Pathologic improvement after high-dose melphalan and autologous stem cell transplantation for primary systemic amyloidosis
On 4 February 2004, a 56-year-old man was referred for admission to our hospital because of worsened nephritic syndrome and weight loss. Laboratory test results on admission were total protein, 5.4 g/dL; serum albumin, 2.5 g/dL; s-UN, 9 mg/dL; s-Cr, 0.6 mg/dL; alkaline phosphatase (ALP), 347 IU/L and urinary protein excretion, 5.36 g/day. Polyneuropathy and septal myocardial hypertrophy (13 mm) were also observed. To elucidate the cause of nephrotic syndrome, skin, fat and open renal biopsies were performed on 3 March 2004. The renal biopsy specimens showed amorphous periodic acid-Schiff (PAS)-positive, Congo red-positive and direct fast scarlet (DFS)-positive deposits in the mesangium, glomerular vascular pole, tubulo-interstitium and walls of interlobular arteries and arterioles (Figure A and B). These deposits were present in all 23 glomeruli (100%) and 29 of 38 arterial and arteriolar walls (76%), in which 22 walls had circumferential deposits. These deposits show characteristic apple-green birefringence in polarized light and potassium permanganate resistance. Immunohistologic staining was positive for amyloid P and negative for amyloid A. These deposits were also observed in skin, adipose tissue and gastric biopsy specimens. Bone marrow aspirates showed a slight excess of plasma cells without abnormal morphology. We diagnosed him with primary systemic AL amyloidosis of λ (lambda) type.\nBeginning in February 2004, the patient received two courses of VAD (vincristine, 0.4 mg/day, and doxorubicin, 9 mg/m2/day, on Days 1–4, and dexamethasone, 40 mg/day by infusion on Days 1–4, 9–12 and 17–20), with the second course initiated 4 weeks later. After the second course, the granulocyte colony-stimulating factor (G-CSF) was administered subcutaneously at 10 g/kg/day for 4 days to mobilize haematopoietic stem cells in the peripheral blood, and 3.35 × 106/kg CD34-positive cells were collected.\nOn 20 September 2004, melphalan (230 mg or 140 mg/m2) was administered intravenously; 7 days later, cryopreserved stem cells were infused just after thawing. After these therapies, proteinuria was gradually abating (Figure ): 5.91 g/day on 24 December 2004; 0.85 g/day on 7 March 2005 and 0.12 g/day on 11 January 2006. Serum albumin increased from 1.9 g/dL on 26 July 2004 to 2.2 g/dL on 7 March 2005 and 3.4 g/dL on 11 January 2006. Monoclonal protein in both serum and urine continued to be negative on immunofixation after therapies.\nOn 15 January 2007, the patient was readmitted to our hospital for follow-up evaluation. Laboratory findings on admission were total protein, 6.0 g/dL; serum albumin, 3.5 g/dL; s-UN, 21 mg/dL; s-Cr, 1.0 mg/dL; AST, 25 IU/L; ALT, 25 IU/L and ALP, 480 IU/L. Urinary protein excretion was 0.03 g/day. Echocardiography showed a decrease in septal myocardial hypertrophy from 13 mm to 9 mm. Nerve conduction velocity examination still showed polyneuropathy. Complete haematologic and clinical responses (cardiac, renal, gastrointestinal and factor X response) were evident according to the criteria described by Skinner et al. [] and Gertz et al. []. A second renal biopsy was performed about 2 years following the first. The specimen showed a mottled reduction in amyloid staining in interlobular arterial walls and arteriolar walls. Furthermore, decreased amounts and intensities of Congo red and DFS staining were observed in the mesangium and glomerular vascular pole (Figure C and D). We scored all glomeruli and vascular walls in each sample. Amyloid-positive glomeruli were decreased from 100% to 89% (16 of 18 glomeruli) and amyloid-positive vascular walls were decreased from 76% to 50% (6 of 12 walls). By electron microscopic examination, small electron-dense deposits were seen in the subepithelial region. However, randomly arranged fibrils, characteristic of amyloid, were slightly obscure (Figure F). A gastric biopsy specimen also disclosed the disappearance of amyloid deposition. Thus, these therapies resolved AL amyloidosis not only clinically but also pathologically in our patient.