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Renal Dysfunction and Elevated Blood Pressure in Long-Term Childhood Cancer Survivors Sebastiaan L. Knijnenburg,*† Monique W. Jaspers,† Helena J. van der Pal,* Antoinette Y. Schouten-van Meeteren,* Antonia H. Bouts,‡ Jan A. Lieverst,* Arend Bo¨kenkamp,§ Caro C.E. Koning,| Foppe Oldenburger,| James C.H. Wilde,¶ Flora E. van Leeuwen,** Huib N. Caron,* and Leontien C. Kremer*

Summary Background and objectives Little is known about renal function and blood pressure (BP) in long-term childhood cancer survivors. This cross-sectional study evaluated prevalence of these outcomes and associated risk factors in long-term childhood cancer survivors at their first visit to a specialized outpatient clinic. Design, Setting, Participants, & Measurements Estimated GFR; percentages of patients with albuminuria, hypomagnesemia, and hypophosphatemia; and BP were assessed in 1442 survivors $5 years after diagnosis. Multivariable logistic regression analyses were used to estimate effect of chemotherapy, nephrectomy, and radiation therapy on the different outcomes. Results At a median age of 19.3 years (interquartile range, 15.6–24.5 years), 28.1% of all survivors had at least one renal adverse effect or elevated BP. The median time since cancer diagnosis was 12.1 years (interquartile range, 7.8–17.5 years). High BP and albuminuria were most prevalent, at 14.8% and 14.5%, respectively. Sixty-two survivors (4.5%) had an estimated GFR ,90 ml/min per 1.73 m2. Survivors who had undergone nephrectomy had the highest risk for diminished renal function (odds ratio, 8.6; 95% confidence interval [CI], 3.4–21.4). Combined radiation therapy and nephrectomy increased the odds of having elevated BP (odds ratio, 4.92; 95% CI, 2.63–9.19), as did male sex, higher body mass index, and longer time since cancer treatment. Conclusion Almost 30% of survivors had renal adverse effects or high BP. Therefore, monitoring of renal function in high-risk groups and BP in all survivors may help clinicians detect health problems at an early stage and initiate timely therapy to prevent additional damage. Clin J Am Soc Nephrol 7: 1416–1427, 2012. doi: 10.2215/CJN.09620911

Introduction Major improvements in the treatment of childhood malignancies have led to increased survival, with 5year survival rates reaching .80% in Europe (1). As survival has greatly improved, the effect of late adverse effects after treatment for childhood cancer has increased correspondingly (2–4). Renal toxicity is one of these late effects, manifesting as a decline in GFR, proteinuria, deterioration of tubular function, or hypertension. Chemotherapeutic agents with well documented early nephrotoxicity are ifosfamide, cisplatin, and carboplatin (5–10). Few studies have evaluated long-term risk and risk factors for renal toxicity, and these studies were performed only in selected groups of survivors with a maximum of 10 years’ follow-up (5,8,9). A mild reduction in GFR and proximal tubular damage were the most common toxicities 10 years after ifosfamide use (5). Tubular toxicity seemed to resolve during followup, but after 10 years GFR was still decreased in 13% of the survivors (8). Platinum nephrotoxicity was persistent during follow-up, but late deterioration of glomerular and tubular function did not occur (9). The studies 1416

Copyright © 2012 by the American Society of Nephrology

by both Skinner et al (8,9) and Oberlin et al (5) did not include patients treated with both ifosfamide and platinum derivates, although this combination is used in the treatment of certain tumors. Besides these agents, high-dose methotrexate and cyclophosphamide are known for their acute nephrotoxicity, but evidence regarding their long-term effects is lacking (11). Additionally, kidney surgery and radiation therapy may cause renal impairments, such as hyperfiltration or radiation nephropathy, characterized by hypertension, decline in GFR, and proteinuria (12– 14). The long-term effect of radiation nephropathy and hypertension have not been studied previously. In this cross-sectional study, we evaluate the prevalence of and possible risk factors for renal dysfunction and elevated BP in a large and complete cohort of childhood cancer survivors after a minimum of 5 years since cancer diagnosis.

*Department of Pediatric Oncology and ‡Department of Pediatric Nephrology, Academic Medical Center/Emma Children’s Hospital, Amsterdam, the Netherlands; † Department of Medical Informatics and |Department of Radiation Oncology, Academic Medical Center, Amsterdam, the Netherlands; § Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands; ¶ Department of Pediatric Surgery, Pediatric Surgical Center, Amsterdam, the Netherlands; and **Department of Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands Correspondence: Mr. Sebastiaan L. Knijnenburg, Department of Pediatric Oncology, Academic Medical Center, Amsterdam/ Emma Children’s Hospital, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Email: S.L.Knijnenburg@ amc.uva.nl

Materials and Methods Study Population In 1996, a long-term follow-up outpatient clinic (AMC/LATER) was established at the Emma Children’s www.cjasn.org Vol 7 September, 2012

