Li Ping Tan Nephrologist & Senior Lecturer Renal Division University of Malaya Medical Center

GLOMERULAR DISEASES AND THE NEPHROTIC SYNDROME

A little jab at medical subspecialities

The General Practitioner he who knows little and does little
The Surgeon he who knows little but tries to

do everything The Physician he who knows everything, but does nothing The Pathologist he who knows everything, but its too late

Objectives
General Principles
Detection of Glomerular Disease Differential diagnosis of Glomerular Diseases Nephrotic Syndrome Representative diseases

General Principles Detection of Glomerular disease Differential Diagnosis Representative diseases

GLOMERULAR DISEASES

Prerenal / Renal / Postrenal

Intrarenal Vasc/Glom/TI

Glomerular Compartment

Glomerulus exposed

Glomerulus under a microscope

Podocyte Biology
Epithelium
Capillary wall: 1. Fenestrated capillary endothelium 2. GBM 3. Podocytes (with slit pores and slit diaphragm)

Endothelium

Under normal circumstances, the glomerular wall is permeable to

water and small solutes but relatively impermeable to albumin Defects in the glomerular capillary wall result in increase permeability to albumin and other proteins / cells of similar size or larger.

Pathogenesis of Glomerular injury

Most human GN are likely forms of autoimmune disease whereby there is loss of tolerance to self-Ag as opposed to foreign Ag. Immune response exhibits humoral (Ig formation and complement deposition) and cellular components (infiltration by leukocytes and crescent formation)
Immune deposits localize in the glomerulus either actively (target Ag is there) or passively (filtered)

Localization of Deposit=Key!
Localization of immune complexes in the subendothelial areas of the glomerular capillaries where they are exposed to blood

leads to recruitment of inflammatory cells

and typically manifests as nephritic
Localization of immune complexes in

subepithelial areas where they are not exposed to blood typically results in

nephrotic picture.

Subendothelial / Subepithelial

Detection of Glomerular Disease

Suspected by the following:
History Proteinuria ( especially if nephrotic range)

Hematuria (especially if dysmorphic RBC)

Lipiduria RBC casts

Proteinuria
3 types of proteinuria Glomerular
Increased filtration of proteins across the

GBM. Tubular Decreased reabsorption of proteins by the proximal tubule Overflow Increased production of LMW proteins leading to increased excretion (i.e. light chains)

There is only minimal amounts of proteinuria in healthy states

Normally, small amounts of LMW proteins

and albumin are filtered, almost all are then reabsorbed and catabolized by the proximal tubule.
Normal daily protein excretion is thus

<150mg/day, of which 10mg is albumin

Differential Diagnosis for proteinuria

Transient Proteinuria can be seen in 4-7%

of patients (resolve on subsequent examination).

Can also be seen during fever, UTI

Orthostatic proteinuria should also be

ruled out if patient is young 2nd to its benign cause.

Pathology of Glomerular Proteinuria

Urine Protein measurement

Urine dipstick detects protein (albumin) by a

colorimetric change upon binding of albumin to a dye (tetrabromophenol blue)

is macroalbuminuria)

read as trace to 4+ ( 1-2+ is microalbuminuria, >3+

Dipstick measurement is not sensitive as it

only detects albumin, can be altered by concentration and pH of the urine Glomerular proteinuria

Urine dipstick only able to tell you about

Proteinuria Quantification
Although useful as a brief screening

tool, if concern for glomerular diseases are present, should do

Gold Standard 24hr urine protein collection Random Urine Protein / Creatinine ratio * *NB Early morning urine!!

Can you think of a condition where the Urine Dipstick is negative, but 24 hr urine protein is positive?

