Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 2  |  Page : 229-234

The effect of pentoxifylline on the glomerular function in patients with severe pre-eclampsia


1 Department of Anesthesiology and Intensive Care, Ain-Shams University, Cairo, Egypt
2 Department of Clinical Pathology, Ain-Shams University, Cairo, Egypt
3 Department of Obstetrics and Gynecology, Ain-Shams University, Cairo, Egypt

Date of Submission27-May-2015
Date of Acceptance06-Jun-2015
Date of Web Publication11-May-2016

Correspondence Address:
Rania M Ali
Department of Anesthesiology and Intensive Care, Ain-Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.182263

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  Abstract 

Introduction
Pentoxifylline (PTX) is a phosphodiesterase inhibitor that directly upregulates the expression of vascular endothelial growth factor mRNA. Pre-eclampsia (PE) is a pregnancy-specific vascular endothelial disorder with a characteristic glomerular lesion, glomerular endotheliosis, that is due to vascular endothelial growth factor deprivation. This study aimed to investigate the effect of PTX on the functional manifestations of the glomerular endothelial injury in patients with severe PE.
Patients and methods
Forty patients with severe PE admitted to the Ain Shams Obstetric ICU were assigned randomly in the immediate postpartum period to one of two groups (20 in each group): the PTX group received a continuous intravenous infusion of PTX 400 mg every 8 h daily for 3 days; the control group received normal saline solution as placebo every 8 h daily for 3 days. The primary endpoint was the improvement of renal assessment data in the form of the serum creatinine level, the urine protein/creatinine (P/C) ratio, and urine nephrin levels.
Results
PTX administration in patients with severe PE was associated with significant reduction of urinary nephrin compared with baseline values (day 1) as well as with the values on day 3 in the control group (P = 0.007 and P < 0.001, respectively). Further, administrating PTX showed significant reduction of the urine P/C ratio and serum creatinine levels. Acute kidney injury developed overall in 10 and 40% of the patients in the PTX group and the control group, respectively.
Conclusion
The current study demonstrates that PTX administration to patients with severe PE, as an additional treatment to standard therapy on admission to the ICU, exhibits a renoprotective effect.

Keywords: glomerular function, pentoxifylline, severe pre-eclampsia


How to cite this article:
Ali RM, Bondok RS, Rabie AH, Shaaban MA, Rabie NH. The effect of pentoxifylline on the glomerular function in patients with severe pre-eclampsia. Ain-Shams J Anaesthesiol 2016;9:229-34

How to cite this URL:
Ali RM, Bondok RS, Rabie AH, Shaaban MA, Rabie NH. The effect of pentoxifylline on the glomerular function in patients with severe pre-eclampsia. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Oct 23];9:229-34. Available from: http://www.asja.eg.net/text.asp?2016/9/2/229/182263


  Introduction Top


Pentoxifylline (PTX) is a phosphodiesterase inhibitor that increases intracellular cyclic adenosine monophosphate [1]. PTX was found to directly upregulate the expression of vascular endothelial growth factor (VEGF) mRNA by the stabilization of its mRNA [2].

Pre-eclampsia (PE) is a pregnancy-specific vascular endothelial disorder with a characteristic glomerular lesion, endotheliosis, which is exacerbated in severe PE [3]. Glomerular endotheliosis is due to VEGF deprivation. Excessive antiangiogenic substances made by the placenta act as an endogenous inhibitor of VEGF signaling [4]. VEGF is synthesized constitutively in the glomerulus by podocytes [5]. Podocytes are shed from the glomerular basement membrane in cases of PE [6]. Podocyte markers [7], in particular nephrin, are a transmembrane protein involved in the maintenance of the renal filtration capacity [7]. Recently, nephrin was found to be a predictive marker for PE [8].

The aim of the present study was to investigate the effect of PTX on the functional manifestations of the glomerular endothelial injury in patients with severe PE.


  Patients and methods Top


The study was conducted in the ICU of the Obstetrics and Gynecology Hospital of Ain-Shams University as a randomized, double-blind, and placebo-controlled study on patients diagnosed with severe PE from January to July 2014. The study was approved by the Ethical Research Committee at the Ain-Shams University, and all participants provided written informed consent.

