Glomerulonephritis Flashcards
Summary of GN and damage involved
- Nephrotic Disease: podocyte damage
- Nephritic Syndomre: sub-endothelium (GBM) damage
What are crescent lesions in GN?
- Extracapillary proliferation or crescentic lesions
are associated with accumulations of macrophages, fibroblasts, proliferating epithelial cells, and fibrin within
Bowman’s space; represent rupture of the glomerular membrane; and signify severe injury to the glomerular capillary wall. - Interstitial fibrosis, which accompanies uncontrolled
glomerular disease, is a poor prognostic sign.
Features of Nephrotic Syndrome
Protein > 3.5g/day
Oedema
Hypoalbuminemia
Hyperlipidaemia
Hypercoagulable state due to low levels of protein C and S (natural anticoagulants)
Increased risk of developing infections
4 common types include - primary glomerular pathology
- Minimal Change Disease
- Focal Segmental Glomerulosclerosis
- Membranous Glomerulonephritis
- Membranoproliferative GN (MPGN)/ Mesangiocapillary (MCGN) - most commonly nephritic but severe forms can be nephrotic
Systemic Diseases
- Diabetic Nephropathy (secondary nephrotic syndrome, also include: SLE, amyloidosis, Hep B and C, HIV)
- Amyloidosis
- Lupus nephritis (can manifest as nephrotic or nephritic)
Ix: ANA, anti-dsDNA, C3, C4
- Children: most common cause is minimal change
- Adults: most common are membranous glomerulopathy and FSGS are the most common
Membranous glomerulopathy is the most common cause in white persons and FSGS in black persons.
Diabetes is not only the most common secondary cause of the nephrotic syndrome but also the most common cause of the nephrotic syndrome in adults.
Different Glomerular Pathologies in Nephrotic Syndrome
Review of Different Glomerular Pathologies in Nephrotic Syndrome
1. MCD: Foot process effacement on EM (normal LM and IF)
- FSGS: LM shows sclerosis in parts (segmental) of some (focal) glomeruli with EM showing foot process effacement
- MN: Thickened GBM with no cellular proliferation; LM and EM show sub-EPITHELIAL deposits (spikes and domes with thickened GBM) and IF shows IgG
Thick GBM with sub-epithelial deposits causing spikes with NO mesangial or sub-endothelial deposits
- MESANGIUM characteristically normal and no sub-endothelial deposits - MCGN (MPGN): increased mesangial and endocapillary hypercellularity causing obliteration of capillaries and double contour/tram track appearance of glomerular capillary walls.
IF may show Ig or only complements depending on the type ( immune vs complement mediated MCGN
Minimal Change Disease
- Most common cause of nephrotic syndrome in children
- Cytokine mediated damage of podocytes - T cells release cytokines causing effacement of podocyte pedicles
PATHOGENESIS
- Primarily podocyte abnormality
- Activated T cells secrete increased IL-13
- IL-13 leads to CD80 expression on podocytes
- CD80 leads to decreased expression of nephrin
- Nephrin is the major negative protein on the filtration barrier
CLNICAL FEATURES
- HEAVY PROTEINURIA AND ACUTE, RAPID NEPHROTIC SYNROME
- Characterised by periorbital oedema, selective proteinuria (comprised primarily of albumin, loss of albumin but not immunoglobulin), hypalbuminaemia, hypercholesterolaemia, and a normal glomerular filtration rate.
- EM: effacement of podocytes, normal LM, IF
- Tx: Pred (normally respond well within 8-16 weeks)
- Low Na diet and diuretics, statins
- Relapse is common
- Other options: cyclophosphamide or calcineurin
inhibitors (tacrolimus or cyclosporine)
If fails: mycophenolate mofetil, and rituximab. Although uncommon, progressive kidney failure may occur.
