Kidney allograft recipients, immunosuppression, and coronavirus disease-2019: a report of consecutive cases from a New York City transplant center.

BACKGROUND: Kidney graft recipients receiving immunosuppressive therapy may be at heightened risk for coronavirus disease 2019 (Covid-19) and adverse outcomes. It is therefore important to characterize the clinical course and outcome of Covid-19 in this population and identify safe therapeutic strategies. METHODS: We performed a retrospective chart review of 73 adult kidney graft recipients evaluated for Covid-19 from 13 March to 20 April 2020. Primary outcomes included recovery from symptoms, acute kidney injury, graft failure and case fatality rate. RESULTS: Of the 73 patients screened, 54 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-39 with moderate to severe symptoms requiring hospital admission and 15 with mild symptoms managed in the ambulatory setting. Hospitalized patients were more likely to be male, of Hispanic ethnicity and to have cardiovascular disease. In the hospitalized group, tacrolimus dosage was reduced in 46% of patients and mycophenolate mofetil (MMF) therapy was stopped in 61% of patients. None of the ambulatory patients had tacrolimus reduction or discontinuation of MMF. Azithromycin or doxycycline was prescribed at a similar rate among hospitalized and ambulatory patients (38% versus 40%). Hydroxychloroquine was prescribed in 79% of hospitalized patients. Graft failure requiring hemodialysis occurred in 3 of 39 hospitalized patients (8%) and 7 patients died, resulting in a case fatality rate of 13% among Covid-19-positive patients and 18% among hospitalized Covid-19-positive patients. CONCLUSIONS: Data from our study suggest that a strategy of systematic triage to outpatient or inpatient care, early management of concurrent bacterial infections and judicious adjustment of immunosuppressive drugs rather than cessation is feasible in kidney transplant recipients with Covid-19.

Deceased-donor kidney transplantation: improvement in long-term survival.

BACKGROUND: Despite marked improvement in short-term renal allograft survival rates (GSR) in recent years, improvement in long-term GSR remained elusive. METHODS: We analysed the kidney transplant experience at our centre accrued over four decades to evaluate how short-term and long-term GSR had changed and to identify risk factors affecting graft survival. The study included 1476 adult recipients of a deceased-donor kidney transplant who were transplanted between 1963 and 2006 and who had received one of five distinct immunosuppressive protocols. RESULTS: Five-year actual GSR steadily improved over the years as immunosuppressive therapy evolved (22-86%, P < 0.001) in spite of an increasing trend in the transplantation of higher-risk donor-recipient pairings. For those whose grafts functioned for the first year, subsequent 4-year GSR (5-year conditional GSR) also improved significantly (63-92%, P < 0.001). Acute rejection and delayed graft function (DGF) were the most significant risk factors for actual graft survival, while acute rejection was the only significant risk factor for conditional GSR. Use of kidneys from expanded-criteria donors (ECD) was not a risk factor, compared to the use of standard-criteria donor kidneys for either 5-year actual or conditional GSR. There was an impressive decline in the incidence of acute rejection events (77.4-5.8%, P < 0.001). While the DGF rate had decreased, it still remained high (68.7-38.5%, P < 0.001). CONCLUSIONS: We found a significant improvement in both short-term and long-term GSR of deceased-donor kidney transplants over the last four decades. These improvements are most likely related to the decreased incidence of acute rejection episodes. Minimizing acute rejection events and preventing DGF could result in further improvement in the GSR. Our experience in the judicious use of ECD kidneys suggests that this source of kidneys could be expanded further.

Cholesterol and interleukin-6 concentrations relate to outcomes in burn-injured patients.

The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.

Effect of administration of a phospholipid emulsion on the initial response of horses administered endotoxin.

