Kidney stone development is the composite end-result of multiple factors including genetic, dietary and environmental, and can have serious consequences. They are often painful and if left unaddressed can lead to more severe conditions such as obstruction of urinary flow and permanent damage to the kidneys. Recurrent kidney stones are one of the common causes of CKD. Here we will discuss the genetics of kidney stones.
In this series we’re focusing on the integrative approach to preventing kidney stone formation.
Conventional approaches to kidney stones tend to focus on medications, surgical removal, and using ultrasonic waves to break up stone. It rarely approaches the root cause including risk factors to prevent stone formation.
We covered the impact of diet, the microbiome and gut health, and electrolyte imbalances on kidney stones in previous blogs. Here we will discuss the role genetics play in kidney stone formation.
The Genetics of Kidney Stones
There seems to be a familial link when it comes to the development of kidney stones. In fact, two thirds of patients with calcium-containing kidney stones have a relative with kidney stones. Recently, genome-wide association studies uncovered several genetic sequence variants (SNPs) that lead to increased risk of kidney stone development. Although we are still scratching the surface in understanding the contribution of genetic factors to stone formation, we do know that we can modulate these risks through environmental and dietary modifications.
Genetic Variations in Calcium Handling
In a previous blog, we discussed the role of the kidney filtration units (specifically the nephrons). The kidneys are responsible for filtering large volumes of blood daily. This function is crucial, and, the unique design of the nephrons make it able to adjust this filtrate and prevent dehydration. This intricate design also makes the kidneys crucial in the balance of water and many electrolytes.
Calcium is one of the electrolytes filtered and reabsorbed in the kidneys. Calcium sensing receptors (CaSR) are present in kidney cells and are essential for the reabsorption of calcium. These receptors increase and decrease the amount of calcium reabsorbed based on the calcium level in the blood. In other words, activating these receptors increases the amount of calcium lost in the urine.
Single nucleotide polymorphisms (SNPs) in CaSR have been found to alter the function of these receptors leading to increased urinary excretion of calcium. Of particular interest, SNPs in rs7652589 and rs1501899 were associated with kidney stones in patients with normal citrate excretion. SNPS in rs1801725, rs1042636 of the CaSR gene were also associated with kidney stones in various populations.
Another gene that has been associated with increased calcium in the urine is the gene coding for the protein Claudin-14, responsible for forming tight junctions. This protein helps connect adjacent cells to form a barrier which acts like a gate, separating blood from urine. Tight junctions are also responsible for ensuring that minerals don’t pass between the cells. SNPs in the genes that code Claudin-14 (CLDN14) alters the integrity of these “gates” and allows for calcium to “sneak” between cells into the urine, increasing the risk for kidney stone formation. Specifically, SNPs at the locations rs219778, and rs219780 of the CLDN14 gene were significantly associated with kidney stones.
Genetic Variations in Vitamin D Receptors (VDR)
Vitamin D plays a crucial role in calcium balance. Studies have shown that vitamin D increases the absorption of calcium from the gut and also increases calcium excretion in the urine. Vitamin D receptors are essential for vitamin D to exert its action on calcium balance.
Some mutations or SNPs in the VDR are associated with increased absorption and excretion of calcium, significantly increasing the risk of kidney stones. It is worth mentioning here that there is some controversy about the link between vitamin D supplementation and kidney stone formation. Vitamin D deficiency appears to be common among kidney stone formers. This is likely because low vitamin D causes calcium loss from the bone in order to maintain normal calcium range in the blood for cardiovascular protection. Even though vitamin D3 supplementation may increase calcium excretion in the urine, it has not been conclusively found to increase the risk of kidney stone formation.
Therefore, genetic assessment may be a key to identify patients who are at risk of kidney stone formation from taking vitamin D supplements.
Genetic Variations in the Handling of Other Minerals
The kidneys are crucial for balancing many minerals in our bodies such as magnesium, phosphate, oxalate and others. Genetic mutation or SNPs affecting the genes that code for the channels or receptors that regulate these minerals can also impact the risk of kidney stones. Some SNPs on the other hand can be protective against kidney stones such as SNPs in the UMOD gene. Discussion of this long list of SNPs requires details beyond the scope of this blog, but we summarized most of the genes that have been associated with kidney stones in the table below.
| Gene symbol | Gene name | Phenotype |
| ADCT10 | Adenylate cyclase 10 | Increased calcium excretion |
| AGXT | Alanine-glyoxylate aminotransferase | Increased oxalate excretion |
| CA2 | Carbonic anhydrase II | Osteoporosis + decreased acid excretion |
| CASR | Calcium-sensing receptor | Increased calcium excretion |
| CLCN5 | Chloride channel, voltage-sensitive 5 | Dent disease |
| CLCNKB | Chloride channel, voltage-sensitive Kb | Bartter Syndrome, type 3 |
| CLDN14 | Claudin 14 | Increased calcium excretion |
| CLDN16 | Claudin 16 | Increased calcium and magnesium excretion |
| CLDN19 | Claudin 19 | Increased calcium and magnesium excretion |
| CYP24A1 | Cytochrome P450 | Decreased breakdown of vitamin D3 |
| GRHPR | Glyoxylate reductase | Increased oxalate excretion |
| HOGA1 | 4-Hydroxy-2-oxoglutarate aldolase 1 | Increased oxalate excretion |
| HPRT1 | Hypoxanthine phosphoribosyltransferase 1 | Increased uric acid excretion |
| SLC12A1 | Solute carrier family 12, member 1 | Bartter syndrome, type 1 |
| SLC26A1 | Solute carrier family 26, member 1 | Calcium oxalate kidney stones |
| SLC22A12 | Solute carrier family 22, member 12 | Decrease uric acid excretion |
| SLC2A9 | Solute carrier family 2, member 9 | Decreased uric acid excretion |
| SLC34A1 | Solute carrier family 34, member 1 | Calcium phosphate kidney stones |
| SLC34A3 | Solute carrier family 34, member 3 | Calcium phosphate kidney stones |
| SCL3A1 | Solute carrier family 3, member 1 | Increased Cystine excretion |
| SLC4A1 | Solute carrier family 4, member 1 | Decrease acid excretion (dRTA) |
| SLC7A9 | Solute carrier family 7, member 9 | Increased Cystine excretion |
| SLC9A3R1 | Solute carrier family 9, subfamily A, member 3, regulator 1 | Calcium phosphate kidney stones |
| UMOD | Uromodulin (most common urine protein) | Protective against kidney stones |
| VDR | Vitamin D (1,25-dihydroxy D3) receptor | Increased calcium excretion |
| XDH | Xanthine dehydrogenase | Increased xanthine excretion |
The Bottom Line
There are many factors that impact the risk of kidney stone development. Although there are pure genetic diseases that are associated with kidney stones, often the increased risk is subtle or offset by other factors. Increased risk, when combined with other factors including nutrient depletion, dysbiosis, electrolyte imbalances and dehydration, may lead to the development of kidney stones in some. Assessing the genetic profile of kidney stone patients can help identify the root cause of the disease to tailor appropriate, personalized management. Practitioners working with individuals to prevent kidney stone formation should formulate a comprehensive and individualized intervention that modifies all relevant components in their integrative approach.
