NDT Advance Access originally published online on May 3, 2007
Nephrology Dialysis Transplantation 2007 22(8):2375-2378; doi:10.1093/ndt/gfm250
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Circadian variation in urine pH and uric acid nephrolithiasis risk
1Department of Internal Medicine, 2Department of Urology, Children's Medical Center and 3Center for Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
Correspondence and offprint requests to: M. A. Cameron, MD, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8885, USA. Email: MaryAnn.Cameron{at}UTSouthwestern.edu
Keywords: circadian variation; insulin resistance; nephrolithiasis; pediatric; uric acid stone; urine pH
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Introduction |
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The proportion of uric acid stones in paediatric stone formers is estimated at 3–4% in the United States [1], although reports from Armenia and Turkey indicate higher proportions of 7 and 15%, respectively [2,3]. Risk factors for uric acid stones include hyperuricosuria, low urinary volume and unduly acidic UpH (<5.5) [4]. Acidic UpH is a recognized risk factor in children consuming a ketogenic diet [5], or those with chronic diarrhoea. In adults, an acidic urine pH is the most common abnormality that predisposes to idiopathic uric acid nephrolithiasis [4]. Urinary alkalinization with potassium citrate is an effective treatment for uric acid kidney stones in adults [6]. We report the case of a 13-year-old boy who presented with recurrent uric acid stones that did not respond to a conventional regimen of potassium citrate therapy.
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Case report |
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A 13-year-old Caucasian boy was referred for management of recurrent uric acid nephrolithiasis. He first noted symptoms of dysuria and haematuria at the age of 8 years. At 11.5 years he developed recurrent episodes of abdominal pain, nausea, vomiting and haematuria, requiring repeated hospitalizations. The diagnosis of renal colic was not made until he spontaneously passed a kidney stone 12 months later.
His past medical and surgical history were otherwise negative. His family history was unremarkable except that his mother had gestational diabetes mellitus. Physical examination revealed a well developed, obese 12-year-old boy, with age appropriate cognitive skills. Blood pressure was 120/50 mmHg with a pulse of 95 beats/min. He weighed 81.6 kg and measured 156 cm with a body mass index of 33.1 kg/m2. He had central obesity without thyromegaly or cushingoid features. Lungs and cardiac examination were unremarkable. There was no abdominal or costovertebral tenderness. There was no oedema.
Laboratory investigation demonstrated normal serum electrolytes, uric acid and creatinine. Kidney stone analysis revealed 40% ammonium acid urate and 60% uric acid. Examination of an out-patient 24-h urine revealed a pH of 5.01, uric acid of 106 mg/day (630 µmol/day), undissociated uric acid content of 72.6 mg/day (432 µmol/day), and low urine volume (0.89 l/day). All other parameters were normal. He was initiated on potassium citrate (KCit) [10 mEq three times daily (tid)] and allopurinol (100 mg tid) and was encouraged to augment fluid intake to 3 l/day. These medications were titrated to 80 mEq/day KCit and 400 mg/day allopurinol.
Despite 5 months of therapy, he continued to experience dysuria, haematuria and renal colic with stone passage every 2–3 weeks. Twenty-four hour UpH was 6.09 and urine potassium was 86 mEq/day, indicating appropriate urinary alkalinization and therapeutic compliance. The undissociated uric acid content was 81.2 mg/day (483 µmol/day).
The patient was admitted to the General Clinical Research Center (GCRC) at UT Southwestern Medical Center in Dallas for Institutional Review Board-approved investigations. He provided informed consent. Immediately prior to this admission, he was diagnosed with type 2 diabetes mellitus, and was initiated on metformin (500 mg bid). He weighed 82.3 kg and measured 159 cm in height, with a body mass index of 32.6 kg/m2.
He was placed on a fixed metabolic diet for 5 days (30% fat, 55% carbohydrate and 15% protein; the daily diet contained: 300 mg cholesterol, 400 mg calcium, 800 mg phosphorus, 100 mEq sodium, 10 mEq acid ash and 3000 cc distilled water) and KCit and allopurinol were discontinued for 1 week prior to admission. Urine collected under oil for 24 h and obtained on the metabolic diet revealed a UpH of 5.04, uric acid of 338 mg/day (2010 µmol/day), undissociated uric acid 231.5 mg/day (1377 µmol/day) and citrate of 2.66 mEq/day (Table 1).
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An ammonium chloride load was performed to evaluate the renal ammonium response to acid ingestion, and these results were compared with previously published values from uric acid stone formers with impaired urinary ammonium excretion [7]. Urine pH fell from 5.44–5.02 (control subjects 6.16–5.64; uric acid stone-formers 5.47–5.26). The increment of urinary ammonium normalized to creatinine was 4.4 µmol/mg (control subjects 15.8 ± 9.7; uric acid stone-formers 2.2 ± 4.4). Insulin sensitivity was measured as the glucose disposal rate (GDR, mg/kg/min) during the hyperinsulinaemic euglycemic clamp [8]. The GDR was 4.19 mg/kg/min, which is within the range of insulin resistance (Figure 1).
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), compared with adult controls and uric acid stone formers [To evaluate the cause for recurrent nephrolithiasis despite appropriate therapy, UpH diurnal variation was measured (Figure 2). He was instructed to eat the same foods prior to each admission, and the same diet was provided during each inpatient stay. Meals were eaten at 08:00, 12:00 and 18:00. Urine was collected hourly for 2 h following meals, every 2 h throughout the rest of the day and every 4 h overnight (22:00–02:00, 02:00–06:00). Twenty-four hour urine collections were obtained on the day prior to diurnal studies 1 and 2 (Table 1). All urines were collected under mineral oil except those processed immediately by the laboratory.
