You Keep Getting Kidney Stones. Your Genes May Be Why.

SLC34A1 encodes a transporter protein that sits on the inside of your kidney tubule cells. Its job is to reabsorb phosphate from the filtrate so your body doesn’t waste it. It’s a tightly regulated process, and when it works correctly, your kidneys recover the phosphate you need while excreting the excess.

Variants in SLC34A1, present in roughly 5-10% of the population, disrupt this precise balance. Instead of excreting excess phosphate in your urine, your kidneys reabsorb too much, and phosphate accumulates in the tubular fluid where it can bind to calcium and form stones. The effect is particularly strong in acidic urine.

What this means for you: you may notice stones forming even when you’re drinking water and following standard prevention advice. Your urine chemistry labs might show elevated phosphate. You may be prone to nephrocalcinosis, where calcium deposits form directly in the kidney tissue itself, causing chronic low-grade inflammation and pain.

Uromodulin is one of the most abundant proteins in your urine, and its job is remarkably specific: it coats calcium oxalate crystals and prevents them from sticking to your urinary tract and to each other. Your kidneys secrete uromodulin constantly as a protective mechanism. When uromodulin is working properly, it acts like a microscopic shield against stone formation.

Variants in UMOD, carried by roughly 10-20% of the population, reduce how much uromodulin your kidneys produce and secrete. With less uromodulin in your urine, calcium oxalate crystals are left undefended, and they stick to your tubule walls and to each other, initiating stone growth. The same variants also impair your urinary tract’s defense against bacterial infections.

What this means for you: you form stones more easily despite normal urine chemistry on standard labs. You may also notice you’re prone to urinary tract infections, because the same protein that blocks stones also protects against UTI pathogens. Your stones may grow faster once they start forming.

The vitamin D receptor is a protein that sits inside your cells and acts as a master switch for calcium and phosphate homeostasis. When vitamin D binds to VDR, it turns on genes that regulate calcium absorption in your gut, phosphate handling in your kidneys, and the expression of other stone-protective proteins. Without functional VDR signaling, your whole mineral balance falls apart.

Common variants in VDR affect how efficiently the receptor binds vitamin D and activates these downstream genes. People with certain VDR variants have reduced capacity to regulate urinary calcium and phosphate, leading to higher urine saturation with respect to calcium oxalate. This effect is particularly pronounced in people who are also deficient in vitamin D itself.

What this means for you: your kidney stone risk is directly tied to your vitamin D status. When your vitamin D is low, your VDR-mediated regulation is worse. You may form stones seasonally, worse in winter when sun exposure is lower. Standard calcium supplementation (especially without adequate vitamin D) may actually increase your stone risk.

MTHFR catalyzes one of the most fundamental reactions in your body: converting dietary folate into methylfolate, the active form that powers one-carbon metabolism. This reaction is essential for DNA synthesis, methylation, and hundreds of other cellular processes. When MTHFR works normally, your body has a steady supply of methylfolate to keep these processes running.

The MTHFR C677T variant, carried by roughly 40% of the population, reduces enzyme efficiency by 40-70%. This means your cells have less methylfolate available, which impairs one-carbon metabolism and leads to elevated homocysteine, a known risk factor for kidney disease and stone formation. Additionally, reduced methylation capacity affects the expression of genes that control urinary phosphate and oxalate handling.

What this means for you: if you have MTHFR variants, your homocysteine may be elevated even with normal folate levels on standard bloodwork. This elevated homocysteine damages your kidneys over time and contributes directly to stone formation. You may also notice that generic folate supplementation doesn’t help, because your body can’t convert it efficiently.

AGXT encodes alanine-glyoxylate aminotransferase, an enzyme that sits in your liver and metabolizes a precursor compound called glyoxylate before it can be converted into oxalate. This is a critical control point: if your AGXT is working, you convert dietary and endogenous sources of oxalate into a form that can be excreted safely. If it’s not working, oxalate accumulates in your urine at dangerous levels.

Loss-of-function variants in AGXT are rare but devastating. People with two copies of certain AGXT variants have primary hyperoxaluria, a condition where oxalate production is so high that kidney stones form repeatedly and early-stage chronic kidney disease develops. Even carriers of single variants show elevated urinary oxalate and early-onset stone disease.

What this means for you: if you have AGXT variants, your urinary oxalate is likely elevated, and dietary oxalate restriction alone is insufficient. Your stones are extremely likely to recur unless you address the metabolic cause directly. You may develop kidney damage over time if left untreated.

SLC7A9 encodes a transporter that reabsorbs cystine from your urine back into your bloodstream. Cystine is a dimer of the amino acid cysteine, and it’s normally filtered and then reclaimed by your kidneys. When this transporter works properly, almost all cystine is reclaimed, so your urine stays cystine-free and stone-free.

Loss-of-function variants in SLC7A9 cause cystinuria, a rare but serious condition where cystine is not reabsorbed and accumulates in your urine instead. Cystine has very low solubility in urine, which means even small amounts crystallize and form stones. People with cystinuria form stones repeatedly, often starting in childhood, and these stones are notoriously difficult to treat because cystine is resistant to many of the drugs that dissolve other types of stones.

What this means for you: if you have SLC7A9 variants causing cystinuria, your stones are not calcium oxalate stones in the classical sense. They are cystine stones, and they require completely different management. Your urinary cystine levels are high even with normal dietary protein. You may have formed multiple stones by now, and standard prevention hasn’t worked.