Presence of Sarcopenia before Kidney Transplantation Is Associated with Poor Outcomes.

INTRODUCTION: Kidney transplantation is the treatment of choice for patients with renal failure. It is crucial to select which patients may benefit from renal transplantation and which are at high risk for post-transplant complications. Sarcopenia is associated with poor outcome in various conditions, including in chronic kidney disease patients. The gold standard for measuring sarcopenia is computed tomography (CT) imaging to estimate muscle mass and quality since it is objective, reproducible, and reflects the overall health condition. The data regarding those measurements among kidney transplant recipients are limited, therefore we aimed to describe it in patients before kidney transplantation, assess the parameters associated with sarcopenia, and evaluate the clinical significance of those markers on outcomes following transplantation. METHODS: We retrospectively analyzed 183 kidney transplant recipients who had a CT scan 90 days prior to transplant. Sarcopenia was assessed by measuring the cross-sectional area (CSA) and mean muscle density of the psoas muscle at the third and fourth lumbar vertebrae levels and paravertebral muscles at the 12th thoracic vertebra level. RESULTS: There was a strong linear correlation between muscle size measured as CSA of the psoas muscle at the L3 and L4 vertebral body level and the CSA of the paravertebral muscles at the D12 vertebra level, and a moderate correlation to muscle density at those levels. Age was independently associated with risk of sarcopenia, defined as psoas CSA in the lowest tertile, with every year of age increasing the risk by 5%. CSA at the L3 level had a significant independent association with post kidney transplantation mortality, with an adjusted hazard ratio of 0.86 per cm2. There was a significantly longer hospitalization period postoperation in kidney recipients in the lower tertile of psoas CSA and density. CONCLUSIONS: Sarcopenia as measured by psoas CSA is associated with poor short- and long-term outcomes following kidney transplantation and should be included as part of the assessment of kidney transplantation candidates.

Nonalcoholic Fatty Liver Disease before Kidney Transplantation Correlates with New Onset Diabetes and Poor Metabolic Outcomes.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality after kidney transplantation. Metabolic syndrome is common in renal transplant recipients and is associated with increased CVD risk in those patients. Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of a multi-system disorder, including CVD and metabolic syndrome. The data about prevalence of NAFLD before kidney transplantation and its consequences following transplantation are scarce. METHODS: A retrospective study of metabolic parameters and sonographic evidence of NAFLD, and an analysis of its metabolic outcomes, was performed in 341 consecutive kidney transplant recipients. RESULTS: One-hundred twenty-four (36.4%) kidney recipients had NAFLD before transplantation. The risk of NAFLD before kidney transplantation was independently and significantly related to diabetes (OR = 1.8), male gender (OR = 1.4), older age (every year of age increased the risk by 4%), higher BMI (every increase of 1 kg/m2 increased the risk by 15%), and higher triglycerides level. Mean levels of liver enzymes were similar in patients with and without NAFLD. Recipients with NAFLD before transplantation had a higher prevalence of new onset diabetes, even after adjustment to covariables. In addition, they had a higher increase in liver enzymes, triglycerides, and FIB-4 score, as an indication of liver fibrosis, after transplantation. Furthermore, NAFLD pre-transplantation was independently associated with cardiovascular mortality (HR = 4.4) following kidney transplantation. CONCLUSIONS: Sonographic evidence of NAFLD before kidney transplantation is associated with significant metabolic outcomes including de novo diabetes and cardiovascular mortality following transplantation and should be included as part of the assessment of kidney transplant candidate.

Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus.

