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:
- 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).
1.1.3 Pathophysiology of Hypertension
Fig. 1: Factors affecting arterial pressure
In most people with established essential (primary) hypertension, increased resistance to blood flow (total peripheral resistance) accounts for the high pressure while cardiac output remains normal. There is evidence that some younger people with prehypertension or ‘borderline hypertension' have high cardiac output, an elevated heart rate and normal peripheral resistance, termed hyperkinetic borderline hypertension. These individuals develop the typical features of established essential hypertension in later life as their cardiac output falls and peripheral resistance rises with age (Palatini et al., 2009). Whether this pattern is typical of all people who ultimately develop hypertension is disputed. The increased peripheral resistance in established hypertension is mainly attributable to structural narrowing of small arteries and arterioles although a reduction in the number or density of capillaries may also contribute. Hypertension is also associated with decreased peripheral venous compliance which may increase venous return, increase cardiac preload and, ultimately, cause diastolic dysfunction. Whether increased active vasoconstriction plays a role in established essential hypertension is unclear (Struijker et al., 1992).
Pulse pressure (the difference between systolic and diastolic blood pressure) is frequently increased in older people with hypertension. This can mean that systolic pressure is abnormally high, but diastolic pressure may be normal or low, a condition termed isolated systolic hypertension.The high pulse pressure in elderly people with hypertension or isolated systolic hypertension is explained by increased arterial stiffness, which typically accompanies aging and may be exacerbated by high blood pressure (Zieman et al., 2005). Many mechanisms have been proposed to account for the rise in peripheral resistance in hypertension. Most evidence implicate either disturbances in renal salt and water handling, particularly abnormalities in the intrarenal renin-angiotensin system
1.1.4 Abnormalities of the sympathetic nervous system
These mechanisms are not mutually exclusive and it is likely that both contribute to some extent in most cases of essential hypertension. It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension (Marchesi et al., 2008).
1.1.5 Diagnosis of Hypertension
Hypertension is diagnosed on the basis of a persistently high blood pressure. Traditionally, this requires three separate sphygmomanometer measurements at monthly intervals. Initial assessment of the hypertensive people should include a complete history and physical examination. With the availability of 24-hour ambulatory blood pressure monitors and home blood pressure machines, the importance of not wrongly diagnosing those who have white coat hypertension has led to a change in protocols. In the United Kingdom, current best practice is to follow up a single raised clinic reading with ambulatory measurement, or less ideally with home blood pressure monitoring over the course of 7 days (National Clinical Guidance Centre, 2011).
Once the diagnosis of hypertension has been made, physicians will attempt to identify the underlying cause based on risk factors and other symptoms, if present. Secondary hypertension is more common in preadolescent children, with most cases caused by renal disease. Primary or essential hypertension is more common in adolescents. Laboratory tests can also be performed to identify possible causes of secondary hypertension, and to determine whether hypertension has caused damage to the heart, eyes, and kidneys. Additional tests for diabetes and high cholesterol levels are usually performed because these conditions are additional risk factors for the development of heart disease and require treatment (Carretero et al., 2000).
Serum creatinine is measured to assess the presence of kidney disease, which can be either the cause or the result of hypertension. Serum creatinine alone may overestimate glomerular filtration rate and recent guidelines advocate the use of predictive equations such as the Modification of Diet in Renal Disease (MDRD) formula to estimate glomerular filtration rate (eGFR). eGFR can also provide a baseline measurement of kidney function that can be used to monitor for side effects of certain antihypertensive drugs on kidney function. Additionally, testing of urine samples for protein is used as a secondary indicator of kidney disease. Electrocardiogram (EKG/ECG) testing is done to check for evidence that the heart is under strain from high blood pressure. It may also show whether there is thickening of the heart muscle (left ventricular hypertrophy) or whether the heart has experienced a prior minor disturbance such as a silent heart attack. A chest X-ray or an echocardiogram may also be performed to look for signs of heart enlargement or damage to the heart (O'Brien et al., 2007).
