Abstract
Objective
The objective of this study was to describe the burden of adverse kidney and hypertension outcomes in patients evaluated by pediatric nephrology in a multidisciplinary survivorship clinic.
Study design
Retrospective chart review of all patients followed up by nephrology in our multidisciplinary survivorship clinic from August 2013 to June 2021. Data included clinic blood pressure, longitudinal ambulatory blood pressure monitoring (ABPM), echocardiography, serum creatinine, and first-morning urine protein/creatinine ratios. For patients with multiple ABPMs, results of initial and most recent ABPMs were compared.
Results
Of 422 patients followed in the multidisciplinary cancer survivorship clinic, 130 were seen by nephrology. The median time after therapy completion to first nephrology visit was 8 years. The most common diagnoses were leukemia/myelodysplastic syndrome (27%), neuroblastoma (24%), and Wilms tumor (15%). At the last follow-up, 68% had impaired kidney function, 38% had a clinical diagnosis of hypertension, and 12% had proteinuria. There were 91 ABPMs performed in 55 (42%) patients. Patients with multiple ABPMs (n = 21) had statistically significant reductions in overall median blood pressure loads: systolic initial load 37% vs most recent 10% (P = .005) and diastolic load 36% vs 14% (P = .017). Patients with impaired kidney function were more likely to have received ifosfamide. Patients with hypertension were more likely to have received total body irradiation or allogeneic stem cell transplant.
Conclusions
History of leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor was frequent among survivors seen by nephrology. There was significant improvement in cardiovascular measures with increased recognition of hypertension and subsequent treatment.
With continued improvements in childhood cancer treatment, there is an increasing number of survivors who are prone to long-term adverse effects involving multiple organ systems.1 Survivors of childhood cancer are at especially increased risk of late kidney comorbidities including chronic kidney disease (CKD), proteinuria, and hypertension due to a variety of factors, including chemotherapy, radiation, nephrectomy, and prior acute kidney injury.2,3 Patients who have received hematopoietic stem cell transplant or antiangiogenesis agents may have additional risks from thrombotic microangiopathy and glomerulopathies.4
CKD decreases life expectancy primarily through increased cardiovascular morbidity,5 making early detection and management of CKD and hypertension even more critical in cancer survivors who may independently have increased risk of cardiovascular disease from anthracycline or cardiac radiation exposure.1 Ambulatory blood pressure monitoring (ABPM) is the gold standard for diagnosing hypertension and has the additional capability to detect nocturnal and masked hypertension.6 Prior studies utilizing ABPM have shown abnormal ABPM results in 10%–76% of childhood cancer survivors, particularly in Wilms tumor, acute lymphoblastic leukemia, neuroblastoma, and stem cell transplant recipients.7–11 However, there are no studies to date that report longitudinal ABPM outcomes in childhood cancer survivors. Proteinuria is an additional independent risk factor for CKD progression and cardiovascular morbidity, which may be mitigated with use of antiproteinuric agents.12 A Cochrane review including 52 studies of childhood cancer survivors who had received nephrotoxic chemotherapies found decreased estimated glomerular filtration rate (eGFR) in 0%–73.7%, proteinuria in 3.5%–84%, and elevated blood pressure (BP) in 0%–50% of patients.13
Our institution has a multidisciplinary survivorship clinic that allows survivors who need evaluation by nononcology specialists to complete all their subspecialty and survivorship care within the same clinic visit.14 We aimed to highlight the role of pediatric nephrology in survivorship care by describing the burden of adverse kidney outcomes in patients evaluated by pediatric nephrology in this multidisciplinary survivorship clinic and report longitudinal BP outcomes.
Methods
This was a retrospective medical record review of all patients followed up by pediatric nephrology in a multidisciplinary cancer survivorship clinic in a large tertiary children’s hospital from August 2013 to June 2021. In general, patients are followed by the general cancer survivorship program at our institution starting at least 5 years after diagnosis and 2 years from completion of therapy. If they require follow-up or screening with nononcology subspecialists, they are referred to the multidisciplinary cancer survivorship clinic. Approximately one-third of survivorship patients at our institution are seen in the multidisciplinary cancer survivorship clinic, which is held monthly and was first established in 2005. Endocrinology, cardiology, pulmonology, nephrology, nutrition, and psychology subspecialists come to the oncology clinic during the multidisciplinary cancer survivorship clinic to see patients. Nephrology first joined the multidisciplinary cancer survivorship clinic in August 2013. As part of the general survivorship program, all patients receive routine screening laboratory tests, including serum creatinine and urinalysis. Patients are referred to nephrology in the multidisciplinary cancer survivorship clinic if they were previously followed by nephrology, need CKD screening (eg, patients with a single kidney), have elevated BP noted in previous survivorship visits, have incidentally identified kidney imaging abnormalities, or if noted to have rising serum creatinine, proteinuria, or hematuria (Figure 1). If the pediatric nephrologists deem that patients will require ongoing nephrology care after aging out of the multidisciplinary cancer survivorship clinic (typically after college graduation or after starting a first job for adults who do not attend college), their care is typically transitioned to nephrologists from the University of Pennsylvania with expertise in onconephrology. This study was reviewed by the Children’s Hospital of Philadelphia Institutional Review Board and determined to meet criteria for exemption. Some of the patients in this study were included in another previously published manuscript by Hobbie et al on neuroblastoma survivors.15 The studies were not combined due to different follow-up periods, and the study by Hobbie et al did not include evaluation by pediatric nephrology.
