A living donor kidney transplant recipient with mycobacterium senegalense bacteremia: A case report.

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.

Management and Outcome of COVID-19 Infection Using Nirmatrelvir/Ritonavir in Kidney Transplant Patients.

BACKGROUND: Nirmatrelvir/ritonavir has been shown to reduce the risk of 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 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) based on 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 acute kidney injury (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 timepoint, 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 ug/L [4.0, 6.2] versus 4.8 ug/L [4.3, 5.7] 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.

Successful Endovascular Management of Resistant Hypertension Post Kidney Transplant: A Case Report.

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.

Justification: La sténose de l'artère du rein transplanté (SART) est une cause bien connue et potentiellement réversible d'hypertension résistante qui touche de 1 à 23% des receveurs après l'intervention. La sténose du segment iliaque proximal de l'artère du rein transplanté (SARTprox), laquelle cause un dysfonctionnement du greffon, est moins fréquente (incidence rapportée: 2 à 3%). Elle se produit généralement entre 3 mois et 2 ans après la transplantation, mais peut se produire à tout moment. Les examens non invasifs tels que l'échographie Doppler, l'angiographie par tomodensitométrie (TDM) et l'angiographie par résonance magnétique sont utiles pour l'évaluation initiale, mais le diagnostic définitif d'une sténose hémodynamiquement significative nécessite souvent une angiographie formelle. Les SART doivent être suspectées chez tout receveur d'une greffe rénale présentant une aggravation de l'hypertension et/ou une détérioration de la fonction rénale, autrement inexpliquées. Nous présentons le cas d'une receveuse souffrant d'hypertension résistante et d'une altération de la fonction du greffon résultant d'une grave altération du flux sanguin dans le greffon causée par l'occlusion du système iliaque proximal. Présentation du cas: Une femme de 74 ans, greffée 15 ans auparavant avec un rein de donneur vivant, présentait un dysfonctionnement du greffon (Cr sérique: 229 µmol/L) et une hypertension résistante nécessitant huit médicaments antihypertenseurs. À l'examen physique, la pression artérielle était de 160/92 mm Hg et la patiente ne présentait aucune sensibilité au-dessus du greffon rénal dans le quadrant inférieur droit de l'abdomen, ni bruit audible au niveau de l'artère rénale. Diagnostic: L'échographie Doppler du greffon a montré une inversion du flux dans l'artère iliaque externe droite, ce qui suggérait une occlusion iliaque proximale ipsilatérale. La TDM avant l'intervention avait montré une charge athérosclérotique sévère dans l'aorte et les systèmes iliaques bilatéraux. L'artère rénale droite anastomosée semblait non obstruée. Intervention: L'angiographie conventionnelle a montré une occlusion de l'artère iliaque commune droite et de l'artère iliaque externe proximale, avec une perfusion rétrograde du rein transplanté via le système iliaque gauche controlatéral et l'aorte. La recanalisation sous-intimale du système iliaque droit a été réalisée par angioplastie et on a procédé à la pose d'une endoprothèse au niveau de la bifurcation aortique avec des extenseurs s'étendant dans l'artère iliaque externe droite proximale. L'angiographie post-déploiement a démontré une perméabilité renouvelée du système iliaque droit, avec restauration de la perfusion antérograde vers le rein transplanté. Résultats: Après la procédure, la pression artérielle de la patiente s'est abaissée significativement et la fonction du greffon s'est améliorée. Après 6 mois, la pression artérielle demeurait bien contrôlée (avec trois médicaments) et la fonction du greffon était stable (Cr sérique: 74 µmol/L). Enseignements tirés: Notre cas décrit une SARTprox et la contribution de l'hypoperfusion rénale à l'hypertension et à l'altération de la fonction du greffon, avec un potentiel de réversibilité.

Association of anti-neutrophil cytoplasmic antibody-associated vasculitis and cardiovascular events: a population-based cohort study.

