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. 2016 Mar;27(3):903-13.
doi: 10.1681/ASN.2015020157. Epub 2015 Sep 24.

Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia

Ravi Thadhani  1 , Henning Hagmann  2 , Wiebke Schaarschmidt  3 , Bernhard Roth  4 , Tuelay Cingoez  2 , S Ananth Karumanchi  5 , Julia Wenger  6 , Kathryn J Lucchesi  6 , Hector Tamez  7 , Tom Lindner  8 , Alexander Fridman  9 , Ulrich Thome  10 , Angela Kribs  4 , Marco Danner  4 , Stefanie Hamacher  11 , Peter Mallmann  9 , Holger Stepan  3 , Thomas Benzing  12
Affiliations

Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia

Ravi Thadhani et al. J Am Soc Nephrol. 2016 Mar.

Abstract

Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasma-specific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20-38 years of age) with very preterm preeclampsia (23-32 weeks of gestation, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, new onset protein/creatinine ratio >0.30 g/g, and sFlt-1/placental growth factor ratio >85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%-28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2-11) and 15 days (range 11-21) in women treated once and multiple times, respectively, compared with 3 days (range 0-14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.

Keywords: clinical trial; preeclampsia; pregnancy; sFlt-1; therapeutic apheresis; vascular endothelial growth factor.

