Fanconi’s Syndrome, Kappa Light-Chain Myeloma, Non-Amyloid Fibrils and Cytoplasmic Crystals in Renal Tubular Epithelium

Abstract

A 59-year-old woman with kappa light-chain myeloma had Fanconi’s syndrome characterized by renal glycosuria, generalized aminoaciduria, bicarbonaturia and decrease of phosphorus and uric acid reabsorption. A bone marrow biopsy showed the presence of 27% of dystrophic plasma cells; the cytoplasm of these cells was intensely stained with anti-kappa light-chain monoclonal antibodies. By light microscopy, the renal biopsy revealed a tubulointerstitial nephritis without glomerular lesions and with intratubular casts. By immunofluorescence, no deposits were observed along the glomerular and tubular basement membranes, but a positivity with anti-kappa light chain was noticed in some tubular epithelia and casts. By electron microscopy, fibrils (35-nm diameter) were observed in the cytoplasm of proximal tubular cells. These fibrils were situated in vesicles (100- to 600-nm diameter) in the luminal side of tubular cells. In the basal pole of the cell, fibrils seemed to group in crystals (120- to 200-nm diameter). Only kappa light-chain protein was demonstrated in these fibrils and crystals by an immunoelectron microscopic technique. These data suggested the pathogenic role of the fibrils and crystals present in tubular epithelium in the tubular proximal syndrome.

Histiocytes containing immunoglobulin crystals in the urine of a patient with IgA κ plasmacytoma of the bladder

“…In the kidney, these cells are seen in the renal interstitium and glomerular mesangium, 11 but crystalline inclusions have also been reported in renal tubular epithelial cells, particularly in PN associated with acquired Fanconi syndrome. [12][13][14] The lack of plasma cell nuclear features and presence of immunohistochemical staining for CD68 (PGM-1) in the current case supports a histiocytic line of origin for the cells we observed.…”

Effect of Myeloma Light Chains on Phosphate and Glucose Transport in Renal Proximal Tubule Cells

“…Many nephrotoxins have been demon strated to cause renal cell injury initially by di rectly interacting with plasma membranes thereby altering their permeability characteris tics and interfering with important transport pumps [27], In multiple myeloma the spectrum of renal involvement ranges from mild tubular dysfunction including Fanconi's syndrome to overt renal failure [9][10][11][12][13][14][15][16]], Fanconi's syndrome is characterized by subtle clinical renal trans port abnormalitites, such as, glycosuria, phosphaturia, bicarbonaturia, uricosuria, and ami noaciduria. Thus, the findings presented here indicate that direct cell toxicity by light chains is responsible for this phenomenon.…”

“…Clinically, approximately 50% o f myeloma patients develop renal failure, and over 90% of those with acute renal failure have light chain proteinuria [9][10][11][12][13][14][15][16], indicating potential nephro toxicity. Our finding that light chains inhibit phosphate and glucose transport in primary cul tures o f rat proximal tubule cells, and our previ ous observations that light chains inhibit glu cose and amino acid transport by brush border membranes [3,14,30] provide evidence that light chains can cause alterations in membrane integrity the earliest phenomenon in toxic re nal injury at the cell level.…”

“…They are filtered at the glomerulus, endocy-plasms [9][10][11][12]. Light chain proteinuria is asso ciated with a variety of renal disorders ranging from subtle tubular dysfunction (Fanconi's syndrome, acidification and concentration de fects, hypouricemia, hyperuricosuria) to frank renal failure [3,[9][10][11][12][13][14][15], In addition to kidney dis ease in myeloma, light chains also play a role in the pathogenesis of amyloidosis and light chain glomerulopathy [9,10], The variability of renal dysfunction and the absence of a relationship between the magnitude o f light chain proteinu ria and the associated renal disorder suggest the variable nephrotoxicity of light chains. Light chains isolated from the urine of patients with multiple myeloma have been reported to induce renal tubular lesions [15][16][17][18], inhibit glucose transport in the isolated perfused rat nephron in vivo [19], and inhibit kidney slice uptake of paminohippuric acid and tetraethylammonium in vitro [20], In a previous study, we demon strated that light chains inhibit the Na -depend ent uptake of glucose and alanine by rat renal brush-border membrane vesicles [14], The ef fect of light chains on glucose and phosphate transport has not been examined previously in intact cells.…”

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma

“…Literature on this identity consists of generally isolated case reports and small case series. [1][2][3][4][5][6][7][8][9] The largest series reported so far included 11 patients. 10 To better characterize the clinical presentation of these patients, we studied all 32 patients who were evaluated at Mayo Clinic (Rochester, MN) over a 34-year period.…”