Version May 2024
INTRODUCTION — Normal pregnancy is characterized by profound changes in almost every organ system to accommodate the demands of the fetus. Thus, pregnancy results in both structural and functional changes of the kidney and urinary tract. This topic will review physiologic changes in the kidney and urinary tract.
Related topics on kidney disease in pregnancy and other maternal adaptations can be found separately.
●(See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)
●(See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".)
●(See "Maternal adaptations to pregnancy: Hematologic changes".)
●(See "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome".)
RENAL CHANGES — Pregnancy leads to an increase in kidney size, renal plasma flow, and glomerular filtration rate (GFR (table 1)).
Size — Both kidneys increase 1 to 1.5 cm in length during pregnancy [1]. Kidney volume increases by up to 30 percent [2], primarily due to an increase in renal vascular and interstitial volume. There are no histologic changes or changes in number of nephrons, but the GFR is also increased. (See 'Renal plasma flow and glomerular filtration rate disconnect in late gestation' below.)
The renal pelvises and caliceal systems may be dilated as a result of progesterone effects and mechanical compression of the ureters at the pelvic brim. (See 'Ureters' below.)
Hemodynamic changes — Normal pregnancy is characterized by widespread vasodilation, with increased arterial compliance, leading to decreased systemic vascular resistance, increased cardiac output, and a small decrease in blood pressure (figure 1) (see "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes"). These global hemodynamic changes include increased renal perfusion and GFR (table 2).
Glomerular filtration rate, renal plasma flow, and serum creatinine — Renal plasma flow increases by up to 80 percent by 12 weeks of gestation [3], but then decreases in the third trimester. (See 'Renal plasma flow and glomerular filtration rate disconnect in late gestation' below.)
The increase in GFR is observed within one month of conception, peaks at approximately 40 to 50 percent above baseline levels by the early second trimester, and then declines slightly toward term [4,5]. Of note, in late gestation, left lateral positioning increases GFR and sodium excretion [6].
The physiologic increase in GFR during pregnancy results in a decrease in serum creatinine concentration in early pregnancy [7]. In a retrospective database study including over 240,000 pregnancies in Canada, the mean serum creatinine concentration dropped in the first trimester (beginning at four weeks of gestation), leveled off in the second trimester, and then gradually rose again in the third trimester to near prepregnancy levels [8]. The mean serum creatinine level was 0.68 mg/dL (60 micromol/L) prepregnancy, fell to 0.53 mg/dL (47 micromol/L) between 16 and 32 weeks of gestation, and then increased to 0.72 mg/dL (64 micromol/L) at 18 weeks postpartum. In midgestation (16 to 32 weeks), the 95th percentile (a reasonable estimate of the upper limit of normal) for serum creatinine was >0.67 mg/dL (>59 micromol/L).
Thus, a serum creatinine of 0.75 mg/dL (70.7 micromol/L) or above, while normal in a nonpregnant individual, usually reflects renal impairment in a pregnant patient [5]. Blood urea nitrogen levels fall to approximately 8 to 10 mg/dL (2.9 to 3.9 mmol/L) for the same reason.
A small rise in serum creatinine usually reflects a marked reduction in renal function. For example, in a physiologic study, patients with preeclampsia had a 40 percent reduction in GFR as compared with control pregnant patients (89 versus 149 mL/min/1.73 m2 body surface area), but the serum creatinine levels remained within the normal range (0.89 mg/dL in preeclampsia versus 0.60 mg/dL in control pregnancies) [9]. Careful attention to small fluctuations in serum creatinine is required to detect renal injury in pregnancy.
Mechanisms of increased glomerular filtration rate — Several mechanisms contribute to decreased vascular resistance, increased renal plasma flow, and increased GFR during pregnancy. Reduced vascular responsiveness to vasopressors such as angiotensin 2, norepinephrine, and antidiuretic hormone (ADH) is well documented [10]. This may be mediated, in part, by altered vascular receptor expression. For example, vascular expression of the AT2 receptor, which produces vasodilation rather than vasoconstriction in response to angiotensin II, is increased in pregnancy [11]. Nitric oxide synthesis increases during normal pregnancy and may contribute to the systemic and renal vasodilation and the fall in blood pressure [12,13].