Beware- relapses more common with cyclosporine and so needed long term continuation
Mostly unknown aetiology
Associations
- Drugs- NSAIDs, Interferon-alpha, antibiotics(ampicillin, rifampicin, cephalosporins),pamidronate, lithium
- Neoplasm- Hodgkin lymphoma and less commonly non-Hodgkin lymphoma and leukemia
- Allergy- atopy/asthma/eczema history in up to 30%
NOTE
- More acute presentation than other causes of nephrotic syndrome
- AKI in the setting of acute nephrotic syndrome in adults is seen most commonly in MCD ( 25- 35% cases)
Consider FSGS if REFRACTORY
Focal Segmental Glomerulosclerosis
· Most common cause of nephrotic syndrome in adults, especially in African American and Hispanic populations
· Clinically: Patients typically present with non-selective proteinuria, often hypertensive, decreased GFR +/- microscopic haematuria
- Defined as sclerosis in parts (segmental) of some (focal) glomeruli
- The non sclerotic glomeruli in FSGS show foot process effacement
- Juxtamedullary nephrons involved first
PRIMARY
- > 80% are primary (idiopathic) and 2/3 of primary FSGS most in this group have elevated plasma ‘soluble urokinase type plasminogen activator receptor’ (suPAR)
- suPAR leads to increase in alpha-v-b3 integrin activity which in turn leads to foot process effacement and proteinuria
- Increased serum levels of suPAR before renal transplantation associated with an increased risk of recurrent disease in the allograft
- FSGS recurs in approximately 30% of transplanted kidneys and may lead to graft loss
- Plasmapheresis after transplantation in recurrent FSGS leads to decreased suPAR and improvement in proteinuria
- Polymorphisms in the apolipoprotein L1 (APOL1) gene on chromosome 22 has association with FSGS in people of African origin
- APOL1 provides innate immunity against trypanosomiasis (parasitic infection, causing disturbed sleep)
SECONDARY FSGS
- Associated with diabetes, longstanding reflux, previous injury eg: nephritis, HIV, heroin use and sickle cell disease
- Hyperfiltration injury to the glomerulus: chronic hypertension, diabetes
- Kidney mass is reduced: progressive kidney
disease, obesity, sickle cell disease, reflux nephropathy, congenital small kidneys, and after nephrectomy).
- Direct podocyte injury: infections (HIV, parovirus B19)
and drugs (pamidronate, interferon, heroin).
- Usually presents with non-nephrotic proteinuria and renal insufficiency
- Nephrotic-range proteinuria with little or no hypoalbuminemia common in secondary FSGS
Renal Biopsy:
- Light Microscopy: Focal (some glomeruli) and segmental (involving only part of the glomerulus) sclerosis on H&E stain - sclerosis in parts (segmental) of some (focal) glomeruli
- Electron Microscopy: Effacement of podocyte foot processes
- Immunofluorescence: No immune complexes, negative IF. But deposition of IgM, C1 and C3 may be present in the mesangium or in the areas of segmental sclerosis.
TREATMENT:
- STEROIDS over 3 months
- Calcineurin Inhibitors (cyclosporin, tacrolimus)
For severely symptomatic, steroid non responsive patients
High rate of relapse on withdrawa, nephrotoxicity.
- Patients who enter remission (even partial) have a
good prognosis compared with patients who have refractory disease.
- HIGH RECURRENCE IN TRANSPLANT
- ACEi/ARB for proteinuria and reduce BP
- Primary FSGS: Upto 40 to 60% achieve complete or partial remission with prednisolone (not secondary FSGS though)
- Concerns with big dose of steroids or steroid dependent or steroid resistant disease: Calcineurin inhibitor (Tacrolimus or cyclosporine)
- Important to differentiate primary from secondary FSGS: > 80% foot process effacement in primary (lesser in secondary FSGS) with no obvious cause for
glomerular injury/ hyperfiltration /hypertension - FSGS relapse in transplant kidney: plasmapheresis if< 1 year post transplant/
cyclophosphamide if >1 year post transplant
Prognosis
20% have rapid course with massive proteinuria and ESKD within 2 years, 50% develop ESKD within 10 years, 25-50% recurrence after allografts
What genes are involved in MCD and FSGS?
CD80 overexpression on podocytes in MCD
SUPAR association in primary FSGS but not MCD - soluble urokinase Plasminogen Activating Receptor
What are the 5 subtypes of histological classification for FSGS?
- Classic or FSGS not otherwise specified (NOS): characterized by segmental areas of mesangial collapse and sclerosis in some but not all glomeruli
- Collapsing: can be induced by HIV infection. With >1 glomeruli with global or segmental collapse. Worst prognosis and progress more rapidly to ESRD.