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Figures

Figure 1.
Figure 1.
Patient G: changes in circulating sFlt-1 levels and corresponding parameters after two apheresis treatments. Patient G was a 31-year-old gravida 0 para 1 who, prior to treatment, was 28+4/7 weeks of gestation with BP 171/117 mmHg, P/C ratio of 1.7 g/g, and sFlt-1 of 11,276 pg/ml. Her sFlt-1/PlGF ratio was 150. She underwent two apheresis treatments without complications (see Table 1). Following the first treatment, sFlt-1 fell to 9800 pg/ml (13% reduction). Her second pretreatment sFlt-1 level had climbed to 12,245 pg/ml and fell to 10,836 pg/ml post-treatment (12% reduction). The P/C ratios post-treatments (within about 12 hours post-treatment) were not available; however her overall P/C ratios did not appear to markedly change during hospitalization. Estimated fetal birthweight before the first treatment was 1048 g. The mother’s pregnancy continued for an additional 14 days (counting from day of admission). At birth (30+0/7 weeks), actual neonatal weight was 1310 g. At 41 days post-delivery (neonate discharge date), the infant weighed 1905 g. At the most recent follow-up conducted 2 months post-discharge, the baby’s growth percentiles were normal. There were no persistent complications associated with treatment, only transient reductions in BP which were managed as detailed in the manuscript.
Figure 2.
Figure 2.
Patient H: changes in circulating sFlt-1 levels and corresponding parameters after two apheresis treatments. Patient H was a 26-year-old gravida 2 para 1 who, prior to treatment, was 25+4/7 weeks of gestation with a BP of 152/96 mmHg, P/C ratio of 19.3 g/g, sFlt-1 of 19,550 pg/ml and sFlt-1/PlGF ratio of 1150. She underwent two treatments of apheresis without complications (see Table 1). Following the first treatment, sFlt-1 fell to 17,320 pg/ml (11% reduction). Her second pretreatment sFlt-1 had risen to 23,569 pg/ml and following the treatment was 23,162 pg/ml (2% reduction). The corresponding P/C ratio after the first treatment was 7.7 g/g (60% reduction). P/C ratios before and after the second treatment were 14.5 g/g and 9.4 g/g, respectively, a 35% reduction. Estimated fetal birthweight before the first treatment was 571 g. Her pregnancy continued for an additional 11 days (counting from day of admission). At birth (26+4/7 weeks), actual neonatal weight was 580 g. The infant’s weight was 1640 g at the time of hospital discharge (day 90). There were no persistent complications with treatment.
Figure 3.
Figure 3.
Patient I: changes in circulating sFlt-1 levels and corresponding parameters after two apheresis treatments. Patient I was a 23-year-old gravida 0 para 1 who, prior to treatment, was 29+3/7 weeks of gestation with a BP of 178/120 mmHg, P/C ratio of 9.9 g/g, sFlt-1 of 19,019 pg/ml and sFlt-1/PlGF ratio of 674. She underwent two apheresis treatments without complications (see Table 1). Following the first treatment, sFlt-1 fell to 14,955 pg/ml (21% reduction). Her second pretreatment sFlt-1 had risen to 25,024 pg/ml and following the treatment was 20,063 pg/ml (20% reduction). P/C ratio immediately after the first treatment was 11.8 g/g (19% increase). With the second treatment, before and after P/C ratios were 11.1 g/g and 2.4 g/g (78% reduction). Estimated fetal birthweight before the first treatment was 1206 g. The mother’s pregnancy continued for an additional 11 days (counting from day of admission). At birth (30+3/7 weeks), actual neonatal weight was 1280 g. At discharge from the hospital (39 days after delivery) the infant’s weight was 1860 g. There were no persistent complications with treatment.
Figure 4.
Figure 4.
Patient J: changes in circulating sFlt-1 levels corresponding parameters after two apheresis treatments. Patient J was a 26-year-old gravida 0 para 2 who, prior to treatment, was 30+5/7 weeks of gestation with a BP of 150/90 mmHg, P/C ratio of 3.8 g/g, sFlt-1 of 7069 pg/ml and sFlt-1/PlGF ratio of 95. She underwent two apheresis treatments without complications (see Table 1). Following the first treatment, sFlt-1 fell to 5161 pg/ml (27% reduction). Her second pretreatment sFlt-1 had risen to 8763 pg/ml and following the treatment was 7731 pg/ml (12% reduction). Before and after treatment P/C ratios for the first treatment were 3.8 and 2.2 g/g (42% reduction) and for the second treatment were 2.7 and 2.4 g/g (11% reduction). Estimated fetal birthweight before the first treatment was 1307 g. The mother’s pregnancy continued for an additional 18 days (counting from day of admission). At birth (32+4/7 weeks), actual neonatal weight was 1490 g. At discharge from the hospital (38 days after delivery) the infant’s weight was 2030 g. There were no persistent complications with treatment.
Figure 5.
Figure 5.
Patient K: changes in circulating sFlt-1 levels and corresponding parameters after three apheresis treatments. Patient K was a 20-year-old gravida 0 para 1 who, prior to treatment, was 29+1/7 weeks of gestation with BP 165/115 mmHg, P/C ratio of 1.4 g/g, sFlt-1 level of 7546 pg/ml and sFlt-1/PlGF ratio of 245. She underwent three apheresis treatments without complications (see Table 1). Following the first treatment, sFlt-1 fell to 5222 pg/ml (31% reduction). Her second pretreatment sFlt-1 level had risen to 12,928 pg/ml and following the treatment was 8814 pg/ml (32% reduction). Her third pretreatment sFlt-1 rose again to 12,525 pg/ml and following the third and final treatment was 9750 pg/ml (22% reduction). Corresponding P/C ratios following each treatment were as follows: Treatment 1, 1.4 g/g decreased to 0.5 g/g (64% reduction); Treatment 2, 5.2 g/g decreased to 1.9 g/g (63% reduction); Treatment 3, 6.2 g/g decreased to 1.8 g/g (71% reduction). Estimated fetal birthweight before the first treatment was 1076 g. The mother’s pregnancy continued for an additional 21 days (counting from day of admission). At birth (31+6/7 weeks), actual neonatal weight was 1256 g. At discharge from the hospital (44 days after delivery), the infant’s weight was 2100 g. At 1 month after delivery, the mother had normal BP 110/70 mmHg, no proteinuria, and her sFlt-1 level was 86 pg/ml. At 4, 8, and 12 months after delivery, the child’s growth centiles were normal. There were no persistent complications with treatment.
Figure 6.
Figure 6.
Prolongation time of pregnancy in women with preeclampsia. (A) Pregnancy prolongation in contemporaneous untreated women with preeclampsia (n=22 controls) by sFlt-1 levels (pg/ml) at baseline. (B) Pregnancy prolongation in women with preeclampsia treated with apheresis (n=11) and untreated contemporaneous controls (n=22) by pretreatment sFlt-1/PlGF ratios.
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