**1.3.2 Renal physiology**

#### **1.3.2.1 Systemic haemodynamics**

Detailed discussion of systemic haemodynamics of normal pregnancy is beyond the scope of this chapter. Briefly, changes start as early as the first trimester with reduced systemic vascular resistance, increase in cardiac output by 40-50% and resting tachycardia by 24th week (Davison & Dunlop, 1980). There is progressive expansion of the plasma and

Epidemiology, Causes and Outcome of Obstetric Acute Kidney Injury 75

reasons explained in previous sections. AKI may also complicate postpartum eclampsia. HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count) is a variant of severe pre-eclampsia, which usually resolves following delivery (Weinstein, 1985) and occurs in around 20% of the severe pre-eclampsia cases (Sibai et al, 1993). AKI may also occur as a direct consequence of disseminated intravascular coagulation (one of the dreaded complications in upto 20% of women with HELLP syndrome), and sepsis (Sibai et al, 1993). Similarly, other microangiopathies like acute fatty liver of pregnancy which occurs commonly in the third trimester and haemolytic uremic syndrome/ thrombotic thrombocytopenic purpura occurring ante- or post-partum share several pathophysiologic mechanisms which is difficult to differentiate and eventually may contribute to the development of AKI (Ganesan, 2011). Acute fatty liver of pregnancy is an obstetric emergency, which if untreated may progress to fulminant hepatic failure and proves life threatening to both mother and foetus. Variable degree of AKI has been reported in upto 90% of women with acute fatty liver of pregnancy, which is usually reversible with the recovery of liver failure (Hou, 2001). HUS/TTP occurs typically in the early postpartum period but delays of several months postpartum have also been reported. Renal failure was previously thought to be irreversible but complete and partial recovery does occur in about

Pathogenesis of sepsis-induced renal dysfunction is still poorly understood. Though it has been demonstrated that septic AKI can occur in the setting of marked Hyperaemia and vasodilatation; and renal ischemia is not necessary for the loss of GFR (Bellomo et al, 2008); various inflammatory factors have also been shown to be generated following ischemia which contributes to development of AKI and ATN (Kribben, 1999). Experimental studies continue to report newer concepts for pathogenesis of septic AKI (Bellomo, 2011). Similar

Pregnant women are at greater risk of urinary tract infection due to the altered anatomy and urinary stasis as discussed in previous sections. Untreated timely and correctly this can lead to urosepsis. Acute pyelonephritis may occur as part of urinary tract infection and may be severe enough to cause AKI as a result of sepsis or prerenal azotemia from vomiting. Improved availability and better management of abortion has led to decrease in the incidence of post-abortal sepsis especially in the developed countries (Gul et al, 2004). Sepsis is still a major cause including septic abortions and puerperal sepsis in developing countries

A total of 99% of all maternal deaths occur in developing countries, where 85% of the population lives. More than half of these deaths occur in sub-Saharan Africa and one third in South Asia. Globally, around 80 per cent of maternal deaths are due to obstetric complications; mainly haemorrhage, sepsis, unsafe abortion, pre-eclampsia and eclampsia, and prolonged or obstructed labour (United Nations Children's Fund [UNICEF], 2003; United Nations Development Programme [UNDP], 2006). An estimated 21.6 million unsafe abortions took place worldwide in 2008, almost all in developing countries. Numbers of unsafe abortions have increased from 19.7 million in 2003 (Department of Reproductive

30% of these cases (Beaufils, 2001).

(Sivakumar, 2011; Khanal, 2010).

**1.4 Prevention and model of care** 

**1.3.4 Pyelonephritis, septic abortion and puerperal sepsis** 

studies in man are required to confirm these experimental findings.

extracellular fluid volume, reaching a maximum of 1.25 litres at times. The volume of the total extracellular fluid space is determined principally by sodium and hence water accumulation. The combination of increased cardiac output and peripheral vasodilatation means that organ blood flow increases in pregnancy, with the most dramatic changes occurring in the kidney and skin circulation throughout gestation and in the uterus in the second part of the pregnancy. These changes result in a small reduction in arterial blood pressure, typically reaching a nadir in the mid-trimester of about 10 mmHg systolic, rising towards pre-pregnancy levels at term (Brown & Gallery, 1994). Table 4 illustrates changes in some common indices during pregnancy.


Table 4. Changes in some common indices during pregnancy **(**Modified from Source: Baylis & Davison, 2010; Brown et al 2010).

