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The long-term outcomes of idiopathic hypercalciuria in children
Journal of Pediatric Urology (2006) 2, 453e458
The long-term outcomes of idiopathic hypercalciuria in children Yılmaz Tabel*, Sevgi Mir Ege University, School of Medicine, Department of Pediatric Nephrology, Bornova, Izmir, Turkey Received 21 May 2005; accepted 18 October 2005 Available online 5 December 2005
KEYWORDS Idiopathic hypercalciuria; Renal type; Absorptive type; Nephrolithiasis; Children
Abstract Objective: Idiopathic hypercalciuria (IH) is a metabolic risk factor in patients with urinary calcium stones and implicated in 30%e50% of all urinary stone diseases. Clinical manifestations and distribution of types of IH are reviewed, as well as current treatment methods and long-term outcomes. Patients: A total of 131 patients (70 boys and 61 girls), aged 1e15 years (mean 7.9 3.19 years), were studied. Follow up was between 6 months and 16 years (mean 4.1 6.8 years). Results: Fifty-three patients (40%) were diagnosed following calcium challenge as renal type, and 51 (39%) as absorptive type of hypercalciuria. Whereas 72 patients (54.9%) had a family history of nephrolithiasis, 59 patients did not. Nephrolithiasis was found in 27 patients (20%) on admission (absorptive ¼ 9.9%, renal ¼ 4.5%, undetermined ¼ 6.1%), but developed in eight other patients (6.1%) (absorptive ¼ 2.2%, renal ¼ 0.7%, undetermined ¼ 3.8%). Urinary calcium excretion reversed in 65 patients with the suggested diet therapy; it recurred in 30 patients (22.9%) (absorptive ¼ 9.1%, renal ¼ 11.4%, undetermined ¼ 2.2%) but 35 returned to normal definitively (26.7%) (absorptive ¼ 11.4%, renal ¼ 12.9%, undetermined ¼ 2.2%). No change was seen in the status of 50 patients (38.1%) (absorptive ¼ 18.3%, renal ¼ 16%, undetermined ¼ 3.8%). Conclusion: IH may be accompanied by nephrolithiasis; type must be determined and those patients with absorptive type should be followed for nephrolithiasis. Our results suggest that formation of new stones could be prevented with diet and thiazide therapies in IH. ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction * Corresponding author. Ege Universitesi Hastanesi, Cocuk Klinigi, 6 Kat, Bornova, 35100 Izmir, Turkey. Tel.: þ90 232 375 84 19; fax: þ90 232 388 52 70. E-mail address: [email protected] (Y. Tabel).
Idiopathic hypercalciuria (IH), first described by Albright et al. [1] in 1953, is a condition of children and adults that affects approximately 5% of the
1477-5131/$30 ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2005.10.009
454 population at an equal rate in both sexes [2e6]. IH currently is considered as a metabolic risk factor in individuals with urinary calcium stones and is implicated in 40% of all urinary stone diseases [7]. Urinary excretion of calcium depends on glomerular filtration of calcium as well as its tubular reabsorption. Normally, the amount of calcium in extracellular fluid and calcium excreted in the urine is balanced independently from the intestinal absorption rate of calcium and resorption of calcium from bone [8]. IH is defined as a pathophysiological syndrome occurring as a consequence of interactions between negative calcium balance, excessive intestinal absorption of calcium and bone resorption [9]. The worldwide frequency of IH is reported to be about 5% (6.5e12.5%) [2e6]. This figure has been variously reported as 2.5% and 12.5% in Turkey [10]. There is uncertainty surrounding the best treatment method for IH and the long-term outcomes of therapeutic procedures in children. The present study reviews clinical manifestations and distribution of IH types as well as treatment methods and long-term outcomes. This is the first study to evaluate long-term follow-up results of the syndrome in Turkey.
Patients and methods Patients The study population consisted of 131 patients who presented to the Pediatric Nephrology Division of the Pediatrics Department of the Medical School of Ege University with hematuria, abdominal pain and urination disorders, and who were diagnosed as having IH between 1984 and 2004. Data were collected for all patients on family history, gender, complaints on admission, clinical and laboratory findings, therapeutic methods applied, and duration and course of the disease.
Y. Tabel, S. Mir acidosis, granulomatous diseases, hypercalcemia, cancer, hyperparathyroidism, vitamin D intoxication, hyperthyroidism and treatment with diuretics or steroids. One hundred and four of the patients diagnosed with IH received a diet containing 400 mg/day of calcium and 100 mg/day sodium for 3 consecutive days, and urine samples were collected for 2 h after starvation for 12 h. Subsequently, the patients were loaded with 1000 mg/1.73 m2 of oral calcium and their urine samples were collected for 4 h. Urinary calcium and creatinine were measured in 2and 4-h urine samples (Synchron Cx9, Beckman Coulter). In addition, serum calcium, creatinine and parathyroid hormone (using the RIA method) levels were determined at the end of urine collection periods, and type of IH was determined according to Table 1. The diagnosis of absorptive type of hypercalciuria occurring as a result of increased calcium absorption from the intestine was based on an increase in urinary calcium following calcium load. The diagnosis of renal hypercalciuria occurring as a result of decreased reabsorption of calcium from the renal tubuli was made in those patients having hypercalciuria during starvation that did not change upon calcium loading.
