Study of the effect of loading pyrazinamide (PZA) and probenecid (PBD) on urate excretion in HRH patients was a major instrument employed in the determination of the etiology of HRH. The new developments concerning renal urate handling and the etiology of HRH, as described earlier, call for reevaluation of the significance of these tests in determining the etiology and classification of HRH to various etiological subtypes. In normal subjects, administration of PBD results in marked uricosuria, and administration of PZA results in a marked antiuricosuric effect.16 As further discussed in Chap. 198, the PBD and PZA loading tests identified two main patterns of response of urate excretion to the administration of the drugs in HRH patients. Most patients were found to exhibit attenuated response of urate excretion to the administration of both drugs, speculated to reflect a defective presecretory urate reabsorption mechanism. A smaller group of HRH patients was found to exhibit a normal response to PZA administration but an attenuated response to PBD administration, speculated to reflect a defective postsecretory urate reabsorption mechanismn (see Chap. 198). The classification of HRH patients into these two main groups according to the preceding two different patterns of response to the loading of the drugs appears to be valid, but interpretation of the different patterns to reflect different site-specific presecretory and postsecretory transport defects is probably wrong. PZA and PBD share affinity for the hURAT1 transporter. 1,3,5 Accordingly, the uricosuria caused by PBD loading is explained by inhibition of the hURAT1 transporter by the extracellular drug, whereas the antiuricosuric effect caused by PZA loading is explained by enhancement of urate reabsorption from the lumen in exchange for intracellular PZA 1,3,5 (previously, the pronounced antiuricosuric effect of PZA was attributed to blocking of urate secretion by the drug17). Accordingly, a defective hURAT1 transporter should be associated with an attenuated response of urate excretion to the administration of both PBD and PZA Indeed, HRH patients with mutations in the SLC22A12 gene were found to be characterized by an attenuated pattern of response to both drugs.13 This finding may be taken to suggest that HRH patients affected with mutations in the SLC22A12 gene represent the major group of HRH patients previously classified as being affected with the presecretory reabsotption defect. The connection of the previously postulated second site-specific transport defect, the postsecretory reabsorption defect, to a specific transporter defect is not yet known. Yet the existence of a second (new) urate transporter that is defective in this group of patients may be speculated in view of the recently reported failure to detect a mutation in the SLC22A12 gene in one such patient.15 Corroboration of absence of SLC22A12 mutations in HRH patients with the postsecretory type of defect will strengthen this possibility.