Renal Function

• RENAL PHYSIOLOGY

  • The kidneys are bean shaped and are located on the posterior abdominal wall in the area known as the retroperitoneum. An adult human kidney has a mass of approximately 150 g and measures roughly 12.5 cm in length, 6 cm in width, and 2.5 cm in depth
  • Each kidney contains approximately 1 TO 1.5 MILLION functional units called nephrons
• Part of NEPHRONS

  1. Tubules (PCT & DCT)
  2. Collecting Ducts
  3. Glomerulus
  4. Loop of Henle
• 2 TYPES OF NEPHRONS

  1. Cortical nephron- makes up approximately 85% of the total nephron. Found mainly in the cortex of the kidney and are responsible primarily for removal of waste products and reabsorption of nutrients.
  2. Juxtamedullary nephrons- have loops of Henle that extend deep into the medulla of the kidney. Their primary function is the concentration of urine
• PCT - most metabolically active site of nephrons
• GENERAL FUNCTIONS OF THE KIDNEY

  1. EXCRETORY FUNCTION - urine function
  2. Glomerular Filtration
  3. Tubular Reabsorption
  4. Tubular Secretion
  5. Regulation of water balance in the body.
  6. Regulation of acid-base balance
  7. Regulation of electrolytes
  8. Regulation of Blood pressure through secretion of Renin
  9. Stimulates Erythropoiesis through secretion of EPO
  10. Regulation of body temperature
• Renal Blood flow

  • The renal artery supplies blood to the kidney
  • The human kidney receives approximately 25% of the blood pump.
  • Total renal blood flow: 1200mL/min
  • Renal plasma flow: 600-700mL/min
• An afferent arteriole at the vascular pole supplies blood individually to the glomerulus of each nephron
• Order of Urine formation from the nephron (Urinary Filtrate Flow)

  • Glomerulus > Bowman's space > PCT > DLH > ALH > DCT > Collecting Ducts > Renal Calyces > Ureter > Bladder > Urethra
• FORCES INVOLVED IN GLOMERULAR FILTRATION

  Hydrostatic pressure - pressure that is created by the varying sizes of the arterioles, which is important for glomerular filtration and to maintain consistency of glomerular capillary pressure and renal blood flow within the glomerulus. This hydrostatic blood pressure averages 55 mm Hg, approximately half of the mean arterial blood pressure, and is the driving force behind glomerular filtration. The plasma ultrafiltrate already in Bowman's space exerts a hydrostatic pressure of 15 mm Hg that opposes filtration
• FORCES INVOLVED IN GLOMERULAR FILTRATION

  An oncotic (protein in blood and not in ultrafiltrate) pressure of 30 mm Hg caused by the higher protein concentration

  in the plasma opposes glomerular filtration as well
• FORCES INVOLVED IN GLOMERULAR FILTRATION

  The outcome of these three pressure differences is a net filtration pressure of 10 mm Hg, which favors the

  formation of a plasma ultrafiltrate in Bowman's space
• Order of Blood Flow In the Nephron [RAGE PVR]

  Renal artery > Afferent arteriole > Glomerulus > Efferent arteriole > Peritubular capillaries > Vasa recta > Renal vein
• GLOMERULAR FILTRATION CHARACTERISTICS

  • The glomerulus consists a coil of approximately eight capillary lobes referred to collectively as the capillary tuft.
  • Glomerulus resembles as "sieve"
  • The glomerulus is located within the Bowman's capsule.
  • A non-selective filter for plasma substances with molecular weights of less than 70,000 Da
  • Normally, the fluid leaving the glomerulus has a specific gravity of 1.010
• GLOMERULAR FILTRATION CHARACTERISTIC

  • Analysis of the fluid as it leaves the glomerulus shows the filtrate to have a specific gravity of 1.010 and confirms that it Is chemically an ultrafiltrate of plasma.
  • Approximately 120 mL/min, or one fifth, of the renal plasma is filtered through the glomeruli forming what is known as the ultrafiltrate, which is further processed as it travels through the nephron. The ultrafiltrate has the same composition as blood plasma but it is normally free of protein except for about 10 mg/dL of low molecular-weight protein
• Cellular Structure of Glomerulus:

  • Plasma filtrate must pass through three cellular layers:

  1. Capillary wall membrane
  2. basement membrane
  3. Visceral epithelium of Bowman's capsule
• Barrier's that Prohibits the Filtration of Large molecules

  • The capillary wall of glomerulus is fenestrated (fenestrated endothelium: endothelial cell wall with pores)
  • Intertwining foot processes known as podocytes
  • Shield of Negativity - repel molecules with negative charge even molecules are small enough to pass (Example is Albumin with a negative charge under normal body pH)
• GLOMERULAR PRESSURE

  • Juxtaglomerular apparatus - maintains the glomerular blood pressure

  1. Juxtaglomerular cells - found in the offerent arteriole, secretes the Renin enzyme
  2. macula densa - found in the DCT, sensor of change in blood pressure

  • Decrease Blood Pressure = Dilation of afferent arteriole, Constriction of efferent arteriole
  • Increase Blood pressure = Constriction of afferent arteriole, Dilation of efferent arteriole
• RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)

  • System regulates the flow of blood to and within the glomerulus. The system responds to changes in blood pressure and plasma sodium content that are monitored by the juxtaglomerular apparatus, which consists of the juxtaglomerular cells in the afferent arteriole and the macula densa of the distal convoluted tubule
  • controls the regulation of the flow of blood to and within the glomerulus.
  • Primary electrolyte affected when activated: Sodium
• Functions and Effects: RAAS

