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Late Effects of Treatment for Childhood Cancer (PDQ®)

  • Last Modified: 10/27/2014

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Late Effects of the Urinary System

Cancer treatments predisposing to late renal injury and hypertension include specific chemotherapeutic drugs (cisplatin, carboplatin, and ifosfamide), renal radiation therapy, and nephrectomy.[1] Cisplatin can cause glomerular and tubular damage resulting in a diminished glomerular filtration rate (GFR) and electrolyte wasting (particularly magnesium, calcium, and potassium). Approximately 50% of patients may experience long-lasting hypomagnesemia. The use of ifosfamide concurrently with cisplatin increases the risk of renal injury.[2]

Carboplatin is a cisplatin analog and is less nephrotoxic than cisplatin. In a prospective, longitudinal, single-center, cohort study of children followed up for more than 10 years after cisplatin or carboplatin therapy, older age at treatment was found to be the major risk factor for nephrotoxicity, especially for patients receiving carboplatin, while cisplatin dose schedule and cumulative carboplatin dose were also important predictors of toxicity. Platinum nephrotoxicity did not change significantly over 10 years.[3] The combination of carboplatin/ifosfamide may be associated with more renal damage than the combination of cisplatin/ifosfamide.[3-5] As with ototoxicity, however, additional follow-up in larger numbers of survivors treated with carboplatin must be evaluated before potential renal toxicity can be better defined.

Ifosfamide can also cause glomerular and tubular toxicity, with renal tubular acidosis, and Fanconi syndrome, a proximal tubular defect characterized by impairment of resorption of glucose, amino acids, phosphate, and bicarbonate. Ifosfamide doses greater than 60 g/m2 to 100 g/m2, age younger than 5 years at time of treatment, and combination with cisplatin and carboplatin increase the risk of ifosfamide-associated renal tubular toxicity.[6-8] Abnormalities in glomerular filtration are less common, and when found, are usually not clinically significant. More common are abnormalities with proximal tubular function greater than distal tubular function, although the prevalence of these findings is uncertain, and further study of larger cohorts with longer follow-up is required.[2,9-12]

A French study that evaluated the incidence of late renal toxicity after ifosfamide reported normal tubular function in 90% of pediatric cancer survivors (median follow-up of 10 years); 79% of the cancer survivors had normal GFR, and all had normal serum bicarbonate and calcium. Hypomagnesemia and hypophosphatemia were seen in 1% of cancer survivors. Glycosuria was detected in 37% of cancer survivors but was mild in 95% of cases. Proteinuria was observed in 12% of cancer survivors. In multivariate analysis, ifosfamide dose and interval from therapy were predictors of tubulopathy, and older age at diagnosis and interval from therapy were predictors of abnormal GFR.[8]

High-dose methotrexate (1,000–33,000 mg/m2) has been reported to cause acute renal dysfunction in 0% to 12.4% of patients. This has resulted in delayed elimination of the drug, but long-term renal sequelae have not been described.[13]

Irradiation to the kidney can result in radiation nephritis or nephropathy after a latent period of 3 to 12 months. Doses greater than 20 Gy can result in significant nephropathy.[14] In a report from the German Registry for the Evaluation of Side Effects after Radiation in Childhood and Adolescence (RISK consortium), 126 patients who underwent radiation therapy to parts of the kidneys for various cancers were evaluated. All patients also received potentially nephrotoxic chemotherapy. Whole kidney volumes exposed to greater than 20 Gy (P = .031) or 30 Gy (P = .003) of radiation were associated with a greater risk for mild degrees of nephrotoxicity.[15]

The effect of radiation therapy on the kidney has best been examined in survivors of pediatric Wilms tumor. Generally, studies have shown that the risk of renal insufficiency is higher among children receiving higher doses of radiation.[16-18] A correlation between functional impairment and the renal radiation dose was reported in a study of 100 children treated for Wilms tumor. The incidence of impaired creatinine clearance was significantly higher for children receiving more than 12 Gy to the remaining kidney, and all cases of overt renal failure occurred after more than 23 Gy.[19] In a cohort of Wilms tumor survivors evaluated 5 years after receiving abdominal radiation, the prevalence of renal insufficiency, as defined by hypertension, was approximately 7%.[20]

Data from the National Wilms Tumor Study Group and the U.S. Renal Data System indicate that the 20-year cumulative incidence of end-stage renal disease (ESRD) in children with unilateral Wilms tumor and Denys-Drash syndrome is 74%, 36% for those with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome, 7% for male patients with genitourinary anomalies and 0.6% for 5,347 patients with none of these conditions.[21] For patients with bilateral Wilms tumors, the incidence of ESRD is 50% for Denys-Drash syndrome, 90% for WAGR, 25% for genitourinary anomaly, and 12% for patients for all others.[21,22] ESRD in patients with WAGR and genitourinary anomalies tended to occur relatively late, and often during or after adolescence.[21]

