David Cohen, M.D.·Published 25 April 2008·12 min read
Key points
When you detect proteinuria in a pregnant woman, a number of conditions should come to mind.
Normal pregnancy causes dramatic changes in systemic and renal hemodynamics.
With an increase in renal blood flow during pregnancy, approximately 6,000 g of albumin travel through the renal circulation each day.
Ideally, clinicians should know if their patients have been proteinuric before pregnancy or whether this finding is new.
When you detect proteinuria in a pregnant woman, a number of conditions should come to mind. It can mean a lupus flair or suggest the presence of preeclampsia. But in many women, it may signal the existence of a previously undiagnosed renal condition. While proteinuria after 20 weeks' gestation may indicate preeclampsia, its existence earlier suggests underlying renal disease, most commonly diabetic nephropathy.
But other important causes exist in young women (Table 1). To explore all these options, we will first review the normal changes in the kidney during pregnancy, briefly touch on mechanisms of proteinuria, and then focus mostly on evaluation and management. All women with proteinuria should be evaluated by a nephrologist, particularly during their pregnancies, as renal conditions can decline rapidly in this setting.
Kidney physiology in normal pregnancy
Normal pregnancy causes dramatic changes in systemic and renal hemodynamics. Cardiac output increases, plasma volume expands, and there is a decrease in systemic vascular resistance and blood pressure starting early in the first trimester. This retention of 6 to 8 L of water and increased plasma volume is accompanied by significant sodium (Na) retention, averaging approximately 1,000 mEq.
Despite total body volume expansion, the kidney senses a relative "under-filling" and the plasma renin-angiotensin-aldosterone system (RAAS) is activated. This provides a checks and balances system to the massive systemic vasodilation of pregnancy.1 In the end, systemic blood pressure falls, despite the increasing cardiac output, with a nadir at about 16 to 20 weeks' gestation.
Throughout gestation, the glomerular filtration rate (GFR) increases by 50% and renal plasma flow by 50% to 85%.2 The increased GFR is caused by renal vasodilatation, mediated in large part by the ovarian hormone relaxin. GFR rises by 25% by the fourth gestational week, peaking by week 9. Because of this increase, serum blood urea nitrogen (BUN) and creatinine concentrations fall.
The change in GFR has important implications for patients with either preexisting or de novo proteinuria. As GFR increases, proteinuria increases. Clinicians should expect this as pregnancy progresses and not be alarmed. However, it is concerning if the level of proteinuria starts to change rapidly.
What's the mechanism behind proteinuria?
With an increase in renal blood flow during pregnancy, approximately 6,000 g of albumin travel through the renal circulation each day. Albumin plays a critical role in maintaining serum oncotic pressure, and its concentration must be conserved.
Three mechanisms exist to prevent albumin/protein loss by filtration in the normal kidney.
Written and revised by
David Cohen, M.D.
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* First, the pore size of the fenestrated capillary endothelium in the glomerular capillary loops are too small for the bulkier albumin to routinely pass through. * Second, the glomerular basement membrane is made up of negatively charged proteins that repel the negatively charged albumin proteins acting as a "charge" barrier to their filtration. * Lastly, the structure of the epithelial slit diaphragms act as a barrier to albumin passing.
{pagebreak} As a result, only about 2,000 mg of the 6,000 g that pass through are filtered each day by the glomerulus. Most normal pregnant women will develop low levels of albuminuria because of the combination of an increased filtered load from an increased GFR and a physiologic impairment of proximal tubular reabsorption of protein.4 Normal levels, however, should not exceed 300 mg over a 24-hour period.5
Damage to any part of the barrier system can lead to proteinuria. This can result from chronic kidney diseases such as diabetes. Other nephrotic syndromes, including minimal change disease and membranous nephropathy, and lupus also affect the glomerular basement membrane (GBM) and epithelial podocytes and cause proteinuria as well. Proteinuria may also result from acute injury to the glomerular capillary endothelial cell, which occurs in preeclampsia.
How to evaluate proteinuria
Ideally, clinicians should know if their patients have been proteinuric before pregnancy or whether this finding is new. Often, the only way to know if a preexisting problem existed is to track down old urinalysis results from primary-care physicians. Detecting new onset proteinuria can be done by the methods outlined.
