Safety and efficacy of skin patches containing loxoprofen sodium in diabetic patients with overt nephropathy.

BACKGROUND: Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. METHODS: Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. RESULTS: The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. CONCLUSIONS: Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.

Oleate and eicosapentaenoic acid attenuate palmitate-induced inflammation and apoptosis in renal proximal tubular cell.

Free fatty acid (FFA)-bound albumin, which is filtrated through the glomeruli and reabsorbed into proximal tubular cells, is one of the crucial mediators of tubular damage in proteinuric kidney disease. In this study, we examined the role of each kind of FFA on renal tubular damage in vitro and tried to identify its molecular mechanism. In cultured proximal tubular cells, a saturated fatty acid, palmiate, increased the expression of monocyte chemoattractant protein-1 (MCP-1), but this effect was abrogated by co-incubation of monounsaturated fatty acid, oleate, or ω-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). Palmitate led to intracellular accumulation of diacylglycerol (DAG) and subsequent activation of protein kinase C protein family. Among the several PKC inhibitors, rottlerin, a PKCθ inhibitor, prevented palmitate-induced MCP-1 expression via inactivation of NFB pathway. Overexpression of dominant-negative PKCθ also inhibited palmitate-induced activation of MCP-1 promoter. Furthermore, palmitate enhanced PKCθ-dependent mitochondrial apoptosis, which was also prevented by co-incubation with oleate or EPA through restoration of pro-survival Akt pathway. Moreover, oleate and EPA inhibited palmitate-induced PKCθ activation through the conversion of intracellular DAG to triglyceride with the restoration of diacylglycerol acyltransferase 2 expression. These results suggest that oleate and EPA have protective effects against the palmitate-induced renal tubular cell damage by inhibiting PKCθ activation.

Structural and functional changes in the kidneys of high-fat diet-induced obese mice.

Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear. Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce systemic metabolic abnormalities and subsequent renal injuries, such as albuminuria, similar to human metabolic syndrome, alterations in HFD-induced renal injuries have not been fully elucidated in detail. We therefore investigated the structural and functional changes in the kidneys of C57BL/6 mice on a HFD. Six-week-old mice were fed a low-fat diet (LFD; 10% of total calories from fat) or a HFD (60% fat) for 12 wk. Mice fed a HFD showed significant increases in body weight, systolic blood pressure, plasma insulin, glucose, and triglycerides compared with those on a LFD. Accompanying these systemic changes, mice on a HFD showed albuminuria, an increase in glomerular tuft area, and mesangial expansion. These systemic and renal alterations in mice on a HFD were prevented by body weight control with the dietary restriction of feeding a HFD. Furthermore, mice on a HFD showed renal pathophysiological alterations including renal lipid accumulation, an increased accumulation of type IV collagen in glomeruli, an increase in macrophage infiltration in the renal medulla, an increase in urinary 8-hydroxy-2'-deoxyguanosine excretion, and impaired sodium handling. In conclusion, this study suggests that local metabolic alterations in the kidney play important roles in the development of renal injury associated with metabolic syndrome in addition to systemic metabolic changes and an increase in body weight.

Iron status and the use of non-steroidal anti-inflammatory drugs in hemodialysis patients.

We examined whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) can affect the anemia and iron status of hemodialysis patients. We recruited patients from six dialysis centers who had undergone maintenance hemodialysis for at least four months. We examined the use of NSAIDs during the past three months based on their medical records and assigned the patients to three groups (group A, non-NSAID group; group B, aspirin group; and group C, non-aspirin NSAID group). Of the 446 patients, 95 (21.3%) were treated with aspirin and 103 (23.1%) were treated with non-aspirin NSAIDs. The serum iron level and transferrin saturation (TSAT) were significantly lower in group C patients than those in group A. However, the ratio of the patients who were administrated iron preparations during the past three months was significantly higher than that in the other two groups. The incidences of positive fecal occult blood tests did not differ substantially between the three groups. The ratios of the patients who were administrated recombinant human erythropoietin were the same between three groups. Using a multiple regression analysis, the administration of non-aspirin NSAIDs was identified as an independent factor for the decreased serum iron and the decreased TSAT levels. A multiple logistic regression analysis revealed that the patients using non-aspirin NSAIDs had an increased the requirement for iron preparation therapy (OR 2.03, 95% CI, 1.28-3.22). The use of non-aspirin NSAIDs may therefore increase the risk of the iron deficiency in patients undergoing hemodialysis.

Scleroderma renal crisis in a patient with anticentromere antibody-positive limited cutaneous systemic sclerosis.

We have encountered a 68-year-old Japanese woman with limited cutaneous systemic sclerosis who developed de novo onset of accelerated hypertension and renal dysfunction; thus we diagnosed scleroderma renal crisis. Anticentromere antibody alone was identified, and not anti-DNA topoisomerase I antibody, anti-RNA polymerase antibodies, anti-Th/To antibodies, or antiribonucleoprotein antibodies, even with use of immunoprecipitation assay. She was successfully treated with angiotensin-converting enzyme inhibitor. This case, scleroderma renal crisis with detection of anticentromere antibody, is thought to be extremely uncommon.

Cytomegalovirus-induced small-bowel hemorrhage in a patient with nonsystemic vasculitic neuropathy.

A 73-year-old man who was being treated with corticosteroids for nonsystemic vasculitic neuropathy developed small-bowel hemorrhage after ileostomy for ileus. Immunohistochemical staining for cytomegalovirus (CMV) antigen in the ulcer in the resected ileum was positive; thus, cytomegalovirus infection of the small intestine caused his gastrointestinal manifestations. Cytomegalovirus infection should be considered in the differential diagnosis of gastrointestinal diseases in patients with collagen vascular diseases receiving immunosuppressive agents.