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The Kidney in Normal Pregnancy and Preeclampsia
Editor's Comment : The Editors gratefully acknowledge the invaluable contributions of Marshall D. Lindheimer, recently retired, who served as Editor and coauthor of this chapter in the second–fourth editions. The revision of the chapter for the current edition (previously Chapter 16 in the fourth edition) includes the welcome addition of a new first author, Kate Wiles, a Nephrologist and Consultant in Obstetrics with expertise in the kidney during normal and pathologic pregnancy. A major goal of this revision in the fifth edition was to shorten those sections from the fourth edition dealing with physiology without undermining the take-home messages, in order to expand the discussion of clinical aspects, thereby offering a more balanced presentation—one that would be useful to both basic scientists and clinicians. To this end, the clinical implications of the basic science were greatly expanded, and a new section was added on the intersection of preeclampsia and chronic kidney disease (Superimposed Preeclampsia in Women with Kidney Disease). Another important goal, of course, was to update and revise accordingly the other parts of this chapter including the section on Renal Morphology in Normal Pregnancy and Preeclampsia. Much of the older (historical) literature was omitted so as to accommodate and emphasize more recent publications on the various topics. Our intention, however, was not to diminish the significance of this older , and not infrequently, seminal literature! Readers interested in learning more about the earlier research on the kidney in normal pregnancy and preeclampsia are referred to the fourth edition of this book, where it is extensively covered.
Introduction
Leon Chesley was among a special group of investigators who, between 1930 and 1960, pioneered the modern era of renal physiology. One of his earliest contributions was a formula for calculating urea clearance at low urine flow rates. Thus, it was only natural that Dr. Chesley's interest in normal and pathological pregnancies centered on the kidney. Indeed, his description of renal physiology and pathophysiology of pregnancy in the first edition of this book, which was authored solely by Dr. Chesley, was encyclopedic in scope. In an attempt to emulate Dr. Chesley's comprehensive approach, the current chapter in the fifth edition aims to provide a thorough understanding of the changes in maternal kidney physiology that occur during normal pregnancy including the profound renal vasodilation, which underpins the marked increases of renal blood flow and glomerular filtration. It further describes possible mechanisms for these hemodynamic changes in pregnancy including the potential role of several hormones and the molecular changes occurring within the arterial wall that mediate vasodilation. The chapter presents guidance on the clinical assessment of kidney function during pregnancy in the context of these physiological changes. It also examines changes in protein excretion, osmolality, and uric acid homeostasis in normal and preeclamptic pregnancies. The renal pathophysiology and histopathology of preeclampsia including indications and contraindications for renal biopsy in pregnancy are discussed. Finally, this chapter includes a new section, which examines the unique relationship between chronic kidney disease (CKD) and preeclampsia, exploring shared pathophysiological mechanisms and the complexities that arise from their overlapping clinical phenotypes. Emerging data on the interpretation of angiogenic markers in the context of kidney disease in pregnancy are also presented.
Renal Hemodynamics and Glomerular Filtration Rate During Normal Pregnancy
Decreased vascular resistance within nonreproductive organs is one of the earliest physiological adaptations in normal pregnancy leading to the marked decrease in total systemic vascular resistance. The kidneys contribute to this reduction in total systemic vascular resistance with a fall in renal vascular resistance, and as a consequence, there is a marked increase in renal blood flow and a concomitant rise in glomerular filtration with maximum changes being reached between the end of the first and middle of the second trimester.
Glomerular Filtration and Renal Plasma Flow
Glomerular filtration rate (GFR) can be accurately measured by the renal clearance of substances that are filtered, but otherwise not secreted, reabsorbed or metabolized by the kidney, e.g., inulin. Specifically, after intravenous administration of inulin and reaching a steady-state plasma concentration, the ratio of the urinary excretion and plasma concentration provides a measure of the renal clearance of inulin (C IN ), which is equal to GFR. In the same vein, the renal clearance of substances that, as a result of the combination of filtration and secretion, are virtually removed from the blood in one pass through the kidney, e.g., para-aminohippurate, provide an estimate of renal plasma flow or effective renal plasma flow (ERPF), which does not account for the ∼10% para-aminohippurate that escapes renal clearance. Thus, inulin and para-aminohippurate were used in detailed investigations of gestational kidney function as early as 1958. Several comprehensive studies are worthy of special note due to their superior methodologies that included:
- 1.
