Thrombosis is a known complication of SARS-CoV-2 infection, particularly within a severely symptomatic subset of patients with COVID-19 disease, in whom an aggressive host immune response leads to cytokine storm syndrome (CSS). The incidence of thrombotic events coinciding with CSS may contribute to the severe morbidity and mortality observed in association with COVID-19. This review provides an overview of pharmacologic approaches based upon an emerging understanding of the mechanisms responsible for thrombosis across a spectrum of COVID-19 disease involving an interplay between immunologic and pro-thrombotic events, including endothelial injury, platelet activation, altered coagulation pathways, and impaired fibrinolysis.

It is now well established that infection with SARS-CoV-2 resulting in COVID-19 disease includes a severely symptomatic subset of patients in whom an aggressive and/or dysregulated host immune response leads to cytokine storm syndrome (CSS) that may be further complicated by thrombotic events, contributing to the severe morbidity and mortality observed in COVID-19. This review provides a brief overview of cytokine storm in COVID-19, and then presents a mechanistic discussion of how cytokine storm affects integrated pathways in thrombosis involving the endothelium, platelets, the coagulation cascade, eicosanoids, auto-antibody mediated thrombosis, and the fibrinolytic system.

Membranoproliferative glomerulonephritis is known to recur after kidney transplantation and may lead to allograft loss. Although an optimal treatment has not been determined, B-cell targeted therapies are now increasingly used as first-line agents, based on growing data showing antibodies as key players in the pathogenesis of membranoproliferative glomerulonephritis. Here, we report a case of recurrent immune complex-mediated membranoproliferative glomerulonephritis 3 years after a living-donor kidney transplant. Treatment with plasmapheresis and rituximab resulted in immediate and sustained improvement in allograft function.

Renal cell carcinoma (RCC) has a high incidence in the kidney transplant population and annual surveillance detects these tumors early in their natural history. Minimal guidelines exist regarding RCC surveillance in ESRD patients awaiting transplant. A retrospective review of our kidney transplant database examined the outcomes of annual ultrasonographic surveillance during initial kidney transplant evaluation and upon annual reassessment. Of 2642 patients listed for transplant, 145 patients were found to have masses during initial kidney transplant evaluation or annual imaging consistent with new complex cystic disease or RCC. A total of 71 patients had RCC identified, with 52 found on initial kidney transplant evaluation and 19 identified on annual surveillance. Male gender and African-American race were independently associated with RCC (P<.05). RCC was detected a median of 2.0 years after listing (two annual ultrasonography studies). Patients with complex cysts were more likely to undergo transplantation (48.7%) compared to patients with RCC (21.1%; P<.001). There was no significant difference in survival between RCC patients and those found to have complex cystic disease, suggesting incidental RCC can be diagnosed early in the natural history and at a curable stage through implementation of a biennial surveillance program.

BACKGROUND:In 2012, the United States experienced one of its worst West Nile virus (WNV) epidemics, reporting 5,387 human cases and final death toll of 243. Texas was at the epicenter of the outbreak, with 1,875 reported cases and 89 deaths that year. The Texas outbreak centered mainly in the Dallas-Fort Worth area where 30 deaths were reported. We report three cases of severe WNV infection complicated by meningoencephalitis in our organ transplant population.METHODS:Clinical data were collected from chart review. Therapy and outcomes on three identified patients were reviewed and compared with previously reported cases of WNV infection in kidney/pancreas transplant recipients and the general population.RESULTS:Two recipients of kidney and one recipient of a combined kidney and pancreas transplant were treated at our center for WNV infection. All three patients presented with a rapid decline in mental status within 24 hours of admission consistent with meningoencephalitis. Diagnosis was made based on detection of WNV IgM in the serum. All patients received intravenous immunoglobulin (IVIG) therapy at 400 mg/kg × 3 to 4 doses. As a result, two patients had a full recovery, and one patient died.CONCLUSION:Transplant recipients have a higher risk of neurologic complications from WNV infection. In areas where WNV is endemic, clinicians must have a high index of suspicion when treating patients presenting with fever, headache, and confusion. Full recovery in two of three patients suggests a potential role of IVIG therapy in controlling active WNV infection, particularly in immunosuppressed patients.

One key cell-signaling event central to inflammation in kidney diseases, including chronic renal allograft dysfunction or disease (CRAD), is the activation of NF-kappa B, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3 beta is an indispensable element of NF-kappa B activation, however, the exact role of GSK3 beta in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3 beta was weak in normal kidneys, but was markedly induced in inflamed allograft kidneys, with prominent cytoplasmic staining of tubular cells in areas of inflammation. Net GSK3 beta activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3 beta inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3 beta overexpression augmented, while GSK3 beta silencing diminished proinflammatory cellular responses to TNF-alpha stimulation, including NF-kappa B activation and expression of chemokines MCP-1 and RANTES. These inflammatory responses were obliterated by GSK3 beta inhibitors. Collectively, GSK3 beta plays an important role in mediating proinflammatory NF-kappa B activation and renal inflammation. Suppression of GSK3 beta activity might represent a novel therapeutic strategy to treat CRAD.

Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, mostly seen in children after viral or bacterial infection and vaccinations. Cases of ADEM, albeit rare, have been reported in renal transplant recipients. The pathophysiology of posttransplant ADEM remains unclear but has been hypothesized to be due to aberrant T-cell reactivity to myelin basic protein triggered by a bacterial or viral infection. We report an unusual case of a 34-year-old white female with ADEM developing 5 years after a living related renal transplant.

