Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System

BACKGROUND: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far. PROCEDURE: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria. RESULTS: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence. CONCLUSION: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.     

Increased renal parenchymal echogenicity in ifosfamide-induced renal fanconi syndrome

Three children who presented with a Fanconi syndrome induced by the chemotherapeutic drug ifosfamide were found to have renal abnormalities on sonogram examinations. Renal echographic changes consisted in hyperechogenicity of the parenchyma with good corticomedullar differentiation. After discontinuation of the chemotherapy, the serum and urine metabolic abnormalities due to proximal tubulopathy were completely or greatly improved. Imaging studies at that time showed a complete resolution of the renal hyperechogenicity. We suggest that in patients exposed to ifosfamide, renal sonogram may be of value to monitor the tubular toxicity of this drug. In these patients, urine and serum monitoring as well as prospective echographic follow-up kidney abnormalities may lead to earlier detection of ifosfamide-induced Fanconi syndrome as well as earlier detection of disease reversibility. © 1995 Wiley-Liss, Inc.     

Ifosfamide-induced subclinical nephrotoxicity and its potentiation by cisplatinum

Renal function was assessed in 72 children and adolescents 3.5 to 123 months after completion of chemotherapy employing ifosfamide (n = 39) or ifosfamide plus cisplatinum (n = 33). No patient had preexisting renal parenchymal disease. Whereas reduction in glomerular filtration rate was present in six of 69 patients (8.7%), impairment of tubular transport for phosphate, glucose, and amino acids was more frequent: 32.8% of the patients showed reduction in phosphate reabsorption, and glucose and amino acid reabsorption was lowered in 16.4% and 55.0%, respectively. Elevated sodium excretion was found only occasionally, and there was no evidence of renal tubular acidosis. Proximal tubular damage is related to ifosfamide chemotherapy, but correlation between ifosfamide dose and phosphate reabsorption was not linear. The most severe depletion of phosphate reabsorption was seen in patients treated with both ifosfamide and cisplatinum. On reexamination of phosphate reabsorption after a median interval of 8 months, the majority of patients with initially reduced values showed further deterioration of this function. © 1994 Wiley-Liss, Inc.     

Ifosfamide nephrotoxicity in children: Histopathological features in two cases

We report on two children with rhabdomyosarcoma who received ifosfamide as part of their chemotherapy schedule. Both children subsequently developed severe ifosfamide-induced nephrotoxicity, necessitating electrolyte supplementation. We describe the histopathological findings of renal biopsies performed in these children after the onset of renal dysfunction and comment on the possible mechanisms involved in ifosfamide nephrotoxicity. © 1996 Wiley-Liss, Inc.     

Incidence and etiology of ifosfamide nephrotoxicity: Report of a meeting held in Rhodes,Greece, October 3, 1991, sponsored by Asta Medica,Frankfurt, Germany

The nephrotoxic potential of Ifosfamide is now clearly recognized but the true incidence is unknown and risk factors are uncertain. There are, as yet, few studies which systematically explore these issues although many centers have collected data from patients receiving Ifosfamide. These support the need for collaborative studies to look at the influence of probable risk factors such as age, cumulative dose, schedule, and exposure to other nephrotoxic drugs. The ability to detect acute subclinical changes in renal function may provide the opportunity to predict subsequent clinical toxicity. The consensus of opinion recorded so far provides the basis of recommendations for future studies. © 1993 Wiley-Liss, Inc.     

Reversible hypophosphatemic rickets following ifosfamide treatment

A 7-year-old boy developed renal tubular dysfunction and hypophosphatemic rickets following treatment for relapsed embryonal rhabdomyosarcoma. Multi-agent chemotherapy included ifosfamide; the child received a total of 108 g/m². The complete Fanconi syndrome which ensued, including excessive loss of calcium, resolved spontaneously and progressively 18 months after the last dose of ifosfamide. The patient had no further symptoms of rickets and radiological signs had almost completely normalized. Further follow-up was not possible as, despite further treatment, the child died of progressive disease. © 1992 Wiley-Liss, Inc.     

