Effect of BMI and Urinary ph on Urolithiasis and Its Composition

Transcription

1 Saudi J Kidney Dis Transpl 2013;24(1): Saudi Center for Organ Transplantation Original Article Saudi Journal of Kidney Diseases and Transplantation Effect of BMI and Urinary ph on Urolithiasis and Its Composition Qazi Najeeb 1, Imran Masood 2, Neeru Bhaskar 1, Harnam Kaur 1, Jasbir Singh 1, Rajesh Pandey 1, K. S. Sodhi 1, Suvarna Prasad 1, Sheikh Ishaq 1, Ruhi Mahajan 1 Departments of 1 Biochemistry and 2 Internal Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala, Haryana, India ABSTRACT. Urolithiasis is a common urological disease predominantly affecting males. The lifetime risk of urolithiasis varies from 1% to 5% in Asia, 5% to 9% in Europe, 10% to 15% in the USA and 20% to 25% in the middle-east; lowest prevalence is reported from Greenland and Japan. Such differences have been explained on the basis of race, diet and climate factors. Furthermore, changing socio-economic conditions have generated changes in the prevalence, incidence and distribution for age, sex and type of lithiasis in terms of both the site and the chemical as well as the physical composition of the calculi. The aim of our study was to determine the association between body mass index (BMI) and urine ph in patients with urolithiasis and the influence of body size, as reflected by the BMI, on the composition. The study was conducted in the Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, on urolithiatic patients. The data included patient s age, sex, BMI, urine ph, serum calcium, serum uric acid, serum creatinine and stone composition. Data from 100 patients, 70 men (70%) and 30 women (30%), were analyzed, with 28 patients having normal weight, 38 patients being overweight and 34 patients being obese. The mean age of the patients was ± 9.91 years in group I, ± years in group II and ± years in group III (P > 0.05). The stone composition was calcium oxalate (CaOx) in 66 patients, calcium phosphate (CaP) in 60 patients, uric acid (UA) in 38 patients, combined calcium oxalate and calcium phosphate in 28 patients and three stones in 10 patients. The urinary ph levels (mean ± SD) were 7.78 ± 1.49 in group I, 7.15 ± 1.11 in group II and 6.29 ± 1.14 in group III patients (P = ). Urine ph showed a stepwise decrease with increasing BMI (inverse correlation). Urine ph is inversely related to BMI among patients with urolithiasis, as is the occurrence of urate, calcium oxalate and calcium phosphate stones. Similarly, the serum creatinine increased as the BMI and number of stones increased among the study population. Correspondence to: Dr. Qazi Najeeb, Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, Ambala, Haryana, , India qnajeeb@gmail.com Introduction The chemistry of a stone is a reflection of what chemical groups or moieties are available in the urine at the time of formation and growth of the stone. Despite saying that, the epidemiology of urolithiasis differs according to geographical area. The lifetime risk of uro-

2 Effect of BMI and urinary ph on urolithiasis 61 lithiasis varies from 1% to 5% in Asia, 5% to 9% in Europe, 10% to 15% in USA and 20% to 25% in the middle east, with the lowest prevalence being reported from Greenland and Japan. 1 Such differences have been explained on the basis of race, diet and climate factors. Furthermore, changing socio-economic conditions have generated changes in the prevalence, incidence and distribution for age, sex and type of lithiasis in terms of both the site and the chemical as well as the physical composition of the calculi. 2 Among urinary calculi 70 90% are calcium-containing stones, which include calcium oxalate and calcium phosphate, 3 and 5 10% are uric acid stones. 4 Although urolithiasis is a multifactorial disease, it has been speculated that there is an association between urolithiasis and obesity. 5 Recently, a common pathophysiology has been advocated for both diseases, wherein the prevalence of urolithiasis has been increasing in parallel with obesity. 6 Various studies have shown that the prevalence and incidence of stone disease is associated with body weight and body mass index (BMI). 