Impact of an ultrasensitive Cytomegalovirus quantitative nucleic acid test on Cytomegalovirus detection and therapy in renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection has broad implications for morbidity and mortality in renal transplant recipients (RTR). Routine surveillance for CMV replication with PCR-based quantitative nucleic acid testing (qNAT) assays is standard practice in most transplant centers, but the impact of assay sensitivity on antiviral decision-making and virologic outcomes has not been studied. We investigated the effects of an ultrasensitive CMV qNAT assay on multiple clinical outcomes, including time to detection and duration of CMV DNAemia. METHODS: We conducted a single-center cohort study contrasting RTRs monitored with a qNAT with a higher lower limit of quantification (LLOQ >300 IU/mL) with those monitored with a more sensitive qNAT (LLOQ >35 IU/mL). Patients were stratified by donor (D)/recipient (R) CMV serostatus (D+/R-: high risk; any R+: moderate risk). CMV viral load monitoring was performed monthly post transplantation, with the primary outcomes being time to CMV DNAemia and its duration. RESULTS: Total 1382 patients were analyzed from 2014 to 2016 and 2019 to 2021. Moderate-risk RTRs monitored with the more sensitive assay experienced a greater hazard for the development of a first episode of CMV DNAemia (aHR: 1.95, 95% confidence interval [CI]: 1.55-2.46) and an average of 24 (95% CI: 16.40-31.98) additional days of DNAemia. There was no difference in CMV end-organ disease or 1-year all-cause mortality between moderate-risk RTRs. CONCLUSIONS: The more sensitive assay was associated with earlier detection and extended durations of CMV DNAemia in moderate-risk RTRs, without altering clinical outcomes. These findings inform optimal use of these assays and antiviral stewardship in RTRs. KEY SUMMARY: The use of ultrasensitive CMV qNAT assays in moderate-risk CMV renal transplant recipients is associated with earlier detection and longer durations of CMV DNAemia without impacting CMV end-organ disease or 1-year mortality.

Effects of CYP3A4*22 and POR*28 variations on the pharmacokinetics of tacrolimus in renal transplant recipients: a meta-analysis of 18 observational studies.

PURPOSE: This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus. METHODS: Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0/Dose). RESULTS: The study included 2931 renal transplant recipients from 18 publications. Weight-adjusted daily dose of CYP3A4*1/*1 carriers was 0.04 (WMD = 0.04, 95% CI: 0.02 to 0.06), 0.03 (WMD = 0.03, 95% CI: 0.02 to 0.05), 0.02 (WMD = 0.02, 95% CI: 0.01 to 0.03), or 0.02 mg/kg/day (WMD = 0.02, 95% CI: 0.00 to 0.04) higher than CYP3A4*22 carriers in Caucasians at 1 month, 3 months, 6 months, or 12 months post-transplantation. Conversely, C0/Dose was lower for CYP3A4*1/*1 carriers at 3 days (SMD = -0.35, 95% CI: -0.65 to -0.06), 1 month (SMD = -0.67, 95% CI: -1.16 to -0.18), 3 months (SMD = -0.60, 95% CI: -0.89 to -0.31), 6 months (SMD = -0.76, 95% CI: -1.49 to -0.04), or 12 months post-transplantation (SMD = -0.69, 95% CI: -1.37 to 0.00). Furthermore, C0/Dose of POR*1/*1 carriers was 22.64 (WMD = 22.64, 95% CI: 2.54 to 42.74) or 19.41 (ng/ml)/(mg/kg/day) (WMD = 19.41, 95% CI: 9.58 to 29.24) higher than POR*28 carriers in CYP3A5 expressers at 3 days or 7 days post-transplantation, and higher in Asians at 6 months post-transplantation (SMD = 0.96, 95% CI: 0.50 to 1.43). CONCLUSIONS: CYP3A4*22 variant in Caucasians restrains the metabolism of tacrolimus, while POR*28 variant in CYP3A5 expressers enhances the metabolism of tacrolimus for renal transplant recipients. However, further well-designed prospective studies are necessary to substantiate these conclusions given some limitations.

