Several hormones and multiple mechanisms have been implicated in the aforementioned changes. Early on, luteal phase progesterone may play a role in increasing the RPF and GFR, and this role may continue during pregnancy . Increased renin is produced by extra-renal sources, namely, the ovaries and decidua, angiotensinogen production by the liver increases under the influence of estrogen, and aldosterone levels are higher during normal pregnancy [5,6]. Vasodilation, however, takes place during pregnancy despite the revved up rennin–angiotensin–aldosterone system (RAAS) due to several factors. Progesterone and vascular endothelial growth factor (VEGF)-mediated prostacyclins increase refractoriness to angiotensin II . In addition, angiotensin II type I (AT1) receptors are less responsive during normal pregnancy as they exist in a monomeric state .
Relaxin, produced by the corpus luteum, decidua and placenta, increases RPF, GFR and solute clearance by afferent and efferent vasodilation in rats [25,26]. This is mediated through upregulation of nitric oxide-dependent vasodilation . In human studies, however, inconsistencies were noted. Relaxin increased RPF but not GFR in healthy volunteers . Moreover, in a recent study comparing relaxin levels between women with pre-eclampsia and normal pregnancies, no difference in relaxin levels was found between the two groups, and no clear correlation was found between relaxin levels and GFR, mean arterial pressure, RPF or renal vascular resistance in late pregnancy .
Sodium retention and volume expansion are, at least in part, mediated by the increased RAAS activity. Some of the stimulus for this increased activity could primarily be because of systemic vasodilation, leading to a relatively lower volume and pressure state [5–7]. This leads to retention of about 900 to 1000 mEq of sodium and about 6–8 l increased total body water, of which 4–6 l is located in the extracellular compartment [30,31].
It is helpful to use the classic approach categorizing causes of reduced kidney function into prerenal, intrinsic renal and postrenal causes. Causes incriminated in nonpregnant states should be considered. However, certain causes are either unique to or more common during pregnancy. Table 1 lists the differential diagnosis of renal dysfunction in pregnancy based on physiology and timing.
Fluid losses secondary to excessive vomiting, as in hyperemesis gravidarum, or blood loss from pregnancy-related complications such as antenatal bleeding, can cause prerenal dysfunction. Bilateral hydronephrosis, albeit rare, is a possible cause of postrenal dysfunction. Acute cortical necrosis can result from several obstetric complications including septic abortion or abruptio placentae. Intrinsic renal disease specific to pregnancy is seen with pre-eclampsia, eclampsia and the syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP). Many other forms of thrombotic microangiopathies (see below), can be triggered or contributed to by pregnancy. The remainder of this review focuses on pre-eclampsia and other thrombotic microangiopathies.
Histologically, there is glomerular endothelial cell swelling and detachment, subendothelial fibrinoid deposits, occlusion of glomerular capillaries, reduced density and size of endothelial fenestrae, and thickening of the glomerular basement membrane [36,38]. These changes, typical of thrombotic microangiopathy, impair the glomerular capillary hydraulic permeability and reduce filtration surface area, resulting in a diminished GFR. Despite hypertension and increased renal vascular resistance, no difference was found in RPF between women with pre-eclampsia and normal pregnancy, or in afferent oncotic pressure (πA) in one study. However, πGC was slightly lower than in pregnant controls owing to the increased filtration fraction in the latter group  (see Fig. 2).
Imbalances between angiogenic and antiangiogenic factors have been implicated in the pathogenesis of pre-eclampsia [62–64]. Increased levels of soluble Fms-like tyrosine kinase-1 (sFlt1, the soluble form of VEGF receptor 1) and soluble endoglin (sEng), both secreted by the placenta, reduce the levels of free VEGF, placental growth factor (PlGF) and other factors, contributing to endothelial dysfunction, reduced vasodilatation and proteinuria [64–66].
Links between these angiogenic factors and RAAS were suggested by several studies. Higher urinary sFlt1 and total VEGF levels were noted in diabetic patients with proteinuria. These correlated positively with the level of angiotensin II, and were nicely blocked by losartan . AT1 autoantibodies and angiotensin II activated AT1 receptor induced sFlt production in vitro . This relationship, however, did not hold true in a rat model with increased renin and AT1-agonistic autoantibody (AA), wherein there was no increase in sFlt levels . In addition, no correlation was found between AT1-AAs and sFlt in some human studies [70,71], except for one human study, wherein the level of AT1-AA correlated with the severity of the disease and with sFlt levels .
