The Kidney in Normal Pregnancy and Preeclampsia




Keywords

glomerular filtration, renal blood flow, relaxin, proteinuria, podocyturia, renal vascular resistance, preeclampsia, glomerular endotheliosis, renal biopsy

 


Editors’ comment: The revision of this chapter includes the welcoming of a new coauthor, Isaac Stillman, a pathologist who has recently added substantially to the literature regarding the pathological changes in the kidney during preeclampsia both in animal models and in humans. It also contains new topics, gestational changes in osmoregulation, and urinary concentration and dilution. In earlier editions, this subject was relegated to the chapter on volume homeostasis, but as a true kidney function it has found its way home, chapter-wise!


The chapter authors have also updated the section on renal biopsy in pregnancy. This procedure, already quite restricted indication-wise in pregnant women when discussed in the previous edition, appears even more so as of 2014, probably reflecting the ever-improving technology of non-invasive testing. The marked decline in performing renal biopsies in suspected preeclamptics following the large series that appeared during the last few decades of the 20th century is important to appreciate. That is, interpretive dilemma or misinformation is more likely to appear when the biopsy process focuses more and more on atypical or complicated preeclampsia. This point, already noted in our comments in the previous edition, underscores the importance of the older, larger and extensive series, as well as the signal work of Sheehan and Lynch. The latter is a unique and unrepeatable study whose first author, then at the Glasgow Royal Maternal Hospital, performed most of his autopsies within 2 hours after death (between 1935 and 1946), eliminating substantial postmortem tissue autolysis. The late Harrold Sheehan, then near his 80th year, published an article comparing the value of this autopsy material to renal biopsy descriptions in preeclamptic women, an article that bears reading.


Finally, this chapter contains the exciting progress made by the first author regarding relaxin’s role in mediating the striking increases in renal hemodynamics during pregnancy, findings that have been extended to understanding the general vasodilated state of pregnancy, and possible new therapy for preeclampsia.




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 was encyclopedic in scope. Therefore, it is only fitting to Dr. Chesley’s memory that we try to be as thorough as he was in the following discussion of the kidney in normal pregnancy and preeclampsia.


Familiarity with the changes in maternal renal and cardiovascular physiology as well as osmoregulation and volume homeostasis during normal pregnancy is prerequisite to complete understanding, proper diagnosis, and medical management of preeclampsia. General cardiovascular and volume alterations in normal pregnancy are reviewed elsewhere in this book ( Chapter 14 , Chapter 15 ). Here, the alterations in renal hemodynamics, glomerular filtration, and osmoregulation during normal pregnancy will be considered first. Then, the dysregulation of renal hemodynamics and glomerular filtration occurring in preeclampsia will be addressed. Although filtration, reabsorption, and excretion of many solutes change in pregnancy, only the renal handling of uric acid and of proteins will be presented here because of their special clinical significance to preeclampsia. Last, we discuss the pathology of the kidney in preeclampsia with focus on its characteristic lesion, glomerular endotheliosis.




Renal Hemodynamics and Glomerular Filtration Rate During Normal Pregnancy


Decreased vascular resistance of nonreproductive organs is one of the earliest adaptations to transpire in normal pregnancy, leading to a marked decrease in total systemic vascular resistance. The kidneys contribute to this reduction in total systemic vascular resistance in a major way. Indeed, the nadir in renal and systemic vascular resistances and peak in renal blood flow, glomerular filtration and cardiac output coincide, and are attained by the end of the first or beginning of the second trimester. The early gestational rise in cardiac output occurs well before major increases in absolute uteroplacental blood flow, and oxygen and nutrient demands of the nascent fetus and placenta. This temporal dissociation is reflected by the oxygen content difference between arterial and mixed-venous blood, which narrows during early pregnancy in both humans and rats. In summary, the reduction in vascular resistance of nonreproductive organs such as the kidney is one of the earliest and most fundamental maternal adaptations to occur in pregnancy, and insight into the hormonal signals and molecular mechanisms may be particularly critical because in preeclampsia, both renal and systemic vasodilatation are compromised.


Renal Clearances of para-Aminohippurate and Inulin


The most comprehensive investigations of renal hemodynamics and glomerular filtration rate (GFR) were published by Sims and Krantz, de Alvarez, Assali et al., Dunlop, Roberts et al., and Chapman et al. These studies stand out because of their superior experimental design and methodologies, i.e., (1) the same women were longitudinally studied during gestation and either preconception or postpartum; (2) the renal clearances of para-aminohippurate (C PAH ) and inulin (C IN ) that measure effective renal plasma flow (ERPF) and GFR, respectively, were determined by the constant infusion technique; and (3) the potential problem of urinary tract dead space, which can lead to inadequate collection of urine, thereby introducing error into the determination of C PAH and C IN , was avoided by instituting a water diuresis and/or by irrigating the bladder after each clearance period. *


* Although irrigation of the bladder with water and then air helps to improve urine collection, largely because of the increased risk of urinary tract infection, this procedure is currently considered to be inappropriate for research purposes. On the other hand, increasing urine flow rate by initiating a water diuresis is an acceptable and effective means to minimize urinary tract dead space error.

Taking precautions to avoid dead space error is especially important in pregnancy when the urinary tract is dilated and the bladder may fail to drain completely.


To facilitate comparison of the studies, data of GFR and ERPF (or RPF ~ ERPF/0.9) from each investigation are illustrated in Fig. 16.1 with the exception of Chapman et al. Because the work of Chapman et al. was particularly thorough, including the evaluation of renal function in women during the midfollicular phase before conception and then on six occasions throughout gestation, these data are presented separately in Fig. 16.2 . On balance these studies reveal that both GFR and ERPF markedly increased during the first half of pregnancy. Peak levels were 40 to 65% and 50 to 85%, resepectively, above nonpregnant levels of GFR and ERPF. In general, the filtration fraction (FF; GFR/ERPF or GFR/RPF) fell during the first half of gestation. The pattern of change for GFR was comparable in all the studies except that of de Alvarez, in which GFR declined during the last half of pregnancy toward nonpregnant levels, whereas in the other investigations GFR remained elevated throughout gestation. The explanation for this discrepancy is unclear, but ERPF also fell earlier and more precipitously in the study by de Alvarez. ERPF declined modestly during the last stages of pregnancy in all studies except that of Assali et al. Thus, again with the exception of the investigation by Assali et al., FF gradually rose during the final stages of pregnancy, mostly because ERPF fell while GFR was relatively preserved. Certain body positions (e.g., supine, sitting, etc.) may compromise ERPF and GFR during the clearance experiments by mechanical effects of the enlarged gravid uterus, particularly in late gestation (see “Postural Infuences on Renal Function,” below). Nevertheless, when Ezimokhai et al. measured C IN and C PAH with subjects positioned in left lateral recumbency, a posture that helps prevent compression of major vessels by the gravid uterus, they observed that ERPF but not GFR significantly declined during the final stages of pregnancy (748±20 to 677±20 mL/min), suggesting the decline in ERPF is not solely an artifact of posture.




Figure 16.1


(A) Serial studies of glomerular filtration rate (GFR; C IN ) during pregnancy and in the postpartum period (nonpregnant values). (B) Serial studies of effective renal plasma flow (ERPF; C PAH ) or renal plasma flow during pregnancy and in the postpartum period (nonpregnant values).



Figure 16.2


(A) Serial study of glomerular filtration rate before pregnancy in the midfollicular phase of the menstrual cycle and then throughout pregnancy in 10 women. (B) Serial study of effective renal plasma flow (ERPF) in the same women. All values during pregnancy are significantly different from those obtained during the midfollicular phase of the cycle before pregnancy.


Elevated GFR during pregnancy is reflected by reciprocal changes in 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 glomerular filtration increases, plasma levels must fall. Although renal handling of urea is more complicated, it is freely filtered like creatinine; consequently, plasma levels are also lower during pregnancy, again primarily because renal clearance of urea is increased. Average concentrations for plasma creatinine and urea nitrogen during gestation are 0.5 and 9.0 mg/dL, respectively, compared to nonpregnant values of 0.8 and 13.0 mg/ dL. Of interest, GFR was noted to increase 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. Because the renal allograft is a denervated kidney, renal nerves are unlikely to be involved in the gestational increases in GFR. In the same vein, the kidneys of both pregnant women and rats demonstrated further elevation in GFR and ERPF in response to intravenous infusion of amino acids, and the percentage elevation was comparable to that observed in the nonpregnant condition.


