Chronic kidney disease (CKD) is a leading public health problem. It is understood to affect 13.4% of the world’s population, and the number of patients with end-stage kidney disease (ESKD) needing renal replacement therapy is estimated at between 4.902 and 7.083 million.
Phosphate balance is central to many metabolic pathways, and the kidneys play a key role in the reabsorption and excretion of phosphate to achieve this balance. In CKD, however, the phosphate balance is significantly altered.
Patients suffering from CKD lose renal mass, including proximal tubule cells (PTCs), the cells responsible for the reabsorption and excretion of proteins and solutes such as phosphate. A loss in PTCs causes a reduction of phosphate clearance by the kidney, leading to an increase in phosphate in the blood. This state of hyperphosphatemia results in vascular calcification, a hallmark of cardiovascular disease (CVD), and major risk factor for CKD.
PTCs are well-equipped to form a physical exchange barrier between the blood and the urine due to the large number of transporters they present on their cell surface. These transporters are asymmetrically distributed between the apical (top) and the basolateral (bottom) side of these polarised cells. Among these transporters are phosphate transporters, NaPi-IIa, NaPi-IIc, PIT2 and NTPs, which reabsorb phosphate into the blood. The activity of these transporters are regulated by hormones, including parathyroid hormone and klotho.
Figure: The disturbance of phosphate balance has profound effects on health. Chronic kidney disease (CKD) leads to high levels of phosphate in the blood (hyperphosphatemia), which in turn leads to vascular calcification and increased risk of cardiovascular disease. Phosphate levels are regulated by hormones such as klotho and parathyroid hormone. In CKD, klotho is downregulated, whilst parathyroid hormone is upregulated. Klotho and parathyroid hormone (and fibroblast growth factor 23, FGF23), are potential therapeutic targets for the treatment of CKD.
A high level of phosphate in the blood can also be caused by a reduction in circulating klotho, which in turn induces expression of parathyroid hormone leading to bone remodelling. More phosphate is reabsorbed from the bones and deposited in blood vessels leading to vascular calcification. Thus, klotho and parathyroid hormone are potential therapeutic targets for CKD treatments. Klotho mimetic drugs and modulators of parathyroid hormone could restore the balance of phosphate in our bodies and reduce the burden of debilitating diseases such as CKD.
One of the hurdles to developing effective therapeutics for the treatment of CKD is the ability to perform in vitro screening and in vitro evaluation of their mode of action.
Newcells Biotech has remedied this issue and has developed the aProximate™ platform, the most advanced near-physiological in vitro model of kidney proximal tubule cells for kidney disease modelling.
How can Newcells Biotech’s aProximate™ help model CKD and identify novel therapeutics for CKD?
aProximate™ expresses the full range of relevant transporters involved in phosphate uptake – sodium-dependent phosphate transporters NaPi-IIa, NaPi-IIc, PIT2, NPT1, NPT4 and NPT5. The aProximate™ platform has been validated as a model for phosphate transport by demonstrating dose dependent inhibition of these transporters by klotho and parathyroid hormone, highlighting the relevance of this platform as an in vitro model for CKD.
aProximate™ also expresses all the relevant transporters critical for drug handling (including major transporters OAT1, OAT3, OCT2 and MATE and endocytic receptors megalin and cubilin) and allows detection of FDA qualified kidney-specific biomarkers in response to injury such as KIM-1, NGAL and Clusterin.
aProximate™ is available from humans and four preclinical species including rat, mouse, dog and non-human primate (NHP) simplifying cross species comparison and improve prediction of clinical outcomes (Bajaj et al., 2020)
Newcells Biotech also offers a high quality and reliable service for assessment of customer compounds carried out by our experienced scientists. Our service includes the design, development, and completion of study protocols in our UK laboratories, working closely with our customers with our leading kidney expert Dr Collin Brown, to define a tailored study design that best delivers the data that they require.
Interested in our aProximate™ model?
For more information contact us.
For further details, watch our webinar ‘Kidney as a Target: The Important Role of SLCs (Sodium Linked Co-Transporters)’.
Join our mailing list to stay up to date with our latest publications and developments.