Clin J Am Soc Nephrol 7: 1416–1427, September, 2012

Hospital/Academic Medical Center Amsterdam (EKZ/ AMC). All 5-year childhood cancer survivors were identified using the Childhood Cancer Registry of the EKZ/ AMC, which was established in 1966 and contains data on all patients treated in the EKZ/AMC regarding cancer diagnosis, treatment, and follow-up. All childhood cancer survivors who survived for at least 5 years were invited to this outpatient clinic to receive specialized screening and care based on guidelines tailored to their previous treatment modalities. Patients gave informed consent for data collection on late effects. A specially designed database was used to register symptomatic or asymptomatic late effects (15). Eligibility criteria for the current study were as follows: (1) diagnosis or treatment for a primary malignancy in the EKZ/AMC between January 1966 and January 2003; (2) age , 18 years at diagnosis; (3) survival $5 years after diagnosis; and (4) still alive at the start of the outpatient clinic (January 1996) or born since. Follow-Up and Data Collection All survivors who visited AMC/LATER received a full medical assessment according to the previously mentioned guidelines. Regarding renal function, the screening guidelines recommended measurement of serum creatinine, urinary dipsticks for proteinuria, and BP measurement for all survivors. Survivors treated with ifosfamide, cisplatin, carboplatin, high-dose cyclophosphamide ($1 g/m2 per course), or high-dose methotrexate ($1 g/m2 per course), radiation of the kidney region, total-body irradiation, or nephrectomy were screened according to an additional nephrotoxicity guideline. This guideline prescribed measurements of serum magnesium and phosphate. For this study we collected data on diagnosis, treatment, serum and urine analyses, and BP at survivors’ first visit to the AMC/LATER outpatient clinic, at least 5 years after diagnosis. Definition of Renal Dysfunction To assess glomerular function, we measured serum creatinine using an enzymatic, isotopic dilution mass spectrometry–traceable method (Roche P800, Roche Diagnostics, Almere, the Netherlands) and estimated the GFR using the Schwartz formula as adapted by Zappitelli for survivors up to 18 years of age (0.469 3 [height in cm/ serum creatinine in mg/dl]) (16). The Chronic Kidney Disease Epidemiology Collaboration formula was used for all adult survivors (17). We defined decreased GFR as an estimated GFR ,90 ml/min per 1.73 m2, as recommended by the Kidney Disease Outcomes Quality Initiative guidelines (18). Institutional reference values were used to determine abnormal levels of serum magnesium (males, ,0.75 mmol/L; females, ,0.71 mmol/L; ,15 years of age, ,0.68 mmol/L) and phosphate (adults, ,0.81 mmol/L; children, age-dependent). Additionally, survivors receiving a magnesium or phosphate supplement were regarded as having abnormal serum levels. Random daytime spot urine samples were collected during the visit to the outpatient clinic. Dipsticks for albuminuria were considered normal only if they were negative; high (150 mg/dl), moderate (75 mg/dl), and equivocal proteinuria (25 mg/dl) were all considered abnormal for

Renal Function after Childhood Cancer, Knijnenburg et al.

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the purpose of this study. In adult survivors, elevated BP was defined as having a systolic or diastolic BP .140 or 90 mmHg, respectively. In pediatric survivors, elevated BP was defined as having a systolic and/or diastolic BP that was in the 95th percentile or higher for sex, age, and height (19), using height z-scores for Dutch children (20). Survivors using antihypertensive medication were considered hypertensive. Statistical Analyses Descriptive statistics are presented as a mean 6 SD for normally distributed variables or median (range) for variables without a normal distribution. The differences between values of two independent groups were assessed by a t test or a chi-squared/Fisher exact test as appropriate. To model the effect of potential risk factors on the different outcome variables, we performed multivariable logistic regression analyses. On the basis existing evidence, we included the following predictor variables: cisplatin, carboplatin, and ifosfamide (continuous variables, cumulative doses); high-dose cyclophosphamide (yes/no) and high-dose methotrexate (yes/no); nephrectomy (yes/no); radiation therapy on the abdomen (yes/no); total-body irradiation (yes/no); and sex. We corrected all models for age at cancer diagnosis and duration of follow-up since cancer diagnosis. The hypertension model was also corrected for body mass index. All aforementioned predictors were entered at once into the regression model. Because recent data were available on the national prevalence of elevated BP, we also calculated prevalence ratios corrected for age group and sex by dividing the prevalence found in

Figure 1. | Composition of the study group. *None of the 136 survivors who died before they could visit the outpatient clinic died of renal disease. †Study group (n=1442) versus original cohort (n=1845) (78.2%).

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our study by the prevalence found in the healthy population (21). All computations were carried out in SPSS, version 16.0 (SPSS Inc., Chicago, IL).

Results Study Population, Follow-Up, and Data Collection Between January 1966 and January 2003, 1845 patients were treated for a malignant disease, survived at least 5 years since cancer diagnosis, and were alive at the start of AMC/LATER (January 1996) and thus were eligible for

inclusion. This study consists of 1442 survivors who visited the outpatient clinic (78.2%). Of these 1442 survivors, 896 had received potentially nephrotoxic treatment (62.1%). Figure 1 shows the cohort composition. Patient and treatment characteristics are listed in Tables 1 and 2. Prevalence of Therapy-Related Renal Dysfunction In total, 405 survivors (28.1%) sustained at least one renal adverse effect or elevated BP. Table 3 shows the prevalence

Table 1. Clinical characteristics of 1442 patients who were >5-year survivors of childhood cancer

Characteristic Male sex Tumor type bone tumors hepatic tumors germ cell tumors renal tumors soft tissue sarcoma neuroblastoma retinoblastoma CNS tumors leukemia lymphoma other tumors Age at diagnosis (yr)a 0–4 yr 5–9 yr 10–14 yr 15–18 yr Age at follow-up (yr)a 5–9 yr 10–14 yr 15–19 yr 20–24 yr 25–29 yr 30–34 yr 35–39 yr $40 yr Time since diagnosis (yr)a 5–10 yr 10–15 yr 15–20 yr 20–25 yr 25–30 yr .30 yr Treatment period 1960–1969 1970–1979 1980–1989 1990–1999 2000–2002 BMI at follow-upb 25 kg/m2 $25–29 kg/m2 $30 kg/m2 Total

Nephrotoxic Therapy

No Nephrotoxic Therapy

Overall

498 (55.6)

293 (53.7)

791 (54.9)

80 (8.9) 13 (1.5) 32 (3.6) 206 (23.0) 82 (9.2) 40 (4.5) 3 (0.3) 35 (3.9) 249 (27.8) 144 (16.1) 12 (1.3) 5.3 (2.9–9.8) 434 (48.4) 245 (27.3) 167 (18.6) 50 (5.6) 18.2 (13.7–21.4) 79 (8.8) 198 (22.1) 322 (35.9) 179 (20.0) 77 (8.6) 32 (3.6) 9 (1.0) 0 (0.0) 9.9 (7.4–14.8) 452 (50.4) 229 (25.6) 138 (15.4) 49 (5.5) 26 (2.9) 2 (0.2)

