RENAL BIOCHEMICAL CHANGES OF PREGNANCY-INDUCED HYPERTENSION IN PREGNANT WOMEN ATTENDING TERTIARY HOSPITALS IN ENUGU STATE

ABSTRACT

Pregnancy induced hypertensive disorders have become very common medical complication in Nigeria  with  its  attendant  morbidity  and  mortality.  The  morbidity  and  mortality  may  be associated with its possible effect on the kidneys which was studied. Results of the electrolyte changes from this study showed that there was non-significant difference (p>0.05) in sodium ion concentration of subjects with pregnancy induced hypertension in second and third trimesters (groups 4 and 5 respectively) compared with the control groups (groups 1,2,and 3) who are non- hypertensives in first, second and third trimesters respectively. Similarly, the potassium ion (K+) concentration showed non-significant difference (p>0.05) between the groups 4 and 5 and the control groups even though the highest concentration of potassium ion was seen in the group 4 subjects. From the study, chloride ion (Cl-) and bicarbonate ion (HCO3-) were found to have no significant difference (p>0.05) in concentration between groups 4 and 5 and the control groups. From the estimation of urea and creatinine, it was found that there was no significant difference (p>0.05) in the urea and creatinine concentration between the hypertensives and normotensives in different trimesters however it was found that both urea and creatinine increased in the third trimesters in the hypertensive. The total protein, albumin and globulin level of the subjects in groups 4 and 5 were found to decrease significantly (p<0.05) compared to the control subjects in the corresponding trimesters.

CHAPTER ONE

INTRODUCTION

Hypertension is a multi-factorial process prevalent in both developed and developing countries with a common end result of elevated blood pressure (Wu et al., 2009). Hypertension affects 25% of adults in resource-rich countries (Pierdomenico et al., 2009). If untreated, it carries a high mortality rate. Risk factors for hypertension include family history, race (most common in blacks), stress, obesity, a diet high in saturated fats or sodium, tobacco use, sedentary lifestyle, and aging (Pierdomenico et al., 2009). Hypertension is more prevalent among adults between 35 – 60 years of age and could lead to cardiovascular disease (Pierdomenico et al, 2009).

Human pregnancy is the carrying of one or more offsprings, known as fetus or embryo, in the womb of a woman. In pregnancy, there can be multiple gestations, as in the case of twins or triplets.  Childbirth  usually  occurs  about  38  weeks  after  conception;  in  women  who  have  a menstrual  cycle  length  of  four  weeks,  this  is  approximately  40  weeks  from  the  last  normal menstrual period (LNMP).

Pregnancy induced hypertension is the most common medical complication of pregnancy ( Hjartardottir   et al., 2004).   Pregnancy-induced hypertension (PIH) is defined as a rise in blood pressure above 140/90mmHg on two or more occasions, at least 6 hours apart during pregnancy. It occurs in the second half  of pregnancy (usually after 20 weeks  of gestation) in a woman who previously had normal blood pressure (Zhang, 2007). Pregnancy-induced hypertension affects 10% of pregnancies, and pre-eclampsia complicates 2–8% of pregnancies.   Eclampsia occurs in about

1/2000 deliveries in resource-rich countries. In resource-poor countries, estimates of the incidence

of eclampsia vary from 1/100–1/1700 . Pregnancy induced hypertension is associated with high blood pressure, oedema and proteinuria (Vintch et al., 2008)

Pregnancy induced hypertensive disorders are the most common medical complications of pregnancy in Nigeria with a reported incidence ranging between 70-80% (Jones, 1992). The incidence  vary  among  different  hospitals  ,clinics,  health  centres  and  communities.  PIH  strikes mostly primigravidae after 20th – 24th weeks of gestation and frequent occurrences are often seen at term (Jones 1992). Hypertension was found   to have some effect on the kidneys leading to derangement  of  some  biochemical  parameters.  These  biochemical  parameters  assists  in  early

detection of renal dysfunction.This study may contribute in reducing the morbidity and mortality associated with this condition.

1.1        Hypertension

Hypertension or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels. Blood pressure involves two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole). Normal blood pressure at rest is within the range of

100-140mmHg systolic and 60-90mmHg diastolic. High blood pressure is said to be present if it is

persistently at or above 140/90 mmHg (Carretero et al., 2000).

Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are categorized as “primary hypertension” which means high blood pressure with no obvious underlying medical cause. The remaining 5–10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system. Hypertension is a major risk factor   for stroke, myocardial infarction (heart attacks), heart failure, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and chronic kidney disease. Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy. Dietary and lifestyle changes can improve blood pressure control and decrease the risk of associated health complications, although drug treatment is often necessary in people for whom lifestyle changes prove ineffective or insufficient.

