Cystine Stones: A Single Tertiary Center Experience

Introduction

Cystinuria represents the single sole clinically significant outcome of the congenital defect in intestinal and renal tubular transportation of cystine, arginine, lysine, and ornithine. ¹ Cystine hypersaturation may result in stone formation. Cystinuria is the result of two genes mutation. ^{2 –5} SLC3A1 is found in 2p21 chromosome and its mutations are associated with autosomal recessive mode of inheritance while SLC7A9 is found in chromosome 19q12 and it is responsible for a variety of clinical manifestations.

Although stone formation may occur in any age, up to 80% of patients with cystinuria will present their first clinical episode, correlated with cystine calculi, within the first 2 decades of life. ⁵ In contrast, 6% of cystinuric patients will never present urolithiasis. ⁶ Male patients have an earlier presentation of the disease with more severe clinical manifestations.

Traditionally, cystinuria was divided in type I, II, and III or alternatively in type I patients with mostly normal cystine excretion and in non-type I heterozygotes with high excretion of cystine, arginine, lysine, and ornithine. ^2,7 Following the identification of SLC genes, a new classification mode has been proposed dividing patients in three groups depending on the location of gene mutations. ⁵ Although there is a significant difference in cystine concentrations in urine samples among these three groups, no differences were identified regarding the clinical presentation, providing the hypothesis that other factors may contribute to the severity of the disease.

It is believed that patients with cystine stones suffer an increased number of associated complications while their management, either for stone removal or for prevention of stone recurrence, is challenging. A category of cystine stones, actually the smooth stones, have been characterized as hard stones making them resistant to shockwave lithotripsy, while cystine stones may often present as partial or complete stanghorn stones demanding challenging treatment modalities. In addition, therapeutic armamentarium for preventing recurrences includes a small number of pharmaceutical agents that are usually accompanied by significant adverse events, and the latter negatively affects patients' compliance.

In this study, we conducted an analysis of patients with a history of cystinuria and cystine stones, to evaluate the epidemiological, clinical, and prognostic characteristics of the disease. Furthermore, we compare and analyze these findings with the characteristics of patients with calcium oxalate stones, aiming to identify differences in the clinical course and treatment outcomes of these two categories of patients.

Patients and Methods

After the approval from the Scientific Board (Ethics Committee) of our institution, we retrospectively reviewed the medical records of patients treated and followed up in our department for renal and urinary tract calculi. We identified 30 patients who were diagnosed with cystine stones and they were treated in our department for stone removal from January 1972 until December 2013. These patients were matched and paired to 30 calcium oxalate stone formers who were diagnosed and treated in our department, as well, from January 2011 until December 2013. Stone composition was based on calculi analysis or quantitative cystine excretion measurement in 24 hours urine sample by aminoacid chromatography. In some patients, stone analysis was not available as a separate study report and stone composition was extracted through information by the medical history reports that are saved in our institution digital database. All patients were treated and followed up in our department. Demographic, clinical, and laboratory information were extracted by our institution digital storage system while imaging films were evaluated through a picture archiving and communication system of our hospital network. Information regarding patients who were treated in the time period before the initiation of our institution digital medical database was extracted through hard copy written medical history and records.

We analyzed the demographic data, disease characteristics, types of treatments, treatment compliance, and schedules of follow-up. To assess treatment compliance and to collect information regarding the present renal function and stone status, we conducted an interview with the patient.

The study design had two actual objectives. First, to evaluate and present the characteristics of patients with cystinuria and cystine stone disease and second, to analyze and present, if any, the differences in demographics and disease characteristics and compliance between the two groups. An exclusion criterion was age under 18.

Matched pairing was based on age and gender, and the following parameters were collected from patients files: origin, family history of renal stones, age at diagnosis, unilateral or bilateral disease, size of largest calculi documented, stone location, number of emergency room admissions, number of hospitalizations, number of times the patients needed urgent nephrostomy, number and type of procedures performed for stone removal, type of adjuvant medicine prescribed, and number of clinic visits per year following primary diagnosis.

Statistical analysis was performed by using SPSS version 17 (SPSS, Inc., Chicago, IL). The descriptive statistics are presented as the mean±standard deviation and interquartile range for continuous variables and as the absolute and percent frequency for categorical variables. Mann–Whitney U test was used to compare means between numerical groups, Chi-square test to compare means between categorical variables, and Pearson test to analyze correlation between numerical variables. All tests were two-tailed with p<0.05 considered statistically significant.

