Significant Renal Dysfunction Research Articles

Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4−/−), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4−/−). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogen-activated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4−/− and Tg-CAST mice but not in LYZ/Capn4−/− mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.

Impact Of Accessory Renal Artery Exclusion During Fenestrated Endovascular Repair For Juxtarenal Aortic Aneurysm

Introduction - The purpose of this study is to determine the clinical impact of accessory renal artery coverage on the renal function after fenestrated endovascular repair (f-EVAR) for juxtarenal aortic aneurysm. Methods - Between January 2005 and December 2016, 77 patients had f-EVAR for juxtarenal aneurysm with the Cook Zenith fenestrated endograft. Retrospectively, pre-operative CT was reviewed for the number and the diameter of accessory renal artery and post-operative CT was analyzed for accessory renal artery thrombosis and renal infarct. Patients with at least one renal accessory artery covered by the endograft were in group Acc and patients without renal accessory artery covered were in group NoAcc. Immediate postoperative renal insufficiency was compared between both groups. During follow-up, significant renal dysfunction was defined by a 25% or more deterioration of estimated glomerular filtration rate asses on two or more successive control. Results - Sixty-one patients (79%) were included in group NoAcc and sixteen patients (21%) were included in group Acc, 21 accessory renal arteries were covered, 8 had a diameter ≥ 3mm and 4 patients had 2 renal accessory arteries. The demographics of the patients were similar, the median pre-operative serum creatinine levels (group NoAcc vs group Acc) were 92 mmol/L (range 49-156 mmol/L) and 99 mmol/L (range 72-163 mmol/L) (p = .692), median aneurysm diameters were 54 mm (range 50-89 mm) and 55.5 mm (range 52 - 63 mm) (p=.138), respectively. Median quantity of contrast medium was 204 ml (range 67 – 540) and 230 ml (range 120 – 450) (p=.526). On post f-EVAR CT, 4 patients had an identified renal infarct, all of them were secondary to intentional coverage of an accessory renal artery, no immediate renal stent thrombosis was observed. New onset of postoperative renal insufficiency was detected in 8% versus 12% (p=.630), mortality was 2% vs 6% (p=.374), in NoAcc and Acc groups, respectively. At 3 years, patient survival was 89% vs 84% (p=.358), freedom from renal function deterioration was 78% vs 74% (p=.702). Conclusion - This retrospective analysis found no immediate postoperative renal failure or late renal function deterioration resulting from accessory renal arteries coverage during f-EVAR for Juxta renal aneurysms.

Optimizing The Management of Obese HFpEF Phenotype: Can We Mind Both The Heart and The Kidney?

The adverse prognostic implications of significant renal dysfunction during treatment of acute decompensated heart failure (HF) in patients with obese HF and preserved ejection fraction (HFpEF) provide strong rationale for development of therapeutic strategies that enhance decongestion while preserving renal function in this cohort. The combination of preload sensitivity, intrinsic renal dysfunction related to obesity, glomerular hyperfiltration, reversible renal hypoperfusion (poor renal arterial perfusion and renal venous congestion), and decreased systemic vascular resistance in obesity may predispose patients to renal hemodynamic compromise during diuresis. Thus, serum creatinine increase should not be evaluated in isolation but rather considered in the context of the entire clinical picture in patients with obese HFpEF.

