Renal Physiology Integrated Control of Na Transport along the Nephron Lawrence G. Palmer* and Ju¨rgen Schnermann† Abstract The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine. Although almost every nephron segment participates in the reabsorption of Na in the normal kidney, the proximal segments (from the glomerulus to the macula densa) and the distal segments (past the macula densa) play different roles. The proximal tubule and the thick ascending limb of the loop of Henle interact with the filtration apparatus to deliver Na to the distal nephron at a rather constant rate. This involves regulation of both *Department of Physiology and filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback. Biophysics, Weill- The more distal segments, including the distal convoluted tubule (DCT), connecting tubule, and collecting Cornell Medical duct, regulate Na reabsorption to match the excretion with dietary intake. The relative amounts of Na reabsorbed College, New York, in the DCT, which mainly reabsorbs NaCl, and by more downstream segments that exchange Na for K are variable, New York; and †Kidney Disease allowing the simultaneous regulation of both Na and K excretion. Branch, National Clin J Am Soc Nephrol 10: 676–687, 2015. doi: 10.2215/CJN.12391213 Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Introduction The precise adaptation of urinary Na excretion to di- Health, Bethesda, Daily Na intake in the United States averages approx- etary Na intake results from regulated processing of an Maryland imately 180 mmol (4.2 g) for men and 150 mmol (3.5 g) ultrafiltrate of circulating plasma by the renal tubular for women (1). Because Na is an immutable ion, mass Correspondence: epithelium. Perhaps the most striking aspect of this re- Dr. Lawrence G. balance requires that an equal amount must be removed markable process is the gross inequality in the quan- Palmer, Department of from the body daily to prevent inappropriate gains or tities of Na removed from plasma by ultrafiltration and Physiology and losses of Na and its accompanying anions, chloride and those removed from the body by urinary excretion. The Biophysics, Weill bicarbonate. Because these ions are the prime determi- staggering mass of .500 g of Na is extracted daily from Medical College of fl fi Cornell University, nants of extracellular uid volume, maintenance of the plasma by ultra ltration in order to excrete the in- 1300 York Avenue, extracellular fluid volume, arterial blood pressure, and gested 3 g. The large filtered load results from the high New York, NY 10065. organ perfusion depends on control of body Na content. extracellular Na concentration and the high rate of Email: lgpalm@med. Under most conditions, the kidneys excrete .95% of glomerular ultrafiltration. Whatever the evolutionary cornell.edu the ingested Na at rates that match dietary Na intake. pressure behind this functional design may be, the Under steady-state conditions, this process is remark- necessity to retrieve almost all of the filtered Na before ably precise in both healthy and diseased kidneys, and it reaches the urine represents a challenging regulatory determinations of excretion are used to estimate Na and energetic demand that the tubular epithelium has intake (e.g., in determining adherence to a prescribed to meet. Just as Na intake dictates the rate of Na excre- dietary regimen). Recent studies have shown the pres- tion, Na filtration dictates the rate of Na reabsorption. ence of a sizable subcutaneous Na pool that is not in solution equilibrium with the freely exchangeable ex- tracellular Na. Long-term observations suggest that Na Reabsorption along the Nephron cyclical release of Na from this pool can lead to excre- Micropuncture and microperfusion studies have tion rates that deviate from Na intake (2). The speed of shown that all nephron segments contribute to the achieving an intake/excretion match or a new steady retrieval of filtered Na (with the exception of the thin state when Na intake varies is relatively slow; body Na descending limbs of the loop of Henle) (Figure 1). The content usually increases somewhat when Na intake reabsorption of Na is an energy-consuming process increases and decreases somewhat when Na intake de- that is powered by a Na- and K-activated ATPase in creases (3). These changes in body Na content and the basolateral membranes of all Na-reabsorbing cells blood volume are the likely cause for the relation be- in the kidney. Oxygen consumption of the kidneys is tween Na intake and BP. In normotensive individuals, similar to that of other major organs (approximately 6– the effect of variations in daily Na intake on BP is 8 ml/min per 100 g) and is extracted from a seemingly small, about 2 mmHg for a 50% reduction in Na intake excessive blood supply. While the kidneys consume (4). Nevertheless, such a reduction is associated with de- between 7% and 10% of total oxygen uptake, they re- monstrable health benefits, particularly in salt-sensitive ceive about 20%–25% of cardiac output at rest. Two persons, such as those with hypertension, patients with thirds or more of renal oxygen uptake are expended diabetes, African Americans, and individuals with for the needs of the Na,K-ATPase, which is for active chronic renal disease (4). Na reabsorption. 