Solid organ transplant recipients may be at a high risk for SARS‐CoV‐2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with ...SARS‐CoV‐2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty‐six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual‐organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty‐two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID‐19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID‐19 has the potential to severely impact solid organ transplant recipients.
In this multicenter study of 90 solid organ transplant recipients diagnosed with COVID‐19 during the first three weeks of the outbreak in New York City, the authors report on the clinical presentation, laboratory abnormalities, risk factors, disease severity, and outcomes.
Kidney Biopsy Findings in Patients with COVID-19 Kudose, Satoru; Batal, Ibrahim; Santoriello, Dominick ...
Journal of the American Society of Nephrology,
09/2020, Letnik:
31, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury by a variety of mechanisms. To date, pathologic analyses have been limited to patient reports and autopsy series.
We evaluated ...biopsy samples of native and allograft kidneys from patients with COVID-19 at a single center in New York City between March and June of 2020. We also used immunohistochemistry,
hybridization, and electron microscopy to examine this tissue for presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The study group included 17 patients with COVID-19 (12 men, 12 black; median age of 54 years). Sixteen patients had comorbidities, including hypertension, obesity, diabetes, malignancy, or a kidney or heart allograft. Nine patients developed COVID-19 pneumonia. Fifteen patients (88%) presented with AKI; nine had nephrotic-range proteinuria. Among 14 patients with a native kidney biopsy, 5 were diagnosed with collapsing glomerulopathy, 1 was diagnosed with minimal change disease, 2 were diagnosed with membranous glomerulopathy, 1 was diagnosed with crescentic transformation of lupus nephritis, 1 was diagnosed with anti-GBM nephritis, and 4 were diagnosed with isolated acute tubular injury. The three allograft specimens showed grade 2A acute T cell-mediated rejection, cortical infarction, or acute tubular injury. Genotyping of three patients with collapsing glomerulopathy and the patient with minimal change disease revealed that all four patients had
high-risk gene variants. We found no definitive evidence of SARS-CoV-2 in kidney cells. Biopsy diagnosis informed treatment and prognosis in all patients.
Patients with COVID-19 develop a wide spectrum of glomerular and tubular diseases. Our findings provide evidence against direct viral infection of the kidneys as the major pathomechanism for COVID-19-related kidney injury and implicate cytokine-mediated effects and heightened adaptive immune responses.
Context:
Diabetes is associated with a deficit of insulin-producing β-cells. Animal studies show that β-cells become dedifferentiated in diabetes, reverting to a progenitor-like stage, and partly ...converting to other endocrine cell types.
Objective:
To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors.
Design:
We scored dedifferentiation using markers of endocrine lineage, β-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3.
Results:
By these criteria, dedifferentiated cells accounted for 31.9% of β-cells in type 2 diabetics vs 8.7% in controls, and for 16.8% vs 6.5% of all endocrine cells (P < .001). The number of aldehyde dehydrogenase 1A3-positive/hormone-negative cells was 3-fold higher in diabetics compared with controls. Moreover, β-cell-specific transcription factors were ectopically found in glucagon- and somatostatin-producing cells of diabetic subjects.
Conclusions:
The data support the view that pancreatic β-cells become dedifferentiated and convert to α- and δ-“like” cells in human type 2 diabetes. The findings should prompt a reassessment of goals in the prevention and treatment of β-cell dysfunction.
Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and ...influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using
human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (
,
,
,
, and
) indicative of endothelial activation, IFN
response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval 95% CI, 38% to 74% versus 19%; 95% CI, 8% to 35%;
=0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%;
=0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.
The feasibility, safety, and clinical utility of percutaneous coronary intervention (PCI) without radio-contrast medium in patients with advanced chronic kidney disease (CKD) are unknown. In this ...series, we investigated a specific strategy for 'zero contrast' PCI with the aims of preserving renal function and preventing the need for renal replacement therapy (RRT) in patients with advanced CKD.
A total of 31 patients with advanced CKD creatinine = 4.2 mg/dL, inter-quartile range (IQR) 3.1-4.8, estimated glomerular filtration rate = 16 ± 8 mL/min/1.73 m
who had clinical indication for PCI based on a prior minimal contrast coronary angiogram were included. Zero contrast PCI was performed at least 1 week after diagnostic angiography using real-time intravascular ultrasound (IVUS) guidance, with pre- and post-PCI measurements of fractional flow reserve and coronary flow reserve to confirm physiological improvement. This approach resulted in successful PCI, no major adverse cardiovascular events and preservation of renal function without the need for RRT within a follow-up time of 79 days (IQR 33-207) in all patients.
In patients with advanced CKD who require revascularization, PCI may safely be performed without contrast using IVUS and physiological guidance with high procedural success and without complications.
We report results of a phase 2, randomized, multicenter, open‐label, two‐arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody‐mediated rejection (AMR) in sensitized ...recipients of living‐donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy‐proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow‐up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living‐donor kidney transplants (EudraCT 2010‐019630‐28).
In this study of terminal complement inhibition to prevent acute antibody‐mediated rejection in living‐donor kidney transplant recipients with preformed donor‐specific antibodies, prophylactic eculizumab does not significantly reduce the treatment failure rate compared with standard of care, but biopsy reanalysis suggests a benefit for eculizumab in preventing AMR in these patients. See the article by Glotz et al on page 2865.
Kidney allograft biopsy findings after COVID‐19 Daniel, Emily; Sekulic, Miroslav; Kudose, Satoru ...