Tubular function and histological findings in ifosfamide-induced renal Fanconi syndrome — a report of two cases

Two patients developed renal Fanconi syndrome (RFS) after intensive long-term chemotherapy for metastatic Ewing sarcoma and disseminated neuroblastoma. Whereas RFS was diagnosed in patient 1 before he developed osteomalacia, patient 2 experienced severe rickets and growth retardation. Renal function studies revealed slight glomerular impairment and severe tubular defects leading to increased excretion of glucose, amino acids, inorganic phosphate and low molecular weight proteins, indicating proximal tubular damage. Patient 2 additionally showed distal tubular dysfunction with acidosis and diminished concentrating capacity. Renal biopsy in patient 1 revealed marked proximal tubular defects without interstitial lymphocytic infiltration. In both patients renal damage could most likely be ascribed to previous ifosfamide (IFOS) therapy. Our patients showed no improvement in renal function after cessation of IFOS treatment, indicating a poor prognosis of once established RFS after IFOS therapy. Measurement of tubular reabsorption capacities provides exact information on the extent of tubular toxicity induced by IFOS and may be used to monitor IFOS treated patients.     

Ifosfamide nephrotoxicity in paediatric cancer patients

Ifosfamide is an alkylating agent which has been incorporated into frontline therapy for a number of malignant paediatric tumours. Recent data appears to suggest that tubular dysfunction may result from incorporation of this drug into chemotherapy schedules and that toxicity may be dose related. A detailed investigation of renal function was performed in a group of patients, ranging in age from 8 months to 15.9 years (median 8.6 years) with rhabdomyosarcoma (n=11) and Ewing's sarcoma (n=9) who were currently receiving (n=4) or had completed ifosfamide (n=16) therapy a mean of 16 months at the time of study. All but one patient demonstrated some degree of renal dysfunction and toxicity did not necessarily appear to be dose related. Implications for incorporation of this agent into future schedules for childhood sarcomas, which can expect to cure more than 60% of such children, must be addressed. The importance of ongoing monitoring is emphasised.     

儿童急性胰腺炎肾损害临床特征

目的探讨儿童急性胰腺炎肾损害的临床、病理特点。方法对4例急性胰腺炎肾损害患儿进行肾脏活检,尿β2微球蛋白(β2-MG)、视黄醇结合蛋白(RBP),血清白蛋白、肌酐,24h尿蛋白定量等检查;所有患儿均应用糖皮质激素及免疫抑制剂联合治疗。结果急性胰腺炎肾损害患儿血尿、蛋白尿持续时间长,尿24h蛋白定量、尿β2-MG和RBP水平均升高。肾脏病理损害表现为肾间质水肿、弥漫性炎性细胞浸润,肾小球系膜细胞、基质增生,有IgG、IgE、IgA、IgM、C3等免疫复合物沉积。经皮质激素及免疫抑制剂联合治疗6～8个月缓解。结论儿童急性胰腺炎肾损害作为一种独立的继发性肾脏损害性疾病,应当引起临床的关注。     

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??Objective??To analyze the clinical features and the results of genetic diagnosis in children with hypokalemic renal tubular diseases. Methods??The clinical data of 38 patients with hypokalemic renal tubular diseases were analyzed retrospectively??who were treated in Children’s Hospital Affiliated to Shanghai Jiao Tong University from Jan. 2010 to Jan. 2016. Results??Totally 38 patients with hypokalemic renal tubular diseases were enrolled in this study. There were 18 cases of renal tubular acidosis??RTA?? including 17 cases of type??RTA and 1 case of type?? RTA. There were 11 cases of Bartter syndrome??5 cases of Gitelman syndrome and 4 cases of Fanconi syndrome. The common clinical manifestations of hypokalemic renal tubular diseases included myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. One case of Fanconi syndrome progressed to chronic Kidney disease??phase ????while the other
children had normal renal function. Glomerular proteinuria was found in 1??1 and 3 children with Bartter syndrome??Gitelman syndrome and Fanconi syndrome??respectively. Additionally??1 case with Fanconi syndrome has tubular proteinuria. However??urinary trace proteins associated with glomerular and tubular injury commonly elevated in these hypokalemic renal tubular diseases. Genetic analysis showed a new potential heterozygous mutations of ATPV0A4 in type??RTA and three heterozygous mutations of SLC12A3 in Gitelman syndrome. Conclusion??The clinical symptoms vary in patients and are featured mainly by myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. Glomerular and tubular injuries are commonly found in hypokalemic renal tubular diseases. Moreover??genetic diagnosis may be helpful in diagnosis??treatment and genetic counseling.     

Renal Fanconi syndrome and myopathy after liver transplantation: Drug‐related mitochondrial cytopathy?

