Tubular Secretion in CKD

Abstract

Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD

“…Regarding tubular function, an independent association between higher mortality and diminished renal clearance of hippurate, another solute with high tubular secretion, albeit with a protein-bound fraction of .50%, has recently been shown. 26 Although these observations need confirmation in other larger patient populations, they suggest that a better understanding of renal tubular function is necessary not only to identify solutes that are prone to accumulation and thus, potentially harmful but also, in an attempt to improve current risk stratification of patients with CKD on the basis of eGFR and proteinuria.…”

An overview of renal metabolomics

“…For example, 112 of 488 measured metabolites in 1735 participants of the KORA F4 study were associated with eGFR at a conservative Bonferroni adjusted significance threshold. 51 Some of these metabolites have the potential to add prognostic information beyond serum creatinine, perhaps because they are more accurate markers of filtration, because they report on other renal functions such as tubular secretion, 52 or because they may play a functional role in disease pathogenesis. Although investigators have begun to explore all of these possibilities for select metabolites, there has been a relative paucity of work characterizing short and long term variation and the sources of variation of the metabolome in health and in CKD.…”

The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease

“…Tubular function can be highly variable at any given eGFR and often depends on the underlying CKD aetiology. 40 In addition to the key confounding issue of reduced renal TMAO clearance, gut-related factors specific to CKD are likely to contribute to elevated blood TMAO levels. Gut microbiome subpopulation composition may shift from symbiotic to dysbiotic under the influence of "uraemic" factors such as gut oedema, reduced transit time, anorexia or adherence to a low phosphorus or potassium diet along with oral phosphate binders and iron replacement.…”