- Tip: segmental lesion that occur at the “tip” of the glomerulus near the origin of the proximal tubule (behave like MCD-present acutely and respond to steroids)
- Cellular: presence of at least one glomerulus with segmental endocapillary hypercellularity that occludes the capillary lumen - hypercellularity of the capillary space
- Perihilar: Sclerosis of >50% glomeruli at glomerular vascular pole (common in secondary FSGS)
Best prognosis for the “tip” variant and worse for “collapsing”
Membranous Nephropathy
· Most common cause of nephrotic syndrome in Caucasian adults
· Accounts for approximately 30% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30 and 50 years and a male to female ratio of 2:1. Rare in childhood and most common cause of nephrotic syndrome in the elderly.
· Most patients present with heavy proteinuria.
CAUSES
○ Primary (idiopathic 2/3) - anti PLA2R antibodies positive
- Anti-PLA2 antibodies bind to PLA2R and form immune complexes that activate the complement system (C5-9) leading to podocyte injury
- Anti-PLA2R levels have a strong association with prognosis, marker of disease activity and response to treatment
- Thrombospondin type-1 domain-containing 7A (THSD7A) is the podocyte antigen in 10% cases of anti-PLA2R negative (so 3% of all primary MN) - associated with malignancy
○ Secondary (1/3) which is due to autoantibodies generated in response to:
- Infections: Hep B (commonest), Hep C, malaria, syphilis
- Autoimmune disease: SLE (MOST COMMON), RA
- Tumours: SOLID TUMOURS - lung cancer, prostate cancer, lymphoma
- Medications: NSAIDs, gold, anti TNF, penicillamine
- Approximately 10-20% of cases are secondary to systemic disease. In Australia, the most common causes of secondary membranous GN include drugs, SLE and neoplasms.
CLINICAL
- The clinical presentation of MG is indistinguishable
from other causes of the nephrotic syndrome
(edema, hypertension, microhematuria), but the propensity to thromboembolic events (particularly renal vein thrombosis) is much higher.
- Secondary causes should be sought, particularly
occult malignancy in older patients.
Characterised by immune complexes (IgG and C3) depositing in the GBM leading to diffuse thickening of glomerular capillary wall and a “spike and dome” appearance seen on electron microscopy leading to nephrotic syndrome.
- GBM thickening with no cellular proliferation or infiltration
- Immune deposits beneath podocytes (SUBEPITHELIAL)/No hypercellularity/No mesangial involvement
Subepithelial: between the podocytes (epithelial) and basement membrane.
RENAL BIOPSY
○ Light Microscopy: thick glomerular basement membrane on H&E
○ Electron Microscopy: Immune complex (IgG and C3) deposition in the GBM causes a “spike and dome appearance” and effacement of foot processes.
SUBEPITHELIAL DEPOSITS
○ Immunofluorescence: demonstrates diffuse granular deposits of IgG and C3 in the GBM, PLAR-2 ab
TREATMENT
- Poor response to steroids, progresses to chronic renal failure
- Secondary: treat underlying cause
- IN PRIMARY: ACEi/ARB for proteinuria/BP for 6 months, some will resolve spontaneously.
If fail to resolve and proteinuria still >4g/day or 50% baseline consider immunosuppression - steroids+ cyclo or CNI or rituximab
- Angiotensin inhibition and BP control, diuresis, lipid lowering, salt restriction
- Treatment of underlying disease in secondary MN
- Prophylactic anti-coagulation if serum albumin< 20g/L and 1 of the following (cease when albumin> 30g/L):
- Proteinuria>10g/d
- BMI >35kg/m2
- Prior or family history of thromboembolism
- NYHA class III or IV CCF
- Recent abdominal or orthopaedic surgery
- Prolonged immobilization
- Corticosteroids and cyclophosphamide most common
- CNI (cyclosporine or tacrolimus) if cyclophosphamide contraindicated
- Rituximab
- Low risk: No immunosuppression
- Medium risk:
If proteinuria < 4g/day after 6 months of conservative management then no
immunosuppression
If proteinuria >4 to 6g after 6 months then immunosuppression - High risk: Immunosuppression
Up to one third of patients with idiopathic membranous
glomerulopathy remit spontaneously in 6 to 12 months;
conservative management is appropriate during this
period.
