Association between chronic lung allograft dysfunction and human Cytomegalovirus UL40 peptide variants in lung-transplant recipients.

Natural-Killer cells play an important role in the pathogenesis of chronic lung allograft dysfunction (CLAD) in lung-transplant recipients. Activating NKG2C+ and inhibitory NKG2A+ NK cells proliferate in response to human Cytomegalovirus (HCMV) infection via the presentation of virally encoded UL40 peptides on HLA-E molecules. We aimed to clarify whether infection with HCMV strains carrying different UL40 peptide variants is associated with the development of CLAD. We included 82 lung-transplant recipients, 18 patients developing CLAD and 64 matched control patients without CLAD. In all patients 1 episode of high-level HCMV-replication occurred. HCMV UL40 variants and Natural-Killer-cell proliferation with distinct UL40 peptides were assessed. The VMTPRTLIL variant was significantly overrepresented in patients developing CLAD (p < 0.0001) and lead to a significantly lower proliferation of inhibitory NKG2A+ cells, compared to the VMAPRTLIL, VMAPRTLVL and VMAPRTLLL variants (p < 0.0001). Thus, HCMV UL40 variants may contribute to development of CLAD over the NK cell response.

Routine immunohistochemistry study for polyomavirus BK nephropathy in transplanted kidney biopsies, is it recommended?

BACKGROUND: Early diagnosis and treatment of Polyomavirus BK Nephropathy (PVBKN) is a challenging issue in the management of patients with kidney transplantation. Currently, histopathologic diagnosis is the gold standard method for diagnosis of PVBKN. However, typical viral inclusions may not be found in early stages of the PVBKN and should, instead, be diagnosed using immunohistochemistry (IHC) study. There is no clear consensus about routine IHC tests in the pathologic evaluation of transplanted kidney biopsy samples. MATERIAL AND METHODS: The current study was conducted on transplanted kidney biopsy samples, since 2016 to 2019. The patients who have presented with new onset of allograft dysfunction, at least 2 weeks after transplantation surgery, were included in our study. All these biopsy samples were evaluated with routine renal biopsy stains as well as IHC for SV40 (Simvian Virus 40) antigen. The identification of typical nuclear virus inclusion body and any nuclear positive staining on IHC (≥1+ positive result) were considered as definite evidence of PVBKN. Sensitivity, specificity, Positive Predictive and Negative Predictive Values (PPV and NPV) of histopathologic assessment without IHC study were evaluated. RESULTS: Among 275 included cases, 18 (6.5%) patients with PVBKN were diagnosed. In patients with PVBKN, typical viral inclusions were detected in 14 samples (77.7%), on primary histopathological examination. However, virus-infected cells were identified just after IHC study in 4 (22.2%) of patients. Sensitivity, Specifity, PPV and NPV of morphologic histopathological assay without IHC for detection of PVBKN was 77.7, 100, 100 and 98.4% respectively. CONCLUSION: Routine IHC study for SV40 in all transplanted kidney biopsy samples with new onset of allograft dysfunction, will enhance the diagnostic sensitivity of early stage disease detection.

Kidney transplant dysfunction in a patient with COVID - 19 infection: role of concurrent Sars-Cov 2 nephropathy, chronic rejection and vitamin C-mediated hyperoxalosis: case report.

BACKGROUND: COVID-19 infection in kidney transplant recipients often lead to allograft dysfunction. The allograft injury has various histopathological manifestations. Our case illustrates the unusual combination of allograft rejection, acute kidney injury secondary to oxalate nephropathy and SARS CoV-2 nephropathy as the cause of irreversible allograft failure. CASE PRESENTATION: A 56 year old renal allograft recipient presented with a history of fever and diarrhoea for the preceding 4 weeks, tested positive for Sars-CoV2 on nasal swab and was found to have severe allograft dysfunction, necessitating haemodialysis. He subsequently underwent an allograft biopsy, which demonstrated antibody mediated rejection along with the presence of extensive oxalate deposition in the tubules. Ultrastructural examination demonstrated spherical spiked particles in the glomerular capillary endothelium and the presence of tubulo-reticular inclusions suggestive of an active COVID-19 infection within the kidney. The intra-tubular oxalate deposition was considered to be the result of high dose, supplemental Vitamin C used as an immune booster in many patients with COVID - 19 infection in India. CONCLUSIONS: This case highlights the complex pathology that may be seen in following COVID-19 disease and the need for kidney biopsies in these patients to better understand the aetiology of disease.