The UK Experience of Renal Transplantation in AL Amyloidosis

Systemic AL amyloidosis, caused by monoclonal light chain depositing as amyloid fibril protein, commonly presents with renal involvement. A third of patients with renal involvement have or develop significant renal dysfunction leading to end-stage renal failure (ESRF). In an era of improving life expectancy for patients with AL amyloidosis, renal transplantation, with its marked impact on improving quality of life and reducing the cost burden, is increasingly considered. We report the outcomes of fifty patients who had received a renal allograft between 2004-2019, seen at the UK National Amyloidosis Centre Patient characteristics were: 60% male; median age at diagnosis was 53.5 years (38-69 years); median ECOG performance status 1 (0-3); median presenting creatinine, eGFR and proteinuria were 199μmol/L (69-756 μmol/L), 27ml/min and 8.95g/24h (0.4-19.7g/24h) respectively. Involved light chains were - lambda - 36 (72%) and kappa - 14 (28%). 40 patients were evaluable (5 transplanted for non-amyloid conditions prior to diagnosis, 4 lost to follow up, 1 transplanted for amyloidosis overseas prior to referral). Thirteen (32.5%) had isolated renal involvement whilst 35 (87.5%) patients had other multi-organ involvement including 13/40 (32.5%) with cardiac involvement. Median time from diagnosis to ESRF was 15 months (0-115 months) and from renal replacement therapy to renal allograft was 28 months (3-83 months). Four (10%) received a pre-emptive renal allograft. At time of renal transplantation, patients had a median of 2 prior lines of chemotherapy (range 1-4) whilst 10/40 patients (25%) had a prior autologous stem cell transplant. At transplant, haematological responses (HR) were: complete response (CR) - 22 (55%), very good partial response (VGPR) - 12 (30%), partial response (PR) - 4 (10%) and stable disease - 2 (5%). Median time from HR to renal transplant was 29 months (0-93 months). From renal transplant, haematological PFS was 82.7 months (95% CI 61.2-104.2). Patients achieving a CR achieved a markedly higher PFS of 102.5 months (95% CI 68.8-136.3 months) (p=0.023) as did those with a dFLC <10mg/L at renal transplantation, 121.1 months (95% CI 91.5-150.6 months) (p=0.0001). At a median follow up of 107 months (26-231 months), 14 (35%) patients died, of whom only one had graft failure at the time of death. One patient (with stage 3 cardiac AL) died within 2 days of a renal allograft after a post-operative hypotensive episode. Nine (22.5%) patients had post-transplant chemotherapy for relapse. Median OS from renal transplantation was 106.6 months (95% CI 85.0-128.3 months); significantly better in patients achieving a CR (133.0 months, p=0.005) or dFLC <10mg/L (137.8 months, p=0.0001) prior to transplant. Stage of chronic kidney disease at presentation, plasma cell burden, age at renal transplantation and multi-organ involvement did not impact overall survival. Of the patients experiencing graft failure, 1 graft failed within a week of implantation due to primary non-function after a prolonged cold ischaemia time, 1 functioned poorly from implantation and failed within 4 months and a third failed after 45 months with evidence of amyloid recurrence in the graft. In conclusion, the outcomes of carefully selected patients with AL amyloidosis undergoing renal transplantation is promising and justifies careful consideration. There was only 1 peri-operative death. Patients in a complete response or who have a dFLC <10mg/L prior to renal allograft implantation have significantly better outcomes. At a median follow ~9 years, graft failure is rare (only 7.5%). Disclosures No relevant conflicts of interest to declare.

The Bigger Picture in Stroke Prevention and Anticoagulation: Think Beyond Atrial Fibrillation

This symposium brought together experts in cardiology, nephrology, diabetology, and clinical pharmacology to discuss best practice when caring for patients with atrial fibrillation (AF) and comorbidities. They urged delegates to not only consider the issue of AF but also to think about protection in a broader sense, including comorbidities to improve outcomes for patients when it comes to stroke prevention. Dr Ruff spoke of the tremendous opportunity to reduce the burden of stroke by addressing important modifiable risk factors for stroke, focussing on AF and diabetes, and their link to chronic kidney disease (CKD). Dr Bonnemeier and Dr Kreutz discussed patients with AF and renal dysfunction, noting that CKD is a frequent comorbidity associated with increased risk of stroke and bleeding among patients with AF. The associated patient case study inspired debate about the challenges of oral anticoagulant (OAC) therapy in this patient group and highlighted that while decline in renal function is common in AF patients treated with OAC, the extent of decline may depend on which anticoagulant is used. Furthermore, available data from randomised control trials and recent retrospective analyses were shared which showed differences in the progression of CKD associated with vitamin K antagonists (VKA) versus the novel OAC (NOAC), such as rivaroxaban. Dr Patel and Dr Rossing focussed on diabetes and AF, stating that their frequent coexistence is a bad combination associated with substantially increased risks of death and cardiovascular (CV) events. Exploring the link between diabetes and CKD, they demonstrated the significant impact renal dysfunction has on the prognosis of Type 2 diabetes mellitus (T2DM). They additionally presented recent evidence from retrospective analyses comparing renal outcomes in patients with AF and diabetes treated with NOAC or VKA, noting that choice of anticoagulation may impact risk for renal outcomes.

