Glomerular disease

Dr Chak
 Introduction
- clinically as acute glomerulonephritis (GN) , nephrotic syndrome , or
asymptomatic proteinuria and /or hematuria
- primary glomerular disease vs secondary glomerular disease
-
Clinical presentation and laborary evaluation
-Nephritic urinary sediment : hematuria, red+/- white blood cells and
granular casts ,HTA + edema,some degree of renal dysfunction
- when presentation is severe with acute kidney injury (AKI) often with
oliguria , the clinical syndrome is called rapidly progressive
glomerulonephritis ( RPGN ) and requires immediate hospitalization
- second major presentation of glomerular disease – nephrotic
syndrome , marked proteinuria > 3.5 g/day with pitting edema of the
lower extremities ,hypoalbuminemia , hyperlipidemia and fatty casts in
the urine.
Clinical presentation and laborary evaluation
- most common cause is diabetic nephropathy
- some subjects with glomerular disease may manifest asymptomatic
micro or macroscopic hematuria , esp those with immunoglobulin ( Ig )
- the spectrum of disease – with low grade proteinuria is wide and can
include glomerular ( membranous nephropathy, alport syndrome ) ,
tubular ( chronic tubulointerstitial disease ) or other ( eg monoclonal
gammopathies ) causes
GN RBC , RBC casts, proteinuria , HTA, renal PIGN, staphylococcus aureus,
dysfunction staphylococcus epidermidis, abscess,
endocarditis , osteomyelitis ,Ig A
nephropathy, lupus

Rapidly progressive GN Presents as GN with AKI ( oliguria, rising
serum creatinine )
Nephrotic syndrome Proteinuria > 3.5 g/day ,edema, high
serum cholesterol , low serum albumin ,
urine lipids
Asymptomatic proteinuria Proteinuria < 2 g/day +/- CKD
Asymptomatic hematuria Urinary RBCs > 2 / high power field ( spun
sediment )
Antiglomerular basement membrane
glomerulonephritis ( kidney alone ) or
disease ( kidney + lung involvement –
goodpasture sd
ANCA associated vasculaitis ( microscopic
polyangiitis , granulomatosis with
polyangiitis , eosinophilic granulomatosis
with polyangiitis )
Immune complex –associated IgA/IgA
vasculitis, mixed cryoglobulinemia , SLE ,
PIGN )
Minimal change disease, Focal segmental
glomerulosclerosis , MN , MPGN , diabetic
nephropathy , amyloid Fbrillary GN
Ig A nephropathy , MN ,MPGN , MGRS,
alport syndrome, tubulointerstitial disease
Low grade glomerular disease ( igA
nephropathy , thin basement membrane
disease , alport syndrome )
Clinical presentation and laborary evaluation
+ Specific serologie tests for secondary causes :
 For nephrotc syndrome : HIV ( focal segmental glomerulosclerosis )
HBV-membranous , HCV –antibody ( membranous , MPGN, and
cryoglobulinemia ) ,c3 and c4 low level suggest MPGN and/or
cryoglobulinemia or types V or III or IV + V lupus )
- marked proteinuria with hyaline casts and sediment minimal numbers
of red cells and leukocytes suggests nephrotic syndrome, whereas a
sediment with red cells +/- white cells ,and red +/- white cells casts
suggest acute GN often secondary to lupus nephritis or PIGN.
 Glomerulonephritis and rapidly progessive
glomerulonephritis
A/. Postinfectious glomerulonephritis :
- children 5 to10 years, streptococcal infection , most commonly in
children
- 2 weeks following throat infection or 3 weeks
- nephritic urinary sediment
- due to immune reaction to certain streptococcal antigens
-low serum C3 levels
Biopsy : glomerular hypercellularity due to both an infiltration of leukocyte
and proliferation of endothelial and mesangial cells in IF while electron
micro – subepithelial deposits or humps alone the capillary loops
 Glomerulonephritis and rapidly progessive
glomerulonephritis
A/. Postinfectious glomerulonephritis :
- there may be an Ig A dominant infection related GN usually with
bacterimia with methicillin resistant of sensitive S aureus,E coli ,S
epidermidis and Klebsiella in patients with comorbidities such as diabetes
B/. Immunoglobulin A nephropathy :
- elevated galactose deficient O glycan Ig A 1  immune complex of
antiglycan autoantibodies and galactose deficient Ig A I and anti O glycan
- classic presentation observed 10 to 15 % of the recently with upper
respiratory tract infection
 Glomerulonephritis and rapidly progessive
glomerulonephritis
B/. Immunoglobulin A nephropathy :
- renal histology demonstrates a mild to moderate mesangial cell
proliferation with extracellular matrix expansion
- Ig A deposit in mesangium coexistent Ig G and C3 as demonstrated by IF
microscopy. Electron micro—mesangial immune deposits
- histology using Oxfort MEST-C
- 20 years –end stage kidney
- extreme caution with corticosteroid  in those with eGFR < 30 ml
/min/1.73 m2, diabete, obesity ,active peptic ulceration , uncontrolled
psychiatric illness , secondary disease ,and latent infections.
