Impaired Renal Autoregulation Research Articles

Abstract 03: Glomerular Hyperfiltration Promotes Chronic Kidney Disease through Interleukin 17A-Mediated Inflammation

Impaired renal autoregulation in obesity, diabetes and hypertension (HTN) causes elevated glomerular capillary pressure and glomerular hyperfiltration, initiating progressive glomerulosclerosis (GS), nephron loss and chronic kidney disease (CKD). Increased renal perfusion pressure drives renal T cell infiltration. T helper (Th) 17 cells promote vascular stiffening in HTN and renal interstitial fibrosis post AKI, but their roles in GS and CKD are poorly understood. We hypothesized that glomerular hyperfiltration promotes CKD through Th17-mediated GS and tested the hypothesis in 129S6 mice using the reduced kidney mass model (RKM) induced by uninephrectomy and partial renal artery ligation in the remaining kidney (functional renal mass reduced by ~ 5/6). BP (radiotelemetry) and GFR (FITC-sinistrin) of RKM mice were identical to sham controls at baseline (BL, n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. Mean BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p<0.05, 2-way ANOVA) and remained elevated through week 12, exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, BUN and urinary albumin were significantly elevated after 5/6 ablation. In RKM mice, GFR gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic HTN and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Importantly, the early adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by a striking increase of renal interleukin (IL)-17A+ T cells, which preceded the late infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages, and T regulatory cells. Anti-IL17A antibodies (eBioMM17F3, 100 μg i.p. twice weekly) attenuated the early hyperfiltration, abolished aortic/renal inflammation, and prevented GFR decline and GS at week 8 in male but not female RKM mice, likely due to the anti-hypertensive and anti-inflammatory effects of IL-17A neutralization. We conclude that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis in CKD, at least in part, through IL-17A mediated renal inflammation.

Glomerular Hyperfiltration and Th17 Responses Promote Glomerulosclerosis Following Nephron Loss

Objective: Chronic kidney disease (CKD) affects 37 million Americans resulting in $87 billion healthcare cost annually. Impaired renal autoregulation in obesity, diabetes and hypertension causes elevated glomerular capillary pressure and whole-kidney hyperfiltration, leading to progressive glomerulosclerosis and CKD. In advanced CKD with less than 50% functional nephron mass, single-nephron hyperfiltration causes further nephron loss, ultimately leading to hypofiltration and end-state kidney disease. Increased renal perfusion pressure directly drives T cell infiltration to the kidney. We and others have shown that T helper (Th) 17 cells promote vascular stiffening in hypertension and renal interstitial fibrosis after ischemia-reperfusion injury, but their roles in glomerulosclerosis and CKD are poorly understood. We hypothesized that glomerular hypertension and hyperfiltration promote renal fibrosis through Th17-mediated immune responses. Methods: We investigated the causal roles of glomerular hyperfiltration and Th17 responses in a mouse CKD model induced by reduced kidney mass (RKM), which involved right kidney nephrectomy and partial renal artery ligation in the left kidney such that the functional renal mass is reduced by ~ 5/6. Male 129/S6 mice received sham or RKM surgery at 8 weeks of age, and blood pressure (BP, by radiotelemetry), glomerular filtration rate (GFR, by transcutaneous FITC-sinistrin) and serum/urine CKD markers were assessed at baseline (BL) and week 1, 2, 3, 4, 8, and 12 post-surgery. Results: BP and GFR of RKM mice were identical to sham controls at BL (n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p<0.05, 2-way ANOVA), exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, blood urea nitrogen and urinary albumin were significantly elevated by week 2. BP and CKD markers remained elevated through week 12 in the 5/6 ablation mice. The GFR of ablated mice gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic hypertension and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney mass. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8-12 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Supporting a causal role of hemodynamic derangements in CKD progression, calcium channel blocker amlodipine, a potent vasodilator, dose dependently (5-10 mg/kg/day, n=7-9) exacerbated glomerular hyperfiltration, glomerulosclerosis and mortality despite marked BP-lowering effects. Importantly, the adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by significant increase of renal Th17 cells, which not only preceded the infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages and T regulatory cells, but also the glomerulosclerosis and GFR decline in week 8. Conclusions: Our data suggest that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis, at least in part, through Th17-mediated renal inflammation. To further establish causality, ongoing studies will assess if Th17 blockade ameliorates glomerulosclerosis and retard CKD progression. Funding: This work was supported by NIDDK R01 DK094907, R01 DK113632, R01 DK128677 to THL, and K01 DK126972 to JW. JW is also supported by an American Heart Association Second Century Early Faculty Independence Award (23SCEFIA1148464), a University of Rochester Environmental Health Science Center pilot award (Prime sponsor: NIEHS P30ES001247), and a University of Rochester Program for Advanced Immune Bioimaging Pilot Award (Prime Sponsor: NIAID P01AI102851). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hepatorenal Syndrome-Novel Insights into Diagnostics and Treatment.

Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.

Impaired renal autoregulation and pressure-natriuresis: any role in the development of heart failure in normotensive and angiotensin II-dependent hypertensive rats?

The aim of the present study was to assess the autoregulatory capacity of renal blood flow (RBF) and of the pressure-natriuresis characteristics in the early phase of heart failure (HF) in rats, normotensive and with angiotensin II (ANG II)-dependent hypertension. Ren-2 transgenic rats (TGR) were employed as a model of ANG II-dependent hypertension. HF was induced by creating the aorto-caval fistula (ACF). One week after ACF creation or sham-operation, the animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. In ACF TGR the basal mean arterial pressure, RBF, urine flow (UF), and absolute sodium excretion (UNaV) were all significantly lower tha n in sham-operated TGR. In the latter, reductions in renal arterial pressure (RAP) significantly decreased RBF whereas in ACF TGR they did not change. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Our data show that compared with sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and improved slope of the pressure-natriuresis relationship. Thus, even though in the very early HF stage renal dysfunction was demonstrable, in the HF model of ANG II-dependent hypertensive rat such dysfunction and the subsequent HF decompensation cannot be simply ascribed to impaired renal autoregulation and pressure-natriuresis relationship.

Renal Transplantation in Pure Autonomic Failure.

Renal Transplantation in Pure Autonomic Failure.

Purinoceptors, renal microvascular function and hypertension.

Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).

Potential Effects of Empagliflozin in L-NAME- Induced Hypertensive Nephropathy in Albino Rats

Introduction Hypertensive Nephropathy (HN) is a state of renal damage due to chronic high blood pressure (BP). It is a widely spread disease of increasing incidence [1]. Hypertension-induced renal injury is attributed to impaired renal autoregulation or due to a complex interaction between ren

Aging Impairs Renal Autoregulation in Mice.

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

BP Fluctuations and the Real-Time Dynamics of Renal Blood Flow Responses in Conscious Rats.

Renal autoregulation maintains stable renal function despite BP fluctuations and protects glomerular capillaries from hypertensive injury. However, real-time dynamics of renal autoregulation in conscious animals have not been characterized. To develop novel analytic methods for assessing renal autoregulation, we recorded concurrent BP and renal blood flow in conscious rats, comparing animals with renal autoregulation that was intact versus impaired (from 3/4 nephrectomy), before and after additional impairment (from the calcium channel blocker amlodipine). We calculated autoregulatory indices for adjacent short segments of increasing length (0.5, 1, 2.5, 5, 10, and 20 seconds) that exhibited a mean BP difference of at least 5 mm Hg. Autoregulatory restoration of renal blood flow to baseline after BP changes in conscious rats occurs rapidly, in 5-10 seconds. The response is significantly slower in states of impaired renal autoregulation, enhancing glomerular pressure exposure. However, in rats with severe renal autoregulation impairment (3/4 nephrectomy plus amlodipine), renal blood flow in conscious animals (but not anesthetized animals) was still restored to baseline, but took longer (15-20 seconds). Consequently, the ability to maintain overall renal blood flow stability is not compromised in conscious rats with impaired renal autoregulation. These novel findings show the feasibility of renal autoregulation assessment in conscious animals with spontaneous BP fluctuations and indicate that transient increases in glomerular pressure may play a greater role in the pathogenesis of hypertensive glomerulosclerosis than previously thought. These data also show that unidentified mechanosensitive mechanisms independent of known renal autoregulation mechanisms and voltage-gated calcium channels can maintain overall renal blood flow and GFR stability despite severely impaired renal autoregulation.