676 Copyright © 2015 by the American Society of Nephrology www.cjasn.org Vol 10 April, 2015 Clin J Am Soc Nephrol 10: 676–687, April, 2015 Integrated Control of Sodium Transport, Palmer and Schnermann 677 Figure 1. | Na transport along the nephron. The fraction of Na remaining in the ultrafiltrate is plotted as a function of distance along the nephron under conditions of normal (approximately 100 mmol/d) salt intake. The cartoon indicates the major nephron segments. The symbols below show the key Na transport mechanisms in each segment. CCD, cortical collecting duct; CNT, connecting tubule; DCT, distal convoluted tubule; IMCD, inner medullary collecting duct; OMCD, outer medullar collecting duct; PCT, proximal convoluted tubule; PST, proximal straight tubule; S, solute (various); tAL, thin ascending limb; TAL, thick ascending limb; tDL, thin descending limb. As much as 60%–70% of total Na reabsorption takes place low transepithelial osmotic gradients, and near-isotonic fluid along the proximal convoluted tubule (PCT) and proximal transport. Results from micropuncture studies indicate avid straight tubule, and because reabsorption is near isotonic in reabsorption of Na without measurable changes in Na con- this part of the nephron, this is also true for the reabsorption centration along the PCT. The magnitude of Na reabsorp- of water. While the thin descending limbs of the loop of tion per millimeter of nephron length in the rat is on the Henle absorb water, but not Na, another 25%–30% of the order of 300 pEq/min in PCT from superficial nephrons and filtered Na is reabsorbed by the ascending portion of this even higher in PCTs from juxtamedullary nephrons. Trans- loop, mostly the thick limbs (TALH). Thus, by the time the port rates along the proximal tubule decrease substantially filtered fluid reaches the macula densa cells at the transition with distance from the glomerulus, and this is accompanied to the distal convoluted tubule (DCT), about 90% of the fil- by reductions in the number of mitochondria and the ex- tered Na has been retrieved. In quantitative terms, Na reab- tent of surface membrane amplification both apically and sorption, therefore, is mostly a function of the proximal basolaterally. For example, micropuncture studies have nephron (proximal tubule and loop of Henle) while the shown that fluid and, presumably, Na reabsorption in the DCT and the cortical (CCD) and medullary (MCD) collect- rat fell by 75% over the initial 5 mm of proximal tubule ing ducts contribute no more than 5%–10% of total Na length (5). As discussed in a previous article in this series, reabsorption. Nevertheless, because of the magnitude of all Na absorption in the PCT is driven directly or indirectly therateofultrafiltration, 10% of the total daily filtered by the action of the basolateral Na,K-ATPase (6). Active load is still an amount that is in the order of the rapidly translocation of Na creates driving forces for Na-dependent exchangeable extracellular Na (about 60 g). In fact, it is Na cotransport and ion exchange, as well as diffusive gradients reabsorption along the distal nephron that is highly regu- for paracellular ion movement. Quantitatively, apical Na/H lated, and failure of the distal nephron to reabsorb Na is exchange mediated by NHE3 is the most important reab- generally more deleterious to Na homeostasis than prox- sorptive mechanism. It mediates NaHCO3 uptake, gener- imal nephron malabsorption. ates an electrochemical gradient for paracellular salt absorption, and operates in tandem with Cl/base exchange in the later part of the proximal tubule. Active transport, Rates and Mechanisms of Na Transport along the electrodiffusion, and solvent drag each contribute approx- Nephron imately one third to total Na reabsorption in the proximal Proximal Tubule tubule (7). The renal proximal tubule is a prototypical low-resistance The discovery of claudin2 as a tight junction protein epithelium characterized by low transepithelial voltage, high highly expressed along the PCT has greatly improved the ion permeabilities, constitutively high water permeability, understanding of the paracellular shunt properties in this 678 Clinical Journal of the American Society of Nephrology part of the nephron. Expression studies in Madin-Darby enhances the natriuretic effect of furosemide and the canine kidney cells and the use of claudin2-deficient mice salt-losing phenotype of disease-causing mutations of strongly indicate that claudin2 provides a cation-selective NKCC2. and water-permeable paracellular conductance in the PCT (8–11).