Search

The mortality rate for septic patients with acute renal failure is extremely high. Since sepsis is often caused by lipopolysaccharide (LPS), a model of LPS challenge was used to study the development of kidney injury. Intravital video microscopy was utilized to investigate renal peritubular capillary blood flow in anesthetized male C57BL/6 mice at 0, 2, 6, 10, 18, 24, 36, and 48 h after LPS administration (10 mg/kg ip). As early as 2 h, capillary perfusion was dramatically compromised. Vessels with continuous flow were decreased from 89 [+ or -] 4% in saline controls to 57 [+ or -] 5% in LPS-treated mice (P < 0.01), and vessels with intermittent flow were increased from 6 [+ or -] 2% to 31 [+ or -] 5% (P < 0.01). At 2 h, mRNA for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were elevated 50- and 27-fold, respectively, suggesting that vascular inflammation is an early event that may contribute to capillary dysfunction. By 10 h, vessels with no flow increased from 5 [+ or -] 2% in saline controls to 19 [+ or -] 3% in LPS-treated mice (P < 0.05). By 48 h, capillary function was returning toward control levels. The decline in functional capillaries preceded the development of renal failure and was paralleled by induction of inducible nitric oxide synthase in the kidney. Using NAD(P)H autofluorescence as an indicator of cellular redox stress, we found that tubular cell stress was highly correlated with the percentage of dysfunctional capillaries ([r.sup.2] = 0.8951, P < 0.0001). These data show that peritubular capillary dysfunction is an early event that contributes to tubular stress and renal injury. intravital video microscopy; sepsis; inducible nitric oxide synthase; intercellular adhesion molecule-1; vascular cell adhesion molecule-1

Recently, we demonstrated that peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha]) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990-F998, 2004). In the following studies, we examined the protective effect of PPAR[alpha] ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-[micro] RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPAR[alpha] ligands, before cisplatin signifcantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPAR[alpha] ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPAR[alpha] null mice. In addition, we observed that cisplatin-induced NF-[kappa]B binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPAR[alpha] ligand. These results demonstrate that PPAR[alpha] exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-[kappa]B DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF. peroxisome proliferator-activated receptor-[alpha]; inflammation; cisplatin; acute renal failure

PPAR-[alpha] ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G. Am J Physiol Renal Physiol 287: F990-F998, 2004. First published July 27, 2004; doi:10.1152/ajprenal.00206.2004.--Cisplatin injury to the kidney is characterized, in part, by inhibition of substrate oxidation, inflammation, and tubular cell death in the form of apoptosis and necrosis. Recently, we demonstrated that cisplatin-induced inhibition of substrate oxidation can be reversed by the administration of peroxisome proliferator-activated receptor-[alpha] (PPAR-[alpha]) ligands, resulting in amelioration of renal function. We therefore hypothesize that by improving fatty acid oxidation in vivo might protect renal function by reducing both apoptosis and necrosis in cisplatin-treated mice. Mice subjected to a single intraperitoneal injection of cisplatin developed acute renal failure (ARF) at days 3 and 4. At day 4 after cisplatin injection mRNA, protein levels and enzyme activity of proapoptotic renal endonuclease G (Endo G) were increased compared with saline-treated mice. In situ hybridization and immunohistochemical studies localized the increased expression of Endo G mRNA to the cytosolic compartment and Endo G protein to the nuclear compartment of proximal tubules in cisplatin-treated mice. Pretreatment of PPAR-[alpha] wild-type mice with PPAR-[alpha] ligand WY-14643 reduced significantly cisplatin-induced increased protein expression and enzyme activity of Endo G and prevented the nuclear translocation of mitochondrial Endo G. Morphological examination of tubular injury in the PPAR-[alpha] wild-type mice that received PPAR-[alpha] ligand and cisplatin did show significant amelioration of acute tubular necrosis, as well as a significant reduction in the number of apoptotic cells in the proximal tubule when compared with the cisplatin-treated group. In contrast, in PPAR[alpha]-null mice treated with the ligand and cisplatin, Endo G protein expression was not reduced and this was accompanied by lack of protection of kidney function. We conclude that PPAR-[alpha] ligand protects against cisplatin-induced renal injury via a PPAR-[alpha]-dependent mechanism by reducing the expression and enzyme activity of proximal tubule Endo G, which results in amelioration of both proximal tubule cell apoptosis and necrosis. peroxisome proliferator-activated receptor-[alpha]; fatty acid oxidation

Pembrolizumab, a selective anti-PD-1 humanized monoclonal antibody, reactivates T cells to fight cancer. Immune-related adverse events such as autoimmune colitis, pneumonitis, hepatitis, nephritis, hypophysitis, and thyroiditis may occur during, or weeks to months after therapy. Pemprolizumab-induced synovitis is rarely reported. With the wide use of immunotherapy to treat cancers, physicians need to be aware of this rare immune-related adverse event and provide immediate treatment to avoid permanent joint damage. [ABSTRACT FROM AUTHOR]

Mixed epithelial stromal tumor (MEST) is rare and typically benign renal cystic neoplasm that cannot be clinically distinguished from cystic renal cell carcinoma. Its mainstay course of diagnosis and treatment remains surgical excision. Recurrence and malignant transformation is rare but has previously been described. To our best knowledge, we present the first case of peritoneal seeding resulting in a paracolonic MEST following incomplete resection in a patient with benign MEST. This signifies a new pathological behavior for MEST, predominantly, a benign kidney tumor. In addition, documentation with more cases of MEST is needed to further understand its pathogenesis, clinical behavior, malignant potential, and optimal management. [ABSTRACT FROM AUTHOR]