Kidney Function after Treatment for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study

Significance Statement

Although associations of treatment for childhood cancer with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust. The authors evaluated the prevalence of and factors associated with increased odds for kidney impairment in a large cohort of adult survivors of childhood cancer diagnosed ≥10 years earlier. About 2.1% had stages 3–5 CKD. Factors associated with stages 3–5 CKD included treatment ever with a calcineurin inhibitor, increasing cumulative dose of certain chemotherapy agents, increasing volume of kidney irradiated to ≥5 or ≥10 Gy, nephrectomy (in patients who received radiation to the kidney) in models for higher–radiation therapy dose-volume exposures, and others. These findings may inform surveillance guidelines for survivors of childhood cancer and the design of future treatment regimens.

Abstract

Background

Survivors of childhood cancer may be at increased risk for treatment-related kidney dysfunction. Although associations with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust.

Methods

To define the prevalence of and risk factors for impaired kidney function among adult survivors of childhood cancer who had been diagnosed ≥10 years earlier, we evaluated kidney function (eGFR and proteinuria). We abstracted information from medical records about exposure to chemotherapeutic agents, surgery, and radiation treatment and evaluated the latter as the percentage of the total kidney volume treated with ≥5 Gy (V5), ≥10 Gy (V10), ≥15 Gy (V15), and ≥20 Gy (V20). We also used multivariable logistic regression models to assess demographic and clinical factors associated with impaired kidney function and Elastic Net to perform model selection for outcomes of kidney function.

Results

Of the 2753 survivors, 51.3% were men, and 82.5% were non-Hispanic White. Median age at diagnosis was 7.3 years (interquartile range [IQR], 3.3–13.2), and mean age was 31.4 years (IQR, 25.8–37.8) at evaluation. Time from diagnosis was 23.2 years (IQR, 17.6–29.7). Approximately 2.1% had stages 3–5 CKD. Older age at evaluation; grade ≥2 hypertension; increasing cumulative dose of ifosfamide, cisplatin, or carboplatin; treatment ever with a calcineurin inhibitor; and volume of kidney irradiated to ≥5 or ≥10 Gy increased the odds for stages 3–5 CKD. Nephrectomy was significantly associated with stages 3–5 CKD in models for V15 or V20.

Conclusions

We found that 2.1% of our cohort of childhood cancer survivors had stages 3–5 CKD. These data may inform screening guidelines and new protocol development.

Adult survivors of childhood cancer may be at increased risk for both acute chronic and late-onset treatment-related kidney dysfunction. Although associations with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust. Known risk factors include specific surgical procedures, radiation therapy, and specific chemotherapeutic exposures, most notably ifosfamide and platinating agents. Exposures having distinct mechanisms of injury affect unique populations, resulting in late effects studies limited to small populations with heterogeneous outcomes.¹ For example, unilateral or partial nephrectomy may produce slowly progressive damage (“hyperfiltration injury”),² whereas cisplatin,^3,4 carboplatin,⁴ and ifosfamide cause direct kidney toxicity.^5,6 Cyclophosphamide may damage the urothelium and manifest as acute or chronic hemorrhagic cystitis, but evidence of direct glomerular or tubular damage related to this agent is scant.⁷ Similarly, although high-dose methotrexate has been clearly associated with AKI, evidence for late toxicity is lacking.⁸ Conversely, abdominal irradiation has been associated with both acute and chronic kidney damage.^9,10 Finally, although pharmaceuticals, such as aminoglycoside antibiotics,^11–13 amphotericin B,^14,15 angiotensin-converting enzyme inhibitors (ACEis),^16,17 angiotensin receptor blockers (ARBs),^16,17 and calcineurin inhibitors,^18–21 have been associated with acute kidney dysfunction, their effect on long-term kidney function in childhood cancer survivors remains unknown.

More detailed data describing the relationships of cumulative pharmaceutical and chemotherapeutic agents and organ-specific radiation therapy dose and volume exposures to the prevalence of and risk factors for kidney damage in long-term adult survivors of childhood cancer are needed to inform both the treatment of future patients and the surveillance and management of current survivors. We undertook this study to determine the prevalence of impaired kidney function in a clinically well-characterized cohort of adult survivors of childhood cancer.

