Lupus nephritis: through the looking-glass

In Through the Looking Glass, Lewis Carroll’s sequel to Alice in Wonderland, Alice learns that things on the other side of the metaphorical mirror (looking glass) are not always what they seem. She enters a world of riddles and challenges, and learns that she cannot always expect to find logic in the situations she encounters. Over the last 60 years, as we similarly ‘‘reflect’’ on the history of our understanding of lupus nephritis, our world has been consumed with the obvious immune aggregates seen in the glomeruli on immunofluorescence microscopy and likewise tries to explain many, if not all, of the clinical manifestations of this disease by these immune complexes. In fact, lupus nephritis is commonly known as the ‘‘prototypical immune complex mediated disease.’’ The unwillingness to look beyond the immune aggregates has made alternative views on pathophysiology of this complicated disease difficult to appreciate. In the classic description of severe lupus nephritis, immune aggregates found in the subendothelial space, subepithelial space, or glomerular basement membrane are thought to be responsible for the clinical findings of proteinuria, hematuria, and acute and subsequent chronic kidney disease. However, a pauci-immune lesion, akin to that seen in segmental necrotizing vasculitis, is common in severe lupus nephritis (World Health Organization (WHO) Class III and International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III and IV-s) and presents with similar clinical findings. In the same way, the nephrotic syndrome, which is the most common clinical presentation of lupus nephritis, has been classically considered to be related to immune aggregates in the subendothelial space or in the glomerular basement membrane. However, the nephrotic syndrome in mesangial (WHO and ISN/RPS Class II) as well as pure membranous (WHO and ISN/RPS Class V) lupus nephritis has been correlated with epithelial cell foot process fusion as opposed to the degree of immune complex deposition. This positive correlation between foot process fusion and proteinuria remains true even in severe lupus nephritis (WHO and ISN/RPS Class III and IV). Clearly, the answer to the question of the cause of proteinuria, or even of active lupus nephritis, is not as simple as immune aggregates. Therefore, looking into the mirror to see what is on the other side, challenging the dogma that has been accepted over the years, is an important step forward. In this issue of Lupus, Qin et al. expand on the previous correlation of foot process effacement and proteinuria in lupus nephritis, with the hypothesis that the soluble urokinase plasminogen activator receptor (suPAR) may be associated with the nephrotic syndrome, foot process fusion, immunologic activity, and/or clinical outcomes in systemic lupus erythematosus (SLE). They found that total suPAR levels were elevated in active lupus nephritis compared with non-renal lupus and normal controls, and the levels were significantly lower in remission. This remained consistent regardless of the estimated glomerular filtration rate (eGFR) (greater than or less than 60ml/min). In addition, higher levels of suPAR were associated with diffuse proliferative lupus nephritis, reduced eGFR, acute kidney injury, and the nephrotic syndrome, as well as the important pathologic features of cellular crescents, endocapillary proliferation, and foot process effacement measured by foot process width. A role of suPAR in lupus nephritis has been suspected recently. Previous studies have shown that Correspondence to: William Luke Whittier, Department of Medicine, Division of Nephrology, Rush University Medical Center Chicago, IL 60612, USA. Email: william_whittier@rush.edu