Introduction
Electrolyte disturbances are common in oncology patients, as many
chemotherapy agents are nephrotoxic.1 Platinum-based
chemotherapy is well known to be associated with electrolyte imbalances.2,3 One of its side effects is renal salt wasting
syndrome (RSWS), which is characterised by hyponatraemia, in conjunction
with polyuria and hypovolaemia.4–7
Patients with iGCTs are at risk of electrolyte disturbances, even before
the administration of nephrotoxic chemotherapy. This is because iGCTs
often arise in the suprasellar region, thereby potentially compressing
on the pituitary gland.8 This results in pituitary
dysfunction, such as central DI or central adrenal insufficiency (AI),
which can in turn cause electrolyte disturbances.9
Platinum-based chemotherapy agents are highly active against a variety
of solid tumours and are the main backbone of treatment for
iGCTs.10 We describe the first case series of
paediatric patients with central DI secondary to iGCT, all of whom
developed concomitant RSWS following the administration of carboplatin.
The combination of DI and RSWS and their respective effects on serum
sodium levels, urine output and fluid balance made the diagnosis elusive
and the management of these patients challenging.
Methods We performed a retrospective review of all paediatric patients (age
=/<19 years at diagnosis), with newly diagnosed iGCTs and
central DI managed at Hong Kong Children’s Hospital from July 2019 until
January 2021. Patients with the diagnosis of iGCT and DI were identified
using the Clinical Data Analysis and Reporting System. Using electronic
patient records, we reviewed the blood results, medications, and
clinical details of this cohort. Patients were treated according to the
Children’s Oncology Group ACNS1123 study; induction chemotherapy
consisted of 4 cycles of carboplatin (600mg/m2/day on Day 1) and
etoposide (150mg/m2/day on Day 1-3) for patients with germinomas, and
alternating cycles of carboplatin-etoposide, and ifosfamide-etoposide
for total of 6 cycles in patients with non-germinomatous germ cell
tumours (NGGCT).
Results A total of 14 patients were identified to have newly diagnosed iGCT
from July 2019 to January 2021, 10 had germinomas and 4 had NGGCTs.
Table 1 describes their clinical characteristics. In addition to central
DI, all patients also had anterior pituitary hormonal deficiencies,
including 13 who had central AI. Seven patients underwent tumour biopsy,
2 underwent tumour resection and 5 had no neurosurgical procedures
performed prior to chemotherapy. All patients were administered
carboplatin 600mg/m2/day for 1 day and etoposide
150mg/m2/day for 3 days as their first induction cycle. One patient had
adipsic DI and had a baseline serum sodium level of 160mmol/L; all
others had normal baseline serum sodium levels prior to chemotherapy.
All 14 patients were found to have hyponatraemia on routine bloods
following the first cycle of carboplatin despite significant diuresis of
more than 3L/m2/day and negative fluid balance. The nadir sodium level
ranged from 122 to 134mmol/L (mean 128mmol/L). Paired urine sodium
levels at times of hyponatremia were noted to be inappropriately high,
ranging from 40 to >250mmol/L (urine sample saved before
commencement of sodium supplementation). In anticipation of
chemotherapy-related emesis, all patients with AI were covered with
stress-dose hydrocortisone at 30mg/m2/day.
Ten patients required sodium supplementation (range:
1.6-11.8mmol/kg/day), of which 8 patients required intravenous
supplementation. In addition to hyponatraemia, all patients concurrently
had at least one of following: hypokalaemia, hypocalcaemia or
hypophosphataemia. Two patients developed hypotension and 3 required
fludrocortisone treatment.
All 14 patients in this series received a total of 36 subsequent cycles
of carboplatin following the first cycle of chemotherapy. Hyponatraemia
with serum sodium ranging 118-134mmol/L (median 132mmol/L) was noted
following 16 (44.4%) of these cycles. Paired urinary sodium was again
noted to be high during these episodes (97 to >250mmol/L).
