Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy.

BACKGROUND: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. METHODS: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. FINDINGS: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples. INTERPRETATION: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. FUNDING: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].

Vaccine: friend or foe? Double seropositive vasculitis following influenza vaccination.

Administration of the influenza vaccine has been associated with development of several autoimmune phenomena. We describe the case of a 72-year-old male who developed double seropositive vasculitis following seasonal influenza vaccination. On presentation, he was positive for both myeloperoxidase anti-neutrophil cytoplasmic antibody and anti-glomerular basement membrane antibody. He had stage three acute kidney injury requiring dialysis and was treated with methylprednisolone, intravenous cyclophosphamide and plasma exchange. He was also noted to have an incidental seven centimetre abdominal aortic aneurysm. He achieved remission with recovery in renal function and became haemodialysis independent. We hypothesize that the temporal relationship between influenza vaccination and double seropositive vasculitis directly triggered a systemic immune response in a susceptible patient, although a causal relationship cannot be proved. To the best of our knowledge, this is the first case of double seropositive vasculitis occurring in close temporal association with seasonal influenza vaccination.

Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation.

Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.

Cardiorenal syndrome: review of our current understanding.

Renal and cardiac diseases are both prevalent and carry significant morbidity and mortality. They share common vascular risk factors and are physiologically interlinked. Dysfunction in one organ affects the other. Concurrent renal and cardiac disease is associated with a poor prognosis. This close relationship is reflected through cardiorenal syndrome. A classification system has been proposed; however, the underlying process is complex and multifactorial. Management of this syndrome focuses on improving heart function, reducing volume overload, and managing heart failure and chronic kidney disease. This, however, is challenging, limited by paucity of evidence and may lead to suboptimal therapy. Increased recognition of this syndrome should raise awareness in providing early therapy and avoiding adverse outcomes due to under-treatment. In this article, we provide an overview of our current understanding of cardiorenal syndrome, as well as its pathophysiology and treatment options.

Nephrotic and anti-phospholipid syndromes: multisystem conditions associated with acute myocardial infarction in young patients.

Acute myocardial infarction is relatively uncommon in patients under the age of 40 years. Unlike the older patients where rupture of coronary artery atherosclerotic plaque is the main underlying pathology, the pathogenesis in younger patients can be varied and may require different diagnostic and therapeutic approaches. Hypercoagulable state associated with nephrotic syndrome and antiphospholipid syndrome can lead to the development of occlusive coronary artery thrombus in absence of atherosclerotic coronary artery disease. Acute myocardial infarction in such a setting can sometimes be the first manifestation of an underlying disease. We describe a case of myocardial infarction in a young man with both nephrotic and antiphospho-lipid syndromes and present a brief literature review.

Rapid development of renal failure secondary to AA-type amyloidosis in a patient with polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a common chronic inflammatory disorder affecting patients over the age of 50. Renal involvement in PMR is extremely rare and very few cases of AA amyloidosis secondary to PMR have been described in literature. We present a case of a patient with history PMR who developed nephrotic range proteinuria and rapidly deteriorating renal function secondary to AA amyloidosis within 18 months of the onset of symptoms of PMR. This case reinforces the association of PMR with secondary AA amyloidosis and highlights the importance of monitoring renal function in patients with PMR.