Urolithiasis continues to be a heavy burden on the worldwide medical infrastructure with an estimated 106 million cases recorded internationally in 2021 [1]. Whilst incidence rates have started to decline across Europe and high-income North America, there are emerging hotspots of stone disease, particularly in the Caribbean, Central and South America. Equally, deaths attributed to stones have been increasing in 179 countries worldwide [1].
It is therefore imperative to reduce the risk of stone disease recurring and treat any preventable underlying causes. Multiple guidelines advocate metabolic stone analysis, given that 26–50% of stone cases will recur within five years [2]. The aim of this feature is to provide urology trainees with an overview of the key aspects of metabolic stone disease, enabling greater confidence in the diagnosis and treating of patients with modifiable stone disease in both emergency and outpatient settings.
Why test?
Meta analysis evidence suggests that appropriate pharmacological intervention for stone disease can reduce the rate of recurrence, from 23 per 100 to 9 per 100 person-years, compared to patients receiving only basic stone diet and hydration advice [3]. Surgical management options for stone disease include ESWL, URS/RIRS or PCNL. All are associated with major complications, reported at 0.3–31.7% for URS and 2–17.1% for PCNL respectively [4]. Given the increasing stone burden in developing nations along with the potential anaesthetic and surgical complications from intervention, investigating patients for stone-forming diseases where treatment may reduce recurrence is essential practice.
Who to test?
The EAU advocates for metabolic screening and genetic testing in all patients who develop stones under 25 years old, and in those over 25 deemed high-risk or where there is a strong suspicion of metabolic stone disease. These features include two or more discrete episodes of stones, bilateral stones, those with a single kidney or a strong family history of urolithiasis [5]. Any stone collected should be sent for analysis, and findings that suggest an underlying metabolic disease (e.g. cystine or uric acid stones) should be referred for further investigation.
How to test?
As a baseline, every patient should have a serum sample for creatinine, uric acid, ionised calcium, sodium, potassium, a full blood count and a C-reactive protein, alongside analysis for any stone passed or collected in surgery [5]. For those who warrant specific metabolic investigation, the mainstay is a collection of two consecutive 24-hour urine samples, prepared with 1g of thymol per litre and stored at temperatures below 8°C during collection to reduce bacterial proliferation [5]. This allows calculation of urinary pH and rates of excretion for creatinine, calcium, oxalate, uric acid, citrate, magnesium, inorganic phosphate, ammonium and cystine.
Common Metabolic Stone Diseases
Hypercalciuria
Hypercalciuria is a major risk factor for stone disease, especially given that around 80% of all stones are composed of calcium oxalate [6]. Stones form when increased urinary calcium levels supersaturate the oxalate excreted in the urine. Once both ions exceed their solubility limits, they precipitate to form crystal nuclei which slowly aggregate into a larger stone [7].
There are many causes for hypercalciuria, which can broadly be separated into the following categories:
Absorptive causes: Excessive gastrointestinal absorption of calcium or increased intake of vitamin D.
Resorptive causes: increased bone turnover leading to excess serum calcium, e.g. hyperparathyroidism, bony metastasis in malignancy, Paget’s disease, osteoporosis.
Renal Leak: Renal tubular acidosis Type 1.
Secondary to medical therapies: thiazides and loop diuretics.
Hypercalciuria is also closely related to salt intake. Calcium is reabsorbed throughout the nephron, predominately through a passive paracellular mechanism in the proximal convoluted tubule, down an electro-chemical gradient established by sodium [8]. Excessive sodium consumption reduces this gradient, thus inhibiting calcium reabsorption and increasing urinary concentration levels [9]. This underpins why stone formers are advised to reduce dietary sodium levels to prevent future recurrence.
Primary Hyperparathyroidism
Primary hyperparathyroidism is an important cause of hypercalciuria, and metabolic stone evaluation can provide an opportunity for its diagnosis. Approximately 90% of cases are primary, often caused by a benign secretory adenoma of the parathyroid gland [10]. In these patients, excess parathyroid hormone (PTH) is excreted outside its usual regulatory mechanism, even when serum calcium levels are high.
PTH drives osteoclast activity, leading to increased bone resorption and release of calcium and phosphate, and enhances renal 1,25 dihydroxyvitamin D3, which increases gastrointestinal calcium absorption. Urinary calcium rises as a result and can lead to stone formation. Serum blood tests will typically demonstrate a raised calcium, PTH, phosphate and potentially a raised ALP due to the osteoclast activity and rate of bony turnover [11].
Surgical management remains the sole definitive treatment option by way of a parathyroidectomy. For non-surgical candidates, the calcimimetric drug cinacalcet can be prescribed as it increases the calcium receptor sensitivity on the parathyroid cells, reducing PTH and therefore calcium levels.
Renal Tubular Acidosis Type 1 (RTA1)
RTA comprises a group of renal disorders whereby acid is unable to be excreted by the renal tubule. Unlike the other subtypes, RTA1 prevents typical H+ ion excretion in the distal nephron, preventing acidification of the urine to its usual level <5.3. This alkaline environment predisposes to calcium oxalate stones, which are more likely to precipitate in alkaline solutions.