1.1.1   Primary (essential) hypertension

Essential hypertension (also called primary hypertension or idiopathic hypertension) is the form of hypertension that by definition, has no identifiable cause. It is the most common type of hypertension, affecting 95% of hypertensive patients. It tends to be familial and is likely to be the consequence of an interaction between environmental and genetic factors (Hall et al., 2006). Prevalence of essential hypertension increases with age, and individuals with relatively high blood pressure at younger ages are at increased risk for the subsequent development of hypertension. Hypertension can increase the risk of cerebral, cardiac, and renal disorders (Hall et al., 2006).

In almost all contemporary societies, blood pressure rises with aging and the risk of becoming   hypertensive  in   later  life   is  considerable.  Hypertension   results   from  a  complex interaction of genes and environmental factors (Ehret  et al., 2011). Numerous common genes with small effects on blood pressure have been identified, as well as some rare genes with large effects on blood pressure, but the genetic basis of hypertension is still poorly understood (MacGregor,

2009). Several environmental factors influence blood pressure. Lifestyle factors that lower blood pressure, include reduced dietary salt intake, increased consumption of fruits and low fat products (Dietary Approaches to Stop Hypertension (DASH diet), exercise, weight loss and reduced alcohol intake (Dickinson et al., 2006). The possible role of other factors such as stress, caffeine consumption, and vitamin D deficiency are less clear cut. Insulin resistance, which is common in obesity  and  is  a  component  of  syndrome  X  (or  the  metabolic  syndrome),  is  also  thought  to contribute to hypertension. Recent studies have also implicated events in early life (for example low birth weight, maternal smoking and lack of breast feeding) as risk factors for adult essential hypertension, although the mechanisms linking these exposures to adult hypertension remain obscure (Whelton  et al., 2002).

1.1.1.1 Classification of primary hypertension

A recent classification recommends blood pressure criteria for defining normal blood pressure,  pre-hypertension,  hypertension  (stages  I  and  II),  and  isolated  systolic  hypertension, which is a common occurence among the elderly. These readings are based on the average of seated blood pressure readings that were properly measured during 2 or more office visits. In individuals older than 50 years, hypertension is considered to be present when a person’s blood pressure is consistently at least 140 mmHg systolic or 90 mmHg diastolic. Patients with blood pressures over

130/80 mmHg along with Type 1 or Type 2 diabetes, or kidney disease require further treatment

(Chobanian  et al., 2003).

Table 1: Classification of primary hypertension

Classification	Systolic pressure		Diastolic pressure
	mmHg	kPa (kN/m2)	mmHg	kPa (kN/m2)
Normal	90–119	12–15.9	60–79	8.0–10.5
Prehypertension	120–139	16.1–18.5	81–89	10.8–11.9
Stage 1	140–159	18.7–21.2	90–99	12.0–13.2
Stage 2	≥160	≥21.3	≥100	≥13.3
Isolated  systolic   hypertension	≥140	≥18.7	<90	<12.0

SOURCE: AMERICAN HEART ASSOCIATION (2003)

1.1.1.2   Risk factors for primary hypertension

The etiology of hypertension differs widely amongst individuals within a large population, and  from definition  essential hypertension  has  no identifiable cause (Chobanian    et  al., 2003). However, several risk factors have been identified which include:

(a)      Family history

A personal family history of hypertension increases the likelihood that an individual may develop hypertension (Loscalzo et al., 2008). Essential hypertension is four times more common in black than white people, accelerates more rapidly and is often more severe with higher mortality in black patients ( Haffner et al., 1998). More than 50 genes have been examined in association studies with   hypertension,   and   the   number   is   constantly   growing.   One   of   these   genes   is   the angiotensinogen (AGT) gene. Reports show that increasing the number of AGT increases the blood pressure and hence this may cause hypertension. Twins have been included in studies measuring ambulatory blood pressure; from these studies it has been suggested that essential hypertension

contains a large genetic influence (Dickson et al., 2006). Supporting data has emerged from animal studies as well as clinical studies in human populations. The majority of these studies support the concept that the inheritance is probably multifactorial or that a number of different genetic defects each has an elevated blood pressure as one of its phenotypic expressions. However, the genetic influence upon  hypertension is  not  fully understood  at  the moment. It  is  believed  that  linking hypertension-related phenotypes with specific variations of the genome may yield definitive evidence of heritability (Kotchen et al., 2000). Another view is that hypertension can be caused by mutations in single genes, inherited on a Mendelian basis (Williams et al., 2006).

