Search

Background: Nirmatrelvir/ritonavir has been shown to reduce the risk of coronavirus disease 2019 (COVID-19)-related complications in patients at high risk for severe COVID-19. However, clinical experience of nirmatrelvir/ritonavir in the transplant recipient population is scattered due to the complex management of drug-drug interactions with calcineurin inhibitors. We describe the clinical experience with nirmatrelvir/ritonavir at The Ottawa Hospital kidney transplant program., Methods: Patients who received nirmatrelvir/ritonavir between April and June 2022 were included and followed up to 30 days after completion of treatment. Tacrolimus was withheld for 24 hours and resumed 72 hours after the last dose of nirmatrelvir/ritonavir (on day 8) on the basis of the drug level the day before. The first 30 patients had their dose adjusted according to drug levels performed twice in the first week and as needed thereafter. Subsequently, a simplified algorithm with less frequent calcineurin inhibitor-level monitoring was implemented. Outcomes, including tacrolimus-level changes, serum creatinine and AKI (defined as serum creatinine increase by 30%), and clinical outcomes were described globally and compared between algorithms., Results: Fifty-one patients received nirmatrelvir/ritonavir. Tacrolimus levels drawn at the first time point, 7 days after withholding of calcineurin inhibitor, and 2 days after discontinuing nirmatrelvir/ritonavir were within the therapeutic target in 17/44 (39%), subtherapeutic in 21/44 (48%), and supratherapeutic in 6/44 (14%). Two weeks after, 55% were within the therapeutic range, 23% were below, and 23% were above it. The standard and simplified algorithms provided similar tacrolimus level (median 5.2 [4.0-6.2] µg/L versus 4.8 [4.3-5.7] µg/L, P = 0.70). There were no acute rejections or other complications., Conclusions: Withholding tacrolimus starting the day before initiation of nirmatrelvir/ritonavir with resumption 3 days after completion of therapy resulted in a low incidence of supratherapeutic levels but a short period of subtherapeutic levels for many patients. AKI was infrequent. The data are limited by the small sample size and short follow-up., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_07_10_CJN0000000000000186.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Rationale: Transplant renal artery stenosis (TRAS) is a well-recognized and potentially reversible cause of resistant hypertension post transplantation and can affect 1% to 23% of recipients. Stenosis of the iliac segment proximal to the transplant renal artery (proximal TRAS) causing dysfunction of the transplanted kidney is less common with reported incidence of 2% to 3%. Presentation typically occurs between 3 months and 2 years post transplant but may happen at any time. Noninvasive investigations such as Doppler ultrasound, computed tomography (CT) angiogram, and magnetic resonance angiogram are useful in initial evaluation, but definitive diagnosis of hemodynamically significant stenosis often requires formal angiogram. Transplant renal artery stenosis should be suspected in any kidney transplant recipient with worsening hypertension and/or deterioration in kidney function which is otherwise unexplained. We present the case of a kidney transplant recipient with resistant hypertension and impaired graft function, secondary to severe impairment of graft blood flow from proximal iliac system occlusion., Presenting Concerns of the Patient: A 74-year-old female 15 years post live donor kidney transplant presented with graft dysfunction (serum Cr 229 μmol/L) and resistant hypertension, requiring use of 8 antihypertensive medications. On physical examination, blood pressure was 160/92 mm Hg with no tenderness over the renal graft in the right lower abdominal quadrant and no audible bruit in kidney allograft area., Diagnosis: Transplant Doppler ultrasound showed reversal of flow in the right external iliac artery suggestive of ipsilateral proximal iliac occlusion. Pre-procedure CT demonstrated severe atherosclerotic burden within the aorta and bilateral iliac systems. The anastomosed right renal artery appeared patent., Interventions: Conventional angiogram showed occlusion of the right common and proximal external iliac arteries with retrograde perfusion of the transplant kidney via the contralateral left iliac system and aorta. Subintimal recanalization of the right iliac system was performed with angioplasty and kissing stent placement at the aortic bifurcation with stents extending into the proximal right external iliac artery. Post deployment angiogram demonstrated renewed patency of the right iliac system, with restoration of antegrade perfusion to the transplant kidney., Outcomes: The patient's blood pressure decreased significantly after the procedure, with improvement in graft function. After 6 months, the patient continued to have optimally controlled blood pressure (on 3 medications) and stable graft function (serum Cr 74 μmol/L)., Teaching Points: Our case describes proximal TRAS and the contribution of renal hypoperfusion to hypertension and impaired graft function, with the potential for reversibility., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Glomerulonephritis (GN) is a leading cause of kidney failure and accounts for 20% of incident cases of end-stage kidney disease (ESKD) in Canada annually. Reversal of kidney injury and prevention of progression to kidney failure is possible; however, limited knowledge of underlying disease mechanisms and lack of noninvasive biomarkers and therapeutic targets are major barriers to successful therapeutic intervention. Multicenter approaches that link longitudinal clinical and outcomes data with serial biologic specimen collection would help bridge this gap., Objective: To establish a national, patient-centered, multidimensional web-based clinical database and federated virtual biobank to conduct human-based molecular and clinical research in GN in Canada., Design: Multicenter, prospective observational registry, starting in 2019., Setting: Nine participating Canadian tertiary care centers., Patients: Adult patients with a histopathologic pattern of injury consistent with IgA nephropathy, focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy, C3 glomerulopathy, and membranoproliferative GN recruited within 24 months of biopsy., Measurements: Initial visits include detailed clinical, histopathological, and laboratory data collection, blood, urine, and tonsil swab biospecimen collection, and a self-administered quality of life questionnaire. Follow-up clinical and laboratory data collection, biospecimen collection, and questionnaires are obtained every 6 months thereafter., Methods: Patients receive care as defined by their physician, with study visits scheduled every 6 months. Patients are followed until death, dialysis, transplantation, or withdrawal from the study. Key outcomes include a composite of ESKD or a 40% decline in estimated glomerular filtration rate (eGFR) at 2 years, rate of kidney function decline, and remission of proteinuria. Clinical and molecular phenotypical data will be analyzed by GN subtype to identify disease predictors and discover therapeutic targets., Limitations: Given the relative rarity of individual glomerular diseases, one of the major challenges is patient recruitment. Initial registry studies may be underpowered to detect small differences in clinically meaningful outcomes such as ESKD or death due to small sample sizes and short duration of follow-up in the initial 2-year phase of the study., Conclusions: The Canadian Glomerulonephritis Registry (CGNR) supports national collaborative efforts to study glomerular disease patients and their outcomes., Trial Registration: NCT03460054., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Reich is a national coordinating investigator for the Calliditas NEFIGARD study, and is a site investigator for therapeutic trials in IgAN funded by Alnylam and Omeros. She has provided consultation outside of the submitted work for Novartis, Chinook, and Travere. She is a site investigator for a study in FSGS sponsored by Pfizer. The GN Fellowship at University Health Network is supported by the Louise Fast Foundation., (© The Author(s) 2022.)

