Renal impairment and hypertension in brain tumor patients treated in childhood are mainly associated with cisplatin treatment

BACKGROUND: This study was designed to evaluate the renal consequences of the treatment of brain tumor patients diagnosed in childhood. PROCEDURE: One hundred four primary brain tumor patients diagnosed before 17 years of age from 1983 to 1997 had been treated in Tampere University Hospital, Finland. Of the 80 survivors 52 (65.0%) were examined at a median age of 14.4 years (range 3.8-28.7) and median 6.0 years (range 1.2-14.8) after the last treatment. The main outcome measures were blood pressure (BP), renal function, and calcium metabolism. RESULTS: Eight patients (15.4%) were hypertensive. Elevated BP was observed especially after exposure both to cisplatin and cranial irradiation. Spinal radiation did not increase the risk of elevated BP. Other adverse effects were observed only in patients treated with cisplatin. Five out of 14 patients treated with cisplatin evinced renal glomerular dysfunction (GFR < 87 mL/min/1.73 m2) immediately after treatment. They had a high cumulative dose of cisplatin (490-880 mg/m2). Recovery from renal glomerular dysfunction was observed in one patient. Nine of 14 patients were hypomagnesemic at the close of cisplatin treatment. Thereafter the magnesium level decreased in 10/14 cases (P = 0.006). During the study 10/14 were hypomagnesemic (P < 0.001); one evinced severe symptomatic hypomagnesemia. Low plasma phosphate (P = 0.016) and potassium levels (P = 0.026), tubular proteinuria (P = 0.055), metabolic alkalosis (P = 0.071), and hyperuricemia (P = 0.114) were also more common in patients on cisplatin treatment. CONCLUSIONS: Elevated BP is common among brain tumor patients treated in childhood. After cisplatin treatment renal glomerular dysfunction appears mostly to be permanent. Persistent and even progressive changes in renal tubular function are seen.     

Toxicity prevention with amifostine in pediatric osteosarcoma patients treated with cisplatin and doxorubicin

Amifostine has emerged as a pancytoprotectant shown protection against nephrotoxicity, neurotoxicity and ototoxicity in preclinical studies. Methods: We designed a prospective comparative randomized trial to evaluate the cytoprotective effects of amifostine in patients with osteosarcoma receiving cisplatin and doxorrubicin. Patients were evaluated for renal, hearing and cardiac toxicity. Results: We included 28 patients, mean age was 11.6 years, five had metastatic disease. Fifteen patients received amifostine and 13 did not. 20% of patients receiving amifostine developed renal toxicity compared to 30% in the control group (p = 0.318). Grade 1 and 2 audiologic toxicity was present in 100% of the experimental group against 85% of the controls (p = 0.501). Grade 1 cardiac toxicity was present in 2 patients in the control group (p = 0.175). There were no statistical significant differences between the two groups for chemotherapy-related toxicity. Response to chemotherapy was significantly better in the amifostine group. Conclusion: amifostine did not reduce the ototoxicity and nephrotoxicity of our treatment regime. It was not well tolerated due to emesis. It is a selective cytoprotectant without reducing the effect of chemotherapy.     

Evaluation of arterial structure and function in pediatric patients with end-stage renal disease on dialysis and after renal transplantation

CVD is a major cause of morbidity and mortality in pediatric patients with CKD. It is unclear whether vascular abnormalities in these patients are reversible, and if transplantation portends salutary effects on arterial function. We compared FMD, PWV, AI75, and CIMT in 15 dialysis (D), 14 transplant patients (T), and 15 controls (C), and their associations with cardiovascular risk factors. There was stepwise lower FMD (p < 0.001), higher AI75 (p < 0.001), higher PWV (p = 0.01), and higher CIMT SDS for age (p = 0.03) and height (p = 0.006) in the D group than T and C groups. FMD, PWV, and CIMT were unrelated to dialysis duration or time from transplantation. On multivariate analysis, group status was independently associated with FMD (β = 3.15, p = 0.002), AI75 (β = -5.95, p = 0.01), PWV (β = -0.57, p = 0.07) and CIMT (β = -0.02, p = 0.04) and CIMT SDS for height (β = -0.541, p = 0.009). FMD is lower and AI75, PWV and CIMT are higher in pediatric patients maintained on D than T/C. T patients have similar AI75, PWV and CIMT to C although FMD remains reduced. These findings suggest that transplantation stabilizes or improves CKD associated arteriopathy.     