Results

Calcium oxalate group and cystine group included 30 patients each. Patients were matched paired, as described above, by age and gender. The clinical characteristics of patients of both groups are seen in Table 1. Significant differences in stone size (p<0.001) and stone location (p=0.002) were observed among groups. Patients of the cystine group suffered bigger stones and mainly located within the kidney. As it was expected, patients with cystine stones had their first stone episode at an early age (p<0.001). No significant differences were observed in frequency and severity of clinical presentations. Both groups present similar rates in visits per year in outpatient clinic, emergency room admissions, and episodes of febrile urinary tract infections (Table 2). In contrast, cystine stone formers had significantly higher serum creatinine levels (p=0.005) while two patients of the study cohort developed end–stage chronic renal failure needing hemodialysis on a regular basis. Both patients belonged to the cystine group.

As it can be seen in Table 3, patients with cystine stones have undergone significantly higher number of procedures for stone removal (p<0.001). When different surgical approaches were compared, statistical difference was noticed in the number of percutaneous nephrolithotripsies and shockwave lithotripsies performed for stone removal. No difference was observed in the number of ureteroscopies and retrograde intrarenal surgeries performed. Stone size was not correlated with the number of procedures performed for stone removal in both calcium oxalate (p=0.467) and cystine group (p=0.139). When the association between the number of procedures and stone size was analyzed separately for each procedure, there was statistically significant association with the number of percutaneous nephrolithotripsies performed in calcium oxalate (p<0.001) and cystine stone formers (p=0.011). No association was found between stone size and the number of ureteroscopies and shockwave lithotripsies performed.

Dietary guidelines and medical adjuvant treatment was proposed in 8 (26.7%) and 7 patients (23.3%) of the calcium oxalate group and in 10 (33.3%) and 14 patients (46.7%) of the cystine group, respectively. No statistical differences were found in the compliance rates between the groups (Table 2).

Discussion

Patients with cystinuria and cystine stone formation represent a challenging group of patients who will possibly need a multidisciplinary therapeutic approach. Management of stone disease should always be accompanied by a chronic follow-up with main goal the prevention of new stone formation or at least the elongation of time periods between the episodes.

The rarity of the disease represents probably the reason for the limited published data and the absence of large series reports. Thus, no reliable results can be extracted regarding the prevalence, clinical behavior, course, and prognosis of the disease. In the largest series reported so far, Dello Strologo et al. ⁵ reported similar clinical findings between patients with cystinuria irrespective of the genetic classification. The mean age of presentation was 13.1 and 11.7 years for type I and non-type I respectively. This comes in relation with our results where the age of presentation was 15 years and was significantly higher than the age at presentation of calcium oxalate stone formers.

It has been reported that Libyan Jewish have the highest rate of cystinuria and they mostly suffer non-type I disease. ^8,9 This may be the combined result of genetic defects, which are transferred through generations and environmental, dietary, and socioeconomic factors. In our cohort, Jewish origin was not involved in the cystinuria defect and cystine stone formation. This finding may represent a limitation due to small-sized study cohort or it may reflect the potential role of Libyan origin in cystinouria inheritance.

Cystine stones tend to be bigger in size compared to calcium oxalate stones. The above hypothesis was confirmed in the results of our study. In addition, this may be a potential explanation for the higher rate of kidney stones compared with ureteral stones.

