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1 Saudi J Kidney Dis Transpl 2013;24(4): Saudi Center for Organ Transplantation Saudi Journal of Kidney Diseases and Transplantation Renal Data from Asia Africa Metabolic Evaluation in First-Time Renal Stone Formers in North India: A Single Center Study Akhil Joshi 1, Sushil Kumar Gupta 1, Aneesh Srivastava 2 1 Departments of Endocrinology and 2 Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India ABSTRACT. The risk of stone recurrence in first-time stone formers (FTSF) varies from 26% to 53%. There is no consensus regarding metabolic evaluation in these individuals. We evaluated the metabolic abnormalities in first-time renal stone forming patients in North India. Thirty-nine patients, (29 males and 10 females with mean age 39.3 ± 12.9 years) who presented with nephrolithiasis for the first time were evaluated. We evaluated the calcium homeostasis [serum corrected total calcium, phosphorous, creatinine, alkaline phosphatase, albumin, parathormone (ipth), 25-hydroxy cholecalciferol (25(OH)D 3 ), 1-25 di-hydroxy cholecalciferol (1,25(OH) 2 D 3 )] and performed the calcium load test also. Two 24-h urine collections were taken for citrate, oxalate, calcium and uric acid. Ammonium chloride loading test for diagnosis of distal renal tubular acidosis was performed in all patients. For each of the diagnostic categories, descriptive statistics were computed for all biochemical variables. A two-tailed P-value <0.05 was regarded as significant. Metabolic abnormalities were detected in 92.3% of the patients (n = 39) studied. Of them, almost 60% had two or more metabolic abnormalities. The most common metabolic abnormality was hypo-citraturia (82%), followed by hyper-oxaluria (56%) and hyper-calciuria (41%). Five percent of the patients had incomplete renal tubular acidosis, signifying the importance of the ammonium chloride loading test in patients with renal stones. None of the study patients were detected to have primary hyperparathyroidism. In three patients, the etiology could not be detected. Our findings suggest that an underlying disorder is present in majority of first-time renal stone formers. Intervention with appropriate treatment can prevent recurrences. Hence, comprehensive metabolic evaluation is recommended in all FTSF. Correspondence to: Dr. Sushil Kumar Gupta, Department of Endocrinology and Metabolism, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow , India sushilguptasgpgi@gmail.com Introduction The natural history of renal calculus disease (RCD) is characterized by recurrence; recurrence rates of 26 53% after 10 years have been reported. 1-5 Studies have suggested the presence of metabolic abnormalities in a significant proportion of first-time stone formers

2 Metabolic evaluation in renal stone formers in north India 839 (FTSF). 5-7 However, because there is no consensus among clinicians, detailed metabolic evaluation is generally not performed in these patients. 8 Metabolic evaluation and selective treatment of metabolic abnormalities decreases the incidence of new stone formation RCD varies both in frequency and in type of stone in different climates 13,14 and in different racial groups. 15 Indians are different from the Western populations in dietary pattern and climatic conditions. We evaluated the metabolic profile in FTSF in a North Indian population at a single center. Subjects and Methods Thirty-nine consecutive patients with unilateral renal stones were recruited from the outpatient departments of Urology and Endocrinology at the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. All these patients had renal stone for the first time. Informed consent was obtained from all patients. The inclusion criteria were first documented episode of renal colic or hematuria due to renal stone and presence of a single stone on imaging either by ultrasonography or enhanced computerized tomography in either kidney. Exclusion criteria were bilateral stones, recurrent stones, solitary kidney, pregnancy and age less than 18 years. Subjects who were currently on pharmacologic doses of vitamin D, calcium, antacids, diuretics, potassium citrate and vitamin C were asked to discontinue the medications for at least one month. Metabolic evaluation was performed after one month of stone removal by percutaneous nephrolithotomy (PCNL) or