7 Recently, urinary ph has also shown a strong, graded inverse association with body weight in patients with urinary stones. 8 However, the correlation among urinary stone disease, body weight and urinary ph is unclear. Therefore, the aim of our study was to determine whether there is an association between BMI and urine ph in patients with urolithiasis and the influence of body size, as reflected by the BMI on the composition. Subjects and Methods This study was conducted in the Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, on 100 urolithiatic patients. The data included patient s age, sex, BMI, urine ph, serum calcium, serum uric acid, serum creatinine and stone composition. BMI was calculated as weight in kilograms divided by the square of the height in meters. BMI cut-off were adopted as suggested by the World Health Organization, including the normal ( kg/m 2 ), overweight ( kg/m 2 ) and obese (>30 kg/m 2 ) categories. Patients having familial history or history of recurrent kidney stones were excluded from the study. The composition of stones was analyzed by using chemical methods. 9 Before stone removal, a spot urine sample was collected from the patients and ph was analyzed using a ph meter. 10 The patients were also analyzed for serum total calcium by the O-Cresolphthalein complexone method, 11 uric acid by Uricase method 12 and creatinine using Jaffe s method 13. The normal values of different parameters included were taken as: Serum total calcium 9 11 mg/dl Serum uric acid mg/dl ( mg/dl for females) Serum creatinine mg/dl Urinary ph 5 9 The present study was approved by the ethical committee of the Maharishi Markandeshwar Institute of Medical Science and Research and the study was conducted after taking informed and written consent from the patients. Statistical analysis The statistical analysis was done with the help of computer software Statistical Package for Social Sciences (SPSS) version Baseline comparability was assessed using Pearson s chi-square/t-test. All values were presented as mean ± standard deviation. Patients were grouped as group I ( normal BMI), group II (overweight) and group III (obese). Difference in mean values was evaluated using one-way analysis of variance (ANOVA). Intergroup comparison was assessed post hoc using the Bonferroni t-test. Correlation between BMI values and urinary ph was assessed using product moment correlation coefficient. All P- values reported were two tailed. A P-value of <0.05 was considered as statistically significant. Results In the present study, patients were categorized according to BMI as normal group I (BMI = ), overweight group II (BMI

3 62 Najeeb Q, Masood I, Bhaskar N, et al Table 1. Showing comparison of urinary ph levels between the three groups. Group I Group II Group III Correlation F value P-value (n = 28) (n = 38) (n = 34) coefficient (r) Urinary ph (±SD) 7.78 ± ± ± < Figure 1. Demonstrating variability of urinary ph, serum uric acid and serum creatinine with BMI. = ) and obese group III (BMI 30). Data from 100 patients, 70 men (70%) and 30 women (30%), were analyzed with 28 patients having normal weight, 38 patient being overweight and 34 patients being obese. The mean age of the patients was ± 9.91 in group I, 40.47± in group II and ± in group III (P >0.05). The stone composition was calcium oxalate (CaOx) in 66 patients, calcium phosphate (CaP) in 60 patients, uric acid (UA) in 38 patients, combined calcium oxalate and calcium phosphate in 28 patients and three stones in 10 patients. The urinary ph levels (mean ± SD) were 7.78 ± 1.49 in group I, 7.15 ± 1.11 in group II and 6.29 ± 1.14 in group III patients (P = ) (Table 1). Correlation coefficient (r) was -0.6, revealing an inverse correlation between the two variables. Urine ph showed a stepwise decrease with increasing BMI (Figure 1). The serum uric acid levels (mean ± SD) of the normal weight, overweight and obese patients were 5.27 ± 0.47, 6.00 ± 1.66 and 7.52 ± 1.69 mg/dl, respectively, which was statistically significant between the groups ( P <0.001). The mean (±SD) serum calcium