Treatment and follow up All patients were advised to receive a diet with restricted sodium (1e2 mg/kg/day), rich in potassium (according to RDA) and with excessive fluid intake (at least 1500 ml/m2/day). While on this diet, calcium/creatinine and Na/K rates were followed in spot urinary samples monthly for the first 3 months and then once every 3 months. Oral hydrochlorothiazide was given at a dose of 1e2 mg/kg for 3e18 months (mean 8.85 7.12 months) to 20 patients with renal type of IH who were unresponsive to dietary treatment after 1 year. For these patients monthly urinary calcium/creatinine rates
Definitions Diagnosis of hypercalciuria was based on the urinary calcium/creatinine ratio (mg/mg). The diagnosis was made when this ratio was greater than 0.21 in the second urine sample in the morning for 3 consecutive days, or on finding urinary calcium excretion to be >4 mg/kg/day in those patients able to collect 24-h urine samples [11]. A diagnosis of primary IH was reached in patients diagnosed as having hypercalciuria by means of history, clinical and laboratory findings, and by excluding other secondary causes such as immobilization, renal tubular
Table 1 Differential diagnosis from oral calcium loading test in idiopathic hypercalciuria Laboratory
Absorptive Renal Resorptive
Serum calcium Starvation hypercalciuria Load hypercalciuria Restrict hypercalciuria Parathyroid hormone
N
N þ
[ þ
[ þ/ Y/N
/ þ [
[ þ [
N: normal, [: increase, Y: decrease, /: stable, : none, and þ: present.
Idiopathic hypercalciuria in children
455
(urinary calcium excretion in those patients with high rates) and Na/K rates were also followed. All patients underwent US examination of the urinary tract at least once (Toshiba Sonolayer, SSA 250A, Tokyo, Japan). Those patients in whom a stone was determined underwent plain films of the urinary tract and US examinations were repeated at intervals of 3e6 months.
hypercalciuria and type determination could not be achieved in 27 (21%) of the patients. The most common complaint, abdominal pain, was made by 79 patients (60.3%) (absorptive ¼ 23%, renal ¼ 27%, undetermined ¼ 10%). It was followed by hematuria found in 73 (55.7%) patients (absorptive ¼ 20%, renal ¼ 27%, undetermined ¼ 9%), 66 (50.3%) of whom had macroscopic hematuria (absorptive ¼ 20%, renal ¼ 22%, undetermined ¼ 8%). Other complaints were as follows: dysuria/pollacuria in 59 (45%) (absorptive ¼ 16%, renal ¼ 21%, undetermined ¼ 7%), UTI in 31 (23.6%) (absorptive ¼ 9%, renal ¼ 10%, undetermined ¼ 4%) and enuresis in 19 patients (14.5%) (absorptive ¼ 3%, renal ¼ 3%, undetermined ¼ 7%) (Fig. 1). Whereas a total of 72 patients (54.9%) had a family history of nephrolithiasis (absorptive ¼ 19.8%, renal ¼ 25.1%, undetermined ¼ 9.9%), 59 patients (45.1%) did not have such a family history. Nephrolithiasis was found in 27 patients (20%) on admission (absorptive ¼ 9.9%, renal ¼ 4.5%, undetermined ¼ 6.1%), but the condition developed in eight patients during follow up (6.1%) (absorptive ¼ 2.2%, renal ¼ 0.7%, undetermined ¼ 3%). The only one of 20 patients receiving thiazide therapy (5%) who did not have nephrolithiasis on admission developed the condition in follow up. Ten patients (7.63%) with recurrent and persistent hematuria underwent renal biopsy. The biopsy samples of these patients were found to be normal (absorptive ¼ 1.5%, renal ¼ 2.2%, undetermined ¼ 3.8%). Although urinary calcium excretion reversed in 65 patients with the suggested diet therapy, it recurred in 30 patients (22.9%) (absorptive ¼ 9.1%,
Statistical analysis All data were evaluated with SPSS software (version 11.0). The results were presented as mean, mean SD and percent values. Additionally, Student’s -test and unpaired t-test were performed and P values less than 0.05 were considered as significant.
Results Demographic findings Of the total 131 patients there were 70 boys and 61 girls. The patients were aged 1e15 years (mean 7.9 3.19 years) and the follow-up period was between 6 months and 16 years (mean 4.1 6.8 years).
