A Prospective Longitudinal Study of BK Virus Infection in 104 Renal Transplant Recipients

BK virus (BKV) infection during the first year after renal transplantation was studied prospectively in 104 unselected consecutive patients. Viral DNA in urine (DNAuria) and plasma (DNAemia) samples was detected and quantified by real-time PCR. The noncoding control region (NCCR) of BKV isolates was sequenced. DNAuria and DNAemia occurred in 57% and 29% of patients, respectively. Three groups were defined, uninfected patients (group 1, n=45), patients with DNAuria (group 2, n=29) and patients with positive DNAemia (group 3, n=30). Active infection started within the first 3 months in 80% of patients. Cold ischemia duration over 24 h and the administration of tacrolimus were identified as significant risks factors for DNAuria, whereas it remains more frequently negative in patients receiving cyclosporine A. The risk for positive DNAemia was higher in patients with DNAuria (notably for viral load (VL)>4 log/mL) or treated with tacrolimus. No relationship was found with genetic variability in the NCCR sequence. Our data highlight the high frequency of active BKV infection after renal transplantation. Although high VL was detected in some patients, none developed a BKV nephropathy. A prospective follow-up of the whole population during the first year post renal transplantation is thus not useful to predict BKV disease.     

BK Virus Infection in Thai Kidney Transplant Recipients: A Single-Center Experience

Introduction

BK virus-associated nephropathy (BKVAN) is a significant cause of allograft dysfunction and failure in kidney transplant recipients. Early detection and proper adjustment of immunosuppression is the best method for treatment of this condition and to improve long-term allograft outcome. Here, we reported the prevalence and risk factors of BK virus (BKV) infection in our population.

Epidemiologic Study and Genotyping of BK Virus in Renal Transplant Recipients

BK virus (BKV) infection occurs during childhood and remains latent in the urinary tract. The virus is reactivated in immunosuppressed patients, particularly in those with cellular immunity deficiency, allowing its detection in urine and blood. Nephropathy caused by the virus in renal transplantation recipients may lead to graft failure. The purpose of this study is to know the prevalence of BKV variables in renal transplantation recipients and to evaluate their clinical evolution through molecular methods of “in house” development. Urine and peripheral blood samples from 66 renal transplantation recipients from the province of Buenos Aires, Argentina, were systematically analyzed every 3 months as well as when there was graft dysfunction. Renal biopsies, which were included in the BKV detection study, were performed on those patients with graft dysfunction. Genotyping of 24 BKVs was performed, and the following distribution was found: 21 (87.5%) belonged to subtype I, 3 (12.5%) to subtype II. BKV belonging to subtypes III or IV were not found. As regards subtype I subgroups, the following were identified: 1 (4.76%) from Ia, 10 (47.61%) from Ib1 and 10 (47.61%) from Ib2. Presence of subgroup Ic was not shown. Viremia presented in 33.33% of cases, whereas 75% corresponded to subgroup Ib 1. Genotype Ib1 is prevailing in Southeast Asia, while Ib2 is prominent in Europe. Although an important proportion of the inhabitants of the province of Buenos Aires are European descendants, the prevailing genotype is Ib1, the Asian type. Genotyping might be related to the evolution of the disease in the recipient.     

BK Virus Infection in Transplant Recipients: An Overview and Update

BK virus infection after kidney transplantation has been a subject of great interest in the past decade. This article traces the discovery of BK virus and the subsequent development of our knowledge about this emerging pathogen. The pathobiology of the virus is summarized with particular reference to epidemiology, interactions with host cell receptors, cell entry, cytoplasmic trafficking and targeting of the viral genome to the nucleus. This is followed by a discussion of clinical features, laboratory monitoring and therapeutic strategies. Finally, we present potential cellular mechanisms that explain the basis of virus-mediated damage to the human kidney.     

