Postischemic Acute Renal Failure Research Articles

Stimulation of Structural and Functional Recovery of the Kidney in Rats with Postischemic Acute Renal Failure of Different Severity by Embryonic Protein-Peptide Complex Therapy.

In male rats, acute renal failure was simulated by clamping the vascular pedicle of the left kidney for 60 or 90 min and right-sided nephrectomy. In the control series, no therapy was performed. In the experimental series, the animals were daily injected subcutaneously with Cellex, a protein-peptide complex (PPC) chromatographically isolated from the brain tissue of pig embryos with a molecular weight of its components from 10 to 250 kDa. PPC was administered 5 times a week (10 injections) in a dose of 0.1 ml/kg (0.1 mg active substance per 1 kg body weight). Ischemia of a single kidney led to the development of acute renal failure, more severe after 90-min ischemia. PPC therapy reduced the severity of functional disorders mainly at the early stages (3 and 7 days) with normalization of blood concentrations of urea and creatinine, creatinine clearance, tubular reabsorption of sodium and calcium, including the cases with 90-min ischemia, which did not occur in the control series. PPC therapy also contributed to hypertrophy of many glomeruli, prevented the development of glomerulosclerosis, and reduced damage to the epithelium of the renal tubules. At the same time, neither pronounced lymphohistiocytic infiltration, nor focal nephrosclerosis typical of control series were observed.

Angiotensin 2 type 1 receptor blockade different affects postishemic kidney injury in normotensive and hypertensive rats.

Many studies demonstrated that angiotensin 2 type 1 receptor (AT1R) blockade accelerates renal recovery in post-ischaemic kidney but there are many controversies related to its net effect on kidney structure and function. During the past years, our research group was trying to define the pathophysiological significance of the renin-angiotensin system on post-ischemic acute renal failure (ARF) development in normotensive Wistar as well as hypertensive rats (SHR). This review mostly summarizes our experience in that field. Our previous studies in normotensive rats revealed that AT1R blockade, except slightly renal vascular resistance improvement, had no other obvious beneficial effects, and therefore implies angiotensin 2 (Ang-2) overexpression as non-dominant on kidney reperfusion injuries development. Similarly it was observed in Wistar rats with induced mild (L-NAME, 3mg/kg b.w.) nitric oxide (NO) deficiency. Expectably, in strong induced (L-NAME, 10mg/kg b.w.) NO deficiency associated with ARF, massive tubular injuries indicate harmful effects of AT1R blockade, implying strongly disturbed glomerular filtration and suggesting special precaution related to AT1R blockers usage. Opposite to previous, by our opinion, AT1R antagonism promises new advance in treatment of essentially hypertensive subjects who develop ARF. Increased glomerular filtration, diminished oxidative stress, and most importantly improved tubular structure in postishemic SHR treated with AT1R blocker losartan, implicate Ang-2 over production as potently agent in the kidney ischemic injury, partly trough generation of reactive oxygen species. These data contribute understanding the pathogenesis of this devastating illness in hypertensive surroundings.

Atorvastatin treatment attenuates renal injury in an experimental model of ischemia–reperfusion in rats

BackgroundRecent studies in animal models have shown that statins can protect against renal failure independent of their lipid-lowering actions, and there is also an association between statin use and improved renal function after suprarenal aortic clamping. We investigated the hypothesis that post-ischemic acute renal failure could be ameliorated with atorvastatin (ATO) treatment and the possible molecular mechanisms in a model of ischemia–reperfusion (IR) in rats.MethodsTwenty-four male Sprague–Dawley rats were divided into three groups: sham, IR, and IR + ATO. ATO was given by a single intraperitoneal injection (10 mg/kg) 30 min before reperfusion in the IR + ATO group. The IR group and sham group received saline vehicle via the intraperitoneal route.ResultsAfter 24 h of IR, serum creatinine levels were increased in the IR group compared with the sham group (p < 0.001). ATO treatment reduced the elevation of serum creatinine level by 18% (p < 0.05) and significantly increased the creatinine clearance rate (p < 0.001). Concentrations of advanced oxidation protein products and malondialdehyde were reduced in the ATO group, approaching levels observed in sham-group rats. ATO treatment alleviated pathological changes in renal tubular cells. Protein and mRNA levels of intercellular adhesion molecule-1 and monocyte chemotactic protein-1 were reduced significantly.ConclusionsThese data suggest that direct protection of injured kidneys by ATO was possible even though the drug was injected 30 min before reperfusion, and that ATO may reduce IR injury by anti-inflammatory effects and by reducing oxidation stress.

