Tacrolimus Intrapatient Variability on Graft Outcomes in Adherent Renal Transplantation Patients: A Cross-Sectional Study.

INTRODUCTION: Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients. METHODS: In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated. RESULTS: Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05).  However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/mL (P = .015, .032; respectively). CONCLUSION: Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. DOI: 10.52547/ijkd.7815.

Measured GFR in Donor Selection, to Do or Not to Do? That is the Question.

INTRODUCTION: The accurate assessment of the pre-donation glomerular filtration rate (GFR) is a crucial step in donor selection. We conducted a prospective cross-sectional study to identify the best equation to estimate GFR and the necessity of a radio-nuclear scan in GFR evaluation. METHODS: In this study, 154 potential donors were enrolled, and GFR equations (the MDRD study, the CKD-EPI study, and the full age spectrum [FAS]), and creatinine clearance were compared with measured GFR (mGFR) by the radio-nuclear method. RESULTS: The study results indicate that Potential donors had an mGFR of 95.56 ± 15.57 mL/min per 1.73 m2. Though body surface area (BSA) adjusted full age spectrum (FAS) and CKD-EPI equations were most correlated with mGFR, the correlation coefficients were weak (ICC: 0.3 and 0.32, respectively). Misclassification at the cut-off of 80 cc/min/ 1.73 m2 was about 42% for both equations. Besides, 16.8% of donors with eGFR more than 80 cc/min/ 1.73 m2 had a difference in split renal function, and 57.1% of participants had a > 2% probability of having an mGFR < 90 mL/min per 1.73 m2. CONCLUSION: If the nuclear scan is easily available, we suggest measuring GFR by 99mTc -DTPA scan as the preferred method. Otherwise, our data suggest utilizing mGFR in patients with high body mass index, size asymmetry in CT-scan, eGFR less than 90 mL/min per 1.73 m2 with FAS and/or CKD-EPI equation as these factors deviated the estimated GFR, and also in those with inaccurate creatinine clearance measurements or with posttest probability of having mGFR less than 90 mL/min per 1.73 m2 more than 2%.  DOI: 10.52547/ijkd.7271.

Immunogenicity and Safety of SpikoGen, an Adjuvanted Recombinant SARS-CoV-2 Spike Protein, as a Heterologous Third Booster Dose in Kidney Transplant Patients: A Single-arm Clinical Trial.

PURPOSE: Studies have found that immunocompromised patients have suboptimal responses to COVID-19 vaccines, leading to approval of a need for booster doses in this population. SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant to protect against COVID-19. Previous clinical trials found this vaccine to be tolerable, immunogenic, and efficacious in reducing the risk of COVID-19, including severe disease. However, the effects of this vaccine have not been assessed in immunocompromised patients. This study sought to assess the immunogenicity and safety of the SpikoGen vaccine as a third booster dose in patients undergoing kidney transplant who were receiving immunosuppressive therapy and had received their primary vaccination based on an inactivated whole virus platform (Sinopharm). METHODS: This single-arm trial was performed with 43 patients undergoing kidney transplant. The participants received a single booster dose of the SpikoGen vaccine 1 to 3 months after primary vaccination with 2 doses of the Sinopharm vaccine. Immunogenicity assessments were performed at baseline and 30 days after the booster dose. The primary outcomes were seroconversion rates of anti-S1 and surrogate virus neutralizing antibodies. Safety outcomes included the incidence of solicited and unsolicited adverse events in the 7 days and 1 month after the booster dose, respectively. FINDINGS: The SpikoGen vaccine induced positive humoral and cellular responses 30 days after the booster dose in those patients who were seropositive or seronegative after 2 primary doses of the Sinopharm vaccine. Thirty days after the SpikoGen vaccine booster, seroconversion rates were 35.29% (95% CI, 19.75%-53.51%) to anti-S1 and 29.41% (95% CI, 13.27%-46.57%) to surrogate neutralizing antibodies. The most common local and systemic reported solicited adverse events were injection site pain and fatigue, which were largely mild and transient. No serious adverse events were reported. IMPLICATIONS: A single booster dose of SpikoGen vaccine given 1 to 3 months after primary vaccination with 2 doses of Sinopharm vaccine induced positive humoral and cellular immune responses in immunosuppressed patients undergoing renal transplant, thereby achieving spike antibody levels predictive of protection. This study was performed as a single-center study, and it will be important for future large multicenter studies to extend these results to other immunocompromised patient groups.