P4560The efficacy and safety of mineralocorticoid-receptor antagonists: spironolactone and eplerenone in resistant hypertension and chronic kidney disease stages 3

Abstract Chronic kidney disease (CKD) is the most frequent comorbidity associated with resistant hypertension (RH). Despite mineralocorticoid-receptor antagonists (MRAs) have been proven to be effective in RH, this drugs are underused in this patients and must be used very carefully in CKD due to the higher risk of hyperkalemia (HK) and significant renal dysfunction (RD), particularly in combination with renin angiotensin inhibitors. The aim was to compare the efficacy and safety of using of MRAs: spironolactone (SP) and eplerenone (EP) in RH and CKD stages 3 and determine predictors of developing HK and worsening of renal function (RF). Methods 54patients with true RH (antihypertensive treatment mean of 3.4±1.4 drugs per patient including diuretic, ACE-I or an ARB) and CKD 3 (baseline eGFR between 30 and 60 ml/min) were included in the study. The potassium (K) and creatinine (C) levels, plasma aldosterone (AS) and active renin concentration (ARC) were estimated at baseline. After chemical evaluation, 28 patients started on SP treatment with a mid-dose 18 mg daily (titrated), 26 patients started on EP with a mid-dose 24 mg (titrated). K and RF were checked at weeks 1, 4, 8, 12. At baseline and after 12 weeks of therapy, patients underwent clinic and 24-hour BP measurement. Results SP and EP both effectively decreased BP (9.5/-3.7 mm Hg; P<0.05 for both; 9.9±3.9 mm Hg; P<0.05 for both; respectively), changes in BP were dose dependent and not significantly different. K and C levels increased significantly after the start of MRAs treatment for both SP and EP patients: mean of K on SP increased from 4.26±0.61 to 5.25±0.69 mEq/l and on EP from 4.29±0.71 to 5.13±0.71 mEq/l (P<0.001; P<0.001; respectively) and was dose dependent. After 12 weeks of treatment the incidence of sever HK (K ≥6.0 mmol/L) was <4% (two on SP 25 mg and two on EP 25 mg). A K 5.5–5.9 mmol/L occurred in 9 patients (four on SP) and was predicted by baseline K ≥5.0 mmol/L, eGFR ≤40 ml/min/1.73m2 and dose of diuretic. Mean of eGFR on SP decreased from 45.26±3.19 to 40.15±2.88 ml/min/1.73m2 and on EP from 46.29±3.56 to 39.13±2.99 ml/min/1.73m2 (P<0.001; P<0.001; respectively). Three patients (one on SP) experienced significant RD result in withdrew MRAs. Two cases of gynecomastia were reported with SP use resulting in a switch to EP. Female, ARC >20 ng/ml and eGFR≤40 ml/min/1.73m2 at baseline had modest discriminative powers for predicting decline RF (P<0.05; P<0.01; P<0.001; respectively). Conclusion SP and EP demonstrated comparable efficacy in RH and CKD 3, but EP was well tolerated. In both groups MRAs treatment resulted in a significant dose dependent rise in K and C levels. Female, higher levels of ARC and eGFR were identified as potential predictors of worsening of RF. The occurrence of HK was predicted by baseline K level and eGFR. So, caution should be advised when using MRAs in RH with CKD 3 and an ARC >20 ng/ml, P of ≥5.0 mmol/L and eGFR ≤40 ml/min/1.73m2 for safety reasons.

Kidney-liver pathophysiological crosstalk: its characteristics and importance.

The kidney plays a crucial role in controlling the blood volume and pressure, electrolyte and acid-base balance, erythropoietin secretion, as well as renin-angiotensin-aldosterone system activity. All these renal activities have important repercussion in the organism, explaining why morbidity and mortality rates are high in patients with significant renal dysfunction. In this sense, there are renal-induced liver damages in acute kidney injury, as well as liver-induced renal damages in hepatic disease. Ischemia, reperfusion, cytokine outflow, pro-inflammatory cascades, metabolic acidosis, oxidative stress, and changes in enzymatic and metabolic pathways provide the bases for this bidirectional kidney-liver damage. In conclusion, knowing the characteristics of this kidney-liver crosstalk is crucial for handling the complications induced by this vicious circle.

Application of flexible ureteroscopy combined with holmium laser lithotripsy and their therapeutic efficacy in the treatment of upper urinary stones in children and infants.