Relaxin — Additionally, the ovarian hormone and vasodilator relaxin is a key mediator of enhanced nitric oxide signaling in pregnancy. Relaxin is a peptide hormone in the insulin family; it is normally produced in the corpus luteum and, in pregnancy, is secreted in large amounts by the placenta and decidua in response to human chorionic gonadotropin (hCG (figure 2)) [14]. Relaxin increases endothelin and nitric oxide production in the renal circulation, leading to generalized renal vasodilation, decreased renal afferent and efferent arteriolar resistance, and a subsequent increase in renal blood flow and GFR [15]. Chronic administration of relaxin in rats mimics the renal hemodynamic changes of pregnancy (20 to 40 percent increase in GFR and renal plasma flow); these changes can be abolished by the administration of a nitric oxide synthase inhibitor [16]. In pregnant rats, increases in GFR and renal plasma flow can also be abolished by the administration of antirelaxin antibodies or by oophorectomy [17].
Renal plasma flow and glomerular filtration rate disconnect in late gestation — The gestational increase in GFR is primarily driven by increased renal plasma flow [18]. In fact, through most of pregnancy, the rise in renal plasma flow exceeds the increase in GFR, with a fall in the filtration fraction. Late in gestation, renal plasma flow falls slightly, while GFR is maintained, resulting in an increased filtration fraction [19]. However, not all studies support an increase in filtration fraction in the third trimester [20-24]. The maintenance of a high GFR despite a fall in renal plasma flow in late pregnancy may be due to decreased capillary oncotic pressure, increased glomerular capillary pressure, and/or increased hydraulic permeability and surface area of the glomerular filtration barrier.
Estimation of glomerular filtration rate — Endogenous creatinine clearance, measured by 24-hour urine collection, remains the standard of care for estimation of GFR in pregnancy [25,26]. All creatinine-based formulas to estimate GFR, including the Modification of Diet in Renal Disease Study (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, consistently underestimate GFR in pregnancy [25-29]. The 2021 CKD-EPI creatinine estimated GFR equation, which uses age and sex but omits race as a factor, did not include pregnant participants and has not been validated in this population [30]. Thus, creatinine-based estimating formulas should not be used in pregnant patients. Similarly, use of cystatin C to estimate GFR has not been validated for use in pregnant individuals. In one prospective study including 12 healthy pregnant patients, serum cystatin C did not correlate with GFR measured by inulin clearance, indicating it is unlikely to be a useful marker of GFR in pregnancy [31].
While 24-hour urine collection is the standard of care, it is cumbersome for the patient, and both over- and under-collection are common [32]. Inaccurate collection may be due, in part, to urinary stasis from dilation of the lower urinary tract in pregnancy: Several hundred milliliters of urine can be trapped in the dilated ureters, resulting in a significant lapse between urine formation and urine collection. For this reason, it is important to assess the adequacy of the collection by measuring urine creatinine excretion. Although the normal range for creatinine excretion in pregnancy has not been established, a reasonable estimate is that a complete collection will contain 15 to 20 mg of creatinine per kg body weight, using either prepregnancy or current maternal weight [32,33]. (See "Assessment of kidney function".)
Laboratory tests — Changes in renal hemodynamics and solute handling during pregnancy result in alterations in laboratory test results. Normal values vary slightly by gestational age [34-36].
Hyponatremia — The plasma osmolality in normal pregnancy falls to a new set point of approximately 270 mOsmol/kg (from a nonpregnancy level of 275 to 290 mOsmol/kg), with a proportional decrease in plasma sodium concentration to 4 to 5 mEq/L below nonpregnancy levels [37]. The physiologic responses to changes in osmolality above or below the new set point (ie, thirst and release of ADH from the pituitary) are intact.
