Abstract
We hypothesized an association between renal calculi and bone mineral density (BMD) deficits, shown in adults, exists in survivors of childhood ALL. Thus, we analyzed associations between quantitative computed tomography (QCT)-determined renal calcifications and clinical parameters (gender, race, age at diagnosis, age at time of QCT), BMD, treatment exposures, Tanner stage. We investigated associations between stone formation and nutritional intake, serum and urinary calcium and creatinine levels, and urinary calcium/creatinine ratio. Exact Chi-square test was used to compare categorical patient characteristics and Wilcoxon-Mann-Whitney test to compare continuous measurements. Of 424 participants, 218 (51.4%) were male; 371 (87.5%) were non-black. Most (n=270; 63.7%) were ≥ 3.5 years at ALL diagnosis. Mean (SD) and median (range) BMD Z-scores of the entire cohort was -0.4 (1.2) and -0.5 (-3.9 to 5.1), respectively. Nineteen (10 males; 10 Caucasians) had kidney stones (observed prevalence of 4.5 %; 19/424) with significant negative association between stone formation and body habitus (BMI, 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 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.
Keywords: asymptomatic kidney stones, bone mineral density, acute lymphoblastic leukemia
Introduction
Treatment of acute lymphoblastic leukemia (ALL) with multiagent chemotherapy including glucocorticoid therapy increases a patient's risk for both renal calcifications (1) and reduced BMD (2-4). Both of these conditions are associated with a high rate of bone turnover (5-9). 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;10-15). 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 there exists a correlation between renal calcifications, identified by quantitative computed tomography (QCT), and low BMD in survivors of childhood ALL.
Methods
From a large cohort of survivors of childhood ALL (n=424) enrolled on an ongoing IRB-approved interventional trial to improve BMD(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 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 study enrollment. All participants, parents, or guardians signed informed consent or assent as appropriate. The study was conducted in compliance with the Health Information Privacy and Accountability Act (HIPAA) of 1996.
QCT was performed for BMD assessment as previously described (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 (FFQ; Block `98 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 USDA Nutrient Database for Standard Reference.
Statistical Analysis
Patients were divided into two groups based on the presence or absence of kidney stones by the QCT scan. To maintain consistency of reporting with our prior ALL survivor studies of BMD, we divided the cohort into two groups depending on the age at time of diagnosis as < 3.5 years versus ≥ 3.5 years (4).
Exact Chi-square test was used to compare categorical patient characteristics (age groups, treatment, BMI groups, etc.) and the Wilcoxon-Mann-Whitney test was used to compare continuous measurements. Z-score of BMD was categorized as normal versus abnormal, using cut off value of -0.999. The study cohort was grouped as normal vs overweight vs obese using BMI percentile as delineated in age- and sex-specific growth charts provided by the Centers for Disease Control (threshold for participants under age 18 years: normal- BMI less than the 85th percentile, overweight- BMI between the 85th and 95th percentile, obese- BMI exceeding the 95th percentile; threshold for participants older than 18 years: normal- BMI less than 25, overweight: between 25 and 30, obese- over 30). The effect of ALL treatment was analyzed by leukemia risk groups (high risk vs 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 SAS (SAS Institute, Cary, NC 2003) and Cytel Studio 7 (Cytel, Cambridge, MA) for exact chi-square tests.
Table 1.
Summary of Post-Remission (Continuation) Therapy in Total Therapy Studies XI-XIII.
| Protocol | Era | Total patients enrolled | Preventive CNS Therapy | Continuation therapy* |
|---|---|---|---|---|
| Total XI | 1984-1988 | 358 | All patients triple IT for first year Cranial RT at 1 y post CR for Worse risk (18 Gy) and CNS disease at diagnosis (24 Gy) | 6-MP, MTX, PDN, VCR (39 lower-risk cases) cyclophosphamide+ etoposide, cytarabine + teniposide, 6-MP + MTX, PDN + VCR (the remaining patients) |
| Total XII | 1988-1991 | 188 | Similar to XI | Cytarabine, 6-MP, MTX, teniposide |
| Total XIII Low risk | 1991-1997 | 118 | IT chemotherapy only* | Asparaginase, DEX or PDN, 6-MP, MTX, VCR |
| Total XIII High risk | 1991-1997 | 191 | Similar to XI | Etoposide + Cyclophosphamide, 6-MP + MTX, MTX + cytarabine, etoposide + cytarabine, DEX + VCR |
18 Gy cranial radiation therapy received for very high-risk patients (e.g. leukemia involvement of cranial nerves at diagnosis).
