PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1α, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1α(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1α(-/-) mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product ß-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of ß-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1α-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1α-dependent stress resistance.

Cytomegalovirus mismatch still negatively affects patient and graft survival in the era of routine prophylactic and preemptive therapy: A paired kidney analysis.

The impact of cytomegalovirus (CMV) serostatus on kidney transplant outcomes in an era when CMV prophylactic and preemptive strategies are used routinely is not clearly established. Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, recipients with first deceased donor kidney transplant (≥18 years, 2010-2015) were stratified into 4 groups in the main cohort: CMV-seronegative donor (D-)/CMV-seronegative recipient (R-), CMV-seropositive donor (D+)/R-, D+/CMV-seropositive recipient (R+), and D-/R+. In a paired kidney cohort, we identified 2899 pairs of D- kidney transplant with discordance of recipient serostatus (D-/R- vs D-/R+) and 4567 pairs of D+ kidney transplant with discordance of recipient serostatus (D+/R- vs D+/R+). In the main cohort, D+/R- was associated with a higher risk of graft failure (hazard ratio [HR] = 1.17, P = .01), all-cause mortality (HR = 1.18, P < .001), and infection-related mortality (HR = 1.38, P = .03) compared with D-/R-. In the paired kidney analysis, D+/R- was an independent risk factor for all-cause mortality (HR = 1.21, P = .003) and infection-related mortality (HR = 1.47, P = .04) compared with D+/R+. No difference in graft loss between D+/R- and D+/R+. CMV mismatch is still an independent risk factor for graft loss and patient mortality. The negative impact of D+/R- serostatus on mortality persists after fully matching for donor factors.

C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab.

Background: C3 glomerulonephritis (C3GN) is caused by alternate complement pathway over-activation. It frequently progresses to end-stage renal disease, recurs in two-thirds of transplants and in half of these cases progresses to allograft loss. There is currently no proven treatment for C3GN. Case Presentation: We describe a family segregating pathogenic alleles of complement factor H and I (CFH and CFI). The only member carrying both mutations developed C3GN. Prolonged delayed graft function after deceased donor transplantation, heavy proteinuria and isolated C3 hypocomplementemia prompted an allograft biopsy confirming diagnosis of recurrent C3GN. Discussion: This is the first report of early recurrence of C3GN in an allograft in a patient with known mutations in complement regulatory genes and no preexisting para-proteinemia. Complement activation resulting from ischemia-reperfusion injury from prolonged cold ischemia time unabated in the setting of deficiency of two major complement regulators likely led to the early and severe recurrence. In atypical hemolytic uremic syndrome, the terminal complement cascade activation in the sentinel event initiating endothelial injury; blockade at the level of C5 convertase with eculizumab is uniformly highly effective in management. C3 glomerulopathies (C3GN and dense deposit disease) are a more complex and heterogeneous group. The relative degree of dysregulation at the levels of C3 and C5 convertases and therefore response to eculizumab varies among patients. In our patient, the clinical response to eculizumab was dramatic with recovery of allograft function and complete resolution of proteinuria. We review all cases of recurrent C3 glomerulopathy treated with eculizumab and discuss how complement biomarkers may aid in predicting response to therapy.

Recurrence of IgA nephropathy after kidney transplantation in steroid continuation versus early steroid-withdrawal regimens: a retrospective analysis of the UNOS/OPTN database.

In the past 20 years, there has been an increase in use of steroid-withdrawal regimens in kidney transplantation. However, steroid withdrawal may be associated with an increased risk of recurrent IgA nephropathy (IgAN). Using United Network of (Organ Sharing/Organ Procurement and Transplantation Network) UNOS/OPTN data, we analyzed adult patients with end-stage renal disease (ESRD) due to IgAN who received their first kidney transplant between 2000 and 2014. For the primary outcome, we used a competing risk analysis to compare the cumulative incidence of graft loss due to IgAN recurrence between early steroid-withdrawal (ESW) and steroid continuation groups. The secondary outcomes were patient survival and death-censored graft survival (DCGS). A total of 9690 recipients were included (2831 in ESW group and 6859 in steroid continuation group). In total, 1238 recipients experienced graft loss, of which 191 (15.43%) were due to IgAN recurrence. In multivariable analysis, steroid use was associated with a decreased risk of recurrence (subdistribution hazard ratio 0.666, 95% CI 0.482-0.921; P = 0.014). Patient survival and DCGS were not different between the two groups. In the USA, ESW in transplant for ESRD due to IgAN is associated with a higher risk of graft loss due to disease recurrence. Future prospective studies are warranted to further address which patients with IgAN would benefit from steroid continuation.

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

A large, international study on post-transplant glomerular diseases: the TANGO project.