Invasive Fungal Infections in Low-Risk Liver Transplant Recipients: A Multi-Center Prospective Observational Study

Prevention of invasive fungal infections (IFIs) in orthotopic liver transplant (OLT) recipients utilizing postoperative systemic antifungal prophylaxis, typically with fluconazole, is justified among those at high risk for IFI. Use of postoperative antifungal prophylaxis for low-risk OLT recipients is widely practiced but not universally accepted nor supported by data. We conducted a prospective observational study among 200 OLT recipients who were at low risk for IFI and did not receive postoperative antifungal prophylaxis. Patients were considered low risk if they had /=units of 40 blood products or return to the operating room for intra-abdominal bleeding; return to the operating room for anastomotic leak or vascular insufficiency; preoperative serum creatinine of >/=2 mg/dL; and perioperative Candida colonization. Patients were followed 100 d post-transplantation for evidence of IFI. Of 193 eligible patients, 7 (4%) developed an IFI. Three (2%) IFIs were due to Candida spp. and potentially preventable by standard fluconazole prophylaxis. Three patients developed invasive aspergillosis; one developed late onset disseminated cryptococcosis. Liver transplant recipients at low risk for IFI can be identified utilizing pre-determined criteria, and post-transplantation antifungal prophylaxis can be routinely withheld in these patients.     

Identification of BK Virus Genotypes in Recipients of Renal Transplant in Vietnam

ObjectivesThis study aims to investigate the prevalence and distribution of BK polyomavirus (BKV) genotypes in recipients of renal transplant in Vietnam.MethodsOne hundred six patients who underwent renal transplantation were included in this study. These patients were from the Department of Nephrology, Military Hospital 103, Vietnam Military Medical University. Quantification and genotyping of the BK virus was performed using in-house molecular methods from urine and plasma samples.ResultsBKV infection was detected in 82 patients (77.4%), including 58 patients who had the presence of both BK viremia and BK viruria, and 24 patients (22.60%) with BKV positive findings in the urine alone. Particularly, 16 patients (15.09%) had high BK viremia >10⁴ copies/mL and 20 patients (18.9%) had BK viruria >10⁷ copies/mL. BK virus nephropathy (BKVN) was confirmed in 6 patients (5.66%) by immunohistochemistry examination. Genotyping of BKV was performed successfully in 50 out of the 82 patients, with 36 out of 50 (72%) belonging to the BKV-I subtype and 14 out of 50 (28%) belonging to the BKV-IV subtype; no cases of genotypes II or III were observed. Using phylogenetic analysis of the subgroups, the BKV-I/b-1 subtype was found the predominant subgroup (100%), whereas BKV-IV included 21.43% of IV/a-1, 6.67% of IV/a-2, and 50% of IV/c-1, respectively. There remain 3 cases of BKV-IV (21.43%) that could not be categorized into any subgroups. In the 6 patients diagnosed BKVN, 5 of them were infected with subgroup I/b-1 (83.3%) and 1 patient was infected with subgroup IV/c-1 (16.7%). No significant difference between BKV genotypes was observed in relation to age, sex, HLA mismatch, viral load, BKVN, and immunosuppressive therapy.ConclusionsThis research indicated a high prevalence of BKV infection and BKV-I was predominant, followed by BKV-IV among recipients of renal transplant in Vietnam.     

HLA Mismatching Increases the Risk of BK Virus Nephropathy in Renal Transplant Recipients

BK virus (BKV) nephropathy is a serious complication in kidney transplant recipients that may lead to irreversible graft failure. We have analyzed the degree of donor/recipient HLA compatibility and HLA antigen association in 40 kidney transplant patients with BKV nephropathy in comparison with a control group of 404 unaffected transplant recipients who were on tacrolimus-based immunosuppression with no induction. HLA compatibility was assessed by determining the number of HLA-A, -B, -DR-mismatched antigens. BK virus nephropathy was diagnosed histologically and confirmed by immunochemistry. Univariate and multiple logistic regression statistical analyses have shown a significant association between BKV nephropathy and HLA mismatching. This analysis showed also that BKV nephritis is associated with a greater number of rejection episodes and a higher incidence of steroid-resistant rejection requiring antilymphocyte treatment. There was no association between BKV nephropathy and any specific HLA allele. We propose that HLA mismatching promotes the development of BKV nephropathy through rejection-related inflammatory processes and heavy immunosuppression which cause virus reactivation and injury of the tubular epithelium.     

Prospective Study of Infection and Nephropathy Due to BK and JC Polyomavirus in 76 Kidney Transplant Recipients

Introduction

Nephropathy due to polyomavirus is usually diagnosed by renal biopsy after worsening of renal function. This is normally at an advanced stage of the disease.

Aim

To study the early detection of the presence of BK and JC polyomavirus in urine by monthly real-time quantitative polymerase chain reaction (PCR) assay.

Material and methods

The study included 76 kidney transplant recipients from cadaveric donors between August 2005 and July 2006 with a 1-year follow-up.

