Evidence shows that the secretion of organic solutes is an essential intrinsic kidney function. However, current clinical assessment of kidney function is primarily based on glomerular filtration, explains Bryan Kestenbaum, MD. Thus, the clinical significance of kidney secretory solute clearance remains ill-defined. “Developing reliable procedures to measure tubular secretory clearance could advance understanding of kidney health,” says Dr. Kestenbaum.

A Prospective Cohort Study

For a prospective cohort study published in the Journal of the American Society of Nephrology, Dr. Kestenbaum and colleagues first developed a procedure to estimate tubular secretory clearance based on quantification of secretory solutes in blood and urine. The study team obtained previously collected blood plasma and 24-hour urine samples from the Chronic Renal Insufficiency Cohort (CRIC) Study, a national prospective study of chronic kidney disease. They used targeted liquid chromatography–tandem mass spectrometry to estimate tubular secretory clearance in 3,416 CRIC participants who had available blood and urine samples from the baseline visit, which was conducted in 2003-2008.

Cox proportional hazards regression was used to test whether estimates of secretory-solute clearances were associated with subsequent CKD progression—defined by a 50% or greater decline in estimated glomerular filtration rate (eGFR), initiation of maintenance dialysis, or kidney transplantation—and mortality, adjusting for eGFR, albuminuria, and other potential risk factors. Participants had a mean age of 58, 41% were African American, and the median eGFR was 43 ml/min per 1.73 m2.

Multiple Associations

“We found that lower kidney clearance of most secretory solutes were associated with a greater chance of kidney disease progression over a median follow-up of 6 years,” says Dr. Kestenbaum. Indeed, even after adjustment, lower clearances of kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine were all associated with significantly greater risks of CKD progression (Figure). The strongest association was seen with clearance of the highly protein-bound solute kynurenic acid. Effect sizes ranged from an 11% to 21% greater risk per 50% lower clearance. Lower kidney clearances of secretory solutes were also associated with significantly quicker eGFR decline, after full adjustment and correction for multiple comparisons. The largest effect size was seen with indoxyl sulfate, with each 50% lower clearance associated with a 2% greater annual eGFR decline.

“Lower clearances of several secretory solutes—isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid—were also significantly associated with a higher risk of all-cause mortality after adjustment,” adds Dr. Kestenbaum. Among the more than 1,000 deaths over a median of 9.6 years, similar associations were also observed for the composite outcome of CKD progression or all-cause death. Mortality rates were higher for lower quartiles of the summary secretion score when analyzed across categories of eGFR and albuminuria. Taken together, the “associations suggest that measures of tubular secretory solute clearance may provide complementary information to existing kidney function measurements for associations with long-term prognosis,” says Dr. Kestenbaum.

Providing a Clearer Picture

Dr. Kestenbaum notes that additional research is needed to refine these measurements to include more reliable solutes for clinical application and investigation of disease states in which such measurements may be most useful. In the meantime, he says the study findings “suggest that incorporating measures of tubular secretory clearance into the evaluation of kidney function could provide new insights into disease causation, prognosis, and kidney drug dosing. However, our methods for estimating tubular secretory clearance are still too raw for clinical use—there is too much variability in these measures within a person over time and lingering uncertainty as to how strongly they relate to gold-standard secretory clearance.”


Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study