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Glomerulopathies Associated with Multisystem
Diseases
Jinn-Yuh Guh, M.D.
Case
A 38 y/o female p’t with DM for 15 years has blurred vision, both limbs
numbness, intermittent claudication, foot ulcer, edema, residual urine,
nephritic syndrome, hypertension, Blood: glucose 350 mg/dl, HbA1C 8.0,
creatinine 1.8 mg/dl.
What is your Dx?
What would you do?
Introduction
Secondary GN
Dx: Clinical syndromePathologic featuresSpecific diseases
Diabetic Nephropathy (DN)
Introduction
The leading cause of ESRD in USA and 2nd most common cause of
ESRD in Taiwan (2nd only to chronic GN)
Occurs in 30% of IDDM and 20% of NIDDM p'ts, but most diabetic
ESRD p'ts have NIDDM
Clinical & morphologic features of DN are similar in IDDM & NIDDM
Clinical staging
Hyperfiltration
Glomerular hypertension
Renal hypertrophy
Silent
2-3rd year
Thick GBM
Mesangial expansion
Incipient (microalbumiuria)
7-15th year
Urinary albumin excretion=30-300 mg/day=30-300 mg/g
creatinine=20-200 g/min (Avoid exercise, UTI, other diseases)
>2/3 within 3 months
"Point of no return" beyond this stage!
Overt (clinical proteinuria)
10-20th year
Dipstick + proteinuria
With or without nephrotic syndrome
Hypertension
Progressive GFR
Normal sized kidneys
D.D. of CRF with normal sized kidneys
DM, polycystic kidneys, amyloidosis, obstructive
uropathy, multiple myeloma
Retinopathy (90% in IDDM, 60% in NIDDM)
Bland urinary sediment
1
Renal failure (end-stage renal disease)
Dialysis is indicated at an earlier stage (serum creatinine  6
mg/dl) than the other uremic p'ts
Pathology
Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion)
Classic lesion for DN
Thick GBM
IgG linear deposition along GBM
Wide mesangium
Hypertensive nephrosclerosis
Treatment
1. Glycemic control
Less effective beyond stage 3
2. Blood pressure control
Goal is BP<125/75 mmHg
3. Angiotensin-converting enzyme inhibitor
Inhibiting angiotensin II
Proteinuria 
Retard progression of GFR 
Efferent arteriole resistance Intraglomerular hypertension

Glomerular cell growth 
Mesangial matrix 
Glomerulosclerosis 
Indicated for DM p'ts normotensive or hypertensive with
greater than microalbuminuria stage
4. Low protein diet
0.6-0.8 g/kg/day
5. Renal replacement therapy
Introduction
Diabetic ESRD p'ts has higher mortality than the other
uremic p'ts
HD and CAPD has similar survival rates
Hemodialysis (HD)
Continuous ambulatory peritoneal dialysis (CAPD)
Renal transplantation
The preferred treatment
Case
A 30 y/o female p’t has malar rash, polyarthritis, edema, oliguria, ANA+,
anti-DsDNA+, hypertension, Blood: creatinine 1.6 mg/dl (1 month ago)6
mg/dl (now); Urine: protein 6 g/day, RBC casts+, WBC 10-15/HPF
What is your Dx?
What would you do?
Immunologically Mediated Multisystem Diseases
Vasculitis
Large vessel
Takayasu's disease & giant cell arteritis
Glomerular injury is exceedingly rare
Classic polyarteritis nodosa
Proteinuria, hypertension, CRF
2
Bland urinary sediment
Normal serum complement
ANCA (antineutrophil cytoplasmic antibody) negative
Rx
If untreated, 5-year survival 10%
Glucocorticoids & cyclophosphamide5-year survival 80%
ANCA-associated small-vessel vasculitis
ANCA
May also be positive (in low titers) in other diseases
Anti-GBM disease, inflammatory bowel disease, primary
biliary cirrhosis, some autoimmune disorders
Pathogenic role is not clear
The correlation between titer and disease activity is not good
Classification
1. Wegener's granulomatosis
Renal injury in 80% p'ts
Rarely recurs in renal transplants
2. Microscopic polyarteritis
Plasmapheresis may be effective for severe RPGN and
lung hemorrhage
3. Churg-Strauss syndrome
Renal injury is rare and mild
Granulomatous vasculitis
Necrotizing GN is rare
4. Pauci-immune renal-limited GN
Clinical features
Elderly
Viral-like prodrome
Nonspecific constitutional symptoms
BW loss, fatigue, fever, arthralgia, myalgia
Nonspecific laboratory findings
ESR & CRP, leukocytosis, thrmbocytosis, normocytic
anemia
Normal serum complement
Nephritic syndrome or RPGN
Pathology
"Pauci-immune GN"
Focal, segmental necrotizing crescentic GN
Treatment
Corticosteroids and cyclophosphamide
If adequately treated, 5-year survival>75%
Henoch-Schönlein purpura
GN occurs in 80% p'ts