Paraproteinemias like Multiple Myeloma

Hematuria
Defined as >3 RBC / hpf Asymptomatic hematuria occurs

in 5-10% of the population Most hematuria is not of glomerular origin

Glomerular Hematuria
Glomerular diseases cause <10% of

haematuria in patients without accompanying proteinuria Hematuria of glomerular origin leads to dysmorphic appearing RBC (exposed to osmotic changes as they pass through the renal tubules)

Dysmorphic RBC

Differential Diagnosis of Glomerular Disease

History, patient age and urine characteristics typically assist

in narrowing the diagnosis prior to renal biopsy Nephrotic Nephritic

Proliferation of glomerular cells (mesangial, endothelial, epithelial) and influx of leukocytes (esp.. neutrophils and macrophages)

Focal
Inflammatory lesions in <50% of glomeruli seen on LM Patients are usually asymptomatic and present with haematuria +/proteinuria

Diffuse
Inflammatory lesions in >50% of glomeruli seen on LM Proteinuria (which may be heavy), hypertension, edema and renal insufficiency may be seen

Differential Diagnosis based on Clinical Presentation

Nephrotic Syndrome (edema, hypoalbuminemia, urine prot>3-3.5g/d, hyperlipidemia)
Heavy proteinuria, bland sediment although some haematuria allowed <15yrs 15-40yrs >40yrs

Minimal Change Disease Membranous GN (MCD)

Focal Segmental Glomerulosclerosis (FSGS) MCD

Membranous GN
MCD

FSGS Diabetic Nephropathy

FSGS Diabetic Nephropathy Amyloidosis

Light Chain Deposition Disease

Focal GN (<50% of glomeruli seen on the renal biopsy are involved) Active Urine Sediment without renal insufficiency or nephrotic syndrome <15yrs
IgA Nephropathy Mild postinfectious GN Membranoproliferative GN Thin Basement Membrane Disease Henoch Schonlein Purpura (HSP) Hereditary Nephritis

15-40yrs
IgA Nephropathy Lupus Nephritis MPGN Thin Basement Membrane Disease

>40yrs
IgA Nephropathy

Diffuse GN (>50% of glomeruli seen on the renal biopsy are involved) Active Urine Sediment with renal insufficiency and variable proteinuria (can be nephrotic range) <15yrs
Postinfectious GN MPGN

15-40yrs
Postinfectious GN Rapidly Progressive GN (RPGN)

>40yrs
Postinfectious GN RPGN

MPGN Lupus Nephritis

Vasculitis

Differential Diagnosis based on Etiology (Antibody mediated GN)

Circulating anti-GBM Antibody (with linear glomerular IF staining) Goodpastures Syndrome (with pulmonary hemorrhage) Anti-GBM GN (without pulmonary hemorrhage) Glomerular Immune Complex deposition (with granular glomerular IF staining) IgA Nephropathy HSP Lupus Nephritis Wegener's Granulomatosis Microscopic Polyangiitis Churg-Strauss Syndrome MPGN Membranous GN Post-infectious GN

Pauci-immune GN (circulating ANCA but with no glomerular IF staining)

Glomerular Diseases associated with low Complements (C3, C4)

Lupus Nephritis
Post-infectious GN (typically post-strep, SBE) MPGN Cryoglobulin associated GN (can be due to

HepC) Others
Atheroembolic phenomenon

Definition Differential Diagnosis Representative Diseases Complications

NEPHROTIC SYNDROME

Definition of the Nephrotic Syndrome

Urine protein >3-3.5g/24hrs
Peripheral edema Hyperlipidaemia Hypoalbuminaemia <3g/dL

Diseases commonly associated with the Nephrotic Syndrome

In children, the most common cause is Minimal Change Disease
In adults, 30% Secondary to other illness (DM,

Amyloid, Lupus). 70% are due to Primary GN (most commonly Membranous GN, Minimal Change disease, Focal Segmental Glomerulosclerosis)

Minimal Change Disease

Almost always associated with nephrotic syndrome Normal light microscope and immunoflouresence Electron microscopy shows effacement / fusion of podocyte foot processes FSGS can sometimes be mistaken for MCD Although presents in both children and adults, more typically noted in earlier decades of life (95% preadolescence with nephrotic syndrome to 50% in adolescences and young adults to 20% in age >40yrs)

Minimal Change Diseasecontd.