COVID-19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS-CoV-2 vaccines. We analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer-BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS-CoV-2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p < .001). Mean IgG anti-spike level was higher in the controls (31.05 [41.8] vs. 200.5 [65.1] AU/mL, study vs. control, respectively, p < .001). Variables associated with null humoral response were older age (odds ratio 1.66 [95% confidence interval 1.17-2.69]), high-dose corticosteroids in the last 12 months (1.3 [1.09-1.86]), maintenance with triple immunosuppression (1.43 [1.06-2.15]), and regimen that includes mycophenolate (1.47 [1.26-2.27]). There was a similar rate of side effects between controls and recipients, and no correlation was found between the presence of symptoms and seroconversion. Our findings suggest that most kidney transplant recipients remain at high risk for COVID-19 despite vaccination. Further studies regarding possible measures to increase recipient's response to vaccination are required.

Kidney transplant recipients vaccinated before transplantation maintain superior humoral response to SARS-CoV-2 vaccine.

Majority of transplant recipients did not develop an appreciable humoral response following SARS-CoV-2 vaccine, in contrast to dialysis patients and healthy individuals. We analyzed the serologic response to BNT162b2 (Pfizer-BioNTech) vaccine in a cohort of 19 kidney transplant recipients, vaccinated prior to transplantation, compare to 109 recipients vaccinated after transplantation, and to 39 healthcare workers, by determining the level of anti-spike antibodies after transplantation. All controls and 17 of 19 (90%) of recipients vaccinated before transplant were seropositive, while only 49 of 109 (45%) recipients vaccinated post-transplant had positive serology (P < .001). Median anti-spike IgG in the group of kidney transplant recipients vaccinated after transplantation (10.7 AU/ml, [IQR 0-62.5]) was lower than the patients vaccinated before transplantation (66.2 AU/ml [21.6-138]), which was significantly lower than in the controls (156 AU/ml [99.7-215.5]). Negative humoral response was associated with vaccination post transplantation (odds ratio 22.4), older age (OR = 1.04), and longer time on dialysis (OR = 1.02), while higher lymphocyte count at time of vaccination was protective (OR = .52). Our findings of sustained superior humoral response to SARS-CoV-2 vaccine in kidney transplant recipients vaccinated prior to transplantation strongly support the recommendations of SARS-CoV-2 vaccination of transplant candidates, especially those younger than 60 years.

Posttransplantation Hypomagnesemia as a Predictor of Better Graft Function after Transplantation.

BACKGROUND: Hypomagnesemia is frequently seen after transplantation and is particularly associated with the use of calcineurin inhibitors (CNIs). METHODS: We conducted a retrospective, single-center analysis (2000-2013, N = 726) to explore the relationship between hypomagnesemia and long-term allograft outcome in kidney transplant recipients. For this study, a median serum magnesium (Mg) level of all measured Mg levels from 1 month to 1 year after renal transplantation was calculated. RESULTS: For every increase in Mg by 0.1 mg/dL, the GFR decreased by 1.1 mL/min at 3 years posttransplant (p < 0.01) and by 1.5 mL/min at 5 years posttransplant. A median blood Mg level of ≥1.7 was found to be an independent predictor of a GFR <60 mL/min at 3 years posttransplant. The odds of having a GFR <60 mL/min 3 years posttransplant was almost 2-fold higher in the high Mg group than in the low Mg group. CONCLUSIONS: Hypomagnesemia from 1 to 12 months after renal transplantation is associated with a better allograft function up to 5 years posttransplant. This relationship was found to hold true after accounting for baseline allograft function and the presence of slow graft function.

Kidney transplantation in patients with inflammatory bowel diseases (IBD): analysis of transplantation outcome and IBD activity.

Inflammatory bowel diseases (IBD) is a systemic disorder with possible renal involvement, yet data regarding the outcome of kidney transplantation (KT) in those patients, and IBD course post KT, are scarce. In this retrospective analysis, we studied the outcome of 12 IBD kidney recipients (seven Crohn's disease, five ulcerative colitis; primary kidney disease was IgA nephropathy in five, polycystic disease in four), compared to two control groups: matched controls and a cohort of recipients with similar kidney disease. During a follow-up period of 60.1 (11.0-76.6) months (median, interquartile range), estimated 5-year survival was 80.8 vs. 96.8%, with and without IBD, respectively (P = 0.001). Risk of death with a functioning graft was higher with IBD (HR = 1.441, P = 0.048), and with increased age (HR = 1.109, P = 0.05). Late rehospitalization rate was higher in IBD [incidence rate ratio = 1.168, P = 0.030], as well as rate of hospitalization related to infection [1.42, P = 0.037]. All patients that were in remission before KT, remission was maintained. Patients that were transplanted with mild or moderate disease remained stable or improved with Infliximab or Adalimumab treatment. In conclusion, IBD is associated with an increased risk of mortality, hospitalization because of infection and late rehospitalization after KT. Clinical course of IBD is stable after KT.