Predictors and Adverse Outcomes of Acute Kidney Injury in Hospitalized Renal Transplant Recipients.

Data about in-hospital AKI in RTRs is lacking. We conducted a retrospective study of 292 RTRs, with 807 hospital admissions, to reveal predictors and outcomes of AKI during admission. In-hospital AKI developed in 149 patients (51%). AKI in a previous admission was associated with a more than twofold increased risk of AKI in subsequent admissions (OR 2.13, p < 0.001). Other major significant predictors for in-hospital AKI included an infection as the major admission diagnosis (OR 2.93, p = 0.015), a medical history of hypertension (OR 1.91, p = 0.027), minimum systolic blood pressure (OR 0.98, p = 0.002), maximum tacrolimus trough level (OR 1.08, p = 0.005), hemoglobin level (OR 0.9, p = 0.016) and albumin level (OR 0.51, p = 0.025) during admission. Compared to admissions with no AKI, admissions with AKI were associated with longer length of stay (median time of 3.83 vs. 7.01 days, p < 0.001). In-hospital AKI was associated with higher rates of mortality during admission, almost doubled odds for rehospitalization within 90 days from discharge and increased the risk of overall mortality in multivariable mixed effect models. In-hospital AKI is common and is associated with poor short- and long-term outcomes. Strategies to prevent AKI during admission in RTRs should be implemented to reduce re-admission rates and improve patient survival.

The Clinical Manifestation of Immunosuppressive Therapy as a Tool to Improve Immune Monitoring in Renal Transplant Recipients.

INTRODUCTION: Metrics for posttransplant immune monitoring to prevent over or under immunosuppression in renal transplant recipients (RTRs) are lacking. METHODS: We surveyed 132 RTRs, 38 in the first year posttransplant and 94 >1-year posttransplant, to study the clinical expression of immunosuppressive therapy. A questionnaire administered to these RTRs was divided into physical (Q physical) and mental (Q mental) symptoms. RESULTS: In multivariable models for the association between the calculated Q physical and Q mental scores and different clinical and biochemical variables in the 38 RTRs who filled out the questionnaire 130 times during the first year posttransplant, it was found that mycophenolic acid (MPA) and prednisone use increased the mean Q physical score by 0.59 (95% CI: 0.21-0.98, p = 0.002) and 0.53 (95% CI: 0.26-0.81, p = 0.00), respectively, while MPA use increased the mean Q mental score by 0.72 (95% CI: 0.31-1.12, p = 0.001). Among the 94 RTRs who each completed the questionnaire only once, the odds for the mean Q mental score to be above the median value were more than 3 times higher for RTRs treated versus non-treated with MPA (OR 3.38, 95% CI: 1.1-10.3, p = 0.03). MPA-treated RTRs had higher mean scores for questions related to sleep disorders (1.83 ± 1.06 vs. 1.32 ± 0.67 for not treated, p = 0.037), to difficulty falling asleep (1.72 ± 1.11 vs. 1.16 ± 0.5, p = 0.02), and to depression and anxiety. CONCLUSION: We concluded that prednisone and MPA use are associated with an increased Q physical and Q mental scores in RTRs. Routine monitoring of physical and mental status of RTRs should be implemented to improve the diagnosis of overimmunosuppression. Dose reduction or discontinuation of MPA should be considered in RTRs who report sleep disorders, depression, and anxiety.

Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients: results of the TransplantLines Biobank and cohort Studies.

BACKGROUND: New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention. METHODS: This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1-5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured). RESULTS: Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5-1.2] mmol/L vs. 0.6 [0.4-0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64-3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01). CONCLUSIONS: This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors.

The adverse effects of high-dose corticosteroid on infectious and non-infectious sequelae in renal transplant recipients with coronavirus disease-19 in India.