Treatment for Wilms tumor without flank or abdominal radiation therapy was not associated with significant nephrotoxicity in a study of 40 Wilms tumor survivors treated in England.[18]

Few large-scale studies have evaluated late renal-health outcomes and risk factors for renal dysfunction among survivors treated with potentially nephrotoxic modalities. In a large cross-sectional study of 1,442 childhood cancer survivors (median attained age, 19.3 years; median time from diagnosis, 12.1 years), Dutch investigators assessed the presence of albuminuria, hypomagnesemia, hypophosphatemia, and hypertension and estimated glomerular filtration rate among survivors treated with ifosfamide, cisplatin, carboplatin, high-dose cyclophosphamide (>1 g/m2 or more per course), or high-dose methotrexate (>1 g/m2 or more per course), radiation of the kidney region, total-body irradiation, or nephrectomy. At least one abnormality of renal function or hypertension was detected in 28.1% of survivors. History of nephrectomy (OR, 8.6; 95% CI, 3.4–21.4) had the strongest association with a GFR less than 90 ml/min per 1.73 m2. The prevalence of decreased GFR was highest among those treated with multimodality therapy including nephrectomy, nephrotoxic chemotherapy, and abdominal radiation. Abdominal irradiation was the only significant treatment-related risk factor for hypertension (OR, 2.5; 95%CI, 1.4–4.5).[23]

In the setting of hematopoietic cell transplantation, fewer than 15% of children will develop chronic renal insufficiency or hypertension; the risk is related to the nephrotoxic agents used and the cumulative total-body irradiation dose, fractionation scheme, and interfraction interval. More specifically, the radiation-associated risk rises when the total dose exceeds 12 Gy, the individual fraction size is greater than 2 Gy, or the interval-fraction is less than 4 to 6 hours.[24-27]

Childhood cancer survivors treated with pelvic or central nervous system surgery, alkylator-containing chemotherapy including cyclophosphamide or ifosfamide, or pelvic radiation therapy may experience urinary bladder late effects including hemorrhagic cystitis, bladder fibrosis, neurogenic/dysfunctional bladder, and bladder cancer.[28]

Table 17. Kidney and Bladder Late Effects
Predisposing Therapy Renal/Genitourinary Effects Health Screening 
BUN = blood urea nitrogen; NSAIDs = nonsteroidal anti-inflammatory drugs; RBC/HFP = red blood cells per high-field power (microscopic exam).
Cyclophosphamide/Ifosfamide; radiation impacting bladder/urinary tractBladder toxicity (hemorrhagic cystitis, bladder fibrosis, dysfunctional voiding, vesicoureteral reflux, hydronephrosis)History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
Urinalysis
Urine culture, spot urine calcium/creatinine ratio, and ultrasound of kidneys and bladder for patients with microscopic hematuria (defined as ≥5 RBC/HFP on at least 2 occasions)
Nephrology or urology referral for patients with culture-negative microscopic hematuria AND abnormal ultrasound and/or abnormal calcium/creatinine ratio
Urology referral for patients with culture negative macroscopic hematuria
Cisplatin/carboplatin; ifosfamideRenal toxicity (glomerular injury, tubular injury [renal tubular acidosis], Fanconi syndrome, hypophosphatemic rickets)Blood pressure
BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
Urinalysis
Electrolyte supplements for patients with persistent electrolyte wasting
Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Methotrexate; radiation impacting kidneys/urinary tractRenal toxicity (renal insufficiency, hypertension)Blood pressure
BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
Urinalysis
Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
NephrectomyRenal toxicity (proteinuria, hyperfiltration, renal insufficiency)Blood pressure
BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
Urinalysis
Discuss contact sports, bicycle safety (e.g., avoiding handlebar injuries), and proper use of seatbelts (i.e., wearing lapbelts around hips, not waist)
Counsel to use NSAIDs with caution
Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Nephrectomy; pelvic surgery; cystectomyHydroceleTesticular exam
CystectomyCystectomy-related complications (chronic urinary tract infections, renal dysfunction, vesicoureteral reflux, hydronephrosis, reservoir calculi, spontaneous neobladder perforation, vitamin B12/folate/carotene deficiency [patients with ileal enterocystoplasty only])Urology evaluation
Vitamin B12 level
Pelvic surgery; cystectomyUrinary incontinence; urinary tract obstructionHistory: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
Counsel regarding adequate fluid intake, regular voiding, seeking medical attention for symptoms of voiding dysfunction or urinary tract infection, compliance with recommended bladder catheterization regimen
Urologic consultation for patients with dysfunctional voiding or recurrent urinary tract infections

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for urinary late effects information including risk factors, evaluation, and health counseling.

