Renal dysfunction and podocyturia in pre-eclampsia may be explained by increased urinary VEGF

Nephrology Dialysis Transplantation, vol. 37, pp. 1109–1117

Abstract

BACKGROUND: Pre-eclampsia has a major impact on renal function as shown by the development of proteinuria and podocyturia. How the systemic, soluble Fms-like tyrosine kinase-1 (sFlt-1)-driven inhibition of vascular endothelial growth factor (VEGF) activity detected in pre-eclampsia directly affects renal function remains unknown. The aim of the study was to clarify whether a non-canonical, renal-centred escape from VEGF inhibition in the case of pre-eclamptic pregnancy might have a direct impact on renal function. METHODS: We evaluated plasma and urinary VEGF and placental growth factor (PlGF), plasma sFlt-1 and carbonic anhydrase IX (CAIX), albuminuria and podocyturia in 18 women with uncomplicated pregnancy, 21 with pre-eclampsia and 18 non-pregnant. The three groups were matched for age and the pregnant groups also for gestational age at enrolment. RESULTS: Plasma VEGF was reduced in uncomplicated (P = 0.001) and pre-eclamptic (P = 0.0003) pregnancies when compared with controls. In uncomplicated pregnancy, the dysfunction was balanced by an increase (P = 0.009) of plasma PlGF. Increased (P = 0.0001) plasma CAIX in pre-eclampsia was in line with hypoxia. Pre-eclampsia resulted in a paradoxical increase (P = 0.0004) of urinary excretion of VEGF. Urinary concentrations of VEGF and podocytes were correlated to each other (r2 = 0.48, P < 0.0005) but also to plasma sFlt-1 (r2 = 0.56, P < 0.0001 and r2 = 0.23, P = 0.03, respectively). CONCLUSIONS: In the case of pre-eclampsia, the systemic VEGF inhibition leads the kidney, possibly the podocyte, to increase the VEGF synthesis. The mechanisms leading to local VEGF overproduction or the overproduced VEGF itself are reasonably involved in the pathogenesis of podocyturia and, as a consequence, renal dysfunction in pre-eclampsia.

Authors 12

1. Luca Valsecchi

   IRCCS Ospedale San Raffaele

   Affiliation as printed

   Department of Obstetrics and Gynecology, IRCCS San Raffaele Scientific Institute, Milan, Italy

2. Alessandro Galdini

   IRCCS Ospedale San Raffaele

   Affiliation as printed

   Department of Obstetrics and Gynecology, IRCCS San Raffaele Scientific Institute, Milan, Italy

3. Daniela Gabellini

   IRCCS Ospedale San Raffaele · Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

   Affiliation as printed

   Complications of Diabetes Unit, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

4. Giacomo DellʼAntonio

   IRCCS Ospedale San Raffaele

   Affiliation as printed

   Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy

5. Silvia Galbiati

   IRCCS Ospedale San Raffaele · Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

   Affiliation as printed

   Complications of Diabetes Unit, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

6. Andrea Fanecco

   IRCCS Ospedale San Raffaele

   Affiliation as printed

   Department of Obstetrics and Gynecology, IRCCS San Raffaele Scientific Institute, Milan, Italy

7. Ilaria Viganò

   IRCCS Ospedale San Raffaele · Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

   Affiliation as printed

   Complications of Diabetes Unit, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

8. Maddalena Smid

   IRCCS Ospedale San Raffaele

   Affiliation as printed

   Department of Obstetrics and Gynecology, IRCCS San Raffaele Scientific Institute, Milan, Italy

9. Rosa Bernardi

   IRCCS Ospedale San Raffaele

   Affiliation as printed

   Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

10. Silvia Maestroni

    IRCCS Ospedale San Raffaele · Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

    Affiliation as printed

    Complications of Diabetes Unit, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

11. Hans J. Baelde Aachen Department of Pathology, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

12. Gianpaolo Zerbini corresponding

    IRCCS Ospedale San Raffaele · Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

    Affiliation as printed

    Complications of Diabetes Unit, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy