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Nephrotoxicity among young patients with cancer: Not only an acute problem
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Balancing long-term risks and benefits of potentially toxic therapies, while achieving a cure, remains a delicate challenge in cancer treatment.
Nephrotoxicity — a common finding among children and adolescents treated for cancer — is a known adverse effect of cancer therapies resulting in a number of renal impairments, including a decline in glomerular filtration rate (GFR), renal tubular dysfunction and hypertension.
Renal toxicity can occur as a result of the malignant process itself or from standard chemotherapies, such as ifosfamide and platinum-based therapies; radiation therapy; surgery; immunotherapy; and supportive therapies, such as antibiotic therapy.
APPs play a critical role in identifying and managing nephrotoxicity. During therapy, APPs deliver care focused on prevention and early detection of renal toxicity. Despite preventive measures and monitoring, children and adolescents treated for cancer are at great risk for developing chronic renal impairment or renal insufficiency, declining GFR, proteinuria, renal tubular dysfunction and hypertension.
The impact of nephrotoxicity
Therapy options for pediatric cancer include highly effective modalities that are known to cause nephrotoxicity, but their use remains vital to maximize the chances of cure.
Although the kidneys are highly vulnerable to adverse effects of treatment, these organs also are remarkable in their ability to compensate when problems occur in their functioning to a certain extent. The type, timing and extent of renal impairment correlates to the patient’s risk factors and exposure to various treatment modalities.
The prevalence of acute nephrotoxicity is widely variable, with studies ranging from no renal toxicity to those describing universal development of acute nephrotoxicity in children treated with cisplatin. Prevalence is dependent on many factors, with the highest incidence among children aged younger than 5 years and patients with preexisting renal disease, prior nephrectomy and cumulative exposure to nephrotoxic agents, both alone and in combination.
Acute nephrotoxicity can manifest as glomerular impairment, tubular damage leading to electrolyte losses, proteinuria and hypertension. Irradiation of the kidney can result in acute radiation nephritis or nephropathy manifesting with proteinuria, hypertension, renal insufficiency and anemia. Among patients who require nephrectomy as treatment for a malignant process, such as Wilms tumor, complications include hypertension, hyperfiltration injury and compensatory hypertrophy of the remaining kidney, causing lasting effects. Supportive care with antibiotic use, most commonly aminoglycosides and amphotericin B, is known to cause acute toxicity manifesting as glomerular impairment, hyperfiltration and renal tubular dysfunction.
Guidelines for the evaluation and surveillance of acute nephrotoxicity are well-established, including evidenced-based supportive measures to attempt to prevent and mitigate renal toxicity. APPs are well-positioned to implement these strategies, such as hydration protocols, aggressive electrolyte replacement, limiting concurrent use of other nephrotoxic drugs and limiting cumulative exposure to nephrotoxic treatment to prevent nephrotoxicity.
Acute kidney injury and exposure to these treatment modalities can have long-lasting renal effects; however, information is limited on incidence and risk for the development of chronic kidney disease (CKD) as a late effect of therapy.
Long-term renal toxicity
Incidence of CKD is difficult to define among young survivors of cancer secondary to the myriad of treatment modalities, differing diagnoses, individual risk factors and variable follow-up.
Studies estimate the prevalence of CKD to range from 0% to 60% based on these variabilities, and childhood survivors of cancer have a ninefold higher risk for developing renal failure than their siblings. Recent studies have shown ifosfamide and platinum toxicities may persist up to 10 years after treatment.
Long-term renal abnormalities include advancement of CKD, renal tubular dysfunction leading to electrolyte abnormalities and proteinuria, and hypertension. Both glomerular and tubular function may deteriorate together or separately after therapy is complete. Proximal tubular toxicity is the most common chronic manifestation associated with ifosfamide and cisplatin, manifesting mainly as hypomagnesemia, but it can be seen with glycosuria, aminoaciduria and proteinuria among survivors as well.
Abdominal and total body radiation have been shown to cause late effects of nephropathy, characterized by a decline in GFR, hypertension and proteinuria. Survivors who underwent nephrectomy are at risk for hyperfiltration by the remaining kidney, leading to hypertension and glomerular impairment.
Although severe nephrotoxicity is often attributed to well-known risk factors, CKD may exist in children without exposure to causative agents or apparent risk factors. Normal renal function during or at completion of therapy does not preclude later development of significant renal impairment. For instance, studies have shown cisplatin remains bonded to human tissues as long as 20 years after delivery, highlighting the importance of long-term monitoring.
Surveillance and management
It is important for APPs to understand the burden of nephrotoxicity during therapy and implement surveillance strategies to protect the kidneys and prevent further impairment in cancer survivors. APPs recognize the associated risk for individual patients and ensure adequate surveillance measures are followed.
The Children’s Oncology Group published risk-based, exposure-related guidelines that recommend all patients at risk for nephrotoxicity undergo regular blood pressure monitoring, monitoring of electrolytes, urinalysis for proteinuria and close monitoring of growth. Findings of hypertension, proteinuria or decline in GFR should be investigated further, and referral to a nephrologist is warranted.
The focus of management of chronic renal impairment centers on blood pressure control, electrolyte supplementation, and measures to stabilize and prevent further decline in function. In addition, red blood cell indices, bone health and growth should be monitored for anemia and bone disease in advanced-stage chronic renal impairment.
Further investigation is needed to determine the extent to which acute nephrotoxicity is linked to chronic renal impairment and mechanisms to identify patients at greatest risk for progression to chronic renal damage.
As evidence continues to expand, APPs are paramount in identifying and developing evidence-based practices to prevent late effects of kidney damage and improve outcomes for survivors. Newer therapy modalities have unknown long-term risks for late renal effects, and practitioners must develop best practices as more research becomes available.
References:
Jones DP, et al. Pediatr Blood Cancer. 2008;doi:10.1002/pbc.21695.
McMahon KR, et al. Pediatr Nephrol. 2018;doi:10.1007/s00467-018-3976-5.
Ruggiero A, et al. Br J Clin Pharmacol. 2017;doi:10.1111/bcp.13388.
Skinner R. J Pediatr Hematol Oncol. 2011;doi:10.1097/MPH.0b013e3181f8cac0.
Skinner R. Pediatr Nephrol. 2018;doi:10.1007/s00467-017-3662-z.
For more information:
Lisa Triche, DNP, RN, CPNP, is pediatric nurse practitioner at Children’s Cancer Hospital of The University of Texas MD Anderson Cancer Center. She can be reached at lltriche@mdanderson.org.
Disclosure: Triche reports no relevant financial disclosures.
HemOnc Today collaborated with Association of Pediatric Hematology/Oncology Nurses (APHON) on the submission of this column. To contribute to this column, contact Alexandra Todak at stodak@healio.com.