Explore the vast range of titles available.

Kidney damage varies according to the primary insult. Different aetiologies of acute kidney injury (AKI), including kidney ischaemia, exposure to nephrotoxins, dehydration or sepsis, are associated with characteristic patterns of damage and changes in gene expression, which can provide insight into the mechanisms that lead to persistent structural and functional damage. Early morphological alterations are driven by a delicate balance between energy demand and oxygen supply, which varies considerably in different regions of the kidney. The functional heterogeneity of the various nephron segments is reflected in their use of different metabolic pathways. AKI is often linked to defects in kidney oxygen supply, and some nephron segments might not be able to shift to anaerobic metabolism under low oxygen conditions or might have remarkably low basal oxygen levels, which enhances their vulnerability to damage. Here, we discuss why specific kidney regions are at particular risk of injury and how this information might help to delineate novel routes for mitigating injury and avoiding permanent damage. We suggest that the physiological heterogeneity of the kidney should be taken into account when exploring novel renoprotective strategies, such as improvement of kidney tissue oxygenation, stimulation of hypoxia signalling pathways and modulation of cellular energy metabolism.In this Review, the authors examine the physiological heterogeneity of different kidney compartments and consider how the local oxygen supply and the capacity for metabolic adaptation of different nephron segments might influence their response to changes in oxygen availability and their susceptibility to injury.

Pathophysiology of contrast medium–induced nephropathy. Contrast medium–induced nephropathy (CIN) is a well-known cause of acute renal failure, but the development of CIN remains poorly understood. A number of studies have been performed with the one aim, to shed some light onto the pathophysiology of CIN. These have led to manifold interpretations and sometimes contradicting conclusions. This review critically surveys mechanisms believed to mediate CIN by highlighting the complex pathophysiologic entity, including altered rheologic properties, perturbation of renal hemodynamics, regional hypoxia, auto- and paracrine factors [adenosine, endothelin, and reactive oxygen species (ROS)], and direct cytotoxic effects. Moreover, the importance of physicochemical properties of contrast media are made clear. The more recently developed iso-osmolar contrast media are dimers, not monomers as the widely used nonionic low osmolar contrast media. The dimers have physicochemical features different from other contrast media which may be of clinical importance, not only with respect to osmolality. The viscosity of the commercially available dimers is considerably higher than blood. Many experimental studies provide evidence for a greater perturbation in renal functions by dimeric contrast media in comparison to nonionic monomeric contrast media. Clinical trials have yielded conflicting results.

Long-term adverse effects of the immunosuppressant tacrolimus (Tac), such as nephrotoxicity, hepatotoxicity and diabetes, have been widely reported. Up to 33.6% of solid organ transplantation patients receiving Tac treatment develop hyperglycemia; however, the underlying mechanisms remain poorly understood. Here, using a mouse model of Tac-induced hyperglycemia, we found that Tac-induced body-weight loss, hyperglycemia, hypoinsulinemia, glucose intolerance and insulin resistance were improved by valsartan, a renin-angiotensin system (RAS) inhibitor. Histological and immunofluorescence analysis of the pancreas showed reduced islet areas and β-cell mass in Tac-treated mice. Moreover, when compared to control mice, isolated islets from Tac-treated mice showed a downregulation of cell-proliferation markers (Ki67, Ccna2 and Ccnd1) while an upregulation of apoptotic markers (DNA fragmentation, Bax and Caspase3). Tac also upregulated hypoxia-related markers in the pancreas, including hypoxia-inducible factor-1α (HIF-1α) and its downstream factors (Adm, Hmox1 and Vegfa), CD31 and pimonidazole adducts. Furthermore, treatment with Tac led to vascular dysfunction in pancreatic arteries. All of these adverse effects could be partially or fully abrogated by valsartan. Tac also increased levels of renin in renal tissue (1.00 ± 0.06 vs 1.29 ± 0.04, p  < 0.05) and serum (28.35 ± 4.29 ng/mL vs 51.99 ± 4.95 ng/mL, p  < 0.05). Inhibition of RAS by valsartan protected against Tac-induced vascular dysfunction in renal interlobar arteries. Collectively, our data illustrate a previously undescribed mechanism, in which Tac-induced vascular dysfunction in renal interlobar arteries leads to RAS activation. Blocking RAS by valsartan alleviates vascular dysfunction in dorsal pancreatic arteries and hypoxia in islets, which in turn prevents Tac-induced β-cell dysfunction and glucose metabolism disorder.

