Cream Purple Abstract Thesis Defense Presentation_20241030_032742_0000.pptx

Presentation for kidney and stones and the removal and kidney structure

1. KIDNEY ANATOMY, P H Y S I O L O G Y AND FUNCTIONS Presented By : Nouf, Hamna, Ameena, Sameen, Natasha 30 t h O c t | 202 4

2. TABLE OF CONTENTS 01 ANATOMY 02 PHYSIOLOGY 03 FUNCTIONS

3. INTRODUCTION PRESENTED BY NOUF BABAR

4. A pair of bean-shaped structures The two kidneys lie on the posterior wall of the abdomen outside the peritoneal cavity Each kidney of the adult human weighs about 150 grams About the size of a clenched fist INTRODUCTION

5. The kidneys are surrounded by three layers The outermost layer is a tough connective tissue layer called the renal fascia The second layer is called the perirenal fat capsule, which helps anchor the kidneys in place The third and innermost layer is the renal capsule INTERNAL ANATOMY

6. GENERAL ORGANIZATION OF KIDNEYS Internally, the kidney has three regions an outer cortex a medulla in the middle the renal pelvis in the region called the hilum of the kidney The medial side of each kidney contains an indented region called the hilum through which pass the renal artery and vein, lymphatics, nerve supply, and ureter, which carries the final urine from the kidney to the bladder, where it is stored until emptied.

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8. The renal cortex is granular due to the presence of nephrons—the functional unit of the kidney The medulla consists of multiple pyramidal tissue masses, called the renal pyramids In between the pyramids are spaces called renal columns through which the blood vessels pass. The tips of the pyramids, called renal papillae , point toward the renal pelvis.

9. There are, on average, eight renal pyramids in each kidney. The renal pyramids along with the adjoining cortical region are called the lobes of the kidney. The renal pelvis leads to the ureter on the outside of the kidney. On the inside of the kidney, the renal pelvis branches out into two or three extensions called the major calyces Which further branch into the minor calyces . The ureters are urine-bearing tubes that exit the kidney and empty into the urinary bladder.

10. RENAL BLOOD SUPPLY Blood flow to the two kidneys is normally about 22 percent of the cardiac output, or 1100 ml/min. The renal artery enters the kidney through the hilum and then branches progressively to form the interlobar arteries arcuate arteries interlobular arteries (also called radial arteries) afferent arterioles , which lead to the glomerular capillaries, where large amounts of fluid and solutes(except the plasma proteins) are filtered to begin urine

11. The distal ends of the capillaries of each glomerulus coalesce to form the efferent arteriole which leads to a second capillary network the peritubular capillaries, that surrounds the renal tubules. The renal circulation is unique in having two capillary beds: the glomerular peritubular capillaries Which are arranged in series and separated by the efferent arterioles, which help regulate the hydrostatic pressure in both sets of capillaries

12. High hydrostatic pressure in the glomerular capillaries (about 60 mm Hg) causes rapid fluid filtration, whereas a much lower hydrostatic pressure in the peritubular capillaries (about 13 mm Hg) permits By adjusting the resistance of the afferent and efferent arterioles, the kidneys can regulate the hydrostatic pressure The peritubular capillaries empty into the vessels of the venous system, which run parallel to the arteriolar vessels The blood vessels of the venous system progressively form the interlobular vein, arcuate vein, interlobar vein, and renal vein, which leaves the kidney beside the renal artery and ureter

13. NEPHRON- THE FUNCTIONAL UNIT OF THE KIDNEY

14. Each kidney in the human contains about 800,000 to 1,000,000 nephrons, each capable of forming urine Kidney cannot regenerate new nephrons Due to renal injury, disease, or normal aging, there is a gradual decrease in nephron number. After age 40, the number of functioning nephrons usually decreases about 10 percent every 10 years At age 80, many people have 40 percent fewer functioning nephrons than they did at age 40.

15. TYPES OF NEPHRON There are two types of nephrons Cortical nephrons (85 percent), which are deep in the renal cortex Juxtamedullary nephrons (15 percent), which lie in the renal cortex close to the renal medulla

16. PARTS OF NEPHRON A nephron consists of three parts a renal corpuscle a renal tubule the associated capillary network, which originates from the cortical radiate arteries

17. RENAL CORPUSLE The renal corpuscle, located in the renal cortex, is made up of A network of capillaries known as the glomerulus The capsule, a cup-shaped chamber that surrounds it, called the glomerular or Bowman’s capsule

18. RENAL TUBULE The renal tubule is a long and convoluted structure that emerges from the glomerulus and can be divided into three parts based on function Proximal convoluted tubule (PCT) due to its proximity to the glomerulus; it stays in the renal cortex Loop of Henle , or nephritic loop, because it forms a loop (with descending and ascending limbs) that goes through the renal medulla Distal convoluted tubule (DCT) and this part is also restricted to the renal cortex

19. The DCT, which is the last part of the nephron, connects and empties its contents into collecting ducts that line the medullary pyramids. The collecting ducts amass contents from multiple nephrons and fuse together as they enter the papillae of the renal medulla.