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is implicated in elevating the risk for cardiovascular (CV) disease; whether the elevated risk applies to all types of CV diseases or specific types is unclear. This study examined the association of AAV and adverse CV outcomes compared with the non-AAV population., Methods: We conducted a population-based, retrospective cohort study of adults (mean age 61 years, 51% female) with a new diagnosis of AAV in Ontario, Canada from 2007 to 2017. Weighted models were used to examine the association of AAV ( n  = 1520) and CV events in a matched (1:4) control cohort ( n  = 5834). The main outcomes were major adverse CV events (MACE), defined as myocardial infarction (MI), stroke or CV death, its components, atrial fibrillation (AF) and congestive heart failure (CHF)., Results: Over a mean follow-up of 3.8 years, AAV (compared with non-AAV) was associated with a higher risk of stroke: cumulative incidence 7.0% versus 5.2%, sub-distribution hazard ratio (sHR) 1.49 [(95% confidence interval (95% CI) 1.10-2.02]; AF: cumulative incidence 16.4% versus 11.5%, sHR 1.51, 95% CI 1.30-1.75; and CHF: cumulative incidence 20.8% versus 13.3%, sHR 1.41, 95% CI 1.22-1.62; but not for MACE, MI or CV death. The risks for all CV events, except CV death, were significantly elevated in the early period after AAV diagnosis, in particular AF (365-day sHR 2.06, 95% CI 1.71-2.48; 90-day sHR 3.33, 95% CI 2.66-4.18) and CHF (365-day sHR 1.75, 95% CI 1.48-2.07; 90-day sHR 2.65, 95% CI 2.15-3.26)., Conclusion: AAV is associated with a high risk of certain types of CV events, particularly in the early period following diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Mycobacterium senegalense is primarily known in sub-Saharan Africa to cause bovine farcy, a chronic granulomatous inflammation of the skin and lymphatics in cows. Reports of M. senegalense are rare among humans. We report a unique case of M. senegalense bloodstream infection in a living donor kidney transplant recipient with multiple possible sources of infection., (© 2021 Wiley Periodicals LLC.)