Clinical and laboratory findings Fifty-three (40%) of the patients whose type of disease was determined following calcium challenge were diagnosed as renal type and 51 (39%) were diagnosed as absorptive type of hypercalciuria. There were no cases of resorptive type of renal type IH 30
percent of patients
undetermined type IH
27
27
25
absorptive type IH
23 21
20 20
16 15 10
10
9
10
10
9 7
7 4
5
6
5
3 3
is
s
as hi lit ro ne ph
ac ti tr ur
in
ar y
re si
nf ec
la ol /p ria
en u
n to
ria cu
ur ia at he m dy su
ab d
om
in
al
pa
in
0
Figure 1
Clinical and laboratory properties according to type of hypercalciuria on admission.
456
Y. Tabel, S. Mir
renal ¼ 11.4%, undetermined ¼ 2.2%), but 35 returned to normal definitively (26.7%) (absorptive ¼ 11.4%, renal ¼ 12.9%, undetermined ¼ 2.2%). No change was seen in the status of 50 patients (38.1%) (absorptive ¼ 18.3%, renal ¼ 16%, undetermined ¼ 3.8%). Only one of 20 patients receiving hydrochlorothiazide for 3e18 months (mean 8.85 7.12 months) has not improved; hypercalciuria returned to normal definitively in nine out of the 19 remaining patients (47.4%) but recurred in the other 10 patients (52.6%). Four of the 20 patients receiving thiazide had to discontinue their treatment (one for leucopenia and three for abdominal pain). Treatment outcomes of the patients are shown in Table 2.
Discussion Idiopathic hypercalciuria (IH), defined as increased urinary calcium excretion without any detectable cause with a reported incidence of 5%, has been reported in approximately half (30e50%) of patients with urinary stone disease [1,12e16]. In the present study, while the incidence of nephrolithiasis on admission was 20% in children with IH, nephrolithiasis was subsequently found in 6.1% of the patients without nephrolithiasis on admission. These figures are consistent with the literature and affirm that IH is a risk factor for nephrolithiasis [14,15,17,18]. A family history of nephrolithiasis in IH has been reported with different rates. Whereas Garcia et al. [19] found the rate of a history of nephrolithiasis in the families of IH patients to be 17.2%, Polito et al. [20] reported 69%. The present study found that the rate of a familial history of nephrolithiasis for IH patients with nephrolithiasis on admission was significantly higher than for those without nephrolithiasis on admission (66.6% vs 54.9%) (P < 0.05). It has been reported from studies on IH that type determination was difficult, and most of these studies did not give information on the Table 2
type distribution of IH. It is well known that the renal, absorptive and resorptive types of IH exhibit complex interactions with each other in a physiopathological aspect. Rendina et al. [21] found the renal type in 38.9% and the absorptive type in 61.1% of 159 adult patients, Garcia et al. [19] found these types of IH at a rate of 19% and 41.37%, Stapleton [22] found at the rate of 34.21% and 19.73%, and Perrone et al. [23] found at the rate of 15.8% and 40%. Our study, however, found these types at approximately equal rates (renal 40% vs absorptive 39%). No significant difference was found in prognosis of hypercalciuria between groups when our patients were evaluated by type of IH (P > 0.05), but both presence on admission and occurrence in the followup period of nephrolithiasis were found at a higher rate in the patients with the absorptive type of IH. Children with IH may present with different symptoms. Stapleton [22] reported macroscopic hematuria as the most frequent complaint on admission. We found that macroscopic hematuria was present in 50.3% of all patients and 62.9% of patients with nephrolithiasis on admission (P < 0.05). Vachvanichsanong et al. [24] reported in a retrospective study that they found IH in 52 of 124 children presenting with recurrent abdominal pain. In the present study, abdominal pain was found in 60.3% of patients. Garcia et al. [19] reported that presentation most frequently occurred with dysuria. We found the complaint of dysuria on admission for 59 of our patients (45.03%). These results suggest that IH should definitely be considered in children presenting with hematuria, abdominal pain and dysuria. No consensus has been reached on treatment and long-term follow up of IH in children despite its strong association with nephrolithiasis. This has been attributed to a scarcity of patients and short follow-up times [14e19]. Alon and Berenbom [17] reported that hypercalciuria persisted at a rate of 50% in follow up of 7 years, Garcia et al. [19] reported 52.3% in follow up of 3 years and Rodrı´guez
Results of patients according to type of hypercalciuria and treatment
Absorptive (n ¼ 51) Renal (n ¼ 53) Diet (n ¼ 33) Thiazide (n ¼ 20) Undetermined (n ¼ 11)
Improvement of hypercalciuria* (n ¼ 35)
Persistent hypercalciuria* (n ¼ 30)
Recurrent hypercalciuria* (n ¼ 50)
New nephrolithiais** (n ¼ 8)
29.4 32.0 24.2 45.0 27.7
23.5 28.3 15.1 5.0 27.7
47.0 39.6 60.6 50.0 45.4
5.8 1.8 0 5.0 36.3
Values are percentages. *P ¼ 0.07 (absorptive vs renal), **P < 0.05 (absorptive vs renal).
