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The Kidney in Pregnancy
Jeffrey J. Kaufhold, MD FACP Update 2010
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Renal Physiology Overview of Physiology 101 Nitric Oxide Physiology
Endothelin Physiology Normal Changes in Pregnancy Pathophysiology in Pregnancy.
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Glomerular Physiology Blood flow determinants
Systemic AT-II ANS Afferent Efferent PG's Local TGF Filtration
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Renal Physiology 201 Explosion of Research in NO and ET
In the last 4 years, over 3000 publications each.
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Nitric Oxide Functions: Studies describe Pathophys. in: Regulate BP
Neurotransmitter Suppress Pathogens Studies describe Pathophys. in: Pregnancy/Pre-ecclampsia HTN Hepatic Failure
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Endothelin Function: Most potent vasoconstrictor Studies describe broad range of Pathophysiologic conditions.
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Why is this Important? Inhibitors and Antagonists being developed which you will use soon You already use some: Nitroprusside Isordil/NTG Viagra
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Nitric Oxide - NO Uncharged molecule - can go anywhere
Unpaired electron - highly reactive Chemical generation: Arginine + O2-----> NO + Citrulline NOS
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Enzyme Production Nitric Oxide Synthase (NOS) Two Types Constitutive
vasodilator neurotransmitter Inducible Free radical scavenger Pathogen killer
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NITRIC OXIDE
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Nitric Oxide Targets: Effects: Vascular Smooth Muscle Neurons
Pathogenic bacteria Effects: Vasodilator Feedback for ET-1 Neurotransmitter Free Radical/Killer
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Progesterone Stimulates Nitric Oxide Synthase Stimulates Relaxin
See below Stimulates Relaxin to soften Ligaments/ allow opening of Birth Canal Hydroureter Stimulates Ventilation Chronic Resp Alkalosis, Useful in Sleep apnea
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Normal Changes in Pregnancy
Systemic Vasodilation Lower BP Increased Aldosterone Volume expansion / edema Increased GFR / RBF Angiogenesis
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Normal Changes in Pregnancy
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Normal Changes in Pregnancy
Chapter 6, part 1, Medical Care of the Pregnant Patient
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Glomerular Physiology Blood flow determinants
Systemic AT-II ANS Afferent Efferent PG's Local Increase Calcium excretion Decrease uric acid reabsorption Due to reduced filtration fraction TGF Filtration
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Why do these Changes Occur?
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Progesterone Stimulates Nitric Oxide Synthase
Decreased response to Angiotensin
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Progesterone Stimulates Nitric Oxide Synthase
Leads to systemic Vasodilation Which causes lower BP, Which stimulates Aldosterone Which leads to volume expansion Which increases GFR/RBF Decreased response to Angiotensin
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NonVascular Functions of NO
Modulates immune response reduces toxicity of oxygen radicals reduces adhesion of neutrophils, etc inhibits mast cell degranulation Pregnancy is an Immune Tolerant Condition
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Pathophysiology Hypertension Proteinuria Pre-ecclampsia HELLP syndrome
Pre-existing renal disease Pre-existing Hypertension
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Pathophysiology Hypertension Proteinuria
Return of Responsiveness to Angiotensin
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Pathophysiology Pre-ecclampsia HELLP syndrome
Severe HTN with risk for seizures Vacuole formation in endothelial cells Circulating Inhibitors of NOS HELLP syndrome Hepatic dysfunction due to underperfusion Low platelets due to fibrin deposition and scything of cells in capillaries Increased Endothelin
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Normal Glomerulus
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Ecclampsia vacuoles Hyaline thrombus
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Pathophysiology Pre-existing renal disease Pre-existing Hypertension
General rule is 1/3 worsen 1/3 stable 1/3 improve Pre-existing Hypertension Tends to improve Which drugs to use?
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Pathophysiology Hypertension Which drugs?
First Line: Aldomet, Labetolol Second Line: Hydralazine, Pindolol, Acebutolol, Nifedipine. Third Line: Atenolol, Inderal, clonidine, diltiazem, verapamil, HCTZ Contraindicated: ACE inhibitors
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ENDOTHELIN Three Types
Produced by endothelial cells, most renal cell types. Two receptor types, A and B
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ENDOTHELIN Stimulators: Vasoconstrictors Thrombin Hypoxia
Low shear stress Cytokines
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ENDOTHELIN Inhibitors of production Vasodilators Heparin
High shear stress
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ENDOTHELIN Feedback inhibition by Nitric Oxide, PGI2 (prostacyclin)
Also inhibited by activation of ET-B receptor on the endothelial cell
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ENDOTHELIN
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ENDOTHELIN Effect Target Vasoconstriction Vascular Smooth M.
Sodium excretion Proliferation, accumulation of Matrix, and contraction. Vascular Smooth M. Renal Tubules Mesangial cells
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ENDOTHELIN Clinical Aspects
ATN Contrast nephrotoxicity Cyclosporine nephrotoxicity Endotoxic shock Hypertension Chronic renal failure
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Clinical Aspects of N.O. Cirrhosis Pregnancy
decreased BP, low SVR, angiogenesis NOS inhibitors work, sort of. Pregnancy reduced response to angiotensin natural inhibitor found in pre-ecclampsia
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Pre-eclampsia Mediators
Soluble fms-like Tyrosine Kinase-1 sFLT1 Antagonizes VEGF, Placental Growth Factor (PlGF) Soluble Endoglin sENG Cleavage product of TGF-B receptor Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p
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Pre-eclampsia Mediators
Autoantibodies to Angiotensin I receptor Found in pre-eclampsia and other conditions May play a role but are not specific 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
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Future Markers for Pre-eclampsia
Placental Protein 13 (PP13) Placental artery doppler in 3rd trimester Genetic predisposition with certain Gene markers Uric Acid level increases. Why? Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p
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Glomerular Physiology Blood flow determinants
Systemic AT-II ANS Afferent Efferent PG's Local Due to increased filtration fraction Reduce Calcium excretion Increase uric acid reabsorption TGF Filtration
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Future Treatments for Pre-eclampsia
VEGF Vascular Endothelial Growth Factor L-arginine Substrate for Nitric Oxide Synthase Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p
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Summary Physiology and Pathophysiology of
Nitric Oxide Endothelin Physiology and Pathophysiology of the kidney in Pregnancy
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References Medical Care of the Pregnant Patient
RV Lee, K Rosene-Montella et al. Published by the American College of Physicians (acponline.org), 2000 Kidney Disease and Pregnancy Dr Phyllis August Pregnancy Outcomes after kidney Donation Ibrahim et al. Am J Transplant. 2009 Apr;9(4):825-34 Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p
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