DISCUSSION
In this cross-sectional study, we found a high incidence of AKI in
children diagnosed with ALL, with 33% of subjects having at least one
AKI episode and the majority of AKI episodes noted at time of ALL
diagnosis. Most patients had mild AKI (KDIGO stage 1). Patients with
high-risk ALL had a higher prevalence of AKI compared to patients with
standard-risk ALL. This may have been due to greater likelihood of
leukemic infiltration in the kidneys at diagnosis, greater risk of tumor
lysis syndrome with initial chemotherapy, and/or the more toxic
chemotherapy regimens used in high-risk ALL which can be directly
nephrotoxic and increase risk for complications such as sepsis.
No patients were found to have CKD in this early follow-up study, a
better short-term outcome than that reported by studies from previous
decades, and perhaps a reflection of better supportive care now
available for children with ALL.4,6,7 Almost a third
of patients were noted to have hyperfiltration, however, and in other
populations this identifies increased risk for subsequent renal injury
and progressive CKD.33,34 The mean last recorded GFR
of the overall group was supraphysiologic, worrisome for potential
future renal complications. Additionally, 24% of patients who completed
a urinalysis were noted to have either proteinuria, albuminuria or both.
The low prevalence of CKD in our cohort is likely related to short
duration of follow-up time. In a recent Israeli study evaluating the
risk of ESRD in childhood cancer survivors with median follow-up time of
30 years, participants with history of malignancy in childhood had
adjusted HR of 3.2 of developing ESRD compared to participants without
no history of tumors/malignancy in childhood.35 In the
1990’s, Krawczuk-Rybak et al. found 5/37 (13.5%) childhood ALL
survivors had abnormal creatinine clearance when followed 3.9±3.7 years
after completion of chemotherapy6. Yetgin et al.
detected reduced GFR in 22/116 (19%) of pediatric ALL patients treated
mostly in the 1990’s who were assessed 18-96 months after completion of
chemotherapy4. Yetgin also performed urinalysis on all
subjects post chemotherapy and found no evidence of proteinuria in these
patients. However, 7/116 (6%) of patients had high urine
B2-Microglobulin, a marker of renal tubular proteinuria.
Hovi et al. reported GFR < 85ml/min/1.73m2in 6/60 (10%) of children with ALL followed 1-9 years after completion
of chemotherapy, but this study presents data from over 25 years
ago.7
The high prevalence of hyperfiltration, proteinuria, and/or albuminuria
noted in our cohort suggests that these children with ALL, treated since
2015, are at risk of developing CKD in the long term. This phenomenon is
well-described in patients with diabetic nephropathy. Glomerular
hyperfiltration commonly occurs early in diabetes secondary to increased
glomerular capillary pressure. Over time, sustained elevated GFR can
result in mesangial and podocyte injury and eventually glomerular
scarring leading to CKD progression and ESRD. 33,34,36The presence of albuminuria/proteinuria in patients with diabetes or CKD
has been strongly associated with increased risk of subsequent renal
function decline and measures that are successful at reducing
albuminuria/proteinuria have been shown to slow the renal disease
progression in these populations.36,37
Our study also found that children with ALL have a high prevalence of
HTN.
Almost half of our study patients (42%) fulfilled criteria for
outpatient diagnosis of HTN based on clinic BP measurements, termed
casual BP readings. Our findings are consistent with prior ALL
survivorship research, which has reported incidences of HTN in children
with ALL ranging from 5-65%, with variations likely affected by study
methodology and HTN definitions.5,10,15,20,21 The high
incidence of HTN is likely multifactorial, related to past or present
corticosteroid therapy, chemotherapy, prior AKI, and/or renal leukemic
infiltration. Prior studies have also proposed metabolic syndrome and
obesity as risk factors for developing chronic HTN in adults who survive
childhood leukemia.5,8,9,12-14
In the 21 patients who completed an ABPM study, we found that the
percentage of individuals with HTN was much higher, since 67% had an
abnormal high BP value. The majority of patients with abnormal ABPM had
abnormal nocturnal dipping pattern. Ociepa et al. is the only other
study to report ABPM results as a method to diagnose HTN in children
with ALL. This study detected a higher prevalence of childhood survivors
of ALL with HTN via ABPM (37%, 30/81), although it is perhaps
noteworthy that their study had a longer mean time of follow-up (60
months) compared to our study (36 months). Similar to our study, Ociepa
et al. found that childhood survivors of ALL were more likely to have
abnormal nocturnal dipping pattern (non-dippers, reverse-dippers, and
extreme-dippers) compared to control population. In healthy children
during sleep, a 10-20% physiologic decrease of BP is normally noted.
