Urine-plasminogen as a Predictor for Development Of Preeclampsia in Pregnant Women With Type 1 Diabetes Mellitus
Condition: Preeclampsia; Type 1 Diabetes
MeSH terms: Pre-Eclampsia; Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Observational

Summary: 
      A tonic active epithelial Na+ channel (ENaC) in pre-eclampsia (PE) escaped normal hormonal
      control may offer an attractive explanatory model for the pathophysiology of established PE.
      The channel is activated by plasmin. Microalbuminuria predicts the development of
      pre-eclampsia in pregnant patients with pregestational diabetes type 1. The investigators
      hypothesize that urine-plasmin excreted in the kidneys, when proteinuria occurs, could be the
      cause. The investigators want to test the correlation between measurable plasmin/plasminogen
      in the urine early in pregnancy and the development of preeclampsia in pregnant patients with
      type 1 diabetes.
    

Detailed description: 
      Study aim and hypothesis:

      Aim:

      To test whether there is a measurable correlation between plasmin/plasminogen, abnormally
      excreted in the kidneys, and the development of pre-eclampsia in pregnant women with Type 1
      diabetes.

      Hypothesis:

      1. The amount of proteases ( plasmin/plasminogen ), excreted in urine, predicts development
      of preeclampsia in pregnant patients with type 1 diabetes.

      If a correlation between excreted plasmin/plasminogen, in urine, in patients with type 1
      diabetes and development of preeclampsia, are seen, proteases might be used as a marker for
      pre-eclampsia in this group of patients. Prospectively perhaps also as a marker for disease
      severity.

      In these high risk groups it is possible that outpatient visits could be optimized and thus
      lower the amount of preterm births.

      Study design:

      The study is an observational, longitudinal - prospective study. Women with pregestational
      type 1 diabetes are included when they show up for their first outpatient pregnancy visit
      around pregnancy week 9.

      Selection of patients:

      Patients are selected from Gynecological- obstetric department, Aarhus University hospital -
      Skejby, and Gynecological- Obstetric department, Odense University Hospital. To be included
      they must be singleton-pregnant, have turned 18 years and have Type 1 diabetes.

      Background information:

      Date of birth, sex, weight, height, BMI, smoking status, current medical treatment, duration
      of diabetes and parity are registered.

      Length of gestation, placental weight, way of delivery (natural birth or cesarean section),
      umbilical cord pH, apgar score and infant weight are registered post-partum.

      Effect variables:

      Clinical:

      Weight, height, BMI, smoking status, microalbuminuria/proteinuria. Blood pressure (systolic,
      diastolic, mean arterial pressure). Weight of placenta.

      Blood test measurements:

      Se-creatinine, p-Na+, p-K+. P-plasminogen, P-albumin, Aldosterone.

      Measurements in 50 ml "spot urine":

      Plasmin, plasminogen, ENaC peptide fragment (analyses in location of development,)
      Proteolytic activity, Prostatin, Creatinine, Na+, K+, Aldosterone, Albumin

      Study process:

      Collection of blood- and spot-urine samples:

      Urine-samples are collected in pregnancy week 9-14. Blood pressure is measured. Samples and
      blood-pressures are re-collected in pregnancy-week 20, 28,32, 36 and perhaps 38.

      Following outcomes are observed: Development of preeclampsia, defined by hypertension ( >
      140/90 mmHg), and proteinuria ( >0,3 g/24 hour). Preterm delivery and light for gestational
      age.

      Data- analysis methods:

      This is an observational longitudinal-prospective study which includes approximately 130
      pregnant patients with Type 1 diabetes. Patients are included from Skejby and Odense
      University Hospitals in cooperation.

      Results are evaluated statistically by uni - and multivariate logistic regression analysis.

      Population size estimation:

      Similar (Danish) observational prospective studies on urine- biomarkers (including albumin)
      ability to predict preeclampsia/preterm delivery, in patients with pre-gestational type 1
      diabetes, have been made. They achieved high significance data with spot-samples of 130 -170
      patients. With the participation of two centers it seems realistic and adequately to include
      130 patients within the settings of a Ph. D. study. Every year an amount of 50-60 patients
      are seen in the outpatient ward at Skejby- and Odense University Hospitals (in all
      approximately 100-120 patients).
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        pregnant women with pregestational type 1 diabtes are included when they show up for their
        first outpatient pregnancy visit around the 9th weeks gestation.
      
Biospecimen description: 
      whole blood serum plasma urine
    
Keywords: Preeclampsia; Pregestational Type 1 diabetes; diabetes mellitus; proteinuria; plasminogen; plasmin; renin; aldosterone; angiotensin; epithelial sodium channel; ENaC