Patients eligible for this study were aged between 20 and 40 years and had severe PE. Severe PE was diagnosed by severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg on two occasions at least 6 h apart), severe proteinuria (≥5 g/day or proteinuria of more than 3+ on two random urine samples collected at least 4 h apart). Exclusion criteria included collagen-vascular disease, HELLP syndrome (hemolysis, elevated liver enzymes ≥70 IU/l, and low platelets ≤100 000 cells/ml), platelet disorder (platelet count ≤100 000 cells/ml, bleeding time >4 min), coagulopathy (international normalized ratio >1.5, prothrombin time >18 s, partial thromboplastin time>40, clotting time >8 min), diabetes mellitus, sepsis, renal failure (serum creatinine >2 mg/dl), hepatic failure (aspartate aminotransferase or alanine aminotranserase>40 U/l), or urinary tract infection as well as patients receiving corticosteroid (>3 days) or methylxanthine therapy.

Forty patients with severe PE admitted to the ICU were randomly assigned in the immediate postpartum period to one of two groups (20 in each group): the intervention group (PTX) received a continuous intravenous infusion of PTX 400 mg in a total of 100 ml isotonic saline infused over 120 min every 8 h daily for 3 days; the control group received normal saline solution as placebo, in a total of 100 ml isotonic saline infused over 120 min every 8 h daily for 3 days. Randomization was attained using orderly numbered, opaque-sealed envelopes containing computer-generated random allocations in a ratio of 1 : 1 in balanced blocks of 5.

Patients received full intensive care treatment for PE according to the standard protocol of the obstetric ICU of the Ain-Shams University including antihypertensive medications, fluid balance, and magnesium sulfate as seizure prophylaxis; its dose was adjusted according to the renal function, in addition to PTX and placebo according to the study group for 3 days. On postpartum day 1, samples were withdrawn before drug therapy as baseline values. On day 3, samples were withdrawn again for evaluation of the drug effect. All treatments were provided by physicians who are not involved in the study. All patients were followed up throughout their ICU stay. Vital signs were monitored at admission and during the 48 h until patients were discharged from the ICU.

The following data were collected from all patients enrolled in the study: demographic information including age and parity, clinical data including the heart rate, systolic and diastolic blood pressures, the urine output (UOP), and renal assessment data in the form of the serum creatinine level, the urine protein/creatinine ratio, and urine nephrin levels. Acute kidney injury (AKI) was considered as a 50% or 0.3 mg/dl increase in the serum creatinine level after ICU admission. The primary endpoint was the improvement of renal assessment data.

Random, clean-catch urine specimens (50-100 ml) were obtained from the patients. Urine specimens were collected and frozen at −20°C immediately after centrifugation, and the supernatant was obtained. Urine nephrin concentrations were measured with an enzyme-linked immunosorbent assay kit according to the manufacturer's protocol (Glory Science Co. Ltd, Texas, USA). The assay range was 0.031-2.0 mg/ml. Serum creatinine, urinary protein, and urinary creatinine were determined by standard methods with an automatic analyzer (Cobas Integra 400; Roche Diagnostics, Tokyo, Japan). The amount of proteinuria was estimated as the ratio of urinary protein-to-urinary creatinine.

Statistical analysis

Using PASS 13 (NCSS LLC, Kaysville ,Utah, USA) for sample size calculation, it was calculated that a sample size of 17 patients per group would achieve 80% power to detect a decrease in the urinary nephrin of 19.8 with an estimated group SD of 20.0 and a significance level (a) of 0.05 using a two-sided two-sample t-test. This number has increased to 20 in each group to allow for a predicted dropout from treatment of 10%.

Statistical analysis was performed on a personal computer using the Statistical Package for Social Sciences version 17.0 (SPSS© v. 16.0; SPSS Inc., Chicago, Illinois, USA). Qualitative data were analyzed with the Pearson c2 -test and were presented as number (%). Quantitative data were analyzed using an unpaired Student t-test for between-group comparison, and data were presented as the mean (SD). A P-value of less than 0.05 was considered statistically significant.


