Savin V, Karniski L, Cuppage F, Hodges G, Chonko A
Lab Invest. 1985 Jan;52(1):93-102.
Alterations in both glomerular filtration rate and tubular transport occur in clinical gentamicin nephrotoxicity. We have studied the function of isolated tubules and glomeruli from rabbits treated with gentamicin. Gentamicin was administered subcutaneously to sexually immature (1400 to 1800 gm) or sexually mature (3800 to 4600 gm) New Zealand White rabbits in a dose of 15 mg/kg twice a day. Immature rabbits were treated for 28 to 31 days and developed only minimal renal insufficiency. About one-half of the mature rabbits developed azotemia. The mature rabbits that did not become azotemic were sacrificed after 28 to 30 days, and those that became azotemic were killed when their serum creatinine reached 2.5 mg/dl or higher (10 to 24 days). Animals were anesthetized and kidneys were removed for histologic examination and isolation of tubules and glomeruli. The ratio of p-aminohippuric acid (PAH) concentration in isolated tubule cells to that in medium after incubation in 3H-PAH (1 microM) at 37 degrees C for 30 minutes (T/M PAH) was used as an indicator of transport capacity of tubules. T/M PAH ratios averaged 196 +/- 18 and 111 +/- 21 for control immature and mature rabbits, respectively, and 135 +/- 22, 80 +/- 16, and 9 +/- 2 for gentamicin-treated immature and mature nonazotemic and mature azotemic rabbits, respectively. Glomeruli were isolated and filtration induced in vitro by a transcapillary oncotic gradient. Ultrafiltration coefficient, Kf, of glomeruli of immature and mature control rabbits averaged 3.78 +/- 0.29 and 5.84 +/- 0.51 nl/minute X mm Hg. Kf from gentamicin-treated immature rabbits averaged 2.82 +/- 0.20 and from mature azotemic rabbits 3.14 +/- 0.44 nl/minute X mm Hg. Kf of both mature and immature rabbits were decreased compared with controls (p less than 0.01). When all animals were considered, relative glomerular filtration rate, estimated from 1/serum creatinine, was positively correlated with the T/M PAH and Kf. When only experimental animals were studied, 1/serum creatinine and T/M PAH were also correlated. Decreased glomerular filtration rate and dysfunction of proximal tubules were also correlated with abnormal tubule histology. We suggest that injury to glomeruli and tubules may represent independent manifestations of gentamicin toxicity. Dysfunction may be present even when there are only mild histologic changes and glomerular filtration rate is near normal. Kf does not appear to limit glomerular filtration rate after treatment with gentamicin; rather, some direct or indirect effect of tubular injury may determine the decrement in glomerular filtration rate.
在临床庆大霉素肾毒性中，肾小球滤过率和肾小管转运均会发生改变。我们研究了用庆大霉素处理的兔子的离体肾小管和肾小球的功能。将庆大霉素以15mg/kg的剂量皮下注射给性未成熟（1400至1800克）或性成熟（3800至4600克）的新西兰白兔，每天两次。未成熟兔子治疗28至31天，仅出现轻微肾功能不全。约一半的成熟兔子出现氮质血症。未发生氮质血症的成熟兔子在28至30天后处死，发生氮质血症的兔子在其血清肌酐达到2.5mg/dl或更高时（10至24天）处死。动物麻醉后取出肾脏进行组织学检查以及肾小管和肾小球的分离。将3H-对氨基马尿酸（PAH，1μM）在37℃孵育30分钟后，离体肾小管细胞中PAH浓度与培养基中PAH浓度的比值（T/M PAH）用作肾小管转运能力的指标。对照未成熟和成熟兔子的T/M PAH比值分别平均为196±18和111±21，庆大霉素处理的未成熟和成熟非氮质血症以及成熟氮质血症兔子的T/M PAH比值分别为135±22、80±16和9±2。分离肾小球并通过跨毛细血管胶体渗透压梯度在体外诱导滤过。未成熟和成熟对照兔子肾小球的超滤系数Kf分别平均为3.78±0.29和5.84±0.51nl/分钟×mmHg。庆大霉素处理的未成熟兔子的Kf平均为2.82±0.20，成熟氮质血症兔子的Kf平均为3.14±0.44nl/分钟×mmHg。与对照组相比，成熟和未成熟兔子的Kf均降低（p<0.01）。当考虑所有动物时，根据1/血清肌酐估算的相对肾小球滤过率与T/M PAH和Kf呈正相关。当仅研究实验动物时，1/血清肌酐和T/M PAH也相关。肾小球滤过率降低和近端肾小管功能障碍也与肾小管组织学异常相关。我们认为，肾小球和肾小管损伤可能是庆大霉素毒性的独立表现。即使只有轻微的组织学改变且肾小球滤过率接近正常，也可能存在功能障碍。庆大霉素治疗后，Kf似乎并不限制肾小球滤过率；相反，肾小管损伤的某些直接或间接影响可能决定了肾小球滤过率的降低。