Idiopathic hypercalciuria in children et al. [14] reported 70% in follow up of 4 years. In our study, the number of subjects (n ¼ 131) is higher and the follow-up period is longer (6 months to 6 years) than in other published studies. Whereas hypercalciuria reversed in a total of 35 (26.7%) of our patients, no improvement was observed in 50 (38.1%) patients, and hypercalciuria first reversed but then recurred in 50 (22.9%) patients (diet group: 49; thiazide group: 1). Studies have shown that urinary excretion of calcium is altered by diet. Polito et al. [25] reported that urinary calcium levels are directly proportional to the urinary Na/K ratio and that this ratio was significantly higher in patients with hypercalciuria than those with improved hypercalciuria. Similarly, Alon and Berenbom [17] reported that hypercalciuria improved in parallel to a reduction in the urinary Na/K ratio. All of the patients in the present study were advised to increase ingestion of a sodium-restricted and potassium-enhanced diet, and ingestion of fluid. It was observed that they complied well to the diet rich in potassium and excessive fluid intake but were unable to follow sodium restriction. With dietary treatment, both calcium/creatinine and Na/K ratios were found to be normal in 26.7% of the patients (on the first monthly visits). The urinary Na/K ratio was found to be high in all patients with sustained hypercalciuria who did not follow the dietary regulations. There was no significant difference in response to dietary treatment between disease types. It can also be concluded that the urinary Na/K ratio is a good indicator in monitoring patient compliance to the dietary regulations. Diuretics of the thiazide group are used in patients unresponsive to dietary treatment. Hymes and Warshaw [26] reported that IH reversed in 14 patients receiving thiazide and no patient developed stones. In the present study, we found a twofold higher rate of improvement in 20 IH patients of the renal type who received hydrochlorothiazide than in those who did not receive the drug (26.7% vs 45%, P < 0.05). This showed that treatment with thiazide was effective in the renal type of IH which is unresponsive to dietary interventions. In conclusion, it is important that IH is considered in patients presenting with macroscopic hematuria and recurrent abdominal pain. IH may be accompanied by nephrolithiasis; the type must be determined and those patients with the absorptive type followed for nephrolithiasis. Dietary treatment is of equal efficacy for both types of IH (about 27%) and should be the first-line choice. Treatment with thiazide is quite effective in the renal type (about 45%). Taken together, these
457 results suggest that formation of new stones could be prevented with diet and thiazide therapies in IH.
References [1] Albright F, Henneman P, Benedict PH, Forbes AP. Idiopathic hypercalciuria: a preliminary report. Proc R Soc Med Lond 1953;46:1077e81. [2] Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg 1958;46:10e8. [3] Coe FL, Parks JH, Moore ES. Familial idiopathic hypercalciuria. N Engl J Med 1979;300:337e40. [4] Aladjem M, Modan M, Lusky A, Georgi R, Orda S, Eshkol A. I_diopathic hypercalciuria: a familial generalized renal hyperexcretory state. Kidney Int 1983;24:549e54. [5] Mehes K, Szelid Z. Autosomal dominant inheritance of hypercalciuria. Eur J Pediatr 1980;133:239e42. [6] Pak CY, McGuire J, Peterson R, Britton F, Harrod MJ. Familial absorptive hypercalciuria in a large kindred. J Urol 1981;126:717e9. [7] Ghazali S, Barratt TM. Urinary excretion of calcium and magnesium in children. Arch Dis Child 1974;49:97e101. [8] Flocks RH. Calcium urolithiasis: the role of calcium metabolism in the pathogenesis and treatment of calcium urolithiasis. J Urol 1940;43:214. [9] Coe FL, Favus MJ. Nephrolithiasis. In: Brenner B, editor. The kidney. Baltimore, MD: WB Saunders; 1991. p. 1728e67. [10] Calıskan S, Erkan T, Sever L, Arısoy N. Istanbul’da cocuklarda hiperkalsiuri taraması. Istanbul Cocuk Klinigi Dergisi 1992;27:36e8. [11] Shaw NJ, Wheeldon J, Brocklebank T. Indices of serum parathyroid hormone and renal excretion of calcium, phosphate and magnesium. Arch Dis Child 1990;65:1208e11. [12] Moxey-Mims MM, Stapleton FB. Hypercalciuria and nephrocalcinosis in children. Curr Opin Pediatr 1993;5:186e90. [13] Kingwatanakul P, Alon US. Hypercalciuria and urolithiasis in childhood. In: Trachtman