Glomerular Diseases

Roshan Rajani MD

Clinical Assistant Professor of Medicine

Division of Nephrology

Glomerular Disease

• Primary Glomerular Disease

– Disorders in which the glomeruli are the sole or

predominant tissue involved. Usually these

diseases are idiopathic.

• Secondary Glomerular Disease

– Glomerular injury is a feature of a systemic disease involving multiple organs or systems.

Nephritic Syndrome

• Acute onset

• Hematuria (microscopic or macroscopic)

– Dysmorphic RBC

– RBC casts

• Acute renal failure

• Proteinuria

• Hypertension

• Complements may be low or normal

A B

CA: Normal red cells with round

apperance.

B: Dysmorphic red cells in

the urine.

C: Red cells and red cell

casts in the urine.

Nephritic Syndrome

• Low Complements:

– Post-infectious GN

– SLE

– Membranoproliferative GN

• Normal Complements:

– IgA

– Anti-GBM (Goodpasture’s)

Major Causes of Glomerular Diseases According

to Urinary Findings and Age

Common causes of acute glomerulonephritis

I. Hypocomplementemic glomerulonephritisA. Primary renal diseases

Acute poststreptococcal GN

Membranoproliferative GN (MPGN)

B. Systemic diseases: SLE, Infective endocarditis, Cryoglobulinemia,

HCV-associated MPGN, Shunt nephritis.

II .Normocomplementemic glomerulonephritisA. Primary renal diseases

IgA nephropathy

Idiopathic RPGN

Anti-GBM glomerulonephritis

B. Systemic diseases

Vasculitis, Goodpasture’s syndrome, Henoch-Schonlein purpura,

TTP/HUS, etc.

Laboratory abnormalities of APIGN

Urinalysis: proteinuria, hematuria, casts

Serum creatinine: GFR initially decreased (>2 ml/min in 25%)

Streptococcal antibody profile(streptozyme)>95 % positive in patients with pharyngitis80% positive in patients with skin infection5% false-positive Early antibiotic use prevents antibody production

C3, C4, and/or CH50 depressed in >90%

Hypergammaglobulinemia - 90%

Cryoglobulinemia - 75%

Nephropathy associated with other infections

Mycobacterium leprae - amyloidosis,but interstitial nephritis with antibiotic therapy or APS-like GN can be observed.

Plasmodium faciparum - transient proteinuriais common, nephrotic syndrome in less than 1%. MPGN with coexisting AIN is the typical lesion. Renal function ussually improves with antimalarial therapy.

Plasmodium malariae - relativly common in children living in endemic areas.Histology includes Membranous GN, Minimal Change, Diffuse and Focal Proliferative. Nephrotic syndromemay persist after effective therapy for parasitemia.

Schistosoma mansoni - NS associated with MPGN or Mesangial GN. Schistosome eggs are present in feces.Treatment of anti-schistosomal drugs has been ineffective for NS.

Filatriasis - Membranous GN.

Common etiologies of ARF in HIV-infected patients

Pre-renal Causes

Dehydration ,NSAIDs

Renal Causes

Acute tubular necrosisHypotension and sepsisDrugs: aminoglycosides, pentamidine, acyclovir, forscarnet,

amphotericin B, cidofovir.HUS/TTP

GlomerulopathyPost-infectious GN, HIV GN, MPGN

Acute interstitial nephritisNSAIDs, Bactrim, rifampin

Obstructive uropathyAcyclovir, indinavir, sulfadiazine

Glomerular diseases diagnosed by renal biopsy in 136 consecutive HIV-positive patients

Type of glomerular disease N =127 Type of TID N=9

FSGS 88 Interstitial Neph. 5Membranoproliferative GN 13 ATN 3Minimal change disease 6 Lymphoma 1Membranous GN 5SLE - like nephritis 4Amyloidosis 4Post-infectiuos GN 2HUS 1Others 3

Nephrotic syndrome

Minimal change glomerulopathy

Membranous glomerulopathy

Idiopathic (Primary)

Secondary(e.g.,SLE, mixed connective tissue disease,

RA, drugs, infections, neoplasia)

Focal segmental glomerulosclerosis(FSG)

Membranoproliferative GN(type I and II)

Fibrillary GN

Diabetic glomerulosclerosis

Amyloidosis

Light-chain deposition disease

Molecular structure of the podocyte foot procsses

Pavenstadt H, Kriz W et al Physiol Rev 83,253,2003

History: preexisting diseases, previous infections, drugs, arthritis,

rash, current pregnancy, family history, risk factors (HIV, etc.).