#### **1.3.2.2 Renal haemodynamics**

There is approximately 25% increase in glomerular filtration rate (GFR) by 4 weeks. This reaches a nadir of ~50% by mid pregnancy and is maintained until the last few weeks of pregnancy after which it starts to decrease however still remaining above the non-pregnant level. This leads to fall in serum creatinine (see Table 4). More pronounced is the increased renal plasma flow and decline in filtration fraction; both return to non pregnant level towards the term (Baylis & Davison, 2010).

In pre-eclampsia both renal plasma flow (RPF) and GFR decreases. There is salt retention and contraction of plasma volume as compared to normal pregnancy (Brown & Gallery, 1994). Although the absolute values of RPF and GFR may remain above non-pregnant level, this is probably the most likely mechanism of hypofiltration in this condition. The endothelium is involved inclusive of glomerulus, causing vascular endothelial cell dysfunction (glomerular endotheliosis) and results in swollen bloodless glomeruli and the loss of glomerular barrier size and charge selectivities (Baylis & Davison, 2010). This pattern is also seen in normal pregnancy and not pathognomonic of pre-eclampsia (Strevens, 2003).

#### **1.3.3 Pathophysiology of AKI in preeclampsia/ eclampsia and other microangiopathies**

In severe pre-eclampsia/ eclampsia, renal failure is most probably due to acute tubular necrosis (Sibai et al, 1993). ATN in these women is frequently due to haemorrhage; for

extracellular fluid volume, reaching a maximum of 1.25 litres at times. The volume of the total extracellular fluid space is determined principally by sodium and hence water accumulation. The combination of increased cardiac output and peripheral vasodilatation means that organ blood flow increases in pregnancy, with the most dramatic changes occurring in the kidney and skin circulation throughout gestation and in the uterus in the second part of the pregnancy. These changes result in a small reduction in arterial blood pressure, typically reaching a nadir in the mid-trimester of about 10 mmHg systolic, rising towards pre-pregnancy levels at term (Brown & Gallery, 1994). Table 4 illustrates changes in

 **Non-Pregnant Pregnant Hematocrit (%)** 41 33 **Plasma creatinine (µmol/L)** <120 <90 **mg/dl** <1.3 <1 **Plasma urea (mmol/L)** 11.2-31 9-12 **mg/dl** 4-11 3.2-4.4 **Plasma albumin (g/L)** 35-45 25-35 **(g/dl)** 3.5-4.5 2.5-3.5 **Plasma uric acid mg/dl (µmol/L)** 4 (240) 3.2 (190) early

**Plasma bicarbonate (mmol/l, meq/l)** 22-28 18-20 **Urinary protein excretion (mg/d)** <150 <300

Table 4. Changes in some common indices during pregnancy **(**Modified from Source: Baylis

There is approximately 25% increase in glomerular filtration rate (GFR) by 4 weeks. This reaches a nadir of ~50% by mid pregnancy and is maintained until the last few weeks of pregnancy after which it starts to decrease however still remaining above the non-pregnant level. This leads to fall in serum creatinine (see Table 4). More pronounced is the increased renal plasma flow and decline in filtration fraction; both return to non pregnant level

In pre-eclampsia both renal plasma flow (RPF) and GFR decreases. There is salt retention and contraction of plasma volume as compared to normal pregnancy (Brown & Gallery, 1994). Although the absolute values of RPF and GFR may remain above non-pregnant level, this is probably the most likely mechanism of hypofiltration in this condition. The endothelium is involved inclusive of glomerulus, causing vascular endothelial cell dysfunction (glomerular endotheliosis) and results in swollen bloodless glomeruli and the loss of glomerular barrier size and charge selectivities (Baylis & Davison, 2010). This pattern is also seen in normal pregnancy and not pathognomonic of pre-eclampsia (Strevens, 2003).

In severe pre-eclampsia/ eclampsia, renal failure is most probably due to acute tubular necrosis (Sibai et al, 1993). ATN in these women is frequently due to haemorrhage; for

**1.3.3 Pathophysiology of AKI in preeclampsia/ eclampsia and other** 

4.3 (260) late

some common indices during pregnancy.

& Davison, 2010; Brown et al 2010).

towards the term (Baylis & Davison, 2010).

**1.3.2.2 Renal haemodynamics** 

**microangiopathies** 

reasons explained in previous sections. AKI may also complicate postpartum eclampsia. HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count) is a variant of severe pre-eclampsia, which usually resolves following delivery (Weinstein, 1985) and occurs in around 20% of the severe pre-eclampsia cases (Sibai et al, 1993). AKI may also occur as a direct consequence of disseminated intravascular coagulation (one of the dreaded complications in upto 20% of women with HELLP syndrome), and sepsis (Sibai et al, 1993).

