ATN is the most common finding for persistent AKI in peurpepant patients with severe hemorrhage[11]. However, TMA is rarely described in renal pathological investigations. The pathogenesis of TMA is not very clear, which might result from endothelial injury in the microcirculation, with activation of the complement and coagulation systems. However, TMAs could also be triggered by non-pregnancy related conditions such as thrombotic thrombocytopenic purpura (TTP), as well as pregnancy-related conditions, such as preeclampsia with severe features or eclampsia with HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome[12–14]. TMA is associated with adverse maternal and fetal outcomes due to the development of ESRD and ultimately leading to increased maternal mortality[15, 16]. Three puerperant patients were recruited in this study with severe hemorrhage and AKI, and following renal histopathology, TMA was found to coexist with ATN. Preeclampsia/eclampsia or HELLP syndrome were ruled out in these three postpartum women with TMA, which was rarely reported in the past. We speculated that the occurrence of TMA may have be related to severe postpartum hemorrhage, and thus we summarized the cases in our center and reviewed the literature.
It is generally considered that ATN should be the pathogenesis of AKI in severe hemorrhage puerperant women, especially when the impairment in renal perfusion is either severe or prolonged in duration. The clinical course was the typical oliguria/anuria stage and followed by polyuria stage, and generally had a good renal outcome. This implies that when the renal function has not improved, other factors should be considered[17]. Although TMA induced by severe postpartum hemorrhage is rarely reported, once it happens, it indicates that the condition is critical and the prognosis is poor. As poor outcome was also demonstrated in our study as none of the patients had recovered normal kidney function at the last follow-up, with two-thirds of the patients requiring a hysterectomy. The mechanism of TMA caused by severe postpartum hemorrhage is still not fully understood. However, based on the three cases evaluated at our hospital, we deduce that the following pathological mechanism is involved: Initially, uterine contraction dysfunction leads to severe postpartum hemorrhage[18, 19]. This is followed by insufficient circulating blood volume which in turn leads to renal hypoperfusion and epithelial cell injury[7, 20–22] as was demonstrated by the intimal mucoid swelling and thickening of the vascular wall in interlobular arteries identified during renal pathology. As a result of the severe postpartum hemorrhage, the patients required the transfusion of a large amount of red blood cells, plasma, and resuscitation fluid. This could potentially have caused an ischemia-reperfusion injury in renal epithelial cells[23, 24], further promoting the alternative complement pathway activation, and the amplification of the complement-mediated injury[25, 26]. The dysregulation of the alternative complement pathway may induce TMA[27]. Ischemia-reperfusion injury is also one of the known causes of TMA after kidney transplantat[25, 28]. The intravascular stenosis caused by TMA reduced the glomerular perfusion and filtration rate eventually leading to downstream tubular ischemia, ATN, and ultimately lead to renal failure. Hypoperfusion, epithelial cell injury, and complement activation might lead to a vicious circle, which leads to TMA in severe postpartum hemorrhage.
TMAs include several conditions, like TTP and hemolytic uremic syndrome (HUS), which are characterized by the formation of fibrin and platelet microthrombi in small vessels in multiple organ systems leading to organ damage. Although these syndromes have very similar pathological and clinical features, they have distinct etiologies and pathogenesis. TTP is a rare, life-threatening TMA characterized by a severe deficiency in ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13)[29]. Pregnancy is a known trigger of TTP[1–3, 30–32]. However, TTP was excluded by normal ADAMTS13 in these three patients[33], and complement-mediated thrombotic microangiopathy (C-TMA) also known as atypical hemolytic–uremic syndrome was considered. Pregnancy-associated aHUS has been considered as a prototypic secondary HUS[34]. aHUS is characterized by excessive unregulated activation of the alternative complement pathway (ACP) likely due to genetic mutations in complement regulatory proteins[13], the most common being complement factors H (CFH), and complement factors I (CFI). Other factors include C3, membrane cofactor protein (MCP), a combination of the above, as well as novel and rare variants[13, 35, 36]. Plasma exchange (PE) can be only temporarily or partially effective in the majority of cases of aHUS, with no recovery of renal function in up to 80% of cases[13]. Definitive treatment, instead, is with the administration of eculizumab, an anti-C5 antibody that inhibits C5 cleavage and prevents the generation of the membrane attack complex[37–40].
AKI in late pregnancy and postpartum may be associated with preeclampsia with or without HELLP syndrome, TTP, or HUS. It is difficult to distinguish these syndromes based on clinical features alone. The differential diagnosis between HELLP and pregnancy-associated atypical hemolytic uremic syndrome (p-ahus) is difficult due to the similar biochemical characteristics[41, 42]. The diagnostic criteria for aHUS were proposed in 2011, and the incidence is increased in pregnancy and postpartum[43]. Renal biopsy is rarely required to identify ATN due to postpartum hemorrhage, as the renal outcome for AKI with ATN is generally good, and also since chronic renal dysfunction was developed with aHUS[44–46]. At present, there are few studies on renal pathology of AKI complicated with postpartum hemorrhage. If AKI persists for a long time, renal biopsy may be required to confirm the diagnosis and determine the prognosis. In this study, a renal biopsy was performed in all three patients at the appropriate time, confirming the diagnosis of TMA which has important implications on providing the appropriate treatment and ultimately prognosis.
Renal biopsy was essential for identifying the etiology of AKI and to distinguish it from other pathological types of TMAs. Severe postpartum hemorrhage could induce a first shot phenomenon of tubular ischemia; since the renal tubular epithelium is very sensitive to hypoxia and procoagulant factors leading to ATN[38]. Patients with ATN alone exhibited complete recovery of renal function in general[44, 47]. The main lesion of AKI is ischemic acute tubular necrosis, which can explain the reversibility of acute renal injury in most patients. However, renal histological features on electron microscopy in the patients in our study revealed endothelial swelling, and typical TMA and ATN changes. Endothelium injury-induced thrombotic microangiopathy also induced tubular ischemia, sequentially aggravated by postpartum hemorrhage and ischemia-reperfusion. It is worth noting that some studies have shown that the occurrence of TMA with ATN might increase the severity of CKD [48, 49] as also demonstrated by the development CKD in our study. Since the renal prognosis of TMA combined with ATN induced by severe postpartum hemorrhage is relatively poor we recommend the use of early renal biopsy to confirm the disease and thus limit disease progression.
The mechanism of AKI induced by TMA caused by severe postpartum hemorrhage is very complicated, involving numerous factors. A better understanding of the potential key role for the complement system in the mechanism of TMA and HELLP might offer opportunities for early diagnosis, monitoring, and therapy. Apart from supportive care, other therapies including plasma exchange and eculizumab may also be used to treat this disease. The long-term renal outcomes of AKI and TMA caused by severe postpartum hemorrhage are still not clear.