Membranoproliferative (MPGN) or
Mesangiocapillary (MCGN)
- Characterised by increased mesangial and endocapillary cellularity (proliferative lesions) with thickened GBM leading to a double-contour appearance
Divided into 3 types based on location of deposits
TYPE 1: Immune complex mediated (IMMUNE complexes and COMPLEMENT deposits in SUBENDOTHELIUM + MESANGIUM)
- Activated CLASSICAL complement pathway
- Main causes: immune complex disease such as SLE, Hep C (can be associated with cryoglobulins), monoclonal gammopathy
- Low C3 and C4
- LM shows increased mesangial and endocapillary cellularity ( leading to less open capillaries visible) and thickened GBM (often tram track)
TYPE 2: Complement mediated - dense deposit disease ( COMPLEMENT deposits in basement membrane)
- Activated ALTERNATE complement pathway
- Low C3, normal C4
- Electron Microscopy: electron dense deposits within the lamina densa of the glomerular basement membrane.
- Immunofluorescence: reveals C3 in a granular pattern in the peripheral capillary loops with ring-like patterns in the mesangium.
- Nephritic Factor stabilises C3 convertase allowing conversion of C3 to C3a and C3b allowing deposition of ONLY COMPLEMENT in the basement membrane (compared to subendothelium like in type 1) causing inflammation in the GBM and low circulating C3.
- Complement mediated MPGN includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN); DDD and C3GN are rare diseases associated with uncontrolled activation of the alternative complement pathway.
- Dysproteinaemia – isolated complement in dense deposit disease [DDD]
- Dysproteinaemia – C3 glomerulonephritis [C3GN]
TYPE 3: IMMUNE complexes and COMPLEMENT deposits found SUBENDOTHELIAL and SUBEPITHELIAL
TYPE 1: Immune complex mediated MCGN: ‘ chronic antigenemia causing activated CLASSICAL complement pathway’
- Main causes: immune complex disease such as SLE, Hep C, monoclonal gammopathy
-Infections: HCV (often causing cryoglobulinemia), HBV, Infective endocarditis,
HIV, malaria, schistosomiasis
-Autoimmune disorders: SLE, Sjogren’s syndrome, Rheumatoid Arthritis
-Monoclonal Gammopathies: Myeloma, MGUS, MGRS
TYPE 2 Complement mediated: ‘complement dysregulation causing uncontrolled activation of the ALTERNATIVE complement pathway’
Complement deposits (no immune complexes)
-Associated with C3Nef (nephritic factor) which stabilises C3 convertases and allow C3 to be converted to C3a/b (with/without partial lipodystrophy/retinal defects)
-Inherited mutation of Factor H
-Monoclonal Gammopathies (commoner in adults)
- Complement mediated MPGN includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN); DDD and C3GN are rare diseases associated with uncontrolled activation of the alternative complement pathway.
TREATMENT
- Steroids (suppress immune system), immunosuppressants and antiplatelet drugs are not materially effective
- Poor response to steroids, all 3 types progresses to chronic renal failure
(Type 1) Immune Complex Mediated MPGN/MCGN
- Associated with chronic antigenemia and/or circulating immune complexes (chronic infections e.g.Hep C or B, autoimmune diseases and monoclonal gammopathies)
- Glomerular deposition of immune complexes leads to activation of classical pathway (normal or mildly LOW C3 and LOW C4 levels)
- LM shows increased mesangial and endocapillary cellularity (leading to less open capillaries visible) and thickened GBM (often tram track)
- EM typically shows subendothelial and mesangial deposits (occ. subepithelial)
- Co-existence of cryoglobulinemia common in Hep C and B associated MCGN
Tx:
- Supportive therapy as in all NS i.e. antiproteinuric and antihypertensive
- Identification and treatment of aetiology e.g. anti-HCV and no immunosuppression
- In case of severe cryoglobulinemia with HCV advised immunosuppression for 1 to 4 months with/without plasma exchange before starting anti-viral
- Idiopathic cases treated with prednisolone and cyclophosphamide or MMF
- Predictors of renal prognosis: Non-nephrotic proteinuria, normal BP, normal
creatinine, presence of crescents and severity of tubulointerstitial disease
(interstitial inflammation, fibrosis, and tubular atrophy) on biopsy
Type 2 (Complex Mediated MPGN)
- Pathogenesis involves excessive activation of alternative complement pathway(so LOW serum C3 but NORMAL C2 and C4)
- May involve antibodies to C3 convertase (called C3 nephritic factor) that stabilize the C3 convertase by
