Role of intratubular pressure during the ischemic phase in acute kidney injury

Acute kidney injury (AKI) induced by clamping of renal vein or pedicle is more severe than clamping of artery, but the mechanism has not been clarified. In the present study, we tested our hypothesis that increased proximal tubular pressure (Pt) during the ischemic phase exacerbates kidney injury and promotes the development of AKI. We induced AKI by bilateral clamping of renal arteries, pedicles, or veins for 18 min at 37°C, respectively. Pt during the ischemic phase was measured with micropuncture. We found that higher Pt was associated with more severe AKI. To determine the role of Pt during the ischemic phase on the development of AKI, we adjusted the Pt by altering renal artery pressure. We induced AKI by bilateral clamping of renal veins, and the Pt was changed by adjusting the renal artery pressure during the ischemic phase by constriction of aorta and mesenteric artery. When we decreased renal artery pressure from 85 ± 5 to 65 ± 8 mmHg, Pt decreased from 53.3 ± 2.7 to 44.7 ± 2.0 mmHg. Plasma creatinine decreased from 2.48 ± 0.23 to 1.91 ± 0.21 mg/dl at 24 h after renal ischemia. When we raised renal artery pressure to 103 ± 7 mmHg, Pt increased to 67.2 ± 5.1 mmHg. Plasma creatinine elevated to 3.17 ± 0.14 mg·dl·24 h after renal ischemia. Changes in KIM-1, NGAL, and histology were in the similar pattern as plasma creatinine. In summary, we found that higher Pt during the ischemic phase promoted the development of AKI, while lower Pt protected from kidney injury. Pt may be a potential target for treatment of AKI.

The Gomez equations and renal hemodynamic function in kidney disease research

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. A major challenge in preventing DKD is the difficulty in identifying high-risk patients at a preclinical stage. Existing methods that are used to assess renal function, including albuminuria and eGFR, do not give detailed insight into the location of the renal hemodynamic effects of pharmacological agents at the segmental level. To gain additional information about the intrarenal circulation in vivo in humans, equations were developed by Gomez et al. in the 1950s. These equations used measurements of glomerular filtration rate, renal blood flow, effective renal plasma flow, renal vascular resistance, hematocrit, and serum protein to calculate afferent and efferent arteriolar resistances, glomerular hydrostatic pressure, and filtration pressure. The Gomez equations are, however, indirect and based on physiological assumptions derived from animal models, which may not hold true in human pathophysiology, including the assumption of a normal gross filtration coefficient and not considering changes in intratubular pressure that may affect the pressure gradient across the glomerular capillaries. Nevertheless, the equations have the potential to improve researchers' ability to identify early preclinical changes in renal hemodynamic function in patients with a variety of conditions, including DKD, thereby offering potential in mechanistic human research studies. In this review, we focus on the application of Gomez' equations and summarize the potential and limitations of these techniques in DKD research. We also summarize illustrative data derived from Gomez' equations in patients with type 1 and type 2 diabetes and hypertension.

Abstract 298: Protective Role of Endogenous 20-HETE in Renal Ischemia-Reperfusion Injury

The present study compared renal ischemia-reperfusion (IR) injury in Dahl salt-sensitive (SS) rats that have a deficiency in the renal formation of 20-HETE versus CYP4A1 transgenic SS (SS.4A1) rats in which the renal production of 20-HETE is restored. The concentrations of free 20-HETE in the renal cortex and outer medulla were significantly greater in SS.4A1 than in SS rats. Renal 20-HETE levels rose to a greater extent in SS.4A1 than in SS rats following renal IR. Plasma creatinine level rose to 3.7 ± 0.1 in SS versus 1.8 ± 0.3 mg/dl in SS.4A1 rats (respectively, n=6) following 30 min of ischemia and 24 h reperfusion. The % of necrotic tubules and apoptotic cells were 4-fold higher in SS than in SS.4A1 rats. Administration of the 20-HETE synthesis inhibitor (HET0016, 10 mg/kg) abolished the resistance of SS.4A1 rats to renal IR injury and plasma creatinine level rose to 3.8 ± 0.1 mg/dl (n=6). Cortical blood flow in SS, SS.4A1 and HET0016 treated SS.4A1 rats immediately returned to control following IR. However, medullary blood flow in SS and HET0016 treated SS.4A1 rats fell to 30 % of control 3 h after IR (n=5), and it remained depressed for 24 h. In contrast, medullary blood flow did not decline following IR in SS.4A1 rats. Proximal intratubular pressure rose from 13 to approximately 40 mmHg, 2 h after IR in both SS and SS.4A1 rats. Proximal intratubular pressure remained much higher in SS than in SS.4A1 rats 24 h after IR (32 vs 19 mmHg). These data indicate that normalization of renal CYP4A activity and 20-HETE production opposes renal IR injury by preventing secondary fall in medullary blood flow and the prolonged renal medullary ischemia.

