Vol 16 No 03 May-June 2019 242 ENDOUROLOGY AND STONE DISEASE Evaluation and Comparison of Metabolic Disorders between Patients with Unilateral and Bilateral Staghorn Renal Stones Mehrdad Mohammadi Sichani1, Amir Jafarpisheh2, Alireza Ghoreifi2,3* Purpose: Metabolic disorders are common in patients with staghorn renal stones. Aim of this study was to evaluate and compare the metabolic disorders in patients with unilateral and bilateral staghorn stones. Materials and Methods: In this cross sectional study, 78 patients who underwent percutaneous nephrolithotomy (PCNL) for staghorn renal stones were included. The urine volume, the level of calcium, oxalate, uric acid, phos- phate, sodium, citrate, creatinine, and cystine from 24 hour urine collection as well as the serum levels of calcium, phosphorus, magnesium, creatinine, blood urea nitrogen (BUN), parathyroid hormone (PTH) and uric acid were recorded and compared among the two groups with unilateral and bilateral renal stones. Results: 56 patients (71.8%) had unilateral and 22 (28.2%) had bilateral renal stones. At least one abnormal meta- bolic factor was found in 32 (57.1%) and 15 (68.2%) patients with unilateral and bilateral renal stones, respectively (P = .044). Cystine urine levels and serum levels of BUN were higher in cases with bilateral compared to unilateral renal stones (36.4% vs. 12.5%, P = .025 and 27.3% vs. 1.8%, P = .002, respectively). Conclusion: Metabolic factors are strongly correlated with the formation of staghorn renal stones specially bilat- eral ones. In our study among different metabolic factors, cystine urine levels and serum levels of BUN were sig- nificantly higher in patients with bilateral renal stones. Proper metabolic assessments are recommended in patients with staghorn urolithiasis. Keywords: metabolic diseases; risk factors; staghorn calculi; urinary calculi chemistry INRTRODUCTION Staghorn stones represent 10 to 20% of all nephro-lithiasis cases. However, currently, in developed countries, this incidence has decreased con¬siderably due to early prevention and treatment of urinary tract infections (UTIs).(1) These stones are mainly composed of struvite followed by calcium or cysteine based mate- rials. Despite several published papers focusing on the significant role of UTIs as the most important etiology of such conditions, it is also believed that other fac- tors like metabolic diseases could finally lead to such morbidities.(2,3) Furthermore, the existence of metabolic disorders is highly expected to be accompanied by bi- lateral staghorn stones.(4) The treatment of staghorn stones still remains contro- versial as the patients with sustained staghorns in their kidneys could end up in renal failure. Mostly, the thera- peutic pathways consist of 3 steps as follows: complete extraction of the stone, looking for the underlying met- abolic etiologies and final treatment with the maximum basic anatomy preservation for optimal renal functions. (4,5) Thus, it is assumed that proper treatment of patients with such renal stones must also include metabolic as- 1Isfahan Kidney Transplantation Research Center, Department of urology, AL-Zahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. 2Department of Urology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 3Kidney Transplantation Complications Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. *Correspondence: Department of Urology, Imam Reza Hospital, Ebne Sina St, Mashhad University of Medical Sciences, Mashhad, Iran, Tel: +985138583885, Fax: +985138591057, E-mail: aghoreifi@yahoo.com, Ghoreifina@mums.ac.ir Received December 2017 & Accepted June 20, 2018 sessments in different aspects covering the possible re- currence.(6) Considering the fact that metabolic disorders can play an important role in occurrence of staghorn stones and the critical role of diagnosis of these conditions in pre- vention of nephrolithiasis, we conducted this study to evaluate the metabolic disorders in patients with unilat- eral and bilateral renal stones. MATERIALS AND METHODS In this analytic cross-sectional study, 78 patients with staghorn stones who referred to our urology department from 2014 to 2016 were enrolled. All patients were candidates for unilateral or bilateral percutaneous neph- rolithotomy (PCNL). The study protocol was approved by the ethical and scientific review committee of Isfa- han University of Medical Sciences (ethics committee reference number: IR.IUMS.fm.REC.101947). Written consents were obtained and the patients were assured that all the data will remain completely confidential by the authors and results will be reported as overall statis- tics and not addressing to any specific individual. The inclusion criteria were as follows: patients with unilateral or bilateral staghorn renal stone (defined as any branched stone occupying more than one portion of the collecting system), availability of the necessary in- formation in patients' admission