Glomerular Diseases Glomerular Diseases

Dr. Paula BlancoDr. Paula Blanco

&&

Dr. Peter MagnerDr. Peter Magner

April 27th, 2015

1491 List and describe the clinical syndromes with which patients with glomerular disease may present and name actual diseases for

each syndrome.

1492 Explain the effect of glomerular changes on normal glomerular function, i.e. how the changes in the glomerulus affect the following: proteinuria, hypoalbuminemia, edema, hematuria, hypertension, hyperlipidemia and glomerular filtration rate.

1494 Describe an immunopathogenic mechanism involved in one of the various forms of glomerulonephritis and how it affects glomerular morphology.

1913 Propose a diagnostic approach for a patient with hematuria, and differentiate glomerular from non glomerular hematuria. 

2879 Define nephrotic syndrome.

Objectives

Manifestations of Glomerular Disease

• Proteinuria

• Hematuria

• Hypertension

• Decreased GFR– Rapid/acute– Slow/chronic

Proteinuria

• 3+ protein on dipstick:– What protein(s)?– How much?

– Where from?– What diseases?

What proteins?

• Small plasma proteins (freely filtered)

– enzymes– light chains– etc.

• Albumin (should not be filtered)

• Immunoglobulins (IgG) (should not be filtered)

Normal Renal Handling of Protein

• Albumin: < 15 mg / 24 hr

• other small proteins: < 100 mg / 24 hr

So 24 hour urine protein < 150 mg

* more small proteins are filtered, but most is reabsorbed

Quantifying Proteinuria

• Traditional to use 24 hour urine protein– Inconvenient, expensive, innaccurate– Should factor for body size

(but many do not in adults)

• Random urine: • Protein:creatinine ratio “PCR”

or • Albumin:creatinine ratio “ACR”

Proteinuria

• Tubular proteinuria – up to 1 gm/ 24 hr mixed small proteinsPCR 30 – 100 mg/mmol but ACR low

• Glomerular proteinuria– Albumin is the majority

• normal glomeruli can leak albumin transiently with fever, exercise, severe CHF

Stages of Diabetic renal involvement according to the urinary albumin  

Stage of nephropathy

Urine dipstick for

protein

Urine ACR(mg/mmol)

24-hour urine collection for

albumin*

Normal Negative <~ 30 mg/day

Mild (“Microalbuminuria”)

Negative ~ 30–300 mg/day

Overt nephropathy(“macroalbuminuria” )

+, ++, +++

++, +++, +++

+++, ++++

>~ 300 mg/day 

>~ 1000 mg/day

>~ 3000 mg/day

 

< 3

3 - 30

30 – 60

>60

> 200

Nephrotic Syndrome

• proteinuria (mostly albumin)– ACR > 200 or PCR > 300

(traditional threshold is > 3 gm /24 hr)

• hypoalbuminemia• edema• hyperlipidemia (mostly LDL)• lipiduria

• THIS MEANS GLOMERULAR DISEASE

Manifestations of Glomerular Disease

• Proteinuria (albuminuria)

– If severe may have other features of nephrotic syndrome

• Hematuria• Hypertension• Decreased GFR

– Rapid/acute– Slow/chronic

Glomeruli

• Anatomy

• Mechanisms of injury

• Pathological changes

Normal Glomerulus

Capillary Capillary lumenlumen

Immune Mechanisms in Glomerular diseases

• Circulating immune complex deposition– most common mechanism (~ 70% of all

glomerulonephritis)– many different diseases have a similar

pathogenesis in terms of immune complexes activating complement

– antigens may be endogenous or exogenous

Circulating immune Circulating immune complex depositioncomplex deposition

GBMGBM

Immune Complex Deposition

• Sites of deposition may be:– subendothelial– mesangial– subepithelial

• Immune complexes may be detected by immunofluorescence or by electron microscopy