INTRODUCTION: The corticosteroid dosing modulation in renal transplant recipients (RTRs) with coronavirus disease-19 (COVID-19) is not well defined. We aimed to analyze the outcomes and infectious and non-infectious sequelae in RTR with COVID-19 with reference to corticosteroid dosing and the first and second pandemic waves of COVID-19. MATERIALS AND METHODS: This study included RTRs admitted during two pandemic waves between March 25, 2020, and July 31, 2021. Patients were categorized into mild, moderate, and severe COVID-19. The outcomes and predictors of survival at 4 weeks were analyzed. The survivors were also followed for 6 months and were studied for mortality, readmission rates, and infectious and non-infectious sequelae with reference to high-dose and standard-dose corticosteroids. RESULTS: A total of 251 RTRs, 104 during the first wave and 147 during the second wave, were treated. Overall mortality was 15.1% (11.5% in the first wave vs. 17.5% in the second wave, p = .23). The use of high-dose steroids was also significantly high in non-survivors (85.8% vs. 11.3%, p = .001). On multivariate analysis, the severity of COVID-19, graft dysfunction, and high dose of corticosteroid therapy were associated with increased odds of mortality. Among survivors, 6-month mortality (17.3% vs. 0.5%, p = .001), readmission rate (91.3% vs. 23.7%, p = .001), fungal infection (30.4% vs. 2.2%, p < .001), and post-COVID lung sequelae (21.7% vs. 4.4%, p = .008) were significantly higher in the high-dose corticosteroid group than in the standard-dose group. CONCLUSION: High-dose corticosteroid dosing in RTRs with COVID-19 was associated with increased infections, particularly fungal infections, and non-infectious sequelae with higher mortality on subsequent follow-up.

Immunocryosurgery is a safe and feasible treatment for basal cell carcinoma and Bowen disease in renal transplant recipients.

Keratinocyte skin carcinomas (squamous cell carcinoma, basal cell carcinoma [BCC], Bowen disease [BD]) inflict significant morbidity and constitute a treatment challenge in renal transplant recipients (RTR). Immunocryosurgery has shown efficacy >95% in the treatment of BCC and BD in immunocompetent patients. The present study evaluated the safety, feasibility and efficacy, of immunocryosurgery in the treatment of BCC and BD in a series of RTR. During a 3-year period, biopsy-confirmed cases of BCC and BD were treated with a standard immunocryosurgery cycle (5 weeks daily imiquimod and a session of cryosurgery at day 14). Safety was evaluated by comparing graft function markers between immunocryosurgery treated RTR patients and matched controls. Ten BCC (8 nodular, 1 basosquamous, 1 superficial; diameter 6-14 mm; mean 9.2 mm) and nine BD disease lesions in nine patients (7 men, 2 women; age range: 54-70 years, mean: 62.1 years) were treated with immunocryosurgery and followed-up for two to 5 years. Five BCC were located on the "H area" of the face. No patient showed clinical or laboratory signs of transplant dysfunction during treatment or follow-up. Seven out of 10 BCC lesions cleared completely after one 5-week immunocryosurgery cycle, two cleared after repeat and intensified treatment cycles and one responded only partially (clearance rate: 90%). Seven out of nine BD lesions cleared after one 5-week immunocryosurgery cycle and one lesion after two cycles (clearance rate: 88.9%). In conclusion, immunocryosurgery is a safe, feasible and effective minimally invasive treatment alternative to standard surgical modalities for BCC and BD in RTR.

Variants of HCMV UL18 Sequenced Directly from Clinical Specimens Associate with Antibody and T-Cell Responses to HCMV.

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host's burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2- γδ T-cells-populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden.

Sequencing of the Viral UL111a Gene Directly from Clinical Specimens Reveals Variants of HCMV-Encoded IL-10 That Are Associated with Altered Immune Responses to HCMV.

Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ~80% of adults worldwide. Acute infections are often asymptomatic in healthy individuals but generate diverse syndromes in neonates, renal transplant recipients (RTR), and people with HIV (PWH). The HCMV gene UL111a encodes a homolog of human interleukin-10 (IL-10) that interacts with the human IL-10 receptor. Deep sequencing technologies were used to sequence UL111a directly from 59 clinical samples from Indonesian PWH and Australian RTR, healthy adults, and neonates. Overall, 93% of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous variation. Carriage of these variants differed between neonates and adults, Australians and Indonesians, and between saliva and blood leukocytes. The variant alleles of N41D and S71Y occurred together in Australian RTR and were associated with higher T-cell responses to HCMV pp65. The variant P122S was associated with lower levels of antibodies reactive with a lysate of HCMV-infected fibroblasts. L174F was associated with increased levels of antibodies reactive with HCMV lysate, immediate-early 1 (IE-1), and glycoprotein B (gB) in Australian RTR and Indonesians PWH, suggesting a higher viral burden. We conclude that variants of UL111a are common in all populations and may influence systemic responses to HCMV.

Risk of Anal High-grade Squamous Intraepithelial Lesions Among Renal Transplant Recipients Compared With Immunocompetent Controls.

BACKGROUND: Renal transplant recipients (RTRs) have increased risk of human papillomavirus (HPV)-related cancers, including anal cancer. We investigated the prevalence of anal high-grade intraepithelial lesions (HSILs) in RTRs compared with immunocompetent controls and risk factors for anal HSIL in RTRs. METHODS: We included 247 RTRs and 248 controls in this cross-sectional study. We obtained anal samples for HPV testing with INNO-LiPA and performed high-resolution anoscopy on all participants. The participants completed a questionnaire on lifestyle and sexual habits. We used logistic regression to estimate odds ratios (ORs) of histologically confirmed anal HSIL in RTRs vs controls and risk factors for anal HSIL in RTRs, stratified by sex and anal high-risk (hr) HPV status, adjusting for age, smoking, lifetime sexual partners, and receptive anal sex. RESULTS: RTRs had higher anal HSIL prevalence than controls, both among men (6.5% vs 0.8%; adjusted OR [aOR], 11.21 [95% confidence interval {CI}, 1.46-291.17]) and women (15.4% vs 4.0%; aOR, 6.41 [95% CI, 2.14-24.10]). Among those with anal hrHPV, RTRs had higher anal HSIL prevalence than controls (33.8% vs 9.5%; aOR, 6.06 [95% CI, 2.16-20.27]). Having had receptive anal sex (aOR, 6.23 [95% CI, 2.23-19.08]) or genital warts (aOR, 4.21 [95% CI, 1.53-11.48]) were risk factors for anal HSIL in RTRs. All HSIL cases occurred in individuals with anal hrHPV. CONCLUSIONS: RTRs had increased risk of anal HSIL compared with immunocompetent controls, with particularly high prevalence in female RTRs. Receptive anal sex, previous genital warts, and anal hrHPV infection were risk factors for anal HSIL in RTRs. Screening for anal HSIL in RTRs should be considered. CLINICAL TRIALS REGISTRATION: NCT03018927.

Zoonotic sporotrichosis in renal transplant recipients from Rio de Janeiro, Brazil.