Methods

This analysis used the St. Jude Lifetime Cohort Study (SJLIFE). Eligibility included (1) treatment for a childhood malignancy at St. Jude Children’s Research Hospital (SJCRH), (2) survival ≥10 years from diagnosis, and (3) current age ≥18 years. The detailed methods for ascertainment, recruitment, and evaluation of the members of this cohort have been reported previously.^22–24 Data for 36 of the patients with Wilms tumor were included in a previous more detailed evaluation of kidney function after nephrectomy and either no or whole-abdomen irradiation.²⁵ All participants or their guardians provided written informed consent, and the study was approved by the SJCRH Institutional Review Board.

Renal Function Measurements

Creatinine was measured at SJCRH in plasma using the Roche/Hitachi Cobas C system (Roche Diagnostics, Indianapolis, IN) with Creatinine Plus version 2 reagent and an National Institute of Standards and Technology traceable standard. Creatinine results were reported to one decimal place until September 25, 2013. A morning urine sample was evaluated for protein using iChem VELOCITY Urine Chemistry Strips (Iris Diagnostics, Chatsworth, CA).

eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration estimating equations, and eGFR and proteinuria were categorized per the cause, GFR, and albuminuria criteria of the Kidney Disease International Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.²⁶ For these analyses, 1+ and 2+ proteinuria were combined, and 3+ and 4+ proteinuria were combined. CKD was staged using the Kidney Disease Outcomes Quality Initiative classification.²⁷ Patients who underwent kidney transplantation or initiated dialysis prior to their SJLIFE clinical evaluation were designated as stage 5 CKD on the date of their transplant or initiation of dialysis, and their subsequent laboratory data were evaluated as “missing.”

Exposure Definitions

Nephrotoxic surgical procedures included cystectomy and nephrectomy. Nephrotoxic chemotherapy included cisplatin, carboplatin, and/or ifosfamide. The definitions of nephrotoxic surgical procedures and radiation were on the basis of the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancer.²⁸

Exposure Quantification

The cumulative doses for 32 specific chemotherapeutic agents, including carboplatin, cisplatin, cyclophosphamide (intravenous or oral), ifosfamide, and methotrexate (intravenous, intramuscular, intrathecal, or oral), surgical procedures, and radiation treatment (fields, dose, and energy source) were abstracted from the medical records according to previously described methods.²⁴ In addition, cumulative exposures (milligrams per kilogram) of aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, and amikacin) and amphotericin B (total number of doses of both original [deoxycholate] and liposomal formulations) were similarly abstracted. Cumulative exposures to ACEi, ARB, and calcineurin inhibitors were not evaluated. High-dose methotrexate was defined as any single dose ≥1000 mg/m², and high-dose cyclophosphamide was defined as any single dose/course (5–7 consecutive days) ≥1000 mg/m.^2,7

Radiation fields potentially exposing the kidney included the following: extended mantle, hepatic, renal, right or left upper quadrant, partial or entire spleen, para-aortic, right or left flank/hemiabdomen, whole abdomen, inverted Y, total lymphoid irradiation, subtotal lymphoid irradiation, or total body irradiation. Kidney dosimetry was quantified by reconstructing each patient’s individual radiation treatment on a computed tomography–based phantom with an organ library for calculation of normal organ radiation doses (calculated in Eclipse; Varian Medical Systems, Milpitas, CA). For each patient’s reconstructed radiation treatment plan, the volume of radiation received by each kidney was estimated and reported as the percentages of the total kidney volume (per 1% of kidney volume) receiving specific radiation doses as follows: ≥5 Gy (V5), ≥10 Gy (V10), ≥15 Gy (V15), and ≥20 Gy (V20). This dose range allowed us to explore the effect of both higher therapeutic (20 Gy) and lower scatter (5 Gy) doses of radiation on subsequent kidney function.

Statistical Analyses

Descriptive statistics were used to summarize demographic and treatment variables for participants and nonparticipants; t test or chi-squared test was used to compare initial differences between these two groups.

Elastic Net is a regularization and variable selection method that simultaneously performs automatic variable selection and continuous shrinkage. In addition, it can select groups of correlated variables and is particularly useful in the case P (the number of covariates) >> n and when the covariates may be highly correlated. Simulations studies have shown that Elastic Net outperforms least absolute shrinkage and selection operator (lasso) in such settings.²⁹ The Elastic Net imposes two penalty parameters (α and λ) compared with lasso, which has only one penalty parameter. Given little a priori information about α, we fixed it over a fine grid from 0 to 1 in increments of 0.1 and estimated λ using a crossvalidation approach (to give minimum mean crossvalidated error). Thus, for each, a λ was obtained using the above approach, and the model corresponding to the pair α of (α, λ) that had the smallest Akaike Information Criteria was chosen as the final model. Because the estimates obtained from Elastic Net are biased toward zero, a two-step approach was used to obtain the debiased estimates of the risk factors. The first step is to perform model selection using Elastic Net as discussed above. The second step is to fit the multivariable logistic regression model with the variables selected using Elastic Net.³⁰ These analyses were conducted using SAS software (SAS 9.4; Cary, NC).