20. CAPILLARY NETWORK Once the efferent arteriole exits the glomerulus, it forms the peritubular capillary network, which surrounds and interacts with parts of the renal tubule In cortical nephrons, the peritubular capillary network surrounds the PCT and DCT In juxtamedullary nephrons, the peritubular capillary network forms a network around the loop of Henle and is called the vasa recta .

21. Presented by Hamna tahir

22. Renal Cortex The outer region of the kidney, containing millions of tiny filtering units called nephrons It contains the glomerulus, which filters blood, and the proximal tubule, where reabsorption of water, ions, and nutrients occurs.

23. Located deeper in the kidney, it consists of: Renal pyramids Renal columns The medulla contains the loop of Henle, responsible for concentrating urine by reabsorbing water and electrolytes. Renal Medulla

24. A funnel-shaped structure that collects urine from the nephrons drains into the ureter, which carries the urine to the bladder for storage and eventual elimination. Renal Pelvis

25. The functional units of the kidney Each kidney contains millions of nephrons responsible for filtering blood and producing urine The nephron consists of the glomerulus, Bowman's capsule, proximal tubule, loop of Henle, distal tubule, and collecting duct. Nephrons

26. Glomerulus A network of tiny capillaries where blood filtration occurs. It filters waste products, excess water, and electrolytes from the blood, forming a filtrate that will eventually become urine.

27. Bowman’s Capsule A cup-shaped structure surrounding the glomerulus. It collects the filtrate from the glomerulus and directs it to the proximal tubule.

28. Proximal Tubule Located after Bowman's capsule, it is responsible for reabsorbing essential substances such as glucose, amino acids, water, and electrolytes back into the bloodstream

29. A hairpin-shaped tube that extends from the proximal tubule. It plays a crucial role in reabsorbing water and electrolytes to maintain the body's fluid balance. The descending limb of the loop of Henle is permeable to water, but not to solutes. As the filtrate moves down through the descending limb, water is passively reabsorbed into the surrounding interstitial fluid. This reabsorption helps concentrate the urine. The ascending limb of the loop of Henle actively transports sodium and chloride ions out of the filtrate and into the interstitial fluid. This creates a concentration gradient that allows for the reabsorption of water in the collecting ducts later on. Loop of Henle

30. Located after the loop of Henle, it regulates the final concentration and composition of urine by further reabsorbing or secreting specific substances. Distal Tubule

31. Collecting Duct Receives urine from multiple nephrons and carries it towards the renal pelvis. It also plays a role in reabsorbing water and concentrating urine before excretion

32. Regional Differences in Nephron Structure

33. Nephrons having their glomeruli present in the outer cortex are cortical nephrons. Their loop of henle is also shorter It enters a very short distance inside the medulla. Their tubular system is surrounded by extensive network of peritubular capillaries. Cortical Nephrons

34. Juxtamedullary Nephrons

35. Consist of 20-30% nephrons in the body Have a glomerulus deep inside the renal cortex, closer to the medulla and are called juxtamedullary nephrons. Have longer loop of henle that dip deeply into the medulla In some cases even go deeper to the tips of renal papillae Have different vascular structures than cortical nephrons Long efferent arterioles extend from glomeruli into the outer medulla and then divide into specialised peritubular capillaries called vasa recta. Vasa recta extend down into the medulla, lying side by side with the loop of henle. They go back to the cortex and empty into cortical veins

36. FUNCTIONS OF KIDNEY

37. Primary Purposes of the Kidney

38. Waste elimination As byproducts of metabolism, urea and uric acid are expelled from the body via the kidneys into the urine. Reabsorption Reabsorbing essential nutrients, such as water, salt, chloride, potassium, magnesium, calcium, bicarbonate, phosphate, glucose (at normal plasma level), and amino acids. Acid-Base homeostasis Often known as body pH, is the preservation of equilibrium between chemical acids and bases.

39. Preservation Preserving the electrolyte-water balance, also known as plasma osmolarity. Hormone secretion The kidneys secrete calcitriol, an active form of vitamin D that keeps bones strong, renin, which regulates blood pressure, and erythropoietin, which controls the generation of red blood cells in the bone marrow.

40. 01 Urine F o r m a t i o n Presented by Nitasha Junaid

41. The kidneys filter unwanted substances from the blood and produce urine to excrete them.

42. Steps of Urine Formation

43. There are three main steps of urine formation: Glomerular filtration Reabsorption Secretion These processes ensure that only waste and excess water are removed from the body.

44. Step 1: G l o m e r u l a r Filtration

45. Urine formation begins with filtration of large amounts of fluid through the glomerular capillaries into Bowman’s capsule. Like most capillaries, the glomerular capillaries are relatively impermeable to proteins, so the filtered fluid (called the glomerular filtrate ) is essentially protein free and devoid of cellular elements, including red blood cells The concentrations of other constituents of the glomerular filtrate, i n c l u d i n g m o s t s a l t s a n d o r g a n i c m o l e c u l e s , a r e s i m i l a r t o t h e concentrations in the plasma Composition of the Glomerular Filtrate

46. Exceptions to this generalization include a few low molecular-weight substances, such as calcium and fatty acids, that are not freely filtered because they are partially bound to the plasma proteins. For example, almost one half of the plasma calcium and most of the plasma fatty acids are bound to proteins and these bound portions are not filtered through the glomerular capillaries.

