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Journal of Clinical Medicine 7 (10): 318 (2018)
Piccoli, Giorgina
Zakharova, Elena
Attini, Rossella
Ibarra Hernandez, Margarita
Covella, Bianca
Alrukhaimi, Mona
Liu, Zhi-Hong
Ashuntantang, Gloria
Orozco Guillen, Alejandra
Cabiddu, Gianfranca
Li, Philip Kam Tao
Garcia-Garcia, Gulliermo
Levin, A. (Adeera)
Pregnancy-related acute kidney injury (pAKI), preeclampsia (PE), and the hypertensive disorders of pregnancy are closely related conditions, which are, in turn, frequently linked to pre-existing and often non-diagnosed chronic kidney disease (CKD). The current literature and research mainly underline the effects of pregnancy complications on the offspring; this review strongly emphasizes the maternal health as well. These conditions not only negatively affect pregnancy outcomes, but have a relevant effect on the future health of affected mothers and their children. Therefore, dedicated diagnostic and follow-up programs are needed, for optimizing materno-foetal health and reducing the impact of pregnancy-related problems in the mothers and in the new generations. This narrative review, performed on the occasion of the 2018 World Kidney Day dedicated to women’s health, focuses on three aspects of the problem. Firstly, the risk of AKI in the hypertensive disorders of pregnancy (the risk is the highest in developing countries; however PE is the main cause of pregnancy related AKI worldwide). Secondly, the effect of AKI and the hypertensive disorders of pregnancy on the development of CKD in the mother and offspring: long-term risks are increased; the entity and the trajectories are still unknown. Thirdly, the role of CKD in the pathogenesis of AKI and the hypertensive disorders of pregnancy: CKD is a major risk factor and the most important element in the differential diagnosis; pregnancy is a precious occasion for early diagnosis of CKD. Higher awareness on the importance of AKI in pregnancy is needed to improve short and long term outcomes in mothers and children.
Journal ofClinical MedicineReviewAcute Kidney Injury in Pregnancy: The Need forHigher Awareness. A Pragmatic Review Focused onWhat Could Be Improved in the Prevention and Careof Pregnancy-Related AKI, in the Year Dedicated toWomen and Kidney DiseasesGiorgina Barbara Piccoli 1,2,* , Elena Zakharova 3,4,5, Rossella Attini 6,Margarita Ibarra Hernandez 7, Bianca Covella 2, Mona Alrukhaimi 8, Zhi-Hong Liu 9 ,Gloria Ashuntantang 10, Alejandra Orozco Guillen 11, Gianfranca Cabiddu 12 ,Philip Kam Tao Li 13, Gulliermo Garcia-Garcia 7 and Adeera Levin 141 Department of Clinical and Biological Sciences, University of Torino, 10100 Torino, Italy2 Néphrologie, Centre Hospitalier Le Mans, 72000 Le Mans, France; biancacovella@gmail.com3 Nephrology, Moscow City Hospital n.a. S.P. Botkin, 101000 Moscow, Russia; helena.zakharova@gmail.com4 Nephrology, Moscow State University of Medicine and Dentistry, 101000 Moscow, Russia5 Nephrology, Russian Medical Academy of Continuous Professional Education, 101000 Moscow, Russia6 Obstetrics, Department of Surgery, University of Torino, 10100 Torino, Italy; rosella.attini@gmail.com7 Nephrology Service, Hospital Civil de Guadalajara “Fray Antonio Alcalde”, University of GuadalajaraHealth Sciences Center, 44100 Guadalajara Jal, Mexico; maribaher@yahoo.es (M.I.H.);ggarcia1952@gmail.com (G.G.-G.)8 Department of Medicine, Dubai Medical College, P.O. Box 20170, Dubai, UAE; mona_539@yahoo.co.uk9 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School ofMedicine, Nanjing 210000, China; zhihong–liu@hotmail.com10 Yaounde General Hospital & Faculty of Medicine and Biomedical Sciences, University of Yaounde I,P.O. Box 337, Yaounde, Cameroon; maglo09@hotmail.com11 Instituto Nacional de Perinatologia, Mexico D.F. 01020, Mexico; ale_gaba@hotmail.com12 Nefrologia Ospedale Botzu, 09100 Cagliari, Italy; gianfranca.cabiddu@tin.it13 Prince of Wales Hospital, Department of Medicine and Therapeutics, Chinese University of Hong Kong,Hong Kong; philipli@cuhk.edu.hk14 Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver,BC V6T 1Z4, Canada; alevin@providencehealth.bc.ca* Correspondence: gbpiccoli@yahoo.it; Tel.: +33-66-973-3371Received: 17 August 2018; Accepted: 19 September 2018; Published: 1 October 2018Abstract: Pregnancy-related acute kidney injury (pAKI), preeclampsia (PE), and the hypertensivedisorders of pregnancy are closely related conditions, which are, in turn, frequently linked topre-existing and often non-diagnosed chronic kidney disease (CKD). The current literature andresearch mainly underline the effects of pregnancy complications on the offspring; this review stronglyemphasizes the maternal health as well. These conditions not only negatively affect pregnancyoutcomes, but have a relevant effect on the future health of affected mothers and their children.Therefore, dedicated diagnostic and follow-up programs are needed, for optimizing materno-foetalhealth and reducing the impact of pregnancy-related problems in the mothers and in the newgenerations. This narrative review, performed on the occasion of the 2018 World Kidney Daydedicated to women’s health, focuses on three aspects of the problem. Firstly, the risk of AKI inthe hypertensive disorders of pregnancy (the risk is the highest in developing countries; howeverPE is the main cause of pregnancy related AKI worldwide). Secondly, the effect of AKI and thehypertensive disorders of pregnancy on the development of CKD in the mother and offspring:long-term risks are increased; the entity and the trajectories are still unknown. Thirdly, the role ofJ. Clin. Med. 2018, 7, 318; doi:10.3390/jcm7100318 www.mdpi.com/journal/jcmJ. Clin. Med. 2018, 7, 318 2 of 22CKD in the pathogenesis of AKI and the hypertensive disorders of pregnancy: CKD is a major riskfactor and the most important element in the differential diagnosis; pregnancy is a precious occasionfor early diagnosis of CKD. Higher awareness on the importance of AKI in pregnancy is needed toimprove short and long term outcomes in mothers and children.Keywords: pregnancy acute kidney injury (AKI); chronic kidney disease (CKD); preeclampsia;maternal death; adverse pregnancy outcomes1. IntroductionAcute kidney injury (AKI) is still an enormous unsolved health-care problem worldwide [1–3].Pregnancy-related AKI (p-AKI) is one of the most common causes of acute kidney injury in youngwomen: it has not disappeared in high-income countries and is the leading cause of AKI in womenin the developing world [1–13]. Even though in the past AKI was generally considered to be anall-or-nothing situation, in which complete reversal was the rule in surviving patients, this conditionis now known to be associated with future risk for chronic kidney disease (CKD), hypertension, andcardiovascular diseases [14–18].This narrative review, performed on the occasion of World Kidney Day 2018, dedicated to womenand kidney diseases, will discuss the complex relationship between preeclampsia (PE), CKD andAKI, in order to identify fields for future intervention and research, and enable us to improve thesefundamental aspects of women’s health.2. Pregnancy-Related AKI and Its Relationship with the Hypertensive Disorders of PregnancyPregnancy is a physiological situation involving the risk of death. The risk varies widely: itis modulated not only by genetic background and environmental factors, but also by country andindividual income, and disempowered women in low-income countries have the highest rate of deathfrom pregnancy-related causes, among which AKI plays a major role [13,19–21]. These women are notonly economically disempowered, they are socially and educationally disempowered as well, leadingto their inability to make informed health choices and, thus, avoid adverse outcomes.According to Women Aid International, the probability that a pregnant African woman will diefrom pregnancy-related complications has been reported to be as high as 1:20, in sharp contrast with1:2000 in the developed world. The main causes are haemorrhage, sepsis, preeclampsia-eclampsia andseptic abortion, all of which also cause of AKI [13]. According to the World Health Organisation, theMaternal Mortality Ratio is 12/100,000 in developed regions and 239/100,000 in developing ones [14].As a consequence, the pattern of p-AKI can serve as an indirect, but interesting marker of the qualityof health-care delivery in pregnancy (Table 1).J. Clin. Med. 2018, 7, 318 3 of 22Table 1. A general, but non-exhaustive classification of the main causes of pregnancy-related AKI, in the early and late phases of pregnancy.Main ClinicalFeature Phase Condition Main Clinical FeaturesPrerenalHypovolemic Early Hyperemesis gravidarumMay be severe, associated with severe nutritional deficits, so more common in patients with anutritional disorder or malnutrition; may reflect psychological problems. More commonly diagnosed indeveloped countries, it is probably underestimated in developing ones.Any time Other causes of hypovolemia Infectious diseases, nutritional disorders; acute fatty liver of pregnancy; metabolic acidosis, uremia.Haemorrhagic Early AbortionEarly foetal loss can cause severe haemorrhaging, but unsafe, illegal abortions are the most commoncause of massive bleeding, usually associated with sepsis. More common in low- and middle-incomecountries, and where abortion is illegal.Late Placental abruption Can cause massive bleeding, as well as foetal loss, usually occurs in late pregnancy.Hypotensive Any time Hypovolemia, cardiopathy, sepsisHypotension is usually a concomitant cause and a marker of severity of the above. The rare, butsometimes severe, cardiomyopathy of pregnancy can lead to severe hypotension and AKI. Sepsis (anycause, any phase) is often associated with hypotension up to hypotensive shock, and associated withtubular necrosis (see below).Combinedpathogenesis Any timeSeptic abortion, placentalabruption, puerperal sepsisSevere bleeding is associated with hypovolemia and hypotension. While the “usual” classification ofAKI may be of help, focusing on one element only may avert attention from treating allassociated factors.Parenchymal (for PE, and related disorders, see further tables)GlomerularAny time CKD (known or undiagnosed)The presence of CKD is associated with adverse pregnancy outcomes starting from the early stages.Immunologic diseases may relapse or appear in pregnancy. CKD worsening is described in 20–80%of patients.Usually late Microangiopaties Haemolytic uremic syndrome and related diseases are an emerging concern in particular in