Tubuloglomerular Feedback Synchronization in Nephrovascular Networks.

To perform their functions, the kidneys maintain stable blood perfusion in the face of fluctuations in systemic BP. This is done through autoregulation of blood flow by the generic myogenic response and the kidney-specific tubuloglomerular feedback (TGF) mechanism. The central theme of this paper is that, to achieve autoregulation, nephrons do not work as single units to manage their individual blood flows, but rather communicate electrically over long distances to other nephrons via the vascular tree. Accordingly, we define the nephrovascular unit (NVU) to be a structure consisting of the nephron, glomerulus, afferent arteriole, and efferent arteriole. We discuss features that require and enable distributed autoregulation mediated by TGF across the kidney. These features include the highly variable topology of the renal vasculature which creates variability in circulation and the potential for mismatch between tubular oxygen demand and delivery; the self-sustained oscillations in each NVU arising from the autoregulatory mechanisms; and the presence of extensive gap junctions formed by connexins and their properties that enable long-distance transmission of TGF signals. The existence of TGF synchronization across the renal microvascular network enables an understanding of how NVUs optimize oxygenation-perfusion matching while preventing transmission of high systemic pressure to the glomeruli, which could lead to progressive glomerular and vascular injury.

Changes in Proximal Tubular Reabsorption Modulate Microvascular Regulation via the TGF System.

This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium-glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium-hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.

Chronic elevation of renal venous pressure induces extensive renal venous collateral formation and modulates renal function and cardiovascular stability in rats.

Acutely increased renal venous pressure (RVP) impairs renal function, but the long-term impact is unknown. We investigated whether chronic RVP elevation impairs baseline renal function and prevents exacerbation of renal dysfunction and cardiovascular instability upon further RVP increase. RVP elevation (20-25 mmHg) or sham operation (sham) was performed in rats. After 1 wk (n = 17) or 3 wk (n = 22), blood pressure, RVP, renal blood flow (RBF), renal vascular conductance (RVC), and glomerular filtration rate (GFR) were measured at baseline and during superimposed RVP increase. Chronic RVP elevation induced extensive renal venous collateral formation. RVP fell to 6 ± 1 mmHg at 1 wk and 3 ± 1 mmHg at 3 wk. Baseline blood pressure and heart rate were unaltered compared with sham. RBF, RVC, and GFR were reduced at 1 wk but normalized by 3 wk. Upon further RVP increase, the drop in mean arterial pressure was attenuated at 3 wk compared with 1 wk (P < 0.05), whereas heart rate fell comparably across all groups; the mean arterial pressure-heart rate relationship was disrupted at 1 and 3 wk. RBF fell to a similar degree as sham at 1 wk (-2.3 ± 0.7 vs. -3.9 ± 1.2 mL/min, P = 0.066); however, at 3 wk, this was attenuated compared with sham (-1.5 ± 0.5 vs. -4.2 ± 0.7 mL/min, P < 0.05). The drop in RVC and GFR was attenuated at 1 and 3 wk (P < 0.05). Thus, chronic RVP elevation induced by partial renal vein ligation elicits extensive renal venous collateral formation, and although baseline renal function is impaired, chronic RVP elevation in this manner induces protective adaptations in kidneys of healthy rats, which attenuates the hemodynamic response to further RVP increase.

Fluid management in chronic kidney disease: what is too much, what is the distribution, and how to manage fluid overload in patients with chronic kidney disease?