β-Blockade attenuates renal blood flow in experimental endotoxic shock by reducing perfusion pressure.

Clinical data suggests that heart rate (HR) control with selective β1‐blockers may improve cardiac function during septic shock. However, it seems counterintuitive to start β‐blocker infusion in a shock state when organ blood flow is already low or insufficient. Therefore, we studied the effects of HR control with esmolol, an ultrashort‐ acting β1‐selective adrenoceptor antagonist, on renal blood flow (RBF) and renal autoregulation during early septic shock. In 10 healthy sheep, sepsis was induced by continuous i.v. administration of lipopolysaccharide, while maintained under anesthesia and mechanically ventilated. After successful resuscitation of the septic shock with fluids and vasoactive drugs, esmolol was infused to reduce HR with 30% and was stopped 30‐min after reaching this target. Arterial and venous pressures, and RBF were recorded continuously. Renal autoregulation was evaluated by the response in RBF to renal perfusion pressure (RPP) in both the time domain and frequency domain. During septic shock, β‐blockade with esmolol significantly increased the pressure dependency of RBF to RPP. Stopping esmolol showed the reversibility of the impaired renal autoregulation. Showing that clinical diligence and caution are necessary when treating septic shock with esmolol in the acute phase since esmolol reduced RPP to critical values thereby significantly reducing RBF.

P4565Effect of distal renal denervation on kidney function in patients with resistant hypertension, associated with type 2 diabetes mellitus

Abstract Background Diabetic patients with resistant hypertension (RHT) are characterized by accelerated annual decline in estimated glomerular filtration rate (eGFR) (from 10 to 14 mL/min/1,73m2). The distal renal denervation (RD) can preserve renal function within first year follow-up in these patients. However, whether this effect will persist at a later period is unknown, especially taking into account the potential risks of kidney damage due to deep introduction of the catheter and contrast into the segmental branches of the artery, as well as exposure to radiofrequency energy near to the kidney. In addition, RHT and diabetes mellitus (DM) contribute to impaired renal autoregulation which can lead to a decrease in GFR in response to a decrease in BP, but the long-term safety of a powerful BP reduction for renal function in these patients remains unexplored. The purpose of this study was to assess the renal safety and efficacy of a distal RD compared to conventional intervention in diabetic patients with RHT during 3 years of follow-up. Methods Twenty seven patients with true RHT and type 2 DM were included in single-arm prospective interventional study (number NCT02667912 on ClinicalTrial.gov) (mean age 61.6±7.3 years, mean office (systolic/diastolic) BP 171.8±21.9/87.7±17.7 mmHg, mean eGFR 72.1±19.9 mL/min/1.73m2, 7 patients with CKD (stage 3), 11 patients with albuminuria (>30 mg/day), 8 men), among them 13 – undergone distal RD and 14 – conventional RD. Offices BP, ABPM, renal Doppler ultrasound, renal function (eGFR (CKD-EPI) and 24-hour urinary albumin excretion (UAE)) were assessed at baseline and annually for 3 years follow up. There were no any difference in sex, old, eGFR, UAE, BP level, and frequency both of CKD and albuminuria between distal RD group and conventional RD group. The patients were asked to refrain from changing their medication regimen for the duration of the study. Nineteen patients completed 36 months follow-up (8 treated by distal RD and 11 – by conventional mode). Results The change in eGFR for distal RD during 3 years follow-up was not significant (−5.3±0.4 mL/min/1.73m2, P=0.63) and was comparable with that for conventional RD (−6.7±4.2, P=0.3), (P=0.7 for the between-group difference), despite of a more powerful decrease in 24h-systolic BP and 24h-puls BP in the distal RD group than in the conventional RD group (−25.3±15.3 vs. −4.4±22 mmHg, P=0.04, and −14.3±15.1 vs. 0.1±7.7 mmHg, respectively). The degree of annual decline in GFR for the distal RD was the same as for the conventional RD (p=0.9), and was −2.7±2.4 mL/min/1.73m2/year, and −2.7±4.0 mL/min/1.73m2/year, respectively. There were no significant changes in mean values of renal blood flow, albuminuria, and the numbers of patients with albuminuria and CKD in both groups after 3 years of follow-up. Conclusions Distal RD in diabetic patients with RHT has a good renal safety profile and can slow the progression of CKD within 3 years of follow-up.

Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne's Thread.

Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein products produced during oxidative stress (advanced oxidation protein products—AOPPs) have been directly linked to podocyte damage, proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) as well as tubulointerstitial fibrosis. Vascular oxidative stress is considered to play a critical role in CKD progression, and ROS are potential mediators of the impaired myogenic responses of afferent renal arterioles in CKD and impaired renal autoregulation. Both oxidative stress and inflammation are CKD hallmarks. Oxidative stress promotes inflammation via formation of proinflammatory oxidized lipids or AOPPs, whereas activation of nuclear factor κB transcription factor in the pro-oxidant milieu promotes the expression of proinflammatory cytokines and recruitment of proinflammatory cells. Accumulating evidence implicates oxidative stress in various clinical models of CKD, including diabetic nephropathy, IgA nephropathy, polycystic kidney disease as well as the cardiorenal syndrome. The scope of this review is to tackle the issue of oxidative stress in CKD in a holistic manner so as to provide a future framework for potential interventions.

Administration of Tempol Improves Renal Autoregulation in Ischemia‐reperfusion Induced Acute Kidney Injury

Renal autoregulation is critical for protecting the kidney from fluctuations in arterial pressure by regulating renal vascular resistance to maintain stable renal perfusion and glomerular filtration rate (GFR). Renal ischemia‐reperfusion (IR) induced acute kidney injury (IR‐AKI) is characterized by reduced renal blood flow and a decline in GFR. We hypothesized that increased reactive oxygen species (ROS) contribute to impairment of renal autoregulatory capability in IR‐AKI. Afferent arteriole autoregulatory behavior was assessed using the in vitro blood‐perfused juxtamedullary nephron preparation. IR‐AKI was induced by 60 minutes of bilateral renal artery occlusion followed by 24 hours of reperfusion. We found that plasma creatinine was increased in IR rats (3.86 ± 0.2 mg/dl) compared to 0.93 ± 0.07 mg/dl in sham rats (n=6–7, p<0.05). Baseline afferent arteriole diameter averaged 13.0 ± 0.4 μm (n=5) in kidneys from sham rats and these arterioles exhibited normal autoregulatory behavior. Decreasing renal perfusion pressure from 100 to 65 mmHg increased arteriole diameter from 13.0 ± 0.4 to 15.1 ± 0.8 μm, corresponding to 116 ± 5% of the baseline diameter. Subsequent stepwise increases in perfusion pressure (15 mmHg) caused pressure‐dependent afferent arteriole vasoconstriction to 66 ± 2% of baseline diameter at 170 mmHg. In contrast, pressure‐mediated afferent arteriole responses were markedly attenuated in IR‐AKI rats. Baseline diameter averaged 11.7 ± 0.6 μm and remained between 91 and 101% of baseline over the 65–170 mmHg pressure range tested, indicating a loss of autoregulatory function. In another set of IR‐AKI rats, acute administration of the ROS scavenger, tempol (10−3 M), to afferent arterioles increased baseline diameter by 10 ± 2% from 11.3 ± 0.8 to 12.2 ± 0.9 μm (n=5). Furthermore, scavenging ROS production improved autoregulatory behavior of afferent arterioles from IR‐AKI rats. During exposure to tempol, decreasing renal perfusion pressure from 100 to 65 mmHg resulted in a diameter increase to 110 ± 2 % of the control diameter while increasing perfusion pressure to 170 mmHg decreased arteriole diameter to 78 ± 1% of control (P<0.05 vs IR). In conclusion, these results suggest that renal ischemia‐reperfusion leads to impaired autoregulatory behavior of afferent arterioles. Acutely scavenging endogenous ROS with tempol improves afferent arteriole autoregulatory responsiveness, suggesting that excessive ROS production contributes to impaired renal autoregulation in IR‐AKI.Support or Funding InformationThis study is supported by a Grant‐in‐Aid (15GRNT25240015) from the American Heart Association for ZG and by grants from NIH (DK044628, HL074167, HL098135 and HL095499) for EWI.

Arterial stiffness and decline of renal function in a primary care population.

Arterial stiffness is an important pathophysiological factor linking cardiovascular disease and kidney disease. Controversy exists as to whether arterial stiffness causes renal function decline, or kidney dysfunction leads to stiffening or whether the association is mutual. We aimed to investigate the longitudinal association between arterial stiffness and annual rate of renal function decline. We prospectively investigated in a primary care population whether carotid-femoral pulse wave velocity (PWV) was associated with estimated glomerular filtration rate (eGFR) and annual decline in eGFR in participants aged ⩾40 years without overt kidney disease. Baseline data on PWV and eGFR were available for 587 participants; follow-up measurements with a mean duration of 5.6 years were available for 222 patients. PWV, female gender and mean arterial pressure were independently associated with eGFR at baseline, although age confounded this association. More importantly, baseline PWV, age and eGFR were independent predictors of renal function decline. Stratification for age showed that the effect of PWV on rate of eGFR decline was amplified with advancing age. On the other hand, baseline eGFR did not determine annual change in PWV, suggesting a unidirectional association between arterial stiffness and eGFR. Arterial stiffness amplifies age-related renal function decline, suggesting that arterial stiffness plays a causal role in the development of renal damage, at least at later stages of age-related renal function decline, possibly through impaired renal autoregulation and increased arterial blood pressure pulsatility.

Impaired Renal Autoregulation after Ischemia‐Reperfusion Results from Loss of Dynamic Stability Normally Conferred by Tubuloglomerular Feedback

BackgroundAutoregulation of renal blood flow (Q) results from combined actions of myogenic (Myo) and tubuloglomerular feedback (TGF) systems. Surprisingly little is known about intra‐renal hemodynamics or autoregulation after acute kidney injury.MethodWe subjected rats (n=13) to renal ischemia‐reperfusion (IR, bilateral pedicle clamp × 1h) or sham ischemia. After 4 or 24 hrs, rats were re‐anesthetized (inactin) and 2‐hr recordings made of spontaneous left renal blood flow (Q) and arterial pressure (BP) while measuring 2‐kidney inulin clearance (GFR). We examined the dynamic relationship between Q and BP by two methods: First, we generated admittance spectra from short‐term Fourier transforms. This is a proven method for detecting TGF and Myo systems, which give respective resonance peaks at 0.03 and 0.15 Hz. Second, we generated autoregulatory step responses by applying the projection theorem to approximate Q as a linear sum of past BP and expressed the result as the fractional compensation following an idealized unit step in BP. The step response out‐performs spectral methods for quantifying the efficiency of autoregulation.ResultsData from 4 and 24h were similar and are pooled. GFR was depressed after IR (0.5± 0.3 vs 2.1±0.3 ml/min, P<0.002) but Q was not (14.8±1.9 vs 13.6±2.0 ml/min, P=0.7). Spectral analysis detected Myo activity in both Sham and IR but detected TGF activity only in Sham. Step responses diverged during the 10–20s window where TGF normally contributes most. For BP disturbances lasting longer than 15s, fractional compensation was less by ~50% in IR vs Sham.InterpretationQ is rapidly restored after IR, while GFR remains low enough that BP fluctuations cannot produce a TGF signal, which derives from flow in the tubule. Without a contribution from TGF, overall autoregulatory efficiency is diminished and Q is susceptible to changes in BP. This has implications for how to manage patients recovering from acute kidney injury.Support or Funding InformationVeterans Administration Research Service and UCSD‐UAB O'Brien Center for Acute Kidney Injury (P30‐DK‐79337).

Mathematical Model‐based Analysis of the Acute and Chronic Mechanisms of Diabetic Hyperfiltration