Physical exam: severe obesity, rash, arthritis, diabetic retinopathy,

evidence of malignancy, lymphadenopathy.

Urine sediment

Laboratory studies:Cr Cl, serum protein electrophoresis, lipids,

cholesterol, complement level, ANA, cryoglobulin, Hep serology,

serum and urine electrophoresis.

Renal biopsy: all cases in which no clear cause is evident or

possible cause present, but course is atypical.

Diagnostic Approach in Nephritic Presentation

Focal Segmental Glomerulosclerosis

(FSGS)

Pathogenesis: circulating factors which

induce GBM permeability?, Soluble Urokinase

Receptor (suPAR), APOL1 gene

Clinical presentation: nephrotic

syndrome with or without hematuria,

HTN and impaired renal function:

<10% in children,>90% in adults with heroin, HIV, ureterovesical

reflux.

5-12% adults with GN, more in African-American

population.

Laboratory: normal C4, C3, C2, >3.5g, non-selective proteinuria,

microscopic hematuria.

Pathology: LM- focal & segmental sclerosis, IF-IgM & complement,

EM-increase in mesangial matrix, collapse of capillary loops, fused

podocytes, interstitial fibrosis.

Therapy: steroids (20-40% adults may respond), ACE inhibitor.

Etiologic Classification of FSGS

AJKD 2004,43,368 Pathologic Classification of FSGS: a Working Proposal

AJKD 2004.43(2),368

Treatment Algorithm for FSGS

FSGS

NOS

Perihillar

variant

Cellular

variant Tip

variant

Collapse

variant

B.Bose, D.Cattran: CJASN 2013.doi 10.2215

Treatment Algorithm for FSGS

Membranous Glomerulopathy

Pathogenesis: Ab to M-type phospholipase -A2

receptora(PLA2R) reacting with an endogenous Ag in

GBM. Genetics: HLA-DQA1 Secondary causes in 30%.

Clinical presentation: 30-50% of all cases of

idiopathic NS in adults, NS in 85%, microscopic

hematuria in 15-30%.Frequent renal vein thrombosis,

PE may occur. Look for possible secondary causes (immunological -SLE, neoplasms,

infections, medications).

Laboratory data: normal C3, C4, C2 in idiopathic MGN. Ig G1 and G4 in IF in PMGN

Pathology: LM-no proliferation,thickening of GBM, spikes(I-IV stages)with silver staining,

IF-IgG and C3, granular pattern, EM-subepithelial deposits.

Prognosis: worse- adults, men, proteinuria>10g, severity of pathology,

genetics (DRw3,B18).

Therapy: 25-30% will achieve complete or partial remissions with no medication.

20-30%-ESRD over 10 years. 10-15% NS without renal failure over 10 years. Short course

(8 weeks) of steroids (controversial).Steroid+Cytoxan for patients with poor prognosis.

Membranoproliferative GN (MPGN)/C3 Glomerulopathy

Primary: Type I -mesangiocapillary (more common),

TypeII-dense deposit disease(5%),TypeIII (mixed pattern).

Secondary: Mix cryo , HCV, HBV, visceral abscesses

HIV, EBV, malaria, schistosomiasis, SLE etc.,

sickle cell anemia, dysproteinemia. Clinical presentation: a) asymptomatic with micro-

hematuria or non-nephrotic proteinuria, b) NS-60%

c) acute nephritic syndrome, d) RPGN. Most common in ages 7 to 30. Renal

survival-50% over 6-12 year period. Type II worse prognosis.

Laboratory data: Low C3 in 80% of patients with Type II, 70% with type I.

Type II -C3N F and activation of alternative pathway of complement, C4 normal.

Hep C-associated MPGN- frequent cryo, low C4, +RF, skin leukocytoclastic

vasculitis.Pathology: Type I-subendothelial and mesangial deposits and mesangial interpo-

sition within capillary wall, Type II- electron dense material within GBM.

Therapy: Interferon alpha for Hep C, dipyridamole and aspirin with /without

Cytoxan and steroids (children, IV in RPGN) for idiopathic MPGN.

IgA Nephropathy

(Berger’s disease)

Pathogenesis: deposition of CIC of IgA1 in the mesangium.

IgA1 is overproduced and undergalactosylated

Can present as: a) asymptomatic, b) microscopic hematuria, c) nephrotic

(<15%) or non-nephrotic proteinuria, d) acute GN, e) RPGN.

