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Late Effects of Treatment for Childhood Cancer (PDQ®)

Late Effects of the Urinary System

Acute toxicity of the urinary system from cancer therapy is well known. Less is known about the genitourinary outcomes in long-term survivors.[1] Cancer treatments predisposing to renal injury and/or high blood pressure later in life include chemotherapeutic drugs (cisplatin, carboplatin, ifosfamide, methotrexate), renal radiation therapy, and nephrectomy. The risk and the degree of renal dysfunction depend on type and intensity of therapy and interpretation of the studies is compromised by variability in testing.

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 (GFR) 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 to 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 (odds ratio [OR], 8.6; 95% confidence interval [CI], 3.4–21.4) had the strongest association with a GFR of 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. Nearly 5% of these survivors had a GFR of less than 90 ml/min per 1.73 m2. Abdominal irradiation was the only significant treatment-related risk factor for hypertension (OR, 2.5; 95% CI, 1.4–4.5).[2]

Therapy-related factors affecting the kidney

Cancer treatments predisposing to late renal injury and hypertension include the following:[3-5]

  • Nephrectomy. Survivors of childhood cancer who have undergone nephrectomy are at risk for hyperfiltration injury. Compensatory hypertrophy of the remaining kidney typically occurs following nephrectomy, but over time, renal injury may manifest as reduced glomerular filtration, microalbuminuria and proteinuria, hypertension, and rarely, focal glomerulosclerosis leading to chronic renal failure. In a cross-sectional study of 1,442 5-year childhood cancer survivors (median 12.1 years from diagnosis), 28.1% of all survivors had at least one renal adverse effect with hypertension (14.8%) and albuminuria (14.5%) being the most prevalent. Survivors who had undergone nephrectomy had the highest risk for diminished renal function (OR, 8.6; 95% CI, 3.4–21.4).[2,4]
  • Chemotherapy.
    • Cisplatin. Cisplatin can cause glomerular and tubular damage resulting in a diminished GFR and electrolyte wasting (particularly magnesium, calcium, and potassium). [6-8] Acute cisplatin-related nephrotoxicity has been reported in 30% to 100% of exposed children.[9] However, the prevalence of persistent renal dysfunction in long-term survivors appears to be considerably lower. Among 63 children treated with platinum agents, GFR was less than 60 ml/min/1.73 m2 in 11% of children and hypomagnesemia requiring oral supplements in 7% of children at 10 years from completion of therapy. Among 651 sarcoma patients evaluated after cessation of antineoplastic therapy (median follow-up 2 years), hypomagnesemia occurred in 12.1% of patients after cisplatin therapy and in 15.6% after carboplatin therapy, compared with 4.5% who did not receive any platinum derivatives. In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum-treated patients throughout the study period.[8,10]
    • Carboplatin. Carboplatin is a cisplatin analog and is less nephrotoxic than cisplatin. In a prospective, longitudinal, single-center, cohort study of children monitored 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.[8] The combination of carboplatin/ifosfamide may be associated with more renal damage than the combination of cisplatin/ifosfamide.[6-8] Additional follow-up in larger numbers of survivors treated with carboplatin (without other nephrotoxic agents and modalities) must be evaluated before potential renal toxicity can be better defined.
    • Ifosfamide. 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.[11-13] 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.[13]
    • High-dose methotrexate. 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.[4,14]
  • Radiation therapy. Radiation to the kidney can result in radiation nephritis or nephropathy after a latent period of 3 to 12 months. The kidney is relatively radiosensitive, with a tolerance dose of 20 Gy (5% complications in 5 years).[15] Doses of 18 Gy are considered unlikely to cause severe or chronic renal sequelae. In contrast, up to 50% of individuals treated with 20 Gy may develop glomerular dysfunction or hypertension within 20 years.[16] 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.[17]
  • Hematopoietic stem cell transplantation. Chronic kidney disease is a long-term complication of HSCT that has been variably associated with acute kidney injury, lower pre-transplant renal function, total-body irradiation, conditioning regimens including fludarabine, graft-versus-host disease, and use of calcineurin inhibitors.[18-20] Most reports of renal outcomes among long-term survivors of childhood cancer treated with HSCT are limited to descriptive outcomes of very small cohorts.

    Refer to the Urinary System Late Effects section of the Childhood Hematopoietic Cell Transplantation summary for more infomation.

Genetic factors predisposing to renal dysfunction

Many childhood survivors of Wilms tumor who develop chronic renal failure have syndromes accompanying WT1 mutations or deletions that predispose to renal disease. 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 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 end-stage renal disease is 50% for Denys-Drash syndrome, 90% for WAGR, 25% for genitourinary anomaly, and 12% for patients for all others.[21,22] End-stage renal disease in patients with WAGR and genitourinary anomalies tended to occur relatively late, and often during or after adolescence.[21]

Therapy-related bladder complications

Pelvic or central nervous system surgery, alkylator-containing chemotherapy including cyclophosphamide or ifosfamide, pelvic radiation therapy, and certain spinal and genitourinary surgical procedures have been associated with the following urinary bladder late effects:[23]

  • Chemotherapy. The oxazophorine alkylating agents (cyclophosphamide and ifosfamide) and radiation therapy exposing the bladder have been implicated in the development of hemorrhagic cystitis. Chemotherapy-associated hemorrhagic cystitis presents as an acute toxicity and appears to be a rare persistent effect among clinically well characterized long-term survivor cohorts.[24,25]

    Previous exposure to cyclophosphamide has been linked to risk of bladder carcinoma. An excess prevalence of bladder tumors has also been observed in survivors of specific diagnostic types (e.g., heritable retinoblastoma) supporting the contribution of genetic factors in the development of subsequent neoplasms.[26,27]

  • Radiation therapy. Pelvic radiation is also associated with an increased risk of hemorrhagic cystitis that may be either acute or chronic in presentation. The risk of radiation-induced hemorrhagic cystitis is greatest among survivors treated with radiation doses of more than 30 Gy to the whole bladder or more than 60 Gy to a portion of the bladder. Long-term bladder fibrosis and contracture may result as a sequelae of hemorrhagic cystitis or radiation.[28]
  • Surgery. Surgical procedures involving the lower genitourinary tract have the potential to impair normal function of the bladder and normal voiding mechanisms. Likewise, any cancer therapy or tumor infiltration that disrupts innervation of the bladder can have deleterious effects on bladder function that may manifest as impaired bladder storage, inability to void and/or incontinence.
Table 17. Kidney and Bladder Late Effects
Predisposing TherapyRenal/Genitourinary EffectsHealth 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

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  2. 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]
  3. 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]
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  19. 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]
  20. 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]
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  • Updated: December 12, 2014