Renal function outcome in pediatric liver transplant recipients

The orthotopic liver transplantation (OLT) allows survival of children followed for severe hepatic injury, provided that the immunosuppressive treatment is prolonged. The nephrotoxicity of cyclosporine predicts the long-term outcome of the adult patients receiving a liver transplant. The aim of this study was to determine the long-term outcome of renal function in children receiving OLT. This study included 12 children, with a median for age of 7.1 yr (2-15 yr) at the time of OLT. The duration of follow-up was at least 4 yr, being 7 yr in 10 patients and more than 10 yr in seven. Renal function was evaluated with the serum level of creatinine, calculated glomerular filtration rate (cGFR), and measurement of glomerular filtration rate using chrome 51 ethylenediaminetetraacetate ((51)Cr EDTA) clearance performed at least once during follow-up. The doses and the serum concentrations (C(0)) of cyclosporine were reported at each study time. The cGFR decreased significantly 2 yr after the OLT [median (range): 106 mL/min/1.73 m(2) (71-150) at the time of OLT vs. 85 mL/min/1.73 m(2) (57-128) 2 yr after the OLT, p = 0.03], and decreased again between 7 and 10 yr after OLT [median (range): 99 mL/min/1.73 m(2) (76-125) 7 yr after OLT vs. 81 mL/min/1.73 m(2) (66-140) 10 yr after OLT, p = 0.04]. Six patients developed chronic renal failure (cGFR from 57 to 80 mL/min/1.73 m(2)) 2 yr after OLT associated with high doses of cyclosporine [median (range): 8.8 mg/kg/day (3.5-13)]. The cGFR overestimated renal function by 16% compared with the isotopic measurement of GFR (p = 0.03). Using the (51)Cr EDTA measurement, six of seven patients followed up more than 10 yr after OLT presented mild (n = 3) or moderate (n = 3) chronic renal failure. In our study, the majority of OLT recipients developed a chronic renal failure 10 yr after transplantation. Cyclosporine seems to be the most important factor responsible for the impairment of renal function. The use of the mycophenolate mofetil, a new immunosuppressive agent, allowing a reduction in the dose of cyclosporine, could minimize renal dysfunction. While awaiting the results of a prospective long-term study, close drug monitoring is advised.     

Hypertension and end-organ damage in pediatric renal transplantation

The prevalence of hypertension in pediatric patients with renal transplant (Tx) has not changed for the last three decades, remaining at 50-80%. Long-standing and uncontrolled hypertension is associated with the development of end-organ damage including allograft dysfunction, early cardiomyopathy and premature atherosclerosis. Aggressive treatment of elevated BP is an essential part of Tx care with the goal to delay graft failure and prevent the development of symptomatic cardiovascular disease in young recipients of renal Tx.     

Phase II trial of etoposide and cisplatin in patients with refractory and relapsed non-Hodgkin's lymphoma: Cancer and leukemia group B study 8351

A phase-II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed non-Hodgkin's lymphoma (NHL) to assess the activity of the combination of etoposide and cisplatin. Sixty-five patients were entered on study, and 51 patients were evaluated for this report. The treatment regimen consisted of etoposide, 80 mg/m² IV daily times 5 and cisplatin 20 mg/m² IV daily times 5, repeated every 21 days. All patients had failed 1–3 prior chemotherapeutic regimens, had measurable disease, and had a performance status of 0–2. In the 51 evaluable patients, there were 4 complete responses (8%) and 12 partial responses (23%), for an overall response rate of 31% (95% Cl: 19%, 46%). In addition, 15 patients (29%) had some improvement in disease and 6 (12%) had stable disease. Failure-free survival for the 51 eligible patients was 40% at 3 months, 23% at 6 months, and 15% at 1 year. Significant toxicity was observed with this regimen. Severe neutropenia occurred in 20 patients (39%), severe anemia in 8 patients (16%), and severe thrombocytopenia in 18 patients (35%). One patient died of infection. Severe neurotoxicity (1) and hemorrhage (3) were also seen. The etoposide, cisplatin combination is active in NHL; however, in this dose and schedule their combined activity is only minimally better than published reports of etoposide alone. Further studies of related combinations are under evaluation by the CALGB. © 1993 Wiley-Liss, Inc.     