developedcountries probably because they fail to be diagnosed in low-income settings.InterstitialdamageAny time Iatrogenic, associated with othercauses of AKIThe causes are the same encountered outside of pregnancy but the consequences may be more severe.Whether the “pregnant kidney” is associated with increased risk is a matter of debate. History ofobstructive renal disease and vesicoureteral reflux may contribute to loss of parenchymal volume whichfor still unknown reasons may be facilitate PE and possibly AKIAny time Pyelonephritis and upper urinarytract infectionsThese infections seldom cause AKI, even though they can be severe and life threatening. In this context,AKI is usually linked to sepsis or is iatrogenic.Combinedpathogenesis Any time Tubular necrosis- cortical necrosis Tubular necrosis may result from any severe AKI, and may be multifactorial.J. Clin. Med. 2018, 7, 318 4 of 22Table 1. Cont.Main ClinicalFeature Phase Condition Main Clinical FeaturesPostrenal-ObstructiveObstruction ofthe urinarytractAny time Stone disease Hypercalciuria can occur in pregnancy. Pain due to the passage of a stone may be misinterpreted,especially at term; infection and undiagnosed obstruction may be life- and function-threatening.Post partum Iatrogenic Ligature of the ureters is a rare but serious iatrogenic complication of caesarean section orreinterventions.Any time Neoplasia Kidney and urinary tract neoplasia are rare in young women. Diagnosis should be considered inmacroscopic haematuria, in particular if there are clots.Usually late ADPKD and other cystic diseasesof the kidneyCystic diseases of the kidney may go unrecognized in younger women. Large non-symptomatic cystsmay become symptomatic, cause pain or obstruction, or become infected in pregnancy.Functional Usually late Functional obstruction andhydronephrosisMild urinary tract dilatation (usually on the right side) is common, and usually without consequences;pyelo-ureteral junction anomaly, may decompensate, leading to giant hydronephrosis. Severe urinarytract dilatation is described in patients with reflux nephropathy.Combinedpathogenesis Any timeInfection, bleeding inobstructed kidneyDifferent causes may be associated; when sepsis (mainly Gram negative), is superimposed, AKI may beof combined parenchymal (septic), prerenal (hypovolemia, shock) and obstructive pathogenesis.J. Clin. Med. 2018, 7, 318 5 of 22The causes of p-AKI vary from one country to another, and laws on abortion and assistedfertilization are important factors as well. Septic abortion after an illegal procedure is the leadingcause of early p-AKI in countries where legal abortions are not available, while PE after assistedfertilization (e.g., donation in particular) is now becoming a potential cause of p-AKI or of subsequentrenal damage in developed countries [22–28].As will be further discussed, the role of undiagnosed CKD, presenting as AKI in pregnancyis probably higher in developing countries, thus posing difficult clinical and ethical problems,in particular with regard to the start of chronic dialysis in pregnancy [6,29].An in-depth discussion of all the causes of p-AKI is beyond the scope of this review, as it touchestoo many fields of medicine (nephrology, urology, infectious diseases, haematology, and immunology)and involves too many sensitive issues, such as availability and access to health care or legalisation onabortion. Many of these issues are addressed in the International Society of Nephrology’s wide-ranging“0 by 25” project, aimed at avoiding all preventable deaths due to AKI worldwide by 2025 [1–3].Therefore, while referring to the project for all issues of general importance, we will focus on themultifaceted relationship between kidney and placenta: CKD is a risk factor for PE; most of the riskfactors for PE are also risk factors for CKD (diabetes, immunologic diseases, hypertension, obesity, andthe metabolic syndrome); PE is a risk factor for the development of CKD later in life (Figures 1 and 2).The following issues will be therefore discussed: (a) The risk of AKI in the hypertensive disordersof pregnancy; (b) the effect of AKI and the hypertensive disorders of pregnancy on the developmentof CKD in the mother and in the offspring; (c) the role of CKD in the pathogenesis of AKI and thehypertensive disorders of pregnancy (the latter point will be further developed in a twin review onCKD and pregnancy).J. Clin. Med. 2018, 7, x FOR PEER REVIEW 5 of 22 The causes of p-AKI vary from one country to another, and laws on abortion and assisted fertilization are important factors as well. Septic abortion after an illegal procedure is the leading cause of early p-AKI in countries where legal abortions are not available, while PE after assisted fertilization (e.g., donation in particular) is now becoming a potential cause of p-AKI or of subsequent renal damage in developed countries [22–28]. As will be further discussed, the role of undiagnosed CKD, presenting as AKI in pregnancy is probably higher in developing countries, thus posing difficult clinical and ethical problems, in particular with regard to the start of chronic dialysis in pregnancy [6,29]. An in-depth discussion of all the causes of p-AKI is beyond the scope of this review, as it touches too many fields of medicine (nephrology, urology, infectious diseases, haematology, and immunology) and involves too many sensitive issues, such as availability and access to health care or legalisation on abortion. Many of these issues are addressed in the International Society of Nephrology’s wide-ranging “0 by 25” project, aimed at avoiding all preventable deaths due to AKI worldwide by 2025 [1–3]. Therefore, while referring to the project for all issues of general importance, we will focus on the multifaceted relationship between kidney and placenta: CKD is a risk factor for PE; most of the risk factors for PE are also risk factors for CKD (diabetes, immunologic diseases, hypertension, obesity, and the metabolic syndrome); PE is a risk factor for the development of CKD later in life (Figures 1 and 2). Figure 1. The kidney-placenta crosstalk in pregnancy (modified from the World Kidney Day 2018 editorial). Placenta and kidney are highly vascularized; filt er blood; divide com partm ents; are sophisticated m etabolic m achines Pregnancy is a precious occasion to diagnose C K D . From the placenta to the kidney PE may induce permanent kidney damage, via AKI, tubular damage, podocyte loss From the kidney to the placenta CKD may induce placental dysfunction with an increased risk of pre-term delivery, hypertensive disorders of pregnancy and PE Figure 1. The kidney-placenta crosstalk in pregnancy ( odified fro the orld Kidney Day 2018editorial).J. Clin. Med. 2018, 7, 318 6 of 22J. Clin. Med. 2018, 7, x FOR PEER REVIEW 6 of 22 Figure 2. Preeclampsia is a multifaceted syndrome: some pathophysiology insights. PE may be result from a deficit in placentation, in the absence of maternal diseases; the presence of maternal diseases, mainly affecting the kidney (hypertension, diabetes, immunologic diseases) and of CKD may act at different levels modulating onset and severity of the “PE syndrome”. The following issues will be therefore discussed: (a) The risk of AKI in the hypertensive disorders of pregnancy; (b) the effect of AKI and the hypertensive disorders of pregnancy on the development of CKD in the mother and in the offspring; (c) the role of CKD in the pathogenesis of AKI and the hypertensive disorders of pregnancy (the latter point will be further developed in a twin review on CKD and pregnancy). 3. The Risk of AKI in the Hypertensive Disorders of Pregnancy The hypertensive disorders of pregnancy encompass a wide range of conditions of different severity, impact on kidney function and on future health [30–35]. To some extent their incidence varies according to how the conditions are defined, and to whether “superimposed” disorders are included. Overall, preeclampsia (PE) accounts for about one third of all hypertensive disorders, with a prevalence ranging from about 2%, considering only the cases developing in the absence of predisposing factors (“low-risk” pregnancy), to over 5% in unselected populations [30–35]. The modifications in the definitions over time may partially impair comparisons of historic data [30–35]. The classifications are however different, in particular for severity, as one condition (mild PE) can develop into another (severe PE); furthermore, while early PE is often severe, and is usually associated with altered biomarkers, in keeping with a primary defect of placentation, late PE may be severe and life threatening (Table 2)Figure 2. Preeclampsia is a multifaceted syndrome: some pathophysiology insights. PE may be resultfrom a deficit in placentation, in the absence of maternal diseases; the presence of maternal diseases,mainly affecting the kidney (hypertension, diabetes, immunologic diseases) and of CKD may act atdifferent levels modulating onset and severity of the “PE syndrome”.3. The Risk of AKI in the Hypertensive Disorders of PregnancyThe hyperte sive disorders of pregnancy encompass a wide range of conditions of differentse erity, impact on kidney function and on future health [30–35]. To some extent their incidence variesaccording to how the conditions are defined, and to whether “superimposed” disorders are i cluded.O erall, preeclampsia (PE) accounts for about one third of all hypertensive disorders, with a prevalenceranging from about 2%, considering only the cases developing in the absence of predisposing factors(“low-risk” pregnancy), to ov 5% in un elected populations [30–35]. The modifications in thedefinitions over time may partially impair comparisons of historic data [30–35]. The classifications arehowever different, in particular for severity, as one condition (mild PE) can develop into another (severePE); furthermore, while early PE is often severe, and is usually associated with altered biomarkers,in keeping with a primary defect of placentation, late PE may be severe and life threatening (Table 2).Similar considerations apply to the hypertensive disorders of pregnancy, ranging from less than10% to over 15% of pregnancies, according to whether the following disorders are included: chronicpre-conception hypertension; HELLP syndrome, the acronym for haemolysis-low platelets elevatedliver enzymes, and intrauterine growth restriction (IUGR) [36–40]. In fact, the relationship between PE,pregnancy-induced hypertension (PIH), and HELLP is not fully clear and other conditions, such asintrauterine growth