fanconi syndrome ( fs ) is a rare disease characterized by defects in proximal tubular function , including impairment of reabsorption of solutes such as glucose , uric acid , phosphate , amino acid , and bicarbonate .
patients with fs may present normoglycemic glycosuria , low molecular weight proteinuria , hypophosphatemia , and normal anion gap metabolic acidosis .
multiple myeloma is a neoplastic bone marrow disease characterized by clonal proliferation of plasma cells and overproduction of monoclonal protein .
free light chain overproduction is associated with toxic effects to proximal tubular cells in the kidneys , which may induce fs . in this case , the patient who had presented proteinuria initially was diagnosed with fs and multiple myeloma , after reviewing her results from blood laboratory work , urine analysis , and bone marrow examination .
in addition , kidney pathology confirmed the presence of rod - shaped casts in proximal tubules .
a 48-year - old woman visited the nephrology clinic for proteinuria , which was detected at a local hospital .
she had been producing foamy urine and experiencing nocturia for 2 months , and she was suffering from bilateral flank pain for 6 months .
she had no specific underlying disease or related family history . however , she had been taking a course of chinese medicine for the past 6 months . at presentation , her vital signs were stable ( blood pressure : 128/80  mmhg , heart rate : 62 beats / minute , respiration rate : 18 breaths / minute , body temperature : 36.4c ) , and her general physical examination was unremarkable .
results from the blood testing , which included complete blood count , coagulation test , total bilirubin , aspartate transaminase , alanine transaminase , cholesterol , glucose , erythrocyte sedimentation rate , c - reactive protein , and thyroid function test were in the normal range .
the patient s protein level was 6.6  g / dl and her albumin level was 4.9  g / dl , so her globulin was low ( 1.6  g / dl ) .
her creatinine was 1.02  mg / dl , with a mildly decreased estimated glomerular filtration rate of 58  ml / minute/1.73  m. hypouricemia ( 0.9  mg / dl ) and hypophosphatemia ( 2.3  mg / dl ) were observed .
serum sodium / potassium / chloride ( 139/3.5/109  mmol / l ) and calcium ( 8.8  mg / dl ) were in normal ranges .
arterial blood gas analysis showed normal anion gap metabolic acidosis ( ph 7.324 , pco2 31.2  mmhg , po2 108.9  mmhg , hco3 15.9  mmol / l ) .
urine dipstick testing showed the following characteristics : specific gravity ( 1.036 ) , ph ( 6.5 ) , blood ( + ) , albumin ( + + ) , and glucose ( + + ) .
a urine electrolyte test showed 51  mmol / l of sodium and 23.5  mmol / l of potassium .
a spot urine test showed a urine protein / creatinine ratio of 10.61  mg / mgcr and a urine albumin creatinine ratio of 401.69  g / mgcr .
based on the above information , we concluded that the patient had generalized proximal tubular dysfunction and overflow proteinuria .
the patient had an elevated serum kappa / lambda ratio of 5,113.1 . through urine protein electrophoresis
, the m peak was observed behind the beta globulin region ( 2,911.6  mg / day ) .
bone marrow examination showed normocellular marrow with 24% cd138 + plasma cell staining with kappa restriction .
a renal biopsy was performed for accurate diagnosis of fs and to exclude renal amyloidosis or monoclonal immunoglobulin ( ig ) deposition disease .
immunofluorescence staining for iga , igg , igm , c3 , kappa , and lambda was negative . under electron microscopy ,
the glomerular basement membrane was slightly irregular in contour with mild effacement of epithelial foot processes . numerous rod- or rhomboid - shaped crystalline inclusions were present in the cytoplasm of proximal tubular epithelial cells ( fig .
most of the crystalline inclusions were electron dense and floating in the cytoplasm ( fig .
however , they were not found in the glomerular cells including podocytes . there were no amyloid fibrils , granular deposits , or immune type electron densities .
finally , she was diagnosed as having multiple myeloma ( kappa type ) with fs .
kidney pathology confirmed the presence of rod - shaped crystalline inclusions in proximal tubular cells .
plasma cells were observed in<5% of aspirated bone marrow , although cd138 + cells were counted in up to 5% of bone marrow with kappa restriction .
currently , the patient has survived for 1 year after autologous stem cell transplantation and she has received thalidomide maintenance ; however , her proximal tubular dysfunction has not improved ( table 1 ) .
hypouricemia ( 1.3  mg / dl ) and glycosuria were still observed in her last laboratory tests .
phosphate level was normal ( 3.0  mg / dl ) under intake of 2,040  mg of phosphate and 0.75  g of calcitriol daily . to maintain a potassium level of 4 
mmol / l and prevent metabolic acidosis , the patient was taking 3,600  mg of potassium chloride , 100  mg of spironolactone , and 3,000  mg of sodium bicarbonate daily .
