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
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