Humoral immunity of BBIBP-CorV (Sinopharm) in kidney transplant recipients: Is it time to revise vaccination strategies.

BACKGROUND: The mortality of coronavirus disease 2019 (COVID-19) is high in transplant patients, and effective vaccination is aimed to reduce severe disease and mortality. METHODS: We conducted a cross-sectional study to evaluate humoral and cellular response to two 4-µg doses of BBIBP-CorV vaccine in 100 kidney transplant recipients, using anti-spike IgG, total anti-receptor-binding domain, neutralizing antibody (Ab) level (enzyme-linked immunoassay), and interferon-gamma release assay (IGRA). RESULTS: Seroconversion was evaluated 85.84 ± 30.72 days after the second dose. Note that, 58% of all and 43.05% of infection-naïve participants have developed at least one of the tested antibodies. IGRA was positive in 30.7% of tested transplant recipients. Sixty percent of the participants had either humoral or cellular responses to COVID-19. Only age was independently linked to seropositivity of any degree after vaccination (p < .05). COVID-naïve patients older than 60 years developed significantly less neutralizing Abs. (p = .011). Six patients developed mild COVID infection more than a month after the second dose of the vaccine (54.5 ± 20.8 days). No vaccine-related adverse effects were reported, except self-limited mild to moderate fever and injection site pain. CONCLUSION: BBIBP-CorV vaccine can be used safely in kidney transplant recipients, although impaired cellular and humoral immunity necessitate adjustments in vaccination strategies, like higher (8-µg doses), fourth booster dose, or boost with different platform vaccine.

Agreement between the results of tuberculin skin test and Interferon-Gamma Release Assays in renal transplant candidates.

INTRODUCTION: Identification of latent tuberculosis (TB) infection is important in kidney transplant candidates. Due to the absence of a gold standard, both tuberculin skin test (TST) and interferon-gamma release assays (IGRA) are used to screen patients. The aim of this study was to evaluate the agreement of these two tests in patients undergoing renal transplantation. MATERIALS AND METHODS: Two hundred kidney transplant candidates at a referral center in 2014-2017 were included in this study. TST and Quantiferon-Gold (QFT-G) tests were performed for all patients before transplantation. In case of a positive result in any of the tests, patients were administered a 9-month prophylaxis treatment using isoniazid. Cohen's kappa coefficient (k) test was used to determine the agreement between the two tests. RESULTS: The mean age of patients was 40.72 ± 18.33. Nine (4.5%) patients had positive TST and 16 (8%) had positive IGRA. Concordance of the two tests was evaluated as medium (κ = 0.44 and P < 0.001). No association was found between the underlying causes of renal failure and skin test positive or IGRA. The tests showed a poor agreement among diabetics, candidates of re-transplantation, and those who were on dialysis for longer than a year (κ < 0.20). CONCLUSION: TST or IGRA can be used to screen TB in kidney transplant candidates with a moderate agreement. However, we suggest using both TST and QFT-G in diabetics, re-transplant candidates, and those on dialysis for >1 year.

Time-Varying Covariates and Risk Factors for Graft Loss in Kidney Transplantation.

