Renal Physiology and Disease in Pregnancy

Mechanisms of Renal Hemodynamic Changes During Pregnancy

Our understanding of mechanism(s) underlying the gestational rise in ERPF and GFR continues to evolve. In part due to both ethical and logistical concerns, most studies designed to determine mechanisms of gestational changes in renal function have utilized animal models as there are several species also known to manifest increases in GFR and ERPF during pregnancy [referenced in ]. Thus, by applying the renal micropuncture technique to Munich-Wistar rats during midgestation, the period when ERPF and GFR are maximally increased in this species, Baylis demonstrated the gestational rise in single nephron GFR (SNGFR) to be secondary to an increase in glomerular plasma flow, the latter due to a decline in renal vascular resistance. In her rat model, transglomerular hydrostatic pressure difference remained unchanged because there were comparable decreases in both afferent and efferent arteriolar resistances. Plasma oncotic pressure was not significantly different between nonpregnant and midterm pregnant rats and thus not involved in altering SNGFR. Because the animals were in filtration equilibrium, only a minimum value for the ultrafiltration coefficient, K _f could be calculated, which was similar between nonpregnant and midterm pregnant rats; nevertheless, this determinant of glomerular ultrafiltration most likely contributed little to the gestational rise in SNGFR in the gravid rat model. To summarize, SNGFR rises mainly because glomerular plasma flow increases in the gravid rat model.

Whether similar mechanisms occur in pregnant women is unknown as glomerular dynamics cannot be directly measured. Moreover, human glomeruli may be in filtration disequilibrium, a condition in which alterations in ERPF are predicted to have less impact on GFR. Nevertheless, the parallel increases in ERPF and GFR suggest a similar mechanism governing the rise in GFR in gravid women.

Using an indirect approach, investigators measured the fractional clearance of neutral dextrans ( C _dextran / C _inulin ) in normal pregnant women serially studied throughout early and late gestation followed by retesting 6 weeks postpartum. Such data can be analyzed by mathematical models, which incorporate clearance values and plasma oncotic pressures to predict glomerular capillary pressure, the ultrafiltration coefficient ( K _f ) and glomerular capillary membrane porosity. Permselectivity to neutral dextrans was altered during gestation ( Figure 81.5 ), and the theoretical analysis of the sieving curves, using two different models, suggested that hyperfiltration during pregnancy was mainly due to increments in ERPF with a minor contribution from decreased glomerular oncotic pressure (the latter being greater during late gestation). Membrane porosity appeared to be altered, but comparable to micropuncture studies in rats, there was no evidence of increased glomerular capillary pressure in human pregnancy ( Figure 81.5 ). It should be emphasized, however, that this approach is theoretical in nature being dependent on several assumptions that may or may not be valid.

Further insight into the causes of the altered renal hemodynamics during pregnancy arose from studies in a rat model. Conrad adapted methodologies developed by Gellai and Valtin for measurement of renal function in chronically instrumented, conscious rats and applied them to pregnancy. Because physiology is markedly perturbed by anesthesia and surgical stress and the effects of anesthetics and surgical stress can differ in the nonpregnant and pregnant states, studies in chronically instrumented, conscious animals are an essential first step in the investigation of mechanisms underlying maternal circulatory adaptations to pregnancy. Thus, when the same chronically instrumented, conscious rats were serially studied before, during, and after pregnancy, both renal vasodilation and hyperfiltration were observed throughout most of gestation, making it an excellent model to explore the mechanisms underlying these changes.

Vascular Matrix Metalloproteinase-2

Jeyabalan and coworkers proposed that relaxin enhances vascular gelatinase activity during pregnancy that, in turn, mediates renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small renal arteries ultimately through activation of the endothelial ET _B receptor–NO pathway ( Figure 81.6 ). The hypothesis that vascular gelatinase activity plays a pivotal role was founded upon the confluence of several observations: first, the essential role of relaxin, the endothelial ET _B receptor, and NO in pregnancy-mediated renal vasodilation as described above; second, the publications reporting stimulation of matrix metalloproteinase (MMP) expression by relaxin in fibroblasts; and third, the ability of vascular MMPs, such as MMP-2, to hydrolyze big ET at the gly–leu bond to yield ET _1–32 with activation of ET receptors.

The best (if not the only) approach to testing the potential role of MMP-2 in mediating renal vasodilation, hyperfiltration, and inhibited myogenic reactivity of small renal arteries mediated by pregnancy or relaxin is to block MMP-2 production or its activity. Accordingly, short-term infusion of gelatinase inhibitors abrogated relaxin-mediated renal vasodilation and hyperfiltration in conscious rats; moreover, the inhibited myogenic reactivity of small renal arteries isolated from pregnant or relaxin-treated nonpregnant rats was reversed by gelatinase inhibitors in vitro . In contrast, there was no effect of the traditional ET-converting enzyme inhibitor, phosphoramidon, which inhibits the processing of big ET to ET _1–21 . In small renal arteries harvested from relaxin-treated nonpregnant and midterm pregnant rats, MMP-2 activity is increased by ~50% relative to nonpregnant control arteries. Thus, vascular gelatinase activity is not only part of the relaxin-endothelial ET _B receptor–NO vasodilatory pathway, but it is a major locus of regulation by relaxin in this species, because neither endothelial NO synthase nor ET _B receptor abundance is increased by relaxin or pregnancy, but not all investigators agree.

It is unlikely that vascular MMP-2 and endothelial ET _B receptor–NO are components of separate vasodilatory pathways acting in parallel. If this was the case, then one might predict that after inhibition of either vascular MMP-2 or the endothelial ET _B –NO pathway, compensation of one for the other should be observed. However, no compensation or even partial compensation was noted: each and every inhibitor of the ET _B receptor, NO synthase, or MMP completely abolished the renal circulatory changes during pregnancy or relaxin treatment of nonpregnant rats. Nevertheless, experimental confirmation of a common vasodilatory pathway shared by vascular gelatinase activity and the endothelial ET _B receptor–NO vasodilatory pathway was obtained. That is, small renal arteries isolated from relaxin-treated, ET _B receptor-deficient rats showed upregulation of vascular MMP-2 activity, but failed to show inhibition of myogenic reactivity. This dissociation of the biochemical and functional consequences of relaxin administration in small renal arteries harvested from 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.

