Introduction
Lupus nephritis (LN) is a form of glomerulonephritis that constitutes one of the most severe organ manifestations of the autoimmune disease systemic lupus erythematosus (SLE). Lupus nephritis is present in approximately 25% of patients at the time of diagnosis and eventually develops in up to 60% of adults and 80% of children. Treatment of LN usually involves immunosuppressive therapy, typically with mycophenolate mofetil or cyclophosphamide and with glucocorticoids, although these treatments are not uniformly effective. But, early and accurate diagnosis of LN and prompt initiation of therapy are of vital importance to improve outcomes in patients with lupus nephritis.
Epidemiology
Lupus nephritis (LN) occurs in ~50% of patients with SLE . LN typically develops early in the disease course, generally within the first 6 to 36 months, and maybe present at initial diagnosis. The incidence of LN is higher in Asians (55%), followed by Africans (51%), and Hispanics(43%) when compared with Caucasians (14%). The other factors which determine the outcomes are gender, genetics, higher baseline creatinine, nephrotic syndrome, severe anemia, hypertension, low levels of complement, antiphospholipid antibodies, class IV histology, high activity, and chronicity index, and treatment type.
Genetics and Pathophysiology of LN
Genome-wide association studies have identified risk genes in LN that are not otherwise seen in patients with SLE without nephritis, including apolipoprotein L1 (APOL1), platelet-derived growth factor receptor alpha (PDGFRA), and hyaluronan synthase 2 (HAS2). HLA-DR4 and HLA-DR11 appear to protect against LN, while HLA-DR3 and HLA-DR15 confer increased risk. The pathogenesis of LN involves extrarenal and intrarenal pathogenic mechanisms. Extrarenal influences include complicated genetic variation combinations that are unique to each patient, explaining the wide range of clinical symptoms. The nucleic acid content of nuclear particles from apoptotic neutrophils activates innate and adaptive immunity by TLR7 and TLR9, which triggers an IFN-α–mediated antiviral host defense program that accounts for many of the nonspecific SLE symptoms. The intrarenal pathology of LN involves antibody binding to intrarenal nuclear autoantigens, local complement, and FcR activation. Tertiary lymph follicles, to some degree, form inside the kidney, which includes B cells with local proinflammatory effects as well as plasma cells that secrete autoantibody inside the kidney.
Treatment Response Criteria in LN
Treatment response in LN is defined clinically and generally stratified into complete (CR), partial (PR), and no response. Guideline definitions for clinical response in LN have been suggested by several organizations (Table 1).
Treatment of LN
The treatment of LN consists of two phases – induction and maintenance. Induction therapy refers to the initial therapeutic regimen given in an attempt to produce remission of active disease. The induction phase is followed by the maintenance phase to sustain remission over a long period and to prevent disease fiare. Most patients with active proliferative LN are initially treated with a pulse of an intravenous steroid followed by a high-dose oral steroid, or by this method in conjunction with other immunosuppressive agents. These include cyclophosphamide, mycophenolate mofetil, and azathioprine. The common treatment protocol is as shown in Fig 1. Cyclophosphamide can be given orally or intravenously, and if intravenously, it can be administered in either a standard dose (NIH regimen) or a low-dose (NIH regimen) regimen (called low-dose or Euro-lupus regimen). For the first 3–6 months, high-intensity immunosuppression is utilized, followed by MMF or azathioprine to keep autoimmune and infiammation under control and prevent flare. Because of toxicity concerns surrounding cyclophosphamide, MMF and NIH cyclophosphamide were directly compared in a large randomized controlled trial and found to be equivalent for the induction of renal responses after 6 months of treatment. In another aempt to reduce the long- and short-term toxicity of cyclophosphamide, low-dose, Euro-lupus cyclophosphamide was found to be equivalent to NIH cyclophosphamide for remission induction and preservation of renal function at 5 and 10 years, but with fewer adverse effects. Recently, low-dose cyclophosphamide was found to be effective in more severe LN. (Fig 1)
Other Emerging Therapies
A variety of biologics have been developed and tested in clinical trials, with a special focus on this subset of individuals whose condition is uncontrollable by current treatment regimens. Unfortunately, the majority of these trials have shown disappointing outcomes. Despite these drawbacks, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. These biologic agents may enhance the therapeutic efficacy when combined with standard therapies.
Conclusions
For SLE patients, LN continues to be a major cause of morbidity and mortality. The majority of patients get LN during their prime years of life, which harms their livelihoods and families, as well as society as a whole. An improved understanding of disease pathogenesis has not yet resulted in major therapeutic advances. However, the availability of a variety of novel drugs to modify the immune system, coupled with a thoughtful approach to clinical trial design, is anticipated to overcome this slow progress in advancing LN management.
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