Clinical efficacy of cabozantinib in two pediatric patients with recurrent renal cell carcinoma

Advanced‐stage renal cell carcinoma (RCC) carries a dismal prognosis for pediatric patients with few studied therapeutic options. Cabozantinib is a small molecule tyrosine kinase inhibitor against the oncoprotein MET. It is currently approved by the U.S. Food and Drug administration for second‐line treatment of RCC in adults. There is no published data on its use in children with RCC. We report here two pediatric patients with recurrent metastatic RCC whose tumors expressed MET and were treated with cabozantinib. Both patients had significant disease regression and symptomatic improvement for over 15 months with tolerable adverse effects. Cabozantinib can maintain prolonged disease control in pediatric RCC and warrants further study.     

Obstructive uropathy is associated with polyomavirus viremia in pediatric kidney transplantation

Matossian D, Langman CB, Cohn RA, Ali FN. Obstructive uropathy is associated with polyomavirus viremia in pediatric kidney transplantation. Abstract: BKVN leads to allograft dysfunction following kidney transplantation and is preceded by BK viremia. Studies in pediatric kidney transplant recipients reveal an incidence of viruria ranging from 18% to 33%, viremia 6–16%, and BKVN 2–8%. Specific risk factors have not been clearly elucidated. Retrospective chart review of pediatric kidney transplants performed from January 2005 through December 2009; to identify risk factors associated with BK viremia in pediatric kidney transplant recipients from a single center. Of the 93 patients who received kidney transplants in the study period, 22 (24%) developed BK viruria, including 12 (13%) who developed viremia. One patient with viremia (1.6%) had BKVN. Obstructive uropathy was identified as the cause of ESKD in 22 (24%) of all recipients. 27% (n = 6) of these 22 patients developed viremia, while only 8.5% (6/71) with ESKD from another cause had viremia (p = 0.001). No other examined variable differed between the two groups. Although the overall incidence was no higher than other reported series, we identified that BK disease was more frequent in children with OU. A higher index of suspicion for invasive BK disease is necessary in patients with OU who receive kidney allografts. Transplant protocols may need to consider underlying cause of ESKD when designing screening protocols for BK disease in children after kidney transplantation.     

Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system

BACKGROUND: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents. PROCEDURE: Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments. RESULTS: There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). 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. CONCLUSION: Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment.     

Hyperaminoaciduria identifies patients at risk of developing renal tubular toxicity associated with ifosfamide and platinate containing regimens

We monitored renal tubular function in 18 neuroblastoma patients treated with chemotherapeutic regimens containing Ifosfamide and platinates. The total IFO dose ranged from 30 to 48 g/m². After each IFO course and at regular intervals during follow-up 24 hour urinary excretion of aminoacids, qualitative excretion of protein and glucose, tubular reabsorption of phosphate, serum pH, and liver enzyme (SGOT and SGPT) were measured. The ratio of α-amino-Nitrogen/total-Nitrogen (normal <2.5%) and the urinary excretion pattern were used to quantify the aminoaciduria In 12 out of 15 evaluable patients some degree of tubular toxicity occurred during treatment, slowly progressing to a Debré-de Toni-Fanconi syndrome (DTFS) in 7 patients. The DTFS was fully developed in most cases 3–9 months after the end of treatment and was reversible in 3 cases. Hyperaminoaciduria (HAA) occurred in all patients during treatment, preceding other signs of tubular toxicity. The maximum ratio measured before development of a DTFS was significantly higher in the patients with severe toxicity (P < .01). HAA characterized by a ratio >10% predicts the development of a DTFS with a sensitivity of 71.4% and a specificity of 87.4%.     

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.     

Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient

This case report presents the pharmacokinetics of doxorubicin and etoposide in a 14-year-old morbidly obese (body mass index: 46.3 kg/m²) male patient with Hodgkin disease. Dosing based on an adjusted body surface area resulted in a dose reduction by approximately 25% as compared to dosing based on actual body surface area. Plasma clearance of doxorubicin as well as plasma clearance and elimination rate of etoposide for this patient was comparable to pharmacokinetic data from nonobese pediatric patients. The therapy was well tolerated without any specific toxicity and a complete response was obtained after 2 scheduled courses, with the patient in complete remission 25 months after end of treatment.     