H, Gauthier B, editors. Pediatric nephrology. Amsterdam: Harwood Academic Press; 1999. p. 253e68. [14] Rodrı´guez LM, Santos F, Ma ´laga S, Mola P, Rey C, Orejas G, et al. Follow-up of children with idiopathic hypercalciuria. Pediatr Nephrol 1992;6:C114. [15] Feld LG, Meyers KEC, Kaplan BS, Stapleton FB. Limited evaluation of microscopic hematuria in pediatrics. Pediatrics 1998;102:42. [16] Lerolle N, Lantz B, Paillard F, Gattegno B, Flahault A, Ronco P. Risk factors for nephrolithiasis in patients with familial idiopathic hypercalciuria. Am J Med 2002;113: 99e103. [17] Alon US, Berenbom A. Idiopathic hypercalciuria of childhood: 4- to 11-year outcome. Pediatr Nephrol 2000;14: 1011e5. [18] Polito C, La Manna A, Cioce F, Villani J, Nappi B, Di Toro R. Clinical presentation and natural course of idiopathic hypercalciuria in children. Pediatr Nephrol 2000;15:211e4. [19] Garcia CD, Miller LA, Stapleton FB. Natural history of hematuria associated with hypercalciuria in children. Am J Dis Child 1991;145:1204e7. [20] Polito C, La Manna A, Nappi B, Villani J, Di Toro R. Idiopathic hypercalciuria and hyperuricosuria: family prevalence of nephrolithiasis. Pediatr Nephrol 2000;14: 1102e4. [21] Rendina D, Mossetti G, Viceconti R, Sorrentino M, Castaldo R, Manno G. Association between vitamin D
458 receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology 2004;64:833e8. [22] Stapleton FB. The Southwest Pediatric Nephrology Study Group. Idiopathic hypercalciuria: association with isolated hematuria and risk for urolithiasis in children, Dallas. Kidney Int 1990;37:807e11. [23] Perrone HC, Ajzen H, Toporovski J, Schor N. Metabolic disturbance as a cause of recurrent hematuria in children. Kidney Int 1991;39:707e10.
Y. Tabel, S. Mir [24] Vachvanichsanong P, Malagon M, Moore ES. Recurrent abdominal and flank pain in children with idiopathic hypercalciuria. Acta Paediatr 2001;90:643e8. [25] Polito C, La Manna A, Maiello R, Nappi B, Sicilliano MC, Di Domenico MR. Urinary sodium and potassium excretion in idiopathic hypercalciuria of children. Nephron 2002; 91(1):7e12. [26] Hymes LC, Warshaw BL. Thiazide diuretics for the treatment of children with idiopathic hypercalciuria and hematuria. J Urol 1987;138:1217e9.
The long-term outcomes of idiopathic hypercalciuria in children Yılmaz Tabel*, Sevgi Mir Ege University, School of Medicine, Department of Pediatric Nephrology, Bornova, Izmir, Turkey Received 21 May 2005; accepted 18 October 2005 Available online 5 December 2005
KEYWORDS Idiopathic hypercalciuria; Renal type; Absorptive type; Nephrolithiasis; Children
Abstract Objective: Idiopathic hypercalciuria (IH) is a metabolic risk factor in patients with urinary calcium stones and implicated in 30%e50% of all urinary stone diseases. Clinical manifestations and distribution of types of IH are reviewed, as well as current treatment methods and long-term outcomes. Patients: A total of 131 patients (70 boys and 61 girls), aged 1e15 years (mean 7.9 3.19 years), were studied. Follow up was between 6 months and 16 years (mean 4.1 6.8 years). Results: Fifty-three patients (40%) were diagnosed following calcium challenge as renal type, and 51 (39%) as absorptive type of hypercalciuria. Whereas 72 patients (54.9%) had a family history of nephrolithiasis, 59 patients did not. Nephrolithiasis was found in 27 patients (20%) on admission (absorptive ¼ 9.9%, renal ¼ 4.5%, undetermined ¼ 6.1%), but developed in eight other patients (6.1%) (absorptive ¼ 2.2%, renal ¼ 0.7%, undetermined ¼ 3.8%). Urinary calcium excretion reversed in 65 patients with the suggested diet therapy; it recurred in 30 patients (22.9%) (absorptive ¼ 9.1%, renal ¼ 11.4%, undetermined ¼ 2.2%) but 35 returned to normal definitively (26.7%) (absorptive ¼ 11.4%, renal ¼ 12.9%, undetermined ¼ 2.2%). No change was seen in the status of 50 patients (38.1%) (absorptive ¼ 18.3%, renal ¼ 16%, undetermined ¼ 3.8%). Conclusion: IH may be accompanied by nephrolithiasis; type must be determined and those patients with absorptive type should be followed for nephrolithiasis. Our results suggest that formation of new stones could be prevented with diet and thiazide therapies in IH. ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction * Corresponding author. Ege Universitesi Hastanesi, Cocuk Klinigi, 6 Kat, Bornova, 35100 Izmir, Turkey. Tel.: þ90 232 375 84 19; fax: þ90 232 388 52 70. E-mail address: [email protected] (Y. Tabel).
