Kidney Metabolism Chapter

Metabolism and Kidney Function

• Metabolism refers to the entire set of interconnected chemical reactions within living organisms that form and maintain tissue and govern the storage and release of energy to sustain life.
• The kidney consumes the second-highest amount of oxygen per gram of tissue (2.7 mmol/kg/min vs. 4.3 mmol/kg/min for the heart).
• Most of the potential energy provided by renal oxidative metabolism is committed to epithelial transport, which determines the volume and composition of the urine.

Energy Requirements for Urine Formation

• The minimum net energy required for reabsorption does not depend on the amount of fluid that is reabsorbed.
• Forming a volume of urine with a solute composition equal to that of the body fluid from which it is formed requires no net energy.
• Energy is required to form a urine that differs in solute composition from that of the body fluids (i.e., plasma).
• The minimum amount of energy required is equal to the temperature multiplied by the decrease in mixing entropy associated with the differential solute composition of urine versus plasma.

Thermodynamic Approach to Metabolism and Transport

• The theoretical minimum amount of energy required to make urine was determined from the laws of equilibrium thermodynamics nearly a century ago.
• For a human in balance on a typical diet, the cost of converting the glomerular filtrate into urine by an idealized process is about 0.5 cal/min/1.73 m2.
• In reality, the kidney consumes more than 50-fold this amount of energy.

Thermodynamic Analysis of Kidney Function

• The thermodynamic requirement may be a small fraction of the actual expenditure, but before one concludes that the kidney is horribly inefficient, added costs are imposed by the requirement to make urine in a finite amount of time, the need for flexibility to rapidly alter the volume and composition of the urine, and the stoichiometric constraints of biochemistry.

Application of the Laws of Thermodynamics to Kidney Function

• The macroscopic laws of equilibrium thermodynamics apply to kidney metabolism.
• The first law of thermodynamics states that total energy is conserved during any process that occurs in a closed system.
• The second law of thermodynamics states that all spontaneous processes generate entropy.
• The laws of equilibrium thermodynamics determine the direction of any spontaneous process, but they do not address the rate of change.

Nonequilibrium Thermodynamics

• Nonequilibrium thermodynamics entails certain assumptions and approximations that make it more of a tool and less of an edifice than classical equilibrium thermodynamics.
• The theory asserts that the flow of any extensive property (e.g., mass, volume, charge) is the product of a driving force and a proportionality constant, which has units of conductance.
• The theory applies to both macro- and micro-processes involved in forming the urine.

Metabolism and Kidney Function

• Metabolism refers to the entire set of interconnected chemical reactions within living organisms that form and maintain tissue and govern the storage and release of energy to sustain life.
• The kidney consumes the second-highest amount of oxygen per gram of tissue (2.7 mmol/kg/min vs. 4.3 mmol/kg/min for the heart).
• Most of the potential energy provided by renal oxidative metabolism is committed to epithelial transport, which determines the volume and composition of the urine.

Energy Requirements for Urine Formation

• The minimum net energy required for reabsorption does not depend on the amount of fluid that is reabsorbed.
• Forming a volume of urine with a solute composition equal to that of the body fluid from which it is formed requires no net energy.
• Energy is required to form a urine that differs in solute composition from that of the body fluids (i.e., plasma).
• The minimum amount of energy required is equal to the temperature multiplied by the decrease in mixing entropy associated with the differential solute composition of urine versus plasma.

Thermodynamic Approach to Metabolism and Transport

• The theoretical minimum amount of energy required to make urine was determined from the laws of equilibrium thermodynamics nearly a century ago.
• For a human in balance on a typical diet, the cost of converting the glomerular filtrate into urine by an idealized process is about 0.5 cal/min/1.73 m2.
• In reality, the kidney consumes more than 50-fold this amount of energy.

Thermodynamic Analysis of Kidney Function

• The thermodynamic requirement may be a small fraction of the actual expenditure, but before one concludes that the kidney is horribly inefficient, added costs are imposed by the requirement to make urine in a finite amount of time, the need for flexibility to rapidly alter the volume and composition of the urine, and the stoichiometric constraints of biochemistry.

Application of the Laws of Thermodynamics to Kidney Function

• The macroscopic laws of equilibrium thermodynamics apply to kidney metabolism.
• The first law of thermodynamics states that total energy is conserved during any process that occurs in a closed system.
• The second law of thermodynamics states that all spontaneous processes generate entropy.
• The laws of equilibrium thermodynamics determine the direction of any spontaneous process, but they do not address the rate of change.

Nonequilibrium Thermodynamics

• Nonequilibrium thermodynamics entails certain assumptions and approximations that make it more of a tool and less of an edifice than classical equilibrium thermodynamics.
• The theory asserts that the flow of any extensive property (e.g., mass, volume, charge) is the product of a driving force and a proportionality constant, which has units of conductance.
• The theory applies to both macro- and micro-processes involved in forming the urine.

Energy and the Sodium Pump

• Na+-K+-ATPase (sodium pump) is a ubiquitous plasma membrane protein that transports intracellular sodium out of the cell and extracellular potassium into the cell, generating opposite concentration gradients for sodium and potassium ions across the cell membrane.
• The sodium pump is fueled by the hydrolysis of adenosine triphosphate (ATP), with each cycle consuming 1 ATP molecule and transporting 3 Na+ and 2 K+ ions across the cell membrane.
• The process is an example of primary active transport, with nearly full conversion from chemical to mechanical energy and minimal dissipation.

