Lec 55.pdf

Rise in PBS impedes glomerular filtration Favoring filtration: Opposing filtration: PH = Hydrostatic pressure in glomerular capillary (mm Hg) Afferent arteriole PBS NFP? NFP = PH - PBS - PO PBS = Hydrostatic pressure in Bowmen’s space (mm Hg) PO = Oncotic pressure in glomerular capillary (mm Hg...

Rise in PBS impedes glomerular filtration Favoring filtration: Opposing filtration: PH = Hydrostatic pressure in glomerular capillary (mm Hg) Afferent arteriole PBS NFP? NFP = PH - PBS - PO PBS = Hydrostatic pressure in Bowmen’s space (mm Hg) PO = Oncotic pressure in glomerular capillary (mm Hg) Glomerular Capillary PH PO PBS Bowman’s Space Proximal tubule Efferent arteriole Sydney Poitier is prostate cancer survivor. Adrenal Gland Renal Artery Renal Vein PBS Compression of urethra by cancer builds up pressure all the way to the Bowman’s space. Rise in PBS impedes glomerular filtration. Ureter Urinary bladder Normal prostate Urethra Prostate cancer Normal kidney and ureters Obstruction of urethra (postrenal kidney failure and hydronephrosis) From Kelly and Burnam. Diseases of the Kidneys, Ureters and Bladder. Sydney Poitier was awarded the nation’s highest civilian medal, the Medal of Freedom, for his contribution to the fields of theater, humanities and politics. "Sidney Poitier PMF" by The White House - White House video (around 29:10). Licensed under Public Domain via Commons https://commons.wikimedia.org/wiki/File:Sidney_Poitier_PMF.jpg#/media/File:Sidney_ Poitier_PMF.jpg Changes in Starling Forces Affect Glomerular Filtration Rate Change Renal Plasma Flow (RPF) 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 Glomerular Filtration Rate (GFR) Plasma is an aqueous component of blood = water and dissolved substances (no blood cells, 90% water, 7% proteins) Plasma occupies 55% of blood volume the rest 45% - red blood cells (RBC’s) = Hematocrit (Ht) Plasma Plasma White cells Red cells Platelets WBCs & platelets Ht 45% Plasma 55% RBCs (Ht or PCV= packed cell volume ) Renal Blood Flow = 55 % renal plasma flow (RPF) + 45% flow of RBC’s (Ht) Renal blood flow (RBF), renal plasma flow (RPF) and GFR RBF 1200 A portion of total RPF that passes through the glomerular filtration barrier in a unit of time is GFR 1000 Flow (ml/min) RPF= RBF x (1 – Ht) = RBF x (1- 0.45) Renal plasma flow, thus, represents a fraction of renal blood flow, which is slightly above 50%. RPF 670 GFR = FF x RPF, where FF – filtration fraction GFR normally is close to 1/5 of RPF GFR 120 0 80 180 Mean arterial blood pressure (mm Hg) Quiz: True or False? 1. Intense physical activity causes elevation of blood pressure in healthy individuals. True 2. Elevation of blood pressure leads to rise of the glomerular hydrostatic pressure and increased GFR. False, autoregulation prevents it Strenuous physical activity dramatically elevates arterial blood pressure. If this increase in arterial blood pressure extends to the glomerular capillaries, one should expect a rise of hydrostatic pressure and a surge in filtration, tubular flow and urinary excretion. However, marathon runners do not seem to be disturbed by frequent need for urination. GFR stays relatively constant despite changes in arterial blood pressure. What are the major mechanisms which regulate nephronal blood supply and GFR? "Berlin marathon" by KJohansson - Own work. Licensed under CC BY 3.0 via Commons https://commons.wikimedia.org/wiki/File:Berlin_maratho n.jpg#/media/File:Berlin_marathon.jpg GFR is Controlled via 3 Mechanisms: 1. neural control – sympathetic nerves; 2. hormones and other vasoactive agents (angiotensin II etc.); 3. intrinsic control – autoregulation Mechanisms of autoregulation of renal blood flow (RBF) and glomerular filtration rate Initial quick rise in renal perfusion after a rapid increase in blood pressure is followed within 3 seconds by myogenic constriction of blood vessels (intrinsic response to stretch) and a decrease in blood flow towards the initial level. In addition, there may be some other mechanisms of autoregulation (tubuloglomerular feedback) Blood Pressure Renal Blood Flow 0 3 Time in seconds Autoregulation