A model of calcium transport along the rat nephron

We developed a mathematical model of calcium (Ca2+) transport along the rat nephron to investigate the factors that promote hypercalciuria. The model is an extension of the flat medullary model of Hervy and Thomas ( Am J Physiol Renal Physiol 284: F65–F81, 2003). It explicitly represents all the nephron segments beyond the proximal tubules and distinguishes between superficial and deep nephrons. It solves dynamic conservation equations to determine NaCl, urea, and Ca2+ concentration profiles in tubules, vasa recta, and the interstitium. Calcium is known to be reabsorbed passively in the thick ascending limbs and actively in the distal convoluted (DCT) and connecting (CNT) tubules. Our model predicts that the passive diffusion of Ca2+ from the vasa recta and loops of Henle generates a significant axial Ca2+ concentration gradient in the medullary interstitium. In the base case, the urinary Ca2+ concentration and fractional excretion are predicted as 2.7 mM and 0.32%, respectively. Urinary Ca2+ excretion is found to be strongly modulated by water and NaCl reabsorption along the nephron. Our simulations also suggest that Ca2+ molar flow and concentration profiles differ significantly between superficial and deep nephrons, such that the latter deliver less Ca2+ to the collecting duct. Finally, our results suggest that the DCT and CNT can act to counteract upstream variations in Ca2+ transport but not always sufficiently to prevent hypercalciuria.

Effect of intrarenal volume expansion on proximal sodium reabsorption

The objective of the present study was to examine the effect of direct expansion of the renal interstitial volume on sodium reabsorption by proximal tubules of superficial and deep nephrons in the absence of systemic extracellular volume expansion. Renal interstitial volume expansion was achieved by injection of 50 microliter of 2.5% albumin in 0.9% saline into the renal interstitium via a polyethylene matrix that was chronically implanted in the interstitium of the rat kidney. Renal interstitial volume expansion increased renal interstitial hydrostatic pressure from 3.8 +/- 0.5 to 6.8 +/- 1.1 mmHg, P less than 0.05 (n = 5 rats). Fractional reabsorption of sodium by the superficial late proximal tubule decreased from 45.7 +/- 5.6 to 34.2 +/- 5.4%, P less than 0.05, and by the proximal tubule and descending limb of Henle's loop of deep nephrons it decreased from 73.9 +/- 2.9 to 57.2 +/- 6.3%, P less than 0.05 (n = 8 rats). Thus expansion of the renal interstitial volume increased renal interstitial hydrostatic pressure and decreased sodium reabsorption by the proximal tubules of superficial and deep nephrons.

Effect of renal perfusion pressure on sodium reabsorption from proximal tubules of superficial and deep nephrons

Previous studies in rats have demonstrated that superficial proximal tubule sodium reabsorption does not change in response to alterations in renal perfusion pressure (RPP). The first objective of the present study was to estimate sodium reabsorption in response to acute changes in RPP utilizing fractional lithium reabsorption (FRLi) as an index of fractional sodium reabsorption (FRNa) by the proximal tubule of the kidney as a whole. FRLi decreased in response to increases in RPP, suggesting that sodium reabsorption by the proximal tubule of some nephron population is decreased. Therefore, the second objective of the present study was to test the hypothesis that superficial and deep proximal tubules respond differently to changes in RPP by comparing proximal tubule sodium reabsorption from both nephron populations. In response to an acute change in RPP from 114 +/- 4 to 138 +/- 5 mmHg, FRNa by the proximal tubule and descending limb of Henle's loop in deep nephrons decreased from 71.3 +/- 2.3 to 55.8 +/- 5.6%, but FRNa by the superficial late proximal tubule was not changed: (44.3 +/- 4.8 to 45.1 +/- 3.9%). The urinary fractional reabsorption of sodium decreased from 96.7 +/- 0.6 to 94.5 +/- 0.5%. In summary, these studies demonstrate that increases in RPP have no effect on sodium reabsorption by the proximal tubule of superficial nephrons. In contrast, sodium delivery to the point of micropuncture in the descending limb of Henle's loop of deep nephrons was increased, suggesting inhibition of sodium reabsorption by proximal tubules of deep nephrons in response to increases in RPP.