To summarize, during pregnancy relaxin accentuates the endothelial ET _B receptor–NO renal vasodilatory pathway by increasing vascular MMP-2 activity (via increases in MMP-2 mRNA and protein ). A more recent study also suggests the participation of vascular endothelial growth factor (VEGF) and placental growth factors (PlGF) in the renal vasodilatory pathway of relaxin. Interestingly, higher doses of gelatinase inhibitors also decreased GFR and ERPF, and elevated arterial pressure when administered to control rats, albeit less so than in relaxin-treated rats, whereas phosphoramidon was again without effect. These results suggest that vascular gelatinase activity rather than the traditional ET-converting enzyme may be the main physiological mechanism for big ET processing (and consequent vasodilation) at least in the renal circulation of rats. 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 ( Figure 81.6 ).

Other factors in addition to relaxin are likely to contribute to gestational renal vasodilation and hyperfiltration especially during late pregnancy, when circulating levels of placental hormones are particularly high. For example, placental growth hormone may contribute. In addition, local factors within the kidneys themselves may participate. Mesangial cell expression of iNOS, the angiotensin (AT)-2, and relaxin receptors was reported to increase during midgestation in rats. Moreover, upregulation of the n NOSβ isoform in the renal cortex of midterm pregnancy rats was noted. Intriguingly, Morgan and colleagues observed increased histidine decarboxylase and histamine production in the superficial cortical zone of pregnant mice. Finally, increased renal production of epoxyeicosatrienoic acid may also play a role in renal vasodilation and hyperfiltration of pregnancy.

To conclude, evidence from both animal and human studies suggests that renal hyperfiltration in pregnancy is secondary to increased RPF, the latter resulting from profound decreases in renal vascular resistance. There has been considerable progress in identifying mechanisms responsible for gestational renal vasodilation, and those most promising so far were reviewed in detail above. Of importance, whatever the primary vasodilatory stimulus, it must be a powerful one, for the pregnancy-induced rise in GFR is not restricted to women with two normally functioning kidneys but occurs also in subjects with previously hypertrophied single kidneys (following uninephrectomy) and in transplant recipients.

Significance of the Changes in Renal Hemodynamics During Pregnancy

The GFR increase during pregnancy has important clinical consequences. Production of creatinine changes little, so that increases in creatinine clearance lead to a reduction in its plasma level. This is also true of urea, which may be decreased even further by enhanced protein synthesis. Therefore, levels of creatinine and urea nitrogen decrease from a mean of 0.7 and 12 mg/dl (62 and 4.3 mmol/L), respectively, in the nonpregnant state, to 0.5 and 9 mg/dL (44 and 3.2 mmol/L). The implication of these observations is that values considered normal in nonpregnant women may reflect compromised renal function during pregnancy. Concentrations of serum creatinine and urea nitrogen exceeding 0.8 and 13 mg/dL (80 mmol/L and 5 mmol/L), respectively, should alert the clinician to evaluate renal function further.

The augmented filtered load consequent to increased GFR also contributes to the glucosuria, aminoaciduria, and enhanced urinary excretion of water-soluble vitamins that occur during normal pregnancy. Urinary protein excretion may double as well, but the greatest increments seem to occur in late gestation, long after changes in renal hemodynamics are maximal. Also, there are still discrepancies about whether there are increases in albuminuria during pregnancy, but the majority of studies suggest so. It should be borne in mind, though, that many factors affect urinary protein excretion in addition to glomerular filtration, including the pore size and number of fixed charges in the glomerular filtration barrier, and tubular reabsorption rates, a topic discussed elsewhere in this text.

There are also changes, usually increments, in the renal excretion of various low-molecular weight proteins and enzymes during pregnancy. Whether the alterations result from increased filtration and/or changes in tubular handling, or even in production is unclear (see Ref. ) for further details and citations). The increments in urinary glucose, amino acids, and proteins mentioned above also have pathophysiological consequences, i.e., the nutrient content of the urine is increased, which may predispose pregnant women to symptomatic urinary tract infection. Finally, awareness that the normal limit of urinary protein excretion is increased during gestation to 300 mg/24 h suggests that this event will also occur and may even be exaggerated in women with preexisting kidney disorders, so that increased proteinuria during pregnancy does not necessarily signify progression or exacerbation of their disease.

Glucose, Other Sugars, and Water-Soluble Vitamins

Glucosuria may occur normally during pregnancy. In one study, 30 women with normal glucose tolerance were evaluated serially beginning early in gestation and continuing through the sixth postpartum week (reviewed in Ref. ). Daily urinary excretion of glucose was measured by a sensitive and specific enzymatic assay, an important methodological consideration, because excretion of many other reducing substances also increases during pregnancy. All subjects excreted <100 mg/24 h when not pregnant, but during gestation this value was exceeded in 26 women (86%) ranging up to 500 mg in 12, between 0.5 and 1.0 g in 4, and exceeding 1 g/24 h in 10 others. Glucosuria was intermittent and not necessarily related to blood glucose levels or gestational stage. A comparable high incidence of glucosuria in normal pregnancy was reported by others (reviewed in Ref. ). Gestational glucosuria reverts to normal within 1 week postpartum.