OBJECTIVE: To evaluate the effect of a phospholipid emulsion (PLE) on the initial response of horses to administration of endotoxin. ANIMALS: 12 healthy adult horses. PROCEDURES: Horses were assigned to 2 treatment groups (6 horses/group). The control group was administered 1 L of saline (0.9% NaCl) solution, and the treated group was administered PLE (200 mg/kg, IV); treatments were administered during a period of 120 minutes. An infusion of endotoxin was initiated in both groups starting 1 hour after initiation of the saline or PLE solutions. Physical examination and hemodynamic variables were recorded, and blood samples were analyzed for concentrations of tumor necrosis factor (TNF)-alpha, interleukin-6, thromboxane B2 (TxB2), 6 keto-prostaglandin F (PGF)1alpha, total leukocyte count, and PLE concentrations. An ANOVA was used to detect significant differences. RESULTS: Administration of PLE resulted in significantly lower rectal temperature, heart rate, cardiac output, right atrial pressure, and pulmonary artery pressure and higher total leukocyte counts in treated horses, compared with values for control horses. The TNF-alpha concentration was significantly less in treated horses than in control horses. The TxB2 and 6 keto-PGFF1alpha concentrations were significantly different between treated and control horses at 30 minutes (TxB2) and at 30 and 60 minutes (6 keto-PGF1alpha). CONCLUSIONS AND CLINICAL RELEVANCE: Prior infusion of PLE in horses administered a low dose of endotoxin decreased rectal temperature, heart rate, pulmonary artery pressure, and TNF-alpha concentrations. Results of this study support further evaluation of PLE for use in the treatment of horses with endotoxemia.

Sublingual tacrolimus: a pharmacokinetic evaluation pilot study.

STUDY OBJECTIVE: To evaluate and compare the pharmacokinetic parameters of sublingual and oral tacrolimus in the presence and absence of a drug that interacts with tacrolimus at the intestinal level. DESIGN: Prospective, randomized, open-label, parallel-group pilot study. SETTING: Large, urban, academic medical center. PATIENTS: Six adults with end-stage renal disease who were awaiting kidney transplantation; five completed the study. INTERVENTION: Patients were randomized in a 1:1 ratio to receive tacrolimus plus a clotrimazole troche (a drug that interacts with tacrolimus at the intestinal level) or tacrolimus plus nystatin suspension. For the tacrolimus route of administration, patients first received sublingual tacrolimus for five doses; after a 2-day washout period, they received oral tacrolimus for five doses. MEASUREMENTS AND MAIN RESULTS: Demographic characteristics, concomitant medications, tacrolimus dosing information, and steady-state venous whole blood specimen values after tacrolimus administration were collected. Noncompartmental pharmacokinetics were calculated from the tacrolimus blood concentrations in samples collected at multiple time points after drug administration. The area under the concentration-time curve from 0-6 hours for sublingual and oral tacrolimus ranged from 27.2-66 and 32.4-76 mg·hour/L, respectively, in the tacrolimus plus clotrimazole group and from 9.3-63 and 4.9-23.2 mg·hour/L, respectively, in the tacrolimus plus nystatin group. The average maximum concentration was higher during sublingual administration than during oral administration: 16.7 versus 12.9 ng/ml in the tacrolimus plus clotrimazole group and 9.5 versus 6 ng/ml in the tacrolimus plus nystatin group. CONCLUSION: An oral-to-sublingual tacrolimus dose conversion should be evaluated on an individual basis. A 1:1 dose conversion may be appropriate in the presence of clotrimazole, whereas a 2:1 oral-to-sublingual conversion may be appropriate when there are no concomitantly interacting drugs. These findings should be investigated further in pharmacokinetic studies conducted in solid organ transplant recipients.

Excellent outcomes with expanded criteria donor kidneys: the role of the recipient's age.

At the present time, the number of deceased donor kidney transplants performed annually has remained unchanged for 4 years. Desire for standard criteria donor (SCD) kidneys by recipients, coupled with high discard rates of donor kidneys, contributes to a lack of procedures being performed. A subgroup of recipients, those under age 50, may fare as well with an expanded criteria donor (ECD) allograft as those who receive an SCD kidney. The use of ECD allografts in recipients over 50 years of age, while projected to have poorer allograft survival than that produced with an SCD graft, still results in better recipient survival than patients who have elected to remain on dialysis.

Managing the atazanavir-tacrolimus drug interaction in a renal transplant recipient.