Figure 1.
Pathway to nephrology in survivorship care. MDSC, multidisciplinary survivorship clinic; PFTs, pulmonary function tests; TBI, total body irradiation; UA, urinalysis; XRT, radiation.
Study Procedures
We abstracted data on demographics, cancer diagnosis and therapy, cancer outcomes, kidney complications, casual clinic BP, longitudinal ABPM results, antihypertensive therapy, echocardiography, serum creatinine measures, and first-morning urine protein/creatinine ratios into a REDCap database. Serum creatinine measures were obtained in the setting of routine clinical care. The majority of creatinine measures was completed at our institution. The serum creatinine assay at our institution is standardized/traceable to a gold standard method (Gas Chromatography Isotope Dilution Mass Spectrometry and National Institute of Standards and Technology SRM 914 creatinine standard reference material).
Clinic BP was collected from the BP in the vitals section of the nephrologist’s note. It was not possible to determine based on chart abstraction how every BP was obtained (eg, manual vs oscillometric) due to inconsistencies in documentation, but our usual practice pattern was to obtain an upper extremity oscillometric BP, with repeat manual BP by the nephrologist if there were concerns for abnormal oscillometric BP. BP percentiles were collected from the automated calculation of percentiles in the vital signs section of the nephrologist’s note, which reflected the contemporaneous National Heart, Lung, and Blood Institute guidelines on BP percentiles.6,16 ABPMs were obtained and repeated in a subset of patients based on the nephrologists’ clinical discretion.
Patients were followed up from the date of initial nephrology visit in the survivorship period until the date of their most recent nephrology visit. If patients were followed up by nephrology prior to entering the survivorship period, the date of their first oncology survivorship visit was used as the start date for their follow-up. Laboratory test results, echocardiography, and imaging were collected within 1 year of and most proximal to the initial and most recent nephrology survivorship clinic visits and at the time of ABPM completion. Cancer diagnoses for multidisciplinary survivorship patients who were not referred to nephrology were collected from clinic scheduling records.
Outcomes
Creatinine-based eGFR was calculated using the Chronic Kidney Disease in Children U25 equation, as cystatin C was not routinely collected in survivorship clinic.17 Patients were defined as having impaired kidney function if the most recent eGFR was <90 mL/min/1.73 m2. Proteinuria was defined as a first morning urine protein/creatinine ratio >0.2 mg/mg.
ABPM reports were categorized according to the following criteria: normotensive (clinic systolic and diastolic BP < 90th percentile, ABPM with mean ambulatory systolic and diastolic BP < 95th percentile, and BP loads <25%); white coat hypertension (systolic or diastolic clinic BP ≥ 95th percentile, ABPM with mean ambulatory systolic and diastolic BP < 95th percentile, and BP loads <25%); prehypertension (systolic or diastolic clinic BP ≥ 90th percentile or >120/80, ABPM with mean ambulatory systolic and diastolic BP < 95th percentile, and any BP load ≥25%); masked hypertension (systolic and diastolic clinic BP < 95th percentile, ABPM with mean systolic or diastolic BP > 95th percentile, and any BP load ≥25%); ambulatory hypertension (systolic or diastolic clinic BP > 95th percentile, ABPM with mean systolic or diastolic BP > 95th percentile, and any BP load 25%–50%); severe ambulatory hypertension (systolic or diastolic clinic BP > 95th percentile, ABPM with mean ambulatory systolic or diastolic BP > 95th percentile, and any BP load >50%); or unclassified if the ABPM did not fulfill criteria to be classified into one of the aforementioned categories.18
ABPM reference percentiles were based on the recommendations of the German Working Group on Pediatric Hypertension and the American Heart Association guidelines, revised after each update was published.6,18,19 Nocturnal nondipping was defined as an ABPM with <10% nocturnal dipping.
