The present report deals with an interesting association, not extensively studied thus far and possibly underreported, between symptomatic and/or excessive urinary tract dilatation and proteinuria in pregnancy. Indeed, our extensive Medline search revealed only one recently published case of an association between severe proteinuria, urinary tract dilatation and pregnancy in the last decade; a few other cases in which a pre-eclamptic syndrome was probably triggered by dilatation had been previously reported [13, 15, 20–22].
Our cases were less extensively studied than the one reported by Afzali and co-workers, also because proteinuria decreased below 0.3 g/day shortly after pregnancy in all, thus limiting the diagnostic potential which is higher after delivery . Interestingly, in both our small series and the recently reported case, renal function was normal and no history of kidney disease (with particular reference to reflux nephropathy) was available nor was a different cause of kidney disease suggested by the ultrasound patterns. This differentiates our cases from reports of the risks of pregnancy in women with vescico-ureteral reflux in infancy, a potential risk factor even in the presence of normal kidney function [20–23].
It is well known that proteinuria may develop late in urological disease. This is usually considered to be caused by nephron loss and a poor prognostic sign, occurring in late stages of the disease when significant reduction of the kidney parenchyma is usually evident at ultrasounds [19, 24, 25]. However, neither our patients nor the case reported by Afzali displayed such a picture and the kidney function was normal in all cases. A “renal reflex” has been postulated in experimental animals and in humans, and was called into question in the case report by Afzali and co-workers [13, 26, 27].
It is very difficult to suggest a univocal interpretation of the observed data.
First of all, our cases were symptomatic or displayed excessive dilatation (over 3 cm); this referral pattern differentiates our observations from those of other studies, in which mild or minimal dilatations are reported, in the assessment of the frequency of urinary tract dilatation in pregnancy [24, 25]. Thus, our series may be considered as negatively selected, as small symptomless dilatations are neither identified nor referred (the use of maternal kidney ultrasounds in pregnancy is very limited in the clinical practice). Furthermore, in the presence of proteinuria, ultrasounds are not routinely performed in all settings, and a relationship between the so-called pregnancy-induced proteinuria and non symptomatic urinary tract dilatation may escape diagnosis.
Therefore, we will limit our report to the description of an association that might be more frequent than previously reported, possibly because of a trigger effect of pregnancy on the development of proteinuria in the context of various kidney diseases, including symptomatic or severe urinary tract dilatation. As urinary picture normalized in all patients after delivery and ureteral stent removal; it was impossible to disentangle the effect of each ones. However, the clinical relevance in the differential diagnosis with preeclampsia is unaffected by the cause of proteinuria.
A role for the increase in abdominal pressure may be postulated, together with a facilitating role of the urinary tract infections, where present. However, possibly to the negative selection of the cases, mentioned above, a clear-cut relationship was not identified.
Pregnancy may facilitate the development of proteinuria in the context of severe-symptomatic urinary tract dilatation via the changes in the metabolic milieu, through hyperfiltration or both, thus suggesting to further investigate in these fields. One possible explanation is that proteinuria increases steadily in pregnant women as the levels of the soluble fms-like tyrosine kinase-1(sFlt-1) rise, whose effect on podocytes is to increase proteinuria. Patients with chronic interstitial nephritis might have reached the tubular maximum of reabsorbtion and display proteinuria near term, when circulating sFlt-1 is at its highest [28, 29].
The striking association with ureteral stenting in our series needs further confirmation on a larger scale; indeed, there is a strong selection bias, as only the most symptomatic cases usually undergo invasive procedures. A role of iatrogenic vescico-ureteral reflux (linked to the presence of a ureteral stent) in the persistence of tubular damage (and/or of the inflammatory changes associated with urinary reflux and infection) can be postulated, but once again this awaits further confirmation in a prospective larger-scale analysis.
Our study has several limitations, partly shared by other observational studies in pregnancy: the problem of low grade proteinuria is very important in particular in a situation in which the upper physiological limits “touch” the limit for the definition of a severe disease (pre-eclampsia). Hence, we may have missed some cases with low-grade proteinuria and urinary tract dilatation, who tested negative at conventional urinalysis; conversely, the cases who tested positive at urinalysis or who were diagnosed with proteinuria at 24 hour urine collections were repeatedly controlled, thus ensuring against false positives (Tables 1, 2).
The interest in our report is mainly clinical, since it raises the hypothesis of an alternative source of proteinuria in a context in which pre-eclampsia is the most likely diagnosis. The clinical management would be different, for example the controversial “fluid management” often employed to offset the pre-eclamptic response may even be harmful in the context of urinary tract dilatation.
The treatment of the pregnant patient presenting with upper urinary pain and fever, or a kidney stone is quite obvious, but the differential diagnosis may be difficult in the absence of these symptoms. Hence, our case series suggests that an obstructive origin should be considered in the differential diagnosis of proteinuria in pregnancy, particularly in cases presenting without hypertension and with normal renal function. Further research in this field, with coordinated nephro-urological and gynaecological teams, is recommended.