Subepithelial deposits

IgG

Expansion of mesangial areas

IgA

IgA

Anti-GBM Autoantibodies

• antigen is part of collagen IV in the GBM

• antigen also in alveolar basement membranes, hence lung + kidney syndrome

• autoantibody (IgG class) fixes to GBM forming an in situ immune complex, activates complement

• antibody can be detected in kidney and in serum

IgG

Clinical- Pathological relationships

• 3 cases as examples

Case 1

• 22 year old woman complaining of swelling of the legs and a 9 kg weight gain

• no shortness of breath

• B.P. 120/70, weight 69 kg

• serum albumin 20 gm /L

• serum creatinine 80 umol/L

Case 1

• Urinalysis findings:– 4+ protein– 0-2 RBC’s/HPF

• random urine ACR 450 mg/mmol

(PCR 600)

Why do a renal biopsy?

• Prognosis:– many different diseases present in similar ways– some are relatively “benign”, others progressive to chronic

renal failure– some diseases (e.g.. SLE) have different degrees of

severity

• Treatment– some are treatable and some are not– some diseases require immediate treatment with potentially

toxic drugs

How is a renal biopsy done?

• done with biopsy gun under U/S guidance

• tissue divided up for examining by:– light microscopy– immunofluorescence– electron microscopy

• complications rare, most important is bleeding requiring transfusion, or embolization

Light microscopy

Immunofluorescence

                                                                    

Electron Microscopy

Normal glomerulus

Thickened basement membranes

““Spikes” along GBMSpikes” along GBM

IgG - Granular GBM pattern

Subepithelial Subepithelial dense depositsdense deposits

LumenLumen

Case 1Case 1““PurePure”” Nephrotic Syndrome Nephrotic Syndrome

• Clinical Differential diagnosis (before we did the biopsy) includes:

• minimal change glomerulopathy• focal glomerulosclerosis (FSGS)• Membranous glomerulopathy• IgA nephropathy (usually hematuria too)

• Diabetes (should be able to diagnose this without a biopsy!)• Amyloidosis (rare)

Case 1Case 1““PurePure”” Nephrotic Syndrome Nephrotic Syndrome

Pathology Diagnosis:

Membranous Glomerulopathy– Usually ”primary”– Sometimes “secondary”

(we’ll come to this later)

Nephrotic Proteinuria - Points to remember

• High ACR implies glomerular pathology• glomerular changes in all causes of nephrotic

syndrome include – visceral epithelial cell “foot process fusion”

• features such as immune complex deposition point to specific disorders

• Permeability changes in GBM that permit heavy proteinuria may or may not be associated with breaks large enough for hematuria

What about lesser degrees of proteinuria?eg. PCR < 150 ( < 1.5 gm/24 hr )

• Tubular proteinuria? (< 50 % albumin)

• Normal glomeruli (transient albuminuria)

• Non-nephrotic glomerular diseases– Suspect if other clues that point to glomerular

disease• Hematuria (especially with RBC casts) • hypertension • decreased GFR• Systemic illness that may be associated with

secondary glomerular involvement

Case 2

• 27 year old east asian man complaining of recent onset of dark colored urine

• had flu-like illness with sore throat 3 days ago

• no frequency or dysuria (pain on urination)

• feels well

Case 2Physical Examination

• BP 130/80

• no skin rashes

• no edema

• rest of exam normal

Case 2Laboratory findings

• Urinalysis:– 1+ proteinuria– 20-30 RBC’s / HPF

• urine ACR 50 mg/mmol (~750 mg/24hr)

• serum creatinine = 116 umol/L

• Hb = 126 gm/L

Case 2Special Laboratory Studies

• ANA - negative

• Complement levels normal

• Streptococcal serology negative

Increased mesangial matrix - Mesangial proliferation

Increased mesangial matrix - Mesangial proliferation

IgA

Mesangial dense deposits

Lumen

RBCRBC

Mesangial dense deposits

Case 2Case 2Clinical presentation: “Nephritic” syndrome: some or all of

• Hematuria, • mild proteinuria, • reduced GFR• high BP

Pathology Diagnosis:

IgA Nephropathy–Mesangial proliferation on LM– IgA deposits on IF – dense deposits EM

How can we classify glomerular diseases?

