The kidney in pregnancy: A journey of three decades

Renal manifestations of preeclampsia

Preeclampsia is a pregnancy-specific vascular endothelial disorder with varying degrees of multiple organ involvement, of which kidney bears the main crunch, being a highly vascular organ. In this section, spectra of kidney manifestations of preeclampsia are discussed, and they include: (i) hypertension, (ii) proteinuria, (iii) acute kidney injury (AKI), and (iv) postpartum recovery.

Sepsis-associated AKI

Sepsis is frequently associated with hypotension, inflammation, DIC, HUS, and AKI. Most cases of sepsis occur during late pregnancy and the postpartum period. Early recognition and treatment of sepsis-associated PR-AKI may prevent complications. In an European study about 1% of all pregnant women required ICU admission, and 4% of them had severe sepsis or septic shock.[48] The most common infection was chorioamnionitis (40%) and endomyometritis (20%).[48] The common infections causing sepsis in pregnancy in developing countries are septic abortion, pyelonephritis, and postpartum fever.[4549] Puerperal sepsis is the most common cause of PR-AKI in our country.[434950] Septic abortion-related AKI has decreased in recent years. In the Chandigarh study, ARF due to septic abortion, which constituted 13.7% of total ARF during 1965–1974, had declined to 3.5% by 1981–1986. Post-abortal ARF decreased to 7% in 1992–2002 from 9% in 1982–1991 of total ARF cases.[39] However, despite declining trends in post-abortal ARF, it is still high in some parts of the country. The social stigma attached to abortion is probably the main cause of high incidence of septic abortions in our society. Despite legalization of abortion law, a good number of pregnant women seek abortion from untrained and unlicensed abortionists under unhygienic conditions.[47] Prevention of unwanted pregnancy and avoidance of septic abortion are key to eliminate abortion-associated ARF in early pregnancy. In addition, sepsis also accounts for the majority of maternal mortality in PR-ARF in developing countries.[4950]

Severe preeclampsia/HELLP syndrome

Severe preeclampsia and the HELLP syndrome account for about 40% of cases of AKI in pregnancy.[19] Preeclampsia/eclampsia/HELLP syndrome was the most common (38.3%) cause of ARF in late pregnancy in our study.[49] Acute renal failure occurs in approximately 1% of women with severe preeclampsia and 3–15% of women with HELLP syndrome; and renal failure can occur either antepartum or in early postpartum period.[22–25] The HELLP syndrome almost always occurs in the setting of preeclampsia, and is considered to be a form of severe preeclampsia. The characteristic features of HELLP syndrome include hemolysis (schistocytes on peripheral smear, anemia, increased LDH, and decreased haptoglobin), elevated liver enzymes, and low platelet count. The platelet count is a marker of the severity of disease and coincides with liver impairment.[20] Thrombocytopenia is often the first sign of HELLP syndrome; hence any patient with a significant drop in platelet count during the antenatal period should be suspected of the disease. When HELLP syndrome is complicated by AKI, the risk of perinatal death is higher (26%) and increases with the severity of the renal injury.[23] AKI most often develops in the setting of severe complications (placental abruption, DIC, postpartum bleeding or fetal death) and the likelihood of renal failure increase with the severity of HELLP syndrome.[82021] The exact prevalence of AKI in patients with HELLP syndrome is not well known. However, a large study estimated that AKI complicates 3% of severe HELLP syndrome.[51]

About 30-50% of patients with HELLP syndrome and AKI require dialysis.[2139] Renal function typically improves following delivery. Persistent renal dysfunction and/or need for long-term dialysis is unusual, but can occur in women with preexisting hypertension or CKD.[3940] Acute tubular necrosis is a nearly universal pathological lesion in patients with HELLP syndrome-associated AKI.[52–54] However, occasionally, RCN has been reported.[424955] Maternal mortality in AKI complicating HELLP syndrome was high (13%) in studies performed in the 1980s;[21] more recent reports suggest a much lower incidence.[2356]

Pregnancy-associated TTP/HUS

TTP and HUS are rare during pregnancy and postpartum period. HUS/TTP is characterized by thrombocytopenia, hemolysis, and variable organ dysfunction, which can include neurological changes and ARF.[57] Patients are believed to have TTP when neurological symptoms dominate and HUS when renal failure is the dominant presenting feature. TTP usually present prior to 24 weeks and HUS typically occurs near term or postpartum. However, pregnancy-associated TTP can occur in third trimester or during the postpartum period as well.[5859] TTP can develop de novo in pregnancy, or pregnancy can precipitate relapse in women with history of TTP.[60] Patients with congenital or familial TTP frequently have their first episode during pregnancy. Increasing concentration of procoagulant (factor VIIa, factor VIII, von Willebrand factor, and fibrinogen) factors, decreased fibrinolytic activity, and deficiency of von Willebrand factor-cleaving protease (ADAMTS 13) may contribute to development of TTP/HUS in susceptible individuals. In pregnancy-associated TTP, the deficiency of ADAMTS13 can be quite severe, with about 20% of women having ADAMTS13 levels less than 5%.[61]

