Metabolic Abnormalities Associated With Renal Calculi in Patients with Horseshoe Kidneys

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1 JOURNAL OF ENDOUROLOGY Volume 18, Number 2, March 2004 Mary Ann Liebert, Inc. Metabolic Abnormalities Associated With Renal Calculi in Patients with Horseshoe Kidneys GANESH V. RAJ, M.D., 1 BRIAN K. AUGE, M.D., 2 DEAN ASSIMOS, M.D., 3 and GLENN M. PREMINGER, M.D. 1 ABSTRACT Background and Purpose: Horseshoe kidneys are a complex anatomic variant of fused kidneys, with a 20% reported incidence of associated calculi. Anatomic causes such as high insertion of the ureter on the renal pelvis and obstruction of the ureteropelvic junction are thought to contribute to stone formation via impaired drainage, with urinary stasis, and an increased incidence of infection. In this multi-institutional study, we evaluated whether metabolic factors contributed to stone development in patients with horseshoe kidneys. Patients and Methods: A retrospective review of 37 patients with horseshoe kidneys was performed to determine if these patients had metabolic derangements that might have contributed to calculus formation. Stone compositions as well as 24-hour urine collections were examined. Specific data points of interest were total urine volume; urine ph; urine concentrations of calcium, sodium, uric acid, oxalate, and citrate; and number of abnormalities per patient per 24-hour urine collection. These data were compared with those of a group of 13 patients with stones in caliceal diverticula as well as 24 age-, race-, and sex-matched controls with stones in anatomically normal kidneys. Results: Eleven (9 men and 2 women) of the 37 patients (30%) with renal calculi in horseshoe kidneys had complete metabolic evaluations available for review. All patients were noted to have at least one abnormality, with an average of 2.68 abnormalities per 24-hour urine collection (range 1 4). One patient had primary hyperparathyroidism and underwent a parathyroidectomy. Low urine volumes were noted in eight patients on at least one of the two specimens (range ml/day). Hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia were noted in seven, three, six, and six patients, respectively. No patients were found to have gouty diathesis or developed cystine stones. Comparative metabolic analyses of patients with renal calculi in caliceal diverticula or normal kidneys revealed a distinct profile in patients with horseshoe kidneys, with a higher incidence of hypocitraturia. Conclusions: All patients with renal calculi in horseshoe kidneys were noted to have metabolic abnormalities predisposing to stone formation. In this initial series of 11 patients, hypovolemia, hypercalcuria and hypocitraturia were most common metabolic defects. These findings suggest that metabolic derangements play a role in stone formation in patients with a horseshoe kidney. Patients with calculi in anatomically abnormal kidneys should be considered for a metabolic evaluation to identify their stone-forming risk factors in order to initiate preventative selective medical therapy and reduce the risk of recurrent calculus formation. INTRODUCTION THE HORSESHOE KIDNEY is the most common of all renal fusion anomalies and has a prevalence of 0.25% of the population, or about 1 in 400. During the fourth to sixth week of development, the metanephric buds contact and undergo fusion, with the formation of an isthmus or connection between the two developing kidneys, resulting in a horseshoe shape. Because this fusion occurs prior to the ascent and rotation of the kidneys, the mature kidneys are often lower in the abdomen 1 Division of Urology, Duke University Medical Center, Durham, North Carolina. 2 Naval Medical Center, San Diego, California. 3 Wake Forest University School of Medicine, Winston-Salem, North Carolina. 157

2 158 RAJ ET AL. TABLE 1. DEMOGRAPHICS OF THREE STUDY GROUPS Mean age (yrs) Renal anomaly N (range) Race M/F Horseshoe kidney Caucasian 8/3 (29 76) 2 other Caliceal diverticulum Caucasian 5/8 (24 58) 3 other None Caucasian 18/6 (30 72) 4 other than normal kidneys, with anteromedial displacement of the collecting system. The renal calices are oriented posteriorly, and the insertion of the ureter on the renal pelvis is displaced superiorly and laterally. Further, the ureter has a characteristic bend as it courses over the isthmus, with a deviation proportional to the thickness of the midline structure. Horseshoe kidneys are associated with a significant rate of obstruction at the ureteropelvic junction. These anatomic factors contribute to impaired drainage of the collecting system resulting in stasis, a higher incidence of infection (30%), and a predisposition to calculus formation. 