• Clinical presentation (but lots of overlap)

– Nephrotic– Nephritic– rapidly progressive (~ bad nephritic)

• Etiology – Primary vs. Secondary

• Pathology

Pathologic Classification of GN• Usually Nephrotic

– Minimal change– Focal segmental glomerulosclerosis (FSGS)– Membranous

• Usually Nephritic– Mesangial proliferative (IgA)– Diffuse proliferative +/- crescents

• Others – diabetes, amyloid– Etc…

Secondary Causes of GN

• Infections– Viruses: HBV, HCV, HIV, – malaria, bacterial endocarditis– post-streptococcal

• Drugs- NSAIDs• Neoplasia (a “paraneoplastic syndrome”)

• SLE & vasculitis• Diabetes• Amyloidosis (may be associated with myeloma)

Case 3

– 72 year old woman admitted to hospital with recent history of increasing fatigue, weakness and swelling of legs

– no joint pains, skin rashes or shortness of breath

– serum creatinine one year ago was 160 umol/L

Case 3

• Physical Examination– BP 160/88, pulse 78/min & regular,

afebrile– peripheral edema to knees– rest of exam normal

Case Studies - 3

• Laboratory Findings– Hemoglobin 91 gm/L– Serum Creatinine 364 umol/L– Urinalysis -

• 3+ protein• 30-40 RBC’s/HPF and RBC casts

– Urine ACR 100

RBC castRBC cast

Normal glomerulus

Crescent formation

Crescent

Crescent

IgG

Crescentic Glomerulonephritis

• Pathologic manifestation of many different diseases

• Three groups by immunofluorescence– Linear antibody deposits along the GBM:

• Anti-GBM (+/- lungs involved)

– Immune complexes (esp. SLE, infections)– No (or very few) immune deposits: “Pauci-immune”

• Vasculitis

Rapidly Progressive GN

• the clinical correlate of crescentic GN

– proteinuria (usually PCR < 150 )– active urine sediment

• RBC’s, casts (granular casts, RBC casts)

– decreased GFR (days to weeks)– usually feel “sick”

Case 3Case 3Clinical presentation: RPGN (rapidly Progressive GN)- Nephritic syndrome with rapidly worsening GFR

Pathology Diagnosis:

Anti GBM syndrome with– inflammation & crescents on LM– Linear IgG along GBM on IF – often not much on EM

Clinical- Pathological relationships

3 cases as examples of

•Nephrotic presentation

•Nephritic presentation

•RPGN

Summary

Manifestations of Glomerular Disease

• Proteinuria– Mostly albuminuria

+/- edema, hypoalbuminemia, hyperlipidemia

(“nephrotic syndrome”)

• Hematuria (usually microscopic +/- casts)

• Hypertension• Decreased GFR

– acute: consider “RPGN” (with crescents on biopsy)

– chronic

Syndromes (presentations) of Glomerular Disease

• Nephrotic Syndrome– Lots of proteinuria (ACR>200)

+/- edema, hypoalbuminemia, hyperlipidemia

• Nephritic Syndrome– hematuria (usually microscopic +/- casts)

– Proteinuria: ACR usually 30-200; – High BP (usually)

– Declining GFR (usually)

• RPGN– Severe Nephritic syndrome with rapid decline in

GFR

Hematuria

• Urologic

(plumbing)Microscopic or GrossClots very suggestiveOften pain or other

plumbing symptomsOccasionally “initial”

or “terminal”

• Nephrologic (interesting diseases)Usually microscopicCasts are very specific

(but not sensitive)Proteinuria is very

suggestiveConsider if systemic

illness (eg. Lupus)

Think anatomically from glomerulus down to urethra Then think about aetiology, investigations/referral