Longitudinal studies of the same woman including a nonpregnant assessment either preconception or postpartum.
- 2.
Constant infusion of inulin and para-aminohippurate to achieve steady-state plasma concentrations.
- 3.
Elimination of urinary dead space by water diuresis (or bladder irrigation that is no longer performed for research purposes), which is potentially increased with gestational changes in the urinary tract leading to inadequate collection of urine. ,
Data from these studies collated in Fig. 14.1 revealed a marked increase in both GFR and ERPF during the first half of pregnancy. Peak levels were as high as 40%–65% and 50%–85% above nonpregnant levels of GFR and ERPF, respectively.
An alternative method of measuring GFR utilizes the 24-hour renal clearance of endogenous creatinine (C CR ), which does not require an infusion, and therefore is a more convenient way to measure GFR. However, 24-hour urine collections are not always accurately performed, and although the renal clearance of creatinine is mainly achieved through glomerular filtration, tubular secretion contributes to a small degree, which can lead to an overestimation of GFR. Nevertheless, using the 24-h C CR , Davison and Noble provided evidence that GFR rises ∼25% by the second week postconception (4 weeks after the last menstrual period) showing that physiologic adaptations in the renal circulation during human pregnancy are among the earliest to occur ( Fig. 14.2 ).
Understanding of the changes in GFR over the last few weeks of pregnancy is largely derived from Davison and colleagues, who performed weekly 24-hour C CR measurements in 10 subjects. This study demonstrated that 24-hour C CR decreased and plasma creatinine increased over this period to levels not significantly different from nonpregnant values. Similarly, Davison and Hytten, who also examined GFR in 10 women, showed that the 24-hour C CR declined at 35–38 gestational weeks to 130 mL/min from a pregnancy peak of 150 mL/min, compared to a prepregnancy C CR of 100 mL/min. The decline in GFR during late pregnancy reported in these studies was not observed when GFR was measured by constant infusion of inulin or creatinine suggesting that intrinsic renal function was preserved. This discrepancy likely arose, at least in part, from the artificial posture often used in the constant infusion technique, i.e., left lateral decubitus or sitting position, which eliminated the postural changes that women typically undergo during the course of normal daily activities including standing and lying supine both of which can compromise cardiac output and renal perfusion due to postural hypotension and impairment of venous return by the enlarged uterus at this late gestational stage. In one sense, therefore, 24-h C CR rather than C IN may be a more physiologic reflection of renal function toward the end of gestation, which can be affected by factors extrinsic to the kidney.
In 2019, a systematic review and meta-analysis of 29 studies substantiated the increase of GFR in pregnancy measured by both C IN and 24-h C CR . This data synthesis included a total of 1037 healthy pregnancy measurements of GFR compared to 642 nonpregnant or postpartum values and demonstrated an increase in GFR throughout pregnancy, with a fall in the third trimester toward nonpregnancy values. On average, C IN increased by 41 mL/min (38%), 48 mL/min (47%), 45 mL/min (40%), 40 mL/min (36%), and 54 mL/min (56%), while C CR increased by 22 mL/min (24%), 37 mL/min (38%), 29 mL/min (27%), 16 mL/min (15%), and −9 mL/min (−8%) at <14, 15–21, 22–28, 29–35, and 36–41 weeks' gestation respectively ( Fig. 14.3 ).
Although potential explanations for the discrepancy between C IN and 24-h C CR during late pregnancy were described above, the reasons for the difference in magnitude between the elevations of C IN and 24-h C CR in early pregnancy relative to the postpartum period are not entirely clear ( Fig. 14.3 ). Although the gravid uterus should not impede venous return in early pregnancy, postural changes including standing and stressful daily activities leading to elevated sympathetic outflow could have an outsized influence during pregnancy, thereby dampening the gestational rise in the 24-hour C CR. As mentioned previously, a major difference between the renal handling of inulin and creatinine is that, in addition to filtration, creatinine also undergoes active secretion into the proximal tubule from the peritubular capillaries. Whether this secretory component of creatinine may in some way contribute to the lower gestational rise in 24-h C CR during early pregnancy relative to C IN is unclear. Historically, quantification of creatinine used a Jaffe method, which is potentially subject to interference by endogenous and exogenous substances that can undermine analytical specificity. Serum creatinine concentration can also be subject to non-GFR determinants including muscle mass and dietary intake, and most gestational creatinine clearance research predates a recommendation for isotope dilution-mass spectrometry-traceable creatinine assay methods. Although C IN is considered to be the “gold standard,” accuracy of C IN may have been affected by the concurrent intravenous administration of solutions such as saline, which could augment GFR as a consequence of volume expansion. Reassuringly, however, when the 24-hour C CR has been compared to C IN or C Cr in the same pregnant woman using the constant infusion technique, GFR was comparable up until the last few weeks before delivery (vide supra). , , Methodology aside, the overall message of an increase in GFR beginning during early gestation, with a variable decline in the third trimester toward nonpregnancy values, is consistent.
