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van Dalfsen, A. (2011). Preeclampsia, intra-abdominal pressure and the renal veins.. PHILICA.COM Article number 240.

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Preeclampsia, intra-abdominal pressure and the renal veins.

Arjen van Dalfsenunconfirmed user (Franciscus hospital)

Published in medi.philica.com

Abstract
The aim of this article is to look at a possible hypothesis explaining the pathogenesis of preeclampsia. This hypothesis starts out with assuming that a rise in intra-abdominal pressure (IAP) could lead to a compression of the renal veins. A hampering of the renal veins might activate the renin-angiotensin system (RAS) which could result in the symptoms of preeclampsia. We examine whether this compression theory could explain the risk factors and try to explain why renin and angiotensin II levels aren’t raised in preeclampsia. We conclude that the compression theory could explain the pathogenesis of preeclampsia. Finally we suggest possibilities for further research and look at a possible effect of body position on preeclampsia.

Article body

Background

Preeclampsia is a disorder that occurs only during pregnancy and the postpartum period. Affecting at least 5% of all pregnancies, it is a rapidly progressive condition characterized by high blood pressure and the presence of protein in the urine. Swelling, sudden weight gain, headaches and changes in vision are important symptoms. The only effective treatment is delivery of the fetus and placenta. Typically, preeclampsia occurs after 20 weeks gestation (in the late 2nd or 3rd trimester), though it can occur earlier. Globally, preeclampsia and other hypertensive disorders of pregnancy are a leading cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal and 500,000 infant deaths each year [1].There are many theories concerning the etiology of preeclampsia. Inadequate blood supply to the placenta, abnormalities in the immune system and maternal endothelial cell dysfunction are suspected to be involved. The cause however, is still considered to be unknown [2].

The hypothesis

In this article we investigate whether preeclampsia could be explained as a cascade of effects following a compression of the renal veins. This compression theory starts out with the fact that during a pregnancy, the growth of the fetus and uterus causes a rise in the intra abdominal pressure (IAP). This pressure not only results in the expansion of the woman's waistline, it also results in the compression and shifting of the abdominal organs.

The growing uterus, together with the raised IAP, may in some women press on the kidneys and their supplying blood vessels. This is likely to happen especially when the woman is lying on her back, as the weight of the uterus then compresses the major abdominal blood vessels. Arterial vessels are less vulnerable than venous vessels, due to their higher blood pressure. Although possibly all abdominal blood vessels could be affected, especially the left renal vein is at risk of compression due to its position in front of the vertebra, between the aorta and the superior mesenteric artery.(Figure 1) When the IAP rises, the kidneys could be pushed up and backwards by the growing uterus. This could result in the stretching and bending of the renal veins and consequently a hampered renal blood flow.

 

Figure 1: The renal veins: 1: left renal vein, 2:right renal vein, 3: kidneys , 4: vena cava

In case the renal venous blood pressure rises, this will lead to a decrease in renal perfusion, threatening the adequate functioning of the kidneys. This reduction in renal perfusion will activate the renin-angiotensin system (RAS) through the juxtaglomular apparatus. Firstly this will trigger renin secretion in the kidneys, which is followed by angiotensin II. Activation of the RAS (figure 2) is known to have many effects, including:

  • increased reabsorption of sodium and fluid.
  • arteriolar vasoconstriction and a rise of blood pressure.
  • through anti-diuretic hormone (ADH) stimulation of thirst[3].

Figure 2: The RAS; taken from Wikipedia: http://en.wikipedia.org/wiki/Raas

In case of a hampered renal blood flow, the RAS will stay activated until the arterial blood pressure is high enough to compensate for the high venous renal pressure and normalize the renal perfusion. In this new balance we would have a relatively active RAS despite the high blood pressure. A relatively raised angiotensin II could explain much of the symptomatology of preeclampsia, like hypertension, vasospasm and fluid retention. It could also result in an increase in sFit-1(soluble fms-like tyrosine kinase-1) and a simultaneous decrease in free VEGF (vascular endothelial growth factor) and PIGF (placental growth factor) levels resulting in a maternal endothelial dysfunction [4] [5] [6]. Finally these changes could lead to vascular damage, thrombocytopenia, hemolysis and organ damage. These changes could also give rise to symptoms like proteinuria, edema, headache, nausea or vomiting, convulsions, changes in vision and epigastric pain.

Some history on IAP and the RAS in
preeclampsia.