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 Canadian Glomerulonephritis Registry (CGNR) and Translational Research Initiative: Rationale and Clinical Research Protocol.

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.

Contexte: Les glomérulonéphrites (GN) sont des causes importantes d'insuffisance rénale; elles représentent 20 % des cas incidents d'insuffisance rénale terminale (IRT) au Canada chaque année. Inverser la néphropathie et prévenir la progression vers l'insuffisance rénale est possible, mais deux obstacles majeurs freinent la réussite de l'intervention thérapeutique: une compréhension limitée des mécanismes sous-jacents de la maladie, de même que l'absence de biomarqueurs non invasifs et de cibles thérapeutiques. Les approches multicentriques reliant les données cliniques longitudinales et les résultats de santé à la collecte d'échantillons biologiques en série permettraient de combler cette lacune. Objectif: Créer une base de données cliniques nationale en ligne, multidimensionnelle et axée sur le patient, de même qu'une biobanque virtuelle fédérée pour permettre de mener des recherches moléculaires et cliniques humaines sur les GN au Canada. Type d'étude: Registre d'observation prospectif multicentrique débuté en 2019. Cadre: Neuf centres de soins tertiaires canadiens. Sujets: Des patients adultes recrutés dans les 24 mois suivant la biopsie et présentant un profil histopathologique de lésion compatible avec une néphropathie à IgA, une hyalinose segmentaire et focale, une maladie à changement minime, une glomérulonéphrite extra-membraneuse, une glomérulopathie à C3 et une glomérulonéphrite membranoproliférative. Mesures: La première visite comporte une collecte détaillée des données cliniques, histopathologiques et de laboratoire, la collecte d'échantillons biologiques (sang, urine et écouvillonnage des amygdales), ainsi qu'un questionnaire autoadministré sur la qualité de vie. Pour le suivi, la collecte des données cliniques et de laboratoire, la collecte des échantillons biologiques et les questionnaires s'effectuent tous les six mois. Méthodologie: Les patients reçoivent des soins comme établi par leur médecin, et les visites d'étude sont programmées tous les six mois. Les patients sont suivis jusqu'au décès ou jusqu'à la dialyse, à la transplantation ou au retrait de l'étude. Un critère de jugement combiné (IRT, ou diminution de 40 % du débit de filtration glomérulaire estimé après deux ans), ainsi que le taux de déclin de la fonction rénale et la rémission de la protéinurie sont les principaux critères de jugement. Les données phénotypiques cliniques et moléculaires seront analysées par sous-types de GN afin d'identifier les prédicteurs de la maladie et de découvrir de nouvelles cibles thérapeutiques. Limites: Le recrutement des sujets demeure un des principaux défis puisque les maladies glomérulaires prises individuellement sont relativement rares. La faible taille des échantillons et la courte durée du suivi pendant les deux ans de la phase initiale de l'étude pourraient faire en sorte que les études initiales issues du registre ne soient pas assez puissantes pour détecter de légères différences dans les résultats cliniquement significatifs comme l'IRT ou le décès. Conclusion: Le Canadian Glomerulonephritis Registry (CGNR) appuie les efforts de collaboration nationale visant à étudier les patients atteints de maladies glomérulaires et leur évolution clinique. Enregistrement de l'essai: NCT03460054.

Recurrent glomerular disease after kidney transplantation.

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.

Receptor-interacting protein-2 deficiency delays macrophage migration and increases intracellular infection during peritoneal dialysis-associated peritonitis.

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.

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection.

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.

Pneumocystis pneumonia outbreak among renal transplant recipients at a North American transplant center: Risk factors and implications for infection control.

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.

Mouse Nkrp1-Clr gene cluster sequence and expression analyses reveal conservation of tissue-specific MHC-independent immunosurveillance.

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.

The future of RIP2/RICK/CARDIAK as a biomarker of the inflammatory response to infection.

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.