Chapter Outline
THERMODYNAMIC APPROACH TO METABOLISM AND TRANSPORT, 123
Thermodynamic Analysis of Kidney Function, 123
Application of the Laws of Thermodynamics to Kidney Function, 123
ENERGY AND THE SODIUM PUMP, 124
Structure of the Sodium Pump, 124
Other Adenosine Triphosphatases, 124
Pump-Leak Process and the Sodium Potential, 124
Harnessing the Sodium Potential for Work, 125
CELL POLARITY AND VECTORIAL TRANSPORT, 126
METABOLIC SUBSTRATES FUELING ACTIVE TRANSPORT ALONG THE NEPHRON, 126
Metabolism Basics, 126
Whittam Model, 127
Energy Requirements and Substrate Use along the Nephron, 128
Renal Gluconeogenesis and Lactate Handling, 130
NEPHRON REGION–SPECIFIC METABOLIC CONSIDERATIONS, 132
Proximal Tubule, 132
Thick Ascending Limb, 132
Cortical Collecting Duct, 133
Medullary Collecting Duct, 133
CONTROL OF RENAL OXYGENATION, 133
Renal Blood Flow and Oxygen Consumption, 133
Tubuloglomerular Feedback, 135
Metabolic Cost of Sodium Reabsorption, 135
REGULATION OF METABOLIC EFFICIENCY OF TRANSPORT DURING NORMAL PERTURBATIONS AND DISEASE, 138
Physiologic Regulation: Filtration Fraction and Oxygen Consumption, 138
Hypoxia and Ischemia, 139
Adenosine Monophosphate–Activated Protein Kinase, 140
Mitochondrial Diseases, 142
SUMMARY, 142
The term 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. This chapter is dedicated to one aspect of kidney metabolism—namely the storage, release, and utilization of energy by the nephron as it transforms the glomerular filtrate into urine.
How much energy is required to make the urine? Of the major body organs, the kidney consumes the second highest amount of oxygen per gram of tissue (2.7 mmol/kg/min for the kidney 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. It has been asserted that because the kidney reabsorbs 99% of the glomerular filtrate, it must use a lot of energy—but this logic is incorrect. 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 is the thermodynamic equivalent of partitioning a bucket into two compartments by the use of a divider, which requires no net energy. On the other hand, energy is required to form a urine that differs in solute composition from that of the body fluids (e.g., plasma). To appreciate this, consider that the hypothetical remixing of urine with plasma would cause the formation of entropy, known as mixing entropy. Thus, energy is required to form urine from plasma and attain a state of reduced entropy. The minimum amount of energy required for this is equal to the temperature multiplied by the decrease in mixing entropy associated with the differential solute composition of urine versus plasma.
This chapter provides an overview of the interdependence of renal solute transport and renal metabolism, including the following: (1) role of the sodium pump, Na + -K + -ATPase, in epithelial transport; (2) metabolic substrates fueling active transport along the nephron and regional metabolic considerations; (3) role of renal blood flow, glomerular filtration rate, and tubuloglomerular feedback in controlling fluid and electrolyte filtration and tissue oxygenation; (4) amount of oxygen consumed per sodium reabsorbed (Q o 2 /T Na ); and (5) metabolic efficiency of transport during normal perturbations and disease.
Thermodynamic Approach to Metabolism and Transport
Thermodynamic Analysis of Kidney Function
Interest in kidney metabolism antedates most knowledge of the kidney’s inner workings or of biochemistry. 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 that is 100% efficient, infinitely slow, completely reversible, involves no backleak, and generates no entropy and heat is about 0.5 cal/min/1.73 m 2 . In reality, the kidney consumes more than 50-fold this amount of energy. On this basis alone, one might argue that the kidney is horribly inefficient, even after one subtracts the cost to the kidney of maintaining itself. On the other hand, added costs are imposed by the requirement to make urine in a finite amount of time, need for flexibility to alter the volume and composition of the urine rapidly, stoichiometric constraints of biochemistry, known limits on the thermodynamic efficiency of oxidative phosphorylation, and intrinsic permeabilities of tissues to electrolytes, gases, and urea.
The thermodynamic requirement may be a small fraction of the actual expenditure, but before one concludes that the body is unconcerned with thermodynamics, it may be noted that the thermodynamic energy required of the kidney to maintain salt and nitrogen balance with consumption of a typical diet is minimized with the usual water intake of 1 to 2 L/day. This is consistent with an evolutionary process geared to minimize the thermodynamic energy requirements of the kidney.
Moreover, the thermodynamic cost of excreting urea declines as blood urea nitrogen (BUN) concentration increases. Thus, as the BUN level rises in kidney disease, less energy is required to maintain the nitrogen balance. In kidney disease, the urine composition is also restricted to a narrower range. Using a classic thermodynamic approach, Newburgh suggested that the composition of the urine and body fluids in kidney disease are determined by the available free energy and noted that the declining flexibility of the diseased kidney to vary the urine composition could be predicted from the reduced free energy available for transport.
Application of the Laws of Thermodynamics to Kidney Function
The macroscopic laws of equilibrium thermodynamics apply to kidney metabolism; any theory of metabolism is necessarily incorrect if it violates these laws. The laws of thermodynamics essentially describe transitions of a system from one state to another. The first law of thermodynamics states that total energy is conserved during any process that occurs in a closed system. When a system is open to its environment, the combined energy of the system plus environment remains constant. When the total internal energy, temperature, pressure, and volume of a system remain constant, any process that yields a change in free energy also yields a reciprocal change in entropy. Doing work on the system is equivalent to adding free energy to the system, which determines the upper limit of how much useful work the system can do against its environment.