“Hypertension” was defined as clinical diagnosis of hypertension, receiving antihypertensive therapy, or patients with any ABPM result of ambulatory, severe, or masked hypertension. “No hypertension” was defined as no clinical diagnosis of hypertension and only normal or white coat hypertension findings on ABPM. We did not base the hypertension diagnosis on the clinic BP measures and percentiles alone, as this may have led to misclassification due to BP potentially being elevated in the setting of white coat hypertension or normalized in the setting of antihypertensive therapy. Patients were categorized as having elevated left ventricular mass index (LVMI) on echocardiogram if LVMI was >40 g/m2.7 in females or >45 g/m2.7 in males.20
Statistical Analyses
Patient characteristics were summarized overall and stratified by hypertension and impaired kidney function. Standard descriptive statistics were used. Continuous variables were compared using the Wilcoxon rank-sum test. Continuous variables were reported as median (IQR) unless otherwise specified. Categorical variables were compared using χ2 or Fisher exact tests. When comparing cancer diagnoses, leukemia/myelodysplastic syndrome and lymphoma were combined into one group, Wilms tumor and other kidney tumors were combined into one group, neuroblastoma was analyzed as its own group, and all other diagnoses were combined due to small numbers (n < 5) for many of the cancer diagnoses. Race and ethnicity prevalence were presented for descriptive purposes only and were not compared with statistical testing. For patients with multiple ABPMs, continuous results of initial and most recent ABPMs were compared using the Wilcoxon signed-rank test; hypothesis testing was not performed on categorical variables for longitudinal ABPM studies due to small sample size. A 2-sided significance level of <0.05 was used. We repeated all analyses excluding patients who received kidney transplants and did not find any meaningful difference in results (data available upon request). Therefore, the decision was made to include the transplanted patients in our analyses, particularly because they required kidney transplantation due to CKD that developed secondary to their oncologic treatment. Analyses were performed using SAS 9.4.
Results
Of 422 patients followed by the multidisciplinary survivorship clinic from August 2013 to June 2021, 130 patients (31%) were seen by nephrology, 28 of whom (21.5%) were followed by nephrology prior to being seen in the survivorship clinic (Table I). Patients were first evaluated by nephrology in the survivorship period a median of 8 years (range 2–18 years) after completion of therapy. The median eGFR at the time of presentation to nephrology was 85.5 mL/min/1.73 m2 (68.7–107.8 mL/min/1.73 m2). The most common cancer diagnoses were leukemia/myelodysplastic syndrome (26.9%), neuroblastoma (23.9%), and Wilms tumor (15.4%). Of the entire multidisciplinary survivorship clinic population, nephrology evaluated 25.5% of patients with leukemia/myelodysplastic syndrome/lymphoma, 40.8% of patients with neuroblastoma, and 71.0% of patients with Wilms/other kidney tumor (Table II; available at www.jpeds.com). Nearly all patients had received nephrotoxic chemotherapies. More than two-thirds of patients had received radiation (n = 92, 70.8%) and approximately one-half had received a stem cell transplant (n = 71, 54.6%).
Table I.
Demographics and cancer characteristics
| Total (n = 130) | Hypertension* (n = 66) | No hypertension (n = 64) | P-value† | Impaired kidney function‡ (n = 88) | Normal kidney function‡ (n = 42) | P value§ | |
|---|---|---|---|---|---|---|---|
| Months followed by nephrology in MDSC | 21 (0–48.0) | 21 (0–46.0) | 22 (0–51.5) | .98 | 23.5 (0–51.5) | 13.5 (0–44.0) | .42 |
| Followed by nephrology prior to MDSC | 28 (21.5%) | 18 (27.3%) | 10 (15.6%) | .11 | 20 (22.7%) | 8 (19.0%) | .63 |
| Age at cancer diagnosis, years | 3 (1.8–8.0) | 3 (1.5–8.0) | 3 (2.0–7.5) | .98 | 3 (1.8–8.5) | 3 (2.0–7.0) | .9 |