Results

Kidney function was evaluated in 2753 SJLIFE participants (Figure 1), including 1413 (51.3%) men and 2272 (82.5%) non-Hispanic Whites. Median age at diagnosis was 7.3 years (interquartile range [IQR], 3.3–13.2), median age at evaluation was 31.4 years (IQR, 25.8–37.8), and median time from diagnosis was 23.2 years (IQR, 17.6–29.7) (Table 1).

Figure 1.

Study recruitment flow diagram. SJLIFE, St. Jude Lifetime Cohort Study; N, number.

Table 1.

Demographic and anthropometric characteristics of participants

Variable and Category	SJLIFE Participants, n=2753		SJLIFE Nonparticipants, n=1668		P Value
	Frequency	Percentage	Frequency	Percentage
Sex
Men	1413	51.3	996	59.7	<0.001
Women	1340	48.7	672	40.3
Race/ethnicity
Non-Hispanic White	2272	82.5	1337	80.2	0.12
Non-Hispanic Black	384	14.0	258	15.5
Hispanic and other	97	3.5	73	4.4
Age at diagnosis, yr
0–4	1027	37.3	615	36.9	0.44
5–9	647	23.5	413	24.8
10–14	641	23.3	359	21.5
≥15	438	15.9	281	16.9
Mean (SD)	8.3 (5.6)		8.3 (5.6)		0.91a
Median (IQR)	7.3 (3.3–13.2)		7.4 (3.4–13.1)
Age at renal function evaluation, yr
18–29	1201	43.6
30–39	1036	37.6
40–49	439	16.0
≥50	77	2.8
Mean (SD)	32.4 (8.3)
Median (IQR)	31.4 (25.8–37.8)
Elapsed time from diagnosis to renal function evaluation, yr
Mean (SD)	24.1 (8.1)
Median (IQR)	23.2 (17.6–29.7)
Body mass index, kg/m2
Missing	45	1.6
≥13 to <25	985	35.8
≥25 to <30	764	27.8
≥30 to <35	503	18.3
≥35 to <40	247	9.0
≥40	209	7.6
Hypertension
Grade 0 or 1	2098	76.2
Grade 2 or 3	655	23.8
Diabetes
Grade 0 or 1	2516	91.4
Grade 2 or 3	237	8.6
Diagnosis
Acute lymphoblastic leukemia	934	33.9	487	29.2	<0.001
Acute myeloid leukemia	85	3.1	64	3.8
Central nervous system	259	9.4	165	9.9
Ewing sarcoma family of tumors	88	3.2	39	2.3
Hodgkin lymphoma	340	12.4	174	10.4
Neuroblastoma	122	4.4	78	4.7
Non-Hodgkin lymphoma	200	7.3	162	9.7
Osteosarcoma	108	3.9	53	3.2
Other	348	12.6	265	15.9
Rhabdomyosarcoma	91	3.3	64	3.8
Wilms tumor	178	6.5	117	7.0

^at test.

Participants were slightly more likely than nonparticipants to have been treated for acute lymphoblastic leukemia, Ewing sarcoma family of tumors, Hodgkin lymphoma, or osteosarcoma (Table 1) and to have received high-dose methotrexate (27.1% versus 24.0%; P=0.02) and/or ifosfamide (7.1% versus 5.5%; P=0.04) (Table 2). Nephrotoxic pharmaceutical exposures included aminoglycoside antibiotics (38.8%), amphotericin B (original or liposomal; 9.2%), current ACEi treatment (4.8%), current ARB treatment (0.9%), and treatment ever with a calcineurin inhibitor (2.1%) (Table 3). Six patients who had undergone nonkidney solid organ transplants (heart: three; liver: three) received calcineurin inhibitors after these transplants. Two of these (heart: one; liver: one) who underwent kidney transplants related to calcineurin nephrotoxicity were analyzed as receiving calcineurin inhibitors until the time of the kidney transplant. Among 439 participants who received radiation to at least a portion of one kidney, 62 (14.0%) had inadequate records for dose-volume calculations. Of the 377 who had records that allowed estimation of kidney dose-volume exposures, ten received >0 but <5 Gy to any portion of their kidney(s). V5, V10, V15, and V20 were calculated for the remaining patients (Table 3).