extra-corporeal shock wave lithotripsy (ESWL). Subjects with active urinary tract infection (UTI) were treated appropriately with antibiotics and then underwent evaluation. During the first visit, a detailed history regarding the duration of stone formation and intervention performed and various metabolic etiologies was elicited. Dietary history regarding daily fluid, calcium and oxalate intake were taken. Fasting blood sample was collected for serum calcium, phosphorous, albumin and creatinine (Sigma Diagnostics, St. Louis, MO, USA). A 24-h urine sample was collected for analysis of oxalate (oxalate oxidase, Sigma), citrate, uric acid, calcium and phosphorous. A second 24-h urine sample was collected for measurement of calcium and creatinine. A baseline arterial blood gas analysis was performed followed by ammonium chloride (NH 4 Cl) loading test in all individuals to rule out distal renal tubular acidosis (RTA). The patients were given NH 4 Cl (0.1 g/kg body weight) and the arterial blood ph was measured at 3 h and urine ph was measured hourly for 5 h. Distal RTA was diagnosed when the urine ph failed to reach below 5.5 despite achieving adequate systemic acidosis. The patients were advised metabolic diet containing 400 mg of dietary calcium/day, oxalate 50 mg/day and sodium 100 mmol/day for 7 14 days. Subjects were re-evaluated with the calcium loading test. During the second visit, samples for intact PTH (ipth, IRMA, DiaSorin, Stillwater, OK, USA), 25-hydroxy cholecalciferol (25(OH)D 3 ) and 1-25 di-hydroxy cholecalciferol (1,25(OH) 2 D 3 ) were collected and stored at -70 C until being measured. The calcium load test was performed with administration of 1 g of elemental calcium. A fasting 2-h urine collection was performed, followed by administration of 1 g of elemental calcium and a 4- h urine collection. A fasting calcium creatinine ratio of >0.11 was taken as suggestive of fasting hyper-calciuria and a post-load ratio of >0.22 consistent with post-load hyper-calciuria. 16 Table 1 describes the diagnostic criteria of various metabolic abnormalities. Table 1. Diagnostic criteria of various metabolic abnormalities in patients with nephrolithiasis. Metabolic abnormality Criteria Hyper-calciuria >4 mg/kg/day Hyper-oxaluria >44 mg/day Hyper-uricosuria Males >850 mg/day Females >750 mg/day Hypo-citraturia <320 mg/day Low urine volume <1000 ml/day Urine ph >5.5 with Renal tubular acidosis non-anion gap metabolic acidosis

3 840 Joshi A, Gupta SK, Srivastava A Statistical Analysis All analyses were performed using SPSS version Descriptive statistics were computed for all biochemical variables for each of the diagnostic categories. A two-tailed P-value <0.05 was regarded as significant. Results Clinical and biochemical characteristics Metabolic evaluation for renal stones was performed in 39 patients (29 males and 10 females). The mean age at presentation was 39.3 ± 12.9 years. The mean duration from diagnosis of renal stone to evaluation was 17.6 ± 13.1 months (range 1 48 month). Thirteen patients (33%) underwent the extraction procedure for renal stone before analysis. Family history of renal stone in first-degree relatives was present in nine patients (23%). Twentyfive patients were either hypertensive at presentation or were taking anti-hypertensive medications. None of the patients had bowel disorders or history of immobilization. Metabolic abnormalities The biochemical parameters in the study patients are shown in Table 2. Thirty-six patients (92.3%) had at least one identifiable metabolic risk factor, with 23 patients (58.9%) having two or more metabolic abnormalities. The most common etiologies detected were hypocitraturia (82%) and hyper-oxaluria (56%). No metabolic abnormality was found in three patients (7.7%). There was no statistically significant difference in urinary citrate, oxalate, phosphates and magnesium between males and females. Hypo-citraturia renal calculus disease Hypo-citraturia was found in 32 patients (82%). Incomplete distal RTA was diagnosed in two patients with hypo-citraturia. Other metabolic abnormalities associated with hypocitraturia are shown in Table 3. Hyper-oxaluric RCD Hyper-oxaluric RCD was diagnosed in 56% Table 2. Clinical and biochemical parameters of the study subjects. Mean (range) Number of patients (number) 39 Mean age at presentation 39.9 ± 12.9 (years) Mean duration of diagnosis of RCD (months) Sex distribution (M/F) 29/10 Family history 9 Interventions 13 Serum calcium (mg/dl) Serum phosphorous (mg/dl) Serum alkaline phosphatase (IU/L) Serum creatinine (mg/dl) Serum 25 (OH) 2 D 3 (ng/ml) Serum ipth (pg/ml) Serum 1,25 (OH) 2 D 3 (pg/ml) (9 65) ± 13.1 (1 48) 9.2 ± 0.8 ( ) 3.5 ± 0.5 ( ) ± 47.4 (49 254) 0.9 ± 0.5 ( ) 17.4 ± 13.8 ( ) 33.0 ± 19.7 ( ) 47.0 ± 23.1 ( ) RCD: Renal calculus disease, 25(OH) 2 D 3 : 25- dihydroxy cholecalciferol, PTH: Parathormone, 1,25 (OH) 2 D 3 : 1-25-dihydroxy cholecalciferol Table 3. Biochemical presentation of subjects with hypo-citraturia. Number of patients 32 Age at presentation 37.9 ± 13.1 Sex (M/F) 24/8 Corrected serum calcium 9.1 ± 0.9 (mg/dl) Urinary citrate (mg/day) ± 81.7 Urinary calcium (mg/day) ± Concurrent abnormalities (n) Hyper-calciuria 9 Hyper-oxaluria 20 Renal tubular acidosis 2 of the cases. Seven patients had very high levels of urinary oxalates (>100 mg/day), but none of them had deranged liver, renal or bowel disorder. Clinical and biochemical parameters of hyper-oxaluric patients are shown in Table 4. Hyper-calciuric RCD Hypercalciuria was seen in 16 patients (41%).

4 Metabolic evaluation in renal stone formers in north India 841 Table 4. Biochemical presentation of subjects with hyper-oxaluria. Number of patients 22 Age at presentation 37.5 ± 10.5 Sex (M/F) 17/5 Corrected serum calcium 9.2 ± 0.7 (mg/dl) Urinary oxalate (mg/day) ± 13.4 Urinary calcium (mg/day) ± Concurrent abnormalities (n) Hyper-calciuria 8 Hypo-citraturia 20 Hyper-uricosuria 0 The hyper-calciuric patients were subdivided into renal hyper-calciuria and absorptive hypercalciuria based on the calcium loading test. Nine patients had renal hyper-calciuria while seven patients had absorptive hyper-calciuria. The clinical characteristics of hyper-calciuric patients are shown in Table 5. Primary hyperparathyroidism was not encountered in any of the study patients. Two patients (5%) were diagnosed to have distal RTA. Both had incomplete RTA, diagnosed after the ammonium chloride loading test. Both patients had associated hypo-citraturia. Family history of renal stone was present in one case. Discussion Our study shows a high prevalence of metabolic abnormalities in FTSF. Majority of our patients (92.3%) had one or more metabolic abnormalities. Almost 60% of the patients had two or more metabolic abnormalities. The most common metabolic abnormality was hypocitraturia (82%), followed by hyper-oxaluria (56%) and hyper-calciuria (41%). Incomplete distal RTA was found in 5% of the patients. We did not encounter any subject with primary hyperparathyroidism. In three patients, no etiology could be identified. There are only few studies of metabolic evaluation in FTSF. 5-7 Strauss et al reported in Caucasians that 51% of the subjects had idiopathic hyper-calciuria or hyper-uricosuria, while 19.8% had a systemic disorder producing stones. Importantly, 29.1% of the patients had no metabolic disorder. 5 Pak 6 reported absorptive hyper-calciuria in 55.9% (23.5% type-i and 32.4% type-ii), renal hyper-calciuria in 11.8%, primary hyperparathyroidism in 2.9%, hyperuricosuric calcium oxalate nephrolithiasis in 8.8% and no metabolic abnormality in 20.6% of their patients. Hosseini et al 7 reported from Iran that the most common abnormality observed was low 24-h urine volume (58.24%), followed by hyper-calciuria (17.18%) and hyperuricosuria (15.15%). In our study, we noticed hypo-citraturia in 82% and hyper-oxaluria in 56% of the patients; the prevalence of these metabolic abnormalities in our patients is significantly higher in our study as compared with other studies. 5-7 Possibly, low dietary calcium intake 17 and absence of colonization of the gut with Oxalobacter formigenes could be responsible for this high prevalence of hyperoxaluria. 18 Renal tubular acidosis was diagnosed in 5% of the patients, who idiopathic incomplete distal RTA. This signifies the importance of the ammonium chloride loading test and testing the urine ph in all patients. Diagnosing and treating distal RTA may help not only in the prevention of recurrent renal Table 5. Biochemical presentation of patients with hyper-calciuria. Renal hyper-calciuria Absorptive hyper-calciuria Number of patients 9 7 Age at presentation (years) 31.0 ± ± 10.6 Sex (M/F) 4/5 3/4 Corrected serum calcium (mg/dl) 9.1 ± ± 0.4 Urinary citrate (mg/day) ± ± Urinary calcium (mg/day) ± ± Concurrent abnormalities (n) Hypo-citraturia 9 4 Hyper-oxaluria 5 6

