1. Protein casts, nodular glomerulosclerosis in a graft biopsy samples Agnieszka Perkowska-Ptasinska Transplantation Institute, Medical University of Warsaw, Poland

2. 55 years old male with end-stage native kidneys insufficiency of unknown reason, renal transplant from 3 HLA mismatched, cadaveric, 57 years old female donor, the donor and recipient: HIV (-), HCV (-), HBV (-), at the time of Tx: mild anemia, the initial immunosuppression: cyclosporine, mycophenolan-mofetil and prednisone in typical doses. Case 1

3. Three weeks after transplantation the patient was still oliguric, and dialysis-dependant, the urine protein content was 25 mg/dl, on the day 21 the graft biopsy was performed. Case 1

4. Case 1 – graft biopsy

7. Light chain kappa Light chain lambda

8. The initial diagnosis: cast nephropathy due to light chain gammapathy accompanied by mild thrombotic microangiopathy, trepanobiopsy, blood, and urine immunofixation tests: findings consistent with the diagnosis of myeloma multiplex IIB. INR, APTT, LDH, bilirubin concentration - within normal limits, Pt received chemioterapy, but the graft function remained very poor. Case 1

9. Procoagulant factors myloma-related : Acute thrombotic microangiopathy - an impaired fibrinolysis (mostly secondary to increased PAI-1 activity), - the influence of monoclonal proteins with fibrin structure, - a procoagulant antibody production, - the impact of the inflammatory cytokines on the endothelium. Transplantation-related : -rejection -acute CNI toxicity

10. 6 weeks after transplantation patient was still dialysis-dependant, on the 51 post transplant day the graft was removed due to it’s constant dysfunction. Case 1

11. Protein casts in kidney transplant Recipients treated with rapamycin: quite common DGF due to acute tubular injury associated with casts indistinguishable from myeloma casts. Casts composition: Smith et al.: degenerating renal tubular epithelial cells (JASN 14: 1037–1045, 2003) Pelletier et al.: myoglobin (Transplantation 2006 15;82(5):645-50)

12. Male, born in 1953 medical problems: diabetes type 2, insulinotherapy (retinopathy? no data) monoclonal gammapathy (no detailed information, patient received chemiotherapy with leukeran, azatiophryne and prednisone) 2007: proteinuria 9g/d, crea: 2,7mg/dl native kidney biopsy Case 2

13. Case 2 – native kidney biopsy

14. IFL: negative for Ig, C3, C1q and light chains

15. Case 2 – native kidney biopsy

16. Morphological picture: nodular glomerulosclerosis severe arteriolar hyalinistaion interstitial fibrosis and tubular atrophy Diagnosis: Diabetic nephropathy LCDD?

17. Case 2 2010 : Serum free light chains ratio within normal limits preemptive kidney transplantation, kidney graft received from patient’s younger brother (no HLA match) the donor and recipient: HIV (-), HCV (-), HBV (-), the initial immunosuppression: tacrolimus, mycophenolan-mofetil and prednisone in typical doses. the lowest serum crea conc. 1,2 mg/dl

18. Case 2 July 2012: serum crea conc. 1,6 mg/dl proteinuria: 100 mg/dl Serum FLC: marked excess of kappa LC Kidney transplant biopsy

19. Case 2 – transplant kidney biopsy

21. IFL: kappa light chain C4d

22. Case 2 – transplant kidney biopsy

23. Morphological picture: nodular glomerulosclerosis interstitial fibrosis and tubular atrophy Diagnosis: LCDD

24. Plasma cell dyscrasias A spectrum of diseases that include : MGUS (monoclonal gammapathy of uncertain significance) ( 2% - 4% of all individuals > 50 years) multiple myeloma (MM) ( 10% of all hematologic malignancies) solitary plasmacytoma, AL amyloidosis

25. Often associated with monoclonal immunoglobulin-dependant kidney injury three distinct morphological forms: - cast nephropathy (abnormal Ig obstructing tubular casts), - monoclonal immunoglobulin deposition disease (MIDD), (light chains, heavy chains, or both deposit along glomerular and tubular basement membranes) - AL amyloidosis (monoclonal Ig associates with other serum proteins form insoluble fibril deposits) Plasma cell dyscrasias

26. ESRD and KTX in patients with plasma cell dyscrasias ERA-EDTA Registry study: 1,54% ESRD cases due to MM or LCDD KTX for pts with plasma cell dyscrasias is rare (case reports, small series) 1.4% of patients with MM-related ESRD receives kidney transplant In majority of cases MM-related kidney disease reoccurs in the transplant

27. L(H)CDD may manifest as: mesangial proliferation MPGN-like pattern crescentic GN-like nodular glomerulosclerosis (most common) in majority of cases there is a recurrence of light chain deposition disease (LCDD) with the same pattern of injury as in native kidney early, severe recurrence in the allograft more common in crescentic, and MPGN-like types of LCDD

28. AL amyloidosis Small series of patients subjected to KTX No patient lost the graft because of transplant amyloidosis

29. Plasma cell dyscrasias Patients with plasma cell dyscrasias and end-stage renal disease (ESRD) may be candidates for kidney transplantation if their monoclonal Ig has been adequately controlled. allograft outcomes are determined by: - the type of plasma cell dyscrasia - the histology of the native renal disease - the responsiveness of the underlying plasma cell disorders to chemotherapy -the inherent toxicity of the monoclonal Ig.