Creatinine Clearance


The 24-hour renal clearance of endogenous creatinine (C CR ) is not uncommonly used as a measure of GFR. However, this is due to a fortuitous chain of events. Creatinine undergoes glomerular filtration, and a small degree of proximal tubular secretion, but plasma levels are overestimated because of the presence of a chromagen, which is unavoidably detected in the assay along with creatinine. When GFR is normal, these two events cancel. However, as GFR falls, tubular secretion represents a greater proportion of urinary creatinine, and the influence of the chromagen on plasma levels diminishes. Under such circumstances, creatinine clearance overestimates GFR sometimes by as much as 25 to 50%.


Measuring the 24-hour C CR , Davison and Noble provided evidence that GFR rises 25% by the second week post-conception (or 4 weeks after the last menstrual period ( Fig. 16.3 ). This study is one of the first to show that the physiologic adaptations in the renal circulation during human pregnancy are among the earliest to occur. A report by Chapman et al. both supports and extends these findings, insofar as both C IN (and C CR ) were significantly increased by 4 weeks post-conception (or 6 weeks after the last menstrual period), the earliest time-point investigated ( Fig. 16.2 ).




Figure 16.3


Alterations in the 24-hour renal creatinine clearance evaluated weekly before conception and throughout early pregnancy in 11 women. Solid line, mean; stippled area, range for nine women with normal pregnancy outcomes. Two women designated by the thin and dashed lines had uncomplicated spontaneous abortions.


Several researchers measured the renal clearance of inulin throughout pregnancy and in the postpartum period using the constant infusion technique, and compared these values to the 24-hour endogenous C CR in the same women. The changes in GFR during pregnancy as measured by C IN and the 24-hour C CR were comparable except possibly in the last few weeks before delivery. Although 24-hour C CR declined at 35 to 38 weeks of gestation in the study by Davison and Hytten, the short-term C CR , as assessed by constant infusion of creatinine in the same study, did not decrease and was similar to C IN . This last finding suggested that the renal handling of creatinine did not change at this stage of pregnancy, and substantiated the C CR as a valid measure of GFR in this setting.


In what appears to be the only comprehensive study of the last few weeks of pregnancy immediately before delivery that we could find, Davison et al. performed weekly, 24-hour C CR measurements in 10 subjects, demonstrating that 24-hour C CR decreased and plasma creatinine increased over this period to levels not significantly different from nonpregnant values. Because creatinine is not only filtered but also secreted as discussed above, the authors chose not to conclude that this decline reflected a fall in GFR. On the other hand, taken together with the study by Davison and Hytten, ( vide supra ) it is likely that the fall in 24-hour C CR which occurred prior to delivery did reflect a true decline in GFR. Because the 24-hour C CR is performed while the subject goes about her normal daily activities, it may actually be a more realistic and physiologic measure of GFR. Extended periods of standing during the day or lying supine at night during late pregnancy may compromise renal perfusion and GFR, which is then reflected by a reduced 24-hour C CR (also see next section). Such potentially protracted periods of reduced GFR would be missed by short-term measurements of C IN or C CR performed under the artificial conditions of a laboratory setting in the left lateral decubitus or sitting positions.


Postural Influences on Renal Function


Pritchard et al. as well as Sims and Krantz observed no compromise of C PAH and C IN when gravid subjects turned from the lateral recumbent to the supine position. In contrast, Chesley and Sloan studied 10 women between 34 and 43 weeks of gestation showing decreases of 19±3% and 21±5% in C PAH and C IN , respectively, upon assuming the supine position. These decreases were accompanied by reciprocal increases in plasma para-aminohippurate and inulin concentrations, indicating a true reduction in renal function rather than an artifact of inadequate urine collection. The authors concluded that in late gestation when a subject assumes a supine position, the enlarged uterus compresses the great veins, which in turn impairs venous return, decreasing both cardiac output and renal perfusion. Similar findings and conclusions were made by Pippig.


Dunlop studied 18 healthy women at approximately 36 weeks of gestation and again 8 weeks postpartum, measuring C PAH and C IN in three positions: supine, sitting, and lateral recumbency. Although the subjects demonstrated the expected gestational elevations in ERPF and GFR, there was no significant influence of posture. In particular, these variables were not reduced by the supine position. Lindheimer and Weston, in a study designed to determine mechanisms of renal salt handling during pregnancy, noted decrements in GFR in 11 of 13 volume-expanded third-trimester women when they changed from a lateral recumbent to a supine position. Assali et al. showed that ERPF and GFR declined markedly in response to quiet standing especially in the third trimester. This decline in renal function persisted even after postural hypotension had subsided. In summary , change of position from lateral recumbency to supine or even standing has been frequently reported to compromise renal hemodynamics and GFR during late pregnancy.


Mechanisms for Alterations of Renal Hemodynamics and GFR


Our understanding of the mechanism(s) responsible for the increase of ERPF, and consequently of GFR, in pregnancy is improving. Ultimately, the fall in renal vascular resistance underlies the phenomena. An attractive and plausible theory is that the altered hormonal environment is causal. Unfortunately, so many hormones change during pregnancy that it has been difficult to know which ones to investigate first. Because of obvious ethical considerations as well as feasibility issues, many of the studies exploring the potential mechanisms of gestational changes in renal hemodynamics and GFR have employed animal models.


Renal Hyperfiltration During Pregnancy


The Munich-Wistar rat has been extensively investigated by renal physiologists because this strain has glomeruli belonging to superficial cortical nephrons at the kidney surface, which are accessible by micropuncture. Thus, much of our current understanding of glomerular hemodynamics stems from studies of this rat strain. The single nephron GFR (SNGFR) is determined by Starling forces, both hydrostatic and oncotic pressures within the glomerular capillary and Bowman’s space, as well as the ultrafiltration coefficient, K f , which is the product of the glomerular capillary hydraulic permeability and surface area. Applying the renal micropuncture technique to Munich-Wistar rats during midgestation when whole kidney RPF and GFR are increased, Baylis showed that the gestational rise in SNGFR can be attributed to an increase in glomerular plasma flow and the transglomerular hydrostatic pressure difference remains unchanged. Thus, the higher glomerular plasma flow effectively decreases the rate of rise of oncotic pressure along the glomerular capillary, leading to increased net pressure of ultrafiltration and SNGFR. In essence, comparable reductions in afferent and efferent arteriolar resistances account for both the unchanged glomerular hydrostatic pressure and increase in glomerular plasma flow and SNGFR during rat gestation. In this study, plasma oncotic pressure was not significantly different between nonpregnant and pregnant rats, and, because the animals were in filtration equilibrium, only a minimum value for K f could be derived; nevertheless, these determinants of glomerular ultrafiltration most likely contributed little to the gestational rise in SNGFR in the gravid rat model. To summarize, SNGFR rises because glomerular plasma flow increases during pregnancy.


Whether similar mechanisms occur in human gestation is difficult to determine, because glomerular dynamics cannot be directly evaluated as in the Munich-Wistar rat. Recent mathematical modeling based on renal clearances and other measurements performed in pregnant women suggested that renal hyperfiltration of human pregnancy is mainly due to a rise in RPF. Although decrements in plasma oncotic pressure particularly during late pregnancy and increases in K f especially during early pregnancy may contribute, there was no evidence for alterations in the transglomerular hydrostatic pressure. However, a note of caution is necessary here. The mathematical formulae used can skew the results when very small measurement errors occur. Such errors are most likely to occur when values entered into the equation are obtained indirectly, the case here. Finally, there is one group of investigators who cite changes of oncotic pressure as the sole cause of increased GFR.