Renal tubular handling of glucose, including the transport maximum ( T _m ), threshold, and splay of the titration curve were evaluated during pregnancy. Many reports had weaknesses in experimental design, but there were exceptions. With exquisite attention to methodology, Welsh and Sims assessed the T _m of glucose in normal nonpregnant subjects, nonglycosuric pregnant women, and normoglycemic glycosuric gravidas. The T _m of glucose was lower in the latter group in comparison to the nonglycosuric pregnant subjects, and the authors proposed that gestational glucosuria resulted from increased GFR, and hence filtered load, in women with a low T _m for glucose. Fifteen years later, Davison and colleagues suggested that both the T _m and fractional reabsorption of glucose decrease in all pregnant women. In their study, renal glucose reabsorption was measured in subjects with normal carbohydrate metabolism during and after gestation. Care was taken to avoid extremely high plasma glucose concentrations during infusions, which can affect renal hemodynamics. All women demonstrated lower fractional reabsorption of glucose during pregnancy compared to after delivery. Those most severely glycosuric in pregnancy had the lowest fractional reabsorption rates both during and after gestation; however, they were not glycosuric postpartum because GFR and the filtered load of glucose had decreased substantially. Said otherwise, even if the splay in the glucose titration curve increases or the glucose T _m decreases slightly, the striking gestational increment in GFR and consequent filtered load of glucose remains the major cause of glucosuria in pregnancy.

Gravid rats may also display glucosuria. Renal micropuncture studies in this species reveal that proximal tubular glucose reabsorption is actually enhanced, commensurate with the increment in filtered load; thus, the increased urinary glucose is due mainly to decreased distal tubular reabsorption, and perhaps to changes in epithelial permeability causing backleak in Henle’s loop.

Excretion of other sugars, including lactose, fructose, xylose, and fucose, but not arabinose, also increases during pregnancy [citations in Ref. ]; lactosuria is present in 50% of gravidas by the end of gestation, when excretion may be as much as 10-fold higher than nongravid women. During pregnancy, certain oligosaccharides are excreted in the urine not found in the urine of nonpregnant women, and thus, they are suspected to be of mammary origin. It should be emphasized, however, that the excretion of these sugars combined is minimal compared to that of glucose, and consequently, they do not amount to a significant nutrient loss to the mother.

The renal excretion of several water-soluble vitamins is also increased during pregnancy including nicotinic, ascorbic, and folic acids. Plasma folate levels actually decrease in pregnancy, and the increased urinary excretion may be largely due to reduced tubular reabsorption rather than enhanced filtered load.

Amino Acids

Urinary excretion of many amino acids rises during pregnancy. In fact, urinary histidine concentration was once used as a method to detect pregnancy, and its disappearance from the urine was noted in preeclampsia. The most detailed studies are by Hytten and Cheyne, who conducted serial measurements in 10 women from early pregnancy through the eighth postpartum week. Renal excretion of glycine, histidine, threonine, serine, and alanine increased early in gestation and urinary losses became substantial near term. In contrast, increments in urinary excretion of lysine, cystine, taurine, tyrosine, phenylalanine, valine, and leucine occurred during the first half of pregnancy, but declined thereafter, and the urinary excretion of asparagine, glutamic acid, and arginine was unchanged during gestation. It is noteworthy that gestational aminoaciduria can reach ~2 g/day, a loss that could adversely affect fetal growth, if protein intake is suboptimal. In some subjects, urinary glycine and histidine excretion exceeded 50% of the filtered load, suggesting a role for inhibition of tubular reabsorptive process. However, these data reflect 24-h renal clearance measurements, and the little information concerning threshold or T _m during short-term infusion studies is inconclusive.

Uric Acid

Although uric acid production has been described as unchanged during pregnancy, more recent evidence disputes this conclusion. In either case, gravidas excrete considerably more urate than when they are not pregnant. The renal clearance of uric acid, typically 6–12 mL/min in nonpregnant women, rises to 12–20 mL/min during pregnancy, and consequently, plasma concentrations decline at least 25% and are only 2.5–4.0 mg/dL in many pregnant women. In most centers, 5–5.5 mg/dL is considered to be the normal upper limits for pregnancy, but the upper limit is different depending on the stage of gestation. Circulating urate tends to be higher in women with multiple gestations, displays circadian rhythm with higher and lower levels at morning and night, respectively, and the normal range may be subject to racial variations.

Whereas both the filtered load and absolute tubular reabsorption of urate increase during gestation, most investigators have documented increments in fractional excretion, i.e., the C _urate / C _inulin ratio is greater in pregnancy than in the nonpregnant state (reviewed in Refs and ). However, there have been only two well-monitored serial studies in which investigators determined urate concentrations with specific enzymatic assays, and the results vary. In one study, no difference in fractional clearance of urate during and after pregnancy was reported, whereas in the other, C _urate / C _inulin increased during the first two trimesters but returned to nonpregnant values in the third.

The peak in renal clearance of urate and the nadir in plasma concentration are observed in early gestation; subsequently, C _urate declines and plasma urate levels rise near term. It is not clear whether these findings are confounded by postural artifacts, nonrenal metabolic effects in relation to the oxidant/antioxidant balance during gestation, or possibly by inadvertent inclusion of women with subclinical preeclampsia. In this regard, decrements in the C _urate / C _inulin or increments in P _urate concentrations may precede the clinical manifestations of preeclampsia.

Potassium Secretion

There are few data on body potassium stores in pregnancy. One study suggests that body stores decline early in gestation and then rise to values ~100 mEq above prepregnancy levels. These findings are consistent with the theoretical considerations that pregnant women should lose potassium in their urine, because they eat and excrete normal quantities of sodium, but manifest very high levels of aldosterone and other potent mineralocorticoids (see below). Furthermore, they develop bicarbonaturia at substantially lower plasma bicarbonate levels than do nonpregnant women. Observations that plasma and serum potassium levels decrease 0.2–0.3 mEq/L between gestational weeks 10 and 28 are also consistent with this formulation.

