Lecture 54: Kidney Filtration PDF

Filtration, the first step in urine formation Path of urine drainage: Papillary duct in renal pyramid Minor and major calices Renal Pelvis Ureter Elements of Renal Function Koeppen, Bruce M., MD, PhD, Berne and Levy Physiology, 33, 581-602 Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rig...

Filtration, the first step in urine formation Path of urine drainage: Papillary duct in renal pyramid Minor and major calices Renal Pelvis Ureter Elements of Renal Function Koeppen, Bruce M., MD, PhD, Berne and Levy Physiology, 33, 581-602 Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rights reserved. Filtration in the renal corpuscle: fluid passage across the wall of glomerular capillaries into the Bowman’s space and proximal tubule Bowman’s capsule epithelium Efferent arteriole Proximal Tubule Blood Out Filtrate Thick Ascending Limb of Loop of Henle Glomerular capillaries Perfusion of glomerular capillaries Afferent arteriole Blood In Filtration of plasma Formation of urine Cells of Renal Corpuscle 1. Bowman’s capsule: Parietal epithelial cells – external squamous epithelium 2. Glomerulus: a. Endothelial cells - inner lining of the capillaries b. Podocytes - external layer of glomerular capillaries of epithelial origin (the inner ? visceral epithelium) Podocytes with foot-like processes pedicels, 3. Mesangial cells - immunoreactive transformed smooth muscle cells between glomerular capillaries, which can contract in response to circulating vasoactive substances impeding glomerular blood flow and filtration. ANATOMY OF THE URINARY TRACT ${parentCitation.authFull}, Netter Collection of Medical Illustrations: Urinary System, The, SECTION 1, 1-28 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Granular cells? Granular cells = Juxtaglomerular cells Juxtaglomerular Apparatus – – specialized cells located at the junction of the glomerulus and transition of thick ascending limb of loop of Henle into the distal tubule 1. macula densa, specialized epithelial cells of the renal tubule 2. granular or juxtaglomerular cells, mostly of afferent arterioles 3. external mesangial cells The Physiology of the Loop of Henle Capasso, Giovambattista, Critical Care Nephrology, CHAPTER 25, 139-145 Copyright © 2009 Copyright © 2009 by Saunders, an imprint of Elsevier Inc., Copyright © 1998 by Claudio Ronco, MD, and Rinaldo Bellomo, MD ? Juxtaglomerular Apparatus (JGA): 1. granular cells, arterioles 2. macula densa, specialized cells of the renal tubule 3. external mesangial cells Functions of the cells of JGA: Granular cells = renin release Macula densa = sensing flow of filtrate ANATOMY OF THE URINARY TRACT ${parentCitation.authFull}, Netter Collection of Medical Illustrations: Urinary System, The, SECTION 1, 1-28 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Sympathetic Innervation Bowman’s capsule epithelium Efferent arteriole Proximal Tubule Extraglomerular mesangial cells Macula densa cells sense filtrate flow Thick Ascending Limb of Loop of Henle . .. renin .. Granular cells release renin Smooth muscle cells Afferent arteriole Sympathetic nerves project to the granular and smooth muscle cells of the afferent arterioles. Constant blood flow in a tuft of glomerular capillaries is necessary for filtrate formation The wall of glomerular capillaries = blood filtration barrier Renal Anatomy Kriz, Wilhelm, Comprehensive Clinical Nephrology, Chapter 1, 2-13 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. The wall of glomerular capillaries = glomerular filtration barrier - controls passage of substances from plasma into the renal tubule; - 3 layers: leaky endothelium (pores or fenestrae); basement membrane (porous matrix of negatively charged glycoproteins); podocytes = specialized epithelial cells with interdigitating pedicels separated by filtration slits ANATOMY OF THE URINARY TRACT ${parentCitation.authFull}, Netter Collection of Medical Illustrations: Urinary System, The, SECTION 1, 1-28 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Podocytes that cover glomerular capillaries in the rat The capillary is covered by the highly branched podocytes. The interdigitating system of primary processes (PP) and foot processes (FP) lines the entire surface of the tuft, also extending beneath the cell bodies. The foot processes of neighboring cells interdigitate but spare the filtration slits in between. (Scanning electron microscopy; magnification ×2200.) Renal Anatomy Kriz, Wilhelm, Comprehensive Clinical Nephrology, Chapter 1, 2-13 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Substances are filtered through endothelial cell fenestrae , across the porous matrix of the glomerular basement membrane (GMB) and through the filtration slits between pedicels into the capsular space. Filtration slits between pedicels Filtrate Capsular space Plasma Endothelial pores Capillary lumen Glomerular capillary. The layer of interdigitating podocyte processes and the GBM do not completely encircle the capillary. At the mesangial angles (arrows), both deviate from a pericapillary course and cover the mesangium. MF – mesangial microfilaments At the capillary-mesangial interface, the Renal Anatomy capillary endothelium directly abuts the Kriz, Wilhelm, Comprehensive Clinical Nephrology, Chapter 1, 2-13 mesangium. Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Filtrate = water and dissolved solutes such as ions, glucose, amino acids, etc. pass through the glomerular capillary wall and move into the Bowmen’s space and proximal tubule. What are the factors that determine filterability of substances? Renal Anatomy Kriz, Wilhelm, Comprehensive Clinical Nephrology, Chapter 1, 2-13 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Bowman’s space Plasma Filtrate Filterability of substances (fitrate/filtrand) depends on 2 factors: 1. molecular weight (radius in angstroms) 2. molecular (negative -) charge Large molecular radius and negative charge impedes filtration Substance Mol. Wt. g Radius Filterability water 18 1.0 1.0 urea 60 1.6 1.0 glucose 180 3.6 1.0 inulin 5,500 15 0.98 myoglobin 17,000 20 0.75 hemoglobin 68,000 33 0.03 albumin 69,000 36 0.01 Plasma substances are filtered, except for proteins! The wall of glomerular capillaries is more permeable than the wall of systemic capillaries Filtration coefficient (Kf, a measure of permeability) is a 100 times greater for the glomerular capillaries compared to systemic capillaries (-) Blood cells and most of plasma proteins (Pr-) do not pass normally through the wall of glomerular capillaries! Section of Glomerulus Negative charge (-) of the glomerular basement membrane and podocyte processes impede filtration of albumins. RBC Lumen of glomerularCapillary wall capillary Pr- (-) Pedicels Proteins H2O Na+ Renal Anatomy Kriz, Wilhelm, Comprehensive Clinical Nephrology, Chapter 1, 2-13 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. (-) PrBasement membrane Endothelial cell Filtrate Bowman’s capsule space A small fraction of proteins that can pass through the glomerular capillaries is reabsorbed in the proximal tubule by endocytosis. Tamm - Horsfall protein is synthesized within the renal tubule and normally is detected in urine. The function of Tamm-Horsfall protein is unclear, it may prevent calcification and formation of kidney stones. How much proteins should be present in urine? Only traces of proteins are present in the urine of healthy individuals. Elevation of proteins in urine indicates a problem! Proteins with a molecular weight below 50,000 to 60,000 daltons can pass through the glomerulus to be reabsorbed in the proximal tubule. Normal passage of protein in urine is less than 150 mg/24 hours, or approximately 10 mg/dL of urine. Approximately 10% to 33% of urinary protein is albumin, 33% is TammHorsfall glycoprotein (secreted by renal tubular cells), and the balance is made up of a variety of immunoglobulins and other proteins. Proteinuria is a finding noted in approximately 5% of routine urine screens in men. This may represent a normal variant as 3% to 5% of healthy adults have postural proteinuria (when standing but not when recumbent), still even low levels of proteins in urine can be indicative of some degree of renal dysfunction. Source :A. J. Dean and D. C. Lee. Bedside Laboratory and Microbiologic Procedures. In: Roberts and Hedges’ Clinical Procedures in Emergency Medicine and Acute Care, Chapter 67, 1442-1469.e5 Filtration barrier can leak if the glomerulus is not healthy Proteinuria = loss of proteins in urine due to the damaged leaky glomerular capillaries Profound proteinuria (3 g per day) can lead to low plasma protein concentration and a decrease of plasma oncotic (colloid osmotic) pressure! proteins Urine How does abnormally low oncotic pressure affect the vascular and renal system? Plasma oncotic pressure decreases in all vessels if proteins are lost with urine Systemic capillary Interstitial space Oncotic pressure helps to keep H2O inside & depends on protein concentration Hydrostatic pressure “pushes” H2O into the interstitial space Decrease in oncotic pressure facilitates shift of fluid from the vasculature into the interstitial space = swelling. Nephrotic edema. Periorbital edema in the early morning in a nephrotic child Swelling or edema (accumulation of fluid in the interstitial space) due to