Similarly, other microangiopathies like acute fatty liver of pregnancy which occurs commonly in the third trimester and haemolytic uremic syndrome/ thrombotic thrombocytopenic purpura occurring ante- or post-partum share several pathophysiologic mechanisms which is difficult to differentiate and eventually may contribute to the development of AKI (Ganesan, 2011). Acute fatty liver of pregnancy is an obstetric emergency, which if untreated may progress to fulminant hepatic failure and proves life threatening to both mother and foetus. Variable degree of AKI has been reported in upto 90% of women with acute fatty liver of pregnancy, which is usually reversible with the recovery of liver failure (Hou, 2001). HUS/TTP occurs typically in the early postpartum period but delays of several months postpartum have also been reported. Renal failure was previously thought to be irreversible but complete and partial recovery does occur in about 30% of these cases (Beaufils, 2001).

#### **1.3.4 Pyelonephritis, septic abortion and puerperal sepsis**

Pathogenesis of sepsis-induced renal dysfunction is still poorly understood. Though it has been demonstrated that septic AKI can occur in the setting of marked Hyperaemia and vasodilatation; and renal ischemia is not necessary for the loss of GFR (Bellomo et al, 2008); various inflammatory factors have also been shown to be generated following ischemia which contributes to development of AKI and ATN (Kribben, 1999). Experimental studies continue to report newer concepts for pathogenesis of septic AKI (Bellomo, 2011). Similar studies in man are required to confirm these experimental findings.

Pregnant women are at greater risk of urinary tract infection due to the altered anatomy and urinary stasis as discussed in previous sections. Untreated timely and correctly this can lead to urosepsis. Acute pyelonephritis may occur as part of urinary tract infection and may be severe enough to cause AKI as a result of sepsis or prerenal azotemia from vomiting. Improved availability and better management of abortion has led to decrease in the incidence of post-abortal sepsis especially in the developed countries (Gul et al, 2004). Sepsis is still a major cause including septic abortions and puerperal sepsis in developing countries (Sivakumar, 2011; Khanal, 2010).

#### **1.4 Prevention and model of care**

A total of 99% of all maternal deaths occur in developing countries, where 85% of the population lives. More than half of these deaths occur in sub-Saharan Africa and one third in South Asia. Globally, around 80 per cent of maternal deaths are due to obstetric complications; mainly haemorrhage, sepsis, unsafe abortion, pre-eclampsia and eclampsia, and prolonged or obstructed labour (United Nations Children's Fund [UNICEF], 2003; United Nations Development Programme [UNDP], 2006). An estimated 21.6 million unsafe abortions took place worldwide in 2008, almost all in developing countries. Numbers of unsafe abortions have increased from 19.7 million in 2003 (Department of Reproductive

Epidemiology, Causes and Outcome of Obstetric Acute Kidney Injury 77

underlying condition which may be complicated by AKI is the only way to prevent it from happening. The physiologic changes in renal system that occur with pregnancy increasing the risk of infection are in itself non-modifiable, so is preeclampsia. Acute on chronic deterioration of renal function can probably be prevented by selecting women who are at lowest risk of progression of their existing kidney disease and perhaps counselling others for contraception is the only solution. Hence development of model of care is of utmost importance to reduce the maternal/ foetal mortality and morbidity; as has been long recognized by WHO (WHO, 2011); which is probably made worse by poor renal outcome in pregnant mothers. Widespread availability of improved prenatal care through midwives and timely recognition/ referral of high risk cases have decreased the incidence of pregnancy related AKI in developed world. An estimated 74 per cent of maternal deaths could be averted if all women had access to the interventions for preventing or treating pregnancy and birth complications, in particular emergency obstetric care (Barbinard & Roberts, 2006). There is need to improve the provision of quality services in developing countries. Factors such as poverty, gender inequalities, illiteracy, poor health systems, political instability, cultural barriers, and lack of infrastructure (e.g. lack of transport) in certain areas making it difficult to access the facility all contribute to increased burden

Measures to decrease maternal mortality also aim to reduce the consequences women face as a result of these complications. AKI is one of them. Below are our recommendations in keeping with the guidelines proposed by WHO and UNFPA (United Nations family planning association) in Millennium Summit as Millennium development goal 5 (MDG5)

