The circulating renin-angiotensin-aldosterone system is down-regulated in dogs with glomerular diseases compared to other chronic kidney diseases with low-grade proteinuria

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin—low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

Terlipressin Attenuates Hemorrhagic Shock-Induced Acute Kidney Injury in Rats

Hemorrhagic shock (HS), a major cause of trauma-related mortality, is mainly treated by crystalloid fluid administration, typically with lactated Ringer’s (LR). Despite beneficial hemodynamic effects, such as the restoration of mean arterial pressure (MAP), LR administration has major side effects, including organ damage due to edema. One strategy to avoid such effects is pre-hospitalization intravenous administration of the potent vasoconstrictor terlipressin, which can restore hemodynamic stability/homeostasis and has anti-inflammatory effects. Wistar rats were subjected to HS for 60 min, at a target MAP of 30–40 mmHg, thereafter being allocated to receive LR infusion at 3 times the volume of the blood withdrawn; at 2 times the volume, plus terlipressin (10 µg/100 g body weight); and at an equal volume, plus terlipressin (10 µg/100 g body weight). A control group comprised rats not subjected to HS and receiving no fluid resuscitation or treatment. At 15 min after fluid resuscitation/treatment, the blood previously withdrawn was reinfused. At 24 h after HS, MAP was higher among the terlipressin-treated animals. Terlipressin also improved post-HS survival and provided significant improvements in glomerular/tubular function (creatinine clearance), neutrophil gelatinase-associated lipocalin expression, fractional excretion of sodium, aquaporin 2 expression, tubular injury, macrophage infiltration, IL-6 levels, IL-18 levels, and NF-κB expression. In terlipressin-treated animals, there was also significantly higher ANG II type 1 receptor expression and normalization of AVP 1a receptor expression. Terlipressin could be a viable therapy for HS-induced acute kidney injury, likely attenuating such injury by modulating the inflammatory response via the AVP 1a receptor.

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatics regulate inflammation through clearance of immune cells and excess interstitial fluid. Previously, we demonstrated increasing renal lymphangiogenesis prevents hypertension in mice. We hypothesized that targeted nanoparticle delivery of vascular endothelial growth factor-C (VEGF-C) to the kidney would induce renal lymphangiogenesis, lowering blood pressure in hypertensive mice. A kidney-targeting nanoparticle was loaded with a VEGF receptor-3-specific form of VEGF-C and injected into mice with angiotensin II-induced hypertension or LNAME-induced hypertension every 3 days. Nanoparticle-treated mice exhibited increased renal lymphatic vessel density and width compared to hypertensive mice injected with VEGF-C alone. Nanoparticle-treated mice exhibited decreased systolic blood pressure, decreased pro-inflammatory renal immune cells, and increased urinary fractional excretion of sodium. Our findings demonstrate that pharmacologically expanding renal lymphatics decreases blood pressure and is associated with favorable alterations in renal immune cells and increased sodium excretion.

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

Background The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80–85 mmHg) and a low-target period (65–70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. Results 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (− 10 (95% CI − 17, − 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine–plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. Conclusions In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

Abstract P213: Furosemide-mediated Suppression Of P 38 MAPK Signaling Abrogates Cholinergic-mediated Salt Sensitive Hypertension In Young Spontaneously Hypertensive Rats

Hypertension is a major cause of premature death worldwide. Inflammatory macrophages play a key role in the pathogenesis of hypertension. Our lab has observed that nicotinic acetylcholine receptors (nAChR) activation potentiates salt-sensitive hypertension in Spontaneously Hypertensive Rats (SHR). Cholinergic receptor activation causes infiltration of CD68 + macrophages into the renal cortex/medulla junction and results in enhanced expression of renal sodium-potassium chloride cotransporter (NKCC2). To determine whether or not NKCC2 plays a role in the activation of inflammatory pathway furosemide, a selective pharmacologic blocker of NKCC2, was used to block NKCC2 expression in SHR in current study. Young pre-hypertensive SHR, receiving nicotine infusion (15mg/kg/day), were fed HSD (4% NaCl) and treated with either saline or furosemide (20mg/kg/day) intraperitoneal injections. There was a 16% increase (158.5±7.3 mmHg to 183.6±7.0 mmHg) in the systolic blood pressure in SHR that received saline injections, compared to no increase in SHR that received furosemide (155±6.0 mmHg to 148±3.6 mmHg) (p<0.0016). There was over a two-fold increase in fractional excretion of sodium (FENa, p=0.03) in the furosemide group, compared to saline controls. Although furosemide injections did not alter renal NKCC2 expression, there was nearly 50% reduction in phosphorylated p38 MAPK (p=0.0002) and a 25% decrease in renal infiltration of inflammatory CD68 + macrophages in SHR receiving furosemide injections, compared to saline controls. Interestingly, there was also a significant reduction in urinary albumin in response to furosemide injections (14.7±5.7 control vs 3.3±0.9 furosemide, p=0.027). Based on these findings, we conclude that furosemide results in cessation of the development of hypertension via interruption of a p38-MAPK dependent inflammatory pathway.