Conrad adapted the Gellai and Valtin method for chronic instrumentation of rats to the investigation of renal function in pregnancy. Because renal, cardiovascular, and endocrine parameters are markedly perturbed by anesthesia and acute surgical stress, physiologic studies in chronically instrumented, conscious animals are critical for interrogation of underlying mechanisms. Thus, the same chronically instrumented, conscious rats were serially examined before, during, and after gestation. Comparable to human pregnancy, the conscious rat demonstrates both renal vasodilatation and hyperfiltration throughout most of gestation. Thus, the gravid rat has been extensively investigated to determine the mechanisms underlying these remarkable changes in the renal circulation during pregnancy.


Plasma Volume Expansion


Pregnancy is accompanied by tremendous expansion of extracellular and plasma volume (see Chapter 15 ). Acute expansion of plasma volume by 10 to 15% failed to increase the GFR, SNGFR, or glomerular plasma flow in virgin female Munich-Wistar rats. Volume expansion was previously shown to suppress tubuloglomerular feedback activity, which could conceivably permit the gestational increases in both glomerular plasma flow and SNGFR. However, tubuloglomerular feedback activity was not suppressed in gravid Munich-Wistar rats, rather the mechanism was reset to the higher level of SNGFR manifested by the pregnant animals. The authors concluded that the volume expansion of pregnancy may be perceived by the gravid rat as “normal.” This contention logically follows from the concept that reductions in total peripheral vascular resistance (the “arteriolar underfilling” stimulus theory of normal pregnancy) and vascular refilling are tightly linked and temporally inseparable, although a dissociation has been 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 comparable to that of pregnancy underlies the gestational changes in the renal circulation is difficult to test. Most instances of chronic volume expansion occurring in nature, other than pregnancy of course, result from pathology such as congestive heart failure or cirrhosis in which renal function is often reduced rather than elevated. However, in the 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 chronically instrumented rats allowed water ad libitum results in expansion of total body water, reduction in plasma osmolality, as well as increases in both ERPF and GFR comparable in magnitude to those observed in gestation. Thus, chronic volume expansion may initiate, abet or maintain elevated ERPF and/or GFR during pregnancy.


Pseudopregnancy


Study of the renal circulation in rats that become pseudopregnant may provide insights into the mechanisms contributing to renal vasodilatation and hyperfiltration of pregnancy. By mating a female rat with a vasectomized male, pseudopregnancy – a condition that physiologically mimics the first half of gestation in rats, but lacks fetoplacental development – is produced. Pseudopregnancy mimics the increases in ERPF and GFR that are observed during early pregnancy in rats. Thus, maternal factors alone may be sufficient to initiate the changes in the renal circulation during pregnancy.


Menstrual Cycle


Davison and Noble demonstrated that the 24-hour endogenous C CR increased by 20% in the luteal phase of the menstrual cycle ( Fig. 16.3 ). This finding was corroborated by other investigators using C CR , chromium 51-EDTA clearance, or C IN . Moreover, ERPF measured either by C PAH or renal clearance of iodine 125-hippuran was also reported to be increased during the luteal phase in two studies, but not significantly so in another. Therefore, the gestational increases in ERPF and GFR are observed, albeit to a lesser degree, in the luteal phase. This finding may shed light on the mechanisms underlying renal vasodilatation and hyperfiltration of pregnancy, because several hormones that increase in the luteal phase also rise during early gestation, e.g., the corpus luteal hormones, progesterone and relaxin.


Hormonal Regulation: Sex Steroids


Based on studies involving both acute and chronic administration of estrogen to humans and laboratory animals, this hormone appears to have little or no influence on ERPF or GFR, although it clearly increases blood flow to other nonreproductive and reproductive organs. On the other hand, progesterone is a potential candidate. Chesley and Tepper administered 300 mg/d intramuscular (IM) progesterone to 10 nonpregnant women for 3.5 days, and found that the hormone produced a 15% increase in C IN and C PAH . They speculated that more prolonged administration might elicit the magnitude of increase in GFR and ERPF observed in normal pregnancy. Similar findings were reported by Atallah et al. In a 4-hour period following the IM administration of 200 mg of progesterone to nine nonpregnant women, plasma concentration rose on average from 7 to 30 ng/mL, and endogenous C CR increased from 103 to 118 mL/min – a significant rise of 15%. By extrapolation, the authors suggested that the circulating levels of progesterone observed in pregnancy, which can be considerably higher than that attained in their study, might fully account for the 40 to 65% gestational increase of GFR. It should be noted, however, that these higher levels of circulating progesterone are not reached until well after the gestational peak in ERPF and GFR. Nevertheless, progesterone could help maintain elevated renal function later in pregnancy. In another report, 3 hours after IM administration of 310 μmol progesterone to male subjects, ERPF rose significantly by 15%, irrespective of the sodium content in the diet, although GFR was unaffected. In the same report, IM administration of 155 μmol progesterone twice daily for 3 days produced comparable changes in ERPF, but, again, no change in the GFR. Finally, subcutaneous injection of 2 mg/kg/d progesterone for 3 days to intact female rats produced a 26% increase in GFR (ERPF was not measured in this study). Based on the results from these reports, progesterone or its metabolites may contribute in a small way to the early rise in ERPF and GFR of early pregnancy. They may also participate in maintaining elevated renal function in the second half of gestation when circulating levels of the steroid are considerably higher.


Hormonal Regulation: Peptide Hormones


It follows from the studies in pseudopregnant rats and women in the luteal phase ( vide supra ) that peptide hormones of maternal origin may participate in the early gestational increases of ERPF and GRF. Prolactin surges in both pseudopregnant and pregnant rats coincident with the gestational increases in ERPF and GFR. Unfortunately, whether prolactin can raise renal hemodynamics and GFR remains controversial and, as such, requires further investigation. Placental lactogen , which activates the same receptor as prolactin, is another candidate peptide hormone at least in maintaining elevated ERPF and GFR later in pregnancy when the hormone circulates. However, based on the one relevant study that we could locate, if anything, human placental lactogen decreases RBF at least when administered acutely in the renal artery of anesthetized pigs and human pregnancies accompanied by placental lactogen gene deletion (Rygaard et al., Hum Genet, 1998) have been reported.


Relaxin may contribute to the vasodilatory changes in renal and possibly other circulations during pregnancy. Circulating relaxin originates from the corpus luteum in both rats and humans. In the latter, human chorionic gonadotrophin (hCG) is a major stimulus for relaxin secretion. There were compelling, albeit circumstantial, reasons to consider relaxin as a potential mediator of renal vasodilatation and hyperfiltration during pregnancy.


First, plasma relaxin rapidly rises after conception in women, corresponding with the large first-trimester increments in GFR and ERPF. Second, relaxin also increases during the luteal phase associated with a transient 10–20% increase in GFR and ERPF. Third, the early gestational rise in plasma relaxin coincides with another early physiologic adaptation in human pregnancy; namely, changes in osmoregulation (see below). Indeed, osmoregulatory changes were mimicked by administering hCG to women in the luteal phase and intact female rats, but not to men or ovariectomized rats, suggesting the intermediary role of an ovarian hormone. In other studies, infusion of rat relaxin-neutralizing antibodies prevented the reduction in plasma osmolality at midterm pregnancy in the rat. Furthermore, administration of synthetic human relaxin to ovariectomized rats for 7 days produced a significant decrease in plasma osmolality without a change in plasma arginine vasopressin similar to the osmoregulatory changes observed in normal pregnancy. Similar findings were observed using recombinant human or porcine relaxin. Finally, chronic administration of relaxin reduced blood pressure and vasoconstrictor responses in the mesenteric circulation of awake spontaneously hypertensive rats while acute treatment increased coronary blood flow and reduced platelet aggregation via nitric oxide and guanosine 3′,5′-cyclic monophosphate.


Although renal vasodilatation and hyperfiltration occur in rodent pregnancy before gestational day 8, when serum relaxin is undetectable, there is a marked jump in renal function between gestational days 8 and 12, at which time ovarian and plasma relaxin levels surge. The increases in GFR and RPF that occur during rat gestation before gestational day 8 or during pseudopregnancy when circulating relaxin is undetectable are apparently mediated by other, as yet, undiscovered mechanisms.