restriction, probably share a common pathogenesis [40–45].Whatever the causes, even if proteinuria, which is one of the hallmarks of PE, is usually consideredas a marker of glomerular involvement, and podocyte damage is regarded as a main pathogeneticpathway, tubular damage is probably more common than previously considered [46]. In PE andall the kidney structures may be affected, ultimately resulting in p-AKI, the common pathway ofother pregnancy- related noxae, such as sepsis and shock [47–50] (Table 3, Figure 3). Once more,socioeconomic status is a major component of the risk of both incidence and severity [51–53].J. Clin. Med. 2018, 7, 318 7 of 22Table 2. Preeclampsia: focus on classifications and definitions.Term Definition Main Problems and LimitsPreeclampsia (PE)Hypertension and proteinuria or end-organdamage in a previously healthy woman;involvement is reversible 1–3 monthsafter deliveryUsually defined as new onset of proteinuria above 300 mg/day and hypertension after the 20th gestational week (GW) in a patientwho was previously normotensive and without proteinuria or kidney disease.The syndrome resolves within three months from delivery. New definitions include hypertension in the absence of proteinuria butin the presence of end-organ damage, including creatinine increase. Does not apply to patients with chronic kidney disease or ondialysis, due to baseline hypertension, proteinuria, or to no urine output.Eclampsia Same as above, with neurological damage andconvulsionsThis definition is no longer universally accepted. Some authors consider it synonymous with untreated (or inadequatelytreated) PE.Mild PEPA ≥140/90 <160/110 proteinuria≥0.3 <5.0 g/day in the absence of the criteriaset forth aboveThe definition of mild and severe PE is somewhat static; mild PE can abruptly evolve into severe PE. Therefore, this definitionshould be used to: identify ALL cases of severe PE, that should be followed accordingly; identify cases in which the disease is notsevere, allowing pregnancy to continue under careful surveillance, keeping in mind that mild PE can abruptly progress tosevere PE.Severe PECentral nervous system involvementLiver damagePoorly controlled hypertensionProteinuria ≥5 g/24 hPlatelets <100.000Oliguria <500 mL/24 hPulmonary oedemaIntrauterine growth restriction (IUGR)Early PE Before 34 completed GW This pragmatic definition has the advantage of simplicity, and makes the early identification of cases possible; however a latediagnosis of early PE may in fact be identified as “late” PE.Late PE After 34 completed GWMaternal PE With maternal predisposing diseaseThis pragmatic definition is clinically relevant (maternal PE is usually, but not uniformly milder); the definition of maternaldisease is elusive, and the equation early = placental = severe; late = maternal = mild is imperfect and may be misleading.Placental PE Severe placental involvement in the absence ofthe aboveAngiogenic PE Altered angiogenic/non-angiogenic balance This is a promising approach, with the advantage of simplicity and of employing numeric values, and is possibly more objective;however, there is no agreement on how best to test for the condition: cut-points are not univocal, the levels and the ratio betweenfactors may change over time and the availability of the tests is limited.Non angiogenic PE Absence of the aboveSuperimposed PE PE with underlying CKDSome but not all CKD are proteinuric or hypertensive before pregnancy; this definition tries to correct for the baseline values.However, there is no agreed level of “worsening” of proteinuria or hypertension, in part because of the adaptation ofanti-hypertensive treatments in pregnancy. Albeit of potential interest, this definition is ambiguous and less frequentlyencountered.Postpartum PE A clinical syndrome with the clinical features ofPE, occurring postpartumA rare occurrence, probably accounting for less than 5% of PE. The clinical picture is often severe and onset is abrupt; diagnosismay be difficult and delayed, since it may occur after hospital discharge.J. Clin. Med. 2018, 7, 318 8 of 22Table 2. Cont.Term Definition Main Problems and LimitsOther related definitions (other hypertensive disorders of pregnancy)Pregnancy inducedhypertension (PIH) “Isolated” hypertension in pregnancyHypertension occurring after the 20th week of pregnancy in a previously normotensive woman; the definition is the same as forPE; the absence of proteinuria is however no longer sufficient to exclude PE (see above).Pregnancy inducedproteinuria “Isolated” proteinuria in pregnancy.Proteinuria above 300 mg/day occurring after the 20th week of pregnancy in a previously non-proteinuric woman. Often a sign ofunderlying CKD.HELLP syndrome A virulent syndrome of endothelial damageThe acronym stands for hypertension, elevated liver enzymes, low platelets (HELLP); it is a severe syndrome, often abrupt,potentially occurring in the immediate postpartum period. Some authors consider it as the end of the spectrum of PE (severestdisease); others consider it a separate disease, due to the frequent lack of prodromal PE.IUGR Intrauterine growth restriction Some authors relate IUGR to the hypertensive disorders of pregnancy, due to its pathogenesis, which is related to insufficientplacental vascularization. See Table 3 for details.Table 3. Kidney involvement in pregnancy: pathologic findings.Structure Main Clinical Feature Pathologic Findings Long-Term EffectsGlomerular Isolated proteinuria, PE, AKIGlomerular endotheliosis (PE),focal-segmental glomerulosclerosis (FSGS);podocyte loss.Differential diagnosis with CKDEndotheliosis is the hallmark of PE. It is considered reversible, and may also be found in normalpregnancies. FSGS is not reversible. Its frequency has been differently assessed, and thesymptoms of severe endotheliosis may merge with it. Podocyte loss, with permanent damage tothe basal membrane seems to be the unifying cellular lesion.Tubular AKI, severe PE, HELLP Acute tubular necrosis, tubulitis,no alterationAKI can be an outcome of ischemic, hypovolemic. septic or toxic (iatrogenic) damage. Thelong-term effects of AKI are not fully understood, but severe dialysis-requiring AKI even whenreversible in the short term, is associated with CKD and ESRD later in life.Vascular Hypertensive disorders, PE, AKIVascular hypertrophy, up to “onion skin”lesions; ischemic or necroticglomerular changesHypertensive crises in pregnancy may exhibit the features of “malignant” or acceleratedhypertension. While onion-skin changes indicate a progressive onset, necrotic changes are thehallmark of the abrupt development of severe hypertension.Global AKI followed by CKD Cortical necrosisThe irreversible loss of function associated with necrotic changes is often multifactorial(hypovolemic or haemorrhagic shock, sepsis, HELLP); can be diagnosed using magneticresonance imaging.J. Clin. Med. 2018, 7, 318 9 of 22J. Clin. Med. 2018, 7, x FOR PEER REVIEW 10 of 22 Figure 3. Endotheliosis is defined by endothelial changes in renal glomeruli, combining swollen endothelial cells leading to narrowed capillary lumen (A,B). Foci of acute tubular necrosis are present (C). Electronic microscopy shows endothelial changes (D) (modified from [47], with permission of the authors). While our understanding of pathogenic mechanisms is improving, we have to acknowledge that our knowledge of the incidence of these complications of the hypertensive disorders of pregnancy is still severely limited, in particular in middle- and low-income countries, a gap which is all the more important, given the estimation of a higher incidence of both AKI and the hypertensive disorders of pregnancy in these settings [54,55]. 4. The Effect of AKI and the Hypertensive Disorders of Pregnancy on the Development of CKD in Mother and Child AKI, PE and CKD are intrinsically related, and kidney damage may represent the common link (Figure 1). A large body of evidence is accumulating on the effect of all kinds of AKI on the future development of CKD, and, in a circular spiral of risk, also affecting the hypertensive disorders of pregnancy [15–18,56–60]. Evidence of the long-term effect of p-AKI on the future development of CKD is limited. However, there is a growing number of studies addressed to describing the relationship between PE and the hypertensive disorders of pregnancy and the development of cardiovascular diseases and CKD [61–87]. The data from the literature are somewhat conflicting, as a result of the heterogeneity of the studies and the differences in the definitions they adopt. None of the available studies is prospective. Within these limits, previous PE is associated with a short-term risk of albuminuria and long-term risk of end-stage renal disease (ESRD) [64–87]. Further research on this topic is needed to make it possible to tailor long- term interventions. Figure 3. Endotheliosis is defined by endothelial changes in renal glomeruli, combining swollenendothelial cells leading to narrowed capillary lumen (A,B). Foci of acute tubular necrosis are present(C). Electronic microscopy shows endothelial changes (D) (modified from [47], with permission ofthe authors).While our understanding of pathogenic mechanisms is improving, we have to acknowledge thatour knowledge of the incidence of these complications of the hypertensive disorders of pregnancy isstill severely limited, in particular in middle- and low-income countries, a gap which is all the moreimportant, given the estimation of a higher incidence of both AKI and the hypertensive disorders ofpregnancy in these settings [54,55].4. The Effect of AKI and the Hypertensive Disorders of Pregnancy on the Development of CKDin Mother and ChildAKI, PE and CKD are intrinsically related, and kidney damage may represent the common link(Figure 1). A large body of evidence is accumulating on the effect of all kinds of AKI on the futuredevelopment of CKD, and, in a circular spiral of risk, also affecting the hypertensive disorders ofpregnancy [15–18,56–60].Evidence of the long-term effect of p-AKI on the future development of CKD is limited. However,there is a growing number of studies addressed to describing the relationship between PE and thehypertensive disorders of pregnancy and the development of cardiovascular diseases and CKD [61–87].The data from the literature are somewhat conflicting, as a result of the heterogeneity of the studiesand the differences in the definitions they adopt. None of the available studies is prospective. Withinthese limits, previous PE is associated with a short-term risk of albuminuria and