| Age at presentation to nephrology in MDSC, years | 15.4 (11.8–18.4) | 16.2 (12.2–18.4) | 15.0 (11.4–18.4) | .52 | 15.5 (11.4–18.6) | 15.3 (12.3–18.4) | .84 |
| eGFR at presentation, mL/min/1.73 m2 | 85.5 (68.7–107.8) | 86.6 (71.4–109.4) | 84.1 (67.6–103.0) | .29 | 81.3 (67.2–97.1) | 109.7 (103.0–122.7) | |
| Time off cancer therapy at time of presentation, years, median (range) | 8.0 (2–18) | 8 (3–18) | 8.0 (2–18) | .81 | 8.0 (2–18) | 7.5 (2–18) | .88 |
| Male | 76 (58.5%) | 40 (60.6%) | 36 (56.2%) | .61 | 62 (70.4%) | 14 (33.3%) | .0003 |
| Race | |||||||
| White or Caucasian | 97 (74.6%) | 48 (72.7%) | 49 (76.6%) | 65 (73.9%) | 32 (76.2%) | ||
| Asian or Asian American | 11 (8.5%) | 5 (7.6%) | 6 (9.4%) | 8 (9.1%) | 3 (7.1%) | ||
| Multiracial or other | 11 (8.5%) | 5 (7.6%) | 5 (7.6%) | 8 (9.1%) | 3 (7.1%) | ||
| Black or African American | 10 (7.7%) | 7 (10.6%) | 3 (4.7%) | 6 (6.8%) | 4 (9.5%) | ||
| Unknown/not reported | 1 (0.8%) | 0 (0.0%) | 1 (1.6%) | 1 (1.1%) | 0 (0.0%) | ||
| Ethnicity | |||||||
| Not Hispanic/Latino/Spanish | 119 (91.5%) | 61 (92.4%) | 58 (90.6%) | 79 (89.8%) | 40 (95.2%) | ||
| Hispanic/Latino/Spanish | 11 (8.5%) | 5 (7.6%) | 6 (9.4%) | 9 (10.2%) | 2 (4.8%) | ||
| Primary cancer diagnosis¶ | .08 | .20 | |||||
| Leukemia/MDS | 35 (26.9%) | 23 (34.8%) | 12 (18.8%) | 18 (20.4%) | 17 (40.5%) | ||
| Neuroblastoma | 31 (23.9%) | 18 (27.8%) | 13 (20.3%) | 24 (27.3%) | 7 (16.7%) | ||
| Wilms tumor | 20 (15.4%) | 10 (15.2%) | 10 (15.6%) | 15 (17.0%) | 5 (11.9%) | ||
| Nonmalignant SCT | 10 (7.7%) | 7 (10.6%) | 3 (4.7%) | 5 (5.7%) | 5 (11.9%) | ||
| Neurooncologic | 8 (6.2%) | 1 (1.5%) | 7 (10.9%) | 5 (5.7%) | 3 (7.1%) | ||
| Ewing sarcoma | 6 (4.6%) | 1 (1.5%) | 5 (10.9%) | 6 (6.8%) | 0 (0%) | ||
| Lymphoma | 5 (3.9%) | 2 (3.0%) | 3 (4.7%) | 4 (4.6%) | 1 (2.4%) | ||
| Rhabdomyosarcoma/Synovial sarcoma | 5 (3.9%) | 2 (3.0%) | 3 (4.7%) | 3 (3.4%) | 2 (4.8%) | ||
| Hepatoblastoma | 3 (2.3%) | 1 (1.5%) | 2 (3.1%) | 2 (2.3%) | 1 (2.4%) | ||
| Other kidney tumor | 2 (1.5%) | 0 (0.0%) | 2 (3.1%) | 1 (1.1%) | 1 (2.4%) | ||
| Osteosarcoma | 1 (0.8%) | 0 (0.0%) | 1 (1.6%) | 1 (1.1%) | 0 (0%) | ||
| Other | 4 (3.1%) | 1 (1.5%) | 3 (4.7%) | 4 (4.6%) | 0 (0%) | ||
| Received chemotherapy | 129 (99.2%) | 66 (100%) | 63 (98.4%) | 1.00 | 87 (98.9%) | 42 (100%) | 1.00 |
| Cyclophosphamide | 97 (74.6%) | 51 (77.3%) | 46 (71.9%) | .48 | 64 (72.7%) | 33 (78.6%) | .47 |
| Carboplatin | 39 (30.0%) | 19 (28.8%) | 20 (31.2%) | .76 | 30 (34.1%) | 9 (21.4%) | .14 |
| Cisplatin | 39 (30.0%) | 18 (28.3%) | 21 (32.8%) | .49 | 30 (34.1%) | 9 (21.4%) | .14 |
| Ifosfamide | 33 (25.4%) | 13 (19.7%) | 20 (31.2%) | .13 | 28 (31.8%) | 5 (11.9%) | .02 |
| Methotrexate | 32 (24.6%) | 17 (25.8%) | 15 (23.4%) | .76 | 21 (23.9%) | 11 (26.2%) | .78 |
| cis-retinoic Acid | 23 (17.7%) | 12 (18.2%) | 11 (17.2%) | .88 | 15 (17.0%) | 8 (19.0%) | .78 |
| Received radiation | 92 (70.8%) | 47 (71.2%) | 45 (70.3%) | .91 | 60 (68.2%) | 32 (76.2%) | .35 |
| Local/other | 44 (33.9%) | 17 (25.8%) | 27 (42.2%) | .05 | 27 (30.7%) | 17 (40.5%) | .27 |
| Total body | 42 (32.3%) | 27 (40.9%) | 15 (23.4%) | .03 | 26 (29.6%) | 16 (38.1%) | .33 |
| Flank | 19 (14.6%) | 10 (15.2%) | 9 (14.1%) | .86 | 13 (14.8%) | 6 (14.3%) | .94 |
| Abdominal | 18 (13.9%) | 9 (13.6%) | 9 (14.1%) | .94 | 14 (15.9%) | 4 (9.5%) | .42 |
| Received SCT | 71 (54.6%) | 41 (62.1%) | 30 (46.9%) | .08 | 45 (51.1%) | 26 (61.9%) | .25 |
| Allogeneic | 38 (29.2%) | 25 (37.9%) | 13 (20.3%) | .03 | 20 (22.7%) | 18 (42.9%) | .02 |
| Autologous | 35 (26.9%) | 16 (24.2%) | 19 (29.7%) | .48 | 27 (30.7%) | 8 (19.0%) | .17 |
| Outcomes | |||||||
| History of relapse | 21 (16.2%) | 13 (19.7%) | 8 (12.5%) | .26 | 12 (13.6%) | 9 (21.4%) | .25 |
| History of secondary malignancy | 11 (8.5%) | 6 (9.1%) | 5 (7.8%) | .79 | 9 (10.2%) | 2 (4.8%) | .5 |
MDS, myelodysplastic syndrome; MDSC, multidisciplinary survivorship clinic; SCT, stem cell transplant.
