Cytomegalovirus prevention strategies and the risk of BK polyomavirus viremia and nephropathy

Polyomavirus BK (BKV) is the cause of polyomavirus‐associated nephropathy resulting in premature graft loss. There are limited data regarding the role of cytomegalovirus (CMV) infection and its prevention in developing BKV viremia and PVAN. In a prospective study, we analyzed 207 consecutive renal transplant recipients previously enrolled in 2 randomized trials evaluating different CMV prevention regimens with routine screening for BKV and CMV. Of these, 59 received valganciclovir and 100 valacyclovir prophylaxis; 48 patients were managed by preemptive therapy. At 3 years, the incidence of BKV viremia and PVAN was 28% and 5%, respectively. CMV DNAemia developed in 55% and CMV disease in 6%. Both BKV viremia (42% vs 23% vs 21%, P = .006) and PVAN (12% vs 2% vs 2%, P = .011) were increased in patients treated with valganciclovir prophylaxis compared to valacyclovir and preemptive therapy. Using multivariate Cox proportional hazard regression, valganciclovir prophylaxis was independent predictor of BKV viremia (hazard ratio [HR] = 2.38, P = .002) and PVAN (HR = 4.73, P = .026). In contrast, the risk of subsequent BKV viremia was lower in patients with antecedent CMV DNAemia (HR = 0.50, P = .018). These data suggest valganciclovir prophylaxis may be associated with increased risk of BKV viremia and PVAN. CMV DNAemia did not represent a risk for BKV.     

Ciprofloxacin for BK viremia prophylaxis in kidney transplant recipients: Results of a prospective,double‐blind,randomized, placebo‐controlled trial

In kidney transplantation, BK virus infection has historically resulted in high rates of graft dysfunction and graft loss. Unlike other opportunistic infections, no therapies have been shown to prevent BK. The purpose of the current study was to evaluate the safety and efficacy of ciprofloxacin for the prevention of BK viremia in kidney transplant recipients. Two hundred kidney transplant recipients were enrolled in a prospective, randomized, double‐blind, placebo‐controlled trial comparing a 3‐month course of ciprofloxacin (n = 133) vs placebo (n = 67) for the prevention of BK viremia. The primary endpoint of BK viremia at month 6 posttransplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P = .03). Higher rates of BK viremia (23.3% vs 11.9%; P = .06) and BK nephropathy (5.8% vs 1.5%; P = .26) remained at 12 months in the ciprofloxacin group. Ciprofloxacin use was associated with a significantly higher rate of fluoroquinolone‐resistant gram‐negative infections (83.3% vs 50%; P = .04). A 3‐month course of ciprofloxacin was ineffective at preventing BK viremia in kidney transplant recipients and was associated with an increased risk of fluoroquinolone‐resistant infections. Clinical trial registration number: NCT01789203.     

BK Polyomavirus Infection and Renourinary Tumorigenesis

BK polyomavirus (BKPyV) infection represents a major problem in transplantation, particularly for renal recipients developing polyomavirus‐associated nephropathy (PyVAN). The possibility that BKPyV may also be oncogenic is not routinely considered. Twenty high‐grade renourinary tumors expressing polyomavirus large T antigen in the entirety of the neoplasm in 19 cases, including the metastases in six, have been reported in transplant recipients with a history of PyVAN or evidence of BKPyV infection. Morphological and phenotypical features consistent with inactivation of the tumor suppressors pRB and p53 were found in the bladder tumors, suggesting a carcinogenesis mechanism involving the BKPyV large tumor oncoprotein/antigen. The pathogenesis of these tumors is unclear, but given the generally long interval between transplantation and tumor development, the risk for neoplasms after BKPyV infections may well be multifactorial. Other elements potentially implicated include exposure to additional exogenous carcinogens, further viral mutations, and cell genomic instability secondary to viral integration, as occurs with the Merkel cell PyV–associated carcinoma. The still scarce but increasingly reported association between longstanding PyVAN and renourinary neoplasms requires a concerted effort from the transplant community to better understand, diagnose, and treat the putative association between the BKPyV and these neoplasms.     