of renal blood flow and glomerular filtration rate If mean arterial blood pressure is in the range of 80 to 180 mm Hg (lower and upper autoregulation limits), shifts in blood pressure have only marginal effects on renal blood flow (RBF) and glomerular filtration rate, i.e. RBF and GFR stay relatively constant despite changes in blood pressure within these limits. This is an intrinsic mechanism and can be modulated or overridden by extrinsic factors. If blood pressure decreases to 80 mm Hg, a drastic reduction in renal blood flow & GFR can occur due to sympathetic activation. Renal Physiology Bailey, Matthew A., Comprehensive Clinical Nephrology, Chapter 2, 14-27 Copyright © 2015 Copyright © 2015, 2010, 2007, 2003, 2000 by Saunders, an imprint of Elsevier Inc. Changes in the afferent arteriolar diameter underlie the autoregulatory response Afferent arteriole constriction plays a crucial role, although other arteries (e.g. renal) might also contribute to the autoregulatory response. If blood pressure is rising, these vessels constrict, minimizing an increase in blood flow and GFR. Dilation occurs if blood pressure drops. An increase (or decrease) in renal vascular resistance results in relatively constant renal blood flow (RBF) and GFR upon changes in blood pressure Glomerular Filtration and Renal Blood Flow Giebisch, Gerhard, Medical Physiology, Chapter 34, 739-753.e2 Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved. Hydrostatic pressures in different renal vascular segments Hydrostatic pressure in the glomerular capillaries does not fall much along their length, which is necessary for filtration! Sharp decreases in pressure across the afferent and efferent arteriole indicate high resistance of these segments. Hydrostatic pressure in the peritubular capillaries is low Glomerular Filtration and Renal Blood Flow Giebisch, Gerhard, Medical Physiology, Chapter 34, 739-753.e2 Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved. What are the forces which underlie water reabsorption? Hydrostatic and Oncotic Pressure Changes in Renal Portal System Vascular Segment Hydrostatic Pressure (mm Hg) Oncotic Pressure (mm Hg) Afferent Arteriole Glomerular capillary, Relatively High (45) proximal end Normal (20) Glomerular capillary, Relatively High (43) distal end High (33) Efferent Arteriole Drops from 43 to 15 Constant Peritubular capillary, proximal end Relatively Low (15) High (33) Peritubular capillary, distal end Relatively Low (11) Normal (20) Efferent Arteriole Afferent Arteriole Hydrostatic pressure: from 43 mm Oncotic pressure: 33 mm Blood Peritubular capillaries Bowmen’s capsule F Tubular epithelial cells Lumen of renal tubule Hydrostatic pressure: 15 mm Hg Oncotic pressure: 33 mm Hg R Elevated oncotic pressure (& low H2O hydrostatic pressure) in E Renal vein the peritubular capillaries promotes water reabsorption from interstitial space back into the capillary lumen Compared to the afferent arterioles, the efferent arterioles theoretically should have higher: a. hydrostatic pressure b. oxygen pressure c. filtration d. cholesterol concentration Higher oncotic pressure of the efferent arterioles indicate higher concentration of various proteins, which theoretically should include lipoproteins responsible for cholesterol transport Answer d. Determination of GFR Glomerular filtration rate = amount of filtrate produced per unit of time - major indicator of renal function - normally 100 - 120 ml/min GFR = Kf x Net Filtration Pressure (NFP), where Kf – filtration coefficient NFP = Plasma creatinine as an index of GFR Creatinine = final endogenous product of muscle metabolism; - freely filtered, not reabsorbed and only slightly secreted Either plasma creatinine or creatinine clearance test can be used to estimate GFR What does plasma creatinine tell? High plasma creatinine (> 1.3 mg/dl) = the kidney does not filter much of plasma! Renal insufficiency! 