The first law of thermodynamics stipulates that total energy is conserved throughout any process, but provides no other indication of whether a given process will occur spontaneously. The glomerular filtrate contains a mixture of salt and urea. The tubule partitions this into urine and reabsorbate. The urine has a different ratio of urea to salt than the reabsorbate, so the entropy has decreased. However, the total internal energy of the combined urine and reabsorbate is the same as the original filtrate. Hence, the first law would be satisfied if the urine were to form spontaneously from the filtrate. The fact that NaCl and urea never sort themselves spontaneously into regions of higher and lower concentration is a consequence of the second law of thermodynamics, which states that all spontaneous processes generate entropy. Conversely, all spontaneous processes dissipate free energy and will cease when the supply of free energy is exhausted. It is possible to reduce entropy or elevate free energy in a system, but only if the system imports energy from its surroundings, in which case there will be an increase in entropy of the surroundings that exceeds the decrease in entropy of the system. Some processes in the kidney, such as conversion of chemical to mechanical energy by Na + -K + -ATPase, are highly efficient and generate almost no entropy. Other processes, such as the countercurrent multiplier, are inefficient and generate a lot of entropy. As a rule, those processes that generate the least entropy work over short distances and short times.
The laws of equilibrium thermodynamics determine the direction of any spontaneous process, but they do not address the rate of change. Hence, the laws of equilibrium thermodynamics are not adequate for a full description of a living system that is displaced from equilibrium and characterized by flow of matter and energy within the system itself, as well as between the system and its environment. Thermodynamic principles are extended to incorporate time as a variable by the theory of nonequilibrium thermodynamics. Nonequilibrium thermodynamics entails certain assumptions and approximations that make it more of a tool and less of a foundation than classic equilibrium thermodynamics, but the theory performs well in many areas of physiology, including transport physiology. Basically, 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. It applies to macroprocesses and microprocesses involved in forming the urine. Examples include all mechanisms for secondary active transport and the conversion of chemical to translational free energy by adenosine triphosphatases (ATPases).
Energy and the Sodium Pump
Na + -K + -ATPase, also known as the sodium pump, is a ubiquitous plasma membrane protein that transports intracellular sodium out of the cell and extracellular potassium into the cell, thereby generating opposite concentration gradients for sodium and potassium ions across the cell membrane. This process of separating sodium from potassium across the cell membrane is fueled by the hydrolysis of adenosine triphosphate (ATP). Each cycle of the pump consumes one ATP molecule while transporting three Na + and two K + ions across the cell membrane. The hydrolysis of ATP and the associated transport of ions are mutually dependent and constitute an example of primary active transport. In this process, there is almost full conversion from chemical to mechanical energy, with minimal dissipation. The translational energy that develops after ATP hydrolysis results from electrostatic repulsion between the product ions, adenosine diphosphate (ADP) and inorganic phosphate (Pi), in accordance with Coulomb’s law. Although this energy could be dissipated through subsequent collisions, such events are unlikely over very short time scales and short distances. For a relative kinetic energy of the phosphate of 0.6 electron volt (eV), for example, the phosphate ion moves about 0.1 nm in 0.3 picosecond. If no other collisions occur in that short time interval, the phosphate can then transfer its entire kinetic energy to the sodium pump in the form of a molecular strain. Given the intrinsic free energy of ATP hydrolysis, the pump can generate gradients that store up to approximately 0.6 eV of electrochemical potential per three Na + plus two K + ions. For a typical cell in a typical environment, about 0.4 eV is required to cycle the pump against the existing sodium and potassium gradients, which means that cells tend to operate with some reserve to reduce their sodium or increase their potassium concentrations further.
Structure of the Sodium Pump
The sodium pump is composed of an α-catalytic subunit, which hydrolyzes ATP and transports Na + and K + across the membrane, a β-subunit that is critical for functional maturation and delivery of Na + -K + -ATPase to the plasma membrane, and an FXYD protein that can modulate the kinetics of Na + -K + -ATPase in a tissue-specific manner ( Figure 5.1 ). There are multiple isoforms of each subunit. The α 1 β 1 heterodimer is likely the exclusive Na + -K + -ATPase in renal epithelia, whereas several FXYD protein subunits are expressed differentially along the nephron. Biophysical models describing the turnover of the sodium pump through its functional cycle have been described in a review by Horisberger.
Other Adenosine Triphosphatases
In addition to Na + -K + -ATPase, additional ion-translocating ATPases are expressed in renal epithelia along the nephron, including H + -K + -ATPase, Ca 2+ -ATPases, and H + -ATPases. These transport ATPases play important roles in maintaining urinary acidification and calcium homeostasis, as discussed in Chapter 6 , Chapter 7 , Chapter 9 . These ATPases do not contribute significantly to the reabsorption of the bulk of the filtrate.
Pump-Leak Process and the Sodium Potential
For a cell in steady state, 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. The backleak of ions is an example of electrodiffusion. This diffusion of ions generates an electric field to retard diffusion of the most mobile charged species, thereby transferring free energy from the chemical potential of the mobile species to an electrical potential acting on the less mobile species. If the electric field is constant within the cell membrane, then the electrical potential difference across the membrane is given by the Goldman voltage equation, which is shown here for a membrane that is permeable to Na, K, and Cl:
ψ = RT F ln ( P K [ K ] o + P Na [ Na ] o − P Cl [ Cl ] o P K [ K ] i + P Na [ Na ] i − P Cl [ Cl ] i )
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