Background: Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer., Case Presentation: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient's immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response., Conclusions: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis.

The serology of patients with Rheumatoid arthritis (RA) is characterized by persistently raised levels of autoantibodies: Rheumatoid Factors (RhF) against Fc of IgG, and to citrullinated (Cit) protein/peptide sequences: ACPA, recognizing multiple Cit-sequences. B cell depletion therapy based on rituximab delivers good clinical responses in RA patients, particularly in the seropositive group, with responses sometimes lasting beyond the phase of B cell reconstitution. In general, ACPA levels fall following rituximab, but fluctuations with respect to predicting relapse have proved disappointing. In order to identify possible immunodominant specificities within either IgG- or IgA-ACPA we used a Multiplex bead-based array consisting of 30 Cit-peptides/proteins and 22 corresponding native sequences. The kinetics of the serum ACPA response to individual specificities was measured at key points (Baseline, B cell depletion phase, Relapse) within an initial cycle of rituximab therapy in 16 consecutive patients with severe, active RA. All had achieved significant decreases in Disease Activity Scores-28 and maintained B cell depletion in the peripheral blood (<5 CD19+cells/μl) for at least 3 months. At Baseline, mean fluorescence intensity shown by individual IgG- and IgA-ACPA were strongly correlated (R(2) = 0.75; p < 0.0001) but IgA-ACPA were approximately 10-fold lower. Data were Z-normalised in order to compare serial results and antibody classes. At Baseline, a total of 68 IgG- and 51 IgA-ACPA had Z-scores ≥ 1 (above population mean) were identified, with at least one Cit-antigen identified in each serum. ACPA to individual specificities subsequently fluctuated with 3 different patterns. Most 51/68 (75%) IgG- and 48/51 IgA-ACPA (94%) fell between Baseline and Depletion, of which 57% IgG- and 65% IgA-ACPA rebounded pre-Relapse. Interestingly, 17/68 IgG-ACPA (25%) and some IgA-ACPA (3/51; 6%) transiently increased from Baseline, subsequently falling pre-Relapse. Individual responses to particular Cit-epitopes were not linked to particular patterns of fluctuation, but IgG- and IgA-ACPA to individual Cit-antigens often followed similar courses. Some new IgG- and IgA-ACPA, generally to different Cit-antigens however, arose at Relapse in 4 patients. The complexities of the ACPA response after rituximab may therefore reflect its ability to deplete or modify the function of parent B cell clones, which varies between patients. Although relapse following rituximab invariably follows naïve B cell exit from the bone marrow, these studies show that interactions between both 'new' and residual autoreactive memory B cells may be key to resumption of symptoms. The lack of identification of any immunodominant specificity suggests that the process of citrullination, rather than any particular Cit-antigen drives the autoimmune response in RA patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Pneumocystis pneumonia is a severe opportunistic fungal infection. Outbreaks among renal transplant recipients have been reported in Europe and Japan, but never in North America., Methods: We conducted a retrospective case-control study among adult renal transplant recipients at a Canadian center, using a 3:1 matching scheme. Ten cases and 30 controls were matched based on initial transplantation date, and all patients received prophylaxis with trimethoprim-sulfamethoxazole for 1 year posttransplantation., Results: The median time between transplantation and infection was 10.2 years, and all patients survived. Compared with controls, case patients had statistically lower estimated glomerular filtration rate (29.3 mL/min vs 66.3 mL/min; P = .028) and lymphopenia (0.51 × 10(9)/L vs 1.25 × 10(9)/L; P = .002). Transmission mapping revealed significant overlap in the clinic and laboratory visits among case vs control patients (P = .0002). One hundred percent of patients (4 out of 4) successfully genotyped had the same strain of Pneumocystis jirovecii., Conclusions: Our study demonstrated an outbreak of pneumocystis more than 10 years following initial transplantation, despite using recommended initial prophylaxis. We identified low estimated glomerular filtration rate and lymphopenia as risk factors for infection. Overlapping ambulatory care visits were identified as important potential sources of infection transmission, suggesting that institutions should re-evaluate policy and infrastructure strategies to interrupt transmission of respiratory pathogens., (Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Seasonal and pandemic influenza virus infections in renal transplant patients are associated with poor outcomes. During the pandemic of 2009-2010, the AS03-adjuvanted monovalent H1N1 influenza vaccine was recommended for transplant recipients, although its immunogenicity in this population was unknown. We sought to determine the safety and immunogenicity of an adjuvant-containing vaccine against pandemic influenza A H1N1 2009 (pH1N1) administered to kidney transplant recipients., Methods: We prospectively enrolled 124 adult kidney transplant recipients in the fall of 2009 at two transplant centers. Cohort 1 (n = 42) was assessed before and after pH1N1 immunization, while Cohort 2 (n = 82) was only assessed post immunization. Humoral response was measured by the hemagglutination inhibition assay. Vaccine safety was assessed by adverse event reporting, graft function, and human leukocyte antigen (HLA) alloantibody measurements., Results: Cohort 1 had a low rate of baseline seroprotection to pH1N1 (7%) and a low rate of seroprotection after immunization (31%). No patient <6 months post transplant (n = 5) achieved seroprotection. Seroprotection rate was greater in patients receiving double as compared with triple immunosuppression (80% vs. 24%, P = 0.01). In Cohort 2, post-immunization seroprotection was 35%. In both cohorts, no confirmed cases of pH1N1 infection occurred. No difference was seen in estimated glomerular filtration rate before (54.3 mL/min/1.73 m(2) ) and after (53.8 mL/min/1.73 m(2) ) immunization, and no acute rejections had occurred after immunization at last follow-up. In Cohort 1, 11.9% of patients developed new anti-HLA antibodies., Conclusion: An adjuvant-containing vaccine to pH1N1 provided poor seroprotection in renal transplant recipients. Receiving triple immunosuppression was associated with a poor seroresponse. Vaccination appeared safe, but some patients developed new anti-HLA antibodies post vaccination. Alternative strategies to improve vaccine responses are necessary., (© 2012 John Wiley & Sons A/S.)

