Acute Renal Failure

Terry Cook

Imperial College London

Acute Renal Failure

• Rapid loss of glomerular filtration and tubular function leading to abnormal water, electrolyte and solute balance

• Occurs over hours to days• Usually associated with oliguria. Some

patients develop non-oliguric ARF eg. After radiocontrast media

• Acute-on chronic renal failure

Aetiology of ARF

• Pre-renal

• Renal– Glomerular– Tubulointerstitial– Vascular

• Post-renal

Aetiology of ARF• Glomerular

– RPGN

• Tubulointerstitial– Acute tubular necrosis– Acute tubulointerstitial nephritis– Infection– Cast nephropathy

• Vascular– Thrombotic microangiopathy– Cholesterol emboli– Vasculitis

Rapidly Progressive Glomerulonephritis (RPGN)

• RPGN is a clinical term for clinical manifestations that suggest severe crescentic glomerulonephritis

• Crescentic glomerulonephritis – may be used for glomerulonephritis with any crescents but WHO suggests >50%

Crescentic glomerulonephritis

• Crescents are an indication of severity of glomerulonephritis rather than its cause

• Complete pathological diagnosis requires analysis of immunofluorescence, electron microscopy and serology

Natural history of crescents

Breach in integrity of GBM – ROS, proteases etc from inflammatory cells

Cells and fibrin in Bowman’s space

Accumulation of macrophages and proliferating epithelial cells

Apoptosis of cells and laying down of collagenFibrocellular crescents and fibrous crescents

Causes of crescentic glomerulonephritis

• Anti-GBM disease

• Immune complex disease

• Pauci-immune

Frequency of types of crescentic GN

Any Crescents

>50% crescents

Arteritis in Biopsy

Anti-GBM 5% 11% 3%

Immune complex 49% 29% 14%

Pauci-immune 47% 61% 84%

After Jenette and Falk

Frequency of types of crescentic GN

Age (years)

10-19 20-39 40-64 >65

Anti-GBM 15% 24% 2% 11%

Immune complex 50% 48% 30% 8%

Pauci-immune 35% 28% 69% 82%

Crescent formation in different glomerular diseases

Patients with any crescents

Patients with >50%

crescents

Anti-GBM disease 95 81

Pauci-immune (ANCA-associated) 90 48

Lupus GN (class III and IV) 40 11

Henoch-Schonlein purpura 53 5

IgA nephropathy 27 5

Postinfectious GN 25 3

Fibrillary GN 20 7

Type I membranoproliferative GN 20 3

Crescentic GN – Differential diagnosis

Light microscopy

Immuno-fluorescence

Other

Anti-GBM Synchronous crescents

Linear IgG and C3

Circulating anti-GBM antibody

Pauci-immune Focal and segmental necrosis

+/- vasculitis

Scanty ANCA

Immune complex

Focal and segmental or global hypercellularity

Various Various

e.g lupus serology, cryoglobulins etc

Anti-GBM disease

• Presents with RPGN often accompanied by lung haemorrhage

• Rare disorder (1 pmp) predominantly in Caucasian populations

• Characterised by circulating and deposited anti-GBM antibodies

Immune complex crescentic GN

Immunofluorescence Electron microscopy Clinical

Lupus WHO Class III or IV “Full House” Deposits at all sites

Tubulo-reticular bodies

Serology, anti-C1q etc

Henoch Schonlein purpura IgA, C3 Mesangial +/- capillary wall deposits

Rash, arthralgia, abdominal pain

IgA nephropathy IgA, C3 Mesangial +/- capillary wall deposits

History of sore throat

Membranoproliferative GN

Type I

Capillary wall C3 +/- others

Subendothelial deposits

Double contours

Infections eg. Hep C

Cryoglobulins

Post-infectious GN Capillary wall C3 +/- IgG

“humps” ASOT

Fibrillary GN Mesangial IgG, C3 Fibrils

Pauci-immune crescentic GN

• Basic lesion is focal and segmental necrosis

• Often associated with vasculitis either in kidney or elsewhere

Pauci-immune crescentic GN - syndromes

1. Limited to kidney

2. Microscopic polyangiitis – necrotizing vasculitis in other systems including skin, mucous membranes, lungs, brain, gastrointestinal tract and muscle

