Nephrotoxicity of Cancer Treatment in Children

Roderick Skinner


Pediatr Health. 2010;4(5):519-538. 

In This Article


Cisplatin has a well established role in the treatment of several pediatric solid malignancies, including brain tumors, osteosarcoma, neuroblastoma, germ-cell tumors and liver tumors. Children treated with cisplatin may suffer substantial impairment of glomerular or tubular function, or both (Box 4). Although the time of onset and the clinical manifestations of nephrotoxicity due to cisplatin show less variability than that caused by ifosfamide, the severity and reversibility of toxicity may differ greatly between patients.[70]


The reported incidence of glomerular toxicity has varied from 10–20 to over 80% depending on the nature and timing of investigation, and that of hypomagnesemia from approximately 30–100%.[8,71–74]

Clinical Features

Glomerular impairment may cause a transient or persistent fall in GFR, a rise in serum creatinine concentration, or even ARF,[73–76] whilst CRF may develop insidiously in a minority of patients.[77] However, serum creatinine levels and endogenous creatinine clearance are insensitive indicators of cisplatin-induced glomerular toxicity,[78] and underestimate the true frequency of nephrotoxicity. Magnesuria and resultant hypomagnesemia are the most common manifestations of both acute and chronic proximal tubular toxicity.[79] Although there have been very few specific investigations of distal tubular function after cisplatin treatment in children, chronic magnesuria, hypomagnesemia, hypocalciuria, with normocalcemia or mild hypercalcemia and mild hypokalemic metabolic alkalosis, may result from dissociation of magnesium and calcium handling resulting from a distal convoluted tubular lesion.[79–81] Alternatively, hypocalcemia may occur due to hypomagnesemia-induced impairment of parathyroid hormone release.[82,83] Similarly, kaluria and hypomagnesemia may both contribute to hypokalemia, while natriuria may lead to hyponatremia.[81,82,84,85] Polyuria is described, perhaps due to distal nephron resistance to vasopressin.[86] Subclinical acute tubular toxicity may lead to aminoaciduria, glycosuria, phosphaturia and increased urine excretion of RBP, β2-M, N-acetylglucosaminidase, alanine aminopeptidase and β–galactosidase.[81,87] Hypertension may occur,[88] probably caused by renovascular mechanisms.[89]

The clinical consequences of cisplatin nephrotoxicity include ARF, CRF and more commonly hypomagnesemia, which may cause paresthesia, tremor, tetany and convulsions.[70,76,82] Hemolytic uremic syndrome (HUS) is a rare but well-recognized complication of cisplatin.[90]

Natural History

Two studies in children published in the 1990s suggested that glomerular impairment, but not hypomagnesemia, may improve partially with time.[74,91] However, several other reports have emphasized the apparent irreversibility of cisplatin nephrotoxicity, and a recently published longitudinal LTFU study of 27 children concluded that there was no evidence of recovery of cisplatin nephrotoxicity (measured by GFR and serum magnesium) over 10 years follow-up.[70]

Risk Factors

There is relatively little clear information concerning the importance of patient- and treatment-related risk factors for cisplatin nephrotoxicity in children. However, those factors that appear to be important include high total dose and dose rate, patient age, concurrent treatment with other potential nephrotoxins, and inter-individual differences in cisplatin pharmacokinetics. Two studies have suggested that the dose intensity of cisplatin is an important determinant of risk. Daugaard found less glomerular and tubular toxicity in adults after low-dose (20 mg/m2/day) than after high-dose cisplatin (40 mg/m2/day),[78,81] whilst moderate or severe glomerular impairment and hypomagnesemia at 1–2 years post-treatment were significantly more frequent in children receiving a high cisplatin dose rate (>40–120 mg/m2/day) than in those receiving a low dose rate (40 mg/m2/day).[70,91] The influence of total dose is uncertain; some studies in adults and children have suggested a relationship between cumulative dose and nephrotoxicity,[79,80] but others have failed to confirm this relationship.[70,74,91] Until recently, no clear relationship between age and GFR or hypomagnesemia in children has been identified,[74,91] but recent evidence suggests that very long-term glomerular (low GFR) and tubular (hypomagnesemia) toxicity may be more common in those children treated at an older age.[70] Treatment with other potential nephrotoxins, including ifosfamide and methotrexate, may exacerbate cisplatin-induced renal toxicity.[52,92] Interindividual variability in cisplatin pharmacokinetics may be important. For example, analysis in 12 adults receiving cisplatin identified a relationship between the peak plasma concentration of ultrafilterable platinum and glomerular toxicity after four treatment courses,[93] but there is no evidence that the risk of nephrotoxicity can be reduced in clinical practice by pharmacokinetically-guided dose modifications.


Platinum is still detectable in blood up to 20 years after treatment with cisplatin[94] and it is likely that the chronicity of cisplatin nephrotoxicity is related to its retention in renal tissue. Most histopathological studies in adults have revealed a variety of tubular lesions but a striking lack of glomerular abnormalities.[95]

However, the pharmacology of cisplatin is complex and several pathogenetic mechanisms have been suggested to explain its nephrotoxicity.[96,97] Following initial rapid plasma distribution, considerable protein-binding of platinum occurs, mainly to plasma proteins but also to cellular proteins, with both reversible and irreversible components.[98] Subsequently, slow excretion of protein-bound platinum leads to a long terminal half-life (20–80 h) of total platinum. The details of the renal tubular handling of cisplatin are not clear, but both reabsorption and secretion may be involved with net tubular secretion. In the relatively high chloride concentration of plasma, the neutral dichlorocisplatin complex prevails, whereas in the low-chloride intracellular environment, the more reactive aquated species predominates, potentially leading to increased formation of nephrotoxic metabolites.[99] This is the rationale for the use of hypertonic saline hydration with cisplatin.

Cisplatin nephrotoxicity may be mediated by renal tubular transport and accumulation of the drug or a (so far, unidentified) toxic metabolite.[100,101] Alternatively, renal damage may be initiated by renal arteriolar vasoconstriction,[84,102] possibly via mechanisms involving adenosine, platelet-activating factor or thromboxane A2, although the evidence is conflicting.[103–105] There is similar uncertainty about the subcellular basis of cisplatin nephrotoxicity. Numerous mechanisms have been postulated including direct cytotoxicity mediated by reactive oxygen species, activation of mitogen-activated protein kinase intracellular signal pathways, apoptosis mediated via caspases and TNF, binding to biological nucleophiles and proteins, such as glutathione, inhibition of ATPase and other intracellular enzymes, reduction in cellular and nuclear synthetic activity, especially of DNA and RNA, and damage to mitochondrial DNA, glutathione or enzymes.[96,97,106,107] However, the relationship between these findings and the development of nephrotoxicity remains unclear.