Long-term administration of purified porcine or recombinant human relaxin (rhRLX) to chronically instrumented, conscious nonpregnant rats over a 2–5-day period increased both ERPF and GFR (and decreased plasma osmolality) to levels observed during midgestation when renal function peaks in this species, and was also observed in ovariectomized female and male rats. Long-term relaxin administration also blunted the renal vasoconstrictor response to angiotensin II infusion, thereby mimicking the diminished effect of the latter peptide during rat gestation. Furthermore, myogenic constriction of small renal arteries isolated from relaxin-treated, nonpregnant rats was inhibited and comparable to that observed in arteries harvested from midterm pregnant animals. Short-term (1–4 hours) administration of rhRLX to chronically instrumented conscious rats also produced renal vasodilatation and hyperfiltration. Administering relaxin-neutralizing antibodies or ovariectomy while maintaining pregnancy with exogenous sex steroids completely prevented gestational hyperfiltration, renal vasodilatation and inhibited myogenic constriction, and the osmoregulatory adaptations as well. Thus, relaxin appears to be essential for the renal circulatory and osmoregulatory changes in midterm pregnant rats.


In normal human volunteers, short-term (~6 hours) intravenous infusion of rhRLX increased RPF by 60%, but, surprisingly, not GFR . (See Discussion in ref. for possible explanations of this apparent discrepancy.) Renal vasodilatation occurred both in men and in women, and as soon as 30 minutes after starting the infusion without any significant changes in blood pressure, heart rate or serum osmolality. After 26 weeks of rhRLX administration to patients with mild scleroderma, predicted creatinine clearance (calculated by the Cockcroft-Gault equation: GFR=(140−age)×(Wt in kg)×(0.85 if female) / (72×serum Cr) rose by 15–20%, and serum osmolality and blood pressure declined slightly but significantly throughout the study in a dose-dependent fashion. Finally, in infertile women who conceived through donor eggs, IVF and embryo transfer, the gestational increase in GFR and decrease in serum osmolality were significantly attenuated. Because these women lacked ovarian function and a corpus luteum, serum relaxin was undetectable. Thus, similar to gravid rats, circulating relaxin appears to have a role in establishing the renal and osmoregulatory responses to pregnancy in women. However, unlike gravid rats, partial responses may persist despite the absence of circulating relaxin.


Long-term administration of rhRLX for up to 10 days in either normotensive or hypertensive male and female rats mimicked the changes in systemic hemodynamic and global arterial compliance observed in pregnancy, and increased the passive compliance of isolated small renal arteries. In contrast, short-term rhRLX administration over hours produced systemic vasodilatation only in the angiotensin II model of hypertension, and not in spontaneously hypertensive or normotensive rats. Thus, by inference, relaxin apparently acted more rapidly in the renal circulation of normotensive rats ( vide supra ) compared to other organ circulations. A critical role for relaxin in the alterations of systemic hemodynamics and global arterial compliance in midterm rats was also identified. Specifically, relaxin-neutralizing antibodies prevented the gestational increases in cardiac output and global arterial compliance, as well as the reduction in systemic vascular resistance. Whether neutralization of circulating relaxin has similar inhibitory effects during late gestation is unknown. It is possible that hormones emanate from the placenta when it becomes sufficiently developed to conspire with relaxin in maintaining systemic vasodilatation and the osmoregulatory changes during late pregnancy. (See Chapter 14 , Chapter 15 for further details.)


Cellular and Molecular Mechanisms of Renal Vasodilatation


Endothelium-derived relaxing factors have been postulated to mediate the gestational increases of ERPF and GFR including vasodilatory prostaglandins (PG) and nitric oxide (NO). A potential role for PG has been investigated in gravid animal models and in humans. The gestational increases in ERPF and/or GFR were unaffected by administration of PG synthesis inhibitors to chronically instrumented, conscious gravid rats and rabbits. Further, vasodilatory PG synthesis in vitro by renal tissues from pregnant and nonpregnant animals was similar. 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 trivial increase compared to the marked decrease in total peripheral resistance characteristic of pregnancy. Similarly, another cyclooxygenase inhibitor, meclofenamate, did not significantly augment peripheral vascular resistance in conscious, gravid guinea pigs. These data support the conclusion that vasodilatory PG plays a minimal or no role in the rise of ERPF, GFR and cardiac output, as well as the reduction in renal and total peripheral vascular resistances during pregnancy.


Guanosine 3’, 5-cyclic monophosphate (cGMP), a second messenger of nitric oxide, may contribute to the renal vasodilatation and hyperfiltration of pregnancy. Because extracellular levels of cGMP generally reflect intracellular production, the plasma level, urinary excretion, and “metabolic production” of cGMP were investigated in conscious rats. Increases in all of these variables were observed throughout pregnancy and pseudopregnancy. Similar elevations in urinary excretion and plasma concentration were described for human gestation.


The 24-h urinary excretion of nitrite and nitrate (NOx), the stable metabolites of nitric oxide, also increased during pregnancy and pseudopregnancy in rats consuming a low-NOx diet, and they paralleled the rise in urinary cGMP excretion. This gestational rise in urinary NOx was prevented by chronic administration of the NO synthase inhibitor nitro- l -arginine methyl ester (L-NAME), implicating nitric oxide as the source. Plasma NOx concentration was also increased during pregnancy, and NO-hemoglobin was detected in red blood cells from pregnant, but not from nonpregnant rats by electron paramagnetic resonance spectroscopy. These data suggested that endogenous NO production is increased in gravid rats, and although the tissue source(s) was not identified, the authors suggested that the vasculature might contribute. Plasma level and urinary excretion of NOx were also reported to be increased in gravid ewes. The status of NO biosynthesis during normal pregnancy in women (and in women with preeclampsia) is unclear.


The renal circulation participates in the overall maternal vasodilatory response to pregnancy. In chronically instrumented conscious, midterm pregnant and virgin rats, the former having reached the peak of their gestational renal vasodilatory increase, acutely administered l -arginine analogs that inhibit NO synthase led to a convergence of renal hemodynamics and vascular resistance in the two animal groups. That is, when compared to the virgin control animals, midterm pregnant rats responded more robustly to acute NO synthase inhibition, manifesting a larger decrease in GFR and ERPF, and a greater rise in effective renal vascular resistance. Consistent with these in vivo data was the myogenic constriction of small renal arteries isolated from midterm pregnant rats that was attenuated compared to virgin control animals, and inhibitors of NO synthase added to the bath or endothelial removal restored this attenuated myogenic constriction to robust virgin levels.


A critical role for NO of endothelial origin in the renal circulation was also established for relaxin-treated nonpregnant rats. Thus, NO plays an essential role in the renal circulatory changes in both midterm pregnant and in relaxin-treated nonpregnant rats. Although pregnancy and relaxin administration to nonpregnant rats both stimulate renal vasodilatation and hyperfiltration and inhibit myogenic constriction of small renal arteries, which depend upon NO ( vide supra ), the urinary excretion of cGMP and NO metabolites is only augmented during pregnancy. Ironically, therefore, the increased production of cGMP and NO metabolites initially reported for rat gestation, and which stimulated further interrogation of this vasodilatory pathway in pregnancy, may not be of vascular origin or of hemodynamic consequence! Finally, the mechanism for increased NO in the renal circulation of midterm pregnant rats or of relaxin-infused nonpregnant rats is not a consequence of increased expression of endothelial nitric oxide synthase.


Of additional interest in one study, but not in another, vasodilatory prostaglandins served a compensatory role by maintaining relative renal hyperfiltration and vasodilatation in gravid rats compared to virgin controls during chronic blockade of NO synthase with l -arginine analogs. That is, in the setting of chronic NO synthase inhibition, renal function converged in the virgin and pregnant rats, but only after acutely inhibiting prostaglandin synthesis with meclofenamate. Prostaglandin blockade alone, however, did not affect renal function in conscious virgin or pregnant rats.