To investigate the efficacy and safety of retrograde intrarenal surgery (RIRS) for the treatment of pediatric patients. A total of 45 patients with upper urinary stones treated using flexible ureteroscopy combined with holmium laser lithotripsy at our department between June 2015 and January 2017 were examined in this study. The operative success rate of treatment using holmium laser lithotripsy via flexible ureteroscopy was 97.8% (44/45); one patient (1/45, 2.2%) was converted to laparoscopic pyelolithotomy, and the calculus was successfully removed. Lithotripsy via flexible ureteroscopy was successful during the first phase in 38 patients (38/45, 84.4%), and second or third phase lithotripsy was needed for six patients (6/45, 13.3%). Intraoperative ureteral fracture in the middle and lower sections occurred in one pediatric patient who was converted to laparoscopic pyelolithotomy and ureter bladder reimplantation. This patient was discharged after recovery at 2 weeks postoperative and showed no significant renal dysfunction over the 12-month follow-up period. Severe postoperative gross hematuria occurred in one patient, who improved after hemostasis and other symptomatic treatments. High fever occurred in two patients (body temperature >39°C), who later improved. These pediatric patients were discharged after active anti-infection and other conservative treatments for 4 days. All of the included patients were followed up for 2-15 months, with an average follow-up period of 8 months. The total calculus clearance rate was 100% (45/45), with no recurrence of the calculus. In this study, most upper urinary stones in children and infants were treated successfully with holmium laser lithotripsy applied via flexible ureteroscopy.

MiR-146b-5p has a sex-specific role in renal and cardiac pathology in a rat model of chronic kidney disease

Chronic kidney disease presents a complex and distinct pathological landscape in men and women, yet this difference is poorly understood. microRNAs are powerful molecular regulators of pathophysiology in the kidney and other organs. We previously reported a significant upregulation of miR-146b-5p in the 5/6 nephrectomy rat model of chronic kidney disease. Here we investigated the sex-specific contribution of miR-146b-5p to renocardiac pathology by generating a novel miR-146b-/- rat and characterized the expression of miR-146b-5p in both wild-type and knockout animals. The 5/6 nephrectomy or sham surgery was performed on rats of each genotype and sex. Renal pathology was examined through gross histology, plasma and urinary analysis of electrolytes and metabolites, and by chronic blood pressure monitoring. Cardiac pathology was monitored via echocardiography and pressure-volume analysis. The miR-146b-/- rats show functional knockout of miR-146b-5p in both the kidney and heart. While 5/6 nephrectomy induced tissue hypertrophy, miR-146b-/- female rats displayed exacerbated renal hypertrophy. Additionally, miR-146b-/- female rats exhibited a marked elevation of renal fibrosis and significant renal dysfunction yet lower blood pressure and less pronounced cardiac remodeling. These phenotypic differences were not exhibited in miR-146b-/- male rats. Ovariectomy ameliorated renal pathology and abolished genotypic differences. Invitro examination of transforming growth factor-β signaling in combination with miR-146b-5p manipulation supports a role for miR-146b-5p in mediating the protective benefit of estrogen from renal pathologies. Thus, our data highlight an important role of miR-146b-5p in modulating kidney disease progression and provide new avenues for the study of sex-specific pathology.

Malate Protects the Kidneys From Hemorrhagic Shock-Induced Injury in an Experimental Rat Model

BackgroundIn the past, protective effects in terms of prolonged survival of malate-containing solutions were demonstrated in the treatment of experimental hemorrhagic shock (HS). The objective of the present study was to investigate malate's impact on the kidneys. Therefore, renal function and morphological and histological anomalies were examined. Materials and methodsMale Wistar rats were subjected to severe HS by dropping the mean arterial blood pressure to 25-30 mmHg. The depth was held for 60 min. Subsequently, reperfusion with Ringer's solution or a 10 mM malate-containing solution was performed both together with blood in a 2:1 relation, followed by an observation period of 150 min. ResultsCompared with the control group (Ringer's solution), malate increased diuresis and, thus, enhanced excretion of creatinine and urea. Shock-induced histopathological changes were reduced by malate administration. Renal hemorrhages in the straight proximal tubule and in the distal tubule were reduced and even significantly reduced in the proximal convoluted tubule. Malate significantly preserved the endothelial glycocalyx in the proximal tubule. Surprisingly, malate induced glucosuria in the absence of a significant renal dysfunction, morphological damage, or hyperglycemia. ConclusionsThe protective effect of malate observed in the treatment of severe HS in the rat may be explained by a certain protective effect of this substance for the kidney.

