Takahashi T, Iwasaki K, Malchesky P S, Harasaki H, Matsushita M, Nosé Y, Rolin H, Hall P M
Department of Artificial Organs, Cleveland Clinic Foundation, Ohio.
Artif Organs. 1993 Mar;17(3):153-63. doi: 10.1111/j.1525-1594.1993.tb00424.x.
Pyridoxalated-hemoglobin-polyoxyethylene conjugate (PHP), which is made from out-dated human red blood cells by two major chemical modifications, namely pyridoxalation and conjugation with polyoxyethylene (POE), is currently under development as a physiological oxygen carrier. This study assessed the effects of PHP-88 solution, which contains 8% (wt/vol) each of hemoglobin (Hb) and maltose, on renal function when it was infused 3 times every other day into the intact circulation of 8 dogs (5 dogs for the PHP group and 3 for the control group; 20 ml/kg for the first infusion, and 10 ml/kg each for the second and third infusions, at the rate of 2.5 ml/h/kg). Serial determinations of glomerular filtration rate (GFR) and renal plasma flow (RPF) were carried out pre- and postinfusion for up to 3 months along with measurements of blood and urine analyses, urine output rate, fractional excretion of sodium (FES), and free water clearance (CH2O). The results showed that plasma colloid osmotic pressure (COP) elevated an average of 3.3 mm Hg (p = 0.0085), and GFR and RPF tended to increase by 13% (NS) and 38% (NS), respectively, immediately after the third infusion with PHP solution. Urine output rate increased during and after the infusion, and FES and CH2O also increased for 24 h after the infusion in both groups. Blood urea nitrogen, serum creatinine, and serum Na+ concentrations were not affected greatly by the infusions, but hematocrit was decreased by 8% in the PHP group, indicating approximately a 42% expansion of plasma volume. These changes were observed to return to their preinfusion levels by 1 week postinfusion. Renal histology of the PHP group obtained at 2 weeks postinfusion revealed vacuole formation in the proximal tubules which was not associated with any pathologic changes indicative of cell death or regeneration. In 4 out of 5 dogs at 3 months postinfusion (necropsy), the vacuoles were not present. Though urinary N-acetyl-beta-glucosaminidase (NAG) activity had significantly increased after infusion, it returned to the preinfusion level by 1 month postinfusion. No detrimental effect of vacuoles on the assessed renal tubular functions was confirmed in the present study. The results demonstrated that multiple infusions of PHP solutions were well tolerated in normal dogs, and the observed effects were conceived predominantly attributable to the physiological response of the kidneys to an oncotic load into the circulation, which produced plasma volume expansion.
吡哆醛化血红蛋白 - 聚氧乙烯共轭物（PHP）是通过两项主要化学修饰，即吡哆醛化以及与聚氧乙烯（POE）共轭，由过期人红细胞制成的，目前正作为一种生理性氧载体进行研发。本研究评估了PHP - 88溶液（其中血红蛋白（Hb）和麦芽糖各含8%（重量/体积））每隔一天输注3次进入8只犬的完整循环系统时对肾功能的影响（PHP组5只犬，对照组3只犬；首次输注剂量为20 ml/kg，第二次和第三次输注剂量均为10 ml/kg，输注速率为2.5 ml/h/kg）。在输注前和输注后长达3个月的时间里，连续测定肾小球滤过率（GFR）和肾血浆流量（RPF），同时进行血液和尿液分析、尿量输出率、钠分数排泄（FES）以及自由水清除率（CH2O）的测量。结果显示，在第三次输注PHP溶液后即刻，血浆胶体渗透压（COP）平均升高3.3 mmHg（p = 0.0085），GFR和RPF分别有升高13%（无统计学意义）和38%（无统计学意义）的趋势。输注期间及输注后尿量输出率增加，两组在输注后24小时内FES和CH2O也增加。血液尿素氮、血清肌酐和血清Na⁺浓度受输注影响不大，但PHP组血细胞比容降低了8%，表明血浆量大约扩充了42%。观察到这些变化在输注后1周恢复到输注前水平。输注后2周获取的PHP组肾脏组织学检查显示近端小管中有空泡形成，但未伴有任何表明细胞死亡或再生的病理变化。在输注后3个月（尸检）时，5只犬中有4只犬的空泡不存在。尽管输注后尿N - 乙酰 - β - 氨基葡萄糖苷酶（NAG）活性显著增加，但在输注后1个月恢复到输注前水平。在本研究中未证实空泡对所评估的肾小管功能有有害影响。结果表明，多次输注PHP溶液在正常犬中耐受性良好，观察到的效应主要归因于肾脏对循环中胶体渗透压负荷的生理反应，这导致了血浆量扩充。