Advances have been made in using the levels of angiogenic factors to predict development of pre-eclampsia or its severity, and to help differentiate pre-eclampsia from other forms of hypertension or chronic kidney disease (CKD). Development of automated methods to measure these markers, and standardization for use in clinical practice is under way [73▪▪].
Small vessel thrombosis is followed variably by platelet consumption with or without a consumptive coagulopathy, hemolysis of red blood cells, endothelial damage and end-organ damage. Renal involvement is more common in HUS, CNS involvement in TTP and liver involvement in HELLP syndrome. Beyond thrombosis, histological findings in the kidney include endothelial cell swelling, protein deposits in the subendothelial layer and double contouring of the basement membrane .
HUS is caused by excessive complement activation. In its typical form, this can be triggered by verotoxin. In the atypical form (a-HUS), an acquired or inherited imbalance between factors involved in activation and regulation of the complement system can be identified in most cases. Factors H, I and membrane cofactor protein are the main inhibitors of the complement alternative system. Lack of suppression of these inhibitory factors secondary to inactivating mutations in their respective genes [77,78▪], or secondary to acquired factor H antibodies , can result in excessive complement activation. Complement activation can alternatively result from activating mutations in factor B or C3 coding genes [79,80]. Resultant excessive activation of C3 convertase leads to endothelial damage .
TTP on the other hand can be secondary to low levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member-13 (ADAMTS-13), which can be due to acquired inhibitory antibodies or to constitutional deficiency. ADAMTS-13 cleaves multimers of von Willibrand factor (vWF), reducing the ability of clots to form. Deficiency in ADAMTS-13 thus results in increased clotting activity and platelet consumption, leading to TTP [24,82].
Not all cases of HUS or TTP are clearly secondary to the abnormalities described above. However, identification of these factors in an individual patient has important implications for the management. ADAMTS-13 deficiency has better outcomes after plasmapheresis to remove inhibitory antibodies. There may also be a role for using rituximab in these cases [83,84]. Plasmapheresis is also used in complement-mediated a-HUS. Eculizumab, a monoclonal humanized antibody, blocks the common terminal complement activation, and is an effective treatment for a-HUS [85▪,86▪▪,87,88].
Papers of particular interest, published within the annual period of review, have been highlighted as:
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This is a nice review of findings over the past decade, laying out changes over the course of pregnancy.
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73▪▪. Polsani S, Phipps E, Jim B. Emerging new biomarkers of preeclampsia. Adv Chronic Kidney Dis 2013; 20:271–279.
Nice review of potential markers and findings regarding their relevance to diagnosis and prognosis.
74. Dragon-Durey MA, Blanc C, Garnier A, et al. Antifactor H autoantibody-associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS. Semin Thromb Hemost 2010; 36:633–640.
75. Vesely SK, George JN, Lämmle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003; 102:60–68.
76. Noris M, Remuzzi G. Thrombotic microangiopathy
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77. Le Quintrec M, Roumenina L, Noris M, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome associated with mutations in complement regulator genes. Semin Thromb Hemost 2010; 36:641–652.
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Demonstrates specific abnomalities in a-HUS that are helpful in diagnosis and determining monitoring and therapy. Provides review of the contribution of the complement system.
79. Fakhouri F, Jablonski M, Lepercq J, et al. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood 2008; 112:4542–4545.
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83. Fakhouri F, Vernant JP, Veyradier A, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005; 106:1932–1937.
84. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011; 118:1746–1753.
85▪. Ardissino G, Wally Ossola M, Maria Baffero G, et al. Eculizumab for atypical hemolytic uremic syndrome in pregnancy
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Helpful case report regarding the potential of new therapies to impact the outcome of complicated pregnancy.
86▪▪. Fakhouri F, Vercel C, Frémeaux-Bacchi V. Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy
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An important review of where things stand for differentiating diseases in pregnancy and better grasping pathogenesis.
87. Köse O, Zimmerhackl LB, Jungraithmayr T, et al. New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost 2010; 36:669–672.
88. Schmidtko J, Peine S, El-Housseini Y, et al. Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis 2013; 61:289–299.