Microalbuminuria and Hypertension in Pregnancy: Role of Aldosterone and Inflammation

Authors


Abstract

Women with a history of hypertension in pregnancy are at increased risk of microalbuminuria later in life. Microalbuminuria is a marker of kidney dysfunction frequently related to an inflammatory event. Pregnancy is a dynamic process characterized by immune tolerance, angiogenesis, and hormonal regulation. Menstruation and pregnancy are associated with a physiological inflammation, which is altered in preeclampsia and probably in other hypertensive situations of pregnancy. An imbalance between pro-oxidant factors and the ability to scavenge these factors produces oxidative stress, which has been evaluated in many cells, but leukocytes are the main source of inflammatory cytokines and experimental and clinical evidence support a possible role of aldosterone as a mediator of placental and renal damage mediated by growth factors, reactive oxygen species, and cytokines. Angiotensin-converting enzyme inhibitors and aldosterone receptor blockers are frequently effective in reducing the risk of progression of cardiovascular and renal disease.

Kattah and colleagues[1] have reported evidence that women with a history of hypertension in pregnancy are at significantly increased risk for microalbuminuria later in life as compared with those with normotensive pregnancies. Women who reported having had at least one pregnancy with hypertension were also significantly more likely to be hypertensive, diabetic, and have higher body mass index than those with normotensive pregnancies. Previous studies[2] in polycystic ovary syndrome (PCOS) have shown a relationship between microalbuminuria and cardiovascular disease (CVD). PCOS affects 10% of women in the reproductive age and the screening for the presence of microalbuminuria can help in early identification of a subset of women with PCOS who have a high risk for future hypertension preeclampsia (PE) and CVD.[3] All of these studies underline the importance of the measurement of preclinical markers in predisposed healthy women to prevent the development or delay the onset of a disease that could be related both to genetic and epigenetic factors. This concept is very important during pregnancy and, in particular, in patients with PE or other forms of hypertension in pregnancy. The authors have found a significantly greater risk of microalbuminuria in patients who reported at least one pregnancy with hypertension, than those with normotensive pregnancies, after adjusting for risk factors for chronic kidney and CVD. This observation does not exclude that in these patients, microalbuminuria could be present even prior to pregnancy, maybe when the patients were normotensive, or maybe these women had PCOS.

It is well known that microalbuminuria is a marker of progression of diabetic nephropathy and it should be measured not only in patients with insulin resistance or insulin deficiency but also in patients with other factors predisposing to cardiovascular risk. Treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) can reduce the progression of kidney dysfunction, particularly in patients with diabetes and/or hypertension. This kind of treatment is also prescribed in patients with microalbuminuria and normal BP. In patients with hypertension in pregnancy and in particular in PE, the evaluation of renal function is very important and, in particular, microalbuminuria should be monitored to prevent overt eclampsia. It has also been reported that a similar effect is obtained in patients with microalbuminuria using ARBs,[4] which underlines the importance of aldosterone suppression. This treatment cannot be used in pregnancy because of the additional antiandrogen activity of most of the spironolactone derivatives.[5] Eplerenone should be tested in this regard, being a pure antagonist of mineralocorticoid receptors (MRs). ARBs have the advantage of providing higher protection, as treatment with ACE inhibitors is frequently associated with the escape of aldosterone to the effects of these drugs.[6]

Aldosterone contributes along with angiotensin II to the adverse actions of the renin-angiotensin-aldosterone system (RAAS) in progressive chronic kidney disease (CKD). Several trials in patients with CKD have shown a further reduction of proteinuria when MR blockade or inhibition of renin was added to an ACE inhibitor or ARB. In primary aldosteronism (PA), microalbuminuria decreases after treatment with eplerenone or spironolactone.[7]

Pregnancy is a dynamic process characterized by immune tolerance, angiogenesis, and hormonal regulation. Menstruation and pregnancy are associated with physiological inflammation, which is altered in PE and probably in other hypertensive situations of pregnancy.[8] The syndrome of hypertension, proteinuria, and edema is part of a severe systemic inflammatory response that includes leukocyte and endothelial cell activation. The pathogenesis of PE is still debated and the disease is characterized by an altered placentation, but the cause of this phenomenon is still unknown. There is evidence that PE is related to pathological changes in the maternal vascular endothelium. Inadequate placental trophoblast invasion of the maternal uterine spiral arteries produces a poor placental perfusion.[9]

