Proximal tubular secretion, cardiovascular events, and kidney clearance of medications

Background: Current detection and monitoring of chronic kidney disease (CKD) rely primarily on glomerular filtration rate (GFR) and albuminuria. However, the kidneys perform many important functions outside of the glomerulus. Among them, the secretion of organic anions and cations by kidney proximal tubules is a vital non-glomerular function for removing retained metabolic wastes, toxins, and drugs from the circulation. We have previously developed a novel assay to estimate proximal tubular secretory clearance based on the quantification of endogenous secretory solutes in blood and urine and detected associations of compromised tubular secretory function with more severe metabolic complications, and higher risks of CKD progression and all-cause mortality in patients with mild-to-moderate CKD. However, the association between lower proximal tubular secretory clearance and cardiovascular events, the most common cause of death among patients with CKD, is uncertain. In addition, despite the primacy of tubular secretion in kidney drug handling, current medication dosing strategies are based on estimates of GFR (or creatinine clearance) under the assumption that secretion and filtration are tightly linked within an individual. This assumption has been challenged by multiple pharmacokinetics studies in recent years. However, few studies have empirically determined relationships between tubular secretory clearance and kidney drug elimination. Objectives: The overall goal of this dissertation is to further determine the clinical significance of kidney secretory clearance in the setting of CKD by determining associations with cardiovascular events and kidney drug elimination. Specifically, we aim to: 1) test associations of estimated proximal tubular secretory clearances with cardiovascular events in a national cohort study of CKD; 2) compare proximal tubular secretory clearances with measured GFR for the prediction of the kidney drug elimination in a population with a wide range of kidney function. Methods: For aim 1, we included 3,407 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured the plasma and urine concentration of eight secretory solutes using liquid chromatography tandem mass spectrometry (LC-MS/MS). We used Cox proportional hazards regression to estimate associations of secretory solute clearances at baseline with incident heart failure, myocardial infarction, and stroke events, adjusting for estimated GFR and other potential confounding characteristics. For aim 2, we evaluated 54 individuals with a wide range of estimated GFRs (21–140 ml/min/1.73m2). We administered single doses of furosemide and famciclovir (converted to penciclovir) and calculated their kidney clearances based on sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using LC-MS/MS, and we measured GFR by iohexol disappearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances. We used linear regression and leave-one-out cross-validation to calculate prediction statistics. Results: Secretion and cardiovascular events: In a national, representative cohort of CKD, we found kidney clearances of secretory solutes to be modestly correlated with estimated GFR. Lower 24-hour kidney clearances of secretory solutes were associated with incident heart failure and myocardial infarction, but not incident stroke, over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were removed by adjustment for estimated GFR. Secretion and kidney drug clearance: In participants with and without CKD, the kidney clearance of furosemide was correlated with iGFR (r = 0.84) and the summary secretion score (r = 0.86). The average proportionate difference between model-predicted and measured drug clearance, i.e., the mean proportionate error (MPE), between iGFR-predicted and measured furosemide clearance was 30.0%. MPEs for individual secretory solute clearances ranged from 27.3% – 48.0%, with the lowest MPE observed for the summary secretion score (24.1%). These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r = 0.78) and with the summary secretion score (r = 0.85), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with pyridoxic acid, indoxyl sulfate, and the summary secretion score modestly improved the prediction of furosemide clearance. Conclusions: In summary, we found no clinically or statistically relevant association between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, and stroke after adjustment for eGFR in a national cohort study of CKD. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular events beyond GFR among patients with mild-to-moderate CKD. We also found that the kidney clearance of secretory solutes and iGFR demonstrated relatively similar accuracy for predicting the clearances of furosemide and penciclovir, with some improvement from combining both kidney measures. These findings provide some reassurance that GFR is a useful surrogate for predicting secretory drug clearance in stable persons and suggest cautious optimism for future improvements in kidney drug dosing strategies by incorporating measures of secretory clearance.