PURPOSE: The management of the drug interaction between atazanavir and tacrolimus in a renal transplant recipient is described. SUMMARY: A 53-year-old African-American man with human immunodeficiency virus (HIV) received a renal transplant and was treated in accordance with a corticosteroid-sparing immunosuppressive protocol and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. His highly active antiretroviral therapy included atazanavir 400 mg daily, abacavir 600 mg daily, and lamivudine 100 mg daily. Because of the potential for a significant interaction between tacrolimus and atazanavir, the tacrolimus dosage was to be based on serum tacrolimus concentrations. The patient was initially administered one dose of tacrolimus 0.5 mg on the morning of postoperative day 2. Evaluation of the tacrolimus profiles revealed that a higher dosage was necessary because serum tacrolimus levels decreased to subtherapeutic levels by 6 hours after dose administration. In an attempt to minimize tacrolimus toxicity and limit the duration of a subtherapeutic tacrolimus level, dosing was adjusted to 1 mg every 8 hours. After 48 hours of this regimen, peak serum tacrolimus levels were lower, and the drug concentrations remained at a relatively steady level throughout the dosing interval. One final dosage adjustment (1.5 mg every 12 hours) was performed to optimize serum tacrolimus levels and patient compliance. CONCLUSION: In a 53-year-old man with HIV infection who underwent renal transplantation, the drug interaction between atazanavir and tacrolimus was managed by modifying the tacrolimus dosage regimen after determining the patient's blood tacrolimus concentration profile.

Use of bortezomib for prevention and treatment of rejection in sensitized patients.

We report 2 cases of sensitized patients who were successfully treated with bortezomib therapy resulting in reduction of donor-specific antibodies (DSA). Our cases illustrate the synergistic effects of combination therapy that includes bortezomib on prevention and treatment of AMR in highly sensitized patients. Moving forward, long-term data on sensitized patients treated with bortezomib are needed to fully evaluate the impact of this therapy.

Neutralization of endotoxin by a phospholipid emulsion in healthy volunteers.

BACKGROUND: An approach to endotoxin (lipopolysaccharide [LPS]) blockade makes use of the ability of lipoproteins, via surface phospholipids, to bind and neutralize LPS. The aim of the present study was to determine whether the intravenous administration of a protein-free, phospholipid-rich emulsion is an effective method for neutralizing the effects of LPS in healthy persons. METHODS: This was a double-blind, placebo-controlled study in 20 volunteers. Volunteers received Escherichia coli endotoxin (2 ng/kg) intravenously 2 h into a 6-h infusion of either emulsion (210 mg/kg) or placebo (Intralipid diluted 1 : 64). RESULTS: The volunteers who received emulsion had a lower mean clinical score (P<.01), temperature (P<.05), pulse rate (P<.05), neutrophil count (P<.05), tumor necrosis factor- alpha level (P<.05), and interleukin-6 level (P<.05) than did the volunteers who received placebo. Response was related to serum phospholipid level. The greatest effects were observed in the volunteers achieving phospholipid levels of approximately 500 mg/dL or higher. CONCLUSION: Phospholipid emulsion attenuates the clinical and laboratory effects associated with the administration of LPS in humans, suggesting a novel approach to the treatment of endotoxemia.

LDL Apheresis: an effective and safe treatment for refractory hypercholesterolemia.

Through the efforts of Edward H. Ahrens, LDL apheresis became available for the treatment of patients, often with familial hypercholesterolemia, who have no alternative therapy for severely elevated LDL cholesterol levels. In the U.S., the FDA has approved this treatment for individuals on maximum diet and drugs with an LDL cholesterol greater than 300 mg/dL or greater than 200 mg/dL with coronary artery disease. Unlike plasmapheresis, apolipoprotein B-containing lipoproteins (LDL, Lp(a), and VLDL) are selectively removed by heparin precipitation or columns containing dextran sulfate cellulose or antibodies to apolipoprotein B. The acute lowering of LDL-cholesterol by a typical 2 - 3 h treatment is up to 80%, and the time-averaged lowering in the 1 to 2 week interval between treatments is up to 50%, with very few side effects. The lowering of LDL-cholesterol and other cardioprotective effects of LDL apheresis have reduced chest pain, prevented new disability and prolonged life. Whole blood compatible columns in development offer the possibility of simpler and less expensive treatments.

A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers.