Adenovirus Infection as a Cause of Fever of Unknown Origin and Allograft Dysfunction in a Kidney Transplant Recipient.

With the recent introduction of more potent modern immunosuppressive regimens in solid-organ transplant, new types of viral infections such as adenovirus are emerging as a potential cause for graft dysfunction and loss. We report a case of 41-year-old male patient with end-stage renal disease from recurrent kidney stones who underwent kidney transplant from a deceased 12-year-old female donor. He developed adenoviral infection with acute cystitis, microscopic hematuria, and necrotizing interstitial nephritis associated with graft dysfunction within the first month of the postoperative period. Diagnosis was made by graft biopsy that showed more than 60% necrosis with tubulointerstitial hemorrhage, thrombotic microangiopathy, and histologic features suggestive of viral infection with negative Cytomegalovirus and polyomavirus stains in the graft and elevated adenovirus PCR in the blood. Simultaneously, the patient had very low absolute total lymphocyte count of 70 cells/µL during which he received supratherapeutic tacrolimus at whole blood trough levels and mycophenolate mofetil. This prompted the tapering of immunosuppression and the discontinuation of all antimicrobial drugs. Within a 2-week period, the immune reconstitution was sufficient for the clearance of the infection and the subsequent gradual recovery of graft function.

Posttransplant Lymphoproliferative Disorders in Epstein-Barr Virus Donor Positive/Recipient Negative Lung Transplant Recipients.

BACKGROUND: Epstein-Barr virus (EBV) donor positive/recipient negative (D+/R-) status is a significant risk factor for posttransplant lymphoproliferative disorder (PTLD) in lung transplant. There are, however, no studies that identify the risk factors for PTLD in the EBV D+/R- lung transplant population to guide the decision to proceed with an EBV-positive donor. METHODS: This was a retrospective cohort study of adults listed in the Scientific Registry of Transplant Recipients between May 5, 2005, and August 31, 2016. Cox proportional hazards models were used to assess the impact of EBV D+/R- status on the development of PTLD, the impact of PTLD on survival, and survival differences between EBV D+/R- and EBV D-/R- recipients. RESULTS: The incidence of PTLD was 6.2% (79 of 1,281) versus 1.4% (145 of 10,352) in EBV D+/R- versus all other recipients (adjusted odds ratio 4.0; 95% confidence interval: 2.8 to 5.9, p < 0.001). Among EBV D+/R- recipients, age less than 40 years and white race were associated with PTLD. The EBV D+/R- patients who had PTLD had increased adjusted risk of death (hazard ratio 1.91; 95% confidence interval: 1.35 to 2.71; p < 0.001). Compared with EBV D+/R- recipients, EBV D-/R- recipients did not have improved adjusted survival (hazard ratio 0.82; 95% confidence interval: 0.57 to 1.18; p = 0.30). CONCLUSIONS: Despite increased rates of PTLD and associated mortality in the EBV D+/R- population, EBV seronegative patients did not have worse mortality when transplanted with lungs from EBV seropositive donors compared with lungs from EBV seronegative donors. Consideration should be given for close monitoring for PTLD among EBV D+/R- recipients, particularly those who are white and less than 40 years of age.

Occurrence of the polyomavirus among kidney transplant recipients: a single-center study.

