Renal Physiology Quiz

Urinary System Lecture 2

• The lecture was given by Fadhal Allah Najhe and edited by Hussain Jawad, part of the Medlogic Team.

Objectives

• Physiologic control of glomerular filtration (GFR) and renal blood flow (RBF).
• Renal Tubular Reabsorption and Secretion.
• Reabsorption and Secretion along different parts of the Nephron.

Physiologic control of GFR and RBF

• GFR is mainly determined by glomerular hydrostatic pressure and glomerular capillary colloid osmotic pressure (previous lecture).
• These variables are influenced by extrinsic mechanisms, intrinsic mechanisms and autoregulation of GFR and RBF.

1- Extrinsic Mechanisms

1- Sympathetic nervous system activation

• Sympathetic nerve fibers innervate afferent and efferent renal arterioles.
• A large drop in blood pressure (e.g., severe hemorrhage) strongly stimulates the renal sympathetic nerves, constricting the afferent arterioles, decreasing RBF and GFR, reducing urine production.

2- Hormonal control

• Norepinephrine (Nep) and epinephrine (Ep) hormones from the adrenal medulla constrict afferent and efferent arterioles, which decreases GFR and RBF.
• Their influence on GFR is small except during strong sympathetic activation.
• Endothelin is a peptide vasoconstrictor released by damaged vascular endothelial cells. Elevated endothelin levels contribute to decreased GFR.

B- Angiotensin II

• Angiotensin II is a powerful renal vasoconstrictor, acting both as a circulating and local hormone, produced in the kidneys and systemically.
• It constricts afferent and efferent arterioles.
• Increased Ang II constricts efferent arterioles, preventing decreased glomerular hydrostatic pressure (e.g., low sodium diet, volume depletion) which tends to decrease GFR.
• Increased angiotensin II helps maintain GFR and normal excretion of metabolic waste products (urea and creatinine). It increases sodium and water reabsorption, restoring blood volume and pressure.
• The preglomerular blood vessels (afferent arterioles) are relatively protected from Ang II-mediated constriction by vasodilators such as prostaglandins and nitric oxide.

C- Endothelial-derived Nitric Oxide (EDNO)

• Normally maintains renal vasodilation and GFR, enabling the kidneys to excrete normal amounts of sodium and water.
• Impaired nitric oxide production, such as in atherosclerosis or damage to vascular endothelium, can contribute to increased renal vasoconstriction and elevated blood pressure.

D- Prostaglandins and bradykinin

• These hormones/autacoids cause vasodilation, decrease renal vascular resistance, and increase renal blood flow and GFR.
• They oppose vasoconstriction of afferent arterioles and prevent excessive reductions in GFR and renal blood flow.
• NSAIDs such as aspirin may reduce GFR due to their inhibition of prostaglandin synthesis.

2- Intrinsic Mechanisms

• Renal autoregulation allows the kidney to adjust afferent arteriole dilation/constriction to counter blood pressure changes.
• This mechanism is effective over a broad range of blood pressures, but can be impaired with kidney disease.
• Two main lines of defense against spontaneous GFR changes affecting urine output:
  • Renal autoregulatory mechanisms (especially tubuloglomerular feedback).
  • Glomerulotubular balance.

3- Autoregulation of GFR and RBF

1- Tubuloglomerular Feedback

• This intrinsic feedback mechanism of the kidneys helps maintain constant renal blood flow and GFR regardless of systemic arterial pressure (from 75 mm Hg to 160 mm Hg).
• It involves special anatomical arrangements of the juxtaglomerular complex, including macula densa cells and juxtaglomerular cells in afferent and efferent arteriolar walls.
• Decreasing GFR leads to slow flow rate in the loop of Henle and increased Na and Cl reabsorption, which decreases NaCl concentration in macula densa cells.
• This triggers a signal to dilate afferent arterioles to raise glomerular hydrostatic pressure returning GFR towards normal.
• An efferent arteriolar vasoconstrictor feedback mechanism is involved via renin release from juxtaglomerular cells in response to a signal. Renin helps form angiotensin II, which constricts efferent arterioles and increases glomerular hydrostatic pressure restoring GFR toward normal.

2- Myogenic autoregulation

• Increased arterial pressure stretches vascular smooth muscle cells, leading to calcium ion movement, which causes muscle contraction and rises vascular resistance, preventing excessive increases in renal blood flow and GFR.

3- Other factors

• Chronic high protein intake: stimulates amino acid/Na+ reabsorption in the proximal tubule, leading to elevated Na+ levels in the macula densa and increased RBF and GFR, allowing Na+ excretion and restoring normal levels.
• High blood glucose levels: in diabetes results in increased glucose/Na+ reabsorption in the proximal tubules with reduced Na+ delivery to the macula densa, eliciting tubuloglomerular feedback.
• Other factors: Proximal tubular reabsorption is reduced by damage, metal poisoning from large dosages of drugs, and leads to lower NaCl, without appropriate compensation causing volume depletion.

Renal Tubular Reabsorption and Secretion

• Urine formation in the nephron occurs through glomerular filtration, selective reabsorption, and tubular secretion.
• Urinary excretion = Glomerular filtration - Tubular reabsorption + Tubular secretion.