Nearly a century ago Paramore [7] studied the theory that preeclampsia may be secondary to an increased IAP. Since then, many authors have focused on this topic. Evidence that the constriction of the renal veins can lead to a syndrome much alike preeclampsia came in 1999, when Doty et al. [8] showed that acute constriction of the renal vein in swine leads to decreased renal artery blood flow and glomerular filtration rate. They found an increase in plasma renin activity, serum aldosterone and urinary protein leak. They concluded that these changes are consistent with the renal pathophysiology seen in acute abdominal compartment syndrome, morbid obesity, and preeclampsia. Experimental research by Bloomfield et al. [9] showed that chronically increased IAP causes a significant increase in systolic and diastolic blood pressure in dogs, but to their disappointment, it did so without causing detectable changes in plasma renin activity. Currently raised IAP is not accepted as being the underlying cause of preeclampsia, mainly because renin and angiotensin II levels are not raised in women developing preeclampsia. Nevertheless most authors agree that angiotensin II could account for most of the symptoms seen in preeclampsia.

For example Shah [10] gives a detailed explanation of the mechanism by which angiotensin II could play a role in the primary pathogenic features of preeclampsia. She states that much of vascular pathogenesis in preeclampsia appears to be due to angiotensin type I receptor activation, despite the fact that convincing evidence of the elevation of angiotensin II in preeclampsia does not exist. As we will try to show, it is incorrect to assume that if a rise in IAP is to explain the pathophysiology of preeclampsia, renin and angiotensin II levels should be raised. This assumption does not take into account the behavior of a self-regulating system like RAS. Recent research has focused on other mechanisms linked with the role of the RAS in preeclampsia. For example angiotensin II type 1 receptor agonistic autoantibodies, ANG-(1-7), AT1-B2 hetrodimerization, uteroplacental renin secretion and a redox switch in angiotensinogen.[6] [10] [11] [12] As they are not essential to the compression theory, they go beyond the scope of this article.

Evaluation of the hypothesis

For a hypothesis on preeclampsia to be satisfying, it should explain the pathogenesis, the symptoms and the risk factors. To investigate this for the compression theory we ask ourselves a number of questions.

Is there evidence that the renal veins are compressed?

Research by Bateman et. al.[13] using Doppler sonography showed an increased venous impedance index in patients with preeclampsia compared to normal pregnancies. (0.50 ± 0.12 to 0.37 ± 0.06) Venous impedance index being 0.47 ± 0.14 and 0.52 ± 0.11 in respectively right and left hypertensive kidneys. There was no significant difference in the arterial resistive indices. Apart from Doppler there is another indication that compression of the renal veins plays a role in preeclampsia. The roll-over test is a test which is performed between the 28th and 32nd week of pregnancy. One rolls the patient from lying on her left side to her back and measures the raise in venous blood pressure. A raise of more than 20 mmHg is predictive for developing preeclampsia. This shows that bodily position does influence the blood pressure in preeclampsia, probably by compressing the (renal) blood vessels caused by the weight of the uterus [14].

Is preeclampsia comparable with blockage of the renal vessels or with intra-abdominal hypertension syndrome?

In both syndromes there are symptoms which are also present in preeclampsia: hypertension, edema, proteinuria, headache, nausea and vomiting. [8] [15] [16].

Is there evidence for hyperactivity of he RAS in preeclampsia?

During a normal pregnancy, plasma levels of renin and angiotensin II are increased. In preeclampsia these levels commonly decrease toward the normal nonpregnant range. Secondly, women developing preeclampsia are shown to have an increased hypertensive reaction to angiotensin II infusion, even preceding the onset of developing preeclampsia [6] [10] [17]. At first, these results might look contradictory to a hyperactivity of the RAS in preeclampsia. They are in fact what one would expect if one is familiar with the behaviour of a self-regulating system [18].

To comprehend this, one can look at the analogy of a thermostatically regulated heating system. Suppose the thermostat is set to 20°C and the outdoor temperature rises to 30°C. How would the heating system react? It would turn itself off.

Therefore: If the hypertension in preeclampsia was caused by a factor outside the system, the RAS should have turned itself down and the levels of renin and angiotensin II should have been reduced to lower levels. The fact that they aren't, is an indication that the hypertension is caused by a factor inside the RAS. This could very well be the blocked feedback loop due to a decrease in renal perfusion. 

Like an overactive heating system which raises the room temperature to 30°C, while the thermostat is set to 20°C.

In other words, the combination of hypertension and "normal" levels of renin and angiotensin II can be seen as an indication of a hyperactive RAS.