KIDNEY LESIONS IN HIV-INFECTED PATIENTS

Introduction. HIV prevalence is one of the most important issues of contemporary medicine. Over a 30-year history of this disease more than 75 million people have been infected with HIV, nearly 30 million adults and children of died. In the future decades, its significance in world premature mortality rates continues to rise. The objective of the study was to establish clinical and laboratory features of kidney lesions in HIV infection.
 Methods. The study involved 292 HIV-infected patients, who were managed outpatiently at the Chernivtsi Regional AIDS Center. Taking into account the main markers of kidney lesions: persistent proteinuria and glomerular filtration rate <60 mL/min/1.73 m2, 48 persons were diagnosed with chronic kidney disease (CKD), which was very frequently accompanied by dysfunction of these organs.
 Results. Increasing proteinuria rate is accompanied by a significant renal dysfunction and more frequently is combined with arterial hypertension as well as hematuria without significant differences in the incidence of opportunistic diseases. The mean reciprocal correlation between the levels of proteinuria and glomerular filtration rate (r=-0.562, p<0.01), as well as between the levels of proteinuria and hemoglobin (r=-0.596, p<0.01) have been established as well.
 Conclusions. Kidney lesions in HIV-infected are most often characterized by tubulointerstitial lesions. At the same time, glomerular kidney lesion, which is much less common, is accompanied by a significantly higher level of HIV RNA.

Renal functions in patients with metabolic syndrome

Introduction: Metabolic syndrome consists of a constellation of metabolic abnormalities that confer increased risk of diabetes mellitus. The aim of the present study was to study renal functions in patients with metabolic syndrome. Materials and methods: 50 controls and 50 individuals with metabolic syndrome were selected by purposive sampling technique. Waist circumference and blood pressure was measured and serum levels of fasting blood sugar, triglycerides and HDL were estimated and eGFR was calculated in controls and cases. Results: We found that serum urea andcreatininelevels were significantly increased andeGFR levels were significantly decreased in metabolic syndrome when compared to controls. Conclusion: Our study concluded that there is significant renal dysfunction in patients with metabolic syndrome.

Measurement of Vitamin B12 and Serum Methylmalonic Acid Levels: Role of Stepwise Cascade Testing in Diagnosing Vitamin B12 Deficiency

