Impact of Nanographene Oxide on Cisplatin Induced Acute Kidney Injury Managed by Stem Cells Therapy.

INTRODUCTION: Graphene-based nanomaterials have shown some degrees of stem cell protection against cell death. Due to their distinctive function, the kidneys are exposed to many toxic substances. On the other hand, minor and trivial effects of stem cells have been reported for the treatment of acute kidney injury (AKI). Here, we explain the use of Graphene oxide (GO) for improving the efficacy of mesenchymal stem cells (MSCs) in the treatment of Cisplatin-induced AKI. METHODS: In this study, GO particles were synthesized in our lab. Cisplatin-induced AKI was modeled on rats. Thirty adults male Wistar Albino rats were divided into five groups: control group (did not receive any treatment), Cisplatin group (received 5 mg/ kg cisplatin intraperitoneally), sham group (received 500 µL saline intraperitoneally 5th days after Cisplatin injection), [Cisplatin + MSCs] group (received 5×106 /kg MSCs after Cisplatin injection), and [Cisplatin+ MSCs + GO] group (received 1.5 mg/kg GO + MSCs after Cisplatin injection. Biochemical analysis of serum creatinine (Cr) and blood urea nitrogen (BUN) levels, as well as histological study of the kidneys in diverse groups were compared. The oneway analysis of variance (ANOVA) and Dunnett's test were used for comparisons between the study groups. RESULTS: GO improved the effects of MSCs transplantation on serum Cr and BUN in AKI rat models. It also reduced cell death, hyaline casts, and cell debris in the animal models compared to the MSCs group. CONCLUSION: It could be concluded that GO can enhance the efficacy of MSCs transplantation in the treatment of damaged kidneys.  DOI: 10.52547/ijkd.7472.

Investigating the relationship between the number and activity of natural killer cells with increased cytomegalovirus and CMV disease after kidney transplantation.

BACKGROUND: Cytomegalovirus (CMV) infections caused by the cytomegalovirus are one of the most common problems in patients after kidney transplant. We examined the association of the relationship between the number and activity of natural killer cells with increased cytomegalovirus and its related disease after kidney transplantation. MATERIAL AND METHODS: In this analytical study, 58 new transplant patients in the Labbafinejad Hospital, who did not have any evidence of CMV infection, were evaluated based on the number and percentage of CD56+/16+, CD56+/16-, and CD69+ Natural Killer (NK) cells. RESULTS: The results of this study showed that CD16+ and CD56+ cells in the group of CMV Ag-positive patients are less than negative patients (p = 0.003) and the difference between the two groups are significant (p = 0.01). However, CD69+ cells did not differ significantly between the two groups (p = 0.1). Moreover, the absolute number of CD16+ and CD56+ cells declined significantly after infection with CMV unlike the CMV Ag - group(p = 0.003). DISCUSSION: These results indicate that kidney transplant patients suffering from CMV infection after transplantation have a significantly reduced total number of NK cells. On the other hand, a slight decrease in the number of NK subgroups was observed with an increase in the peak serum levels of cyclosporine. As a consequence of these findings, it can be assumed that more dosage and a higher level of the drug will result in more severe immunosuppression and, consequently, increased susceptibility to CMV infections. Thus, taking the right dose of the drug would prevent viral infections and immune system from over-activation.

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.

The relationship between CT value and clinical outcomes in renal patients with COVID-19.

