Urolithiasis: Don’t forget the rarities

The article published earlier in this journal by Kotaska et al. ¹ described a very rare presentation of a renal tract calculus. They described urolithiasis derived from ‘super’ glue (polycyanoacrylate) used by surgeons during a bilateral inguinal hernia mesh repair. Urolithiasis can present diagnostic challenges to the clinical biochemical laboratory which needs to be knowledgeable and proficient in its investigation.

The global prevalence of urolithiasis is about 5–15% and is increasing; ² , ³ males are more likely to have renal calculi than females with male-to-female ratio around 2:1. ³ Urolithiasis is commoner in areas with higher mean annual temperature secondary to decreased urine volume. Moreover, the rate of recurrent urolithiasis is high – up to 75% in 20 years. ² , ⁴ In one study, hypercalciuria was present in 60% of stone formers and hyperoxaluria in 25%; 41% had a urine volume of < 1 L per 24 h; 9% had a high urine urate excretion and 5% had either a low urine citrate or low urine magnesium. A majority of calculi were calcium oxalate or phosphate. ⁵

Clinical presentation of renal tract calculi may include severe flank pain of acute-onset radiating to the groin. Patients might report haematuria and fever depending on the severity. In paediatric cases with nephrolithiasis, the family history could be positive in > 50% of cases. ⁶ Urinary tract abnormalities can also predispose children to renal tract calculi. ⁶ , ⁷

Dipstick urine analysis is a simple yet effective initial bed-side test, detecting haematuria, proteinuria and leucocyturia. For example, concurrent cystitis and/or pyelonephritis detected by positive urine dipstick analysis for nitrites and leucocytes can point towards struvite calculus (ammonium-magnesium-phosphate). These are produced in alkaline environment due to ammonium generated by urea-splitting organisms such as Proteus, Klebsiella or Pseudomonas. ⁷ Not all ‘staghorn’ calculi are infection related, as cystine and calcium calculi can also form staghorns.

Measurement of a premeal urine pH, ideally with a pH meter can also be useful. It is important to exclude renal tubular acidosis in cases of renal calculi. Urinary pH varies throughout the day and is affected by diet. ⁵ Increased storage temperature and prolonged storage times are associated with increased urine pH. This can be lessened by obtaining a fresh fasting early-morning, second void and mid-stream urine sample in a plain container.^7–9 An acidic urine predisposes the formation of calcium oxalate calculi. ¹⁰

A 24-h urine chemical analysis is the ‘gold-standard’ for metabolic evaluation of urolithiasis and should be accompanied with a thorough dietary and medication history along with checking plasma electrolytes, renal and liver function, bone profile, magnesium, bicarbonate, chloride, uric acid, glucose, parathyroid hormone and 25 hydroxy-vitamin D. ⁵ , ⁷ , ⁸ However, 24-h urine analysis can sometimes be misleading mainly because of variability in accurate and complete collection; it can be time-consuming and inconvenient for patients. One should discard the first void in the morning and start collecting from the second void and finish with the first-void of urine next day to complete the 24-h urine collection. The sample should be analysed for volume, pH, calcium, sodium, phosphate, magnesium, oxalate, citrate and urate. ¹⁰

The first 24-h urine collection should ideally be acidified, as it helps prevent precipitation of calcium oxalate, calcium phosphate and magnesium ammonium phosphate. ⁷ , ¹¹ A separate 24-h urine collection is required for urinary uric acid, as its measurement may not be reliable in the acidified urine. However, providing patients with a collection-bottle with preadded acid can be a safety issue and some authors have suggested 5% thymol in isopropanol or boric acid. Some laboratories may provide patients with an empty plastic bottle and acidify the urine on receipt of the sample in the laboratory. Before addition of the acid, urinary creatinine and urate concentration can be measured.^10,12

If hypercalcaemia is confirmed, assess for its causes: e.g. primary hyperparathyroidism. The distinction between ‘absorptive type 1’, ‘absorptive type 2’ and ‘renal’ hypercalciuria may be helpful for calculi aetiology. ⁵ Hyperuricaemia should also be considered in the aetiology of renal calculi.^7,8 Urinary sodium concentration is related to higher calcium and cystine excretion.^10–12

Diagnostic imaging plays an important role in the evaluation of urolithiasis when it comes to determining numbers of calculi, estimating size and their location. It is important to note that, the distinction between radiolucent calculi (e.g. urate, cystine) and radio-opaque calculi (calcium oxalate or phosphate and struvite) is not absolute. Smaller calculi (<2 mm in diameter) can be challenging to visualize on radiographs.^5,13 Ultrasound is useful in children given radiation risk. If nephrocalcinosis is suspected due to known genetic mutation or tubulopathies, urolithiasis can be looked for utilizing computed tomography (CT). ⁶ The non-contrast CT kidney–ureter–bladder has superseded plain X-ray especially in adults due to its high sensitivity (97–100%) and specificity (96–100%).^7,13 Dual-energy CT may enable urate calculi determination. ¹⁴

Urinary spot amino acid determination is used to help diagnose cystinuria when elevated basic amino acids cystine, ornithine, arginine and lysine are usually observed. Severity and response to intervention in cystinuria may be aided by a 24-h urine cystine concentration determination. Raised urine retinol-binding protein may be seen in Dent’s disease. Detection of causative genetic mutations can be useful in distinguishing types 1, 2 and 3 hyperoxaluria. ¹⁵

Currently, NICE recommends the following: ‘consider calculus analysis for adults with ureteric or renal calculus’. ¹⁶ Calculi can be either patient collected, e.g. by passing urine through a strainer during colic episodes or medically retrieved. Different analytical technologies include wet chemistry tests, X-ray crystallography, infrared spectroscopy and stereomicroscopic studies. ¹⁵ Calculus composition by infrared spectroscopy is recommended by the European Association of Urology.^14,17 Such techniques can help identify rare renal calculi, such as xanthine, dihydroxyadenine, matrix, fake or ‘Munchausen’ calculi, drug-containing calculi or atypical ones such as polycyanoacrylate.^14–16

In summary, accurate and timely laboratory diagnosis of urinary tract calculi is important for prompt clinical management as is the awareness of rare calculi as reported by Kotaska et al. ¹