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1 The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010.

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Presentation on theme: "1 The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010."— Presentation transcript:

1 1 The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010

2 2 Renal Physiology l Overview of Physiology 101 l Nitric Oxide Physiology l Endothelin Physiology l Normal Changes in Pregnancy l Pathophysiology in Pregnancy.

3 3 Glomerular Physiology Blood flow determinants AfferentEfferent Filtration Systemic PG's TGF Local AT-II ANS

4 4 Renal Physiology 201 l Explosion of Research in NO and ET l In the last 4 years, over 3000 publications each.

5 5 Nitric Oxide l Functions: –Regulate BP –Neurotransmitter –Suppress Pathogens l Studies describe Pathophys. in: –Pregnancy/Pre-ecclampsia –HTN –Hepatic Failure

6 6 Endothelin l Function: »Most potent vasoconstrictor l Studies describe broad range of Pathophysiologic conditions.

7 7 Why is this Important? l Inhibitors and Antagonists being developed which you will use soon l You already use some: »Nitroprusside »Isordil/NTG »Viagra

8 8 Nitric Oxide - NO l Uncharged molecule - can go anywhere l Unpaired electron - highly reactive l Chemical generation: »Arginine + O2-----> NO + Citrulline NOS

9 9 Enzyme Production l Nitric Oxide Synthase (NOS) »Two Types –Constitutive l vasodilator l neurotransmitter –Inducible l Free radical scavenger l Pathogen killer

10 10 NITRIC OXIDE

11 11 Nitric Oxide l Targets: »Vascular Smooth Muscle »Neurons »Pathogenic bacteria l Effects: »Vasodilator »Feedback for ET-1 »Neurotransmitter »Free Radical/Killer

12 12 Progesterone l Stimulates Nitric Oxide Synthase »See below l Stimulates Relaxin »to soften Ligaments/ allow opening of Birth Canal »Hydroureter l Stimulates Ventilation »Chronic Resp Alkalosis, »Useful in Sleep apnea

13 13 Normal Changes in Pregnancy l Systemic Vasodilation l Lower BP l Increased Aldosterone l Volume expansion / edema l Increased GFR / RBF l Angiogenesis

14 14 Normal Changes in Pregnancy

15 15 Normal Changes in Pregnancy Chapter 6, part 1, Medical Care of the Pregnant Patient

16 16 Glomerular Physiology Blood flow determinants AfferentEfferent Filtration Systemic PG's TGF Local AT-II ANS Increase Calcium excretion Decrease uric acid reabsorption Due to reduced filtration fraction

17 17 Why do these Changes Occur?

18 18 Progesterone l Stimulates Nitric Oxide Synthase l Decreased response to Angiotensin

19 19 Progesterone l Stimulates Nitric Oxide Synthase »Leads to systemic Vasodilation »Which causes lower BP, »Which stimulates Aldosterone »Which leads to volume expansion »Which increases GFR/RBF l Decreased response to Angiotensin

20 20 NonVascular Functions of NO l Modulates immune response l reduces toxicity of oxygen radicals l reduces adhesion of neutrophils, etc l inhibits mast cell degranulation l Pregnancy is an Immune Tolerant Condition

21 21 Pathophysiology l Hypertension l Proteinuria l Pre-ecclampsia l HELLP syndrome l Pre-existing renal disease l Pre-existing Hypertension

22 22 Pathophysiology l Hypertension l Proteinuria l Return of Responsiveness to Angiotensin

23 23 Pathophysiology l Pre-ecclampsia »Severe HTN with risk for seizures »Vacuole formation in endothelial cells »Circulating Inhibitors of NOS l HELLP syndrome »Hepatic dysfunction due to underperfusion »Low platelets due to fibrin deposition and scything of cells in capillaries »Increased Endothelin

24 24 Normal Glomerulus

25 25 Ecclampsia Hyaline thrombus vacuoles

26 26 Pathophysiology l Pre-existing renal disease »General rule is –1/3 worsen –1/3 stable –1/3 improve l Pre-existing Hypertension »Tends to improve »Which drugs to use?

27 27 Pathophysiology l Hypertension Which drugs? »First Line: Aldomet, Labetolol »Second Line: Hydralazine, Pindolol, Acebutolol, Nifedipine. »Third Line: Atenolol, Inderal, clonidine, diltiazem, verapamil, HCTZ l Contraindicated: ACE inhibitors

28 28 ENDOTHELIN l Three Types l Produced by endothelial cells, most renal cell types. l Two receptor types, A and B

29 29 ENDOTHELIN l Stimulators: »Vasoconstrictors »Thrombin »Hypoxia »Low shear stress »Cytokines

30 30 ENDOTHELIN l Inhibitors of production »Vasodilators »Heparin »High shear stress

31 31 ENDOTHELIN l Feedback inhibition by Nitric Oxide, PGI2 (prostacyclin) l Also inhibited by activation of ET-B receptor on the endothelial cell

32 32 ENDOTHELIN

33 33 ENDOTHELIN l Vascular Smooth M. l Renal Tubules l Mesangial cells l Vasoconstriction l Sodium excretion l Proliferation, accumulation of Matrix, and contraction. Target Effect

34 34 ENDOTHELIN Clinical Aspects l ATN l Contrast nephrotoxicity l Cyclosporine nephrotoxicity l Endotoxic shock l Hypertension l Chronic renal failure

35 35 Clinical Aspects of N.O. l Cirrhosis »decreased BP, low SVR, angiogenesis »NOS inhibitors work, sort of. l Pregnancy »reduced response to angiotensin »natural inhibitor found in pre-ecclampsia

36 36 Pre-eclampsia Mediators l Soluble fms-like Tyrosine Kinase-1 »sFLT1 »Antagonizes VEGF, Placental Growth Factor (PlGF) l Soluble Endoglin »sENG »Cleavage product of TGF-B receptor –Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p

37 37 Pre-eclampsia Mediators l Autoantibodies to Angiotensin I receptor »Found in pre-eclampsia and other conditions »May play a role but are not specific l Deficiency of Catechol-O-Methyl Transferase (COMT) placental enzyme which breaks down catecholamines. –Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p

38 38 Future Markers for Pre-eclampsia l Placental Protein 13 (PP13) l Placental artery doppler in 3rd trimester l Genetic predisposition with certain Gene markers l Uric Acid level increases. Why? –Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p

39 39 Glomerular Physiology Blood flow determinants AfferentEfferent Filtration Systemic PG's TGF Local AT-II ANS Due to increased filtration fraction Reduce Calcium excretion Increase uric acid reabsorption

40 40 Future Treatments for Pre-eclampsia l VEGF »Vascular Endothelial Growth Factor l L-arginine »Substrate for Nitric Oxide Synthase –Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p

41 41 Summary l Physiology and Pathophysiology of »Nitric Oxide »Endothelin l Physiology and Pathophysiology of the kidney in Pregnancy

42 42 References l Medical Care of the Pregnant Patient »RV Lee, K Rosene-Montella et al. Published by the American College of Physicians (acponline.org), 2000 l Kidney Disease and Pregnancy »Dr Phyllis August »www.kidneyatlas.org/book4/adk4-10.pdf l Pregnancy Outcomes after kidney Donation »www.nephrologynow.com/publications/pregnancy- outcomes-after-kidney-donationwww.nephrologynow.com/publications/pregnancy- outcomes-after-kidney-donation »Ibrahim et al. Am J Transplant Apr;9(4): l Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p


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