a profound decrease in plasma protein concentration (hypoalbuminemia) is a typical feature of the nephrotic syndrome Introduction to Glomerular Disease: Clinical Presentations Floege, Jürgen, Comprehensive Clinical Nephrology, Chapter 15, 184-197 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Diseases of the glomerulus cause breakdown of the glomerular capillaries, protein leak and reduction in: - glomerular perfusion, - glomerular filtration (GFR), - urine formation, - renal clearance of plasma Clinical presentation of glomerular diseases: Nephritic and Nephrotic Syndromes Glomerulonephritis = a variety of glomerular disorders in which antigen-antibody complexes stuck into the wall of capillaries causing immune or inflammatory mediated injury of the glomerulus Symptoms vary and may include: - appearance of erythrocytes (hematuria - typical sign), RBC casts, white blood cells & proteins in urine (not much) - proteins accumulation of leukocytes in the glomerulus mesangial cell contraction and proliferation, The damage can rapidly lead to - reduced renal blood flow and filtration = renal insufficiency (very low filtration = renal failure!) - decreased urine formation (oliguria < 500 ml per day) or even anuria (cessation, less than 100 ml per day) Urine Nephrotic syndrome, sometimes reversible, may become permanent like sclerotic damage or scaring Nephritic syndrome -hematuria, which can be associated with oliguria, hypertension and low or moderate proteinuria Typical features 1. profound proteinuria 2. hypoalbuminemia – depressed plasma albumin level 3. edema – increased volume of interstitial fluid, puffiness 4. hyperlipidemia proteins Treatment of many glomerular diseases are steroids. proteins Urine Mechanisms of proteinuria. Negatively charged proteins such as albumin (blue circles) are normally repelled by the negatively charged proteins of the capillary wall so that only small amounts of albumin pass into the urinary (Bowman’s) space and renal tubule. In most proteinuric states, the podocytes are injured, and negative charge of the capillary wall can be diminished. Thus, large amounts of albumin can pass through the filtration barrier (red arrows). Capillary lumen Example: Minimal Change Disease Introduction to Glomerular Disease : Histologic Classification and Pathogenesis Johnson, Richard J., Comprehensive Clinical Nephrology, Chapter 16, 198-207 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Minimal Change Disease - typically affects children and appears as classical nephrotic syndrome characterized by diffuse loss of foot processes - the capillary damage is not detectible by light microscope (i.e. “minimal change”) Treatment - steroids. Marked eyelid edema in a 2-year-old boy with minimal change disease and nephrotic syndrome. Eyelid edema in any child should prompt the performance of urinalysis, rather than the presumption of allergy. Nephrology Ellis, Demetrius, Atlas of Pediatric Physical Diagnosis, 13, 531-557 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Decrease of glomerular filtration can be either acute (fast - hours) or chronic (slow - years) Acute kidney injury (acute renal failure) = rapid severe drop in the rate of filtration, frequently reversible Chronic kidney disease = progressive long-standing loss of kidney functions Factors which can cause glomerular diseases: Antigens may pass through endothelium, enter the basement membrane and mesangial matrix, triggering inflammation. Inflammation causes proteinuria and proliferation of mesangial cells, which can narrow or ultimately close the lumen of glomerular capillaries. Mesangial cells = transformed smooth muscle cells, which can contract decreasing perfusion and filtration, react to antigens, and are capable of macrophage-like behavior Diseases of the urinary system Stevens, Alan, MB BS, FRCPath, Core Pathology, 17, 355-396 Copyright © 2009 © 2009, Elsevier Limited. All rights reserved. Mesangial cell proliferation can impede filtration: diabetic nephropathy Chronic kidney disease known also as diabetic nephropathy develops within 10 years in every third patient with diabetes mellitus. Diabetic nephropathy usually begins with an increase in glomerular filtration and proteinuria. With time filtration declines as mesangial cells proliferate and compress the glomerular capillaries, impeding perfusion and, therefore, reducing filtration. Normal glomerulus Moderate mesangial expansion Diabetic Nephropathy Avancini Caramori, Maria Luiza, Endocrinology: Adult and Pediatric, Chapter 54, 934-957.e12 Copyright © 2016 Copyright © 2016, 2010, 2006, 2001, 1995, 1989, 1977 by Saunders, an imprint of Elsevier Inc. Severe