Abstract Introduction Varied presentations of vitamin B12 (B12) deficiency include hematologic (megaloblastic anemia) and neurologic (myelopathy, peripheral neuropathy). Delayed recognition and treatment may have serious consequences. Assessing B12 status can be challenging due to diverse laboratory assays and thresholds, resulting in a wide range of reported prevalence of B12 deficiency from 3-26%. Comorbidities may also spuriously elevate or suppress B12 levels. Methylmalonic acid (MMA) level, often used as a companion test to assess for B12 deficiency, may also be affected by differing laboratory thresholds and other medical comorbidities, such as renal dysfunction. Our institutional approach to B12 assessment, termed the pernicious anemia (PA) cascade, consists of reflexive testing to 1) document low B12 stores (B12 levels with or without MMA), and 2) diagnose pernicious anemia (intrinsic factor binding antibody [IFBA] with or without gastrin assay). In this study, our objectives were: (1) assess the usefulness of our B12 testing algorithm and associated laboratory thresholds for identifying B12 deficiency, and (2) evaluate clinical follow-up of test results as part of a quality project. Methods In this retrospective study, adult (age ≥18 years) inpatients who had B12 testing from 2007 to 2013 were identified. Medical records for those patients with B12 levels 150-400 ng/L were reviewed. Data abstracted included patient demographics, indication for B12 testing, B12 levels, results for MMA, IFBA, gastrin, serum creatinine, complete blood count, and clinical outpatient follow-up. The PA cascade algorithm is as follows: 1) for B12 <150 ng/L, IFBA is performed; 2) if IFBA is negative or indeterminate, then gastrin is performed; 3) for B12 150-400 ng/L, MMA is performed; 4) if MMA is >0.40 nmol/mL, then IFBA is performed. Reference range for B12 is 180-914 ng/L. Patients were determined to be B12 deficient if B12 level was <180 ng/L, or if B12 was 150-400 ng/L with elevated MMA and macrocytosis in the absence of significant renal dysfunction, defined as serum creatinine ≥2.0 mg/dL. Results Records of 326 patients (150 female) were reviewed. Indications for B12 testing were: hematologic, 175 patients (53.7%); neurologic, 127 patients (39.0 %), psychiatric, 18 patients (5.5%); other, 4 patients (1.2%). Fifty-nine of 326 (18.1%) patients were B12 deficient, of whom 17 of 59 (28.8%) had PA. There were 54 cases of elevated MMA, >0.40 nmol/mL, of which 30 cases had mildly elevated MMA, >0.40 nmol/mL and ≤0.60 nmol/mL, considered to be the MMA "gray zone". Thirty-two of the total 326 patients had serum creatinine ≥2.0 mg/dL, of which 23 patients also had elevated MMA. Elevated MMA in 13 of these 23 patients was more likely due to renal dysfunction than to B12 deficiency. B12 testing results were not mentioned in hospital discharge summaries for 173 patients, including 8 patients with B12 deficiency. For 22 B12-deficient patients, there was no documentation of B12 replacement. Conclusions The PA cascade detected B12 deficiency in a significant number of inpatients with low-normal B12 levels that might have otherwise been missed; 28.8% of this group had PA for whom long-term B12 replacement is indicated. As treatment for B12 deficiency is inexpensive, non-toxic, and non-invasive, it is reasonable to evaluate B12 status by cascade testing which may provide additional diagnostic data beyond B12 level. Notable clinical practice findings from this study include the lack of B12 results in 173 of 326 discharge summaries, and no record of B12 supplementation in 22 of 59 patients with B12 deficiency. These gaps in documentation and follow-up may be associated with the relatively long turnaround time of MMA testing. Efforts at improving documentation, communication, and treatment of B12 deficiency are ongoing. Disclosures No relevant conflicts of interest to declare.

Left Renal Vein Ligation for Spontaneous Splenorenal Shunts During Deceased-Donor Orthotopic Liver Transplant Is Safe and Can Mitigate Complications from Portal Steal: A Case Series

Large spontaneous splenorenal shunts can result in portal vein steal syndrome and is a risk factor for portal vein thrombosis after orthotopic liver transplant. Disconnection of these shunts by left renal vein ligation has been suggested as a potential technique for improving portal venous flow and mitigating risk of portal vein thrombus, thus improving graft perfusion. We present a series of 6 patients who underwent left renal vein ligation for spontaneous splenorenal shunts and their outcomes. This retrospective analysis included all orthotopic liver transplant recipients who underwent left renal vein ligation for spontaneous splenorenal shunts between 2016 and 2017. Portal venous flow, patency, and renal function were assessed postoperatively. Liver Doppler ultrasonography scans were obtained 1, 3, and 5 days postligation, and serum creatinine was evaluated at 1 and 2 weeks and 1, 3, 6, and 12 months postligation. Over the 1-year study period, 92 orthotopic liver transplants were performed. In 6 patients who underwent left renal vein ligation, spontaneous splenorenal shunts were identified preoperatively. One patient received a retransplant complicated by portal vein thrombus and underwent thrombectomy with left renal vein ligation. Concurrent left renal vein ligation and liver transplant were performed in 5 patients, 2 with known portal vein thrombus at the time of transplant requiring thrombectomy. All patients had subjective intraoperative improvements in portal venous flow after ligation. Zero patients developed postoperative portal vein thrombus. No patients developed clinically significant renal dysfunction at 1-year follow-up. Left renal vein ligation is technically feasible, has minimal and transient effects on renal function, and can improve portal venous flow, thus mitigating the risk for portal vein thrombus, graft hypoperfusion, and possible dysfunction.

