**2.1.3 Hypertensive disorders of pregnancy**

Hypertensive disorders are the commonest cause of renal failure in pregnancy. These are seen in two settings: young primigravidas and older multiparous women.

### **2.1.3.1 Classification**

Terminology of hypertensive disorders varies, but following 5 entities have been described by National High Blood Pressure Education Program (NHBPEP, 2000):

**Gestational hypertension/ Transient hypertension** - is defined as blood pressure of 140/90 mm Hg or greater with no hypertension before pregnancy. It usually affects nulliparous females mostly in third trimester. Preeclampsia does not develop and blood pressure returns to normal levels within 12 weeks postpartum. Patients are usually asymptomatic or

Acute Kidney Injury in Pregnancy 155

(Hemolysis, ELevated liver enzymes, and Low Platelets) is observed when severe preeclampsia or eclampsia is accompanied by significant liver involvement. Acute renal

**Eclampsia**-is the occurrence of seizure activity with no other explainable cause in setting of

**Preeclampsia superimposed on chronic hypertension-** defined as new-onset proteinuria (ie, >300 mg/d) after 20 weeks' gestation in a hypertensive patient or as a sudden increase in proteinuria or blood pressure in a patient with hypertension and proteinuria before 20

Utero-placental ischemia: A combination of genetic and environmental factors results in inadequate invasion of uterine spiral arteries by placental trophoblasts resulting in inability of uterine vessels to transform from high resistance channels to a low resistance system. This results in utero-placental ischemia. In normal pregnancy Vascular endothelial growth factor (VEGF ) and Placental induced growth factor (PIGF) are made by placenta and circulate in high concentrations in the blood. VEGF is also synthesized by glomerular podocytes and vascular endothelial cells. VEGF and PIGF induce synthesis of nitric oxide and vasodilating prostacylin in endothelial cells decreasing vascular tone and blood pressure. In PIH the utero-placental ischemia results in oxidative stress and release of a soluble cytokine, the sFlt-1 (soluble fms-like tyrosine kinase-1). sFlt-1 is a potent antagonist of VEGF and PIGF. In PET concentrations of sFlt-1 rise in the 2nd trimester with a decrease in VEGF and PIGF. Overproduction of sFlt-1 explains increased susceptibility to PET in multiple gestation, hydantidiform mole, trisomy 13 and first pregnancy. In addition, increased concentration of circulating pre-ecclamptic factorsangiotensin 1 /Bradykinin B2 receptor heterodimers, agonistic antibodies to angiotensin I receptor(AT 1 receptor antibody) and soluble endoglin are seen in PET. (Maynard,S 2003;

There is an imbalance of vasoconstrictors and vasodilator substances hence there is a state of generalized vasoconstriction in preeclampsia. The levels of prorenin, angiotensin, thromboxane and endothelin are high while the levels of vasodilator prostaglandin ie Prostacyclin, PGE2, nitric oxide and bradykinin are low. In normal pregnancy there is less sensitivity of vascular bed to the hypertensive effects of angiotensin but this is lost in

A myriad of markers for generalized endothelial dysfunction are seen in preeclampsia which include von Willebrand factor, Platelet activating factor (PAF-1), Endothelin and

The increase in blood volume, increased GFR and vasodilatation seen in normal pregnancy are lost in preeclampsia. Though the blood volume in preeclampsia is decreased there is an increase in effective circulating volume with suppressed renin and aldosterone with

Laboratory evaluation helps to determine disease severity by characterizing the extent of

Hematocrit — Hemoconcentration supports the diagnosis of preeclampsia but hemolysis, if

failure (ARF) may develop.(Lindheimer, 1991)

Venkatesha,S 2006; Zhou,C.C,2008; Levine, RJ 2006)

preeclampsia.

weeks' gestation.

preeclampsia.

cellular fibronectin.

**2.1.3.3 Screening tests** 

end organ involvement.

elevation of brain natriuretic peptide.

present, can decrease the hematocrit.

