Faculty Bibliography

Effective treatment of lupus nephritis requires an understanding of disease pathogenesis, risk stratification by World Health Organization (WHO) classification and therapeutic options. Mesangial lupus nephropathy is generally associated with an excellent prognosis, whereas proliferative lupus nephropathy, especially the diffuse variant, is often characterised by hypertension, red blood cell casts and significant deterioration of renal function. Nephrotic syndrome in the absence of hypertension, active urinary sediment or significant hypocomplementaemia suggests the membranous variant of lupus nephropathy. Membranous nephropathy generally confers a good prognosis. However, persistent nephrotic range proteinuria may be accompanied by loss of renal function and end stage renal disease. Glucocorticoids, usually prednisone or methylprednisolone, remain the most effective, rapidly acting immunomodulatory therapy for both the initial episode or recurrence of active renal disease. A role for cyclophosphamide in the treatment of lupus nephritis has been established in prospective, randomised trials. The benefits of intravenous cyclophosphamide were seen in groups of patients failing prednisone, establishing cyclophosphamide as salvage or rescue therapy for patients unresponsive to glucocorticoids. Additional therapeutic strategies include azathioprine, cyclosporin, and plasmapheresis. Ancillary management can consist of hypertension control, use of angiotensin-converting enzyme inhibitors, dietary restriction of salt and protein, and lipid lowering drugs. Current treatment of lupus nephritis is associated with preservation of renal function in the vast majority of patients; however, novel agents that are more effective and less toxic are required

The chronic elevation of complement split products seen in many patients with systemic lupus erythematosus should be regarded as equivalent to silent hypertension, or hyperglycemia in a patient with incipient diabetes mellitus. Although the consequences may not be immediately evident, such patients should be monitored and perhaps even treated

OBJECTIVE: To investigate whether systemic lupus erythematosus (SLE) is accompanied by increased serum nitrite levels, whether active compared with inactive disease is associated with greater nitric oxide (NO) production, and whether endothelial cells or keratinocytes serve as cellular sources of NO by virtue of their increased expression of either constitutive nitric oxide synthase (cNOS) or inducible NOS (iNOS). METHODS: Fifty-one serum samples (46 from patients with SLE) were analyzed for NO production by measuring nitrite levels in a calorimetric assay. Skin biopsy samples from 21 SLE patients and 11 healthy volunteers were evaluated immunohistochemically, using monoclonal antibodies, for endothelial cell and keratinocyte cNOS and iNOS expression. RESULTS: Serum nitrite levels were significantly elevated in the 46 patients with SLE (mean +/- SEM 37 +/- 6 microM/liter) compared with controls (15 +/- 7 microM/liter; P < 0.01), and were elevated in patients with active SLE compared with those with inactive disease (46 +/- 7 microM/liter versus 30 +/- 7 microM/liter; P < 0.01). Serum nitrite levels correlated with disease activity (r = 0.47, P = 0.04) and with levels of antibodies to double-stranded DNA (r = 0.35, P = 0.02). Endothelial cell expression of iNOS in SLE patients (mean +/- SEM score 1.5 +/- 0.2) was significantly greater compared with controls (0.6 +/- 0.2; P < 0.01), and higher in patients with active disease compared with those with inactive SLE (1.7 +/- 0.2 versus 1.2 +/- 0.2; P < 0.01). Keratinocyte expression of iNOS was also significantly elevated in SLE patients (0.9 +/- 0.1) compared with controls (0.4 +/- 0.1; P < 0.001). With regard to expression of cNOS, there were no differences between patients with active SLE, those with inactive SLE, and normal controls in either the vascular endothelium or the keratinocytes. CONCLUSION: NO production is increased in patients with SLE, and 2 potential sources of excessive NO are activated endothelial cells and keratinocytes via up-regulated iNOS