Pregnancy-related acute kidney injury at high altitude: a retrospective observational study in a single center

Pregnancy-related acute kidney injury(Pr-AKI) is an important obstetric complication, featured by a rapid decline in renal function and a series of consequential clinical disorders, making it one of the leading causes of maternal and fetal morbidity and mortality. As a heterogeneous disease with various underlying etiologies, it encompasses a wide range of clinical manifestations of different severity and can occur at any time of the pregnancy. Not only is Pr-AKI strongly associated with adverse outcomes of both mothers and their offspring, but also has a profound impact on their future health by increasing the risks of developing hypertension, chronic kidney disease(CKD) and cardiovascular diseases later in their lives[1, 2].

Over the last few decades, there has been a dramatic decrease in the overall incidence of Pr-AKI worldwide, especially in developing countries, largely owning to the promotion of antenatal supervision and the improvement in maternal-infant care. However, in areas where adequate antenatal care and sanitary facilities are not available, pregnancy-related diseases still remain a huge public health problem. Etiology spectrum has also changed. Hypertensive diseases, especially preeclampsia and its related complications, have replaced traditional causes of Pr-AKI, such as septic abortion and hemorrhage, becoming the predominant etiologies of AKI in pregnant women[3‐5]. For women living at high altitude, there is another challenge. As the arterial oxygen saturation begins to decrease with ascending altitude, the risk of arterial hypoxia and its associated complications increases and may have a negative effect on pregnancy. Previous studies have found that long exposure to hypoxia increases the incidence of preeclampsia and other obstetric complications, including intrauterine growth restriction(IUGR), stillbirth and neonatal mortality[6‐8], but further investigations and detailed demonstrations are needed to support these observations.

The incidence of Pr-AKI reported in Chinese population ranged from 0.02 to 1.84 % in recent years[3, 9], depending on different criteria they used to define AKI. However, most of the data came from tertiary hospitals in big cities. Data from undeveloped mountainous highlands was rare. Apart from social-economic factors, whether environmental factors play a role in the development of Pr-AKI and what influence they have on these patients deserve further discussion. Therefore, we conducted this research to investigate the incidence, etiology and clinical features of Pr-AKI at high altitude, and also looked into the risk factors of adverse pregnancy outcomes in these patients.

The landscape of pregnancy-related AKI has been changing dramatically over the last few decades. There has been a sharp decline in the overall incidence of Pr-AKI, not just in the developed world but also in the low-middle-income countries, mostly due to improvement in antenatal care and a significant decrease of septic abortion. The incidence of Pr-AKI in developed countries has remarkably reduced from approximately 1/3000 to 1/15,000–1/20,000 pregnancies from the 1960 s to the end of last century[14]. In developing countries such as India and China, the overall condition is also greatly improving. India has revealed a considerable decline in the proportion of Pr-AKI among hospitalized patients from 15.2 % in the 1980 s to 1.5–4.6 % in the 2010 s[15, 16]. In the meantime, maternal mortality has reduced to 5.79 % from initial high value 20 % in the 1980 s, and the progression of Pr-AKI to ESRD decreased to 1.4 % from 6.15 %[15].

As a developing country and also the world’s most populous nation, China has made impressive progress in fighting against severe obstetric diseases and reducing maternal-neonatal mortalities. The maternal mortality ratios have declined fast from 108.7/100,000 to 21.8/100,000 livebirths from 1996 to 2015[17], and the infant mortality has also decreased from 46.7 ‰ to 8.1 ‰ from 1992 to 2015[18]. In recent years, reported incidence of Pr-AKI in China is ranging from 0.02 to 1.84 %[3, 9], along with declining maternal and neonatal mortalities. Despite these encouraging achievements, huge regional discrepancies still exist within the country. In less economically developed western provinces, pregnancy-related diseases including Pr-AKI remain a critical public health problem to local people due to limited medical resources. According to the 2010 population census of China[19, 20], 58.6 % of the population in western China live in rural areas (eastern China: 40 %), 34.2 % of them belong to ethnic minority groups (eastern China: 2.1 %) and 10.1 % of women are illiterate (eastern China: 4.7 %). Underdevelopment, ethnic diversity, and geographical conditions all present great challenges to ensuring universal access to medical resources. In our study, the incidence of Pr-AKI in the region of Shangrila was 2.09 %, higher than previous data reported by other Chinese authors. Given that we had excluded patients who delivered out of hospital as well as those unable to provide baseline renal function, this figure was likely to be by far underestimated.