Paradoxically, endothelin (ET) appears to play a critical role in the renal vasodilatation and hyperfiltration of midterm pregnant and relaxin-treated nonpregnant rats. ET, known primarily as a potent vasoconstrictor by interacting with vascular smooth muscle ET A and ET B receptor subtypes, also increases cytosolic calcium in endothelial cells, thereby stimulating prostacyclin, NO and possibly other relaxing factors via an endothelial ET B receptor subtype. Blockade of the ET B receptor subtype in chronically instrumented conscious male rats with the pharmacologic antagonist RES-701-1 elicited marked renal vasoconstriction. This unexpected finding is consistent with a major contribution of endogenous ET towards maintaining the signature low vascular tone of the kidney by an RES-701-1-sensitive, endothelial ET B receptor subtype through tonic stimulation of endothelial-derived relaxing factors and/or restraint of ET production. RES-701-1 appeared to be relatively selective for the “vasodilator” ET B receptor subtype on the endothelium. However, under pharmacological or pathophysiological conditions, ET-mediated vasoconstriction may predominate.


Based on these findings in male rats, a logical question was whether the endothelial ET B receptor-NO vasodilatory mechanism might be accentuated by pregnancy, thereby mediating the gestational changes in the renal circulation. Short-term infusion of the endothelial ET B receptor antagonist RES-701-1 to conscious virgin and gravid rats completely abolished gestational renal vasodilatation and hyperfiltration, producing convergence of GFR, ERPF, and effective renal vascular resistance in the two groups of animals. The inhibited myogenic constriction of small renal arteries from midterm pregnant rats was also reversed by adding RES-701-1 or a mixed ET B +ET A antagonist (SB209670), but not a specific ET A receptor antagonist (BQ123) to the bath. These findings paralleled those observed using inhibitors of NO synthase ( vide supra ). Indeed, evidence was subsequently obtained supporting the role of the NO/cGMP pathway in mediating the vasodilatory action of endogenous ET in the renal circulation during rat pregnancy. A critical role for the endothelial ET B receptor subtype in mediating inhibited myogenic constriction of small renal arteries during rat pregnancy was also revealed by studies in ET B receptor-deficient rats, and a similar role for this receptor was also established for relaxin-treated nonpregnant rats. Whether expression of the endothelial ET B receptor increases, thereby representing a primary alteration that mediates renal vasodilatation, hyperfiltration and attenuated myogenic constriction during pregnancy or after chronic administration of rhRLX to nonpregnant rats, seems unlikely, but is disputed.


Jeyabalan and colleagues proposed that relaxin enhances vascular gelatinase activity ( vascular matrix metalloproteinase-2 (MMP-2)) during pregnancy, thereby mediating renal vasodilatory changes through activation of the endothelial ET B receptor-NO pathway ( Fig. 16.4 ). This hypothesis was based on the confluence of several observations: (i) the essential role of relaxin, the endothelial ET B receptor and NO in pregnancy-mediated renal vasodilatation as described above, (ii) the stimulation of MMP expression by relaxin at least in fibroblasts, and (iii) the ability of vascular MMPs such as MMP-2 to hydrolyze big ET at a Gly-Leu bond to ET 1–32 with subsequent activation of endothelin receptors.




Figure 16.4


Working model for the sustained vasodilatory responses of relaxin. Inhibitors of relaxin vasodilatation are shown in the boxes. ET, endothelin; MMP, matrix metalloproteinase; RBF, renal blood flow; GFR, glomerular filtration rate; GM6001, a general MMP inhibitor; cyclic CTT, a specific peptide inhibitor of MMP-2; TIMP-2, tissue inhibitor of matrix metalloproteinase; RES-701-1, a specific ET B receptor antagonist; SB209670, a mixed ET A and ET B receptor antagonist; L-NAME, nitro- l -arginine methyl ester; L-NMMA, N G -monomethyl- l -arginine. Note that phosphoramidon (an inhibitor of the classic endothelin converting enzyme), STT (control peptide for cyclic CTT); heat inactivated TIMP-2, BQ-123 (a specific ET A receptor antagonist), D-NAME and IgGs (control antibodies for MMP neutralizing antibodies) did not affect the slow vasodilatory responses of relaxin. Not depicted in this schema are the essential roles of the Lgr7 (RXFP1) receptor, and vascular endothelial and placental growth factors in mediating the vasodilatory actions of relaxin. See text for further details.


The ideal way to test the physiological role of MMP-2 is by blocking MMP-2 production or inhibiting its action. To this end, inhibition of gelatinase activity using a specific inhibitor of MMP-2/-9, a general inhibitor of MMPs, as well as TIMP-2 and specific neutralizing antibodies abrogated relaxin-mediated renal vasodilatation and hyperfiltration, and/or attenuated myogenic constriction of small renal arteries in relaxin-infused nonpregnant and/or pregnant rats. In contrast, there was no effect of the traditional endothelin converting enzyme blocker, phosphoramidon, which inhibits the hydrolysis of big ET to ET 1–21 . In small renal arteries harvested from relaxin-treated nonpregnant or midterm pregnant rats, vascular MMP-2 activity is increased by approximately 50%. Thus, vascular gelatinase activity is not only a player in the endothelial ET B receptor-NO vasodilatory pathway, but it is a major locus of regulation by relaxin and pregnancy, because neither endothelial NO synthase nor ET B receptor abundance is increased by relaxin or pregnancy, although not all agree.


It is highly 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. Each and every inhibitor of the ET B receptor, nitric oxide synthase or MMP completely abolished the renal circulatory changes during pregnancy or in relaxin-treated nonpregnant rats (citations in ). Nevertheless, experimental confirmation of the link between vascular gelatinase activity and the endothelial ET B receptor-NO vasodilatory pathway was sought. 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 ET B receptor-deficient rats, when taken in the context of the other results ( vide supra ), strongly suggests that vascular gelatinase is in series with, and upstream of, the endothelial ET B receptor-NO signaling pathway.


The mechanism for the increase in vascular MMP-2 induced by rhRLX or pregnancy is not completely understood. Both pro and active MMP-2 activities were increased to a similar extent on gelatin zymography, MMP-2 protein and mRNA were also elevated, and there was no apparent change in TIMP-1 or -2. MMP-2 protein localized to both endothelium and vascular smooth muscle by immunohistochemistry, but further study is required to ascertain in which of these compartment(s) it increases in response to pregnancy or chronic rhRLX administration. (Another caveat is that immunohistochemical localization may be misleading because MMP-2 is a secreted protein.) More recently, arterial-derived vascular endothelial and placental growth factors were both identified to be essential players in the relaxin vasodilatory pathway as described above, although how they are involved remains unclear at the present time. Finally, preliminary evidence implicates the major relaxin receptor, RXFP1, in mediating the inhibition of myogenic constriction by relaxin.


An emerging concept is that the vasodilatory mechanisms of relaxin change according to the duration of exposure to the hormone. The mechanisms involved after long-term administration of hormone to nonpregnant rats or during pregnancy when endogenous relaxin circulates were detailed above. Jeyabalan and colleagues demonstrated that matrix metalloproteinase-9 (MMP-9) rather than MMP-2 activity is increased in small renal and mesenteric arteries isolated from rats after more short-term administration of rhRLX for 4–6 hours ( Fig. 16.4 ). Small renal arteries manifested loss of myogenic constriction, but robust myogenic constriction was restored by incubation with a specific MMP-9, rather than specific MMP-2 antibody as observed following chronic relaxin administration ( vide supra ). Like MMP-2, MMP-9 can hydrolyze big ET at a Gly-Leu bond; the inhibition of myogenic constriction after short-term rhRLX administration was also mediated by the endothelial ET B receptor-NO vasodilatory pathway. Finally, relaxin can rapidly relax within minutes some, but not all, pre-constricted arteries from humans and rats. This rapid response ultimately involves NO stimulation via endothelial Gα i/o protein coupling to PI3 kinase, Akt, and eNOS.


To summarize, relaxin accentuates the endothelial ET B receptor-NO renal vasodilatory pathway during pregnancy by increasing arterial MMP-2 mRNA, protein and activity. Interestingly, higher doses of the specific gelatinase or general MMP inhibitors administered in vivo to nonpregnant control rats also decreased GFR and ERPF and raised blood pressure, albeit to a lesser extent than in relaxin-treated rats, whereas phosphoramidon was without effect. These results suggest that arterial gelatinase activity rather than the traditional endothelin converting enzyme might be the main mechanism for big ET processing, at least in the renal circulation of rats, leading to low vascular tone relative to other organ circulations, thus enabling 20–25% of the cardiac output to be distributed to the kidneys. Possibly, the colocalization of MMP-2 and associated proteins in the caveolae of endothelial cells with the ET B receptor and eNOS facilitates this interaction ( and citations therein).