28 (5.1) 7 (1.3) 20 (3.7) 1 (0.2) 71 (13.0) 56 (10.3) 10 (1.8) 50 (9.2) 127 (23.3) 158 (28.9) 18 (3.3) 7.3 (3.1–11.8) 202 (37.0) 150 (27.5) 161 (29.5) 33 (39.8) 22.6 (18.8–29.3) 17 (3.1) 42 (7.7) 124 (22.7) 144 (26.4) 97 (17.8) 75 (13.7) 30 (5.5) 17 (3.1) 16.5 (10.2–21.0) 131 (24.0) 100 (18.3) 157 (28.8) 89 (16.3) 45 (8.2) 24 (4.4)

108 (7.5) 20 (1.4) 52 (3.6) 207 (14.4) 153 (10.6) 96 (6.7) 13 (0.9) 85 (5.9) 376 (26.1) 302 (20.9) 30 (2.1) 5.9 (2.9–10.9) 636 (44.1) 395 (27.4) 328 (22.7) 83 (5.8) 19.3 (15.6–24.5) 96 (6.7) 240 (16.6) 446 (30.9) 323 (22.4) 174 (12.1) 107 (7.4) 39 (2.7) 17 (1.2) 12.1 (7.8–17.5) 583 (40.5) 329 (22.8) 295 (20.5) 138 (9.6) 71 (4.9) 26 (1.8)

6 (0.7) 91 (10.2) 315 (35.2) 388 (43.3) 96 (10.7)

21 (3.8) 176 (32.2) 220 (40.3) 108 (19.8) 21 (3.8)

27 (1.9) 267 (18.5) 535 (37.1) 496 (34.4) 117 (8.1)

734 (85.7) 93 (10.9) 29 (3.4) 896 (62.1)

391 (75.3) 98 (18.9) 30 (5.8) 546 (37.9)

1125 (81.8) 191 (13.9) 59 (4.3) 1442 (100.0)

Unless otherwise noted, data are the number (percentage) of patients. CNS, central nervous system; BMI, body mass index. a Median (interquartile range). b BMI missing for 67 survivors (4.6%).



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Table 2. Nephrotoxic therapy received by childhood cancer survivors

Nephrotoxic Therapy

Median Cumulative Dose (Interquartile Range)

Patients, n (%)

Ifosfamide Cisplatin Carboplatin High-dose methotrexate High-dose cyclophosphamide Abdominal XRT Total-body XRT Nephrectomy (including partial)

30.0 (17.3–54.0) g/m2 320 (276–480) mg/m2 2.0 (1.2–2.8) g/m2 15.0 (6.0–36.0) g/m2 3.0 (3.0–6.8) g/m2 20.0 (15.0–30.0) Gy 7.5 (7.5–12.0) Gy

202 (14.0) 112 (7.8) 111 (7.7) 368 (25.5) 124 (8.6) 103 (7.1) 22 (1.5) 212 (14.7)

XRT, radiation therapy.

of the outcome measures at the first visit to AMC/LATER, at least 5 years after diagnosis. We could estimate the GFR for 1313 survivors (91%). Mean estimated GFR was 121619 ml/min per 1.73 m2. Sixty-two survivors (4.5%) had an estimated GFR ,90 ml/min per 1.73 m2. No survivors had ESRD. Only 534 (37%) survivors had both magnesium and phosphate measurements, including 408 patients (45.5%) who had received potentially nephrotoxic treatment and 126 patients (23.0%) who had not. Thirty-six of these 534 patients (8.8%) had hypomagnesemia, including two patients receiving supplementation. In relation to therapy, 17 of 75 (22%) patients treated with cisplatin and 9 of 44 (20%) nephrectomy patients had hypomagnesemia. The overall prevalence of hypophosphatemia was 3.0% (17 of 572 patients). In the ifosfamide subgroup of 202 patients, serum phosphate was available for 139 survivors. Six survivors (4%) had mild hypophosphatemia. No survivor required phosphate supplementation. Urine was tested for albuminuria in 1269 survivors (88%) and was positive in 184 (14.5%). Table 4 shows the distribution of the albuminuria dipstick results in relation to glomerular function. In 1328 of the 1442 survivors (92.1%), BP measurements were available. BP was elevated in 169 survivors (12.7%). An additional 18 (1.4%) were receiving antihypertensive medication and did not have a high BP measurement in the registry; 9 more did have hypertension despite antihypertensive medication (0.7%). High BP was less prevalent in the group of survivors treated with potentially nephrotoxic therapies than in the group treated without (12.3% versus 18.7%; P=0.002). The prevalence of high BP in our cohort was significantly increased for men age 30–39 years (prevalence ratio, 2.4; 95% confidence interval [CI], 1.5–3.8) and women age 20–29 years (prevalence ratio, 3.0; 95% CI, 1.2– 7.5) compared with the general population (Table 5) and seemed to be raised for almost all other subgroups. Risk Factors Associated with Therapy-Related Renal Dysfunction The results of the multivariable logistic regression analyses of the five outcomes of interest are presented in Tables 6 and 7. The first shows all therapies modeled as independent risk factors and the second shows therapy