PURPOSE: Concomitant kidney diseases raise the mortality rate due to the SARS-CoV-2 virus as an independent factor. Although a qualitative PCR test's result is sufficient for diagnosis, Cycle threshold value may present relevant information to the physicians in providing faster treatment in patients with chronic conditions, including kidney diseases, to prevent morbidity and subsequent mortality. Thus, the present study was conducted to determine the relationship between the Cycle threshold value and clinical outcomes in renal patients with the coronavirus 2019. METHODS: This retrospective study was conducted on renal patients with the coronavirus 2019 infection admitted to Labbafinejad Hospital in Tehran, the capital of Iran, within a period of one year, from late February 2020 to February 2021. Data were collected per the prepared checklist. Cycle threshold values were measured by performing PCR on nasopharynx and oropharynx swab samples of patients. RESULTS: According to the adjusted analysis, having high viral load increased the odds of in-hospital mortality (aOR = 11.65, 95% CI 3.93-34.54), ICU admission (aOR = 5.49, 95% CI 2.16-13.97), and invasive ventilation (aOR = 7.18, 95% CI 2.61-19.74). Having high viral load also increased the odds of O2 therapy (aOR = 3.08, 95% CI 0.79-12.01), although the difference was not statistically significant (P = 0.105). CONCLUSION: Cycle threshold value was a significant predictor of mortality in renal patients. Nevertheless, further studies are required on how to render optimal use of the Cycle threshold value, given that the quality of the test sample and the different groups of patients under study affect the effectiveness of this marker in predicting disease severity.

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.

Frequency of CD39+, LAG3+, and CTLA4+ Regulatory T Cells in Two Different Immunosuppressive Protocols in Renal Allograft Recipients (Sirolimus vs Mycophenolate mofetil): A Cohort Report.

BACKGROUND: Impaired renal function is considered as a significant risk factor for cardiovascular events in chronic kidney disease patients. Several immunosuppressive drugs are used in these patients, which necessitates to minimize the drug-related side effects by employing alternative strategies. OBJECTIVE: This study aimed to evaluate prospectively the influence of low dose ATG induction therapy with two different protocols (Sirolimus versus Mycophenolate mofetil) on the expression of functional markers (LAG-3, CD39, and intracellular CTLA-4) on conventional Tregs in renal recipients. METHODS: Thirty-eight renal transplant recipients were enrolled in this study. The patients were randomly assigned into two groups, including TMP: Tacrolimus (Tac), Mycophenolate mofetil (MMF), and Prednisolone (n=23); and TSP: Tac, Sirolimus (SRL), and Prednisolone (n=15). The frequency of LAG-3, CD39, and intracellular CTLA-4 on circulating Tregs was analyzed by flow cytometry before and after transplantation. RESULTS: Analysis of the flow cytometry data showed that the frequency of CD4+CD25+FOXP3+ Tregs increased 4 months post-transplantation compared to pre-transplantation in both groups, although this increase was only significant in TMP group. In TMP treated patients, the frequency of LAG-3+ Tregs and CD39+ Tregs increased, whereas the frequency of intracellular CTLA-4+ Tregs decreased 4 months post-transplantation. In TSP group, while the frequency of CD39+ Tregs increased, the frequency of CTLA-4+ Tregs decreased in post-transplantation compared to pre-transplantation. CONCLUSIONS: it seems that both treatment regimen protocols with a low dose ATG induction therapy may be clinically applicable in kidney transplant recipients.

Influence of cytotoxic T lymphocyte antigen 4 genetic variants on acute rejection in kidney transplant patients: precision medicine perspective.

Background: The most effective and common treatment for end-stage renal disease is kidney transplantation.The personalized approach to kidney transplantation, which utilizes precision medicine principles, determines distinctive genomics characteristics of candidates/recipients that must be taken into account. Cytotoxic T lymphocyte associated protein 4 (CTLA4) may be a suitable candidate gene for studying allograft rejection. The aim of this study was to understand whether we can consider two common variants of the CTLA4 gene as a risk factor of transplant rejection in a group of Iranian population. Methods: Totally, 169 kidney transplant recipients, including acute rejections (N=39) and non-rejection (N=130) groups who underwent transplantation were included in this study. The genotyping of rs5742909 (-318C/T) and rs231775 (+49A/G) variants of the CTLA4 gene were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: The AG genotype frequency of rs231775 variant was the same in both patients with and without a history of rejection while, none of those groups had homozygote genotype. In rs5742909, both CT and TT frequencies of patients with rejected transplant were lower than patients with a normal outcome. Conclusions: The results of the presented study suggest that rs231775 and rs5742909 of CTLA4 genetic variants are not linked to acute rejection who underwent kidney transplantation. So, these variants cannot be considered as risk factors of acute allograft rejection in a group of Iranian renal transplantation recipients. However, the transplantation precision medicine may be an important area for the improvement of patients outcome as the precision medicine has already entered clinical practice in kidney transplantation.