The Toll-IL-1R member Tir8 modulates post-transplant kidney ischemia/reperfusion injury by inhibiting resident leukocyte expansion

Event Abstract Back to Event The Toll-IL-1R member Tir8 modulates post-transplant kidney ischemia/reperfusion injury by inhibiting resident leukocyte expansion Paola Cassis1, Sistiana Aiello1*, Nadia Azzollini1, Samantha Solini1, Giuseppe Remuzzi1 and Marina Noris1 1 IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Italy Ischemia/reperfusion injury (IRI), occurring after transplantation, activates TLRs/IL-1R on inflammatory leukocytes amplifying adaptive immune response. In a mouse model of renal artery clamp deficiency of Tir8, a IL-1R/TLR negative regulator, aggravated post-ischemic acute renal failure in association with intrarenal leukocyte accumulation. We investigated the role of TIR8 in modulating post-transplant IRI and inflammatory response in mouse model of syngeneic kidney transplant. Donor and recipient C57BL/6 mice were congenic for CD45 leukocyte antigen to allow discriminating between intragraft recipient and donor leukocytes. Wild-type (wt-group n=5) or Tir8-/- (Tir8-/--group, n=5) donor kidneys were exposed to 30 min cold ischemia before transplant. Transient impairment of graft function was found at 1day post-transplant in wt-group (BUN: 1day 53±19, 30day: 27±3mg/dl). At variance the Tir8-/--group showed irreversible severe graft dysfunction (BUN: 1day 95±23, 30day: 67±23 mg/dl, P<0.05 vs wt-group). Both at 10 and 30 days post-transplant lower numbers (P<0.05) of intragraft leukocytes were found in the wt-group (20±9/field, 61±18/field, respectively) vs the Tir8-/--group (104±17/field, 117±24/field, respectively). At 10 days the majority of leukocytes were of donor origin both in the wt and the Tir8-/- groups (79±8%, 78±2%, respectively). At 30days, in the wt-group the majority of intragraft leukocytes were of recipient origin (63±6%) while 63±2% of intragraft leukocytes were of donor origin in the Tir8-/--group. These results indicate that TIR8 modulates post-transplant IRI possibly by suppressing expansion and activation of resident leukocytes within the kidney graft. Keywords: Ischemia, TLRs (Toll-like receptors), Kidney Transplantation, Dendritic Cells, congenic mice Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Cassis P, Aiello S, Azzollini N, Solini S, Remuzzi G and Noris M (2013). The Toll-IL-1R member Tir8 modulates post-transplant kidney ischemia/reperfusion injury by inhibiting resident leukocyte expansion. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00691 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 13 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Sistiana Aiello, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy, sistiana.aiello@marionegri.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Paola Cassis Sistiana Aiello Nadia Azzollini Samantha Solini Giuseppe Remuzzi Marina Noris Google Paola Cassis Sistiana Aiello Nadia Azzollini Samantha Solini Giuseppe Remuzzi Marina Noris Google Scholar Paola Cassis Sistiana Aiello Nadia Azzollini Samantha Solini Giuseppe Remuzzi Marina Noris PubMed Paola Cassis Sistiana Aiello Nadia Azzollini Samantha Solini Giuseppe Remuzzi Marina Noris Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Steroid Pretreatment of Deceased Donors Does Not Prevent Postischemic Acute Renal Failure

Steroid Pretreatment of Deceased Donors Does Not Prevent Postischemic Acute Renal Failure

Ischemia Reperfusion Induces IFN Regulatory Factor 4 in Renal Dendritic Cells, which Suppresses Postischemic Inflammation and Prevents Acute Renal Failure