Results

Viruria was positive in 31 patients (40.7%) and viremia in 7 (9.2%), three of whom (3.9%) developed nephropathy. After reduction of the immunosuppression, the viruria became negative in 32.0% and the viremia in 42.8% of the patients. Renal function (creatinine clearance, aMDRD) at 1 year was 49.2 mL/min/1.73 m² in the patients with nephropathy and 64.3 mL/min/1.73 m² in the others. One-year patient and graft survival was 96%. No patient lost the graft due to nephropathy.

Conclusions

The detection of BK and JC polyomavirus by protocolized PCR enabled an early diagnosis of nephropathy, preventing graft loss with good renal function at 1 year.     

Outcome of HCV/HIV‐Coinfected Liver Transplant Recipients: A Prospective and Multicenter Cohort Study

Eighty‐four HCV/HIV‐coinfected and 252‐matched HCV‐monoinfected liver transplant recipients were included in a prospective multicenter study. Thirty‐six (43%) HCV/HIV‐coinfected and 75 (30%) HCV‐monoinfected patients died, with a survival rate at 5 years of 54% (95% CI, 42–64) and 71% (95% CI, 66 to 77; p = 0.008), respectively. When both groups were considered together, HIV infection was an independent predictor of mortality (HR, 2.202; 95% CI, 1.420–3.413 [p < 0.001]). Multivariate analysis of only the HCV/HIV‐coinfected recipients, revealed HCV genotype 1 (HR, 2.98; 95% CI, 1.32–6.76), donor risk index (HR, 9.48; 95% CI, 2.75–32.73) and negative plasma HCV RNA (HR, 0.14; 95% CI, 0.03–0.62) to be associated with mortality. When this analysis was restricted to pretransplant variables, we identified three independent factors (HCV genotype 1, pretransplant MELD score and centers with <1 liver transplantation/year in HIV‐infected patients) that allowed us to identify a subset of 60 (71%) patients with a similar 5‐year prognosis (69%[95% CI, 54–80]) to that of HCV‐monoinfected recipients. In conclusion, 5‐year survival in HCV/HIV‐coinfected liver recipients was lower than in HCV‐monoinfected recipients, although an important subset with a favorable prognosis was identified in the former.     

Spontaneous Clearance of HCV in HIV-Hepatitis C Virus Coinfected Liver Transplant Patients: Prospective Study

Background

Hepatitis C virus (HCV) clearance is an independent predictive factor for long-term survival in HIV-HCV liver transplantation patients. After 46 months of antiviral therapy it is achieved in up to 80% of cases. Little is known, however, about spontaneous viral clearance. We performed prospective study of HIV-HCV coinfected liver transplant patients.

Methods

Between January 1, 2001, and December 31, 2011, we analyzed the parameters from among HIV-HCV coinfected liver transplant patients of donor and recipient ages, transplant cause, Model for End-Stage Liver Disease (MELD) score, donor and recipient serology, transplant date, viral load before and after transplantation, immunosuppressive therapy, HCV recurrence, HCV viral clearance (spontaneous and duration), retransplant cause, and viral load before and after retransplant, as well as survival.

Results

The seven transplanted HIV-HCV coinfected patients had most commonly HCV-related hepatocarcinoma (n = 5, 71.42%). Three subjects (42.85%) developed HCV recurrences. Two patients (28.57%) were retransplanted, both due to HCV recurrence with one of them developing a spontaneous clearance of HCV (14.28%). This patient showed a preoperative HIV viral load < 50 copies IU/mL, CD4+ count 486/μL, HCV-RNA 2564 IU copies/mL, Anti-HBc+, and MELD 30. The donor was an 81-year-old female who was Anti-HBc+. Immunosuppressive therapy consisted of cyclosporine, mycophenolate, and prednisone. One month after transplantation, the patient developed an acute cellular rejection episode with progression of liver disease secondary to the HCV recurrence (56.5 × 105 copies IU/mL). He started antiviral treatment (α-interferon and ribavirin), but due to side effects and interactions with the antiretrovirals, they were stopped after four doses. The viral load decreased spontaneously and progressively until it became negative at 146 days after transplantation; he was retransplanted and HCV-RNA has continued to be negative after 772 days.

Conclusion

Spontaneous clearance of HCV among HIV-HCV coinfected liver transplant patients is possible. Despite no treatment, one patient still has no detectable HCV viral load after retransplantation.     