A more traditional view, however, is that pregnant women do not waste potassium but undergo a cumulative retention of ~350 mEq of the cation, most of which is stored in the products of conception, as well as in the organs of reproduction ( Table 81.1 ). Moreover, in striking contrast to nonpregnant women, gravidas are resistant to the kaliuresis provoked by the combination of exogenous mineralocorticoids and a high-sodium diet ( Figure 81.7 ). This remarkable capacity to conserve potassium in the face of high concentrations of potent mineralocorticoids such as aldosterone and deoxycorticosterone (DOC), and the delivery of substantial quantities of sodium to distal nephron sites, may be secondary to the increased circulating levels of progesterone during pregnancy, a view supported by studies in both humans and animals but not accepted by all.

Resistance to the kaliuretic influence of mineralocorticoids may benefit gravid women with certain potassium-wasting diseases. On the one hand, excessive potassium loss of primary aldosteronism may be easier to control in gestation ( Figure 81.8 ). On the other, if the kidneys resist kaliuretic stimuli, women with underlying disorders that impair their ability to excrete potassium may be jeopardized by gestation. Finally, there is a rare disorder in which the renal mineralocorticoid receptor is genetically altered in a manner that hormones antagonizing the salt-retaining actions of corticoids become agonist in nature. During pregnancy, progesterone levels increase 100-fold, and women heterozygous for the disorder manifest severe hypertension, renal potassium wasting, and marked hypokalemia, but suppressed aldosterone levels.

Regulation of Acid–Base Balance

Acid–base balance is affected by pregnancy. Blood levels of hydrogen ion decline 2–4 nmol early in gestation, a decrement that is maintained throughout pregnancy, and arterial (or arterialized capillary) blood pH is typically 7.42–7.44 in gravidas, as compared with 7.38–7.40 in nonpregnant women. This mild alkalemia is respiratory in origin, because pregnant women hyperventilate (believed to be a central effect of progesterone effect), and consequently, their arterial PCO ₂ decreases from a nonpregnant mean of 39 to 31 torr during gestation. Supporting the causal role of progesterone are data showing that arterial PCO ₂ also falls 3–4 torr during the luteal phase of the menstrual cycle. These decrements in PCO ₂ are compensated by decreases in plasma bicarbonate levels of ~4 mEq/L, normal values in gestation ranging from 18 to 22 mEq/L, thereby establishing a blood pH that is only slightly alkalotic.

There have been few studies addressing renal bicarbonate reclamation and regeneration during pregnancy. Lim et al. infused a hypertonic bicarbonate solution in women during the third trimester. The bicarbonate titration curve from that study is shown in Figure 81.9 (left). Despite large filtered loads of bicarbonate, reabsorption continued to increase, and even when plasma levels reached 31 mEq/L, reabsorption virtually matched the filtered load. These results were unexpected, because pregnant women are hypocapnic and have increased extracellular volumes, conditions that should lead to an exaggerated “splay” in the titration curve and/or a decrease in the apparent T _m for bicarbonate. However, a small but persistent bicarbonate leak was noted at lower plasma bicarbonate concentrations during pregnancy than postpartum ( Figure 81.9 , right). This modest bicarbonaturia was occasionally present at plasma bicarbonate levels as low as 15–16 mEq/L.

Urinary acidification as well as titratable acid and ammonium excretion have been measured in gravid women after being challenged with both acute and chronic administration of NH ₄ Cl. The results were comparable to those of nonpregnant control subjects. It is noteworthy that the decrement in urine pH and the increases in titratable acid and ammonium excretion occurred even though blood pH decreased only slightly from 7.44 to 7.40. Thus, substantial bicarbonate regeneration can already be demonstrated at a pH higher than in nonpregnant women, and in fact it starts when values are still alkaline relative to the nonpregnant state. Distal hydrogen secretory capacity, as measured by the increment in urinary PCO ₂ during the bicarbonaturia that accompanied the hypertonic bicarbonate loading, appeared to be intact during pregnancy. Finally, the decrease in blood pH during exercise is similar in the pregnant and nonpregnant states.

Osmotic Thresholds for AVP Release and Thirst

P _osm decreases 8–10 mOsm/kg during normal gestation. This decline, which starts in the luteal phase of the menstrual cycle, continues through conception and reaches a nadir about gestational week 10, after which it is maintained until term. Only about 1.5 mOsm/kg of the fall can be accounted for by decreases in urea concentration, most of the change resulting from a decline in the concentrations of plasma sodium and its attendant anions. Thus, pregnancy is characterized by a true decrease in effective P _osm .

A decrease in P _osm of such magnitude in a nonpregnant subject would suppress antidiuretic hormone secretion and result in a state of massive and continuous water diuresis, which does not happen in pregnant women. Rather, gravidas are able to maintain the new, lower P _osm within a narrow range, and water loading or fluid restriction, respectively, lead to appropriate dilution and concentration of their urine. These events are made possible because osmotic thresholds for both AVP secretion and thirst decrease by 8–10 mOsm/kg each during gestation, decrements which are already demonstrable during gestational weeks 5–8 and are sustained through term ( Figure 81.10 ). It should be emphasized that parallel declines in both the osmotic thresholds for AVP release and thirst are required, in order to maintain the new steady state P _osm within a narrow range. That is, P _osm would rise in the face of persisting circulating levels of AVP at the lower P _osm of gestation, if the subject is not simultaneously stimulated to drink water; conversely, considerable polydipsia would be required to maintain a lower P _osm in the absence of AVP secretion.

The metabolism of AVP also changes in gestation, hormonal disposal rates rising four-fold between early and midgestation. This rather striking increase in the metabolic clearance rate (MCR) of AVP parallels the marked increase in both placental trophoblastic mass and circulating levels of cystine aminopeptidase (vasopressinase). Thus, the rise in MCR of AVP is likely due to the extremely high circulating vasopressinase emanating from the placenta, a concept supported by studies showing that the metabolic clearance of 1-deamino 8-D-AVP (DDAVP, Desmopressin), the AVP analogue resistant to inactivation by vasopressinase, does not change in pregnancy ( Figure 81.11 ).