Long term metabolic and renal outcomes of kidney donors compared to controls with excellent kidney function.

BACKGROUND: Only few studies of living kidney donors have included controls that were similarly healthy, including excellent kidney function. METHODS: In this study, we aimed to estimate long term metabolic and renal outcome in a cohort of 211 living donors compared to two control groups: paired-matched controls, and another control group of 2534 healthy individuals with excellent kidney function. RESULTS: Donors presented with higher estimated Glomerular Filtration Rate (eGFR): (97.6 ± 15.2 vs 96.1 ± 12.2 vs 94.5 ± 12.4 ml/min/1.73m2) and lower urine albumin to creatinine ratio (UACR) (4.3 ± 5.9 vs 5.9 ± 6.1 vs 6.1 ± 6.9 mg/g) for donors, matched controls and healthy controls, respectively (p <  0.001). In a mean follow up period of 5.5 for donors, donors presented with positive eGFR slopes during the first 3 years post donation, followed by negative slopes, compared to constantly negative slopes presented in the control group (p <  0.05). The variables related to the slope were being a donor, baseline eGFR, Body Mass Index (BMI) and age but not eGFR on the last day of follow-up or increased delta UACR. There was a significant increase in UACR in donors, as well as a higher rate of albuminuria, associated with a longer time since donation, higher pre-donation UACR and higher pre-donation BMI. Healthy controls had a lower BMI at baseline and gained less weight during the follow up period. Donors and controls had similar incidence of new onset diabetes mellitus and hypertension, as well as similar delta systolic and diastolic blood pressure. Donors were more likely to develop new onset metabolic syndrome, even after adjustment for age, gender and BMI. The higher incidence of metabolic syndrome resulted mainly from increased triglycerides and impaired fasting glucose criteria. However, prevalence of major cardiovascular events was not higher in this group. CONCLUSIONS: Donors are at increased risk to develop features of the metabolic syndrome in addition to the expected mild reduction of GFR and increased urine albumin excretion. Future studies are needed to explore whether addressing those issues will impact post donation morbidity and mortality.

Ultrapure Filter does not Confer Short-Term Benefits over Two Reverse Osmosis Systems in Chronic Hemodialysis Patients.

BACKGROUND: Dialysate purity contributes to the inflammatory response that afflicts hemodialysis patients. OBJECTIVES: To compare the clinical and laboratory effects of using ultrapure water produced by a water treatment system including two reverse osmosis (RO) units in series, with a system that also includes an ultrapure filter (UPF). METHODS: We performed a retrospective study in 193 hemodialysis patients during two periods: period A (no UPF, 6 months) and period B (same patients, with addition of UPF, 18 months), and a historical cohort of patients treated in the same dialysis unit 2 years earlier, which served as a control group. RESULTS: Mean C-reactive protein, serum albumin and systolic blood pressure worsened in period B compared to period A and in the controls. CONCLUSIONS: A double RO system to produce ultrapure water is not inferior to the use of ultrapure filters.

Mineralocorticoid receptor blockade improves arginine transport and nitric oxide generation through modulation of cationic amino acid transporter-1 in endothelial cells.