PURPOSE OF REVIEW: Assessment of fluid status to reach normovolemia in patients with chronic kidney disease (CKD) continues to be a tough task. Besides clinical observation, technological methods have been introduced, yet, the best approach is still uncertain. The present review looks at fluid overload in CKD from three perspectives: the critical fluid threshold leading to adverse cardiovascular outcomes, fluid distribution and its clinical correlates, and direct effect of fluid overload on vascular function related to disturbance of the sodium-skin axis and endothelial glycocalyx dysfunction. RECENT FINDINGS: To determine fluid status, both the absolute and relative fluid overload is used as parameter in clinical practice. In addition, the definition of fluid overload is ambivalent and its relation to symptom burden has not been studied well. Studies on the impact of distribution of fluid are scarce and the limited evidence suggests differences based on the cause of CKD. So far, no standardized technologies are available to adequately determine fluid distribution. After discovering the 'third compartment' of total body sodium in skin and muscle tissue and its potential direct effect on vascular function, other biomarkers such as VEGF-C are promising. SUMMARY: We propose a multimodal clinical approach for volume management in CKD. Because there are currently no studies are available demonstrating that correction of fluid overload in CKD will lead to better outcome, these are strongly needed.

Extracellular fluid volume expansion, arterial stiffness and uncontrolled hypertension in patients with chronic kidney disease.

BACKGROUND: Hypertension is prevalent in patients with chronic kidney disease (CKD) and is related to extracellular fluid volume (ECFV) expansion. Arterial stiffening is another implication of CKD that can be caused by ECFV expansion. In this study, we hypothesized that CKD patients with uncontrolled hypertension are more likely to be fluid volume expanded than normotensive patients, which in turn is associated with increased arterial stiffness. METHODS: Adult hypertensive patients with mild-severe CKD (n = 82) were recruited. ECFV was assessed using multifrequency bioimpedance and arterial stiffness by applanation tonometry and oscillometry. RESULTS: Patients with uncontrolled hypertension had fluid volume expansion compared with controls (1.0 ± 1.5 versus 0.0 ± 1.6 L, P < 0.001), and had a higher augmentation index (AIx) and pulse wave velocity. Fluid volume expansion was more prevalent in patients with uncontrolled hypertension (58%) than patients who were at target (27%). Fluid volume expansion was correlated with age, AIx and systolic blood pressure. In a binary logistic regression analysis, AIx, age and fluid volume status were independent predictors of uncontrolled hypertension in both univariate and multivariate models. DISCUSSION: In summary, uncontrolled hypertension among hypertensive CKD patients is associated with ECFV expansion. Our data suggest a relationship between ECFV expansion, increased arterial stiffness and uncontrolled hypertension.

Kidney care in low- and middle-income countries.

Optimal kidney care requires a trained nephrology workforce, essential healthcare services, and medications. This study aimed to identify the access to these resources on a global scale using data from the multinational survey conducted by the International Society of Nephrology (ISN) (Global Kidney Health Atlas (GKHA) project), with emphasis on developing nations. For data analysis, the 125 participating countries were sorted into the 4 World Bank income groups: low income (LIC), lower-middle income (LMIC), upper-middle income (UMIC), and high income (HIC). A severe shortage of nephrologists was observed in LIC and LMIC with < 5 nephrologists per million population. Many LIC were unable to access estimated glomerular filtration rate (eGFR) and albuminuria (proteinuria) tests in primary-care levels. Acute and chronic hemodialysis was available in most countries, although acute and chronic peritoneal dialysis access was severely limited in LIC (24% and 35%, respectively). Most countries had kidney transplantation access, except for LIC (12%). HIC and UMIC funded their renal replacement therapy (RRT) and renal medications primarily through public means, whereas LMIC and LIC required private and out-of-pocket contributions. In conclusion, this study found a huge gap in the availability and access to trained nephrology workforce, tools for diagnosis and management of CKD, RRT, and funding of RRT and essential medications in LIC and LMIC.

NHE8 attenuates Ca2+ influx into NRK cells and the proximal tubule epithelium.