Secondary causes are drugs (NSAIDs), toxins (Mercury, Lead), infections (HIV), malignancy (CA, Hodgkins) Benchmark for therapy is the response to corticosteroids (good), especially in children
In steroid responsive individuals, progression

to renal failure is rare. In general, in adults, 80-90% 10 year renal failure free survival is typical

Minimal Change Disease-Renal Biopsy

Membranous Nephropathy
Most common entity causing nephrotic syndrome in adults 80% idiopathic 20% due to CA (solid organ, lymphoma, leukemia), Infections (HepB/C, malaria, syphylis, leprosy), Drugs (gold, penicillamine), Immune (SLE), sickle cell Immune complexes deposit in subepithelial areas of the GBM causing thickening of the GBM and formation of new BM around the deposits.

Membranous GN-contd.
1/3 with idiopathic Membranous GN achieve spontaneous remission, 1/3 has stable renal function while 1/3 progress to develop renal

failure (60% renal failure free at 15yrs) Treatment is with corticosteroids combined with immune modulating agents (Chlorambucil, cyclophosphamide etc)

Membranous GN-Renal Biopsy

Thickened capillary loops, spikes

Granular IgG deposition on IF

Focal Segmental Glomerulosclerosis

Accounts for 7-20% of nephrotic syndrome in children, but up to 35% cases in adults Proteinuria can be variable Most common cause of nephrotic syndrome in African Americans Pathologic hallmark is glomerular scarring in some glomeruli (focal lesions) and in some parts of a single glomeruli (segmental lesions) on light microscopy Under electron microscopy, effacement of podocyte foot processes are seen in all glomeruli

FSGS-contd.
Secondary causes are HIV, Heroin, Sickle cell, single kidney, aging kidney, reflux nephropathy. Treatment is controversial. Corticosteroids and immunosuppresive agents have been tried with some success, but typically,

management is via control of associated hypertension and proteinuria Most develop renal failure within 5-20 years.

FSGS-Renal Biopsy

Diabetic Nephropathy
Usually clinically diagnosed in patients with

macroalbuminuria ( proteinuria >0.3g/24hrs), history of DM >10yrs with signs of other microvascular complications (best predictor is presence of DM retinopathy) In Type 1 DM patients, 30-45% with microalbuminuria will progress to overt proteinuria within 10 yrs ( 20-25% may revert to normal while the rest remain microalbuminuric) Pathologic lesions appear to be mainly 2nd to accumulation of Extracellular Matrix (occurs in GBM and Tubular BM) leading to mesangial and interstitial expansion.

Diabetic Nephropathy-contd.
In renal biopsies, classical changes are Kimmelstiel-Wilson nodules (nodular mesangial expansion), arteriolar hyalinosis

(replacement of smooth muscle walls of arterioles with hyaline) Management is via control of attendant diseases (hypertension), reduction of proteinuria (ACEi) and most importantly good DM control.

Diabetes-Renal Biopsy

Kimmelstiel-Wilson nodules with glomerulosclerosis. Linear deposition of IgG on IF

Nephrotic Syndrome Complications

Hyperlipidaemia
Increased T.Chol and Trig, often also with lipoprotein

(a) Total HDL usually normal or slightly reduced LDL component is raised Enhanced liver lipoprotein generation combined with decreased catabolism is thought to be the cause of the abnormal lipid profile The lipid abnormalities resolve with treatment of the underlying disease Can treat symptomatically with the administration of HMG-CoA reductase inhibitors and bile acid sequestrants (cholestyramine)

Nephrotic Syndrome Complications-contd

Hypercoagulability
Risk of all thrombosis is increased, but especially Deep Vein

Thombosis and Renal Vein Thrombosis Risk is highest with Membranous GN > MPGN > Minimal Change Risk is Duration / Severity of the nephrotic state Risk is increased when serum Albumin <2g/dL Increased loss of ATIII, protein C, protein S and plasminogen, increased platelet activation, hyperfibrinogenemia and inhibition of plasminogen Even with the increased risk, no evidence exists to suggest the role of prophylactic anticoagulation in asymptomatic patients.

