Metabolomic profiling of uremic solutes in CKD patients

Abstract

Early detection and accurate monitoring of patients with chronic kidney disease (CKD) is likely to improve care and decrease the risk of cardiovascular and cerebrovascular diseases. As a new diagnostic tool, we examined the retention of uremic solutes as a simpler, more accurate method to assess renal function. To achieve this, we comprehensively evaluated these solutes in CKD patients. By capillary electrophoresis with mass spectrometry, we found 22 cations and 30 anions that accumulated significantly as the estimated glomerular filtration rate (eGFR) decreased. These compounds included 9 cations and 27 anions that were newly identified in this study. In contrast, we also found 7 cations (2 new) and 5 anions (all new) that decrease significantly as eGFR declines. We evaluated each substance for its suitability to detect early CKD stage. Compounds that are highly correlated with eGFR and whose plasma concentration changed in a manner approximated by the first-degree equation are excellent candidates for detecting CKD and identifying uremic toxins that might aggravate kidney function in the early stage of CKD. These results identify a number of uremic compounds, many of which are novel and which predict worsening renal function. These compounds provide diagnostic information and may be targets for therapies designed to treat the complications of CKD patients. Keywords: biomarker; CE-MS; CKD; uremic toxin INTRODUCTION Chronic kidney disease (CKD) is an important public health problem and determination of the glomerular filtration rate (GFR) has been essential for the evaluation of CKD patients. 1-3 Early detection of impairment of renal function allows treatment to prevent further deterioration and complications. With the progression of CKD, various uremic toxins accumulate, subsequently causing renal damage and hypertension. 4,5 Recently, we revealed that many compounds accumulate during renal failure, and that the kidney-specific organic anion transporter SLCO4C1 excretes uremic toxins, resulting in the reduction of blood pressure and renal inflammation. 6 To generalize these results for clinical use, it is necessary to examine the accumulation of uremic solutes precisely. Therefore, the aims of this study were (1) to identify new uremic retention solutes that accumulate in CKD patients comprehensively by capillary electrophoresis with mass spectrometry (CE-MS) and (2) to determine substances that are more sensitive for detecting early renal damage than serum creatinine (Cr) or cystatin C.

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…It also was confirmed by CE-MS analysis of 41 CKD patients that not only ADMA and GSA, but also transaconitate, exists in human beings and that their concentrations are increased in accordance with CKD progression. 50 ADMA and the other guanidino compounds are discussed in more detail by Schepers et al in this issue. 56 Recently, Toyohara et al showed the pathophysiological function and transcriptional regulation of human SLCO4C1 and introduced novel transporterbased therapeutic strategies for CKD by up-regulating SLCO4C1 expression in the kidney.…”

“…In vitro studies using cloned transporters have greatly expanded our knowledge concerning the interaction of identified uremic toxins with OATs (Tables 1 and 2 50 ) values. Seven of these uremic solutes, p-hydroxyhippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanopropanoic acid (CMPF), hippuric acid, indoleacetic acid, indoxyl sulfate, uric acid, and xanthine, have reported both increased in vivo plasma levels in uremic patients and in vitro kinetic parameters showing interaction with OATs.…”

“…84 BCRP shows overlapping substrate specificities with P-gp and the MRPs. 85 50 value, 7 mmol/L, respectively). In contrast, putrescine, oxalate, and quinolinic acid did not alter transport mediated by MRP4 or BCRP.…”

“…Together, these values can be used to quantitatively estimate the potential for these uremic solutes to cause clinically relevant transporter-mediated drugdrug interactions (DDI) in vivo ( Table 2). This DDI index is defined as the ratio of the peak unbound plasma concentration (unbound C max ) after administration of the highest therapeutic dose of a drug divided by the in vitro K i or IC 50 value determined for that drug on a particular transporter. 13 A cut-off value of 0.1 or higher ( 9%-10% inhibition of transport) is considered to indicate the potential for clinically relevant DDIs.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Over 100 molecules have been implicated in the pathogenesis of uremic syndrome (57)(58)(59)(60). Their precise roles are debated, but many of these are small organic anions, such as indoxyl sulfate, carboxy-methyl-propyl-furanpropionate, p-cresol sulfate, and kynurenine; molecules associated with CKD that can accumulate between dialysis sessions (57,59).…”