47. The glomerular capillary membrane is similar to that of other capillaries, except that it has three (instead of the usual two) major layers: Endothelium of the capillary Basement membrane A layer of epithelial cells (podocytes) surrounding the outer surface of the capillary basement membrane Together, these layers make up the filtration barrier, which, despite the three layers, filters several hundred times as much water and solutes as the usual capillary membrane. Glomerular Capillary Membrane

48. The high filtration rate across the glomerular capillary membrane is due partly to its special characteristics. The capillary endothelium is perforated by thousands of small holes called fenestrae. Although the fenestrations are relatively l a r g e , e n d o t h e l i a l c e ll s a r e endowed with fixed negative r i c h l y c h a r g e s plasma t h a t h i n d e r t h e p a ss a g e o f proteins.

49. Surrounding the endothelium is the basement membrane , which consists of a meshwork of collagen and proteoglycan fibrillae that have large spaces through which large amounts of water and small solutes can filter. The basement membrane effectively prevents filtration of plasma proteins, in part because of strong negative electrical charges associated with the proteoglycans.

50. T h e f i n a l p a r t o f t h e g l o m e r u l a r m e m b r a n e i s a l a y e r o f epithelial cells that line the outer surface of the glomerulus. T h e s e c e ll s a r e n o t c o n t i n u o u s b u t h a v e l o n g f oo t l i k e p r o c e ss e s ( p o d o c y t e s ) t h a t e n c i r c l e t h e o u t e r s u r f a c e o f t he capillaries. The foot processes are separated by gaps called slit pores through which the glomerular filtrate moves. The epithelial cells, which also have negative charges, provide additional restriction to filtration of plasma proteins. T hu s , a l l l a y e r s o f t h e g l o m e r u l a r c a p i ll a r y w a l l p r o v i d e a barrier to filtration of plasma proteins.

51. A : B a s i c u l t r a s t r u c t u r e o f the glomerular capillaries B : C r o s s s e c t i o n o f t h e g l o m e r u l a r c a p i ll a r y m e m b r a n e a n d i t s m a j o r components:capillary endothelium,basement m e m b r a n e , a n d epithelium (podocytes)

52. Step 2: Tubular Reabsorption

53. Tubular reabsorption occurs when the kidneys reabsorb useful substances, such as glucose, amino acids, and electrolytes, from the filtrate back into the bloodstream This process occurs primarily in the proximal t u b u l e o f t h e n e p h r o n a n d i s c r i t i c a l i n t h e b o d y ' s e l e c t r o ly t e a n d f l u i d m a i n t a i n i ng balance This process is known as reabsorption, because this is the second time they have been absorbed; the first time being when they were absorbed into the bloodstream from the digestive tract after a meal

54. Tubular reabsorption includes passive and active mechanisms Passive transport is when substances use specific transporters to move down their concentration gradient (from areas of high concentration to areas of low concentration) or in the case of charged ions, down their electrochemical gradient Active transport is when substances are moved up (or against) their concentration or electrochemical gradients (from low to high). In this case, the substances are transported back into the bloodstream via energy-dependent, or active transport proteins

55. How does reabsorption in the nephrons work? The nephrons in your kidneys are specifically designed to maintain body fluid homeostasis This means keeping extracellular body fluid volumes stable, as well as maintaining the right levels of the salts and minerals that are essential for the normal function of your tissues and organs; regardless of how much you eat, or how active you are Nephrons are divided into five segments, with different segments responsible for reabsorbing different substances

56. W o r k i n g

57. Proximal Tubular Reabsorption: Normally, about 65 percent of the filtered load of sodium and water and a slightly lower percentage of filtered chloride are reabsorbed by the proximal tubule before the filtrate reaches the loops of Henle. T h e s e p e r c e n t a g e s c a n b e i n increased or decreased different physiologic conditions.

58. The surface of the cells facing the lumen of the proximal convoluted tubule are covered in microvilli (tiny finger-like structures) called a brush border. The brush border and the extensive length of the proximal tubule dramatically increase the surface area available for reabsorption of substances into the blood. They are densely packed with mitochondria. Proximal Tubules have a high capacity for Active and Passive Reabsorption

59. Solute and Water Transport in the Loop of Henle The loop of Henle consists of three functionally distinct segments: Thin descending segment Thin ascending segment, and Thick ascending segment The thin descending and thin ascending segments, have thin epithelial membranes with no brush borders, few mitochondria, and minimal levels of metabolic activity

60. The thick segment of the loop of Henle has thick epithelial cells that have high metabolic activity and are capable of active reabsorption of sodium, chloride, and potassium About 25 percent of the filtered loads of sodium, chloride, and potassium are reabsorbed in the loop of Henle, mostly in the thick ascending limb.