modeled as a categorical risk factor. A higher cumulative ifosfamide dose (odds ratio [OR], 1.6 per additional 10 g/m2; 95% CI, 1.4–1.8), use of high-dose cyclophosphamide (OR, 7.1; 95% CI, 2.7–18.5), and having had a nephrectomy (OR, 8.6; 95% CI, 3.4–21.4) had the strongest association with a GFR ,90 ml/min per 1.73 m2. The combination of nephrectomy with nephrotoxic chemotherapy seemed particularly detrimental (Table 7). Cumulative cisplatin dose (OR, 1.7 per additional 100 mg/m2; 95% CI, 1.3–2.1) and having had a nephrectomy (OR, 17.5; 95% CI, 4.6–65.8) were both significant treatmentrelated risk factors for hypomagnesemia. No treatmentrelated risk factors could be identified for the occurrence of hypophosphatemia. Regression analysis on albuminuria showed a significant association only with cumulative ifosfamide dose when all treatments were evaluated as independent risk factors (OR, 1.3 per additional 10 g/m2; 95% CI, 1.2–1.5). Compared with no nephrotoxic therapy, the use of carboplatin was an additional significant risk factor for albuminuria (Table 6). Abdominal irradiation was the only significant treatmentrelated risk factor for an elevated BP (OR, 2.5; 95% CI, 1.4–4.5). A higher body mass index and male sex were other risk factors. When we looked at the mutually exclusive treatment groups, survivors treated with a nephrectomy and abdominal irradiation had the highest risk of developing a high BP (OR, 4.9; 95% CI, 2.6–9.2). The higher prevalence in the group treated with non-nephrotoxic therapies may be explained in part by a significantly higher mean body mass index in that group (22.7 kg/m 2 versus 20.9 kg/m 2 ; P,0.001). High-dose methotrexate and total-body irradiation were not significantly associated with any outcome measures.

Discussion

To our knowledge, this is the first study investigating the prevalence of and risk factors for long-term renal adverse effects and hypertension in a cohort of childhood cancer survivors who represent a broad spectrum of diagnoses and treatment modalities, including surgery, radiation therapy, and different types of chemotherapy. After a median of 12 years since cancer diagnosis and at a median age of 18 years, almost 30% of all survivors had impaired GFR or tubular function or an elevated BP. Only a few studies have investigated long-term renal effects in

4/524 (0.8) 29/190 (15.3) 6/108 (5.6) 9/100 (9.0) 5/349 (1.4) 9/119 (7.6) 23/206 (11.2) 14/102 (13.7) 1/22 (4.5) 4/524 (0.8) 11/72 (15.3) 2/51 (3.9) 1/21 (4.8) 9/75 (12.0) 2/248 (0.8) 0/19 (0.0) 8/117 (6.8) 1/28 (3.6) 3/13 (23.1) 9/65 (13.8) 3/11 (27.3) 7/114 (6.1) 2/20 (10.0) 62/1378 (4.5)

546 75 53 23 82 265 20 122 28 13 65 12 118 20 1442

Decreased GFRa

546 202 112 111 368 124 212 103 22

Patients (n)

3/126 (2.4) 1/49 (2.0) 7/31 (22.6) 0/9 (0.0) 7/48 (14.6) 1/136 (0.7) 0/8 (0.0) 6/22 (27.3) 0/8 (0.0) 0/4 (0.0) 3/14 (21.4) 0/4 (0.0) 8/62 (12.9) 0/13 (0.0) 36/534 (6.7)

3/126 (2.4) 8/123 (6.5) 17/75 (22.7) 2/50 (4.0) 7/188 (3.7) 5/58 (8.6) 9/44 (20.5) 3/25 (12.0) 0/14 (0.0)

Hypomagnesemiaa

5/144 (3.5) 2/58 (3.4) 2/29 (6.9) 0/11 (0.0) 3/53 (5.7) 2/130 (1.5) 0/9 (0.0) 1/23 (4.3) 1/10 (10.0) 0/4 (0.0) 0/15 (0.0) 0/6 (0.0) 1/65 (1.5) 0/15 (0.0) 17/572 (3.0)

5/144 (3.5) 6/139 (4.3) 4/71 (5.6) 2/58 (3.4) 2/188 (1.1) 1/64 (1.6) 1/48 (2.1) 1/32 (3.1) 0/14 (0.0)

Hypophosphatemiaa

49/477 (10.3) 21/69 (30.4) 8/44 (18.2) 7/20 (35.0) 12/73 (16.4) 31/239 (13.0) 1/16 (6.2) 13/102 (12.7) 5/26 (19.2) 5/13 (38.5) 12/60 (20.0) 3/9 (33.3) 14/102 (13.7) 3/19 (15.8) 184/1269 (14.5)

49/477 (10.3) 48/181 (26.5) 13/94 (13.8) 19/93 (20.4) 42/331 (12.7) 13/108 (12.0) 33/184 (17.9) 18/93 (19.4) 5/21 (23.8)

Albuminuriaa

96/513 (18.7) 8/68 (11.8) 5/49 (10.2) 1/19 (5.3) 8/71 (11.3) 17/238 (7.1) 1/18 (5.6) 13/114 (11.4) 5/26 (19.2) 2/12 (16.7) 27/61 (44.3) 1/11 (9.1) 9/109 (8.3) 3/19 (15.8) 196/1328 (14.8)

96/513 (18.7) 19/179 (10.6) 15/107 (14.0) 6/92 (6.5) 25/337 (7.4) 10/112 (8.9) 43/198 (21.7) 33/96 (34.4) 3/21 (14.3)

Elevated BPa

NCTx, nephrotoxic chemotherapy, defined as high-dose cyclophosphamide, high-dose methotrexate, cisplatin, carboplatin, or ifosfamide; XRT, abdominal radiation therapy and/or total-body irradiation. a Values are the number of survivors with a positive test result/total number of survivors tested (percentage). Survivors can belong to more than one therapy subgroup but have received only one therapy combination.

