Furosemide and Creatinine Tubular Stress Test in Order to Measure Proximal Tubule Residual Function

Overview

This is a two phase study. The first part will take place at the National Institute of Cardiology in Mexico, the second phase will be made in collaboration with the University of California San Diego and University of Minnesota. This is a non blind experimental study, 72 patients with different stages of CKD from the outpatient unit of the institute will be included. Each patient will receive a furosemide stress test of 1 mg/kg in non diuretic users and 1.5 mg/kg in diuretic users, in addition of 5 grams of creatinine oral intake, as well as Iohexol 5ml IV to measure GFR. After the intervention, blood and urine samples will be drawn at baseline, 60 minutes, 180 minutes, and 240 min. Urine output will be maintained during the study by the intravenous administration of Hartman's solution 1 -2 ml/kg body weight every hour, in addition to the volume of urine output in the preceding hour plus oral water ingestion as tolerated. Blood and urine will be analized to measure creatinine (blood and urine), then samples will be processed for measurement of furosemide (HPLC-Uv vis), indoxyl sulphate, p-cresol, hippurate, and iohexol (mass spectometry). The aim of this stiudy is to asses the differences between GFR and proximal tubule function.

Residual kidney function (RKF) its a critical tool in the CKD evolution and prognosis. It's well known that preserving RKF increases survival in patients with CKD. Traditionally Glomerular Filtration Rate (GFR), and proteinuria have been the variables used to asses RKF, wich are glomerular residual function (GRF) variables. This glomerulocentric assestment of RKF has been challenged recently. It is knows that urea is not the principal uremic toxine, the protein boud uremic toxins are particullary important because it's elimination depends of the proximal tubular organic anionic transporters (OAT), and the organic cationic transporters (OCT). The functional integrity of this transporters are lost in advanced CKD stages, and it´s accumulation increases cardiovascular and renal damage because they activate proinflammatory citokines, increasing mortality, this was shown specially with the accumulation and clearance of hippurate and p-cresol independently of GFR. The purpose of this study is to asses the functional capacity of two AOT (hOAT1, and hOAT3, that can be blocked by furosemide), and one OCT (OCT2 blocked by creatinine) using an stress test. The stress test will be performed in healthy subjects as well as in CKD from different stages. Protein bound uremic toxins such as indoxyl sulphate, p-cresol, and hippurate will be measured. In the stress the typical furosemide stress test described previously by Mehta will be implemented, in addition to an oral load of 5 grams of creatinine oral load. This levels should be efficient enough to assess the functionality of the OCT2. A comparison between the tubular creatinine secretine to filtrated creatinine measuring GFR using Iohexol will be performed. In conclusion this is a pilot study aimed to establish a practical methodology for the assesment of proximal tubular function.