All patients were noted to have normal long-term renal function.
DiscussionWe report the first case series of patients with iGCT and central DI,
complicated with concomitant RSWS following the administration of
carboplatin. Central DI is characterized by hypernatraemia and the
passing of large amounts of dilute urine, due to a lack of antidiuretic
hormone (ADH).11 The lack of ADH renders the kidneys
unable to concentrate urine and consequently, patients with DI
experience hypernatraemia, polyuria and hypovolaemia. The treatment of
central DI is by the administration of desmopressin, a synthetic form of
ADH.
RSWS similarly presents with excessive diuresis, but is characterized by
hyponatraemia, rather than hypernatraemia, as large amounts of
electrolytes are lost in the urine due to tubular damage, leading to a
high urinary sodium.4–6,12 RSWS is associated with
the depletion of extracellular volume and in severe cases, hypotension,
as large amounts of fluid are drawn out into the urine. It causes salt
loss and is therefore often associated with other electrolyte
disturbances such as hypokalaemia, hypophosphataemia and
hypocalcaemia.3,13 The treatment of RSWS is with
volume repletion and salt replacement; mineralocorticoids such as
fludrocortisone may also be effective.14
Platinum-based chemotherapy is well-known for causing electrolyte
balances including hyponatraemia, hypophosphataemia, hypocalcaemia and
hypokalaemia. RSWS is a rare reported side effect; however, the
mechanism is not well understood.4,6 Platinum-based
chemotherapy causes renal damage via accumulation in the proximal and
distal epithelial cells and the most likely site for damage in RSWS is
the proximal nephron, which is responsible for the majority of sodium
reabsorption.3,15
Carboplatin has previously been reported in a paediatric patient to
cause recurrent RSWS, but there was no concomitant
DI.4 In adults, cisplatin-induced renal salt wasting
has been previously documented.5 Similar to our case
series, concomitant central DI and RSWS was described in a paediatric
patient following the administration of platinum-based chemotherapy.
However, cisplatin, rather than carboplatin was the
culprit.7 The observation of RSWS after carboplatin in
children with iGCT and concurrent DI is not well reported in the
literature, probably due to the low incidence of iGCT among non-Asians.
The majority of patients in our series have central adrenal
insufficiency. As a routine practice in our centre, these patients are
prescribed stress dose hydrocortisone to prevent relative adrenal
insufficiency related to vomiting during chemotherapy. Therefore, renal
salt wasting secondary to relative adrenal insufficiency can be
excluded. All patients in our cohort developed salt wasting with
hyponatraemia to some extent following the first administration of
carboplatin. This occurred regardless of the type of iGCT, (i.e.,
germinoma or NGGCT), and regardless of any prior neurosurgical
procedure.
All patients were noted to have at least one of the following:
hypocalcaemia, hypophosphataemia and/or hypokalaemia, which are commonly
observed in RSWS. Furthermore, urine β2 microglobulin levels were also
high in some of our patients, confirming renal tubular damage. Some
patients required fludrocortisone for treatment, following which, the
amount of sodium loss through the tubules significantly decreased, as
evidenced by a drop in urinary sodium and stabilization of serum sodium
levels. Of note, some patients experienced only mild hyponatraemia,
which was detected on routine bloods. This indicates that RSWS may
present in a milder form that it is likely under-recognised. Although
RSWS did not always recur with each cycle of carboplatin, recurrence was
common (44.4%), and the ensuing hyponatraemia could still be severe.
The limitations of this case series are its retrospective nature and
small sample size. Though review of clinical notes and laboratory
results consistently showed that hyponatraemia in these patients
occurred following the first cycle of carboplatin, not all had extensive
workup performed, such as pro-BNP, urinary amino acids or β2
microglobulin, particularly if the hyponatraemia was mild and
self-resolved without further intervention. Nevertheless, this case
series illustrates that this group is vulnerable to electrolyte
disturbances following administration of carboplatin and underscores the
need for closer monitoring during treatment.