long-term risk ofJ. Clin. Med. 2018, 7, 318 10 of 22end-stage renal disease (ESRD) [64–87]. Further research on this topic is needed to make it possible totailor long- term interventions.It is likely that p-AKI increases the risk of CKD, which is already higher after PE, for reasons stillto be fully elucidated; as previously mentioned, as podocyte loss is a hallmark of PE, this suggeststhe cause is permanent glomerular damage. Endotheliosis sometimes heralds glomerulosclerosis;tubular and vascular damage may co-exist (Table 3, Figures 1–3). A large recent study providesadditional evidence linking AKI, PE and CKD and suggests that previous AKI is a risk factor for PEand the hypertensive disorders of pregnancy [56]. Conversely, the limit between “physiologic andpathologic” pregnancies is not fully clear, and a consistent overlap exists for pathologic findings [88,89].For this reason, the position of the Italian Society of Nephrology (SIN), the only one so far madeavailable by a nephrology society, is in favour of long-term follow-up of PE patients [90]; it is the onlysociety to explicitly support this approach, based on current data. Adoption of the practice of trackingindividuals longitudinally should be possible in high-income countries, especially those with electronicmedical records, and this should be encouraged. In addition to maternal risks, PE is associated withintrauterine and perinatal death, pre-term delivery, and restricted intrauterine growth, the last two ofwhich result in “small babies” (Table 4) [30–32].Small babies and preterm babies have a highly increased risk of neurological deficits (a risk that isinversely proportional to gestational age), and post-natal complications, in particular those of septicorigin, with further potential long-term detrimental effects [91–102]. The risks are higher in low- andmid-income countries, since survival and deficit-free survival depends to a large extent on providingintensive postnatal care [101–108].Since kidney development is completed in the last phases of pregnancy, delayed, insufficientkidney growth, resulting in a low nephron number is the basis of the increased risk of CKD inadulthood; besides this, CKD, small, and preterm babies are at risk for the development of diabetes,metabolic syndrome, and cardiovascular diseases in adulthood [100–102,109–112]. The question ofwhether all preterm babies or only/mainly babies that are small for gestational age are at increasedrisk for kidney and metabolic diseases is still open, and its clarification will be useful in targetingfuture interventions. Interestingly, delivery of a small for gestational age baby is also a marker of riskof future CKD and cardiovascular diseases in the mother [113–115].J. Clin. Med. 2018, 7, 318 11 of 22Table 4. “Small babies”: focus on classifications and definitions.Term Definition Main Problems and LimitsSmall baby A baby weighing less than 2500 gat birth While there is a trend towards an inverse association between birth weight and clinical problems, the outcome of“small babies” depends on the pathogenesis of low birth weight; hence, measures adjusted for gestational age andgrowth patterns show a better relationship with short- and long-term outcomes.Very small baby A baby weighing less than 1500 gat birthPre-term deliveryDelivery before 37 completedgestational weeks; late pre-term:34–37 gestational weeksThese three widely-used terms were defined in relation to “normal development” (at term); higher risk for milddevelopmental or intellectual deficits (late pre-term is mainly associated with school problems); extreme preterm isassociated with higher frequency of mild deficits, and higher incidence of severe developmentalneurologic problems.The risk for metabolic syndrome, hypertension and CKD, albeit less well explored, may follow a similar pattern.Once more, these definitions should be associated with data on intrauterine growth; outcome may be modifiedby follow-up.Early pre-term delivery Delivery before 34 completedgestational weeksVery early (or extreme)pre-term deliveryDelivery before 28 completedgestational weeksSmall for gestational agebaby (SGA)A baby below the 5th or the 10thcentile for gestational age, adjustedto local growth curvesThis finer definition takes into account the relationship between being small or preterm and the “quality” ofintrauterine growth. This definition does not distinguish between harmonic growth of genetically small children(not pathologic) and stunted growth of children not attaining their genetic growth target. Given the wide ethnicdifferences in growth curves, the absence of local data may impair precise interpretation.Other relevant terms are AGA (adequate for gestational age) and LGA (large for gestational age: above the 90th orthe 95th centile)Intrauterine growthrestriction (IUGR)A baby that does not reach its growthpotential, i.e. one below the 5thcentile for gestational age, or whosegrowth curve flattens in pregnancyGrowth restriction is a dynamic concept that indicates flattening of the growth curve. Data are emerging on thepivotal importance of the “quality” of intrauterine growth, which may be more important than actual birth weight,or prematurity; while babies who are SGA below the 5th centile are so often IUGR that they are included in thedefinitions, a baby may still be adequate for gestational age, be born at term, but be IUGR, if its growth wasseverely reduced in the last gestational weeks.J. Clin. Med. 2018, 7, 318 12 of 225. The Role of CKD in the Pathogenesis of AKI and Hypertensive Disorders of PregnancyStarting in its early stages, in which it is often asymptomatic, CKD is a risk factor for PE,the hypertensive disorders of pregnancy, and preterm delivery; conversely, PE may be the firstsign of undiagnosed CKD [6,90,116–120].CKD and PE share many signs and symptoms (hypertension, proteinuria and increases in serumcreatinine); while differential diagnosis may be difficult, it is not impossible during pregnancy. Whensigns and symptoms are correctly interpreted, and follow-up is continued after delivery, pregnancycan be a precious occasion to diagnose CKD [6,90,116–124].The differential diagnosis can be pragmatically supported by the distinction between placentaland maternal preeclampsia, the first of which is linked to a primary defect in placentation,and associated with high levels of anti-angiogenic factors and by a deep imbalance betweenangiogenic and anti-angiogenic factors, with impaired utero-placental flows, while the latter isa secondary effect exerted by maternal diseases, and can be expected to display a lesser andlater angiogenic/non-angiogenic imbalance, together with relatively well-preserved utero-placentalflows [121,123–127].It is conceivable that this Manichean differentiation does not capture all the important issuesin the pathogenesis of PE, and that a “mixed” pathogenesis may frequently be present. However,the analysis of circulating biomarkers, namely Soluble fms-like tyrosine kinase- (sFlt-1) and placentalgrowth factor (PlGF), the two that have most often been studied in detail), and of utero-placental flows,where available (Doppler study is economically less demanding, and can be performed rapidly at thebedside) can support the differential diagnosis between CKD and PE and help guide post-pregnancyfollow-up (Figure 4) [123–127].J. Clin. Med. 2018, 7, x FOR PEER REVIEW 13 of 22 Figure 4. Flow chart for the differential diagnosis between CKD and PE (modified by the Authors from [90]). Moreover, because making a differential diagnosis between acute damage and chronic kidney disease (AKI vs CKD) may be difficult during pregnancy, it is important to carry out extensive kidney evaluation after delivery, once the physiological changes related to pregnancy have been resolved (Figure 4). Unfortunately, these intentions may be impossible to put into practice in situations where they are in contrast with the harsh reality of insufficient care and inadequate attention to the early diagnosis of CKD. Long-term studies are needed to establish the link between the different clinical and subtle-subclinical changes observed in formerly preeclamptic women, as an ongoing investment in health care for the young. 6. The Role of Immunologic Diseases in the Pathogenesis of the Hypertensive Disorders of Pregnancy and p-AKI Among the immunologic diseases, systemic lupus erythematosus (SLE) principally affects women of childbearing age, and is the most recognized risk factor for the hypertensive disorders of pregnancy and p-AKI [128–131]. The most common feature of kidney damage in SLE is lupus nephritis (LN), characterised by glomerular involvement, but interstitial and vascular lesions also contribute to CKD. Patients affected by SLE share with other CKD patients the traditional risk factors for adverse pregnancy outcomes, but they have also specific risks of p-AKI including lupus flares, preeclampsia, HELLP syndrome, and thrombotic events. The major predictors for acute pregnancy-related complications are Class III and IV lupus nephritis, a previous history of renal flares, longer disease, hypocomplementemia, antiphospholipid syndrome (APS), and the presence of antiphospholipid antibodies [132–136]. In this context, high titres and triple positivity for antiphospholipid antibodies, previous thrombosis and the presence of a lupus anticoagulant are associated with a higher risk of severe maternal and foetal complications, both in primary and secondary APS, and in catastrophic APS (CAPS) the most severe form of the syndrome [136–142]. Conversely, the occurrence of the HELLP syndrome in a patient with APS should raise the suspicion that CAPS will shortly be manifested [139,141–143]. In addition to CAPS, thrombotic thrombocytopenic purpura and atypical haemolytic-uremic syndrome comprise the continuum of pregnancy-related thrombotic microangiopathies (TMA), Normal uteroplacental flows and sflt-1/PlGF : CKD most likely Altered uteroplacental flows and abnormal sflt-1/PlGF : PE most likely Nephrology work-up; long term follow-up probably needed Proteinuria 1 month after delivery: if normal probable PE, if not Repeat 3 months after delivery: if abnormal consider kidney biopsy, probable CKD Isolated alteration of uterine doppler flows or discrepancies between uteroplacental flows and biomarkers: consider CKD, in particular if sflt-1/PlGF is normal Nephrology work-up evidence of CKD No evidence of CKD Figure 4. Flow chart for the differential diagnosis between CKD and PE (modified by the Authorsfrom [90]).Moreover, because making a differential