Chronic Kidney Disease Medical Management 2012 Jeff Kaufhold, MD FACP.
1 The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010.
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Transcript of 1 The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010.
1
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 PhysiologyBlood flow determinants
Afferent Efferent
Filtration
Systemic
PG'sTGF
Local
AT-IIANS
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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:– 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 + CitrullineNOS
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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:» 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» 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 PhysiologyBlood flow determinants
Afferent Efferent
Filtration
Systemic
PG'sTGF
Local
AT-IIANS
Increase Calcium excretionDecrease uric acid reabsorptionDue to reduced filtration fraction
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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» 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
Hyaline thrombus
vacuoles
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Pathophysiology
Pre-existing renal disease» 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
Vascular Smooth M. Renal Tubules Mesangial cells
Vasoconstriction Sodium excretion Proliferation,
accumulation of Matrix, and contraction.
Target Effect
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ENDOTHELINClinical Aspects
ATN Contrast nephrotoxicity Cyclosporine nephrotoxicity Endotoxic shock Hypertension Chronic renal failure
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Clinical Aspects of N.O.
Cirrhosis» 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 14-22.
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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 14-22.
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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 14-22.
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Glomerular PhysiologyBlood flow determinants
Afferent Efferent
Filtration
Systemic
PG'sTGF
Local
AT-IIANS
Due to increased filtration fraction Reduce Calcium excretion Increase uric acid reabsorption
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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 14-22.
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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» www.kidneyatlas.org/book4/adk4-10.pdf
Pregnancy Outcomes after kidney Donation» www.nephrologynow.com/publications/pregnancy-outcom
es-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 14-22.