Hyponatremia of pregnancy appears to be mediated by hormonal factors. The fall in the plasma sodium concentration during pregnancy correlates closely with increased production of hCG [38,39]. Furthermore, the administration of hCG to healthy patients during the luteal phase of the menstrual cycle can induce a similar resetting of the thresholds for ADH release and thirst [38,40]. Rather than acting directly, hCG appears to produce these changes via the release of relaxin [16]. As an example, hyponatremia in pregnant rats can be corrected by the administration of antirelaxin antibodies or by oophorectomy [17]. As noted above, relaxin also plays an important role in the increased GFR in pregnancy. (See 'Hemodynamic changes' above.)
A serum sodium concentration below 130 mEq/L in pregnancy should prompt evaluation for pathologic causes of hyponatremia, such as syndrome of inappropriate ADH secretion. Evaluation of hyponatremia in such cases can be approached similarly to nonpregnant individuals. Hypernatremia, particularly in the setting of polyuria, should spur an evaluation for possible diabetes insipidus. (See "Polyuria and diabetes insipidus of pregnancy".)
●(See "Diagnostic evaluation of adults with hyponatremia".)
●(See "Manifestations of hyponatremia and hypernatremia in adults".)
Attempts to correct the physiologic hyponatremia of pregnancy are both unnecessary (the change is mild and asymptomatic) and ineffective. Resetting of the osmostat means that the plasma sodium concentration will be maintained at the new level despite variations in water or sodium intake.
Proteinuria — Urinary protein excretion rises in normal pregnancy, from the nonpregnant level of approximately 100 mg/day to approximately 150 to 200 mg/day in the third trimester [41]. This may result in a positive dipstick result when a concentrated urine sample is examined. Urinary protein excretion greater than 300 mg/day is considered abnormal and should prompt further evaluation [42]. (See "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome".)
The mechanisms driving the physiologic increase in urinary protein excretion in pregnancy are not well understood but may include increased GFR, increased glomerular basement membrane pore size [43], increased protein transport across the glomerular filtration barrier via the nondiscriminatory shunt pathway [44], and reduced tubular reabsorption of filtered protein. Circulating antiangiogenic factors, which cause glomerular endothelial dysfunction and proteinuria in preeclampsia, increase toward term and may contribute to late gestational proteinuria even when preeclampsia is absent [45].
Urine protein excretion is even higher in uncomplicated twin pregnancy, which can lead to diagnostic confusion when evaluating a patient for preeclampsia because values greater than 300 mg/day are considered abnormal [42]. In a prospective study of 50 twin pregnancies, 15 of 35 patients (43 percent) who never developed hypertension had urine protein excretion of at least 300 mg/day at 30 weeks of gestation [46]. If confirmed in a larger study, these findings suggest that the definition of pathologic proteinuria in singleton pregnancies should not be applied to twin pregnancies. (See "Preeclampsia: Clinical features and diagnosis".)
Glucosuria — Glucosuria by dipstick testing is seen in approximately 50 percent of pregnant patients, and hence is not a useful screening tool for diabetes mellitus [47]. Glucosuria is primarily due to decreased proximal tubular glucose reabsorption [48]. (See 'Other changes' below.)
Other changes
●Chronic respiratory alkalosis – Minute ventilation rises in early pregnancy and remains elevated until term, leading to a modest fall in the pCO2 (to 27 to 32 mmHg) and mild respiratory alkalosis. These changes are due to direct stimulation of the central respiratory centers by progesterone [49]. The increase in minute ventilation allows maintenance of a high-normal pO2 despite the 20 to 33 percent increase in oxygen consumption in pregnancy. There is an appropriate metabolic response to the respiratory alkalosis: plasma bicarbonate levels decrease in normal pregnancy from 26 to approximately 22 mmol/L [50]. (See "Maternal adaptations to pregnancy: Dyspnea and other physiologic respiratory changes", section on 'Physiologic pulmonary changes in pregnancy'.)