Results
Of the 424 participants enrolled on the interventional trial (Table 2), 218 (51.4%) were male and 371 (87.5%) were non-black (Hispanics included). The median (range) of time since completion of front-line ALL therapy to the study time was 8.5 years (range, 4.6 - 19.1 years). The majority of patients (n=270; 63.7%) were 3.5 years of age or older at diagnosis of ALL. The mean (SD) and median (range) BMD Z-scores of the entire cohort (n=424) was -0.4 (1.2) and -0.5 (-3.9 to 5.1), respectively.
Table 2.
Patient characteristics by detection of kidney stone
| Kidney stones | ||||
|---|---|---|---|---|
| Factors | Overall (%) | Yes (%) | No (%) | P-Value |
| Age at Diagnosis | 0.47 | |||
| >= 3.5 | 270 (63.7) | 14 (73.7) | 256 (63.3) | |
| < 3.5 yr | 154 (36.3) | 5 (26.3) | 149 (36.7) | |
| Age at Study | 0.35 | |||
| 0 - 13 | 98 (23.1) | 4 (21.1) | 94 (23.2) | |
| 14 - 17 | 112 (26.4) | 5 (26.3) | 107 (26.4) | |
| 18 - 22 | 101 (23.8) | 2 (10.5) | 99 (24.4) | |
| >22 | 113 (26.7) | 8 (42.1) | 105 (25.9) | |
| Gender | 1.00 | |||
| Female | 206 (48.6) | 9 (47.4) | 197 (48.6) | |
| Male | 218 (51.4) | 10 (52.6) | 208 (51.4) | |
| BMI | 0.003 | |||
| Normal | 199 (46.9) | 16 (84.2) | 183 (45.2) | |
| Overweight | 95 (22.4) | 2 (10.5) | 93 (23.0) | |
| Obese | 130 (30.7) | 1 (5.3) | 129 (31.9) | |
| Race | 0.15 | |||
| Black | 53 (12.5) | 0 (0.0) | 53 (13.1) | |
| Other | 371 (87.5) | 19 (100.0) | 352 (86.9) | |
Nineteen (10 males; 10 Caucasians) of 424 survivors 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% (SD 8.4%) as shown in Figure 1. None of these 19 patients reported a prior history of kidney stones, nor did they report 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 mg/cc) and 163.2 mg/cc (90.4 - 192.3 mg/cc), respectively (p=0.037; Table 3). Age at diagnosis of leukemia or study, gender or race were not associated with the presence of kidney stones (Table 2).
Figure 1.
Curve indicating cumulative incidence of kidney stone in the study cohort, estimated to be 24.7% (SD 8.4%) at 20 years from diagnosis.
Table 3.
