Impaired Tubular Secretion of Organic Solutes in Advanced Chronic Kidney Disease

Abstract

Background The clearance of solutes removed by tubular secretion may be altered out of proportion to the glomerular filtration rate (GFR) in chronic kidney disease (CKD). Recent studies have described considerable variability in the secretory clearance of waste solutes relative to the GFR in patients with CKD. Methods To test the hypothesis that secretory clearance relative to GFR is reduced in patients approaching dialysis, we used metabolomic analysis to identify solutes in simultaneous urine and plasma samples from 16 CKD patients with an estimated GFR of 7±2 ml/min per 1.73m2 and 16 control participants. Fractional clearances were calculated as the ratios of urine to plasma levels of each solute relative to those of creatinine and urea in CKD patients and to those of creatinine in controls. Results Metabolomic analysis identified 39 secreted solutes with fractional clearance >3.0 in control participants. Fractional clearance values in CKD patients were reduced on average to 65%±27% of those in controls. These values were significantly lower for 18 of 39 individual solutes and significantly higher for only one. Assays of the secreted anions phenylacetyl glutamine, p-cresol sulfate, indoxyl sulfate, and hippurate confirmed variable impairment of secretory clearances in advanced CKD. Fractional clearances were markedly reduced for phenylacetylglutamine (4.2±0.6 for controls versus 2.3±0.6 for CKD patients, P<0.001), p-cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for CKD patients, P<0.001), and indoxyl sulfate (23.0±7.3 versus 7.5±2.8, P<0.001), but not for hippurate (10.2±3.8 versus 8.4±2.6, P=0.13). Conclusions Secretory clearances for many solutes are reduced more relative to the reduction in GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.

Phenylacetylglutamine as a novel biomarker of type 2 diabetes with distal symmetric polyneuropathy by metabolomics

“…So far, several studies have reported that PAG showed different levels of content during various disease states [35][36][37], but a strong correlation between PAG and DSPN phenotype has never been reported. As outlined previously, Unabsorbed Phe could be oxidized and metabolized by Clostridium sporogenes in the intestinal flora and involved in PAG synthesis [18,38].…”

Acute Kidney Injury in Patients with Liver Disease

“…In patients with hyperbilirubinemia, cholemic nephropathy (also termed cholemic nephrosis, cholemic nephropathy, or bile cast nephropathy) refers to a condition characterized by intratubular bile casts with impaired kidney function in the setting of cholestasis (30). It was originally described in individuals with cholangiocarcinoma or other causes of obstructive jaundice (38). The notion that cholemic nephropathy is implicated in the pathogenesis of HRS-1 was introduced by human autopsy studies reporting a significant proportion of patients with cirrhosis with histologic evidence of intratubular bile casts who had been diagnosed as having HRS-1 premortem (39,40).…”

Effect of Furosemide on Proximal Tubular Secretion of Organic Solutes in Patients Receiving Hemodialysis

“…They pass through different transporters on the apical membrane into the tubule lumen, where they then act at their respective tubule sites. Numerous uremic solutes are cleared by these same secretory mechanisms, and their secretion may be impeded by competing diuretics (3). However, our study showed no impairment in secretion of four uremic solutes in the setting of furosemide use in patients receiving hemodialysis.…”

“…Among these eight participants, the daily furosemide dose averaged 221±109 mg at week 5 compared with 48±55 mg at baseline ( P =0.01). Four organic acids normally secreted by the kidneys (phenylacetylglutamine, p-cresol sulfate, indoxyl sulfate, and hippurate) and furosemide were measured using liquid chromatography tandem mass spectrometry (3).…”

“…The GFR was estimated as the average of the urea and creatinine clearances, and fractional solute clearances were calculated relative to the GFR. For the protein-bound solutes p-cresol sulfate, indoxyl sulfate, and hippurate, clearances were calculated in terms of the free unbound level in order to detect impaired secretion (3). Baseline and week 5 measurements were compared using the Wilcoxon rank sum test.…”