The Mimic in Pregnancy - Chronic Kidney Disease or Pre-eclampsia?

One of the more challenging consultations in nephrology is evaluating a pregnant patient beyond 20 weeks’ gestation who presents with worsening proteinuria, high blood pressure, and increasing serum creatinine. In these situations, I am faced with deciding whether the findings show preeclampsia or the unmasking or progression of underlying chronic kidney disease (CKD). Preeclampsia often follows a more aggressive course and, in severe cases, may necessitate early delivery. In contrast, CKD is generally managed expectantly, with a more conservative, watchful approach. However, both these conditions are associated with significant maternal and fetal risks, including progression of kidney injury, preterm delivery, and adverse perinatal outcomes (1).

The American College of Obstetricians & Gynecologists (ACOG) defines preeclampsia as hypertension (>140/90 mmHg) after 20 weeks’ gestation with proteinuria (>0.3 g/day) or evidence of end-organ dysfunction such as thrombocytopenia, a serum creatinine > 1.1 mg/dL or a doubling from baseline, impaired liver function, or pulmonary edema. Preeclampsia occurs in about 5% of pregnancies. In contrast, about 3% of pregnancies involve preexisting hypertension or chronic kidney disease (CKD), and 1 in 10 of these patients may already have proteinuria, making the distinction from preeclampsia particularly challenging (2).

Although a careful history and documentation of hypertension or proteinuria before 20 weeks' gestation can reliably distinguish preeclampsia from preexisting hypertension and CKD, this information is often unavailable. In the United States, about 1 in 4 patients begin prenatal care after the first trimester, and in low-income countries, more than 60% present after 20 weeks. Many women with CKD or chronic hypertension remain undiagnosed before pregnancy, which can lead to misclassification as gestational hypertension or preeclampsia. One study found that CKD is diagnosed or first encountered in over one-third of cases during pregnancy (3).

From a diagnostic standpoint, the pattern of presentation can offer clues. In preeclampsia, hypertension usually has an abrupt onset and is accompanied by rapidly increasing proteinuria along with possible signs of end-organ involvement, including a decline in renal function. CKD tends to follow a more gradual course, with slower, steady changes in blood pressure, proteinuria, and creatinine values. However, several overlapping features make this distinction difficult. Preexisting hypertension and CKD increase the risk of preeclampsia several-fold (4). A flare during pregnancy of a known glomerulonephritis or immunologic disease that was previously in remission, such as SLE, makes differentiation even more difficult.

Given the overlap in clinical presentation, biomarkers have proven useful for distinguishing preeclampsia from CKD and for identifying superimposed preeclampsia in patients with underlying kidney disease. The recognition of an imbalance between sFlt‑1 (soluble fms‑like tyrosine kinase‑1) and placental growth factor (PlGF) as a central feature in the pathogenesis of preeclampsia has opened new diagnostic and therapeutic avenues (5).

In normal placental development, proangiogenic factors such as PlGF and vascular endothelial growth factor (VEGF) promote extravillous trophoblast invasion into the spiral arteries of the myometrium, which are initially high-resistance, low-capacitance vessels. Trophoblast invasion remodels these arteries by replacing the endothelial lining and disrupting the elastic and muscular layers, turning them into dilated, low-resistance, high-capacitance vessels that promote adequate placental perfusion (Figure 1).

Figure 1. Schematic comparing normal placentation, characterized by deep trophoblast invasion and dilated spiral arteries, with preeclampsia, marked by shallow invasion and constricted spiral arteries leading to maternal hypertension, proteinuria, and end-organ dysfunction.

In preeclampsia, impaired trophoblast invasion due to improper implantation of the placenta in the uterus leads to incomplete remodeling of the spiral arteries, resulting in reduced placental perfusion, hypoxia, and oxidative stress (Figure 2). This hypoxic environment activates hypoxia-inducible factor 1α (HIF-1α), a key regulator of the cellular response to low oxygen. HIF-1α upregulates several target genes, including VEGF and the antiangiogenic factor sFlt-1, both of which are overexpressed in preeclampsia. Elevated levels of placental and circulating sFlt-1 bind and neutralize VEGF and PlGF, reducing their availability, leading to abnormal placental angiogenesis and widespread maternal endothelial dysfunction (6).

Figure 2. Role of key biomarkers, sFlt-1, PIGF, and VEGF in normal pregnancy and preeclampsia

As in preeclampsia, studies have shown that CKD may mimic preeclampsia due to endothelial dysfunction and an anti-angiogenic imbalance, with increased sFlt-1 and reduced PLGF, but this dysregulation is less pronounced than in preeclampsia. In a smaller study, sFlt-1 and PIGF levels were almost similar to those in normal pregnancies (Figure 3).

