1. Slide Seminar Drugs and Kidney Case 3 Heinz Regele Department of Pathology

2. Clinical history First renal transplant lost in 1995 due to infectious complications 4 weeks after TX Second allograft in October 1999. During the first post-transplantation year serum creatinine (sCr) ranged from 2.2-2.5 mg/dl (194-221 μmol/l). Maintenance immunosuppression: Cy-A, MMF, and low-dose steroids mg/day). Fourteen months after TX recruitment to a clinical trial of cyclosporine withdrawal in patients with chronic allograft dysfunction. Conversion to rapamycin was performed after ruling out rejection or glomerular disease (protocol biopsy). After 9 months of rapamycin therapy (12- 20 ng/ml), sCr increased from 2.5 mg/dl to 4.0 mg/dl (221-354 μmol/l), and proteinuria of 2.5 g/ 24 h developed.

7. Differential diagnosis Chronic TX Glomerulopathy Immune complex mediated GN Thrombotic microangiopathy

8. C4d

9. C3

12. C4d

16. Diagnosis De novo IC mediated Glomerulonephritis (likely related to the switch from CNI to rapamycin) No convincing evidence of acute rejection (C4d negative) Medullary only mononuclear inflammatory infiltrate

17. IC GN after rapamycin switch MGNIgA-GN

18. Clinical course Dittrich E, Transpl Int 2004

19. C4d

21. Evidence for pro-inflammatory properties of rapamycin Recurrent or de-novo GN develops in allografts after conversion to sirolimus and recovery can be achieved by re-introducing of CNI Säemann MD, AJT 2009

22. Immunosuppression and transplant glomerulonephritis A USRDS analysis of 41272 transplant recipients found recurrent GN causing graft loss in 2,6% of patients The likelihood of developing a recurrent GN was not associated with a specific type of immunosuppressive regimen Any change of immunosuppression however increased the risk of developing recurrent GN Mulay AV, AJT 2009

23. Evidence for pro-inflammatory properties of rapamycin Drug dependent occurrence of fever and inflammation (unrelated to infection) in different organs Recurrent or de-novo GN in allografts after conversion to sirolimus and recovery after re- introduction of CNI Sirolimus treatment leads to exacerbation of lesions in some experimental models of autoimmune disease. Säemann MD, AJT 2009

24. Different effects of rapamycin in innate and adaptive immunity Säemann MD, AJT 2009