The lack of this physiologic decrease is termed non-dipping and BP
decrease in excess of 20% is considered extreme dipping. Both
non-dipping and extreme dipping have been associated with increased risk
of cardiovascular or cerebral ischemic/hemorrhagic events in
adults.38-42 In pediatric subjects with systemic lupus
erythematosus, non-dipping has been associated with endothelial
dysfunction and atherosclerotic changes.43 Similarly,
in adolescents with diabetes, non-dipping pattern has been associated
with LVH and increased carotid intimal media
thickness44,45. Further studies of these ABPM
abnormalities and outcomes in children with ALL will help understand the
prognostic implications and identify opportunities for useful
interventions in these children.
Limitations of this study include its single-center design with
relatively small sample size and short duration of follow-up. A
multi-center study with larger sample size could usefully confirm the
findings of this study and help determine distinct risk factors for
developing renal dysfunction and hypertension. It should also be noted
in this study that urine samples were collected at the time of clinic
appointment for convenience and were not first morning samples. Thus,
orthostatic proteinuria (a benign phenomenon occurring in up to 7% of
children and adolescents) could account for some of the
proteinuria/albuminuria noted in our findings46.
In conclusion, our study showed that, among children with ALL, there is
a high prevalence of HTN based on casual BP readings obtained in the
clinic setting and a high prevalence of impaired nocturnal dipping based
on ABPM. Both abnormalities are associated with increased risk of
cardiovascular disease and cerebrovascular events later in life. While
the prevalence of CKD is very low, children with ALL have a high
prevalence of hyperfiltration and/or proteinuria/albuminuria suggesting
increased risk of developing CKD in the future.
Interestingly, screening urinalysis has been removed from the Children’s
Oncology Group long-term follow-up guidelines for children who survive
ALL.47 The value of a screening urinalysis in
detection of early evidence of renal disease is highlighted by the
Prevention of Renal and Vascular End-Stage Disease (PREVEND) study
conducted of over 40,000 adult participants which indicated the
usefulness of albuminuria in early detection of CKD. PREVEND found that
of individuals who required renal replacement therapy after 9-years
follow-up, 58% had moderately increased albuminuria (≥20mg/L) on early
screening urine sample. Increased albuminuria was an independent risk
factor for progression to ESRD independent of GFR.48Based on our findings and other recent studies,3,7,20we propose that children with ALL should undergo regular (yearly) renal
function testing, urinalysis and BP measurements to screen for early
signs of renal abnormalities. Longer term and larger studies will be
needed to confirm our findings and define predictors for these adverse
outcomes in children with ALL.
As the long-term cure rate of ALL has improved to greater than 90%, the
challenge now extends to achieving the same cure rates with reduced
short-term and long-term toxicities for these children. One treatment
modality which shows promise in this goal is immunologic therapy. There
have been several recent trials demonstrating the safety and efficacy of
antibody-based and T cell-based therapies for
ALL.49,50 Our findings demonstrate that current
conventional therapies for childhood ALL are accompanied by concerning
frequencies of early renal dysfunction and hypertension. The shift
towards targeted immunologic therapies may mitigate some of these
long-term renal consequences of conventional therapy and provide better
quality of life in survivors of childhood ALL.
Conflicts of Interest Statement: The authors have no conflicts
of interest
Acknowledgements: This work was supported by an intramural
grant from Nationwide Children’s Hospital