Table 2.

Chemotherapy exposures of participants

Variable and Category	SJLIFE Participants, n=2753		SJLIFE Nonparticipants, n=1668		P Value
	Frequency	Percentage	Frequency	Percentage
Nephrectomy
No	2549	92.6	1550	92.9	0.68
Yes	204	7.4	118	7.1
High-dose methotrexate
No	2006	72.9	1267	76.0	0.02
Yes	747	27.1	401	24.0
High-dose methotrexate, g/m2
Mean (SD)	21.4 (28.7)a		22.3 (28.9)b		0.22c
Median (IQR)	15.2 (4.1–21.7)		15.2 (5.1–21.9)
Ifosfamide
No	2558	92.9	1576	94.5	0.04
Yes	195	7.1	92	5.5
Ifosfamide, g/m2
Mean (SD)	42.5 (20.7)d		36.9 (21.7)e		0.002c
Median (IQR)	41.1 (25.8–57.0)		37.4 (18.0–48.6)
Cisplatin
No	2532	92.0	1545	92.6	0.43
Yes	221	8.0	123	7.4
Cisplatin, mg/m2
Mean (SD)	402.9 (196.6)f		441.9 (231.6)g		0.93c
Median (IQR)	397.6 (287.5–450.6)		400.0 (300.0–531.4)
Carboplatin
No	2618	95.1	1574	94.4	0.29
Yes	135	4.9	94	5.6
Carboplatin, mg/m2
Mean (SD)	3081.0 (2066.9)h		3020.3 (1897.5)i		0.35c
Median (IQR)	2783.3 (1633.8–3789.3)		2750.9 (1834.1–3664.6)
High-dose cyclophosphamide
Missing	14	0.5	52	3.1
No	1805	65.6	1101	66.0	0.13
Yes	934	33.9	515	30.9

Missing data are indicated.

^aTwo patients.

^bTwenty-two patients.

^ct test.

^dOne patient.

^eFour patients.

^fEight patients.

^gFour patients.

^hSeven patients

ⁱTwo patients.

Table 3.

Pharmaceutical and radiation therapy exposures of participants

Variable and Category	Frequency	Percentage
Current ACEi
No	2512	91.3
Yes	133	4.8
Missing	108	3.9
Current ARB
No	2626	95.4
Yes	26	0.9
Missing	101	3.7
Ever calcineurin inhibitor
No	2693	97.8
Yes	58	2.1
Missing	2	0.1
Aminoglycoside
No	1684	61.2
Yes	1069	38.8
Fungal infection
No	2499	90.8
Yes	254	9.2
Total doses (original and liposomal amphotericin B), n=248a
Mean (SD)	23.5 (26.1)
Median (IQR)	14.0 (7.0–31.0)
Doses of AmBisome, n=14a
Mean (SD)	34.0 (22.2)
Median (IQR)	33.5 (26.0–50.0)
Doses of Abelcet, n=12a
Mean (SD)	16.4 (16.7)
Median (IQR)	11.0 (4.5–25.0)
Doses of Abelcet/AmBisome, n=23a
Mean (SD)	29.3 (21.0)
Median (IQR)	31.0 (11.0–38.0)
Doses of amphotericin B (n=233)b
Mean (SD)	18.1 (16.9)
Median (IQR)	13.0 (6.0–24.0)
Renal radiation
No	2314	84.0
Yes	439	16.0
Percentage of total renal mass for V5, n=367 percentage >0c
Mean (SD)	67.5 (34.6)
Median (IQR)	78.3 (34.6–100.0)
Percentage of total renal mass for V10, n=359 percentage >0
Mean (SD)	58.6 (38.0)
Median (IQR)	53.4 (22.3–100.0)
Percentage of total renal mass for V15, n=249 percentage >0
Mean (SD)	30.7 (28.6)
Median (IQR)	22.2 (8.4–44.7)
Percentage of total renal mass for V20, n=197 percentage >0
Mean (SD)	20.3 (21.6)
Median (IQR)	13.0 (4.8–26.7)

Missing data are indicated.