May be the different manifestation of IgA nephropathy
Treatment
Supportive
Prognosis
Exacerbations and remissions within 1st yearLong-term
remission
CRF & hypertension <10% p'ts
3
Essential mixed cryoglobulinemia (EMC)
Mixed cryoglobulinemia
Type II
Polyclonal IgG + monoclonal IgM
Type III
Polyclonal IgG + polyclonal IgM
Clinical features
More common in females, mean age of onset 60 years
Clinical features
Triad (purpura, arthralgia, fatigue), Raynaud's phenomenon
RA factor +
Renal disease occurs in 50% p'ts
Nephrotic syndrome, hematuria, hypertension
Rarely (20-30%) nephritic syndrome
5% RPGN
Hypocomplementemia (esp.C4)
Chronic liver disease (15-50% p'ts)
Anti-HCV +, HCV-RNA +
Pathology
Mesangial proliferative GN or MPGN
Pseudothrombi in glomerular capillaries
Granular depositions
EM: Subendothelial deposits with "thumbprints"
Treatment
Glucocorticoids & cyclophosphamide
Plasmapheresis
-interferon
Systemic lupus erythematosus (SLE)
Introduction
Clinical renal disease (Lupus nephritis) in 40-85% p'ts, but
pathologic abnormalities may occur without clinical
manifestations
All syndromes in nephrology can be found!
Immune complex-mediated lupus nephritis
Clinical features
Urinalysis: “telescoped urine” (simultaneous presence of
nephritic, nephrotic, acute renal failure and chronic renal failure
sediments)
Hypocomplementemia
ANA (95-99%), anti-DsDNA (highly specific), anti-Sm Ab
(17-30%, highly specific)
WHO classification
Introduction
Interstitial changes are mainly seen in Class III & IV
Weak correlation between pathologic classifications and
clinical features
Class I (Normal)
Normal in LM (light microscope)
Occasional deposits in IF (immunofluorescence)
Clinically silent
4
Class II (Mesangial)
Classification
Class IIA
Normal mesangial cellularity
Class IIB
Mesangial hypercellularity
Mesangial deposits in IF
Hematuria, mild to moderate proteinuria
Class III (Focal segmental proliferative)
Necrosis and sclerosis <50% of glomeruli
Rarely nephrotic syndrome (1/3 p'ts) or renal failure (15-25%
p'ts)
Class IV (Diffuse proliferative)
Clinical features
The most aggressive lupus nephritis!
"Telescoped urine"
Nephritic + nephrotic + chronic GN
>50% p'ts have nephrotic syndrome and renal failure
30% p'ts progress to ESRD
Pathology
LM
Often with crescents, fibrinoid necrosis, wire-loops
(GBM thickening, mesangial interposition)
IF
Widely positive
EM (electron microscope)
Mesangial, sub-endothelial and subepithelial deposits
Tubuloreticular structures in endothelial cells
Also seen in HIV nephropathy
"Thumbprinting" similar to EMC
Class V (Membranous)
90% p'ts have nephrotic syndrome
Rarely (10%) has renal failure
Class VI (Diffuse glomerulosclerosis)
Plus advanced tubulointerstitial disease
Clinical features
The end stage of lupus nephritis
Renal failure
Hypertension
Nephrotic syndrome
Transformation between classes is common
Additional pathologic features useful for deciding Rx
Activity index
Endocapillary proliferation, glomerular leukocyte infiltration,
wire loops, cellular crescents, interstitial inflammation
Chronicity index
Glomerulosclerosis, fibrous crescents, tubular atrophy,
interstitial fibrosis
Treatment
Introduction
5
Treat the p't, NOT ONLY the kidneys
Depends on clinical activity and pathologic features!
Class I & II
Rx is not indicated, but may be used for extrarenal
manifestations
Classs III & IV
Glucocorticoids
Pulse therapy is indicated in severe cases
Cyclophosphamide
Pulse therapy is indicated in severe cases
Monthly pulses x 6 monthsPulses every 3-6
monthsTotal treatment period 18-24 months
Corticosteroids are used concomitantly & tapered
Plasmapheresis is NOT indicated
Renal replacement therapy
P'ts may become clinically silent durine ESRD
Renal transplantation
Lupus GN rarely recurs in allografts
Graft survival is comparable to other p'ts
Prognosis
Introduction
Follow-up with urine sediment, proteinuria, GFR,
serum complement, anti-DsDNA lelvels
Class III & IV
If adequately treated, 5-year suvival=60-90%
Class V
1/2 spontaneous remission
5-year survival=70-90 %
Antiphospholipid syndrome and thrombotic microangiopathy
Intravascular microthrombi and endothelial swelling (interlobular
arteries, arterioles, glomerular capillaries)
Tissue plasminogen activator
2--antiplasmin
Treatment
Plasmapheresis (?)
