The Kidney in Pregnancy
Jeffrey J. Kaufhold, MD FACP
Update 2010
1
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
3
Renal Physiology 201
Explosion of Research in NO and ET
In the last 4 years, over 3000
publications each.
4
Nitric Oxide
Functions:
– Regulate BP
– Neurotransmitter
– Suppress Pathogens
Studies describe Pathophys. in:
– Pregnancy/Pre-ecclampsia
– HTN
– Hepatic Failure
5
Endothelin
Function:
» Most potent vasoconstrictor
Studies describe broad range of
Pathophysiologic conditions.
6
Why is this Important?
Inhibitors and Antagonists being
developed which you will use soon
You already use some:
» Nitroprusside
» Isordil/NTG
» Viagra
7
Nitric Oxide - NO
Uncharged molecule - can go anywhere
Unpaired electron - highly reactive
Chemical generation:
» Arginine + O2-----> NO + Citrulline
NOS
8
Enzyme Production
Nitric Oxide Synthase (NOS)
» Two Types
– Constitutive
vasodilator
neurotransmitter
– Inducible
Free radical scavenger
Pathogen killer
9
NITRIC OXIDE
10
Nitric Oxide
Targets:
» Vascular Smooth
Muscle
» Neurons
» Pathogenic bacteria
Effects:
»
»
»
»
Vasodilator
Feedback for ET-1
Neurotransmitter
Free Radical/Killer
11
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
12
Normal Changes in Pregnancy
Systemic Vasodilation
Lower BP
Increased Aldosterone
Volume expansion / edema
Increased GFR / RBF
Angiogenesis
13
Normal Changes in Pregnancy
140
120
100
GFR
MAP
Volume
80
60
40
20
0
Normal 1st Trim
2nd
Trim
3rd
Trim
14
Normal Changes in Pregnancy
16
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
15
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
16
Why do these Changes Occur?
17
Progesterone
Stimulates Nitric Oxide Synthase
Decreased response to Angiotensin
18
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
19
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
20
Pathophysiology
Hypertension
Proteinuria
Pre-ecclampsia
HELLP syndrome
Pre-existing renal disease
Pre-existing Hypertension
21
Pathophysiology
Hypertension
Proteinuria
Return of Responsiveness to
Angiotensin
22
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
23
Normal Glomerulus
24
Ecclampsia
vacuoles
Hyaline
thrombus
25
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?
26
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
27
ENDOTHELIN
Three Types
Produced by endothelial cells, most
renal cell types.
Two receptor types, A and B
28
ENDOTHELIN
Stimulators:
» Vasoconstrictors
» Thrombin
» Hypoxia
» Low shear stress
» Cytokines
29
ENDOTHELIN
Inhibitors of production
» Vasodilators
» Heparin
» High shear stress
30
ENDOTHELIN
Feedback inhibition by Nitric Oxide,
PGI2 (prostacyclin)
Also inhibited by activation of ET-B
receptor on the endothelial cell
31
ENDOTHELIN
32
ENDOTHELIN
Target
Vascular Smooth M.
Renal Tubules
Mesangial cells
Effect
Vasoconstriction
Sodium excretion
Proliferation,
accumulation of
Matrix, and
contraction.
33
ENDOTHELIN
Clinical Aspects
ATN
Contrast nephrotoxicity
Cyclosporine nephrotoxicity
Endotoxic shock
Hypertension
Chronic renal failure
34
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
35
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.
36
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.
37
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.
38
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
39
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.
40
Summary
Physiology and Pathophysiology of
» Nitric Oxide
» Endothelin
Physiology and Pathophysiology of the
kidney in Pregnancy
41
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.
42