5 842 Joshi A, Gupta SK, Srivastava A stone formation but also in the prevention of other systemic manifestations of the disease. The management of hyper-oxaluria is required at an early stage as calcium oxalate crystals can cause marked inflammation, cell proliferation and fibrosis of the renal parenchyma. 19 This may be mediated through generation of free radicals. 20 Hyper-calciuria was seen in 41% of the patients, of whom renal hyper-calciuria was present in 56% of the individuals. The importance of renal hyper-calciuria is the association with low bone mineral density and osteoporosis in adults. 21 We observed hypo-citraturia in 82% of the subjects. This is unusually high as hypocitraturia has been reported in 20 60% of renal stone formers. 22 We did not identify any secondary cause of hypo-citraturia and it merits further investigation. None of our patients had decreased intake of fluid. In spite of adequate urine output in most of our patients, they had active stone disease. This raises the importance of adequate medical management. We did not study the stone formers with recurrent urinary tract infection (UTI). Hence, none of our patients were diagnosed to have stones secondary to UTI. The importance of metabolic evaluation cannot be underestimated with better understanding of the pathophysiology of development of renal stone and impressive results of medical management. 10,11,23 The metabolic abnormalities, except for few, are not significantly different among first time and recurrent renal stone formers. 24 The finding of metabolic abnormality helps to decide about specific medical treatment. Moreover, surgical management is not completely safe. Histological studies in animals have shown that ESWL injures all tissues within the focal region, particularly tubular and vascular structures, and induces disruption of the tubular basement membrane. 25 Development of anti-glomerular basement membrane antibody-mediated glomerulonephritis after ESWL has also been described. 26 A substantial fraction of the damaged tissue becomes fibrotic and probably results in gradual loss of post-glomerular capillaries and loss of renal functions. 27 The comprehensive metabolic evaluation for FTSF is not practiced by all and there is difference in opinion on this matter. The drawback of our study is that no control population was studied. Results of 24-h urine collection are integral to the selection of most appropriate intervention to prevent recurrence of kidney stone. 10 We studied patients who reported to our hospital, which is a tertiary referral center, and this might have created a bias in the results. The measurement of various metabolic parameters was performed in only one 24-h urine collection. In conclusion, comprehensive metabolic evaluation is required even in FTSF. By detecting the etiology of stone formation, we can decrease the possibility of recurrence with medical measures. Thus, significant morbidity and cost associated with renal stones can be decreased. References 1. Trinchieri A, Ostini F, Nespoli R, Rovera F, Montanari E, Zanetti G. A prospective study of recurrence rate and risk factors for recurrence after a first renal stone. J Urol 1999;162: Ljunghall S, Danielson BG. A prospective study of renal stone recurrences. Br J Urol 1984;56: Ahlstrand C, Tiselius HG. Recurrences during a 10-year follow-up after first renal stone episode. Urol Res 1990;18: Uribarri J, Oh MS, Carroll HJ. The first kidney stone. Ann Intern Med 1989;111: Strauss AL, Coe FL, Parks JH. Formation of a single calcium stone of renal origin. Clinical and laboratory characteristics of patients. Arch Intern Med 1982;142: Pak CY. Should patients with single renal stone occurrence undergo diagnostic evaluation? J Urol 1982;127: Hosseini MM, Eshraghian A, Dehghanian I, Irani D, Amini M. Metabolic abnormalities in patients with nephrolithiasis: Comparison of first-episode with recurrent cases in Southern Iran. Int Urol Nephrol 2010;42: Hughes P. The CARI guidelines. Kidney stones: Metabolic evaluation. Nephrology (Carlton) 2007;12 Suppl 1:S Pearle MS, Roehrborn CG, Pak CY. Metaanalysis of randomized trials for medical

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