HTN, HLA-BW3, 20year renal survival 50%.

Poor prognosis: older age, heavy proteinuria, HTN, crescents in biopsy.

Pathology: LM-mesangial proliferation, focal, IF-mesangial IgA,

EM-mesangial deposits.

Therapy: no standard approach at present time, ACE, fish oil (10-12g/24hr)

was beneficial in some studies.Control BP. Steroids for RPGN.

Common form of GN

in Asia (>30%), Europe

(20-25%), US (10%)

Hematuria with mild\proteinuria.

HEMATURIAHistory ,Physical exam, UA, Scr, BUN

Glomerular Nonglomerular Hematuria of uncertain originConsider urgent biopsy

for rapid declining GFR

Biopsy

C3

low normal

Cryoglobulins,ANA,ASO, HBs,anti-HC

ANCA,anti-GBM,S/U PEP,eye exam,audiogram,PT, PTT,sickle screen

Specific diagnosis ?

Yes No

Treatment

Consider biopsy for :progressive azotemia,determination of prognosisproteinuria,unexplained findings

Urine cultureSTD culture Abdominal flat

plain, renal ultrasound

hydronephrosis,cyst, mass, other

stone

stone work-up

furtherwork-up

normal>40years

cystoscopy,IVP, CT, MRI

normal

Urine Ca work-up

C3 ANA, ASO,biopsy?

family UA audiogram,eye exambiopsy ?

consider cystoscopy, IVP

<40years

pyuriadysuria

dysuria,colicky pain

low

high

+

proteinuria, high BP,

RBC casts, dysmorphic

RBCs

Rapidly Progressive Glomerulonephritis

• Clinical term that is defined by the sudden

and accelerated development of renal

insufficiency due to cellular proliferation

within and inflamation of glomeruli

• Diagnostic criteria: loss of 50% of kidney

function in 3 month, active urine sediment,

renal biopsy with crescentic GN( more than

50% of glomeruli contains crescents)

Immunufluorescence pattern of RPGN

I. Antibody mediated:

anti-GBM with lung involvement (Goodpasture’s syndrome)

anti-GBM without lung involvement (30% positive ANCA)

II. Pauci-immune glomerulonephritis:

Microscopic polyangitis (ANCA, both MPO and PR3)

Wegener’s granulomatosis (ANCA, mostly anti-PR3)

Churg -Strauss syndrome

III. Immune-complex mediated glomerulonephritis

Postinfectious GN

Membranoproliferative GN, Membranous GN,

IgA nephropathy

Systemic diseases: SLE, HSP, Cryoglobulinemia

Fibrilary GN, Scleroderma

Laboratory features of RPGNUrine:

Microscopic hematuria(dysmorphic) in 100% of patients

Casts (red cell, granular, leukocyte)

Renal function:Impaired: 100%, GFR<20ml/min:30%

Normal kidney size

Normocytic normochromic anemia

ESR: moderate rise <100mm

Circulating anti-GBM (30%)

Circulating immune complex (10-15%)

Serum complement: normal

ANCA: 80% if absent glomerular immune deposits

Positive results have sensitivity of over 70% and specificity of

99% depending on clinical setting. Positive ANCA + hematuria

has positive value of 95% and negative predictive value of 85%.

Factors determining the outcome of RPGN

Factors Poorer prognosis Better prognosis

Urine output Oliguric Nonoliguric

at presentation 80% RF/12mth 34% RF at 12mth

Extent of crescents > 80% 50-80%

The glomerulus Fibrinoid necrosis Endocapilary prolif.

Glomerular immune

deposits anti-GBM Granular or pauci

Interstitium Fibrosis or atrophy

Segmental necrotizing lesions common for pauci-immune

vasculitis and ant-GBM glomerulonephritis

Patient Renal Survival Depending on Histology of ANCA Associated Vasculitis

JASN 21:1628-1636, 2010

Median age at baseline was 62.6

years

The male-to-female ratio was 54:46.

Diagnosis of Wegener’s

granulomatosis(n 39)

or microscopic polyangiitis (n 61)

with pauci-immune crescentic GN.

ANCA test or ELISA were available

for 97% of patients

(PR3-ANCA n 45,MPO-ANCAn 47).

Thirty-five patients reached ESRD,

(mean time just over 1 year from

baseline).

The median number of glomeruli per

biopsy was 14.8.