61. An important component of solute reabsorption in the thick ascending limb is the sodium-potassium ATPase pump in the epithelial cell basolateral membranes which maintains a low intracellular sodium concentration

62. Reabsorption in the distal tubule and collecting duct The tubular fluid now enters the distal tubule and collecting duct. The early distal tubule reabsorbs a further 5% of the sodium , and the late distal tubule and collecting duct fine tune reabsorption of the last little bit ( around 3% ), determining exactly how much sodium will be excreted. These segments of the nephron have slightly different transporters that drives reabsorption of calcium and chloride. Sodium reabsorption in the late distal tubule and collecting duct is regulated by hormones, which stimulate or inhibit sodium reabsorption as necessary.

63. Others ions Calcium reabsorption throughout the nephron is largely similar to sodium reabsorption with over 99% being reabsorbed. Reabsorption of magnesium differs; majority of the reabsorption occurs in the ascending limb of the loop of Henle.

64. Step 3: Tubular Secretion

65. Explanation The third process, tubular secretion, is the selective transfer of substances from the peritubular capillary blood into the tubular lumen. It provides a second route for substances to enter the renal tubules from the blood, the first being by glomerular filtration. Only about 20 percent of the plasma flowing through the glomerular capillaries is filtered into Bowman’s capsule; the remaining 80 percent flows on through the efferent arteriole into the peritubular capillaries.

66. Renal secretion is different from reabsorption because it deals with filtering and cleaning substances from the blood, rather than retaining them. The substances that are secreted into the tubular fluid for removal from the body include: Potassium ions (K+),Hydrogen ions (H+), Ammonium ions (NH4+), Creatinine, Urea, Some hormones and some drugs (e.g., penicillin).

67. Following Secretion: Urine that is formed via the three processes of filtration, reabsorption, and secretion leaves the kidney through the ureter, and is stored in the bladder before being removed through the urethra. At this final stage it is only approximately one percent of the originally filtered volume, consisting mostly of water with highly diluted amounts of urea, creatinine, and variable concentrations of ions.

68. ATRIAL PRESSURE FUNCTIONS CONTINUED BY : SYEDA AMEENA HAIDER

69. Role of kidneys in maintaining arterial pressure Kidneys plays an important role in long-term regulation of arterial pressure by excreting variable amounts of sodium and water. The kidneys also contribute to short-term arterial pressure regulation by secreting hormones and vasoactive factors or substances ( e.g.,renin ) lead to the formation of vasoactive products(e.g., angiotensin II).

70. Renin Angiotensin-Aldosterone System a . Release of Renin : The glomerular cells in the kidneys release the enzyme renin into the bloodstream in response to low blood pressure or low sodium levels. b. Angiotensinogen Conversion: Renin acts on a protein called angiotensinogen produced by the liver, converting it into angiotensin I. c. Conversion to Angiotensin II: Angiotensin-converting enzyme (ACE), primarily found in the lungs, converts angiotensin I into angiotensin II. d. Angiotensin II Effects: Angiotensin II is a potent vasoconstrictor, causing blood vessels to narrow, which increases blood pressure. It also stimulates the release of aldosterone from the adrenal glands. e. Aldosterone Action: Aldosterone promotes sodium reabsorption in the kidney tubules, leading to increased sodium and water retention. This increases blood volume, further raising blood pressure.

71. Continued… 82

72. Water and Electrolyte Balance

73. Role of kidneys in water and electrolyte balance To maintain homeostasis, excretion of water and electrolytes must precisely match intake. If intake exceeds excretion, the amount of that substance in the body will increase. If intake is less than excretion, the amount of that substance in the body will decrease. Intake of water and many electrolytes is governed mainly by a person’s eating and drinking habits, requiring the kidneys to adjust their excretion rates to match the intakes of various substances. The capacity of the kidneys to alter sodium excretion in response to changes in sodium intake is enormous.

74. Mechanism Filtration: The initial step in maintaining water and electrolyte balance is the filtration of blood in the kidneys' nephrons, where small molecules, including water and ions, are filtered out of the blood into the nephron's tubules. Reabsorption: Essential ions, such as sodium (Na+), potassium (K+), calcium (Ca2+), and magnesium (Mg2+), are reabsorbed from the filtrate back into the bloodstream.

75. Mechanism Concentration and Dilution : This function is primarily controlled by the loop of Henle , where water can be reabsorbed, and concentrated urine is produced when the body needs to conserve water. Conversely, dilute urine is produced when excess water needs to be excreted. Hormonal Regulation: Hormones, such as aldosterone and antidiuretic hormone (ADH), play a crucial role in regulating the reabsorption of water in response to changes in blood osmolarity .

76. Acid Base Balance

77. Role of kidneys in maintaining acid base balance: The kidneys contribute to acid-base regulation, along with the lungs and body fluid buffers, by excreting acids and by regulating the body fluid buffer stores. The kidneys are the only means of eliminating from the body certain types of acids, such as sulfuric acid and phosphoric acid, generated by the metabolism of proteins.