Ischemia reperfusion (IR) activates TLRs causing subsequent sterile inflammation, for example in postischemic acute renal failure. Unexpectedly, TLR signaling predominates in intrinsic renal cells and not in intrarenal APCs in the postischemic kidney. We hypothesized that certain factors suppress APC activation and thereby limit sterile renal inflammation, for example, IFN regulatory factor 4 (IRF-4), an inducible inhibitor of LPS signaling. Oxidative stress was a trigger for IRF4 induction in myeloid cells in vitro as well as in CD45(+)/CD11c+ cells in the postischemic kidney. Lack of IRF4 aggravated acute renal failure 24 h after renal artery clamping together with increased intrarenal expression of TNF-alpha, IL-6, CXCL2, and CCL2 as well as excessive tubular necrosis and peritubular neutrophil influx as compared with wild-type IR kidneys. This effect almost entirely depended on the role of IRF4 to suppress TNF-alpha release by intrarenal APCs because either clodronate liposome depletion of these cells or TNF-alpha blockade with etanercept entirely abrogated the aggravation of cytokine expression and acute renal failure in Irf4-deficient mice. Thus, loss-of-function mutations in the IRF4 gene predispose to IR injury because the postischemic induction of IRF4 in resident APCs like CD11c(+) dendritic cells, suppresses them to secrete TNF-alpha, and thereby limits inappropriate immunopathology.

TEMPOL IMPROVES REGIONAL HEMODYNAMICS IN SPONTANEOUSLY HYPERTENSIVE RATS WITH ACUTE RENAL FAILURE: 3C.06

Objective: Acute renal failure (ARF) and hypertension as a comorbid disorders can be found frequently in intensive care unit patients. The aim of our study was to investigate the antihypertensive effects of 4-Hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl (tempol), synthetic SOD mimetic, on regional haemodynamics in the course of ARF in hypertension. Design and Method: Experiment was performed in anesthetized, six-month-old male spontaneously hypertensive rats (SHR). The right kidney was removed and ARF was induced by clamping the left renal artery for 40 minutes. SHR were divided in 3 experimental groups: sham operated group (SHAM; n = 7); ARF group (ARF; n = 9); and ARF group with tempol treatment (40 mg/kg/h) (ARF+TEM; n = 8). Tempol was given by infusion during the period of three hours after reperfusion. Mean arterial pressure (MAP), carotid blood flow (CBF) and renal blood flow (RBF) were measured and carotid vascular resistance (CVR) and renal vascular resistance (RVR) was calculated 24 h after reperfusion.Conclusion: Our results indicate that in hypertension free oxygen species contribute to renal vasoconstiction, one of the major pathophysiological mechanism of postischemic ARF.

Role of the renal sympathetic nervous system in mediating renal ischaemic injury-induced reductions in renal haemodynamic and excretory functions

We investigated the role of renal sympathetic innervation in the deterioration of renal haemodynamic and excretory functions during the early post-ischaemic phase of renal ischaemia/reperfusion injury. Anaesthetised male Sprague-Dawley rats were subjected to unilateral renal ischaemia by clamping the left renal artery for 30 min followed by reperfusion. Following acute renal denervation clearance experiments were performed. In a different set of experiments, the renal nerves were electrically stimulated at increasing frequencies and responses in renal blood flow and renal vascular resistance were recorded. Denervated post-ischaemic acute renal failure (ARF) rats showed higher urine flow rate, absolute and fractional sodium excretions, urinary sodium to urinary potassium, glomerular filtration rate and basal renal blood flow but lower basal renal vascular resistance (all p < 0.05 vs innervated ARF rats). Potassium excretion was significantly lower in denervated group as per fractional (p < 0.05 vs innervated ARF rats) but not absolute potassium excretion (p > 0.05 vs innervated ARF rats). The rise in mean arterial pressure and renal vasoconstrictor response to renal nerve stimulation were blunted in denervated ischaemic ARF rats (all p < 0.05 vs innervated ARF rats). Renal histopathology in denervated ARF rats manifested a significantly lower medullary congestion, inflammation and tubular injury compared to innervated counterparts (p < 0.05 vs innervated ARF rats). The findings strongly suggest the involvement of renal sympathetic tone in the post-ischaemic events of ischaemic ARF, as the removal of its action to a degree ameliorated the post-ischaemic renal dysfunctions.

