1 The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010.

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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.

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Glomerular PhysiologyBlood flow determinants

Afferent Efferent

Filtration

Systemic

PG'sTGF

Local

AT-IIANS

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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 + CitrullineNOS

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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

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Normal Changes in Pregnancy

Chapter 6, part 1, Medical Care of the Pregnant Patient

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Glomerular PhysiologyBlood flow determinants

Afferent Efferent

Filtration

Systemic

PG'sTGF

Local

AT-IIANS

Increase Calcium excretionDecrease uric acid reabsorptionDue to reduced filtration fraction

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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

Hyaline thrombus

vacuoles

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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

Vascular Smooth M. Renal Tubules Mesangial cells

Vasoconstriction Sodium excretion Proliferation,

accumulation of Matrix, and contraction.

Target Effect

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ENDOTHELINClinical 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 PhysiologyBlood flow determinants

Afferent Efferent

Filtration

Systemic

PG'sTGF

Local

AT-IIANS

Due to increased filtration fraction Reduce Calcium excretion Increase uric acid reabsorption

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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/pregnancy-outcom

es-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.