Key Points The incidence of contrast-induced acute kidney injury (CIAKI) is disputed, but clinically relevant CIAKI is less frequent than previously assumed Individual patient risk factors determine the mechanisms by which contrast media will induce damage to the kidney Pre-existing reduced renal tissue perfusion enhances the cytotoxic effects of contrast agents, which aggravate renal hypoxia; the rheological properties of contrast media have deleterious effects particularly in dehydrated patients Contrast medium induces apoptosis by damaging cell membranes, which increases intracellular Ca 2+ levels, activates the pro-apoptotic unfolded protein response, decreases ATP levels and subsequently inhibits the PI3K/AKT/mTOR axis Volume expansion is effective in preventing CIAKI; oral hydration provides rapid short-term renal protection, whereas intravenous administration of isotonic saline offers long-lasting protection, but must be started hours before exposure to contrast agents Diuretics combined with servo-controlled volume infusion might provide optimum renal protection against CIAKI; urine excretion or central venous pressure can be used as set points in this context Contrast agents can damage the kidney through several mechanisms. Here, the authors discuss current understanding of the incidence and pathophysiology of contrast-induced acute kidney injury and highlight the need to consider individual patient risk factors when considering prevention strategies. Contrast-induced acute kidney injury (CIAKI) occurs in up to 30% of patients who receive iodinated contrast media and is generally considered to be the third most common cause of hospital-acquired AKI. Accurate assessment of the incidence of CIAKI is obscured, however, by the use of various definitions for diagnosis, the different populations studied and the prophylactic measures put in place. A deeper understanding of the mechanisms that underlie CIAKI is required to enable reliable risk assessment for individual patients, as their medical histories will determine the specific pathways by which contrast media administration might lead to kidney damage. Here, we highlight common triggers that prompt the development of CIAKI and the subsequent mechanisms that ultimately cause kidney damage. We also discuss effective protective measures, such as rapidly acting oral hydration schemes and loop diuretics, in the context of CIAKI pathophysiology. Understanding of how CIAKI arises in different patient groups could enable a marked reduction in incidence and improved outcomes. The ultimate goal is to shape CIAKI prevention strategies for individual patients.

Endothelial dysfunction (ED) comes with age, even without overt vessel damage such as that which occurs in atherosclerosis and diabetic vasculopathy. We hypothesized that aging would affect the downstream signalling of the endothelial nitric oxide (NO) system in the vascular smooth muscle (VSM). With this in mind, resistance mesenteric arteries were isolated from 13-week (juvenile) and 40-week-old (aged) mice and tested under isometric conditions using wire myography. Acetylcholine (ACh)-induced relaxation was reduced in aged as compared to juvenile vessels. Pretreatment with L-NAME, which inhibits nitrix oxide synthases (NOS), decreased ACh-mediated vasorelaxation, whereby differences in vasorelaxation between groups disappeared. Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10−6 mol L−1) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10−6 mol L−1) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels. Mesenteric arteries and aortas did not reveal apparent histological differences between groups (van Gieson staining). The mRNA expression of the α1 and α2 subunits of sGC was lower in aged animals, as was PDE5 mRNA expression. In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction.

The renin–angiotensin system (RAS) and hypoxia have a complex interaction: RAS is activated under hypoxia and activated RAS aggravates hypoxia in reverse. Renin is an aspartyl protease that catalyzes the first step of RAS and tightly regulates RAS activation. Here, we outline kidney renin expression and release under hypoxia and discuss the putative mechanisms involved. It is important that renin generally increases in response to acute hypoxemic hypoxia and intermittent hypoxemic hypoxia, but not under chronic hypoxemic hypoxia. The increase in renin activity can also be observed in anemic hypoxia and carbon monoxide-induced histotoxic hypoxia. The increased renin is contributed to by juxtaglomerular cells and the recruitment of renin lineage cells. Potential mechanisms regulating hypoxic renin expression involve hypoxia-inducible factor signaling, natriuretic peptides, nitric oxide, and Notch signaling-induced renin transcription.

Oxygen affinity to haemoglobin is indicated by the p50 value (pO 2 at 50% O 2 Hb) and critically determines cellular oxygen availability. Although high Hb-O 2 affinity can cause tissue hypoxia under conditions of well O 2 saturated blood, individual differences in p50 are commonly not considered in clinical routine. Here, we investigated the diversity in Hb-O 2 affinity in the context of physiological relevance. Oxyhaemoglobin dissociation curves (ODCs) of 60 volunteers (18–40 years, both sexes, either endurance trained or untrained) were measured at rest and after maximum exercise (VO 2 max) test. At rest, p50 values of all participants ranged over 7 mmHg. For comparison, right shift of ODC after VO 2 max test, representing the maximal physiological range to release oxygen to the tissue, indicated a p50 difference of up to 10 mmHg. P50 at rest differs significantly between women and men, with women showing lower Hb-O 2 affinity that is determined by higher 2,3-BPG and BPGM levels. Regular endurance exercise did not alter baseline Hb-O 2 affinity. Thus, p50 diversity is already high at baseline level and needs to be considered under conditions of impaired tissue oxygenation. For fast prediction of Hb-O 2 affinity by blood gas analysis, only venous but not capillary blood samples can be recommended.

