Bevacizumab-associated glomerular microangiopathy.

Bevacizumab is a humanized monoclonal IgG1 antibody, which neutralizes vascular endothelial growth factor and is used for treating multiple cancer types. As a known and frequent adverse event, this therapy can lead to renal damage including proteinuria and nephrotic syndrome. In a retrospective approach, we analyzed 17 renal biopsies from patients receiving bevacizumab treatment. We observed a distinctive histopathological pseudothrombotic pattern different from the previously reported thrombotic microangiopathy. Since this pattern includes some features similar to acute and chronic thrombotic microangiopathy, focal segmental glomerulosclerosis and cryoglobulinemic membranoproliferative glomerulonephritis, biopsies with these diagnoses were included for comparison. Clinical, laboratory, light microscopic, immunohistochemical (including a proximity ligation assay), proteomic and electron microscopic features were assessed. Nephrotic syndrome was present in 15 of the 17 bevacizumab-treated patients. All 17 displayed a patchy pattern of variably PAS-positive hyaline pseudothrombi occluding markedly dilated glomerular capillaries in their biopsies. Mass spectrometry-based proteome analysis revealed a special protein pattern demonstrating some features of thrombotic microangiopathy and some of cryoglobulinemic glomerulonephritis, including a strong accumulation of IgG in the pseudothrombi. Proximity ligation assay did not show interaction of IgG with C1q, arguing for accumulation without classic pathway complement activation. In contrast to thrombi in thrombotic microangiopathy cases, the hyaline pseudothrombi did not contain clusters of CD61-positive platelets. Electron microscopy of bevacizumab cases did not show fibrin polymers or extensive loss of podocyte foot processes. Even though cases of bevacizumab-associated microangiopathy share some features with thrombotic microangiopathy, its overall histopathological pattern is quite different from acute or chronic thrombotic microangiopathy cases. We conclude that bevacizumab therapy can lead to a unique hyaline occlusive glomerular microangiopathy, likely arising from endothelial leakage followed by subendothelial accumulation of serum proteins. It can be diagnosed by light microscopy and is an important differential diagnosis in cancer patients with nephrotic syndrome.

Lymphocyte-specific deletion of IKK2 or NEMO mediates an increase in intrarenal Th17 cells and accelerates renal damage in an ischemia-reperfusion injury mouse model.

Acute kidney injury (AKI) is associated with poor patient outcome and a global burden for end-stage renal disease. Ischemia-reperfusion injury (IRI) is one of the major causes of AKI, and experimental work has revealed many details of the inflammatory response in the kidney, such as activation of the NF-κB pathway. Here, we investigated whether deletion of the NF-κB kinases IKK2 or NEMO in lymphocytes or systemic inhibition of IKK2 would cause different kidney inflammatory responses after IRI induction. Serum creatinine, blood urea nitrogen (BUN) level, and renal tubular injury score were significantly increased in CD4creIKK2f/f (CD4xIKK2Δ) and CD4creNEMOf/f (CD4xNEMOΔ) mice compared with CD4cre mice after IRI induction. The frequency of Th17 cells infiltrating the kidneys of CD4xIKK2Δ or CD4xNEMOΔ mice was also significantly increased at all time points. CCL20, an important chemokine in Th17 cell recruitment, was significantly increased at early time points after the induction of IRI. IL-1ß, TNF-α, and CCL2 were also significantly increased in different patterns. A specific IKK2 inhibitor, KINK-1, reduced BUN and serum creatinine compared with nontreated mice after IRI induction, but the frequency of kidney Th17 cells was also significantly increased. In conclusion, although systemic IKK2 inhibition improved kidney function, lymphocyte-specific deletion of IKK2 or NEMO aggravated kidney injury after IRI, and, in both conditions, the percentage of Th17 cells was increased. Our findings demonstrate the critical role of the NF-κB pathway in Th17 activation, which advises caution when using systemic IKK2 inhibitors in patients with kidney injury, since they might impair the T cell response and aggravate renal disease.

A new therapeutic approach with tocilizumab in a 39-year-old patient with recurrent diabetic myonecrosis.

We report the case of a 39-year-old female patient with acute painful swelling of the left thigh and symmetric muscle weakness in both upper legs. The patient had a history of long-standing, poorly controlled type 1 diabetes which required dialysis. Serum inflammatory markers were highly elevated. Magnetic resonance imaging (MRI) indicated necrotic or inflammatory colliquation. As antibiotic therapy did not lead to clinical improvement, a successful anti-inflammatory therapy with prednisolone was initiated. Three months later, the patient presented with a new onset of progressive and painful muscle swelling of the right thigh. MRI showed pronounced swelling of the right adductor muscles and inflammatory markers were massively elevated. In the absence of autoantibodies or any infectious agents and the recurrent symptomatology, relapsing diabetogenic myonecrosis was diagnosed. Initially, clinical improvement could only be achieved with high-dose glucocorticosteroids. Intravenous immunoglobulins did not show an effect, whereas serological and clinical remission was achieved after we administered tocilizumab intravenously. Diabetic myonecrosis is a rare complication of long-term, poorly controlled diabetes mellitus. Acute muscle pain and elevated inflammatory markers should prompt suspicion. Contralateral muscle involvement is also suggestive of the disease. The optimisation of diabetes treatment is crucial in order to prevent further disease complications.

Neoplasia de células dendríticas plasmocitoides blásticas: presentación de dos casos y revisión de la literatura / Blastic plasmacytoid dendritic cell neoplasm: a report of de cases and review od the literature

Los carcinomas basocelulares gigantes (CBCG) son muy poco frecuentes. Se los puede definir como aquellos mayores de 5 cm de diámetro. La mayoría de estos pacientes no refiere antecedentes deexposición crónica al sol ni presentan otros factores de riesgo conocidos. Existe en cambio una relación estrecha con situaciones de negligencia y tratamientos inadecuados. Se los encuentra frecuentemente en el tronco. Las lesiones mayores de 10 cm de diámetro tienen un alto riesgo de generar metástasis y en consecuencia producir la muerte. Presentamos una paciente de 92 años con dos masas tumorales en área malar y mejilla derecha que fue tratada quirúrgicamente, con buena evolución hasta los dos años de seguimiento posterior.

CD4+ / CD56 malignancy is an extremely rare hematological neoplasm, which was recentlyshown to correspond to the so-called type 2 dendritic cell or plasmacytoid dendritic cell. Clinicalpresentation typically correspond to cutaneous nodules o tumors associated with lymphadenopathyor spleen enlargement or both, cytopenias and circulating malignant cells. The prognosis is rapidlyfatal in the absence of chemotherapy. Bone marrow transplantation is the best option available. Wepresent two new cases of this disease.