preventing its degradation by factor H or loss of function of the C3 convertase inhibitory factor H (rarely
deficiency of serum factors I or MCP) - Commoner in children and young adults (1 in 4 of young patients have complement factor gene variants)
- EM (similar to IF mediated MCGN): subendothelial and mesangial electron-dense deposits(occ. subepithelial
deposits) - Dense deposit disease (DDD)reflects dense linear-appearing electron-dense material in the GBM (on EM)
- Some with DDD have partial lipodystrophy or visual defects (drusen bodies- mottled retinal pigmentation)
- C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States
cohort of patients with C3 glomerulopathy
TREATMENT
- Give usual nephrotic syndrome therapy i.e. antiproteinuric and antihypertensive agents
- No major RCTs done as relatively rare disease
- For C3 nephritic factor disease:7-10 plasma exchanges followed by immunosuppression with corticosteroids and mycophenolate or rituximab
- For Factor H deficiency- plasma infusion every 2-3 weekly
- Solitary therapy with corticosteroids not advised
- Prognosis usually not very good ( Upto 40% progress)
- Limited experience with transplant; relapse rates quite high especially in DDD
Compare type I and II MPGN
Type I MPGN: cryoglobulinaemia, hep C
- Most frequent type of primary MPGN
- Most commonly presents with nephrotic syndrome
- Is often associated with systemic disease, infection and neoplasms.
- MPGN with cyroglobulinaemia is strongly associated with Hep C virus infection.
- Type I MPGN is a slowly progressive disease; in 30-40% of patients, the disease remains stable despite nephrotic range proteinuria. Median period free of renal failure in both children and adults ranges from 9-12 years.
Type II MPGN: partial lipodystrophy
- Most commonly presents with nephritic syndrome or recurrent macroscopic haematuria.
- Most patients are younger than 20 years of age and have more persistent C3 depression than those with Type I MPGN.
- Approximately 20% of patients remain stable for many years and median period free of renal failure ranges from 5-10 years.
Features of C3 Nephropathy
- Characterised by the presence of dominant C3 deposits in the glomeruli with minimal or no Ig deposits on immunofluorescence or immunohistochemistry
- Further characterized as C3GN or Dense Deposit Disease (DDD)on the basis of EM findings
- Occurs due to dysregulation and persistent activation of the ALTERNATIVE complement pathway
C3 convertase activity increased by
- Generation of C3 convertase stabilizing autoabs called C3 nephritic factors
- Loss of functional Factor H activity –mutations or acquired defects of Factor H
- C3 mutation that renders activated C3 resistant to factor H inhibition(DDD)
- C3 mutation leading to functional factor H deficiency (C3GN)
- Activity of the terminal complement pathway is increased by a C5convertase stabilizing autoab called C5 nephritic factor
- Enzymatic cleavage of C3 by renin
In which conditions is low C3 seen?
low C3 levels are seen in:
· Post-streptococcal GN
· Lupus nephritis
· Membranoproliferative GN
What are inhibitors of the alternative complement pathway
Inhibitors of alternative pathway:
Factors H and co-factor Factor I
Soluble urokinase plasminogen activator receptor (SUPAR) is associated with –
a. Focal Segmental Glomerulosclerosis (FSGS)
b. Membranous nephropathy (MN)
c. Minimal change disease (MCD)
d. Amyloidosis
e. IgA nephropathy
a. Focal Segmental Glomerulosclerosis (FSGS)
The best marker of increased susceptibility to thromboembolism in a patient with active NS is –
a. Serum Creatinine
b. Hypertension
c. Degree of proteinuria
d. Leg swelling
e. Serum albumin concentration
e. Serum albumin concentration
Soluble urokinase plasminogen activator receptor (SUPAR) is associated with –
a. Focal Segmental Glomerulosclerosis (FSGS)
b. Membranous nephropathy (MN)
c. Minimal change disease (MCD)
d. Amyloidosis
e. IgA nephropathy
a. Focal Segmental Glomerulosclerosis (FSGS)
Membranous nephropathy is characterised by –
a. Intramembranous immune deposit
b. Sub endothelial immune deposit
c. Mesangial hyper-cellularity
d. Foot process effacement of epithelial cells
e. Sub epithelial immune deposit
e. Sub epithelial immune deposit
Compare Dense Deposit Disease and C3 Glomerulonephritis
DENSE DEPOSIT DISEASE
Affects
- Children
- Young adults
- Older adults (associated with monoclonal gammopathies)
- Associated with lipodystrophy and drusen spots in the retina.