Idiopathic hypercalciuria (IH), first described by Albright et al. [1] in 1953, is a condition of children and adults that affects approximately 5% of the
1477-5131/$30 ª 2005 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2005.10.009
454 population at an equal rate in both sexes [2e6]. IH currently is considered as a metabolic risk factor in individuals with urinary calcium stones and is implicated in 40% of all urinary stone diseases [7]. Urinary excretion of calcium depends on glomerular filtration of calcium as well as its tubular reabsorption. Normally, the amount of calcium in extracellular fluid and calcium excreted in the urine is balanced independently from the intestinal absorption rate of calcium and resorption of calcium from bone [8]. IH is defined as a pathophysiological syndrome occurring as a consequence of interactions between negative calcium balance, excessive intestinal absorption of calcium and bone resorption [9]. The worldwide frequency of IH is reported to be about 5% (6.5e12.5%) [2e6]. This figure has been variously reported as 2.5% and 12.5% in Turkey [10]. There is uncertainty surrounding the best treatment method for IH and the long-term outcomes of therapeutic procedures in children. The present study reviews clinical manifestations and distribution of IH types as well as treatment methods and long-term outcomes. This is the first study to evaluate long-term follow-up results of the syndrome in Turkey.
Patients and methods Patients The study population consisted of 131 patients who presented to the Pediatric Nephrology Division of the Pediatrics Department of the Medical School of Ege University with hematuria, abdominal pain and urination disorders, and who were diagnosed as having IH between 1984 and 2004. Data were collected for all patients on family history, gender, complaints on admission, clinical and laboratory findings, therapeutic methods applied, and duration and course of the disease.
Y. Tabel, S. Mir acidosis, granulomatous diseases, hypercalcemia, cancer, hyperparathyroidism, vitamin D intoxication, hyperthyroidism and treatment with diuretics or steroids. One hundred and four of the patients diagnosed with IH received a diet containing 400 mg/day of calcium and 100 mg/day sodium for 3 consecutive days, and urine samples were collected for 2 h after starvation for 12 h. Subsequently, the patients were loaded with 1000 mg/1.73 m2 of oral calcium and their urine samples were collected for 4 h. Urinary calcium and creatinine were measured in 2and 4-h urine samples (Synchron Cx9, Beckman Coulter). In addition, serum calcium, creatinine and parathyroid hormone (using the RIA method) levels were determined at the end of urine collection periods, and type of IH was determined according to Table 1. The diagnosis of absorptive type of hypercalciuria occurring as a result of increased calcium absorption from the intestine was based on an increase in urinary calcium following calcium load. The diagnosis of renal hypercalciuria occurring as a result of decreased reabsorption of calcium from the renal tubuli was made in those patients having hypercalciuria during starvation that did not change upon calcium loading.
Treatment and follow up All patients were advised to receive a diet with restricted sodium (1e2 mg/kg/day), rich in potassium (according to RDA) and with excessive fluid intake (at least 1500 ml/m2/day). While on this diet, calcium/creatinine and Na/K rates were followed in spot urinary samples monthly for the first 3 months and then once every 3 months. Oral hydrochlorothiazide was given at a dose of 1e2 mg/kg for 3e18 months (mean 8.85 7.12 months) to 20 patients with renal type of IH who were unresponsive to dietary treatment after 1 year. For these patients monthly urinary calcium/creatinine rates
Definitions Diagnosis of hypercalciuria was based on the urinary calcium/creatinine ratio (mg/mg). The diagnosis was made when this ratio was greater than 0.21 in the second urine sample in the morning for 3 consecutive days, or on finding urinary calcium excretion to be >4 mg/kg/day in those patients able to collect 24-h urine samples [11]. A diagnosis of primary IH was reached in patients diagnosed as having hypercalciuria by means of history, clinical and laboratory findings, and by excluding other secondary causes such as immobilization, renal tubular
Table 1 Differential diagnosis from oral calcium loading test in idiopathic hypercalciuria Laboratory
Absorptive Renal Resorptive
Serum calcium Starvation hypercalciuria Load hypercalciuria Restrict hypercalciuria Parathyroid hormone
N
N þ
[ þ
[ þ/ Y/N
/ þ [
[ þ [
N: normal, [: increase, Y: decrease, /: stable, : none, and þ: present.
