Acquired monoclonal Ig light chain-associated Fanconi syndrome (ORPHA:91136)
A rare monoclonalgammopathy characterized by renal proximal tubule dysfunction secondary to monoclonal kappa light chain deposits in proximal tubular cells. Clinical presentation is with variable chronic kidney disease, low molecular weight proteinuria, aminoaciduria, hyperphosphaturia, uricosuria, bicarbonaturia, and non-diabetic glycosuria. Renal phosphate and urate wasting may cause hypophosphatemia and hypouricaemia.
Epidemiology
To date, less than 100 cases have been reported in the medical literature.
Clinical description
Presentation is often in patients over 50 years of age with a degree of chronic kidney disease (CKD). There will be low molecular weight proteinuria, generalised aminoaciduria, uricosuria, phosphaturia, bicarbonaturia (which may cause a mild metabolic acidosis) and normoglycemic glycosuria. Low molecular weight proteinuria is the most sensitive test, and non-diabetic glycosuria is the most specific. There may be hypophosphatemia and hypouricemia and/or a mild metabolic acidosis. Urinary phosphate wasting may be severe enough to cause bone demineralization and rickets in children or osteomalacia in adults. Bone pain or pathological fractures are a possible presentation of this condition. The disease often occurs in the setting of monoclonal gammopathy of undetermined significance and less commonly in multiple myeloma or Waldenstrom macroglobulinemia.
Etiology
Typically, the monoclonal light chains are of the variable kappa-1 (VK1) subgroup which resist proteolysis in the proximal tubular cells, and results in self-aggregation and crystal formation in the endolysosomal compartment.
Diagnostic methods
Diagnosis is made by demonstrating the renal Fanconi syndrome with the presence of low molecular weight proteinuria (and phosphaturia or glycosuria, if present) along with a monoclonal gammopathy. The diagnosis may be confirmed by a kidney biopsy (which may be indicated when establishing the diagnosis of myeloma). Findings on light microscopy include atrophy, dedifferentiation and intracytoplasmic inclusions in the proximal tubule epithelium. Proximal tubule cells are typically positive for kappa LCs (and less frequently lambda LCs) on immunofluorescence. Ultrastructural studies reveal crystals (rhomboid), located in proximal tubular cells lysosomes or free in the cytoplasm. Additional investigations required include bone marrow aspiration or biopsy to identify the clone, and evaluation of serum and urine immunoglobulin free light chains.
Differential diagnosis
Differential diagnosis should include other types of monoclonal gammopathy of renal significance (AL amyloidosis, monoclonal immunoglobulin deposition disease, and myeloma cast nephropathy), in addition to other causes of FS (including autoimmune disorders, drugs, or heavy metal poisoning).
Management and treatment
If there is severe urinary phosphate wasting, or osteomalacia (low bone mineral density) then phosphate supplements should be given. Bone demineralization starts before the serum phosphate falls. All patients with an associated overt lymphoid disorder should receive appropriate chemotherapy. Otherwise, treatment should be adapted to the degree of renal failure. CKD 1-3 stages: chemotherapy should be considered to slow progression to ESRD. Cyclophosphamide, bortezomib or thalidomide-based treatment are the best options. High dose melphalan (HDM) supported by autologous peripheral blood cell transplantation (ASCT) may be performed in selected nonresponding patients, although the benefit of this strategy remains to be proven. CKD 4-5 stages: patients who are eligible for renal allograft, chemotherapy (including HDM/ASCT) should be considered prior to transplantation. In patients not eligible for renal transplantation, introduction of chemotherapy has no benefit.
Prognosis
Progression of CKD is slow.

                            Last update: 
                            September 2019


                            - Expert reviewer(s): 
                            Dr Stephen WALSH | ERKNet*


                                * European Reference Network