To garner insights into the renal regulation of Ca2+ homeostasis, we performed an mRNA microarray on kidneys from mice treated with the Ca2+-sensing receptor (CaSR) agonist cinacalcet. This revealed decreased gene expression of Na+/H+ exchanger isoform 8 (NHE8) in response to CaSR activation. These results were confirmed by quantitative real-time PCR. Moreover, administration of vitamin D also decreased NHE8 mRNA expression. In contrast, renal NHE8 protein expression from the same samples was increased. To examine the role of NHE8 in transmembrane Ca2+ fluxes, we used the normal rat kidney (NRK) cell line. Cell surface biotinylation and confocal immunofluorescence microscopy demonstrated NHE8 apical expression. Functional experiments found 5-(N-ethyl-N-isopropyl)amiloride (EIPA)-inhibitable NHE activity in NRK cells at concentrations minimally attenuating NHE1 activity in AP-1 cells. To determine how NHE8 might regulate Ca2+ balance, we measured changes in intracellular Ca2+ uptake by live cell Ca2+ imaging with the fluorophore Fura-2 AM. Inhibition of NHE8 with EIPA or by removing extracellular Na+-enhanced Ca2+ influx into NRK cells. Ca2+ influx was mediated by a voltage-dependent Ca2+ channel rather than directly via NHE8. NRK cells express Cav1.3 and display verapamil-sensitive Ca2+ influx and NHE8 inhibition-augmented Ca2+ influx via a voltage-dependent Ca2+ channel. Finally, proximal tubules perused ex vivo demonstrated increased Ca2+ influx in the presence of luminal EIPA at a concentration that would inhibit NHE8. The results of the present study are consistent with NHE8 regulating Ca2+ uptake into the proximal tubule epithelium.

Sodium intake but not renal nerves attenuates renal venous pressure-induced changes in renal hemodynamics in rats.

Increased central venous pressure and renal venous pressure (RVP) are associated with worsening of renal function in acute exacerbation of congestive heart failure. We tested whether an acute isolated elevation of RVP in one kidney leads to ipsilateral renal vasoconstriction and decreased glomerular filtration rate (GFR) and whether this depends on dietary salt intake or activation of renal nerves. Male Lewis rats received a normal (1% NaCl, NS) or high-salt (6% NaCl) diet for ≥14 days before the acute experiment. Rats were then randomized into the following three groups: time control and RVP elevation to either 10 or 20 mmHg to assess heart rate, renal blood flow (RBF), and GFR. To increase RVP, the left renal vein was partially occluded for 120 min. To determine the role of renal nerves, surgical denervation was conducted in rats on both diets. Renal sympathetic nerve activity (RSNA) was additionally recorded in a separate group of rats. Increasing RVP to 20 mmHg decreased ipsilateral RBF (7.5 ± 0.4 to 4.1 ± 0.7 ml/min, P < 0.001), renal vascular conductance (0.082 ± 0.006 to 0.060 ± 0.011 ml·min-1·mmHg-1, P < 0.05), and GFR (1.28 ± 0.08 to 0.40 ± 0.13 ml/min, P < 0.05) in NS rats. The reduction was abolished by high-salt diet but not by renal denervation. Furthermore, a major increase of RVP (1.6 ± 0.8 to 24.7 ± 1.2 mmHg) immediately suppressed RSNA and decreased heart rate ( P < 0.05), which points to suppression of both local and systemic sympathetic activity. Taken together, acute elevated RVP induces renal vasoconstriction and decreased GFR, which is more likely to be mediated via the renin-angiotensin system than via renal nerves.

Understanding the Two Faces of Low-Salt Intake.

Fierce debate has developed whether low-sodium intake, like high-sodium intake, could be associated with adverse outcome. The debate originates in earlier epidemiological studies associating high-sodium intake with high blood pressure and more recent studies demonstrating a higher cardiovascular event rate with both low- and high-sodium intake. This brings into question whether we entirely understand the consequences of high- and (very) low-sodium intake for the systemic hemodynamics, the kidney function, the vascular wall, the immune system, and the brain. Evolutionarily, sodium retention mechanisms in the context of low dietary sodium provided a survival advantage and are highly conserved, exemplified by the renin-angiotensin system. What is the potential for this sodium-retaining mechanism to cause harm? In this paper, we will consider current views on how a sodium load is handled, visiting aspects including the effect of sodium on the vessel wall, the sympathetic nervous system, the brain renin-angiotensin system, the skin as "third compartment" coupling to vascular endothelial growth factor C, and the kidneys. From these perspectives, several mechanisms can be envisioned whereby a low-sodium diet could potentially cause harm, including the renin-angiotensin system and the sympathetic nervous system. Altogether, the uncertainties preclude a unifying model or practical clinical guidance regarding the effects of a low-sodium diet for an individual. There is a very strong need for fundamental and translational studies to enhance the understanding of the potential adverse consequences of low-salt intake as an initial step to facilitate better clinical guidance.

