We hypothesized an association between renal calculi and bone mineral density (BMD) deficits, shown in adults, exists in survivors of childhood acute lymphoblastic leukemia (ALL). Thus, we analyzed the associations between quantitative computed tomography (QCT)-determined renal calcifications and clinical parameters (gender, race, age at diagnosis and age at the time of QCT), BMD, treatment exposures and Tanner stage. We investigated the associations between stone formation and nutritional intake, serum and urinary calcium and creatinine levels, and urinary calcium/creatinine ratio. Exact χ2-test was used to compare categorical patient characteristics, and the Wilcoxon–Mann–Whitney test to compare continuous measurements. Of 424 participants, 218 (51.4%) were males; 371 (87.5%) were nonblack. Most (n=270; 63.7%) were ⩾3.5 years at ALL diagnosis. Mean (s.d.) and median (range) BMD Z-scores of the entire cohort were −0.4 (1.2) and −0.5 (−3.9 to 5.1), respectively. Nineteen participants (10 males; 10 Caucasians) had kidney stones (observed prevalence of 4.5%; 19/424) with a significant negative association between stone formation and body habitus (body mass index, P=0.003). Stone formation was associated with treatment protocol (P=0.009) and treatment group (0.007). Thus, kidney stones in childhood ALL survivors could herald the future deterioration of renal function and development of hypertension. Long-term follow-up imaging may be warranted in these patients to monitor for progressive morbidity.
Treatment of acute lymphoblastic leukemia (ALL) with multiagent chemotherapy, including glucocorticoid therapy, increases a patient's risk for both renal calcifications1 and reduced bone mineral density (BMD).2, 3, 4 Both of these conditions are associated with a high rate of bone turnover.5, 6, 7, 8, 9 Thus, the finding of one of these entities in a patient may suggest the need to seek the presence of the other.
Most available information regarding the association of these conditions is based on adults with symptomatic renal calculi.6, 10, 11, 12, 13, 14, 15 We hypothesize that a similar association between renal calculi and BMD deficits may also exist in survivors of childhood ALL. In this study, we explore whether a correlation between renal calcifications, identified by quantitative computed tomography (QCT), and low BMD in survivors of childhood ALL does exist.
From a large cohort of survivors of childhood ALL (n=424) enrolled on an ongoing interventional trial to improve BMD, which was approved by an international review board,16 we identified patients who also had asymptomatic renal calcifications. Renal calcifications were detected by QCT performed for assessment of participants' BMD at the time of enrollment into the study. We analyzed the relationship of stone formation and clinical parameters including gender, race, age at diagnosis, age at the time of QCT, raw BMD (in mg/cc), BMD Z-score, treatment exposures, Tanner stage at diagnosis and Tanner stage at the time of QCT. We also investigated the association of renal stones and nutritional calcium, sodium and magnesium intake, serum and urinary calcium and creatinine levels, and urinary calcium/creatinine ratio obtained at the study enrollment. All participants, parents or guardians signed an informed consent or assent as appropriate. The study was conducted in compliance with the Health Information Privacy and Accountability Act of 1996.
Quantitative computed tomography was performed for BMD assessment as described earlier.4 With this technique, one-half to two-thirds of the kidneys are visualized on the axial images obtained.
Dietary intake of calcium, magnesium and sodium was estimated using the self-administered Block food frequency questionnaire (Block 1998 FFQ from www.nutritionquest.com) at the time of protocol enrollment. The food list used in this questionnaire was developed from the NHANES III dietary recall data (www.nutritionquest.com). The nutrient database was developed from the United States Department of Agriculture Nutrient Database for Standard Reference.
Patients were divided into two groups based on the presence or absence of kidney stones by the QCT scan. To maintain the consistency of reporting with our earlier ALL survivor studies of BMD, we divided the cohort into two groups depending on the age at the time of diagnosis as <3.5 years and ⩾3.5 years.4
Exact χ2-test was used to compare categorical patient characteristics (age groups, treatment, body mass index (BMI) groups and so on) and the Wilcoxon–Mann–Whitney test was used to compare continuous measurements. Z-score of BMD was categorized as normal versus abnormal, using a cut off value of −0.999. The study cohort was grouped as normal versus overweight versus obese using a BMI percentile as delineated in age- and sex-specific growth charts provided by the Centers for Disease Control (threshold for participants under the age of 18 years as follows: normal—BMI less than the 85th percentile, overweight—BMI between the 85th and 95th percentile and obese—BMI exceeding the 95th percentile; threshold for participants older than 18 years as follows: normal—BMI less than the 25th percentile, overweight—BMI between the 25th and 30th percentile and obese—BMI exceeding the 30th percentile). The effect of ALL treatment was analyzed by leukemia risk groups (high risk versus low risk) and therapeutic protocols (Table 1). The potential effect of cranial irradiation was analyzed as none, low (⩽24 Gy) and high (>24 Gy). Cumulative incidence function of kidney stones in the study cohort was estimated using the Kalbfleisch–Prentice method.17 The analyses were performed using a SAS (SAS Institute, Cary, NC, USA) and Cytel Studio 7 (Cytel, Cambridge, MA, USA) for the exact χ2-test.