Sirolimus in Liver Transplant Recipients: A Large Single-Center Experience

Sirolimus (SRL) is a newer immunosuppressant whose possible benefits and side effects in comparison to calcineurin inhibitors (CNIs) still have to be addressed in the liver transplantation setting. We report the results of the use of SRL in 86 liver transplant recipients, 38 of whom received SRL as the main immunosuppressant in a CNI-sparing regimen. Indications for the use of SRL were: impaired renal function (n = 32), CNI neurotoxicity (n = 16), hepatocellular carcinoma (HCC) at high risk of recurrence (n = 21), recurrence of HCC (n = 6), de novo malignancies (n = 4), cholangiocarcinoma (n = 1), and the need to reinforce immunosuppression (n = 6). Among patients on SRL-based treatment, four episodes of acute rejection were observed, three of which occurred during the first postoperative month. Renal function significantly improved when sirolimus was introduced within the third postoperative month, while no change was observed when it was introduced later. Neurological symptoms resolved completely in 14/16 patients. The 3-year recurrence-free survival of patients with HCC on SRL was 84%. Sixty-two patients developed side effects that required drug withdrawal in seven cases. There was a reduced prevalence of hypertension and new-onset diabetes among patients under SRL. In conclusion, SRL was an effective immunosuppressant even when used in a CNI-sparing regimen. It was beneficial for patients with recently developed renal dysfunction or neurological disorders.     

The Change in Muscle Mass Among Kidney Transplant Recipients: A Prospective Cohort Study

BackgroundRecovery of renal function after transplantation leads to improved uremic conditions, increased physical activity, and liberation from severe dietary restrictions. Consequently, the muscle mass of kidney transplant recipients increases for several years after their transplant. However, the change in muscle mass and its associated factors among these patients remain largely unknown. Herein, we carried out a prospective cohort study with 1-year follow-up to investigate how muscle mass changes and to identify its risk factors among kidney transplant recipients.Patients and MethodsWe performed a single-center, 1-year, prospective, observational cohort study from August 2017 to February 2019 at Osaka City University Hospital in Japan. The skeletal muscle mass index (SMI) was measured by bioelectrical impedance analysis. The risk factors related to the change in muscle mass were analyzed using multivariate linear regression models of age, sex, body mass index (BMI), dialysis vintage, transplant vintage, diabetes mellitus, hemoglobin, C-reactive protein, estimated glomerular filtration rate, and SMI at baseline.ResultsA total of 180 kidney transplant recipients were enrolled in the present study. The median age was 55 years, and the median transplant vintage was 78 months. The median rate of change in SMI was +2.07%, and SMI increased in 118 (66%) patients during the 1-year follow-up. By multivariate analysis, the change in SMI at 1-year follow-up was independently associated with age (P = 0.017) and BMI (P = .023).ConclusionsSMI increased in most of the kidney transplant recipients, and age and BMI might be the risk factors for this change in muscle mass among these patients.     

Etiology of DNA Virus Infections in Liver Transplant Recipients With Neonatal Hepatitis

Neonatal hepatitis is a syndrome of symptoms associated with a history that includes any type of infectious, genetic, toxic, or metabolic causation. Various infectious agents have been implicated in hepatic inflammation in neonates including bacterial and viral pathogens, especially DNA viruses. We used molecular and antigenic methods to evaluate the role of DNA viruses, such as hepatitis type B viruses (HBV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and adenovirus, in neonatal hepatitis complications. Twenty-six paraffin-embedded biopsy and autopsy tissues obtained between 1996 and 2007 from 22 infants with neonatal hepatitis were studied retrospectively. The genome prevalence of HBV, HCMV, HSV, and adenovirus were analysed using qualitative polymerase chain reaction (PCR) protocols. The antigenic presentation of HSV-1, HSV-2, HBV, HCMV, and adenovirus were evaluated using immunohistochemistry (IHC) methods. The HCMV genome was detected separately in 1 of 22 (4.5%) paraffin-embedded autopsy and biopsy tissues. Also 3/22 (13.6%) samples were infected with HBV and HSV genomes. HBV and HSV-1 antigens were present in 1/26 (4.5%) neonatal samples and HSV-2 antigens in 5/26 (22.7%) by IHC protocols, but adenovirus and HCMV antigens were not detected among samples from infants with neonatal hepatitis. Detection of separate co-infections of HSV, HCMV, and HBV genomes in autopsy and biopsy tissues of HBV and HSV-1 or HSV-2 antigens in these patients, showed the importance of these viral infections in clinical neonatal hepatitis.     