OBJECTIVES: The present study was designed to evaluate the factors involved in long-term graft survival in recipients of kidney transplantation. MATERIALS AND METHODS: We reviewed 755 Iranian adult recipients who underwent kidney transplantation at Shahid Labbafinejad Medical Center in Tehran, Iran. Patients were followed for 5 years after transplantation. The primary outcome was the time between transplantation and graft loss. Using Cox regression, we studied the effect of time-independent variables (recipients' age and sex, donors' age, and type of donor), time-dependent covariates (body mass index [BMI], systolic blood pressure, diastolic blood pressure, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels, proteinuria and serum creatinine level), and immunosuppressive drugs on graft loss 60 months after transplantation. The results are presented as the hazard ratio (HR) with 95% confidence intervals. RESULTS: Result from Cox proportional hazards model showed that the HR of graft loss was 1.62 (95% CI: 1.03-2.54) in cadaveric donor compared with living donor kidney recipients. The HR of graft loss for recipient age was 1.02 (95% CI: 1.002-1.030). Moreover, according to obtained results, the risk of losing functional transplant increased for each mg/dL rise in serum creatinine at least 9% and at most 40%. Our results also showed that 1 unit increase of BMI has at least a 2% and at most a 15% decremented effect on the hazard ratio of graft loss. CONCLUSIONS: Having lower levels of creatinine and receiving a kidney from a younger living donor were associated with a decreased risk of graft loss. Graft loss is more likely to occur in patients with lower BMI.

Low rate of COVID-19 pneumonia in kidney transplant recipients-A battle between infection and immune response?

BACKGROUND: With COVID-19 pandemic, concerns about kidney transplant recipients are rising. However, the incidence, clinical course, outcome, and predictive factors of disease severity are obscured. METHODS: We describe clinical and laboratory manifestations, radiologic findings, clinical course, and finally outcome of kidney transplant recipients with COVID-19 pneumonia. RESULTS: Of 2493 kidney transplant recipients under follow-up in our clinic, 19 cases (4 cases diagnosed based on radiologic findings) were admitted. The mean age of patients was 47.6 ± 12.4 years, and the mean time from transplantation was 115.6 ± 70.3 months. Lymphopenia and eosinopenia were 84.2% and 78.9%, respectively. Nine patients did not survive the hospital course. History of acute rejection during the past 12 months, diabetes, higher N/L ratio, lower platelet count, elevated N/L x CRP, higher levels of LDH, positive D-dimer, higher troponin, and prolonged PT were associated with mortality. Among patients with positive COVID-19 test, history of acute rejection, low platelet count, and positive D-dimer were associated with poor outcome. Treatment with cyclosporine was associated with better clinical outcome. CONCLUSIONS: Low rate of admission in transplant recipients specially in the very first years of transplantation might be due to protective effects of immunosuppressive agents against cytokine storm or modification of immunity function. We suggest evaluation of T-cell number, function, and cytokine profile as a guide to manage COVID-19 mainly in patients with higher risk of mortality.

Adding Colchicine to the Antiretroviral Medication - Lopinavir/Ritonavir (Kaletra) in Hospitalized Patients with Non-Severe Covid-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomized Controlled Trial.

OBJECTIVES: Colchicine is a well-known drug, which has been used for years to treat a wide range of rheumatic and inflammatory disorders. It helps break the cycle of inflammation through diverse mechanisms including reducing Intereukin-6, Interleukin-8, Tumour Necrosis Factor-alpha besides controlling oxidative stress pathways which all are important and pathologic components in the clinical course and outcome of patients infected with COVID-19. This study aims to assess the anti-inflammatory effects of colchicine in non-severe hospitalized COVID-19 patients. TRIAL DESIGN: Prospective, randomized (1:1 ratio), double blind study with parallel group design. PARTICIPANTS: Hospitalized patients with positive nasopharyngeal swab for COVID-19 infection (RT -PCR) and lung Computed tomography scan involvement compatible with COVID-19 pneumonia. The patients are not severely hypoxic, do not need intubation or invasive oxygenation. EXCLUSION CRITERIA: known hypersensitivity to colchicine; known hepatic failure; estimated glomerular filtration rate (eGFR)<30 ml/min/1.73m2 (by the CKD-EPI Creatinine Equation for Glomerular Filtration Rate (GFR) which estimates GFR based on serum creatinine. ; kidney transplant recipients, using Digoxin, QTc >450 msec. Participants will be recruited from inpatients at Labbafinejad Meidcal Center , Tehran, Iran. INTERVENTION AND COMPARATOR: Eligible enrolled patients will be randomized into two groups. Group A will receive the antiretroviral Lopinavir/Ritonavir (Kaletra) while group B will receive Lopinavir/Ritonavir (Kaletra) + Colchicine 1.5 mg loading then 0.5 mg twice daily orally. All patients in both groups will receive the same amounts of essential minerals, vitamins as antioxidants, and antibiotics. Patients of both groups will be treated under optimal treatment based on the CDC and WHO guidelines and national consensus proposed in Iran including the same dosages of Lopinavir/Ritonavir, antibiotics, trace elements and antioxidants while only in group-B patients Colchicine will be added on top of this protocol. MAIN OUTCOMES: Primary: Time for clinical improvement and lung CT score changes 14 days after treatment. Secondary: 14 days after treatment - C-Reactive Protein test x Neutrophil to Lymphocyte Ratio , Interleukin-6, malondialdehyde (MDA) levels reduction - Percentage of patients who require supplemental Oxygen - Mean hospital stay length RANDOMISATION: Patients will be allocated to each group (ratio 1:1) by using an online randomization tool: http://www.graphpad.com/quickcalcs/index.cfm BLINDING (MASKING): This will be a double-blind study in which participants and those assessing the final outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Regarding the pandemic crisis and our center capacity to hospitalize confirmed COVID-19 patients, a total of 80 patients was found to be logical to be randomized into two groups of 40- patients. TRIAL STATUS: Recruitment is ongoing. Recruitment began on 20/03/2020 and the date by which the recruitment is anticipated to be completed is 30/05/2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04360980, registered 24/04/2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Dietary intakes of fiber and magnesium and incidence of metabolic syndrome in first year after renal transplantation.