1.1.6 Epidemiology of Hypertension
As of 2000, nearly one billion people or ~26% of the adult population of the world had hypertension. It was common in both developed (333 million) and undeveloped (639 million) countries. However, rates vary markedly in different regions with rates as low as 3.4% (men) and 6.8% (women) in rural India and as high as 68.9% (men) and 72.5% (women) in Poland. In 1995 it was estimated that 43 million people in the United States had hypertension or were taking antihypertensive medication, almost 24% of the adult United States population. The prevalence of hypertension in the United States is increasing and reached 29% in 2004. It is more common in blacks and native Americans and less in whites and Mexican Americans, rates increase with age, and is greater in the southeastern United States. Hypertension is more prevalent in men (though menopause tends to decrease this difference) and in those of low socioeconomic status Carretero and Oparil, 2000).
1.1.7 Complications of Hypertension
Fig. 2: Complications of hypertension
Source: Medical Gallery of Mikael Haggstrom (2014)
Complications of hypertension are clinical outcomes that result from persistent elevation of blood pressure. Hypertension is a risk factor for all clinical manifestations of atherosclerosis since it is a risk factor for atherosclerosis itself. It is an independent predisposing factor for heart failure, coronary artery disease, stroke, renal disease and peripheral arterial disease. It is the most important risk factor for cardiovascular morbidity and mortality in industrialized countries. Clinically, macroalbuminuria (a random urine albumin/creatinine ratio > 300 mg/g) or microalbuminuria (a random urine albumin/creatinine ratio 30–300 mg/g) are early markers of renal injury. These are also risk factors for renal disease progression and for cardiovascular disease (Kwoh et al., 2006).
1.2 Pregnancy
Pregnancy is the fertilization and development of one or more offspring, known as embryo or fetus, in a woman's uterus. In a 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 start of the last normal menstrual period (LNMP). Pregnancy begins with implantation, the process leading to pregnancy occurs earlier as the result of the female gamete, or oocyte, merging with the male gamete, spermatozoon. The fused product of the female and male gamete is referred to as a zygote or fertilized egg. The fusion of male and female gametes usually occurs following the act of sexual intercourse, resulting in spontaneous pregnancy. However, the advent of assisted reproductive technology such as artificial insemination and in vitro fertilization have made achieving pregnancy possible without engaging in sexual intercourse (Carver-Ward et al., 1997).
1.2.1 Fertilization
Figure 3 Stages of human embryogenesis
Source: Gray’s Anatomy
Fig. 4: Fertilization and implantation in humans
Source: New England Journal of Medicine (1999)
The process of fertilization occurs in several steps, and the interruption of any of them can lead to failure. Through fertilization, the egg is activated to begin its developmental process, and the haploid nuclei of the two gametes come together to form the genome of a new diploid organism.
At the beginning of the process, the sperm undergoes a series of changes, as freshly ejaculated sperm is unable or poorly able to fertilize. The sperm must undergo capacitation in the female's reproductive tract over several hours, which increases its motility and destabilizes its membrane, preparing it for the acrosome reaction, the enzymatic penetration of the egg's tough membrane, the zona pellucida, which surrounds the oocyte. The sperm and the egg cell, which has been released from one of the female's two ovaries, unite in one of the two fallopian tubes. The fertilized egg, known as a zygote, then moves toward the uterus, a journey that can take up to a week to complete. Cell division begins approximately 24 to 36 hours after the male and female cells unite. Cell division continues at a rapid rate and the cells then develop into what is known as a blastocyst. The blastocyst is made up of three layers: the ectoderm (which will become the skin and nervous system), the endoderm (which will become the digestive and respiratory systems), and the mesoderm (which will become the muscle and skeletal systems). Finally, the blastocyst arrives at the uterus and attaches to the uterine wall, a process known as implantation (Carver-Ward et al., 1997).
The mass of cells, now known as an embryo, begins the embryonic stage, which continues until cell differentiation is almost complete at eight weeks. Structures important to the support of the embryo develop, including the placenta and umbilical cord. During this time, cells begin to differentiate into the various body systems. The basic outlines of the organ, body, and nervous systems are established. By the end of the embryonic stage, the beginnings of features such as fingers, eyes, mouth, and ears become visible.