  Results Top


Forty patients with severe PE admitted to the ICU were randomly assigned in the immediate postpartum period to one of two groups (20 in each group): the PTX group and the control group. Both groups were comparable regarding their demographic data [Table 1].
Table 1 Demographic data

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Regarding hemodynamic parameters, the heart rate and systolic and diastolic blood pressure values were comparable between both groups on postpartum days 1 and 3. However, within-group comparison revealed significantly low systolic and diastolic blood pressure values on day 3 compared with day 1 (baseline values) in both groups (P < 0.001) [Table 2].
Table 2 Hemodynamic data

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Intravenous nitroglycerin drug consumption was similar in both groups on postpartum day 1. There was a significant reduction in nitroglycerine infusion in the PTX group on days 2 and 3 compared with the control group and with baseline. Also, there was a significant increase in the nitroglycerine infusion in the control group on days 2 and 3 as compared with baseline [Table 3].
Table 3 Intravenous nitroglycerin drug consumption

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Regarding renal parameters, the baseline UOP between both groups was comparable on postpartum day 1. The PTX group and the control group showed a significant increase in the UOP on day 3 as compared with baseline values (P < 0.001) [Table 4]. There was no significant difference regarding serum creatinine levels between both groups on postpartum day 1. The level of serum creatinine on postpartum day 3 was significantly low in the PTX group compared with the control group (P < 0.001). On postpartum day 1, urine nephrin concentrations were elevated above normal urinary nephrin levels in both groups. On postpartum day 3, urine nephrin levels were significantly low in the PTX group compared with that on day 1 in the PTX group as well as that on day 3 in the control group (P = 0.007 and P < 0.001, respectively) [Table 4]. On postpartum day 1, the P/C ratio showed no significant difference between both groups, whereas on day 3, the P/C ratio showed a significant decrease in the PTX group compared with baseline values (day 1) as well as with the control group (P = 0.019 and 0.04, respectively) [Table 3]. AKI developed overall in two (10%) and eight (40%) of the patients in the PTX group and the control group, respectively (P = 0.016) [Table 4].
Table 4 Renal parameters

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Common side effects of PTX (i.e. bleeding, nausea, and vomiting) were not noticed in both groups.


  Discussion Top


The present study investigated the effect of PTX on the functional manifestations of the glomerular endothelial injury in patients with severe PE by measuring a specific marker, urine nephrin.

PE is an important cause of maternal morbidity and mortality, and it represents 6-8% of all pregnancies [3]. Women with a history of PE have an increased risk of microalbuminuria with a prevalence similar to that of patients with type 1 diabetes mellitus [9]. Proteinuria is a sign of glomerular diseases and represents a marker of injury to the glomerular permeability barrier. Proteinuria, even in a subnephrotic range, is a risk factor for cardiovascular mortality and morbidity, and is strongly associated with the progression to chronic kidney disease (CKD) and thus end-stage renal disease. Decreasing proteinuria is an effective strategy to delay the progression of CKD and cardiovascular morbidity [10,11].

Despite profound alterations in the glomerular morphology, clinical recovery is usually rapid after delivery of the placenta. However, the characteristic glomerular pathological lesion has been reported to improve within days after delivery; although complete recovery in severe PE can occasionally require in excess of 6 months, the majority of the cases demonstrate complete resolution of the renal pathology within 3 months [12].

Podocyturia is present in gravidas with PE at the time of delivery and contribute to the proteinuria [13]. There are three components of the renal barrier: the glomerular endothelium, the glomerular basement membrane, and the podocyte [3]. Podocytes are composed of podocin, podocalyxin, synaptopodin, and nephrin 5. Several studies have provided evidence for altered nephrin expression in PE [14-19]; also, urinary nephrin can be used as an early marker for the prediction of pregnancies complicated by PE [8]. The result of the current study is consistent with these studies and has demonstrated that the urine nephrin level was elevated immediately in the postpartum period.