Structure of the Sodium Pump

• The sodium pump is composed of an α catalytic subunit, a β-subunit, and an FXYD protein that can modulate the kinetics of Na+-K+-ATPase in a tissue-specific manner.
• There are multiple isoforms of each subunit, with the α1β1 heterodimer being the exclusive Na+-K+-ATPase in renal epithelia.

Other Adenosine Triphosphatases

• Besides Na+-K+-ATPase, additional ion-translocating ATPases are expressed in renal epithelia, including H+-K+-ATPase, Ca2+-ATPases, and H+-ATPases.
• These ATPases play important roles in maintaining urinary acidification and calcium homeostasis.

Pump-Leak Process and the Sodium Potential

• The pumping of ions by the Na+-K+-ATPase must be offset by an equal and opposite diffusion of those ions back across the cell membrane, generating an electric field to retard diffusion of the most mobile charged species.
• The Goldman voltage equation describes the electrical potential difference across the membrane, which approaches the Nernst potential for the most permeable ion (K+ in this case).
• The negative cell voltage, in turn, neutralizes the net driving force for further potassium egress and augments the net driving force for sodium entry.

Harnessing the Sodium Potential for Work

• The difference in electrochemical potential for sodium across the cell membrane is available to drive the unfavorable passage of other solutes across the membrane by a variety of exchangers and cotransporters.
• Examples of secondary active transport include the proximal tubule Na+/H+ exchanger, sodium-glucose cotransporters (SGLTs), and the basolateral Na/α-ketoglutarate (α-KG) cotransporter.
• Tertiary active transport refers to the net flux of a solute against its electrochemical potential gradient coupled indirectly to the Na+ gradient, such as the uptake of organic anions from the peritubular blood into the proximal tubular cell by the organic anion transporters (OATs).

Cell Polarity and Vectorial Transport

• The polar arrangement of transporters in renal cells is essential for vectorial transport.
• The sodium pump (Na+-K+-ATPase) is restricted to the basolateral membrane, removing sodium from the cell.
• Apical transporters, including exchangers, cotransporters, and sodium channels, are restricted to the apical membrane, allowing sodium to enter the cell.
• Key apical transporters include:
  • NHE3 in the proximal tubule
  • SGLTs in the proximal tubule
  • NKCC2 in the thick ascending limb (TAL) of the loop of Henle
  • NCC in the distal convoluted tubule
  • Epithelial sodium channels in the connecting tubule and collecting duct
• Close coordination of sodium uptake across the apical membrane with sodium extrusion across the basolateral membrane is required to avoid osmotic swelling and shrinking of the cell.

Regulation of Vectorial Transport

• The magnitude of transepithelial transport is a function of:
  • The number of transporters in the plasma membrane
  • The activity per transporter
• Factors influencing transporter activity include:
  • Covalent modification (e.g., phosphorylation or proteolysis)
  • Protein-protein interaction (e.g., Na+-K+-ATPase kinetics)
  • Availability of substrates for cotransport
• Many factors and hormones, including angiotensin II, aldosterone, dopamine, parathyroid hormone, and blood pressure, regulate renal sodium reabsorption by affecting the activity, distribution, or abundance of apical transporters and basolateral sodium pumps.

Metabolic Substrates Fueling Active Transport

• Metabolic substrates enter the kidney through renal blood flow (RBF) and glomerular filtration rate (GFR) and enter renal epithelial cells through substrate transporters.
• Substrates face one of three fates in the cell:
  • Transport across the epithelium back into the blood (reabsorption)
  • Conversion into another substrate (e.g., lactate to pyruvate)
  • Oxidation to CO2 in the process of cellular ATP production
• Renal epithelial cells, except in the descending and thin ascending limbs of the loop of Henle, are packed with mitochondria.

Mitochondrial ATP Production

• Substrates in the cytosol can freely cross the outer mitochondrial membrane through integral membrane porins.
• Substrates, ADP, and phosphate cross the inner mitochondrial membrane into the mitochondrial matrix via specific substrate transporters driven by their respective concentration gradients or the H+ gradient created by the electron transport chain (ETC).
• Amino acids, fatty acids, and pyruvate are metabolized to acetyl-coenzyme A and enter the citric acid cycle.
• The citric acid cycle produces:
  • Three molecules of reduced nicotinamide adenine dinucleotide (NADH)
  • One molecule of reduced flavin adenine dinucleotide (FADH2)
  • One molecule of guanosine triphosphate (GTP) or ATP
  • Two molecules of CO2
• Electrons carried by NADH and FADH2 are transferred into the mitochondrial electron transport chain, ultimately reducing oxygen to H2O.
• The release of the potential energy stored in the H+ gradient across the inner mitochondrial membrane drives ATP synthesis from ADP by the ATP synthase.
• The newly synthesized ATP is extruded from the matrix into the intermembrane space via the ADP-ATP countertransporter and then exits the mitochondria across the permeable outer membrane.

This quiz covers the role of kidney metabolism in energy storage, release, and utilization, specifically in the transformation of glomerular filtrate into urine.