diagnosis between acute damage and chronic kidneydisease (AKI vs CKD) may be difficult during pregnancy, it is important to carry out extensive kidneyevaluation after delivery, once the physiological changes related to pregnancy have been resolved(Figure 4).J. Clin. Med. 2018, 7, 318 13 of 22Unfortunately, these intentions may be impossible to put into practice in situations wherethey are in contrast with the harsh reality of insufficient care and inadequate attention to the earlydiagnosis of CKD. Long-term studies are needed to establish the link between the different clinical andsubtle-subclinical changes observed in formerly preeclamptic women, as an ongoing investment inhealth care for the young.6. The Role of Immunologic Diseases in the Pathogenesis of the Hypertensive Disorders ofPregnancy and p-AKIAmong the immunologic diseases, systemic lupus erythematosus (SLE) principally affects womenof childbearing age, and is the most recognized risk factor for the hypertensive disorders of pregnancyand p-AKI [128–131].The most common feature of kidney damage in SLE is lupus nephritis (LN), characterised byglomerular involvement, but interstitial and vascular lesions also contribute to CKD. Patients affectedby SLE share with other CKD patients the traditional risk factors for adverse pregnancy outcomes,but they have also specific risks of p-AKI including lupus flares, preeclampsia, HELLP syndrome,and thrombotic events. The major predictors for acute pregnancy-related complications are ClassIII and IV lupus nephritis, a previous history of renal flares, longer disease, hypocomplementemia,antiphospholipid syndrome (APS), and the presence of antiphospholipid antibodies [132–136]. In thiscontext, high titres and triple positivity for antiphospholipid antibodies, previous thrombosis andthe presence of a lupus anticoagulant are associated with a higher risk of severe maternal and foetalcomplications, both in primary and secondary APS, and in catastrophic APS (CAPS) the most severeform of the syndrome [136–142]. Conversely, the occurrence of the HELLP syndrome in a patient withAPS should raise the suspicion that CAPS will shortly be manifested [139,141–143].In addition to CAPS, thrombotic thrombocytopenic purpura and atypical haemolytic-uremicsyndrome comprise the continuum of pregnancy-related thrombotic microangiopathies (TMA),associated with high maternal and foetal morbidity and mortality, including p-AKI [139,144–147].Pregnancy, itself a procoagulant state, is a trigger for thrombotic thrombocytopenic purpura,especially in the setting of ADAMTS-13 deficiency. A deficiency of ADAMTS-13 is responsible formost cases of thrombotic thrombocytopenic purpura, generally occurring in the second and thirdtrimester of pregnancy. Pregnancy also induces complement activation and is a trigger for atypicalhaemolytic uremic syndrome, associated with complement dysregulation, which mainly occurs postpartum [139,144–147].After delivery, inflammation, the release of foetal cells in the maternal circulation, infections, andhaemorrhage can lead to activation of the alternative complement pathway, which, in the absenceof effective regulatory mechanisms, may induce postpartum atypical haemolytic-uremic syndrome(aHUS); complement dysregulation was also found to be associated with the HELLP syndrome, whichshares several features with pregnancy-associated TMA [148–152]. The new frontiers of treatment witheculizumab make diagnosis of pivotal importance for allowing timely treatment [149–151,153].7. Conclusions: The Need for Research and Clinical InterventionResearch is increasingly being done on the short- and long-term effects of p-AKI and thehypertensive disorders of pregnancy on the health of mothers and children, and studies are generallyin agreement in highlighting an increased risk for both [60–87]. However, study designs and definitionsare heterogeneous and there is need for establishing and validating a common lexicon in this regard,to allow integration of the available data and, more importantly, make possible a detailed, comparableset of information for the future studies.While information on the short-term effects of p-AKI and the hypertensive disorders ofpregnancy is available in differently resourced settings, data on the long-term effects are limitedto highly-resourced countries, and even then tend to be sparse and non-uniform, thus underlining theJ. Clin. Med. 2018, 7, 318 14 of 22need for more research in the fragile populations that are most susceptible both to p-AKI and otherkidney diseases.While the new generation of biomarkers of preeclampsia and related disorders facilitates betterunderstanding of the pathogenesis and prognosis of the hypertensive disorders of pregnancy, thereis a need for reliable, simple and inexpensive prognostic markers of the effects of p-AKI and thehypertensive disorders of pregnancy on future health. Clinical care of p-AKI, including dialysis care,should be a priority, as maternal health is fundamental not only for the patient, but also for her familyand society [1–3].Treatment for p-AKI and the hypertensive disorders of pregnancy should not be discontinuedat delivery or shortly afterwards, and long-term programs should be established at least for womenwith evidence of chronic kidney disease. Children born to p-AKI mothers, born pre-term or small forgestational age should be followed up to optimize prognosis. All these are ambitious tasks. It will beup to the nephrology community to ensure that they are not seen as being overambitious.Author Contributions: Conceptualization, G.B.P., A.L., E.Z., R.A., M.I.H., B.C., M.A., Z.-H.L., G.A., A.O.G.;Writing—Original Draft Preparation, G.B.P., R.A., G.C.; Writing—Review & Editing, G.B.P., A.L., E.Z., R.A., M.I.H.,B.C., M.A., Z.-H.L., G.A., A.O.G.; Supervision, G.C., P.K.T.L., G.G.-G.Acknowledgments: Authors want to thank Susan Finnel for her careful language editing.Conflicts of Interest: The authors declare no conflicts of interest.References1. Mehta, R.L.; Cerdá, J.; Burdmann, E.A.; Tonelli, M.; García-García, G.; Jha, V. International Society ofNephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): A human rightscase for nephrology. Lancet 2015, 385, 2616–2643. [CrossRef]2. Macedo, E.; Mehta, R.L. Preventing Acute Kidney Injury. Crit. Care Clin. 2015, 31, 773–784. [CrossRef][PubMed]3. Perico, N.; Remuzzi, G. Prevention programs for chronic kidney disease in low-income countries.Intern. Emerg. Med. 2016, 11, 385–389. [CrossRef] [PubMed]4. Jim, B.; Garovic, V.D. Acute Kidney Injury in Pregnancy. Semin. Nephrol. 2017, 37, 378–385. [CrossRef][PubMed]5. Fakhouri, F.; Deltombe, C. Pregnancy-related acute kidney injury in high income countries: Still a criticalissue. J. Nephrol. 2017, 30, 767–771. [CrossRef] [PubMed]6. Ibarra-Hernández, M.; Orozco-Guillén, O.A.; de la Alcantar-Vallín, M.L.; Garrido-Roldan, R.;Jiménez-Alvarado, M.P.; Castro, K.B.; Villa-Villagrana, F.; Borbolla, M.; Gallardo-Gaona, J.M.; García-García, G.;et al. Acute kidney injury in pregnancy and the role of underlying CKD: A point of view from México. J. Nephrol.2017, 30, 773–780. [CrossRef] [PubMed]7. Prakash, J.; Pant, P.; Prakash, S.; Sivasankar, M.; Vohra, R.; Doley, P.K.; Pandey, L.K.; Singh, U. Changingpicture of acute kidney injury in pregnancy: Study of 259 cases over a period of 33 years. Indian J. Nephrol.2016, 26, 262–267. [CrossRef] [PubMed]8. Ibrahim, A.; Ahmed, M.M.; Kedir, S.; Bekele, D. Clinical profile and outcome of patients with acute kidneyinjury requiring dialysis–An experience from a haemodialysis unit in a developing country. BMC Nephrol.2016, 17, 91. [CrossRef] [PubMed]9. Bentata, Y.; Housni, B.; Mimouni, A.; Azzouzi, A.; Abouqal, R. Acute kidney injury related to pregnancyin developing countries: Etiology and risk factors in an intensive care unit. J. Nephrol. 2012, 25, 764–775.[CrossRef] [PubMed]10. Jha, V.; Chugh, K.S. Community-acquired acute kidney injury in Asia. Semin. Nephrol. 2008, 28, 330–347.[CrossRef] [PubMed]11. Naicker, S.; Aboud, O.; Gharbi, M.B. Epidemiology of acute kidney injury in Africa. Semin. Nephrol. 2008, 28,348–353. [CrossRef] [PubMed]12. Lombardi, R.; Yu, L.; Younes-Ibrahim, M.; Schor, N.; Burdmann, E.A. Epidemiology of acute kidney injury inLatin America. Semin. Nephrol. 2008, 28, 320–329. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 15 of 2213. Cerdá, J.; Bagga, A.; Kher, V.; Chakravarthi, R.M. The contrasting characteristics of acute kidney injury indeveloped and developing countries. Nat. Clin. Pract. Nephrol. 2008, 4, 138–153. [CrossRef] [PubMed]14. Trends in Maternal Mortality: 1990 to 2015. Available online: http://www.who.int/reproductivehealth/publications/monitoring/maternal-mortality-2015/en/ (accessed on 15 July 2018).15. Parr, S.K.; Matheny, M.E.; Abdel-Kader, K.; Greevy, R.A.; Bian, A., Jr.; Fly, J.; Chen, G.; Speroff, T.; Hung, A.M.;Ikizler, T.A.; et al. Acute kidney injury is a risk factor for subsequent proteinuria. Kidney Int. 2018, 93,460–469. [CrossRef] [PubMed]16. Hsu, R.K.; Hsu, C.Y. The Role of Acute Kidney Injury in Chronic Kidney Disease. Semin. Nephrol. 2016, 36,283–292. [CrossRef] [PubMed]17. Mammen, C.; Al Abbas, A.; Skippen, P.; Nadel, H.; Levine, D.; Collet, J.P.; Matsell, D.G. Long-term risk ofCKD in children surviving episodes of acute kidney injury in the intensive care unit: A prospective cohortstudy. Am. J. Kidney Dis. 2012, 59, 523–530. [CrossRef] [PubMed]18. Silver, S.A.; Siew, E.D. Follow-up Care in Acute Kidney Injury: Lost in Transition. Adv. Chronic Kidney Dis.2017, 24, 246–252. [CrossRef] [PubMed]19. Liu, Y.; Ma, X.; Zheng, J.; Liu, X.; Yan, T. Pregnancy outcomes in patients with acute kidney injury duringpregnancy: A systematic review and meta-analysis. BMC Pregnancy Childbirth 2017, 17, 235. [CrossRef][PubMed]20. Oladapo, O.T.; Adetoro, O.O.; Ekele, B.A.; Chama, C.; Etuk, S.J.; Aboyeji, A.P.; Onah, H.E.; Abasiattai, A.M.;Adamu, A.N.; et al. Nigeria Near-miss and Maternal Death Surveillance Network. When getting there is notenough: A nationwide cross-sectional study of 998 maternal deaths and 1451 near-misses in public tertiaryhospitals in a low-income country. BJOG 2016, 123, 928–938. [CrossRef] [PubMed]21. Theilen, L.H.; Fraser, A.; Hollingshaus, M.S.; Schliep, K.C.; Varner, M.W.; Smith, K.R.; Esplin, M.S. All-Causeand Cause-Specific Mortality After Hypertensive Disease of Pregnancy. Obstet. Gynecol. 2016, 128, 238–244.