1 Stone formation has been reported to occur in approximately 20% of horseshoe kidneys. 2,3 The surgical treatment of renal calculi in patients with complex renal malformations, including those with horseshoe and pelvic kidneys, is often challenging. Shockwave lithotripsy has been successful for the fragmentation of these stones but is plagued by low clearance rates and frequent need for retreatments. 4 6 Ureteroscopy, with and without the use of an access sheath, has been reported to be effective for the treatment of renal calculi in horseshoe kidneys. 7,8 The percutaneous approach, while safe and effective, requires special care and knowledge of the altered renal anatomy to avoid major complications Given the complexity of treatment options for patients with renal calculi in horseshoe kidneys, we decided to evaluate the etiology of stone disease in these patients with an eye toward prevention of recurrence or further growth of existing small stones. While traditional thinking has been to ascribe the cause of stone formation to anatomic variations causing urinary stasis, the true contribution of anatomic and metabolic etiologies is poorly understood. In a prior study, metabolic derangements, including hypercalicuria and hyperuricosuria resulting in calcium stones, were noted in a majority (75%) of patients with horseshoe kidneys. 7 Previous studies of stone formation in patients with ureteropelvic junction obstruction and renal caliceal diverticula also suggested that underlying metabolic derangements, and not obstruction alone, are involved in the development of renal calculi. The goal of our multi-institutional review was to assess the number and degree of metabolic abnormalities in patients with horseshoe kidneys in a contemporary series and to determine the contribution of those abnormalities to stone formation in this group of patients. PATIENTS AND METHODS We retrospectively reviewed the records of all patients with horseshoe kidneys seen at our two institutions (Duke University Medical Center and Wake Forest University Medical Center) between February 1990 and February Medical history was evaluated for the presence of a horseshoe kidney, urolithiasis, and comprehensive metabolic analyses. Eleven patients were identified who had complete metabolic work-ups, and their metabolic stone evaluation was subject to closer review. The data from 26 other patients who had stones in their horseshoe kidneys and incomplete metabolic work-ups (single or no 24-hour urine specimens) were compiled for stone analyses only. Those individuals selected for metabolic stone analysis tended to be those with recurrent stone formation and had undergone at least one prior stone removal procedure, either percutaneous surgery or shockwave lithotripsy. Patients were typically seen 3 months after of their interventional procedure and were asked to submit to two 24-hour urine specimens. The samples were collected by the patients at home using materials mailed or provided in accordance with oral and written in- TABLE 2. METABOLIC DATA OF THREE STUDY GROUPS No. (%) No. of metabolic with serum No. (%) derangements No. (%) Renal anomaly N anomalies serum Ca (range) urine Ca Horseshoe kidney 11 1 (9) 1 (9) (55) (1 4) Caliceal diverticulum 13 1 (7.7) (58) (1 4) None 24 2 (8) (56) (0 5)

3 METABOLIC ABNORMALITIES WITH HORSESHOE KIDNEYS 159 structions detailed by a trained research nurse. Analysis of the urine was performed by one of three central laboratories and examined for volume, ph, and the concentrations of calcium, sodium, creatinine, magnesium, phosphate, oxalate, uric acid, cystine, and citrate. The two urinalyses were generally performed on consecutive days, with range of 1 to 4 days between the two 24-hour collections. If necessary, additional 24 hour urine analyses were performed with patients on salt- and calcium-restricted diets to confirm a diagnosis. Serum chemical analysis, including calcium, phosphate, and parathyroid hormone concentrations, also was done. The initial paired 24-hour urine collections were examined to assess patterns of metabolic abnormalities. Urinary creatinine was measured to assess the adequacy of sample collection. An abnormal value in one of the risk factors in one 24-hour sample was deemed significant regardless of whether it was concordantly elevated in the other 24-hour urinalysis. The number of metabolic abnormalities per 24-hour urine collection per patient was also noted. Stone composition was determined when possible. These data were compared with those of 13 patients