Cystine crystal volume determination: a useful tool in the management of cystinuric patients

Abstract

We prospectively determined cystine crystal volume (Vcys) in urine specimens from all consecutive patients with cystine urolithiasis followed at our institution over the past decade, in order to assess its predictive value as to the risk of recurrent cystine stone formation. A total of 57 patients (29 males, 28 females) with homozygous cystinuria entered in the study between January 1990 and December 2000, including 15 children aged less than 15 years and 42 patients aged 15 years or more. The clinical and radiological course was followed until December 2001, for a total of 243 patient-years of follow-up. From study entry until the end of follow-up, we serially examined first voided morning urine specimens in all patients, with determination of the number of cystine crystals per mm3, and the average size of crystals, thus allowing us to calculate Vcys using a simple formula based on crystal geometry. Recurrence was diagnosed on the basis of serial radiographic examinations using X-rays and echography. Overall, cystine crystals were present in 179 (39%) of the 460 examined urine specimens. Cystine crystalluria was significantly more frequent among the 27 patients who developed new cystine stones (SF) than in the other 30 who remained stone-free (63.3 vs 25.5% of samples, P<0.001). The presence of crystals in > or =50% of serially examined urine samples was more frequently found in patients with recurrent stone formation than in non-recurrent patients (24/27 vs 2/30, P<0.001). The average Vcys value was significantly higher in recurrent SF than in stone-free patients (8,173 +/- 1,544 vs 233 +/- 150 micro3/mm3, P<0.001) and there was no overlap in the individual values of recurrent vs stone-free patients. A Vcys value > or =3,000 micro3/mm3 was observed at least once prior to each of the 63 stone recurrences observed in 27 patients (2.3 per patient on the average). In addition, Vcys reflected the efficacy of treatment, with Vcys mean values of 12,097 +/- 3,214 micro3/mm3 at baseline, falling to 2,648 +/- 658 micro3/mm3 on basic therapy (hyperdiuresis plus alkalinization) alone, 1,141 +/- 522 micro3/mm3 on tiopronin therapy (median dose 1,000 mg/day) and 791 +/- 390 micro3/mm3 on D-penicillamine therapy (median dose 900 mg/day) whereas captopril had no effect (5,114 +/- 2,128 micro3/mm3). Based on the results of the present study, cystine crystalluria appears to accurately reflect active stone formation in cystinuric patients. Determination of total Vcys provides a simple, cheap and accurate means of predicting the risk of cystine stone recurrence with a Vcys value > or =3000 micro3/mm3 as the threshold risk value. We propose that serial Vcys determination be performed simultaneously with the measurement of urine pH and specific gravity to optimally monitor the medical treatment of cystine patients.

Therapy modifies cystine kidney stones at the macroscopic scale. Do such alterations exist at the mesoscopic and nanometre scale?

“…The limited effect of captopril on cystine crystals in comparison to that observed for tiopronine and d-penicillamine is in agreement with clinical findings suggesting the failure of captopril in preventing stone recurrence (Aunsholt & Ahlbom, 1990). Indeed, in our crystalluria studies, we were unable to demonstrate any significant effect of captopril for reducing cystine crystal volume, while a significant decrease in crystal volume was observed in patients treated by either tiopronine or d-penicillamine (Daudon et al, 2003). It is well known that tiopronine and d-penicillamine are able to form soluble complexes with cysteine, thus reducing significantly the amount of cysteine available to form cystine in urine (Meiouet et al, 2011).…”

“…This is in agreement with our studies on cystine crystalluria related to urine pH: the higher the urine pH, the lower the crystal volume of cystine in urine. Moreover, we have already shown that all patients with a high crystal volume of cystine in urine (above 3000 mm 3 mm À3 ), which corresponds to large crystallite aggregates, developed new stones, while patients with a lower crystal volume did not (Daudon et al, 2003).…”

Crystalluria

“…In cystinuric patients, a cystine GCV > 3000 μm 3 /mm 3 of urine was predictive of recurrence of cystine stones, whereas a stable lower value was associated with a lack of recurrence [27]. In all stone formers, crystalluria is more frequent than in healthy subjects, although in these latter some crystals may transiently be found in urine, especially during the hours following a meal.…”

“…This result is most often attainable in patients with calcium or uric acid nephrolithiasis, while a complete disappearance of crystalluria is more difficult to achieve in inherited disorders such as primary hyperoxaluria type 1 (PH1), cystinuria or dihydroxyadeninuria, which have a very active and permanent crystallization. In these conditions, a decrease in the amount of crystals present in urine samples, expressed as global crystal volume (GCV), is often sufficient to efficiently reduce the lithogenic process [27].…”

“…By comparing clinical outcomes and variations in GCV in serial urine samples, we have determined quantitative thresholds of harmful crystalluria in PH1 and cystinuria, thus defining the desirable goals to achieve [27,28].…”