Effect of sustained flow perturbations on stability and compensation of tubuloglomerular feedback

A mathematical model previously formulated by us predicts that limit-cycle oscillations (LCO) in nephron flow are mediated by tubuloglomerular feedback (TGF) and that the LCO arise from a bifurcation that depends heavily on the feedback gain magnitude, γ, and on its relationship to a theoretically determined critical value of gain, γc. In this study, we used that model to show how sustained perturbations in proximal tubule flow, a common experimental maneuver, can initiate or terminate LCO by changing the values of γ and γc, thus changing the sign of γ - γc. This result may help explain experiments in which intratubular pressure oscillations were initiated by the sustained introduction or removal of fluid from the proximal tubule (Leyssac PP and Baumbach L. Acta Physiol Scand 117: 415–419, 1983). In addition, our model predicts that, for a range of TGF sensitivities, sustained perturbations that initiate or terminate LCO can yield substantial and abrupt changes in both distal NaCl delivery and NaCl delivery compensation, changes that may play an important role in the response to physiological challenge.

Tubuloglomerular feedback in Dahl rats

We have previously demonstrated a loss of autoregulation in Dahl salt-sensitive (Dahl-S) rats rendered hypertensive on a high-salt diet. To determine whether this was due to a decreased activity of either the myogenic or the tubuloglomerular feedback (TGF) response, we tested the TGF response in both Dahl-S and salt-resistant Dahl rats on high- and low-salt diets. TGF was investigated in the closed-loop mode with a videometric technique, in which the response in late proximal flow rate to perturbations in Henle flow rate was measured. All Dahl rats showed a similar compensatory response to perturbations around the natural operating point, with a TGF response that was more efficient than in normotensive Sprague-Dawley rats. No evidence of decreased TGF responsiveness in hypertensive Dahl-S rats was found. The results suggest that the loss of autoregulation in hypertensive Dahl-S rats is due to a compromised myogenic response. We also measured the free-flow proximal intratubular pressure in Dahl rats. Perfectly regular oscillations were demonstrated in all Dahl series, including the hypertensive Dahl-S rats. This is the first demonstration of regular oscillations in an experimental rat model of hypertension.

Effect of Intravenous Contrast Media on Proximal and Distal Tubular Hydrostatic Pressure in the Rat Kidney

The effect of i.v. injection of contrast media (CM, 1 600 mg I/kg b.w.) on proximal and distal tubular hydrostatic pressure (PTHP, DTHP) in the rat was investigated using a micropuncture technique. The PTHP and DTHP after injection of diatrizoate, iohexol, ioxaglate, or mannitol returned to control values within approximately 20 min. However, following iotrolan injection PTHP was still elevated above control levels after 35 min while DTHP remained elevated throughout the experiment (50 min). Iotrolan has a lower osmotic potential than the other CM when given in equivalent iodine doses. The concentration of iotrolan may thus increase more along the tubules than the other CM and consequently lead to a higher viscosity of urine, resulting in increases in PTHP and DTHP. The high intratubular pressure induced by iotrolan may explain our previous findings of reduced single nephron glomerular filtration rate caused by this CM.

Intrarenal pressures during direct inhibition of sodium transport

Renal interstitial hydrostatic pressure (RIHP) has been implicated in the regulation of sodium excretion. Studies using vasodilators and other maneuvers to increase RIHP have found a significant correlation between RIHP and sodium excretion. Since correlative studies do not prove a cause-and-effect relationship, it is not known whether the rise in sodium excretion in these studies is the result of increases in RIHP or if RIHP is elevated as a result of decreases in sodium and water reabsorption and increases in intratubular pressure. Therefore, the purpose of the present study was to determine whether elevation of intratubular hydrostatic pressures in response to direct inhibition of tubule transport with loop diuretics results in increases in RIHP in dogs and rats. Intrarenal hydrostatic pressures, renal hemodynamics, and sodium and water excretion were examined in dogs during intravenous administration of furosemide (3 mg/kg bolus followed by 0.03 mg.kg-1 x min-1) or bumetanide (60 micrograms/kg bolus followed by 1 microgram.kg-1 x min-1). Furosemide administration increased urinary flow rate (V; 0.10 +/- 0.02 to 4.6 +/- 0.97 ml/min), urinary sodium excretion (UNaV; 16 +/- 5 to 549 +/- 123 mu eq/min), and proximal tubule hydrostatic pressure (PT; 21 +/- 1 to 28 +/- 1 mmHg) but had no effect on RIHP (7.2 +/- 0.6 to 7.4 +/- 0.7 mmHg) or peritubular capillary hydrostatic pressure (14 +/- 1 to 14 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Oscillations in the proximal intratubular pressure: a mathematical model

This study presents a dynamic continuous time model of the regulation of the renal proximal intratubular pressure in the rat. The model integrates a functional model of the glomerulus, a tubular model, a feedback model, and an afferent arteriolar model. The model has one equilibrium solution for the dependent variables (equilibrium point) for each set of independent variables. An equilibrium point, chosen to be in accordance with experimental data from Sprague-Dawley rats, was used as the initial value for the dependent variables. The model is shown to have parameter ranges in which sustained stable oscillations in proximal pressure are present. For sustained oscillations to appear, it is necessary for the system's operating point to be located on a sufficiently steep portion of the tubuloglomerular feedback curve. The model analyses are compared with various experimental recordings of the proximal intratubular pressure. The model simulations show both spontaneous and induced oscillations in the proximal pressure in close agreement with the experimental results; but the steady-state mean pressure regulation is found to be less efficient in the model than that apparent from the experimental recordings, suggesting the involvement of additional pressure-regulating mechanisms other than those included in the present model. It is concluded that the dynamic systems approach used in the present study yields new insight into the mechanisms underlying the proximal intratubular pressure oscillations and that it can be of further value for the study of the factors regulating the proximal intratubular pressure.