BACKGROUND: Long-term outcomes in kidney transplantation (KT) have not significantly improved during the past twenty years. Despite being a leading cause of graft failure, glomerular disease (GD) recurrence remains poorly understood, due to heterogeneity in disease pathogenesis and clinical presentation, reliance on histopathology to confirm disease recurrence, and the low incidence of individual GD subtypes. Large, international cohorts of patients with GD are urgently needed to better understand the disease pathophysiology, predictors of recurrence, and response to therapy. METHODS: The Post-TrANsplant GlOmerular Disease (TANGO) study is an observational, multicenter cohort study initiated in January 2017 that aims to: 1) characterize the natural history of GD after KT, 2) create a biorepository of saliva, blood, urine, stools and kidney tissue samples, and 3) establish a network of patients and centers to support novel therapeutic trials. The study includes 15 centers in America and Europe. Enrollment is open to patients with biopsy-proven GD prior to transplantation, including IgA nephropathy, membranous nephropathy, focal and segmental glomerulosclerosis, atypical hemolytic uremic syndrome, dense-deposit disease, C3 glomerulopathy, complement- and IgG-positive membranoproliferative glomerulonephritis or membranoproliferative glomerulonephritis type I-III (old classification). During phase 1, patient data will be collected in an online database. The biorepository (phase 2) will involve collection of samples from patients for identification of predictors of recurrence, biomarkers of disease activity or response to therapy, and novel pathogenic mechanisms. Finally, through phase 3, we will use our multicenter network of patients and centers to launch interventional studies. DISCUSSION: Most prior studies of post-transplant GD recurrence are single-center and retrospective, or rely upon registry data that frequently misclassify the cause of kidney disease. Systematically determining GD recurrence rates and predictors of clinical outcomes is essential to improving post-transplant outcomes. Furthermore, accurate molecular phenotyping and biomarker development will allow better understanding of individual GD pathogenesis, and potentially identify novel drug targets for GD in both native and transplanted kidneys. The TANGO study has the potential to tackle GD recurrence through a multicenter design and a comprehensive biorepository.

Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy.

To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody (Ab) beginning on Gestational Day 8 or 12 and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Ab injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at Days 13 and 18. In addition, normal reproductive function was compromised, as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, though arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the Ab-injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetal-placental unit, compromised several indices of vascular remodeling, reduced fecundity, and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.

Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*.

OBJECTIVE: : In sepsis, quiescent blood vessels become leaky and inflamed by mechanisms that are incompletely understood. We hypothesized that angiopoietin-2, a partial antagonist of the endothelium-stabilizing receptor Tie-2 secreted by endothelium, contributes to adverse outcomes in this disease. DESIGN: : Laboratory and animal research. SETTINGS: : Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA. SUBJECTS: : Angiopoietin-2 heterozygous mice, emergency department patients. MEASUREMENTS AND MAIN RESULTS: : Mice with one functional angiopoietin-2 allele developed milder kidney and lung injury, less tissue inflammation, and less vascular leakage compared to wild-type counterparts. Heterozygotes experienced >40% absolute survival advantage following two different models of sepsis (p = .004 and .018). In human subjects presenting to our emergency department with suspected infection (n = 270 combined), circulating angiopoietin-2 was markedly elevated within the first hour of clinical care. First-hour angiopoietin-2 concentrations were proportional to current disease severity (p < .0001), rose further over time in eventual nonsurvivors (p < .0001), and predicted the future occurrence of shock (p < .0001) or death (p < .0001) in the original cohort and an independent validation group. Finally, septic human serum disrupted the barrier function of microvascular endothelial cells, an effect fully neutralized by an angiopoietin-2 monoclonal antibody. CONCLUSIONS: : We conclude that angiopoietin-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.

Leptin exacerbates sepsis-mediated morbidity and mortality.

The adipose-derived hormone leptin is well known for its contribution to energy metabolism and satiety signaling in the hypothalamus. Previous studies suggested that obesity is an independent risk factor for sepsis morbidity and mortality, and it is associated with elevated baseline levels of circulating leptin in normal, nonseptic patients. In mouse endotoxemia and cecal ligation puncture models of sepsis, we observed elevated levels of leptin and soluble leptin receptor (sLR). Exogenously administered leptin increased mortality in endotoxemia and cecal ligation puncture models and was associated with increased expression of adhesion and coagulation molecules, macrophage infiltration into the liver and kidney, and endothelial barrier dysfunction. Conversely, longform leptin receptor-deficient mice were protected from sepsis morbidity and mortality and had less endothelial dysfunction. Furthermore, an in vitro study revealed that leptin-induced endothelial dysfunction is likely mediated, at least in part, by monocytes. Moreover, administration of an sLR conferred a survival benefit. Human septic patients have increased circulating sLR concentrations, which were correlated with disease severity indices. Together, these data support a pathogenic role for leptin signaling during sepsis.

Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality.

A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ∼70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% (n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% (n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.

Normalization of wall shear stress as a physiological mechanism for regulating maternal uterine artery expansive remodeling during pregnancy.

Outward remodeling of the maternal uterine circulation during pregnancy is essential for normal uteroplacental perfusion and pregnancy outcome. The physiological mechanism by which this process is regulated is unknown; we hypothesized that it involved the normalization of wall shear stress (WSS). Pregnant Sprague-Dawley rats underwent unilateral ligation of the main uterine artery and vein at the cervical end of the uterus on gestational day 10, thus restricting inflow/outflow of blood into that uterine horn to a single point at the ovarian end; the contralateral sham-operated side provided an internal control. This procedure alters uterine hemodynamics by increasing WSS, since the entire uterine horn is supplied by one rather than two vessels. Arterial diameter and blood flow velocity values were measured by intravital ultrasonographic pulse-wave Doppler on gestational day 20 and used to calculate WSS. Although both ovarian artery lumen diameter and blood velocity increased, WSS was similar in both horns. These data support the concept that increased WSS secondary to hemochorial placentation is the primary physiological stimulus for uterine vascular remodeling and that its normalization may be the primary mechanism that regulates the extent of arterial circumferential growth required to maintain placental perfusion. We further hypothesize that shallow spiral artery invasion, such as occurs in preeclampsia, limits the increase in upstream shear stress and results in attenuated remodeling and placental under-perfusion.

Placental vasculature in health and disease.

Both angiogenesis and vasculogenesis occur during normal placental development. Additionally, the placenta undergoes a process of vascular mimicry (also referred to as pseudo-vasculogenesis) where the placental cytotrophoblasts that invade the spiral arteries convert from an epithelial to an endothelial phenotype during normal pregnancy. Failure of placental angiogenesis and pseudo-vasculogenesis during placental development has been linked to the pathogenesis of preeclampsia and related disorders such as intrauterine growth restriction. This review discusses placental vascular development during health and in disease with a focus on accumulating recent evidence that the maternal clinical syndrome of preeclampsia may be due to the result of excess antiangiogenic factors liberated by the diseased placenta.

Early-pregnancy soluble Fas levels in idiopathic small-for-gestational-age pregnancies.

OBJECTIVE: We sought to determine first- and second-trimester serum soluble Fas (sFas) and placental growth factor (PlGF) levels in idiopathic small-for-gestational-age (SGA) pregnancies. STUDY DESIGN: We measured sFas and PlGF levels in women who delivered SGA infants uncomplicated by preeclampsia and in control subjects. For sFas there were 34 cases and 318 control subjects in the first trimester and 9 cases and 11 control subjects in the second trimester. For PlGF there were 31 cases and 281 control subjects in the first trimester and 8 cases and 11 control subjects in the second trimester. RESULTS: SGA pregnancies had lower sFas levels than control subjects in the second trimester (3703 + or - 209 pg/mL vs 4562 + or - 241 pg/mL; P = .015), but not in the first trimester (4892 + or - 191 pg/mL vs 4971 + or - 177 pg/mL; P = .68). There was no difference in PlGF levels between SGA and normal pregnancies in both trimesters. CONCLUSION: Serum sFas levels were lower in idiopathic SGA pregnancies in the second trimester, but not in the first. There was no difference in serum PlGF levels in either trimester.

Angiogenic factors and preeclampsia.

Preeclampsia/eclampsia is a major cause of maternal and fetal morbidity worldwide. Although the etiology of preeclampsia is still unclear, the clinical phenotypes of preeclampsia have been demonstrated to be related to high circulating levels of anti-angiogenic proteins secreted by the placenta such as soluble Fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin. Because, alterations in circulating sFlt1 and soluble endoglin precede the onset of clinical disease, these factors may be useful to screen or identify patients at risk for preeclampsia. Investigations are currently underway of various pharmacologic agents to counteract the effects of sFlt1 and/or sEng as a potential treatment for preeclampsia. Recently several isoforms of sFlt1 have been described, such as sFlt1-14 which is expressed only in primates, and is thought to be the primary isoform produced by the placenta in preeclamptic subjects. Although several novel pathways have been proposed to play key roles in inducing sFlt1 production, the exact role of these pathways in human preeclampsia is still not known. Women with a history of preeclampsia have an increased risk of hypertension, and cardiovascular and renal disease. Whether these long-term observations are due to persistent and subtle endothelial damage as result of preeclampsia, or simply reflect the consequences of the vascular risk factors which are more common in these women remains unknown.

