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Background Acute interstitial nephritis (AIN) related to immune checkpoint inhibitors (ICI-AIN) has a not completely understood pathophysiology. Our objectives were to analyze possible biomarkers for the differentiation between acute tubular necrosis (ATN) and AIN, especially in cancer patients, and to study the participation of the immune checkpoint pathway in ICI-AIN. Methods We performed an observational study. We recruited patients with incident diagnosis of ICI-AIN (n  = 19). We measured soluble PD-1 (sPD-1), sPD-L1, and sPD-L2 in serum and urine at diagnosis and compared to it patients with non-ICI-related AIN (non-ICI-AIN) (n  = 18) and ATN (n  = 21). The findings were validated in an independent cohort from another institution (n  = 30). Also, we performed PD-L1 and PD-L2 immunostaining of kidney biopsies from patients with ICI-AIN and compared to patients with non-ICI-AIN. Results Urinary sPD-1 (usPD-1) was higher in patients with AIN compared to ATN (P  = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN (P  = .021).  In cancer patients, usPD-1 <129.3 pg/ml had a 71.43% sensitivity and 94.44% specificity to differentiate ATN from ICI-AIN, with a likelihood ratio of 12.86. In the external validation cohort, the same cutoff showed a sensitivity of 80%.  In kidney biopsies, patients with ICI-AIN showed higher density of PD-L1 positive tubules than patients with non-ICI-AIN (P  = .02). The proportion of patients having >2.64/mm2 PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN (P  = .034). There was a positive correlation (P  = .009, r  = 0.72) between usPD-1 and the number of PD-L1 positive tubules. Conclusions UsPD-1 and ssPD-1 are higher in AIN than ATN. Moreover, there was a strong correlation between usPD-1 and renal tubular PD-L1 expression. Our findings suggest a role of usPD-1 as non-invasive biomarker to differentiate ICI-AIN from ATN, especially in cancer patients, which has been confirmed in an external validation cohort. [ABSTRACT FROM AUTHOR]

With the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies are describing cases of glomerulonephritis arising after vaccination. We present the first case of a kidney transplant patient who, after mRNA vaccination against SARS-CoV-2, developed nephrotic proteinuria and renal dysfunction, with a biopsy diagnostic of collapsing glomerulonephritis. No other triggers for this glomerulonephritis were identified. Antibodies against the spike protein were negative, but the patient developed a specific T-cell response. The close time between vaccination and the proteinuria suggests a possible determinant role of vaccination. We should be aware of nephropathies appearing after COVID-19 vaccination in kidney transplant recipients also. [ABSTRACT FROM AUTHOR]

Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (CYP3A4*22 / CYP3A5*3) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99–79.36, p = 0.007, and HR 4.532, 95% CI 1.10–18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99–6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63–11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22–3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08–0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making. [ABSTRACT FROM AUTHOR]

Background Immunoglobulin G4-related disease (IgG4-RD) is a fibro-inflammatory, immune-mediated disorder, which characteristically affects the glandular tissue but has the potential to affect any organ. Methods We retrospectively reviewed clinical, laboratory, histological characteristics and treatment response during 12 months of follow-up of a cohort of patients with IgG4-RD diagnosed at a tertiary public hospital. Disease activity was assessed by means of the IgG4-RD responder index (IgG4-RD RI). Results In all, 15 patients have been diagnosed at our Institution and herein studied (80% men), with a median age of 60.7 years and a mean affectation of 2.8 organs per patient. We identified six patients with definitive diagnosis and nine with possible IgG4-RD, according to the Japanese diagnostic algorithm. IgG4-RD RI decreased from a median of 11.3 at baseline to 4.0 after 6 months and 6.2 after 12 months. Relapse occurred in five patients and was associated with lower cumulative steroid doses. Five patients (33.3%) required additional immunosuppressive (IS) drugs. Five adverse events were seen during follow-up: three infections, one deep vein thrombosis and one gastrointestinal bleeding. One patient died of pneumonia. Conclusions IgG4-RD is an inflammatory disease that can affect any organ. Glucocorticoids were an effective first line of treatment; however, this treatment is associated with important adverse events and relapses occurred in patients with low cumulative doses. As an alternative, IS treatment with rituximab could be an interesting option in those patients. [ABSTRACT FROM AUTHOR]

Choroidal melanoma may arise de novo or transformed from a previously existing nevus. Modern cytogenetical techniques allow us to determine and classify the genetic aberrations of such tumors. We report a case of a 55-year-old man presenting a malignant transformation of a previously known choroidal nevus in his right eye. Nine years earlier, that same eye was treated with brachytherapy for a malignant melanoma. Enucleation was indicated followed by histopathological study as well as gene mutation analysis of the tumor cells. The second melanoma was anatomically independent from the first one, discarding the possibility of spreading. Cytogenetical study resulted in significant loss of the short arm of chromosome 1 and the long arm of chromosome 3. Only 21 cases of multiple uveal melanoma in the same eye are reported in the literature. To our knowledge this is the first cytogenetical report of one of such cases. It highlights the importance of follow-up in these patients, especially when risk factors like a choroidal naevus are present. [ABSTRACT FROM AUTHOR]

Acute kidney injury in patients who suffer a malignancy is a common complication. Due to its high prevalence and effective treatment, one of the most frequent causes that both oncologists and nephrologists must be aware of is acute tubulointerstitial nephritis (ATIN). ATIN is an immunomediated condition and the hallmark of the disease, with the presence of a tubulointerstitial inflammatory infiltrate in the renal parenchyma. This infiltrate is composed mainly of T lymphocytes that can be accompanied by macrophages, neutrophils, or eosinophils among other cells. One of the major causes is drug-related ATIN, and some antineoplastic treatments have been related to this condition. Worthy of note are the novel immunotherapy treatments aimed at enhancing natural immunity in order to defeat cancer cells. In the context of the immunosuppression status affecting ATIN patients, some pathogen antigens can trigger the development of the disease. Finally, hematological malignancies can also manifest in the kidney leading to ATIN, even at the debut of the disease. In this review, we aim to comprehensively examine differential diagnosis of ATIN in the setting of a neoplastic patient. [ABSTRACT FROM AUTHOR]

Background: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.Methods: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16INK4a/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC.Results: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16INK4a, HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16INK4a, respectively. Being non-smoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16INK4a showed strongest diagnostic accuracy and prognostic value.Conclusions: Double positivity for HPV-DNA/p16INK4a, a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly. [ABSTRACT FROM AUTHOR]