Continuous measurements of factors that may contribute to kidney stone formation
| Kidney Stone (Yes) | Kidney Stone (No) | All | ||
|---|---|---|---|---|
| Factor | Median (Min-Max) | Median (Min-Max) | Median (Min-Max) | P-value |
| Age at Diagnosis (years) | 6.6 (2.0 - 17.4) | 4.4 (0.2 - 18.8 ) | 4.6 (0.2 - 18.8) | 0.12 |
| Age at Study (years) | 21.2 (10.2 - 34.8) | 17.0 (9.0 - 36.1 ) | 17.0 (9.0 - 36.1 ) | 0.29 |
| Height (cm) | 163.2 (138.2 - 182.3 ) | 162.9 (124.6 - 192.6) | 162.9 (124.6 - 192.6) | 0.75 |
| Weight (kg) | 57.5 (38.2 - 111.3) | 63.6 (28.7 - 172.6) | 63.3 (28.7 - 172.6) | 0.10 |
| BMI | 20.9 (17.6 - 38.3) | 24.1 (14.2 - 54.1 ) | 24.0 (14.2 - 54.1 ) | 0.016 |
| Dietary Calcium (mg/day) | 676.5 (313.8 - 1785.8) | 838.0 (129.4 - 4105.9) | 831.1 (129.4 - 4105.9) | 0.42 |
| Dietary Magnesium (mg/day) | 253.6 (89.5 - 426.0) | 263.2 (60.0 - 874.3) | 262.3 (60.0 - 874.3 ) | 0.37 |
| Dietary Sodium (mg/day) | 2104.4 (891.4 - 4922.7) | 2876.5 (570.7 - 9216.5) | 2812.4 (570.7 - 9216.5) | 0.099 |
| Serum Calcium/ Creatinine Ratio | 11.1 (8.1 - 25.3) | 12.7 (5.9 - 34.0 ) | 12.6 (5.9 - 34.0) | 0.51 |
| Serum BUN (mg/dL) | 12.0 (7.0 - 22.0) | 12.0 (4.0 - 24.0 ) | 12.0 (4.0 - 24.0) | 0.92 |
| Serum Calcium (mg/dL) | 9.4 (8.5 - 10.2) | 9.3 (8.3 - 10.2 ) | 9.3 (8.3 - 10.2) | 0.27 |
| Serum Creatinine (mg/dL) | 0.8 (0.4 - 1.1 ) | 0.7 (0.3 - 1.5 ) | 0.7 (0.3 - 1.5) | 0.41 |
| Serum Magnesium (mEq/L) | 1.7 (1.5 - 1.9 ) | 1.6 (1.3 - 2.0) | 1.7 (1.3 - 2.0) | 0.13 |
| Urinary Calcium / Creatinine Ratio | 0.1 (0.0 - 2.0 ) | 0.1 (0.0 - 3.9) | 0.1 (0.0 - 3.9) | 0.13 |
| Urinary Calcium (mg/dL) | 16.5 (3.0 - 47.8) | 13.1 (0.3 - 46.7) | 13.3 (0.3 - 47.8) | 0.30 |
| Urinary Creatinine (mg/dL) | 130.9 (3.5 - 262.1) | 138.3 (0.0 - 702.8) | 137.9 (0.0 - 702.8) | 0.55 |
| Urinary Sodium (mmol/L) | 177.0 (28.0 - 241.0) | 175.0 (13.0 - 334.0) | 175.0 (13.0 - 334.0) | 0.58 |
| Urinary Sodium /Urinary Creatinine Ratio | 1.3 (0.4 - 9.9) | 1.2 (0.1 - 47.7) | 1.2 (0.1 - 47.7) | 0.48 |
| BMD (mg/cc) | 163.2 (90.4 - 192.3 ) | 170.9 (58.5 - 329.7) | 170.4 (58.5 - 329.7) | 0.037 |
| Z-Score | -1.0 (-3.7 - 0.3) | -0.5 (-3.9 - 5.1) | -0.5 (-3.9 - 5.1) | 0.154 |
| Time from Diagnosis to Study (years) | 8.6 (7.1 - 19.9) | 10.9 (7.1 - 21.3 ) | 10.6 (7.1 - 21.3) | 0.57 |
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 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 dose of cranial radiation therapy and kidney stones (Table 4). Nor 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).
Table 4.
Treatment of ALL by detection of kidney stone
| kidney stones |
||||
|---|---|---|---|---|
| Factors | Overall (%) | Yes (%) | No (%) | P-Value |
| Therapeutic Protocol | 0.009 | |||
| Total 11 | 140 (33.0) | 7 (36.8) | 133 (32.8) | |
| Total 12 | 84 (19.8) | 0 (0.0) | 84 (20.7) | |
| Total 13 | 94 (22.2) | 2 (10.5) | 92 (22.7) | |
| Total 13B | 106 (25.0) | 10 (52.6) | 96 (23.7) | |
| Risk Group | 0.22 | |||
| High | 266 (62.7) | 9 (47.4) | 257 (63.5) | |
| Low | 158 (37.3) | 10 (52.6) | 148 (36.5) | |
| Protocol/Risk | 0.007 | |||
| 11H | 86 (20.3) | 3 (15.8) | 83 (20.5) | |
| 11L | 54 (12.7) | 4 (21.1) | 50 (12.3) | |
| 12H | 45 (10.6) | 0 (0.0) | 45 (11.1) | |
| 12L | 39 (9.2) | 0 (0.0) | 39 (9.6) | |
| 13BL | 53 (12.5) | 4 (21.1) | 49 (12.1) | |
| 13BH | 53 (12.5) | 6 (31.6) | 47 (11.6) | |
| 13H | 82 (19.3) | 0 (0.0) | 82 (20.2) | |
| 13L | 12 (2.8) | 2 (10.5) | 10 (2.5) | |
| Radiation Therapy | 0.40 | |||
| High | 35 (8.3) | 0 (0.0) | 35 (8.6) | |
| Low | 115 (27.1) | 5 (26.3) | 110 (27.2) | |
| None | 274 (64.6) | 14 (73.7) | 260 (64.2) | |
There was no association between kidney stones and 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. Though 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).