To take a medical analogy:  Much in the same way as an overproduction of thyroid hormones by the thyroid gland in hyperthyroidism will lower thyroid-stimulating hormone (TSH) through the negative feedback loop, the hypertension in preeclampsia should lower the RAS activity by its negative feedback loop through the juxtaglomerular apparatus in the kidneys. Raised thyroid hormones without a significant decrease of TSH in hyperthyroidism indicates a primary overproduction of TSH (for example a pituitary adenoma), the same way as hypertension in preeclampsia, without a significant decrease in the renin and angiotensin II levels, indicates a primary RAS hyperactivation. (In this case the reduced perfusion pressure in the juxtraglomular apparatus)

The increased hypertensive reaction to angiotensin II infusions can also be explained by the blocking of the normal negative feedback loop. Angiotensin II, when given to normotensive pregnant women, will activate the feedback loop reducing the hypertensive effect of angiotensin II. Due to a decrease in renal perfusion this self-regulating system is less effective in preeclampsia and angiotensin II can have its vasoconstrictive and hypertensive effects, with less inhibition by the negative feedback loop. This mechanism also explains why Doty et al. [8] found an increase in plasma renin levels in there acute constriction of the renal vein, while Bloomfield et. al [9] showed  that chronically increased intra-abdominal pressure caused no detectable changes in plasma renin levels. In the acute phase the RAS is activated, which induces the hypertension seen in preeclampsia. The normal but relatively high RAS levels will maintain the hypertension.

Finally, angiotensin II can cause an increase in sFit-1 and a simultaneous decrease in free VEGF and PIGF, which is shown in women with preeclampsia [5].

Does our model explain the known risk factors for preeclampsia?

Most of the major risk factors for preeclampsia are risk factors for developing higher intra-abdominal pressure or a bigger uterus.

  • Multiple pregnancy
  • Insulin dependent diabetes (bigger children)
  • Nulliparity (the waist is more resilient to expansion)
  • Increased time between pregnancies (the waist regains
    resilience to expansion as time passes)
  • Raised body mass index
  • Preeclampsia develops typically near the end of the
    pregnancy.

Others can be linked to being risk factors for renal damage or arthrosclerosis:

  • Age
  • Pre-existing hypertension
  • Renal disease
  • Chronic autoimmune disease

The increased risk for women with a previous preeclampsia or a family history of preeclampsia could be mediated by many factors such as the hereditary anatomical position of the renal blood vessels or genetic differences in the RAS system [19]. For women who are physically active during pregnancy, the risk for preeclampsia is reduced by approximately 40% [20].  This can be linked to the weight of the pregnancy compressing the renal veins during (prescribed) bed rest. Following the compression hypothesis one would expect increased birth weight to be another risk factor for developing preeclampsia. 

Discussion

Although the theory that IAP could result in preeclampsia is nearly a hundred years old, we think it shouldn't be ignored. The selective compression of the renal veins could explain why some women develop preeclampsia and some don't and the levels of renin and angiotensin II found in preeclampsia don't have to contradict the compression theory. We conclude that the model can explain the pathogenesis of preeclampsia.

Further research will have to show whether the rise in IAP does compress the renal veins in women with preeclampsia. Research using imaging techniques could probably clarify this. It also remains to be seen whether both of the renal veins need to be compressed to develop preeclampsia and whether they are constantly hampered or only intermittently because of shifts in bodyposition. Movement of the fetus could also influence the compression. It would be interesting to study the influence of different body positions in women with preeclampsia, while looking at the renal veins resistance or compression, the renin and angiotensin II levels and the blood pressure at the same time. Compression of other abdominal vessel, like the uterine veins, could also play a role in preeclampsia. Although the renal veins seem more likely to be involved, because of their direct effect on the RAS system.

If the compression theory is proven to be correct, women at risk of preeclampsia should probably be advised not to lie on their back. Sleeping on the right side is possibly preferable to the left side, although this also remains to be studied. A standing or leaning forward position is most likely to take the pressure off the renal veins and reduce the risk of preeclampsia. Prescribed bed rest could increase the risk of preeclampsia and should (if possible) be avoided. Any tight clothing across the waist may also be a risk factor.

To what extent this reduces the risk of preeclampsia remains to be seen. A prospective randomized controlled trial of postural intervention during pregnancy could test the compression model and the effect of the different postural positions. In case these simple measures proof insufficient, stenting of the renal veins could be an interesting treatment option for preeclampsia.