Placental sFLT1 is associated with complement activation and syncytiotrophoblast damage in preeclampsia.

The immune complement system protects against pathogens; however, excess activation results in disease like hemolytic uremic syndrome, a clinical imitator of preeclampsia. Vascular endothelial factor (VEGF) protects against aberrant complement activation and is inhibited by soluble fms-like tyrosine kinase-1 (sFLT1) in other organs. We hypothesize that sFLT1 promotes complement-mediated placental damage through VEGF inhibition in preeclampsia. Objective: Quantify placental complement activity and sFLT1 expression in preeclampsia, and the subgroup of preeclampsia with hemolysis elevated liver enzymes low platelets (HELLP) syndrome. Methods: Placental complement activation marker C4d, membrane attack complex (MAC), and sFLT1 expression was quantified using immunofluores cence microscopy. Results: Placentas from 18 controls, 25 preeclampsia, including 6 cases of HELLP syndrome were identified. Placental C4d expression was greater in PE (median 6.4 [IQR: 5.1, 8.3]) compared to controls (4.4 [3.6, 5.5]; p = 0.003). MAC expression was also increased in preeclampsia compared to controls (6.5 [5.8, 8.7]; 5.4 [2.9, 5.9], p = 0.001). Placental sFLT1 expression was also higher in preeclampsia (p <0.0001). C4d and MAC were strongly correlated with sFLT1 levels in the placenta (R = 0.72; p < 0.0001 and R = 0.59; p = 0.01, respectively). Complement and sFLT1 expression was elevated in HELLP compared to preeclampsia without laboratory abnormalities, but this difference did not reach statistical significance. Conclusion: Increased placental complement activation and damage was seen in preeclampsia and correlates with sFLT1 expression. Our findings support the importance of the complement pathway in preeclampsia.

Unusual Presentation of Hemophagocytic Lymphohistiocytosis in a Kidney Transplant Patient.

We are presenting a case of a middle-aged woman with history of remote kidney transplantation who had multiple admissions for septic shock-like picture, recurrent fever, and hypotension. Her shock manifestation would resolve after stress dose steroid administration and less than 24 hours of vasopressor administration. Initially, extensive workup was performed without revealing etiology. Eventually, a bone marrow biopsy was carried out leading to the diagnosis of hemophagocytic lymphohistiocytosis, most likely related to recent cytomegalovirus infection.

Renal PGC1α May Be Associated with Recovery after Delayed Graft Function.

BACKGROUND: Delayed renal graft function (DGF) contributes to the determination of length of hospitalization, risk of acute rejection, and graft loss. Existing tools aid the diagnosis of specific DGF etiologies such as antibody-mediated rejection, but markers of recovery have been elusive. The peroxisome proliferator gamma co-activator-1-alpha (PGC1α) is highly expressed in the renal tubule, regulates mitochondrial biogenesis, and promotes recovery from experimental acute kidney injury. OBJECTIVES: We aimed to determine the association between renal allograft PGC1α expression and recovery from delayed graft function. METHODS: We retrospectively analyzed patients undergoing renal transplantation at a single center from January 1, 2008 to June 30, 2014. PGC1α expression was assessed by immunostaining and ultrastructural characteristics by transmission electron microscopy. Of 34 patients who underwent renal biopsy for DGF within 30 days of transplant, 21 were included for analysis. RESULTS: Low PGC1α expression was associated with a significantly longer time on dialysis after transplant (median of 35.5 vs. 16 days, p < 0.05) and a significantly higher serum creatinine (sCr) at 4 weeks after transplantation among those who discontinued dialysis (5 vs. 1.65 mg/dL, p < 0.0001). Low PGC1α expression was not associated with higher sCr at 12 weeks after transplantation. Ultrastructural characteristics including apical membrane blebbing and necrotic luminal debris were not informative regarding clinical outcomes. CONCLUSIONS: These data suggest that higher PGC1α expression is associated with faster and more complete recovery from DGF. Mitochondrial biogenesis may be a therapeutic target for DGF. Larger studies are needed to validate these findings.

HLA-DQ Mismatching and Kidney Transplant Outcomes.

BACKGROUND AND OBJECTIVES: Recent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection. RESULTS: A total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P<0.01), but not in deceased kidney donor recipients (HR, 1.05; 95% CI, 0.98 to 1.12; P=0.18) (P value for interaction <0.01). When taking cold ischemic time into account, HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P=0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P=0.49) (P value for interaction <0.01). Recipients with one or two HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P<0.01) in deceased donor and 1.14 (95% CI, 1.03 to 1.27; P=0.02) in living donor kidney transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not. CONCLUSIONS: HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.