Sporotrichosis is the main subcutaneous mycosis in the world. In the last two decades, zoonotic sporotrichosis transmitted by cats has become hyperendemic in Rio de Janeiro, Brazil. Renal transplant recipients are subject to invasive fungal infection because of the effects of immunosuppressive therapy, but sporotrichosis is rarely reported. The authors conducted a retrospective study describing epidemiological, clinical, and therapeutic data related to adult renal-transplant-recipient patients diagnosed with sporotrichosis. The molecular identification of fungal isolates was performed. Minimal inhibitory concentration (MIC) of amphotericin B (AMB), itraconazole (ITZ), posaconazole (POS), isavuconazole, and terbinafine (TRB) against the strains was determined using the protocol described by the Clinical and Laboratory Standards Institute (CLSI). Six cases were identified from a cohort with 2429 sporotrichosis patients. They were five men and one woman, with a mean age of 44.2 years (range: 34-54 years). Four of them had cutaneous limited forms, and two patients had disseminated forms. The mean time between transplant and the onset of sporotrichosis symptoms was 25.5 (range: 6-36) months. Sporothrix brasiliensis was identified as the causative agent. The isolates were classified as wild type for all antifungal drugs tested. Treatment schemes included AMB (deoxycholate and liposomal), ITZ, and TRB. Five patients evolved to cure, and one died as a result of disseminated disease. Renal transplant recipients may be a vulnerable group for sporotrichosis in endemic countries. The authors highlight the importance of sporotrichosis prevention, early diagnosis, and treatment to prevent disseminated disease and poor prognosis.

Molecular detection and genotyping of ß-human papillomavirus and it's association with epithelial skin neoplasms.

Epidemiological and molecular biological data suggest that ß-human papillomavirus (HPV) can cause epithelial skin tumors, but the relationship remains unclear. A new approach to the diagnosis of HPV is based on the measurement of viral consistence. We examined 52 immune-compromised and immune-competent patients in order to identify the association of epithelial neoplasms with ß-HPV. Determination of HPV was performed by polymerase chain reaction with hybridization-fluorescence detection in real-time. Amplification and detection were carried out with "Rotor-Gene" 3000 ("Corbett Research," Australia). To quantify the beta HPV genus, we used recombinant plasmid positive controls as well as control plasmid of ß-globin fragments taken from human genes (Central Scientific Institute of Epidemiology Rospotrebnadzor). We have found that ß-HPV DNA predominated in fibroepithelial polyps (64%) and in the apparently healthy skin (54%) of immune-compromised patients versus 47% in the skin of healthy donors. Mixed infection was detected in fibroepithelial polyps of 57% in the immune-compromised patients. Viral consistence in the fibroepithelial polyps was higher than in the apparently normal donors' skin. The high detection of HPV DNA was found in fibroepithelial polyps and in the apparently healthy skin of immune-compromised patients whereas a high level of HPV DNA was only found in fibroepithelial polyps.

Risk of Anogenital Warts in Renal Transplant Recipients Compared with Immunocompetent Controls: A Cross-sectional Clinical Study.

Renal transplant recipients have increased risk of human papilloma virus-related anogenital (pre)cancers. Less is known about their risk of anogenital warts. The aim of this study was to estimate the prevalence and odds of anogenital warts in renal transplant recipients compared with immunocompetent controls, and to assess risk factors for intra- and perianal warts in renal transplant recipients. The study examined 248 renal transplant recipients and 250 controls for cutaneous and mucosal anogenital warts. Participants completed a questionnaire on lifestyle and sexual habits. For external anogenital warts (including penile, vulvar and perianal warts), renal transplant recipients had higher prevalence and odds than controls, both in men (8.1% vs 1.6%, adjusted odds ratio (ORadjusted)=5.09, 95% confidence interval (95% CI), 1.03-25.04) and women (11.3% vs 1.6%, ORadjusted=8.09, 95% CI 1.69-38.82). For intra-anal warts, there was no clear pattern of higher odds in renal transplant recipients than controls. Current smoking and having had receptive anal sex increased the risk of intra-/perianal warts in renal transplant recipients. In conclusion, renal transplant recipients in this study had higher odds of external anogenital warts than controls.

Radical prostatectomy outcomes in renal transplant recipients: a retrospective case series of Thai patients.