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.

The relationship between T-cell infiltration in biopsy proven acute T-cell mediated rejection with allograft function and response to therapy: A retrospective study.

AIM: To evaluate the degree of CD3, CD20, Th17, and Tregs infiltration in kidney biopsy of the patients with acute cellular rejection and the possible relation with graft outcome. MATERIALS AND METHODS: In this retrospective study, fifty patients with Acute T Cell-Mediated Rejection (ATCMR) were enrolled. Previous and one year clinical follow-up data were collected. The kidney specimens were evaluated for infiltration of CD3, CD20, FOXP3, and Th17 with IHC. According to the serum creatinine level in one-year follow-up of the patients after rejection therapy and function of the transplanted organ from the day admitted into the hospital, they were respectively categorized in Stable graft function versus impaired graft function; appropriate response to treatment versus failure to response. RESULTS: Treg (P = 0.96) and Th17 (P = 0.24) cells were more in the unstable group than the stable group, but the difference wasn't significant. On the other hand, the FOXP3/Th17 ratio was higher in the stable group (P = 0.22). Moreover Treg (P = 0.1) and Th17 (P = 0.15) were higher in failure to response group, but FOXP3/Th17 was higher in proper response group (P = 0.8). CONCLUSION: From the results, it can be concluded that TH17 infiltration has a more significant effect on graft outcome and response to rejection therapy.

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.

Association of IL-15 and IP-10 Serum Levels with Cytomegalovirus Infection, CMV Viral Load and Cyclosporine Level after Kidney Transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is the most common complications following kidney transplantation. Natural killer (NK) cells demonstrated critical anti-viral role in controlling and elimination of CMV after transplantation. Interleukin-15 (IL-15) is a pleiotropic cytokine that promotes the activity of NK cells and strengthens the acquired immune system. Also, IP10 (CXCL10) is a chemotactic factor which regulates NK cell recruitment and antiviral immune response. We aimed to determine the correlation between the serum levels of IL-15 and IP-10 cytokines with CMV infection, CMV viral load, and cyclosporine as a major immunosuppressive treatment after transplantation. METHODS: Fifty-eight kidney transplant recipient patients without evidence of CMV virus disease before transplantation surgery were included in the study. From the day of transplant surgery, the patients were evaluated based on the presence of CMV Ag pp65, CMV viral load, serum levels of IL-15 & IP-10, Cyclosporine levels (C0 & C2), Glomerular Filtration Rate (GFR), and hematological & biochemical Index, up to 75 days. RESULTS: Comparison analysis of serum levels of IL-15 and IP-10 showed no significant association with CMV infection in kidney transplant recipients. In addition, CMV viral load and cyclosporine levels at C0 and C2 did not affect patients' IL-15 and IP-10 levels. CONCLUSION: The levels of IP-10 and IL-15 cytokines are not affected with CMV infection, even if a viral infection occurs in the early days after transplantation or long afterwards. In addition, taking the different levels of cyclosporine did not affect the cytokines levels. Other mechanisms may play a role in maintaining the levels of these cytokines.

Predictive Biomarker Panel in Proliferative Lupus Nephritis- Two-Dimensional Shotgun Proteomics.