American journal of transplantation,
December 2021, Letnik:
21, Številka:
12
Journal Article
Recenzirano
Odprti dostop
COVID‐19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy ...findings in the setting of COVID‐19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS‐CoV‐2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID‐19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS‐CoV‐2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS‐CoV‐2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow‐up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID‐19, the most common being acute rejection with arteritis.
Allograft biopsies from kidney transplant recipients with COVID‐19 with acute kidney injury or proteinuria shows a high incidence of acute rejection with arteritis that is not always associated with decreased immunosuppression.
The proportion of deceased donor kidneys procured for transplant but subsequently discarded has been growing steadily in the United States, but factors contributing to the rising discard rate remain ...unclear. To assess the reasons for and probability of organ discard we assembled a cohort of 212,305 deceased donor kidneys recovered for transplant from 2000-2015 in the SRTR registry that included 36,700 kidneys that were discarded. ‘Biopsy Findings’ (38.2%) was the most commonly reported reason for discard. The median Kidney Donor Risk Index of discarded kidneys was significantly higher than transplanted organs (1.78 vs 1.12), but a large overlap in the quality of discarded and transplanted kidneys was observed. Kidneys of donors who were older, female, Black, obese, diabetic, hypertensive or HCV-positive experienced a significantly increased odds of discard. Kidneys from donors with multiple unfavorable characteristics were more likely to be discarded, whereas unilaterally discarded kidneys had the most desirable donor characteristics and the recipients of their partner kidneys experienced a one-year death-censored graft survival rate over 90%. There was considerable geographic variation in the odds of discard across the United States, which further supports the notion that factors beyond organ quality contributed to kidney discard. Thus, while the discard of a small fraction of organs procured from donors may be inevitable, the discard of potentially transplantable kidneys needs to be avoided. This will require a better understanding of the factors contributing to organ discard in order to remove the disincentives to utilize less-than-ideal organs for transplantation.
Purpose: Patients referred for pancreas transplantation represent a subset of difficult to treat diabetics, who may have clinical factors preventing them from achieving a goal Hgb A1C of ≤7%. ...Advanced insulin delivery systems with continuous glucose monitor (CGM) have been developed to offer less invasive treatment options in this population. We wanted to see how pancreas transplant performed compared to alternative modalities.
Methods: We conducted a retrospective review of pancreas transplantation at our institution from January 1, 20 through August 1, 2021. All patients were ≥18 years who underwent either simultaneous kidney pancreas (SPK) , pancreas after kidney (PAK) , or pancreas transplant alone (PTA) . Outcomes were assessed by HgbA1C level at evaluation (eval) , at transplant (pre) , between 3-5 months posttransplant (post) and the most recent (MR) (avg 62 months SD 75.4 months) .
Results: 133 patients underwent pancreas transplant during the study period, 85 SPK (62%) 39 PAK (30%) and PTA (8%) . (14%) patients suffered graft loss in the first year and were excluded from analysis. Overall, 1, and 5-year pancreas graft survival was 86% and 82%. 96 (84%) had type 1 diabetes (T1D) and 18 (16%) had type 2 diabetes (T2D) . Of the 114 patients, 33 (29%) utilized CGM with or without pump (CGM) prior to transplant and had a lower Hgb A1C (%) than those without (nonCGM) (8.18 SD 1.5 vs. 8.75 SD 1.9 p=0.04) . Hgb A1C then improved for the nonCGM group during their time on the waitlist (8.75 to 8.36 SD 1.8 p=0.004) but not the CGM group (8.18 to 8.SD 1.3 p=0.24) . Post-transplant saw significant improvement in CGM pre 8.to post 5.0 (SD.6 p=2.7E-17) and MR 5.3 (SD 0.7 p=9.9E-14) and in nonCGM pre 8.4 to post 5.2 (SD 0.62 p= 2.9E-29) and MR 5.4 (SD 0.7 p= 7.3E-29) .
Conclusion: Considering the clinical challenges of staying in range for difficult to treat diabetes, leading to HgbA1C goal of ≥7%, solid organ pancreas transplantation offers superior glycemic control compared to advanced insulin delivery systems with CGM.
Disclosure
K.R.Mccune: None. G.Dube: None. L.E.Ratner: Advisory Panel; CareDx, Immunocore, Ltd., Natera, Stock/Shareholder; Gilead Sciences, Inc., Hansa BioPharma.
Factors contributing to the high rate of discard among deceased donor kidneys remain poorly understood and the influence of resource limitations of weekends on kidney transplantation is unknown. To ...quantify this we used data from the Scientific Registry of Transplant Recipients and assembled a retrospective cohort of 181,799 deceased donor kidneys recovered for transplantation from 2000–2013. We identified the impact of the day of the week on the procurement and subsequent utilization or discard of deceased donor kidneys in the United States, as well as report the geographic variation of the impact of weekends on transplantation. Compared with weekday kidneys, organs procured on weekends were significantly more likely to be discarded than transplanted (odds ratio: 1.16; 95% confidence interval: 1.13–1.19), even after adjusting for organ quality (adjusted odds ratio: 1.13; 95% confidence interval: 1.10–1.17). Weekend discards were of a significantly higher quality than weekday discards (Kidney Donor Profile Index: 76.5% vs. 77.3%). Considerable geographic variation was noted in the proportion of transplants that occurred over the weekend. Kidneys available for transplant over the weekend were significantly more likely to be used at larger transplant centers, be shared without payback, and experienced shorter cold ischemia times. Thus, factors other than kidney quality are contributing to the discard of deceased donor kidneys, particularly during weekends. Policy prescriptions, administrative or organizational solutions within transplant programs may potentially mitigate against the recent increase in kidney discards.
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