COVID‐19 in kidney transplant recipients

There is minimal information on coronavirus disease 2019 (COVID‐19) in immunocompromised individuals. We have studied 10 patients treated at 12 adult care hospitals. Ten kidney transplant recipients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by polymerase chain reaction, and 9 were admitted. The median age was 57 (interquartile range [IQR] 47‐67), 60% were male, 40% Caucasian, and 30% Black/African American. Median time from transplant to COVID‐19 testing was 2822 days (IQR 1272‐4592). The most common symptom was fever, followed by cough, myalgia, chills, and fatigue. The most common chest X‐ray and computed tomography abnormality was multifocal patchy opacities. Three patients had no abnormal findings. Leukopenia was seen in 20% of patients, and allograft function was stable in 50% of patients. Nine patients were on tacrolimus and a mycophenolic antimetabolite, and 70% were on prednisone. Hospitalized patients had their antimetabolite agent stopped. All hospitalized patients received hydroxychloroquine and azithromycin. Three patients died (30%), and 5 (50%) developed acute kidney injury. Kidney transplant recipients infected with COVID‐19 should be monitored closely in the setting of lowered immunosuppression. Most individuals required hospitalization and presenting symptoms were similar to those of nontransplant individuals.     

High‐grade urothelial carcinoma in a kidney transplant recipient after JC virus nephropathy: The first evidence of JC virus as a potential oncovirus in bladder cancer

Kidney transplant (KT) recipients have an increased risk for urothelial carcinoma. A role for JC virus (JCV) in human cancers is not yet proved but there is an increasingly reported association between BK virus (BKV) nephropathy and renourinary neoplasms. We report a KT recipient who developed a high‐grade urothelial carcinoma 5 years after a diagnosis of JCV nephropathy and 9 years after kidney transplantation. Neoplastic tissue was positive for JCV DNA by real‐time polymerase chain reaction (PCR). Immunochemical staining showed strong positivity for cell cycle markers (p16, p53, and Ki67) and for early viral protein JCV large T antigen (JCV LTag; using a broad polyomavirus antibody); however, late viral protein (VP1) stained negative. In contrast, in non‐neoplastic urothelium, JCV DNA and all immunochemical markers were negative. These facts suggest that malignancy was induced by JCV. To the best of our knowledge, this is the first report of urothelial high‐grade carcinoma associated with JCV nephropathy in a KT recipient.     

Two distinct cases with COVID‐19 in kidney transplant recipients

The fatality of novel coronavirus disease 2019 (COVID‐19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID‐19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36‐year‐old man who underwent KT 3 years ago. He was diagnosed with COVID‐19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID‐19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug‐to‐drug interaction. The second case was developed in a 56‐year‐old man without any symptoms. He received a second KT from an ABO‐incompatible donor 8 years ago. He was diagnosed with COVID‐19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors.     

COVID‐19 in elderly kidney transplant recipients

The SARS‐Cov‐2 infection disease (COVID‐19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed COVID‐19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti‐retroviral and tocilizumab. Short‐term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D‐dimer, C‐reactive protein, and IL‐6 at their first tests. COVID‐19 is frequent among the elderly KT population and associates a very early and high mortality rate.     

Donor-derived Cryptococcus gattii sensu stricto infection in two kidney transplant recipients,southeastern United States

Cryptococcus gattii infection is a rare cause of severe pulmonary disease and meningoencephalitis that has only recently been detected in the southeastern United States. We describe an organ transplant-associated outbreak of C. gattii infection involving an HIV-negative immunosuppressed donor in this region who died following new-onset headache and seizure of unknown cause. Retrospective cryptococcal antigen (CrAg) testing of donor serum was positive. Two of the three transplant recipients developed severe C. gattii infection 11 and 12 weeks following transplantation. One recipient died from severe pulmonary infection, identified on autopsy, and the other ill recipient survived following treatment for cryptococcal meningitis. This outbreak underscores the importance of considering cryptococcosis in patients with clinical findings suggestive of subacute meningitis or other central nervous system (CNS) pathology, and the potential benefit of routine pre-transplant donor CrAg screening using lateral flow assay to guide recipient antifungal prophylaxis. The case also adds to emerging evidence that C. gattii is a potential threat in the southeastern United States.     