Therapy subgroup no nephrotoxic therapy ifosfamide cisplatin carboplatin high-dose methotrexate high-dose cyclophosphamide nephrectomy abdominal irradiation total-body irradiation Therapy combinations no nephrotoxic therapy ifosfamide only cisplatin only carboplatin only platinum agent + ifosfamide high-dose methotrexate only high-dose cyclophosphamide only nephrectomy only radiation therapy only nephrectomy + NCTx nephrectomy + XRT nephrectomy + NCTx + XRT other NCTx combinations radiation therapy + NCTx Total

Variable

Table 3. Prevalence of outcomes

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Table 4. Distribution of estimated GFR versus albuminuria

Albuminuria Dipstick Result eGFR (ml/min per 1.73 m2)

No Albuminuria

Albumin Level 25 mg/dl



Total

$90 60–89 30–59 15–29 ,15 Total

1038 27 2 0 0 1067

128 17 0 2 0 147

14 2 2 0 0 18

5 1 2 1 0 9

1185 47 6 3 0 1241

Values are the number of patients.

Table 5. Elevated BP prevalence ratios

Sex

Age Group (yr)

Patients with Observed Elevated BP, n/n (%)

Prevalence in General Population (%)

Prevalence Ratio (95% CI)

Male Female Male Female Male Female Male Female

0–19 0–19 20–29 20–29 30–39 30–39 40–49 40–49

32/390 (8.2) 22/302 (7.3) 65/267 (24.3) 32/213 (15.0) 28/74 (37.8) 10/65 (15.4) 5/10 (50.0) 2/7 (28.6)

2.0 1.0 17.0 5.0 16.0 10.0 34.0 31.0

4.10 (0.78–21.61) 7.29 (0.56–95.24) 1.44 (0.88–2.32) 3.00 (1.21–7.45)a 2.36 (1.49–3.76)a 1.54 (0.74–3.21) 1.47 (0.76–2.82) 0.92 (0.28–3.04)

Comparison of the age- and sex-specific elevated BP prevalences with prevalences in the normal population. CI, confidence interval. a P,0.05.

survivors of childhood cancer, focusing on the effects of ifosfamide and platinum derivates (5,8,9). However, studies of long-term renal adverse effects and hypertension that have evaluated other types of chemotherapy, radiation therapy, and surgery are lacking. The most important strength of this study is the long-term follow-up of a complete cohort of childhood cancer survivors and the large number of survivors included in the analysis. We were also able to thoroughly assess most patients, including for GFR, albuminuria, and BP. We used multivariable analysis that included precise information about the treatment-related risk factors. We found a diminished GFR in 4.5% of all survivors in our cohort, with a much higher prevalence in some subgroups. Notably, in the subgroup of 190 survivors treated with ifosfamide (median cumulative dose, 30 g/m2), 15.3% had a lowered GFR. Earlier studies on diminished GFR were performed in subgroups of survivors, and in most cases the investigators reported the findings after a short follow-up period. Reported prevalences vary widely, from 7.6% in 137 bone marrow transplant patients 2 years after transplantation (22) to 50% in 148 patients treated with ifosfamide after a median follow-up of 6 months (23). Differences in study population, treatment (doses), follow-up duration, and outcome definition may explain a large part of the variation in prevalence. In our multivariable analysis, a higher cumulative dose of ifosfamide, cisplatin, and carboplatin; administration of high-dose cyclophosphamide;

nephrectomy; and abdominal radiation therapy increased the risk for a diminished GFR. Additionally, a longer time since cancer diagnosis increased the risk of having a lower GFR, a finding recently confirmed by Oberlin et al. after 10 years of follow-up in 183 childhood cancer survivors treated with ifosfamide (5). It should, however, be noted that time since cancer diagnosis is strongly correlated with attained age and that the decline in eGFR is a physiologic consequence of senescence. In our study we used the (adapted) Schwartz- and the Chronic Kidney Disease Epidemiology Collaboration formula to calculate estimated GFR. It is well established that neither formula is as reliable as a gold standard clearance measurement, such as the 51Cr-EDTA clearance (24). However, clearance measurement is a cumbersome, invasive test. Furthermore, a recent meta-analysis showed that even a low estimated GFR is associated with all-cause mortality and cardiovascular mortality in the general population (25). Hypomagnesemia, caused by magnesium wasting due to proximal tubular toxicity, can cause fatigue, paresthesia, convulsions, tetany, and ultimately fatal cardiac arrhythmia (9,10,26). In our study, 22.7% of all survivors treated with cisplatin and 4.0% of those treated with carboplatin had hypomagnesemia at a median of 12.1 years since cancer diagnosis. At a median follow-up of 2 years, Stöhr et al. found prevalences of 2.3% and 3.0% in 148 patients with sarcoma treated with cisplatin or carboplatin, respectively

BMI ,25 kg/m2

Cumulative ifosfamide dose (per 10 g/m2) Cumulative cisplatin dose (per 100 mg/m2) Cumulative carboplatin dose (per 100 mg/m2) High-dose cyclophosphamide (no/yes) High-dose methotrexate (no/yes) Nephrectomy (no/yes) Total-body irradiation (no/yes) Abdominal irradiation (no/yes) Age at diagnosis (in yr) Time since diagnosis (per 5 yr) Male sex

Variable

–b

0.21

1.45 (0.72– 2.57)

–b

0.02

1.34 (1.04– 1.72)

–a

0.62

0.22

17.46 (4.63–65.79)

,0.001

8.56 (3.42– 21.42) 1.72 (0.20– 15.13)

1.05 (0.97– 1.13)

1.32 (0.43–4.05)

0.37

0.60 (0.19– 1.85)

0.37

–a

2.98 (0.92–9.63)

,0.001

7.08 (2.72– 18.45)

1.50 (0.62– 3.63)

,0.001

0.97 (0.87–1.07)

0.05

–b

0.97 (0.46–2.05)

1.55 (1.09–2.20)

1.05 (0.96–1.16)

0.30 (0.06–1.47)

–b

0.93

0.02

0.27

0.14

0.63

0.07

0.51

–b

0.36 (0.12–1.05)

0.97 (0.61–1.55)

1.10 (0.98–1.24)

1.16 (0.11–12.47)

–a

0.70 (0.06–8.26)

0.34 (0.07–1.76)