Conflict of interest: The authors have no conflicts of interest to
declare.
References
1. Ruggiero A, Ferrara P, Attinà G, Rizzo D, Riccardi R. Renal toxicity
and chemotherapy in children with cancer. Br J Clin Pharmacol .
2017;83(12):2605-2614. doi:10.1111/bcp.13388
2. English MW, Skinner R, Pearson AD, Price L, Wyllie R, Craft AW.
Dose-related nephrotoxicity of carboplatin in children. Br J
Cancer . 1999;81(2):336-341. doi:10.1038/sj.bjc.6690697
3. Oronsky B, Caroen S, Oronsky A, et al. Electrolyte disorders with
platinum-based chemotherapy: mechanisms, manifestations and management.Cancer Chemother Pharmacol . 2017;80(5):895-907.
doi:10.1007/s00280-017-3392-8
4. Tscherning C, Rubie H, Chancholle A, et al. Recurrent renal salt
wasting in a child treated with carboplatin and etoposide.Cancer . 1994;73(6):1761-1763.
doi:10.1002/1097-0142(19940315)73:6<1761::aid-cncr2820730635>3.0.co;2-#
5. Cao L, Joshi P, Sumoza D. Renal salt-wasting syndrome in a patient
with cisplatin-induced hyponatremia: case report. Am J Clin
Oncol . 2002;25(4):344-346. doi:10.1097/00000421-200208000-00005
6. Hamdi T, Latta S, Jallad B, Kheir F, Alhosaini MN, Patel A.
Cisplatin-induced renal salt wasting syndrome. South Med J .
2010;103(8):793-799. doi:10.1097/SMJ.0b013e3181e63682
7. Cortina G, Hansford JR, Duke T. Central Diabetes Insipidus and
Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging
Combination. Pediatr Blood Cancer . 2016;63(5):925-927.
doi:10.1002/pbc.25910
8. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors:
natural history and pathogenesis. J Neurosurg .
1985;63(2):155-167. doi:10.3171/jns.1985.63.2.0155
9. García García E, Gómez Gila AL, Merchante E, et al. Endocrine
manifestations of central nervous system germ cell tumors in children.Endocrinol Diabetes Nutr . 2020;67(8):540-544.
doi:10.1016/j.endinu.2019.11.012
10. Frazier AL, Stoneham S, Rodriguez-Galindo C, et al. Comparison of
carboplatin versus cisplatin in the treatment of paediatric extracranial
malignant germ cell tumours: A report of the Malignant Germ Cell
International Consortium. Eur J Cancer Oxf Engl 1990 .
2018;98:30-37. doi:10.1016/j.ejca.2018.03.004
11. Maghnie M, Cosi G, Genovese E, et al. Central Diabetes Insipidus in
Children and Young Adults. N Engl J Med . 2000;343(14):998-1007.
doi:10.1056/NEJM200010053431403
12. Inamori M, Inohara H, Horii A. Differential diagnosis of
hyponatremia induced by cisplatin-containing chemotherapy: syndrome of
inappropriate secretion of antidiuretic hormone (SIADH) or renal salt
wasting syndrome (RSWS). Acta Oto-Laryngol Case Rep .
2016;1(1):33-35. doi:10.1080/23772484.2016.1198231
13. Liamis G, Milionis H, Elisaf M. A review of drug-induced
hyponatremia. Am J Kidney Dis Off J Natl Kidney Found .
2008;52(1):144-153. doi:10.1053/j.ajkd.2008.03.004
14. Ghosh S. Cisplatin: The first metal based anticancer drug.Bioorganic Chem . 2019;88:102925. doi:10.1016/j.bioorg.2019.102925
15. Hanigan MH, Devarajan P. Cisplatin nephrotoxicity: molecular
mechanisms. Cancer Ther . 2003;1:47-61.