For decades, the predominant endogenous biomarker of kidney function has been serum creatinine. An emerging alternative endogenous biomarker is cystatin C, with the advantage over serum creatinine that it is less influenced by muscle mass and dietary protein intake. Estimation of GFR utilizing a combination of serum creatinine and cystatin C has been shown to be more accurate than calculations based on either marker alone with increasing validation and utilization in the prediction of long-term kidney outcomes. In pregnancy, the placenta produces cystatin C, but does not contribute to circulating levels, insofar as no significant plasma concentration gradient between uterine and antecubital veins was detected. However, serum concentrations of maternal cystatin C fail to correlate with other measures of GFR in pregnancy including iohexol clearance and serum creatinine, leading to the hypothesis that an increase in glomerular negative charge reduces the filtration, and hence excretion of anionic cystatin C in pregnancy. Utility of cystatin C in the measurement of GFR during pregnancy has therefore not been demonstrated.
Mechanisms
The gestational fall in renal vascular resistance facilitates the increase of blood flow to the kidney and consequently, the rise of GFR in pregnancy. This section of the chapter examines the potential mechanisms underlying these hemodynamic renal adaptations to pregnancy including hormonal changes, tubuloglomerular feedback, endothelial changes, and renal nerve activity. Because of ethical considerations and feasibility, many of the studies have employed animal models including the pseudopregnant rat model in which a female rat is mated with a vasectomized male. Pseudopregnancy physiologically mimics the first half of gestation in rats, including increases in ERPF and GFR, but lacks fetoplacental development. , Potential mediators of the hemodynamic changes of the kidney in pregnancy are hypothesized to include the hormones progesterone and relaxin, vascular angiogenic and placental growth factors, as well as vascular matrix metalloproteinases, the endothelin-B (ET B ) receptor, and nitric oxide. A multifactorial pathway including these elements is presented below.
Pregnancy Hormones
Davison and Noble demonstrated that the 24-hour C CR increased by 20% in the luteal phase of the menstrual cycle ( Fig. 16.2 ). This finding was corroborated by other investigators using 24-h C CR , , chromium 51-EDTA clearance, , and C IN . , ERPF was also found to be increased during the luteal phase. , This means that the renal hemodynamic and GFR changes of pregnancy are mirrored, albeit to a lesser degree, in the luteal phase of the menstrual cycle. It can therefore be hypothesized that hormone concentrations, which increase similarly in the luteal phase and early pregnancy, contribute to the gestational changes in renal hemodynamics and GFR.
Estrogen and Progesterone
Based on studies involving both acute and chronic administration of estrogen to humans and laboratory animals, estrogen appears to have little or no influence on ERPF or GFR, although it increases blood flow to other nonreproductive and reproductive organs. (To our knowledge, whether vasodilatory estrogen metabolites might contribute has not been tested). In contrast, intramuscular administration of progesterone to nonpregnant women was shown to increase GFR by ∼15%, , leading to the hypothesis that prolonged administration to achieve the circulating concentrations of progesterone in pregnancy might mimic the 40%–65% gestational increase in GFR that occurs. A comparable increase in GFR of ∼26% was demonstrated in a rat model given subcutaneous progesterone. Changes in ERPF (without a change in GFR) were also demonstrated following progesterone administration to men. However, high circulating concentrations of progesterone are not reached in pregnancy until after the gestational peak in GFR, so other factors likely contribute. Nevertheless, progesterone or its metabolites may contribute to the rise of GFR during early pregnancy, as well as the gestational increase of GFR in the second half of gestation, when circulating concentrations of progesterone are high.
