The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010
Renal Physiology • Overview of Physiology 101 • Nitric Oxide Physiology • Endothelin Physiology • Normal Changes in Pregnancy • Pathophysiology in Pregnancy.
Glomerular PhysiologyBlood flow determinants Systemic AT-II ANS Afferent Efferent PG's Local TGF Filtration
Renal Physiology 201 • Explosion of Research in NO and ET • In the last 4 years, over 3000 publications each.
Nitric Oxide • Functions: • Regulate BP • Neurotransmitter • Suppress Pathogens • Studies describe Pathophys. in: • Pregnancy/Pre-ecclampsia • HTN • Hepatic Failure
Endothelin • Function: • Most potent vasoconstrictor • Studies describe broad range of Pathophysiologic conditions.
Why is this Important? • Inhibitors and Antagonists being developed which you will use soon • You already use some: • Nitroprusside • Isordil/NTG • Viagra
Nitric Oxide - NO • Uncharged molecule - can go anywhere • Unpaired electron - highly reactive • Chemical generation: • Arginine + O2-----> NO + Citrulline NOS
Enzyme Production • Nitric Oxide Synthase (NOS) • Two Types • Constitutive • vasodilator • neurotransmitter • Inducible • Free radical scavenger • Pathogen killer
Targets: Vascular Smooth Muscle Neurons Pathogenic bacteria Effects: Vasodilator Feedback for ET-1 Neurotransmitter Free Radical/Killer Nitric Oxide
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
Normal Changes in Pregnancy • Systemic Vasodilation • Lower BP • Increased Aldosterone • Volume expansion / edema • Increased GFR / RBF • Angiogenesis
Normal Changes in Pregnancy Chapter 6, part 1, Medical Care of the Pregnant Patient
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
Progesterone • Stimulates Nitric Oxide Synthase • Decreased response to Angiotensin
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
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
Pathophysiology • Hypertension • Proteinuria • Pre-ecclampsia • HELLP syndrome • Pre-existing renal disease • Pre-existing Hypertension
Pathophysiology • Hypertension • Proteinuria • Return of Responsiveness to Angiotensin
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
Ecclampsia vacuoles Hyaline thrombus
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?
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
ENDOTHELIN • Three Types • Produced by endothelial cells, most renal cell types. • Two receptor types, A and B
ENDOTHELIN • Stimulators: • Vasoconstrictors • Thrombin • Hypoxia • Low shear stress • Cytokines
ENDOTHELIN • Inhibitors of production • Vasodilators • Heparin • High shear stress
ENDOTHELIN • Feedback inhibition by Nitric Oxide, PGI2 (prostacyclin) • Also inhibited by activation of ET-B receptor on the endothelial cell
Vascular Smooth M. Renal Tubules Mesangial cells Vasoconstriction Sodium excretion Proliferation, accumulation of Matrix, and contraction. ENDOTHELIN Effect Target
ENDOTHELINClinical Aspects • ATN • Contrast nephrotoxicity • Cyclosporine nephrotoxicity • Endotoxic shock • Hypertension • Chronic renal failure
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
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.
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.
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.
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
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.
Summary • Physiology and Pathophysiology of • Nitric Oxide • Endothelin • Physiology and Pathophysiology of the kidney in Pregnancy
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-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 14-22.