Other factors in addition to RLX are likely to contribute to gestational increases in GFR and RPF. PlGF may play a role particularly after the first trimester when serum concentrations begin to rise as the placenta grows and matures. Another candidate is calcitonin gene related peptide (CGRP), which rises in the blood during early gestation in women. CGRP is a potent vasodilator, and therefore may 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 aorta from gravid rats, thus suggesting a potential role for AT2 receptor activation in the renal vasodilatation of pregnancy. Intriguingly, histidine decarboxylase and histamine, a potent vasodilator, were both reported to be increased in the superficial 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 mechanisms may be activated by RLX in pregnancy is unknown.


In conclusion, evidence from both animal and human investigations suggests that renal hyperfiltration during pregnancy is mainly secondary to increased RPF, the latter being due to decrements in renal vascular resistance. However, increased K f and reduced plasma oncotic pressure also contribute. There has been considerable progress in identifying mechanisms responsible for this renal vasodilatation, and those where findings appear particularly promising were reviewed in detail above. Of importance, whatever the primary stimulus, it must be a powerful one, because the pregnancy-induced rise in GFR is not confined to women with two normally functioning kidneys, but occurs also in subjects with previously hypertrophied single kidneys (following uninephrectomy), and in transplant recipients.




Osmoregulation in Normal Pregnancy


Plasma sodium levels decrease 4–5 mEq/L in normal gestation. This decrement is often mistaken as a sign of changing sodium balance but in reality P Na is but a surrogate for plasma osmolality ( P osmol ), the latter decreasing ~10 mosm/kg during pregnancy. The decrease commences during the luteal phase, falling to a new steady state (~10 mosm/kg) very early in pregnancy and remaining at this new lower level until term. Analysis of data from both human and rodent pregnancy leads to the following explanation of how this occurs. The osmotic thresholds for thirst and arginine vasopressin (AVP) release decrease in parallel ( Fig 16.5 ). Lowering the thirst threshold stimulates increased water intake and dilution of body fluids. Because inhibition of AVP release also occurs at a lower level of body tonicity, the hormone continues to circulate and the ingested water is retained. P osmol then declines until it is below the new osmotic thirst threshold and a new steady state is established with only modest retention of water.




Figure 16.5


Relationship between plasma vasopressin (ordinate) and osmolality (abscissa) during serial hypertonic infusions loading through each trimester and postpartum (as a surrogate in the graph for “preconception”). Each dot represents a single plasma determination. The graph at the bottom contains the highly significant regression lines, the abscissal intercepts defining the marked and significant decrease in the osmotic threshold for vasopressin release. Of further interest is the decreased slope of the line (the gain in plasma vasopressin per unit rise of osmolality). This apparent decrease in the sensitivity of the system was not observed near term in rodents, a species that does not produce vasopressinase. This led to further human protocols that suggested the slope was related to the marked increases in plasma vasopressinase during the last half of pregnancy.

(Modified from ref .)


Figure 16.5 further reveals that the rate of rise in P AVP as P osmol increases decreases as pregnancy progresses. There are two possible interpertations for this finding. The first is that the sensitivity of the system may be decreasing (i.e., less secretion per unit rise in P osmol ), and the second that the disposal rate (the metabolic clearance, MCR) of AVP is increasing. It is the latter that appears to be the case, AVP’s MCR rising four-fold between early and midgestation. This rise in MCR also parallels the increase in trophoblast mass accompanied by a concomitant rise in circulating levels of cystine aminopeptidase (vasopressinase), the latter phenomenon being the most likely explanation of the striking increase in the MCR of AVP as gestation progresses. This hypothesis is strongly supported by the observation that the disposal rate of infused 1-desamino-8- d -arginine vasopressin (DDAVP: desmopressin), an AVP analog resistant to inactivation by vasopressinase, is virtually unaltered in pregnancy.


Mechanisms responsible for altered osmogegulation are obscure though hCG, constuitive NOS, and relaxin have all been implicated. Relaxin, though, being a hormone secreted by the corpus luteum, is the prime candidate as it explains the effects of hCG decreasing P osmol and osmotic thresholds in premenopausal women, but not men, the osmoregulatory changes during the menstrual cycle, and the alterations in osmoregulation during rodent gestation described earlier in this chapter. Also the decrease in P osmol is blunted in women with primary ovarian failure who successfully carry donated ova, and sheep, which lack relaxin due to a stop codon in the coding sequence, do not show reductions in P osm during pregnancy.


It has also been argued that the osmoregulatory changes reflect changes in how gravidas sense their altered volume, and that hypoosmolality relates to nonosmotic stimuli, the pregnant woman sensing her effective volume as “underfilled.” This relative hypovolemia is then said to be the reason for AVP secretion at lower P osmol . Volume regulation is detailed further in Chapter 15 but of interest here is a report that there are borderline or undetectable elevations in vasopressin levels in gravid rats that lead to upregulation of aquaporin-2 mRNA and its water channel protein in the apical membranes of collecting ducts. These observations, though, appear inconsistent with patterns of renal water handling of both pregnant rodents and humans, who handle water loads similar to the they way they do in the nonpregnant state (unlike patients with cirrhosis and heart failure, who are prototypes for decreased “effective circulating volume” and where nonosmotic AVP secretion leads to decreased abilities to excrete water loads rapidly). That is, there should be a decreased response to water loading tests in human and rodent pregnancies if the density of the water channels was increased and this does not appear to be the case.




Renal Hemodynamics and Glomerular Filtration Rate in Preeclampsia


Chesley appears to have been the first to measure ERPF and GFR in women with normal gestations or with preeclampsia, and his pioneering work was followed by numerous reports on the subject. Table 16.1 is a summary of those investigations where both women with preeclampsia and normal gravidae were studied as a control cohort. We located 23 publications that met these criteria, although in several instances the data from the two cohorts were published separately. In nine of 23 publications, a second control group of nonpregnant women was also studied. Inclusion in Table 16.1 required a reasonably clear presentation of the criteria for diagnosing preeclampsia. These criteria included onset of hypertension in late gestation and proteinuria, and, in many instances, evidence for the absence of hypertension before midpregnancy or normalization of blood pressure postpartum. Several investigators noted that most of their preeclamptic subjects were primiparous, which in retrospect may have improved their likelihood of correctly diagnosing the disease based on the clinical evidence alone.



Table 16.1

Renal Hemodynamics and Glomerular Filtration Rate in Preeclampsia a

















































































































































































































































































































































































































1st Author & Reference No. Nonpregnant Women Normal Pregnancy – Last Trimester Preeclampsia–eclampsia
No. GFR ERPF FF (%) No. GFR ERPF FF (%) No. GFR ERPF FF (%)
Chesley 8–9 57±1 518±15 11.4±0.4 8 79±6 b 610±38 12.2±0.5 17 77±4 b 560±39 14.8±1.3
Wellen, Welsh 7–17 c 121±6 588±40 19.9±1.0 4–6 d 94±15 636±70 14.7±1.6
Dill 7 113±7 614±45 18.6±0.9 6–7 e 83±15 432±58 17.7±2.5
Kariher 8 f 150 754 20.9 17 f 102 512 19.8
Schaffer 9 117±9 7 g 86±14
Chesley 10 125±9 8 h 93±7
Bucht 23 122±5 557±30 22.7±1.0 10 156±10 571±25 28.9±1.2 8 (<33 wks) 102±18 495±72 22.0±3.6
18 (>33 wks) 98±8 423±36 24.6±3.1
Assali 7 109 i 699 15.7 9 77±6 l 557±47 14.7±1.4
Brandstetter 10 117±4 584±30 20.1±0.7 11 128±4 661±27 19.4±0.6 5 (preeclampsia) 77±5 466±27 16.5±0.8
3 (eclampsia) 59±8 399±36 14.5±0.8
Friedberg 6 112±7 635±58 18±1 10 93±5 571±36 17±1
Lanz 12 115±4 k 585±25 20±1 5 j 125 k 700 18 8 91±5 k 529±27 17±1
Page 12 181±10 9 75±6
Lovotti 5 121±7 k 551±54 22.3±1.4 5 151±9 k 641±34 23.6±1.5 10 101±5 k 452±40 23.6±3.0
Hayashi 14 (<32 wks) 129±1 5 (<32 wks) 63±9
23 (>32 wks) 108±6 21 (>32 wks) 99±6
Chesley 17 124±6 11 145±7 13 103±8
Buttermann 11 122±5 624±29 19.3±0.9 26 132±5 647±28 20.9±0.8 33 59±5 341±21 17.0±0.6
Schlegel 10 133±8 659±21 21±1 12 132±6 593±28 23±1 11 93±11 454±59 21.6±1.7
Friedberg 10 132±5 586±15 22.5±0.8 14 105±3 480±16 22.2±0.8
McCartney 7 133±8 6 90±12
Bocci 16 573±36 14 560±24 5 391±43
Sarles 5 175 l 825 l 21.2 9 115 l 550 l 20.9
Sismondi 24 601±6 12 406±15
Chesley 14 170±9 755±45 22.5 13 114±9 606±42 19.6±1.3
Grand mean 114 581 19.5 133 649 20.4 90 487 18.7