Of the 424 participants enrolled on the interventional trial (Table 2), 218 (51.4%) were males and 371 (87.5%) were nonblack (Hispanics included). The median (range) of time since the completion of frontline ALL therapy to the study time was 8.5 years (range, 4.6–19.1). The majority of patients (n=270; 63.7%) were 3.5 years of age or older at the diagnosis of ALL. The mean (s.d.) and median (range) BMD Z-scores of the entire cohort (n=424) were −0.4 (1.2) and −0.5 (−3.9 to 5.1), respectively.
Of the 424 survivors, 19 (10 males; 10 Caucasians) had CT evidence of kidney stones, yielding an overall observed prevalence of 4.5% (19/424) regardless of the follow-up time. The estimated cumulative incidence of silent kidney stones at 20 years after diagnosis of ALL in this cohort is 24.7% (s.d. 8.4%) as shown in Figure 1. None of these 19 patients reported an earlier history of kidney stones, nor they reported the symptoms that could be associated with renal calculi. None of the patients had hematuria detected by urinalysis. Those who developed kidney stones had a mean and median BMD below that of the entire cohort, 157.5 mg/cc (21.7) and 163.2 mg/cc (90.4–192.3), respectively (P=0.037; Table 3). Age at diagnosis of leukemia, study, gender or race was not associated with the presence of kidney stones (Table 2).
We found a significant negative association between the development of kidney stones and body habitus (BMI, P=0.003). Thus, patients with normal BMI seem to be more likely to develop kidney stones compared with those who had an elevated BMI. Stone formation was associated with treatment protocol (P=0.009) and treatment group (0.007) (Table 4). We did not find sufficient evidence for correlation between the dose of cranial radiation therapy and kidney stones (Table 4). Neither did we find sufficient evidence for association between kidney stones and urinary calcium/creatinine ratio, serum vitamin D level, fracture history, family history of osteoporosis or renal failure and the development of kidney stones (data not shown).
There was no association between kidney stones and the use of nutritional supplements (P=0.48). Analysis of nutritional intake of calcium, sodium and magnesium was limited to the 184 of 424 (41%) participants in the study who completed the food frequency questionnaire. Although patients who developed kidney stones consumed lower quantities of calcium, magnesium and sodium, their serum and urinary values were not statistically significantly different from those who did not form kidney stones. We also found no significant association between nutritional intake of calcium, sodium or magnesium and the development of kidney stones (Table 5).
The 4.5% prevalence of asymptomatic renal stones in this large cohort of survivors of childhood ALL is almost five times higher than the prevalence of symptomatic renal calcifications of 0.9% reported earlier by us for pediatric patients treated for ALL.1 As neither study prospectively monitored patients for the occurrence of renal stones; the timing of their development is indeterminate.
Not surprisingly, treatment is an important determinant for stone formation. In this regard, none of the patients treated in Total Therapy XII, in which glucocorticoid was only used during remission induction, were found to have renal stones. Indeed, none of the 84 (of 424; 19.8%) participants in this study, who had no exposure to glucocorticoids during continuation therapy, developed kidney stones. Corticosteroids are associated with reduced bone formation and loss of mineral from bone. In addition, corticosteroids may reduce gastrointestinal calcium absorption and renal tubular calcium reabsorption, resulting in a negative calcium balance.18
The strongest risk factor for developing kidney stones in this cohort was having a normal BMI compared with an overweight/obese BMI. However, weight itself was not significantly related to the formation of kidney stones. Earlier adult studies have reported an increased risk of stone formation in individuals with both increased weight19, 20 and with rapid weight loss.21, 22, 23 As we analyzed the BMI status at a single time point, we cannot correlate weight gain or loss with renal stone formation in our study group.
Available information regarding the development of renal stones in children and adults has been based on the studies of clinically symptomatic cases.1, 11, 24, 25 Renal stones, typically remain unidentified until they cause symptoms.26 Long-term morbidity from kidney stones can be significant and includes hypertension, compromised renal function, pain and potentially the need for invasive intervention.1, 26 The development of renal stones in pediatric patients has been associated with many factors including dietary intake,1 metabolic disorders24, 25, 26, 27 and anatomic abnormalities.24 Other risk factors for kidney stone formation include dehydration,28 infection, immobilization,28 medication use adversely impacting urinary calcium resorption (loop diuretics),29 inflammatory disorders such as sarcoidosis and juvenile rheumatoid arthritis29 and bone density loss.1, 26 In children with cancer, both tumor lysis syndrome30 and treatment with glucocorticoids1 have also been implicated in stone formation.