Tubular capacity for phosphate reabsorption in superficial and deep nephrons

The present studies were performed to determine the capacity for phosphate reabsorption in superficial and deep nephron proximal tubules in vivo. Micropuncture experiments were performed in 20 acutely thyroparathyroidectomized (TPTX) Munich-Wistar rats fed a normal phosphate diet (0.7%). Four groups were infused with differing amounts of phosphate (0,2,4, or 6 mumol/min) to increase the filtered phosphate load. The sites selected for micropuncture were the superficial early distal tubule and the deep nephron loop of Henle, which reflect fractional phosphate delivery (FDPi%) from superficial and deep nephron proximal tubules, respectively. In response to phosphate infusions, plasma phosphate increased from 3.03 +/- 0.09 to 7.01 +/- 0.58 mM, and fractional phosphate excretion rose from 2 +/- 1 to 58 +/- 5%. FDPi% increased from both superficial (14 +/- 1 to 58 +/- 2%) and deep nephron proximal tubules (4 +/- 1 to 27 +/- 5%) but always remained lower from deep nephrons, reflecting more avid reabsorption by deep nephron proximal tubules. The maximal rate of phosphate reabsorption (max RPi/SNGFR) in the superficial proximal tubule was significantly less than in the deep nephron proximal tubule (3.2 +/- 0.4 vs. 5.1 +/- 0.1 pmol/nl). In seven of the phosphate-infused rats, parathyroid hormone (PTH, 33 U/kg bolus; 1 U X kg-1 X min-1) was added to the infusion following the initial collections. In the presence of PTH, the RPi/SNGFR was significantly lower in deep than in superficial proximal tubules (0.4 +/- 0.5 vs. 1.6 +/- 0.4 pmol/nl). Thus, the maximum capacity for phosphate reabsorption was greater in deep than in superficial nephrons in TPTX rats. Furthermore, in the presence of phosphate infusions, PTH inhibited phosphate reabsorption to a greater extent in deep than in superficial proximal tubules.

Changes in anatomy, glomerular filtration, and solute excretion in aging rat kidney

Changes in kidney function were studied in anesthetized female WAG/Rij rats 6, 18, and 30 mo old. The growth in kidney size measured between 6 and 18 mo and 18 and 30 mo was due to enlargement of the glomeruli and lengthening of the proximal tubules, without significant changes in the number of nephrons. Glomerular filtration per gram kidney was unaffected between 6 and 18 mo but diminished 27% between 18 and 30 mo. This reduction was accompanied by an intrarenal redistribution of individual filtration rates for the superficial and deep nephrons. Fractional excretion of sodium, potassium, calcium, and magnesium declined sharply between 6 and 18 mo but did not change further between 18 and 30 mo, whereas the fractional excretion of amino acids and glucose remained constant between 6 and 18 mo but rose in the 30-mo group. Taken together, these observations indicate that, in the rat, kidney aging cannot be reduced to a loss in the number of functional nephrons but is the result of several differential and specific processes.

Nephron heterogeneity of phosphate reabsorption: effect of parathyroid hormone

We evaluated the response of superficial and deep nephron proximal tubules to PTH in thyroparathyroidectomized (TPTX) rats fed a normal phosphate diet (0.7%). As phosphate reabsorption is not detectable in the ascending limb of the loop of Henle, fractional phosphate delivery (FDPi%) to the superficial early distal tubule and papillary loop of Henle reflects delivery from superficial and deep nephron proximal tubules, respectively. Re-collection micropuncture experiments were performed in nine acutely TPTX rats before and after the infusion of PTH (33 U/kg bolus; 1 U X kg-1 X min-1). In response to PTH, fractional phosphate excretion increased from 3.3 to 26.2% (P less than 0.05). FDPi% was less from the deep than from the superficial proximal tubule (5.7 vs. 15.7%, P less than 0.05) prior to PTH, indicating enhanced phosphate reabsorption by deep compared with superficial proximal tubules. During PTH infusion, FDPi% was increased in both nephron groups compared with control (P less than 0.05), but there were no differences in phosphate delivery between deep (28.0%) and superficial (29.7%) proximal tubules. We conclude that in acutely volume-expanded TPTX rats, infusion of a pharmacologic dose of PTH decreases phosphate reabsorption in both superficial and deep nephrons. Furthermore, the heterogeneity of FDPi% from deep compared with superficial proximal tubules seen in TPTX rats is absent during PTH infusion.