Resident Dendritic Cells Prevent Postischemic Acute Renal Failure by Help of Single Ig IL-1 Receptor-Related Protein

Ischemia-reperfusion (IR) triggers tissue injury by activating innate immunity, for example, via TLR2 and TLR4. Surprisingly, TLR signaling in intrinsic renal cells predominates in comparison to intrarenal myeloid cells in the postischemic kidney. We hypothesized that immune cell activation is specifically suppressed in the postischemic kidney, for example, by single Ig IL-1-related receptor (SIGIRR). SIGIRR deficiency aggravated postischemic acute renal failure in association with increased renal CXCL2/MIP2, CCL2/MCP-1, and IL-6 mRNA expression 24 h after IR. Consistent with this finding interstitial neutrophil and macrophage counts were increased and tubular cell necrosis was aggravated in Sigirr-deficient vs wild-type IR kidneys. In vivo microscopy revealed increased leukocyte transmigration in the postischemic microvasculature of Sigirr-deficient mice. IL-6 and CXCL2/MIP2 release was much higher in Sigirr-deficient renal myeloid cells but not in Sigirr-deficient tubular epithelial cells after transient hypoxic culture conditions. Renal IR studies with chimeric mice confirmed this finding, as lack of SIGIRR in myeloid cells largely reproduced the phenotype of renal IR injury seen in Sigirr(-/-) mice. Additionally, clodronate depletion of dendritic cells prevented the aggravated renal failure in Sigirr(-/-) mice. Thus, loss of function mutations in the SIGIRR gene predispose to acute renal failure because SIGIRR prevents overshooting tissue injury by suppressing the postischemic activation of intrarenal myeloid cells.

Morphological Changes in the Kidneys of Rats with Postischemic Acute Renal Failure after Intrarenal Administration of Fetal Mesenchymal Stem Cells from Human Bone Marrow

Chronic experiments on outbred albino rats were performed to compare the dynamics of histological signs for postischemic renal injury (90-min thermal ischemia) after intraparenchymal injection of cultured fetal MSC from human bone marrow. Functional indexes of the ischemic kidney were predetermined. In the early period after ischemia (day 4), administration of human bone marrow MSC was followed by the increase in blood flow in the microcirculatory bed and decrease in the degree of alteration in renal tubules. An increase in the area of zones with histological signs for normal function of tubules was accompanied by the improvement of biochemical indexes for renal function. In the delayed period, a protective effect of cell therapy was manifested in the prevention of death of renal tubules. Mild calcification of the necrotic tubular epithelium served as a marker of this process. Human bone marrow MSC were labeled with the fluorescent probe Calcein. These cells migrated from the site of injection, spread in the interstitium, and retained viability for 7 days. During this period, some cells were incorporated into the lumen of renal tubules.

Ischemic Postconditioning Prevents Ischemic Acute Renal Failure

Introduction Delayed graft function (DGF), a frequent complication after kidney transplantation, decreases graft survival. Ischemia/reperfusion (I/R) injuries play a major role in DGF pathophysiology. Because ischemic postconditioning (IP) is efficient to prevent myocardial I/R injuries and reduce infarct size, we sought to describe renal effects of IP. Materials and Methods Swiss mice were divided into three groups after left nephrectomy. Thirty minutes of right kidney ischemia followed by three cycles of 30 seconds of ischemia and reperfusion (IP group: n = 12) versus immediate reperfusion ( n = 7). Left nephrectomized and right kidney sham operated mice were used as control groups ( n = 6). Mice were followed for an 8-day survival analysis. Serum levels of creatinine and protein as well as weights were determined 2 days before and at days 2 and 8 after surgery. Results IP improved kidney function on day 2; the mean serum creatinine level was 1.25 ± 0.71 versus 2.9 ± 1.3 mg/dL in the immediate reperfusion group ( P < .02). We also observed a trend toward increased animal survival (25% vs. 0% in the immediate reperfusion group; P = .10). Despite a significant increase in proteinuria among all groups, there was no significant difference. Conclusion In a mouse model, IP seems to prevent postischemic acute renal failure after 30 minutes of kidney ischemia.