Idiopathic hypercalciuria in children
455
(urinary calcium excretion in those patients with high rates) and Na/K rates were also followed. All patients underwent US examination of the urinary tract at least once (Toshiba Sonolayer, SSA 250A, Tokyo, Japan). Those patients in whom a stone was determined underwent plain films of the urinary tract and US examinations were repeated at intervals of 3e6 months.
hypercalciuria and type determination could not be achieved in 27 (21%) of the patients. The most common complaint, abdominal pain, was made by 79 patients (60.3%) (absorptive ¼ 23%, renal ¼ 27%, undetermined ¼ 10%). It was followed by hematuria found in 73 (55.7%) patients (absorptive ¼ 20%, renal ¼ 27%, undetermined ¼ 9%), 66 (50.3%) of whom had macroscopic hematuria (absorptive ¼ 20%, renal ¼ 22%, undetermined ¼ 8%). Other complaints were as follows: dysuria/pollacuria in 59 (45%) (absorptive ¼ 16%, renal ¼ 21%, undetermined ¼ 7%), UTI in 31 (23.6%) (absorptive ¼ 9%, renal ¼ 10%, undetermined ¼ 4%) and enuresis in 19 patients (14.5%) (absorptive ¼ 3%, renal ¼ 3%, undetermined ¼ 7%) (Fig. 1). Whereas a total of 72 patients (54.9%) had a family history of nephrolithiasis (absorptive ¼ 19.8%, renal ¼ 25.1%, undetermined ¼ 9.9%), 59 patients (45.1%) did not have such a family history. Nephrolithiasis was found in 27 patients (20%) on admission (absorptive ¼ 9.9%, renal ¼ 4.5%, undetermined ¼ 6.1%), but the condition developed in eight patients during follow up (6.1%) (absorptive ¼ 2.2%, renal ¼ 0.7%, undetermined ¼ 3%). The only one of 20 patients receiving thiazide therapy (5%) who did not have nephrolithiasis on admission developed the condition in follow up. Ten patients (7.63%) with recurrent and persistent hematuria underwent renal biopsy. The biopsy samples of these patients were found to be normal (absorptive ¼ 1.5%, renal ¼ 2.2%, undetermined ¼ 3.8%). Although urinary calcium excretion reversed in 65 patients with the suggested diet therapy, it recurred in 30 patients (22.9%) (absorptive ¼ 9.1%,
Statistical analysis All data were evaluated with SPSS software (version 11.0). The results were presented as mean, mean SD and percent values. Additionally, Student’s -test and unpaired t-test were performed and P values less than 0.05 were considered as significant.
Results Demographic findings Of the total 131 patients there were 70 boys and 61 girls. The patients were aged 1e15 years (mean 7.9 3.19 years) and the follow-up period was between 6 months and 16 years (mean 4.1 6.8 years).
Clinical and laboratory findings Fifty-three (40%) of the patients whose type of disease was determined following calcium challenge were diagnosed as renal type and 51 (39%) were diagnosed as absorptive type of hypercalciuria. There were no cases of resorptive type of renal type IH 30
percent of patients
undetermined type IH
27
27
25
absorptive type IH
23 21
20 20
16 15 10
10
9
10
10
9 7
7 4
5
6
5
3 3
is
s
as hi lit ro ne ph
ac ti tr ur
in
ar y
re si
nf ec
la ol /p ria
en u
n to
ria cu
ur ia at he m dy su
ab d
om
in
al
pa
in
0
Figure 1
Clinical and laboratory properties according to type of hypercalciuria on admission.
456
Y. Tabel, S. Mir
renal ¼ 11.4%, undetermined ¼ 2.2%), but 35 returned to normal definitively (26.7%) (absorptive ¼ 11.4%, renal ¼ 12.9%, undetermined ¼ 2.2%). No change was seen in the status of 50 patients (38.1%) (absorptive ¼ 18.3%, renal ¼ 16%, undetermined ¼ 3.8%). Only one of 20 patients receiving hydrochlorothiazide for 3e18 months (mean 8.85 7.12 months) has not improved; hypercalciuria returned to normal definitively in nine out of the 19 remaining patients (47.4%) but recurred in the other 10 patients (52.6%). Four of the 20 patients receiving thiazide had to discontinue their treatment (one for leucopenia and three for abdominal pain). Treatment outcomes of the patients are shown in Table 2.