I read with interest Nichola McCarthy's letter (May 2). She says that all nursing students should be taught electrocardiogram (ECG) recording, cannulation, venepuncture and IV administration skills.

The Nkrp1 (Klrb1)-Clr (Clec2) genes encode a receptor-ligand system utilized by NK cells as an MHC-independent immunosurveillance strategy for innate immune responses. The related Ly49 family of MHC-I receptors displays extreme allelic polymorphism and haplotype plasticity. In contrast, previous BAC-mapping and aCGH studies in the mouse suggest the neighboring and related Nkrp1-Clr cluster is evolutionarily stable. To definitively compare the relative evolutionary rate of Nkrp1-Clr vs. Ly49 gene clusters, the Nkrp1-Clr gene clusters from two Ly49 haplotype-disparate inbred mouse strains, BALB/c and 129S6, were sequenced. Both Nkrp1-Clr gene cluster sequences are highly similar to the C57BL/6 reference sequence, displaying the same gene numbers and order, complete pseudogenes, and gene fragments. The Nkrp1-Clr clusters contain a strikingly dissimilar proportion of repetitive elements compared to the Ly49 clusters, suggesting that certain elements may be partly responsible for the highly disparate Ly49 vs. Nkrp1 evolutionary rate. Focused allelic polymorphisms were found within the Nkrp1b/d (Klrb1b), Nkrp1c (Klrb1c), and Clr-c (Clec2f) genes, suggestive of possible immune selection. Cell-type specific transcription of Nkrp1-Clr genes in a large panel of tissues/organs was determined. Clr-b (Clec2d) and Clr-g (Clec2i) showed wide expression, while other Clr genes showed more tissue-specific expression patterns. In situ hybridization revealed specific expression of various members of the Clr family in leukocytes/hematopoietic cells of immune organs, various tissue-restricted epithelial cells (including intestinal, kidney tubular, lung, and corneal progenitor epithelial cells), as well as myocytes. In summary, the Nkrp1-Clr gene cluster appears to evolve more slowly relative to the related Ly49 cluster, and likely regulates innate immunosurveillance in a tissue-specific manner.

