Case Conference

1. Case Conference 報告者： R3 潘恆之 指導老師：方基存醫師 報告日期：2010.11.24

2. Outline • Case report: A 35-year-old female with newly onset of hypertension and proteinuria since the 3rd trimester suffered from postpartum acute renal failure • Differential diagnosis of hypertension disorder related to pregnancy • Differential diagnosis of proteinuria • Review of preeclampsia • Future direction

3. Case General Data • No: 39036654 • Gender: female • Age: 35-year-old • Ethnic: Taiwanese • Marriage: married • Occupation: Electronics • Travel history: denied in recent three months • admission date : 2010/10/04

4. Chief Complaint • Progressive dyspnea for 5 days.

5. Present Illness • The 35-year-old woman had pregnancy with estimated date of confinement on 2010/10/11. • Pre-partum exam recorded progressively elevated blood pressure up to 130/80 mmHg without proteinuria in third trimester. • Progressive bilateral leg edema was noted since 09/14. • She was admitted in 聖保祿 hospital and received Cesarean section on 09/28.

6. Present Illness • After the operation： 1. Post-partum hemorrahge with hypovolemic shock  intensive blood transffusion and fluid resuscitation. 2. Acute kidney injury with decreased urine output and pulmonary edema.  Furosemide • Dyspnea improved gradually after urine output increase  transffer to our ER on 10/04.

7. Past history • Maternal History: G2P2A1, delivered 1 female baby with birth body weight:3395 • Medical history: Denied any systemic disease • Operative history: 1. Left indirect inguinal hernia post herniorrhaphy on 2006/11/23. 2. Primary Cesarean section on 2010/9/28.

8. Personal history • Alcohol usage: denied • Cigarette: denied • Betel nut: denied • OTC drugs: denied • Chinese Herbs: denied • Food allergy: never • Drug allergy: never

9. Family history □ ○ └┬┘ ┌┼┐ □□⊕ □ └┬┘ ○ Her grandpa, grandma, aunt and uncle had history of hypertension. Pedigree was shown as following figure. (□:male; ○:female; ■:dead male; ●:dead femle; ⊕:patient)

10. Physical examination • Vital Sign: T:37.3 degree; P:90bpm; R:16cpm; BP:149/96mmhg • Height: 152cm; weight: 42.4kg. • HEENT: conjunctiva: non-pale; sclera:anicteric; • CHEST: breathing sound: bilateral clear; heart sound: regular heart beats without audible murmur • ABD.: soft and flat; no tenderness; surgical scar (+) normoactive bowel sounds no Murphy’s sign; no McBurney tenderness. • EXT.: Free movable without limitation. Bilateral minimal pitting edema.

11. 10/04 Lab Exam at ER

12. 10/04 Lab Exam at ER

13. 2010/10/04 CXR A-P view (Supine) • Patchy opacities in bil. lower lungs suspect pulmonary edema, r/o pleural effusion or pneumonia • Suspect Cariomegaly • No obvious fracture • No mediastinalwiding • No large airway anomaly

14. 2010/10/05 Abdominal Sonography • Value: Spleen Index:5.1 x 3.1 cm CBD: 0.47 cm • Impression: - Parenchymal liver disease, score 6 - Liver nodules - Ascites and right pleural effusion; - Right hydronephrosis; - Cholecystopathy.

15. 2010/10/5 Cardiac 2D echo: • Value:IVS(mm) = 10 LVPW(mm) = 9 LVEDD(mm) = 52 LVESD(mm) = 34 LVEF: M-mode(Teichholz)= 63 % • Conclusion: - Adequate LV systolic function with normal wall motion - Mild MR,AR and TR - Mild pulmonary hypertension - Dilated LV

16. ER Impression • Acute renal failure with pulmonary congestion • Hypokalemia • Postpartum hemorrahge

17. ER Management • Medication: Rocephin(500mg/vial) 2PC Q12h Furosemide (20mg/amp) 1PC Q12h Potassium chloride(600mg/tab) 1PC TID Amlodipine(5mg/tab) 1PC QD • IVF: N/S 500cc + KCl 15meq run 60cc/hr • Admission to Nephro ward on 10/06

18. 2010/10/06 2010/10/08 2010/10/07 2010/10/09 2010/10/10 Rocephin Amlodipine Isorsobide-5-mononitrate Kidney echo Cardic echo Abd. echo

19. 2010/10/11 2010/10/12 2010/10/15 2010/10/13 2010/10/14 2010/10/16 MBD Rocephin Amlodipine Valsartan Isorsobide-5-mononitrate Chest echo EKG

20. Impression • Acute kidney injury, RIFLE-F, favor due to hypovolemic shock from postpartum hemorrahge • Fever with leukocytosis, favor sepsis from post-partum hemorrahge • Hypokalemia, favor loop diuretic effect

21. Outline • Differential diagnosis of hypertensive disorder related to pregnancy • Differential diagnosis of proteinuria • Review of preeclampsia • Future direction • Review of this case

22. Hypertensive disorders related to pregnancy • Preclampsia • Chronic hypertension • Preeclampsia superimpsed upon chronic hypertension • Gestational hypertension

23. Hypertensive disorders related to pregnancy • Preclampsia--- Hypertension and proteinuria after 20thwks of gestation in a previously hypertensive disorders related to pregnancy normotensive woman • Chronic hypertension --- Hypertension antedates pregnancy or before the 20thwks of pregnancy or persists longer than 12thwks postpartum.