Once cell differentiation is mostly complete, the embryo enters the final stage and becomes known as a fetus. The early body systems and structures that were established in the embryonic stage continue to develop. Sex organs begin to appear during the third month of gestation. The fetus continues to grow in both weight and length, although the majority of the physical growth occurs in the last weeks of pregnancy ( Kieler et al., 1995)..
1.2.2 Diagnosis of Pregnancy
Most pregnant women experience a number of symptoms which can signify pregnancy. The symptoms include nausea and vomiting, excessive tiredness and fatigue, cravings for certain foods that are not normally sought out, and frequent urination particularly during the night.
Pregnancy detection can be accomplished using one or more pregnancy tests which detect hormones generated by the newly formed placenta. Clinical blood and urine tests can detect pregnancy 12 days after implantation. Blood pregnancy tests are more sensitive than urine tests (giving less false negatives). A quantitative blood test can determine approximately the date the embryo was conceived (NHS, 2010).
1.2.3 Signs of Pregnancy
A number of early medical signs are associated with pregnancy. These signs typically appear, if at all, within the first few weeks after conception. Although not all of these signs are universally present, nor are all of them diagnostic by themselves, taken together they make a presumptive diagnosis of pregnancy. These signs include the presence of human chorionic gonadotropin (hCG) in the blood and urine, missed menstrual period, implantation bleeding that occurs at implantation of the embryo in the uterus during the third or fourth week after last menstrual period, increased basal body temperature sustained for over 2 weeks after ovulation, Chadwick's sign (darkening of the cervix, vagina, and vulva), Goodell's sign (softening of the vaginal portion of the cervix), Hegar's sign (softening of the uterus isthmus), and pigmentation of linea alba – Linea nigra, (darkening of the skin in a midline of the abdomen, caused by hyperpigmentation resulting from hormonal changes, usually appearing around the middle of pregnancy). Breast tenderness is common during the first trimester, and is more common in women who are pregnant at a young age (Qasim et al., 1996).
1.2.4 Physiology of Pregnancy
Pregnancy is typically broken into three periods, or trimesters, each of about three months. These distinctions are useful in describing the changes that take place over time.
1.2.4.1 First trimester
The first 12 weeks of pregnancy are considered to make up the first trimester. The first two weeks from the first trimester are calculated as the first two weeks of pregnancy even though the pregnancy does not actually exist. These two weeks are the two weeks before conception and include the woman's last period.
The third week is the week in which fertilization occurs and the 4th week is the period when implantation takes place. In the 4th week, the fecundated egg reaches the uterus and burrows into its wall which provides it with the nutrients it needs. At this point, the zygote becomes a blastocyst and the placenta starts to form. Moreover, most of the pregnancy tests may detect a pregnancy beginning with this week
The 5th week marks the start of the embryonic period. This is when the embryo's brain, spinal cord, heart and other organs begin to form. At this point the embryo is made up of three layers, of which the top one (called the ectoderm) will give rise to the embryo's outermost layer of skin, central and peripheral nervous systems, eyes, inner ear, and many connective tissues. The heart and the beginning of the circulatory system as well as the bones, muscles and kidneys are made up from the mesoderm (the middle layer). The inner layer of the embryo will serve as the starting point for the development of the lungs, intestine and bladder. This layer is referred to as the endoderm. An embryo at 5 weeks is normally between 1⁄16 and 1⁄8 inch (1.6 and 3.2 mm) in length.
In the 6th week, the embryo will be developing basic facial features and its arms and legs start to grow. At this point, the embryo is usually no longer than 1⁄6 to 1⁄4 inch (4.2 to 6.3 mm). In the following week, the brain, face and arms and legs quickly develop. In the 8th week, the embryo starts moving and in the next 3 weeks, the embryo's toes, neck and genitals develop as well. According to the American Pregnancy Association, by the end of the first trimester, the fetus will be about 3 inches (76 mm) long and will weigh approximately 1 ounce (28 g). Once pregnancy moves into the second trimester, all the risks of miscarriage and birth defects occurring drop drastically.