The cause of the osmoregulatory changes in pregnancy is obscure. hCG, constitutive NOS, and relaxin have each been suggested to play etiologic roles. Of further interest, decrements in P _osm do not occur in every species ; they do so, however in rodents (along with decreases in the osmotic thresholds for AVP release and drinking), and the rat has become the model in which to explore mechanisms responsible for changes that occur in humans. In this latter model, injection of hCG yielded equivocal results (Barron and Lindheimer, unpublished observations), but relaxin lowers P _osm , as well as the osmotic threshold for AVP release. These data suggest that the osmoregulatory effects of hCG in premenopausal women, ineffective in males, is through stimulation of ovarian relaxin secretion. This hypothesis remains to be explored.

Of interest is a group of investigators that ascribed the decreased P _osm in pregnancy to the decreased “effective” circulating volume of pregnancy (so-called “nonosmotic” release mechanism, see below). Ohara et al. suggested that plasma AVP is detectable at low P _osm during pregnancy due to nonosmotic release, and gravid rats also manifest upregulation of aquaporin-2 (AQ2) mRNA and protein in apical membranes of the collecting duct, thus abetting water retention and lower body tonicity. However, the mechanism underlying increased AQ2 expression is uncertain, because circulating AVP, although detectable despite the lower P _osm , are not elevated above nonpregnant values (as in congestive heart failure). As discussed below, others have accumulated evidence against decreased or “underfill” of the arterial circulation as an explanation for the control of vasopressin secretion during pregnancy. We note here that the observations of Ohara et al may be paradoxical, insofar as an increase in AQ2 might be expected to blunt the animals ability to excrete a water load, yet gravid rats excrete water as well as or better than virgin controls.

Significance of the Osmoregulatory Changes

The physiological significance of the changes in body tonicity, as well as in the osmotic threshold for AVP release and thirst is unclear. They may represent an epiphenomenon secondary to hormonal changes of pregnancy, but it is noteworthy that they may facilitate the increments in intravascular and extracellular volume that occur in pregnancy. Some believe the “physiological hypervolemia” of gestation optimizes fetal development, and in this respect, hypoosmolality results in a need for less solute per liter of extracellular water retained, certainly an advantage when sodium is scarce. Another idea is that the retention of water during pregnancy, which is distributed mainly to the intracellular space, creates a reservoir for maintaining extracellular and intravascular volume when water is scarce.

One very clinically relevant consequence of the altered osmoregulation in pregnancy is related to the striking increase in the MCR of AVP. In the past, women with central diabetes insipidus (DI) required increasing amounts of AVP administration during pregnancy. This is no longer the case since virtually all patients are currently managed with DDAVP, which escapes metabolism by circulating placental vasopressinase ( vide supra ). Still there are patients with partial central DI and sufficient hormone secretory capacity to escape detection when nonpregnant, whose disease is unmasked by the marked increase in AVP disposal rates of pregnancy. More frequent and dramatic, however, is another syndrome called “transient DI of pregnancy,” which presents during the second half of gestation and remits postpartum. It is important to recognize this entity as women may become dangerously hypernatremic especially if they undergo cesarean sections using general anesthesia or are water restricted in the delivery suite. These patients have markedly high levels of circulating vasopressinase that may still be above those of normal gestation when measured during the first week of the puerperium. Others may have subclinical central DI, their pituitary gland unable to respond to the increases in MCR of AVP during pregnancy. Polyuria in these women is usually unresponsive to large doses of AVP (pitressin), but they concentrate their urine rapidly when treated with DDAVP ( Figure 81.12 ). Some of these patients have hepatic dysfunction usually associated with preeclampsia, but in a few the DI has been associated with acute fatty liver of pregnancy. Thus, it is tempting to speculate that failure of the liver to inactivate vasopressinase, coupled with continuous placental production of large quantities of the enzyme, are causal. Consistent with this reasoning is documentation in one patient of excessive pitocin requirements during labor (vasopressinase destroys oxytocin as well as AVP).

The ability to excrete water during pregnancy can be altered in other ways as well. Changing from lateral recumbency to a supine position decreases urine flow, and quiet standing may be more antidiuretic in pregnant than nonpregnant subjects (reviewed in Refs ). The effect of supine posture is independent of circulating levels of antidiuretic hormone, since it has been noted in a pregnant patient with central DI. It should be underscored, however, that these “nonosmotic” influences on water handling are not sufficient, of themselves, to explain the gestational decline in P _osm . No single body position is maintained all day, and in addition the posturally induced antidiuresis rarely retards urine flow sufficiently to account for the chronically reduced P _osm (and thus the decreased plasma sodium levels ) observed in pregnancy.

Nonosmotic Stimulus for AVP Secretion in Pregnancy

The relative contribution of nonosmotic factors to the regulation of AVP secretion during pregnancy is uncertain, but in the nonpregnant human, volume is an important determinant of AVP release: hypovolemia stimulates, whereas hypervolemia blunts hormone secretion. In gestation, absolute blood volume increases markedly, but how the “effective volume” is sensed is a subject of considerable speculation, ( and discussed below). In this respect, the pregnant rat, which also undergoes a 40–50% increase in plasma volume near term, resets its volume-sensing, vasopressin secretory mechanisms such that the increased volume is sensed as normal. Hypovolemia may decrease the osmotic thresholds for hormone release and thirst (see the chapters by Robertson, MacKnight et al., and Fitzsimons, Vol. 2), and some have ascribed the osmoregulatory changes in human pregnancy to an “underfilling” of the dilated intravascular space, ( and see below). However, expansion of the central volume by head-out water immersion during the first or last trimester had no effect on either the reduced tonicity or the decreased osmotic thresholds in pregnant women, and P _osm could not be restored by overexpansion of volume (produced by administration of exogenous mineralocorticoids) maintained throughout gestation in rats.