 Glomerulonephritis and rapidly progessive
glomerulonephritis
B/. Immunoglobulin A nephropathy :
- patients with Ig A nephropathy who present with sd of RPGN( > 50% decine in
eGFR in < 3 months ) and have cresentic nephritis on kidney biopsy  treated
aggressively with high dose corticosteroid and cyclophosphamide
C/. Rapidly progessive glomerulonephritis :
- clinically as AKI in setting of nephritic urianry sediment ( red cell +/- white cell
casts, proteinuria , microscopic hematuria )
-kidney biopsy : reveals a cresentic GN.
- presence of IgG in linear pattern along glomerular basement membrane (GBM)
defines anti GBM GN when confined to kidney or anti-GBM disease ( goodpasture
syndrome ) when thereis lung involvement.
 Glomerulonephritis and rapidly progessive
glomerulonephritis
C/. Rapidly progessive glomerulonephritis :
- granular pattern on capilalry wall suggests an immune complex-
associated disease such as lupus nephritis ,Ig A nephropathy or PIGN
-absence of immune deposits is observed with ANCA associated
vasculitis ( microscopic polyangiitis , granulomatosis with
polyangiitis ,eosinophilic granulomatosis with polyangiitis ) known as
pauci immune GN
 Glomerulonephritis and rapidly progessive
glomerulonephritis
C/. Rapidly progessive glomerulonephritis :
-anti GBM disease or good pasture disease vs goodpasture syndrome –pulmonary
hemorrhage and nephritis ; classically patient present with hemoptysis following
an upper respiratory infection and nephritic urinary sediment
- antibody has been shown directed against the alpha 3 chain of type IV
collagen ,which present in the glomerular and alveolar basement membranes.
- treatment include ( anti GBM ) or syndrome includes high dose IV steroids ( eg
methylprednisolone 500 to 1k mg dialy x 3 days follow a course of prednisone for
6 months and cyclophosphamide for 3 months
- plamaparesis conduted daily until anti GBM antibody titer is no longer
detectable
 Glomerulonephritis and rapidly progessive
glomerulonephritis
C/. Rapidly progessive glomerulonephritis :
- RPGN from crescentic Ig A nephropathy induction therapy involves
methlyprednisolone 500 to 1k mg IV x 3 days followed by oral steroids
with oral or IV cyclophosphamide followed by azathioprine to reduce
the potential toxicity occur with long term cyclophosphamide including
infertility, bladder cancer and leukemia
 Nephrotic syndrome
A. Minimal change disease :
- also call nil disease or lipoid nephrosis - most common in children age of 2 and
12 years , 20 % adults
- precipitated by viral infection , allergy, bee sting or immunization
- in adult with hodgkin lymphoma or other T cell malignancies
- minimal change disease alone or with interstitial nephritis and AKI reported
with nonsteroidal anti iflammatory drugs
- clinical finding : pitting edema ,weight gain ,presence of normal blood
pressure.
- urinary sediment –show hyaline casts and oval fat bodies, while red cells are
usually absent.
 Nephrotic syndrome
A. Minimal change disease :
- biopsy no show in IF , but show in electroscopy – diffuse fusion or effacement of the
foot processes of glomerular visceral epithelial cells.
Treatment : oral corticosteroid ( prednisone 1 mg/kg/day ) , more than 90% of
children MCD experience a complete remission within 4 to 8 weeks
-relapse 3 or more times within a year – 8 to 12 weeks of oral cyclophosphamide
thearapy
- in adults : logner daily or alternate day adminsitration of prednisone starting at 2
mg/kg every other day 70-80% responsding by 12 weeks of therapy – relpasing –
repsond to cyclophosphamide
- steroid sparing agents such as mycophenolate mofetil , calcineurin inhibitors and
rituximab used in frequently relapsing disease with success.