^aSix patients.

^bSeven patients.

^cSixty-two patients.

The prevalence rates of the KDIGO 2012 eGFR and proteinuria categories are shown in Table 4. CKD was present in a total of 200 patients (7.4%), of which 143 had stage 1 or 2 CKD, and the remaining 57 had stages 3–5 CKD (Table 5, Supplemental Table 1). The mean eGFR for those with no CKD was 107.8 ml/min per 1.73 m² (±17.9 ml/min per 1.73 m²).

Table 4.

Distribution of KDIGO eGFR and proteinuria categories in the SJLIFE study population

eGFR, ml/min per 1.73.m2	KDIGO 2012 eGFR Category	KDIGO 2012 Proteinuria Category and Urine Dipstick Qualitative Protein, mg/dl
		Missing	A1	A2		A3
			None or Trace (0 and ≤30)	1+ (≥30 and <100)	2+ (≥100 and <300)	3+ (≥300 and <2000)	4+ (≥2000)
Missing		9	2	0	0	0	0
≥90	G1	46	2065a	97b	14c	1c	1c
≥60 and <90	G2	5	435a	24b	5c	1c	0c
≥45 and <60	G3a	0	25b	5c	5d	1d	0d
≥30 and <45	G3b	0	5c	2d	0d	0d	0d
≥15 and <30	G4	0	1d	3d	1d	0d	0d
<15	G5	0	0d	0d	0d	0d	0d

KDIGO 2012 indicates the KDIGO 2012 Clinical Practice Guideline. Estimated risk of concurrent complications and future outcomes of CKD are indicated.

^aLow risk (if no other markers of kidney disease, no CKD).

^bModerately increased risk.

^cHigh risk.

^dVery high risk.

Table 5.

Distribution of Kidney Disease Outcomes Quality Initiative CKD stage and eGFR by CKD stage

CKD Stage	eGFR, ml/min per 1.73.m2			% (N)
	eGFR	Mean (SD)	Median (IQR)
None	≥60, no kidney damage	107.8 (17.9)	109.1 (95.6–120.4)	92.6 (2500)
1	≥90	114.5 (15.0)	111.2 (103.0–124.5)	4.2 (113)
2	≥60 and <90	77.0 (8.7)	78.8 (68.9–84.5)	1.1 (30)
3	≥30 and <60	50.7 (6.0)	51.2 (46.4–56.4)	1.7 (43)
4	≥15 and <30	26.0 (2.8)	25.4 (25.2–28.6)	0.2 (5)
5	<15			0.2 (9)

Univariable associations between variables of interest, stages 3–5 CKD, and grades A2 and A3 proteinuria are shown in Supplemental Table 2. In multivariable models, the odds for stages 3–5 CKD were increased by older age at evaluation, current hypertension grade ≥2 (odds ratio [OR], 8.63); cumulative dose of ifosfamide [OR, 1.04; so, for a patient treated with a cumulative dose of 60 g/m², the OR for ifosfamide exposure alone would be (1.04)⁶⁰=10.52], cisplatin, and carboplatin; and treatment ever with a calcineurin inhibitor (OR, 4.60) in all models (example provided for V5 model). However, nephrectomy increased the odds only in the models for V15 (OR, 3.55) and V20 (OR, 3.74), models in which the percentage of kidney volume that was irradiated was no longer significant (Table 6).

Table 6.

Elastic Net multivariable analysis for stages 3–5 CKD versus normal or stages 1 and 2 CKD

