Glomerulonephritis notes ! Neil Turner ! University of Edinburgh ! - - PDF document

24/10/2013' 1'

Glomerulonephritis notes!

Notes to accompany online lectures at edrep.org/resources. They won’t make so much sense without seeing those. ! !

This work carries a Creative Commons Attribution-Noncommerical-Share Alike 2.5 UK: Scotland license. That means you may re-use it for non-commercial purposes as long as you clearly attribute it to us. For all other uses, contact us at renal@ed.ac.uk!

Neil Turner!

University of Edinburgh! www.edren.org www.edrep.org !

Glomerulonephritis 1 Neil Turner

Beth Shortt

Pre-renal

!

Heart failure! Shock !!

Systemic diseases !

Many and various:! Inflammatory/ immune! Metabolic! Other!

Collecting system and lower !

Congenital! Infection! Stones! Inflammation! Tumour!

Renal vasculature

!

Arterial stenosis! Venous thrombosis! Disease of arterioles!

Glomerular

!

Primary disease! Component of systemic disorder

!!

Interstitial

!

ATN (misnomer)! Toxic! Infective! Inflamm./ immune! Inherited!

Diseases of the urinary tract

• Leaky glomeruli!

– Proteinuria, haematuria!

• High blood pressure!
• Loss of GFR!

Glomerulonephritis causes: !

• It causes 25%+ of end stage renal

failure!

• It is treatable!

It is important because: !

24/10/2013' 2'

Clinical effects of glomerular disease

… clinical signs of renal disease are

• ften late or non-specific

Physical signs: problems with fluid

Increased intravascular fluid ! This and similar figures from Kinsey Smith

Physical signs: problems with fluid

Increased extravascular fluid ! (e.g. nephrotic syndrome, liver failure, generalized chronic volume overload) !

Physical signs: loss of filtration

Proteinuria

> 60kD < 20kD

Tubular metabolism (saturable)

Proteinuria

Glomerular filtration barrier Albumin β2 microglobulin Ig light chain 67kD 12kD 25kD

24/10/2013' 3' Glomerular proteinuria

• Albumin is the hallmark
• Albuminuria may be transient in:

– Fever, CHF, exercise – Orthostatic

• Otherwise implies significant glomerular

disease … and microalbuminuria

Glomerular proteinuria

• Microalbuminuria can be helpful

– occurs before overt proteinuria in glomerular disease – also in vascular disease (why?)

• Quantity is helpful

Proteinuria: quantitative

per 24h prot/creat

• rigin

<150mg <15 normal 1-3g 100-300 equivocal >3g 300mg/mmol glomerular

Haematuria

and microscopy

Causes haematuria

INFECTION CANCER Stones Trauma Interstitial disease (incl. papillae) Glomerular disease inflammatory degenerative Vascular malformation Tumour Cysts Infarction Clotting disorders Myoglobin Metabolites (porphyria) Colour (eg beetroot) Drugs

HAEMATURIA

Repeat if could be:!

Exercise Menstruation

Schematic glom

24/10/2013' 4'

Alp/N GBM

Alport/N GBM pic

Normal and Alport GBM ANT Pic of tablets

Urine analysis by cell sorter

There are some important!

• Inherited (e.g. Alport syndrome)!
• Metabolic (e.g. diabetes)!
• Other!

causes of glomerulopathies, but …..!

Causes of glomerular disease !

The evidence for this is !

• Immunoglobulin deposits!
• Inflammatory cells!
• Response to treatment!
• Evidence from animal models!

– induced by immunisation/ sensitisation! – dependence on antibodies or CMI!

Most glomerulonephritis is autoimmune ! Antigens in glomerulonephritis

Podocyte Membranous nephropathy GBM Goodpastureʼs disease Endothelium ?Small vessel vasculitis Circulating immune complexes Cryoglobulinaemia Serum sickness ?Endocarditis Planted antigens ?SLE ?infections

The glomerulus has a restricted range of responses to injury

24/10/2013' 5'

Proteinuria Haematuria

The spectrum of glomerular diseases

Minimal change nephropathy Membranous nephropathy FSGS Diabetic nephropathy Small vessel vasculitis Post-streptococcal glomerulonephritis Anti-GBM disease MCGN SLE IgA nephropathy

Nephritic

Mechanism

• Inflammation
• Reactive cell

proliferation

• Breaks in GBM
• Crescent formation

Nephrotic

Mechanism

• Injury to podocytes
• Changed

architecture:

• Scarring
• Deposition of

matrix or other elements

Amyloidosis

www.edren.org

Glomerulonephritis 2 Neil Turner

Beth Shortt

Proteinuric diseases !

!

Haematuric diseases

! Individual glomerular diseases !

• Proteinuria > 3.5 g/day!
• Albumin < 30 g/l!
• Oedema!

!

!A variety of complications arise,

beginning at lower levels of

• proteinuria. !

Nephrotic syndrome !

