ANESTHETIC MANAGEMENT OF A CASE OF TAKAYASU'S ARTERITIS POSTED FOR AUTORENAL TRANSPLANTATION

Takayasu's arteritis is a rare, chronic progressive pan endarteritis involving the aorta and its main branches.It is one of the most important causes of renovascular hypertension.The best treatment is autorenal transplantation.Though it is a safe procedure to perform, a stable perioperative haemodynamics with adequate renal perfusion pressure is required for a successful outcome.

Abstract MP02: Acute Increases Of Renal Perfusion Pressure Activate Mechanistic Target Of Rapamycin Complex 1 And Increase Macrophage Infiltration In The Kidney Of Sprague Dawley Rats.

Studies were carried out to determine whether acute elevation of renal perfusion pressure (RPP) activates the mechanistic target of rapamycin complex 1 (mTORC1) and inflammation-related genes which may trigger a rapid infiltration of immune cells. RPP was elevated by 40 mmHg (HP group) for 30 minutes in male SD rats (n=5, 10-12 weeks of age) while measuring renal blood flow (RBF; Transonic ultrasonic probe) and urine flow rate. Sham rats (Sham group) were studied in the same way, but RPP was not changed. Since initial studies found that the acute increase of RPP resulted in activation of mTORC1 (pS6 S235/6 /S6; P<0.05) but not mTORC2 (pAKT T308 /AKT ), the effects of inhibition of mTORC1 with rapamycin (Rapa) pretreatment (1.5 mg/kg; n=10) were then determined (HP+Rapa group). RBF was well autoregulated in both HP and HP+Rapa treated rats averaging 6.9 ± 0.5 vs 7.0 ± 0.8 ml/min/gkw in HP (p=0.72) and 8.1 ± 0.8 vs 8.4 ± 0.5 in HP+Rapa group (p=0.34) with a 40 mmHg elevation of RPP. Pressure-natriuresis was unexpectedly blunted in HP+Rapa treated rats increasing from 0.40 ± 0.21 to 4.0 ± 1.1 in HP rats compared to 0.21 ± 0.07 to 2.3 ± 0.5 μmol/min/gkw; p<0.05) in the HP+Rapa treated rats. Urine volumes were similarly affected. Elevation of RPP increased the mTORC1 activity (pS6 S235/6 /S6) in renal cortex (2.8 ± 0.4 vs 4.8 ± 0.5 A.U.; p<0.05, n=5) and outer medulla (2.0 ± 0.3 vs 5.0 ± 0.6 A.U.; p<0.05, n=5) of HP rats compared to Sham. Rapa treatment suppressed this activation. rtPCR analysis found increased mRNA expression of lipocalin-2 (Lcn2; involved innate immune responses; p<0.05), heme oxygenase (Hmox1; p<0.05) and cyclooxygenase 2 (Cox2; p=0.08) in HP rats compared to Sham, responses which were generally blunted by Rapa. Importantly, as determined by immunohistochemistry, CD68 positive macrophage staining was significantly increased (p<0.001) with elevation of RPP in HP compared to sham rat kidneys. This was significantly reduced by Rapa treatment (p<0.001). We conclude that the mTORC1 pathway can be activated very quickly following elevations of RPP and appears to be responsible for rapid macrophage infiltration which is prevented by Rapa treatment. So too, inhibition of mTORC1 with Rapa reduced the pressure-diuresis response through yet unknown mechanisms.

Renal Perfusion Pressure Determines Infiltration of Leukocytes in the Kidney of Rats With Angiotensin II–Induced Hypertension

The present study examined the extent to which leukocyte infiltration into the kidneys in Ang II (angiotensin II)-induced hypertension is determined by elevation of renal perfusion pressure (RPP). Male Sprague-Dawley rats were instrumented with carotid and femoral arterial catheters for continuous monitoring of blood pressure and a femoral venous catheter for infusion. An inflatable aortic occluder cuff placed between the renal arteries with computer-driven servo-controller maintained RPP to the left kidney at control levels during 7 days of intravenous Ang II (50 ng/kg per minute) or vehicle (saline) infusion. Rats were fed a 0.4% NaCl diet throughout the study. Ang II–infused rats exhibited nearly a 50 mm Hg increase of RPP (carotid catheter) to the right kidney while RPP to the left kidney (femoral catheter) was controlled at baseline pressure throughout the study. As determined at the end of the studies by flow cytometry, right kidneys exhibited significantly greater numbers of T cells, B cells, and monocytes/macrophages compared with the servo-controlled left kidneys and compared with vehicle treated rats. No difference was found between Ang II servo-controlled left kidneys and vehicle treated kidneys. Immunostaining found that the density of glomeruli, cortical, and outer medullary capillaries were significantly reduced in the right kidney of Ang II–infused rats compared with servo-controlled left kidney. We conclude that in this model of hypertension the elevation of RPP, not Ang II nor dietary salt, leads to leukocyte infiltration in the kidney and to capillary rarefaction.

Abstract P025: Hyperinsulinemia Causes Renal Hyperperfusion And Increases Glomerular Basement Membrane Thickness Independent Of Renal Perfusion Pressure And Glycemic Status: Potential Role Of Connecting Tubule Glomerular Feedback?