Abstract P203: Time-restricted Feeding Attenuates Hypertension In Mice

Hypertension is associated with inflammation and decreased kidney function. Studies of cardiovascular function have observed that time-restricted feeding (TRF), a form of intermittent fasting, is associated with decreased blood pressure, decreased inflammation, and improved kidney function. We hypothesized that implementation of a time-restricted feeding protocol in hypertensive mice would decrease systolic blood pressure and increase kidney function. C57BL6/J mice were randomly assigned to either an L-arginine methyl ester hydrochloride (LNAME)-induced hypertension (LHTN) model, where they received LNAME in their drinking water, or a salt-sensitive hypertension (SSHTN) model, where they received a 4% high salt diet following LNAME priming and a washout period. Two days following introduction of LNAME or the high salt diet, mice were either provided food ad libitum or placed on a 12-hour TRF protocol, where they were only allowed to eat from 8PM to 8AM. Hypertensive mice receiving TRF treatment displayed a significantly decreased systolic blood pressure (SBP) after 4 weeks when compared to the control hypertensive groups (LHTN SBP: 164±1 vs. 149±2 mmHg, p<0.001; SSHTN SBP: 139±1 vs. 130±1 mmHg, p<0.001). When kidney function was examined in the LHTN group, TRF mice had decreased serum creatinine (Sc) levels along with decreased fractional excretion of sodium (FENa) when compared to their respective control mice (Sc: 0.19±0.01 vs. 0.13±0.01 mg/dL, p=0.007; FENa: 0.59±0.05 vs. 0.32±0.05 %, p=0.009). Glomerular filtration rate was significantly increased in TRF treated LHTN mice. Overall, these data indicate that TRF treatment reduces blood pressure in hypertensive mice, which is associated with an improvement in renal function. These findings could establish TRF as a potential therapeutic option for hypertensive patients.

Renal Negative Pressure Treatment as a Novel Therapy for Heart Failure Induced Renal Dysfunction

Congestion is the primary pathophysiologic lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80 kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow® catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of L vs. R kidney to -30mmHg rNPT or no rNPT mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20-22.5mmHg throughout the experiment. Prior to HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney (p<0.001 for all). Natriuresis, diuresis, and mGFR, decreased following HF (p<0.001 for all) but were higher in rNPT kidney vs. control (p<0.001 for all). RPF decreased during HF (p<0.001) without significant differences between rNPT treatments. During HF the rNPT kidney had similar diuresis and natriuresis (p>0.5 for both), and higher fractional excretion of sodium (p=0.001) compared with the non-rNPT kidney in the no-HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardio-renal phenotype.

Diuretic Resistance Treated with Low-Dose Hydralazine: A Case Report and Review of the Literature

We present a case of severe diuretic resistance and edema from acute cardiorenal syndrome complicating heart failure with preserved ejection fraction (HFpEF) and mild alcoholic liver disease. High doses of intravenous (iv) furosemide plus iv doses of chlorothiazide failed to increase the daily urine output (UV) above 1,500 mL or the fractional excretion of sodium (FE_Na) above 2%. The addition of a relatively low dose of hydralazine (10 mg thrice daily PO) during 5 days of constant iv infusion of furosemide plus iv bolus chlorothiazide doubled the UV and FE_Na while reducing the serum creatinine concentration from 3.3 to 2.0 mg/dL. Hydralazine may have restored a response to the diuretics by increasing the renal blood flow and thereby the renal diuretic delivery, or by reducing the filtration fraction or reducing the renal congestion and thereby reducing the proximal reabsorption during blockade of distal reabsorption with diuretics. Further mechanistic studies of low-dose hydralazine for diuretic resistance are warranted.