Discussion Idiopathic hypercalciuria (IH), defined as increased urinary calcium excretion without any detectable cause with a reported incidence of 5%, has been reported in approximately half (30e50%) of patients with urinary stone disease [1,12e16]. In the present study, while the incidence of nephrolithiasis on admission was 20% in children with IH, nephrolithiasis was subsequently found in 6.1% of the patients without nephrolithiasis on admission. These figures are consistent with the literature and affirm that IH is a risk factor for nephrolithiasis [14,15,17,18]. A family history of nephrolithiasis in IH has been reported with different rates. Whereas Garcia et al. [19] found the rate of a history of nephrolithiasis in the families of IH patients to be 17.2%, Polito et al. [20] reported 69%. The present study found that the rate of a familial history of nephrolithiasis for IH patients with nephrolithiasis on admission was significantly higher than for those without nephrolithiasis on admission (66.6% vs 54.9%) (P < 0.05). It has been reported from studies on IH that type determination was difficult, and most of these studies did not give information on the Table 2
type distribution of IH. It is well known that the renal, absorptive and resorptive types of IH exhibit complex interactions with each other in a physiopathological aspect. Rendina et al. [21] found the renal type in 38.9% and the absorptive type in 61.1% of 159 adult patients, Garcia et al. [19] found these types of IH at a rate of 19% and 41.37%, Stapleton [22] found at the rate of 34.21% and 19.73%, and Perrone et al. [23] found at the rate of 15.8% and 40%. Our study, however, found these types at approximately equal rates (renal 40% vs absorptive 39%). No significant difference was found in prognosis of hypercalciuria between groups when our patients were evaluated by type of IH (P > 0.05), but both presence on admission and occurrence in the followup period of nephrolithiasis were found at a higher rate in the patients with the absorptive type of IH. Children with IH may present with different symptoms. Stapleton [22] reported macroscopic hematuria as the most frequent complaint on admission. We found that macroscopic hematuria was present in 50.3% of all patients and 62.9% of patients with nephrolithiasis on admission (P < 0.05). Vachvanichsanong et al. [24] reported in a retrospective study that they found IH in 52 of 124 children presenting with recurrent abdominal pain. In the present study, abdominal pain was found in 60.3% of patients. Garcia et al. [19] reported that presentation most frequently occurred with dysuria. We found the complaint of dysuria on admission for 59 of our patients (45.03%). These results suggest that IH should definitely be considered in children presenting with hematuria, abdominal pain and dysuria. No consensus has been reached on treatment and long-term follow up of IH in children despite its strong association with nephrolithiasis. This has been attributed to a scarcity of patients and short follow-up times [14e19]. Alon and Berenbom [17] reported that hypercalciuria persisted at a rate of 50% in follow up of 7 years, Garcia et al. [19] reported 52.3% in follow up of 3 years and Rodrı´guez
Results of patients according to type of hypercalciuria and treatment
Absorptive (n ¼ 51) Renal (n ¼ 53) Diet (n ¼ 33) Thiazide (n ¼ 20) Undetermined (n ¼ 11)
Improvement of hypercalciuria* (n ¼ 35)
Persistent hypercalciuria* (n ¼ 30)
Recurrent hypercalciuria* (n ¼ 50)
New nephrolithiais** (n ¼ 8)
29.4 32.0 24.2 45.0 27.7
23.5 28.3 15.1 5.0 27.7
47.0 39.6 60.6 50.0 45.4
5.8 1.8 0 5.0 36.3
Values are percentages. *P ¼ 0.07 (absorptive vs renal), **P < 0.05 (absorptive vs renal).
Idiopathic hypercalciuria in children et al. [14] reported 70% in follow up of 4 years. In our study, the number of subjects (n ¼ 131) is higher and the follow-up period is longer (6 months to 6 years) than in other published studies. Whereas hypercalciuria reversed in a total of 35 (26.7%) of our patients, no improvement was observed in 50 (38.1%) patients, and hypercalciuria first reversed but then recurred in 50 (22.9%) patients (diet group: 49; thiazide group: 1). Studies have shown that urinary excretion of calcium is altered by diet. Polito et al. [25] reported that urinary calcium levels are directly proportional to the urinary Na/K ratio and that this ratio was significantly higher in patients with hypercalciuria than those with improved hypercalciuria. Similarly, Alon and Berenbom [17] reported that hypercalciuria improved in parallel to a reduction in the urinary Na/K ratio. All of the patients in the present study were advised to increase ingestion of a sodium-restricted and potassium-enhanced diet, and ingestion of fluid. It was observed that they complied well to the diet rich in potassium and excessive fluid intake but were unable to follow sodium restriction. With dietary treatment, both calcium/creatinine and Na/K ratios were found to be normal in 26.7% of the patients (on the first monthly visits). The urinary Na/K ratio was found to be high in all patients with sustained hypercalciuria who did not follow the dietary regulations. There was no significant difference in response to dietary treatment between disease types. It can also be concluded that the urinary Na/K ratio is a good indicator in monitoring patient compliance to the dietary regulations. Diuretics of the thiazide group are used in patients unresponsive to dietary treatment. Hymes and Warshaw [26] reported that IH reversed in 14 patients receiving thiazide and no patient developed stones. In the present study, we found a twofold higher rate of improvement in 20 IH patients of the renal type who received hydrochlorothiazide than in those who did not receive the drug (26.7% vs 45%, P < 0.05). This showed that treatment with thiazide was effective in the renal type of IH which is unresponsive to dietary interventions. In conclusion, it is important that IH is considered in patients presenting with macroscopic hematuria and recurrent abdominal pain. IH may be accompanied by nephrolithiasis; the type must be determined and those patients with the absorptive type followed for nephrolithiasis. Dietary treatment is of equal efficacy for both types of IH (about 27%) and should be the first-line choice. Treatment with thiazide is quite effective in the renal type (about 45%). Taken together, these
457 results suggest that formation of new stones could be prevented with diet and thiazide therapies in IH.
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