INTRODUCTION: Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematous (SLE). With no specific clinical or laboratory manifestation to predict response to treatment, this study was aimed to provide a panel of predictive biomarkers of response before initiation of treatment. METHODS: Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was performed on plasma and urine samples of 11 patients with biopsy proven proliferative LN at the time of biopsy. Unsupervised principal component analysis (PCA), orthogonal projection to latent structures discriminant analysis (OPLS-DA), gene ontology annotation and protein mapping were performed on 326 proteins in plasma and 1381 proteins in urine samples. RESULTS: Samples of eight patients achieved complete remission and three reached partial remission were analyzed. The mean 24-hour protein excretion was 3259 mg/day and the mean eGFR was 87.73 cc/min. OPLS-DA analysis of plasma samples showed a clear discrimination for complete and partial remission patients. Twenty plasma proteins and ten urine proteins with the highest fold changes and AUCs were selected as candidate biomarkers (IGHV1-18, PI16, IGHD, C3, FCER2, EPS8L2, CTTN, BLVRB). This plasma and urine biomarker panel is involved in oxidative stress, acute inflammation, reduction in regulatory T cells, complement pathway consumption, and proximal tubule bicarbonate reclamation. CONCLUSION: Our suggested panel of plasma and urine biomarkers can precisely discriminate patients with possibility of complete response to treatment. It seems that the higher indices of inflammation will associate with better chance of achieving complete remission.

Urinary epidermal growth factor is a novel biomarker for early diagnosis of antibody mediated kidney allograft rejection: A urinary proteomics analysis.

Although antibody mediated rejection (AMR) accounts for 20-30% of all acute renal allograft rejections, introducing biomarkers for a timely detection of allograft rejection has been remained challenging. This study investigated novel diagnostic biomarkers of AMR by examining of urine proteome in renal transplant patients. Thirty-six patients with kidney transplantation including 22 AMR patients and 14 patients with stable renal function (control group) were enrolled in this study. Urinary samples were collected and Label free quantification (LFQ) proteomics technique was applied on urine samples and data was subjected to Random Forest (RF) algorithm to predict main candidate proteins contributing in AMR. Finally, applicability of candidate diagnostic biomarkers was evaluated in new sets of AMR subjects, stable patients and healthy volunteers. A total of 1020 proteins were detected in urine proteome. RF algorithm predicted 20 differentially expressed proteins with the highest sensitivity and specificity and combination of EGF, COL6A, and NID-1 was identified as possible panel for early diagnosis of AMR. Applicability of EGF as diagnostic biomarker was validated in urine samples of independent set of AMR subjects. This is the first urinary proteomics study in AMR patients demonstrating that urinary EGF might be used as early diagnostic biomarker for AMR. SIGNIFICANCE: Renal antibody mediated rejection (AMR) accounts for 20-30% of all acute rejections of allografted kidneys. Although several possible biomarkers have been proposed to predict AMR, ineffectiveness of current urinary biomarkers in early diagnosing of AMR patients and in distinguishing AMR subjects from patients with stable kidney function casts doubts on their applicability in clinic. Here for the first time and based on the analysis of urinary proteome we showed that uEGF and uEGF/Cr might be candidate biomarkers to predict AMR with high diagnostic power.

Methylation of the PKD1 Promoter Inversely Correlates with its Expression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), a multisystem disorder, is the most prevalent type of hereditary kidney disease. Here, we aimed to evaluate methylation of the PKD1 gene (PKD1) promoter and its correlation with PKD1 expression in peripheral blood. METHODS: In this case-control study methylation of the PKD1 promoter was evaluated using methylation-sensitive high-resolution melt (MS-HRM) analysis. PKD1 expression was assessed by quantitative real-time PCR. The correlation was evaluated using the Pearson correlation test. RESULTS: Twenty subjects from both the patient and control groups (n= 40 for each) were methylated at the PKD1 promoter to various levels (18.9% in patients and 62.5% in controls). This difference was statistically significant (p< 0.0001). PKD1 expression in blood samples was significantly greater in ADPKD patients than in controls (p= 0.0081). Significant correlation was seen between PKD1 expression and its promoter methylation status in peripheral blood (r case= -0.5300, p= 0.0162, and r control = -0.6265, p= 0.0031). CONCLUSION: Methylation of the PKD1 promoter in ADPKD patients was inversely correlated with PKD1 expression.