Prolactin and Placental Lactogen
Increase in circulating concentrations of prolactin in both pseudopregnant and pregnant rats coincided with gestational increases in ERPF and GFR, though there is little experimental evidence that prolactin itself modifies renal hemodynamics and GFR. Chronic administration of prolactin in female rats increased GFR and single nephron GFR, but only in those animals that became pseudopregnant. , In contrast, Baylis and colleagues did not observe increases in either whole kidney or single nephron GFR or ERPF in ovine prolactin-induced pseudopregnancy in rats. While Conrad and coworkers documented rises of both GFR and ERPF in male rats made hyperprolactinemic by implanting anterior pituitaries obtained from sibling donors under the renal capsule; unfortunately, this model also leads to hypercortisolemia. In the same vein, placental lactogen, which activates the same receptor as prolactin, has not been not well studied, but was actually found to decrease renal blood flow when administered acutely in the renal artery of anesthetized pigs.
Relaxin
Circulating relaxin originates from the corpus luteum and was hypothesized to be important in the renal hemodynamic adaptation to pregnancy based on a number of observations. Firstly, increased concentrations are measurable in the luteal phase with a rapid rise after conception, in part under the influence of human chorionic gonadotrophin (hCG), both occurring at the same time as measurable increments in GFR and RPF. , , Secondly, in the gravid rat model, there is marked increase in kidney function between gestational days 8 and 12, corresponding to the rise in ovarian and plasma relaxin concentrations. , , In the nonpregnant rat model or Langendorff heart preparation, vascular changes are demonstrable with relaxin administration leading to a reduction in the vasoconstrictor responses of the mesenteric circulation in hypertensive animals , and an increase coronary blood flow (Langendorff heart preparation) and reduction of platelet aggregation via nitric oxide and guanosine 3′,5′-cyclic monophosphate. , Finally, in women who conceived following in vitro fertilization (IVF) using artificial cycles, the gestational increase in GFR and decrease in serum creatinine were significantly attenuated. , Because these women lacked a corpus luteum, serum relaxin was undetectable. Thus, circulating relaxin may have a role in the renal hemodynamic responses to pregnancy. However, more definitive studies are needed of renal clearances of inulin and para-aminohippurate in women conceiving by IVF using artificial cycles, in which the corpus luteum does not develop and serum relaxin is undetectable.
Long-term administration of purified porcine or recombinant human relaxin (rhRLX) to nonpregnant intact and ovariectomized rats, as well as male rats increased both ERPF and GFR to the same peak levels as observed during pregnancy. , Long-term relaxin administration also blunted the renal vasoconstrictor response to angiotensin II infusion, thereby mimicking rat gestation. Inhibition of small renal artery myogenic constriction in relaxin-treated, nonpregnant rats was comparable to that seen in arteries harvested from midterm pregnant animals. , Even short-term (1–4h) administration of rhRLX to rats produced renal vasodilatation and hyperfiltration. Ovariectomy (removal of the corpus luteum and relaxin production while maintaining pregnancy with exogenous sex steroids) and relaxin-neutralizing antibodies each prevented gestational hyperfiltration, renal vasodilatation, as well as inhibited myogenic constriction and physiological osmoregulatory adaptations to pregnancy. Finally, the gestational fall in systemic vascular resistance and rise in cardiac output were also inhibited by relaxin neutralizing antibodies administered to midterm pregnant rats.
Small cohort studies have attempted to the elucidate the pharmacology of relaxin in human subjects. In one study, 5 h intravenous infusion of rhRLX in nonpregnant female and male healthy volunteers to reach plasma concentrations comparable to those observed in the first trimester was associated with a ∼50% increase in ERPF and surprisingly without any change in GFR. In another study of patients with chronic heart failure, short-term (6–24 h) intravenous rhRLX administration increased RPF by 29%–60%, again without a simultaneous increase in GFR. Differential responses of the afferent and efferent arterioles to rhRLX were one explanation hypothesized to account for the discrepant responses of ERFP and GFR to short-term infusion of rhRLX in these human investigations. Indeed, using the technique of renal micropuncture in which glomerular hydrostatic pressure can be measured, Deng and colleagues demonstrated a greater reduction in efferent than afferent resistances, as well as a fall in glomerular hydrostatic pressure after both acute and chronic administration of relaxin to nonpregnant rats. In contrast, long-term (28 weeks) use of rhRLX in nonpregnant patients with scleroderma was associated with significant increase in the predicted creatinine clearance by 10%–15%, suggesting an increase in GFR.