Table 5.
Nutrition intake questionnaire by detection of kidney stone
| kidney stones |
||||
|---|---|---|---|---|
| Factors | Overall (%) | Yes (%) | No (%) | P-Value |
| Dietary Calcium | 1.00 | |||
| Low | 127 (69.0) | 10 (71.4) | 117 (68.8) | |
| Normal | 57 (31.0) | 4 (28.6) | 53 (31.2) | |
| Dietary Magnesium | 0.78 | |||
| Low | 123 (66.8) | 10 (71.4) | 113 (66.5) | |
| Normal | 61 (33.2) | 4 (28.6) | 57 (33.5) | |
| Dietary Sodium | ||||
| Low | 29 (15.8) | 3 (21.4) | 26 (15.3) | 0.70 |
| Normal | 155 (84.2) | 11 (78.6) | 144 (84.7) | |
| Supplements | 0.48 | |||
| Yes | 185 (43.6) | 10 (52.6) | 175 (43.2) | |
| No | 239 (56.4) | 9 (47.4) | 230 (56.8) | |
Discussion
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% we previously reported 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 negative calcium balance (18).
The strongest risk factor for developing kidney stones in this cohort was having a normal BMI compared to an overweight/obese BMI. However, weight itself was not significantly related to the formation of kidney stones. Prior adult studies have reported an increased risk of stone formation in individuals with both increased weight (19;20) and with rapid weight loss (21-23). Since 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 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 disorders (24-27) 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 arthritis (29), and bone density loss (1;26). In children with cancer, both tumor lysis syndrome (30) and treatment with glucocorticoids (1) 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 five-fold increased incidence in symptomatic stones over the past 30 years. VanDervoort et al (25) reported that about 28% of patients were less than 1 year of age at presentation and 76% had at least one abnormality of 24-hour 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 previously reported in conditions associated with resorptive processes such as those induced by inflammatory mediators (26). Renal calcium wasting also begets BMD deficits in concert with hypercalciuria (26;31) and possibly renal stones, an association that we were unable to confirm. In the general population, children with higher BMD deposit and retain more calcium, resulting in less bone turnover and, possibly associated with fewer renal calcifications. The significant negative relationship 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 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 metabolic turnover of calcium, which in turn limits renal clearance of blood calcium. Increased dietary intake of sodium is associated with 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 subjects in this series reside in the southeast region of the United States (data not shown) which is often called the “stone belt” of the U.S. (36). Factors that have been postulated to contribute to stone formation include the higher temperatures, higher humidity with resultant mild dehydration, and higher dietary sodium intake in this region (36). As noted, a high dietary sodium intake has been associated with low bone density and stone formation (7). It is possible that we are detecting clinically silent stones earlier than the general population due to 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 BMD status in ALL survivors. No information regarding a family history of kidney stones or familial hypercalciuria was gathered. QCT of the spine showed only a portion (50-67%) of total renal mass, so that information about stone formation in non-imaged portions of the kidneys is unknown. Though we found treatment protocol regimen to be highly significant in the development of kidney stones, we were unable to adequately compare causative roles of individual chemotherapeutic agents due to 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 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.
Acknowledgements
We thank Dr. Cheng Cheng for his input regarding statistical analyses and critical editorial review and Sandra Gaither for manuscript preparation.
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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