Endotoxemia is associated with rapid and marked declines in serum levels of LDL and HDL by unknown mechanisms. Six normal volunteers received a single, small intravenous (iv) dose of endotoxin (Escherichia coli 0113, 2 ng/kg) or saline in a random order, cross-over design. After endotoxin treatment, volunteers had mild, transient flu-like symptoms and markedly increased serum levels of tumor necrosis factor and its soluble receptors, interleukin-6, cortisol, serum amyloid A, and C-reactive protein. Triglyceride (TG), VLDL-TG, and nonesterified fatty acid increased (peak at 3-4 h), then TG declined (nadir at 9 h), and then cholesterol, LDL cholesterol, apolipoprotein B (apoB), and phospholipid declined (nadirs at 12-24 h). HDL cholesterol and apoA-I levels were not affected, but half of the decrease in phospholipid was HDL phospholipid. Lipopolysaccharide binding protein (LBP) rose 3-fold (peak at 12 h), with smaller and later decreases in the activities of phospholipid transfer protein and cholesteryl ester transfer protein. In conclusion, a decline in LDL was rapidly induced in normal volunteers with a single iv dose of endotoxin. The selective loss of phospholipid from HDL may have been mediated by LBP and, after more intense or prolonged inflammation, could result in increased HDL clearance and reduced HDL levels.

Protein-free phospholipid emulsion treatment improved cardiopulmonary function and survival in porcine sepsis.

Lipoprotein phospholipid (PL) plays a major role in neutralization of endotoxin. This study tested the hypothesis that prophylactic administration of a PL-enriched emulsion (PRE), which augments PL content of serum lipoproteins and neutralizes endotoxin in vitro, would preserve cardiovascular function and improve survival in porcine septic peritonitis. A control group was compared with low-, mid-, and high-dose treatment groups that received PRE by primed continuous infusion for 48 h. A fibrin clot containing live Escherichia coli 0111.B4 was implanted intraperitoneally 30 min after the priming dose. Survival increased in a dose-dependent manner and was correlated with serum PL. Infused PL was associated with high-density lipoprotein in the low-dose group and all serum lipoproteins at higher doses. Treatment significantly lowered serum endotoxin and tumor necrosis factor (TNF)-alpha, preserved cardiac output and ejection fraction, and attenuated increases in systemic and pulmonary vascular resistances. This study demonstrated that augmentation of lipoprotein PL via administration of PRE improved survival and offered a novel therapeutic approach to sepsis.

Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion.

BACKGROUND: Lipids and lipoproteins have been shown to bind and neutralize endotoxin and to improve outcomes in animal models of sepsis. OBJECTIVE: To provide safety and pharmacokinetic data for a protein-free, phospholipid-rich emulsion developed as an agent to neutralize endotoxin, and to study the changes in lipids and lipoproteins following emulsion administration. METHODS: Thirty healthy male volunteers (aged 18-45 y) were given an emulsion containing 92.5% soy phospholipid, 7.5% soy triglyceride, and 18 mM sodium cholate using a double-blind, placebo-controlled crossover protocol. Emulsion at 3 escalating doses (75, 150, 300 mg/kg) based on phospholipid content was administered by intravenous infusion over 2 hours in the low- and mid-dose groups and 6 hours in the high-dose group. RESULTS: All subjects completed the protocol without significant toxicities. A slight dose-dependent increase in indirect bilirubin at the 24-hour time point was observed in the emulsion treatment period, with a maximum difference between placebo and emulsion of 0.9 mg/dL. Mean +/- SD peak phospholipid levels were 316 +/- 30, 533 +/- 53, and 709 +/- 86 mg/dL, and phospholipid half-lives were 5.4 +/- 0.6, 5.4 +/- 0.5, and 8.0 +/- 0.8 hours for the low, mid, and high doses, respectively. Increases in total cholesterol, low-density lipoprotein cholesterol and apolipoprotein A-I and B levels were observed. High-density lipoprotein cholesterol decreased immediately following emulsion infusion, but rebounded to above placebo levels by 24 hours. CONCLUSIONS: A unique phospholipid-rich emulsion was shown to have a favorable safety profile and to expand the blood lipid and lipoprotein pool without the use of human-derived blood products. Lipid levels expected to protect against the physiologic effects of bacterial endotoxin were achieved.