Purpose of Review: Recurrent glomerulonephritis is the third most common cause of graft failure, ranking only behind immunologic rejection and death with a functioning graft. Knowledge of the rates and timing of recurrent glomerular disease are important in counseling potential transplant recipients and preventive and therapeutic treatment strategies are necessary for those patients at risk., Recent Findings: Large observational studies that have analyzed posttransplant biopsies have confirmed the high rates of glomerular disease recurrence in renal allografts. Newer immunosuppressive protocols over the past 10 years have not affected the rate of disease recurrence or graft loss. There is emerging evidence that rituximab may be efficacious in treating recurrent membranous nephropathy and focal segmental glomerulosclerosis; however, larger clinical trials are warranted., Summary: Recurrent glomerulonephritis is an important determinant of long-term outcomes after transplantation, requiring appropriate counseling to potential transplant recipients. Currently, there are no proven strategies to prevent recurrent glomerulonephritis in renal transplant recipients. Despite the high rates of recurrent disease, long-term graft survival is still very good and transplantation remains the best treatment option for patients with end-stage renal disease from primary glomerulonephritis.

Mandy Dervis (readers panel June 17) states that nurse training should be to degree level. She adds: 'Those who do not feel up to it because they are too busy or only have a "handful of GCSEs" can undertake further education or work as nursing assistants.'

Two previous reports that receptor-interacting protein (RIP)-2 knockout (RIP2-/-) mice had defective nuclear factor-kappa B (NF-kappaB) signaling and T helper (Th)1 immune responses had led us to believe that this putative serine-threonine kinase might be a possible target for transplant immunosuppression. Thus, we tested whether RIP2-/- mice were able to reject vascularized allografts. Surprisingly, we found that T cells from RIP2-/- mice proliferated and produced interferon (IFN)-gamma after allostimulation in vitro. Moreover, naïve RIP2-/- CD4+ T cells differentiated normally into Th1 or Th2 cells under appropriate cytokine microenvironments. Consistent with these findings, no difference in allograft survival was observed between wild-type and RIP2-/- recipient mice, and rejection had similar pathology and cytokine profiles in both types of recipients. RIP2 deficiency was associated with defective NOD signaling, but this did not affect T-cell receptor (TCR)-dependent activation of the canonical NF-kappaB signaling or expression of NF-kappaB genes in rejecting allografts. Our data demonstrate that RIP2-deficient mice have intact canonical NF-kappaB signaling and can mount Th1-mediated alloresponses and reject vascularized allografts as efficiently as wild-type mice, thus arguing against RIP2 as a primary target for immunosuppression.

Biological markers of disease have become increasingly important for the clinician to diagnose, predict and monitor progression, and assess the therapeutic effect of interventions on underlying pathogenic mechanisms. Robust and specific biomarkers would be very useful in inflammation, where they may facilitate early identification of tissue injury, predict disease progression and help to modify disease outcomes. However, at present, there are no robust biomarkers to predict the course of inflammation. Here, we discuss emerging data indicating that RIP2, a putative serine/threonine protein kinase, may serve as a biomarker for the resolution of peritoneal dialysis-associated peritonitis and, more generally, of the acute inflammatory response to infection.