OBJECTIVE: Considering the high prevalence of metabolic syndrome (MetS) and the associated cardiovascular disease mortality after renal transplant, and considering that the lack of prospective studies regarding the role of fiber and magnesium in MetS prevention after transplant precludes definitive recommendations, we prospectively evaluated the potential role of fiber and magnesium intake in the incidence of MetS at 1 year after renal transplantation. DESIGN: This was a prospective cohort study. SETTING, PARTICIPANTS, AND MEASUREMENTS: We included 160 recipients of kidney transplant (100 men and 60 women) aged over 18 years who were free of MetS or diabetes at time of transplant, and followed these patients for 1 year. METHODS: The usual dietary intakes were assessed with a Willett-format 168-item food-frequency questionnaire. We defined MetS according to modified Adult Treatment Panel III guidelines. We categorized participants by tertiles of dietary fiber and magnesium. To determine associations of fiber and magnesium intake with MetS incidence 1 year posttransplant, we used multivariable logistic regression. RESULTS: After controlling for potential confounders, including baseline body mass index and energy intake, subjects within the highest tertile of fiber intake had a lower odds ratio for incident MetS (odds ratio, 0.41; 95% confidence interval, 0.08 to 0.99; P < .05 for trend) than those in the lowest tertile. There was no significant overall association between magnesium intake and MetS. CONCLUSIONS: These findings support current dietary recommendations to increase intakes of fiber-rich foods as a primary preventive approach against MetS and cardiovascular disease, which are very prevalent after renal transplant.

Mediterranean diets are associated with a lower incidence of metabolic syndrome one year following renal transplantation.

Considering the high prevalence of metabolic syndrome and its association with cardiovascular mortality, we prospectively evaluated the role of diet in the incidence of metabolic syndrome in renal transplant recipients. Our prospective cohort of 160 adult renal allograft recipients was followed for 1 year and had no existing metabolic syndrome or diabetes mellitus. Routine dietary intakes were assessed with food-frequency questionnaires, and metabolic syndrome was defined according to the Adult Treatment Panel III guidelines. We identified 3 major patterns by factor analysis, consisting of those recipients predominantly consuming fats and sugars, those predominantly consuming whole grain, and the Mediterranean diet. When analyzed by multivariable logistic regression and after controlling for potential confounders, subjects in the highest tertile of scores for the Mediterranean diet had a significantly lower odds of metabolic syndrome than those in the lowest tertile. Subjects in the highest tertile of scores for consuming fats and sugars had significantly greater odds of metabolic syndrome compared with those in the lowest tertile. Our study shows that the Mediterranean dietary pattern is associated with a reduced risk of metabolic syndrome in renal transplant recipients.