FINAL DIAGNOSIS:

FANCONI SYNDROME SECONDARY TO KAPPA LIGHT CHAIN BENCE JONES PROTEINURIA

DISCUSSION:

Fanconi syndrome (FS) is a generalized dysfunction of proximal renal tubule transport with no primary glomerular involvement. It is characterized by variable degrees of phosphaturia, aminoaciduria, glycosuria, and urinary wasting of various ions and uric acid. In children, the clinical presentation is usually rickets and impaired growth. In adults, bone disease is manifested as osteomalacia and osteoporosis. In addition, polyuria, renal salt wasting, hypokalemia, acidosis, hypercalciuria, and low-molecular weight proteinuria can be part of the clinical spectrum. Although FS may be related to inherited defects or to toxicity of certain drugs or heavy metals, most adult cases are secondary to the urinary secretion of a monoclonal immunoglobulin (Ig) light chain that forms crystals inside cells of the proximal tubule.

The proximal tubule is responsible for reclaiming almost all the filtered load of bicarbonate, glucose, and amino acids, as well as most of the filtered load of sodium, chloride and phosphate. The renal proximal tubule exhibits a very extensive apical endocytic apparatus consisting of an elaborate network of coated pits and small coated and noncoated endosomes. In addition, the cells contain a large number of late endosomes/prelysosomes, lysosomes, and so-called dense apical tubules involved in receptor recycling from the endosomes to the apical plasma membrane. This endocytic apparatus is involved in the reabsorption of molecules filtered in the glomeruli. The process is very effective, as demonstrated by the fact that although several grams of protein are filtered daily in the human glomeruli, human urine is virtually devoid of proteins under physiologic conditions. Reabsorption of solutes by proximal tubule cells is achieved by transport systems at the brush border membrane that are directly or indirectly coupled to sodium movement, by energy production and transport from the mitochondria, and by the Na⁺/K⁺-ATPase transport at the basolateral membrane. The Na⁺/K⁺-ATPase transport lowers intracellular Na⁺ concentration and provides the electrochemical gradient that allows Na + coupled solute entry into the cell. A second pathway, the paracellular route, is responsible for reclaiming up to one half of the sodium and most of the water through tight junctions. Given that multiple transport anomalies characterize the renal Fanconi syndrome and amino acids, glucose, phosphate, and bicarbonate are transported by multiple carriers, defects responsible for the Fanconi syndrome must lead to the disruption of the functions of the proximal tubule cell.

A review published by Maldonado, et al. (1975) described 17 cases of FS with monoclonal Ig light chain proteinuria. They concluded that these cases had a distinct type of plasma cell disorder characterized by a slow progression of the tumor and by an early phase dominated by the metabolic complications of the renal proximal tubular dysfunction. They also stressed that adult patients with FS should be investigated carefully for the presence of a latent form of myeloma. Furthermore, they noted that the Ig light chain was of the kappa type in the 7 cases in which it was analyzed. The disease seems to be characterized by prominent crystal formation in proximal tubule cells in the absence of myeloma casts in the distal tubule, and seems to occur mostly in patients with low-mass kappa light chain-excreting myeloma.

A more recent review by Messiaen, et al. (2000) of 11 cases of light chain FS showed clinical and pathologic heterogeneity. Seven of the patients presented with crystals in tubule cells, no myeloma casts, and low-mass myeloma or monocloncal gammopathy of uncertain significance (MGUS), thus corresponding to the typical form of FS described by Maldonado et al. Three of the patients presented with myeloma cast formation in the setting of high-mass myeloma, with 2 patients not showing crystal inclusions in tubule cells even on electron microscopic examination. The last patient of the study group had MGUS and full-blown FS responsible for osteomalacia but neither crystals nor casts. However, contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V_kappaI variability subgroup, which indicated that FS light chains are related by the sequence of their variable regions. Third, the 8 V_kappaI light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30 which may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V_kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in the series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. They concluded that resistance of V_kappa to proteolysis in FS patients might explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

In our case, the presence of Fanconi syndrome with predominantly tubular proteinuria and a kappa light chain Bence Jones urine protein, proximal tubular epithelial cell crystalline inclusions and absence of glomerular pathology establishes the diagnosis of an acquired Fanconi syndrome secondary to kappa light chain Bence Jones proteinuria. Failure of the tubular cells to show obvious kappa light chain restricted staining by immunofluorescence is typical, suggesting biochemical alteration of the protein within the crystalline inclusions. There are no identified glomerular causes of the proteinuria; in particular, there was no evidence of a monoclonal light chain glomerular deposition disorder, immune complex disorder, cryoglobulinemia, paraprotein disorder (such as amyloidosis, fibrillary / immunotactoid glomerulonephropathy), minimal change disease, nor focal segmental glomerulosclerosis. The cause of the renal dysfunction (elevated serum creatinine) was not established; acute tubular injury is one possibility. There was focally moderate arterial and arteriolar sclerosis, with approximately 15% of the sampled glomeruli being obsolescent in this patient who has no history of hypertension or diabetes.