levels were 9.81 ± 0.65, 9.89 ± 1.01 and 9.91 ± 0.79 in groups I, II and III, respectively (P = 0.896) (Table 2). Among the 100 patients, 46 (28 males and 18 females) had a single stone, 44 patients (38 males and six females) had two stones and ten ( four males and six females) patients had three stones. Serum calcium (mean ± SD) among the patients with single, double and three stones was 9.63 ± 0.22 mg/dl, ± 1.01 mg/dl and ± 1.42 mg/dl ( P = 0.014). The mean (±SD) serum creatinine levels were 0.98 ± 0.19 mg/dl, 1.08 ± 0.36 mg/dl and 1.52 ± 0.52 mg/dl among patients with single, double and three stones, respectively (P <0.001). The mean urinary ph was 7.29 ± 1.35, 6.96 ± 0.96 and 6.17 ± 0.59 in patients with single, double and three stones, respectively ( P = 0.018). Intergroup comparison was done between the three groups by applying the Bonferroni t-test. The difference of urinary ph levels was statistically significant between group I and group III (P = 0.001), between group

4 Effect of BMI and urinary ph on urolithiasis 63 Table 2. Baseline characteristics of group I, group II and group III patients. Variables Group I Group II Group III P- Fisher (n = 28) (n = 38) (n = 34) value Age in years (±SD) ± ± ± Gender Male Female Calcium oxalate stones Present Absent <0.001 Calcium phosphate stones Present Absent <0.001 Urate stones Present Absent <0.001 BMI ± ± ± <0.001 Serum calcium levels (mg/dl) 9.81 ± ± ± Serum uric acid levels (mg/dl) 5.27 ± ± ± <0.001 Serum creatinine levels (mg/dl) 0.93 ± ± ± <0.05 Table 3. Showing intergroup comparison of urinary ph levels. Comparison (mean urinary ph levels) P-value Group I vs. group II Group I vs. Group III Group II vs. Group III 0.04 I and group II (P = 0.001) and between group II and group III ( P = 0.04) (Table 3). Thus, patients with obesity had the lowest mean urinary ph levels, followed by overweight patients and then the normal weight group, and these values were highly statistically significant. Intergroup comparison between the three groups after applying the Bonferroni t-test was also statistically significant for subjects with urate, calcium oxalate and calcium phosphate stones (Table 4). Discussion People with larger body size have a higher risk of renal stone formation. In a study by Chou et al, the authors investigated whether obesity was related to the formation of every kind of urinary stone. Although they demonstrated a higher risk of calcium oxalate and uric acid stone formation in obese patients, no significant increase was noted for calcium phosphate stones. 6 The mechanism that explains this relationship is still unclear. Urine ph is one of the important factors for urinary stone formation. We found that urine ph significantly decreases with increasing BMI. Studies of several groups of individuals with urolithiasis have also demonstrated that higher weight is associated with lower urine ph. 8,14 Several epidemiological studies concluded to an association between body size and nephrolithiasis. Based on two large cohorts in the USA (the Nurse s Health Study I, or NHS I, and the Health Professionals Follow-up Study, or HPFS), Curhan et al found the prevalence of a stone history and the incidence of stone episodes to be directly associated with BMI. 15 The reasons for a progressive decline in urine Table 4. Showing intergroup comparison of urate, calcium oxalate and calcium phosphate stones. Comparison (number of stones) Urate stones (P-value) Calcium oxalate (P-value) Calcium phosphate (P-value) Group I vs. Group II < <0.01 <0.001 Group I vs. Group III < < Group II vs. Group III <