Early Graft Function in Deceased Donor Renal Recipients: Role of N-Acetylcysteine.

Reduced graft function (RGF) in donor renal transplant recipients is caused by oxidative damage due to extensive ischemia-reperfusion (I/R) injury during transplantation. Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker to detect tubular injury early after renal transplantation. N-acetylcysteine (NAC) is a potent antioxidant that can reduce I/R injury by improving oxidative damage. The aim of the present study is to assess the efficacy of NAC in improving graft function and reducing renal tubular injury in deceased donor renal transplant recipients. A double-blind, randomized clinical trial was conducted on 50 deceased donor renal transplant recipients. The patients were randomized into two groups, receiving either 600 mg NAC twice daily, or placebo (days 0 to 5). Results were assessed based on the rate of RGF, levels of plasma NGAL (p-NGAL) and the estimated glomerular filtration rate (eGFR). The rate of RGF was significantly lower in the patients receiving NAC vs. placebo (21.4% vs. 50%). The measurement of p-NGAL levels showed that the patients in the NAC group had significantly greater reduction of p-NGAL by both days 1 and 5 post-transplantation than those in the placebo group. A near steady-state eGFR level was reached by week 1 in the NAC group, however, the improvement of eGFR was significantly slower in the placebo group and a near steady-state was only achieved by week 4. NAC has promising potential in reducing tubular injury and improving graft function, evidenced by significant reduction in the rate of RGF and levels of p-NGAL.

Biomarkers in Primary Membranous Nephropathy, A Guide to Precision Medicine.

Membranous nephropathy (MN) as one of the most common glomerulonephritis still relies on an invasive procedure of kidney biopsy for precise recognition. Over the recent past years noninvasive methods using wide range of biomarkers have been developed in order to diagnose and estimating the final prognosis of MN. Plasma, urine and tissue are readily accessible specimens for identification of these biomarkers. In order to utilize a single biomarker or a panel of them for detection of a specific entity, many factors should taking into consideration like the accuracy, precision, and validity, accompanying with being available and cost effective. This review is focused on recently developed biomarkers and their application on the diagnosis besides determining the prognosis of MN. The clinical utilities and limitations of each biomarker are discussed in details.

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.

Clinical and Radiologic Characteristics of COVID-19 in Patients With CKD.

INTRODUCTION: In this study, we aimed to evaluate the presentation and outcome of COVID-19 in patients with chronic kidney disease (CKD). METHODS: We included 43 patients with a past history of CKD and confirmed diagnosis of COVID-19. Patients were evaluated for demographic characteristics, clinical and laboratory data and findings of initial chest computed tomography (CT) and were followed until either death or discharge occurred. Then, study variables were compared based on final outcome and stage of CKD. RESULTS: Mean age ± SD of patients was 60.65 ± 14.36 years; 65.1% were male. Five of 43 patients (11.6%) died on follow-up and the rest were discharged. Disease outcome did not differ across CKD stages (P > .05). More than half of the patients (58.1%) presented with severe disease on admission. Clinical symptoms were similar to those of non-CKD individuals. Mean duration of hospitalization was higher in those who died, although not significant (16.6 ± 8.38 vs. 11 ± 6.26, P > .05). The only hematologic parameter that significantly differed between survivors and non-survivors was lactase dehydrogenase level (P < .05). Ground-glass opacification and reticular pattern were the most frequent patterns on CT and pleural effusion existed in about one-fifth of all patients. A greater lower zone score was noted in deceased patients (P < .05). CONCLUSION: Patients with CKD are vulnerable to a more severe form of COVID-19 and experience a higher mortality rate than the general population; however, higher CKD stage is not related to worse prognosis or different imaging manifestation compared with lower stage.

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.