Everything we always wanted to know about furosemide but were afraid to ask.

Furosemide is a widely used, potent natriuretic drug, which inhibits the Na(+)-K(+)-2Cl(-) cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion.

A gap junction inhibitor, carbenoxolone, induces spatiotemporal dispersion of renal cortical perfusion and impairs autoregulation.

Renal autoregulation dynamics originating from the myogenic response (MR) and tubuloglomerular feedback (TGF) can synchronize over large regions of the kidney surface, likely through gap junction-mediated electrotonic conduction and reflecting distributed operation of autoregulation. We tested the hypotheses that inhibition of gap junctions reduces spatial synchronization of autoregulation dynamics, abrogates spatial and temporal smoothing of renal perfusion, and impairs renal autoregulation. In male Long-Evans rats, we infused the gap junction inhibitor carbenoxolone (CBX) or the related glycyrrhizic acid (GZA) that does not block gap junctions into the renal artery and monitored renal blood flow (RBF) and surface perfusion by laser speckle contrast imaging. Neither CBX nor GZA altered RBF or mean surface perfusion. CBX preferentially increased spatial and temporal variation in the distribution of surface perfusion, increased spatial variation in the operating frequencies of the MR and TGF, and reduced phase coherence of TGF and increased its dispersion. CBX, but not GZA, impaired dynamic and steady-state autoregulation. Separately, infusion of the Rho kinase inhibitor Y-27632 paralyzed smooth muscle, grossly impaired dynamic autoregulation, and monotonically increased spatial variation of surface perfusion. These data suggest CBX inhibited gap junction communication, which in turn reduced the ability of TGF to synchronize among groups of nephrons. The results indicate that impaired autoregulation resulted from degraded synchronization, rather than the reverse. We show that network behavior in the renal vasculature is necessary for effective RBF autoregulation.

Cardiac Hepcidin Expression Associates with Injury Independent of Iron.

BACKGROUND: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. METHODS: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. RESULTS: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (ß = 0.734, p < 0.001) and connective tissue growth factor (ß = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups. CONCLUSIONS: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure.

Laser speckle contrast imaging reveals large-scale synchronization of cortical autoregulation dynamics influenced by nitric oxide.

Synchronization of tubuloglomerular feedback (TGF) dynamics in nephrons that share a cortical radial artery is well known. It is less clear whether synchronization extends beyond a single cortical radial artery or whether it extends to the myogenic response (MR). We used LSCI to examine cortical perfusion dynamics in isoflurane-anesthetized, male Long-Evans rats. Inhibition of nitric oxide synthases by N(ω)-nitro-l-arginine methyl ester (l-NAME) was used to alter perfusion dynamics. Phase coherence (PC) was determined between all possible pixel pairs in either the MR or TGF band (0.09-0.3 and 0.015-0.06 Hz, respectively). The field of view (≈4 × 5 mm) was segmented into synchronized clusters based on mutual PC. During the control period, the field of view was often contained within one cluster for both MR and TGF. PC was moderate for TGF and modest for MR, although significant in both. In both MR and TGF, PC exhibited little spatial variation. After l-NAME, the number of clusters increased in both MR and TGF. MR clusters became more strongly synchronized while TGF clusters showed small highly coupled, high-PC regions that were coupled with low PC to the remainder of the cluster. Graph theory analysis probed modularity of synchronization. It confirmed weak synchronization of MR during control that probably was not physiologically relevant. It confirmed extensive and long-distance synchronization of TGF during control and showed increased modularity, albeit with larger modules seen in MR than in TGF after l-NAME. The results show widespread synchronization of MR and TGF that is differentially affected by nitric oxide.