[CrossRef] [PubMed]22. Acharya, A. Management of Acute Kidney Injury in Pregnancy for the Obstetrician. Obstet. Gynecol. Clin.N. Am. 2016, 43, 747–765. [CrossRef] [PubMed]23. Lombardi, R.; Rosa-Diez, G.; Ferreiro, A.; Greloni, G.; Yu, L.; Younes-Ibrahim, M.; Burdmann, E.A. Acutekidney injury in Latin America: A view on renal replacement therapy resources. Nephrol. Dial. Transplant.2014, 29, 1369–1376. [CrossRef] [PubMed]24. Nwoko, R.; Plecas, D.; Garovic, V.D. Acute kidney injury in the pregnant patient. Clin. Nephrol. 2012, 78,478–486. [CrossRef] [PubMed]25. Srinil, S.; Panaput, T. Acute kidney injury complicating septic unsafe abortion: Clinical course and treatmentoutcomes of 44 cases. J. Obstet. Gynaecol. Res. 2011, 37, 1525–1531. [CrossRef] [PubMed]26. Sabban, H.; Zakhari, A.; Patenaude, V.; Tulandi, T.; Abenhaim, H.A. Obstetrical and perinatal morbidity andmortality among in-vitro fertilization pregnancies: A population-based study. Arch. Gynecol. Obstet. 2017,296, 107–113. [CrossRef] [PubMed]27. Storgaard, M.; Loft, A.; Bergh, C.; Wennerholm, U.B.; Söderström-Anttila, V.; Romundstad, L.B.;Aittomaki, K.; Oldereid, N.; Forman, J.; Pinborg, A. Obstetric and neonatal complications in pregnanciesconceived after oocyte donation: A systematic review and meta-analysis. BJOG 2017, 124, 561–572. [CrossRef][PubMed]28. Blázquez, A.; García, D.; Rodríguez, A.; Vassena, R.; Figueras, F.; Vernaeve, V. Is oocyte donation a riskfactor for preeclampsia? A systematic review and meta-analysis. J. Assist. Reprod. Genet. 2016, 33, 855–863.[CrossRef] [PubMed]29. Orozco-Guillen, A.; Merodio-Anguiano, R.; Iyune-Cojab, E.; Piccoli, G.B.; Rodriguez-Bosh, M. A baby and akidney neoplasia: A question of priorities. Kidney Int. 2016, 90, 1133. [CrossRef] [PubMed]30. Mol, B.W.; Roberts, C.T.; Thangaratinam, S.; Magee, L.A.; de Groot, C.J.; Hofmeyr, G.J. Pre-eclampsia. Lancet2016, 387, 999–1011. [CrossRef]31. Brown, M.A.; Magee, L.A.; Kenny, L.C.; Karumanchi, S.A.; McCarthy, F.P.; Saito, S.; Hall, D.R.; Warren, C.E.;Adoyi, G.; Ishaku, S. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & managementrecommendations for international practice. Pregnancy Hypertens. 2018, 23, 24–43.32. Tranquilli, A.L.; Dekker, G.; Magee, L.; Roberts, J.; Sibai, B.M.; Steyn, W.; Zeeman, G.G.; Brown, M.A.The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revisedstatement from the ISSHP. Pregnancy Hypertens. 2014, 4, 97–104. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 16 of 2233. Brown, M.A.; Lindheimer, M.D.; de Swiet, M.; van Assche, A.; Moutquin, J.M. The classification anddiagnosis of the hypertensive disorders of pregnancy: Statement from the International Society for the Studyof Hypertension in Pregnancy (ISSHP). Hypertens. Pregnancy 2001, 20. [CrossRef] [PubMed]34. Kallela, J.; Jääskeläinen, T.; Kortelainen, E.; Heinonen, S.; Kajantie, E.; Kere, J.; Kivinen, K.; Pouta, A.;Laivuori, H. The diagnosis of pre-eclampsia using two revised classifications in the Finnish Pre-eclampsiaConsortium (FINNPEC) cohort. BMC Pregnancy Childbirth 2016, 16, 221. [CrossRef] [PubMed]35. Tranquilli, A.L.; Brown, M.A.; Zeeman, G.G.; Dekker, G.; Sibai, B.M. The definition of severe and early-onsetpreeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP).Pregnancy Hypertens. 2013, 3, 44–47. [CrossRef] [PubMed]36. Helewa, M.E.; Burrows, R.F.; Smith, J.; Williams, K.; Brain, P.; Rabkin, S.W. Report of the CanadianHypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensivedisorders in pregnancy. CMAJ 1997, 157, 715–725. [PubMed]37. Ferrazzi, E.; Stampalija, T.; Monasta, L.; di Martino, D.; Vonck, S.; Gyselaers, W. Maternal hemodynamics:A method to classify hypertensive disorders of pregnancy. Am. J. Obstet. Gynecol. 2018, 218, 124. [CrossRef][PubMed]38. Sjaus, A.; McKeen, D.M.; George, R.B. Hypertensive disorders of pregnancy. Can. J. Anaesth. 2016, 63,1075–1097. [CrossRef] [PubMed]39. Magee, L.A.; Pels, A.; Helewa, M.; Rey, E.; von Dadelszen, P. The hypertensive disorders of pregnancy.Best Pract. Res. Clin. Obstet. Gynaecol. 2015, 29, 643–657. [CrossRef] [PubMed]40. Wagner, S.J.; Barac, S.; Garovic, V.D. Hypertensive pregnancy disorders: Current concepts. J. Clin. Hypertens.(Greenwich) 2007, 9, 560–566. [CrossRef]41. Muñoz-Hernández, R.; Medrano-Campillo, P.; Miranda, M.L.; Macher, H.C.; Praena-Fernández, J.M.;Vallejo-Vaz, A.J.; Dominguez-Simeon, M.J.; Moreno-Luna, R.; Stiefel, P. Total and Fetal Circulating Cell-FreeDNA, Angiogenic, and Antiangiogenic Factors in Preeclampsia and HELLP Syndrome. Am. J. Hypertens.2017, 30, 673–682. [CrossRef] [PubMed]42. Schaarschmidt, W.; Rana, S.; Stepan, H. The course of angiogenic factors in early-vs. late-onset preeclampsiaand HELLP syndrome. J. Perinat. Med. 2013, 41, 511–516. [CrossRef] [PubMed]43. Lind Malte, A.; Uldbjerg, N.; Wright, D.; Tørring, N. Prediction of severe pre-eclampsia/HELLP syndromeby combination of sFlt-1, CT-pro-ET-1 and blood pressure: Exploratory study. Ultrasound Obstet. Gynecol.2018, 51, 768–774. [CrossRef] [PubMed]44. Jim, B.; Karumanchi, S.A. Preeclampsia: Pathogenesis, Prevention, and Long-term Complications.Semin. Nephrol. 2017, 37, 386–397. [CrossRef] [PubMed]45. Verlohren, S.; Perschel, F.H.; Thilaganathan, B.; Dröge, L.A.; Henrich, W.; Busjahn, A.; Khalil, A. AngiogenicMarkers and Cardiovascular Indices in the Prediction of Hypertensive Disorders of Pregnancy. Hypertension2017, 69, 1192–1197. [CrossRef] [PubMed]46. Martinez-Fierro, M.L.; Hernández-Delgadillo, G.P.; Flores-Morales, V.; Cardenas-Vargas, E.; Mercado-Reyes, M.;Rodriguez-Sanchez, I.P.; Delgado-Enciso, I.; Galván-Tejada, C.E.; Galván-Tejada, J.I.; Celaya-Padilla, J.M. Currentmodel systems for the study of preeclampsia. Exp. Biol. Med. (Maywood) 2018, 243, 576–585. [CrossRef][PubMed]47. Villie, P.; Dommergues, M.; Brocheriou, I.; Piccoli, G.B.; Tourret, J.; Hertig, A. Why kidneys fail post-partum:A tubulocentric viewpoint. J. Nephrol. 2018. [CrossRef] [PubMed]48. Wagner, S.J.; Craici, I.M.; Grande, J.P.; Garovic, V.D. From placenta to podocyte: Vascular and podocytepathophysiology in preeclampsia. Clin. Nephrol. 2012, 78, 241–249. [CrossRef] [PubMed]49. Henao, D.E.; Saleem, M.A.; Cadavid, A.P. Glomerular disturbances in preeclampsia: Disruption betweenglomerular endothelium and podocyte symbiosis. Hypertens Pregnancy 2010, 29, 10–20. [CrossRef] [PubMed]50. Koizumi, M.; Yahata, K.; Ohno, S.; Koga, K.; Kikuchi, Y.; Hasegawa, C.; Seta, K.; Kuwahara, T.; Sugawara, A.Glomerular endotheliosis in a pregnant woman with severe gestational proteinuria. Intern. Med. 2013, 52,1943–1947. [CrossRef] [PubMed]51. Von Dadelszen, P.; Magee, L.A. Preventing deaths due to the hypertensive disorders of pregnancy. Best. Pract.Res. Clin. Obstet. Gynaecol. 2016, 36, 83–102. [CrossRef] [PubMed]52. Barbosa, I.R.; Silva, W.B.; Cerqueira, G.S.; Novo, N.F.; Almeida, F.A.; Novo, J.L. Maternal and fetal outcomein women with hypertensive disorders of pregnancy: The impact of prenatal care. Ther. Adv. Cardiovasc. Dis.2015, 9, 140–146. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 17 of 2253. Von Dadelszen, P.; Ansermino, J.M.; Dumont, G.; Hofmeyr, G.J.; Magee, L.A.; Mathai, M.; Sawchuck, D.;Teela, K.; Donnay, F.; Roberts, J.M. Improving maternal and perinatal outcomes in the hypertensive disordersof pregnancy: A vision of a community-focused approach. Int. J. Gynaecol. Obstet. 2012, 119, 30–34.[CrossRef] [PubMed]54. Cerdá, J.; Mohan, S.; Garcia-Garcia, G.; Jha, V.; Samavedam, S.; Gowrishankar, S.; Bagga, A.; Chakravarthi, R.;Mehta, R. Acute Kidney Injury Recognition in Low- and Middle-Income Countries. Kidney Int. Rep. 2017, 2,530–543. [CrossRef] [PubMed]55. Kashani, K.; Macedo, E.; Burdmann, E.A.; Hooi, L.S.; Khullar, D.; Bagga, A.; Chakravarthi, R.; Mehta, R. AcuteKidney Injury Risk Assessment: Differences and Similarities Between Resource-Limited and Resource-RichCountries. Kidney Int. Rep. 2017, 2, 519–529. [CrossRef] [PubMed]56. Tangren, J.S.; Powe, C.E.; Ankers, E.; Ecker, J.; Bramham, K.; Hladunewich, M.A.; Karumanchi, S.A.;Thadhani, R. Pregnancy Outcomes after Clinical Recovery from AKI. J. Am. Soc. Nephrol. 2017, 28, 1566–1574.[CrossRef] [PubMed]57. Chawla, L.S.; Kimmel, P.L. Acute kidney injury and chronic kidney disease: An integrated clinical syndrome.Kidney Int. 2012, 82, 516–524. [CrossRef] [PubMed]58. Kaballo, M.A.; Elsayed, M.E.; Stack, A.G. Linking acute kidney injury to chronic kidney disease: The missinglinks. J. Nephrol. 2017, 30, 461–475. [CrossRef] [PubMed]59. Pannu, N. Bidirectional relationships between acute kidney injury and chronic kidney disease. Curr. Opin.Nephrol. Hypertens. 2013, 22, 351–356. [CrossRef] [PubMed]60. He, L.; Wei, Q.; Liu, J.; Yi, M.; Liu, Y.; Liu, H.; Sun, L.; Peng, Y.; Liu, F.; Venkatachalam, M.A.; et al. AKI onCKD: Heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int. 2017, 92, 1071–1083.[CrossRef] [PubMed]61. Brown, M.C.; Best, K.E.; Pearce, M.S.; Waugh, J.; Robson, S.C.; Bell, R. Cardiovascular disease risk in womenwith pre-eclampsia: Systematic review and meta-analysis. Eur. J. Epidemiol. 2013, 28, 1–19. [CrossRef][PubMed]62. Bellamy, L.; Casas, J.P.; Hingorani, A.D.; Williams, D.J. Pre-eclampsia and risk of cardiovascular disease andcancer in later life: Systematic review and meta-analysis. BMJ 2007, 335, 974. [CrossRef] [PubMed]63. Ahmed, R.; Dunford, J.; Mehran, R.; Robson, S.; Kunadian, V. Pre-eclampsia and future cardiovascular riskamong women: A review. J. Am. Coll. Cardiol. 2014, 63, 1815–1822. [CrossRef] [PubMed]64. Wu, P.; Haththotuwa, R.; Kwok, C.S.; Babu, A.; Kotronias, R.A.; Rushton, C.; Zaman, A.; Fryer, A.A.;Kadam, U.; Chew-Graham, C.A.; et al. Preeclampsia and Future Cardiovascular Health: A SystematicReview and Meta-Analysis. Circ. Cardiovasc. Qual. Outcomes 2017, 10, e003497. [CrossRef] [PubMed]65. McDonald, S.D.; Han, Z.; Walsh, M.W.; Gerstein, H.C.; Devereaux, P.J. Kidney disease after preeclampsia:A systematic review and meta-analysis. Am. J. Kidney. Dis. 2010, 55, 1026–1039. [CrossRef] [PubMed]66. Paauw, N.D.; van der Graaf, A.M.; Bozoglan, R.; van der Ham, D.P.; Navis, G.; Gansevoort, R.T.; Groen, H.;Lely, A.T. Kidney Function After a Hypertensive Disorder of Pregnancy: A Longitudinal Study. Am. J.Kidney Dis. 2017, 71, 619–626. [CrossRef] [PubMed]67. Van Balen Lopes, V.A.; Spaan, J.J.; Cornelis, T.; Heidema, W.M.; Scholten, R.R.; Spaanderman, M.E.A.Endothelial and kidney function in women with a history of preeclampsia and healthy parous controls:A case control study. Microvasc. Res. 2017, 116, 71–76. [CrossRef] [PubMed]68. Tooher, J.; Thornton, C.; Makris, A.; Ogle, R.; Korda, A.; Hennessy, A. All Hypertensive Disorders ofPregnancy Increase the Risk of Future Cardiovascular Disease. Hypertension 2017, 70, 798–803. [CrossRef][PubMed]69. Bokslag, A.; Teunissen, P.W.; Franssen, C.; van Kesteren, F.; Kamp, O.; Ganzevoort, W.; Paulus, W.J.; deGroot, C.J.M. Effect of early-onset preeclampsia on cardiovascular risk in the fifth decade of life. Am. J.Obstet. Gynecol. 