Short-Term Prospective Study of Metabolic Syndrome in Renal Transplant Recipients

Background

Metabolic syndrome (MS) may affect patient and graft survival in renal transplant recipients. However, the evolution of MS during prospective follow-up remains uncertain.

Methods

Renal transplant patients were recruited for a study of MS in 2010 and then prospectively followed for 2 years. The modified Adult Treatment Panel III criteria adopted for Asian populations were used to define MS.

Results

A total of 302 cases (male:female = 154:148) with a mean duration of 10.5 ± 5.7 years after transplantation were enrolled. At initiation, 71 cases (23.5%) fulfilled the criteria of MS. At the end of follow-up, 11 cases had died and 21 had graft failure. Nine cases had insufficient data for reclassification. The remaining 261 cases completed a 2-year follow-up, and the prevalence of MS was 26.1% at the end of study. Of these, 7.79% (18 cases) of patients without MS had developed new-onset MS. Conversely, 16.9% (12 cases) with MS were free from MS at the end of study (P = .362). Patients with MS were associated with older age (57.1 ± 10.4 vs 52.6 ± 12.4 y; P = .006), more chronic allograft nephropathy (17.4% vs 7.1%; P = .01), proteinuria (22.5% vs 10.8%; P = .012), and use of more antihypertensive agents (1.49 ± 0.86 vs 0.80 ± 0.98; P < .0001). There was no significant change in serum creatinine in each subgroup.

Conclusions

The status of MS in renal transplant patients is dynamic. MS patients were associated with more chronic allograft nephropathy and proteinuria.     

Tacrolimus Monotherapy in Recipients of Liver Transplant: A Single-Center Experience

IntroductionFollowing liver transplantation (LT), the majority of patients are treated with reduced-dose calcineurin inhibitors (CNIs) in combination with mycophenolate mofetil. The optimal timing for subsequent conversion to CNI monotherapy is not clearly defined. This study aims to evaluate the safety of conversion to CNI monotherapy after LT.MethodsThis was a single-center retrospective study of 100 consecutive patients who received CNI and mycophenolate mofetil combination regimen after LT at Singapore General Hospital from 2006 to 2018. Patient demographics, clinical parameters, and posttransplant complications (ie, rates of graft rejection, de novo malignancy, cytomegalovirus infection and renal impairment) were recorded.ResultsOne hundred patients were recruited and mean follow-up time in months ± standard deviation was 60.36 ± 41.73. Patients were divided into 2 groups based on institution of CNI monotherapy within (group 1) or beyond (group 2) 6 months. Twenty-five (25%) patients were on CNI monotherapy within 6 months post-LT. Overall patient survival was 83.7% at 5-years posttransplant. There was no statistical difference in the rates of posttransplant complications including liver graft rejection (4.0% vs 18.7%, P = .11); de novo malignancy (0.0% vs 8.0%, P = .33); cytomegalovirus infection (4.0% vs 1.3%, P = .44); and renal impairment (20.0% vs 40.0%, P = .069) between the 2 groups.ConclusionsSuccessful institution of CNI monotherapy within 6 months is safe, and does not increase the risk of rejection.     

Mycophenolate Mofetil Withdrawal With Conversion to Everolimus to Treat BK Virus Infection in Kidney Transplant Recipients

Background

BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies.

Pneumocystis jirovecii Pneumonia in Liver Transplant Recipients: A Systematic Review

BackgroundPneumocystis jirovecii is a fungus that causes pneumonia in immunocompromised patients, such as liver transplant recipients.MethodsWe searched the Medline database in September 2013 for articles referring to infections from P. jirovecii in liver transplant recipients, using the terms “liver transplantation” and “pneumocystis.” Our search yielded 60 articles, 35 of which were used for our review.ResultsP. jirovecii pneumonia (PJP) has an incidence of 1%–11% in liver transplant recipients without prophylaxis and mortality rates of 7%–88%. Most cases occur within the first 7 months after transplantation. When prophylactic treatment with oral trimethoprim-sulfamethoxazole is used, its incidence is only 0%–3%. The duration of its use varies from 3 months to 1 year after the liver transplantation.ConclusionsPJP has relatively high incidence and high mortality rates in liver transplant recipients without prophylactic treatment, which diminishes or even eliminates its occurrence. Therefore, oral trimethoprim-sulfamethoxazole should be used as prophylaxis for 1 year after the liver transplantation in this population.