piperidines and Nephritis--Interstitial

Few cases of immunoallergic tubulointerstitial nephritis associated with tyrosine kinase inhibitors have been described. We describe the first report case associated with vandetanib, a tyrosine kinase inhibitor indicated for the treatment of aggressive and symptomatic medullary thyroid cancer (CMT) in patients with locally advanced or metastatic non-resectable disease.

Topics: Aged; Humans; Male; Nephritis, Interstitial; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m

Topics: Acute Kidney Injury; Adenine; Aged; Cytokines; Glucocorticoids; Humans; Kidney; Leukemia, Prolymphocytic; Male; Nephritis, Interstitial; Piperidines; Protein Kinase Inhibitors; Proteinuria

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

Topics: Animals; Antigens, Differentiation; Arginase; Atrophy; Benzoxazines; Chemokine CCL2; Cytoprotection; Disease Models, Animal; Hypertension, Renovascular; Kidney; Lectins, C-Type; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Nephritis, Interstitial; Nitric Oxide Synthase Type II; Piperidines; Protective Agents; Receptors, CCR2; Receptors, Cell Surface; Renal Artery Obstruction; Signal Transduction; Time Factors

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-β1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Topics: Acute Disease; Animals; Arachidonic Acids; Cells, Cultured; Chemokine CCL2; Collagen; Diabetes Mellitus; Disease Models, Animal; Endocannabinoids; Fibrosis; Gene Expression Profiling; Glomerulonephritis, IGA; Glycerides; Humans; Kidney; Ligands; Macrophages; Mice; Mice, Knockout; Myofibroblasts; Nephritis, Interstitial; Oligonucleotide Array Sequence Analysis; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; RNA, Messenger; Transforming Growth Factor beta1; Up-Regulation; Ureteral Obstruction

CC chemokines mediate leukocyte infiltration into inflamed tissue. We have recently shown that blockade of the CC chemokine receptor CCR1 reduces interstitial inflammation and fibrosis in murine obstructive nephropathy. However, it is not known whether CCR 1 blockade is protective in progressive renal injury associated with severe proteinuria. We therefore studied the effect of the small-molecule CCR1 antagonist BX471 in a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome and progressive interstitial inflammation and fibrosis.. Adriamycin nephropathy with persistent proteinuria was induced in male BALB/c mice by two intravenous injections of adriamycin (13 mg/kg) at day 0 and 14. BX471 treatment was started at day 14 when proteinuria and interstitial inflammation had developed. At 6 weeks, renal histology was studied by morphometry and immunohistochemistry.. At week 6, adriamycin-treated mice showed FSGS, associated with tubulointerstitial injury consisting of tubular dilation and atrophy, interstitial leukocyte infiltration, and fibrosis. The mRNA expression of CCR1 and CC chemokines, including the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES), was up-regulated in diseased kidneys, with a prominent interstitial expression of CCL5. Compared to vehicle-treated controls BX471 significantly reduced the amount of macrophages and T lymphocytes in interstitial lesions by 51% and 22%, respectively. Markers of renal fibrosis such as interstitial fibroblasts (48%) and interstitial volume (23%) were significantly reduced by BX471 treatment. In contrast, the extent of proteinuria and glomerular sclerosis was not affected by BX471 treatment.. Blockade of CCR1 substantially reduced interstitial leukocyte accumulation and the subsequent renal fibrosis in a murine model of nephrotic syndrome and FSGS. These findings support a role for CCR1 in interstitial leukocyte recruitment and suggest that CCR1 blockade might be a new therapeutic strategy in progressive nephropathies such as FSGS.

Topics: Animals; Antibiotics, Antineoplastic; Chemokines; Doxorubicin; Fibrosis; Glomerulosclerosis, Focal Segmental; Kidney; Leukocytes; Male; Mice; Mice, Inbred BALB C; Nephritis, Interstitial; Nephrotic Syndrome; Phenylurea Compounds; Piperidines; Proteinuria; Receptors, CCR1; Receptors, Chemokine