0.63 (0.08–5.22)

1.00 (0.92–1.07)

1.00 (0.77–1.30)

,0.001

1.03 (1.00– 1.07)

1.66 (1.34–2.05)

0.005

1.29 (1.08– 1.54)

1.02 (0.82–1.27)

,0.001

1.62 (1.44– 1.82)

OR for Hypophosphatemia (n = 17/572) (95% CI)

0.48

1.08 (0.87–1.34)

P Value

P Value

OR for Hypomagnesemia (n = 36/534) (95% CI)

OR for Decreased GFR (n = 62/ 1378) (95% CI)

Table 6. Multivariable logistic regression analysis on the five outcome variables

–b

0.06

0.90

0.11

0.91

–a

0.78

0.20

0.67

0.87

0.99

0.87

P Value

–b

0.80 (0.58– 1.11)

1.13 (0.98– 1.31)

1.02 (0.98– 1.06)

1.10 (0.57– 2.16)

1.70 (0.97– 2.96) 2.73 (0.95– 7.90)

1.37 (0.87– 2.14)

0.82 (0.43– 1.57)

1.02 (1.00– 1.04)

0.95 (0.81– 1.12)

1.34 (1.23– 1.46)

Albuminuria (n = 184/ 1269) (95% CI)

–b

0.18

0.09

0.41

0.77

0.06

0.06

0.17

0.55

0.13

0.54

,0.001

P Value

1.00 (reference)

2.09 (1.47– 2.98)

1.47 (1.28– 1.69)

1.07 (1.02– 1.11)

2.48 (1.36– 4.54)

1.55 (0.88– 2.71) 1.91 (0.52– 6.94)

0.66 (0.39– 1.11)

1.16 (0.56– 2.43)

0.98 (0.95– 1.02)

1.13 (0.98– 1.28)

1.05 (0.94– 1.18)

OR for Elevated BP (n = 196/1328) (95% CI)

,0.001

,0.001

0.002

0.003

0.33

0.13

0.12

0.69

0.35

0.09

0.36

P Value


,0.001

0.002

$30 kg/m2

All therapies were modeled as independent risk factors. BMI, body mass index; CI, confidence interval; OR, odds ratio. a Not included in regression model because of too few individuals. b Not included in regression model.

–b

$25–, 30 kg/m2

–b

–b

–b

–b

–b

–b

–b

1.94 (1.27– 2.96) 5.93 (3.18– 11.07) –b –b –b –b –b –b –b

Variable

–b

OR for Decreased GFR (n = 62/ 1378) (95% CI) Table 6.

(Continued)

P Value


P Value


P Value

Albuminuria (n = 184/ 1269) (95% CI)

P Value

OR for Elevated BP (n = 196/1328) (95% CI)

P Value



1423

(10). Prevalence of hypomagnesemia in their cisplatin group was much lower than in our study, although the median cumulative doses were similar. Hypomagnesemia may develop later in follow-up, as supported by the results of Skinner et al., who found a prevalence of 32% in cisplatin-treated patients and 17% in carboplatin-treated patients after 10 years of follow-up (9). Only long-term longitudinal studies can provide insight into the course of hypomagnesemia after platinum treatment in childhood cancer survivors. Renal phosphate loss can lead to development of hypophosphatemic rickets, osteomalacia, and renal Fanconi syndrome and has been associated with ifosfamide use (27). Because bone mineral density deficits already pose a large problem in childhood cancer survivors because of nonrenal factors, hypophosphatemia due to renal toxicity increases the risk for later bone mineral density and osteoporosis even more (28,29). In our study hypophosphatemia occurred in 3.0% of the overall group and in 4.3% of the ifosfamide subgroup. No treatment-specific risk factors could be identified. Because we were able to assess serum phosphate, the prevalence of renal phosphate wasting is probably higher because dietary intake can mask the renal phosphate loss. As other studies report different prevalences and risk factors, including age at diagnosis, time since cancer diagnosis, and cumulative ifosfamide dose, more research is needed on the causes and extent of renal phosphate wasting in order to identify high-risk survivors for surveillance and adequate treatment. A limitation of this study is that serum magnesium and phosphate levels were measured in only 46% of patients for whom such measurement was recommended by the screening guideline. This finding illustrates that implementation of the guideline is suboptimal and needs attention. In a post hoc missing-variables analysis, we could not detect possible sampling bias (e.g., differences in age or treatment exposure). Nevertheless, the conclusions regarding magnesium and phosphate should be interpreted with caution. Another limitation is that we assessed many predictor variables, even for the outcomes that were measured and present in relatively few survivors, thereby limiting the power to assess the predictors and leading to wide CIs. The prevalence of albuminuria (.25 mg/dl in a random spot urine sample) was 14.5%, much higher than in the normal population (0.7% for .20 mg/dl in early morning urine) (30). If we would use a cutoff of .75 mg/dl to compensate for the overestimation of proteinuria caused by using random daytime samples, the prevalence would still be three-fold higher (2.2%). Other studies found similar results: Mäkipernaa et al (31) and Mancini et al (32) both investigated albuminuria in survivors of Wilms tumors treated with nephrectomy and found prevalences of 16.7% and 11.6%, which is similar to our nephrectomy subgroup (17.9%). Oberlin et al (5) investigated proteinuria in 24-hour urine samples of survivors who received ifosfamide and found a prevalence of 11.3%. The high prevalence of albuminuria is clinically important in this relatively young population: Even though glomerular function is still normal in most survivors, this early onset of albuminuria may have a marked effect on glomerular

BMI ,25 kg/m2

Nephrectomy + NCTx + XRT Other NCTx combinations Radiation therapy + NCTx Age at diagnosis (in yr) Time since diagnosis (per 5 yr) Male sex

Radiation therapy only Nephrectomy + NCTx Nephrectomy + XRT

Platinum agent + ifosfamide High-dose methotrexate only High-dose cyclophosphamide only Nephrectomy only