**2.1.3.2 Pathophysiology** 

have symptoms or signs like preeclampsia. It is a retrospective diagnosis and is confused with preeclampsia at the time of onset and with essential hypertension postpartum until the blood pressure returns to normal. Proteinuria does not occur, serum uric acid is normal. It may predict the development of hypertension later in life. It should be managed as preeclampsia when first diagnosed.

**Chronic hypertension**- is associated with underlying or preexisting hypertension. The diagnosis is established by a blood pressure of 140/90 mm Hg or greater before pregnancy or before 20 weeks' gestation, or by persistent hypertension after delivery. Renal biopsy shows nephrosclerosis rather than preeclampsia. Complications of chronic hypertension include superimposed preeclampsia and renal failure, abruptio placentae, growth restriction and fetal death. Methyldopa is the preferred treatment agent, but in mild cases, no therapy may be necessary. In women whose blood pressure is well controlled when they enter pregnancy, the same therapy should be continued. However, angiotensin II receptor blocking (ARB) agents and angiotensin converting enzyme inhibitors (ACEIs) are contraindicated in pregnancy due to the risk of fetal renal agenesis.

**Preeclampsia** - It is the leading cause of acute kidney injury in the last trimester and occurs in 7% of all pregnancies mostly in primigravidas. However it can be seen in multigravidas if the interpregnancy interval is prolonged. It is the leading cause of maternal and fetal mortality in the world. It is associated with intrauterine growth retardation and small for gestational age (SGA) babies. It is a triad of hypertension, proteinuria and oedema occurring after the 20th week of gestation with few cases developing postpartum within hours, usually in the first 24 to 48 hours. Preeclampsia does not occur before twenty weeks gestation except in molar pregnancies and in the presence of antiphospholipid antibody syndrome. Hypertension is defined as rise in systolic BP >30 mmHg and diastolic BP >15 mmHg. Proteinuria is defined as >300mg protein in urine per day. Oedema is not essential for diagnosis but sudden oedema and weight gain are common presenting features. Oedema is due to overfill with reduced GFR as in nephritic illnesses with suppressed renin and aldosterone and differs from oedema of CHF, cirrhosis and neprhotic syndrome which is associated with underfilling of vascular bed with high renin and aldosterone. Though increased capillary permeability and hypoalbuminemia may be seen they are not the sole contributing factors for oedema. The risk factors associated with the development of preeclampsia include age older than 35 years or younger than 16 years, chronic hypertension, obesity, preexisting diabetes , renal disease, insulin resistance, Anti phospholipid antibody syndrome, African American race and pregnancy with a new partner. Fetal risk factors may be twin or multiple gestations, trisomy 13 and hydatidiform mole. Some genetic factors contribute to the development of preecclampsia. It is four times more common if there is history of precclampsia in mother or sister. Polymorphisms of genes associated with control of blood pressure or coagulation system have been implicated. Some mutations described involve Endothelial nitric oxide synthetase (e NOS), renin angiotensinogen (T235), Leyden factor V, Prothrombin and Methyl tetra hydrofolate reductase(MTHFR) genes. A locus on 2p was described in Icelandic and Australian families. A Dutch study reported linkage to 12 q locus in HELLP syndrome which shows the genetic factors responsible for Preclampsia and HELLP may be different. Association with trisomy 13 indicates a linkage to chromosome 13. An activating mutation of mineralocorticoid receptor was described in patients with PIH but no proteinuria. Preclampsia is more commonly seen in women at high altitude or in third world countries suggesting the possible role of hypoxia or environmental pollution in genesis . HELLP syndrome

have symptoms or signs like preeclampsia. It is a retrospective diagnosis and is confused with preeclampsia at the time of onset and with essential hypertension postpartum until the blood pressure returns to normal. Proteinuria does not occur, serum uric acid is normal. It may predict the development of hypertension later in life. It should be managed as