The Duffy antigen receptor for chemokines in acute renal failure: A facilitator of renal chemokine presentation.

Acute renal failure remains a major challenge in critical care medicine. Both neutrophils and chemokines have been proposed as key components in the development of acute renal failure. Although the Duffy antigen receptor for chemokines (DARC) is present in several tissues and a highly specific ligand for various chemokines, its exact role in vivo remains unclear. Prospective, controlled experimental study. University-based research laboratory. C57BL/6 wild-type and DARC gene-deficient mice (DARC-/-). To unravel the functional relevance of DARC in vivo, we compared wild-type and DARC-/- using neutrophil-dependent models of acute renal failure, induced by either local (renal ischemia-reperfusion) or systemic (endotoxemia, lipopolysaccharide) injury. Plasma creatinine and blood urea nitrogen concentrations served as indicators of renal function or dysfunction. Enzyme-linked immunosorbent assays were used to measure tissue and plasma chemokine concentrations. We also performed immunostaining to localize chemokine expression and flow cytometry to evaluate neutrophil recruitment into the kidney. Following renal injury, wild-type mice developed moderate renal ischemia-reperfusion(lipopolysaccharide, 300% increase in plasma creatinine concentrations) to severe acute renal failure (renal ischemia-reperfusion, 40% mortality) as well as extensive renal neutrophil recruitment. DARC-/- mice exhibited no renal dysfunction (renal ischemia-reperfusion) or only very mild renal dysfunction (lipopolysaccharide, 20% increase in serum creatinine concentrations). DARC-/- mice showed no postischemic neutrophil infiltration. Although DARC-/- and wild-type mice exhibited similar global renal neutrophil-recruitment during endotoxemia, DARC-/- mice showed significantly impaired neutrophil extravasation. Total renal concentrations of the chemokine macrophage inflammatory protein 2, which has been shown to bind to DARC and to be crucial in postischemic acute renal failure, were either identical (lipopolysaccharide) or only moderately different (renal ischemia-reperfusion) between wild-type and DARC-/- mice. Immunostaining revealed an absence of macrophage inflammatory protein-2 in renal endothelial cells of DARC-/- mice. We suggest that DARC predominantly exerts its effects by controlling spatial chemokine distribution, which in turn regulates neutrophil recruitment and subsequent acute renal failure.

Bosentan and losartan ameliorate acute renal failure associated with mild but not strong NO blockade

Acute renal failure (ARF) is a devastating illness, especially when it occurs in various conditions with impaired nitric oxide (NO) synthesis, such as arterial hypertension, heart failure and some renal diseases. We have directed our investigations to effects of both angiotensin II (AII) and endothelin (ET) receptor blockade associated with mild or strong NO deficiency on haemodynamic, biochemical and morphological parameters in experimental post-ischaemic ARF. In this study, we used bosentan (dual, ETA/ETB-receptor antagonist), losartan (non-peptide, competitive antagonist of type I AII receptor), and NG-nitro-L-arginine methyl ester (L-NAME), inhibitor of NO synthesis. Experiments were performed in anaesthetized, adult male Wistar rats. The right kidney was removed and the renal ischaemia was performed by clamping the left renal artery for 45 min. Experimental groups received receptor antagonists (bosentan or losartan) or vehicle (saline) in the femoral vein 20 min before, during and 20 min after the period of ischaemia. L-NAME was given as i.v. bolus before each antagonist infusion. All parameters were measured 24 h after reperfusion. Our results showed that strong NO blockade overcame effects of both ET and AII receptor blockade in experimental post-ischaemic ARF. In addition, the AII receptor blockade had a harmful effect on this condition, probably due to disturbed autoregulatory renal function. On the other hand, ET and AII receptor blockade in mild NO blockade associated with reperfusion injury, improves the most haemodynamic, biochemical and morphological parameters. We concluded that experimental post-ischaemic ARF is neither AII nor ET mediated in case of strong NO blockade, but, in more realistic conditions of mild NO deficiency, these peptides represent significant players whose receptor blockade expressed relevant therapeutic potential.