1.2.4.2 Second trimester
Weeks 13 to 28 of the pregnancy are called the second trimester. Most women feel more energized in this period, and begin to put on weight as the symptoms of morning sickness subside and eventually fade away. The uterus, the muscular organ that holds the developing fetus, can expand up to 20 times its normal size during pregnancy. Although, the fetus begins to move and takes a recognizable human shape during the first trimester, it is not until the second trimester that movement of the fetus, often referred to as “quickening“, can be felt. This typically happens in the fourth month, more specifically in the 20th to 21st week, or by the 19th week if the woman has been pregnant before. However, it is not uncommon for some women not to feel the fetus move until much later. The placenta fully functions at this time and the fetus makes insulin and urinates. The reproductive organs distinguish the fetus as male or female.
1.2.4.3Third trimester
Final weight gain takes place, which is the most weight gain throughout the pregnancy. The fetus will be growing the most rapidly during this stage, gaining up to 28 g per day. The woman's belly will transform in shape as the belly drops due to the fetus turning in a downward position ready for birth. During the second trimester, the woman's belly would have been very upright, whereas in the third trimester it will drop down quite low, and the woman will be able to lift her belly up and down. The fetus begins to move regularly, and is felt by the woman. Fetal movement can become quite strong and be disruptive to the woman. The woman's navel will sometimes become convex, “popping” out, due to her expanding abdomen. This period of her pregnancy can be uncomfortable, causing symptoms like weak bladder control and backache. Movement of the fetus becomes stronger and more frequent and via improved brain, eye, and muscle function the fetus is prepared for ex utero viability. The woman can feel the fetus “rolling” and it may cause pain or discomfort when it is near the woman's ribs and spine.
There is head engagement in the third trimester, that is, the fetal head descends into the pelvic cavity so that only a small part (or none) of it can be felt abdominally. The perenium and cervix are further flattened and the head may be felt vaginally. Head engagement is known colloquially as the baby drop, and in natural medicine as the lightening because of the release of pressure on the upper abdomen and renewed ease in breathing. However, it severely reduces bladder capacity, increases pressure on the pelvic floor and the rectum, and the mother may experience the perpetual sensation that the fetus will “fall out” at any moment.
1.2.5 Hypertension in Pregnancy
Several hypertensive states of pregnancy exist and they include the following;
1.2.5.1 Pregnancy-induced hypertension
Pregnancy-induced hypertension (PIH) is a serious complication of pregnancy and is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks gestation without the presence of protein in the urine.
1.2.5.2 Gestational hypertension
Gestational hypertension is usually defined as having a blood pressure higher than 140/90 without the presence of protein in the urine and diagnosed after 20 weeks of gestation
1.2.5.3 Preeclampsia
Pre-eclampsia is gestational hypertension (blood pressure greater than 140/90) plus proteinuria (>300 mg of protein in a 24-hour urine sample). Severe preeclampsia involves a blood pressure greater than 160/110, with additional medical signs and symptoms.
1.2.5.4 Eclampsia
This is when tonic-clonic seizures appear in a pregnant woman with high blood pressure and proteinuria.
1.2.6 Risk factors associated with hypertension during pregnancy include
- Family history of pre-eclampsia
- Pre-existing hypertension
- Renal disease
- Diabetes mellitus
- Obesity
- Placental abnormalities:
- Hyperplacentosis: Excessive exposure to chronic villi.
- Placental ischemia.
- Multiple gestation (twins or triplets, etc.)
