Staining for adiponectin in a kidney biopsy from a patient with class IV SLE nephritis shows injury. Dr. Brad H. Rovin
NEW YORK — Monitoring the urinary excretion of monocyte chemoattractant protein-1 and adiponectin may prove to be a novel and specific means of evaluating renal activity and injury in patients with systemic lupus erythematosus, according to Dr. Brad H. Rovin.
There is substantial evidence suggesting that the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of renal injury in nephritis associated with systemic lupus erythematosus (SLE). “The main function of inflammatory chemokines is to regulate the deployment of leukocytes to tissue sites undergoing pathological change. These chemokines also activate leukocytes and may promote tissue fibrosis,” Dr. Rovin said at a rheumatology meeting sponsored by New York University.
The relationship of MCP-1 with lupus nephritis has now been investigated in patients enrolled during the past 5 years in the longitudinal Ohio SLE Study. The cohort includes 71 patients with lupus nephritis and 35 patients with SLE but with no evidence of renal involvement.
With a mean follow-up time of approximately 32 months, there have been 70 renal flares and 88 nonrenal flares in the patients.
Urinalysis performed every 2 months found that the mean level of MCP-1 of patients at renal flare was significantly higher than that of any of controls, with 73% of flare values being above the 95th percentile of those of disease control patients (J. Am. Soc. Nephrol. 2005;16:467–73). Patients with class IV glomerulonephritis, with crescents and necrosis, had the highest levels of MCP-1, which reached 12,000 pg/mg creatinine.
High levels of MCP-1 during flare also were associated with manifestations of renal injury including changes in serum creatinine levels and proteinuria.
Among patients with impaired renal function whose serum creatinine was elevated at 1.2–5.5 mg/dL, the mean MCP-1 was significantly higher, at 2,719 pg/mg creatinine, than in those with normal renal function, who had a mean level of 846 pg/mg creatinine.
At the time of flare, most patients had been receiving immunosuppressive therapy with prednisone and agents such as mycophenolate mofetil, and even such substantial therapy was inadequate to suppress MCP-1. “This shows that the current therapies we have to treat lupus nephritis do not adequately suppress the expression of this particular chemokine,” said Dr. Rovin, professor and director of the division of nephrology, Ohio State University, Columbus.
Response to increased immunosuppressive treatment following flare also correlated with MCP-1. In the majority of patients, MCP-1 decreased with treatment, although only gradually, but in a subset, MCP-1 remained persistently elevated. “We wonder if this is a biomarker for ongoing inflammatory injury in the kidney, and if these patients might benefit from prolonged therapy. We don't know the answer to that,” he said.
These findings suggest that monitoring this cytokine might be a novel way of monitoring disease activity and response to treatment, he said. And because MCP-1 appears not to be simply a biomarker but actually is involved in organ injury, therapies directed at the cytokine itself may be beneficial and are being investigated.
A proteomic approach also has identified the adipocyte-derived cytokine adiponectin as another “totally unexpected” marker of lupus nephritis, he said.
Adiponectin, which is also produced by other cells such as fibroblasts and synovial cells during periods of inflammation, originally was studied in metabolic disorders and was found to enhance insulin sensitivity and to be underexpressed in obesity and diabetes.
It has now been shown to modulate inflammation, with both anti-inflammatory and proinflammatory effects. Its proinflammatory effects include the activation of the transcription factor NF-κ B (NF-KB) and increasing the production of MCP-1 and interleukin-8 by endothelial cells and blood monocytes (Clin. Immunol. 2006;120:99–105).
Recent work has found that both adiponectin and its receptor are expressed in the kidney, suggesting the possibility that this cytokine also has a direct, but as yet unspecified, effect on renal cell function, Dr. Rovin said.
As is the case with MCP-1, levels of adiponectin in the urine are increased during renal flare but not during nonrenal flare, correlating with plasma levels and magnitude of proteinuria (Kidney Int. 2005;64:1825–33).