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The first evaluation was performed after he had discontinued KCit and allopurinol for 1 week. The 24-h urine values on the home diet were similar to those on the metabolic diet (Table 1). Diurnal studies indicated the UpH was >5.5 in the afternoon and evening, but was <5.5 throughout the morning (Figure 2A). From 8:00–9:00 the UpH was as low as 4.69. With the exception of one reading from 10:00 to 12:00, the UpH was <5.5 from 02:00 to 13:00.
For the second study, the patient received KCit (30 mEq) at 08:00, 12:00 and 18:00. The 24-h urinary potassium was 100 mEq/day and UpH was 6.27, indicating good compliance. In this study, UpH was >5.5 from 10:00 to 02:00 (Figure 2B). However, the UpH fell to <5.5 for the entire period from 02:00 to 09:00, with a value of 5.06 from 02:00 to 06:00. The undissociated uric acid content during this time was 41.8 mg/total volume (249 µmol/total volume). Despite high alkali doses, he had a non-therapeutic UpH for 
7 h, with values as low as 4.67.
In the third study, the subject received 10 mEq KCit at 08:00 and 12:00, and 60 mEq at 21:00 (Figure 2C). The UpH was higher during the night, with the lowest value at 5.47 between 22:00 and 02:00. Of significance, the morning urine pH (06:00–08:00) was 5.57, in contrast to values of 5.08 and 4.67 found in the previous studies. This medication regimen prevented the excessively acidic pH found during the early morning hours. The subject was instructed to maintain this medication regimen, and he reported a significant reduction in stone volume after 1 year of follow-up.
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Discussion |
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TopIntroductionCase reportDiscussionAcknowledgementsReferences |
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Three interesting and novel findings emerge from this study. First, paediatric uric acid stone formers may manifest features of insulin resistance in association with acidic UpH, as seen in adult uric acid stone formers. This report is the first, to our knowledge, to demonstrate such an association in a paediatric patient. Secondly, UpH from a 24-h collection may not adequately reflect periods of extreme urine acidity. Finally, standard regimens of KCit may be insufficient in situations of low nocturnal UpH.
The predominant urinary finding in our patient was an acidic UpH, the most prevalent feature in adult idiopathic uric acid stone formers [4]. This patient's blunted ammoniagenic response to an acid load (ammonium chloride) was similar to that of adult uric acid stone formers [7]. Furthermore, the acidic UpH was associated with insulin resistance, indicated by the recent diagnosis of type 2 diabetes mellitus and low GDR assessed by the hyperinsulinemic euglycaemic clamp (Figure 1). This patient's GDR fell just outside the range of adult uric acid stone formers, and well below the range of normal subjects.
When the subject was treated with an aggressive regimen, his 24-h urine pH increased to 6.27; a response deemed appropriate by most clinicians. Despite this improvement, his uric acid stones recurred every 2–3 weeks. Circadian changes in urine composition, particularly urine pH, have not been well elucidated, either in stone formers or in control subjects. Although prior studies have evaluated UpH diurnal changes in uric acid stone formers, these studies did not compare results of 24-h UpH with values obtained throughout the day. Diurnal studies in our patient revealed the urine was significantly acidic during the night despite daytime KCit therapy (Figure 2).
Standard KCit administration (30 mEq tid) only alkalinized the urine during the day while nocturnal UpH remained acidic <5.5 for 7 h. Stones may easily form because of uric acid precipitation at night. Adjustment of the regimen, with greater alkali dosing at night, ameliorated the early morning acidic urine and, per the patient's history, has diminished further stone development. To our knowledge, this report is the first to identify excessively acidic nocturnal urine as a cause for KCit therapy failure. Furthermore, it suggests treatment outcomes may improve with adjustments in KCit dosing.
In conclusion, these data suggest that insulin resistance may contribute to uric acid nephrolithiasis in the paediatric population. Because of escalating rates of childhood obesity [9], this relationship may become increasingly recognized and the prevalence of uric acid stones in this population may increase. Twenty-four hour urine collections may not accurately reflect stone risk due to diurnal fluctuations in UpH. Diurnal variations in urine composition should be considered in the development of a treatment regimen and particularly in situations of treatment failure. Patients may identify periods of excessive urine acidity by measuring UpH throughout the day by dipstick. The factors responsible for diurnal variation in UpH as well as those responsible for more acidic urine in uric acid stone formers require further investigation.
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Acknowledgements |
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The authors are supported by the National Kidney Foundation (NKF fellowship grant), Children's Medical Center at Dallas CCRAC Grant #2001-5. and the National Institutes of Health (M01-RR000633, P01-DK20543 and R01-DK48482).
Conflict of interest statement. None declared.
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References |
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[Abstract/Free Full Text] - Abate N, Chandalia M, Cabo-Chan AV, Moe OW, Sakhaee K. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int (2004) 65:386–392.[CrossRef][Web of Science][Medline]
Accepted in revised form: 2. 4.07
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  B. Boari, R. Salmi, E. Rizzioli, and R. Manfredini Circadian variation in urine pH and uric acid nephrolithiasis risk Nephrol. Dial. Transplant., January 1, 2008; 23(1): 411 - 412. [Full Text] [PDF]
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