BK Virus Nephropathy: Histological Evolution by Sequential Pathology

Reactivation of BK virus in renal allografts causes a destructive chronic infection. This single‐center retrospective cohort study describes the evolution of BK virus allograft nephropathy (BKVAN) from 63 kidneys (from 61 patients) using sequential histopathology (454 biopsies, averaging 7.8 ± 2.6 per kidney) followed for 60.1 mo. Uninfected protocol biopsies formulated time‐matched control Banff scores (n = 975). Interstitial inflammation occurred in 73% at diagnosis, correlating with viral histopathology (r = 0.413, p = 0.008) and amplifying early injury with accelerated interstitial fibrosis and tubular atrophy (IF/TA, p = 0.017) by 3 mo. Prodromal simian virus 40 large T antigen (SV40T)–negative inflammation with viremia preceded the histological diagnosis in 23.8%. Persistent subacute injury from viral cytopathic effect was associated with acute tubular necrosis and ongoing interstitial inflammation, culminating in IF/TA in 86.9%. Overall, cellular interstitial infiltration mitigated the intensity of subsequent tubular injury, SV40T, and tissue viral load, assessed by sequential paired histology (p < 0.001). Graft loss was predicted by high‐level viremia (hazard ratio [HR] 4.996, 95% CI 2.19–11.396, p < 0.001), deceased donor (HR 3.201, 95% CI 1.149–8.915, p = 0.026), and late acute rejection (HR 3.124, 95% CI 1.037–9.413, p = 0.043). Transplant failure occurred in 38.1%, with uncontrolled infection (58.3%) and SV40T‐negative chronic rejection (41.7%) causing losses. BKVAN is characterized by subacute virus‐induced tubular injury, inflammation, and progressive nephron destruction. Effective antiviral therapy remains an unmet clinical need.     

Histological Evolution of BK Virus–Associated Nephropathy: Importance of Integrating Clinical and Pathological Findings

Long‐term clinicopathological studies of BK‐associated nephropathy (PyVAN) are not available. We studied 206 biopsies (71 patients), followed 3.09 ± 1.46 years after immunosuppression reduction. The biopsy features (% immunostain for PyV large T ag + staining and inflammation ± acute rejection) were correlated with viral load dynamics and serum creatinine to define the clinicopathological status (PyVCPS). Incidence of acute rejection was 28% in the second biopsy and 50% subsequently (25% mixed T cell–mediated allograft rejection (TCMR) + antibody‐mediated allograft rejection (AMR); rejection overall affected 38% of patients (>50% AMR). Graft loss was 15.4% (0.8–5.3 years after PyVAN); 76% had complete viral clearance (mean 28 weeks). The only predictors of graft loss were acute rejection (TCMR p = 0.008, any type p = 0.07), and increased “t” and “ci” in the second biopsy (p = 0.006 and 0.048). Higher peak viremia correlated with poorer viral clearance (p = 0.002). Presumptive and proven PyVAN had similar presentation, evolution, and outcome. Late PyVAN (>2 years, 9.8%) justifies BK viremia evaluation at any point with graft dysfunction and/or biopsy evaluation. This study describes the histological evolution of PyVAN and corresponding clinicopathological correlations. Although the pathological features overall reflect the viral and immunological interactions, the PyVAN course remains difficult to predict based on any single feature. Appropriate clinical management requires repeat biopsies and determination of the PyVCPS at relevant time points, for corresponding personalized immunosuppression adjustment.     

COVID-19 severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3–73.1) in three French transplant centers. After a median follow-up of 13 days (7–30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2–14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.     

The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter “modern-era” validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.     

BK Polyomavirus Genomic Integration and Large T Antigen Expression: Evolving Paradigms in Human Oncogenesis

Human polyomaviruses are ubiquitous, with primary infections that typically occur during childhood and subsequent latency that may last a lifetime. Polyomavirus‐mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. We present deep sequencing data from a high‐grade BK virus–associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH‐2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK virus was replication incompetent. We propose that the BK virus CH‐2 was integrated into the human genome as a concatemer, resulting in alterations of feedback loops and overexpression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus‐associated malignancy and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations, we present an updated model of polyomavirus‐mediated oncogenesis.     

