The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development

Abstract

Background: Solute carrier family 13 member 5 (SLC13A5) is a Na⁺-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts.

Methods: The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals.

Results: We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10^-4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10^-13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns.

Conclusions: This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.

Keywords: Citrate; Drug development; Kidney; Mendelian randomization; Renal function; SLC13A5.

Fig. 1

Overview of the study design. BUN: blood urea nitrogen, CRP:C-reactive protein, CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate, HDLc: high-density lipoprotein cholesterol, IL6: interleukin 6; LDLc: low-density lipoprotein cholesterol, SNP: single-nucleotide polymorphism, uACR: urine albumin-creatinine ratio

Fig. 2

Mendelian randomization estimates for the association of genetically proxied SLC13A5 inhibition with kidney traits. Mendelian randomization estimates are scaled per 1-standard deviation (SD) increase in plasma citrate through genetically proxied SLC13A5 inhibition. The units for the BUN, creatinine-eGFR, cystatin C-eGFR and uACR are SD change in log transformed levels. The units for CKD and microalbuminuria are log odds ratio. Raw p values are presented. BUN: blood urea nitrogen, chronic kidney disease; eGFR: estimated glomerular filtration rate, urine albumin-creatinine ratio

Fig. 3

Mendelian randomization estimates for the association of genetically proxied SLC13A5 inhibition with biomarkers of glucose and lipid metabolism, and inflammation. Mendelian randomization estimates are scaled per 1-standard deviation (SD) increase in plasma citrate through genetically proxied SLC13A5 inhibition. The units for fasting glucose is mmol/l, the units for C-reactive protein (CRP) is standard deviation (SD) change of log transformed levels, and the remaining exposures are measured in SD units. HDLc: high-density lipoprotein cholesterol, IL6: interleukin 6, LDLc: low-density lipoprotein cholesterol