Case 2

Erik Heyerdahl Strøm

Division of Pathology

Willy Aasebø

Department of Nephrology

Oslo University Hospital, Rikshospitalet Norway

Co-authorLars Ola Thorud

Innlandet Hospital, Lillehammer

Case history -1

Male, born 1955

2002: 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 biopsyAcute 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

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)

C1q C3

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 transplantConsider

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: -- 4-6 %. 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: 220 109 . 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 TxN=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 -5ANCA: 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 (0.10-0.50) (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

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 endocarditis354 Patients with endocarditis

62: Renal tissue for examination (20+42)

Majumdar A, NDT 2000

Findings in the Kidney Renal biopsy (n=20) Autopsi (n=42) Total (n=62)

Localized infarction 0 19 19

Acute glomerulonephritis 9 7 16

Acute tubular damage 4 8 12

Cortical necrosis 0 6 6

Acute Interstitial nephritis 5 1 6

Pre-existing glom disorder or Hydronephrosis

4 1+1 5+1

Normal Kidney 0 3 3

Postinfectious glomerulonephritisin general

Previously associated with streptococcus.

Now: associated with several infectious syndromes and a wide variety of bacteria, fungi, viruses and parasites.

Postinfectious glomerulonephritisclinical manifestationsAcute 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. 4-19 times as common as “classic acute nephritic syndrome”

Postinfectious glomerulonephritis histological findingsIn 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 -9Treatment: Penicillin + Gentamycin for 6 weeks

13.1-2009: 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