Ho P T, Zimmerman K, Wexler L H, Blaney S, Jarosinski P, Weaver-McClure L, Izraeli S, Balis F M
Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cancer. 1995 Dec 15;76(12):2557-64. doi: 10.1002/1097-0142(19951215)76:12<2557::aid-cncr2820761223>3.0.co;2-9.
Ifosfamide has been associated with proximal renal tubular dysfunction resembling Fanconi-like syndrome and leading to rickets in young children. The characteristic manifestations of this nephrotoxicity include phosphaturia and hypophosphatemia, glycosuria, aminoaciduria, renal tubular acidosis, and urinary loss of low molecular weight serum proteins. However, the relationship between acute ifosfamide nephrotoxicity, which is frequently subclinical, and long term renal damage is unclear. In this prospective study, the laboratory features of ifosfamide-induced acute nephrotoxicity were characterized further and correlated with the development of chronic nephropathy.
The renal function of newly diagnosed children and young adults with high risk sarcomas was followed during therapy with a high dose ifosfamide-containing regimen. Serum and urine were collected regularly immediately before and after 5-day cycles of ifosfamide throughout treatment for determination of the fractional excretion of electrolytes (sodium, potassium, phosphate, magnesium, calcium) and glucose and urinary excretion of amino acids and beta 2-microglobulin.
Significant changes in the renal threshold of phosphate excretion, the fractional excretion of calcium and glucose, and the urinary excretion of beta 2-microglobulin were observed when comparing pretreatment values with those at the end of a 5-day treatment cycle. The median renal threshold of phosphate excretion decreased from 1.22 to 0.82 mmol/L (P < 0.0001). The median fractional excretions of calcium and glucose increased from 1.05% to 1.68% (P < 0.0001) and 0.05% to 0.08% (P = 0.0006), respectively. Beta 2-microglobulin excretion increased by 70-fold from 0.02 to 1.42 mg/mmol (P < 0.0001). Except for glucose and beta 2-microglobulin excretion, renal parameters returned to baseline before the next ifosfamide treatment cycle. Acute aminoaciduria was observed in 21 of 23 patients. Chronic nephrotoxicity, as defined by the development of a Fanconi-like syndrome or chronic tubular electrolyte loss requiring oral supplementation, developed in the three patients with the highest urinary excretion of beta 2-microglobulin after ifosfamide therapy.
Prospectively, high dose ifosfamide was associated with a 4% incidence of Fanconi-like syndrome; however, evidence of acute reversible subclinical nephrotoxicity was observed for all patients. Severe beta 2-microglobulinuria appeared to be a prognostic laboratory indicator for the development of chronic nephrotoxicity.
异环磷酰胺与类似范科尼综合征的近端肾小管功能障碍有关，并可导致幼儿佝偻病。这种肾毒性的特征性表现包括磷酸盐尿和低磷血症、糖尿、氨基酸尿、肾小管酸中毒以及低分子量血清蛋白的尿丢失。然而，经常为亚临床的急性异环磷酰胺肾毒性与长期肾脏损害之间的关系尚不清楚。在这项前瞻性研究中，进一步描述了异环磷酰胺诱导的急性肾毒性的实验室特征，并将其与慢性肾病的发生相关联。
在采用含高剂量异环磷酰胺方案治疗期间，对新诊断的高危肉瘤患儿和年轻成人的肾功能进行随访。在整个治疗过程中，于异环磷酰胺5天疗程前后立即定期采集血清和尿液，以测定电解质（钠、钾、磷酸盐、镁、钙）和葡萄糖的排泄分数以及氨基酸和β2-微球蛋白的尿排泄量。
将治疗前的值与5天治疗周期结束时的值进行比较时，观察到磷酸盐排泄肾阈值、钙和葡萄糖排泄分数以及β2-微球蛋白尿排泄量有显著变化。磷酸盐排泄肾阈值中位数从1.22 mmol/L降至0.82 mmol/L（P < 0.0001）。钙和葡萄糖排泄分数中位数分别从1.05%增至1.68%（P < 0.0001）和从0.05%增至0.08%（P = 0.0006）。β2-微球蛋白排泄量从0.02 mg/mmol增至1.42 mg/mmol，增加了70倍（P < 0.0001）。除葡萄糖和β2-微球蛋白排泄外，肾脏参数在下一个异环磷酰胺治疗周期前恢复至基线水平。23例患者中有21例观察到急性氨基酸尿。在异环磷酰胺治疗后β2-微球蛋白尿排泄量最高的3例患者中出现了类似范科尼综合征或需要口服补充剂的慢性肾小管电解质丢失所定义的慢性肾毒性。
前瞻性研究表明，高剂量异环磷酰胺与4%的类似范科尼综合征发生率相关；然而，所有患者均观察到急性可逆性亚临床肾毒性的证据。严重的β2-微球蛋白尿似乎是慢性肾毒性发生的预后实验室指标。