Transient impairment of dynamic renal autoregulation in early diabetes mellitus in rats.

Renal autoregulation is impaired in early (1 wk) diabetes mellitus (DM) induced by streptozotocin, but effective in established DM (4 wk). Furthermore nitric oxide synthesis (NOS) inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) significantly improved autoregulation in early DM but not in established DM. We hypothesized that autoregulation is transiently impaired in early DM because of increased NO availability in the kidney. Because of the conflicting evidence available for a role of NO in DM, we tested the hypothesis that DM reduces autoregulation effectiveness by reducing the spatial similarity of autoregulation. Male Long-Evans rats were divided into control (CON) and diabetic (DM; streptozotocin) groups and followed for either 1 wk (CON1, n = 6; DM1, n = 5) or 4 wk (CON4, n = 7; DM4, n = 7). At the end of the experiment, dynamic autoregulation was assessed in isoflurane-anesthetized rats by whole kidney RBF during baseline, NOS1 inhibition, and nonselective NOS inhibition. Kidney surface perfusion, monitored with laser speckle contrast imaging, was used to assess spatial heterogeneity of autoregulation. Autoregulation was significantly impaired in DM1 rats and not impaired in DM4 rats. L-NAME caused strong renal vasoconstriction in all rats, but did not significantly affect autoregulation dynamics. Autoregulation was more spatially heterogeneous in DM1, but not DM4. Therefore, our results, which are consistent with transient impairment of autoregulation in DM, argue against the hypothesis that this impairment is NO-dependent, and suggest that spatial properties of autoregulation may also contribute to reduced autoregulatory effectiveness in DM1.

Modulation of the expression of connexins 37, 40, and 43 in endothelial cells in a culture.

Connexin (Cx) 37, 40, and 43 are implicated in vascular function, specifically in the electrical coupling of endothelial cells and vascular smooth-muscle cells. In the present study, we investigated whether factors implicated in vascular dysfunction can modulate the gene expression of Cx37, Cx40, and Cx43 and whether this is associated with changes in endothelial layer barrier function in human microvascular endothelial cells (HMEC-1). First, HMEC-1 were subjected to stimuli for 4 and 8 h. We tested their responses to DETA-NONOate, H2O2, high glucose, and angiotensin II, none of which relevantly affected the transcription of the connexin genes. Next, we tested inflammatory factors IL-6, interferon gamma (IFNγ), and TNFα. IFNγ (10 ng/mL) consistently induced Cx40 expression at 4 and 8 h to 10-20-fold when corrected for the control. TNFα and IL-6 resulted in small but significant depressions of Cx37 expression at 4 h. Two JAK inhibitors, epigallocatechin-3-gallate (EGCG) (100-250 µM) and AG490 (100-250 µM), dose-dependently inhibited the induction of Cx40 expression by IFNγ. Subsequently, HMEC-1 were subjected to 10 ng/mL IFNγ for 60 h, and intercellular and transcellular impedance was monitored by electric cell-substrate impedance sensing (ECIS). In response to IFNγ, junctional-barrier impedance increased more than cellular-barrier impedance; this was prevented by AG490 (5 µM). In conclusion, IFNγ can strongly induce Cx40 expression and modify the barrier properties of the endothelial cell membrane through the JAK/STAT pathway. Moreover, the Cx37, Cx40, and Cx43 expression in endothelial cells is stable and, apart from IFNγ, not affected by a number of factors implicated in endothelial dysfunction and vascular diseases.

Detecting physiological systems with laser speckle perfusion imaging of the renal cortex.