Inhibition of NF-κB Pathway with IKK-16 or Linagliptin Attenuates the Cardiac Dysfunction Associated with Polymicrobial Sepsis in Mice with Preexisting Type 2 Diabetes Mellitus (T2DM)

Introduction: Patients with diabetes are more susceptible to infections and sepsis. Activation of nuclear factor-κB (NF-κB) plays a substantial role in the pathophysiology of sepsis and diabetes. Here we investigate i) the effect of preexisting type 2 diabetes mellitus on cardiac dysfunction associated with sepsis and ii) whether inhibition of NF-κB using IKK-16 or linagliptin attenuates cardiac dysfunction in mice with sepsis and diabetes. Methods: Ten-week old male C57BL/6 mice received high fat (HFD) or chow diet for 12 weeks, and were then subjected to caecal ligation and puncture (CLP) or sham surgery for 24 hours. At 1 hour after CLP, mice received IKK-16, linagliptin, or vehicle. Results: Administration of HFD resulted in a significant impairment in glucose tolerance and a small, but significant, reduction in ejection fraction. Immunoblot analysis of hearts tissue showed that HFD caused significant NF-κB pathway activation and expression of inducible nitric oxide synthase (iNOS). Mice on HFD subjected to CLP showed further (i) decline in EF, (ii) increase in NF-κB pathway activation, (iii) increase in iNOS expression, (iv) an increase in serum ALT, and (v) a significant renal dysfunction. Treatment of HFD-CLP mice with IKK-16 or linagliptin resulted in significant reduction of the CLP-induced i) cardiac dysfunction, ii) NF-κB pathway activation, and iii) iNOS expression when compared to mice treated with vehicle. Conclusion: Our results show that HFD results in inflammation and cardiac dysfunction. Moreover, a preexisting diabetic phenotype worsened the cardiac dysfunction associated with CLP-sepsis. Most notably, inhibition of NF-κB reduced the cardiac dysfunction caused by sepsis in animals with preexisting T2DM. Disclosure S. Al Zoubi: None. J. Chen: None. L. Martin: None. C. Murphy: None. G.S. Purvis: None. F. Chiazza: Other Relationship; Self; Boehringer Ingelheim GmbH. D. Collotta: None. M. Collino: None. C. Thiemermann: None.

Safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infections: A single-center study.

Infection with cytomegalovirus (CMV) is an important cause of morbidity and mortality following solid organ transplantation. Resistance to ganciclovir can rarely develop via mutations in UL97 or UL54. There are limited published studies assessing the safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infection and many centers are reluctant to utilize this important therapy because of concerns about toxicity. Solid organ recipients transplanted between January 1, 2006 and December 31, 2014 who received at least 1 dose of foscarnet were retrospectively reviewed to assess treatment outcomes, tolerability, and safety of foscarnet. Ten of 31 (32.3%) patients who received foscarnet during the study period died during treatment with foscarnet, whereas all 21 surviving recipients successfully cleared infection. Of these surviving patients, 3 (14.3%) developed significant renal dysfunction, defined as >25% decline in estimated glomerular filtration rate during treatment; one-third had definitive renal biopsy results consistent with foscarnet-induced toxicity. Although mortality was high in this population, foscarnet use, with proper precautions, was generally safe and significant renal dysfunction was lower than previously reported in other sources, even with extended use.

The Effects of 2'-O-Methoxyethyl Oligonucleotides on Renal Function in Humans.

Systemically administered 2′-O-methoxyethyl (2′MOE) antisense oligonucleotides (ASOs) accumulate in the kidney and metabolites are cleared in urine. The effects of eleven 2′MOE ASOs on renal function were assessed in 2,435 patients from 32 phase 2 and phase 3 trials. The principle analysis was on data from 28 randomized placebo-controlled trials. Mean levels of renal parameters remained within normal ranges over time across dose groups. Patient-level meta-analyses demonstrated a significant difference between placebo-treated and 2′MOE ASO-treated patients at doses >175 mg/week in the percentage and absolute change from baseline for serum creatinine and estimated glomerular filtration rate. However, these changes were not clinically significant or progressive. No dose-related effects were observed in the incidence of abnormal renal test results in the total population of patients, or subpopulation of diabetic patients or patients with renal dysfunction at baseline. The incidence of acute kidney injury [serum creatinine ≥0.3 mg/dL (26.5 μM) increases from baseline or ≥1.5 × baseline] in 2′MOE ASO-treated patients (2.4%) was not statistically different from placebo (1.7%, P = 0.411). In conclusion, in this database, encompassing 32 clinical trials and 11 different 2′MOE ASOs, we found no evidence of clinically significant renal dysfunction up to 52 weeks of randomized-controlled treatment.

