Is salt-wasting the long awaited answer to the hyperuricaemia seen in uromodulin storage diseases?

Sir, Recent articles have revealed that familial juvenile hyperuricaemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD) are caused by mutations in uromodulin, which is also known as Tamm–Horsfall protein [1–3]. These uromodulin storage diseases present with varying degrees of chronic interstitial renal disease, hyperuricaemia, a reduced fractional excretion of uric acid (FeUA) and renal salt-wasting [4,5]. However, the aetiology of the hyperuricaemia seen in these diseases remains a mystery. How can a mutation in THP, a protein produced exclusively in the thick ascending limb (TAL), result in hyperuricaemia when all the uric acid transport is believed to occur only in the proximal tubule? One explanation is that salt-wasting causes a compensatory upregulation of both sodium and uric acid transport in the proximal tubule. Recently, the THP knockout mouse was found to have increased expression of distal tubule sodium transporters [6]. We further examined salt and water balance in these animals (Table 1). These animals have normal renal histology and do not have an elevated serum uric acid level, likely secondary to the presence of the enzyme uricase. We found a striking difference in the ratio of urinary sodium to urinary uric acid (wildtype n = 7, 1.98±0.19 vs knockout n = 14, 0.53±0.03, P = 0.002) (Figure 1). Thus, for a given amount of salt excretion, the knockout animals are excreting less uric acid. To account for this finding, kidney mRNA levels of uric acid transporters were evaluated by real-time RT-PCR and Western blot, but no significant differences were detected. Ratio of urine sodium to urine uric acid. Serum and urine chemistries *P<0.05. Serum and urine chemistries *P<0.05. None of the described uric acid transporters are directly coupled to sodium transport. One possible explanation for this data is the existence of an as yet undescribed sodium linked uric acid transporter. Another explanation is that uric acid transport is upregulated along with sodium transport in the proximal tubule. To further investigate this hypothesis, more formal studies of uric acid transport will be needed. However, the data from our experiment are consistent with the theory that the decreased FeUA seen in FJHN may result from distal salt-wasting and a compensatory upregulation of proximal tubule resorption of sodium and uric acid. Conflict of interest statement. The authors have no conflict of interest to declare. 1University of Florida Department of Medicine Division of Nephrology Dialysis and Transplantation Florida, USA2 Department of Anatomy Charite Universitätsmedizin Berlin Germany3 University of Oklahoma Heath Sciences Center Oklahoma City Oklahoma, USA