Proteinuria is Associated with Urinary Loss of Cubilin and Vitamin D-Binding Protein in Patients with Preeclampsia

Abstract

Women with preeclampsia (PE) form a vulnerable group for vitamin D3 deficiency. Reabsorption of vitamin D3 occurs in the proximal tubule after being endocytosed in combination with DBP (vitamin D binding protein) by the megalin/cubilin receptor. Because proteinuria promotes tubule injury and dysfunction, we hypothesized that the proteinuria present in pe could promote the loss of these components into the urine. Twenty preeclamptic patients and ten normal pregnant women with a gestational age greater than 20 weeks composed three groups: NC, normotensive control pregnant patients; PE, non-proteinuric preeclamptic patients; and PPE, preeclamptic patients with proteinuria. When proteinuria was absent, preeclampsia was diagnosed accordingly to the American college of Obstetricians and Gynecologists' (ACOG) guideline. The presence of 24-hour proteinuria equal to or greater than 300 mg was considered to form the PPE group. Urinary cubilin, megalin, and DBP were measured by ELISA and normalized by urinary creatinine. Regarding gestational age, there was no difference between the groups. NC group had arterial pressure within normal values, whereas PE and PPE groups had a significant increase (p < 0.01). As expected, PPE group presented elevated ACR (p < 0.05), accompanied by large amounts of cubilin and DBP in the urine (p < 0.05 vs. NC and PE). No difference was found in urinary megalin. PPE patients showed more chance of shedding cubilin into the urine compared to non-proteinuric patients (odds ratio 12.7 (1.2-136.3). In conclusion, this study further tightens the relationship between pe and vitamin D 3 deficiency, since proteinuria present in pe induces the loss of molecules responsible for renal tubular vitamin D 3 reabsorption for subsequent activation. Combined with other factors, the proteinuria may intensify vitamin D 3 deficiency in PE. Preeclampsia (PE) is a multisystem disorder of pregnancy in which renal damage has a significant contribution. A set level of proteinuria has been used to predict high-risk groups and define treatment for PE. In terms of physiopathology, proteinuria emerges due to processes that disturb the glomerular filtration barrier. Besides the classical mechanisms of glomerular damage such as endotheliosis and loss of podocytes 1,2 , an evidence for tubular injury have also been reported. Markers of proximal tubule injury such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and retinol-binding protein (RBP) were higher in the urine of PE patients than in urine of healthy pregnancies 3 In addition, urinary lysosomal enzyme excretion is elevated in patients with PE compared to a pregnant woman with chronic hypertension 4. Burwick et al. demonstrated that pregnancies affected by severe PE have high amounts of KIM-1 in the urine, which was closely correlated with urinary complement activation products, suggesting that tubular injury in PE is intensified by inflammation-activated complement 5. Direct effects of proteinuria on tubular cell damage have been ...

Vitamin D-Binding Protein in Pregnancy and Reproductive Health

“…They found that the increased oxidative stress correlated with a downregulated expression of certain proteins including VDBP, suggesting that increased oxidative stress may be responsible for the altered concentration of VDBP and vitamin D metabolism evidenced in the placentae of women with pre-eclampsia [89]. Moreover, pregnancies complicated by pre-eclampsia with proteinuria have been shown to result in a greater urinary loss of VDBP compared to non-proteinuric pre-eclampsia or normotensive pregnancies, suggesting a possible disruption to the vitamin D metabolism and function through reduced VDBP [123].…”

Review: Influence of Vitamin D Blood Concentration and Supplementation during Pregnancy on Preeclampsia Development and Neonatal Outcomes

“…As a result, the authors were able to prove an association between preeclampsia and vitamin D3 deficiency, because proteinuria causes the loss of proteins responsible for reabsorption of vitamin D3 by renal tubules. In combination with other factors, proteinuria can accelerate vitamin D3 deficiency in preeclampsia [66]. Therefore, both the symptoms of preeclampsia, arterial hypertension and proteinuria are both associated with vitamin D deficiency.…”

Review: Influence of 25(OH)D Blood Concentration and Supplementation during Pregnancy on Preeclampsia Development and Neonatal Outcomes

“…As a result, the authors were able to prove an association between preeclampsia and 25(OH)D deficiency, because proteinuria causes the loss of proteins responsible for the reabsorption of 25(OH)D by renal tubules. In combination with other factors, proteinuria can accelerate 25(OH)D deficiency in preeclampsia [ 67 ]. Therefore, both the symptoms of preeclampsia, arterial hypertension and proteinuria, are associated with 25(OH)D deficiency.…”