An increase in glomerular filtration rate (GFR) in early diabetes has been associated with development and progression of diabetic kidney disease. Our understanding of the mechanisms responsible for hyperfiltration and subsequent renal injury is incomplete, but may be critical for developing new approaches to prevent diabetic kidney disease. The tubular hypothesis of hyperfiltration proposes that hyperfiltration is initiated by a primary increase in sodium (Na) reabsorption in the proximal tubule (PT), due to tubular growth and increased Na‐glucose cotransport.The renal response to a primary increase in PT Na reabsorption likely involves multiple mechanisms over both the acute and chronic timescales. A more complete understanding of the relative contributions of the driving mechanisms, as well as the relationship between the acute and chronic response, is needed to better understand how diabetic hyperfiltration is initiated and maintained. In this study, we utilized an integrated mathematical model of the renal vasculature, tubular Na and fluid handling, and systemic blood volume regulation to investigate the mechanisms responsible for the hyperfiltration response to increased Na reabsorption in the PT.We find that both tubuloglomerular feedback (TGF) and decreased PT pressure likely contribute to the acute GFR response to increased PT reabsorption. However, these mechanisms and the acute GFR rise appear insufficient to fully return Na balance. Additional adaptations must occur chronically to restore Na balance – either distal Na reabsorption must be reduced to compensate for the increased PT reabsorption, or GFR must be further augmented to match Na excretion to intake. We find that when preglomerular autoregulation is intact, modest distal reductions in Na reabsorption can fully compensate, with no further increase in GFR needed. The distal effect is driven by true pressure‐natriuresis, but regulation by renal sympathetic nerve activity and the renin angiotensin aldosterone system moderate this effect and allow Na homeostasis with minimal increases in blood pressure. However, when preglomerular autoregulation or downregulation of distal Na reabsorption is impaired (as has been proposed in diabetes), Na balance is returned through a further increase in glomerular pressure/GFR.In summary, these results suggest that the hyperfiltration response to a primary increase in PT Na reabsorption is multifactorial. While the acute response is likely dominated by TGF and tubular pressure changes, impaired renal autoregulation and impaired pressure natriuresis/ neurohumoral distal Na transport regulation contribute to the magnitude of the chronic hyperfiltration response and the associated increase in glomerular pressure. In other words, improving preglomerular autoregulation and/or restoring renal Na transport regulation may attenuate hyperfiltration/glomerular hypertension and thereby the drive to renal damage long‐term. An interactive interface to the model is available at qsp.engr.uga.edu:3838/Hyperfiltration_EB.

Colchicine attenuates renal injury in a model of hypertensive chronic kidney disease

Hypertension is a risk factor for chronic kidney disease, particularly when associated with impaired renal autoregulation and thereby increased intraglomerular pressure (Pgc). Elevated Pgc can be modeled in vitro by exposing glomerular mesangial cells to mechanical strain. We previously showed that RhoA mediates strain-induced matrix production. Here, we show that RhoA activation is dependent on an intact microtubule network. Upregulation of the profibrotic cytokine connective tissue growth factor (CTGF) by mechanical strain is dependent on RhoA activation and inhibited by microtubule disruption. We tested the effects of the microtubule depolymerizing agent colchicine in 5/6 nephrectomized rats, a model of chronic kidney disease driven by elevated Pgc. Colchicine inhibited glomerular RhoA activation and attenuated both glomerular sclerosis and interstitial fibrosis without affecting systemic blood pressure. Upregulation of the matrix proteins collagen I and fibronectin, as well as CTGF, was attenuated by colchicine. Activity of the profibrotic cytokine TGF-β, as assessed by Smad3 phosphorylation, was also inhibited by colchicine. Microtubule disruption significantly decreased renal infiltration of lymphocytes and macrophages. Our studies thus indicate that colchicine modifies hypertensive renal fibrosis. Its protective effects are likely mediated by inhibition of RhoA signaling and renal infiltration of inflammatory cells. Already well-established in clinical practice for other indications, prevention of hypertension-associated renal fibrosis may represent a new potential use for colchicine.

The Role of Early and Sufficient Isolated Venovenous Ultrafiltration in Heart Failure Patients With Pulmonary and Systemic Congestion

Hypervolemia, present in at least 70% of patients with decompensated heart failure, results in renal dysfunction due to increased renal venous pressure, impaired renal autoregulation, and decreased renal blood flow that are associated with increased morbidity and mortality. Loop diuretics, widely used in congested patients, result in the production of hypotonic urine and neurohormonal activation. In contrast, ultrafiltration (UF) removes isotonic fluid without increasing renin secretion by the macula densa. Simplified devices that permit us to perform UF with peripheral venous access, adjustable blood flows, and small extracorporeal blood volumes make this therapy feasible at most hospitals and in less acute care settings. Conflicting results on the effects of UF in heart failure patients underscore the challenges of patient selection and choice of fluid removal rates. Unfavorable outcomes in patients undergoing UF in the midst of cardiorenal syndrome type 1 are in contrast with the sustained benefits of UF initiated before unsuccessful use of high-dose intravenous (IV) diuretics. UF rates should be based on a precise knowledge of the degree of hypervolemia and careful assessment of blood volume changes, so that extracellular fluid gradually refills the intravascular space and volume depletion is avoided. Poor outcomes are likely to occur if fluid removal rates are not tailored to individual patients' clinical characteristics. A large trial is ongoing to determine if a strategy of early UF, initiated before renal function is worsened by other therapies, is superior to IV diuretics in reducing 90-day heart-failure-related hospitalizations in patients with pulmonary and systemic congestion.