Fig 2. Early segmental fibrinoid necrosis with early cellular crescent formation without endocapillary

proliferation or evidence of immune complexes in the remaining glomerular tuft. This light microscopic

finding is that of a pauci-immune necrotizing glomerulonephritis, with a specific diagnosis of anti-GBM

antibody-mediated glomerulonephritis made by immunofluorescence

(Jones silver stain; original magnification x400).

Goodpasture’s (anti-GBM) Syndrome

Fig 4. Lung with linear staining along alveolar walls with antibody for IgG in a patient with

anti-GBM antibody-mediated glomerulonephritis and pulmonary hemorrhage, typical

of Goodpasture's syndrome (immunofluorescence with anti-IgG; original magnification x400).

Fig 3. Smooth, linear staining of glomerular basement membranes with antibody to

IgG and crescent formation in the glomerulus on the left, diagnostic findings of

anti-GBM antibody-mediated glomerulonephritis (immunofluorescence with anti-

IgG; original magnification x200).

Epidemic childhood HUS (D+),Shiga toxin(+)E.coli O157:H7; 1-14 days diarrhea, mild fever, decrease

urine output lethargy, irritability, seizures (10%), jaundice,

petechia,purpura,hemturia/proteinuria(100%). Recovery>95%

Adult HUS/TTP syndromesFever, rarely diarrhea, encephalopathy (90% in TTP),severe thrombocytopenia,

hematuria/proteinuria (75% TTP), oliguria. Recurrence 20%.

Idiopathic/ failure to degradate large multimers of vW factor by protease ADAMTS 13

Hereditary defect of plasma factor H (autosomal dominant)

Drugs: cancer (mitomycin,conditionig for BMT, cisplatin,bleomycin, oral

contraceptive, Cs, tacrolimus, OKT3, quinine, ticlopidine, valacyclovir.

Pregnancy or post partum Malignant hypertension.

Autoimmune disease: SLE, scleroderma, antipospholipid antibody syndrome, HIV.

Pneumococcal infection.

HUS/TTPFeatures:1. Thrombocytopenia

2. Microangiopathic hemolytic anemia

3. Acute renal failure

4. Neurological symptoms and signs

5. Fever

Renal involvment is common (50%).

Full recovery within weeks or months.,

Relapses up to 40% of patients

ESRD occurs in 5-10% of patients. Prognosis worse in

adults

Labs: non specific, ANCA(-), complement usually

normal, elevated ESR.

Treatment of GN: steroids, cyclophosphamide, iv Ig,

Henoch-Schonlein Purpura

Features:

1. Palpable purpura (90%)

2. Bowel angina (60%)

3. Age at onset <20 y

4. Arthralgias or arthritis,muculoskeletal (75%)

5. Vasculitis with IgA dominant deposit

Atheroembolic Renal Disease:

Risk Factors Prior Medical Problems

Male sex Ischemic cardiovascular disease

Age >60 y Cerebrovascular disease

White race Abdominal aortic aneurysm

Hypertension Ischemic nephropathy

Tobacco use Peripheral vascular disease

Diabetes mellitus

Livedo reticularis is a mottled bluish (livid) discoloration of the skin

occurs in a netlike pattern.

Left: idiopathic livedo reticularis

Right: secondary livedo reticularis; indurated nodules, firm, painful;

may undergo necrosis.

Out of 52 patients (Scolari, AJKD) with renal symptomes, 96% had skin

lesions : 79% cyanotic toe, 38% livedo, 15% gangrene.

CCE in an afferent

arterioleCCE in an arcuate

artery

Renal allograft: CCE

in an interlobular artery

CCE in the bone marrow

interstitium

CCE in an artery

of a colon

CCE plus giant cell

in gastric mucosa

Renal manifestation of AERD

Clinical presentation :

asymptomatic

acute (35%) - renal failure 3-7 days after insult

subacute (56%) - deterioration of kidney function

over 2 - 6 weeks

chronic and stable impairment of kidney function

Urine: mild proteinuria, hematuria, eosinophiluria

(3-5% of eosinophils) - 70-80% of patients.

Laboratory: ESR, leukocytosis, thrombocytopenia,

eosinophilia (14-62-71-80%), low serum complement (39%),

ANCA (-),CPK, amylase, LDH (rare renal infarct)

Treatment of Atheroembolic Renal Disease

.