Urine dipstick testing
This is the best method for in-office screening of pregnant patients for proteinuria. Obtain a fresh, midstream specimen before a vaginal exam is done. A positive dipstick reaction (1+) usually occurs once the protein concentration reaches a threshold of 30 mg/dL (Table 2). Although this is a good screening test, don't use it to quantify the amount of proteinuria because it is prone to false-positive and false-negative results (Table 3). Be mindful of these situations so that you don't alarm patients.
The most common false-positive results come from a highly concentrated urine (high specific gravity) in a patient not adequately hydrated. False negatives may result because the urine dipstick only detects albumin in the urine and not other proteins such as immunoglobulins that may occur in diseases like multiple myeloma. If you obtain a low level reaction (1+) on a dipstick, confirm it by repeated morning testing before progressing to more evaluation.
24-hour urine collection
A 24-hour collection of urine has been the gold standard for quantifying proteinuria during pregnancy. It also allows the clinician to quantify protein excretion to measure creatinine clearance for evaluating kidney function.
24-hour collections have their limitations, however, and are only useful if the patient manages to collect a complete sample. Unfortunately only 10% to 20% of nonpregnant patients succeed in a complete collection.6 One can only imagine how much more difficult it is for pregnant patients because of increased urinary frequency and physical limitations to collection. The other major disadvantage to a 24-hour collection is that it can delay the diagnosis of critical problems like preeclampsia.
Because of the awkwardness of collection, the concern over incomplete results, and the time delay to diagnosis, many clinicians use a spot urine test noted below. It is a good screening test and can be used to follow proteinuria. Nevertheless, the 24-hour urine collection remains the gold standard if done correctly.
{pagebreak} The spot urine protein:creatinine ratio
This method of quantifying proteinuria is easier then a 24-hour collection, can be run off a spot urine sample, and nephrologists have substituted this for a 24-hour urine collection in just about all proteinuric conditions. A spot urine sample should be taken and sent for protein and creatinine. The ratio of the two approximates a 24-hour collection by accounting for protein concentration.
If the ratio of protein:creatinine is 125 mg/g , this estimates 125 g of protein on a 24-hour collection. The test has been well-validated in nonpregnant women and in men with a correlation coefficient of 0.97, and it has real advantages over the 24-hour urine collection both because it minimizes collection and laboratory errors and results are usually available in several hours.7 As you can imagine, patients also prefer it.
Most of the studies that have examined its accuracy in pregnancy have included fewer than 200 patients and have included hospitalized patients, outpatients, those at high risk for preeclampsia, and patients who have full-blown nephrotic syndrome.8-11 Despite these limitations, all the studies have found a strong correlation between spot analysis and 24-hour collection, save one; but this one has some methodologic problems.
THE PUBLISHED DIAGNOSTIC CRITERIA for preeclampsia include a 24-hour urine collection with >300 mg of protein. Studies have shown that using a cut-off of a spot protein:creatinine ratio of >190 mg/g had a sensitivity of 97%, specificity of 70%, positive predictive value of 75%, and a negative predictive value of 87%.9 For this reason, some had advocated using a cut-off of >140 mg/g to be used as a threshold to justify a confirmatory 24-hour urine. Once the diagnosis is made, spot urine tests could be measured throughout pregnancy.
For patients with more overt proteinuria, or once the diagnosis of preeclampsia is made, management rarely changes if protein measurements change subtly. Some of these subtle differences may be missed by a spot urine test, although one could argue that that is also true with inadequate collections on a 24-hour urine sample. Given the increased expeditiousness and ease of a spot urine test over a 24-hour collection, clinicians should become comfortable using this test. It can be used to monitor progress during pregnancy in patients who were previously proteinuric or to quantify new proteinuria.
Doing a lab workup once proteinuria is detected
Many patients will be first diagnosed with proteinuria during pregnancy. As mentioned previously, if it is detected early in pregnancy, it's likely from some underlying renal disease. If proteinuria appears later, preeclampsia rises to the top of the differential diagnosis list. Workup depends on when the proteinuria is detected, and all patients should be screened with a urine dipstick during their first trimester.
Early proteinuria (<20 weeks)
Figure 2: Evaluation for proteinuria early in pregnancy (<20 weeks)
If proteinuria is detected early in pregnancy, women should be sent to a nephrologist for full evaluation (Figure 2). If the patient has diabetes, there may be no need to do further workup. If the patient is not diabetic, or if the course is unlikely to be related to diabetes, then a more exhaustive workup should be undertaken.
URINE MICROSCOPY done on freshly spun urine sediment can yield much information. Glomerular disease will usually present with dysmorphic red cells or red cell casts in the urine. White blood cell casts may indicate interstitial nephritis or pyelonephritis.