files and the consent of the patient to enter the study. Furthermore, patients with spinal cord injury and urinary diversion were excluded from the study. In order to collect the data and facilitate the statistical analysis, a compact questionnaire was designed, includ- ing all the variables in details. A 24 hour urine volume and the levels of calcium, oxalate, uric acid, phosphate, sodium, citrate, creatinine, and cystine from a 24 hour urine collection and also the serum levels of calcium, phosphorus, magnesium, creatinine, blood urea nitro- gen (BUN), parathyroid hormone (PTH) and uric acid were recorded from the patients' files. According to the references of our laboratory, cystine > 250 mg, citrate < 450 mg in males and < 550 mg in females, sodium > 220 mEq, oxalate > 40 mg, uric acid > 800 mg and calcium > 200 mg from 24 hour urine collections and also serum levels of calcium > 10.2 mg/dL, phospho- rus > 4.5mg/dL, magnesium > 2.2mg/dL, creatinine > 1.2 mg/dL in males and > 1.1 mg/dL in females, BUN > 20mg/dL, PTH > 65 pg/mL and uric acid > 7 mg/ dL in males and > 6 mg/dL in females were considered abnormal. Finally all the data were analyzed by the SPSS (IBM Corp. Released 2011. IBM SPSS Statistics for Win- dows, Version 20.0. Armonk, NY: IBM Corp). The variables were initially evaluated for normality statis- tical tests and T-tests or non-parametric statistical tests (e.g. Man-Whitney or Chi-square tests) were applied whenever needed. The significance cut-off range was considered as P value < .05. RESULTS Of 78 patients, 56 (71.8%) and 22 (28.2%) cases had unilateral and bilateral renal stones, respectively. The mean age of patients with unilateral and bilateral stones were 48.4 ± 16.8 and 45.6 ± 12.3 years old, respective- ly revealing no significant difference (P = .49). Also, 51.8% of patients in the unilateral group and 40.9 % of bilateral group were under 50 years old (P = 0.26). 33 (58.9%) patients from unilateral and 16 (72.7%) from bilateral group were men (P > .05). The mean size of stones in unilateral and bilateral stones was 3.53 ± 1.51 mm and 4.95 ± 0.21 millimeters, respectively which showed a significant difference be- tween the two groups (P < 0.001). Only one patient suffered from hyperparathyroidism (1.3%) and other co-morbidities relevant to staghorn stones formation like renal tubular acidosis (RTA) or gout were not reported by the patients. High cystine, citrate, sodium, oxalate, uric acid and cal- cium levels from 24 hour urine collections were seen in 19.2%, 18%, 16.7%, 12.8% and 6.4% of patients, re- spectively. These metabolites were the most frequent urine components in our patients. Applying chi-square and fisher exact tests, only cystine levels from 24 hour urine collections were significantly higher in bilateral stones (P = .025). (Table 1) The P values refer to the comparison between the high levels of both groups. High serum levels of creatinine, PTH, BUN, uric acid and phosphorus were seen in 14.1%, 14.1%, 9%, 1%, 3.8% and 3.8% of all patients, respectively. The serum level of BUN was also significantly higher in bilateral stones (P = .002). (Table 1) According to the results, 24 (42.9 %) patients from uni- lateral and 7 (31.8%) from bilateral renal stone groups Metabolic disorders in staghorn renal stones-Mohammadi Sichani et al. Table 1. Frequencies of metabolites in the urine and serum samples of subjects with staghorn urolithiasis. Source Variables Unilateral stone Number (%) Bilateral stone Number (%) P-value 24 hour urine Calcium normal 52 (92.9) 21 (95/5) 0.99 High 4 (7.1) 1 (4/5) Oxalate normal 47 (83.9) 18 (81/8) 0.99 High 9 (16.1) 4 (18/2) Uric acid normal 50 (89.3) 18 (81/8) 0.46 High 6 (10/7) 4 (18/2) Phosphate normal 56 (100) 22 (100) 1 High 0 (0) 0 (0) Sodium normal 43 (76/8) 21 (95/5) 0.12 High 12 (21/4) 1 (4/5) Low 1 (1/8) 0 (0) Citrate Normal 42 (76/4) 20 (90/9) 0.072 Higher than normal 3 (5/5) 2 (9/1) Lower than normal 10 (18/2) 0 (0) Creatinine Normal 56 (100) 22 (100) 1 Abnormal 0 (0) 0 (0) Cystine Normal 49 (87/5) 14 (63/6) 0.025 High 7 (12/5) 8 (36/4) Serum Calcium Normal 55 (98/2) 20 (90/9) 0.19 High 1 (1/8) 2 (9/1) Phosphorus Normal 54 (96/4) 21 (95/5) 0.99 High 2 (3/6) 1 (4/5) Magnesium Normal 56 (100) 22 (100) 1 High 0 (0) 0 (0) Creatinine Normal 51 (91/1) 16 (72/7) 0.07 High 5 (8/9) 6 (27/3) BUN Normal 55 (98/2) 16 (72/7) 0.002 High 1 (1/8) 6 (27/3) Phosphorus Normal 54 (96/4) 20 (90/9) 0.32 Higher than normal 2 (3/6) 2 (9/1) PTH normal 50 (89/3) 17 (77/3) 0.28 abnormal 6 (10/7) 5 (22/7) Endourology and Stones diseases 243 Vol 16 No 03 May-June 2019 244 had no metabolic disorders. 