Laser speckle perfusion imaging (LSPI) has become an increasingly popular technique for monitoring vascular perfusion over a tissue surface. However, few studies have utilized the full range of spatial and temporal information generated by LSPI to monitor spatial properties of physiologically relevant dynamics. In this study, we extend the use of LSPI to analyze renal perfusion dynamics over a spatial surface of ~5 × 7 mm of renal cortex. We identify frequencies related to five physiological systems that induce temporal changes in renal vascular perfusion (cardiac flow pulse, respiratory-induced oscillations, baroreflex components, the myogenic response, and tubuloglomerular feedback) across the imaged surface and compare the results with those obtained from renal blood flow measurements. We find that dynamics supplied from global sources (cardiac, respiration, and baroreflex) present with the same frequency at all locations across the imaged surface, but the local renal autoregulation dynamics can be heterogeneous in their distribution across the surface. Moreover, transfer function analysis with forced blood pressure as the input yields the same information with laser speckle imaging or renal blood flow as the output during control, intrarenal infusion of N(ω)-nitro-L-arginine methyl ester to enhance renal autoregulation, and intrarenal infusion of the rho-kinase inhibitor Y-27632 to inhibit vasomotion. We conclude that LSPI measurements can be used to analyze local as well as global renal perfusion dynamics and to study the properties of physiological systems across the renal cortex.

Assessment of arterial stiffness using applanation tonometry.

Augmentation index (AIx) and pulse wave velocity (PWV) assess functional and structural aspects of the vascular wall and are independent markers of cardiovascular morbidity and mortality. Like blood pressure, many factors, genetic, structural, and physiological, affect AIx and PWV. AIx and PWV can be assessed noninvasively using applanation tonometry. The technique is simple, but comes with a number of practical and technical limitations that have not been well documented and (or) explored. This review considers pulse wave analysis in the context of cardiovascular disease, and considers its limitations. Data are presented indicating that the placement of the probe is critical, and that the amplitude of the obtained signal is related to the variability in measurements. On a more theoretical note, issues are discussed regarding the applied transfer functions that are built in the devices to assess central AIx from peripheral waveforms. Altogether, PWV and its analysis are useful additions to the arsenal of parameters that can be used to assess vascular health and to estimate vascular risk. Yet, our analysis underscores the necessity for precise operating procedures, and calls for transparency regarding the applied transfer functions of commercial devices.

Reduced tubuloglomerular feedback activity and absence of its synchronization in a connexin40 knockout rat.

Introduction: Tubuloglomerular feedback (TGF) is the negative feedback component of renal blood flow (RBF) autoregulation. Neighbouring nephrons often exhibit spontaneous TGF oscillation and synchronization mediated by endothelial communication, largely via connexin40 (Cx40). Methods: We had a knockout (KO) rat made that lacks Cx40. One base pair was altered to create a stop codon in exon 1 of Gja5, the gene that encodes Cx40 (the strain is WKY-Gja55em1Mcwi). Blood pressure (BP)-RBF transfer functions probed RBF dynamics and laser speckle imaging interrogated the dynamics of multiple efferent arterioles that reach the surface (star vessels). Results: The distribution of wild type (WT), heterozygote, and KO pups at weaning approximated the Mendelian ratio of 1:2:1; growth did not differ among the three strains. The KO rats were hypertensive. BP-RBF transfer functions showed low gain of the myogenic mechanism and a smaller TGF resonance peak in KO than in WT rats. Laser speckle imaging showed that myogenic mechanism had higher frequency in KO than in WT rats, but similar maximum spectral power. In contrast, the TGF frequency was similar while peak power of its oscillation was much smaller in KO than in WT rats. In WT rats, plots of instantaneous TGF phase revealed BP-independent TGF synchronization among star vessels. The synchronization could be both prolonged and widespread. In KO rats TGF synchronization was not seen, although BP transients could elicit short-lived TGF entrainment. Discussion: Despite the reduced TGF spectral power in KO rats, there was sufficient TGF gain to induce oscillations and therefore enough gain to be effective locally. We conclude that failure to synchronize is dependent, at least in part, on impaired conducted vasomotor responses.

Bioimpedance-Guided Monitoring of Volume Status in Patients With Kidney Disease: A Systematic Review and Meta-Analysis.