diffuse mesangial expansion Filtration further declines as the situation progresses to end-stage renal disease when the kidneys are no longer able to detoxify plasma and maintain its proper composition. Patients then require dialysis or renal transplant. How is filtration assessed? Glomerular Filtration Rate (GFR) = volume of filtrate produced per unit of time (ml/min) in the nephron Normal GFR in adults (50 years old) is about 100 ml/min GFR decreases – disease progresses GFR increases – recovery of kidney function GFR decreases – disease progresses GFR increases – recovery of kidney function AKI = acute kidney injury Acute Kidney Injury Associated with High Nephrotoxic Medication Exposure Leads to Chronic Kidney Disease after 6 Months Menon, Shina, MD, Journal of Pediatrics, The, Volume 165, Issue 3, 522-527.e2 Copyright © 2014 Elsevier Inc. What are the forces that underlie filtration? Glomerular Filtration and Starling Forces Favoring filtration: Opposing filtration: PH = Hydrostatic pressure in glomerular capillary (mm Hg) Afferent arteriole PBS = Hydrostatic pressure in Bowmen’s space (mm Hg) PO = Oncotic pressure in glomerular capillary (mm Hg) Glomerular Capillary PH PBS PO Efferent arteriole 45 10 25 Bowman’s Space Net Filtration Pressure (NFP) NFP = PH - PBS - PO Proximal tubule GFR = Kf x NFP, where Kf filtration coefficient , which is 100 greater in glomerular than in systemic capillaries Net Filtration Pressure (NFP) Decreases Along the Length of Glomerular Capillary Why? Glomerular Capillary Afferent arteriole PH PBS P O 45 10 25 Efferent arteriole 45 10 33 Bowman’s Space NFP = PH - PBS - PO Plasma protein concentration and Po goes up along the length of capillaries as fluid moves through their walls. Thus, NFP decreases toward the end of capillaries. GFR – ? High plasma oncotic pressure decreases GFR! GFR and hydrostatic pressure in the glomerulus depend on the diameter of afferent and efferent arterioles Glomerulus Constriction of the afferent Afferent arteriole = increase in arteriolar arteriole resistance = decrease in: renal blood flow (RBF), hydrostatic pressure in the glomerular capillaries (PH) and GFR Efferent arteriole PH decreased GFR Constriction of afferent arteriole = RBF GFR *Constriction of efferent arteriole = GFR * Moderate constriction RBF Glomerulus Afferent arteriole PH increased GFR Efferent arteriole Vasoactive substances: effects on glomerular hemodynamics and filtration Resistance Resistance of afferent of efferent arteriole arteriole Renal Blood Flow NFP Kf GFR Sympathetic nerves Epinephrine Angiotensin II ANP * Moderate constriction ? * Homework: How does GFR change if there is a decrease in resistance of the afferent arteriole? efferent arteriole? Low GFR = low urine output Abnormally low GFR – bad! Abnormally high GFR - ? Obesity can lead to glomerular hyperfiltration. Clinical implications: glomerular hypertension at the initial stages of diabetic nephropathy. Normal individuals Individuals with early signs of diabetic nephropathy - increased GFR, hyperperfusion Afferent arteriole Glomerular capillaries Efferent arteriole Afferent arteriole PH PH 45 mm Hg Urine: traces of proteins Efferent arteriole 55 mm Hg Filtration fraction higher? Urine: Albumins! Angiotensin II mediated constriction (microalbuminuria) Increased hydrostatic pressure in the glomerular capillaries = glomerular hypertension; glomerular capillaries leak! Protective effect of anti-angiotensin medications against glomerular hypertension in diabetic nephropathy Early signs of diabetic nephropathy Normalization of glomerular pressure and GFR by cilazapril (increased GFR & albuminuria) Afferent arteriole Glomerulus (ACE inhibitor) Efferent arteriole Afferent arteriole Glomerulus cilazapril PH 55 mm Hg Urine: albumins Efferent arteriole PH Angiotensin II mediated constriction Cilazapril induced relaxation Urine: traces of albumins Dilation of the efferent arteriole by cilazapril reduces hypertension inside the glomerulus, GFR and loss of proteins in diabetic patients (Imanishi et al., 1999, Diabetologia; 42, 999 -1009) Changes in Starling Forces Affect Glomerular Filtration Rate Change Renal Plasma Flow (RPF) Glomerular Filtration Rate (GFR) Constriction of afferent arteriole Constriction of efferent arteriole Decreased plasma protein concentration Increased plasma protein concentration Constriction of ureter No Change No Change No Change Why constriction of ureters decreases GFR? Path of urine drainage: Papillary duct in renal pyramid Minor and major calices Renal Pelvis Ureter Elements of Renal Function Koeppen, Bruce M., MD, PhD, Berne & Levy Physiology, CHAPTER 32, 557-577 Copyright © 2010 Raven