Protein casts,

nodular

glomerulosclerosis

in a graft biopsy

samples Agnieszka Perkowska-Ptasinska

Transplantation Institute, Medical University of Warsaw, Poland

• 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

• 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

Case 1 – graft biopsy

Case 1 – graft biopsy

Case 1 – graft biopsy

Case 1 – graft biopsy

Light chain kappa Light chain

lambda

•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

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

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

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)

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

Case 2 – native kidney biopsy

Case 2 – native kidney biopsy

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

Case 2 – native kidney biopsy

Case 2 – native kidney biopsy

Morphological picture:nodular glomerulosclerosissevere arteriolar hyalinistaioninterstitial fibrosis and tubular atrophy

Diagnosis: Diabetic nephropathyLCDD?

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

Case 2

July 2012:serum crea conc. 1,6 mg/dlproteinuria: 100 mg/dl

Serum FLC: marked excess of kappa LC

Kidney transplant biopsy

Case 2 – transplant kidney biopsy

Case 2 – transplant kidney biopsy

Case 2 – transplant kidney biopsy

IFL: kappa light chain

C4d

Case 2 – transplant kidney biopsy

Case 2 – transplant kidney biopsyMorphological picture:

nodular glomerulosclerosisinterstitial fibrosis and tubular atrophy

Diagnosis: LCDD

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

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 glomerularand tubular basement membranes)- AL amyloidosis (monoclonal Ig associates with other serum proteins form insoluble fibril deposits)

Plasma cell dyscrasias

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

L(H)CDD• may manifest as:

mesangial proliferationMPGN-like patterncrescentic 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

AL amyloidosis

• Small series of patients subjected to KTX

• No patient lost the graft because of transplant

amyloidosis

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.