Molecular Mechanisms
Prostaglandins (PGs)
Experimental data from gravid animal models and humans suggested that vasodilatory PGs play minimal or no role in the rise of ERPF and GFR in pregnancy. Gestational increases in ERPF and/or GFR were unaffected by administration of PG synthesis inhibitors to gravid rats and rabbits. , , Furthermore, vasodilatory PG synthesis in renal tissues was similar in pregnant and nonpregnant animals. , Intravenous infusion of prostacyclin to male volunteers failed to alter ERPF or GFR, though parenteral administration may not mimic the actions of locally produced (autacoid functioning) prostanoids. Finally, the cyclooxygenase inhibitor indomethacin increased total peripheral vascular resistance by only 5% in pregnant women without significantly affecting either mean arterial pressure or cardiac output, a proportional difference, which does not compare to the large (∼40%) decrease in total peripheral resistance characteristic of pregnancy. Similarly, another cyclooxygenase inhibitor, meclofenamate, did not significantly augment peripheral vascular resistance in gravid guinea pigs.
Nitric Oxide (NO)
Quantification of nitric oxide metabolites, nitrite + nitrate (NOx), and a downstream second messenger, guanosine 3′,5-cyclic monophosphate (GMP), highlighted a potential physiological role for nitric oxide (NO) in the renal adaptation to pregnancy. Increases in the plasma concentration, urinary excretion, and metabolic production of GMP were observed throughout pregnancy and pseudopregnancy in rats, , , with similar elevations in urinary excretion and plasma concentration described for human gestation. Plasma concentrations of NOx were increased during pregnancy, and NO-hemoglobin was detected in red blood cells from pregnant, but not from nonpregnant rats, by electron paramagnetic resonance spectroscopy. The 24-hour urinary excretion of nitrite and NOx increased during pregnancy and pseudopregnancy in rats consuming a low-NOx diet, in parallel with a rise in urinary GMP excretion. This gestational rise in urinary NOx excretion was prevented by administration of the NO synthase inhibitor nitro- l -arginine methyl ester ( l -NAME), implicating NO as the source. Plasma concentrations and urinary excretion of NOx were also reported to be increased in gravid ewes. Despite these convincing metabolite data, it cannot be inferred that these gestational changes in NO are endothelial in origin and function. Increased expression of renal endothelial nitric oxide synthase has not been demonstrated in gravid rats. In addition, though the urinary excretion of cGMP and NOx metabolites is augmented during pregnancy, similar findings are not apparent in relaxin-treated nonpregnant rats, despite comparable renal hemodynamic changes. , Finally, in gravid women subjected to a low-NOx diet, neither plasma concentration nor urinary excretion of NOx was increased despite elevations in both plasma concentration and urinary excretion of cGMP.
Functional studies, however, are supportive of a role for NO. Administration of l -arginine analog inhibitors of NO synthase to midterm pregnant rats at the peak of their gestational vasodilatory increased, produced renal hemodynamics and vascular resistance comparable to nonpregnant rats. , Compared to virgin control animals, midterm pregnant rats had a more marked response to acute NO synthase inhibition, manifesting a larger decrease in GFR and ERPF, and a greater rise in effective renal vascular resistance. Interestingly, PGs may play a compensatory role in the setting of chronic NO synthase blockade by maintaining gestational renal vasodilation and hyperfiltration relative to nonpregnant control rats. , , (But not all agree. ) In addition, the attenuation of myogenic constriction of small renal arteries isolated from midterm pregnant compared to virgin rats was reversed with the addition of NO synthase inhibitors.