The prevalence of symptomatic kidney stones has been increasing in the general population. A recent study of pediatric renal stones indicated a nearly fivefold increased incidence in symptomatic stones over the past 30 years. VanDervoort et al.25 reported that approximately 28% of patients were less than 1 year of age at presentation and 76% had at least one abnormality of 24-h urine collection—most commonly, hypocitraturia. Thus far, the reason for such a dramatic increase remains obscure, but prematurity, furosemide use in infancy and improved ascertainment may be contributing factors.29
We found a negative association between asymptomatic renal calcifications and BMD. In the subset of patients described herein, kidney stones may, in part, be caused by a high rate of bone turnover, as has been reported earlier in conditions associated with resorptive processes such as those induced by inflammatory mediators.26 Renal calcium wasting also begets BMD deficits in concert with hypercalciuria26, 31 and possibly renal stones, an association that we were unable to confirm. In the general population, children with higher BMD deposit retain more calcium, resulting in a less bone turnover and possibly associated with fewer renal calcifications. The significant negative relationship that we found between BMD and renal calcifications supports this concept.
Increased dietary intake of calcium has been shown to be associated with the propensity for stone development, but studies have not conclusively supported the benefits of dietary restriction of calcium in individuals at risk for urolithiasis. Among otherwise healthy adult males, dietary calcium was inversely associated with the risk for kidney stones.32 Some studies suggest that a higher calcium intake may reduce the risk for renal stone formation. This surprising finding is likely related to hyperoxaluria resulting from inhibition of intestinal oxalate absorption by dietary calcium, which prevents formation of calcium oxalate stones.33 Higher dietary intake protects skeletal calcium deposits, and thus tempers the metabolic turnover of calcium, which in turn limits a renal clearance of blood calcium. Increased dietary intake of sodium is associated with an increased risk for urolithiasis. Urinary calcium excretion increases and urinary citrate excretion decreases from baseline when dietary sodium is high.34, 35 We failed to find an association between dietary calcium or sodium intake or the use of nutritional supplements and the development of kidney stones. However, as only a small subset (n=184) of the total cohort (n=424) had completed available food frequency questionnaires, ascertainment bias may have contributed to the lack of statistical significance.
Several other factors may have contributed to the formation of renal stones in this population of long-term survivors of ALL. Many of the individuals in this series reside in the southeast region of the United States (data not shown), which is often called as the ‘stone belt’ of the United States.36 Factors that have been postulated to contribute to the stone formation include the higher temperatures, higher humidity with resultant mild dehydration and higher dietary sodium intake in this region.36 It can be noted that a high dietary sodium intake has been associated with a low bone density and stone formation.7 It is possible that we are detecting clinically silent stones earlier than the general population because of accession through BMD monitoring.31
There are certain limitations with our study. The prospective study (Bone-II trial) was not designed to assess the causative factors in the development of kidney stones, but rather to define the BMD status in ALL survivors. No information was gathered regarding a family history of kidney stones or familial hypercalciuria. QCT of the spine showed only a portion (50–67%) of total renal mass; hence, that information about stone formation in nonimaged portions of the kidneys is unknown. Although we found a treatment protocol regimen to be highly significant in the development of kidney stones, we were unable to adequately compare the causative roles of individual chemotherapeutic agents because of the complexities of each regimen and potential drug interactions in this small cohort of patients with kidney stones.
The presence of kidney stones in survivors of childhood ALL could herald the future deterioration of renal function and development of hypertension. Long-term follow-up imaging or urine analysis may be warranted in these patients to monitor for progressive morbidity.
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We thank Dr Cheng Cheng for his input regarding statistical analyses and critical editorial review and Sandra Gaither for manuscript preparation. This study was supported in part by Grants P30 CA-21765 and P01 CA-20180 from the National Institutes of Health, a Center of Excellence grant from the State of Tennessee, and the American Lebanese Syrian Associated Charities (ALSAC).
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Kaste, S., Thomas, N., Rai, S. et al. Asymptomatic kidney stones in long-term survivors of childhood acute lymphoblastic leukemia. Leukemia 23, 104–108 (2009) doi:10.1038/leu.2008.269
- asymptomatic kidney stones
- bone mineral density
- acute lymphoblastic leukemia
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