1. Case report no. 9. Recurrence of amyloid in a kidney allograft Eva Honsová Institute for Clinical and Experimental Medicine Prague, Czech Republic

2. Clinical history A 55-year-old man was admitted to the hospital for severe hypertension in 1989. He was well until half a year before when slowly progressing peripheral edema appeared. He didn’t consult his practitioner until he began to suffer from severe headaches with nausea, and blurred vision. 210/130mmHg proteinuria 6g/day, S-Cr level was 296umol/l (3,3mg/dl) there was a 10 times higher level of antibodies against streptolysin O (ASLO). A renal biopsy was performed with clinical diagnosis of postinfectious glomerulonephritis.

3. Native kidney biopsy sample (from 1989) IF: Igs negative, C3 negat., kappa, lambda: negat. PAS stainingCongo red

4. Dg: Amyloidosis of an uncertain type. Extensive searching for some disease associated with amyloidosis 2 nodules in the liver; biopsy unsuccessful No evidence of inflammatory disease No evidence of plasma cell dyscrasia No other disease in addition to DM type II Half a year later: viral respiratory illness; kidney function rapidly declined and hemodialysis was begun.

5. Family medical history Both parents dead (mother: 40, abdominal tumor; father: 77, DM, IHD; sister: 7, car accident) 2 children, a son and a daughter: healthy No evidence of kidney disease Because of uncertain biological potential of liver lesions, he was not included in the waiting list. Liver masses were stable for 3 years. Patient´s data were reevaluated, 6 years after kidney failure he underwent kidney transplantation.

6. Kidney graft had excellent function for the following 15 years. No kidney graft biopsy was performed. Recently, proteinuria was revealed and a kidney graft biopsy was performed with clinical suspicion of diabetic nephropathy and chronic rejection.

7. Graft biopsy sample IF: C4d negative; Igs negative; C3,C1q: negative; kappa: negative; lambda: weakly positive, AA:neg.

8. Genetic studies were performed and mutation in the fibrinogen gene was confirmed (Glu526Val) G Graft biopsy sample, IF & IH detection fibrinogen A r

9. Skin biopsy sample; subsequent IF and IH for fibrinogenA

10. Follow-up No change in immunosuppressive treatment S-Cr 178μmol/l (2.01mg/dl) PU 3.6g/day DM under control Recently, genetic analysis for his 2 children was offered

11. Diagnosis of the type of amyloidosis The most common types: AA+AL AA (commercial antibodies) AL (low reactivity of commercial Abs in paraffin sections) Hereditary amyloidoses: more frequently recognized, are gaining in clinical importance. Autosomal dominant, variable penetrance, family history is lacking, clinical manifestation at older ages, therefore the correct diagnosis is challenging Each type requires different therapy, dg must be based on identification of the protein

12. Hereditary fibrinogen A amyloidosis Mutation in Fibrinogen Aα-chain gene was first described by Benson et al. in 1993 most frequent hereditary amyloidosis in the UK and also in Europe All cases: renal biopsy samples with massive and exclusively glomerular amyloid deposits Median age of presentation: 55years Fibrinogen: produced exclusively by the liver Kidney transplantation alone associated with rapid recurrence of amyloid Liver or combined liver and kidney transplantation

13. Fascinating story of amyloidosis Not all of patients with „preconditions“ suffer from amyloidosis Genetic factors, different types of degradation Per Westermark: different point of view Comparison with prion diseases: change in the protein structure In experiments, amyloid enhancing factor Amyloid fibrils were identified as the basis of AEF Prion diseases are transmissible by food

14. Is amyloidosis transmissible? Yes, very probably Westermark GT, Westermark P. Serum amyloid A and protein AA: molecular mechanisms of a transmissible amyloidosis. FEBS Lett. 2009;583:2685-2690. AA amyloidosis is transmissible in several animal experimental models AA amyloid can occur in human food (ducks, geese: pate de foie gras) AA amyloidosis is transmissible by blood monocytes Will we change the management of patients at risk of amyloidosis?

16. ESP Congress, Prague 2012