Blockade of the mineralocorticoid receptor (MCR) has been shown to improve endothelial function far beyond blood pressure control. In the current studies we have looked at the effect of MCR antagonists on cationic amino acid transporter-1 (CAT-1), a major modulator of endothelial nitric oxide (NO) generation. Using radio-labeled arginine, {[3H] l-arginine} uptake was determined in human umbilical vein endothelial cells (HUVEC) following incubation with either spironolactone or eplerenone with or without silencing of MCR. Western blotting for CAT-1, PKCα and their phosphorylated forms were performed. NO generation was measured by using Griess reaction assay. Both Spironolactone and eplerenone significantly increased endothelial arginine transport, an effect which was further augmented by co-incubation with aldosterone, and blunted by either silencing of MCR or co-administration of amiloride. Following MCR blockade, we identified two bands for CAT-1. The addition of tunicamycin (an inhibitor of protein glycosylation) or MCR silencing resulted in disappearance of the extra band and prevented the increase in arginine transport. Only spironolactone decreased CAT-1 phosphorylation through inhibition of PKCα (CAT-1 inhibitor). Subsequently, incubation with either MCR antagonists significantly augmented NO2/NO3 levels (stable NO metabolites) and this was attenuated by silencing of MCR or tunicamycin. GO 6076 (PKCα inhibitor) intensified the increase of NO metabolites only in eplerenone treated cells. In conclusion spironolactone and eplerenone augment arginine transport and NO generation through modulation of CAT-1 in endothelial cells. Both MCR antagonists activate CAT-1 by inducing its glycosylation while only spironolactone inhibits PKCα.

Progression and new onset of nonalcoholic fatty liver disease in living kidney donors compared to healthy controls.

BACKGROUND: There is growing evidence linking nonalcoholic fatty liver disease (NAFLD) with reduced glomerular filtration rate (GFR). Living kidney donors do not have underlying kidney disease, but have reduced GFR as a result of nephrectomy. Whether kidney donation is associated with a higher risk for development or progression of NAFLD is currently unknown. METHODS: Retrospective evaluation of metabolic parameters and sonographic evidence of NAFLD were performed in 232 living kidney donors and 162 healthy controls. RESULTS: A total of 25 donors and 44 controls had NAFLD at baseline. During a mean follow-up of 6.8 years, 6 donors (24%) and 17 controls (38.6%) (P = .29) had a remission of NAFLD, related with decreased body mass index (BMI). The progression of NAFLD fibrosis score was similar in both groups. New onset of NAFLD was observed in 14 (6.8%) donors and 13 (11.01%) controls (P = .211), and was related to increased BMI and a higher baseline Fatty Liver Index score. Neither eGFR nor urine albumin excretion in the donors were related to new onset or progression of NAFLD. CONCLUSIONS: Reduced kidney function secondary to kidney donation is not associated with increased incidence or progression of NAFLD.

Vascular Endothelial Growth Factor Augments Arginine Transport and Nitric Oxide Generation via a KDR Receptor Signaling Pathway.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is an endothelium-specific peptide that stimulates angiogenesis via two receptor tyrosine kinases, Flt-1 and KDR. Endothelial nitric oxide synthase (eNOS) plays a major role in VEGF signaling. Delivery of arginine to membrane bound eNOS by the cationic amino acid transporter-1 (CAT-1) has been shown to modulate eNOS activity. The current studies were designed to test the hypothesis that VEGF enhances eNOS activity via modulation of arginine transport by CAT-1. METHODS: Using radio-labeled arginine, {[3H] L-arginine} uptake was determined in human umbilical vein endothelial cells (HUVEC) following incubation with VEGF with and without silencing the VEGF receptors Flt-1 or KDR. Subsequently, western blotting for CAT-1, PKCα, ERK 1/2, JNK, and their phosphorylated forms were performed. NO generation was measured by the Griess reaction. RESULTS: VEGF (50 and 100 ng/ml) significantly augmented endothelial arginine transport in a time dependent manner, an effect which was prevented by Sunitinib (2 µM), a multi targeted receptor tyrosine kinase inhibitor. The increase in arginine transport velocities by VEGF was not affected by silencing Flt-1 while silencing KDR abrogated VEGF effect. Furthermore, incubating cells with 50 and 100 ng of VEGF for 30 minutes significantly augmented CAT-1 abundance. The expression of PKC-α, JNK, and ERK1/2 and their phosphorylated forms were unchanged following incubation of HUVEC with VEGF. The concentration of NO2/NO3 following incubation with VEGF was significantly higher than from untreated cells. This increase was significantly attenuated by silencing KDR. CONCLUSIONS: VEGF increases arginine transport via modulation of CAT-1 in endothelial cells. This effect is exclusively dependent on KDR rather than Flt-1.