**Chronic hypertension**- is associated with underlying or preexisting hypertension. The diagnosis is established by a blood pressure of 140/90 mm Hg or greater before pregnancy or before 20 weeks' gestation, or by persistent hypertension after delivery. Renal biopsy shows nephrosclerosis rather than preeclampsia. Complications of chronic hypertension include superimposed preeclampsia and renal failure, abruptio placentae, growth restriction and fetal death. Methyldopa is the preferred treatment agent, but in mild cases, no therapy may be necessary. In women whose blood pressure is well controlled when they enter pregnancy, the same therapy should be continued. However, angiotensin II receptor blocking (ARB) agents and angiotensin converting enzyme inhibitors (ACEIs) are

**Preeclampsia** - It is the leading cause of acute kidney injury in the last trimester and occurs in 7% of all pregnancies mostly in primigravidas. However it can be seen in multigravidas if the interpregnancy interval is prolonged. It is the leading cause of maternal and fetal mortality in the world. It is associated with intrauterine growth retardation and small for gestational age (SGA) babies. It is a triad of hypertension, proteinuria and oedema occurring after the 20th week of gestation with few cases developing postpartum within hours, usually in the first 24 to 48 hours. Preeclampsia does not occur before twenty weeks gestation except in molar pregnancies and in the presence of antiphospholipid antibody syndrome. Hypertension is defined as rise in systolic BP >30 mmHg and diastolic BP >15 mmHg. Proteinuria is defined as >300mg protein in urine per day. Oedema is not essential for diagnosis but sudden oedema and weight gain are common presenting features. Oedema is due to overfill with reduced GFR as in nephritic illnesses with suppressed renin and aldosterone and differs from oedema of CHF, cirrhosis and neprhotic syndrome which is associated with underfilling of vascular bed with high renin and aldosterone. Though increased capillary permeability and hypoalbuminemia may be seen they are not the sole contributing factors for oedema. The risk factors associated with the development of preeclampsia include age older than 35 years or younger than 16 years, chronic hypertension, obesity, preexisting diabetes , renal disease, insulin resistance, Anti phospholipid antibody syndrome, African American race and pregnancy with a new partner. Fetal risk factors may be twin or multiple gestations, trisomy 13 and hydatidiform mole. Some genetic factors contribute to the development of preecclampsia. It is four times more common if there is history of precclampsia in mother or sister. Polymorphisms of genes associated with control of blood pressure or coagulation system have been implicated. Some mutations described involve Endothelial nitric oxide synthetase (e NOS), renin angiotensinogen (T235), Leyden factor V, Prothrombin and Methyl tetra hydrofolate reductase(MTHFR) genes. A locus on 2p was described in Icelandic and Australian families. A Dutch study reported linkage to 12 q locus in HELLP syndrome which shows the genetic factors responsible for Preclampsia and HELLP may be different. Association with trisomy 13 indicates a linkage to chromosome 13. An activating mutation of mineralocorticoid receptor was described in patients with PIH but no proteinuria. Preclampsia is more commonly seen in women at high altitude or in third world countries suggesting the possible role of hypoxia or environmental pollution in genesis . HELLP syndrome

contraindicated in pregnancy due to the risk of fetal renal agenesis.

preeclampsia when first diagnosed.

(Hemolysis, ELevated liver enzymes, and Low Platelets) is observed when severe preeclampsia or eclampsia is accompanied by significant liver involvement. Acute renal failure (ARF) may develop.(Lindheimer, 1991)

**Eclampsia**-is the occurrence of seizure activity with no other explainable cause in setting of preeclampsia.

**Preeclampsia superimposed on chronic hypertension-** defined as new-onset proteinuria (ie, >300 mg/d) after 20 weeks' gestation in a hypertensive patient or as a sudden increase in proteinuria or blood pressure in a patient with hypertension and proteinuria before 20 weeks' gestation.