Role of Na+/H+ Exchanger in the Pathogenesis of Ischemic Acute Renal Failure in Mice

We evaluated the effects of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a Na+/H+ exchanger (NHE) inhibitor, on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in mice. Ischemic ARF was induced by clamping the left renal artery and vein for 40 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Preischemic treatment with EIPA attenuated the I/R-induced renal dysfunction. Histopathological examination of the kidney of ARF mice revealed severe renal damage such as tubular necrosis and proteinaceous casts in the tubuli. Histologically evident damage was also improved by preischemic treatment with EIPA. In addition, the I/R-induced increase in renal endothelin-1 (ET-1) content was suppressed by preischemic treatment with EIPA, reflecting the difference in immunohistochemical ET-1 localization in necrotic tubular epithelium. However, the postischemic treatment with EIPA failed to improve the I/R-induced renal dysfunction and ET-1 overproduction. These findings suggest that NHE activation, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of I/R-induced renal injury. The inhibition of NHE by EIPA may be considered as a therapeutic approach to protect the postischemic ARF.

Alteration in Renal Organic Anion Transporter 1 After Ischemia/Reperfusion in Cadaveric Renal Allografts

We have previously shown that postischemic injury to renal allografts results in profound impairment of p-aminohippuric acid (PAH) extraction. To elucidate the cellular integrity of the human organic anion transporter 1 (hOAT1) in postischemic acute renal failure (ARF), immunohistochemical analysis of hOAT1 was performed in cadaveric renal allografts using confocal microscopy for three-dimensional reconstruction of serial optical images. Biopsy samples were obtained from 10 cadaveric renal allografts 1 hr after reperfusion during transplant operation. Control tissues were obtained from four living donors of healthy kidneys immediately before an arterial clamp was applied to the renal artery. Control tissues demonstrated hOAT1 distributed to basolateral membrane of proximal tubule cells. In contrast, maldistribution of hOAT1 to cytoplasm and/or diminution of the protein was noted in cadaveric allografts. Characteristics of maldistribution were variable: disappearance of lateral distribution, diffuse cytoplasmic aggregates, apical cytoplasmic aggregates, and disappearance of the staining. In addition, iothalamate and PAH clearances were performed on posttransplant days 3-7 in 18 recipients of a cadaveric renal allograft. PAH clearance was depressed <250 ml/min in all but three subjects. We conclude that reperfused, transplanted kidneys exhibit maldistribution of hOAT1 in proximal tubule cells, resulting in impairment of PAH clearance. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

The Association Between Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use During Postischemic Acute Transplant Failure and Renal Allograft Survival

Postischemic acute renal transplant failure occurs in approximately one fourth of all dead donor transplantations. Uncertainty exists regarding the putative association between the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) and kidney transplant graft survival in patients with delayed allograft function. We conducted an open cohort study of all 436 patients who experienced an acute renal transplant failure out of all 2,031 subjects who received their first kidney transplant at the Medical University of Vienna between 1990 and 2003. Actual and functional graft survival was compared between users and nonusers of ACEI/ARB using exposure propensity score models and time-dependent Cox regression models. Ten-year actual graft survival averaged 44% in the ACEI/ARB group, but only 32% in patients without ACEI/ARB (P=0.002). The hazard ratio of actual graft failure was 0.58 (95% confidence interval: 0.35-0.80, P=0.002) for ACEI/ARB users compared with nonconsumers. Seventy-one percent of subjects with ACEI/ARB had a functional graft at 10 years versus 64% of ACEI/ARB nonusers (P=0.027). The hazard ratio of functional graft loss was 0.48 (95% confidence interval: 0.24-0.91, P=0.025). Use of ACEI/ARB in patients experiencing delayed allograft function was associated with longer actual and functional transplant survival.

