IgD Myeloma with Two Types of Paraproteinemic Kidney Damage : Case Report

fragments thereof, mostly light chains (LC). They may involve the four components of the kidney parenchyma: glomeruli, tubules, interstitium and blood vessels. Organized depositions include Cast Nephropathy (CN), light-chain tubulopathy, AL/AH amyloidosis, glomerulonephritis with an organized microtubular monoclonal deposits, and cryoglobulinemic Glomerulonephritis (GN). Non-organized deposition group comprise Light Chain/ Heavy Chain Deposition Disease (LCDD/HCDD), proliferative GN with monoclonal deposits of IgG/IgA, and non-proliferative GN with monoclonal deposits of IgM. It appears that amino acid sequence of the monoclonal LC and other monoclonal proteins, defining inherent biochemical properties, is the primary determinant of the specific pattern of renal parenchymal deposition and clinical disease. Patients may present with Acute Kidney Injury (AKI), Nephrotic Syndrome (NS), proteinuria and/ or haematuria, arterial hypertension or chronic kidney disease. Differential diagnostics is the major challenge, demanding pathology evaluation of kidney tissue, as the above mentioned lesions cannot be differentiated solely on the basis of clinical features. Importantly, symptoms of kidney damage may dominate over LPD symptoms, and even preclude overt LPD’s [1-13].

The pathology pattern of renal damage in patients with LPD, showing a combination of cast nephropathy and LCDD is also rare -such coexistence is reported in literature like single cases or small series.At least two possible explanations for these findings suggested so far.It was observed, that both fibrillar and non-fibrillar monoclonal LC deposits may coexist in the same patient, and the identity of the amino acid sequence of the deposited protein has been reported.On the other hand, cases with more than one pattern of LC deposition may be explained by the biclonal proliferative process with more than one pathogenic LC, causing damage.Again, only rare MM (2%) result in biclonal gammopathy with the production of two different heavy chains and/or light chains, with the combinations of IgG/IgM, IgA/ IgG, κ/λLC and IgD/IgM described in few reports, unfortunately no data concerning influence of coexistence of two and more patterns on renal outcome is available [22][23][24][25][26][27][28][29][30].
Here we present a case of IgD myeloma, manifested with the combination of LCDD and cast nephropathy.

History of Present Illness
He was suspected with rapidly-progressive GN, possibly cryoglobulinemic, and underwent kidney biopsy.According to the pathology report: Light Microscopy (LM) with standard staining's showed 8 hypertrophied glomeruli with marked hypercellularity (capillary WBC infiltration); interstitial fibrosis with prominent lymphohistiocytic infiltration and tubular atrophy about 30%; massive hyaline casts in preserved tubular lumen; and oedematous arterial walls.Additional Congo red staining for amyloid was negative.Immune staining's were negative for IgA, IgG, IgM,C3 and κ LC, and strongly positive for λ LC -linear deposits along Glomerular Basement Membrane (GBM) and Tubular Basement Membrane (TBM) and also λ LC deposition in casts.Electron microscopy (EM) confirmed dense fine granular GBM and TBM deposits.
He was seen by a local hematologist, diagnosis of multiple myeloma was declined, and patient was diagnosed with "primary" LCDD.Serum and urine immunochemistry were ordered, and the patient was referred to our clinic for the second opinion.

