The Kidney in Pregnancy

1
The Kidney in Pregnancy

• Jeffrey J. Kaufhold, MD FACP
• Update 2010

2
Renal Physiology

• Overview of Physiology 101
• Nitric Oxide Physiology
• Endothelin Physiology
• Normal Changes in Pregnancy
• Pathophysiology in Pregnancy.

3
Glomerular PhysiologyBlood flow determinants
Systemic
AT-II ANS
Afferent
Efferent
PG's
Local
TGF
Filtration
4
Renal Physiology 201

• Explosion of Research in NO and ET
• In the last 4 years, over 3000 publications each.

5
Nitric Oxide

• Functions
• Regulate BP
• Neurotransmitter
• Suppress Pathogens
• Studies describe Pathophys. in
• Pregnancy/Pre-ecclampsia
• HTN
• Hepatic Failure

6
Endothelin

• Function
• Most potent vasoconstrictor
• Studies describe broad range of Pathophysiologic
  conditions.

7
Why is this Important?

• Inhibitors and Antagonists being developed which
  you will use soon
• You already use some
• Nitroprusside
• Isordil/NTG
• Viagra

8
Nitric Oxide - NO

• Uncharged molecule - can go anywhere
• Unpaired electron - highly reactive
• Chemical generation
• Arginine O2-----gt NO Citrulline

NOS
9
Enzyme Production

• Nitric Oxide Synthase (NOS)
• Two Types
• Constitutive
• vasodilator
• neurotransmitter
• Inducible
• Free radical scavenger
• Pathogen killer

10
NITRIC OXIDE
11
Nitric Oxide

• Targets
• Vascular Smooth Muscle
• Neurons
• Pathogenic bacteria

• Effects
• Vasodilator
• Feedback for ET-1
• Neurotransmitter
• Free Radical/Killer

12
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

13
Normal Changes in Pregnancy

• Systemic Vasodilation
• Lower BP
• Increased Aldosterone
• Volume expansion / edema
• Increased GFR / RBF
• Angiogenesis

14
Normal Changes in Pregnancy
15
Normal Changes in Pregnancy
Chapter 6, part 1, Medical Care of the Pregnant
Patient
16
Glomerular PhysiologyBlood 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
17
Why do these Changes Occur?
18
Progesterone

• Stimulates Nitric Oxide Synthase
• Decreased response to Angiotensin

19
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

20
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

21
Pathophysiology

• Hypertension
• Proteinuria
• Pre-ecclampsia
• HELLP syndrome
• Pre-existing renal disease
• Pre-existing Hypertension

22
Pathophysiology

• Hypertension
• Proteinuria
• Return of Responsiveness to Angiotensin

23
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

24
Normal Glomerulus
25
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?

27
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
33
ENDOTHELIN
Effect
Target

• Vasoconstriction
• Sodium excretion
• Proliferation, accumulation of Matrix, and
  contraction.

• Vascular Smooth M.
• Renal Tubules
• Mesangial cells

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ENDOTHELINClinical Aspects

• ATN
• Contrast nephrotoxicity
• Cyclosporine nephrotoxicity
• Endotoxic shock
• Hypertension
• Chronic renal failure

35
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

36
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.

37
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.

38
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.

39
Glomerular PhysiologyBlood 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
40
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.

41
Summary

• Physiology and Pathophysiology of
• Nitric Oxide
• Endothelin
• Physiology and Pathophysiology of the kidney in
  Pregnancy

42
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-outco
  mes-after-kidney-donation
• Ibrahim et al. Am J Transplant.   2009
  Apr9(4)825-34
• Maynard SE, Thadani R. Pregnancy and the Kidney.
  JASN Vol 20, 2009, p 14-22.