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Protein casts, nodular glomerulosclerosis in a graft biopsy samples Agnieszka Perkowska-Ptasinska Transplantation Institute, Medical University of Warsaw, Poland
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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
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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
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Case 1 – graft biopsy
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Light chain kappa Light chain lambda
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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
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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
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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
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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)
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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
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Case 2 – native kidney biopsy
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IFL: negative for Ig, C3, C1q and light chains
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Case 2 – native kidney biopsy
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Morphological picture: nodular glomerulosclerosis severe arteriolar hyalinistaion interstitial fibrosis and tubular atrophy Diagnosis: Diabetic nephropathy LCDD?
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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
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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
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Case 2 – transplant kidney biopsy
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IFL: kappa light chain C4d
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Case 2 – transplant kidney biopsy
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Morphological picture: nodular glomerulosclerosis interstitial fibrosis and tubular atrophy Diagnosis: LCDD
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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
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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
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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
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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
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AL amyloidosis Small series of patients subjected to KTX No patient lost the graft because of transplant amyloidosis
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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.
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