorticoid treatment in those at high risk of progressive disease
C:Slowly progressive loss of renal function leading to end-stage renal disease (ESRD), though in others, renal function is persistently normal
vs post-streptococcal glomerulonephritis:
=1-2 days after URTI vs 1-2 weeks
=Young males
=Macroscopic haematuria vs proteinuria
=Post has low complement
Overview of mesangiocapillary/ membranoproliferative glomerulonephritis
-2 subtypes: deposition of immunoglobulins within glomeruli (chronic infections, autoimmune)/ deposition of complement in glomeruli (inherited or acquired abnormalities in complement pathway- dense deposit disease)
-P: proteinuria and haematuria
-I: renal biopsy: increase in mesangial cellularity with thickening of glomerular capillary walls
=Type 1: electron microscopy: subendothelial and mesangium immune deposits of electron-dense material resulting in a ‘tram-track’ appearance
=Type 2: low circulating levels of C3, C3b nephritic factor is found in 70%, renal biopsy: electron microscopy: intramembranous immune complex deposits with ‘dense deposits’
-M: immunoglobulin deposits consists of the identification and treatment of the underlying disease, if possible, and the use of immunosuppressive drugs such as mycophenolate mofetil or cyclophosphamide.
=There are few specific treatments for MCGN associated with complement dysregulation, although eculizumab, the anti-C5 inhibitor that prevents formation of the membrane attack complex, has shown promise.
Overview of Anti-GBM disease (Goodpasture’s syndrome)
-Rare autoimmune disease in which antibodies develop against the α3 chain of type 4 collagen in the GBM. Goodpasture’s= small vessel vasculitis
-Expression of the α3 chain is largely restricted to the basement membranes of glomeruli and lungs
-Goodpasture’s disease is more common in younger patients, while older adult patients often present with renal-limited disease. More common in men (sex ratio 2:1) and has a bimodal age distribution (peaks in 20-30 and 60-70 age bracket). It is associated with HLA DR2.
-P: rapidly progressive glomerulonephritis (rapid onset AKI, proteinuria, haematuria), lung haemorrhage, or disease of both organs, when it is known as Goodpasture’s disease.
-I: renal biopsy: linear IgG deposits along the basement membrane. Raised transfer factor secondary to pulmonary haemorrhages
-M: plasma exchange combined with glucocorticoids and immunosuppressants (cyclophosphamide), but early diagnosis is essential, as renal function is rarely recoverable in those requiring dialysis at presentation.
The combination of glomerulonephritis and pulmonary haemorrhage may also be observed with small-vessel vasculitis (particularly granulomatosis with polyangiitis, previously known as Wegener’s granulomatosis) and lupus.
Overview of post-infectious glomerulonephritis
-Most common in children or young adults 10 days after streptococcal throat infection or longer after skin infection. It is caused by immune complex (IgG, IgM and C3) deposition in the glomeruli
-P: mild abnormalities on urinalysis to severe AKI, severe sodium and fluid retention, hypertension, haematuria, oliguria. Headache, malaise.
-I: anti-streptolysin (ASO) test is positive in up to 95% of patients with streptococcal throat infections. Low C3. Biopsy: acute, diffuse proliferative glomerulonephritis, endothelial proliferation with neutrophils, sub epithelial humps by lumpy immune complexes, starry sky immunoflueresnce
-M: supportive, with control of blood pressure and fluid overload with salt restriction, diuretics and dialysis if required. Antibiotic therapy is rarely needed, as the renal disease occurs after the infection has subsided.
-C: recovery of renal function typical even in those requiring dialysis therapy. Some patients may develop CKD 20–30 years after the original presentation