- Majority of pts antibodies (C3 nephritic factors –C3Nefs) that stabilise C3 convertase are present in circulation
- LM –MPGN or mesangial proliferative, diffuse proliferative, crescentic glomerulonephritis, and a sclerosing glomerulopathy
- IF –C3 deposits
- EM –characteristic sausage-shaped, waxy, densely osmophilic deposits along the GBM and mesangium
- Fundoscopy –“Drusen” seen
C3 GLOMERULONEPHRITIS
- Excessive activation of the alternative complement cascade
- Mutations in or antibodies to complement regulating proteins
- LM –MPGN or mesangial proliferative, diffuse proliferative,crescentic glomerulonephritis, and a sclerosing glomerulopathy
- IF –C3 deposition along capillary walls and mesangiumwith no Igdeposition
- EM: deposits similar to those seen with IC mediated GN
- Does not show the typical sausage shaped intramembranous and mesangial deposits in DDD
Presentation
- Proteinuria, NS, haematuria, variable HTN and renal impairment
- C3 levels low, C4 levels normal
- Some pts present post nonstrep URTI with GN
The M-type phospholipase A2 receptor (PLA2R) is identified as the major antigen leading to –
a. Primary FSGS
b. Idiopathic MN
c. MCD
d. Good Pasteure syndrome
e. IgA nephropathy
b. Idiopathic MN
The commonest glomerular disease leading to nephrotic syndrome in Caucasian adults over the age of fifty is –
a. FSGS
b. Menbranoproliferative nephropathy
c. IgA nephropathy
d. Mesangiocapillary disease
e. Membranous nephropathy
e. Membranous nephropathy
Solid organ malignancy is most commonly associated with
a. Membranous nephropathy
b. FSGS
c. MCD
d. Mesangiocapillary GN
e. Wegners granulomatosis
a. Membranous nephropathy
Thrombospondin type-1 domain-containing 7A (THSD7A) antibody is found positive in –
a. Idiopathic FSGS
b. Secondary membranous nephropathy
c. Primary nephropathy which is anti PLA2R antibody negative
d. HSP
e. Mesangiocapillary disease
c. Primary nephropathy which is anti PLA2R antibody negative
Pathology of diabetic nephropathy and treatment
- In the glomerulus, there is expansion of
the mesangium and thickening of the basement membrane,
followed by focal (nodular) sclerosis (the Kimmelstiel-Wilson
lesion) then global sclerosis of the glomerulus. Interstitial
fibrosis, tubular atrophy with thickened tubular basement
membranes, and arteriolosclerosis are also seen.
Tx:
- Achieving targets of glycemic control (hemoglobin A1 e
<7%) and blood pressure (<140/90 mm Hg) has been
shown to prevent or delay progression of diabetic
nephropathy.
- ACE inhibitors or angiotensin receptor blockers have
been shown to slow progression of diabetic nephropathy.
What are the stages of diabetic nephropathy?
Stage 1: hyperfiltration (increase in GFR), may be reversible
Stage 2 (silent or latent phase): most patients do not develop microalbuminuria for 10 years, GFR remains elevated
Stage 3: microalbuminuria (albumin excretion 30-300mg/day, dipstick negative)
Stage 4 (overt nephropathy): persistent proteinuria (albumin excretion >300mg/day, dipstick positive), HTN present, histology shows glomerulosclerosis and focal glomerulosclerosis (Kimmelstiel-wilson nodules)
Stage 5: end stage renal disease GFR< 10ml/min
Nephritic Syndrome
Damage to the GBM Glomerular inflammation causing - hematuria with dysmorphic RBCs/RBC casts - reduced GFR, non-nephrotic proteinuria - edema - hypertension
Characterised by:
- Hypertension:
- Oliguria: decreased filtration area
- Haematuria (coca-cola urine)
- Mild-Moderate Proteinuria (<3.5g/24 hours): disruption of GBM
- Azotaemia: due to decreased GFR
- RBC casts and dysmorphic RBCs in urine
• GN may be smouldering and slowly progressive or rapidly progressive (days, weeks or months) and associated with extensive crescent formation
i.e. rapidly progressive glomerulonephritis (RPGN)
NOTE:
- Microscopic hematuria is >2 RBCs per high power field in spun urine
- Dysmorphic RBCs >5% of total urinary RBCs to diagnose nephritis/GN
Types:
- Post-Infectious Glomerulonephritis
- IgA Nephropathy
- Membranoproliferative GN
- Rapidly Progressive Glomerulonephritis/Crescentic Glomerulonephritis
- Three pathophysiologic mechanisms are associated with the nephritic syndrome: anti-GBM antibodies, pauci-immune GN (defined by necrotizing GN with few or no immune deposits), and immune complex deposition.