BACKGROUND:Protocol biopsies after renal transplantation are useful in detecting subclinical rejection. In earlier studies, the incidence of subclinical rejection was high among renal transplant recipients on a cyclosporine-based immunosuppression. However, recent data show that subclinical rejection is low under tacrolimus-based immunosuppression. This study evaluates the utility of 6-month protocol biopsy in renal transplant recipients under induction with rabbit antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids.METHODS:6-month protocol biopsies on 40 transplant recipients were analyzed for borderline and subclinical rejections. Allograft injury at biopsy was evaluated using the chronic allograft damage index score system (CADI) and was compared with initial scores obtained at implantation.RESULTS:Borderline rejection was detected in 1 out of 40 patients. No case of subclinical rejection was detected at protocol biopsy. In 31 patients with corresponding implantation biopsies, mean CADI score increased from 1.1 +/- 1.4 to 2.8 +/- 2.1 at 6 months despite stable graft function. In the subgroup of patients with a 6-month CADI score of 2 or less (n = 11), graft function remained stable at 12 months post transplant (65.3 +/- 16.9 ml/min/1.73 m2 at 6 months vs. 65.2 +/- 16.7 ml/min/1.73 m2 at 12 months, p = 0.96). In contrast, allograft function declined significantly at 12 months in those with a 6-month CADI score of > 2 (n = 20) (64.3 +/- 13.5 ml/min/1.73 m2 at 6 months vs. 51 +/- 9.8 ml/min/1.73 m2 at 12 months, p = 0.0006).CONCLUSIONS:While the incidence of borderline and subclinical is low under antilymphocyte antibody induction and tacrolimus-based immunosuppression, chronic allograft damage is highly prevalent at 6 months post transplantation. Our findings suggest that protocol biopsies under current immunosuppression may be more useful in the early detection of chronic allograft nephropathy (CAN).

Stable 2 mths 47 88 46-179 Stable 2-12mths 285 93 45-152 Stable >12mths 58 156 70-210 Rejection 27 99 54-153 Rej.Post TX 7 58 16-90 Rej+Infect 2 24 14-34 Bact.Pneumonia 7 127 11-137 Fung. Dis 4 45 28-162 Fung. Colonization 11 97 56-200 CMV infect 3 11 3-36 Abstract# 1894 Poster Board #-Session: P221-II 1894 Poster Board #-Session: P221-II AN IN VITRO IMMUNE CELL FUNCTION ASSAY IS SUPERIOR TO CLINICAL ESTIMATES OF OVERALL IMMUNOSUPPRESSION. Paul E Morrissey, Amitabh Gautam, Staci A Fischer, Reginald Y Gohh, Angelito F Yango, Anthony P Monaco. Division of Organ Transplantation, Rhode Island Hospital, Brown Medical School, Providence, R

Background Successful renal transplantation in the elderly offers substantial benefits in quality and life expectancy. However, in this group of patients there is an early increased risk of death compared with those remaining on dialysis. Materials and methods Graft and patient outcomes in 64 older transplant recipients were compared with 338 patients aged 18 - 59 years. We identified potential risk factors that may predict clinical outcomes in older transplant recipients. A log-rank test and Cox regression analyses were performed to assess the impact of various patient characteristics on graft and patient survival. Results Among older patients, graft survival was 76.6% and 67% at 1 and 3 years, respectively. When graft survival was censored for death with functioning graft, the 1- and 3-year graft survival was 83% and 82%, respectively. Patient survival was 78% and 71% at 1 and 3 years, respectively. These survival rates were significantly lower than those of younger recipients. Pretransplant inactivity, delayed graft function, smoking history and longer waiting time predicted poor graft and patient survival. A history of chronic obstructive pulmonary disease, and peripheral vascular disease also predicted a higher mortality among older recipients. Conclusion Older kidney transplant recipients are at high risk for allograft failure and early death. Poor functional capacity predicts a poor outcome for older patients undergoing renal transplantation. Therefore, careful patient selection is paramount, and every effort should be made to initiate timely interventions aimed at increasing physical activity in those with low fitness level.

The majority of patients receiving a renal allograft, including a kidney from an older donor, do well. Renal transplantation from a living donor is associated with distinct advantages, including prolonged allograft survival. When live donors are not available, however, deceased donor kidneys provide suitable renal function that frequently lasts the lifetime of elderly recipients. Elderly patients who receive a kidney transplant enjoy improved survival, better quality of life, and lower medical costs than those who remain on dialysis.

The first-line treatment for PTLD is reduction in immunosuppression, allowing partial reconstitution of cell-mediated immunity. However, there is a risk of inducing acute allograft rejection during clinical resolution of PTLD. A recently available assay, Immuknow(TM), measures the cell-mediated immune response and could be used to monitor reduction of immunosuppression. We report a case of PTLD occurring in a pediatric kidney transplant recipient where the reduction in immunosuppression was serially followed using this assay and quantitative EBV-PCR. A rapid reduction to minimal immunosuppression was followed by resolution of PTLD. Later, when the cell-mediated immune response increased, with negative viral load, immunosuppression was gradually increased utilizing the assay to adjust dosing. Presently, there are no signs of PTLD and renal function remains normal.

Cell mediated immunity (CMI) was assessed by the ImmuKnow assay in 12 patients after kidney transplantation, who presented with viral infection. Treatment included lowering of immunosuppression in all cases and antiviral treatment if indicated. The assay was repeated during the follow up. The ImmuKnow assay at time of presentation of viral infections was 56.8+/-58.2 (range 3-178; median 22) ATP ng/ml. With the clearance of viral infection and lowering of immunosuppression, the assay showed an increase in the level of CMI at 194.5+/-118.9 (range 53-409; median 150) ATP ng/ml. There was viral clearance or stabilization in all cases and there was no incidence of allograft rejection. The ImmuKnow assay of CMI can be used to titrate initial immunosuppression reduction and its subsequent increase, in patients with viral infection after transplantation.