Comparison of acidification parameters in superficial and deep nephrons of the rat

The purpose of this study was to determine and compare pH, PCO2, and fractional bicarbonate delivery in both superficial and juxtamedullary nephrons by microelectrode techniques and microcalorimetry in the rat in vivo in order to define more clearly the role of deeper nephron segments in urinary acidification. Values for pH and total CO2 concentration ([tCO2]) at the bend of Henle's loop (LOH) (7.39 +/- 0.04 units and 20.5 +/- 1.5 mM) were significantly greater and the PCO2 was significantly less (36.6 +/- 1.5 mmHg) than values for these same parameters in the superficial late proximal tubule (LPT) (6.78 +/- 0.03 units, 8.1 +/- 1.2 mM, and 63.2 +/- 1.0 mmHg, P less than 0.001). The fraction of filtered bicarbonate delivered to the LPT and LOH did not differ, however (12.2 +/- 2.5 vs. 9.0 +/- 0.8%). The pH and PCO2 values in the late distal tubule (6.59 +/- 0.04 units and 64.0 +/- 1.3 mmHg) were significantly greater than at the base (6.24 +/- 0.07 units and 34.5 +/- 1.5 mmHg) and tip (6.12 +/- 0.03 units and 35.2 +/- 1.2 mmHg) of the papillary collecting duct. The [tCO2] in the LOH and an adjacent vasa recta was compared and did not differ significantly (20.5 +/- 1.5 vs. 21.2 +/- 1.3 mM, P greater than 0.05). In summary, we have demonstrated significant alkalinization of tubule fluid in the deep LOH as a result of water abstraction and CO2 diffusion from the nephron. Our results suggest that a spontaneous disequilibrium pH may not exist in the LOH. Furthermore, similar values for [tCO2] in vasa recta and the LOH suggest that passive HCO-3 reabsorption in the thin ascending limb of Henle would be unlikely and does not contribute to the "loop" component of bicarbonate reabsorption.

Phosphate transport in superficial and deep nephrons in phosphate-loaded rats

We tested the hypothesis that greater phosphate delivery from deep nephrons than from superficial nephrons contributes to the addition of phosphate to the collecting system during phosphate loading. In the first group of eight anesthetized Munich-Wistar rats infused with phosphate and parathyroid hormone (PTH), fractional delivery of phosphate (FDP%) from superficial distal tubules was 56 +/- 6%, significantly less than the amount appearing in the urine, 67 +/- 6% (P less than 0.01). In the second group of six rats, we determined whether this addition of phosphate could be accounted for by a higher FDP% from the deep nephrons. Free-flow micropuncture collections were taken from deep nephrons (ascending limb of the loop of Henle in the papilla), superficial nephrons (distal tubules in the cortex), and urine (duct of Bellini). The FDP% to the ascending limb of the loop of Henle in deep nephrons was 78 +/- 10%, significantly greater than to the distal convoluted tubules in superficial nephrons, 51 +/- 6% (P less than 0.005), and the fractional excretion of phosphate in urine, 72 +/- 10% (P less than 0.05). Although a difference between FDP% in superficial and deep nephrons due to reabsorption in the ascending limb of the loop of Henle cannot be ruled out from the present data, other studies indicate that this interpretation is unlikely. We conclude that greater phosphate delivery by deep nephrons contributes to the addition of phosphate to the collecting system of phosphate-loaded rats.