BACKGROUND: The incidence of prostate cancer in renal transplant recipients (RTR) is similar to the general population. Radical prostatectomy (RP) is the standard of care in the management of clinically localized cancer, but is considered complicated due to the presence of adhesions, and the location of transplanted ureter/kidney. To date, a few case series or studies on RP in RTR have been published, especially in Asian patients. This study aimed to evaluate the efficacy and safety and report the experience with RP on RTR. METHODS: We retrospectively reviewed data of 1270 patients who underwent RP from January 2008 to March 2020, of which 5 patients were RTR. All available baseline characteristics, perioperative and postoperative data (operative time, estimated blood loss (EBL), complications, length of hospital stay, complication), pathological stage, Gleason score, surgical margin status, and pre/postoperative creatinine were reviewed. RESULTS: Of the 5 RTR who underwent RPs (1 open radical prostatectomy (ORP), 1 laparoscopic radical prostatectomy (LRP), 2 robotic-assisted laparoscopic radical prostatectomies (RALRP), and 1 Retzius-sparing RALRP (RS-RALRP)) prostatectomy, the mean age (± SD) was 70 (± 5.62) years. In LRP and RALRP cases, the standard ports were moved slightly medially to prevent graft injury. The mean operative time ranged from 190 to 365 min. The longest operative time and highest EBL (630 ml) was the ORP case due to severe adhesion in Retzius space. For LRP and RALRP cases, the operative times seemed comparable and had EBL of ≤ 300 ml. All RPs were successful without any major intra-operative complication. There was no significant change in graft function. The restorations of urinary continence were within 1 month in RS-RALRP, approximately 6 months in RALRP, and about 1 year in ORP and LRP. Three patients with positive surgical margins had prostate-specific antigen (PSA) persistence at the first follow-up and 1 had later PSA recurrence. Two patients with negative margins were free from biochemical recurrence at 47 and 3 months after their RP. CONCLUSIONS: Our series suggested that all RP techniques are safe and feasible mode of treatment for localized prostate cancer in RTR.

Human papillomavirus-related anogenital premalignancies and cancer in renal transplant recipients: A Danish nationwide, registry-based cohort study.

In this registry-based cohort study, we estimated the risk of human papillomavirus (HPV)-related anogenital premalignancies and cancer in renal transplant recipients (RTRs) compared to a nontransplanted comparison cohort. We identified all first-time RTRs in Denmark during 1990-2015 in a nationwide nephrology register. For each RTR, we randomly selected 50 age- and sex-matched non-RTRs from the background population. The study population was followed for diagnoses of cervical, vaginal, vulvar, penile and anal intraepithelial neoplasia grades 2-3 (IN2/3) and cancer for up to 27 years. We estimated hazard ratios (HRs) of anogenital IN2/3 and cancer in RTRs vs. non-RTRs by Cox regression separately for men and women using age as underlying timescale, adjusting for income, education, HPV vaccination and immunocompromising conditions. We included 4,261 RTRs and 213,673 non-RTRs. RTRs had increased hazard of cervical (HR = 2.1, 95% CI: 1.7-2.8), vaginal (HR = 35.0, 95% CI: 13.9-87.7), vulvar (HR = 16.4, 95% CI: 10.4-25.8), penile (HR = 21.9, 95% CI: 11.1-43.5) and anal (women: HR = 51.1, 95% CI: 28.0-93.1; men: HR = 39.0, 95% CI: 16.7-91.1) IN2/3. The HRs of anogenital cancers were also increased at most sites. The HR of anogenital IN2/3 in female RTRs tended to be higher during graft function than during dialysis. In female RTRs aged <40 years at transplantation, 10-15% had cervical IN2/3 and 5-12% had vaginal/vulvar/anal IN2/3 within 20 years after transplantation, compared to 4-8 and 0.2-0.4%, respectively, of female non-RTRs. In conclusion, RTRs had substantially higher risk of HPV-related anogenital premalignancies and cancer than non-RTRs.

Consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients: a prospective cohort study.