**Firstly**, it is very important for the pregnant women to understand the benefits of seeking safe abortion, utilizing antenatal follow up and when possible avoid unplanned pregnancies. It is likely that the morbidity and mortality risk would be reduced with adequate antenatal and delivery care (Robinson & Wharrad, 2001; de Bernis et al., 2000). **Secondly**, increasing the number of health personnel in form of midwives and trained birth attendants and making them available for these populations, frequent free health camps at remote areas to identify the population at risk e.g. identifying women with underlying kidney disease, and education on family planning and easy access to contraceptive measures, increasing its availability and legalizing the abortions are beneficial. **Finally**, timely intervention when needed through experts when needed for e.g. timely administration of antibiotics for infection, adequate management of hypovolaemia, performing caesarean section when indicated, and vigilant post partum care of these women all are important steps to prevent complication and thus reduce maternal mortality. Increased use of contraception has an obvious and direct effect on the maternal death rate per 1000 women of reproductive age and on the lifetime risk of maternal death, by reducing the number of pregnancies (Royston & Armstrong, 1989). Unsafe abortions are entirely preventable, and yet continue to occur in almost all developing countries and in Eastern Europe. The evidence suggests that this can be greatly reduced when (Department of

 Counselling and services meet the unmet need for family planning, and appropriate method mix of contraception is offered to all women, including both married and

which will probably help to decrease maternal mortality in developing countries:

Reproductive Health and Research, WHO, 2011):

unmarried women; and

Pregnancies can be planned through effective contraception;

(WHO, 2011).

Health and Research, WHO, 2011). Complications of unsafe abortions account for 13 per cent of maternal deaths worldwide, and 19 per cent of maternal deaths in South America (Ahman et al 2002; WHO, 2004). Preeclampsia is associated with poor maternal outcome including maternal death even in developed countries (SOMANZ, 2009; Isler , 1999).

Fig. 2. Maternal mortality ratio by country.

Fig. 3. Causes of maternal death.

One of the many complications contributing to this burden is AKI occurring as a consequence of these complications. It is very difficult to postulate any specific measure to prevent the occurrence of acute kidney injury. Adequate timely management of the

Health and Research, WHO, 2011). Complications of unsafe abortions account for 13 per cent of maternal deaths worldwide, and 19 per cent of maternal deaths in South America (Ahman et al 2002; WHO, 2004). Preeclampsia is associated with poor maternal outcome

One of the many complications contributing to this burden is AKI occurring as a consequence of these complications. It is very difficult to postulate any specific measure to prevent the occurrence of acute kidney injury. Adequate timely management of the

including maternal death even in developed countries (SOMANZ, 2009; Isler , 1999).

Fig. 2. Maternal mortality ratio by country.

Fig. 3. Causes of maternal death.

underlying condition which may be complicated by AKI is the only way to prevent it from happening. The physiologic changes in renal system that occur with pregnancy increasing the risk of infection are in itself non-modifiable, so is preeclampsia. Acute on chronic deterioration of renal function can probably be prevented by selecting women who are at lowest risk of progression of their existing kidney disease and perhaps counselling others for contraception is the only solution. Hence development of model of care is of utmost importance to reduce the maternal/ foetal mortality and morbidity; as has been long recognized by WHO (WHO, 2011); which is probably made worse by poor renal outcome in pregnant mothers. Widespread availability of improved prenatal care through midwives and timely recognition/ referral of high risk cases have decreased the incidence of pregnancy related AKI in developed world. An estimated 74 per cent of maternal deaths could be averted if all women had access to the interventions for preventing or treating pregnancy and birth complications, in particular emergency obstetric care (Barbinard & Roberts, 2006). There is need to improve the provision of quality services in developing countries. Factors such as poverty, gender inequalities, illiteracy, poor health systems, political instability, cultural barriers, and lack of infrastructure (e.g. lack of transport) in certain areas making it difficult to access the facility all contribute to increased burden (WHO, 2011).

Measures to decrease maternal mortality also aim to reduce the consequences women face as a result of these complications. AKI is one of them. Below are our recommendations in keeping with the guidelines proposed by WHO and UNFPA (United Nations family planning association) in Millennium Summit as Millennium development goal 5 (MDG5) which will probably help to decrease maternal mortality in developing countries:

**Firstly**, it is very important for the pregnant women to understand the benefits of seeking safe abortion, utilizing antenatal follow up and when possible avoid unplanned pregnancies. It is likely that the morbidity and mortality risk would be reduced with adequate antenatal and delivery care (Robinson & Wharrad, 2001; de Bernis et al., 2000). **Secondly**, increasing the number of health personnel in form of midwives and trained birth attendants and making them available for these populations, frequent free health camps at remote areas to identify the population at risk e.g. identifying women with underlying kidney disease, and education on family planning and easy access to contraceptive measures, increasing its availability and legalizing the abortions are beneficial. **Finally**, timely intervention when needed through experts when needed for e.g. timely administration of antibiotics for infection, adequate management of hypovolaemia, performing caesarean section when indicated, and vigilant post partum care of these women all are important steps to prevent complication and thus reduce maternal mortality. Increased use of contraception has an obvious and direct effect on the maternal death rate per 1000 women of reproductive age and on the lifetime risk of maternal death, by reducing the number of pregnancies (Royston & Armstrong, 1989). Unsafe abortions are entirely preventable, and yet continue to occur in almost all developing countries and in Eastern Europe. The evidence suggests that this can be greatly reduced when (Department of Reproductive Health and Research, WHO, 2011):


