No abstract

This case demonstrates the challenge in making a diagnosis. RDD should be considered as a differential diagnosis in case of spinal lesion and non-diagnostic biopsy, especially in steroid sensitive lesions. The implications of the case are discussed.

Studies of the structural and molecular features of the lymphatic vasculature, which clears fluid, macromolecules and leukocytes from the tissue microenvironment, have largely relied on animal models, with limited information in human organs beyond traditional immunohistochemical assessment. Here, we use three-dimensional imaging and single-cell RNA-sequencing to study lymphatics in the human kidney. We found a hierarchical arrangement of lymphatic vessels within human kidneys, initiating along specialised nephron epithelium in the renal cortex and displaying a distinct, kidney-specific transcriptional profile. In chronic transplant rejection we found kidney allograft lymphatic expansion alongside a loss of structural hierarchy, with human leukocyte antigen-expressing lymphatic vessels infiltrating the medulla, presenting a putative target for alloreactive antibodies. This occurred concurrently with lymphatic vessels invading and interconnecting tertiary lymphoid structures at early stages of lymphocyte colonisation. Analysis of intercellular signalling revealed upregulation of co-inhibitory molecule-mediated CD4+ T cell-lymphatic crosstalk in rejecting kidneys, potentially acting to limit local alloimmune responses. Overall, we delineate novel structural and molecular features of human kidney lymphatics and reveal perturbations to their phenotype and transcriptome in the context of alloimmunity.

Background Fumaric acid esters (FAEs) are used to treat chronic plaque psoriasis. Fumarate is a crucial component of the Krebs cycle, and mitochondrial function. Proximal tubule cells have high energy demands, and rely on aerobic respiration. Proximal tubular dysfunction can cause the renal Fanconi syndrome and acute kidney injury. We sought to better understand the mechanism for this in the context of FAE therapy. Methods We describe a case series of 10 patients with FAE-associated Fanconi syndrome. Patients were diagnosed and managed at a tertiary renal tubular disorder clinic, with examination of serum and urine biochemistry. 5 patients had a renal biopsy with examination of the specimens by electron microscopy. Results The median age was 36.5 years (IQR 32.25-54.25 years). The median dose of FAE was 720 mg/day (IQR 390-720mg). There was low molecular weight proteinuria: median urinary retinol binding protein (RBP) at presentation was 8385 μg/ml (IQR 2793-14600μg/ml) and RBP/creatinine ratio was 710 (IQR 390-2415). All patients had hyperphosphaturia (median fractional excretion of phosphate 24.2%, IQR 20.8-26.9%, normal range <20%), as well as relative hypophosphataemia, with a median serum phosphate concentration of 0.93 mmol/L (IQR 0.83-0.97 mmol/L). Renal histology showed proximal tubular damage and abnormal mitochondrial morphology. Two patients had a favourable biochemical response to treatment with probenecid. Conclusions We document for the first time that FAE-associated renal Fanconi syndrome is associated with mitochondrial damage visible on electron microscopy. This effect may be ameliorated by antagonism of the organic anion transporter with probenecid.