Nephrotoxicity of Cancer Treatment in Children

Roderick Skinner

Pediatr Health. 2010;4(5):519-538.

Future Perspective

The improved long-term survival of children with malignancy has been achieved at the cost of significant late toxicity, with chronic renal damage being an important component of long-term morbidity for many survivors. The very long-term outlook for these individuals is guarded given the expected decline in renal function experienced by even healthy individuals in later life.

Therefore, it is very important that future treatments for childhood cancer should have less nephrotoxic potential, ideally as a result of the development of less toxic yet still effective treatments, or alternatively by the introduction of renoprotective strategies that do not impair antitumor efficacy.

Until these goals are achieved, the prediction of patients at higher risk of developing nephrotoxicity remains of fundamental importance, either by better understanding of risk factors or by developing more sensitive and specific investigation strategies to identify incipient yet still reversible toxicity.

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Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Cite this: Nephrotoxicity of Cancer Treatment in Children - Medscape - Oct 01, 2010.

Box 1. The causes of nephrotoxicity in children with cancer.
*Cytotoxic drugs*
Frequent and potentially severe nephrotoxicity Cisplatin Ifosfamide Infrequent but potentially severe nephrotoxicity Carboplatin Methotrexate (especially high dose) Nitrosoureas (especially semustine) Rare reports of nephrotoxicity Actinomycin D Anthracyclines Melphalan Vincristine
*Radiotherapy*
*Surgery*
*Immunosuppressive drugs* Ciclosporin A Tacrolimus
*Hemopoietic stem cell transplantation* Numerous potential causes, often multifactorial with contributions from Nephrotoxic chemotherapy during:, Previous treatment (e.g., ifosfamide) Conditioning treatment (e.g., carboplatin) Total body irradiation during conditioning treatment Reduced renal perfusion due to prerenal factors (e.g., hemorrhage, sepsis and hVOD) Immunosuppressive drugs (see above) Nephrotoxic anti-infective drugs (see below)
*Anti-infective drugs* Aminoglycosides Amphotericin Aciclovir

hVOD: Hepatic veno-occlusive disease.

Box 2. The causes of nephrotoxicity reported in adults with cancer ^†.
*Cytotoxic drugs* 5-azacytidine Cyclophosphamide Cytosine arabinoside Gemcitabine Mithramycin Mitomycin C Pentostatin Streptozotocin 6-thioguanine
*Monoclonal antibodies* Bevacizumab Cetuximab Panitumumab
*Immunotherapeutic drugs* IL-2 Interferon

^† In addition to the causes listed in Box 1.

Box 3. The clinical features of ifosfamide nephrotoxicity.
*Glomerular toxicity* Elevated serum creatinine concentration Reduced glomerular filtration rate Acute renal failure Chronic renal failure
*Proximal tubular toxicity* Aminoaciduria Glycosuria Increased urinary excretion of: Low-molecular-weight proteins (e.g., RBP) Proximal tubular antigens (e.g., ADBP) Fanconi syndrome (as above, plus phosphaturia, bicarbonaturia, kaluria), leading to: Hypophosphatemia and HR Proximal RTA Hypokalemia Calciuria, magnesuria, natriuria (rarely)
*Distal tubular toxicity* Subclinical impairment of urinary acidification Subclinical impairment of urinary concentration Distal RTA NDI
*Tubular toxicity (either proximal or distal tubular)* Increased urinary excretion of renal tubular enzymes (e.g., NAG)
*General aspects of renal toxicity (glomerular or tubular)* Proteinuria Hypertension Growth failure (related to chronic renal failure, HR and/or RTA)

Clinically significant aspects of toxicity are shown in italics.
ADBP: Adenosine deaminase-binding protein; HR: Hypophosphatemic rickets;
NAG: N-acetylglucosaminidase; NDI: Nephrogenic diabetes insipidus; RBP: Retinol-binding protein; RTA: Renal tubular acidosis.

Box 4. The clinical features of cisplatin nephrotoxicity.
*Glomerular toxicity* Elevated serum creatinine concentration Reduced glomerular filtration rate Acute renal failure Chronic renal failure
*Proximal tubular toxicity* Increased urinary excretion of: Magnesium, potassium, sodium and glucose Amino acids Low-molecular-weight proteins The consequences of proximal tubular toxicity include: Hypomagnesemia Hypocalcemia Hypokalemia Hyponatremia
*Distal tubular toxicity* Impairment of water and sodium reabsorption, resulting in polyuria Hypomagnesemia – hypokalemic metabolic acidosis, associated with hypocalciuria
*Tubular toxicity (either proximal or distal tubular)* Increased urinary excretion of renal tubular enzymes
*General aspects of renal toxicity (glomerular or tubular)* Albuminuria and proteinuria Hypertension

Clinically significant aspects of toxicity are shown in italics.

Box 5. The clinical features of carboplatin nephrotoxicity.
*Glomerular toxicity* Elevated serum creatinine concentration Reduced glomerular filtration rate Acute renal failure (very rare)
*Proximal tubular toxicity* Hypomagnesemia (magnesuria not yet demonstrated) Natriuria and hyponatremia Increased urinary excretion of low-molecular-weight proteins
*Tubular toxicity (either proximal or distal tubular)* Increased urinary excretion of renal tubular enzymes
*General aspects of renal toxicity (glomerular or tubular)* Albuminuria, proteinuria

Clinically significant aspects of toxicity are shown in italics.

Sidebar

Executive Summary

Epidemiology

Long-term survivors of childhood cancer have a relative risk of severe renal chronic disease of 8.1 (95% CI: 2.9–23.1)

Importance

Nephrotoxicity is important due to its potential frequency, severity and unpredictability

Etiology

The potential causes of chronic renal impairment in both children and adults with cancer include the malignant process itself as well as adverse effects of treatment

Nephrotoxicity due to specific treatments

Ifosfamide may cause any combination of glomerular, proximal or distal tubular toxicity, with considerable variability in the time of onset, clinical manifestations, severity and reversibility. Tubular damage leads to hypophosphatemia, renal tubular acidosis and, when severe, the Fanconi syndrome
Cisplatin may cause substantial impairment of glomerular or tubular function, or both. Tubular damage causes hypomagnesemia
Carboplatin nephrotoxicity is similar to that seen after cisplatin, but it is less frequent, usually milder and often reversible
Both ifosfamide and cisplatin nephrotoxicity may persist for at least 10 years
Other cytotoxic drugs, renal surgery or radiotherapy, hemopoietic stem cell transplantation and supportive care drugs (e.g., antibiotics) may also cause nephrotoxicity

Clinical management

Patients at risk of nephrotoxicity should be monitored regularly using a defined surveillance protocol

Prevention

Clinical strategies to reduce nephrotoxicity due to specific drugs are usually based on avoidance of established risk factors such as high doses, but effective prevention of nephrotoxicity depends on understanding its pathogenesis, which is not available for most agents

Future perspective

The very long-term prognosis of nephrotoxicity in survivors of childhood cancer is guarded due to the potential interaction with the expected decline in renal function even in healthy individuals in later life
It is very important that the potential nephrotoxicity of future treatments for childhood cancer is reduced by the development of less toxic but still effective treatments or of selectively renoprotective strategies
Until this occurs, the prediction of patients at higher risk of developing nephrotoxicity remains of fundamental importance