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. Low GFR = accumulation of wastes in blood! Shaq may have slightly increased plasma creatinine (1.6 mg/dl)? may be caused by a lot of meat in diet or/and a very large muscle mass (body builders, giants) "Shaq at the white house" by Tina Hager - http://georgewbushwhitehouse.archives.gov/news/releases/2002/01/images/20020128-1-1.html. Licensed under Public Domain via Commons https://commons.wikimedia.org/wiki/File:Shaq_at_the_white_house.jpg#/media/File:Shaq_at_the_white_house.jpg Empirical formulas for determination of GFR A number of approaches and formulas for calculation of GFR have been used: a. inulin clearance (gold standard for research) b. creatinine clearance c. 1976 Cockroft - Gault formula requires plasma creatinine, age and weight d. 1999 MDRD formula (Modification of Diet in Renal Disease) requires plasma creatinine, age, race and gender e. 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Inulin is a non-metabolized sugar which can be injected into circulation GFR Determination by Inulin Clearance Filtration: filtered load – mass of substance z filtered per minute. filtered load = GFR x Pz, where Pz – plasma concentration of substance z Excretion: excretion rate – mass of substance z excreted per minute. excretion rate = UF x Uz, where Uz – urine concentration of substance z, UF – flow of urine GFR = (UF x Uinulin)/Pinulin Organization of the Urinary System Giebisch, Gerhard, Medical Physiology, Chapter 33, 722-738.e1 Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved. In general (but not always), renal clearance = filtration + secretion – reabsorption Since there is no inulin secretion or reabsorption, plasma clearance of inulin is determined exclusively by filtration and corresponds to GFR Definition for renal clearance: ml of plasma that has all of a substance z completely removed per minute Formula for renal clearance: Clz = (UF x Uz)/Pz GFR = (UF x Uinulin)/Pinulin Organization of the Urinary System Giebisch, Gerhard, Medical Physiology, Chapter 33, 722-738.e1 Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved. Definition Equation Clearance = RBF = GFR = Filtration Fraction = Filtered Load = Renal handling of which compound is shown in the center? Urea, inulin, creatinine? Efferent arteriole Renal vein Afferent arteriole Glomerulus Renal vein Renal vein Comparison with inulin clearance is informative If plasma clearance is less than that of inulinreabsorption takes place If plasma clearance is greater than that of inulinsecretion takes place Creatinine clearance overestimates GFR. Filtered load GFR x Pc Excretion rate UF x Uc Clc = (UF x Uc)/Pc GFR = (UF x Uinulin)/Pinulin Like inulin creatinine is not reabsorbed, but a slight secretion takes place! Creatinine is not an ideal marker. This slight secretion leads to overestimation of GFR, especially in elderly with low mass weight (low creatinine in plasma) Substance Clearance Rate (ml/min) Glucose 0 Sodium 0.9 Chloride 1.3 Potassium 12 Phosphate 25 Inulin 120 Creatinine 140 Source: John E. Hall PhD Guyton and Hall Textbook of Medical Physiology. Indexes other than high creatinine can indicate low GFR In addition to creatinine, other wastes such as urea and uric acid are accumulated in the blood of patients with low GFR (renal insufficiency). For example, high BUN (blood urea nitrogen > 20 mg/dl) on the laboratory blood analysis shows azotemia (elevated level of nitrogen in the blood), and indicates impaired renal functions (low filtration) Sudden severe deterioration in renal filtration indicates an acute kidney injury (AKI), also known as acute renal failure. It is often reversable. There are various causes of acute kidney injury One common cause of AKI is a decrease in renal blood flow. What parameters can tell us that renal perfusion is decreased? Low Urine Output? Oliguria Decrease in renal plasma flow and prerenal azotemia A significant decrease in renal blood (plasma) flow slows GFR. As a result, elevation in plasma creatinine and other nitrogenrich compounds (BUN) occurs. BUN elevation caused by renal hypoperfusion is referred to as prerenal azotemia (prerenal - “ before” kidney, What is azotemia? Dalton’s Table of elements, ~ 1810 A- zot - emia How azotemia due to a low renal perfusion can develop? By John Dalton, 1808 / Джон