(b) Age

Hypertension is age related. One possible mechanism involves a reduction in vascular compliance due to the stiffening of the arteries. A decrease in glomerular filtration rate is related to aging and this results in decreasing efficiency of sodium excretion. There is experimental evidence that  suggests  that  renal  microvascular  disease  is  an  important  mechanism  for  inducing  salt- sensitive hypertension (Kosugi et al., 2009).

(c) Obesity

Obesity can increase the risk of hypertension to five-fold as compared with normal weight, and up to two-thirds of hypertension cases can be attributed to excess weight. More than 85% of cases occur in those with a body mass index greater than 25 (Haslam , 2005) A definitive link between obesity and hypertension has been found using animal and clinical studies and from these it has been realized that many mechanisms are involved in obesity-induced hypertension. These mechanisms include the activation of the sympathetic nervous system as well as the activation of the renin–angiotensin-aldosterone system (Rahmouni   et al., 2005). Recent studies showed that obesity is a risk factor for hypertension because of activation of the renin-angiotensin system (RAS) in adipose tissue, and also linked renin-angiotensin system with insulin resistance (Saitoh, 2009).

(d) Salt Sensitivity

Salt (sodium) sensitivity which is an environmental factor that has received the greatest attention is another risk factor. Approximately one third of the essential hypertensive population is responsive to sodium intake. When sodium intake exceeds the capacity of the body to excrete it through the kidneys, vascular volume expands secondary to the movement of fluids into the intra- vascular compartment. This causes the arterial pressure to rise as the cardiac output increases. Local autoregulatory mechanisms counteract this  by increasing vascular resistance to maintain normotension in local vascular beds. As arterial pressure increases in response to high sodium chloride intake, urinary sodium excretion increases and the excretion of salt is maintained at the expense of increased vascular pressures (Loscalzo et al., 2008). The increased sodium ion concentration stimulates antidiuretic hormone (ADH) and thirst mechanisms, leading to increased reabsorption of water in the kidneys, concentrated urine, and thirst with higher intake of water. Also, the water movement between cells and the interstitium plays a minor role compared to this. The relationship between sodium intake and blood pressure is controversial. Reducing sodium intake reduces  blood  pressure, but  the magnitude of  the effect  is  insufficient to recommend  a general reduction in salt intake (Jürgens et al., 2004).

(e) Elevation of Renin

Renin elevation is another risk factor. Renin is an enzyme secreted by the juxtaglomerular apparatus of the kidney and linked with aldosterone in a negative feedback loop. In consequence, some hypertensive patients have been defined as having low-renin and others as having essential hypertension.   Low-renin   hypertension   is   more   common   in   African   Americans   than   white Americans, and may explain why African Americans tend to respond better to diuretic therapy than drugs   that   interfere   with   the   Renin-angiotensin   system.   High   renin   levels   predispose   to hypertension by causing sodium retention through the following mechanism: Increased renin → Increased  angiotensin  II  → Increased   vasoconstriction,    and  aldosterone  → Increased   sodium reabsorption  in  the  kidneys (Distal  convoluted  tubule  and  Collecting  duct)  → Increased blood pressure.

(f) Insulin Resistance

Hypertension can also be caused by Insulin resistance and/or hyperinsulinemia, which are components of syndrome X, or the metabolic syndrome. Insulin is a polypeptide hormone secreted by cells in the islets of Langerhans of the pancreas. Its main purpose is to regulate the levels of glucose in the body antagonistically with glucagon through negative feedback loops. Insulin also exhibits vasodilatory properties. In normotensive individuals, insulin may stimulate sympathetic activity without elevating mean arterial pressure. However, in more extreme conditions such as that of the metabolic syndrome, the increased sympathetic neural activity may over-ride the vasodilatory effects of insulin.

(g) Vitamin D Deficiency

Vitamin D deficiency is associated with cardiovascular risk factors (Lee et al., 2008). Individuals with vitamin D deficiency have higher systolic and diastolic blood pressures than average. Vitamin D inhibits renin secretion and its activity, it therefore acts as a “negative endocrine regulator of the renin-angiotensin system”. Hence a deficiency in vitamin D leads to an increase in renin secretion. This is one possible mechanism of explaining the observed link between hypertension and vitamin D levels in the blood plasma (Forman et al., 2007).

(h) Potassium Level

Some authorities claim that potassium might both prevent and treat hypertension (Sizer et al., 1991).

(i) Cigarette Smoking

Cigarette smoking, a known risk factor for other cardiovascular diseases and may also be a risk factor for the development of hypertension (Halperin, 2008).