●Hypouricemia – Serum uric acid declines in early pregnancy because of the rise in GFR, reaching a nadir of 2.0 to 4.0 mg/dL (119 to 238 micromol/L) and remains low until 22 to 24 weeks of gestation (table 3) [51]. Thereafter, the uric acid level begins to rise, reaching nonpregnant levels by term. The late gestational rise in uric acid is attributed to increased renal tubular absorption of urate.
●Decrease in serum anion gap and albumin – For reasons that are not well understood, the serum albumin concentration falls in normal pregnancy (table 3). The serum anion gap also falls, from 10.7 in the nonpregnant state to 8.5 during pregnancy [52]. Since negatively charged albumin is a major component of the anion gap, the physiologic hypoalbuminemia of pregnancy may account for the fall in the anion gap. Low albumin levels in pregnancy can lead to increased free levels of drugs which are highly protein-bound, such as digoxin, midazolam, and phenytoin [53].
●Impaired tubular function – Pregnancy is associated with decreased fractional reabsorption of amino acids and beta-microglobulin, in addition to glucose, which results in higher rates of urinary excretion. Thus, pregnant patients may exhibit glucosuria and aminoaciduria in the absence of hyperglycemia or renal disease [54].
URINARY TRACT
Ureters — Dilation of the ureters and renal pelvis (hydroureter and hydronephrosis) is seen in up to 80 percent of pregnant patients and is more prominent on the right than the left [55]. These changes can be visualized on ultrasound examination by the second trimester and resolve by 6 to 12 weeks postpartum.
The dilated collecting system can hold 200 to 300 mL of urine. The resulting urinary stasis can serve as a reservoir for bacteria, which may contribute to the increased risk of pyelonephritis in pregnancy. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy".)
Hydroureter and hydronephrosis in pregnancy have been attributed to hormonal effects, external compression, and intrinsic changes in the ureteral wall [56]. The following factors may contribute:
●Progesterone reduces ureteral tone, peristalsis, and contraction pressure.
●More prominent involvement of the right ureter may be due to dextrorotation of the uterus by the sigmoid colon, kinking of the ureter as it crosses the right iliac artery, and/or proximity to the right ovarian vein.
●Enlarged vessels in the suspensory ligament of the ovary may compress the ureter at the brim of the bony pelvis.
●Uterine enlargement may cause the ureters to become elongated, tortuous, and displaced laterally as pregnancy advances.
●Hypertrophy of Waldeyer sheath (the connective tissue that surrounds the ureters within the true pelvis) may prevent hormone-induced dilation below the pelvic brim [57].
In rare cases, compression of the ureters causes pain and true urinary obstruction, which may improve with lateral positioning, ureteral stent placement, and/or delivery [58]. (See "Acute kidney injury in pregnancy".)
Pathologic obstruction (ie, by nephrolithiasis or stricture) will also lead to ureteral dilation. Pathologic hydronephrosis can usually be distinguished from physiologic hydronephrosis by the presence of flank pain or radiographically or sonographically by visualizing the cause of the obstruction. (See "Kidney stones in adults: Kidney stones during pregnancy".)
Bladder — The bladder mucosa is edematous and hyperemic in pregnancy. Although progesterone-induced bladder wall relaxation may lead to increased capacity, the enlarging uterus displaces the bladder superiorly and anteriorly, and flattens it, which can decrease capacity. Studies of bladder capacity during pregnancy have yielded conflicting results [59,60].
Vesicoureteral reflux — Bladder flaccidity may cause incompetence of the vesicoureteral valve. This change, combined with increased intravesical and decreased intraureteral pressure, appears to result in intermittent vesicoureteral reflux [61,62].
Symptoms — Lower urinary tract symptoms of urinary frequency, nocturia, dysuria, urgency, and stress incontinence are common during pregnancy [59].
●Frequency and nocturia – Urinary frequency (voiding >7 times per day) and nocturia (voiding ≥2 times at night) are among the most common pregnancy-related complaints, affecting 80 to 95 percent of patients at some point during gestation [63-65]. Frequency is caused by changes in bladder function and a small increase in urine output. Urinary frequency typically begins in the first trimester; thus, mechanical compression of the bladder by the enlarged uterus is not likely to be the primary cause [63,66].