L‐arginine or tempol supplementation improves renal and cardiovascular function in rats with reduced renal mass and chronic high salt intake

Early life reduction in nephron number and chronic high salt intake cause development of renal and cardiovascular disease, which has been associated with oxidative stress and nitric oxide (NO) deficiency. We investigated the hypothesis that interventions stimulating NO signalling or reducing oxidative stress may restore renal autoregulation, attenuate hypertension and reduce renal and cardiovascular injuries following reduction in renal mass and chronic high salt intake. Male Sprague-Dawley rats were uninephrectomized (UNX) or sham-operated at 3 weeks of age and given either a normal-salt (NS) or high-salt (HS) diet. Effects on renal and cardiovascular functions were assessed in rats supplemented with substrate for NO synthase (L-Arg) or a superoxide dismutase mimetic (Tempol). Rats with UNX + HS developed hypertension and displayed increased renal NADPH oxidase activity, elevated levels of oxidative stress markers in plasma and urine, and reduced cGMP in plasma. Histological analysis showed signs of cardiac and renal inflammation and fibrosis. These changes were linked with abnormal renal autoregulation, measured as a stronger tubuloglomerular feedback (TGF) response. Simultaneous treatment with L-Arg or Tempol restored cGMP levels in plasma and increased markers of NO signalling in the kidney. This was associated with normalized TGF responses, attenuated hypertension and reduced signs of histopathological changes in the kidney and in the heart. Reduction in nephron number during early life followed by chronic HS intake is associated with oxidative stress, impaired renal autoregulation and development of hypertension. Treatment strategies that increase NO bioavailability, or reduce levels of reactive oxygen species, were proven beneficial in this model of renal and cardiovascular disease.

Large BP-dependent and -independent differences in susceptibility to nephropathy after nitric oxide inhibition in Sprague-Dawley rats from two major suppliers

The N(ω)-nitro-l-arginine methyl ester (l-NAME) model is widely employed to investigate the role of nitric oxide (NO) in renal injury. The present studies show that Sprague-Dawley rats from Harlan (H) and Charles River (CR) exhibit strikingly large differences in susceptibility to l-NAME nephropathy. After 4 wk of l-NAME (∼50 mg·kg(-1)·day(-1) in drinking water), H rats (n = 13) exhibited the expected hypertension [average radiotelemetric systolic blood pressure (BP), 180 ± 3 mmHg], proteinuria (136 ± 17 mg/24 h), and glomerular injury (GI) (12 ± 2%). By contrast, CR rats developed less hypertension (142 ± 4), but surprisingly no proteinuria or GI, indicating a lack of glomerular hypertension. Additional studies showed that conscious H, but not CR, rats exhibit dose-dependent renal vasoconstriction after l-NAME. To further investigate these susceptibility differences, l-NAME was given 2 wk after 3/4 normotensive nephrectomy (NX) and comparably impaired renal autoregulation in CR-NX and H-NX rats. CR-NX rats, nevertheless, still failed to develop proteinuria and GI despite moderate hypertension (144 ± 2 mmHg, n = 29). By contrast, despite an 80-90% l-NAME dose reduction and lesser BP increases (169 ± 4 mmHg), H-NX rats (n = 20) developed greater GI (26 ± 3%) compared with intact H rats. Linear regression analysis showed significant (P < 0.01) differences in the slope of the relationship between BP and GI between H-NX (slope 0.56 ± 0.14; r = 0.69; P < 0.008) and CR-NX (slope 0.09 ± 0.06; r = 0.29; P = 0.12) rats. These data indicate that blunted BP responses to l-NAME in the CR rats are associated with BP-independent resistance to nephropathy, possibly mediated by a resistance to the renal (efferent arteriolar) vasoconstrictive effects of NO inhibition.