Prevention of recurrent CCE:

discontinuation of anticoagulant therapy

avoid further aortic catheterization

rescue bypass

Lipid-lowering agents: occasional response, statin can

stabilize the plaque

Corticosteroids : 0.3 mg/kg, relief of pain?, improvement

in food intake, seemed to coincide with a break in

recurrent bouts of cholesterol

Hemodialysis and nutritional support

Classification of Renal Lesions in SLE

Class Glomerular Findings

I No abnormalities

II Mesangial lupus nephritis: mesangial immune deposition

with variable hypercellularity

III Focal segmental lupus nephritis: mesangial and scattered

peripheral glomerular immune deposits with proliferative

lesions in < than 50% of glomeruli

IV Diffuse proliferative lupus nephritis: mesangial and

extensive subendothelial immune deposits with diffuse

proliferative and necrotizing changes

V Membranous lupus nephritis: subepithelial immune

deposits with few or no mesangial deposits.

VI Advanced sclerosing glomerulonephritis

WHO classification of lupus nephritis

Treatment of Different Form of Lupus Nephritis

Class Treatment options

I Treatment guided by extrarenal presentation

II Corticosteroids

III Corticosteroids + some immunosuppressive agents

IV Cyclophosphamide pulses, Methylpredisolone pulses,

oral prednisolone, azathioprine.

V Corticosteroids with/without

immunosuppressive agents .

VI Dialysis, transplantation

Risk Factors for Development of ESRD in SLE

Demographic Male gender, Black race, age<24,

characteristics low socioeconomic status

Clinical Elevated Pcr at initial presentation,

characteristics nephrotic syndrome, low C3, Ht<26%,

HTN, persistent disease activity

Histologic Class IV WHO, Activity index>12,

characteristics Chronicity index >3

Treatment No normalization of Pcr

characteristics Treatment with prednisone only

Antiphospholipid -Antibody Syndrome in SLE

Arteriol and glomerular capilariles filed with thrombi. IF for fibrin(+)

Clinical hallmark:presence of venous and arterial thromboses,

pregnancy loss, particularly during 2nd trimester, thrombocytopenia

Kidney may show thrombotic microangiopathy similar to HUS.

Treatment: prednisone, anticoagulation (low-molecular heparin, warfarin),

plasma exchange,, cyclophosphamide.

Thank you!

roshan.rajani@med.usc.edu

Epidemiology of renal vasculitis

• Incidence of vasculitis is 10-20/million/year

in Europe

• Prevalence in Europe : 150-200/million

• Incidence increases with age , peaking at

65-75 years

• Major cause of RPGN(80%), and is

responsible for 5% of patients on RRT

Clinical manifestation observed in 85 patients with microscopic polyangitis (I)

Clinical manifestation observed in 85 patients with microscopic polyangitis (II)

At the time of diagnosis, ANCA were present in 38 of 51 patients (74.5%); 33 had pANCA and 5 had a

cANCA. Antimyeloperoxidase (anti-MPO) Ab were detected by ELISA in 31 patients and anti–

proteinase 3 (anti-PR3) Ab in 4. Among the patients with GN, ANCA were detected in 15 of the 25

patients tested for these antibodies (60%).

Role of LAMP-2 and NET in ANCA

Associated Vasculitis

Lysosomal membrane protein-2 (LAMP-2): protein, which shuttles between

lysosomes and cell membrane, in neutrophils it is integrated into MPO and PR3.

Ab against LAMP-2 are present in 90% of patients with active pauci-

immune GN

Ab against LAMP-2 cause injure of human endothelium in vitro and can cause

vasculitis in rat

Bacterial adhesin FimH cross- react with LAMP -2 and may initiate vasculitis.

Neutrophil exracellular traps (NETs) are chromatin fiber, DNA

deposit which trap microbes in sepsis but also damage endothelium.

NETs are released by ANCA- stimulated neutrophils and contained

autantigens PR3 and MPO and may trigger vasculitis

Nature Medicine 2008;14,1088 and 2009; 15, 623

Differential diagnosis of acute GNLow serum complement

High serum complement

Systemic diseases Systemic diseases

SLE (focal 75%,diffuse 90%)

SBE (90%)

Visceral abscess"Shunt nephritis" (90%)

Cryoglobulinemia (85%)

Renal diseases

Acute postinfectious GN (>90%)

Membranoproliferative GNType I (50-80%)Type II (80-90%)

Polyarteritis nodosa group

Hypersensitivity vasculitis

Wegener's granulomatosis

Henoch-Schonlein purpura

Goodpasture syndrome

Renal diseases

IgA Nephropathy

Idiopathic RPGNAnti-GBM diseasesImmune complex diseases