Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review

Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations

Sepsis-associated Acute Kidney Injury

Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. Interestingly, sepsis mortality increases with acute kidney injury (AKI) and patients with AKI worsen with sepsis. It is interesting to note that most of the clinical trials on sepsis treatment that derived from the results of translational researches are a failure. This is, in part, because of the complexity of human sepsis in comparison with animal models. Another reason for the failure-translation might be the improper matching of the animal models to the individual patient. It is possible that the main mechanism of sepsis induction in each patient with the variety causes of sepsis might be different. Indeed, immune response to sepsis depends on genetic background, route of immune activation, and organisms. Thus, sepsis treatment classified by “mechanistic approach” to individual patient might be more proper than the classification with “sepsis severity”. Specific treatment of sepsis in individual patient according to the specific immune response characteristic might be a more proper translational strategy. Indeed, the understanding in immune response pattern of sepsis and sepsis pathophysiology is necessary for “sepsis mechanistic approach”. Then, we conclude most of the topics and our hypothesis regarding SA-AKI in this review

Neutrophil Extracellular Traps in Severe SARS-CoV-2 Infection: A Possible Impact of LPS and (1→3)-β-D-glucan in Blood from Gut Translocation.

Due to limited data on the link between gut barrier defects (leaky gut) and neutrophil extracellular traps (NETs) in coronavirus disease 2019 (COVID-19), blood samples of COVID-19 cases-mild (upper respiratory tract symptoms without pneumonia; n = 27), moderate (pneumonia without hypoxia; n = 28), and severe (pneumonia with hypoxia; n = 20)-versus healthy control (n = 15) were evaluated, together with in vitro experiments. Accordingly, neutrophil counts, serum cytokines (IL-6 and IL-8), lipopolysaccharide (LPS), bacteria-free DNA, and NETs parameters (fluorescent-stained nuclear morphology, dsDNA, neutrophil elastase, histone-DNA complex, and myeloperoxidase-DNA complex) were found to differentiate COVID-19 severity, whereas serum (1→3)-β-D-glucan (BG) was different between the control and COVID-19 cases. Despite non-detectable bacteria-free DNA in the blood of healthy volunteers, using blood bacteriome analysis, proteobacterial DNA was similarly predominant in both control and COVID-19 cases (all severities). In parallel, only COVID-19 samples from moderate and severe cases, but not mild cases, were activated in vitro NETs, as determined by supernatant dsDNA, Peptidyl Arginine Deiminase 4, and nuclear morphology. With neutrophil experiments, LPS plus BG (LPS + BG) more prominently induced NETs, cytokines, NFκB, and reactive oxygen species, when compared with the activation by each molecule alone. In conclusion, pathogen molecules (LPS and BG) from gut translocation along with neutrophilia and cytokinemia in COVID-19-activated, NETs-induced hyperinflammation

Innate Immunity Response to BK Virus Infection in Polyomavirus-Associated Nephropathy in Kidney Transplant Recipients

BK polyomavirus (BKV) mainly causes infection in uroepithelial and renal tubular epithelial cells of either immunocompetent or immunocompromised hosts. Despite asymptomatic or mild clinical features in immunocompetent hosts with BK infection, serious complications are frequently found in immunocompromised patients, especially patients with kidney transplantation. Accordingly, BKV-associated nephropathy (BKVN) demonstrates a wide range of clinical manifestations, including ureteric stenosis and hemorrhagic cystitis. In addition, BKV re-infection in post-kidney transplantation is also a main cause of kidney allograft dysfunction and graft loss. Since the direct anti-BKV is unavailable, immune response against BKV infection is the main mechanism for organism control and might be a novel strategy to treat or suppress BKV. As such, the innate immunity, consisting of immune cells and soluble molecules, does not only suppress BKV but also enhances the subsequent adaptive immunity to eradicate the virus. Furthermore, the re-activation of BKV in BKVN of kidney-transplanted recipients seems to be related to the status of innate immunity. Therefore, this review aims to collate the most recent knowledge of innate immune response against BKV and the association between the innate immunity status of kidney-transplanted recipients and BKV re-activation

Innate Immunity Response to BK Virus Infection in Polyomavirus-Associated Nephropathy in Kidney Transplant Recipients

