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 Physiology Blood 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: Studies describe Pathophys. in: 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

NITRIC OXIDE

Nitric Oxide Targets: Effects: Vascular Smooth Muscle Neurons Pathogenic bacteria Effects: Vasodilator Feedback for ET-1 Neurotransmitter Free Radical/Killer

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

Normal Changes in Pregnancy Systemic Vasodilation Lower BP Increased Aldosterone Volume expansion / edema Increased GFR / RBF Angiogenesis

Normal Changes in Pregnancy

Normal Changes in Pregnancy Chapter 6, part 1, Medical Care of the Pregnant Patient

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

Why do these Changes Occur?

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 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

Normal Glomerulus

Ecclampsia vacuoles Hyaline thrombus

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?

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

ENDOTHELIN

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

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

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

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 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

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.