24. Hypertensive disorders related to pregnancy • Preeclampsia superimpsed upon chronic hypertension --- a. Preexisting hypertension develops new onset proteinuria after 20thwks of gestation b. Preexisting hypertension and proteinuria with an exacerbation of blood pressure ( SBP > 160mmhg or DBP > 110mmhg) • Gestational hypertension --- It should resolve by 12thwks postpartum

25. Outline • Differential diagnosis of hypertensive disorder related to pregnancy • Differential diagnosis of proteinuria • Review of preeclampsia • Future direction • Review of this case

26. Etiology of proteinuria

27. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J ObstetGynecol 2000;183:S1–22.

28. Outline • Differential diagnosis of hypertensive disorder related to pregnancy • Differential diagnosis of proteinuria • Review of preeclampsia • Future direction • Review of this case

29. History of Preeclampsia • Eclampsia has been recognized clinically since Hippocrates. • Two thousand years ago, Celsus described pregnancy-associated seizures and named ‘eclampsia’ – the Greek word for ‘lightning’ • In 1843, Rayerand Lever described the association of proteinuria with eclampsia. Hippocrates Celsus

30. History of Preeclampsia • In 1884, SchedoffandPorockjakofffirst observed the link between hypertension and eclampsia. • Twentieth century began to realize that proteinuria and hypertension were strong predictiors for the onset of eclampsia. -- this prequel of eclampsia was termed “preeclampsia”

31. Leon Chesley 1908-2000

32. Introduction of Preeclampsia • Pregnancy-associated hypertension, proteinuria and edema • A systemic disease that results from placental defects • occurs in about 5–7% of pregnancies worldwide, relate to about 15% of preterm births • The incidence is much higher in developing countries. • Emergent delivery of the baby alleviates the maternal symptoms , but may lead to increased morbidity for the baby

33. Definition • 1972 recommendations of the American College of Obstetricians and Gynecologists： a. Increased blood pressure after 20 weeks of gestation (≥140/90 mm Hg) or an increase in systolic pressure of ≥30 mm Hg or in diastolic pressure of ≥15 mm Hg b. Proteinuria (≥0.3 g of protein in a 24-hour urine specimen or a urine dipstick result of ≥1+).

34. Pathophysiology of preeclampsia Placentation Abnormalities a. Placental tissue is necessary for development of the disease, but the fetus is not. b. Preeclampsia is always cured after delivery of the placenta The Maternal Syndrome a. The abnormal placentation release of secreted factors that enters the mother’s circulation. b. All of the clinical features of preeclampsia are maternal responses to generalized endothelial dysfunction Noris M et al. (2005) Mechanisms of Disease: pre-eclampsia Nat ClinPractNeprol1: 98–114 doi:10.1038/ncpneph0035

35. Placentation Abnormalities ( Stage I )-- Abnormal remodeling of spiral arteries

37. The Maternal Syndrome (stage II )

38. VEGF: vascular endothelial growth factor PlGF: placental growth factor FLT-1: fms-like tyrosine kinase 1 sFLT-1:Soluble fms-like tyrosine kinase 1 Membrane –bound receptor

39. Role of the soluble form of Fms-like tyrosine kinase 1 in the maternal syndrome of pre-eclampsia Noris M et al. (2005) Mechanisms of Disease: pre-eclampsia Nat Clin Pract Neprol1: 98–114 doi:10.1038/ncpneph0035

40. sFLT-1:Soluble fms-like tyrosine kinase 1 sEng:Solubleendoglin Glomerular Endolitheosis Placenta Diffuse inflammation at the maternal–fetal junction Hemorrhagic infarction and fibrinoid necrosis with lumen obstruction of vessel Liver Multifocal necrosis Peripheral blood Schistocytes & reticulocytosis Nature Medicine - 12, 642 - 649 (2006) Published online: 4 June 2006; | doi:10.1038/nm1429

41. The Maternal Syndrome (stage II ) sFlt-1, sEndoglin(sEng) All of the clinical features of preeclampsia are maternal responses to generalized endothelial dysfunction !!

42. Other hypotheses… BahaSibai, Gus Dekker, Michael Kupferminc. The Lancet. London: Feb 26-Mar 4, 2005. Vol. 365, Iss. 9461; p. 785

43. The putative role of COMT, HIF-1a and 2-ME

44. Biology of preeclampsia

45. Clinical feature --- hypertension Plasma renin activity

46. Clinical feature --- hypertension

48. Clinical feature --- Proteinuria :J Clin Invest. 2004 November 15; 114(10): 1412–1414

49. Clinical feature --- Proteinuria

50. Clinical feature --- Proteinuria • Method: Renal tissue was obtained from 7 severe preclampsia women