1- Tubular secretion

• This process moves substances from blood into renal tubules, also called tubular excretion, and includes:
  • Potassium secretion (actively by Na+,K+ pumps in proximal and distal convoluted tubules and collecting ducts).
  • Ammonia secretion (proximal convoluted tubule).
  • Hydrogen ion secretion (proximal and distal convoluted tubules, with maximal secretion in the proximal tubule).

2- Tubular reabsorption

• Reabsorbs water and solutes from the tubular lumen into interstitial fluid which then moves into the blood vessels.
• Large amounts of water (over 99%), electrolytes and other substances are reabsorbed by tubular epithelial cells.
• It is mainly in the proximal tubule and loop of Henle and is called selective reabsorption as it reabsorbs necessary substances only.
• Essential substances like glucose, amino acids, and vitamins are fully reabsorbed and enter peritubular capillaries preventing excretion.

3- Active Transport

• Active transport moves molecules against their electrochemical gradient using energy from ATP hydrolysis.

1- Primary active transport

• The Na+-K+ ATPase pump is a primary active transport system that moves sodium ions across the proximal tubular membranes. Steps include:
  • Na+ transported across basolateral membrane from low concentration in renal tubular cell to high concentration at interstitium.
  • K+ is transported vice-versa.
  • Low intracellular Na+ and high intracellular K+ concentration is maintained.

2- Secondary active transport

• Secondary active transport moves substances indirectly by using energy from an existing electrochemical gradient, typically Na+ ions.
• Important secondary active transporters in the kidney reabsorb glucose and amino acids and to secrete substances from proximal tubule, mediated by the Na+/glucose (amino acid) symporters.
• When Na+ diffuses into the cell, it allows other substances (glucose or amino acids) to passively diffuse into the cell as well along its electrochemical gradient.

4- Pinocytosis

• Pinocytosis is an active transport mechanism that reabsorbs proteins, usually at the brush border of proximal tubule, by invaginating the protein into the tubule cell and digesting it into amino acids.

5- Transport Maximum (Tm or Tmax)

• The maximum rate at which a system can transport a substance. It determines the saturation phenomenon, whereby as substance concentration increases, there is a limiting amount of the substance transported up to the transport maximum. After that, there is no increase in transport.
• Filtered glucose is fully reabsorbed in the proximal tubule, so glucose does not appear in the urine. The normal transport maximum for glucose in humans is roughly 375 mg/minute. Filtered load of glucose is about 125 mg/minute, which falls under the transport maximum, so no glucose is excreted.
• Some substances like sodium may be reabsorbed passively due to their electrochemical gradient and tubular flow rate, but they do not have a transport maximum.
• Water is rapidly reabsorbed by osmosis through the proximal tubule and descending loop of Henle secondary to the presence of water channels (aquaporins) and tight junctions.
• In contrast, the ascending limb of the loop of Henle and distal and collecting tubules only reabsorb water if antidiuretic hormone (ADH) is present, affecting water's permeability.
• Chloride (Cl-) is reabsorbed passively due to an electrical gradient produced by Na+ active transport and its concentration gradient. Urea is mainly reabsorbed in proximal tubule due to its concentration gradient following water osmosis. Creatinine is largely excreted due to large molecular size and relative impairment of tubular membrane.

Reabsorption and Secretion along different parts of the Nephron

• 1- Proximal tubular reabsorption: major site of reabsorption for glucose, amino acids, and many Krebs cycle intermediaries. It reabsorbs 65% of Na+ and about the same percentage of water. Osmolarity remains constant at 300mOsm/L. High metabolic rate and extensive brush border are characteristics of the proximal tubule cells. Sodium is reabsorbed by countertransport, secreting H+ into the tubular lumen while the proximal tubule is also a site of secretion of many organic acids and bases, including bile salts, oxalate, uric acid, catecholamines, drugs, toxins and para-aminohippuric acid (PAH).

• The average person can clear about 90 % of PAH from the plasma flowing through the kidneys to be excreted in the urine. Thus, the PAH clearance rate is used to estimate RFB and GFR.

• 2- Solute and water transport in the loop of Henle: has 3 segments: descending thin, and thin ascending, and thick ascending, the first two have thin epithelial membrane, few mitochondria and minimal metabolic activity and thus are highly permeable to water, with low capacity to reabsorb solutes. The thick ascending limb has high metabolic activity, with Na+/2Cl-/K+ cotransporter that reabsorbs these solutes.

• 3- Distal Tubules: Juxtaglomerular complex, early distal tubule reabsorbs Na+, K+, and Cl-,impermeable to urea and water (diluting segment).

• 5% of sodium chloride are reabsorbed with co-transporter (inhibited by thiazide diuretics) . Cl- diffuses to the renal interstitial fluid, through chloride channels in the basolateral membranes.

• 4- Late distal tubule and cortical collecting tubule: Both have the same general function and have two cell types- principal cells and intercalated cells. Principal cells reabsorb Na+ and secrete K+ depending on Na(+)/K+ATPase pump. Intercalated cells secrete H+ and reabsorb HCO3 and K+.

• 5- Medullary collecting duct: The final site process the urine, and reabsorbs less than 10% of filtered H2O and Na+. The cells have smooth surfaces and relatively few mitochondria and their permeability to water is controlled by ADH. It is also permeable to urea and secretes H+, crucial in acid-base balance.