Rheumatoid arthritis (RA)
Classification
1. Direct renal involvement
Rare
2. AA amyloidosis
Esp. duration>10 years, RA factor +, destructive arthropathy
10-20% RA p'ts, 其中只有 3-10%有 GN
Nephrotic syndrome
Renal failure
3. Drug-induced
Gold & penicillamine
Nephrotic syndrome (membranous GN)
NSAID
Minimal change disease
Acute interstitial nephritis
6
Sjögren's syndrome
Tubulointerstitial diseases
Fanconi's syndrome
Distal renal tubular acidosis
Impaired urinary concentrating ability
GN is rare
Polymyositis and dermatomyositis
Occasionally mesangial proliferative GN
Mixed connective tissue disease (MCTD)
SLE+scleroderma+polymyositis
Antiribonucleoprotein +
GN is rare (<15%)
Hematuria & proteinuria
Membranous GN or MPGN
Treatment
Glucocorticoids for rare p'ts with progressive disease
Prognosis
Excellent
Glomerular Deposition Diseases
Amyloidosis
Classification
Primary
Elderly
Secondary
Chronic inflammation (RA, paraplegia, osteomyelitis), multiple
myeloma, cancers, hereditary (FMF)
1. AL (Primary, immunoglobulin light chain)
2. AA (Secondary, serum amyloid A)
3. Dialysis-associated (2-microglobulin)
4. Alzheimer's disease & Down's syndrome (amyloid protein)
Diagnosis
Rectal biopsy or abdominal fat pad biopsy
Congo red +
Apple-green birefringence under polarized light
Renal involvement
AA & AL amyloidosis (75-90%)
Nephrotic syndrome
50% p'ts have renal failure
Tubulointerstitial disease is rare
20-25% p'ts have hypertension
Normal-sized kidneys even in CRF!
Pathology
LM: Mesangial amorphous (nodular) deposits,
tubulointerstitial or vascular deposits
IF: Weakly positive for immunoglobulin light chains (variable
region)
EM: Amyloid fibrils (7.5-10 nm)
Treatment
Melphalan & prednisolone
Eradicate underlying disease for AA amyloidosis
7
Colchicine for familial Mediterranean fever (FMF)
Dialysis
Lower survival than the other uremic p'ts
Renal transplantation
Recurrence in allograft is common but rarely leads to graft
loss
Prognosis
Poor
ESRD within 2-5 years
Died of cardiovascular diseases
Light chain deposition disease (with or without multiple myeloma)
Clinical features
Renal involvement in 90% p'ts
Nephrotic syndrome & renal failure
Tubular abnormalities may be seen
Pathology
Tubular basement membrane thickening
Mesangial expansion & nodular glomerulosclerosis (33%)
Similar to diabetic nephropathy & MPGN
Strongly positive for immunoglobulin light chains (constant
region)
EM: Granular rather than fibrillar deposits
Treatment
Melphalan & prednisolone (?)
Prognosis
Poor if with multiple myeloma (ERSD rapidly)
Waldenström's macroglobulinemia
Monoclonal proliferation of IgM-plasma cells
Hyperviscosity syndrome
Renal failure
Direct renal involvement is rare (deposits in glomerular capillaries)
Renal amyloidosis
Drug-Induced Glomerular Disease
NSAID
1. Acute renal failure
a. Hemodynamic
b. Acute interstitial nephritis
Nephrotic syndrome
Most common with propionic acid NSAIDs, but also occurs in
ampicillin, rifampicin, interferon
Stopping drugs leads to remission
2. Papillary necrosis
3. Fluid & electrolyte disturbances
Salt & water retention
Edema
Hypertension
Hyponatremia
Hyperkalemia
Gold (for RA Rx.)