Background: Early upregulation of receptor-interacting protein-2 (RIP2) expression during peritoneal dialysis (PD)-associated peritonitis correlates with a favorable clinical outcome, while failure to upregulate RIP2 correlates with a protracted course. We noticed that patients who do not upregulate RIP2 during PD-associated peritonitis have more peritoneal macrophages during the early phase of infection., Methods: To study the mechanism behind this observation, we examined the role of RIP2 in the immune response to bacterial challenge in a mouse model of acute peritonitis. We injected RIP2(+/+) and RIP2(-/-) mice intraperitoneally with a Staphylococcus epidermidis cell free-preparation, and peritoneal cells were isolated 3, 6 and 24 h after challenge., Results: Surprisingly, RIP2(-/-) mice had a comparable influx of inflammatory leukocytes, but had a significantly higher number of peritoneal macrophages at 3 h, indicating delayed emigration of these cells. No significant differences were seen at later times suggesting that migration was delayed but not inhibited. In addition, RIP2(-/-) macrophages were more permissive to intracellular infection by Staphylococcus aureus, indicating that, in the absence of RIP2, resident peritoneal macrophages could become reservoirs of bacteria., Conclusion: These findings provide a mechanism for the observation that upregulation of RIP2 expression is required for rapid resolution of peritonitis, by decreasing intracellular infection and by regulating the migration of antigen-presenting cells in the early stages of an inflammatory response., (Copyright 2008 S. Karger AG, Basel.)

Using a novel flow chamber assay system and whole blood, we show that leukocytes from septic individuals have a four-fold elevation of adhesion, but not rolling, on a P-selectin/beta2-integrin substrate. Most leukocytes from septic patients (but not healthy controls) that bound vascular cell adhesion molecule 1 (VCAM-1) were neutrophils. All adhesion was inhibited with an antibody specific for the VCAM-1 ligand alpha4-integrin. The alpha4-integrin was present on neutrophils from septic patients but not on neutrophils from patients with localized bacterial infections. The plasma milieu of septic patients was sufficient to induce neutrophils from healthy subjects to bind VCAM-1 under flow conditions. This is the first description of alpha4-integrin/VCAM-1 pathway of neutrophil recruitment in human disease. This pathway may provide a new therapeutic target to reduce inappropriate neutrophil adhesion without altering the normal yet critical beta2-integrin-mediated adhesive function of neutrophils.

Inhaled nitric oxide (NO) is being used more and more in intensive care units as a modality to improve the outcome of patients with pulmonary complications. Our objective was to demonstrate that inhaled NO could impact upon a distally inflamed microvasculature-improving perfusion, leukocyte adhesive interactions, and endothelial dysfunction. Using intravital microscopy to visualize ischemia/reperfusion of postcapillary venules, we were able to demonstrate that the reduction in perfusion, the dramatic increase in leukocyte rolling, adhesion, and emigration, and the endothelial dysfunction could all be significantly abrogated with 80 ppm, but not 20 ppm inhaled NO. Perfusing whole blood directly over an inert P-selectin and CD18 ligand substratum incorporated in a flow chamber recruited the same number of rolling and adhering leukocytes from NO-ventilated and non-NO-ventilated animals, suggesting that inhaled NO was not directly affecting leukocytes. To demonstrate that inhaled NO was actually reaching the peripheral microvasculature in vivo, we applied a NO synthase inhibitor locally to the feline mesentery and demonstrated that the vasoconstriction, as well as leukocyte recruitment, were essentially abolished by inhaled NO, suggesting that a NO-depleted peripheral microvasculature could be replenished with inhaled NO in vivo. Finally, inhaled NO at the same concentration that was effective in ischemia/reperfusion did not affect vascular alterations, leukocyte recruitment, and endothelial dysfunction associated with endotoxemia in the feline mesentery. In conclusion, our data for the first time demonstrate a role for inhaled NO as a therapeutic delivery system to the peripheral microvasculature, showing tremendous efficacy as an antiadhesive, antivasoconstrictive, and antipermeabilizing molecule in NO-depleted tissues, but not normal microvessels or vessels that have an abundance of NO (LPS-treated). The notion that blood borne molecules have NO carrying capacity is conceptually consistent with our observations.