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

Aims/hypothesisMicrovascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes.MethodsANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1−/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1 (1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.).ResultsPlasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1−/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with non-diabetic WT mice, the degree of the phosphorylation of mitogen-activated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1−/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1–13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8–13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice.Conclusions/interpretationOverall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with type 1 diabetes independent of a significant impairment in renal function. Furthermore, in mouse models with STZ-induced type 1 diabetes, ANXA1 protects against cardiac and renal dysfunction by returning MAPK signalling to baseline and activating pro-survival pathways (Akt). We propose ANXA1 to be a potential therapeutic option for the control of comorbidities in type 1 diabetes.

Aripiprazole prevents renal ischemia/reperfusion injury in rats, probably through nitric oxide involvement

Renal ischemia/reperfusion (I/R) injury is strongly related to morbidity and mortality. Oxidative stress, inflammation, and apoptosis play key roles in renal dysfunction following renal I/R. Aripiprazole is an atypical antipsychotic which used for the treatment of schizophrenia and bipolar disorder. Recent studies have reported aripiprazole as displaying certain anti-inflammatory effects. Regarding the underlying mechanisms of renal ischemia-reperfusion, therefore, nephroprotective effects might be predicted to be seen with aripiprazole. I/R injury was induced by bilateral clamping of the renal pedicles (45min) followed by reperfusion (24h). The mechanism of aripiprazole-mediated nephroprotection was explored by a combined use of aripiprazole and L-NAME (non-selective nitric oxide synthase inhibitor). Animals were given aripiprazole (2.5, 5, 10 and 20mg/kg) intraperitoneally, 30min before ischemia. L-NAME was administered before the aripiprazole injection. Serum creatinine and blood urea nitrogen were assessed after 24h of reperfusion. Serum levels of malondialdehyde (MDA), TNF-α and IL-1β were measured for rats treated with aripiprazole. The extent of necrosis was measured by the stereology method. Ischemia/reperfusion caused significant renal dysfunction and marked renal injury. Aripiprazole reduced creatinine and blood urea nitrogen. Serum levels of MDA, IL-1β and TNF-α were significantly lower in the aripiprazole group. Aripiprazole treatment also decreased the volume of kidney necrosis. The administration of L-NAME reversed the renoprotective effect of aripiprazole on BUN and creatinine, but enhanced the anti-necrotic effect of aripiprazole. The results show that a single dose of aripiprazole significantly improved renal function following ischemia/reperfusion injury – probably through the involvement of nitric oxide.

P 32 Postpartum HELLP syndrome – A case report

Introduction HELLP syndrome is a life-threatening obstetric condition and one of the particularly severe forms of preeclampsia. Objective The purpose of this paper is to present a case of preeclamptic patient with HELLP syndrome diagnosed on 2 day after delivery by the cesarean section. Objective A 32-year-old primigravida at 38 + 1 week of gestation was admitted to the tertiary care hospital with PROM, severe hypertension, proteinuria and generalized oedema. Four weeks earlier i.e., at 35 week of gestation, the patient had her last appointment at an outpatients clinic. She was started on antihypertensive therapy and was transported to the operating theatre. The lower segment caesarean section under general anesthesia was carried out that resulted in a son born. At birth, the boy weighed 2190 g. On the second day after the cesarean section, the patient developed diffused haematoma within the abdominal wall. Laboratory tests revealed clinically significant renal and liver dysfunction and thrombocytopenia. HELLP syndrome was diagnosed. The therapy with intravenous Dexamethasone was initiated. Metyldopa in a dose of 500 mg four times daily was continued, some ice gel packs were applied on the haematoma of the abdominal The antibiotic therapy was administered for 7 days. The patient was under close surveillance. We observed continuous gradual progressive improvement in the patient’s condition and her laboratory tests. The blood coagulation function improved. Liver enzymes began to decrease on day 5 and normalized on day 8 after the C-section. The diffused haematoma on the abdominal wall and pubic symphysis disappeared after 5 days. The patient was discharged on day 11 after the C-section with recommendations that involved taking of Methyldopa, systematic control of blood pressure and a follow-up appointment at the Outpatient Nephrological Clinic. Conclusions Although delivery of the infant and placenta constitutes the curative treatment of HELLP, it may occur also in the postpartum period. HELLP syndrome is always a serious and potentially fatal obstetric condition however, it is reversible if an adequate diagnosis is promptly made and emergency intensive treatment is immediately administered. Patients with HELLP syndrome should be treated in a tertiary perinatal care centre with the intensive care unit.