Dimethyl sulfoxide attenuates nitric oxide generation via modulation of cationic amino acid transporter-1 in human umbilical vein endothelial cells.

Dimethyl sulfoxide (DMSO) is a solvent that is commonly used in medicine. Conflicting data exist as to its effects on endothelial function. Endothelial cell dysfunction (ECD) is characterized by decreased endothelial nitric oxide synthase (eNOS) activity. Cationic amino acid transporter-1 (CAT-1), the specific arginine transporter for eNOS, has been shown to modulate eNOS activity. We hypothesize that DMSO inhibits eNOS activity through modulation of its selective arginine supplier CAT-1. We studied the effect of DMSO on arginine transport, NO2/NO3 generation as an index of NO production, as well as CAT-1 and Protein Kinase C alpha (PKC-α) (CAT-1 inhibitor) protein expression in human umbilical vein endothelial cell cultures (HUVECs). DMSO 2.5% and 3.5% (v/v) significantly attenuated arginine transport, a phenomenon which was prevented by co-incubation with l-arginine (1 mM). The aforementioned findings were accompanied by a decrease in NO2/NO3 generation. DMSO significantly increased the abundance of phosphorylated CAT-1 (the inactive form) and phosphorylated PKC-α protein, an effect that was attenuated by l-arginine. GO 6976 (PKC-α antagonist) prevented the decrease in arginine transport caused by DMSO. DMSO also induced profound transient morphological changes in HUVECs' structure but these were not related to its effect on arginine transport. In conclusion, DMSO inhibits NO generation by endothelial cells through modulation of CAT-1 activity.

Estradiol augments while progesterone inhibits arginine transport in human endothelial cells through modulation of cationic amino acid transporter-1.

Decreased generation of nitric oxide (NO) by endothelial NO synthase (eNOS) characterizes endothelial dysfunction (ECD). Delivery of arginine to eNOS by cationic amino acid transporter-1 (CAT-1) was shown to modulate eNOS activity. We found in female rats, but not in males, that CAT-1 activity is preserved with age and in chronic renal failure, two experimental models of ECD. In contrast, during pregnancy CAT-1 is inhibited. We hypothesize that female sex hormones regulate arginine transport. Arginine uptake in human umbilical vein endothelial cells (HUVEC) was determined following incubation with either 17ß-estradiol (E2) or progesterone. Exposure to E2 (50 and 100 nM) for 30 min resulted in a significant increase in arginine transport and reduction in phosphorylated CAT-1 (the inactive form) protein content. This was coupled with a decrease in phosphorylated MAPK/extracellular signal-regulated kinase (ERK) 1/2. Progesterone (1 and 100 pM for 30 min) attenuated arginine uptake and increased phosphorylated CAT-1, phosphorylated protein kinase Cα (PKCα), and phosphorylated ERK1/2 protein content. GO-6976 (PKCα inhibitor) prevented the progesterone-induced decrease in arginine transport. Coincubation with both progesterone and estrogen for 30 min resulted in attenuated arginine transport. While estradiol increases arginine transport and CAT-1 activity through modulation of constitutive signaling transduction pathways involving ERK, progesterone inhibits arginine transport and CAT-1 via both PKCα and ERK1/2 phosphorylation, an effect that predominates over estradiol.