Carboplatin only

Cisplatin only

No nephrotoxic therapy Ifosfamide only

Variable

–b

19.3 (5.1– 72.9) 4.5 (0.5– 41.7) 108.6 (18.1– 651.1) 22.0 (6.3– 77.1) 125.6 (20.8– 757.1) 17.7 (4.5– 70.3) 21.7 (3.6– 131.9) 1.07 (1.00– 1.14) 1.53 (1.17– 2.00) 1.12 (0.65– 1.93)

1.0 (reference) 38.4 (11.0– 134.4) 8.9 (1.5– 54.3) 15.2 (1.5– 155.5) 37.9 (10.0– 144.2) 2.0 (0.4– 11.8) –a

OR for Decreased GFR (n = 62/ 1378) (95% CI)

–a 14.80 (2.25– 97.12) –a

,0.001 ,0.001

–b

0.70

0.002

0.07

0.001

,0.001

,0.001

0.19

–b

1.10 (1.00– 1.20) 2.65 (1.66– 4.23) 0.91 (0.42– 1.96)

64.29 (8.49– 486.65) –a

121.85 (15.97– 929.97) –a

,0.001

–a

0.445

75.53 (9.75– 584.89) 2.17 (0.17– 27.61) –a

1.0 (reference) 5.53 (0.42– 72.94) 96.31 (12.68– 731.36) –a

,0.001

0.02

0.018

,0.001

P Value


–b

0.80

,0.001

0.05

–a

–b

1.11 (0.99– 1.25) 1.04 (0.64– 1.71) 0.32 (0.11– 0.96)

0.46 (0.05– 4.60) –a

–a

–a ,0.001

–a

2.12 (0.20– 22.39) 3.77 (0.36– 39.40) –a

1.71 (0.34– 8.76) 0.58 (0.10– 3.46) –a

1.0 (reference) 1.32 (0.22– 7.89) 1.21 (0.19– 7.69) –a

0.005

–a

–a

,0.001

–a

0.55

,0.001

–a

,0.001

0.20

P Value


–b

0.04

0.87

0.08

–a

0.51

–a

–a

–a

0.27

0.53

–a

0.55

0.52

–a

0.84

0.76

P Value

Table 7. Multivariable logistic regression analysis on the five outcome variables (using mutually exclusive treatment groups)

–b

1.55 (0.77– 3.09) 2.06 (0.74– 5.73) 6.67 (2.01– 22.14) 2.01 (0.98– 4.11) 5.35 (1.27– 22.63) 1.79 (0.91– 3.54) 1.76 (0.49– 6.29) 1.01 (0.97– 1.05) 1.16 (1.00– 1.35) 0.81 (0.58– 1.12)

1.0 (reference) 4.50 (2.44– 8.31) 2.20 (0.94– 5.14) 6.01 (2.21– 16.35) 2.12 (1.03– 4.36) 1.59 (0.94– 2.66) 0.58 (0.07– 4.47)

Albuminuria (n = 184/ 1269) (95% CI)

–b

0.19

0.05

0.56

0.39

0.09

0.02

0.06

0.002

0.17

0.22

0.60

0.08

0.04

,0.001

0.070

,0.001

P Value

1.00 (reference)

1.00 (0.49– 2.02) 1.02 (0.36– 2.89) 2.87 (0.58– 14.22) 4.92 (2.63– 9.19) 1.21 (0.15– 9.96) 0.73 (0.34– 1.59) 1.36 (0.37– 5.00) 1.07 (1.03– 1.11) 1.42 (1.24– 1.64) 2.16 (1.51– 3.09)

1.0 (reference) 0.80 (0.35– 1.81) 0.83 (0.30– 2.29) 0.46 (0.06– 3.63) 1.09 (0.48– 2.48) 0.57 (0.31– 1.02) 0.40 (0.05– 3.11)

OR for Elevated BP (n = 196/ 1328) (95% CI)

–a

,0.001

,0.001

0.001

0.65

0.43

0.86

,0.001

0.20

0.98

0.99

0.38

0.06

0.84

0.46

0.72

0.59

P Value


$ 25–, 30 kg/m2 $30 kg/m2

Therapies were modeled as mutually exclusive treatment groups and entered into the models as a categorical variable. BMI, body mass index; OR, odds ratio; CI, confidence interval; NCTx, nephrotoxic chemotherapy, defined as high-dose cyclophosphamide, high-dose methotrexate, cisplatin, carboplatin, and/or ifosfamide; XRT: abdominal radiation therapy and/or total-body irradiation. a Not included in regression model. b Not included in regression model because there were too few individuals with the predictor variable for the outcome in question.

0.005 ,0.001 1.83 (1.20–2.79) 5.51 (2.96–10.26) –b –b –b –b –b –b –b –b –b –b –b –b –b –b

Variable

–b –b

OR for Decreased GFR (n = 62/ 1378) (95% CI) Table 7.

(Continued)

P Value


P Value


P Value

Albuminuria (n = 184/ 1269) (95% CI)

P Value

OR for Elevated BP (n = 196/ 1328) (95% CI)