78. Mechanism Kidneys continuously filter blood through nephrons. Nephrons consist of the glomerulus, where filtration begins, and renal tubules for reabsorption and excretion. Filtration and Initial Process: In the glomerulus, one-fifth of plasma leaves, entering the renal tubule. Role of Renal Tubules: Renal tubules reabsorb essential substances (water, electrolytes) and excrete waste products and acids. Overview of Bicarbonate Reabsorption: Process begins in the proximal convoluted tubule. Bicarbonate binds to secreted hydrogen ions and is converted to carbonic acid. Carbonic anhydrase type 4 facilitates the breakdown of carbonic acid into water and carbon dioxide.

79. Buffer System: Ammonia Buffer System: Ammoniagenesis in proximal convoluted tubule. Formation of ammonium ions and their combination with chloride in urine. Phosphate Buffer System: Monohydrogen phosphate and dihydrogen phosphate in the tubules. Role as a buffer in combination with secreted hydrogen ions. Excretion in urine to regulate pH.

80. Role of Kidneys in Glucose Synthesis

81. Introduction… Maintenance of glucose homeostasis is crucial in preventing pathological consequences that may result from hyperglycemia or hypoglycemia. Chronically uncontrolled hyperglycemia leads to a higher risk of macrovascular and microvascular complications, such as cardiovascular disease, nephropathy, neuropathy, and retinopathy. Hypoglycemia , on the other hand, may lead to a myriad of central nervous system complications ( eg , confusion, behavioral changes, seizures, loss of consciousness, and even death), since the brain is the body’s largest consumer of glucose in the fasting or “postabsorptive” state.

82. Maintenance of glucose homeostasis involves several complementary physiologic processes, including glucose absorption (in the gastrointestinal tract), glycogenolysis (in the liver), glucose reabsorption (in the kidneys), gluconeogenesis (in the liver and kidneys), and glucose excretion (in the kidneys). With respect to renal involvement in glucose homeostasis, the primary mechanisms include: release of glucose into the circulation via gluconeogenesis uptake of glucose from the circulation to satisfy the kidneys’ energy needs reabsorption of glucose at the level of the proximal tubule.

83. Endogenous Production: Gluconeogenesis During times of fasting there are two methods by which glucose is produced endogenously to maintain plasma glucose levels: glycogenolysis and gluconeogenesis. Glycogenolysis involves the breakdown of glycogen to glucose-6-phosphate and its consequent hydrolysis by glucose-6-phosphatase to glucose. Gluconeogenesis involves the formation of glucose-6-phosphate from a variety of precursors such as lactate, glycerol, and amino acids, with its subsequent hydrolysis by glucose-6-phosphatase to glucose. Only the liver and kidney have sufficient gluconeogenic enzyme activity and glucose-6-phosphatase activity to contribute significant amounts of glucose via endogenous production. As the kidney usually stores modest quantities of glycogen and those cells that could store glycogen lack the glucose-6-phosphatase required for glycogenolysis, renal glucose production is thought to be principally due to gluconeogenesis.

84. Kidney is responsible for up to 20% of all glucose production by contributing to ∼40% of gluconeogenesis. The kidney differentially regulates glucose metabolism in the medulla and cortex. The poorly vascularized, and hence relatively hypoxic, medulla is a site of considerable glycolysis, and the cortex is the renal site of gluconeogenesis. Therefore, the net organ equilibrium of glucose does not represent a lack of glucose production but rather the difference between renal glucose release by the cortex and renal glucose uptake by the medulla.

85. Renal glycolysis and gluconeogenesis—pathway and enzyme localization. Glycolytic key enzymes (1) hexokinase, (2) phosphofructokinase, and (3) pyruvate kinase are predominantly localized in cells of the renal medulla. The key enzymes of gluconeogenesis, (4) pyruvate carboxylase, (5) phosphoenol pyruvate carboxykinase , (6) fructose-1,6-biphosphatase, and (7) glucose 6-phosphatase, are found mainly in renal cortical cells.

86. The proximal tubule is the only part of the kidney with the appropriate enzymes for gluconeogenesis. Four substrates account for ∼90% of gluconeogenesis in the kidney: lactate, glutamine, glycerol, and alanine. Of these, lactate is the principal precursor for both renal and hepatic gluconeogenesis in humans, and renal gluconeogenesis from lactate is 3.5- to 2.5- and 9.6-fold greater than that from glycerol, glutamine, and alanine, respectively. Renal gluconeogenesis adapts to various stimuli, including fasting, hypoglycemia, and diabetes. Renal gluconeogenesis is more sensitive to insulin and catecholamines than is hepatic gluconeogenesis, whereas glucagon has little to no effect on renal gluconeogenesis but increases hepatic production of glucose.

87. In contrast to the liver, the kidney increases its release of glucose after glucose ingestion, potentially contributing to postprandial hyperglycemia in diabetic patients. Hypoglycemia promotes renal gluconeogenesis by increasing the renal uptake of circulating gluconeogenic substrates. Patients with type-2 diabetes mellitus have an increase in glucose production by as much as 300%, which is equally contributed to by hepatic and renal sources. In the case of the kidney, there is a net glucose uptake during diabetes and it has been proposed that this glucose overload may contribute to the observed excess glycogen deposition. Renal gluconeogenesis is therefore important not only by contributing to the maintenance of normal glucose levels in the fasting state but also by having a role in diabetic postprandial hyperglycemia and the counterproductive increase in glucose production seen in patients with diabetes mellitus.