Endothelin (ET)
Endothelin (ET) acts as a potent vasoconstrictor by interacting with vascular smooth muscle ET A and ET B receptor subtypes. However, when acting via the endothelial ET B receptor subtype, it has vasodilatory activity via an increase in cytosolic calcium in endothelial cells, stimulating prostacyclin, NO, and possibly other relaxing factors. The endothelial ET B receptor subtype is hypothesized to maintain the signature low vascular tone of the kidney in the nonpregnant condition, with blockade of the ET B receptor subtype leading to renal vasoconstriction. , Use of an endothelial ET B (but not ET A ) receptor antagonist in pregnant rats was found to abolish both renal vasodilatation in gravid rats and renal vasodilation mediated by relaxin administration in nonpregnant rats. , A critical role for the endothelial ET B receptor subtype in mediating inhibited myogenic constriction of small renal arteries was also demonstrated for pregnant and relaxin-treated nonpregnant rats. , ,
Combined Pathway: Relaxin, Matrix Metalloproteinases (MMPs), Endothelin, and Nitric Oxide
A unifying hypothesis proposed by Jeyabalan and colleagues is that relaxin acts via matrix metalloproteinases (MMPs), leading to activation of the endothelial ET B receptor–NO pathway ( Fig. 14.4 ). , This hypothesis was based on a combination of observations including the experimental data supporting a role for relaxin, endothelial ET B receptor, and NO as outline above, the stimulation of MMP expression by relaxin demonstrated in fibroblasts, , and the ability of vascular MMPs to hydrolyze big ET to ET 1-32 with subsequent activation of endothelin receptors. , Inhibition of MMPs abrogated renal vasodilation and hyperfiltration and attenuated myogenic constriction of small renal arteries in relaxin-infused nonpregnant and/or pregnant rats. In contrast, these gestational changes were not modified by the traditional endothelin converting enzyme blocker phosphoramidon, suggesting that MMP is important in the hydrolysis of big ET to ET 1-32 and activation of endothelial ET B receptors, as MMP is unaffected by phosphoramidon. In small renal arteries harvested from relaxin-treated nonpregnant or midterm pregnant rats, vascular MMP-2 activity is increased by approximately 50%. ,
It is unlikely that vascular MMP-2 and endothelial ET B receptor-NO are constituents of separate vasodilatory pathways working in parallel. If that was the case, then after inhibition of vascular MMP-2 or the endothelial ET B –NO pathway, compensation of one for the other might be expected. However, not even partial compensation was observed. Inhibitors of the ET B receptor, nitric oxide synthase, or MMP completely abolished the renal circulatory changes during pregnancy and/or in relaxin-treated nonpregnant rats (citations in Ref. ). Small renal arteries isolated from relaxin-treated, ET B receptor-deficient rats showed upregulation of vascular MMP-2 activity, but they failed to demonstrate the typical inhibition of myogenic constriction. This dissociation of the biochemical and functional consequences of relaxin in small renal arteries from ET B receptor-deficient rats strongly suggests that vascular MMP is in series with, and upstream of, the endothelial ET B receptor–NO signaling pathway. It is possible that the colocalization of MMP-2, the ET B receptor, and endothelial nitric oxide synthase facilitates this interaction (Ref. , and citations therein).
Interestingly, the mechanism by which relaxin inhibits myogenic constriction is time-dependent and involves differential upregulation of MMP activity. Chronic (5 days) infusion of relaxin in rats increased MMP-2 activity and inhibited myogenic constriction. In contrast, a short-term relaxin treatment (4–6 h) also inhibited myogenic constriction, but involved a selective increase of MMP-9 activity. Regardless of the activation of either MMP2 or MMP9 by relaxin, both MMPs can convert big ET into ET 1–32 , in turn activating ET B receptors and NO production.
Finally, a role for arterial production of placental and vascular endothelial growth factor was implicated in the MMPs, endothelin, and nitric oxide pathway of relaxin-mediated increases of GFR and ERPF in conscious rats and in relaxin-mediated reduction in myogenic constriction of both rodent and human arteries, but the precise mechanism of their involvement remains uncertain.
Volume Expansion
Chronic volume expansion may play a role in the initiation and/or maintenance of elevated ERPF and GFR during pregnancy. Tubuloglomerular feedback activity was not suppressed in gravid rats, rather the mechanism was reset to the higher level of GFR manifested by the pregnant animals, leading to the conclusion that the volume expansion of pregnancy is perceived by the gravid rat as “normal.” This contention logically follows from the concept that reductions in total peripheral vascular resistance (“arteriolar underfilling”) and subsequent vascular refilling are linked and temporally inseparable, although a dissociation was discerned by some investigators. Thus, in one study of humans and a second in baboons, increases in plasma volume and left atrial or left ventricular end diastolic dimensions indicative of plasma volume expansion lagged behind the decline in systemic vascular resistance. ,
Whether chronic volume expansion of pregnancy underlies gestational changes in the renal circulation is difficult to test directly. With the exception of pregnancy, most instances of chronic volume expansion result from pathology such as congestive heart failure or cirrhosis in which renal function is often reduced rather than elevated. However, in rare cases of primary mineralocorticoid excess, which is associated with volume expansion, GFR rises, but not by the same degree as observed in pregnancy. Interestingly, prolonged administration of either arginine vasopressin or oxytocin to rats allowed water ad libitum resulted in expansion of total body water, reduction in plasma osmolality, and increases in both ERPF and GFR comparable in magnitude to those observed during pregnancy.