Risk factors associated with delayed methotrexate clearance and increased toxicity in pediatric patients with osteosarcoma

High‐dose methotrexate (HD‐MTX; 12 g/m²) is part of standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. We investigated the association between peak MTX levels (four‐hour) and delayed MTX clearance or treatment toxicity. Information was retrieved from electronic medical records of 33 OS patients treated with HD‐MTX at Texas Children's Hospital from 2008 to 2015. We found that the four‐hour MTX level did not contribute to toxicity or delayed MTX clearance. We demonstrated that certain demographic characteristics are associated with delayed clearance and increased toxicity.     

Long-term renal function in pediatric liver and heart recipients

Long-term survivors of pediatric liver and heart transplantation are at risk for progressive renal dysfunction as a result of chronic exposure to calcineuron inhibitors. This class of drugs causes alterations in renal perfusion that can result in irreversible renal injury including afferent arteriopathy, glomerulosclerosis, tubular atrophy and interstitial fibrosis. Approximately 3-6% of pediatric liver and heart recipients will develop end stage renal failure. A much larger percentage has chronic renal insufficiency and hypertension. Children with significant renal compromise in the pretransplant period and those with significantly elevated serum creatinine levels during the first post-transplant year may be at the highest risk to develop irreversible renal injury in long-term follow-up. Serum creatinine is a poor screening tool as it rises late in the course when the injury may no longer be reversible. Strategies to minimize long-term exposure to calcineuron inhibitors may reduce the prevalence of renal insufficiency in this vulnerable population.     

Mortality in pediatric renal transplantation: A study of the French pediatric kidney database

Abstract: Objective and Methods: To assess patient survival in pediatric renal transplantation, we retrospectively reviewed 573 transplants in 553 patients, registered from 1995 to 2005. Results: Mean age at transplantation was 9.9 years. Patient survival at 1, 5 and 10 years was respectively 99%, 97% and 96%. Death occurred at a median time of 2.6 years after transplantation. Long‐term patient survival was significantly lower in recipients younger than 5 years old. Seventeen patients (3.1%) died. Two deaths occurred while under maintenance dialysis. Among the remaining patients, the two main causes of death were infections (33%) and malignancies (27%). Interestingly, initial disease‐related complications were a major cause of death (34%). Conclusion: A low mortality rate was observed, with the majority of deaths due to malignancies and infections, and with a notable participation of complications related to the initial disease. No impact of cardiovascular disease was noted with the given follow‐up period. Improvements in managing immunosuppression may contribute to reducing mortality in pediatric renal transplantation.     

Renal tubular dysfunction following treatment with anti-epileptic drugs

To evaluate renal side-effects of anti-epileptic medication in children, we performed a cross-sectional study of various aspects of renal function. We studied 59 patients from our outpatient clinic. They had been on anti-epileptic monotherapy for at least 3 months. None had a history of renal disease. Twenty-three healthy children of the same age group served as controls. After collecting 24-h urine samples, glomerular function was derived from creatinine clearance and from the excretion of albumin. Proximal tubular function was investigated by the urinary excretion of 1-microglobulin and of the tubular enzymes N-acetyl-ß-D-glucosaminidase, alamine-amino-peptidase and fructose-1,6-di-phosphatase. Distal tubular function was examined by the 24-h excretion of Tamm-Horsfall protein. On treatment with carbamazepine (n=27) and phenytoin (n=8), the excretion of 1-microglobulin was significantly increased, as compared with the healthy controls. On valproate (n=20), ethosuximide (n=9) and phenytoin (n=8), therapies significantly increased excretion of N-acetyl-ß-D-glucosaminidase. This must be interpreted as an indication of a functional disturbance of the proximal tubulus. The other parameters, indicating function of the glomerulus, loop of Henle and distal tubules did not differ from normal.Patients on anti-epileptic treatment with therapeutic drug levels may demonstrate minor signs of tubular dysfunction. These are probably insignificant from a clinical standpoint, but they should be considered in drug overdose.