Proteinuria after 4-6 months of therapy (5-25%)
8
Nephrotic syndrome (33%)
Membranous nephropathy
Rarely progressive renal failure
Withdrawal of the drug leads to remission
Penicillamine
Proteinuria (5-30%)
Membranous nephropathy
Withdrawal of the drug leads to remission
I.V. heroin abuse
More common in blacks
Focal & segmental glomerulosclerosis
Nephrotic syndrome, renal failure, hypertension, ESRD within 3-5
years
Hereditary Diseases with Glomerular Involvement
Alport's syndrome
X-linked dominant trait
Rarely autosomal recessive inheritance
Genetic defect in5 chain of type IV collagen on long arm of X
chromosome which is a major component of GBM
Clinical features
Hematuria, proteinuria, nephrotic syndrome (30%), progressive
renal failure
Sensorineural hearing loss (60%)
Bilateral anterior lenticonus (15-30%)
Mild in female carriers
Pathology
LM: mesangial hypercellularity, FGS, foam cells, tubulointerstitial
fibrosis
EM: Thickening, fragmentation and lamellation of GBM
(lamella densa), patchy thinning of GBM
Prognosis
Males progress to ESRD
Anti-GBM disease occurs in 5% p'ts after renal
transplantation
Sickle cell disease
Exceedingly rare in Taiwan
Fabry's disease
Clinical features
X-linked recessive trait
Hematuria, proteinuria, nephrotic syndrome, progressive renal
failure
Angiokeratoma of skin, corneal and lens opacities, etc.
Diagnosis
Urinary glycoshingolipids
Leukocyte-galactosidase 
Pathology
Accumulation of neutral glycosphingolipids
EM
"Myeloid bodies"
Nail-patella syndrome
9
Rare
AD inheritance
50% nephropathy (hematuria & proteinuria)
Rarely (10%) progress to ESRD
Lipodystrophy
Females (5-15 years old)
MPGN type II (80%), type I (20%)
Low C3 levels
Lecithin-cholesterol acyltransferase (LCAT) deficiency
TG
Proteinuria, hematuria, progressive renal failure
FGS
Infectious Diseases
Viral infections
HBV
Chronic persistent or chronic active hepatitis
1. Membranous nephropathy
Good prognosis in children
2/3 spontaneous remission within 3 years
Poor prognosis in adults
30% progressive renal failure, 10% to ESRD
2. MPGN
3. IgA nephropathy
4. Essential mixed cryoglobulinemia
5. Polyarteritis nodosa
HCV
It should be considered in all p'ts with cryoglobulinemic
proliferative GN, MPGN & membranopus nephropathy
Treatment
Glucocorticoids, cytotoxics, plasmapheresis (?)
-interferon
Usually relapse after drug withdrawal
HIV
FGS (HIV-associated nephropathy)
Clinical features
More common in blacks
Nephrotic syndrome
Rapidly progress to ESRD within weeks to months
EM
Tubuloreticular structures (glomerular endothelial and tubular
cells), leukocyte infiltration, degeneration of tubular nuclei
Bacterial infections
Infective endocarditis
Clinical features
Hematuria, proteinuria, nephrotic syndrome (25%), pyuria,
mild renal failure
RA factor (10-70%)
Hypocomplementemia
Pathology
Immmune-complex GN (Focal proliferative GN)
10
Embolic renal infarction
Septic abscesses
ATN (acute tubular necrosis)
DIC (diffuse intravascular coagulation)
Acute interstitial nephritis (drug-induced)
Rarely crescents
Prognosis
Good, resolve with eradication of underlying disease
Infected ventriculoatrial shunt
1-4% p'ts have immune-complex GN
Hematuria, proteinuria, nephrotic syndrome (50%)
MPGN or diffuse proliferative GN
Prognosis
1/3 has residual renal failure despite eradication of underlying
disease
Suppurative infections
Abscesses (thoracic, abdominal, dental), osteomyelitis
Hematuria, proteinuria, acute renal failure
Syphilis
0.3% p'ts have nephrotic syndrome
Membranous nephropathy with mild cellular proliferation
Leprosy
AA amyloidosis
aGN (like PSGN)
Protozoan and parasitic infections
Plasmodium (malaria)
Eradication of infection does NOT consistently induce remission
of nephrotic syndrome
Schistosoma mansoni
5-10% p'ts have nephrotic syndrome
Filariasis
Loa loa & Oncocerca volvulus
Congenital Toxoplasmosis
Hydatid disease
Trichinosis
Neoplasia
Solid organs
Membranous nephropathy
Hodgkin's lymphoma
Minimal change disease
Non-Hodgkin's lymphoma
Leukemias
GN is rare
Paraproteinemia
Classification
1. Primary amyloidosis
2. Light chain deposition disease
3. Multiple myeloma
Secondary amyloidosis (10-15%)
Light chain nephropathy
11
Myeloma kidney
Fracturing tubular casts (Bence-Jones proteinuria)
Fanconi’s syndrome
Acute renal failure & CRF
4. Cryoglobulinemia
5. Fibrillary/immunotactoid GN
Prognosis
Usually remits after treating underlying disease
Summary
Hypocomplementemia
MPGN, SLE, EMC, infectious endocarditis, lipodystrophy
12