Patients with TTP typically present with non-specific symptoms including easy bruisability, fatigue, nausea, vomiting, and abdominal pain. Neurological manifestations are common (50–80%) and range from mild symptoms, such as lethargy, confusion, and headache, to serious manifestations such as fluctuating focal deficits and seizure.[58] ARF has been reported in 30–80% of women with pregnancy-associated TTP in various case series.[62–64] Although recovery of renal function is typical, persistent renal dysfunction, including need for chronic dialysis or kidney transplantation, is not uncommon.[64] Proteinuria and hematuria are present in the majority of patients with TTP.[65]

The widespread use of plasma exchange for TTP has decreased maternal mortality from 90% to 10%.[66] Antiplatelet agents such as low-dose aspirin or dipyridamole and low-molecular-weight heparin have been used, alone or in combination with glucocorticoids, but none have gained widespread support.[6364] In patients with a prior known history of TTP, serial monitoring of ADAMTS13 levels during pregnancy, with prophylactic plasma exchange and antiplatelet agents if levels are deficient, has been shown to result in good obstetric outcome.[66] For patients who are refractory to these treatments, second-line treatments, including vincristine, rituximab, and splenectomy, have been described during pregnancy, with favorable outcomes.[67] Women who develop TTP/HUS should be aware of the risk of relapse in subsequent pregnancies.[58]

Acute fatty liver of pregnancy

It affects women in the third trimester of pregnancy and is characterized by sudden-onset acute liver failure with coagulopathy. AFLP is estimated to affect between 1/7000 and 1/20,000 pregnancies.[6869] Early diagnosis and immediate delivery are essential for maternal and fetal survival. Maternal and fetal mortality rates were as high as 85% in pregnancies complicated by AFLP in earlier reports.[70] However, recent case series report much lower maternal mortality (0–12.5%).[7172] This improvement in outcome is attributed to earlier diagnosis, intensive obstetric monitoring, and safe emergent delivery of the fetus. Hence, fetal and perinatal mortality rates have also improved, ranging from 6.6% to 15%.[697172]

AFLP characteristically begins in the third trimester with a prodromal phase of nonspecific symptoms including fever, malaise, anorexia, myalgia, nausea, vomiting, and epigastric pain. The severity of liver involvement is variable, ranging from moderate isolated transaminitis to fulminant hepatic failure.[7374] Coagulopathy is a key feature of AFLP, with low fibrinogen level, prolonged prothrombin time, depressed antithrombin III levels, and thrombocytopenia. The other laboratory abnormalities include hyperbilirubinemia, increased transaminases, hypoglycemia, and leukocytosis. AFLP is a diagnosis of exclusion, once viral hepatitis and biliary obstruction have been excluded. The absence of hypertension supports viral hepatitis rather than AFLP.[75] AKI is seen in 20-100% of cases.[72–74] AKI in AFLP is usually nonoliguric.[7374] Proteinuria and peripheral edema are common, as up to 50% have concomitant preeclampsia.[7172]

Early diagnosis, supportive care, and prompt delivery are critical in the management of AFLP. Transfusion of blood products is often needed to correct anemia and coagulopathy. Hepatic encephalopathy is treated with a high-carbohydrate, low-protein diet and oral lactulose. Continuous infusions of 10% dextrose are frequently needed to manage hypoglycemia.[7172] Since most cases resolve spontaneously after delivery, liver transplantation is rarely needed.[7677] Recurrence of AFLP in subsequent pregnancies is rare, with only four cases reported in the literature.[7879]

Diagnosis of AFLP from HELLP syndrome

Distinguishing AFLP from HELLP syndrome can be challenging as up to 50% of women with AFLP have concomitant preeclampsia. The two disorders share many pathophysiological and clinical features. In particular, fetal deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase is a predisposing factor in both conditions, suggesting a common pathophysiological pathway.[80] Even liver biopsy can be non-diagnostic, because findings on liver pathology in HELLP syndrome can include fatty infiltration of the liver, which is the hallmark of AFLP.[8182] The clinical distinction between AFLP and HELLP is arguably academic, since appropriate treatment of both conditions is prompt delivery of the Fetus. Clinical clues to distinguish AFLP vs HELLP syndrome are:

1. AFLP is frequently complicated by coagulopathy and hypoglycemia (key features of AFLP).

2. Thrombocytopenia is moderate to severe in HELLP syndrome, whereas it is mild or absent in AFLP.[72]

Distinguishing TTP from HELLP syndrome

There is substantial clinical and pathological overlap between TTP and preeclampsia/HELLP syndrome, as both have microangiopathic hemolytic anemia and thrombocytopenia [Table 4]. Approximately 20% of women with pregnancy-associated TTP may have concurrent preeclampsia/HELLP syndrome.[58] In addition, maternal mortality in patients with concomitant TTP and preeclampsia/HELLP is very high (44.4%).[58] The following are the clues for the diagnosis of pregnancy-associated TTP:

1. The absence of coagulation abnormalities such as elevated antithrombin, elevated D-dimer, and high fibrinogen levels are suggestive of TTP.

2. Low or undetectable ADAMTS13 level is not helpful for treatment decisions, as levels can be normal in TTP and can be low in HELLP syndrome, without evidence of TTP.[83]