Дальтон, 1808 ([1] here / здесь) [Public domain], via Wikimedia Commons Progressive atherosclerosis and ischemic nephropathy as an example of prerenal azotemia In the early phase (A), there is mild atherosclerosis of the perirenal abdominal aorta and normal renal function. Renal blood flow is normal. The dimensions of the kidneys are normal, and there is no cortical atrophy. The total GFR (100 mL per minute) and the GFR in each kidney (50 mL per minute) are normal. As the disease progresses (B), there is progressive aortic atherosclerosis, notable left renal artery stenosis and left kidney cortical atrophy. The total GFR may be normal (100 mL per minute) owing to compensatory changes in the right kidney, but left kidney GFR is low (35 mL per minute). ( From Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001;344(6):431–42; with permission. Copyright © 2001, Massachusetts Medical Society.) Management of Heart Failure with Renal Artery Ischemia Rao, Madhav V., MD, Cardiology Clinics, Volume 29, Issue 3, 433-445 Copyright © 2011 Elsevier Inc. In advanced disease (C), there is bulky atherosclerotic plaque in the perirenal aorta and severe bilateral renal artery stenosis. Both kidneys are small, and there is marked cortical thinning and irregularity. The total GFR (30 mL per minute) and the GFR in each kidney (15 mL per minute) are depressed. ( From Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001;344(6):431–42; with permission. Copyright © 2001, Massachusetts Medical Society.) Management of Heart Failure with Renal Artery Ischemia Rao, Madhav V., MD, Cardiology Clinics, Volume 29, Issue 3, 433-445 Copyright © 2011 Elsevier Inc. Decreased renal plasma flow and prerenal azotemia Postrenal azotemia Reduction in GFR and BUN elevation may also be caused by other pathophysiological mechanisms, for example, by urine flow obstruction due to kidney stones (“no way out”). In this case, elevation in BUN indicates postrenal azotemia (the cause is “after” kidney). In contrast to prerenal azotemia, reabsorption of Na+ is not increased in the postrenal azotemia Prerenal Azotemia Intrarenal Azotemia Postrenal Azotemia Vascular volume depletion due to gastrointestinal, renal and other fluid loss Glomerular (Glomerulonephritis) Prostatic disease Bilateral Renal Artery Stenosis Tubulo-Interstitial (acute tubular necrosis or interstitial nephritis) Shock due to sepsis, cardiac failure Parenchymal Vascular (vasculitis Urethral obstruction inside the kidney) due to malignancy Ureteral obstruction Long standing substantial decline in renal function is referred as chronic renal failure (chronic kidney injury), and with time it progresses to end-stage renal disease. Patients with chronic renal disease have numerous problems: a. hematological (decreased erythropoetin), thrombocytopenia (low count of thrombocytes) b. osteodystrophy – vitamin D deficit, bone demineralization c. xerostomia (dry mouth), gingival enlargement and other abnormalities Features of chronic renal failure vary among patient and can affect multiple systems. CARDIOVASCULAR Hypertension Congestive heart failure HEMATOLOGICAL Bleeding (platelet dysfunction) Anemia GASTROINTESTINAL Anorexia Nausea and vomiting Gastrointestinal bleeding Hepatitis DERMATOLOGICAL Pruritus Bruising Hyperpigmentation Pallor NEUROLOGIC Weakness Drowsiness Impaired cognition METABOLIC Metabolic acidosis Hyperkalemia High serum urea, creatinine & uric acid Hyperphosphatemia, secondary hyperparathyroidism & osteodystrophy IMMUNOLOGICAL Prone to infections Uremia is a clinical manifestation of end stage renal disease. BUN is always high and dialysis (artificial “cleaning” of blood) is frequently required for patients at this point. Kidneys, Ureters, and Urinary Bladder Buja, L. Maximilian, MD, Netter's Illustrated Human Pathology, Chapter 6, 173-224 Copyright © 2014 Copyright © 2014, 2005 by Saunders, an imprint of Elsevier Inc. Loss of renal reserve – GFR can drop to 60 ml/min without clinical manifestations of renal insufficiency. Renal failure - GFR drops below 30-50 mL/min and BUN exceeds 20 mg/dL. Uremia is rare until BUN reaches 60 mg/dL.