CASE 3 AN UNUSUAL CASE OF NEPHROTIC SYNDROME Dr Seethalekshmy N.V., Dr.Annie Jojo, Dr Hiran K.R., Amrita institute of Medical Sciences, Kochi, Kerala
Case history 34 year old gentleman Nephrotic range proteinuria 1 year ago Treated with steroids and endoxan for a short duration. Renal functions been gradually and steadily deteriorating. No h/o diabetes mellitus/ hypertension. Physical examination revealed moderately built man, uremic with dry skin. BP- 150/90mmHg. USS :Bulky kidneys with preserved CMD, No organomegaly.
Investigations Hb 7gm TC- 9100./cmm Urine sugar- Trace, Urine Albumin +++, Microscopy: Pus Cells 8-10/ HPF, RBC0-1/ HPF, Epithelial cells OCC/ HPF S.creatinine 7.5mg/dl 24hr urine volume : 1750mg/dl 24hr urine protein : 5040mg
Investigations Urine Bence jones protein -Negative Serum electrophoresis : Normal electrophoretic pattern with reduced albumin ( 14-11-.06). No abnormal band Bone marrow No plasmacytosis Renal biopsy done
H&Ex100
CME on Renal Pathology by ISRTP in collaboration with Indian Society of Nephrology H&Ex100, 12th December 2007, New Delhi
H&Ex400
H&Ex400
PASx100
PASx400
Silver x400
MT x400
Congo red x400
IHC kappax400
IHC-lambdax400
Special stain :Nodules are negative for congo red stain,nonpolarising Immunoflulorescence studies: The glomeruli are negative for IgG, IgA, IgM, C3 and C1q. Immunohistochemistry Nodules in glomeruli showed kappa light chain restriction
Diagnosis : Renal Biopsy: LIGHT CHAIN DEPOSITION DISEASE FOLLOW UP Started of hemodialysis, proteinuria persisted, repeat bone marrow evaluation on 22/1/07 (after 2 months of initial biopsy)showed 42% plasma cells with kappa light chain restriction
Algorithm for evaluation of organized deposits in kidney CONGO RED STAIN Positive Negative Amyloid Non-amyloid +ve Ig derived Immunofluorescence -ve Non-Ig derived eg DM Cryoglobulinemia Monoclonal gammopathy SLE Immunotactoid - CLL -Benign glomerulopathy - Mixed essential -CLL - Multiple myeloma -LCDD -Multiple myeloma
Special stains in nodular glomerular lesions LESIONS PAS PAS/ JONES MASSON Trichrome CONGO RED IMMUNOTACT OID +++ Neg Blue Neg DM +++ Black Blue Neg LIGHT/HEAVY CHAIN ++ Neg Blue Neg AMYLOID Neg Neg Blue +++ FIBRONECTIN ++ Neg Red Neg COLLAGEN Neg Neg Blue Neg.
LCDD Light chain deposition disease ( LCDD) is the deposition of monoclonal, amorphous, noncongophilic light chains in multiple organs that do not exhibit a fibrillar structure when examined ultrastructurally.
LCDD-BIOLOGY OF DISEASE Uncommon complication of multiple myeloma / other plasma cell dyscrasias Occurs in 5% of cases of myeloma. 1/3rd of patients do not fulfill the diagnostic criteria of myeloma at the time of diagnosis. Kappa to lambda ratio is approximately 4:1. In 1976, Randall et al recognized LCDD as an infiltration of light chains involving multiple organs. Renal disease usually dominates Deposition found in the heart, liver, lungs, endocrine glands, skin and other organs.
CLINICAL FEATURES Mean age 57 yrs M/F ratio of 4:1 Many patients have heavy proteinurias +/- haematuria. Proteinuria is usually non selective. Progressive renal failure Prognosis of patients with LCDD is generally poor Death - attributed to cardiac disease, heart failure, or infectious complications.
Discussion Glomerulopathic LCs have been reported to play pivotal roles in the pathogenesis of LC-mediated glomerulopathies. Interaction of these LCs with mesangial cells initiates a receptor-mediated process which then controls downstream events. Based on the type and degree of structurally abnormal LC, processes such as endocytosis, activation of growth factors and cytokines, and mesangial matrix alterations are regulated. Two distinct glomerulopathies have been described with different pathogeneses. However, damage to the glomerulus is a sequel shared by both(alamyloidosis and LCDD), which if left uncontrolled eventually results in renal failure. Herrera GA (ed): The Kidney in Plasma Cell Dyscrasias. Contrib Nephrol. Basel, Karger, 2007, vol 153, pp 116 134
Unstimulated mesangial cells c-fos LCs c-fos c-fos Mesangial cells incubated with G-LCs c-fos Am-Lc PDGF- β LCDD-LC TGF- β TGF- β Schematic representation of early events that occur when mesangial cells are exposed to different types of glomerulopathic LCs. Upon incubation of mesangial cells with glomerulopathic LCs, c-fos changes its normal cytoplasmic to a nuclear location. c-fos, through the action of PDGF-β controls cell proliferation and is also responsible for cell surface changes (ruffling) and rounding-up of mesangial cells. PDGF-β is activated in both conditions (AL-amyloidosis and LCDD). TGF-β is increased in LCDD and decreased in AL-amyloidosis.
Keeling J et al.: AL-Amyloidosis and Light-Chain Deposition Disease Light Chains Induce Divergent PhenotypicTransformations of Human Mesangial Cells. Lab Invest 84: 1322 1338, 2004.
Treatment High-dosage chemotherapy with blood stem cell transplantation (LCDD and overt myeloma) Conventional chemotherapy including high-dosage dexamethasone (older than 70 yr) As in AL-amyloidosis, monitoring of LC production should rely on free LC assay, particularly in patients without a blood and urine monoclonal component Kidney transplantation should not be an option for patients with LCDD unless measures have been taken to reduce LC production Future pathophysiology-driven therapeuticdirections include 1.Blocking of LC binding to mesangial receptors, 2.Use of TGF- antagonists, 3.Inhibitors of LC-induced signaling pathways. Clin J Am Soc Nephrol 1: 1342 1350, 2006
References 1. Herrera GA (ed): The Kidney in Plasma Cell Dyscrasias.Contrib Nephrol. Basel, Karger, 2007, vol 153, pp 116 134 2. Pierre Ronco, Emmanuelle Plaisier, Be atrice Mougenot: Immunoglobulin Light (Heavy)-Chain Deposition Disease: From Molecular Medicine to Pathophysiology-Driven Therapy,Clin J Am Soc Nephrol 1: 1342 1350, 2006 3. Keeling J, Teng J, Herrera GA: AL-amyloidosis and light chain deposition disease -light chains induce divergent phenotypic transformations of human mesangial cells. Lab Invest 84: 1322 1338, 2004 4. David J. Salant, Vaishali Sanchorawala, and Vivette D. D Agati A Case of Atypical Light Chain Deposition Disease Diagnosis and Treatment, Clin J Am Soc Nephrol 2: 858 867, 2007 5. Hepstinstall s Pathology of kidney 6 th ed (lippincot-raven)