BACKGROUND: It currently remains understudied whether low consumption of fruits and vegetables after kidney transplantation may be a modifiable cardiovascular risk factor. We aimed to investigate the associations between consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients (RTRs). METHODS: Consumption of fruits and vegetables was assessed in an extensively phenotyping cohort of RTRs. Multivariable-adjusted Cox proportional hazards regression analyses were performed to assess the risk of cardiovascular mortality. RESULTS: We included 400 RTRs (age 52 ± 12 years, 54% males). At a median follow-up of 7.2 years, 23% of RTRs died (53% were due to cardiovascular causes). Overall, fruit consumption was not associated with cardiovascular mortality {hazard ratio [HR] 0.82 [95% confidence interval (CI) 0.60-1.14]; P = 0.24}, whereas vegetable consumption was inversely associated with cardiovascular mortality [HR 0.49 (95% CI 0.34-0.71); P < 0.001]. This association remained independent of adjustment for several potential confounders. The association of fruit consumption with cardiovascular mortality was significantly modified by estimated glomerular filtration rate (eGFR; Pinteraction = 0.01) and proteinuria (Pinteraction = 0.01), with significant inverse associations in patients with eGFR > 45 mL/min/1.73 m2 [HR 0.56 (95% CI 0.35-0.92); P = 0.02] or the absence of proteinuria [HR 0.62 (95% CI 0.41-0.92); P = 0.02]. CONCLUSIONS: In RTRs, a relatively higher vegetable consumption is independently and strongly associated with lower cardiovascular mortality. A relatively higher fruit consumption is also associated with lower cardiovascular mortality, although particularly in RTRs with eGFR > 45 mL/min/1.73 m2 or an absence of proteinuria. Further studies seem warranted to investigate whether increasing consumption of fruits and vegetables may open opportunities for potential interventional pathways to decrease the burden of cardiovascular mortality in RTRs.

Endogenous urinary glucocorticoid metabolites and mortality in prednisolone-treated renal transplant recipients.

BACKGROUND: Chronic corticosteroid treatment suppresses HPA-axis activity and might alter activity of 11ß hydroxysteroid dehydrogenases (11ß-HSD). We aimed to investigate whether the endogenous glucocorticoid production and 11ß-HSD activities are altered in prednisolone-treated renal transplant recipients (RTR) compared with healthy controls and whether this has implications for long-term survival in RTR. METHODS: In a longitudinal cohort of 693 stable RTR and 275 healthy controls, 24-hour urinary cortisol, cortisone, tetrahydrocorisol (THF), allotetrahydrocortisol (alloTHF), and tetrahydrocortisone (THE) were measured using liquid chromatography tandem-mass spectrometry. Twenty-four-hour urinary excretion of cortisol and metabolites were used as measures of endogenous glucocorticoid production; (THF + alloTHF)/THE and cortisol/cortisone ratios were used as measures of 11ß-HSD activity. RESULTS: Urinary cortisol and metabolite excretion were significantly lower in RTR compared with healthy controls (P < .001), whereas (THF + alloTHF)/THE and cortisol/cortisone ratios were significantly higher (P < .001 and P = .002). Lower total urinary metabolite excretion and higher urinary (THF + alloTHF)/THE ratios were associated with increased risk of mortality, independent of age, sex, estimated glomerular filtration rate, C-reactive protein, body surface area, and daily prednisolone dose, respectively. CONCLUSIONS: Endogenous glucocorticoid production and 11ß-HSD activities are altered in prednisolone-treated RTR. Decreased total urinary endogenous glucocorticoid metabolite excretion and increased urinary (THF + alloTHF)/THE ratios are associated with increased risk of mortality.