Nocturia is common and increases with advancing gestation. In a survey of 256 pregnant patients, 86 percent reported nocturia by the third trimester, with 20 percent of patients indicating they voided three or more times nightly [67]. In the latter stages of pregnancy, nocturia may be partially attributable to nocturnal mobilization of dependent edema when the patient is in the lateral position.
The possibility of diabetes insipidus of pregnancy should be considered in pregnant patients with severe polyuria and nocturia. (See "Polyuria and diabetes insipidus of pregnancy".)
●Urgency and incontinence – Urinary frequency, urgency, and incontinence are common during pregnancy [65,66,68,69]. These symptoms may be due to uterine pressure on the bladder, hormonal effects on the suspensory ligaments of the urethra, and/or altered neuromuscular function of the urethral striated sphincter [59,66,70,71]. Treatment includes pelvic floor muscle training. (See "Female urinary incontinence: Treatment", section on 'Pelvic floor muscle (Kegel) exercises'.)
●Urinary retention – The bladder and urethra inevitably experience some trauma during labor and delivery. The traumatic changes include mucosal congestion and submucosal hemorrhage, which are most evident at the trigone [72]. Bladder sensitivity/sensation is also decreased from trauma. As a result, detrusor atony, increased postvoid residual urine, bladder overdistention, and urinary retention are common in the first few days after delivery. These symptoms are typically mild and transient. (See "Acute urinary retention" and "Postoperative urinary retention in females".)
POSTPARTUM — The pregnancy-induced physiologic changes described above return to the nonpregnant state by four to six weeks following delivery [19,73]. However, urinary incontinence may persist. Pregnancy- and delivery-related urinary incontinence is reviewed elsewhere. (See "Effect of pregnancy and childbirth on urinary incontinence and pelvic organ prolapse".)
SUMMARY AND RECOMMENDATIONS
●Kidney size increases by 1.0 to 1.5 cm during pregnancy. Kidney volume increases by up to 30 percent, primarily due to an increase in renal vascular and interstitial volume. (See 'Size' above.)
●Glomerular filtration rate (GFR) and renal blood flow rise markedly during pregnancy, resulting in a physiologic fall in the serum creatinine concentration. A serum creatinine of 0.75 mg/dL or higher in a pregnant patient probably reflects significant renal insufficiency. (See 'Glomerular filtration rate, renal plasma flow, and serum creatinine' above.)
●Several mechanisms contribute to decreased vascular resistance, increased renal plasma flow, and increased GFR during pregnancy. Reduced vascular responsiveness to vasopressors such as angiotensin 2, norepinephrine, and antidiuretic hormone is well documented. Additionally, the ovarian hormone and vasodilator relaxin is a key mediator of enhanced nitric oxide signaling in pregnancy. (See 'Mechanisms of increased glomerular filtration rate' above.)
●The best method to accurately estimate GFR in pregnancy is by 24-hour urine collection for creatinine clearance. Completeness of the collection should be confirmed by checking the 24-hour creatinine excretion (10 to 15 mg creatinine/day per kg body weight is consistent with a complete collection). Estimating equations, such as the Modification of Diet in Renal Disease Study (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, are not accurate in pregnancy. (See 'Estimation of glomerular filtration rate' above.)
●Other physiologic changes in pregnancy include respiratory alkalosis, mild hyponatremia, glucosuria, and proteinuria up to 300 mg/day. (See 'Other changes' above.)
●Physiologic ureteral dilation (hydronephrosis and hydroureter) is common during pregnancy, and results from hormonal effects, external compression, and intrinsic changes in the ureteral wall. (See 'Ureters' above.)
●Urinary frequency and nocturia are common, but usually require no specific treatment. Urinary incontinence also can occur during pregnancy. (See 'Symptoms' above.)
●The pregnancy-induced physiologic changes of the kidneys and urinary tract return to the nonpregnant state by four to six weeks following delivery. (See 'Postpartum' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