88. Glucose Reabsorption in Kidney Plasma glucose is neither protein-bound nor complexed with macromolecules and is therefore freely filtered at the glomerulus, such that in normal individuals renal glomeruli filter ∼180 g of d-glucose per day. This would result in an enormous loss of glucose through the ultrafiltrate if not recovered The main physiological undertaking of the kidney is to regain as much glucose as possible, and in normal situations almost all of it is reabsorbed in the proximal tubule by an insulin-independent process The ability of the proximal tubule to reabsorb glucose amplifies as the filtered load is increased by either an elevation in plasma glucose or an increase in glomerular filtration rate. This enhancement eventually reaches a threshold (Tm glucose) that represents the maximal reabsorptive capacity of the proximal tubule and increases in the filtered load above this point results in glycosuria

89. Urinary glucose excretion and tubular reabsorption as a function of filtered load Tubular reabsorption increases linearly with filtered load as a part of glomerulotubular balance. When reabsorption reaches the tubular capacity (Tm glucose), glucose starts appearing in the urine. The plasma glucose concentration for the given glomerular filtration rate (GFR) is the glycosuric threshold.

90. When the glomerular filtration rate is normal, the level of plasma glucose that results in glycosuria is ∼11 mm; however, when glomerular filtration rate increases in situations such as pregnancy or a unilateral kidney, glycosuria will occur at lower plasma glucose levels. Conversely, in the case of reduced glomerular filtration rate such as in chronic kidney disease, glycosuria would be absent until levels of plasma glucose are higher. Finally, patients with diabetes mellitus have been shown to experience hyperglycemia without resultant glycosuria, and the maximal glucose reabsorptive capacity in these patients has been shown to increase from a normal level of 352 mg/min (19.5  mmol /l/min) to 419 mg/min (23.3  mmol /l/min). This may relate to increases in expression of glucose transporters seen within the proximal tubule in diabetic conditions and probably represents a physiological response to increased glucose delivery to the proximal tubule that is ultimately maladaptive.

91. Glucose Transport across Proximal Nephron The S1 segment of the proximal tubule is characterized by high-flux low-affinity glucose transport, whereas the S3 segment is characterized by the reverse, a low-flux high-affinity glucose transport system. This variation is thought to allow the majority of glucose to be reabsorbed in the S1 segment of the proximal tubule, whereas any glucose that is left in the ultrafiltrate by the time it reaches S3 is avidly reabsorbed. Transport studies and molecular cloning over the last two decades have confirmed the existence of two sequential sodium (Na)-glucose transport systems within the proximal tubule with kinetic characteristics as predicted by these early studies

92. Relative magnitude of glucose transport characteristics in different segments of the proximal tubule. Jmax , maximal glucose transport rate; Km, affinity constant for glucose.

93. The transfer of glucose from the tubular lumen to the interstitial space is executed by the active process of Na-dependent glucose transport on the apical membrane to take glucose from the lumen to the cell, and facilitated diffusion glucose transport on the basolateral membrane to release glucose into the interstitium Glucose reabsorption from the glomerular filtrate through tubule epithelial cells into blood

94. The first step, in which glucose is transported across the apical brush border of kidney epithelial cells, requires the presence of a Na gradient across the cell membrane. A low intracellular Na concentration is created and maintained by the basolaterally located Na-K- adenosinetriphosphatase pump, which forces intracellular Na to exit the cell across the basolateral membrane. The electrochemical gradient thus created provides the driving force for ongoing transport of Na into the cell across the apical membrane, allowing for glucose to be concurrently cotransported by specific Na-dependent glucose transporters (SGLTs), despite a relatively low extracellular concentration. Once glucose has been concentrated in epithelial cells to a level above interstitial glucose levels, it diffuses out to the interstitium across specific facilitative glucose transporters (GLUTs), that are localized to the basolateral membrane. This efflux is more effective when the intracellular glucose level reaches the efflux Km of the facilitative transporter.

95. Glucose Transporters Sodium-dependent Glucose Transporters The SGLT belong to a broader group of solute carriers called SLC5, which currently includes six SGLT members. SGLT1 and SGLT2 are the best-characterized cotransporters in this group The low-affinity high-capacity transporter SGLT2 is abundant in the S1 and S2 segments of the proximal tubule. Given that animal studies have suggested that SGLT2 is responsible for absorbing up to 90% of filtered glucose, and both homozygous nonsense mutations and compound heterozygous mutations in the gene have been associated with glycosuria, it is considered to be the predominant effector of glucose reabsorption in the kidney. The high-affinity low-capacity transporter SGLT1, however, is expressed in the S3 segment of the proximal tubule and scavenges the remaining 10% of the filtered glucose. Proposed functions of SGLT3 , such as glucose sensing and/or transporting, as well as its possible location within the kidney, are yet to be resolved. Additional members such as SGLT4-6 have been named but their functional and structural features have not yet been fully characterized.