Weight Gain

Healthy primigravidas gain ~12 kg during gestation, whereas multiparous women gain about 1 kg less. Most of this gain (~9.5 kg) occurs after the 20th gestational week. Not all of the increase can be accounted for by the products of conception, reproductive tissues, or total body water (discussed below), but 4–6 kg of the added weight may be accounted for by increments in maternal fat stores. The gain of 12 kg cited above was recorded in pregnant women without any edema or with only leg swelling. However, 15% of normal pregnant women may develop generalized edema (including swelling of fingers and face). Their weight gain averaged 14.5 kg, of which 4.9 kg was due to increase in the extracellular-extravascular compartments.

The value of 12 kg is well above averages reported in the older literature. Most surprising, however, is that in the past practitioners tended to regard published averages as upper limits of permissible weight gain, and many pregnant women have been admonished for excessive weight gain and their salt or calorie intake, or both, needlessly restricted. It should be emphasized that some women gain little weight while others may gain twice the average, and gestation proceeds uneventfully in both.

Alterations in Fluid Volume

Most of the weight added in pregnancy represents fluid retention. Total body water has been measured during pregnancy using deuterium, the stable isotope of oxygen [O ¹⁸ ], and by bioelectrical impedance. The results suggest total accumulations of 6–9 L, although they vary due to methodological differences. Of interest, in a serial study starting before conception, Forsum et al. noted higher increments in body fat than other investigators.

The volume of water accumulated in the extracellular compartment remains uncertain due largely to the lack of an ideal tracer for use in pregnant women. Reported estimates vary widely, and there is poor correspondence in those subjects in whom both extracellular and total body water were measured simultaneously. Reports in which thiocyanate was used as the tracer and the gain in extracellular space calculated as 6–7 L appear the most reasonable, since when added to the estimated 1.8–2.5 L of accrued intracellular water, the total approximates that measured directly with deuterium oxide. Nonetheless, more research in this area will be needed before definitive conclusions can be reached.

Intravascular volume increases during pregnancy due mainly to increases in plasma water and a small increment in red blood cell mass ( Table 81.2 ). Plasma volume has been measured in pregnant women by several methods, but usually with Evans blue dye. In the earlier literature, values were recorded as increasing until gestational week 30 and then declining. Such studies were in error, because late in gestation the indicator may not attain complete mixing within 10 min, if the subject is positioned in a supine or sitting position. Subsequent studies were performed serially, with the gravidas positioned in lateral recumbency for each measurement, and increases in plasma volume started in the first trimester, accelerated in the second, peaked near gestational week 32, and remained elevated until term. The maximal gain averages 1,100–1,300 mL, although larger increments may occur when there are multiple fetuses.

Studies in animal models demonstrate increases in both plasma and red cell volume during pregnancy. Of interest is an observation that plasma volume increases during early rat gestation even when the animals have a “zero” sodium intake, suggesting that some of the gain can be from internal redistribution of salt and water under this dietary condition.

Since expansion of the plasma volume accounts for only 20–30% of the increase in extracellular space, increases in interstitial fluid must be substantial. In his analysis of the distribution of body water during pregnancy, Hytten suggested the following: in women with no edema or leg edema only (~80% of normal gravidas), increments in interstitial fluid average 2.5 L at term, whereas in normotensive women with generalized edema the increase in interstitial fluid reaches ~5 L at term. In normal pregnant women, both with and without edema, the greatest accrual of interstitial fluid occurs in the third trimester, thus lagging somewhat behind the increment in plasma volume.

The mechanisms explaining interstitial fluid volume increases are incompletely understood. Unfortunately, there are but sporadic and/or conflicting data from both animal models and humans. Plasma albumin decreases 0.5–1.0 g/dL during pregnancy, but its concentration in interstitial fluid may fall even further; thus, paradoxically, the oncotic pressure difference favors retention of fluid within the capillaries. However, pregnancy is a vasodilated state (see below), and precapillary resistance is decreased, capillary hydrostatic pressure elevated, and, if the capillary ultrafiltration coefficient is unaltered or higher, more fluid will enter the interstitium, especially if interstitial compliance is increased. In the steady state, there would also be enhanced return of fluid to the intravascular compartment and increased removal of protein through the lymphatics.

There is also speculation that some of the interstitial changes during gestation are due to alterations in the properties of connective tissue ground substance. Thus, although low-molecular weight substances (e.g., cellular nutrients) diffuse readily through this material, fluid is “complexed” and poorly mobilized by diuretics. Furthermore, alterations in interstitial compliance, mediated through humorally induced changes in mucopolysaccharides, could conceivably influence blood pressure. Data in favor of such a hypothesis are sparse (reviewed in Refs ) but provocative, and await further study.

On the one hand, the normal gain in interstitial volume during pregnancy may reduce the safety margin for edema formation in pathological states, thus explaining why previously healthy gravidas may develop pulmonary edema when tocolytic therapy or the development of preeclampsia provokes additional fluid retention. On the other, there is the theoretical advantage of providing a large pool of interstitial fluid, which can be mobilized into the intravascular space when sudden depletion occurs, for example, by hemorrhage. Finally, increased fluid filtration across the capillary may protect the gravida from circulatory overload whose total blood volume is already increased.

In summary, pregnancy is characterized by the accumulation of >7 L of fluid, which is stored not only in the products of conception but also in the maternal intracellular, plasma, and interstitial compartments. In essence, there is maternal “physiologic hypervolemia.” However, the volume receptors apparently reset to the hypervolemic state, thus sensing it as normal, and with imposition of salt restriction or diuretic therapy, the maternal response is similar to that observed in salt-depleted nonpregnant subjects (see below).