BLOOD TESTS should be done as appropriate to the patient's history and physical exam (Table 4). Evaluating renal function with a serum creatinine concentration is critical. Serum creatinine concentration normally falls during pregnancy, with normal levels being < 0.6 mg/dL. Autoimmune diseases, such as systemic lupus erythematosis, often present with proteinuria and renal dysfunction before other systemic abnormalities are apparent and may flare during pregnancy. Infections such as human immunodeficiency virus (HIV) or hepatitis can also present first with proteinuria.
ULTRASOUND can also prove useful, as kidneys that have been affected by a disease process over time (as opposed to acutely) will have increased echogenicity and kidney size can be a clue to diagnosis. Obstruction can also be ruled out with U/S. Bear in mind, however, that size increases by approximately 1 cm during pregnancy, and kidneys (particularly the right) may appear mildly obstructed with dilated calices due to the "physiologic obstruction of pregnancy."
This temporary appearance on U/S, which is likely due to progesterone's effect on the collecting system, is totally benign and should resolve by 12 weeks postpartum. Bilateral obstruction can cause kidney failure and may present as mild proteinuria, although alone the obstruction will not cause nephrotic range proteinuria.
WE RESERVE RENAL BIOPSY for those patients in whom a diagnosis of proteinuria is unclear and in whom management decisions depend on actual pathology. With U/S guidance, and an experienced clinician's hand, this is a very safe and well-tolerated procedure.
{pagebreak}Late-onset proteinuria
When proteinuria develops later in pregnancy, it can be from intrinsic renal disease or preeclampsia. Most patients with preeclampsia will develop de novo hypertension and proteinuria with the increase in severity of both occurring over days, not weeks. This is why it is so important to do early screening for proteinuria in pregnancy. Also remember that patients with underlying renal disease are at increased risk for preeclampsia, and at times it can be difficult to determine whether the worsening proteinuria is from progressing renal disease or new-onset preeclampsia. In these cases, it is prudent to assume it is preeclampsia and treat the patient accordingly, as the risks are greater with this diagnosis. Once the patient has delivered, "stand alone" preeclampsia will usually resolve whereas primary renal disease may improve, but not completely resolve. Preeclampsia, unlike other causes of proteinuria, is often an indication for preterm delivery.
How do you manage the patient?
Patients with proteinuria levels <3.0 g/d are usually asymptomatic. However, those who have >3.0 g/d (and a serum albumin <3.0 g/dL) develop edema because of excess sodium and water retention. This edema may worsen hypertension, particularly near term, and can complicate delivery if there is severe vulvar edema. When possible, the underlying cause of nephrotic syndrome should be treated. Standard antiproteinuric therapy, such as ace-inhibitors and angiotensin receptor blockers, must be avoided in pregnancy because of their teratogenic effects.
Management in these cases is largely symptomatic and patients should be put on a low sodium diet (<1.5 g/d), and placed on bed rest if edema is significant. In general, diuretic therapy should be avoided because it may reduce extracellular fluid volume and decrease placental perfusion. There are, however, rare occasions when therapy is needed, and in those cases, diuretics should be used every other day and with a goal of slow diuresis of 1 to 2 lb per day. Diuretics should never be used in preeclampsia (unless patients are postpartum), as this state is characterized by a low circulating plasma volume.
What's the prognosis?
Isolated proteinuria does not seem to be harmful to the developing fetus, although it does predispose to maternal complications such as worsening edema and hypertension.13 If women have proteinuria without hypertension, the outcome of pregnancies is excellent with no increase in fetal death rates. Preeclampsia is a different situation, as that disease clearly carries risks of preterm delivery as well as maternal and fetal complications. However in preeclampsia, the degree of proteinuria (once >300 mg) seems to have little overall effect and should not be used as an argument for preterm delivery if all other markers of maternal and fetal health are acceptable.
Proteinuria in pregnancy results from preexisting underlying renal disease, or from preeclampsia. These two disease states carry very different prognostic implications for both mother and developing baby. Proteinuria detected early in pregnancy should be investigated for underlying causes. You can screen for proteinuria with urinary dipstick, but be mindful of false-positive and false-negative results. The 24-hour urine collection remains the gold standard test for quantification, but evidence is rapidly mounting for the use of a spot urine protein:creatinine ratio that gives faster results with greater ease for patients.
DR. BREWSTER is Assistant Professor of Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT. By: Ursula C. Brewster, MD
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