Obesity is often associated with hyperinsulinemia (HI) and renal damage. However, the role of HI in Obesity related Renal Damage (ORD) is unclear. Renal hyperperfusion/hyperfiltration plays a major role in ORD. Normally, the kidneys autoregulate blood flow by two feedback mechanisms: 1.) Tubuloglomerular feedback (TGF), a vasoconstrictor mechanism and 2.) Connecting Tubule Glomerular Feedback (CTGF), a vasodilator mechanism. Previously, we found that Zucker obese rats had higher CTGF (TGF was unchanged) and were hyperinsulinemic before the development of ORD. Epithelial sodium channel (ENaC) initiates CTGF and Insulin is a known ENaC activator. Hypothesis: HI increases renal cortical blood flow (CBF) by increasing CTGF and causes renal damage. To isolate the effect of HI from the blood glucose (BG) level, HI-euglycemic clamp was created in normal anesthetized Sprague Dawley (SD) rats by simultaneous intravenous (IV) infusion of 10% glucose and insulin. Average baseline BG in non-fasted anesthetized SD rats was 199.0±31.6 mmol/L. Insulin infusion increased CBF significantly by 12.2 ± 1.3% (n=3, p<0.05) from the baseline even before the BG level starts decreasing. Insulin was further infused to attain normoglycemic condition (96.0±2.3 mmol/L) and this was associated with additional increase in CBF by 19.2 ± 4.5% (p<0.05) from the baseline. Subsequent ENaC inhibition by benzamil (BZ) (400 μg/kg, IV) completely reversed the insulin-induced increase in CBF. Neither Insulin nor BZ treatment altered the renal perfusion pressure (RPP) suggesting insulin-induced increase in CBF was independent of RPP. In a separate group of SD rats, renal-HI (1.8 IU/kg/day) was created in only one of the two kidneys for 6 weeks using renal subcapsular catheter to measure glomerular basement membrane (GBM) thickness (a marker of renal damage). GBM was significantly thickened in insulin-infused kidney compared to vehicle-infused kidney (199.4±17 vs. 145.5±3.6nm, n=3, p<0.05). Conclusion: Acute HI increased CBF, that was completely reversed by ENaC inhibition implying a possible role of enhanced CTGF. Chronic renal-HI caused GBM thickening. Perspective: HI observed in obesity or type-2 diabetes may cause renal hyperperfusion by increasing CTGF and contribute to the ORD.

Purinergic P2X1 receptor, purinergic P2X7 receptor, and angiotensin II type 1 receptor interactions in the regulation of renal afferent arterioles in angiotensin II-dependent hypertension

In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (AT1Rs), elevating blood pressure and increasing renal afferent arteriolar resistance (AAR). The increased arterial pressure augments interstitial ATP concentrations activating purinergic P2X receptors (P2XRs) also increasing AAR. Interestingly, P2X1R and P2X7R inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of AT1R influence. To evaluate the interactions between P2XRs and AT1Rs in mediating the increased AAR elicited by chronic ANG II infusions, experiments using the isolated blood perfused juxtamedullary nephron preparation allowed visualization of afferent arteriolar diameters (AAD). Normotensive and ANG II-infused hypertensive rats showed AAD responses to increases in renal perfusion pressure from 100 to 140 mmHg by decreasing AAD by 26 ± 10% and 19 ± 4%. Superfusion with the inhibitor P2X1Ri (NF4490; 1 μM) increased AAD. In normotensive kidneys, superfusion with ANG II (1 nM) decreased AAD by 16 ± 4% and decreased further by 19 ± 5% with an increase in renal perfusion pressure. Treatment with P2X1Ri increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor AT1Ri (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2X1Ri increased AAD by 21 ± 14%; combination with P2X1Ri plus P2X7Ri (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2X1R, P2X7R, and AT1R actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of AT1Rs on AAR in ANG II-dependent hypertension.

Influence of connexin45 on renal autoregulation

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Analysis of the critical determinants of renal medullary oxygenation

We have previously developed a three-dimensional computational model of oxygen transport in the renal medulla. In the present study, we used this model to quantify the sensitivity of renal medullary oxygenation to four of its major known determinants: medullary blood flow (MBF), medullary oxygen consumption rate (V̇o2,M), hemoglobin (Hb) concentration in the blood, and renal perfusion pressure. We also examined medullary oxygenation under special conditions of hydropenia, extracellular fluid volume expansion by infusion of isotonic saline, and hemodilution during cardiopulmonary bypass. Under baseline (normal) conditions, the average medullary tissue Po2 predicted for the whole renal medulla was ~30 mmHg. The periphery of the interbundle region in the outer medulla was identified as the most hypoxic region in the renal medulla, which demonstrates that the model prediction is qualitatively accurate. Medullary oxygenation was most sensitive to changes in renal perfusion pressure followed by Hb, MBF, and V̇o2,M, in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po2 when multiple parameters changed simultaneously. Hydropenia did not induce a significant change in medullary oxygenation compared with the baseline state, while volume expansion resulted in a large increase in inner medulla tissue Po2 (by ~15 mmHg). Under conditions of cardiopulmonary bypass, the renal medulla became severely hypoxic, due to hemodilution, with one-third of the outer stripe of outer medulla tissue having a Po2 of <5 mmHg.