Finally, compression of the renal veins could also be of influence on other forms of (non-pregnant) hypertension. 

Acknowledgements

I would like to thank V. Bastiaenssen, A.S.E. van Dalfsen, K. Dockx and M. McNeill for reading the manuscript and especially my wife for stirring my curiosity in preeclampsia in the first place.

References

[1] http://www.preeclampsia.org/about.asp; July 19, 2008

[2] Kanasaki,K & Kalluri,R. (2009). The biology of preeclampsia. Kidney International, 76(8), 831-837.

[3]Windhager, E.E. (1992). Handbook of Physiology, Oxford, Oxford University press, 1451-1464. [Section 8, Renal Physiology, Volume II.] 

[4] Varughese, B. ,Bhatla, N., Kumar, R., Dwivedi, S.N. & Dhingra, R. (2010) Circulating angiogenic factors in pregnancies complicated by pre-eclampsia. National Medical Journal of India, 23(2), 77-81.

[5] Zhou, C.C., Ahmad, S. & Mi, T. et al. (2007). Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circulation Research, 5 (100), 88-95.

[6] Irani, R.A. & Xia, Y. (2011). Renin angiotensin signaling in normal pregnancy and preeclampsia. Seminars in Nephrology, 31(1), 47-58.

[7] Paramore, R.H. (1913). The Intra-abdominal Pressure in Pregnancy. Proceedings of the Royal Society of Medicine (Obstetrics and Gynaecology Section), 6, 291-334.

[8] Doty, J.M., Saggi, B.H., Sugerman, H.J., Blocher, C.R., Pin, R., Fakhry, I., Gehr, T.W. & Sica, D.A. (1999). Effect of increased renal venous pressure on renal function. The Journal of Trauma, 47(6), 1000-1003.

[9] Bloomfield, G.L., Sugerman, H.J., Blocher, C.R., Gehr, T.W. & Sica, D.A. (2000). Chronically increased intra-abdominal pressure produces systemic hypertension in dogs. International Journal of obesity and related metabolic disorders. 24(7), 819-824.

[10] Shah, D.M. (2005). Role of the renin-angiotensin system in the pathogenesis of preeclampsia. American Journal of Physiology - Renal Physiology, 288(4), 614-625.

[11] Zhou, A., Carrell, R.W., Murphy, M.P., Wei, Z., Yan, Y., Stanley, P.L., Stein, P.E., Broughton, Pipkin, F. & Read, R.J. (2010). A redox switch in angiotensinogen modulates angiotensin release. Nature, 4;468(7320), 108-111.

[12] Anton, L., Merrill, D.C., Neves, L.A., Gruver, C., Moorefield, C. & Brosnihan, K.B. (2010). Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study. Reproductive Biology and Endocrinology, 4,8, 135.

[13] Bateman, G.A., Giles, W. & England, S.L. (2004). Renal venous Doppler sonography in preeclampsia. Journal of Ultrasound in Medicine, 23(12), 1607-1611.

[14]^Yemini, M., Lancet, M., Mass, N., Feinstein, M. & Katz, Z. (1985). Predictive value of roll-over test in women with mild preeclampsia. American Journal of Obstetrics and Gynecology, 153(1), 77-78.

[15] Postma, C.T., Joosten, F.B.M., Claessens, R.A.M.J. & Thien, T. (1999). Maligne hypertensie bij een jongeman met nierarterieafsluiting gediagnosticeerd met magnetische-resonantieangiografie. Nederlands Tijdschrift voor Geneeskunde, 143, 1102-1105.

[16] Richards, W.O., Scovill, W., Shin, B. & Reed, W. (1983) Acute renal failure associated with increased intra-abdominal pressure. Annals of Surgery, 197(2), 183-187.

[17] Cunningham, F.G., MacDonald, P.C. & Gant, N.F. (1989). Williams Obstetrics, Prentice-Hall International, Inc., 658.

[18] Keeney, B.P. (1983). Aesthetics of Change. The Guilford Press, N.Y.

[19] Duckitt, K. & Harrington, D. (2005). Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. British Medical Journal, 330(7491), 549-550.

[20] Dempsey, J.C., Butler, C.L. & Williams, M.A. (2005). No need for a pregnant pause: physical activity may reduce the occurrence of gestational diabetes mellitus and preeclampsia. Exercise and Sport Sciences Reviews, 33(3), 141-149.

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van Dalfsen, A. (2011). Preeclampsia, intra-abdominal pressure and the renal veins.. PHILICA.COM Article number 240.


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