Variable	Category	V5 Model			V10 Model			V15 Model			V20 Model
		OR	95% CI	P Value	OR	95% CI	P Value	OR	95% CI	P Value	OR	95% CI	P Value
Race/ethnicity	Other versus non-Hispanic White	1.69	0.85 to 3.36	0.14	1.72	0.86 to 3.41	0.12	1.81	0.91 to 3.60	0.09	1.83	0.92 to 3.64	0.09
Age at renal function evaluation	Per year	1.07	1.03 to 1.12	<0.001	1.08	1.04 to 1.12	<0.001	1.08	1.04 to 1.12	<0.001	1.08	1.04 to 1.13	<0.001
Hypertension (CTCAE)	Grade ≥2 versus grade <2	8.63	4.19 to 17.75	<0.001	8.72	4.25 to 17.92	<0.001	8.43	4.10 to 17.31	<0.001	8.39	4.08 to 17.25	<0.001
Nephrectomy	Yes versus no							3.55	1.47 to 8.56	0.005	3.74	1.56 to 8.94	0.003
Ifosfamide	Per 1000 mg/m2	1.04	1.02 to 1.05	<0.001	1.04	1.02 to 1.05	<0.001	1.04	1.02 to 1.05	<0.001	1.04	1.02 to 1.05	<0.001
cis-Platinum	Per 100 mg/m2	1.44	1.25 to 1.65	<0.001	1.44	1.25 to 1.65	<0.001	1.43	1.24 to 1.64	<0.001	1.43	1.24 to 1.64	<0.001
Carboplatinum	Per 100 mg/m2	1.03	1.00 to 1.06	0.03	1.03	1.00 to 1.06	0.04	1.03	1.00 to 1.06	0.04	1.03	1.00 to 1.06	0.04
CNI use ever	Yes versus no	4.60	1.48 to 14.30	0.008	4.61	1.42 to 14.92	<0.001	17.51	6.16 to 49.77	<0.001	17.59	6.18 to 50.05	<0.001
V5	Per 1%	1.02	1.01 to 1.02	<0.001
V10	Per 1%				1.02	1.01 to 1.02	<0.001
V15	Per 1%							1.01	1.00 to 1.02	0.19
V20	Per 1%										1.01	0.99 to 1.03	0.43

95% CI, 95% confidence interval; CTCAE, Common Terminology Criteria for Adverse Events; CNI, calcineurin inhibitor.

In models that evaluated the odds for category A2 or A3 proteinuria, other race/ethnicity (OR, 2.34), current hypertension grade ≥2 (OR, 2.62), nephrectomy (OR, 2.21), and number of doses of amphotericin B increased the odds in all models (example provided for V5 model). Higher percentages of the kidney exposed to V5, V10, V15, or V20 Gy radiation were not associated with increased odds for category A2 or A3 proteinuria (Table 7).

Table 7.

Elastic Net multivariable analysis for A2 or A3 versus A1 proteinuria

Variable	Category	V5 Model			V10 Model			V15 Model			V20 Model
		OR	95% CI	P Value	OR	95% CI	P Value	OR	95% CI	P Value	OR	95% CI	P Value
Sex	Men versus women	1.43	1.00 to 2.04	0.05	1.43	1.00 to 2.04	0.05	1.42	1.00 to 2.03	0.05	1.41	0.99 to 2.01	0.06
Race/ethnicity	Other versus non-Hispanic White	2.34	1.59 to 3.44	<0.001	2.34	1.59 to 3.44	<0.001	2.32	1.58 to 3.41	<0.001	2.31	1.57 to 3.39	<0.001
Body mass index, kg/m2	≥25 to <30 versus >13 to <25	0.65	0.39 to 1.09	0.10	0.65	0.39 to 1.09	0.10	0.65	0.39 to 1.08	0.10	0.65	0.39 to 1.09	0.10
Body mass index, kg/m2	≥30 versus >13 to <25	1.51	0.98 to 2.31	0.06	1.50	0.98 to 2.31	0.06	1.50	0.98 to 2.30	0.06	1.51	0.99 to 2.32	0.06
Hypertension (CTCAE)	Grade ≥2 versus <2	2.62	1.81 to 3.79	<0.001	2.62	1.81 to 3.79	<0.001	2.63	1.82 to 3.81	<0.001	2.61	1.80 to 3.77	<0.001
Diabetes mellitus (CTCAE)	Grade ≥2 versus <2	1.19	0.70 to 2.02	0.51	1.19	0.70 to 2.02	0.51	1.19	0.70 to 2.01	0.53	1.19	0.70 to 2.01	0.53
Nephrectomy	Yes versus no	2.21	1.25 to 3.90	0.006	2.21	1.25 to 3.89	0.006	2.37	1.38 to 4.07	0.002	2.36	1.37 to 4.05	0.002
Doses of Abelcet/AmBisome	Per dose	1.03	0.99 to 1.06	0.11	1.03	0.99 to 1.06	0.11	1.03	1.00 to 1.06	0.09	1.03	1.00 to 1.06	0.08
Doses of amphotericin B	Per dose	1.02	1.00 to 1.04	0.02	1.02	1.00 to 1.04	0.02	1.02	1.01 to 1.04	0.006	1.02	1.01 to 1.04	0.006
V5	Per 1%	1.00	1.00 to 1.01	0.26
V10	Per 1%				1.00	1.00 to 1.01	0.24
V15	Per 1%							1.01	1.00 to 1.02	0.17
V20	Per 1%										1.01	1.00 to 1.03	0.07

95% CI, 95% confidence interval; CTCAE, Common Terminology Criteria for Adverse Events.