2017, 216, 523. [CrossRef] [PubMed]70. Paauw, N.D.; Joles, J.A.; Drost, J.T.; Verhaar, M.C.; Franx, A.; Navis, G.; Maas, A.H.; Lely, A.T. High-NormalEstimated Glomerular Filtration Rate in Early-Onset Preeclamptic Women 10 Years Postpartum. Hypertension2016, 68, 1407–1414. [CrossRef] [PubMed]71. Ayansina, D.; Black, C.; Hall, S.J.; Marks, A.; Millar, C.; Prescott, G.J.; Wilde, K.; Bhattacharya, S. Longterm effects of gestational hypertension and pre-eclampsia on kidney function: Record linkage study.Pregnancy Hypertens. 2016, 6, 344–349. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 18 of 2272. Kessous, R.; Shoham-Vardi, I.; Pariente, G.; Sergienko, R.; Sheiner, E. Long-term maternal atheroscleroticmorbidity in women with pre-eclampsia. Heart 2015, 101, 442–446. [CrossRef] [PubMed]73. Wu, C.C.; Chen, S.H.; Ho, C.H.; Liang, F.W.; Chu, C.C.; Wang, H.Y.; Lu, Y.H. End-stage renal disease afterhypertensive disorders in pregnancy. Am. J. Obstet. Gynecol. 2014, 210, 1–8. [CrossRef] [PubMed]74. Sandvik, M.K.; Hallan, S.; Svarstad, E.; Vikse, B.E. Preeclampsia and prevalence of microalbuminuria 10 yearslater. Clin. J. Am. Soc. Nephrol. 2013, 8, 1126–1134. [CrossRef] [PubMed]75. Männistö, T.; Mendola, P.; Vääräsmäki, M.; Järvelin, M.R.; Hartikainen, A.L.; Pouta, A.; Suvanto, E. Elevatedblood pressure in pregnancy and subsequent chronic disease risk. Circulation 2013, 127, 681–690. [CrossRef][PubMed]76. Wang, I.K.; Muo, C.H.; Chang, Y.C.; Liang, C.C.; Chang, C.T.; Lin, S.Y.; Yen, T.H.; Chuang, F.R.; Chen, P.C.;Huang, C.C.; et al. Association between hypertensive disorders during pregnancy and end-stage renaldisease: A population-based study. CMAJ 2013, 185, 207–213. [CrossRef] [PubMed]77. Vikse, B.E.; Irgens, L.M.; Karumanchi, S.A.; Thadhani, R.; Reisæter, A.V.; Skjærven, R. Familial factors in theassociation between preeclampsia and later ESRD. Clin. J. Am. Soc. Nephrol. 2012, 7, 1819–1826. [CrossRef][PubMed]78. McDonald, S.D.; Yusuf, S.; Walsh, M.W.; Lonn, E.; Teo, K.; Anand, S.S.; Pogue, J.; Islam, S.; Devereaux, P.J.;Gerstein, H.C. Increased cardiovascular risk after pre-eclampsia in women with dysglycaemia. Diabet. Med.2012, 30, 1–7. [CrossRef] [PubMed]79. Bhattacharya, S.; Prescott, G.J.; Iversen, L.; Campbell, D.M.; Smith, W.C.; Hannaford, P.C. Hypertensivedisorders of pregnancy and future health and mortality: A record linkage study. Pregnancy Hypertens. 2011,2, 1–7. [CrossRef] [PubMed]80. Shahbazian, N.; Shahbazian, H.; Ehsanpour, A.; Aref, A.; Gharibzadeh, S. Hypertension andmicroalbuminuria 5 years after pregnancies complicated by pre-eclampsia. Iran. J. Kidney Dis. 2011, 5,324–327. [PubMed]81. Vikse, B.E.; Hallan, S.; Bostad, L.; Leivestad, T.; Iversen, B.M. Previous preeclampsia and risk for progressionof biopsy-verified kidney disease to end-stage renal disease. Nephrol. Dial. Transplant. 2010, 25, 3289–3296.[CrossRef] [PubMed]82. Sandvik, M.K.; Iversen, B.M.; Irgens, L.M.; Skjaerven, R.; Leivestad, T.; Søfteland, E.; Vikse, B.E. Are adversepregnancy outcomes risk factors for development of end-stage renal disease in women with diabetes?Nephrol. Dial. Transplant. 2010, 25, 3600–3607. [CrossRef] [PubMed]83. Vikse, B.E.; Irgens, L.M.; Leivestad, T.; Skjaerven, R.; Iversen, B.M. Preeclampsia and the risk of end-stagerenal disease. N. Engl. J. Med. 2008, 359, 800–809. [CrossRef] [PubMed]84. Lampinen, K.H.; Rönnback, M.; Groop, P.H.; Kaaja, R.J. Renal and vascular function in women with previouspreeclampsia: A comparison of low- and high-degree proteinuria. Kidney Int. 2006, 70, 1818–1822. [CrossRef][PubMed]85. Vikse, B.E.; Irgens, L.M.; Bostad, L.; Iversen, B.M. Adverse perinatal outcome and later kidney biopsy in themother. J. Am. Soc. Nephrol. 2006, 17, 837–845. [CrossRef] [PubMed]86. Shammas, A.G.; Maayah, J.F. Hypertension and its relation to renal function 10 years after pregnancycomplicated by pre-eclampsia and pregnancy induced hypertension. Saudi Med. J. 2000, 21, 190–192.[PubMed]87. Kattah, A.G.; Scantlebury, D.C.; Agarwal, S.; Mielke, M.M.; Rocca, W.A.; Weaver, A.L.; Vaughan, L.E.;Miller, V.M.; Weissgerber, T.L.; White, W.; et al. Preeclampsia and ESRD: The Role of Shared Risk Factors.Am. J. Kidney Dis. 2017, 69, 498–505. [CrossRef] [PubMed]88. Wide-Swensson, D.; Strevens, H.; Willner, J. Antepartum percutaneous renal biopsy. Int. J. Gynaecol. Obstet.2007, 98, 88–92. [CrossRef] [PubMed]89. Shiiki, H.; Dohi, K.; Hanatani, M.; Fujii, Y.; Sanai, H.; Ichijo, M.; Shimamoto, I.; Ishikawa, H.; Watanabe, T.Focal and segmental glomerulosclerosis in preeclamptic patients with nephrotic syndrome. Am. J. Nephrol.1990, 10, 205–212. [CrossRef] [PubMed]90. Piccoli, G.B.; Cabiddu, G.; Castellino, S.; Gernone, G.; Santoro, D.; Moroni, G.; Spotti, D.; Giacchino, F.;Attini, R.; Limardo, M.; et al. A best practice position statement on the role of the nephrologist in theprevention and follow-up of preeclampsia: The Italian study group on kidney and pregnancy. J. Nephrol.2017, 30, 307–317. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 19 of 2291. O’Gorman, N.; Wright, D.; Poon, L.C.; Rolnik, D.L.; Syngelaki, A.; de Alvarado, M.; Carbone, I.F.;Dutemeyer, V.; Fiolna, M.; Frick, A. Multicenter screening for pre-eclampsia by maternal factors andbiomarkers at 11–13 weeks’ gestation: Comparison with NICE guidelines and ACOG recommendations.Ultrasound Obstet. Gynecol. 2017, 49, 756–760. [CrossRef] [PubMed]92. Von Dadelszen, P.; Payne, B.; Li, J.; Ansermino, J.M.; Broughton Pipkin, F.; Côté, A.M.; Douglas, M.J.;Gruslin, A.; Hutcheon, J.A.; Joseph, K.S.; et al. Prediction of adverse maternal outcomes in pre-eclampsia:Development and validation of the fullPIERS model. Lancet 2011, 377, 219–227. [CrossRef]93. Linsell, L.; Malouf, R.; Morris, J.; Kurinczuk, J.J.; Marlow, N. Risk Factor Models for NeurodevelopmentalOutcomes in Children Born Very Preterm or With Very Low Birth Weight: A Systematic Review ofMethodology and Reporting. Am. J. Epidemiol. 2017, 185, 601–612. [CrossRef] [PubMed]94. Guellec, I.; Lapillonne, A.; Marret, S.; Picaud, J.C.; Mitanchez, D.; Charkaluk, M.L.; Fresson, J.; Arnaud, C.;Flamand, C.; Cambonie, G. Effect of Intra- and Extrauterine Growth on Long-Term Neurologic Outcomes ofVery Preterm Infants. J. Pediatr. 2016, 175, 93–99. [CrossRef] [PubMed]95. Moore, T.; Hennessy, E.M.; Myles, J.; Johnson, S.J.; Draper, E.S.; Costeloe, K.L.; Marlow, N. Neurologicaland developmental outcome in extremely preterm children born in England in 1995 and 2006: The EPICurestudies. BMJ 2012. [CrossRef] [PubMed]96. Guillén, U.; DeMauro, S.; Ma, L.; Zupancic, J.; Roberts, R.; Schmidt, B.; Kirpalani, H. Relationship betweenattrition and neurodevelopmental impairment rates in extremely preterm infants at 18 to 24 months:A systematic review. Arch. Pediatr. Adolesc. Med. 2012, 166, 178–184. [CrossRef] [PubMed]97. Ranke, M.B.; Schweizer, R.; Rodemann, S.M.; Bevot, A.; Martin, D.D.; Goelz, R.; Wollmann, H.A.;Krägeloh-Mann, I.; Binder, G. Schoolchildren born VLBW or VLGA show height-related changes in bodycomposition and muscle function but no evidence of metabolic syndrome risk factors. Results from theNEOLONG study. J. Pediatr. Endocrinol. Metab. 2016, 29, 163–172. [CrossRef] [PubMed]98. Castanys-Muñoz, E.; Kennedy, K.; Castañeda-Gutiérrez, E.; Forsyth, S.; Godfrey, K.M.; Koletzko, B.;Ozanne, S.E.; Rueda, R.; Schoemaker, M.; van der Beek, E.M. Systematic review indicates postnatal growthin term infants born small-for-gestational-age being associated with later neurocognitive and metabolicoutcomes. Acta Paediatr. 2017, 106, 1230–1238. [CrossRef] [PubMed]99. Ong, K.K.; Kennedy, K.; Castañeda-Gutiérrez, E.; Forsyth, S.; Godfrey, K.M.; Koletzko, B.; Latulippe, M.E.;Ozanne, S.E.; Rueda, R.; Schoemaker, M.H. Postnatal growth in preterm infants and later health outcomes:A systematic review. Acta Paediatr. 2015, 104, 974–986. [CrossRef] [PubMed]100. Low Birth Weight and Nephron Number Working Group. The Impact of Kidney Development on the LifeCourse: A Consensus Document for Action. Nephron Clin. Pract. 2017, 136, 3–49.101. Luyckx, V.A.; Bertram, J.F.; Brenner, B.M.; Fall, C.; Hoy, W.E.; Ozanne, S.E.; Vikse, B.E. Effect of fetal andchild health on kidney development and long-term risk of hypertension and kidney disease. Lancet 2013,382, 273–283. [CrossRef]102. Luyckx, V.A.; Brenner, B.M. Birth weight, malnutrition and kidney-associated outcomes—A global concern.Nat. Rev. Nephrol. 2015, 11, 135–149. [CrossRef] [PubMed]103. Monier, I.; Ancel, P.Y.; Ego, A.; Jarreau, P.H.; Lebeaux, C.; Kaminski, M.; Goffinet, F.; Zeitlin, J. Fetal andneonatal outcomes of preterm infants born before 32 weeks of gestation according to antenatal vs postnatalassessments of restricted growth. Am. J. Obstet. Gynecol. 2017, 216, 516. [CrossRef] [PubMed]104. Lee, A.C.; Kozuki, N.; Cousens, S.; Stevens, G.A.; Blencowe, H.; Silveira, M.F.; CHERGSmall-for-Gestational-Age-Preterm Birth Working Group. Estimates of burden and consequences of infantsborn small for gestational age in low and middle income countries with INTERGROWTH-21 standard:Analysis of CHERG datasets. BMJ 2017, 358, 3677. [CrossRef] [PubMed]105. Temming, L.A.; Dicke, J.M.; Stout, M.J.; Rampersad, R.M.; Macones, G.A.; Tuuli, M.G.; Cahill, A.G. EarlySecond-Trimester Fetal Growth Restriction and Adverse Perinatal Outcomes. Obstet. Gynecol. 2017, 130,865–869. [CrossRef] [PubMed]106. Wang, A.Y.; Chughtai, A.A.; Lui, K.; Sullivan, E.A. Morbidity and mortality among very pretermsingletons following fertility treatment in Australia and New Zealand, a population cohort study.BMC Pregnancy Childbirth 2017, 17, 50. [CrossRef] [PubMed]107. Darmstadt, G.L.; Walker, N.; Lawn, J.E.; Bhutta, Z.A.; Haws, R.A.; Cousens, S. Saving newborn livesin Asia and Africa: Cost and impact of phased scale-up of interventions within the continuum of care.Health Policy Plan 2008, 23, 101–117. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 20 of 22108. Bhutta, Z.A.; Das, J.K.; Bahl, R.; Lawn, J.E.; Salam, R.A.; Paul, V.K.; Sankar, M.J.; Blencowe, H.; Rizvi, A.;Chou, V.B.; et al. Can available interventions end preventable deaths in mothers, newborn babies, andstillbirths, and at what cost? Lancet 2014, 384, 347–370. [CrossRef]109. Luyckx, V.A. Preterm Birth and its Impact on Renal Health. Semin. Nephrol. 2017, 37, 311–319. [CrossRef][PubMed]110. Abitbol, C.L.; Rodriguez, M.M. The long-term renal and cardiovascular consequences of prematurity.Nat. Rev. Nephrol. 