Background and Objective: Bioimpedance technologies are increasingly used to determine fluid status in patients with chronic kidney disease and those with end-stage kidney disease on dialysis. We aimed to determine whether this technology improves clinical outcomes as compared with usual care. Methods: We performed a systematic review and meta-analysis of trials, comparing fluid management guided by bioimpedance technologies to standard of care in patients with chronic kidney disease. Our primary outcome was all-cause mortality. Secondary outcomes included blood pressure control, all-cause hospitalization, major adverse cardiovascular events, and change in left ventricular mass index. Results: Our search identified 819 citations of which 12 randomized controlled trials were included (2420 patients). No studies of non-dialysis-dependent chronic kidney disease patients met inclusion criteria. Mean age was 55 years and mean follow-up was 1 year. There was a statistically significant difference in all-cause mortality between both arms studied (risk ratio [RR] 0.64, 95% confidence interval [CI]: 0.44, 0.99). Better blood pressure control was observed in the bioimpedance arm of the included articles, weighted mean differences (WMD) -3.13 mm Hg (95% CI: -5.73, -0.53 mm Hg) for systolic blood pressure and WMD -2.50 mm Hg (95% CI: -4.36, -0.64 mm Hg) for diastolic blood pressure. No difference was observed concerning the other outcomes. Conclusions: Among patients on maintenance dialysis, bioimpedance-guided volume management showed decreased all-cause mortality and blood pressure but no significant difference in all-cause hospitalization, major adverse cardiac event, or change in left ventricular mass index. This may be due to a younger population sample than previous articles. Moreover, our study identified a knowledge gap by highlighting the lack of studies evaluating this technology in non-dialysis-dependent chronic kidney disease patients.

Contexte et objectif: Les technologies de bio-impédance sont de plus en plus utilisées pour déterminer le statut hydrique des patients atteints d'insuffisance rénale chronique et des patients atteints d'insuffisance rénale terminale sous dialyze. Notre objectif était de vérifier si cette technologie améliore les résultats cliniques des patients par rapport aux soins habituels. Méthodologie: Nous avons procédé à une revue systématique et à une méta-analyze d'essais comparant la gestion des fluides guidée par les technologies de bio-impédance aux normes de soins chez les patients atteints d'insuffisance rénale chronique. Le principal critère de jugement était la mortalité toutes causes confondues. La régulation de la pression artérielle, l'hospitalization toutes causes confondues, les événements cardiovasculaires majeurs indésirables et la modification de l'index de masse ventriculaire gauche constituaient les critères de jugement secondaires. Résultats: Notre recherche a permis de répertorier 819 citations, desquelles 12 essais contrôlés randomisés ont été retenus (2 420 patients). Aucune étude portant sur des patients atteints d'insuffisance rénale chronique non dépendants de la dialyze ne remplissait les critères d'inclusion. L'âge moyen des sujets était de 55 ans et le suivi moyen était d'un an. Une différence statistiquement significative a été observée entre les deux bras étudiés en ce qui concerne la mortalité toutes causes confondues (RR: 0.64; IC 95% entre: 0.44, 0.99). Une meilleure régulation de la pression artérielle a été observée dans le bras de bio-impédance des manuscrits inclus, soit une moyenne pondérée des écarts de −3.13 mm Hg (IC 95% entre: −5.73, −0.53 mm Hg) pour la pression artérielle systolique et de −2.50 mm Hg (IC 95% entre: −4.36, −0.64 mm Hg) pour la pression artérielle diastolique. Aucune différence n'a été observée pour les autres résultats. Conclusion: Chez les patients sous dialyze d'entretien, la prise en charge du volume guidée par la bio-impédance a montré une diminution de la mortalité toutes causes confondues et une meilleure régulation de la pression artérielle. Aucune différence significative n'a été cependant observée dans les hospitalisations toutes causes confondues, les événements cardiaques majeurs indésirables ou la modification de l'index de masse ventriculaire gauche. Ce résultat pourrait être attribuable au fait que l'échantillon de population était cette fois-ci plus jeune que les populations étudiées dans les manuscrits précédents. De plus, notre étude a permis d'identifier un écart dans les connaissances en soulignant le manque d'études évaluant cette technologie chez les patients atteints d'insuffisance rénale chronique non dépendants de la dialyze.