Discussion

Childhood cancer survivors experience an increased risk of kidney injury from a variety of treatment modalities as well as antimicrobial and supportive care interventions. This study uniquely characterized the prevalence of and factors associated with increased odds for kidney damage in a large, prospectively assessed cohort of survivors in the context of detailed treatment (including kidney radiation dosimetry) and supportive care exposures. The prevalence rates of stages 3–5 CKD and proteinuria were low (<10%). Increasing age at evaluation; current hypertension grade ≥2; cumulative dose of ifosfamide, cisplatin, or carboplatin; treatment ever with a calcineurin inhibitor; and in some models, increasing volume and dose of kidney radiation increased the odds for kidney damage. Novel findings of this analysis include current hypertension grade ≥2 and treatment ever with a calcineurin inhibitor in models for stages 3–5 CKD and race/ethnicity, nephrectomy, current hypertension grade ≥2, and number of doses of amphotericin B in models for A2 or A3 proteinuria.

In this study, the overall prevalence of stages 3–5 CKD was 2.1%. Nephrectomy increased the odds for stages 3–5 CKD in models for the higher–radiation therapy dose-volume exposures. Interestingly, the percentage of the kidney volume that received ≥15 Gy (V15) or ≥20 Gy (V20) did not increase the odds for stages 3–5 CKD. This finding may relate to the intentional treatment of a smaller volume of kidney tissue to the higher doses (median 13.0% [V20] to 22.2% [V15]) compared with the volume of kidney tissue treated to the lower doses (median 53.4% [V10] to 78.3% [V5]).

No previous analysis of kidney function in adult survivors of childhood cancer has evaluated the effect of supportive care interventions. Aminoglycosides,^31,32 amphotericin B, and liposomal preparations of amphotericin B^14,15 have known acute kidney toxicity. Although we did not identify prior aminoglycoside therapy as a risk factor, each administered dose of amphotericin B or a liposomal preparation of amphotericin B increased the risk for grade A2 or A3 proteinuria. These results support careful monitoring of long-term survivors who have exposures to nephrotoxic supportive care agents, in addition to well-known nephrotoxic chemotherapeutic agents or lifestyle factors that increase their risk for grade A2 or A3 proteinuria.

Calcineurin inhibitors have been associated with impaired kidney function following allogeneic hematopoietic cell transplantation (allo-HCT), including with clinical findings similar to hemolytic uremic syndrome,¹⁸ and more recently, identified as a manifestation of transplant-associated thrombotic microangiopathy (TA-TMA)^19–21 The frequency of decreased kidney function among allo-HCT recipients with TA-TMA by the Jodele criteria is 31.8%–46.2%.^19,33 The relationship of calcineurin inhibitor exposure to kidney dysfunction among allo-HCT recipients is difficult to analyze as virtually all allo-HCT recipients receive post–allo-HCT treatment with a calcineurin inhibitor.³³ Others have reported TA-TMA in patients undergoing autologous hematopoietic cell transplantation for neuroblastoma, a setting in which there is no exposure to calcineurin inhibitors but significant pretransplantation exposure to cis-platinum (400 mg/m²) and conditioning with carboplatin, etoposide, and melphalan.^34–36 Treatment recommendations include calcineurin inhibitor dose modification or withdrawal, although adequate data supporting these recommendations are lacking.²⁰ Significantly, two participants in this cohort who underwent nonkidney solid organ transplantation subsequently required kidney transplantation due to calcineurin-related kidney toxicity.

We identified causes of stages 3–5 CKD that were unrelated to past cancer therapy, such as autosomal dominant polycystic kidney disease.³⁷ In addition, one eligible patient with Wilms tumor, aniridia, genitourinary malformations, and range of developmental delays syndrome³⁸ and one with Denys–Drash syndrome^39,40 had not undergone SJLFE clinical evaluation prior to the cutoff for this study. Both have undergone kidney transplantation.