Different clinical presentations of two renal transplant recipients with coronavirus disease 2019: a case report.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus-2 has spread rapidly worldwide and disease spread is currently increasing. Data on the clinical picture of transplant recipients and management of the anti-rejection immunosuppressive therapy on COVID-19 infection are lacking. CASE PRESENTATION: We report two cases of COVID-19 infection in renal transplant recipients with variable clinical presentations. The first patient presented with mild respiratory symptoms and a stable clinical course. The second patient had more severe clinical characteristics and presented with severe pneumonia and multi-organ failure. Both patients received a combination therapy including antiviral treatment and reduced immunosuppression therapy and finally recovered. CONCLUSIONS: We report COVID-19 infection in two renal transplant recipients with a favorable outcome but different clinical courses, which may provide a reference value for treating such patients.

Prevalence, type distribution and risk factors for oral HPV in Danish renal transplant recipients.

OBJECTIVE: To assess the prevalence and type distribution of oral human papillomavirus (HPV) among renal transplant recipients (RTRs) and healthy controls and to examine risk factors for oral HPV among RTRs. MATERIALS AND METHODS: During 2016-2017 we recruited 250 RTRs and 250 controls. Oral samples were tested for HPV DNA with INNO-LiPA HPV Genotyping Extra II. All participants answered a questionnaire on lifestyle and sexual behaviour, and characteristics of RTRs were obtained from medical files. We assessed prevalence and type distribution of oral HPV. Using logistic regression, the risk of oral HPV and risk factors for oral HPV among RTRs were estimated as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Overall, 30 RTRs (12.1%) and 26 controls (10.4%) were oral HPV positive (OR = 1.14; 95% CI: 0.64-2.05). Female RTRs tended to have a higher oral HPV prevalence than controls (OR = 1.73; 95% CI: 0.63-4.77), while no difference was observed among men. HPV51 was the commonest genotype. Sexual behaviour tended to be associated with oral HPV among RTRs. CONCLUSIONS: There was no overall difference in oral HPV prevalence between RTRs and controls, but female RTRs tended to have a higher prevalence of oral HPV than controls.

Accuracy and concordance of measurement methods to assess non-adherence after renal transplantation - a prospective study.

BACKGROUND: Non-adherence (NA) to immunosuppressants (IS) among renal transplant recipients (RTRs) is associated with higher risk of allograft rejection, graft loss, and mortality. A precise measurement of NA is indispensable, although its prevalence differs greatly depending on the respective measurement methods. The objective of this study was to assess the accuracy and concordance of different measurement methods of NA in patients after renal transplantation. DESIGN AND METHODS: This was a single-center prospective observational study. At baseline (T0), NA was measured via physicians' estimates (PE), self-reports (SR), and tacrolimus trough level variability (CV%) in 78 RTRs. A Visual Analogue Scale (VAS, 0-100%) was applied both for SR and PE. In addition, we used BAASIS© for SR and a 5-point Likert scale for PE. NA was measured prospectively via electronic monitoring (EM, VAICA©) during a three month period. Meanwhile, all participants received phone calls in a two week interval (T1-T6) during which SRs were given. RESULTS: Seventy-eight RTRs participated in our study. At t0, NA rates of 6.4%, 28.6%, and 15.4% were found for PE, SR, and CV%, respectively. No correlation was found between these methods. During the study, the percentages of self-reported and electronically monitored adherence remained high, with a minimum mean of 91.2% for the strictest adherence measure (Timing Adherence ±30 min). Our results revealed a moderate to high association between SR and EM. In contrast to PE and CV%, SR significantly predicted electronically monitored adherence. Overall, a decreasing effect of electronically monitored adherence was found for both taking and timing adherence (±2 h, ±30 min) over the course of the study. DISCUSSION: The moderate to high concordance of SR and EM suggests that both methods measure NA equally accurately. SR seems to be a method that can adequately depict electronically monitored NA and may represent a good and economical instrument to assess NA in clinical practice. The increased adherence at the beginning of the study and its subsequent decrease suggests an intervention effect. Surveillance of IS intake via EM with intermittent phone calls could improve adherence on a short-term basis. To establish long-term effects, further research is necessary.