Malnutrition

Summary

Glomerulus and podocyte biology How to suspect glomerular pathology Nephrotic vs. Nephritic Differential diagnosis of glomerular diseases Representative glomerular diseases Nephrotic Syndrome Complications of Nephrotic Syndrome Diseases that often present with nephrotic syndrome

IgA Nephropathy Membranoproliferative GN Post infectious GN Rapidly Progressive GN

NEPHRITIC SYNDROME

IgA Nephropathy
Bergers Disease, described in 1969 Most common GN worldwide, with preponderance

in Asian populations ( less in African populations) Typically in 2nd-3rd decade of life, M=F 2nd IgA Celiac disease, IBD, Sjorgens, chronic infections, CA, Lymphoproliferative diseases Defined pathologically by glomerular mesangial deposition of IgA (typically polymeric IgA, subclass 1)

IgA Nephropathy Contd.

Clinically manifested as
microscopic haematuria Often associated with concurrent pharyngitis

(synpharyngitic) Possibly caused by abnormal glycosylation of IgA Deposition of IgA in the mesangium triggers complements and leads to mesangial cell and inflammatory cell recruitment Renal function worsens in 40%. 50% of people develop ESRD in 20yrs Treatment unclear, but typically consists of ACE/ARB, hypertension control. Other possible treatments that may work are fish oil, corticosteroids, tonsillectomy.

IgA Renal Biopsy

Mesangial hypercellularity with IgA deposits noted in Immunoflourescence.

Membranoproliferative GN
aka Mesangiocapillary GN Can be Primary or Secondary 3 types:
MPGN Type 1 Type 2 (Dense Deposit Disease, more in Paediatrics) Type 3

Thickened capillary walls, mesangial proliferation,

increased cellularity, lobulation Type 1 (most common)

Hep C. Subendothelial deposits

Type 3
Subendothelial and subepithelial deposits

Membranoproliferative GNcontd.
Secondary MPGN
Lupus, Hepatitis C, Hepatitis B, cryoglobulins, SBE,

syphylis, malaria, schistosomiasis, leukemia, lymphoma

Can present as nephrotic or nephritic or with features of both.
Patients have a variable rate of renal deterioration with 10yr

renal survival at around 60%

There is no proven therapy other than treating the underlying

disease (if any) and controlling the proteinuria.

MPGN Type 1 Renal Biopsy

Light micrograph in membranoproliferative glomerulonephritis showing a lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls (small arrows). Courtesy of Helmut Rennke, MD.

Granular deposits of c3, IgG and IgM in capillary walls

Postinfectious GN
Typically leads to a nephritic presentation Can present as Rapidly Progressive GN Pathologically, can be
Proliferative with crescents Proliferative without crescents Membranoproliferative GN

Classically, most common offending organisms are

streptococcus species (esp. S.pyogenes) Clinically, rapid onset of acute nephritic syndrome 10-20d after pharyngeal or cutaneous infection. Spontaneous recovery is the rule

Post-Strep GN-Renal Biopsy

Hypercellular and enlarged glomeruli

Granular IgG, IgM, c3 deposition with subepithelial deposits (humps) seen on EM

Rapidly Progressive GN (RPGN)

Defined by the presence of Crescents seen in the renal biopsy (thus also known as Cresentic GN) Crescents are proliferation of cells within Bowman's Capsule that include both mononuclear cells as well as epithelial cells. Crescent formation is caused by glomerular rupture, thus is an indication of severe injury. Leads to >50% loss of renal function within weeks-months.

RPGN-contd.
Immune mediated
Anti-Glomerular Basement Membrane GN Immune Complex GN Lupus Postinfectious GN

Pauci-immune GN (circulating ANCA, no Ig

staining on IF)
Microscopic Polyangiitis Wegener's Granulomatosis Churg-Strauss syndrome

RPGN-Renal Biopsy