Data shown at median (IQR) or n (%) unless otherwise indicated.
Includes anyone who had a clinical diagnosis of hypertension or masked hypertension, ambulatory hypertension, or severe hypertension on ABPM.
Compares hypertension with no hypertension groups.
Patients were categorized as impaired kidney function if their most recent eGFR was <90 mL/min/1.73 m2 or normal kidney function if most recent eGFR was ≥90 mL/min/1.73 m2.
Compares impaired and normal kidney function groups.
For the χ2 analysis, Wilms tumor and other kidney tumors were combined into one group, leukemia/MDS and lymphoma were combined into one group, neuroblastoma was analyzed as its own group, and all other diagnoses were combined into one group.
A higher proportion of patients with hypertension had a history of total body irradiation (TBI) (40.9% vs 23.4%, P = .03) and allogeneic stem cell transplant (37.9% vs 20.3%, P = .03) compared with those without hypertension. There was no significant difference in median eGFR at time of presentation for patients with or without hypertension (86.6 [71.4–109.4] vs 84.1 [67.6–103.0] mL/min/1.73 m2, P = .29). Patients with impaired kidney function were more likely to be male (70.4% vs 33.3%, P = .0003) and have received ifosfamide (31.8% vs 11.9%, P = .02) compared with those with normal kidney function.
Kidney Complications of Therapy
At the last follow-up, two-thirds of patients had an eGFR <90 mL/min/1.73 m2 (n = 88, 67.7%), and 16 patients (12.3%) had proteinuria. More than one-half (n = 66, 50.7%) had either a clinical (n = 50, 38.5%) or ABPM diagnosis of hypertension. Nearly one-quarter (n = 31, 23.4%) had a history of nephrectomy. Twenty-six patients (20%) had a history of acute kidney injury, and fewer than 10% had a history of dialysis (n = 5, 3.8%) and kidney transplant (n = 3, 2.3%). Patients who received a kidney transplant were transplanted due to CKD that developed from complications of their therapy.
Longitudinal ABPM Outcomes
Ninety-one ABPMs were performed among 55 (42%) patients, and 21 patients had multiple ABPMs. The median time interval between initial and most recent ABPM was 27.5 months (range 6–68.6 months). At baseline (eg, the first ABPM for anyone who received an ABPM), there were high proportions of masked hypertension (n = 10, 18.2%), severe ambulatory hypertension (n = 16, 29.1%), and unclassified results (n = 10, 18.2%). The proportion of patients with severe ambulatory hypertension (initial 28.6% vs most recent 14.3%) and masked hypertension (initial 38.1% vs most recent 4.8%) decreased among patients with multiple ABPMs, whereas the proportion with normal BP, white coat hypertension, pre-hypertension, and unclassified results increased (Figure 2). Nocturnal nondipping was found in 23 (41.8%) patients. The majority of patients who had an ABPM had impaired kidney function (n = 43, 78.2%), a normal BMI (n = 37, 67.3%), and were not on antihypertensive therapy (n = 46, 83.6%) at the time of their initial ABPM. Five patients (9.1%) had an elevated LVMI, and 4 patients (7.3%) had proteinuria at baseline (Table III).
Figure 2.
Longitudinal blood pressure categorization on ABPM. a “Baseline ABPM” describes the first ABPM results among all patients who received an ABPM. “Initial ABPM” and “Most Recent ABPM” describe initial and most recent results of patients who had >1 ABPM.
Table III.