The high recurrence rate and the resistance in certain therapeutic modalities are making the treatment of cystine stones a challenging issue. In our cohort, patients with cystine stones received a mean number of 9.80 surgical procedures for stone removal. This was significantly higher compared with the number of interventions needed for the treatment of calcium oxalate stone formers. The appropriate management of cystine stones is missing evidence-based guidelines as a result of disease rarity and small number of published series. Kachel et al. ¹⁰ was the only research group that proposed an endourological treatment algorithm in 1991. Based on it, cystine renal stones <1.5 cm may be treated with shockwave lithotripsy as monotherapy. Stones of 1.5 to 3 cm may be treated with shockwaves or percutaneous lithotripsy, and dissolution. Staghorn calculi may be treated by percutaneous lithotripsy and shockwaves and/or dissolution for retained fragments. Ureteral calculi may be removed by ureteroscopic techniques or manipulated into the renal pelvis and managed as renal stones. Of course, since 1991, many improvements have been achieved in shockwave technology and efficacy, and in endoscopic instrumentation, as well. Thus, the need for updated guidelines is necessary for bounding the best treatment option based on stone location, size, and possibly consistency. Certain chemical properties of cystine stones make them resistant to treatment with shockwaves. ^11,12 Based on the report of Bhatta et al., ¹² cystine stones can be divided in smooth and rough stones. Smooth stones have small, irregular, and poorly formed interlacing crystals and this stereotactic morphology make them readily resistant to shockwaves. On the other hand, rough stones are comprised of well formed blocks of hexagonal crystals and they can be treated with shockwaves with high efficacy. The authors reported that fragmentation with extracorporeal shockwave lithotripsy revealed that smooth cystine stones were the least fragile, followed by rough cystine stones and brushite. Calcium oxalate, struvite, and apatite were the most fragile. Although this categorization is consistent with our experience, the differentiation between rough and smooth cystine stones cannot be easily made preoperatively. Based on our results, cystine stone formers had significantly higher number of shockwave treatments in comparison with patients with calcium oxalate stones.

Medical management represents a significant part in the management of cystinuric patients. The goal of the treatment is to decrease the risk of recurrent stone formation, since poorly controlled disease may lead to irreversible renal impairment. ¹³ The optimum treatment protocol should have two distinct goals. Primary goal is the alkalinization of urine pH and hyperdiuresis. This can be obtained by increased intake of fluids and potassium citrate supplements. The second goal is to decrease the insoluble concentration of free urine cystine. This may be succeeded by using agents who bind to cystine and form soluble chemical compounds. Such agents are tiopronin and D-penicillamine. However, the compliance is very low due to adverse events that follow the chronic use of the above agents. Medical compliance rate was 55% in contemporary series of cystine stone formers and it was associated with higher number of surgical interventions and decreased stone-free rates after a mean follow-up of 42.5 months. ¹⁴ Based on the results of this study, 64.3% of cystinuric patients remained compliant to the adjuvant medical treatment compared to 85.7% of patients with calcium oxalate. Although the difference is significant, it did not reach significance. We also observed that medical treatment withdrawal by cystine stone formers led to the withdrawal of the dietary changes as well, since just 30% of patients remained compliant with the dietary guides.

Reviewing the results of this study, we may conclude that cystinuria represents a rare genetic defect, however, the clinical impact on the affected population is high. Cystine stone formers will possibly suffer by recurrent episodes of the disease and they may need to undergo several surgical interventions for stone removal and management of complications. In addition, pharmaceutical treatment for prevention of stone recurrence encrypts a significant number of serious adverse effects and, consequently, patients' compliance remains low. Thus, the care of patients with cystine stones is challenging. The optimal management should focus on preserving stone-free status either by selecting the appropriate and less invasive treatment option, since many of them may be required in the future, or by motivating them to remain compliant on dietary and pharmaceutical treatment guides.

This study has some limitations that should be reported. Recurrence rates are not available in both groups since this information was not available in all patients. The mean follow-up of patients between the two groups is not the same. This difference may affect several parameters like the exact number of interventions or the number of visits in the emergency department or in the outpatient clinic. Medical prevention of stone recurrence either for calcium oxalate or for cystine stones was not constant within the study period. Serum cystine levels were not available for all patients and therefore we could not check the potential association with several parameters, including cystine levels. Because of the retrospective fashion of our study, the ethnicities in the non-Jewish population are not available for all patients. Therefore, we cannot exclude that a significant number of them may belong to the Middle Eastern groups that may share same genetic ancestors with Jewish people and consequently this could lead to no ethnicity differences in the study. Finally, the efficacy and quality of endourological equipments have been changed in the last decades. For this reason, we could not provide any comparison of the efficacy and complication rates between the groups.

Conclusions

Cystine stones represent a rare form of renal calculi characterized by recurrence. They are usually resistant to shockwave treatment and surgical interventions may be needed for definitive treatment. Recurrence prevention is of paramount importance. However, patients' compliance is low because of the adverse events.