96. Facultative GLUTs There are now 17 known members of the GLUT gene family and these transporters are represented in all cells, wherein they transport glucose across the plasma membrane in a gradient-mediated manner and in almost all cases are responsible for the influx of glucose into cells. However, an exception is GLUT transporters are located on the basolateral aspect of cells and allow for the efflux of glucose from the cell, in particular in the gut lumen and kidney. GLUT1 was the first member of the GLUT family to be discovered, has a high affinity for glucose, and is the portal for glucose exit in S3 and provides the low-capacity high-affinity diffusional counterpart to SGLT1. Because of the high affinity nature of its transport, it is likely to be saturated at or near physiological glucose concentrations. GLUT2 , in contrast, is a high-capacity low-affinity basolateral transporter that tends to be found in tissues with large glucose fluxes in which it is unlikely to become saturated, such as intestine, liver, and pancreas, and the S1 segment of the proximal tubule, in which it is the corresponding basolateral transporter to SGLT2

97. Glucose Transport in Glomerular Cells Because of the likelihood of saturation of individual transport proteins, it is the number of high-affinity GLUT transporters expressed at plasma membranes that controls the flux of glucose into cells and these transporters are therefore more highly expressed in those tissues more dependent on glucose as an energy source. GLUTs 1, 4 and 8 are all high-affinity low-capacity GLUTs found within the glomerulus. GLUT1 is found at various levels in virtually all nephron segments, in which it enables glucose influx into cells at a rate dependent on nutritional requirements of the cell type, and is the predominant GLUT in mesangial cells. Mesangial cells also express GLUT4, podocytes express GLUTs 1, 4, and 8, and endothelial cells express GLUT1. These diffusional GLUTs are all responsible for the influx of glucose into various glomerular cells.

98. Regulation of Erythrocyte Production Presented by Sameen Ahmad

99. Introduction Healthy human adults produce about 200 billion red blood cells (RBCs) daily to replace those lost by senescence. This process, termed erythropoiesis, is exquisitely regulated by an oxygen- sensing mechanism that has evolved to maintain RBC numbers within a narrow physiological range Central to this mechanism is erythropoietin (EPO), a cytokine secreted by the kidney in response to low blood oxygen tension. Erythropoiesis is your body's process of making red blood cells (erythrocytes).

100. Where does erythropoiesis occur? Erythropoiesis starts before people are born. This is fetal erythropoiesis. By the time people are born, erythropoiesis takes place in people's bone marrow. Fetal erythropoiesis The location of erythropoiesis changes as a fetus develops during pregnancy. Week three: Erythropoiesis begins in the yolk sac. A yolk sac is a structure that nourishes a developing embryo. Months two and three: Erythropoiesis occurs in a fetus's liver and spleen. Month five: Erythropoiesis occurs in a fetus s bone marrow. Erythropoiesis in children and adults By the time a baby is born, erythropoiesis happens primarily in the bone marrow. C h i l d r e n : E ry t h r o p o i e s i s o cc u r s i n t h e b o n e m a rr o w o f m a n y d i ff e r e n t t y p e s o f bones. Adults: Erythropoieses occurs in certain bones including your pelvis, vertebrae, ribs and breastbone

101. Stages of Erythropoiesis With erythropoiesis, an originator cell called a hematopoietic stem cell (HSC) matures into a fully mature red blood cell, or erythrocyte. A cell advances through many stages for this to happen. Each type of blood cell (red blood cells, white blood cells and platelets) begin as a Hematopoietic Stem Cell (HSC). For a red blood cell to eventually form, an HSC becomes a common myeloid progenitor (CMP) cell. A CMP may mature into a red blood cell, platelet or some types of white blood cells. A CMP that eventually becomes a red blood cell develops into a megakaryocyte-erythroid progenitor cell (MEP) Once it's developed into a MEP. the cell is on track to become a red blood cell. It progresses through the following stages as it develops: (1) Proerythroblast; (2) Erythroblast; (3) Normoblast; (4) Reticulocyte; (5) Erythrocyte (fully mature red blood cell)

102. Role of Erythropoietin A hormone called erythropoietin (EPO) spurs red blood cell production. Hormones are chemical messengers that coordinate essential body functions. The kidneys secrete most of the body's EPO The process goes like this: The tissues lack oxygen because the red blood cells are low. The kidneys secrete more EPO in response. The EPO stimulates bone marrow to make more red blood cells The kidneys detect an increase in hemoglobin, a key protein in red blood cells, and secrete less EPO in respons The body achieves a balance (homeostasis) where the right amount of red blood cells is maintained.

103. The kidneys constantly secrete low levels of EPO to keep red blood cell production going. About 1% of your red blood cells are lost each day. Erythropoiesis replaces the red blood cells that have reached the end of their lifespan. The kidneys may secrete more or less EPO in response to conditions or injuries affecting your red blood cell levels.