with renal calculi in caliceal diverticula (another anatomic renal anomaly) and 24 age-, race-, and sex-matched control patients with renal calculi but without known renal anomalies. These comparative studies were used to establish whether metabolic derangements contributed to stone formation in patients with anatomic anomalies and whether any specific predisposing factors were more commonly present in these patients. Application of a stricter definition of concordant abnormalities in both urine samples was also used to minimize the number of false-positive results and to clearly establish if patients with horseshoe kidneys had metabolic factors contributing to stone formation. A similar rate of concordance between the two 24-hour samples was noted for the three patient groups. RESULTS FIG. 1. Percentages of various predisposing metabolic factors in three study groups. In our combined patient populations, we identified 37 patients with renal calculi in horseshoe kidneys. Analysis of stone composition revealed a preponderance of calcium (87.5%). Most patients (71%) had calcium oxalate monohydrate stones, with calcium phosphate (42%) and calcium oxalate dihydrate (33%) also seen. Three patients had associated renal anomalies (diverticulum, ureteropelvic junction obstruction, partial duplication). The majority of patients had multiple stones or complex renal calculi, including three with staghorn stones. Among this series were 11 patients (30%) with renal calculi who also had complete metabolic evaluations available for review. We compared their metabolic data with those of 13 patients with symptomatic renal calculi in caliceal diverticula and 24 control patients with renal calculi but with no known renal anatomic abnormalities. The demographics of these three groups are shown in Table 1. A review of the serum chemistries revealed that one patient had primary hyperparathyroidism (elevated serum calcium [11.2 mg/dl] and parathyroid hormone [175 ng/dl]) and underwent a parathyroidectomy to correct the etiology underlying his recurrent nephrolithiasis. All other patients had normal serum calcium, phosphate, creatinine, urea nitrogen, and parathyroid hormone levels. Normal serum values were noted for patients with stones in caliceal diverticula and for those with stones in normal kidneys (data not shown). All patients with horseshoe kidneys were noted to have at least one metabolic abnormality, with an average of 2.8 per 24- hour urine collection (range 1 4; median 3). Only one patient had a single metabolic abnormality. A similar number of abnormalities per 24-hour urine collection was noted in patients FIG. 2. Metabolic profiles of three study groups.

4 with stones in caliceal diverticula (average 2.8) and with normal kidneys (average 2.5), as seen in Table 2. The metabolic findings for patients with horseshoe kidneys compared with those of patients with caliceal diverticula and normal anatomy are demonstrated in Figure 1. Low urine volume (,2000 ml/day) was the most common derangement, being seen in eight patients (72.7%) (range ml/day). In contrast, low urine volume was noted in almost all patients (92.3%) with stones in a caliceal diverticulum and in 50% of the patients with stones in normal kidneys. Seven of the eleven patients with horseshoe kidneys (64%) had hypercalciuria (urinary calcium range mg/day; normal values,200 mg/day for women and,250 mg/day for men). Absorptive hypercalciuria Type II was noted to be predominant among this group of patients (72%). One patient had absorptive hypercalciuria Type I, while another had primary hyperparathyrodism as previously noted. Hypercalciuria was present in a similar proportion of patients with renal calculi in caliceal diverticula (62%) and normal kidneys (70%). Hypocitraturia was found in 6 of 11 patients (55%) with horseshoe kidneys (range mg/day; normal value.400 mg/day). The incidence of hypocitraturia in the patients with horseshoe kidneys was higher than that in patients with renal calculi in caliceal diverticula (31%) or normal kidneys (33%) (Fig. 1). Hyperoxaluria was noted in three patients (27%) with horseshoe kidneys and in a similar proportion of patients with stones in caliceal diverticula (23%) and normal kidneys (29%). Hyperuricosuria was noted in six patients (54%) with horseshoe kidneys and in a similar proportion of patients with caliceal diverticula (54%). In contrast, hyperuricosuria was seen in a smaller number (31%) of patients with normal kidneys. No patients in any of the three groups were found to have gouty diathesis, and no patients formed cystine stones. On the basis of these metabolic problems, 9 of 11 patients (82%) were started on appropriate medical therapy to include increase in fluid intake, moderation of dietary sodium, potassium citrate, thiazide diuretics, and allopurinol either as monotherapy or in combination. 