Renal Nerves
GFR rises during pregnancy in renal allograft recipients and in women with a single kidney (albeit to a lesser degree), showing a pattern of change similar to that observed in normal pregnant women. , Thus, despite compensatory functional and anatomic hypertrophy, the renal allograft, and single kidney adapt even further during pregnancy undergoing gestational hyperfiltration. As the renal allograft is a denervated kidney and assuming little or no reinnervation, this allows the conclusion that renal nerves are unlikely to be involved in gestational increases of GFR.
Other Factors
Other factors in addition to relaxin are likely to contribute to gestational increases in GFR and ERPF. If circulating placental growth factor (PlGF) has a role, it is likely to be a contributory factor in the second and third trimesters when serum concentrations are high, whereas a role in early pregnancy seems less likely. , Another candidate is calcitonin gene-related peptide (CGRP), which increases in the circulation during early gestation. CGRP is a potent vasodilator in several vascular beds including that of the kidney and may therefore contribute to systemic and renal vasodilatation of pregnancy, a possibility that could be tested by administration of CGRP antagonists in gravid animal models. Recent evidence supports an important role for the AT2 receptor in mediating the midterm decline in systolic blood pressure in mice , and in attenuating constrictor responses to phenylephrine in the aorta from gravid rats, thus suggesting a potential role for angiotensin II receptor Type 2 receptor (AGTR2) activation, if similar changes can be demonstrated in the kidney. Moreover, the relaxin receptor, RXFP1, is known to heterodimerize with (AGTR2) suggesting a potential cooperation. Histidine decarboxylase and histamine, a potent vasodilator, were both reported to be increased in the superficial renal cortex of gravid mice. Finally, renal production of epoxyeicosatrienoic acid may also contribute to renal vasodilatation and hyperfiltration of pregnancy. To what degree, if any, these vasodilatory factors may interact with relaxin remains unknown.
Clinical Implications
Measurement of Kidney Function in Pregnancy
Elevated GFR during pregnancy is reflected by reciprocal changes in the plasma concentration of creatinine, , , which is decreased throughout gestation. The reason for this reciprocal relationship is that production of creatinine by skeletal muscle changes little during gestation, and since the glomerular filtration increases leading to a rise in the filtered load of creatinine, plasma concentrations must fall. Yet, a normal range for serum creatinine in pregnancy has not been established. Statements regarding creatinine concentrations in pregnancy have often been based on expert opinion including a “normal” range of 0.40–0.80 mg/dL (35–71 μmol/L) , , an “average” of 0.60 mg/dL (53 μmol/L), and a recommendation that serum creatinine concentrations greater than 0.85 mg/dL (75 μmol/L) should raise suspicion of kidney injury in pregnancy. When serum creatinine has been measured in healthy pregnancy, the upper limit (95–97.5th centile) varies among published cohorts with upper limits for serum creatinine in pregnancy given as 0.81 mg/dL (72 μmol/L), 0.90 mg/dL (80 μmol/L), 1.01 mg/dL (89 μmol/L), and 1.07 mg/dL (95 μmol/L). Historically, the most widely cited study of trimester-specific creatinine concentrations included only 29 healthy pregnant women. Such data have limited generalizability without correction for factors known to cause variance in serum creatinine including ethnicity, gestational age, and different creatinine assay methods. The largest contemporary data are from a retrospective, cross-sectional, population study in Canada, which included just under 250,000 pregnancies and demonstrated a 95th centile value of 0.92 mg/dL (81 μmol) at the time of delivery in women with a least two measurements of serum creatinine in pregnancy. Although women with known CKD, gestational hypertension, and preeclampsia were excluded from these data, the indication for serum creatinine testing, which is not routine during pregnancy in Canada, was unknown, and details of ethnicity were not provided.
