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The Kidney in Pregnancy Jeffrey J. Kaufhold, MD FACP Update 2010 1 Renal Physiology l l l l l Overview of Physiology 101 Nitric Oxide Physiology Endothelin Physiology Normal Changes in Pregnancy Pathophysiology in Pregnancy. 2 Glomerular Physiology Blood flow determinants Systemic AT-II ANS Afferent Efferent Local PG's TGF Filtration 3 Renal Physiology 201 l l Explosion of Research in NO and ET In the last 4 years, over 3000 publications each. 4 Nitric Oxide l Functions: – Regulate BP – Neurotransmitter – Suppress Pathogens l Studies describe Pathophys. in: – Pregnancy/Pre-ecclampsia – HTN – Hepatic Failure 5 Endothelin l Function: » Most potent vasoconstrictor l Studies describe broad range of Pathophysiologic conditions. 6 Why is this Important? l l Inhibitors and Antagonists being developed which you will use soon You already use some: » Nitroprusside » Isordil/NTG » Viagra 7 Nitric Oxide - NO l l l Uncharged molecule - can go anywhere Unpaired electron - highly reactive Chemical generation: » Arginine + O2-----> NO + Citrulline NOS 8 Enzyme Production l Nitric Oxide Synthase (NOS) » Two Types – Constitutive l l vasodilator neurotransmitter – Inducible l l Free radical scavenger Pathogen killer 9 NITRIC OXIDE 10 Nitric Oxide l Targets: » Vascular Smooth Muscle » Neurons » Pathogenic bacteria l Effects: » » » » Vasodilator Feedback for ET-1 Neurotransmitter Free Radical/Killer 11 Progesterone l Stimulates Nitric Oxide Synthase » See below l Stimulates Relaxin » to soften Ligaments/ allow opening of Birth Canal » Hydroureter l Stimulates Ventilation » Chronic Resp Alkalosis, » Useful in Sleep apnea 12 Normal Changes in Pregnancy l l l l l l Systemic Vasodilation Lower BP Increased Aldosterone Volume expansion / edema Increased GFR / RBF Angiogenesis 13 Normal Changes in Pregnancy 140 120 100 GFR MAP Volume 80 60 40 20 0 Normal 1st Trim 2nd Trim 3rd Trim 14 Normal Changes in Pregnancy 16 14 Pulse change 12 10 TPR 8 6 Art. Compliance Cardiac Output 4 2 0 Normal 1st Trim 2nd Trim 3rd Trim Chapter 6, part 1, Medical Care of the Pregnant Patient 15 Glomerular Physiology Blood flow determinants Systemic AT-II ANS Afferent Local PG's TGF Efferent Increase Calcium excretion Decrease uric acid reabsorption Due to reduced filtration fraction Filtration 16 Why do these Changes Occur? 17 Progesterone l l Stimulates Nitric Oxide Synthase Decreased response to Angiotensin 18 Progesterone l Stimulates Nitric Oxide Synthase » Leads to systemic Vasodilation » Which causes lower BP, » Which stimulates Aldosterone » Which leads to volume expansion » Which increases GFR/RBF l Decreased response to Angiotensin 19 NonVascular Functions of NO l l l l l Modulates immune response reduces toxicity of oxygen radicals reduces adhesion of neutrophils, etc inhibits mast cell degranulation Pregnancy is an Immune Tolerant Condition 20 Pathophysiology l l l l l l Hypertension Proteinuria Pre-ecclampsia HELLP syndrome Pre-existing renal disease Pre-existing Hypertension 21 Pathophysiology l l l Hypertension Proteinuria Return of Responsiveness to Angiotensin 22 Pathophysiology l Pre-ecclampsia » Severe HTN with risk for seizures » Vacuole formation in endothelial cells » Circulating Inhibitors of NOS l HELLP syndrome » Hepatic dysfunction due to underperfusion » Low platelets due to fibrin deposition and scything of cells in capillaries » Increased Endothelin 23 Normal Glomerulus 24 Ecclampsia vacuoles Hyaline thrombus 25 Pathophysiology l Pre-existing renal disease » General rule is – 1/3 worsen – 1/3 stable – 1/3 improve l Pre-existing Hypertension » Tends to improve » Which drugs to use? 26 Pathophysiology l Hypertension Which drugs? » First Line: Aldomet, Labetolol » Second Line: Hydralazine, Pindolol, Acebutolol, Nifedipine. » Third Line: Atenolol, Inderal, clonidine, diltiazem, verapamil, HCTZ l Contraindicated: ACE inhibitors 27 ENDOTHELIN l l l Three Types Produced by endothelial cells, most renal cell types. Two receptor types, A and B 28 ENDOTHELIN l Stimulators: » Vasoconstrictors » Thrombin » Hypoxia » Low shear stress » Cytokines 29 ENDOTHELIN l Inhibitors of production » Vasodilators » Heparin » High shear stress 30 ENDOTHELIN l l Feedback inhibition by Nitric Oxide, PGI2 (prostacyclin) Also inhibited by activation of ET-B receptor on the endothelial cell 31 ENDOTHELIN 32 ENDOTHELIN Effect Target l l l Vascular Smooth M. Renal Tubules Mesangial cells l l l Vasoconstriction Sodium excretion Proliferation, accumulation of Matrix, and contraction. 33 ENDOTHELIN Clinical Aspects l l l l l l ATN Contrast nephrotoxicity Cyclosporine nephrotoxicity Endotoxic shock Hypertension Chronic renal failure 34 Clinical Aspects of N.O. l Cirrhosis » decreased BP, low SVR, angiogenesis » NOS inhibitors work, sort of. l Pregnancy » reduced response to angiotensin » natural inhibitor found in pre-ecclampsia 35 Pre-eclampsia Mediators l Soluble fms-like Tyrosine Kinase-1 » sFLT1 » Antagonizes VEGF, Placental Growth Factor (PlGF) l Soluble Endoglin » sENG » Cleavage product of TGF-B receptor – Maynard SE, Thadani R. Pregnancy and the Kidney. JASN Vol 20, 2009, p 14-22. 36 Pre-eclampsia Mediators l Autoantibodies to Angiotensin I receptor » Found in pre-eclampsia and other conditions » May play a role but are not specific l 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. 37 Future Markers for Pre-eclampsia l l l l 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. 38 Glomerular Physiology Blood flow determinants Systemic AT-II ANS Afferent Local PG's TGF Efferent Due to increased filtration fraction Reduce Calcium excretion Increase uric acid reabsorption Filtration 39 Future Treatments for Pre-eclampsia l l 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. 40 Summary l Physiology and Pathophysiology of » Nitric Oxide » Endothelin l Physiology and Pathophysiology of the kidney in Pregnancy 41 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/pregnancyoutcomes-after-kidney-donation » Ibrahim et al. Am J Transplant. 2009 Apr;9(4):825-34 Maynard SE, Thadani R. Pregnancy and the Kidney. 42