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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:!

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Clinical effects of glomerular disease

… clinical signs of renal disease are often 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

Tubularmetabolism(saturable)

ProteinuriaGlomerular filtration barrier

Albuminβ2 microglobulinIg light chain

67kD12kD25kD

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

Haematuria

and microscopy

Causes haematuria

INFECTIONCANCERStonesTrauma

Interstitial disease (incl. papillae)

Glomerular disease inflammatory degenerative

Vascular malformation

TumourCysts

Infarction

Clotting disordersMyoglobinMetabolites (porphyria)Colour (eg beetroot)Drugs

HAEM

ATUR

IA

Repeat if could be:!Exercise Menstruation

Schematic glom

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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

PodocyteMembranous nephropathy

GBMGoodpastureʼs disease

Endothelium?Small vessel vasculitis

Circulating immune complexesCryoglobulinaemiaSerum sickness?Endocarditis

Planted antigens?SLE?infections

The glomerulus has a restricted range of responses to injury

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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

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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!

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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 �!

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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!

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•  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 (Goodpasture�s) 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!

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Scarred kidneys

Beth Shortt

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•  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!

!