Transcript Protein casts, nodular glomerulosclerosis in graft biopsy

Protein casts,
nodular glomerulosclerosis
in a graft biopsy samples
Agnieszka Perkowska-Ptasinska
Transplantation Institute, Medical University of Warsaw, Poland
Case 1
• 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 – graft biopsy
Case 1 – graft biopsy
Case 1 – graft biopsy
Case 1 – graft biopsy
Light chain kappa
Light chain lambda
Case 1
•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.
Acute thrombotic microangiopathy
Procoagulant factors myloma-related:
- 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
Case 1
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.
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)
Case 2
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 – 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 glomerulosclerosis
severe arteriolar hyalinistaion
interstitial fibrosis and tubular atrophy
Diagnosis:
Diabetic nephropathy
LCDD?
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/dl
proteinuria: 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 biopsy
Morphological picture:
nodular glomerulosclerosis
interstitial 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
Plasma cell dyscrasias
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)
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 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
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.