Gene expression and biomarkers in renal transplant ischemia reperfusion injury

The incidence of postischemic acute renal allograft failure (ARF) occurs in roughly 25% of cadaveric donor kidney recipients. This high rate remained virtually unchanged over the last decades despite modification in recipient management and modern immunosuppressive strategies. It has recently been shown that among other reasons, the systemic inflammation in the brain death cadaveric organ donor contributes to subsequent ARF in the recipient. This review focuses on the consequences of ischemia and reperfusion on the cellular level and offers potential solutions for the reduction of ARF. Genome-wide gene expression analysis together with sophisticated biostatistical analysis made it possible to identify several candidate gene products and proteins that may act as specific and sensitive biomarker for renal inflammation and ischemia. These markers may be very helpful in the clinical management of patients with a high a priori risk of subsequent ARF such as recipients of marginal donor kidneys. Ongoing clinical trials will evaluate whether immunosuppression of the cadaveric organ donor before organ harvest will have the potential to reduce inflammation in the transplant kidney and subsequently lead to a reduction in the rate of ARF.

Locally produced extravascular pool of complement is crucial in mediating post-ischemic acute renal failure

Locally produced extravascular pool of complement is crucial in mediating post-ischemic acute renal failure

Local extravascular pool of C3 is a determinant of postischemic acute renal failure

The third complement component (C3) is an acute phase protein that plays a central role in reperfusion injury in several organ models. To investigate the contribution of local synthesis of C3 and distinguish it from that of circulating complement mainly produced by hepatic synthesis, we employed a mouse renal isograft model. Our model demonstrated a close relationship between the extent of intrarenal expression of C3 and cold-ischemia induced injury. Ischemic C3-positive donor kidneys transplanted into C3-positive or C3-negative recipients developed widespread tissue damage and severe acute renal failure. In contrast, ischemic C3-negative isografts exhibited only mild degrees of functional and structural disturbance, even when transplanted into normal C3-positive recipients. Thus local synthesis of C3, mostly identified in the tubular epithelium, was essential for complement-mediated reperfusion damage, whereas circulating C3 had a negligible effect. Our results suggest a two-compartment model for the pathogenic function of C3, in which the extravascular compartment is the domain of local synthesis of C3, and where the role of circulating C3 is redundant. Our data cast new light on the mechanism of complement-mediated tissue injury in nonimmunological disorders, and challenges the longstanding dogma that circulating components are the main complement effectors of extravascular tissue damage.

Magnesium Supplementation Combined with N-Acetylcysteine Protects against Postischemic Acute Renal Failure

Magnesium is a potent vasodilator whose effects have not been evaluated in renal ischemia. The antioxidant properties of N-acetylcysteine (NAC) partially protect animals from ischemic/reperfusion injury. This study was designed to evaluate magnesium supplementation, alone or combined with NAC, on ischemic acute renal failure. Rats were maintained on normal diets, supplemented or not with MgCl(2).6H(2)O (1% in drinking water) for 23 d, and some rats received NAC (440 mg/kg body wt) on days 20 to 23. On day 21, ischemia was induced by clamping both renal arteries for 30 min. Five groups were studied: Normal, ischemia, ischemia+magnesium, ischemia+NAC, and ischemia+magnesium+NAC. GFR (inulin clearance), renal blood flow (RBF), FEH(2)O, and FENa were determined. Serum magnesium was decreased in ischemia-only rats. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. However, NAC completely restored the tubular damage induced by ischemia/reperfusion. Semiquantitative immunoblotting showed that NAC prevented the decreased expression of Na-K-2Cl co-transporter and aquaporin 2 after renal ischemia/reperfusion. Untreated rats with acute renal failure demonstrated markedly decreased endothelial nitric oxide synthase expression. Significantly, treatment with NAC, magnesium, or both completely inhibited downregulation of endothelial nitric oxide synthase. The tubular necrosis scores were lower in rats that were treated with NAC alone or with the magnesium-NAC combination. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. The NAC protected tubules from ischemia, decreased infiltrating macrophages/lymphocytes, and had a mild protective effect on GFR. In ischemic/reperfusion injury, renal function benefits more from the magnesium-NAC combination than from magnesium alone.