1.1.2    Secondary Hypertension

Secondary hypertension results from an identifiable cause. Renal disease is the most common  secondary  cause  of  hypertension.  Hypertension  can  also  be  caused  by  endocrine conditions, such as Cushing’s syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn’s syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma. Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, coarctation of the aorta, excessive liquorice consumption and certain prescription medicines, herbal remedies and illegal drugs.

1.1.2.1   Risk factors for secondary hypertension

(a) Renal disease – Renal parenchymal disease is the most common cause of secondary hypertension.  Hypertension  may  result  from  diabetic  and  inflammatory  glomerular  diseases, tubular   interstitial   disease,   and   polycystic   kidneys.   Most   cases   are   related   to   increased intravascular volume or increased activity of the renin-angiotensin-aldosterone system (Ecder  et al., 2009).

(b) Genetic causes – Hypertension can be caused by mutations in single genes, inherited on a mendelian basis. Although rare, these conditions provide important insight into blood pressure regulation and possibly, the genetic basis of essential hypertension. Glucocorticoid remediable aldosteronism is an autosomal dominant cause of early-onset hypertension with normal or high aldosterone and low renin levels. It is caused by the formation of a chimeric gene encoding both the enzyme responsible for the synthesis of aldosterone (transcriptionally regulated by Angiotensin II) and an enzyme responsible for synthesis of cortisol (transcriptionally regulated by Adrenocorticotrophin hormone, ACTH) (Lifton, 2001).

As   a   consequence,   aldosterone   synthesis   becomes   driven   by   ACTH,   which   can   be suppressed by exogenous cortisol. In the syndrome of apparent mineralocorticoid excess, early- onset hypertension with hypokalemic metabolic alkalosis is inherited on an autosomal recessive basis. Although plasma renin is low and plasma aldosterone level is very low in these patients, aldosterone antagonists are effective in controlling this hypertension. This disease is caused by loss of the enzyme 11β-hydroxysteroid dehydrogenase, which normally protects the otherwise promiscuous mineralocorticoid receptor in the distal nephron from inappropriate glucocorticoid activation,  by  metabolism  of  cortisol.  Similarly,  glycyrrhetinic  acid,  found  in  licorice,  causes increased blood pressure through inhibition of 11β-hydroxysteroid dehydrogenase. The syndrome of hypertension exacerbated in pregnancy is inherited as an autosomal dominant trait. In these

patients, a mutation in the mineralocorticoid receptor makes it abnormally responsive to progesterone and, paradoxically, to spironolactone. Liddle’s syndrome is an autosomal dominant condition  characterized  by early-onset  hypertension, hypokalemic  alkalosis, low  renin  and  low aldosterone  levels.  This  is  caused  by  a  mutation  that  results  in  constitutive  activation  of  the epithelial sodium channel of the distal nephron, with resultant unregulated sodium reabsorption and volume expansion (Giacchetti et al., 2009).

(c) Renal vascular hypertension – Renal artery stenosis is present in 1-2% of hypertensive patients. Its cause in most younger individuals is fibromuscular hyperplasia, particularly in women under 50 years of age. The remainder of renal vascular disease is due to atherosclerotic stenoses of the proximal renal arteries. The mechanism of hypertension is excessive renin release due to reduction in renal blood flow and perfusion pressure. Renal vascular hypertension may occur when a single branch of the renal artery is stenotic, but in as many as 25% of patients both arteries are obstructed.

Renal vascular hypertension should be suspected in the following circumstances: (1) If the documented onset is before age 20 or after age 50 years,

(2) Hypertension is resistant to three or more drugs

(3) If there are epigastric or renal artery bruits

(4) If there is atherosclerotic disease of the aorta or peripheral arteries (15-25% of patients with symptomatic lower limb atherosclerotic vascular disease have renal artery stenosis)

(5) If there is abrupt deterioration in renal function after administration of angiotensin converting enzyme (ACE) inhibitors

(6) If episodes of pulmonary edema are associated with abrupt surges in blood pressure. There is no ideal screening test for renal vascular hypertension. If suspicion is sufficiently high, renal arteriography, the definitive diagnostic test, is the best approach.

