Interpretation
Pregnancy causes structural and functional changes in maternal kidneys. During the first half of pregnancy, maternal cardiac output, RPF, and GFR increase and systemic vascular resistance decreases; as a result, the mean serum creatinine concentration is lower than that of non-pregnant women4,7,8. Several mechanisms have been reported to contribute to decreased vascular resistance. During pregnancy, vascular expression of angiotensin-2 receptors, which causes vasodilation rather than vasoconstriction in response to angiotensin-2, increases17. During normal pregnancy, nitric oxide synthesis increases, which contributes to systemic and renal vasodilation10. Relaxin, which is secreted in large amounts by the placenta and decidua in response to human gonadotropin during pregnancy, increases endothelin and nitric oxide production in the renal circulation, leading to generalized renal vasodilation, decreased renal afferent and efferent arteriole resistance, and a subsequent increase in renal blood flow and GFR18. Conversely, during the second half of pregnancy, RPF decreases slightly, resulting in an increased filtration fraction and proteinuria8,12,19,20. However, not all studies support an increase in the filtration fraction during the third trimester of pregnancy, and the mechanisms that drive the physiological increase in urinary protein excretion during pregnancy are not well-understood. In addition, physical pressure on the blood vessels and organs by the pregnant uterus occurs, especially during the late pregnancy period. This may have a negative effect on the maternal renal function.
This is the first study, to the best of our knowledge, to show that twin pregnancy itself is a significant factor associated with maternal renal dysfunction during the latter half of pregnancy. Below, we discuss how twin pregnancies can cause maternal renal dysfunction. First, the cardiac output of women with twin pregnancies is 20% higher than that in singleton pregnancies, and peaks at 30 weeks of gestation21. On the other hand, compared with the left lateral decubitus position, the supine position can lower cardiac output by as much as 25–30% due to compression of the IVC by the gravid uterus22. Therefore, because of the larger uterus in twin pregnancies compared to singleton pregnancies, the longer the patient is in the supine position, the highly pronounced IVC compression is likely to result in a greater reduction in cardiac output and thus RPF. Decreased RPF can result in decreased GFR. However, there were no data on the posture of the pregnant women in this study, and future studies are needed to investigate this aspect.
Second, hydroureter and hydronephrosis occurs in approximately 80% of pregnant women and is more pronounced on the right side than on the left23. Hydroureters and hydronephrosis during pregnancy have been attributed to hormonal influences, external compression, and intrinsic changes in the ureteral wall24. Progesterone reduces ureteral tone, peristalsis, and contraction pressure, which are further increased in twin pregnancies. As pregnancy advances, an enlarged uterus may cause the ureters to become elongated, tortuous, and laterally displaced. As mentioned above, twin pregnancies are more prominent than singleton pregnancies because of urinary tract compression. Occasionally, obstruction of the ureters by the uterus is sufficient to cause kidney failure25. Acute kidney injury due to urinary obstruction resulting from enlarged uterine fibroids during pregnancy has been reported26, which can be resolved by insertion of a ureteric stent or delivery of the fetus27. In summary, we can assume that twin pregnancies are more likely to cause urinary tract obstruction and, therefore, maternal renal dysfunction. Third, during pregnancy, especially in the third trimester, proteinuria increases, and the rate of pathological proteinuria (300 mg/day or greater) is greater in twin pregnancies than that in singleton pregnancies (adjusted OR = 9.13)20. In recent years, the usefulness of the urine albumin-to-creatinine ratio (UACR) has been introduced, which is strongly predictive of significant proteinuria. The diagnostic accuracy of the UACR (using a threshold between 20 and 60 mg albumin/g creatinine) and the urine protein-to-creatinine ratio (UPCR) (>300 mg protein/day by 24-hour urine collection) are approximately equal, and the UACR is increasingly being replaced by UPCR28-30. Increased albuminuria reflects the impaired permselectivity of glomerular capillaries to macromolecules, which is reported to be a marker of kidney damage31. This suggests that an increase in proteinuria (albuminuria) due to twin pregnancies causes kidney damage, resulting in renal dysfunction. Unfortunately, we have no data regarding proteinuria (albuminuria) in this study, and further investigation is warranted.