ABPM results*
| Baseline ABPM (n = 55) | Initial ABPM (n = 21) | Most recent ABPM (n = 21) | P value† | |
|---|---|---|---|---|
| Office SBP, mmHg | 122 (115–132) | 121 (116–128) | 127 (120–132) | .06 |
| Office DBP, mmHg | 72 (64–81) | 72 (66–82) | 70 (63–78) | .40 |
| Overall systolic load, % | 29.5 (11.7–60.5) | 37.3 (16.7–60.8) | 10.5 (3.6–20.3) | .005 |
| Overall diastolic load, % | 25.7 (16.9–50.0) | 35.6 (21.6–62.7) | 13.6 (7.9–23.5) | .02 |
| Wake systolic load, % | 25.6 (12.8–61.7) | 34.5 (19.2–69.4) | 6.8 (4.8–16.0) | .02 |
| Wake diastolic load, % | 25.8 (11.5 −50.0) | 35.9 (15.4–62.1) | 11.4 (7.7–17.6) | .009 |
| Asleep systolic load, % | 18.9 (7.7–55.0) | 33.3 (11.1–63.6) | 0 (0.0–16.0) | .005 |
| Asleep diastolic load, % | 28.6 (11.1–45.5) | 35.3 (11.1–55.0) | 15.8 (7.7–23.5) | .07 |
| Systolic dipping, % | 11.0 (8.0–14.8) | 10.3 (7.7–15.1) | 12.3 (8.3–18.1) | .63 |
| Diastolic dipping, % | 17.7 (13.1–25.2) | 16.9 (13.1–25.7) | 18.0 (13.8–23.6) | .60 |
| Nocturnal non-dippers | 23 (41.8%) | 10 (47.6%) | 6 (28.6%) | |
| BMI category | ||||
| Underweight | 6 (10.9%) | 3 (14.3%) | 3 (14.3%) | |
| Normal weight | 37 (67.3%) | 12 (57.1%) | 10 (47.6%) | |
| Overweight | 4 (7.3%) | 2 (9.5%) | 4 (19.0%) | |
| Obese | 8 (14.6%) | 4 (19.0%) | 2 (9.5%) | |
| Antihypertensives at time of ABPM‡ | ||||
| None | 46 (83.6%) | 18 (85.7%) | 7 (33.3%) | |
| Amlodipine | 2 (3.6%) | 0 (0.0%) | 2 (9.5%) | |
| Lisinopril | 3 (5.4%) | 1 (4.8%) | 5 (23.8%) | |
| Enalapril | 1 (1.8%) | 0 (0.0%) | 1 (4.7%) | |
| Losartan | 2 (3.6%) | 1 (4.8%) | 5 (23.8%) | |
| Doxazosin | 1 (1.8%) | 1 (4.8%) | 1 (4.8%) | |
| Other | 2 (3.6%) | 1 (4.8%) | 1 (4.8%) | |
| Urine protein/creatinine ratio | 0.07 (0.03–0.12) | 0.07 (0.03–0.12) | 0.06 (0.03–0.08) | .35 |
| Associated proteinuria | 4 (7.3%) | 1 (4.8%) | 2 (9.5%) | |
| Not assessed | 16 (29.1%) | 6 (28.6%) | 6 (28.6%) | |
| eGFR, mL/min/1.73 m2 | 73.8 (59.8–87.2) | 64.1 (57.0–82.6) | 71.6 (56.7–86.3) | .61 |
| eGFR < 90 mL/min/1.73 m2 | 43 (78.2%) | 17 (81.0%) | 14 (66.7%) | |
| Not assessed | 0 (0.0%) | 0 (0.0%) | 4 (19.0%) | |
| LVMI (g/m2.7) | 33 (28.0–38.3) | 34 (27.0–40.0) | 35 (28.0–40.0) | |
| Elevated LVMI§ | 5 (9.1%) | 3 (14.3%) | 1 (4.8%) | |
| Not assessed | 20 (36.4%) | 6 (28.6%) | 8 (38.1%) | |
| Shortening fraction (%) | 33 (31.0–36.0) | 34 (31.0–38.0) | 32 (31.0–36.0) | .39 |
| Not assessed | 18 (32.7%) | 6 (28.6%) | 8 (38.1%) | |
| Related medical conditions¶ | ||||
| CKD | 18 (32.7%) | 7 (33.3%) | 8 (38.1%) | |
| Renal transplant | 1 (1.8%) | 0 (0.0%) | 0 (0.0%) | |
| Diabetes mellitus | 1 (1.8%) | 1 (4.8%) | 1 (4.8%) | |
| Hypertension | 24 (43.6%) | 9 (42.9%) | 9 (42.9%) | |
| History of SCT | 29 (52.7%) | 10 (47.6%) | - | |
| History of radiation | 40 (72.7%) | 15 (71.4%) | - | |
| History of nephrectomy | 19 (34.6%) | 8 (38.1%) | - |
SCT, stem cell transplant.
Data shown at median (IQR) or n (%).
“Baseline ABPM” describes the first ABPM results among all patients who received an ABPM. “Initial ABPM” and “Most Recent ABPM” describe initial and most recent results of patients who had >1 ABPM.
Compares initial ABPM with most recent ABPM for people who completed multiple ABPMs. P values were not reported for categorical variables due to the small number of patients.
No patients were on nifedipine XR, clonidine, labetalol, or metoprolol.
Patients were considered to have elevated LVMI if LVMI was >40 g/m2.7 in females or >45 g/m2.7 in males.
No patients had other solid organ transplants, renovascular hypertension, or obstructive sleep apnea.
