familial renal glucosuria ( frg ) is characterized by the presence of glucose in the urine in the absence of diabetes mellitus or generalized proximal tubular dysfunction . mutations in the slc5a2 gene , encoding sglt2 , are responsible for the large majority of frg pedigrees [ 1 , 2 ] . recently , sglt2 was targeted as an innovative strategy for the treatment of hyperglycaemia in type 2 diabetes mellitus ( t2 dm ) . one interesting and consistent observation with sglt2 inhibitors is the almost dose - proportional decrease in serum uric acid levels [ 3 , 4 ] , which is paradoxical in light of the associated diuretic effect of these compounds . in the current report , we describe an frg individual with increased urate renal excretion and hypouricaemia , and discuss renal hypouricaemia in the setting of severe glucosuria . this study was part of the medical evaluation for glucosuria in a 35-year - old female individual . she presented with a urinary glucose excretion ( uge ) of 487.8 mmol ( 87.8 g)/1.73 m/24 h. the clinical data are detailed in table  1 . the novel c.10331060del ; p.v346afsx17 frameshift mutation was identified in homozygosity ( figure  1a ) . table  1.phenotype evaluation of caseagecountry of originweight ( kg)height ( cm)glucose excretion mmol/1.73 m/24 h ( g/1.73 m/24 h)serum glucose mmol / l ( mg / dl)hba1c ( % ) serum creatinine mol / l ( mg / dl)serum uric acid mol / l ( mg / dl)urinary urate mmol/1.73 m/24 h ref : 1.54.4 ( mg/1.73 m/24 h)mmol / kg 0.04  0.01 ( mg / kg)fractional excretion 10%35portugal65167487.8 ( 87.8)4.1 ( 74)5.453 ( 0.6)113.01 ( 1.9)7.33 ( 1242)0.13 ( 21.5)20ref , reference range for urinary urate.values detail average ( and standard deviation when specified ) in an adult population . 
 fig . the wild - type amino acid sequence is represented in black ; in light gray , the new orf . ( b ) suggested mechanism for the renal hypouricaemia associated with defects of sglt2 . in the presence of normally functioning sglt2 ( left side ) all the glucose is reabsorbed in the early segment ( s1 ) of the proximal tubule , while in the late s3 segment glut9 is normally reabsorbing urate . if sglt2 is disrupted ( right side ) , either by genetic defects or pharmacological inhibition , the presence of significant amounts of glucose in the late segments of the proximal tubule reverses the direction of urate transport , with glut9 exchanging luminal glucose for intracellular urate and actively promoting urate secretion . the wild - type amino acid sequence is represented in black ; in light gray , the new orf . ( b ) suggested mechanism for the renal hypouricaemia associated with defects of sglt2 . in the presence of normally functioning sglt2 ( left side ) all the glucose is reabsorbed in the early segment ( s1 ) of the proximal tubule , while in the late s3 segment glut9 is normally reabsorbing urate . if sglt2 is disrupted ( right side ) , either by genetic defects or pharmacological inhibition , the presence of significant amounts of glucose in the late segments of the proximal tubule reverses the direction of urate transport , with glut9 exchanging luminal glucose for intracellular urate and actively promoting urate secretion . owing to persistent low serum uric acid levels [ 113.01 mol / l ( 1.9 mg / dl ) ] , further evaluation was performed in order to exclude fanconi syndrome . urinary urate values were found to be raised , with an excretion of 7.33 mmol ( 1242 mg)/1.73 m/24 h or 0.13 mmol ( 21.5 mg)/kg of body weight and a fractional excretion of 20% . phosphorus ( urinary and serum ) , bicarbonate ( plasma ) and immunoglobulin light chains ( urine ) were all within normal range ( data not shown ) . by high - performance liquid chromatography , cystine was the only amino acid over - excreted : 639.3 mol ( 153.3 mg)/24 h ( reference range : 0158.5 mol/24 h ) . accordingly , the over - excretion of cystine was considered an incidental finding and unrelated to the glucosuric phenotype . on follow - up , she was hyperfiltrating with a serum creatinine of 35.4 mol / l ( 0.4 mg / dl ) , but there were no further decreases in urate serum levels [ 130.8 mol / l ( 2.2 mg / dl ) ] , compared with her earlier non - pregnant condition . under physiological conditions , sglt2 is responsible for reabsorbing the majority of the filtered glucose . the p.v346afsx17 frameshift mutation in our patient likely leads to a truncated protein between sglt2 transmembrane domains 8 and 9 and , therefore , fully accounts for the severe glucosuria . the handling of urate by the kidney is complex , involving both secretion ( inhibited by pyrazinamide ) and reabsorption ( inhibited by probenecid ) . pregnancy induces an increase in both the urate glomerular filtration and in its tubular reabsorption , with proportionally greater increments observed with the former and , hence , the lowering of serum urate usually observed in the first 24 gestational weeks . since our case did not display such a decrease in serum levels ( and even improved its fractional excretion ) with pregnancy , we can assume the urinary urate over - excretion seen with glucosuria to be a consequence of enhanced secretion rather than impaired reabsorption . two solute carriers that reabsorb urate are known to be expressed in the proximal tubule , urat1 ( slc22a2 ) , the target of probenecid , and glut9 ( slc2a9 ) , mutations of which are responsible for an isolated renal hypouricaemic phenotype [ 11 , 12 ] . two glut9 isoforms , glut9s ( expressed at the apical side ) and glut9l ( at the basolateral side ) , act concertedly to reabsorb uric acid from the glomerular filtrate . we can hypothesize that in the presence of a high glucose concentration in the late proximal tubular lumen , the direction of urate transport could be reversed , with glucose being exchanged for urate and leading to excessive urinary excretion and secondary hypouricaemia ( figure  1b ) . to our knowledge , all six individuals were homozygous for the p.k321r mutation , had a uge of 460.7938.1 mmol ( 83169 g)/1.73 m/24 h and displayed generalized aminoaciduria . in one case , although we have not pharmacologically detailed the involved pathway or screened our patient for mutations in urat1 and glut9 , our findings are in line with previous reports describing renal hypouricaemia in cases of hyperglycaemia induced glucosuria . not only in t2 dm , but also in maturity - onset diabetes of the young ( mody ) , in particular , in hnf1-mutated cases ( mody3 ) , who are characterized by a paradoxically low renal threshold for glucose and , therefore , exceptional glucosuria . this characterization of renal hypouricaemia as an incompletely penetrant feature of frg needs confirmation by similar observations in other patients with severe forms of frg . if replicated , this will argue for glucosuria being directly responsible for the disruption of urate transport in the proximal tubule and renal hypouricaemia in frg as well with pharmacological inhibition of sglt2 .
familial renal glucosuria is a rare co - dominantly inherited benign phenotype characterized by the presence of glucose in the urine . 
 it is caused by mutations in the slc5a2 gene that encodes sglt2 , the na+-glucose cotransporter responsible for the reabsorption of the bulk of glucose in the proximal tubule . 
 we report a case of frg displaying both severe glucosuria and renal hypouricaemia . 
 we hypothesize that glucosuria can disrupt urate reabsorption in the proximal tubule , directly causing hyperuricosuria .