  1. Dilation of the afferent arteriole and constriction of the efferent arteriole
  2. Stimulation of sodium reabsorption in the proximal convoluted tubule
  3. Triggers the adrenal cortex to release the sodium-retaining hormone, aldosterone, to cause reabsorption of sodium and excretion of potassium in the distal convoluted tubule and collectina duct
  4. Trigger release of antidiuretic hormone by the hypothalamus to stimulate water reabsorption in the collecting duct
• Angiotensinogen


  Bloodborne substrate for renin enzyme
• Angiotensin I


  a product formed from enzymatic reaction of renin with angiotensinogen; inert form of angiotensin
• Angiotensin II


  a product formed from enzymatic reaction of ACE with angiotensin I; active form angiotensin and a powerful vasoconstrictor that increases BP
• FUNCTIONS OF ANGIOTENSIN II

  1. Correct renal blood flow
  2. Raises blood pressure (BP) by a number of actions, the most important ones being vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and renal actions
  3. Other actions include induction of growth, cell migration, and mitosis of vascular smooth muscle cells, increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis.
• TESTS FOR GLOMERULAR FILTRATION

  1. Clearance Test - best indicator of overall glomerular function
  2. Inulin Clearance Test 

  • Gold standard / reference method
  • Inulin is a polymer of fructose, is a extremely stable substance that is not reabsorbed or secreted by the tubules. It is not a normal body constituent, however, and must be infused by IV at a constant rate throughout the testing period.
• TESTS FOR GLOMERULAR FILTRATION

  1. Creatinine Clearance Test

  • Most commonly used clearance test
  • Creatinine is a waste product of muscle metabolism that is produced enzymatically by creatine phosphokinase from creatine, which links with ATP to produce ADP and energy

  1. Others: Cystatin C, Beta-2-microglobulin, radioisotopes, urea clearance test
• Urea Clearance Test

  • first clearance test / earliest clearance test
  • Disadvantage: approximately 40% of the filtered urea is reabsorbed back by the kidney
• Formula for the computation of GFR using the creatinine clearance test

  $C =$$Urea Creatine / Plasma Creatine *$$volume of urine / 24 hours *$$1.73/A$
• • By far the greatest source of error in any clearance procedure utlizing urine is the use of improperly timed urine specimens
  • Plasma/serum creatinine can be collected anytime within 24 hours of urine collection
  • Specimen collection, therefore, must include both a 24-hour urine specimen and a serum creatinine value, ideally collected at the midpoint of the 24-hour urine collection. The urine container must be kept refrigerated throughout the duration of both the collection procedure and the subsequent storage period until laboratory analysis can be performed.
• • A blood sample of 1 mL (minimum 0.5 mL) in a labeled tube, preferably stored in refrigerated or frozen temperature
  • The patient is required to drink at least 8 cups of liquid on the day of urine collection.
• Disadvantage of using Creatinine

  1. Some creatinine is secreted by the tubules, and secretion increases as blood levels rise
  2. Medications, including gentamicin, cephalosporins, and cimetidine (Tagamet), inhibit tubular secretion of creatinine, thus causing falsely low serum levels
  3. Bacteria will break down urinary creatinine if specimens are kept at room temperature for extended periods, thus leads to false low result
• Disadvantage of using Creatinine

  1. A diet heavy in meat consumed during collection of a 24-hour urine specimen will influence the results if the plasma specimen is drawn before the collection period = False increase results
  2. Not reliable indicator in athletes, persons involved in heavy exercise, and patients with muscle diseases
  3. Drugs such as trimethoprim-sulfamethoxazole can increase serum creatinine level by approximately 0.4 to 0.5 mg/d
  4. Creatinine clearance is affected by sex and race. Women have less muscle mass and a lower rate of creatinine production in comparison to me
• CYSTATIN C

  • A small protein (molecular weight 13,359) produced at a constant rate by all nucleated cells. It is readily filtered by the glomerulus and reabsorbed and broken down by the renal tubular cells. It has potential as a marker for long-term montoring of renal function
  • Its plasma concentration is inversely related to GFR. (Increase plasma cystatin C = decrease GFR)
  • The rate of production is not affected by muscle mass, sex, or race
• BETA-2-MICROGLOBULIN

  • It dissociates from human leukocyte antigens (MC class 1) at a constant rate and is rapidly removed from the plasma by glomerular filtration. It is a better marker of reduced renal tubular function than of glomerular function
• BETA-2-MICROGLOBULIN

  • can be used to differentiate disorders of kidney as either glomerular or tubular
  • also used to identify end-stage renal disease and early rejection of a kidney transplant
  • test is not reliable in patients who have a history of immunologic disorders or malignancy
• Tubular Damage (Tubular Reabsorption Defect)

  • normal B2M and cystatin C in blood or serum
  • increased B2M and cystatin C in urine
• Glomerular disorder

  • increaed B2M and cystatin C in blood or serum
  • No to decrease B2M and cystatin C in urine
• Radioisotopes

  • radionucleotides such as 125I-iothionate
  • iohexol - nonradioactive contrast agent used for children
• Estimated Glomerular Filtration Rate (eGFR) Computation

  MDRD (Modification of Diet in Renal Disease) - most frequently used formula
• Estimated GFR

  • Cockroft and Gault - BASS (Body weight, age, sex, serum creatine)
  • MDRD - BESS (BUN, Ethnicity, Serum Creatine, Serum Albumin)
• Clearance Test

  • traditional test
  • requires 24 hour urine collection
  • cystatin C and B2M requires blood (plasma) sample