Transcript Kidney-in-Pregnancy

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.
2
Glomerular Physiology
Blood flow determinants
Systemic
AT-II
ANS
Afferent
Efferent
Local PG's
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:
– 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:
» 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
140
120
100
GFR
MAP
Volume
80
60
40
20
0
Normal 1st Trim
2nd
Trim
3rd
Trim
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Normal Changes in Pregnancy
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14
Pulse change
12
10
TPR
8
6
Art.
Compliance
Cardiac
Output
4
2
0
Normal
1st
Trim
2nd
Trim
3rd
Trim
Chapter 6, part 1, Medical Care of the Pregnant Patient
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Glomerular Physiology
Blood flow determinants
Systemic
AT-II
ANS
Afferent
Local PG's
TGF
Efferent
Increase Calcium excretion
Decrease uric acid reabsorption
Due to reduced filtration fraction
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
» 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
» 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
Target
Vascular Smooth M.
Renal Tubules
Mesangial cells
Effect
Vasoconstriction
Sodium excretion
Proliferation,
accumulation of
Matrix, and
contraction.
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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
» 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 Physiology
Blood flow determinants
Systemic
AT-II
ANS
Afferent
Local PG's
TGF
Efferent
Due to increased filtration fraction
Reduce Calcium excretion
Increase uric acid reabsorption
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 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/pregnancyoutcomes-after-kidney-donation
» Ibrahim et al. Am J Transplant. 2009
Apr;9(4):825-34
Maynard SE, Thadani R. Pregnancy and the Kidney.
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