Nephrotoxicity of Cancer Treatment in Children

Roderick Skinner


Pediatr Health. 2010;4(5):519-538. 

In This Article

Clinical Management

Patients at risk of nephrotoxicity should be monitored regularly using a defined surveillance protocol, such as those published by the UK Children's Cancer Study Group (UKCCSG) or the Children's Oncology Group (COG) in the USA.[202,203] For example, the UKCCSG practice statement recommends that all patients at risk of nephrotoxicity should undergo regular blood pressure measurement, dipstick urinalysis for proteinuria and monitoring of growth. Hypertension should be investigated further (to exclude other unrelated causes) and treated if persistent. If proteinuria is positive (++ or greater), the urine protein:creatinine concentration ratio should be measured in a spot urine sample. If this ratio is more than 100 mg/mmol, or more than 50 mg/mmol for 1 year or more, the patient should be discussed with a nephrologist to consider renoprotective treatment, for example an ACE inhibitor and possibly an angiotensin II blocker. Glomerular function should be assessed by measuring the serum creatinine concentration between 1–6 months after completion of treatment with cisplatin, carboplatin, melphalan or methotrexate, or at 1 year after ifosfamide or nitrosourea treatment. If the serum creatinine is normal at these time points, then it should be repeated every 5 years. GFR measurement may be reserved for those patients with high serum creatinine concentrations. If GFR is measured and found to be less than 90 ml/min/1.73m2, serum creatinine should be measured more often (e.g., yearly) and GFR measurement repeated when clinically indicated, whilst if GFR is less than 60 ml/min/1.73m2, it is recommended that the patient should be discussed with a nephrologist. Tubular function monitoring may be tailored according to the previous treatment. Serum magnesium and calcium concentrations should be measured 1–6 months after completion of cisplatin or carboplatin. If normal at this time they should be repeated every 5 years, but if low, more frequent monitoring is recommended, as clinically indicated, allowing appropriate electrolyte supplementation to be instituted or adjusted. Patients who have been treated with ifosfamide should be assessed for a history of polyuria or polydipsia (suggesting NDI), whilst serum bicarbonate, chloride, calcium, phosphate and alkaline phosphatase concentrations should be measured, and the renal tubular threshold for phosphate (Tmp/GFR) calculated,[27] 1 month and 1 year after completion of ifosfamide. If serum bicarbonate and phosphate, and Tmp/GFR, are normal at 1 year they should be repeated every 5 years, but if they are reduced then more frequent monitoring is recommended. A nephrologist should be consulted if there is evidence of renal bone disease. It is important to inform the patient, their family and primary healthcare professionals about the presence or possible future occurrence of glycosuria and/or polyuria due to tubular toxicity in order to avoid a mistaken diagnosis of diabetes mellitus.

The surveillance investigations recommended in the COG guidelines differ only slightly from those in the UKCCSG practice statement. However, rather than specifying precise timings, it is suggested that baseline tests should be performed at entry into LTFU and repeated as clinically indicated.

As recommended earlier, initial evaluation of glomerular function has traditionally been based on the measurement of serum creatinine concentration, but although this is a widely available test, it is known to be a relatively insensitive means of detecting mild glomerular impairment.[201] By contrast, measurement of GFR is more complex, time consuming and expensive, and is not readily available to all units. Some researchers have investigated the possible role of serum cystatin C concentration as a more sensitive measure of glomerular dysfunction (compared with creatinine), but its utility in clinical practice has not been demonstrated clearly yet.[169] Although formulae to calculate GFR (e.g., the Counahan–Barratt and Schwartz formulae based on serum creatinine concentration and patient height) are used by many clinicians and protocols, the reduced accuracy of the resulting GFR estimates compared with those from plasma clearance techniques limits their value in clinical practice.[170]

The prevention or treatment of established severe ifosfamide-induced tubular toxicity, especially that manifest by HR and RTA in growing children, may necessitate treatment with high doses of oral phosphate or bicarbonate for months or even years, whilst supplementation with other electrolytes may be required less commonly. Occasionally, it may be appropriate to consider the use of 1,25-hydroxyvitamin D3 to treat severe hypophosphatemia or HR, but careful monitoring is required in view of the risk of metastatic calcification and nephrocalcinosis especially in normocalcemic patients.

Moderate or severe acute cisplatin-induced hypomagnesemia should be treated with oral or intravenous magnesium supplementation,[82] in view of the potential biochemical (hypocalcemia and hypokalemia, both of which are often improved or corrected by reversal of hypomagnesemia), neuromuscular (muscle weakness and tetany) and cardiovascular complications (arrhythmias). Although there has been no detailed study of the long-term clinical consequences of chronic cisplatin-induced hypomagnesemia in survivors of childhood cancer, it is conceivable that these may include serious diseases such as hypertension, atherosclerosis, myocardial infarction and cerebrovascular accidents.[171] Therefore, further research is necessary to determine whether long-term magnesium supplementation is necessary in chronically hypomagnesemic individuals.

Dose adjustment based on GFR measurement or the use of specific formulae (e.g., for carboplatin dosing),[172] may be necessary in patients with established renal damage who require further treatment with chemotherapy drugs that undergo renal excretion or that may cause further nephrotoxicity.[173]