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 Physiology Blood 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: Studies describe Pathophys. in: 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-----> 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: Effects: Vascular Smooth Muscle Neurons
Pathogenic bacteria
Effects:
Vasodilator
Feedback for ET-1
Neurotransmitter
Free Radical/Killer

12. 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

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 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

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 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

24. Normal Glomerulus

25. Ecclampsia
vacuoles
Hyaline
thrombus

26. 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?

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

28. ENDOTHELIN Three Types
Produced by endothelial cells, most renal cell types.
Two receptor types, A and B

29. ENDOTHELIN Stimulators: Vasoconstrictors Thrombin Hypoxia
Low shear stress
Cytokines

30. ENDOTHELIN Inhibitors of production Vasodilators Heparin
High shear stress

31. ENDOTHELIN Feedback inhibition by Nitric Oxide, PGI2 (prostacyclin)
Also inhibited by activation of ET-B receptor on the endothelial cell

32. ENDOTHELIN

33. ENDOTHELIN Effect Target Vasoconstriction Vascular Smooth M.
Sodium excretion
Proliferation, accumulation of Matrix, and contraction.
Vascular Smooth M.
Renal Tubules
Mesangial cells

34. ENDOTHELIN Clinical Aspects
ATN
Contrast nephrotoxicity
Cyclosporine nephrotoxicity
Endotoxic shock
Hypertension
Chronic renal failure

35. 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

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

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

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

39. 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

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

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
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