SGLT2-inhibitors interfere with measurement of effective renal plasma flow using para-aminohippuric acid

Abstract Para-aminohippuric acid (PAH)-derived effective renal plasma flow (ERPF) is increasingly being used in parallel with the revived interest in kidney hemodynamic function due to the development of sodium glucose co-transporter 2 (SGLT2) inhibitors. In our trial (Kidney Int 2020;97: 202-12) we measured ERPF by urinary PAH clearance and calculated fractional PAH extraction ratios, which initially were very low during both the hyperglycemic clamps at baseline, as well as the euglycemic conditions following treatment with SGLT2 inhibitor dapagliflozin. Previous literature showed that hyperglycemic i.e. glucosuric conditions reduce urinary PAH concentrations, due to a Schiff base that is formed between the para-amino group of PAH and the aldehyde group of glucose. By using hydrochloric acid (HCl) any PAH that has been glycosylated can be reconverted, independent of storage time. After treatment with HCL we indeed found higher PAH extraction ratios in the expected range. In addition, a negative correlation between storage time and PAH extraction ratio in people treated with SGLT2 inhibitor dapagliflozin during a euglycemic clamp before treatment with HCl. Besides these human data, comparable results were observed in male obese ZSF1 rats with hyperglycemia. Therefore, researchers should be aware that even under euglycemic conditions, SGLT2 inhibitors induce glucosuria that interferes with accurate ERPF measurement due to glycosylation of PAH in stored urine samples. Pre-treatment of urine with NaOH or adding HCl prior to measurement will overcome this problem.