160 DISCUSSION In this analysis of patients with stones in horseshoe kidneys, we found that most had calcium stones, in a preponderance similar to that seen in a prior study. 7 We also found that all patients with stones in a horseshoe kidney had at least one metabolic abnormality on the 24-hour urine, with most patients having well over two. These data indicate that patients with anatomic anomalies have a similar if not greater number of metabolic derangements at play in stone formation than stone-forming patients without any anatomic derangements. Chronic dehydration is a significant risk factor in stone formation, with nearly 75% of our patients noted to have low urine volumes (,2000 ml/day) Additional metabolic derangements included hypercalciuria, hypocitraturia, and hyperuricosuria, factors correctable with appropriate medical management. Although the small numbers of patients in this study preclude meaningful statistical analysis, our findings suggest that patients with horseshoe kidneys have their own distinct profile of urinary metabolic derangements (Fig. 2). Moreover, as in patients with other renal anatomic anomalies, including ureteropelvic junction obstruction and caliceal diverticula, it appears that urinary stasis is not the sole cause of stone formation This study represents a more extensive study of the role of metabolic factors in promoting stone formation in patients with horseshoe kidneys. However, the relative contributions of metabolic and anatomic abnormalities to stone formation in these patients remain unclear. Perhaps the actual contribution of the anatomic causes in this subgroup of patients can be examined in those whose metabolic derangements have been corrected, followed by continued monitoring for recurrent calculi. CONCLUSIONS All patients with renal calculi in horseshoe kidneys were noted to have metabolic abnormalities predisposing to stone formation. Low urine volume, hypercalciuria, and hypocitraturia were the most common derangements identified. These findings suggest that metabolic abnormalities, in addition to anatomic variations causing urinary stasis, contribute significantly to the formation of stones in these patients. Patients with calculi in anatomically abnormal kidneys, who provide anatomic challenges for stone removal, should undergo a comprehensive metabolic evaluation to determine their stone-forming risk factors so that appropriate preventative selective medical therapy can be given to reduce the risk of recurrent calculus formation. REFERENCES RAJ ET AL. 1. Pitts WR Jr, Muecke EC. Horseshoe kidneys: A 40-year experience. J Urol 1975;113: Cussenot O, Desgrandchamps F, Ollier P, Teillac P, Le Duc A. Anatomical bases of percutaneous surgery for calculi in horseshoe kidney. Surg Radiol Anat 1992;14: Janetschek G, Kunzel KH. Percutaneous nephrolithotomy in horseshoe kidneys: Applied anatomy and clinical experience. Br J Urol 1988;62: Esuvaranathan K, Tan EC, Tung KH, Foo KT. Stones in horseshoe kidneys: Results of treatment by extracorporeal shock wave lithotripsy and endourology. J Urol 1991;146: Gallucci M, Vincenzoni A, Schettini M, Fortunato P, Cassanelli A, Zaccara A. 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5 METABOLIC ABNORMALITIES WITH HORSESHOE KIDNEYS Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: A 5-year randomized prospective study. J Urol 1996;155: Borghi L, Meschi T, Schianchi T, Briganti A, Guerra A, Allegri F, Novarini A. Urine volume: Stone risk factor and preventive measure. Nephron 1999;81(suppl 1): Pak CY, Sakhaee K, Crowther C, Brinkley L. Evidence justifying a high fluid intake in treatment of nephrolithiasis. Ann Intern Med 1980;93: Hsu TH, Streem SB. Metabolic abnormalities in patients with caliceal diverticular calculi. J Urol 1998;160: Husmann DA, Milliner DS, Segura JW. Ureteropelvic junction obstruction with a simultaneous renal calculus: Long-term followup. J Urol 1995;153: Matin SF, Streem SB. Metabolic risk factors in patients with ureteropelvic junction obstruction and renal calculi. J Urol 2000;163: Tekin A, Tekgul S, Atsu N, Ergen A, Kendi S. Ureteropelvic junction obstruction and coexisting renal calculi in children: Role of metabolic abnormalities. Urology (Online) 2001;57: Address reprint requests to: Glenn M. Preminger, M.D. Division of Urology Box 3167, Room 1572D White Zone Duke University Medical Center Durham, North Carolina glenn.preminger@duke.edu