Epidemiology, Causes and Outcome of Obstetric Acute Kidney Injury 79

Management of these syndromes is usually supportive and revolves around blood pressure control, use of magnesium sulphate to prevent seizures and timing of delivery. There are various guidelines proposed by different obstetric societies around the globe in regards to management. Of interest however are the emerging concepts on its long term cardiovascular and renal consequences (Mc Donald et al, 2008). Similarly acute fatty liver of pregnancy (AFLP) also demands supportive care and prompt delivery. Thrombotic thrombocytopenic purpura; which creates a diagnostic dilemma together with HELLP and AFLP is managed using plasma exchange. Studies have shown significant improvement in maternal mortality

When renal replacement therapy is indicated for medically not amenable acute complications like hyperkalaemia, fluid overload, metabolic acidosis, and uremic encephalopathy either of the modalities (haemodialysis; HD or peritoneal dialysis; PD) can be used during pregnancy however there are no head to head trials comparing the benefit of one over the other. However, studies do suggest that PD may interfere with utero-placental

Attempts have been made to derive factors to predict mortality associated with AKI. In general, AKI associated mortality seems to be variably increasing with increasing age, greater degree of illness severity at presentation, presence of chronic kidney disease, need for organ support in form of mechanical ventilation, hypotension or need for inotrope support and so on (Waikar et al, 2008). Degree of change in serum creatinine and need for dialysis as well are associated with increased mortality rates. These estimates however have

Table 5 summarizes maternal mortality rates and renal outcome in pregnant women with AKI from different studies. In our experience prolonged duration of oliguria is associated with increased rate of dialysis dependency. Most of pregnant women with acute kidney injury come from rural areas and did not have antenatal check up (Khanal et al, 2010; Ahmad et al, 2001; Hassan et al, 2009). Antenatal check up not only helps in creating awareness among the pregnant mothers to seek help from midwives, it also brings high risk cases to notice and increases the likelihood of referral to experts on time. Sepsis including post abortal sepsis has been found to be associated with severe consequences and poor maternal outcome even in modern days in developing countries. This is probably from poor handling techniques and emphasizes the importance of need to increase the number of trained personnel like midwives to conduct delivery. Late referral to the tertiary care centres and delays in actually reaching the centre due to lack of infrastructure all contribute to the poor outcome. Significant and progressive improvement in mortality rates over decades is evident in table 6. This study analysed the data on pregnancy related AKI over 37 years. Although a progressive decline over each decade can be easily noticed, complications like HUS were associated with adverse maternal outcome. Thus close monitoring of high risk cases, timely recognition of complication, and institution of appropriate management intervention on time are of utmost importance (Stratta, 1996). A review on acute renal

not been analysed specifically in the setting of pregnancy related AKI.

**1.5.3 Management of preeclampsia/eclampsia/HELLP syndrome** 

rates since its introduction (Martin et al, 2008).

blood flow (Bui et al, 2003).

**1.6 Outcome of obstetric AKI** 

**1.5.4 Renal replacement therapy in pregnancy** 

Safe abortion services are available and accessible.

In the meantime ill-effects of unsafe abortion should be prevented by:


Similarly, preeclampsia occurs in 3-5% of pregnancies and is associated with increased maternal and foetal mortality especially in developing countries. If women with these problems are identified in antenatal period, safe delivery can be planned before hand (WHO, Dept. of Reproductive Health and Research, Dept. of Maternal, Newborn, Child and Adolescent Health, Dept. of Nutrition for Health and Development, 2011). Some reports have been published where the authors have questioned the importance of presence of skilled birth attendance at delivery and suggested that perhaps partnership between midwives and doctors and timely referral is more important to achieve this target (Cross et al, 2010) of reducing maternal mortality by 2/3 in these regions. Despite efforts from national, international and global health organizations MMR declined by only 5% from 1990-2005. To achieve this target of decline in MMR by 2/3 by 2015 will require tremendous work in this area. Any improvement in the maternal mortality rate will eventually lead to decrease consequences like AKI from various complications during pregnancy in developing countries.