Among the 21 patients who had multiple ABPMs performed, there was statistically significant improvement from the initial to most recent ABPM in overall systolic load (median 37.3% vs 10.5%, P = .005), overall diastolic load (median 35.6% vs 13.6%, P = .017), wake systolic load (median 34.5% vs 6.8%, P = .019), wake diastolic load (median 35.9% vs 11.4%, P = .009), and sleep systolic load (median 33.3% vs 0%, P = .005). Among patients who had more than 1 ABPM, 11 of 18 (61.1%) who were not on any antihypertensives were started on an antihypertensive, 6 of 10 (60%) who were previously nocturnal nondippers had normal nocturnal dipping on their most recent ABPM, and the 3 patients who had elevated LVMI at initial ABPM had normal LVMI at the time of the most recent ABPM. One patient had an echocardiogram done only at the time of their most recent ABPM, which showed elevated LVMI. Two out of 11 (18.1%) patients who initially had normal nocturnal dipping had nocturnal nondipping on their most recent ABPM.
Discussion
We describe the prevalence of CKD, proteinuria, and hypertension in patients evaluated by pediatric nephrology in a multidisciplinary cancer survivorship program. In this high-risk population of childhood cancer survivors, leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor were the most common cancer diagnoses among patients referred to nephrology. Nearly all patients had received nephrotoxic chemotherapy, and the majority had received radiation therapy and had undergone stem cell transplantation. We observed that patients with hypertension were more likely to have received TBI and allogeneic stem cell transplant, while patients with impaired kidney function were more likely to be male and to have received ifosfamide. ABPMs obtained for clinical indications showed high rates of masked and severe ambulatory hypertension, which improved over time. Survivors of childhood cancer with these exposures in their oncologic history may be more likely to need routine nephrology evaluation in the survivorship period. This study highlights the role of nephrology in this novel multidisciplinary cancer survivorship clinic, and reports longitudinal ABPM data in childhood cancer survivors at a large, tertiary care referral center.
Impaired kidney function was present in two-thirds of the patients seen by nephrology. It should be acknowledged that the eGFR estimates in our study were calculated based on creatinine only, and the true prevalence of impaired kidney function among these patients may differ upon incorporation of serum cystatin C. Serum creatinine levels may not be fully reflective of a person’s measured glomerular filtration rate (GFR), as creatinine may be affected by muscle mass or medications which affect the tubular secretion of creatinine. Serum cystatin C is an additional marker of kidney function which is less influenced by muscle mass, and eGFR calculations incorporating both creatinine and cystatin C are the most representative of measured GFR.17 As many survivors may have low muscle mass related to cancer therapies, it is possible that the burden of impaired kidney function may be underestimated if only serum creatinine levels are monitored, creating missed opportunities for timely nephrology involvement.
The underlying etiology of the significantly higher proportion of male survivors among those with impaired kidney function at most recent follow-up is not immediately clear. One possible explanation may be that certain cancer diagnoses present in higher proportions in the impaired kidney function group (ie, neuroblastoma) may have an increased male predominance.21 Another possibility is that male adult patients may have a more rapid GFR decline, perhaps due to the renoprotective effect of estrogen, which is not well-understood.22 Analysis of children and adolescents with non-glomerular CKD in the Chronic Kidney Disease in Children study found that male sex was associated with significantly shorter time to a composite event of renal replacement therapy or 50% decline in iohexol-based GFR measurements after adjusting for baseline GFR,12 while a more recent analysis of the same cohort found that the increased association of male sex with eGFR decline in patients with non-glomerular disease was no longer significant after adjusting for age, baseline GFR, and proteinuria.23 We did not conduct multivariable analyses of risk factors as this study is descriptive in nature, and thus, our results reflect an unadjusted association.22
Approximately one-half of the patients evaluated by nephrology had hypertension. Leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor were the most common diagnoses among patients diagnosed with hypertension. Nearly one-half of the patients who were referred to nephrology had an ABPM, with more than 75% of baseline ABPMs being abnormal. Notably, almost one-fifth of patients (18.2%) had masked hypertension at baseline, and more than one-third (38.1%) of patients who had multiple ABPMs had masked hypertension on their initial ABPM. Of note, the masked hypertension diagnosis was based on the office BP most proximal to the ABPM being normal with hypertension found on ABPM, although there likely were prior elevated office BP readings that prompted the ABPM study. This further highlights the variability of office BP measurements and the benefit of more comprehensive nephrology evaluation with ABPM for cancer survivors with elevated office BPs. Other patient populations known to be at high risk of masked and nocturnal hypertension such as patients with CKD are recommended to have routine ABPM screening regardless of office BP.6
The high proportion of abnormal ABPM results may be related to high pretest probability, as these were “for-cause” ABPMs in patients referred to nephrology. However, our study findings are also consistent with other studies of ABPM performed in childhood acute lymphoblastic leukemia, stem cell transplant, Wilms tumor, and neuroblastoma survivors, in which ABPM was performed in eligible study participants rather than those referred to nephrology.7,8,10,11 Borchert-Morlins et al7 performed ABPM in 46 children who had received stem cell transplant at least 6 months prior and found that based on office BP measurements, only 3% met criteria for hypertension, while 24% of patients with completed ABPMs met criteria when using both office and ambulatory BP measurements; 19% of patients were found to have masked hypertension. Suominen et al11 found that in 18 neuroblastoma survivors who had undergone autologous stem cell transplant with a median of 20 years of follow-up, 10 (55%) had abnormal BP and 4 (22%) had masked hypertension. Chu et al8 found abnormal ambulatory BP in 22 of 29 (76%) childhood Wilms tumor survivors, with masked hypertension in 10 of 29 (34%).