RTA1 also reduces citrate in the urine as the systemic acidosis drives renal reabsorption. Citrate typically acts as an inhibitor to calcium salt crystallisation; the reduced urinary concentration also predisposes to stone formation [12]. On urinalysis RTA1 patients will show a high urinary pH, low urinary citrate and hypercalciuria. Treatment focuses on correcting the systemic metabolic acidosis with either sodium bicarbonate or potassium citrate, which also helps to replace the low urinary citrate levels.
Hyperoxaluria
Elevated oxalate levels are the other half of the calcium oxalate stone story. Hyperoxaluria has multiple causes, one being increased dietary intake of oxalate rich foods such as spinach, rhubarb, beetroot and soy. Free calcium can bind to oxalate in the gastrointestinal tract, just as it does in the urine, causing crystal formation which is not absorbable and therefore lost in excretion. This underpins why patients with raised oxalate are not only given dietary advice on which oxalate rich foods to avoid but to maintain a normal level of calcium to reduce the amount of gastrointestinal oxalate being absorbed [13]. Calcium can also bind to unabsorbed fatty acids in the gastrointestinal tract, forming an insoluble crystal which cannot be absorbed. Therefore, malabsorptive states, such as post bariatric surgery or short-gut syndrome, where there are increased free gastrointestinal fatty acids are at risk of hyperoxaluria and stone formation.
Primary Hyperoxaluria type 1 (PH1)
PH1 is an autosomal recessive genetic cause of oxalate stone formation, resulting from deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). AGT catalyses the conversion of glyoxylate, a mitochondrial metabolite, to glycine; but without it glyoxylate is instead converted to oxalate [14].
PH1 primarily affects the paediatric population, with 70% of diagnoses made between the ages one and seventeen. Patients demonstrate raised serum (>50 µmol/L) and urinary oxalate levels (>0.5 mmol/24 hours) [5]. Where PH1 is suspected, molecular gene testing is required to detect variants in the gene encoding AGT.
Traditional treatment has involved pyridoxine, B6, which reduces liver oxalate production, although in many cases it is ineffective. In 2023, NICE approved the new RNA interference therapy lumasiran for patients unresponsive to pyridoxine. Lumasiran is a double stranded RNA treatment that targets specific hepatic enzymes to reduce liver oxalate production. It has been shown to be highly effective at reducing urinary oxalate levels with a minimal side-effect profile and has also been endorsed by the EAU [5].
Uric Acid Stones
Uric acid stones form in those with raised serum uric acid with a relatively acidic urine of less than 5.5. Hyperuricemia can lead to both gout and stone formation. It is typically caused by increased dietary intake of urate containing foods (game meats, beer, shellfish) or states of high cell turnover that exacerbate purine degradation, including tumour-lysis syndrome, hemolysis, myelo- and lymphoproliferative haematological disorders. Patients demonstrate an elevated serum uric acid level, with a reading of greater than 8 mg/dL being diagnostic for hyperuricemia [15]. Allopurinol, which inhibits the enzyme xanthine oxidase, responsible for converting xanthine to uric acid, is a treatment option but cannot be used for patients with an acute attack of gout.
Cystine Stones
Cystinuria is a relatively rare genetic cause of stone disease, accounting for 1–2% of cases, but is a major cause in the paediatric population, with 50% of cases forming a stone in their first decade of life. It is caused by a mutation in the SLC3A1 or SLC7A9 genes which encode subunits of the basic amino-acid transporter. Consequently, the amino acids cystine, ornithine, lysine and arginine are not all reabsorbed in the proximal tubule. Only cystine is relatively insoluble at urinary pH, thereby leading to precipitation and stone development.
Diagnosis is established through 24‑hour urine collection demonstrating elevated cystine levels, alongside analysis of any collected stone. Molecular genetic testing can be done to confirm the diagnosis. The cornerstone of treatment is to maintain good urinary diuresis with the goal of producing > 3L of urine every 24 hours or 1.5 L/m2 body surface area in children. To achieve this, patients are advised to drink between 4–5 litres of water and reduce sodium intake to <2g per day to reduce water reabsorption and promote diuresis [16].
Alkalisation of the urine can be beneficial as cystine remains soluble at pH greater than 7.5 and can be achieved with alkaline citrates or sodium bicarbonate. If urinary cystine is still greater than 3 mmol/day despite these interventions, then tiopronin can be given. It forms a disulphide bond with urinary cystine to form a more soluble complex but has a large side effect profile and linked to nephrotic syndrome, arthritis and hepatotoxicity [17].
Conclusion
To conclude, urolithiasis remains a common urological condition with a high recurrence rate. Metabolic stone evaluation is a relatively simple set of investigations, although the 24-hour urine collection may be cumbersome to patients, when combined with a simple blood test it provides vital diagnostic information. This enables accurate diagnosis and effective pharmacological treatment, thereby reducing stone recurrence and the need for surgical intervention. A sound understanding of metabolic stone disease is therefore essential for all training urologists to provide the highest level of care in both emergency and outpatient settings.
References
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Declaration of competing interests: None declared.