2012, 8, 265–274. [CrossRef] [PubMed]111. Sutherland, M.; Ryan, D.; Black, M.J.; Kent, A.L. Long-term renal consequences of preterm birth.Clin. Perinatol. 2014, 41, 561–573. [CrossRef] [PubMed]112. Carmody, J.B.; Charlton, J.R. Short-term gestation, long-term risk: Prematurity and chronic kidney disease.Pediatrics 2013, 131, 1168–1179. [CrossRef] [PubMed]113. Almasi, O.; Pariente, G.; Kessous, R.; Sergienko, R.; Sheiner, E. Association between delivery ofsmall-for-gestational-age neonate and long-term maternal chronic kidney disease. J. Matern. FetalNeonatal Med. 2016, 29, 2861–2864. [CrossRef] [PubMed]114. Pariente, G.; Sheiner, E.; Kessous, R.; Michael, S.; Shoham-Vardi, I. Association between delivery of asmall-for-gestational-age neonate and long-term maternal cardiovascular morbidity. Int. J. Gynaecol. Obstet.2013, 123, 68–71. [CrossRef] [PubMed]115. Neiger, R. Long-Term Effects of Pregnancy Complications on Maternal Health: A Review. J. Clin. Med. 2017,6, 76. [CrossRef] [PubMed]116. Cabiddu, G.; Castellino, S.; Gernone, G.; Santoro, D.; Moroni, G.; Giannattasio, M.; Gregorini, G.; Giacchino, F.;Attini, R.; Loi, V.; et al. A best practice position statement on pregnancy in chronic kidney disease: The ItalianStudy Group on Kidney and Pregnancy. J. Nephrol. 2016, 29, 277–303. [CrossRef] [PubMed]117. Blom, K.; Odutayo, A.; Bramham, K.; Hladunewich, M.A. Pregnancy and Glomerular Disease: A SystematicReview of the Literature with Management Guidelines. Clin. J. Am. Soc. Nephrol. 2017, 18. [CrossRef][PubMed]118. Piccoli, G.B.; Cabiddu, G.; Attini, R.; Vigotti, F.N.; Maxia, S.; Lepori, N.; Tuveri, M.; Massidda, M.; Marchi, C.;Mura, S. Risk of Adverse Pregnancy Outcomes in Women with CKD. J. Am. Soc. Nephrol. 2015, 26, 2011–2022.[CrossRef] [PubMed]119. Zhang, J.J.; Ma, X.X.; Hao, L.; Liu, L.J.; Lv, J.C.; Zhang, H. A Systematic Review and Meta-Analysis ofOutcomes of Pregnancy in CKD and CKD Outcomes in Pregnancy. Clin. J. Am. Soc. Nephrol. 2015, 10,1964–1978. [CrossRef] [PubMed]120. Alsuwaida, A.; Mousa, D.; Al-Harbi, A.; Alghonaim, M.; Ghareeb, S.; Alrukhaimi, M.N. Impact of earlychronic kidney disease on maternal and fetal outcomes of pregnancy. J. Matern. Fetal. Neonatal. Med. 2011,24, 1432–1436. [CrossRef] [PubMed]121. De Jesus, G.R.; de Jesus, N.R.; Levy, R.A.; Klumb, E.M. The use of angiogenic and antiangiogenic factors inthe differential diagnosis of pre-eclampsia, antiphospholipid syndrome nephropathy and lupus nephritis.Lupus 2014, 23, 1299–1301. [CrossRef] [PubMed]122. Morton, A. Imitators of preeclampsia: A review. Pregnancy Hypertens. 2016, 6, 1–9. [CrossRef] [PubMed]123. Rolfo, A.; Attini, R.; Tavassoli, E.; Neve, F.V.; Nigra, M.; Cicilano, M.; Nuzzo, A.M.; Giuffrida, D.; Biolcati, M.;Nichelatti, M.; et al. Is It Possible to Differentiate Chronic Kidney Disease and Preeclampsia by means ofNew and Old Biomarkers? A Prospective Study. Dis. Mark. 2015. [CrossRef] [PubMed]124. Piccoli, G.B.; Gaglioti, P.; Attini, R.; Parisi, S.; Bossotti, C.; Olearo, E.; Oberto, M.; Ferraresi, M.; Rolfo, A.;Versino, E.; et al. Pre-eclampsia or chronic kidney disease? The flow hypothesis. Nephrol. Dial. Transplant.2013, 28, 1199–1206. [CrossRef] [PubMed]125. Zeisler, H.; Llurba, E.; Chantraine, F.; Vatish, M.; Staff, A.C.; Sennström, M.; Olovsson, M.; Brennecke, S.P.;Stepan, H.; Allegranza, D.; et al. Predictive Value of the sFlt-1: PlGF Ratio in Women with SuspectedPreeclampsia. N. Engl. J. Med. 2016, 374, 13–22. [CrossRef] [PubMed]126. Masuyama, H.; Nobumoto, E.; Okimoto, N.; Inoue, S.; Segawa, T.; Hiramatsu, Y. Superimposed preeclampsiain women with chronic kidney disease. Gynecol. Obstet. Invest. 2012, 74, 274–281. [CrossRef] [PubMed]127. Zhao, M.; Zhu, Z.; Liu, C.; Zhang, Z. Dual-cutoff of sFlt-1/PlGF ratio in the stratification of preeclampsia:A systematic review and meta-analysis. Arch. Gynecol. Obstet. 2017, 295, 1079–1087. [CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 21 of 22128. Bartsch, E.; Medcalf, K.E.; Park, A.L.; Ray, J.G. Clinical risk factors for pre-eclampsia determined in earlypregnancy: Systematic review and meta-analysis of large cohort studies. BMJ 2016, 353, 1753. [CrossRef][PubMed]129. Wu, J.; Ma, J.; Zhang, W.H.; Di, W. Management and outcomes of pregnancy with or without lupus nephritis:A systematic review and meta-analysis. Ther. Clin. Risk. Manag. 2018, 14, 885–901. [CrossRef] [PubMed]130. Wei, S.; Lai, K.; Yang, Z.; Zeng, K. Systemic lupus erythematosus and risk of preterm birth: A systematicreview and meta-analysis of observational studies. Lupus 2017, 26, 563–571. [CrossRef] [PubMed]131. Smyth, A.; Oliveira, G.H.; Lahr, B.D.; Bailey, K.R.; Norby, S.M.; Garovic, V.D. A systematic review andmeta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis.Clin. J. Am. Soc. Nephrol. 2010, 5, 2060–2068. [CrossRef] [PubMed]132. Carvalheiras, G.; Vita, P.; Marta, S.; Trovão, R.; Farinha, F.; Braga, J.; Rocha, G.; Almeida, I.; Marinho, A.;Mendonça, T.; et al. Pregnancy and systemic lupus erythematosus: Review of clinical features and outcomeof 51 pregnancies at a single institution. Clin. Rev. Allergy Immunol. 2010, 38, 302–306. [CrossRef] [PubMed]133. Vellanki, V.S.; Parvathina, S.; Gondi, S.; Yadla, M.; Chenu, K.K.; Vishnubhotla, S. Post-partum bilateralrenal cortical necrosis in antiphospholipid syndrome and systemic lupus erythematosus. Saudi J. KidneyDis. Transpl. 2013, 24, 549–552. [PubMed]134. Mizuno, R.; Fujimoto, S.; Fujimoto, T.; Nishino, T.; Shiiki, H.; Hashimoto, T.; Nakamura, S.; Dohi, K.Catastrophic antiphospholipid antibody syndrome in systemic lupus erythematosus: An autopsy case reportof a young woman. Intern. Med. 2000, 39, 856–859. [CrossRef] [PubMed]135. Moroni, G.; Doria, A.; Giglio, E.; Imbasciati, E.; Tani, C.; Zen, M.; Strigini, F.; Zaina, B.; Tincani, A.; Gatto, M.Maternal outcome in pregnant women with lupus nephritis. A prospective multicenter study. J. Autoimmun.2016, 74, 194–200. [CrossRef] [PubMed]136. Buyon, J.P.; Kim, M.Y.; Guerra, M.M.; Laskin, C.A.; Petri, M.; Lockshin, M.D.; Sammaritano, L.; Branch, D.W.;Porter, T.F.; Sawitzke, A. Predictors of Pregnancy Outcomes in Patients with Lupus: A Cohort Study.Ann. Intern. Med. 2015, 163, 153–163. [CrossRef] [PubMed]137. Alchi, B.; Griffiths, M.; Jayne, D. What nephrologists need to know about antiphospholipid syndrome.Nephrol. Dial. Transplant. 2010, 25, 3147–3154. [CrossRef] [PubMed]138. Hanouna, G.; Morel, N.; Le Thi Huong, D.; Josselin, L.; Vauthier-Brouzes, D.; Saadoun, D.; Kettaneh, A.;Levesque, K.; Le Guern, V.; Goffinet, F.; et al. Catastrophic antiphospholipid syndrome and pregnancy:An experience of 13 cases. Rheumatology (Oxford) 2013, 52, 1635–1641. [CrossRef] [PubMed]139. Dashe, J.S.; Ramin, S.M.; Cunningham, F.G. The long-term consequences of thrombotic microangiopathy(thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet. Gynecol.1998, 91, 662–668. [PubMed]140. Silver, R.M. Catastrophic antiphospholipid syndrome and pregnancy. Semin. Perinatol. 2018, 42, 26–32.[CrossRef] [PubMed]141. Rao, S.; Jim, B. Acute Kidney Injury in Pregnancy: The Changing Landscape for the 21st Century.Kidney Int. Rep. 2018, 3, 247–257. [CrossRef] [PubMed]142. Cervera, R.; Serrano, R.; Pons-Estel, G.J.; Ceberio-Hualde, L.; Shoenfeld, Y.; de Ramón, E. Morbidity andmortality in the antiphospholipid syndrome during a 10-year period: A multicentre prospective study of1000 patients. Ann. Rheum. Dis. 2015, 74, 1011–1018. [CrossRef] [PubMed]143. Pengo, V.; Banzato, A.; Bison, E.; Bracco, A.; Denas, G.; Ruffatti, A. What have we learned aboutantiphospholipid syndrome from patients and antiphospholipid carrier cohorts? Semin. Thromb. Hemost.2012, 38, 322–327. [CrossRef] [PubMed]144. Ducloy-Bouthors, A.S.; Caron, C.; Subtil, D. Thrombotic thrombocytopenic purpura: Medical and biologicalmonitoring of six pregnancies. Eur. J. Obstet. Gynecol. Reprod. Biol. 2003, 111, 146–152. [CrossRef]145. Sanchez-Luceros, A.; Farias, C.E.; Amaral, M.M. Von Willebrand factor cleaving protease (ADAMTS13)activity in normal non-pregnant women, pregnant and post-delivery women. Thromb. Haemost. 2004, 92,1320–1326. [CrossRef] [PubMed]146. Fakhouri, F.; Roumenina, L.; Provot, F.; Sallée, M.; Caillard, S.; Couzi, L. Pregnancy-associated hemolyticuremic syndrome revisited in the era of complement gene mutations. J. Am. Soc. Nephrol. 2010, 21, 859–867.[CrossRef] [PubMed]J. Clin. Med. 2018, 7, 318 22 of 22147. Fakhouri, F.; Jablonski, M.; Lepercq, J. Factor H, membrane cofactor protein, and factor I mutations in patientswith hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood 2008, 112, 4542–4545.[CrossRef] [PubMed]148. Baghli, S.; Abendroth, C.; Farooq, U.; Schaub, J.A. Atypical Presentation of Pregnancy-Related HemolyticUremic Syndrome. Am. J. Kidney Dis. 2018, 72, 451–456. [CrossRef] [PubMed]149. Barbullushi, M.; Idrizi, A.; Spasovski, G. Familial hemolytic uremic syndrome with occurrence in thepostpartum period. Saudi J. Kidney Dis. Transpl. 2017, 28, 1427–1431. [CrossRef] [PubMed]150. Gately, R.; San, A.; Kurtkoti, J.; Parnham, A. Life-threatening pregnancy-associated atypical haemolyticuraemic syndrome and its response to eculizumab. Nephrology (Carlton) 2017, 22, 32–35. [CrossRef] [PubMed]151. Servais, A.; Devillard, N.; Frémeaux-Bacchi, V.; Hummel, A.; Salomon, L.; Contin-Bordes, C.; Gomer, H.;Legendre, C.; Delmas, Y. Atypical haemolytic uraemic syndrome and pregnancy: Outcome with ongoingeculizumab. Nephrol. Dial. Transplant. 2016, 31, 2122–2130. [CrossRef] [PubMed]152. Noris, M.; Bresin, E.; Mele, C.; Remuzzi, G. Genetic Atypical Hemolytic-Uremic Syndrome. In GeneReviews;Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., Amemiya, A., Eds.;University of Washington: Seattle, WA, USA, 2007.153. Shanmugalingam, R.; Hsu, D.; Makris, A. Pregnancy-induced atypical haemolytic uremic syndrome: A newera with eculizumab. Obstet. Med. 2018, 11, 28–31. [CrossRef] [PubMed]© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Article
eng
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Vancouver : University of British Columbia Library
Multidisciplinary Digital Publishing Institute
CC BY 4.0
Faculty
Pregnancy acute kidney injury (AKI)
Chronic kidney disease (CKD)
Preeclampsia
Maternal death
Adverse pregnancy outcomes
Acute Kidney Injury in Pregnancy: The Need for Higher Awareness. A Pragmatic Review Focused on What Could Be Improved in the Prevention and Care of Pregnancy-Related AKI, in the Year Dedicated to Women and Kidney Diseases
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