Diagnostics Considerations, Treatment and Further
Work-Up: At that point we diagnosed AKI, and concluded that the cause of AKI could be nothing but cast nephropathy on top of LCDD in a patient with myeloma.Patient was urgently started with hemodialysis and normal saline infusions, skeletal X-ray, peripheral lymph nodes ultrasound, and bone marrow biopsy were performed, and immunochemistry results ordered from external lab, and kidney biopsy paraffin blocks were reprocessed and re-evaluated.
Skeletal X-ray: Did not found any lesions.
Immunochemistry: Showed traces of paraprotein D-λ and Bence-Jones-λ in serum, and urinary excretion of Bence-Jones-λ 1.22g/day.Cryoglobulins were not found IgG, IgA and κ/λ coefficients were below the normal range, CRP and β2microglobulin-significantly elevated.
Kidney biopsy re-processing and re-assessment (Figures 1-6): Sections of formalin fixed paraffin-embedded tissue were stained with Masson's trichrome, periodic acid-Schiff, and Jones' silver for LM. 12 glomeruli, slightly enlarged, with normal capillary wall, mild mesangial widening without mesangial or endocapilary proliferation.Total acute tubular necrosis with multiple large tubular casts, PAS-and Jones-negative, and fuxinpositive on Masson's staining, surrounded by giant polynuclear cells.Severe tubulo-interstitial infiltration with lymphocytes, plasma cells and neutrophils, most prominent in zones of casts accumulation.Diffuse tubular atrophy and interstitial fibrosis about 40%.Arterioles and small arterial walls thickened due to muscular layer hypertrophy.Immunofluorescence on formalin fixed/paraffin embedded sections with FITC-conjugated anti IgA, IgG, IgM, C1q, C3, fibrinogen, λ and κ LC antibodies showed diffuse linear expression 4+ for λ LC along all basal membranes -glomerular, tubular, arteriolar and arterial, and also 4+ λ LC expression in the casts.All other immune stainings were negative.EM: toluidine-blue semi-thin sections showed 1 otherwise normal     Final Diagnosis: Multiple myeloma IgDλ and BJλ, cast nephropathy combined with LCDD; AKI, treated with HD; anaemia, thrombocytopenia, hepatosplenomegaly, peripheral, mediastinal and periportal lymphadenopathy, secondary immunodeficiency.
Treatment and Follow-Up: Patient was seen by haematologist and referred to haematology unit for chemotherapy.At the latest evaluation (September15, 2015) patient receiving standard chemotherapy per BCD (Bortezomib-Cyclophosphamide-Dexamethasone) protocol, doing well, but still on hemodialysis.

Conclusions
Presented case demonstrates characteristic features if IgD myeloma, like relatively young age, low grade IgD paraproteinemia, overproduction of LC with LC-proteinuria, lymphadenopathy and renal failure at presentation.Pathology findings with typical picture of LCDD were misleading, and only rapidly-progressive renal failure with kidney enlargement, not consistent with LCDD natural course, demanded re-assessment of kidney biopsy and more detailed work-up, which finally gave a clue to the diagnosis.The pathology pattern of renal damage: a combination of cast nephropathy and LCDD confirms the leading role of cast-nephropathy in the clinical presentation with AKI, dominating over other symptoms.According to our experience such combined renal damage is rare, but not unique -in our cohort of 139 patients with LPD and renal damage, confirmed by pathology, we also have patients with AL amyloidosis and LCDD, and with combination of cast nephropathy, AL amyloidosis and LCDD.This case also illustrates the importance of renal damage pattern, typical for MM, for diagnostics of this disease in patients without clinical MM features.

Figure 1 :
Figure 1: Light microscopy.PAS-negative and slightly positive casts with peripheral cell reaction, acute tubular injury and moderate tubulointerstitial inflammation.Normal glomerulus.Periodic acid-Schiff х200.

Figure 3 :
Figure 3: Immunofluorescence.Medulla fragment with λ-positive casts and diffuse linear expression of λ LC along tubular basement membrane and smooth-muscle walls of small arteries and arterioles; х100.
Ca++ and lactate were normal.ECG and ECHO-CG showed both left and right ventricular hypertrophy; abdomen ultrasound revealed single portal lymph node 12x9mm, other findings were unremarkable.Kidney ultrasound showed enlarged kidneys -both 128x54mm, parenchyma 22mm, without any other significant changes; chest CT found slight enlargement of mediastinal lymph nodes (max 13mm).