In 2019, a systematic review of serum creatinine concentrations in pregnancy was published including a data synthesis of 816 creatinine values (19 studies) from the first trimester, 1183 creatinine values (22 studies) from the second trimester, and 2422 creatinine values (30 studies) from the third trimester. This analysis showed that mean serum creatinine concentrations in pregnancy were 84%, 77%, and 80%, with upper reference limits (97.5th centile) of 85%, 80%, and 86% (83%–89%) in the first, second and third trimesters respectively, compared to nonpregnant women. These data allow generation of a normal range for serum creatinine in pregnancy that is generalizable and not limited to a specific population or creatinine assay technique. For example, based on a normal nonpregnant female range for serum creatinine of 0.51–1.02 mg/dL (45–90 μmol/L), this equates to mean serum creatinine concentrations of 0.63 mg/dL (56 μmol/L), 0.59 mg/dL (52 μmol/L), and 0.61 mg/dL (54 μmol/L) in sequential trimesters. Serum creatinine concentrations greater than 0.86 mg/dL (76 μmol/L) in the first trimester, 0.81 mg/dL (72 μmol/L) in the second trimester, and 0.87 mg/dL (77 μmol/L) in the third trimester should be considered to be outside the upper limit of normal for pregnancy, raising the possibility of either acute kidney injury or undiagnosed CKD predating the pregnancy.
Diagnosis of Chronic Kidney Disease in Pregnancy
Serum creatinine in isolation is an insensitive surrogate marker of GFR because it is influenced by both GFR and non-GFR determinants including muscle mass, dietary intake, tubular secretion, and extrarenal elimination by the gastrointestinal tract. The influence of such non-GFR determinants means that there is a wide range of possible glomerular filtration rates for a single creatinine concentration. For example, a serum creatinine of 1.5 mg/dL (132 μmol/L) can correspond to a measured GFR anywhere from 20 to 90 mL/min/1.73 m 2 . This inaccuracy of isolated serum creatinine measurements has led to the generation of formulae, which estimate GFR from serum creatinine concentrations using a combination of age, gender, and ethnicity as surrogates for unmeasured, non-GFR determinants. Routine reporting of kidney function outside of pregnancy by estimated glomerular filtration rate (eGFR) was introduced using the Modification of Diet in Renal Disease (MDRD) formula. The MDRD formula was generated from a cohort of 1628 patients with kidney disease including 645 women. This was superseded by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, developed from a cohort of 5504 participants both with and without kidney disease, including 2391 women. CKD-EPI was demonstrated to be more precise, less likely to underestimate GFR at higher values, and demonstrated better correlation with adverse outcomes. eGFR derived by CKD-EPI is recommended for the clinical assessment of kidney function by both Kidney Disease: Improving Global Outcomes (KDIGO) and the National Institute for Health and Care Excellence.
The use of eGFR formulae for the diagnosis and staging of CKD requires an awareness of potential sources of error including extremes of body size and diet, and the concomitant use of drugs that modify either tubular secretion or nonrenal clearance of creatinine. In addition, eGFR formulae require serum creatinine concentrations to be in a steady state of generation and excretion. This precludes their use in non-steady-state conditions such as pregnancy, where hemodynamic changes, particularly in the first and third trimester, prevent steady state. MDRD compared to C IN and CKD-EPI compared to C CR both underestimate GFR as gestational volume expansion and hyperfiltration alter the relationship between serum creatinine or inulin concentrations and GFR, and are therefore are not valid for use in pregnancy. Caution should be taken when interpreting data from publications that use eGFR equations in pregnancy, as they may underestimate prepregnancy CKD severity.
Cystatin C is a basic protein produced by all nucleated cells and therefore generated at a relatively constant rate, irrespective of muscle mass. eGFR formulae based on cystatin C have therefore been derived with the aim of providing more accurate estimates in patients with differences in diet, extremes of muscle mass, and in those outside the boundaries of where the creatinine-based formulae have been validated. As discussed above, serum concentrations of maternal cystatin C fail to correlate with other measures of GFR in pregnancy, including iohexol clearance, serum creatinine, and eGFR formulae, a discrepancy hypothesized to be due to a change of glomerular charge in pregnancy. Like creatinine-based formulae, existing cystatin-based eGFR formulae also have no proven utility in the assessment of kidney function in pregnancy.
Serum creatinine concentration therefore remains the only standard, single-point assessment for kidney function in pregnancy. This complicates the diagnosis of CKD when it presents for the first time in pregnancy, a phenomenon that is estimated to occur in up to one-third of women with CKD. In cohort studies, a stable serum creatinine in pregnancy above 1.4 mg/dL (125 μmol/L) has been presumed to represent moderate to severe CKD (CKD stage 3 or more).
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