BK polyomavirus (BKV) mainly causes infection in uroepithelial and renal tubular epithelial cells of either immunocompetent or immunocompromised hosts. Despite asymptomatic or mild clinical features in immunocompetent hosts with BK infection, serious complications are frequently found in immunocompromised patients, especially patients with kidney transplantation. Accordingly, BKV-associated nephropathy (BKVN) demonstrates a wide range of clinical manifestations, including ureteric stenosis and hemorrhagic cystitis. In addition, BKV re-infection in post-kidney transplantation is also a main cause of kidney allograft dysfunction and graft loss. Since the direct anti-BKV is unavailable, immune response against BKV infection is the main mechanism for organism control and might be a novel strategy to treat or suppress BKV. As such, the innate immunity, consisting of immune cells and soluble molecules, does not only suppress BKV but also enhances the subsequent adaptive immunity to eradicate the virus. Furthermore, the re-activation of BKV in BKVN of kidney-transplanted recipients seems to be related to the status of innate immunity. Therefore, this review aims to collate the most recent knowledge of innate immune response against BKV and the association between the innate immunity status of kidney-transplanted recipients and BKV re-activation

Comparative Long-Term Renal Allograft Outcomes of Recurrent Immunoglobulin A with Severe Activity in Kidney Transplant Recipients with and without Rituximab: An Observational Cohort Study

Recurrent IgA nephropathy (IgAN) remains an important cause of allograft loss in renal transplantation. Due to the limited efficacy of corticosteroid in the treatment of recurrent glomerulonephritis, rituximab was used in kidney transplant (KT) recipients with severe recurrent IgAN. A retrospective cohort study was conducted between January 2015 and December 2020. Accordingly, there were 64 KT recipients with biopsy-proven recurrent IgAN with similar baseline characteristics that were treated with the conventional standard therapy alone (controls, n = 43) or together with rituximab (cases, n = 21). All of the recipients had glomerular endocapillary hypercellularity and proteinuria (>1 g/d) with creatinine clearance (CrCl) > 30 mL/min/1.73 m2 and well-controlled blood pressure using renin–angiotensin–aldosterone blockers. The treatment outcomes were renal allograft survival rate, proteinuria, and post-treatment allograft pathology. During 3.8 years of follow-up, the rituximab-based regimen rapidly decreased proteinuria within 12 months after rituximab administration and maintained renal allograft function—the primary endpoint—for approximately 3 years. There were eight recipients in the case group (38%), and none in the control group reached a complete remission (proteinuria < 250 mg/d) at 12 months after treatment. Notably, renal allograft histopathology from patients with rituximab-based regimen showed the less severe endocapillary hypercellularity despite the remaining strong IgA deposition. In conclusion, adjunctive treatment with rituximab potentially demonstrated favorable outcomes for treatment of recurrent severe IgAN post-KT as demonstrated by proteinuria reduction and renal allograft function in our cohort. Further in-depth mechanistic studies with the longer follow-up periods are recommended

Going Micro in Leptospirosis Kidney Disease

Leptospirosis is a zoonotic and waterborne disease worldwide. It is a neglected infectious disease caused by Leptospira spp., as well as a reemerging disease and global public health problem with respect to morbidity and mortality both in humans and animals. Leptospirosis emerges as a leading cause of acute febrile illness along with hepatorenal injury in many countries, including Thailand. While most affected persons are symptomatic in acute disease, which is always difficult to differentiate from other tropical diseases, there is growing evidence of subtle manifestations that cause unrecognized chronic symptoms. The kidney is one of the common organs affected by Leptospires. Although acute kidney injury in the spectrum of interstitial nephritis is a well-described characteristic in severe leptospirosis, chronic kidney disease from leptospirosis is widely discussed. Early recognition of severe leptospirosis leads to reduce morbidity and mortality. Thus, in this review, we highlight the spectrum of characteristics involved in leptospirosis kidney disease and the use of serologic and molecular methods, as well as the treatments of severe leptospirosis

Going micro in leptospirosis kidney disease

Leptospirosis is a zoonotic and waterborne disease worldwide. It is a neglected infectious disease caused by Leptospira spp., as well as a reemerging disease and global public health problem with respect to morbidity and mortality both in humans and animals. Leptospirosis emerges as a leading cause of acute febrile illness along with hepatorenal injury in many countries, including Thailand. While most affected persons are symptomatic in acute disease, which is always difficult to differentiate from other tropical diseases, there is growing evidence of subtle manifestations that cause unrecognized chronic symptoms. The kidney is one of the common organs affected by Leptospires. Although acute kidney injury in the spectrum of interstitial nephritis is a well-described characteristic in severe leptospirosis, chronic kidney disease from leptospirosis is widely discussed. Early recognition of severe leptospirosis leads to reduce morbidity and mortality. Thus, in this review, we highlight the spectrum of characteristics involved in leptospirosis kidney disease and the use of serologic and molecular methods, as well as the treatments of severe leptospirosis