P Value



1425

function during the normal aging process. Additionally, a recent meta-analysis showed that albuminuria measured with dipsticks is an independent predictor for death in the general population (25). The prevalence of elevated BP of 14.8% in this young survivor group is alarmingly high. On average the risk is double that of the general population. However, BP was measured only during a single visit in our study group, while hypertension should be confirmed during two additional consecutive visits. So far, three other studies have assessed hypertension in a heterogeneous and complete cohort of childhood cancer survivors. We previously performed a nested case-control study in 1362 survivors using strict criteria for hypertension (high BP at three consecutive visits). Because of these strict criteria, only 44 cases were identified and only obesity was significantly associated with hypertension (33). Haddy et al. assessed 103 consecutive childhood cancer survivors at a longterm follow-up clinic after a median follow-up of 6 years and found a prevalence of 13.6% (34). In children and young adults, Pietilä et al. found 8 of 54 (14.8%) brain tumor survivors to be hypertensive at a median followup of 6 years (35). Cisplatin treatment, cranial irradiation, decreased GFR, and hypomagnesemia increased the risk for hypertension. Haddy et al. found Wilms tumor survivors to be at the highest risk (34). In our study, abdominal irradiation, especially in combination with a nephrectomy, was significantly associated with an elevated BP compared with no nephrotoxic therapies. However, the prevalence was highest in the group treated without potentially nephrotoxic therapies (18.7%). Future research should focus on investigating risk factors for developing hypertension in this subgroup, as well as on possible interventions. For example, survivors with hypertension or proteinuria who are at risk for progression of CKD may benefit from tight BP control targeting the renin-angiotensin system (36). In conclusion, this study described the prevalence and risk factors for long-term nephrotoxicity in a large and complete cohort of childhood cancer survivors. A high percentage of childhood cancer survivors have a diminished GFR, albuminuria, or elevated BP after a median of 12.1 years since initial diagnosis. This finding is clinically relevant because these outcome measures are associated with a higher risk for death in the general population (25,37). Future research should focus on the development of renal dysfunction over time, including renal function before the start of nephrotoxic treatment, on the clinical relevance of more sensitive markers to detect renal adverse effects (e.g., cystatin C for renal function and echocardiography to assess left ventricular hypertrophy in the context of hypertension), and on identification of interventions that prevent renal dysfunction during and long after treatment. Furthermore, research should focus on additional risk factors for hypertension (e.g., cranial irradiation), possibly incorporating radiation dosimetry data. For clinical practice, continuous monitoring of renal function is necessary in childhood cancer survivors treated with ifosfamide, cisplatin, carboplatin, high-dose cyclophosphamide, abdominal radiation therapy, or nephrectomy. BP should be monitored in all survivors.

1426

Clinical Journal of the American Society of Nephrology

Acknowledgments We would like to thank Stephanie Medlock for her critical review of the manuscript. This study was supported by the Dutch Cancer Society and the Foundation KiKa (Children Cancer-free). The sponsors of the study had no role in the study design and conduct, data collection, data management, data analysis, data interpretation, manuscript preparation, manuscript review, and manuscript approval. Preliminary findings of this work were presented as an oral presentation at the 11th International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer on June 11, 2010, in Williamsburg, Virginia. Disclosures None. References 1. Gatta G, Zigon G, Capocaccia R, Coebergh JW, Desandes E, Kaatsch P, Pastore G, Peris-Bonet R, Stiller CA; EUROCARE Working Group: Survival of European children and young adults with cancer diagnosed 1995-2002. Eur J Cancer 45: 992–1005, 2009 2. Geenen MM, Cardous-Ubbink MC, Kremer LC, van den Bos C, van der Pal HJ, Heinen RC, Jaspers MW, Koning CC, Oldenburger F, Langeveld NE, Hart AA, Bakker PJ, Caron HN, van Leeuwen FE: Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 297: 2705–2715, 2007 3. Oeffinger KC, Nathan PC, Kremer LC: Challenges after curative treatment for childhood cancer and long-term follow up of survivors. Pediatr Clin North Am 55: 251–273, 2008 4. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL; Childhood Cancer Survivor Study: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355: 1572–1582, 2006 5. Oberlin O, Fawaz O, Rey A, Niaudet P, Ridola V, Orbach D, Bergeron C, Defachelles AS, Gentet JC, Schmitt C, Rubie H, Munzer M, Plantaz D, Deville A, Minard V, Corradini N, Leverger G, de Vathaire F: Long-term evaluation of Ifosfamiderelated nephrotoxicity in children. J Clin Oncol 27: 5350–5355, 2009 6. Sto¨hr W, Paulides M, Bielack S, Ju¨rgens H, Treuner J, Rossi R, Langer T, Beck JD: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: A report from the Late Effects Surveillance System. Pediatr Blood Cancer 48: 447–452, 2007 7. Loebstein R, Atanackovic G, Bishai R, Wolpin J, Khattak S, Hashemi G, Gobrial M, Baruchel S, Ito S, Koren G: Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children. J Clin Pharmacol 39: 454–461, 1999 8. Skinner R, Parry A, Price L, Cole M, Craft AW, Pearson AD: Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose. Pediatr Blood Cancer 54: 983–989, 2010 9. Skinner R, Parry A, Price L, Cole M, Craft AW, Pearson AD: Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: Relevance of age and dose as risk factors. Eur J Cancer 45: 3213–3219, 2009 10. Sto¨hr W, Paulides M, Bielack S, Ju¨rgens H, Koscielniak E, Rossi R, Langer T, Beck JD: Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: A report from the late effects surveillance system. Pediatr Blood Cancer 48: 140–147, 2007 11. Hempel L, Misselwitz J, Fleck C, Kentouche K, Leder C, Appenroth D, Rost M, Zintl F: Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function. Med Pediatr Oncol 40: 348–354, 2003 12. Frisk P, Bratteby LE, Carlson K, Lo¨nnerholm G: Renal function after autologous bone marrow transplantation in children: A long-term prospective study. Bone Marrow Transplant 29: 129– 136, 2002 13. Breitz H: Clinical aspects of radiation nephropathy. Cancer Biother Radiopharm 19: 359–362, 2004

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Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, HohbachHohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Mo¨ller K, Wigger M, Peruzzi L, Mehls O, Schaefer F; ESCAPE Trial Group: Strict bloodpressure control and progression of renal failure in children. N Engl J Med 361: 1639–1650, 2009 37. World Health Organization: The World Health Report 2002: Reducing Risks, Promoting Healthy Life, Geneva, Switzerland, World Health Organization, 2002 Received: September 21, 2011 Accepted: June 15, 2012 Published online ahead of print. Publication date available at www. cjasn.org.