Polyoma virus-associated nephropathy is an increasingly recognized cause of graft dysfunction among kidney transplant recipients and could be the result of use of potent immunosuppression following transplantation. Because there is no safe and effective anti-viral therapy available presently, screening-based prevention and pre-emptive strategy are recommended. This study, which was conducted at the Nephrology Unit, Internal Medicine Department, Alexandria University, consisted of two phases: Phase 1 was a cross-sectional study and phase 2 was a 6-month follow-up study only for polyoma virus-positive cases. Phase 1 included 75 renal allograft recipients from living donors. Urine cytology for decoy cells and quantitative real-time blood polymerase chain reaction (PCR) for the BK virus (BKV) were performed on all the study patients. Renal biopsy was performed only in patients with deteriorating renal function associated with positive urine cytology. Patients who showed positive urine cytology for decoy cells and/or positive quantitative BKV PCR assay were followed-up for six months. During follow-up, the serum creatinine level, with or without urine cytology for decoy cells, and BKV PCR viral load assay were performed. Among the 75 kidney transplant recipients studied, eight were positive for decoy cells (11%), three showed viremia by quantitative PCR for BKV (4.1%), while two others showed nephropathy (2.7%) in the form of tubulointerstitial nephritis with intra-nuclear inclusions in the tubular cells. Cases with stable renal function and positive decoy cells or viremia cleared the virus spontaneously during follow-up without any intervention. Only one case with biopsyproven nephropathy and deteriorating graft function, with undetectable BKV in blood, lost the graft while another case with viremia died during follow-up due to septicemia. Our study suggests that polyoma virus should be considered as a cause of nephropathy in renal transplant recipients. Further research is required to understand this entity better.

BKV-infection in kidney graft dysfunction.

INTRODUCTION: BKV nephropathy (BKN) causes kidney graft loss, whose specific diagnosis is invasive and might be predicted by the early detection of active viral infection. OBJECTIVE: Determine the BKV-infection prevalence in late kidney graft dysfunction by urinary decoy cell (DC) and viral DNA detection in urine (viruria) and blood (viremia; active infection). METHODS: Kidney recipients with >1 month follow-up and creatinine >1.5 mg/dL and/or recent increasing >20% (n = 120) had their urine and blood tested for BKV by semi-nested PCR, DC searching, and graft biopsy. PCR-positive patients were classified as 1+, 2+, 3+. DC, viruria and viremia prevalence, sensitivity, specificity, and likelihood ratio (LR) were determined (Table 2x2). Diagnosis efficacy of DC and viruria were compared to viremia. RESULTS: DC prevalence was 25%, viruria 61.7%, and viremia 42.5%. Positive and negative patients in each test had similar clinical, immunosuppressive, and histopathological characteristics. There was no case of viremia with chronic allograft nephropathy and, under treatment with sirolimus, patients had a lower viruria prevalence (p = 0.043). Intense viruria was the single predictive test for active infection (3+; LR = 2.8).1,6-4,9 CONCLUSION: DC, BKV-viruria and -viremia are commun findings under late kidney graft dysfunction. Viremia could only be predicted by intense viruria. These results should be considered under the context of BKN confirmation.

BKV-infection in kidney graft dysfunction

INTRODUCTION: BKV nephropathy (BKN) causes kidney graft loss, whose specific diagnosis is invasive and might be predicted by the early detection of active viral infection. OBJECTIVE: Determine the BKV-infection prevalence in late kidney graft dysfunction by urinary decoy cell (DC) and viral DNA detection in urine (viruria) and blood (viremia; active infection). METHODS: Kidney recipients with >1 month follow-up and creatinine >1.5 mg/dL and/or recent increasing >20 percent (n = 120) had their urine and blood tested for BKV by semi-nested PCR, DC searching, and graft biopsy. PCR-positive patients were classified as 1+, 2+, 3+. DC, viruria and viremia prevalence, sensitivity, specificity, and likelihood ratio (LR) were determined (Table 2x2). Diagnosis efficacy of DC and viruria were compared to viremia. RESULTS: DC prevalence was 25 percent, viruria 61.7 percent, and viremia 42.5 percent. Positive and negative patients in each test had similar clinical, immunossupressive, and histopathological characteristics. There was no case of viremia with chronic allograft nephropathy and, under treatment with sirolimus, patients had a lower viruria prevalence (p = 0.043). Intense viruria was the single predictive test for active infection (3+; LR = 2.8).1,6-4,9 CONCLUSION: DC, BKV-viruria and -viremia are commun findings under late kidney graft dysfunction. Viremia could only be predicted by intense viruria. These results should be considered under the context of BKN confirmation.