Slide Seminar

Drugs and Kidney

Case 3

Heinz Regele

Department of Pathology

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.

Differential diagnosis

•Chronic TX Glomerulopathy

•Immune complex mediated GN

•Thrombotic microangiopathy

C4d

C4d C3

C4dC4d C4d

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

IC GN after rapamycin switch

MGN IgA-GN IgA-GN

Clinical course

Dittrich E, Transpl Int 2004

C4d

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

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

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

Different effects of rapamycin in innate and adaptive immunity

Säemann MD, AJT 2009