(d) Primary hyperaldosteronism – Primary hyperaldosteronism occurs because of excessive secretion of aldosterone by the adrenal cortex. It may, in fact, be the most common potentially

curable and specifically treatable cause of hypertension. In the past, the diagnosis was often suspected when hypokalemia prior to diuretic therapy is associated with excessive urinary potassium excretion (usually > 40 mEq/L on a spot specimen) and suppressed levels of plasma renin activity presented in hypertensive patients. However, the development and application of new screening tests to the population of hypertensive persons have resulted in a marked increase in the detection rate for primary hyperaldosteronism. It now appears that up to 5-15% of patients in whom primary (essential) hypertension is diagnosed actually have primary hyperaldosteronism, with most having normal serum potassium levels. Currently, the best screening test for primary hyperaldosteronism involves determinations of plasma aldosterone concentration (normal: 1-16 ng/dL) and plasma renin activity (normal: 1-2.5 ng/mL/h) and calculation of the plasma aldosterone/renin ratio (normal: < 25). Medications that alter renin and aldosterone levels, including ACE inhibitors, angiotensin receptor blockers (ARBs), and diuretics (especially spironolactone), should be discontinued at least a week before sampling. Patients with aldosterone/renin ratios of ≥ 25 require further evaluation for primary hyperaldosteronism. The lesion responsible is an adrenal adenoma, though some patients have bilateral adrenal hyperplasia. The lesion can be demonstrated by CT or MRI scanning (Freel et al.,2004).

(e) Cushing’s syndrome – Less commonly, hypertension presents in patients with Cushing’s syndrome (glucocorticoid excess). However, among those with spontaneous Cushing’s syndrome, hypertension occurs in about 75-85% of patients. The exact pathogenesis of the hypertension is unclear. It may be related to salt and water retention from the mineralocorticoid effects of the excess glucocorticoid. Alternatively, it may be due to increased secretion of angiotensinogen. While plasma  renin  activity  and  concentrations  are  generally  normal  or  suppressed  in  Cushing’s syndrome, angiotensinogen levels are elevated to approximately twice normal because of a direct effect of glucocorticoids on its hepatic synthesis, and angiotensin II levels are increased by about 40%. Administration of the angiotensin II antagonist saralasin to patients with Cushing’s syndrome causes a prompt 8- to 10-mm Hg drop in systolic and diastolic blood pressure. In addition, glucocorticoids exert permissive effects on vascular tone by a variety of mechanisms (Nussberger ,2003).

(f) Pheochromocytoma – Pheochromocytomas are uncommon; they are probably found in less than 0.1% of all patients with hypertension and in approximately two individuals per million population. In about 50% of patients with pheochromocytoma, hypertension is sustained but the blood pressure shows marked fluctuations, with peak pressures during symptomatic paroxysms. During a hypertensive episode, the systolic blood pressure can rise to as high as 300 mm Hg. In about one-third of cases, hypertension is truly intermittent. In some cases, hypertension is absent. The blood pressure elevation caused by the catecholamine excess results from two mechanisms: α- receptor-mediated vasoconstriction of arterioles, leading to an increase in peripheral resistance, and β1-receptor-mediated increases in cardiac output and in renin release, leading to increased circulating levels of angiotensin II. The increased total peripheral vascular resistance is probably primarily responsible for the maintenance of high arterial pressures. Chronic vasoconstriction of the arterial and venous beds leads to a reduction in plasma volume and predisposes to postural hypotension.

Indeed, the majority of patients have orthostatic decreases in blood pressure, the converse of primary (essential) hypertension. Glucose intolerance develops in some patients. Hypertensive crisis in pheochromocytoma may be precipitated by a variety of drugs, including tricyclic antidepressants, antidopaminergic agents, metoclopramide, and naloxone (Radermacher , 2001)

(g) Hypertension associated with pregnancy – Hypertension occurring de novo or worsening during pregnancy, including preeclampsia and eclampsia, is one of the most common causes of maternal and fetal morbidity and mortality (Marik , 2009).

(h) Estrogen use – A small increase in blood pressure occurs in most women taking oral contraceptives, but considerable increases are noted occasionally. This is caused by volume expansion due to increased activity of the renin-angiotensin-aldosterone system. The primary abnormality is an increase in the hepatic synthesis of renin substrate. Five percent of women taking oral contraceptives chronically exhibit a rise in blood pressure above 140/90 mm Hg, twice the expected prevalence. Contraceptive-related hypertension is more common in women over 35 years of age, in those who have taken contraceptives for more than 5 years, and in obese individuals. It is less  common  in  those taking  low-dose estrogen tablets. In  most, hypertension  is reversible by discontinuing the contraceptive, but it may take several weeks. Postmenopausal estrogen does not generally cause hypertension, but rather maintains endothelium-mediated vasodilation (Chobanian et al., 2003).

(i) Other causes of secondary hypertension – Hypertension has also been associated with hypercalcemia due to any cause: acromegaly, hyperthyroidism, hypothyroidism, and a variety of neurologic disorders cause increased intracranial pressure. A number of other medications may cause  or  exacerbate  hypertension  –  most  importantly  cyclosporine  and  NSAIDs  (Kassim  et  al., 2008).

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