urine albumin to creatinine ratio showed a similar level with baseline ( 440  g / mgcr ) and urinary protein to creatinine ratio was much decreased to 1.69  mg / mgcr , which reflected reduced overflow proteinuria and persistent tubular proteinuria .
this patient presented with proteinuria and upon evaluation was found to have normal anion gap metabolic acidosis , normoglycemic glycosuria , hypophosphatemia , and hypouricemia . therefore , we suspected that she had fs .
bone marrow examination showed normocellular marrow with 24% cd138 + plasma cells in kappa restriction .
therefore , she was diagnosed with multiple myeloma and light chain proximal tubulopathy . in multiple myeloma ,
renal insufficiency is a common complication . up to 50% of patients with multiple myeloma initially present with kidney injury .
acute renal failure in myeloma is often caused by excessive production and filtration of free light chains
. overproduced light chains can exert direct toxic effects onto kidney cells and generate myeloma casts by binding to tamm - horsfall proteins .
cast nephropathy is the most common pattern of renal parenchymal disease associated with multiple myeloma .
amyloidosis and monoclonal immunoglobulin deposition disease are the other types of deposition diseases that occur less frequently .
hypercalcemia , drug toxicity , and volume depletion also contribute to acute kidney injury in multiple myeloma cases .
excessively filtrated monoclonal light chains , usually composed of kappa light chains restricted to the v i subgroup , generate crystals within the cytoplasm of proximal tubular epithelial cells .
these monoclonal kappa light chains have variable domains that are resistant to degradation by proteases in lysosomes .
mutations of variable domains of kappa light chain , which is changing serine 30 to alanine , isoleucine , or leucine residue , increase the hydrophobicity of the cdr - l1 loop .
fragments of the variable domain that accumulate in the cytoplasm are responsible for intracellular crystal formation and tubular dysfunction .
the crystalline inclusions generated from light chains can induce cytotoxicity in the proximal tubular epithelial cells .
they are associated with proximal tubular dysfunction including hypophosphatemia , hypouricemia , aminoaciduria , glycosuria , and metabolic acidosis .
also , disruption of phagocytes that contain crystals may induce tissue injury , subsequently leading to tubular atrophy and interstitial fibrosis .
it is unclear whether achieving a hematologic response by treating multiple myeloma can resolve renal proximal tubular dysfunction .
gailani et al   reported a hematologic response in a myeloma case by irradiation , followed by melphalan , prednisone , and vincristine .
after myeloma treatment , the patient s hypophosphatemia , hypouricemia , and glycosuria were normalized .
uchida et al   found that after treatment for multiple myeloma , urinary bence - jones protein disappeared and glycosuria , aminoaciduria , phosphaturia , and metabolic acidosis all improved .
it was reported by von scheele   that glycosuria improved in a patient with fs with myeloma after 6 weeks of melphalan therapy ; however , despite achieving a partial hematologic response after myeloma therapy , renal tubular acidosis , glycosuria , and hypophosphatemia persisted in the patient .
it is important to prescribe both phosphate and vitamin d to correct hypophosphatemia and to prevent metabolic bone disease , because impairment of vitamin d activation mechanisms also contributes to hypophosphatemia in fs . for normalization of metabolic acidosis , 1015 meq / kg / day of sodium bicarbonate
we report a case of fs without renal failure , where the patient was ultimately diagnosed with multiple myeloma , demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy .
adult patients with fs should be evaluated for the presence of bence - jones proteinuria and plasma cell dyscrasia should be excluded as an underlying factor .
 fanconi syndrome ( fs ) is a rare condition that is characterized by defects in the proximal tubular function . 
 a 48-year - old woman was admitted for evaluation of proteinuria . 
 the patient showed normal anion gap acidosis , normoglycemic glycosuria , hypophosphatemia , and hypouricemia . 
 thus , her condition was compatible with fs . 
 the m peak was found behind the beta globulin region in urine protein electrophoresis . upon bone marrow examination 
 , we found that 24% of cells were cd138 + plasma cells with kappa restriction . from a kidney biopsy 
 , we found crystalline inclusions within proximal tubular epithelial cells . 
 thereafter , she was diagnosed with fs accompanied by multiple myeloma . 
 the patient received chemotherapy and autologous stem cell transplantation , and obtained very good partial hematologic response . 
 however , proximal tubular dysfunction was persistent until 1 year after autologous stem cell transplantation . 
 in short , we report a case of fs accompanied by multiple myeloma , demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy . 
Introduction
Case report
Discussion
Conflicts of interest