Renal Sodium Handling

A pregnant woman accrues ~950 mEq of sodium ( Table 81.1 ), which is distributed between the products of conception and the maternal extracellular space (see above). This positive balance occurs gradually throughout gestation with the third trimester being the period of most rapid accumulation; however, the quantity retained is too small to be detected by conventional balance techniques. Renal sodium handling is the primary determinant of volume homeostasis, thus a brief review of the hemodynamic and humoral changes of normal gestation, which might influence urinary sodium excretion follows.

Circulating levels of many antinatriuretic hormones, mainly mineralocorticoids (e.g., aldosterone and DOC) increase during gestation, often markedly (see the previous edition, and Refs, which provide reviews and monographs with detailed bibliographies). In this regard, the renin–angiotensin system is the control mechanism most studied, and Figure 81.13 summarizes a detailed study by Wilson et al. in which plasma renin substrate, activity (Plasma renin activity), and urinary sodium and potassium excretion were measured throughout gestation. Note the sequential increases in plasma renin substrate and activity, which start early in gestation. Salt excretion (reflecting intake) was similar during gestation and in the postpartum period, suggesting that inadequate sodium intake does not account for these rises. Moreover, despite these high circulating levels of plasma renin substrate and activity, the renin–angiotensin system responds appropriately to provocative maneuvers, e.g., circulating levels decrease after saline infusion or during a high salt diet, or rise further after the administration of diuretics or when dietary sodium is restricted. Furthermore, inhibition of aldosterone biosynthesis causes a diuresis and subtle signs of volume depletion, the salt loss already apparent when aldosterone excretion, though decreasing, is still considerably above nonpregnant levels. Thus, the renin–angiotensin system does not function autonomously during pregnancy as some have presupposed. Rather, the high circulating levels of aldosterone, which often exceed those measured in nonpregnant patients with primary aldosteronism, are appropriate in pregnancy responding to homeostatic demands.

Nevertheless, physical factors do seem to have a greater influence on renal handling of salt during pregnancy then they do in the nonpregnant state including the antinatriuretic potential of the upright or supine position, and perhaps the vascular changes in the uterus especially in late gestation which has been likened to an arteriovenous shunt. In pregnancy, therefore, the supine and upright positions are markedly antinatriuretic, and quiet standing may cause greater reductions in sodium excretion in pregnant than in nonpregnant women. Thus, bed rest in the lateral recumbent position is helpful in the rare instances when a diuretic appears necessary.

Postural influences may also underlie the circadian rhythms of solute and water excretion in pregnant women. Recumbent gravidas typically display patterns of urine flow, creatinine clearance, and aldosterone and electrolyte excretion similar to those of nonpregnant subjects (i.e., daytime peaks and nighttime nadirs). However, ambulation results in more striking changes during pregnancy than in the nonpregnant state, and excretory peaks frequently occur at night (reviewed in Refs ). On the other hand, nighttime excretion of sodium and solute-free water may be greatest early in pregnancy when postural effects are minimal, suggesting that humoral, rather than mechanical factors are responsible for these changes.

Many hormones and autocoids change during pregnancy, which can theoretically enhance renal sodium excretion. These include increased circulating levels of oxytocin, melanocyte stimulating hormone, progesterone, natriuretic peptides, vasodilating PGs, and NO (for literature reviews see Chapter 100 in the first edition and Refs ). Progesterone levels increase markedly even over those observed during the luteal phase of the menstrual cycle, and binds with higher affinity than aldosterone to the mineralocorticoid receptor prompting investigators to question how aldosterone functions in face of such high circulating levels of progesterone. One possibility may be that progesterone actually contributes to antinatriuresis, as it is the major source of DOC production during pregnancy. Because renal steroid 21-hydroxylase activity (the enzyme that converts progesterone to DOC) may be particularly high in pregnancy, a considerable portion of maternal DOC may be produced in the vicinity of the renal receptors whose stimulation enhance sodium reabsorption.

There is considerable literature devoted to the various natriuretic factors and Na ⁺ –K ⁺ ATPase inhibitors in pregnancy, but their influence on renal sodium excretion during pregnancy is also obscure. In particular, the production of atrial natriuretic peptide (ANP) exceeds increases in metabolic clearance, so that circulating levels are increased. However, the increments in P _ANP are quite modest in relation to the marked increases in extracellular volume that occurs in normal pregnancy. Finally, the renal resistance to the natriuretic effects of atrial peptides described in animal models does not seem to occur in human gestation.

Perhaps, the major factor of importance when considering renal salt handling during pregnancy is the profound increase in GFR. Thus, every day more than 10,000 additional milliequivalents of sodium are filtered that must be reabsorbed by the renal tubules, a quantity which greatly exceeds the salt-retaining effects of large amounts of aldosterone, DOC, or estrogens administered experimentally. Quantitatively, the increase in filtered load of sodium is so enormous that one might anticipate that it would render gravidas more vulnerable to salt and volume depletion. Thus, on the one hand, gravid rats tolerate sodium restriction and adrenalectomy more poorly than do the virgin controls but, on the other, all pregnant species including humans are in positive sodium balance, and as noted, many women exhibit edema at some point of their gestation.

Significance of the Volume Changes During Pregnancy

On the one hand, the physiological hypervolemia may be a suboptimal response to the general arterial vasodilation of pregnancy, the so-called “underfill” or “primary arterial dilation” theories. On the other, the volume changes may be a primary event arising from the marked increase in antinatriuretic factors such mineralocorticoids, the so-called “overfill” theory. However, an intermediate possibility is that volume-sensing mechanisms are continually reset as gestation progresses, and as such, the increments in absolute volume are “sensed” as normal (“normal-fill”). These contrasting hypotheses, previously mentioned in the section on osmoregulation, are clarified further below (see Ref. for extensive review).