There have been two prior reports regarding kidney function in 5-year survivors of childhood cancer. Decreased GFR (eGFR<90 ml/min per 1.73 m²) was reported in 4.5% of 1378 and proteinuria was reported in 14.5% of 1269 participants from Emma Children’s Hospital (ECH) in Amsterdam, The Netherlands.⁷ Decreased GFR (eGFR<90 ml/min per 1.73 m²) was reported in 34.3% of 763 and proteinuria was reported in 13.3% of 496 adult (>18 years of age at evaluation) participants from Erasmus University Medical Center.⁴¹ Neither study evaluated cumulative administered dose of chemotherapeutic agents, antibiotics, or antifungal pharmaceuticals, nor was radiation therapy evaluated using dose-volume methods. Proteinuria was documented in 5.7% of patients evaluated for SJLIFE, a lower percentage than was observed among those evaluated at ECH. However, in that study, samples with “equivocal” proteinuria (25 mg/dl) were considered positive, whereas in this study, those with “trace” proteinuria were considered negative. Among those evaluated at ECH, only 2.2% had “moderate” or “high” proteinuria.⁷ The finding that nephrectomy is a significant risk factor for proteinuria suggests that “hyperfiltration injury” may be a risk in this group of patients.²

Radiation therapy is known to impair kidney function.^42,43 Cassady⁴⁴ reviewed the available literature and reported that the threshold for functional impairment was 15.0 Gy and that kidney failure was the likely long-term outcome when the dose given to the entire volume of both kidneys exceeded 25.0–30.0 Gy. The Quantitative Analyses of Normal Tissue Effects in the Clinic review of published data regarding radiation therapy injury to the kidneys and the dose-volume relationship of such injury, supported by the American Society for Radiation Oncology and the American Association of Physicists in Medicine, suggested that V20 for a risk of <5% toxicity was <32% of the total kidney volume⁹ on the basis of calculation of the left/right ratio of activity of ^99mTc mercaptoacetyltriglycine or mertiatide.⁴⁵

This study has several important strengths, including large size; prolonged follow-up (median of 23.2 years); detailed exposure data, including radiation dosimetry and pharmaceutical use; and comprehensive clinical assessment. However, several limitations must be considered in interpreting the results. Although we evaluated the relationship of past treatment with nephrotoxic antimicrobial and antifungal agents, current treatment with ACEi and ARB, and past or current treatment with calcineurin inhibitors to stages 3–5 CKD, we did not examine the possible contributions of episodes of AKI or BK virus cystitis to subsequent chronic kidney dysfunction. On campus evaluations were completed by 62.3% of the 4421 eligible survivors, with nonparticipants more likely to be men and less likely to have been treated with ifosfamide or high-dose methotrexate. More participants than nonparticipants were treated for Ewing sarcoma family of tumors, osteosarcoma, and acute lymphoblastic leukemia. Thus, we cannot rule out the potential for selection bias. In addition, proteinuria was defined using a qualitative method rather than incorporating the spot urine protein-creatinine ratio.⁴⁶

In summary, stages 3–5 CKD is infrequent among adult survivors of childhood cancer. Risk factors for impaired kidney function after treatment for childhood cancer that were previously identified in qualitative studies were specified quantitatively in this study, including age at evaluation, treatment with ifosfamide or platinating agents, nephrectomy, and kidney irradiation. In addition, novel clinical features, such as current hypertension grade ≥2, and exposures, including to calcineurin inhibitors and to both unmodified and liposomal preparations of amphotericin B, were considered in this study. These findings should be considered in follow-up recommendations for survivors and may guide development of treatment regimens aiming to reduce nephrotoxic exposures.

Disclosures

M.M. Hudson reports employment with the American Society of Clinical Oncology (Journal of Clinical Oncology Associate Editor) and Wiley (Pediatric Blood and Cancer Editorial Board). J.Q. Lanctot reports ownership interest in Medtronic, PLC and Occidental Petroleum. D. Srivastava reports consultancy agreements as a scientific reviewer for applications submitted to Congressionally Directed Medical Research Programs for funding. All remaining authors have nothing to disclose.

Funding

This work was supported by National Cancer Institute grants CA 21765 and CA 195547 and the American Lebanese Syrian Associated Charities.

Supplemental Material

This article contains the following supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2020060849/-/DCSupplemental.

Supplemental Table 1. Participants with stages 3–5 CKD.

Supplemental Table 2. Univariable associations between stages 3–5 CKD; grades A2 and A3 proteinuria; and demographic, lifestyle, and treatment variables.