Urinary Citrate Is Associated with Kidney Outcomes in Early Polycystic Kidney Disease

Rocha, Daniel Ribeiro da; Xue, Laixi; Sousa, Hiago Murilo Gomes; Matos, Ana Cristina Carvalho de; Hoorn, Ewout J.; Salih, Mahdi; Heilberg, Ita Pfeferman

doi:10.34067/kid.0004772022

Cited by 10 publications

(9 citation statements)

References 20 publications

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“…This would be expected to have implications for cellular metabolism in cells expressing SLC13A5, with the higher circulating plasma citrate levels also potentially impacting metabolism systemically. Consistent with the results of our main genetic analyses, previous work has identified protective effects of citrate in various animal models of kidney disease [1,6,55,56]. Although the main IVW Mendelian randomization analysis investigating effects of plasma citrate levels did not identify evidence supporting effects on parameters of kidney function, there was strong evidence of heterogeneity in estimates generated by individual SNPs, consistent with the presence of pleiotropic effects that could bias the main IVW analyses [43].…”

Section: Discussionsupporting

confidence: 88%

“…This would be in-keeping with the favourable effects of SLC13A5 on kidney function occurring through its effects on plasma citrate. It has been reported that low citrate levels in urine are associated with various forms of kidney disease, and low urinary citrate is a biomarker for kidney disease progression [55,[57][58][59][60][61][62]. Furthermore, pre-clinical studies with SLC13A5 knockout mice have supported effects on sympathoadrenal mechanisms [63], which may also contribute to nephroprotective effects of genetically proxied SLC13A5 inhibition.…”

Section: Discussionmentioning

confidence: 99%

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

Gill,

Zagkos,

Gill

et al. 2023

Preprint

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BackgroundSolute carrier family 13 member 5 (SLC13A5) is a Na -coupled citrate co-transporter that mediates the entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a therapeutic target for reducing progression of kidney disease via its effects on citrate metabolism. However, evidence of its efficacy in humans is limited. 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.MethodsThe 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 5,023 to 1,320,016 individuals.ResultsWe 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=3×10-3). 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 also 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.ConclusionThis 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. Further study in the form of early-stage clinical trials may now be warranted to help translate these findings towards improving patient care.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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

Gill,

Zagkos,

Gill

et al. 2023

Preprint

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“…In ADPKD, there is an interesting link among crystal formation, citrate, and disease progression, which further underlines the importance of this point. 55 , 56 , 57 …”

Section: Discussionmentioning

confidence: 99%

Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD—a randomized controlled trial

Cukoski,

Lindemann,

Arjune

et al. 2023

Cell Reports Medicine

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“…24,25 Conversely, there is evidence that kidney stone formation accelerates cyst growth, and hypocitraturia is associated with faster eGFR decline. 26,27 Some studies have shown that patients with kidney stones are at risk of exceeding safe levels of radiation. 18 Like ADPKD, the diagnosis and management of kidney stones relies heavily on imaging techniques, specifically CT scans.…”

Section: Discussionmentioning

confidence: 99%

Kidney Stones Account for Increased Imaging Studies in Autosomal Dominant Polycystic Kidney Disease

Simmons,

Ullman,

Dahl

2024

Kidney360

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Introduction: ADPKD patients may have more imaging studies than patients with other forms of chronic kidney disease (CKD). We characterized the imaging burden of ADPKD patients relative to a CKD population to determine which factors lead to increased imaging in ADPKD patients. Methods: We retrospectively reviewed patients seen at Yale Nephrology between January 2012 and January 2021. We collected demographic, clinical, and imaging data through automated query and manual chart review. 807 ADPKD patients were matched to 4,035 CKD controls based on criteria of sex, race, ethnicity, CKD stage, hypertension, and diabetes, but not age. The number of abdominal imaging studies were compared between ADPKD and CKD groups, and the impact of kidney stone diagnosis was further evaluated. Chi-squared and t-tests were used to evaluate demographic variables, and Kruskal Wallace and negative binomial regression models were used to evaluate differences between abdominal imaging studies. Results: Patients with ADPKD had a greater number of total abdominal imaging studies (p<0.0001), ultrasounds (p<0.0001), and MRIs (p=0.02) compared to controls. In patients with preserved renal function (eGFR > 60 ml/min/m2), these differences persisted. Kidney stones were significantly more common among patients with ADPKD (p<0.0001). In multivariable assessment of imaging study counts using a negative binomial model controlling for kidney stones, ADPKD was no longer a significant predictor. In ADPKD patients, pyelonephritis, cyst complications, lower eGFR, diabetes, coronary artery disease, kidney stones, lower BMI, and being male, Black and younger increased the likelihood of having more imaging studies. Conclusion: The higher prevalence of abdominal imaging studies in ADPKD patients correlated with the increased incidence of kidney stones observed in this population.

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Urinary Citrate Is Associated with Kidney Outcomes in Early Polycystic Kidney Disease

Abstract: This is an Early Access article. Please select the PDF button, above, to view it.

Cited by 10 publications

References 20 publications

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

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

Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD—a randomized controlled trial

Kidney Stones Account for Increased Imaging Studies in Autosomal Dominant Polycystic Kidney Disease

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