Evidence supporting the “underfill” theory is detailed by Schrier and Duvekot and their respective colleagues, and includes the marked activation of the renin–angiotensin system, substantiated not only by an increase in all of its circulating components ( Figure 81.13 ) but also by the observation that pregnant women manifest exaggerated increases in aldosterone release in response to low-dose infusion of angiotensin II. There is also evidence that the gestational decline in systemic vascular resistance precedes intravascular volume expansion, thus supporting the “primary arterial vasodilation” theory, and administration of angiotensin-converting enzyme (ACE) inhibitors early in pregnancy evokes exaggerated decrements in blood pressure. Finally, as noted, adrenalectomy, sodium restriction, or both, are tolerated more poorly in pregnant animal models.

The “overfill” theory is supported by increases in renal hemodynamics and GFR, absolute increments in extracellular and intravascular volumes, elevation in the levels of circulating natriuretic factors and inhibitors of Na ⁺ –K ⁺ ATPase, and by a report of increased sodium excretory capacity in response to saline infusions. Gravidas also appear more susceptible to complications of volume overload, especially those with underlying cardiac or renal disorders, or those receiving tocolytic therapy with sympathomimetic agents. In addition, they seem to tolerate blood loss better than do nonpregnant women. Finally, the mean circulatory filling pressure measured in gravid rodents has been consistently described as high normal or increased as discussed further in Ref.

Evidence for “normal-fill” is supported by animal experiments demonstrating the relationship between intravascular volume depletion and AVP release (detailed in the section on osmoregulation and Refs ). Also studies in rats and humans using indices of proximal tubular function such as fractional lithium and free water clearances suggest that sodium and water reabsorption by this nephron segment are unaltered. Moreover, with water loading both species dilute their urine normally or better than nonpregnant controls. Of note here is that failure to dilute the urine normally and excrete water and sodium are major pathophysiological features of hyponatremic patients with cirrhosis or cardiac failure, the prototypic diseases in which absolute extracellular and intravascular volumes are increased while “effective circulating volume” is low. Pregnancy, however, is a physiological condition, and thus salt and water excretory responses to acute sodium and water loads are comparable in pregnant and nonpregnant populations consistent with the concept that pregnancy is a “normal-fill” state (see Refs cited above and ). Finally, as detailed elsewhere, circulatory performance during gestation (including the adequate response to exercise) is further evidence that gravidas “sense” their intravascular volume as normal.

In summary, disputes surrounding the true nature of the volume accrual in pregnancy as noted above are yet to be settled, and it may be that all views are correct with each being apropos depending on the stage of gestation, e.g., early primary vasodilation followed by rapid compensation to normal-fill, and in some cases, overfill during late gestation due to a predominance of antinatriuretic influences such as physical factors at that time. Settling these controversies should perhaps be a priority, because understanding how the pregnant woman “senses” her volume changes may have wider implications for our understanding and management of gravidas with cardiac disease and hypertensive disorders such as preeclampsia.

Patient Evaluation

The approach to gravid women with renal problems is similar to that in nonpregnant populations, although tests which utilize ionizing radiation or radiochemicals should obviously be deferred until after pregnancy unless deemed crucial. Exposures to #5 rads do not appear to harm the fetus. The effect of the enhanced GFR, as well as alterations in acid-base parameters, and osmoregulation, on normal ranges of circulating creatinine, urea nitrogen, bicarbonate, sodium, and osmoles; blood pH and CO ₂ tension were discussed in the previous section and will not be repeated here. Ammonia loading to determine the kidney’s ability to excrete protons and achieve a minimal urine pH is rarely performed in pregnancy, and gravidas may be more susceptible to NH ₄ Cl-induced nausea than nonpregnant women. When assessing GFR by endogenous creatinine clearance the lower limits of normal should be increased by ~30%. Of note, other endogenous proteins easily measured in clinical labs have recently suggested as better markers of GFR than creatinine levels. One, especially, Cystatin-C has been recommended for use in pregnant women, but its validity for use in pregnancy has been recently questioned. Finally, when timed urines are neither practical (e.g., decisions during labor) nor reliable use of the Cockcroft–Gault formula based on preconception body weight can be utilized.

Most, but not all, investigators detect increases in urinary protein excretion in pregnancy. Accepting the relative imprecision and variabilities of the methods used by hospital laboratories (as well as the fact that certain proteins remain undetected by some and not by other tests), 300 mg/day should be considered the upper limit of protein excretion in pregnancy. There are limited data on normal limits and validity of protein and/or albumin creatinine ratios in gestation. As previously discussed, the fate of urinary albumin excretion is disputed. Even if it does rise, the increments are quite small, and thus use of nonpregnant upper limits of normal is probably permissible. Urine albumin excretion may have predictive value in relation to pregnancy outcome in women with diabetes, and those at high risk for preeclampsia but more research is needed here.

One should recall that as many as 5% of healthy adolescents and young adults manifest postural proteinuria, and this may become apparent or be first detected during pregnancy, especially near term when gravidas tend toward lordosis, a posture that augments urinary protein excretion. Finally, studies of tubular proteinuria, as well as enzymuria in either normal gravidas or those with renal disorders have sporadically appeared [summarized in Refs ]. These measurements are yet to be proved useful in the detection and management of renal disorders in pregnant women.

There have been few attempts to quantitate the urine sediment in pregnancy. Whether or not there is an increase in leukocyturia is unclear, but excretion of red blood cells definitely rises, so that 1–2/RBC per high-power field, considered abnormal in nonpregnant patients is probably acceptable in gravidas. One should be aware, though, that microscopic and even gross hematuria may complicate otherwise uneventful gestations. When this occurs, the differential diagnosis includes all causes of urinary tract bleeding in nonpregnant populations, but often a cause cannot be found and the bleeding subsides postpartum. In some cases, the hematuria may be due to the rupture of small veins around the dilated renal pelvis, the bleeding recurring with subsequent pregnancies. When faced with de novo hematuria in a pregnant woman, we follow up the urinalysis with ultrasonographic or magnetic resonance imaging (MRI), deferring more extensive investigations to the postpartum period.