 Nephrotic syndrome
B.Focal segmental glomerulosclerosis
- most common cause of nephrotic syndrome in young adults
20-30% of all cases in many series
- priamry glomerular disease cause end stage kidney diseae in US
-FSGS primary,secondary,genetic and unknown forms – feature of
nephrotic syndrome and microscopic hematuria 50%
-IgM and C3 deposits are often present in sclerotic segments of the
glomeruli
 Nephrotic syndrome
B.Focal segmental glomerulosclerosis
- treatment : prednisone average dose 1 mg/kg body weight /day.
Prolong treatment of 5 to 8 months is often required , partial remission
with a urine protein excretion < 2g/ day or complete remission
observed is only 50% of patients
- favorable prognosis indicators incude absence of tubulointerstitial
disease kidney biopsy
 Nephrotic syndrome
C. Membranous nephropathy :
- most common cause of nephrotic syndrome in middle aged adults
- primary MN caused by autoantibodies againt the podocyte M type
phospholipase A 2 receptor 1 ( PLA2R ) 80% of cases and thrombospondin type
1 domain –containing 7A (THSD7A) 5-10%
-microhematuria ,nephrotic range proteinuria
-thepeak age incidence 40 to 60 years
-secondary MN  certain medications ( penicillamine, captopril , or
nonsteroidal aents ) with certain viral infections ( chronic hepatitis B and c viral
infection ) and with maglignancy ( lung,breast , gastrointestinal origin or others
)
 Nephrotic syndrome
C. Membranous nephropathy :
- SLE may develop MN ( class V lupus glomerular disease )
- kidney biopsy : GBM on light microscopy thickening, silver
methenamine –> spike like protrusions on epithelial side of the GBM
represent extensions of basement mebmraine –like material , IgG and C
3 alone the capillary wall in granular pattern , electron microscopy
reveals immune deposits outer side of GBM under epithelial foot
processes .
- PLAR2 and THSD7A
 Nephrotic syndrome
C. Membranous nephropathy :
- if antibody absent or low – secondary causes of MN can be
investigated by checking for hepatitis viruses ,antinuclear antibodies
and thyroid antibodies and age appropriate malignancy screening
( mammogram ,chest x ray,stool guaiac and colonoscopy and prostate
specific antigen )
- treatment use of the so called ponticelli regimen –IV
methylprednisolone for 3 days followed by oral prednisone on months
1,3,and 5 and oral cyclophosphamide ( 2 to 2.5 mg/kg/day) on months
2,4 and 6 )
 Nephrotic syndrome
D. Membranoproliferative glomerulonephritis
- with hematuria , variable proteinuria with some having nephrotic
syndrome normale or elevated serum creatinine .
- on kidney biospy- glomeruli hypercellular and lobular in appearance
due to increased matrix with both mesangial and endothelial cell
celllularity – immune complex mediated MPGN caused by complement
activation via the classical pathway , patient may have normal / mildly
decreased C3 and low C4 levels , MPGN –commonly with hepatitis C ,
other infections such as endocarditis , infected shunts,abscesses and
parasitic infections can cause immune complex MPGN .
 Nephrotic syndrome
D. Membranoproliferative glomerulonephritis
- other infections such as endocarditis, infected shunts, abscesses and
parasitic inectiosn can cause imune coplex MPGN
-MPGN due to monoclonal gammaopathy may show either kappa or
lambda light chains on IF or no staning.
-thick ribbon-like deposits are seen along the basement membranes of
glomeruli and tubules
-MPGN – do not have immune complexes or complement on IF ,
damage may be via endothelial injury from thrombotic
microangiopathies
 Nephrotic syndrome
D. Membranoproliferative glomerulonephritis
- Treatment : controlling hypertension and nephrotic syndrome with
ACEI / ARB ,low diet and diuretics
-patient with C3GN may be treated with immunosuppression such as
mycophenolate mofetil and steroid while eculizumab has not shown
consistent benefit.
50% of patients may develop CKD after 15 to 20 years
 Nephrotic syndrome
E. Fibrillary and immunotactoid glomerulonephritis :
- nephrotic sd with or without microhematuria , mild to moderate elevated creatinine in
adults between 40 and 60 years of age
-clinical similar to MPG and by biopsy
- serum complement normale, electron microscopy – fibrillar deposits in mesangium and
subendothelial areas of GBM
- IF microscopy –Ig G and c3 in mesangium and capillary walls in granular pattern
- congo red stain negative
- rare form : immunotacdtoid glomeruloneprhitis but fibrile larger in diamete> 30 nm ,
cylindrical and arranged in parallel arrays. – assoicated with dyscrasias , specially chronic
lymphomacytic leukemia , B cell lymphomas and monoclonal gammaopathies.
- Rituximab
END