5 64 Najeeb Q, Masood I, Bhaskar N, et al Table 5. Showing distribution of number of stones according to baseline characteristics of study subjects. Variables Single stone Two stones Three stones (n = 44) (n = 46) (n = 10) P-value Age in years (±SD) 37.7 ± ± ± BMI ± ± ± Serum calcium levels (mg/dl) 9.63 ± ± ± Serum creatinine levels (mg/dl) 0.98 ± ± ± 0.50 < ph with increasing BMI in patients with urolithiasis are uncertain. Hyperinsulinemia or insulin resistance is one of the possible reasons. Insulin resistance may manifest in the kidney as a defect in ammonium production and the ability to excrete acid, and thus affect urine ph. 16,17 Recent data have confirmed that insulin resistance in humans is associated with lower urine ph. Hyperinsulinemia could also lead to decreased urinary citrate and increased urinary excretion of calcium, uric acid and oxalate, which are important risk factors for calcium nephrolithiasis. 18 Another possible reason is gouty diathesis and increasing urinary uric acid excretion, as observed in our study, with statistically significant serum uric acid levels (Table 2). Overweight or obesity are associated with an increased risk of gouty diathesis that often results in increased urine uric acid excretion, an acidic urine environment and uric acid stone formation. 19 In a previous study, Lemann et al demonstrated that urinary oxalate excretion was significantly associated with BMI. 20 However, in another retrospective study, Taylor et al did not find an association between increased oxalate excretion and obesity. 21 Ekeruo et al observed that obese stone formers had higher calcium, uric acid, oxalate and sulfate urinary excretion than their non-obese counterparts. 22 In their cohort of 527 calcium oxalate stone formers, Siener et al observed a higher daily urinary excretion of sodium, calcium, phosphate, sulfate and uric acid in both men and women with a BMI 25, and of oxalate in women only. 23 Lemann et al found body size to be the major determinant of urinary oxalate excretion among healthy adults in both genders. 20 The present study supports the hypothesis that an elevated BMI is associated with an increased risk of calcium oxalate stone formation. Urinary uric acid contributes substantially to the risk of calcium oxalate stone formation because high concentrations of uric acid lead to decreased solubility of calcium oxalate and might also be associated with a reduced inhibitory activity of glycosaminoglycans on the crystallization of calcium oxalate. 23 Urinary stone disease occurs primarily among men, with a male to female ratio of 2~4:1.14. The gender ratio may change according to different compositions of the calculi. 24 Our study showed that the male to female ratio in calcium phosphate stone formers was 1.5:1. Daudon reported that calcium phosphate stone were significantly more frequent in female patients than in male patients. There are an increased percentage of female patients with calcium phosphate stones, and the reason may be due to an increased incidence of urinary tract infections in women or an equal incidence of underlying metabolic disease in both genders. 24,25 The present study confirmed the high proportion of males among calcium phosphate stones formers. As the clinical picture differs between calcium phosphate stone and general stone populations, we believe some unknown fundamental differences exist in the formation of calcium phosphate stones also. In our study, it was found that both serum uric acid and creatinine concentrations were strongly correlated with BMI in all the three groups ( P <0.001 and P <0.05, respectively); no association was established between serum calcium concentration and BMI ( P = 0.896) (Table 4). Similar results were observed by Siener et al, who found a significant correlation between serum uric and creatinine concentrations with BMI in different genders. 23

6 Effect of BMI and urinary ph on urolithiasis 65 Although no correlation was observed between serum calcium and BMI in our study, the rise in both serum calcium and serum creatinine levels was statistically significant between patients having single stone to patients having three stone ( P = and P <0.001, respectively) (Table 5). A limitation of our study was that we had no information as to the urinary biochemistry of patients and, therefore, we could not analyze the relationship between BMI and lithogenic factors in the various types of stones. Further studies are needed to evaluate urinary ph, ammonium excretion and glucose tolerance together with all lithogenic parameters in calcium and uric acid stone formers in a wide range of BMI. Therefore, continued