The pathogenesis of this phenomenon probably resides in a generalized endothelial dysfunction produced by release into circulation of factors that can activate the immunitary cells in an inappropriate way. An imbalance between prooxidant factors and the ability to scavenge these factors produces oxidative stress, which has been evaluated in many cells, but leukocytes are the main source of inflammatory cytokines and experimental and clinical evidence support a possible role of aldosterone as a mediator of placental and renal damage mediated by growth factors, reactive oxygen species, and cytokines.[10]

The evidence of microalbumonuria in PE and the reported usefulness of treatment with ACE inhibitors to prevent the progression of micoroalbuminuria are consistent with a role of the RAAS in the hypertension of pregnancy and in PE. In PA, cardiovascular and renal risk are high and the disease is frequently associated with microalbuminuria even in patients with normal serum potassium levels. Recent studies have reported that ARBs are able to protect from cardiovascular and renal risk in patients predisposed to these situations even in the presence of normal aldosterone and aldosterone to renin ratio in plasma, as reported in the Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Efficacy and Survival (EPHESUS) trials.[11]

As a consequence of these studies, the evaluation of the renin angiotensin aldosterone function has gained more consideration and, in particular, the measurement of upright aldosterone to renin ratio. In 1985, we characterized MR in mononuclear leukocytes (MNLs) and later reported that the number of MRs is similar in T-,B-lymphocytes and monocytes.[12, 13] We also demonstrated a specific action of aldosterone in regulating intracellular sodium and potassium and volume.[14] The effect of aldosterone was reversed by coincubation with canrenone.

Aldosterone is high both in normal pregnancy and in PE, but the aldosterone to renin ratio is higher in PE than in normal pregnancy. We found that the effect of aldosterone on the subtractive potential difference between rectal mucosa and skin is high in PE, similar to that of patients with PA, while it is normal in physiological pregnancy.[15]

From the literature studies it is clear that aldosterone can affect the inflammatory response of immunitary cells. In 2004, we reported a direct inflammatory effect of aldosterone in MNL. Incubating these cells with aldosterone alone and with addition of canrenone showed that aldosterone was able to enhance the protein expression of PAI1 and p22phox in MNL, while coincubation with anemone blocked this effect.[16]

Aldosterone binding to dendritic cells can prime T lymphocytes in Th17 that can also mediate autoimmunitary reaction, inducing glomerular injury and microalbuminuria.[17] Understanding how this subset of CD4 cells mediate proliferate forms of glomerulonephritis may lead to targeted therapies. Abnormalities of the juxtaglomerular apparatus and microalbuminuria are distinctive features of renal pathology in diabetes, suggesting the presence of an autoimmune process. The percentage of CD4+IL-17-producing T cells is lower in healthy compared with PE patients. No such pattern was found to occur in PE, suggesting that this disorder may be associated with a proinflammatory T-cell immune response.[10]

A recent paper has shown that patients who will develop PE have a higher BP in the first trimester of pregnancy than in patients who will have a normal pregnancy.[18] It is important to note that in both groups, BP was within normal range. It is not excluded that patients who will develop PE could also have a microalbuminuria level that will also persist after pregnancy, as reported in the study.

It is important to note that PCOS, which is a syndrome frequently associated with PE and cardiovascular risk, is also associated with a slight increase in BP compared with controls and a slight increase of the aldosterone to renin ratio as reported in our recent study. PCOS affects 10% of fertile women and predisposes to kidney diseases and diabetes later in life.[19] The disease is frequently associated with microalbuminuria. Further evidence of the importance of the renin aldosterone system is the increase of aldosterone during contraceptive treatment. It is well known that contraceptives can increase BP, although, with the current dose of etynylestradiol, this evidence is rare and BP is higher than that in controls but still within the normal range. Regular and long-term oral contraceptive use and hormone replacement therapy are associated with an increased risk for microalbuminuria and CVD.[20]

Conclusions

The measurement of microalbuminuria is an easy way for predicting cardiovascular risk and hypertension risk in pregnancy. This simple assay could be recommended in all women with hormonal dysfunction and PCOS at the onset of pregnancy to consider the possibility of PE or other forms of hypertension in pregnancy. The use of ARBs could be considered, using drugs with low or absent antiandrogen activity as canrenone and eplerenone. These drugs are actually not prescribed in pregnancy because their use has not been previously evaluated in animal studies and in humans but could be considered to prevent inflammation and kidney dysfunction and insulin resistance.

Acknowledgments

We thank Miss Sophie Armanini for English revision.

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