- Age 35 or greater
- Adolescent pregnancy
- New paternity
1.2.7 Aetiopathological factors for pre-eclampsia
- Failure of trophoblast invasion (abnormal placentation)
- Vascular endothelial damage
- Inflammatory mediator (cytokines)
- Immunological intolerance between maternal and fetal tissues
- Coagulation abnormalities
- Increased oxygen free radicals
- Genetic predisposition (polygenic disorders)
- Dietary deficiency or excess
1.2.7.1 Placental Ischemia/Hypoxia and the Aetiology of Preeclampsia
Although, the pathophysiology of preeclampsia remains undefined, placental ischemia/hypoxia is widely regarded as a key factor (Fisher et al., 1999). Inadequate trophoblast invasion leading to incomplete remodeling of the uterine spiral arteries is considered to be a primary cause of placental ischemia (Conrad et al., 1997). Thus the poorly perfused and hypoxic placenta is thought to synthesize and release increased amounts of vasoactive factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), cytokines, and possibly the angiotensin II (ANG II) type 1 receptor autoantibodies (AT1-AA) (Wallukat et al., 1999).
Fig. 5 illustrates a model by which these vasoactive factors and other candidate molecules are thought to induce widespread activation/dysfunction of the maternal endothelium in vessels of the kidney and other organs that ultimately results in hypertension.
Fig. 5: Pathways by which reduced uterine perfusion pressure (RUPP) and placental ischemia may lead to endothelial and cardiovascular dysfunction.
Source: Journal of Clinical Endocrinology and Metabolism (2005)
Placental ischemia results in increased synthesis of soluble fms-like tyrosine kinase-1 (sFlt-1), TNF-α and IL-6, angiotensin II type 1 receptor autoantibodies (AT1-AA), and thromboxane (TX). Elevation of these factors are proposed to result in endothelial dysfunction by decreasing the bioavailable nitric oxide (NO) and increasing reactive oxygen species (ROS) and endothelin-1 (ET-1), which in turn results in altered renal function, increased total peripheral resistance (TPR), and ultimately hypertension.
Perhaps the most prominent molecule postulated to play a key role in the pathogenesis of preeclampsia is sFlt-1. Several lines of evidence support the hypothesis that the ischemic placenta contributes to endothelial cell dysfunction in the maternal vasculature by inducing an alteration in the balance of circulating levels of angiogenic/antiangiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and sFlt-1 (Levine et al., 2006). Although, there is evidence that circulating sFlt-1 concentrations may presage the clinical onset of preeclamptic symptoms, several studies indicate that placental hypoxia and poor placental perfusion may initiate this imbalance of angiogenic factors (Lam et al., 2005). Nevertheless, it remains unclear whether impaired placental perfusion initiates preeclamptic symptoms such as hypertension, endothelial dysfunction, and increased sFlt-1 or whether inadequate placental development occurs initially and is followed by a pathological rise in sFlt-1 expression and secretion (Karumanchi et al., 2004).
Hypertension associated with preeclampsia develops during late pregnancy and remits after delivery or termination of the pregnancy, suggesting that the placenta is a central culprit in the disease. The foremost hypothesis regarding the initiating event in preeclampsia is postulated to be reduced placental perfusion that, in turn, leads to widespread dysfunction of the maternal vascular endothelium. Numerous other factors including genetic, immunological, behavioral, and environmental influences have been implicated in the pathogenesis of preeclampsia.
1.2.8 Complications of pregnancy induced hypertension
Hypertension does complicate as many as 7 to 10 percent of pregnancies and is still one of the leading causes of death among expectant mothers. Severe hypertension increases a mother's risk of heart attack, heart failure, stroke, and kidney failure. When a pregnant mother's blood pressure is severely elevated, oxygen and nutrients cannot pass as easily through the placenta and to the baby. As a result, fetal growth restriction, premature birth, and placental abruption (separation of the placenta from the uterus) may occur.
1.2.9 Justification for the Research
This study will help in early detection of renal complication of pregnancy induced hypertension if any and early management of the disorder. This may contribute in reducing the morbidity and mortality associated with this condition.
1.2.10 Aim and Objectives of the Study
1.2.10.1 Aim of the Study This study is aimed at assessing the renal biochemical changes in pregnancy induced hypertensive patients attending tertiary health institutions in Enugu state.
1.2.10.2 Specific Objectives of the Study
- To investigate the relationship between pregnancy induced hypertension and renal impairment using electrolytes such as (Na+, K+, Cl– and HCO3–).
To determine the effect of hypertension on total protein, albumin and globulin concentrations in pregnancy.