There is also an urgent need to raise the awareness of Pr-AKI among medical practitioners in local medical institutions. Pr-AKI is not rare among women of childbearing age, and the incidence can be extremely high in patients with particular obstetric complications. It affects approximately 5-17 % of patients with severe preeclampsia[4, 9, 21] and 7-60 % of patients with HELLP syndrome[9, 22, 23]. However, a recent study revealed that only 4.0 % of AKI events were initially diagnosed on the discharge record[24]. Patients at early stage of renal impairment sometimes present with Scr levels within normal range due to physiological glomerular hyperfiltration. In our study, the median Scr level was 84umol/l(0.95 mg/dl). Only 24(17.6 %) patients had a Scr level > 105umol/l(1.1 mg/dl). In the setting of pregnancy, any Scr value above 70.72umol/l (0.8 mg/dl) should be considered abnormality. That’s why we used 70umol/l as a cut-off value for screening Pr-AKI candidates in this study. The relative change of Scr within a time period should also be taken into account, rather than just using a fixed upper limit value when making an AKI diagnosis. Judging by Scr levels alone will miss mild AKI events in patients with low baseline Scr, leading to underestimation in clinical practice.

In general, maternal outcome in less severe Pr-AKI is favorable. However, severe Pr-AKI is associated with significantly increased mortality, especially among those requiring dialysis. Recent studies from China and India report that maternal mortality rate associated with severe Pr-AKI ranges from 4.0 to 8 %[3, 17, 25]. In the long run, approximately 4-9 % of women with severe Pr-AKI requiring dialysis will remain dialysis-dependent for another 4–6 months after delivery[26]. The rate of progression to end-stage renal disease from Pr-AKI ranges from 1.4 to 2.5 %[17, 27].

Pr-AKI also presents a harsh challenge for the newborns. Perinatal mortality including intrauterine death, stillbirth and neonatal death occurs in 23.5-54 % of Pr-AKI patients[5, 25], and the odds of perinatal mortality increase 3.39 fold when compared with pregnancies without Pr-AKI[27]. Pr-AKI is also linked to preterm delivery and disturbance of fetal development, resulting in IUGR, low birth weight or infant small for gestational age. This trend is particularly significant in patients suffering from HDP or preeclampsia. Prematurity and small babies are not only associated with prenatal death and fetal distress, but also have potential long-term detrimental impacts. Preterm is a strong risk factor for development of CKD in adulthood because of the delayed and insufficient kidney growth which may result in a low nephron number[28]. Additionally, it has been demonstrated that CKD, small and preterm babies will be at high risk for development of diabetes, metabolic syndrome and cardiovascular diseases in adulthood[29, 30].

We also looked into the impact of high altitude on pregnant women, especially those with HDP. Previous literature has reported a correlation between long exposure to high altitude and adverse fetal outcomes. The odds of stillbirth and preterm increase by 3.9-fold and 1.7-fold respectively at high altitude relative to low altitude[31]. High altitude is also associated with lower birth weight, reducing fetal birth weight by an average of 102 g for every 1000 m increase in elevation[32]. These findings can be partially explained by maternal arterial hypoxia from high altitude exposure. In addition to this, long exposure to high altitude can interfere with effective transportation of oxygenated blood to the utero-placental circulation. High altitude decreases the pregnancy-induced increase in cardiac output and blood volume, likely due to a failure to reduce peripheral vascular resistance[33]. It also interferes with maternal vascular adjustment to pregnancy, such as the growth and remodeling of the uterine artery and other utero-placental vessels, attenuating the normal increase of uterine artery diameter and blood flow[34]. It also alters patterns of blood flow redistribution, for example, by reducing the proportion of common iliac blood flow distributed to the uterine versus the external iliac artery, resulting in lower uterine artery blood flow near term[34, 35]. In the presence of preeclampsia, which is commonly accompanied by utero-placental vascular dysfunction and placental ischemia, insufficient maternal arterial oxygenation and compromised compensatory mechanism from long exposure to high altitude will further aggravate placental insufficiency and fetal intrauterine hypoxia. Moreover, long exposure to high altitude is also responsible for the pathogenesis and development of preeclampsia. The incidence of preeclampsia increases by approximately 3-fold at high altitude[36]. Hypoxia regulates the production of numerous vascular endothelial regulatory factors known to influence vascular function during pregnancy and/or to be associated with preeclampsia, including endothelin-1, thromboxane A2, prostacyclin and tumor necrosis factor alpha[37]. Animal experiments also confirm that long-term high altitude hypoxia during gestation suppresses large conductance Ca2+-activated K+(BKCa) channel function in uterine arteries, which is of critical importance in pregnancy-mediated increase in uterine artery vasodilation and blood flow, resulting in the dysfunction of uterine placental circulation and the development of preeclampsia[38]. Hypoxia can also activate placental renin-angiotensin system, leading to placental dysfunction and oxidative stress response, which enhance the vasoconstrictor effect of locally-generated angiotensin II and contribute to the restricted fetal growth characteristic of preeclampsia[39, 40]. As preeclampsia has proved to be an important contributory factor to adverse fetal outcomes, we believe that the interaction between hypoxia and preeclampsia may have synergistic effects and enhance the adverse impacts of preeclampsia on pregnancy outcomes.