Fine-tuning tumor- and allo-immunity: advances in the use of immune checkpoint inhibitors in kidney transplant recipients.

Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.

Occurrence of Fatal Tubulopathy in an Old, Fit Patient Receiving Nivolumab and Ipilimumab for Metastatic Melanoma: A Case Report.

Introduction: The use of immune checkpoint inhibitors has revolutionized cancer treatment, and their application to older people is considered safe by the scientific community. However, immune-related adverse events (irAEs) remain common, and their management poses significant challenges, especially in this population. Case Presentation: We report the case of a fit 82-year-old woman who developed immune-mediated colitis and Fanconi syndrome during treatment with ipilimumab and nivolumab for metastatic melanoma. Treatment consisted of discontinuation of immunotherapy, use of systemic corticosteroids, and second-line immunosuppressants. Despite well-managed treatment, the patient did not recover and died from a gastrointestinal infection. Conclusion: Although studies have shown identical efficacy and safety in younger patients compared to older patients, the consequences of irAEs can potentially be more serious in the older population. The fatal outcome despite well-managed treatment highlights the need to identify predictive factors of immunotherapy-related adverse events in the older population.

Regulation of CD8 T cell by B-cells: A narrative review.

Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.

Apixaban Prophylactic Anticoagulation in Patients with Nephrotic Syndrome.

Background Nephrotic syndrome (NS) is associated with an increased risk of thromboembolic events (TEs), due to hemostatic derangements. The use of direct oral anticoagulants (DOACs) in the prevention of TE has not been studied intensively in patients suffering from NS. Methods The method included retrospective analysis of consecutive incident patients with NS due to glomerular disease, receiving apixaban for thromboprophylaxis. It is an uncontrolled, single-center study. Results We identified 27 patients treated with apixaban for the prevention of TEs, in the context of NS. During follow-up, apixaban minimal blood concentration (trough level; Cmin) and maximum blood concentration (Cmax) levels were measured. The mean duration of the anticoagulant treatment was 153 days (±132). Patients were followed for a mean of 14.7 months (±8.4) since the introduction of apixaban. Three patients had a TE at the time of NS diagnosis. Two patients had pulmonary embolism (PE) and one patient presented a stroke in a lupus membranous nephropathy context. One patient developed PE approximately 2 months after the introduction of apixaban treatment. No minor or major bleeding events were noticed. Conclusion The present study shows that patients, suffering from severe NS under anticoagulant therapy with apixaban had a reduced risk of venous and arterial TEs compared with patients previously described in the literature, without increased risk of bleeding.

Systemic generalised lymphangiomatosis: unknown aetiology and a challenge to treat.

We describe a case of a woman diagnosed at the age of 35 years with a generalised mediastinal and abdominal lymphangiomatosis associated with a protein losing enteropathy, who successfully improved when treatment with sirolimus was initiated.

Long-Term Treatment with Calcitriol in Postsurgical Hypoparathyroidism Leads to Renal Function Decline.

Hypoparathyroidism is a rare endocrine disease with insufficient parathyroid hormone levels. Replacing the missing hormone is not yet a standard therapy. The objective of this retrospective cohort study was to evaluate if the usual therapy regimens of postsurgical hypoparathyroidism with calcitriol have a negative effect on renal function. We performed a chart analysis of patients who were seen in a tertiary care hospital in Brussels, Belgium. A total of 101 subjects were identified as patients with permanent post-surgical hypoparathyroidism, based on the hospital records of patients who underwent a total thyroidectomy between 1996 and 2016, while still being treated with calcitriol. Patients with pre-existing renal insufficiency and/or active malignancy were excluded. The cohort was predominantly female of Caucasian origin. Renal function was evaluated before and after surgery (with a maximum follow-up of 12 years), using the CKD-EPI equation. A multivariate linear regression model was used to correlate renal function decline with the duration of calcitriol therapy, while correcting for the mean calcium phosphate product and age. We found a statistically significant (p=0.027) relationship between the duration of calcitriol treatment and renal function decline at a rate of 1.06 ml/min/1.73 m2 per year of calcitriol therapy. Our study, although being retrospective, is the first one to demonstrate a relationship between the cumulative use of calcitriol therapy and renal function decline.

Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients.

OBJECTIVES: To characterize renin in critically ill patients. Renin is fundamental to circulatory homeostasis and could be a useful marker of tissue-perfusion. However, diurnal variation, continuous renal replacement therapy and drug-interference could confound its use in critical care practice. DESIGN: Prospective observational study. SETTING: Single-center, mixed medical-surgical ICU in Europe. PATIENTS: Patients over 18 years old with a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m and anticipated ICU stay greater than 24 hours. Informed consent was obtained from the patient or next-of-kin. INTERVENTIONS: Direct plasma renin was measured in samples drawn 6-hourly from arterial catheters in recumbent patients and from extracorporeal continuous renal replacement therapy circuits. Physiologic variables and use of drugs that act on the renin-angiotensin-aldosterone system were recorded prospectively. Routine lactate measurements were used for comparison. MEASUREMENTS AND MAIN RESULTS: One-hundred twelve arterial samples (n = 112) were drawn from 20 patients (65% male; mean ± SD, 60 ± 14 yr old) with septic shock (30%), hemorrhagic shock (15%), cardiogenic shock (20%), or no circulatory shock (35%). The ICU mortality rate was 30%. Renin correlated significantly with urine output (repeated-measures correlation coefficient = -0.29; p = 0.015) and mean arterial blood pressure (repeated-measures correlation coefficient = -0.35; p < 0.001). There was no diurnal variation of renin or significant interaction of renin-angiotensin-aldosterone system drugs with renin in this population. Continuous renal replacement therapy renin removal was negligible (mass clearance ± SD 4% ± 4.3%). There was a significant difference in the rate of change of renin over time between survivors and nonsurvivors (-32 ± 26 µU/timepoint vs +92 ± 57 µU/timepoint p = 0.03; mean ± SEM), but not for lactate (-0.14 ± 0.04 mM/timepoint vs +0.15 ± 0.21 mM/timepoint; p = 0.07). Maximum renin achieved significant prognostic value for ICU mortality (receiver operator curve area under the curve 0.80; p = 0.04), whereas maximum lactate did not (receiver operator curve area under the curve, 0.70; p = 0.17). CONCLUSIONS: In an heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. Renin served as a marker of tissue-perfusion and outperformed lactate as a predictor of ICU mortality.

Platypnea-orthodeoxia syndrome: an unusual presentation of a complex disease.

BACKGROUND: Platypnea-orthodeoxia syndrome (POS) is an uncommon disorder characterized by dyspnea (=platypnea) and desaturation (=orthodeoxia) in upright position and improvement of symptoms and blood oxygenation in supine position. Clinical presentation is heterogeneous and often confuses the clinician. OBJECTIVES: The present case report illustrates a complicated presentation of the underlying syndrome. METHODS: Description of a POS case in a 73-year-old female with thorough workup and tailored treatment. RESULTS: In this case report, we describe a rather unusual presentation of POS, with posture-dependent hypoxemic-induced psychiatric symptoms. Further investigations revealed the presence of a patent foramen ovale with atrial septum aneurysm, an aortic root dilatation up to 41 mm and bilateral lower lobe lung emboli. The ventilation-perfusion mismatch aggravated the desaturation in upright position. Since the patient remained symptomatic after treatment of the functional trigger, we choose for the percutaneous closure of the anatomical defect. We used an Occlutech Figulla Flex II UNI 33/33 mm occluder resulting in a perfect closure of the defect. CONCLUSION: Abnormal shunting in upright position may be the result of different underlying conditions, requiring a thorough workup and a tailored treatment. In case of serious co-morbid conditions, an endovascular procedure to close a patent foramen ovale, after unsuccessful treatment of precipitating conditions, should be considered.