L-arginine improves endothelial function, independently of arginine uptake, in aortas from chronic renal failure female rats.

Endothelial cell dysfunction (ECD) is a common feature of chronic renal failure (CRF). Defective nitric oxide (NO) generation due to decreased endothelial nitric oxide synthase (eNOS) activity is a crucial parameter characterizing ECD. Decreased activity of cationic amino acid transporter-1 (CAT-1), the selective arginine transporter of eNOS, has been shown to inhibit eNOS in uremia. Recently, we failed to demonstrate a decrease in glomerular arginine transport in uremic female rats (Schwartz IF, Grupper A, Soetendorp H, Hillel O, Laron I, Chernichovski T, Ingbir M, Shtabski A, Weinstein T, Chernin G, Shashar M, Hershkoviz R, Schwartz D. Am J Physiol Renal Physiol 303: F396-F404, 2012). The current experiments were designed to determine whether sexual dimorphism which characterizes glomerular arginine transport system in uremia involves the systemic vasculature as well and to assess the effect of L-arginine in such conditions. Contractile and vasodilatory responses, ultrastructural changes, and measures of the L-arginine-NO system were performed in thoracic aortas of female rats subjected to 5/6 nephrectomy. The contractile response to KCl was significantly reduced, and acetylcholine-induced vasodilation was significantly impaired in aortas from CRF dames compared with healthy rats. Both of these findings were prevented by the administration of arginine in the drinking water. The decrease in both cGMP generation, a measure of eNOS activity, and aortic eNOS and phosphorylated eNOS abundance observed in CRF rats was completely abolished by l-arginine, while arginine transport and CAT-1 protein were unchanged in all experimental groups. Arginine decreased both serum levels of advanced glycation end products and the asymmetrical dimethylarginine/arginine ratio and restored the endothelial ultrastructure in CRF rats. In conclusion. arginine administration has a profound beneficial effect on ECD, independently of cellular arginine uptake, in CRF female rats.

Anemia and iron deficiency in COPD patients: prevalence and the effects of correction of the anemia with erythropoiesis stimulating agents and intravenous iron.

BACKGROUND: Little is known about iron deficiency (ID) and anemia in Chronic Obstructive Pulmonary Disease (COPD). The purposes of this study were: (i) To study the prevalence and treatment of anemia and ID in patients hospitalized with an exacerbation of COPD. (ii) to study the hematological responses and degree of dyspnea before and after correction of anemia with subcutaneous Erythropoiesis Stimulating Agents (ESAs) and intravenous (IV) iron therapy, in ambulatory anemic patients with both COPD and chronic kidney disease. METHODS: (i) We examined the hospital records of all patients with an acute exacerbation of COPD (AECOPD) to assess the investigation, prevalence, and treatment of anemia and ID. (ii) We treated 12 anemic COPD outpatients with the combination of ESAs and IV-iron, given once weekly for 5 weeks. One week later we measured the hematological response and the severity of dyspnea by Visual Analogue Scale (VAS). RESULTS: (i) Anemia and iron deficiency in hospitalized COPD patients: Of 107 consecutive patients hospitalized with an AECOPD, 47 (43.9%) were found to be anemic on admission. Two (3.3%) of the 60 non-anemic patients and 18 (38.3%) of the 47 anemic patients had serum iron, percent transferrin saturation (%Tsat) and serum ferritin measured. All 18 (100%) anemic patients had ID, yet none had oral or IV iron subscribed before or during hospitalization, or at discharge. (ii) Intervention outpatient study: ID was found in 11 (91.7%) of the 12 anemic ambulatory patients. Hemoglobin (Hb), Hematocrit (Hct) and the VAS scale scores increased significantly with the ESAs and IV-iron treatment. There was a highly significant correlation between the ∆Hb and ∆VAS; rs = 0.71 p = 0.009 and between the ∆Hct and ∆VAS; rs = 0.8 p = 0.0014. CONCLUSIONS: ID is common in COPD patients but is rarely looked for or treated. Yet correction of the ID in COPD patients with ESAs and IV iron can improve the anemia, the ID, and may improve the dyspnea.

Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine.

Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of l-arginine. The experiments were performed in rats 2 days (early) or 6 wk (late) after UNX and compared with controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21 ± 2 ml·min(-1)·kg(-1) in sham, 30 ± 3 in early, and 26 ± 1 in late, P < 0.05). NO inhibition with N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) caused a greater increase in renal vascular resistance in early UNX compared with Sham and late UNX (138 ± 24 vs. 88 ± 10, and 84 ± 7%, P < 0.01). The lower limit of autoregulation was increased both in early and late UNX compared with Sham (P < 0.05). L-NAME did not affect the ANG II-induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to L-NAME (-57 ± 7 vs. -16 ± 7%, P < 0.05) and in the absence of L-arginine (-41 ± 4%, P < 0.05) compared with both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporter-1 and -2 mRNA was increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO release from the afferent arteriole, which is highly dependent on extracellular L-arginine availability.

Cyclosporine attenuates arginine transport, in human endothelial cells, through modulation of cationic amino acid transporter-1.

BACKGROUND: The spectrum of cardiovascular toxicity by cyclosporine (CsA) includes hypertension, accelerated atherosclerosis, and thrombotic microangiopathy, all of which are the result of endothelial cell dysfunction. Endothelial cell dysfunction is characterized by decreased endothelial nitric oxide synthase (eNOS) activity. Cationic amino acid transporter-1 (CAT-1) is the specific arginine transporter for eNOS. CsA has been shown to attenuate nitric oxide (NO) generation. However, the mechanism remains elusive. We hypothesize that CsA inhibits eNOS activity through modulation of its selective arginine supplier CAT-1. METHODS: We studied the effect of CsA on arginine uptake, NO2/NO3 generation, and CAT-1, protein kinase Cα (PKCα), and phosphorylated PKCα protein expression in human umbilical vein endothelial cell cultures (HUVEC) in the absence and presence of L-arginine. RESULTS: CsA (0.5-2 µg/ml) significantly attenuated arginine transport in a dose- and time-dependent manner, a phenomenon which was prevented by co-incubation with L-arginine (1 mM). The aforementioned findings were accompanied by increased protein nitration, a measure for peroxynitrite accumulation. In contrast, no changes were observed in NO2/NO3 generation. CsA significantly decreased the abundance of CAT-1 protein, an effect that was attenuated by L-arginine. PKCα and phosphorylated PKCα (CAT-1 inhibitors) protein contents were not affected by CsA. CONCLUSION: CsA inhibits arginine transport and induces protein nitration in HUVEC through modulation of CAT-1.

When the chimney is blocked: malignant renovascular hypertension after endovascular repair of abdominal aortic aneurysm.

BACKGROUND: The Chimney graft (CG) procedure is one of the novel modification techniques of the endovascular aneurysm repair (EVAR) surgery to treat suprarenal and juxtarenal abdominal aortic aneurysms. Other indications for the use of CG placement include thoracic and thoracoabdominal aneurysms with supraortic branches orifice involvement and cases of common iliac artery aneurysms with or without internal iliac artery involvement. The technique is used in patients who due to aortic-neck morphology and lack of adequate fixation and/or sealing zones are not eligible for standard EVAR. In this procedure, a parallel stent-graft is placed adjacent to the main body of the aortic endograft to maintain blood supply to renovisceral or supraortic branches, once the body of the aortic stent-graft is deployed. Symptomatic occlusions of the CG with novel renovascular hypertension were not described until now. CASE PRESENTATION: A-64-year-old male patient, presented with new-onset malignant hypertension, 13 months after an EVAR operation with CG placement to the left renal artery. The patient was on preventive clopidrogel therapy, which was withheld temporarily for several days, one month before presentation. Imaging studies revealed a novel form of iatrogenic renovascular hypertension, caused by occlusion of the CG. Any attempt to recanalize the covered stent or revascularize the left kidney was rejected and conservative treatment was chosen. Seven months after presentation, blood pressure was within normal ranges with little need for antihypertensive therapy. CONCLUSIONS: Physicians should be aware that the novel emerging techniques of EVAR to overcome the limitations of the aortic-neck anatomy may still adversely influence the renal outcome with potential development of new-onset hypertension.

