What is damaging the kidney in lupus nephritis?

Abstract

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy is <50% and renal impairment still occurs in 40% of affected patients. An appreciation of the factors that lead to the development of chronic kidney disease following acute or subacute renal injury in patients with systemic lupus erythematosus is beginning to emerge. Processes that contribute to end-stage renal injury include continuing inflammation, activation of intrinsic renal cells, cell stress and hypoxia, metabolic abnormalities, aberrant tissue repair and tissue fibrosis. A deeper understanding of these processes is leading to the development of novel or adjunctive therapies that could protect the kidney from the secondary non-immune consequences of acute injury. Approaches based on a molecular-proteomic-lipidomic classification of disease should yield new information about the functional basis of disease heterogeneity so that the most effective and least toxic treatment regimens can be formulated for individual patients.

Figure 1

Glomerular injury in LN: View of a glomerular loop containing endothelial cells (yellow) lined by a glycocalyx (orange), mesangial cells (ochre) and podocytes (brown). Podocytes are separated from endothelial cells by the glomerular basement membrane (GBM -red). The glomerulus is contained by Bowman’s capsule (BC) that is lined by parietal epithelial cells. Immune deposits (blue) may be found in the mesangium, subendothelium, or subepithelium. Subendothelial deposits are in contact with the vascular space (V) and can recruit myeloid cells (My) into the renal parenchyma. Subepithelial cells are in contact with podocytes and the urinary space (U). Podocytes and endothelial cells communicate with each other by transfer of soluble growth factors across the GBM, whereas mesangial cells and endothelial cells can interact directly via receptors and their ligands. Alterations of these factors in LN are shown by the arrows and color coded according to cell type.

Figure 2

Interstitial injury in LN: A single nephron with its tubular and capillary system is shown. Cellular components that contribute to interstitial injury include tubular cells, endothelial cells (Cap), pericytes (P), fibrobasts (F), inflammatory lymphocytes (Ly), infiltrating and resident macrophages (Mac) and infiltrating dendritic cells (DC). Both pericytes and fibrobasts can differentiate into myofibroblasts (Myo). The sequential processes occurring during the progression to CKD are shown on the right and key molecules are shown on the left.

Figure 3

Shared pathogenic pathways identified in the kidneys of the three different lupus-prone mouse strains. NZB/W and NZW/BXSB mice develop proliferative glomerulonephritis and NZM2410 mice develop glomerulosclerosis with limited inflammation. Pathways that are shared between all three strains and human LN are shown in green. The major functional pathway that is overrepresented in each of the three individual strains is shown in purple. Transcription factors are shown in blue and other pathways shared by two strains are shown in black. (adapted from (122))