- Three different clinical syndromes may result from these mechanisms based on their time course: acute GN, rapidly progressive GN (RPGN), or chronic GN.
- Serum complement levels may be useful in differentiating
the underlying etiology of GN; levels are typically normal in
anti-GBM antibody disease and pauci-immune GN but are low in immune complex GN (with the exception oflgA nephropathy). - Additionally, crescentic lesions on pathologic examination of the kidney in a patient with the nephritic syndrome are associated with RPGN and a poor prognosis without treatment.
Classification of glomerulonephritis/nephritic syndrome
Three pathophysiologic mechanisms are associated with nephritic syndrome
A. Immune complex deposition
B. Pauci-immune GN (defined by necrotizing GN with few or no immune deposits), C
C. Anti-GBM antibodies
(A) Coarse Granular Glomerular Deposits
(1) Low Complements
- Infectious GN
- Lupus GN
- Cryoglobulinemia
- MPGN/MCGN
(2) Normal Complement
- IgA nephropathy
- HSP
(B) Pauci Immune Glomeruli (no findings on IF)
ANCA positive vasculitis: granulomatosis with polangiitis (cANCA), microscopic polyangiitis (pANCA), eosinophilic granulomatosis with polyangiitis (pANCA)
(C) Linear glomerular deposits
Anti-GBM antibody positive - good pasture syndrome
Other one causing renal GN would be SLE
Post Strep GN
- Post Infectious Glomerulonephritis
- Usually affects children 3-12 years of age and elderly patients
- Occurs weeks after group A beta-hemolytic streptococcal infections
§ 1-2 weeks after pharyngitis/tonsillitis
§ 3-4 weeks after skin infections
§ Presents with haematuria, oliguria, hypertension and periorbital oedema
- Other causes include:
○ Viral (HBV, HCV, HIV, mumps, varicella, EBV)
○ Parasitic (malaria, toxoplasmosis)
It involves a type-3 hypersensitivity reaction where immune complexes (IgG, IgM) are deposited in the glomerular basement membrane, resulting in proliferation of glomerular cells, infiltration of leucocytes, particularly neutrophils, and inflammation (activation and deposition of C3 complement, inflammatory cytokines, oxidants and protease).
Risk Factors ○ Male ○ Immunocompromised ○ Alcoholism ○ Malignancy ○ Severe malnutrition ○ Synthetic heart valve, IVDU, AIDs, TB
Diagnostics
Anti-Streptolysin O Titre (ASOT) or Streptozyme Test:
- 95% positive in pharyngitis, 80% with skin infections
- Antibodies Against Group A Strep: Anti-DNAse
- ↓ Serum C3 levels (due to consumption)
Renal Biopsy
-Light Microscopy: glomeruli appear enlarged and hypercellular
-Electron Microscopy: dome shaped, SUBEPITHELIAL immune complex deposits (humps)
- Immunofluorescence:
Granular subepithelial immune complex depositions (IgG, IgM, C3) along the GBM and mesangium
So called “lumpy bumpy” or “starry sky” appearance
Treatment
- It is usually self-limiting and complement levels return to normal within 6 weeks. In most patients, haematuria disappears after 6 months but proteinuria may persist for 2 years in 1/3 of patients.
- Usually supportive
Complications:
- Children rarely (1%) progress to renal failure
- 25% Adults: develop rapidly progressive glomerulonephritis which can lead to renal failure
