Lupus nephritis: histology, diagnosis, and treatment.

The International Society of Nephrology (ISN) and the World Health Organization (WHO) systems for classifying the various forms of lupus nephritis have significantly improved our understanding of the natural history of the disease and facilitated the development of new and effective treatments. The classification of the dif ferent manifestations of lupus nephritis is based upon light, immunofluorescent and electron microscopic changes. As shown in Table 1, the WHO system of nomenclature identifies six different classes of lupus nephritis, with classes III and IV being the “proliferative” forms of the disease. WHO class III, or focal proliferative glomerulonephritis, is defined by the presence of proliferating endocapillary cells within the glomerular capillary loops. As shown in Figure 1, proliferating endocapillary cells lead to occlusion of capillary lumen, leading to a direct reduction in filterable glomerular surface area. By definition, patients with WHO class III have less than 50% of the volume of an individual glomerulus or less than 50% of the total number of glomeruli with endocapillary proliferation. While many patients with severe class III may exhibit focal necrosis (karyorrhexis) or extracapillary proliferation (crescents), these findings are not required for staging a particular biopsy as class III or class IV. The overall prevalence of class III is 25% to 30%. 1 In general, class III is associated with higher titers of anti-DNA antibodies, low complement levels, and active extra-renal manifestations of SLE. Progression from class II to class III (focal proliferative disease) occurs in about 20% to 25% of patients, 2 while conversion from class III to class IV occurs in over two-thirds of patients over 36 months. 3 The longterm renal survival of patients with class III lupus nephritis generally has been thought to be better than for those with class IV. However, Najafi and colleagues reviewed the 10year survival of 85 patients with biopsy-confirmed lupus nephritis and demonstrated that only 52% of patients with class III lupus nephritis had functioning kidney, compared with 75% for patients with class IV. 4 The etiology for this survival difference is unknown but may represent a treatment bias, in which patients with class II receive less aggressive immunosuppression. WHO class IV (diffuse proliferative) lupus nephritis shares many similarities with class III but generally demonstrates more extensive and aggressive histopathology. At the histologic level, class IV is defined by the presence of endocapillary proliferation in greater than 50% of glomeruli. While not required for the diagnosis, patients with class IV lupus nephritis often demonstrate extensive crescents and karyorrhexis. Figure 2 demonstrates a glomerulus from a biopsy of a patient with severe lupus flare. A solitary glomerulus with a large circumferential crescent is shown collapsing the glomerular tuft (black arrow). The large, rounded cells present in the crescent are derived from the parietal epithelial cell layer. Figure 3 demonstrates an area of endocapillary proliferation with an area of focal necrosis or karyorrhexis (white arrow). These histopathologic signs are independent predictors of patients developing progressive renal disease. 5 At the clinical level, patients with class IV lupus nephritis frequently demonstrate severe extra-renal manifestations, including lupus cerebritis and lupus pneumonitis. Renal function at presentation can range from mild renal insufficiency to dialysis-dependent acute kidney injury. The nephrotic syndrome is uncommon with patients presenting a pure class IV, but often accompanies patients presenting with mixed lesions, including WHO class Vc and Vd. In the absence of significant immunosuppression, the long-term renal survival of patients with class IV is poor, with more