AT1 receptors mediate angiotensin II–induced release of nitric oxide in afferent arterioles. Recent studies have indicated that angiotensin II (Ang II) possibly activates the nitric oxide (NO) system. We investigated the role of AT receptor subtypes (AT-R) in mediating the Ang II–induced NO release in afferent arterioles (Af) of mice. Isolated Af of mice were perfused, and the isotonic contraction measured. Further, NO release was determined using DAF-FM, a fluorescence indicator for NO. Moreover, we qualitatively assessed the expression of AT-R at the mRNA level using reverse transcription-polymerase chain reaction (RT-PCR). Ang II reduced luminal diameters dose dependently (67.3 ± 6.3% at 10−6 mol/L). Inhibition of AT2-R with PD123.319 did not change the Ang II contractile response. AT1-R blockade with ZD7155 inhibited contraction. Stimulation of AT2-R during AT1-R inhibition with ZD7155, and preconstriction with norepinephrine (NE) had no influence on the diameter. Drug application via the perfusion pipette changed flow and pressure, and enhanced NO fluorescence by ΔF = 4.0 ± 0.4% (N = 14, background). Luminal application of Ang II (10−7 mol/L) increased the NO fluorescence by ΔF = 9.9 ± 1.2% (N = 8). AT1-R blockade blunted the increase to background levels (ΔF to 4.0 ± 0.3%, N = 6, P < 0.05), but AT2-R blockade did not (8.1 ± 0.9%, N = 9). L-NAME nearly abolished the Ang II effect on the NO fluorescence (ΔF = 1.6 ± 0.5% (N = 8). NE did not increase NO release beyond the background levels. RT-PCR showed expression of both AT1-R and AT2-R. The results indicate an Ang II–induced NO release in Af of mice, which is mediated by AT1-R. Thus, Ang II balances its own constrictor action in Af. This control mechanism is very important in view of high renin and angiotensin II concentration in the juxtaglomerular apparatus.

In hypoxic and acidic tissue environments, nitrite is metabolised to nitric oxide, thus, bringing about novel therapeutic options in myocardial infarction, peripheral artery disease, stroke, and hypertension. Following renal ischemia, reperfusion of the kidney remains incomplete and tissue oxygenation is reduced for several minutes to hours. Thus, in renal ischemia-reperfusion injury, providing nitrite may have outstanding therapeutic value. Here we demonstrate nitrite’s distinct potential to rapidly restore tissue oxygenation in the renal cortex and medulla after 45 minutes of complete unilateral kidney ischemia in the rat. Notably, tissue oxygenation was completely restored, while tissue perfusion did not fully reach pre-ischemia levels within 60 minutes of reperfusion. Nitrite was infused intravenously in a dose, which can be translated to the human. Specifically, methaemoglobin did not exceed 3%, which is biologically negligible. Hypotension was not observed. Providing nitrite well before ischemia and maintaining nitrite infusion throughout the reperfusion period prevented the increase in serum creatinine by ischemia reperfusion injury. In conclusion, low-dose nitrite restores renal tissue oxygenation in renal ischemia reperfusion injury and enhances regional kidney post-ischemic perfusion. As nitrite provides nitric oxide predominantly in hypoxic tissues, it may prove a specific measure to reduce renal ischemia reperfusion injury.

Reduced renal medullary oxygen supply is a key factor in the pathogenesis of acute kidney injury (AKI). As the medulla exclusively receives blood through descending vasa recta (DVR), dilating these microvessels after AKI may help in renoprotection by restoring renal medullary blood flow. We stimulated the NO-sGC-cGMP signalling pathway in DVR at three different levels before and after hypoxia/re-oxygenation (H/R). Rat DVR were isolated and perfused under isobaric conditions. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (10−6 mol/L) impaired cGMP degradation and dilated DVR pre-constricted with angiotensin II (Ang II, 10−6 mol/L). Dilations by the soluble guanylyl cyclase (sGC) activator BAY 60-2770 as well as the nitric oxide donor sodium nitroprusside (SNP, 10−3 mol/L) were equally effective. Hypoxia (0.1% O2) augmented DVR constriction by Ang II, thus potentially aggravating tissue hypoxia. H/R left DVR unresponsive to sildenafil, yet sGC activation by BAY 60-2770 effectively dilated DVR. Dilation to SNP under H/R is delayed. In conclusion, H/R renders PDE5 inhibition ineffective in dilating the crucial vessels supplying the area at risk for hypoxic damage. Stimulating sGC appears to be the most effective in restoring renal medullary blood flow after H/R and may prove to be the best target for maintaining oxygenation to this vulnerable area of the kidney.