Renal Tubular CD24 Upregulation Aggravates Folic Acid Induced Acute Kidney Injury: A Possible Role for T Regulatory Cells Inhibition in Mice.

Acute kidney injury (AKI) is characterized by cell death and inflammation. CD24 is a protein induced during tissue damage and is not expressed in mature renal tissue. We explored the role of CD24 in the pathogenesis of folic acid-induced AKI (FA-AKI) in mice. A single Intraperitoneal (IP) injection of folic acid induced AKI in WT and CD24-/- mice. Renal function tests, histological analysis, immunohistochemistry, Western blot analysis, and ELISA were performed to assess the severity of renal damage and the intensity of the inflammatory response. FA-AKI induced CD24 in the distal tubular epithelial cells. Compared to WT mice, FA-AKI CD24-/- mice exhibited an attenuated reduction in renal function and histological injury, lower serum IL-10 and interferon γ, and decreased expression of renal TNFα. In contrast, renal and systemic IL-33 upregulation were augmented. CD24-/- FA-AKI animals exhibited increased splenic margination and renal infiltration of regulatory T cells (Tregs). At day 7, FA-AKI CD24-/- mice exhibited increased expression of tubular pro-apoptotic and decreased anti-apoptotic proteins compared to WT animals. Anti-CD24 antibody administration to FA-AKI mice attenuated the decrease in renal function as well as the histological injury. Renal biopsies from patients with ATN stained strongly for CD24 in the distal tubules. In conclusion, during AKI, upregulation of CD24 promotes renal inflammation through inhibition of Treg infiltration and diversion of cell death towards necrosis rather than apoptosis. Neutralization of CD24 may prove a target for future therapies in AKI.

The Long-Term Outcome of Kidney Transplant Recipients in the Eighth Decade Compared With Recipients in the Seventh Decade of Life.

BACKGROUND: With the aging of the population, more older patients are being considered for kidney transplantation; therefore, it is crucial to evaluate the risks and benefits of transplantation in this population. This study aimed to assess long-term outcomes of kidney transplantation in a cohort of patients who underwent kidney transplantation at age >70 years, compared with patients aged 60 to 69 years at transplantation. METHODS: Included in the study were 261 consecutive kidney transplant recipients: 52 were aged >70 years, and 209 were aged 60 to 69 years at transplantation. Data were collected retrospectively and analyzed using multivariate logistic regression to identify potential outcome risk factors. RESULTS: The number of transplants in both groups increased during the study period. Mortality after transplantation was strongly correlated to age (hazard ratio [HR] = 1.11; 95% CI, 1.05-1.18; P < .001), deceased donor (HR = 2.0; 95% CI, 1.1-3.8; P = .034), and pretransplant diabetes (HR = 2.9; 95% CI, 1.7-4.9; P = .001). Recipients aged >70 years had an increased risk of death censored graft failure (HR = 2.98; 95% CI, 1.56-5.74; P = .001). In living donor transplants, 3-year survival was 80% in recipients age >70 years, compared with 98% in the 60- to 69-year group. Five-year survival was 71% and 92%, respectively. In deceased donor transplants, 3-year survival was 63% and 78%, and 5-year survival was 58% and 72%, respectively. The risk of malignancy (excluding nonmelanotic skin cancer) was nearly triple in the age >70 years group (HR = 2.96; 95% CI, 1.3-6.8; P = .01). CONCLUSIONS: Patient and graft survival in kidney recipients in the eighth decade is worse compared with recipients in the seventh decade of life. However, it is improved with living kidney donation.