Oedema (a manifestion)!

! !Sodium restriction, diuretics!

!

• 1. Infection!

! !Prevention, immunisation!

• 2. Thrombosis (venous, arterial)!

! !? anticoagulation!

• 3. Hyperlipidaemia!

! !? HMG CoA reductase inhibitors!

Complications of nephrosis !

PODOCYTE DISEASES!!

• Minimal change nephropathy!
• FSGS!
• Membranous nephropathy!

! SYSTEMIC DISEASES!

• Diabetes mellitus!
• Amyloidosis!

!

Causes of nephrotic syndrome !

24/10/2013' 6'

SCARRING !!

!

• after an inflammatory GN or other

cause of glomerular damage! ! !

Causes of nephrotic syndrome !

!

Establish cause!

!Renal biopsy usually required!

Treat cause ! !if possible! Treat / prevent oedema, complications! !!

Management of nephrotic syndrome !

Minimal change nephropathy !

• Normal light microscopy!
• Common in children (esp

Caucasian)!

• Usually steroid-responsive!
• Does not progress to renal failure!
• Focal !
• Segmental !
• GlomeruloSclerosis!
• Little scars!

FSGS: description not a diagnosis!

• Primary FSGS with nephrotic syndrome!
• Old focal injury and other disorders!

– Previous thrombotic microangiopathy ! – Microemboli! – HIV infection! – Morbid obesity! – Reduced nephron number!

FSGS!

• More common as age rises!
• Relatively (?completely) steroid-

resistant!

• May progress to ESRF!
• May recur after renal transplantation!

!

Primary FSGS + nephrotic syndrome !

24/10/2013' 7' Membranous nephropathy !

• Common cause of NS in adults!
• Autoantibody to podocyte antigen!
• Usually idiopathic, but secondary in!

– Reaction to gold, Hg, some other drugs! – As part of some other conditions! – Controversy about how often cancer-related!

• Outcome - 1/3 : 1/3 : 1/3

!!

Membranous: treatment !

• 1. Maximise ‘nephroprotection’!
• 2. Specific therapy!
• Alkylating agents!

– Cyclophosphamide, chlorambucil!

• Cyclosporin!

– Lowers proteinuria transiently!

• Rituximab (anti-B cell)!

– Anecdotally slow but may work! – No RCT evidence. Expensive, toxic!

3 nephritic diseases
 
 
 and 2 systemic ones !

Nephritis and nephritic syndrome

!

• Haematuria – always !
• Proteinuria – usually; requires podo

injury!

• Sodium (fluid) retention!
• Hypertension !

Features found to varying degrees in different conditions !

Primary glomerular diseases!

• Post-Streptococcal (classic nephritic syndrome)!
• IgA nephropathy!
• Goodpastures (anti-GBM)!

Systemic diseases!

• SLE!
• Small vessel vasculitis!

Nephritis and nephritic syndrome

!

• Follows Group A Strep infections!
• Full nephritic syndrome is characteristic,

but severity varies!

• Ig and complement deposits under flom

endothelium and epithelium!

• Low C3!
• Fluid retention prominent; diuretics useful!

!

Post-streptococcal GN

!

24/10/2013' 8'

• Very common!
• IgA in mesangium; cause unknown!
• Spectrum of presentations!

! !Mild to severe!

! !Asymptomatic haematuria to ESRF!

• No proven treatment!

!!

IgA nephropathy !

• Rare (1/million/y)!
• Autoantibody to α3 chain of type IV

(basement membrane) collagen!

• Renal or lung disease, or both

(Goodpasture syndrome)!

• Characteristically very RPGN!
• Plasma exch, cyclophos, steroid!

!!

Anti-GBM (Goodpasture’s) Disease !

• Small vessel vasculitis!
• SLE!
• Anti-GBM (Goodpastures) disease!
• Aggressive phase of other inflamm

nephritis (eg IgA, post-Streptococcal)!

!

Crescentic nephritis

!

Rapidly progressive glomerulonephritis, RPGN!

• Mesangiocapillary =!
• Membranoproliferative!
• Complex!!

What about MCGN (MPGN)? !

It’s not all over: Progressive deterioration after glomerular injury !

www.edren.org Scarred kidneys

Beth Shortt

24/10/2013' 9'

• Creatinine (or GFR) !
• Proteinuria!
• Hypertension!
• Degree of scarring – especially

interstitial scarring!

Prognostic markers in glomerular
 (and other renal) disease !

• Low protein diet

!not recommended!

• Lipid control !

!no, but justified anyway !

• Blood pressure

!YES!

• ACE inhibition

!YES!

Preventing progression of renal injury !

Music of GN with music – www.edrep/resources!

• or … !

historyofnephrology.blogspot.com – to read about!

• Dropsy (nephrotic syndrome)!
• The MDRD study; BP and dietary protein!

Links

!

www.edren.org www.edrep.org

neil.turner@ed.ac.uk!

!