Advances in the field of transplantation provide a better quality of life and allow more favorable conditions for growth and development in children. However, combinations of different therapeutic regimens require consideration of potential adverse reactions. We describe a 15-yr-old girl who had orthotopic liver transplantation because of Wilson's disease. Tacrolimus, MMF, and steroids were given as immunosuppressant. Lamivudine was added because of de nova hepatitis B infection during her follow-up. Three yr after transplantation she developed renal Fanconi syndrome with severe metabolic acidosis, hypophosphatemia, glycosuria, and aminoaciduria. Although tacrolimus was suspected to be the cause of late post-transplant renal acidosis and was replaced by sirolimus, acidosis, and electrolyte imbalance got worse. Proximal muscle weakness has developed during her follow-up. Fanconi syndrome, as well as myopathy, is well recognized in patients with mitochondrial disorders and caused by depletion of mtDNA. We suggest that our patient's tubular dysfunction and myopathy may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine.     

Growth hormone therapy before and after pediatric renal transplant

Children undergoing successful renal transplantation anticipate optimal growth and development. The use of rhGH pre- and post-Tx has been evaluated and supported by randomized control trials. Several strategies are required to maximize the potential benefit of this treatment in the renal population including provision of adequate nutrition intake, following bone parameters with appropriate interventions, and strategies to reduce steroid therapy including utilization of alternate day steroid treatment. Studies are required to further assess the impact of rhGH on renal allograft function, rejection risk, and allograft ultrastructural changes.     

Outcomes after renal transplantation for FSGS in children

Focal segmental glomerulosclerosis (FSGS) is the primary diagnosis resulting in end-stage renal disease in approximately 12% of children receiving renal transplantation. Recurrent FSGS after transplantation is unpredictable and clear risk factors have not been identified. Post-transplantation, the incidence of acute tubular necrosis requiring dialysis is higher in children with FSGS compared with other diagnoses and may represent immediate severe recurrence. Graft survival is decreased in children with FSGS compared with other primary diagnoses, and the impact is greatest in recipients of living donor transplants. Graft loss caused by recurrent FSGS is significantly higher in living donor transplants compared with cadaveric donor transplants in children. Compared with adults, the impact of FSGS on graft survival appears to be greatest in children. White recipient race is associated with a higher risk of graft loss from recurrent FSGS. Efforts to elucidate the mechanisms of recurrent FSGS and to understand risk factors based on genetics, potential circulating cytokines and permeability factors, age and race must move forward before we can significantly impact outcomes in renal transplantation for FSGS.     

Recombinant human granulocyte-macrophage colony-stimulating factor in children with chemotherapy-induced neutropenia

Twenty children 1–17 (median, 5.5) years of age received GM-CSF during chemotherapy-induced neutropenia at the dose of 5 μg/kg/day, continued until the absolute neutrophil count (ANC) exceeded 500 × 10⁶/liter. Twelve children with solid tumors received GM-CSF after courses of conventional chemotherapy (VP-16 + ifosfamide or “6 in 1”). One course followed by GM-CSF was compared to identical courses without GM-CSF in the same patients. Eight children with recurrent/poor risk malignancies received GM-CSF after marrow-ablative therapy and autologous bone marrow transplantation (ABMT). Their engraftment data were compared to matched historical controls. In both groups GM-CSF accelerated myeloid recovery, which was preceded by the appearance of immature myeloid elements in bone marrow. The ANC levels of 200, 500, and 1,000 × 10⁶/liter were exceeded 2, 3 (P<0.05), and 6 (P<0.005) days earlier with GM-CSF in the conventional chemotherapy group, and 6, 10 (P<0.05), and 9 days earlier in the ABMT group, as compared to the controls. All adverse effects observed were mild, including skin rashes, nasal stuffiness, general achiness, nausea, and fever. We conclude that GM-CSF is well tolerated in children and accelerates myeloid recovery in chemotherapy-induced neutropenia. © 1992 Wiley-Liss, Inc.     

A case of Fanconi syndrome whose origin was suspected to be cystinosis

We report a case of 6 year old girl with Fanconi syndrome the origin of which was suspected to be cystinosis. Pathological findings of a renal biopsy showed needle-like materials in the epithelial cells but the cystine content of the white blood cells was normal. Although excessive urinary loss of growth hormone was detected, the height and weight of the patient was normal. Urinary loss of growth hormone did not cause growth retardation in this case.