Case 2 Erik Heyerdahl Strøm Division of Pathology Willy Aasebø Department of Nephrology Oslo University Hospital, Rikshospitalet Norway Co-author Lars Ola Thorud Innlandet Hospital, Lillehammer

Case history -1 Male, born : Nephritis, creatinine >500, SR 120, C-ANCA: positive Renal biopsy

Initial biopsy native kidney 2002 Fibrocellular crescents

Initial biopsy native kidney 2002 Fibrocellular crescents

Initial biopsy native kidney 2002 Immunofluorescence: Negative

Initial biopsy (EM) native kidney 2002 No electron dense immune deposits

Diagnosis native kidney biopsy 2002 Focal segmental necrotizing glomerulonephritis with fibrocellular crescents without immune deposits. Consistent with ANCA-related glomerulonephritis as in Wegener’s granulomatosis

Case history -2 Hemodialysis from – August 2002 Kidney transplantation – January 2006

Case history -3 November - December 2008: gradually increased dyspnoea + oedema, anaemia, and fever. S-creatinine: 120 to 180 µmol/l C-reactive protein: 15 to 70 mg/l Protein/creatinine (urine): 60 to 400 mg/mmol Urine microscopy: Nephritic sediment.

Due to increase in s-creatinine and proteinuria A graft biopsy was obtained 6 weeks after debut of symtoms

What to consider in a transplant biopsy Acute rejection? cellular rejection (T-cell mediated) antibody-mediated rejection (C4d) Chronic rejection? Ischemia? Drug toxicity? CNI (CyA, tacrolimus)? Antibiotics? Infection? Virus (polyoma, CMV) Systemic infection? De novo nephritis? Recurrence of native disease? Other? (Post transplant lymphoproliferative disease - PTLD)

Minimal tubulitis No vasculitis Biopsy of the transplant

Double contour capillary wallMesangial cell interposition Transplant glomerulopathy

Necrosis? Thrombotic material?

Cellular crescent

Diagnosis based on light microscopy No acute rejection (C4d negative) Transplant glomerulopathy Focal necrotizing glomerulopathy with few cellular crescents (thrombi?)

Immunfluorescence (paraffin block) C1qC3 IgA, IgG and IgM were negative

Electron microscopy No glomeruli in the material submitted for EM EM therefore performed on material retrieved from the paraffin block

Electron microscopy (paraffin block) Transplant glomerulopathy (doubling of basement membrane)

Electron microscopy (paraffin block) Mesangial deposits

Subendothelial deposits

Biopsy diagnosis of transplant No definite acute rejection (i1 t1 v0, C4d negative) Transplant glomerulopathy as in chronic rejection Focal necrotizing glomerulonephritis with cellular crescents in 2 of 13 glomeruli (obs thrombi)

Biopsy diagnosis of transplant Consider Recurrence of Wegener’s granulomatosis Systemic infection Thrombotic microangiopathy

Possible diagnosis -1 Thrombotic microangiopathy ? TTP/HUS?

Thrombotic Microangiopathy after Tx As a complication to CNI`s: %. Usually during the first weeks after Tx. Other medicines Acute rejection Infection (viral, bacterial) Carcinoma Anti-cardiolipin antibodies (Associated with OKT3)

Case history -4 Hgb: 9,2. Thrombocytes: Lactate dehydrogenase: 356 U/l, Bilirubin: 15 µmol/l, (Haptoglobine: not analyzed) No symptoms from CNS Conclusion: no TTP-HUS! ! Few crescents are found in 5% of HUS!

Possible diagnosis -2 Recurrence of Wegener’s granulomatosis?

ANCA positive vasculitis after Tx N=35 with ANCA-associated vasculitis 20: microscopic polyangitis 15: Wegener Median time from diagnosis to Tx: 25 months 15: ANCA positive at Tx Overall graft survival 5 years: 94% Death censored graft survival: 100% Relapse: Microscopic polyangitis: 1/20, Wegener: 2/15 All relapses: Non-renal Gera M. Kidney int. 2007

Patient and Graft survival after renal transplantation in Wegener, PKD, IgA-nephropathy and diabetes Schmitt W, Curr Opin Rheumatol, 2003

Case history -5 ANCA: negative PR3 and MPO: <9 (negative) ANA: negative Anti GBM: neg C3 : 1.44 g/l (0.80 – 2.00) (normal) C4: 0.28 g/l ( ) (normal) Conclusion: No recurrence of Wegener

Possible diagnosis -3 Systemic infection?

Case history -7 Bacterial growth in blood cultures: - Streptococcus sanguis

Dr. S. Urheim, Dept. of Cardiology, Rikshospitalet Ultrasound of the heart

Dr. S. Urheim, Dept. of Cardiology, Rikshospitalet

Case history -8 Ecco-cardiography: aortic valve with vegetations on all three cusps. Endocarditis!!!

Possible diagnosis -3b Renal affection related to endocarditis

Renal disease in infective endocarditis Embolic disease --Microbiological emboli Drug-induced disease --Acute interstitial nephritis - antibiotics --Acute tubular necrosis - Aminoglycosides Postinfectious immune complex-mediated glomerulonephritis

Renal pathological findings in infective endocarditis 354 Patients with endocarditis 62: Renal tissue for examination (20+42) Majumdar A, NDT 2000 Findings in the KidneyRenal biopsy (n=20)Autopsi (n=42)Total (n=62) Localized infarction019 Acute glomerulonephritis9716 Acute tubular damage4812 Cortical necrosis066 Acute Interstitial nephritis516 Pre-existing glom disorder or Hydronephrosis Normal Kidney033

Postinfectious glomerulonephritis in general Previously associated with streptococcus. Now: associated with several infectious syndromes and a wide variety of bacteria, fungi, viruses and parasites.

Postinfectious glomerulonephritis clinical manifestations Acute Nephritic Syndrome. --Hematuria, proteinuria, edema, often hypertension, and a mild degree of kidney injury Rapidly progressive nephritic syndrome --Rare (4,6% of biopsies). Rapidly increase in s-creatinine. Crescent formation (often limited) Subclinical or asymptomatic glomerulonephritis --Low grade proteinuria, microscopic hematuria times as common as “classic acute nephritic syndrome”

Postinfectious glomerulonephritis histological findings In light microscopy: - diffuse exudative proliferation without crescents - diffuse endocapillary proliferation with crescents -mild segmental, mesangial proliferation -membranoproliferative glomerulonephritis Immunofluorescence: -most commonly: deposition of C3 often IgG, -occasionally: IgM, rarely: IgA (except in patients with diabetes-particularly Staphylococcal infections) - “Full house”: IgG. IgA, IgM, C3, C4 and C1q is frequently reported Electron microscopy: -mesangial, subendothelial and ”humps” Kanjanabuch T, Nature Reviews Nephrology, 2009

Final diagnosis : Postinfectious glomerulonephritis related to acute endocarditis Transplant glomerulopathy

Case history -9 Treatment: Penicillin + Gentamycin for 6 weeks : removal of the affected aortic valve: Implant: biological aortic valve 8 months after surgery: S-creatinine: 128 µmol/l Urea: 11.5 mmol/l

Take home message 1: Focal glomerulonephritis with crescents -----Don’t forget infection ! 2: ANCA-associated vasculitis vs. postinfectious glomerulonephritis: -----Correct diagnosis is pertinent; treatment and outcome different 3: Histological findings must always be considered in concert with clinical findings

Thank you for your attention