a Mean±SEM. All renal clearances are expressed as mL/min or mL/min×1.73 m 2 body surface area. Glomerular filtration rate (GFR) was measured by the renal clearance of inulin, or estimated by the renal clearances of creatinine, mannitol, or thiosulfate. Effective renal plasma flow (ERPF) was measured by the renal clearances of para-aminohippurate or diodrast. Women with preeclampsia and eclampsia were evaluated separately or together. FF=filtration fraction (GFR/ERPF).


b GFR was measured by the renal clearance of creatinine.


c Four subjects who were in the first or second trimester were excluded from the analyses.


d Patients without proteinuria during pregnancy or persistent hypertension after pregnancy at a follow-up clinic were excluded from the analyses ( n =8).


e Two patients without proteinuria were excluded from the analyses; also, one subject with an average C D of 1189 mL/min/1.73 m 2 was deleted as an outlier. Despite bladder catheterization and oral hydration, the authors suggested that low urine flow rate shown by some of the subjects may have compromised measurements of GFR and ERPF, Therefore, subjects with a urine flow of<1.0 mL/min were also excluded.


f Only mean values were provided. For preeclampsia, mild ( n =7), severe ( n =7), and eclamptic ( n =3) women were combined. However, the mean values for eclampsia provided by the authors were considerably lower than either mild or severe preeclampsia which were comparable.


g One subject without proteinuria was excluded from the analysis.


h Two subjects were excluded from the analysis due to oliguria.


i The renal clearance of mannitol was used as an estimate of GFR. Only mean values were provided for normal pregnancy.


j Only five subjects were apparently studied after 24 weeks of gestation, and the data points were plotted on a graph. Because mean values were not provided, they were estimated from the graph.


k GFR was estimated by the renal clearance of thiosulfate.


l Mean values were not provided, rather they were estimated from bar graphs.



A word about the methodologies used. In the majority of cases, the subjects were hydrated by oral water intake to increase urine flow, thus decreasing dead space error and improving the accuracy of the urine collection, and consequently the renal clearance measurements. An indwelling bladder catheter was routinely used in most of the studies (a practice considered unacceptable today), which also permitted more accurate urine collections. In many instances, the renal clearances of inulin and para-aminohippurate were used to measure GFR and ERPF, respectively, but occasionally the clearance of thiosulfate, mannitol, or creatinine was employed, the latter being more “estimates” of GFR. Similarly, the renal clearance of diodrast was frequently used to estimate ERPF. Few investigators commented on how their subjects were positioned during the study, though for convenience one assumes most were probably studied in the supine position. However, lying supine, especially in late gestation, may depress renal function (see “Postural Influence on Renal Function,” above). Finally, most investigators normalized GFR and ERPF for 1.73 m 2 body surface area as assessed at the time of measurement during pregnancy, a practice which has been abandoned in recent times because gestational changes in renal hemodynamics and GFR are believed to be functional in nature, and not related to renal hypertrophy.


In Table 16.1 , the means±SEM have been recalculated from the individual measurements provided for all subjects, when they were presented in the original publications. In some instances, the measurements for each subject were not provided; rather, mean values and/or standard deviations were reported. These were incorporated directly into Table 16.1 after converting the standard deviations to standard errors. Perhaps the most meaningful way to assimilate all of the data from the 23 studies presented in Table 16.1 is to examine the percentage change in GFR, ERPF, and filtration fraction (FF) between preeclamptic and late-pregnant women, and between preeclamptic and nonpregnant women as depicted in Table 16.2 . In all 23 reports, there was a reduction of GFR in preeclamptic subjects compared to late-pregnant women, on average by 32%. In all but one publication, there was a depression of ERPF, on average by 24%. In all but one of the nine studies that also included data for nonpregnant women, GFR and ERPF were reduced by comparison in the preeclamptic subjects both by 22%. Thus, both GFR and ERPF are impaired in preeclampsia compared to late pregnant and nonpregnant women – a conclusion that Chesley and Duffus reached based on their earlier survey of the literature in 1971.



Table 16.2

Percentage Change in GFR, ERPF, and Filtration Fraction between Preeclampsia/Eclampsia and Late-Pregnant or Nonpregnant Levels a































































































































































































































































1st Author & Reference No. % Change from Late Pregnant % Change from Nonpregnant
GFR ERPF FF GFR ERPF FF
Chesley −2.5 −8.2 +21.3 +35.1 +8.1 +29.8
Wellen, Welsh −22.3 +8.2 −26.1
Dill −26.6 −29.6 −4.8
Kariher −32 −32.1 −5.3
Schaffer −26.5
Chesley −25.6
Bucht
<33 wks −34.6 −13.3 −23.9 −16.4 −11.1 −3.1
>33 wks −37.2 −25.9 −14.9 −19.7 −24.1 +8.4
Assali −29.4 −20.3 −6.4
Brandstetter
preeclampsia −39.8 −29.5 −15.0 −34.2 −20.2 −17.9
eclampsia −53.9 −39.6 −25.3 −49.6 −31.7 −27.9
Friedberg −17.0 −10.1 −5.6
Lanz −27.2 −24.4 −5.6 −20.9 −9.6 −15.0
Page −58.6
Lovotti −33.1 −29.5 0.0 −16.5 −18.0 +5.8
Hayashi
<32 wks −51.2
>32 wks −8.3
Chesley −29.0 −16.9
Buttermann −55.3 −47.3 −18.7 −51.6 −45.4 −11.9
Schlegel −29.6 −23.4 −6.1 −30.1 −31.1 +2.9
Friedberg −20.5 −18.1 −1.3
McCartney −32.3
Bocci −30.2 −31.8
Sarles −34.3 −33.3 −1.4
Sismondi −32.5
Chesley −32.9 −19.7 −12.9
Grand mean −32% −24% −9% −22% −22% −3%

a The percentage changes were calculated based on the mean values for GFR, ERPF, and filtration fraction shown in Table 17.1 . See footnotes to Table 17.1 for an explanation of the abbreviations.



The study by Assali et al. is noteworthy because of the succinct description of the diagnosis of preeclampsia, which was frequently lacking in other reports: “the presence of hypertension, edema, and proteinuria after the 24th week of gestation, together with the absence of a history of hypertension prior to pregnancy, and the return of the blood pressure to normal levels following delivery.” In this study, GFR and ERPF were significantly reduced by 29.4% and 20.3%, respectively, compared to normal women in late pregnancy. Also deserving emphasis are the publications by McCartney et al. and Sarles et al., in which the diagnosis of preeclampsia was based not only on clinical criteria, but also according to the presence of glomerular endotheliosis in renal biopsy obtained in the postpartum or intrapartum period, respectively. McCartney et al. also studied their subjects in the lateral recumbent position, which avoided the potential artifactual decrease in renal function due to compression of the great vessels by the gravid uterus. Thus, using the renal clearance of inulin, McCartney et al. identified a 32.3% reduction of GFR in women with preeclampsia compared to normal women in late pregnancy ( Fig. 16.6(A) ). Similarly, Sarles et al. observed a 34.3% and 33.3% reduction in the renal clearances of inulin and para-aminohippurate, respectively, in women with preeclampsia compared to normal women in late pregnancy. Last, but not least, is the well-controlled investigation by Chesley and Duffus in which women were studied in the lateral recumbent position, and GFR and ERPF were corrected for 1.73 m 2 based on prepregnancy body surface area. The investigators noted a 32.9% and 19.7% decline of GFR and ERPF, respectively, in the women with preeclampsia compared to normal women during late pregnancy.