analysis of the stone composition throughout the course of stone disease is highly warranted. Changes in either the chemical and/or crystal composition that occur in these patients can alert physicians to the impact of underlying metabolic or environmental factors that may influence stone disease activity. Urine ph is inversely related to BMI among patients with urolithiasis, as is the occurrence of urate, calcium oxalate and calcium phosphate stones. Similarly, the serum creatinine increased as the BMI and number of stones increased among the study population. The above-mentioned results may explain why obesity is associated with an increased risk of urolithiasis. Given the significant association of obesity with urinary stone disease, clinicians should encourage obese patients with urolithiasis to reduce weight through a regular diet and recommend a dietician for proper weight loss management. References 1. Bartoletti R, Cai T, Mondaini N, et al. Epidemiology and risk factors in urolithiasis. Urol Int 2007;79: Trinchieri A. Epidemiology of urolithiasis: An update. Clin Cases Miner Bone Metab 2008; 5: Daudon M, Dore JC, Jungers P, Lacour B. Changes in stone composition according to age and gender of patients: A multivariate epidemiological approach. Urol Res 2004;2: Lippman ME, Asplin JR, Cor FL, Favus MJ. Nephrolithiasis. In: Fauci AS, Braunwald E, Kasper DL, et al. Eds. Harrison s Principles of Internal Medicine, 17 th ed. New York: McGraw Hill Co.; p Semins MJ, Shore AD, Makary MA, Magnuson T, Johns R, Matlaga BR. The association of increasing body mass index and kidney stone disease. J Urol 2010;183: Chou YH, Su CM, Li CC, et al. Difference in urinary stone components between obese and non-obese patients. Urol Res 2011;39: Li WM, Chou YH, Li CC, et al. Association of body mass index and urine ph in patients with urolithiasis. Urol Res 2009;37: Maalouf NM, Sakhaee K, Parks JH, Coe FL, Adams-Huet B, Pak CY. Association of urinary ph with body weight in nephrolithiasis. Kidney Int 2004;65: Hodgkinson A. A combined qualitative and quantitative procedure for the chemical analysis of urinary calculi. J Clin Pathol 1971;24 : Durst RA, Andersen OS. Electrochemistry. In: Burtis CA, Ashwood ER Eds. Teitz Textbook of Clinical Chemistry, 3 rd ed. Philadelphia: WB Saunders Co.; p Giteman HJ. An improved procedure for determination of calcium in biological specimens. Anal Biochem 1967;18: Henry RJ. Estimation of uric acid. Am J Clin Pathol 1957;28: Husdan H, Rapoport A. Estimation of creatinine by the Jaffe reaction: A comparison of three methods. Clin Chem 1968;14: Powell CR, Stoller ML, Schwartz BF. Impact of body weight on urinary electrolytes in urinary stone formers. Urology 2000;55: Curhan GC, Willett WC, Rimm EB, Speizer FE, Stampfer MJ. Body size and risk of kidney stones. J Am Soc Nephrol 1998;9: Klisec J, Hu MC, Nief V. Insulin activates the Na + /H + exchanger 3: Biphasic response and glucocorticoid-dependence. Am J Physiol Renal Physiol 2002;283:F Kamel KS, Cheema-Dhadli S, Halperin ML. Studies on the pathophysiology of the low urine ph in patients with uric acid stones. Kidney Int 2002;61: Abate N, Chandalia M, Cabo-Chan AV. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int 2004;65:

7 66 Najeeb Q, Masood I, Bhaskar N, et al 19. Daudon M, Traxer O, Conort P. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol 2006;17: Lemann J, Pleuss JA, Worcester EM, Hornick L, Schrab D, Hoffmann RG. Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 1996;49: Taylor EN, Curhan GC. Body size and 24-hour urine composition. Am J Kidney Dis 2006;48: Ekeruo WO, Tan YH, Young MD, et al. Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol 2004;172: Siener R, Glatz S, Nicolay C, Hesse A. The role of overweight and obesity in calcium oxalate stone formation. Obes Res 2004;12: Daudon M, Donsimoni R, Hennequin C. Sexand age-related composition of calculi analyzed by infrared spectroscopy. Urol Res 1995;23: Daudon M, Dore JC, Jungers P, Lacour B. Changes in stone composition according to age and gender of patients: A multivariate epidemiological approach. Urol Res 2004;32:241-7.