Impaired Tubular Secretion of Organic Solutes in Advanced Chronic Kidney Disease

Abstract

Significance Statement In patients with CKD, the clearance of waste solutes removed by tubular secretion may be altered to an extent that is disproportionate to the reduction in the GFR. However, an average change in the clearance of secreted waste solutes relative to the GFR in CKD has not been reported, possibly because studies performed so far have included few subjects with advanced CKD. The authors found that the secretory clearance of many waste solutes is reduced relative to the GFR in patients with an eGFR<12 ml/min per 1.73 m 2 . As patients approach dialysis, to the extent that secreted solutes contribute to uremic symptoms, reductions in fractional clearances of secreted solutes might cause such symptoms to increase out of proportion to the reduction in GFR. Background The clearance of solutes removed by tubular secretion may be altered out of proportion to the GFR in 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 patients with CKD and an eGFR of 7±2 ml/min per 1.73 m 2 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 patients with CKD 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 patients with CKD 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 patients with CKD; P <0.001), p -cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for patients with CKD; 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 than the GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.

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