Our study found an increased risk of clinical or ABPM-confirmed diagnosis of hypertension with history of TBI or allogeneic stem cell transplant. A study assessing ABPM in 10 survivors of childhood cancer with a history of carboplatin, ifosfamide, and cisplatin diagnosed ambulatory hypertension in 1 of 10 patients and no masked hypertension.9 Although the small sample size makes it challenging to generalize, this is consistent with our study, which did not identify any specific nephrotoxic chemotherapies associated with a clinical or ABPM diagnosis of hypertension. The mechanism of hypertension in childhood cancer survivors may be more related to the vascular injury associated with TBI and stem cell transplant rather than by direct nephrotoxic injury. This is further supported by the similarity in eGFR between patients with and without hypertension in our study.
There were improvements in multiple ABPM measures in the 21 patients who had repeat ABPM performed. Additionally, the 3 patients who had elevated LVMI at the time of their initial ABPM all had normalization of their LVMI at the time of subsequent ABPM, highlighting the cardiovascular benefit from detection and treatment of hypertension. As cardiovascular disease remains one of the most common late adverse effects across multiple cancer diagnoses and tends to increase over time in survivors of childhood cancer,1 screening for and treatment of hypertension as a modifiable risk factor for cardiovascular disease may confer significant long-term benefit. Two large longitudinal studies of childhood cancer survivors also found that hypertension was a significant predictor of late-onset advanced CKD,3,24 and adequate BP control remains a tenet of preventing progression of CKD.25 Our study supports the findings of prior published studies that indicate that survivors of childhood leukemia, neuroblastoma, and Wilms tumor, especially with history of stem cell transplant or TBI, are at increased risk of hypertension and should have a lower threshold for nephrology evaluation of elevated BP by ABPM.
These study findings should be interpreted in the context of the single-center, retrospective design and selected population of cancer survivors who were referred to nephrology. The burden of hypertension, impaired kidney function, and proteinuria may not be reflective of the general survivorship population. Rather, this study describes the beneficial role that nephrology provides in the routine care of survivors who may be at higher risk of late adverse kidney outcomes. The multidisciplinary clinic has benefited patients by increasing efficiency of care, decreasing missed time from school and work, and allowing subspecialists to communicate in real time during clinic, which may lead to improved care coordination, pediatric subspecialist assistance with transitions to adult subspecialty care, and multidisciplinary research collaborations.
The current Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers recommends nephrology referral for hematuria, proteinuria, abnormal renal ultrasound, decreased kidney function, and hypertension.26 However, they recommend screening for these complications in specific groups of cancer survivors based on diagnosis or treatment history. This is a notable difference from our general cancer survivorship program, which has incorporated yearly kidney function and urinalysis screening for all cancer survivors since formalizing its collaboration with nephrology. As nearly 80% of patients followed by nephrology in our multidisciplinary cancer survivorship clinic were not previously followed by nephrology and were likely referred based on abnormal screening, this suggests that there may be benefit to screening in a broader population of cancer survivors. Incorporation of pediatric nephrologists into the survivorship clinic infrastructure may facilitate prompt evaluation, preventive care, and smooth transitions to adult nephrology care for high-risk survivors.
Supplementary Material
Acknowledgments
We thank Jamie Jarrett, Joann Panus, and Kevin Meyers for providing historical context on the nephrology ABPM screening program. K.M. receives grants that are administered through the Institution: Travere and Reata; serves as a consultant for GSK, Alnylam, Paraxel; and additional funding is through the NIH (UO1, UM1, RO1 × 2).
This study was supported by The Children’s Hospital of Philadelphia Pediatric Center of Excellence in Nephrology and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number P50DK114786. B.L. is supported by DK125418. M.D. receives research funding from the National Institutes of Health, Patient Centered Outcomes Research Institute, and Mallinckrodt Pharmaceuticals; she is also on the Editorial Board for Kidney International Reports. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest.
Glossary
- ABPM
Ambulatory blood pressure monitoring
- BP
Blood pressure
- CKD
Chronic kidney disease
- eGFR
Estimated glomerular filtration rate
- GFR
Glomerular filtration rate
- LVMI
Left ventricular mass index
- TBI
Total body irradiation
Footnotes
Presented at Pediatric Academic Societies 2022 (poster) on April 24, 2022, Denver, Colorado.
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