Cellular and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients

According to preliminary data, seroconversion after mRNA SARS-CoV-2 vaccination might be unsatisfactory in Kidney Transplant Recipients (KTRs). However, it is unknown if seronegative patients develop at least a cellular response that could offer a certain grade of protection against SARS-CoV-2. To answer this question, we prospectively studied 148 recipients of either kidney (133) or kidney-pancreas (15) grafts with assessment of IgM/IgG spike (S) antibodies and ELISpot against the nucleocapside (N) and the S protein at baseline and 2 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. At baseline, 31 patients (20.9%) had either IgM/IgG or ELISpot positivity and were considered to be SARS-CoV-2-pre-immunized, while 117 (79.1%) patients had no signs of either cellular or humoral response and were considered SARS-CoV-2-naïve. After vaccination, naïve patients who developed either humoral or cellular response were finally 65.0%, of which 29.9% developed either IgG or IgM and 35.0% S-ELISpot positivity. Factors associated with vaccine unresponsiveness were diabetes and treatment with antithymocytes globulins during the last year. Side effects were consistent with that of the pivotal trial and no DSAs developed after vaccination. In conclusion, mRNA-1273 SARS-CoV-2 vaccine elicits either cellular or humoral response in almost two thirds of KTRs.     

Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation

BK polyomavirus (BKPyV) is recognized as a pathogen that causes diseases such as hemorrhagic cystitis and nephritis after allogeneic hematopoietic stem cell transplantation (HSCT) or renal transplantation. BKPyV‐associated disease is thought to occur through reactivation under immunosuppression. However, the possibility of its nosocomial transmission and the clinical significance of such transmission have not been elucidated. During a 6‐month period, nine adult patients (median age: 47 years) who had hematological disorders and who were treated with HSCT (n = 7) or chemotherapy (n = 2) in a single hematology department developed hemorrhagic cystitis due to BKPyV infection. The polymerase chain reaction products of BKPyV DNA obtained from each patient were sequenced. Of the nine patients, six had subtype I, 2 had subtype IV, and 1 had subtype II or III. In the alignment of sequences, four and two of the six subtype I strains were completely homologous (100%). These results strongly suggest that BKPyV has the potential to cause nosocomial infection within a medical facility, especially among recipients of HSCT. Further studies are clearly warranted to elucidate the route(s) of BKPyV transmission in order to establish optimal infection control.     

Quantifying infection risks in incompatible living donor kidney transplant recipients

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = _0.771.40_2.56,P = .3) and moderately (wIRR = _0.881.35_2.06,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = _1.332.22_3.72,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = _2.623.57_4.88, P < .001) and death-censored graft loss (wHR = _1.154.01_13.95,P = .03). Post–KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.     

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients—Results of a Spanish multicenter cohort

Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram‐negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended‐spectrum β‐lactamase‐producing Enterobacteriaceae [14%] or carbapenem‐resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5‐2) was administered for a median of 7 days (IQR: 3‐10). Clinical cure (remission of UTI‐attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow‐up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98‐112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.     

Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States

There has been a notable rise of BK virus among kidney transplant recipients. Single-center reports have identified risk factors for development of BK virus. However, there has not been an assessment of risk factors and incidence of this complication at a national level. This study utilized newly collected follow-up information from the national SRTR database to investigate incidence, risk factors and outcomes for solitary kidney transplant recipients associated with treatment for BK virus (TBKV) from 2004 to 2006. Logistic and Cox models were utilized to assess risk factors and evaluate graft survival associated with TBKV. Incidence of TBKV was 1.6% at 6 months and 2.6% at 1 year following transplantation. Patients with and without TBKV at 6 months had 79% and 90% 3-year overall graft survival respectively. Risk factors included advanced donor age, pediatric, African American and male recipients, human leukocyte antigen-mismatching and tacrolimus and thymoglobulin induction as baseline immunosuppression. Acute rejection episodes were more frequent prior to and following TBKV. TBKV is a common and rising incidence, varies based on transplant characteristics and should be included as a safety endpoint in studies investigating immunosuppressive protocols. Careful monitoring and further understanding of disease etiology and treatment strategies are needed.     

Novel coronavirus 2019 pneumonia in a kidney transplant recipient

The COVID‐19 pandemic is spreading worldwide and the impact of the disease in transplant patients is evolving. In this case report, we presented a 63‐year‐old female kidney transplant recipient who presented with dyspnea and cough and was diagnosed with COVID‐19 pneumonia. On the fourth day of admission, the patient's condition worsened. Therefore, the immunosuppressive medications were discontinued, and hydrocortisone was started. The patient died on the fifth day.