Nephrotic Syndrome and Lambda Light‐Chain Monoclonal Gammopathy Suggestive of Primary Amyloidosis with Positive Staining for AA Amyloid

To the Editor: Monoclonal gammopathy of undetermined significance (MGUS) is a common finding in elderly adults. More than 3% of individuals aged 50 and older have an M-protein in their serum. The risk of MGUS progressing to multiple myeloma or other lymphoproliferative disorders is approximately 1% per year. Amyloidosis results from the extracellular deposition of a fibrillar amyloid protein in addition to glycosaminoglycans and the serum amyloid P component. Regarding primary amyloidosis (AL), the fibrillar precursors are fragments of free light chains produced in the setting of a plasma cell dyscrasia or in MGUS. In contrast, in secondary (or AA) amyloidosis, the precursor is the serum amyloid A protein (SAA), an acute-phase reactant that is high in inflammatory and chronic infectious conditions. Clinical manifestations of amyloidosis include restrictive cardiomyopathy (75% of patients), nephrotic syndrome (30% of patients), dysautonomia, arrhythmias, peripheral neuropathy, and hepatomegaly. A diagnosis of amyloidosis requires histological demonstration of amyloid deposits. Herein is reported the case of an elderly woman who presented with edema of unknown origin; amyloidosis was diagnosed according to kidney biopsy. An 82-year-old woman was seen at Vall d’Hebron General Hospital (Barcelona, Spain) for worsening edema in the lower extremities. Her medical history included arterial hypertension, diabetes mellitus, and chronic infection with hepatitis C virus (HCV). She reported progressive edema in the lower extremities for the past 5 months with functional disability. Urgent abdominopelvic Doppler revealed correct permeability of the lower cava and iliac veins and normal-size kidneys without evidence of ascites. Analytical tests were significant for high protein measurement of 4.6 g in 24-hour urine and a beta monoclonal peak on serum protein electrophoresis. Immunofixation revealed a monoclonal component formed by lambda light chains. Free light chains quantification showed high lambda chain level of 273 mg/dL (normal range 5.71–26.30 mg/dL), with normal kappa chain level and a kappa:lambda ratio of 0. Other analytical parameters were normal, except for dissociated cholestasis. An echocardiogram revealed nonobstructive hypertrophic cardiomyopathy with minus diastolic dysfunction. Neurophysiological findings were indicative of heart autonomic malfunction with a pathologic heart rate variability index. A mature B polyclonal population, with 3% of plasma cells with aberrant immunophenotype (CD38+CD19 CD56+) was detected in bone marrow aspirate. Primary amyloidosis was suspected because of the coexistence of nephrotic syndrome, autonomic dysfunction, and serum monoclonal peak; thus, subcutaneous fat and hepatic biopsies were performed, without evidence of amyloid material. Finally, Congo Red staining in a kidney sample demonstrated amyloid deposits. Immunohistochemical technique was positive for AA amyloid, showing direct immunofluorescence lambda light chain deposits at the glomeruli. Although histochemical positivity for SAA is characteristic of secondary amyloidosis, deposits of SAA can be demonstrated in up to 20% cases of primary amyloidosis. These SAA deposits would be responsible for fake positivity on the immunohistochemical tests. The patient was positive for HCV, but no clinical symptoms of cirrhosis had been reported in her medical history. In the literature HCV has not been reported to occur with AA amyloidosis, except those cases associated with another predisposing disease (e.g., immunodeficiency). Chronic inflammatory or infectious disease was excluded in this patient, and the presence of an abnormal kappa:lambda ratio, as well as the presence of lambda light chain deposits at the glomeruli on direct immunofluorescence led to the diagnosis of primary amyloidosis. Finally, Congo Red staining was performed, and the apple-green birefringence remained after the administration of potassic permanganate. This result supported the diagnosis of AL. Clinicians should be aware that, in elderly adults with suspected amyloidosis and monoclonal gammopathy, if AA amyloid is documented, AL and AA amyloidosis must be excluded given the high prevalence of gammopathy in elderly adults and the possibility of false positivity with histochemical staining. In case of doubt, another test should be performed to confirm the type of amyloidosis, including, if it is available, proteomic analysis.