104. Mechanism by which erythrocyte production is regulated EPO and Red Blood Cell Production: Yo ur body m akes a hormone called EPO (erythropoietin), mainly in the kidneys, to help make more red blood cells. These cells carry oxygen around your body. 2. Oxygen Levels Trigger EPO: Your body adjusts EPO levels based on how much oxygen is in your blood. When oxygen is low, EPO production goes up to make more red blood cells to carry more oxygen. 3. How Low Oxygen Activates EPO: When oxyge n is low, a special protein called HIF (hyp oxia-inducible factor) turns on the EPO gene, which increases EPO production. 4. What HIF Does: HIF is like an “on switch” for EPO and is made of two parts, HIF- α and HIF- β . When oxygen is normal, HIF is broken down, so it can’t trigger EPO. When oxygen is low, HIF stays stable, attaches to the EPO gene, and increases EPO production. 5. How HIF is Controlled: HIF is managed by enzymes (called PHD prolyl hydroxylase domain and FIH factor inhibiting HIF) that act as “oxygen sensors.” They only work well when there is enough oxygen.

105. Regulation of Vitamin D3 Production

106. Activation of Vitamin D The activation of Vitamin D to its active form involves a series of steps as follows: Skin Production of Cholecalciferol (Vitamin D3): The process begins when the skin is exposed to ultraviolet B (UVB) radiation from sunlight. UVB radiation stimulates the conversion of 7-dehydrocholesterol, a precursor molecule present in the skin, into cholecalciferol (vitamin D3). Transport to the Liver: Cholecalciferol is then transported through the bloodstream to the liver. Liver Conversion to Calcidiol : In the liver, cholecalciferol is enzymatically converted into calcidiol (25-hydroxyvitamin D), which is an inactive form of vitamin D. This step is not under direct control of the kidneys. Kidney Activation - Conversion to Calcitriol : The kidneys are the key site for the conversion of calcidiol into its active form, calcitriol (1,25-dihydroxyvitamin D).

107. Kidney Activation - Conversion to Calcitriol : The kidneys are the key site for the conversion of calcidiol into its active form, calcitriol (1,25- dihydroxyvitamin D). This conversion is tightly regulated and controlled by several factors: Parathyroid Hormone (PTH): The parathyroid glands, located near the thyroid gland, monitor the levels of calcium in the blood. When blood calcium levels drop, the parathyroid glands release parathyroid hormone (PTH) PTH Stimulation: PTH stimulates the kidneys to produce and release an enzyme called 1-alpha-hydroxylase. This enzyme converts calcidiol into calcitriol (the active form of vitamin D). Importance of Calcitriol: Calcitriol plays a critical role in maintaining calcium and phosphorus balance in the body. It does this by increasing the absorption of calcium and phosphorus from the intestines and by reducing calcium loss in the urine.

108. Intestinal Calcium and Phosphorus Absorption: Active vitamin D (calcitriol) acts on the cells of the small intestine, promoting the absorption of dietary calcium and phosphorus. This ensures that the body gets an adequate supply of these minerals for various functions, particularly for bone health. Feedback Mechanism: The regulation of calcitriol production by the kidneys is a negative feedback system. When blood calcium levels are low, PTH is released, which, in turn, triggers the kidneys to produce more calcitriol. This increased calcitriol level enhances calcium absorption from the intestines. As blood calcium levels return to normal, the negative feedback loop reduces PTH secretion and calcitriol production, preventing excessive calcium absorption.

109. Mechanism of Vitamin D activation in kidneys 1. Vitamin D Activation Process: The active form of Vitamin D is called 1,25(OH)2D, and it’s like a hormone that helps with bone health and other body functions. 1,25(OH)2D is made from another form of Vitamin D, called 25(OH)D. This conversion happens with the help of an enzyme in the kidney called CYP27B1. 2. Role of CYP27B1 Enzyme: CYP27B1 is the key enzyme that activates Vitamin D in the kidney. If there are mutations (changes) in the CYP27B1 gene, it can cause a rare disease, pseudovitamin D deficiency rickets, which leads to bone problems.

110. Control of CYP27B1 Activity: Different substances in the body control how active CYP27B1 is, including: Parathyroid Hormone (PTH): Increases CYP27B1 activity to make more active Vitamin D. Calcium: High calcium levels can lower CYP27B1 activity, reducing active Vitamin D production. Phosphate: Low phosphate levels boost CYP27B1 activity, increasing Vitamin D activation. 4. Additional Regulators: FGF23: This hormone decreases CYP27B1 activity and helps prevent too much Vitamin D from being activated. 1,25(OH)2D Itself: The active Vitamin D can also reduce CYP27B1 activity, preventing overproduction by breaking down excess Vitamin D with another enzyme, CYP24A1. 5. Feedback Loop: 1,25(OH)2D limits its own production by reducing CYP27B1 activity. It does this in two ways: Directly (by stimulating CYP24A1 to break it down) Indirectly (by reducing PTH production and increasing FGF23 production) In short, the body controls active Vitamin D levels carefully using CYP27B1, adjusting for calcium, phosphate, and other hormones to keep everything balanced.

111. Thankyou!