Figure 3. Comparison of sFlt-1 and PIGF levels and their ratio in normal pregnancies and in patients with CKD and preeclampsia. (adapted from Rolfo et al., Kidney Int. 2013, 83 (1), 177–181)

A large, multicenter trial, the PROGNOSIS study, suggested that a sFlt‑1/PIGF ratio cutoff of <38 had a negative predictive value of 99.5%, effectively ruling out preeclampsia within 1 week of the test, and a post hoc analysis suggested that a ratio >85 in late gestation correlated with a higher risk of preeclampsia (7). Values between 39 and 84 do not rule in or rule out preeclampsia and require clinical judgement. The recent PRAECIS study showed that an sFlt‑1/PIGF ratio >40 in the US population had a PPV of 65% and an NPV of 99%, confirming earlier studies suggesting that an sFlt‑1/PIGF ratio < 40 can rule out preeclampsia for the next 1 week (8).

Routine use of biomarker studies is unnecessary when the clinical picture is clear enough to distinguish between preeclampsia and CKD. However, they may be useful when no data is available before pregnancy or during the first 20 weeks of gestation, or when kidney disease develops during pregnancy, or when acute glomerulonephritis flares during pregnancy.​

Biomarkers such as sFlt-1 and PlGF can help distinguish CKD in pregnancy when it mimics preeclampsia. With recent ACOG recognition of their usefulness in preeclampsia evaluation in certain situations, more US centers may incorporate these tests (9). They should not replace clinical judgment, but when used appropriately, they improve diagnostic accuracy and support more informed treatment decisions.

References:

1. Sorohan, B. M.; Andronesi, A.; Ismail, G.; Jurubita, R.; Obrisca, B.; Baston, C.; Harza, M. Clinical Predictors of Preeclampsia in Pregnant Women with Chronic Kidney Disease. Medicina (Kaunas) 2020, 56 (5), 213.

2. Williams, D.; Davison, J. Chronic Kidney Disease in Pregnancy. BMJ 2008, 336 (7637), 211–215.

3. Martin, J. A.; Hamilton, B. E.; Osterman, M. J. K. Births in the United States, 2023. NCHS Data Brief 2024, No. 507. https://doi.org/10.15620/cdc/158789.

4. Barrett, P. M.; McCarthy, F. P.; Evans, M.; Kublickas, M.; Perry, I. J.; Stenvinkel, P.; Khashan, A. S.; Kublickiene, K. Hypertensive Disorders of Pregnancy and the Risk of Chronic Kidney Disease: A Swedish Registry-Based Cohort Study. PLoS Med. 2020, 17 (8), e1003255.

5. Verlohren, S.; Galindo, A.; Schlembach, D.; Zeisler, H.; Herraiz, I.; Moertl, M. G.; Pape, J.; Dudenhausen, J. W.; Denk, B.; Stepan, H. An Automated Method for the Determination of the sFlt-1/PIGF Ratio in the Assessment of Preeclampsia. Am. J. Obstet. Gynecol. 2010, 202 (2), 161.e1-161.e11.

6. Rolfo, A.; Attini, R.; Nuzzo, A. M.; Piazzese, A.; Parisi, S.; Ferraresi, M.; Todros, T.; Piccoli, G. B. Chronic Kidney Disease May Be Differentially Diagnosed from Preeclampsia by Serum Biomarkers. Kidney Int. 2013, 83 (1), 177–181.

7. Zeisler, H.; Llurba, E.; Chantraine, F.; Vatish, M.; Staff, A. C.; Sennström, M.; Olovsson, M.; Brennecke, S. P.; Stepan, H.; Allegranza, D.; Dilba, P.; Schoedl, M.; Hund, M.; Verlohren, S. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N. Engl. J. Med. 2016, 374 (1), 13–22.

8. Thadhani, R.; Lemoine, E.; Rana, S.; Costantine, M. M.; Calsavara, V. F.; Boggess, K.; Wylie, B. J.; Moore Simas, T. A.; Louis, J. M.; Espinoza, J.; Gaw, S. L.; Murtha, A.; Wiegand, S.; Gollin, Y.; Singh, D.; Silver, R. M.; Durie, D. E.; Panda, B.; Norwitz, E. R.; Burd, I.; Plunkett, B.; Scott, R. K.; Gaden, A.; Bautista, M.; Chang, Y.; Diniz, M. A.; Karumanchi, S. A.; Kilpatrick, S. Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy. NEJM Evid. 2022, 1 (12), EVIDoa2200161.

9. Biomarker Prediction of Preeclampsia with Severe Features. Obstet. Gynecol. 2024, 143 (6), e153–e154.