Figure 16.6


(A) Individual inulin clearance data and the mean values for six different patient groups. In particular, note the 32% reduction of glomerular filtration rate in pregnant women with preeclampsia (as documented by postpartum renal biopsy) compared to normal pregnant women. (B) Individual inulin clearance data and the mean values for pregnant women with preeclampsia documented by postpartum renal biopsy. AP=antepartum; PP=postpartum day 7. See text for further details.


In more recent work, Irons et al. measured ERPF and GFR by the renal clearances of para-aminohippurate and inulin, respectively, in women with normal pregnancy ( N =10) and women with preeclampsia ( N =10). The normotensive gravidae demonstrated an ERPF and GFR of 766±52 and 153±13 mL/min at 32 weeks of gestation, respectively, which decreased to 486±17 and 87±3 mL/min 4 months postpartum. The preeclamptic women, who were all primiparous and normotensive during gestational weeks 12–18, showed>2 g protein/24 h and blood pressure>140/90 mm Hg at 33.5 weeks of gestation. ERPF and GFR were 609±24 and 97±7 mL/min, respectively, which changed to 514±22 and 109±7 mL/min 4 months postpartum. Thus, consistent with previous investigations ( Table 16.1 ), both ERPF and GFR were compromised in preeclampsia, the latter to a greater extent. Comparable findings were subsequently reported by the same group in another study. However, concurrent analyses of the renal clearances of inulin, para-aminohippurate and neutral dextrans in this study also permitted calculation of K f , which was approximately 50% lower in preeclamptic compared to normal pregnant women.


The mechanism(s) ultimately responsible for the compromise of the renal circulation in preeclampsia remains unknown. It may stem, however, from vascular endothelial damage, first proposed by Stubbs et al., reflected by the finding of glomerular endothelial swelling first reported by Mayer in 1924. Thus, “endothelial dysfunction” is widely believed to be a major mechanism in the pathogenesis of the disease leading to widespread vasospasm and organ hypoprofusion ( Chapter 9 ). Many candidate molecules causing endothelial damage, some arising from the placenta, have been identified in recent years ( Chapter 6 , Chapter 8 , Chapter 9 ). Endothelial mechanisms are also implicated in the renal vasodilatation and hyperfiltration of normal pregnancy as previously described (see “Renal Hemodynamics and Glomerular Filtration Rate during Normal Pregnancy”), and possibly these are compromised by the “endothelial dysfunction” which afflicts women with preeclampsia, thereby contributing to the impairment of GFR and ERPF. Irrespective of the inciting agent(s), renal vascular resistance is inappropriately high, which accounts for impaired renal blood flow. Based on indirect calculations of the renal afferent and efferent arteriolar, as well as venular resistances, the pathologic increase in total renal vascular resistance is largely due to an increase in the afferent arteriolar resistance ( Table 16.3 ). On the one hand, this finding is not entirely unexpected because the FF, which is used in the calculation of the renal segmental arteriolar resistances, shows only a 9% decline in preeclampsia ( Table 16.2 ). That is, if GFR and ERPF are reduced in proportion such that the ratio or FF shows little change or is unchanged, then an increase only in the afferent arteriolar resistance is inferred. On the other hand, although the decline in FF is small, it is a consistent finding in preeclampsia, because the impairment in GFR exceeds that of ERPF ( Table 16.2 ). A simultaneous reduction in renal efferent arteriolar or venular resistance could theoretically account for this finding, but the calculated segmental resistances do not support this argument ( Table 16.3 ). Rather, a reduction in the K f is a more likely explanation stemming from perturbations in the glomerular capillary hydraulic conductivity, surface area available for filtration or both, a deduction recently supported by the study by Moran and co-workers ( vide supra ). Indeed, neutralization of podocyte-derived vascular endothelial growth factor (VEGF) by pathological levels of circulating soluble vascular endothelial growth factor receptor-1 (VEGF-R1 or sFlt-1) emanating from the preeclamptic placenta leads to glomerular endotheliosis epitomized by loss of fenestrae, structures that are crucial for hydraulic conductivity.



Table 16.3

Estimated Segmental Renal Vascular Resistances in Preeclampsia a















































































































1st Author & Reference No. Diagnosis Renal Vascular Resistance (Dynes×s×cm −5 ) b
No. Total Afferent Arteriolar Efferent Arteriolar Venular
Assali Normal pregnancy 7 5178 1883 1531 1751
Preeclampsia 9 10,229 6666 1405 2228
Friedberg Normal pregnancy 6 6144 2085 1781 2333
Preeclampsia 10 11,321 6887 2057 2470
Brandstetter Normal pregnancy 44 6640 2430 2080 2130
Preeclampsia 5 17,643 12,896 1864 2884
Eclampsia 3 21,522 16,611 1694 3417
Buttermann Normal pregnancy 26 7410 3055 2125 1960
Preeclampsia 33 18,740 13,270 1788 3682
Bocci Normal pregnancy 14 7300 3167 1870 2275
Preeclampsia 5 16,509 11,446 1867 3174
Grand mean Normal pregnancy 6534 2524 1877 2090
Preeclampsia/eclampsia 15,994 11,296 1779 2976

a Segmental renal vascular resistances were estimated according to the calculations of Gomez.


b Mean values are shown.



A final consideration is the recovery of renal function during the puerperium in women who suffered preeclampsia during pregnancy. Table 16.4 includes those investigations that reported antepartum and postpartum measurements of GFR and/or ERPF in women with preeclampsia. Also included is the average number of days or weeks after delivery when renal function was measured. Based on the studies by Schaffer et al., Chesley and Williams, as well as McCartney et al. ( Fig. 16.6(B) ), there was notable improvement of the GFR during the first 7 to 8 days postpartum. (Also compare with nonpregnant control values listed in Table 16.1 .) Unfortunately, these investigators did not measure ERPF, but it appears from the other studies listed in Table 16.4 that ERPF may have remained depressed during the same postpartum period. Buttermann studied the women immediately after delivery, and found GFR markedly and ERPF somewhat improved ( Table 16.4 ). In the investigation by Moran et al., the decreased K f observed in the preeclamptic women had recovered by at least 5 months postpartum, but earlier time points were not investigated.



Table 16.4

Antepartum and Postpartum Renal Function in Women with Preeclampsia a





























































































































































1st Author & Reference No. No. Antepartum Postpartum Average Time After Delivery
GFR ERPF FF(%) GFR ERPF FF(%)
Corcoran 3–13 99±7 659±6 13.5±1.2 109±5 478±11 22.3±0.4 13 wks
Dill 6–7 83±15 432±58 17.7±2.5 129±8 429±38 28.5±2.4 Not cited
Wellen 4–6 94±5 636±70 14.7±1.6 107±5 540±28 20.2±0.9 5 wks
Kariher 17 102 512 19.8 124 568 21.3 ≥12 days
Schaffer 3 93±28 121±15 8 days
Chesley 8 93±7 106±6 6–9 days
Odell 4 93±17 182±27 Not cited
Bucht 18–26 98 423 24.6 119 426 27.9 2–7 wks
Lanz 3 78±1 598±10 13±0 108±6 559±50 19±1 10 wks
Page 9 75±6 109±6 Several weeks
Buttermann 33 59±5 341±21 17.0±0.6 98±6 418±17 24.0±1.3 Immediately after delivery
Schlegel 4 92±24 504±143 20.3±2.9 121±19 532±56 23.3±3.9 14–22 days
McCartney 6 90±12 139±13 7 days
Grand mean 88 513 17.6 121 494 22.7

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Sep 20, 2018 | Posted by in GYNECOLOGY | Comments Off on The Kidney in Normal Pregnancy and Preeclampsia
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