3. Wegener’s granulomatosis – similar lesions to microscopic polyangiitis together with necrotizing granulomas of the upper and lower respiratory tract

4. Churg-Strauss syndrome – history of asthma or allergic rhinitis and blood eosinophilia

N.B. These syndromes cannot be distinguished on the basis of renal histology

ANCA in small vessel vasculitis

IIF pattern: C-ANCA P-ANCAAntigen: Proteinase 3 MyeloperoxidaseSyndromes: WG,MP MP, renal-limited vasculitis

Clinical studies of ANCAClinical studies of ANCA

• Specific and sensitive marker for systemic vasculitis

• ANCA pattern and specificity correlate with clinical features

• Levels correlate with disease activity and extent

• Rising levels predict relapse

European Vasculitis Study Group biopsy findings

• Biopsies from 96 patients with ANCA-associated vasculitis and creatinine <500mol/l

• Studied – GFR0 – GFR at presentation

– GFR18 – GFR at 18 months

– CORGFR18 – GFR at 18 months corrected for GFR0

European Vasculitis Study Group biopsy findings

• Predictors for GFR0

– %normal glomeruli– %glomeruli with crescents– Extent of tubular atrophy and interstitial

fibrosis

European Vasculitis Study Group biopsy findings

• Predictors for CORGFR18

– % glomeruli with fibrinoid necrosis– % glomeruli with cellular crescents– Tubulointerstitial inflammation

• Tubular atrophy and interstitial fibrosis did not predict CORGFR18 even though they correlated with GFR18 implying that this was dependent on GFR0

European Vasculitis Study Group biopsy findings

• In ANCA GN the best histological predictors of long-term renal function are– Normal glomeruli, glomerulosclerosis,

interstitial fibrosis and tubular atrophy

• The best predictors of the improvement in renal function from 0 to 18 months are– Crescents, fibrinoid necrosis and interstitial

inflammation

Acute tubular necrosis

• Prolonged hypoperfusion• Drugs – NSAIDs, ACE inhibitors• Direct toxicity

– Drugs – eg. Aminoglycosides, cisplatin– Radiocontrast agents– Haem pigments– Snake venom– Heavy metals – lead , mercury

• Associated with nephrotic syndrome

Acute tubular necrosis

Tubular dilatationLoss of brush borderEpithelial cell vacuolationDetachment of epithelial cellsGranular casts

Hyperchromasia of tubular nucleiMitosesCalcification

Interstitial oedemaInterstitial inflammation

Nucleated rbcs in vasa recta

Acute tubulointerstitial nephritis

• Infectious eg. HIV, BKV, fungi, TB

• Drugs

• Post infectious

• SLE

• ANCA associated

• With uveitis (TINU)

Acute tubulointerstitial nephritis

• Interstitial infiltrate of mononuclear cells– Mainly T cells and macrophages

• Tubulitis

• +/- eosinophils

• May rarely be anti-TBM antibodies

Granulomatous tubulointerstitial nephritis

• Infectious

• Sarcoidosis

• Drugs

• Idiopathic

Myeloma Cast Nephropathy

• Light chains precipitate in tubules• Casts are large and eosinophilic – may be

fractured or fragemented• Multinucleate giant cells my be found

adjacent to casts• In some cases the casts may stain for

amyloid• Interstitium typically shows an infiltrate of

lymphocytes and macrophages

Thrombotic microangiopathy

• Haemolytic-uraemic syndrome– Infection – particularly verotoxin-producing E. coli– Drugs – CNIs, mitomycin– Transplant rejection– Antiphospholipid antibodies– Post-partum– Factor H deficiency– Bone marrow transplantation

• Thrombotic thrombocytopenic pupura• Malignant Hypertension• Scleroderma

Thrombotic microangiopathy

• Glomeruli– Thrombosis– Trapped fragmented rbc– Thickened capillary walls with subendothelial fibrin– Ischaemic changes

• Arterioles – fibrinoid• Interlobular arteries – loose intimal thickening

Cholesterol emboli

• Common cause of unexplained renal failure in elderly

• Predisposing factors– Trauma eg catheterisation, surgery– Anticoagulation– Spontaneous

• May be slowly progressive• May involve glomeruli