32 (57.1%) patients with unilateral and 15 (68.2%) patients with bilateral renal stones reported at least one abnormal metabolic factor (P = .044). Calcium oxalate and uric acid were the most components in unilateral stones and calcium oxalate and struvite were the most in bilateral subjects. Apply- ing Mann-Whitney test, we found that the proportion of calcium phosphate and cystine materials were statis- tically higher in patients with bilateral staghorn stones (Table 2). DISCUSSION To the best of our knowledge, there is no study that compares the metabolic state in unilateral and bilateral staghorn renal stones. Our finding showed the impor- tance of metabolic evaluations in staghorn stones, par- ticularly in bilateral ones. The state of metabolic disorder in urolithiasis may be variable according to the ethnical and geographic dif- ferences. Some previously published papers reported metabolic alternations in 52.9% of men and 40.7% of women with staghorn calculus in western countries. (7) In a recent study done in US patients on 52 kidneys with complete staghorn calculi, 56% were metabolic and 44% were infection stones. Multiple urinary met- abolic abnormalities were noted in all patients with metabolic stones who completed evaluation which the most common findings were increased urinary sodium, low urine volume, hypocitraturia and hypercalciuria while no patient had a corresponding serum abnormal- ity.(8) Some studies showed greater correlation. In two Brazilian studies, metabolic disorders were present in nearly 70% and 95.5% of patients with staghorn calculi, respectively. In both studies hypercalciuria and hypoc- itraturia were the most common disorders.(4,5) Also in a Swedish study among 33 patients with staghorn stones, 24-hour urine composition was normal in only 3 pa- tients. Furthermore, in 59 percent an increased calcium oxalate risk index was observed suggesting that calcium oxalate risk factors might contribute to the development of staghorn stones.(9) On the other hand some eastern studies revealed different results. In a study on Japanese patients with staghorn renal stones, it was shown that hypercalciuria and cystinuria was present in 37.8 % and 2.4% of the patients, respectively.(10) Another Japanese study on 58 patients showed that of 13 patients with in- fectious staghorn stones containing calcium oxalate in the nuclei, only 2 had metabolic disorders.(11) In a Thai study on 5445 urolithiasis patients complete staghorn stones were seen in 1.6% of cases and hyperuricemia was the most common metabolic disorder which was seen in 61.8% of patients with this calculus.(12) In our study the levels of metabolic factors had higher fig- ures than normal ranges and were also found more in bilateral stone group significantly. The most common disorder was hyperuricemia which was seen in 13.1% followed by hypercalciuria (6.4%) but none of them had cystinuria. Also the levels of urine cystine and serum BUN were significantly higher in bilateral ones, while other factors were not statistically different. In our study calcium oxalate was the main compo- nent followed by uric acid and struvite in unilateral and bilateral renal stones, respectively. This could be attributed to the increase of metabolic syndrome even among Iranian people,(13,14) which leads to the increase of urolithiasis specially calcium and uric acid stones.(15) Some previous studies and guidelines have shown that staghorn calculi are most frequently composed of stru- vite and/or calcium carbonate apatite.(16) Also they sug- gest that metabolic stones are uncommon in the com- position of such stones. This is mainly because of the association between urolithiasis and urinary tract infec- tion, although this relationship is complex and difficult to analyze.(17) Recently some other studies showed the changing composition of renal stones.(18,19) In one cohort study metabolic stones comprised a large proportion of complete staghorn calculi and calcium phosphate was the most common stone composition.(11) One of the limitations of our study was that we did not evaluate the urinary cultures. Also the small sample size and the retrospective character of the study are consid- ered major limitations of our study which was mainly based on the number of patients with staghorn renal stone referred to the pointed study center. For future studies we recommend considering multi-centric sim- ilar studies, evaluating other variables in even longer periods. CONCLUSIONS Metabolic factors are strongly involved in the formation of staghorn renal stones which is more significant in bilateral ones. In our study the most common disorder was hyperuricemia followed by hypercalciuria. Fur- thermore, among different metabolic factors, cystine urine levels and serum levels of BUN were significantly higher in patients with bilateral stones. Proper assess- ments are recommended regarding these conditions in patients with staghorn urolithiasis. ACKNOWLEDGEMENT We appreciate all our colleagues, co-operating and par- ticipating in our study, especially the staff of Urology research center at Al-Zahra medical center of Isfahan. Table 2. Frequencies of consisting materials of the stones in subjects with unilateral and bilateral staghorn urolithiasis. 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