References
  1. Jones DP, Spunt SL, Green D, et al.: Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 724-31, 2008.  [PUBMED Abstract]

  2. Loebstein R, Koren G: Ifosfamide-induced nephrotoxicity in children: critical review of predictive risk factors. Pediatrics 101 (6): E8, 1998.  [PUBMED Abstract]

  3. Skinner R, Parry A, Price L, et al.: Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: relevance of age and dose as risk factors. Eur J Cancer 45 (18): 3213-9, 2009.  [PUBMED Abstract]

  4. Marina NM, Poquette CA, Cain AM, et al.: Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol 22 (2): 112-8, 2000 Mar-Apr.  [PUBMED Abstract]

  5. Hartmann JT, Fels LM, Franzke A, et al.: Comparative study of the acute nephrotoxicity from standard dose cisplatin +/- ifosfamide and high-dose chemotherapy with carboplatin and ifosfamide. Anticancer Res 20 (5C): 3767-73, 2000 Sep-Oct.  [PUBMED Abstract]

  6. Skinner R, Cotterill SJ, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group. Br J Cancer 82 (10): 1636-45, 2000.  [PUBMED Abstract]

  7. Stöhr W, Paulides M, Bielack S, et al.: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 48 (4): 447-52, 2007.  [PUBMED Abstract]

  8. Oberlin O, Fawaz O, Rey A, et al.: Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 27 (32): 5350-5, 2009.  [PUBMED Abstract]

  9. Arndt C, Morgenstern B, Wilson D, et al.: Renal function in children and adolescents following 72 g/m2 of ifosfamide. Cancer Chemother Pharmacol 34 (5): 431-3, 1994.  [PUBMED Abstract]

  10. Arndt C, Morgenstern B, Hawkins D, et al.: Renal function following combination chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma. Med Pediatr Oncol 32 (2): 93-6, 1999.  [PUBMED Abstract]

  11. Prasad VK, Lewis IJ, Aparicio SR, et al.: Progressive glomerular toxicity of ifosfamide in children. Med Pediatr Oncol 27 (3): 149-55, 1996.  [PUBMED Abstract]

  12. Skinner R, Pearson AD, English MW, et al.: Risk factors for ifosfamide nephrotoxicity in children. Lancet 348 (9027): 578-80, 1996.  [PUBMED Abstract]

  13. Widemann BC, Balis FM, Kim A, et al.: Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28 (25): 3979-86, 2010.  [PUBMED Abstract]

  14. Dawson LA, Kavanagh BD, Paulino AC, et al.: Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S108-15, 2010.  [PUBMED Abstract]

  15. Bölling T, Ernst I, Pape H, et al.: Dose-volume analysis of radiation nephropathy in children: preliminary report of the risk consortium. Int J Radiat Oncol Biol Phys 80 (3): 840-4, 2011.  [PUBMED Abstract]

  16. Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 26 (2): 75-80, 1996.  [PUBMED Abstract]

  17. Smith GR, Thomas PR, Ritchey M, et al.: Long-term renal function in patients with irradiated bilateral Wilms tumor. National Wilms' Tumor Study Group. Am J Clin Oncol 21 (1): 58-63, 1998.  [PUBMED Abstract]

  18. Bailey S, Roberts A, Brock C, et al.: Nephrotoxicity in survivors of Wilms' tumours in the North of England. Br J Cancer 87 (10): 1092-8, 2002.  [PUBMED Abstract]

  19. Mitus A, Tefft M, Fellers FX: Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics 44 (6): 912-21, 1969.  [PUBMED Abstract]

  20. Paulino AC, Wen BC, Brown CK, et al.: Late effects in children treated with radiation therapy for Wilms' tumor. Int J Radiat Oncol Biol Phys 46 (5): 1239-46, 2000.  [PUBMED Abstract]

  21. Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174 (5): 1972-5, 2005.  [PUBMED Abstract]

  22. Hamilton TE, Ritchey ML, Haase GM, et al.: The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group. Ann Surg 253 (5): 1004-10, 2011.  [PUBMED Abstract]

  23. Knijnenburg SL, Jaspers MW, van der Pal HJ, et al.: Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors. Clin J Am Soc Nephrol 7 (9): 1416-27, 2012.  [PUBMED Abstract]

  24. Leiper AD: Non-endocrine late complications of bone marrow transplantation in childhood: part II. Br J Haematol 118 (1): 23-43, 2002.  [PUBMED Abstract]

  25. Hoffmeister PA, Hingorani SR, Storer BE, et al.: Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant 16 (4): 515-24, 2010.  [PUBMED Abstract]

  26. Abboud I, Porcher R, Robin M, et al.: Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15 (10): 1251-7, 2009.  [PUBMED Abstract]

  27. Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008.  [PUBMED Abstract]

  28. Ritchey M, Ferrer F, Shearer P, et al.: Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (4): 439-46, 2009.  [PUBMED Abstract]