In PE, inadequate trophoblast invasion of spiral arteries initiates ischemia and hypoxia in the placenta, resulting in an increased release of proinflammatory cytokines in the placenta. Placental ischemia and hypoxia also cause the enhanced release of trophoblast microparticles into the maternal circulation, which stimulates increased induction of proinflammatory cytokines and the activation of maternal endothelial cells. This activation results in a systemic, diffuse endothelial cell dysfunction, which is the fundamental pathophysiological feature of this syndrome [20].

Glomerular endotheliosis, the characteristic glomerular lesion in severe PE, is due to VEGF deprivation. Podocytes are the major source of VEGF in the glomerulus [21]. Podocyte-derived VEGF has paracrine functions on endothelial cells as well as autocrine functions on the podocytes themselves [22]. Functions of VEGF include the induction of matrix metalloproteinases, the regulation of angiogenesis, lymphangiogenesis, and hematopoiesis, and cell signalling. Recently, quantitative PCR for podocyte-specific markers was found to be a rapid method to detect PE. Significantly elevated mRNA levels of nephrin, podocin, and VEGF were detected in pre-eclamptic women compared with healthy controls [23].

A number of drugs have been reported to increase VEGF release [24], among which is PTX, which is a methylxanthine derivative and a phosphodiesterase inhibitor. PTX was found to directly upregulate the expression of VEGF mRNA by stabilization of its mRNA [2]. Several clinical studies have investigated the effect of PTX on VEGF [25-27]. PTX can also reduce proteinuria in diabetic patients and in nondiabetic patients with CKD [28-34] because of its hemorheologic action and its ability to downregulate the production of proinflammatory cytokines [35,36].

PTX was also found to prevent AKI after cardiopulmonary bypass [37,38]. PTX together with albumin protect against AKI during endotoxemic shock in mice [39]. It has been demonstrated that PTX may be used as a renoprotective agent against a number of nephrotoxic drugs, including cyclosporine or cisplatin in clinical and animal studies [40] and also on contrast-induced AKI in hypercholesterolemic rats [41]. Pretreatment with PTX and N-acetylcysteine before liver ischemia reperfusion may be useful to ameliorate renal injury [42]. In contrast, PTX was not found to exert any protective effect on ischemia-induced AKI in rats. It is possible that at the time of PTX administration after submitting the kidney to ischemia by clamping the renal artery for 45 min, the mitochondria had already been damaged by the process of ischemia, and its effect may have been insufficient to reverse cell damage [43]. Serum creatinine is still a standard method for evaluating renal function. The effect of PTX in reducing renal injury by measuring serum creatinine was investigated in many studies [44].

Currently, the treatment for PE is largely supportive, but as there is significant progress in the understanding of the molecular mechanisms of PE, targeted therapies to ameliorate or even prevent the development of end-organ damage and AKI become crucial. The result of the current study showed that PTX administration in patients with severe PE is associated with significant reduction in the P/C ratio as a parameter for proteinuria and urine nephrin levels. Further, administrating PTX showed a significant increase in the UOP, reduction of serum creatinine levels, and was associated with a significant decrease in the overall development of AKI.

PTX has only minor effects on the peripheral vascular resistance [45]. In our study, although there was no difference between the groups regarding hemodynamic parameters, there was a significant reduction in the total intravenous Nitroglycerin infusion that was used in our ICU as a treatment protocol for regulating high blood pressure for severe PE; these findings reveal the dual benefit of PTX in reducing the patient's blood pressure along with nitroglycerine and magnesium sulfate. This finding may reflect a synergistic effect of PTX on blood pressure control, which may need further investigation.

Animal studies have identified that PTX can prevent the development of PE [46,47]; however, there are no studies on humans. We suggest future human studies to investigate the inhibitory effects of PTX on the progression of PE and the development of end-organ damage through early PTX administration to patients with PE before the initial insult of organ dysfunction.


  Conclusion Top


The current study demonstrated that PTX administration to patients with severe PE, as an additional treatment to standard therapy on admission to the ICU, exhibits a renoprotective effect as determined by a reduction of urinary nephrin, the urine P/C ratio, and serum creatinine levels in association with a significant decrease in the overall development of AKI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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