Pathogenesis

Genetics and environmental and hormonal factors all play a role in the predilection to SLE and perhaps to LN.[18, 19] Autoimmunity is important in the pathogenesis of SLE.[20] The disease process, including a breakdown in self-tolerance, polyclonal hyperactivity of B cells along with defective auto-regulation of T cells that leads to autoantibody production, and deposition of immune deposits with a subsequent inflammatory responses.[18, 19, 20, 21] There is evidence that increased apoptosis and impaired clearance and defective clearance of apoptotic cells facilitate the emergence of anti-DNA antibodies and immune complex formation. The deposition of circulating immune complexes, the in situ formation of others and the activation of complement are major components of glomerular involvement in LN.[21, 22] Many factors influence the localization of glomerular immune complexes. These include the size, charge, and avidity of the immune complexes as well as the clearing ability by the mesangium and local hemodynamics.[21] The glomerular localization of immune complexes activates complement-mediated damage, procoagulant factors, leukocyte chemo-attraction, and release of cytokines associated with cellular proliferation and matrix formation. In some patients, vascular and tubulointerstitial damage are prominent.[20, 21]

Clinical manifestations

The presentation of childhood LN can be quite variable, often few signs or symptoms exist.[22, 23, 24, 25] From 30% to 50% of patients have clinically evident renal disease at presentation,[23, 24] but renal involvement occurs in as many as 60-80% of patients during the disease course and the risk of progression to ESRD is 18-50%.[23, 24, 25] LN is manifested by proteinuria, micro hematuria with dysmorphic erythrocytes and erythrocyte casts. In some, development of LN is associated with high serum creatinine level and a decline in glomerular filtration rate. Other patients, including those with proliferative disease and some with membranous lupus nephropathy, develop the nephrotic syndrome, hypertension, and anemia. Nephrotic patients with membranous lupus and lupus patients with anti-phospholipid antibodies are particularly pre-disposed to thrombotic complications such as deep vein thrombophlebitis, renal vein thrombosis, and pulmonary emboli.[26] Clinical risk factors at the time of initial presentation include elevated serum creatinine, hypertension, nephrotic range proteinuria, anemia and black and hispanic race and ethinicity.[11]

Renal pathology

All patients with clinical and laboratory evidence of active LN should undergo renal biopsy in order to determine the type and severity of glomerular lesion according to International Society of Nephrology/Renal Pathology Society (ISN/RPS) Classification of LN.[27, 28] Biopsy is most highly recommended in patients with SLE who present with abnormal serum creatinine, hematuria, proteinuria >0.5 g/24 h or spot urine protein/creatinine ratio of >0.5 and active urine sediment. In general, clinical renal manifestations correlate well with ISN biopsy classification. With treatment or over time, serial biopsies often show transformation from one histological class to another.

ISN/RPS Class I denotes normal glomeruli by light microscopy but with mesangial immune deposits by immunofluorescence (IF) and electron microscopy. ISN/RPS Class II, which is mesangial proliferative LN, is characterized by mesangial hypercellularity demonstrated by LM, with greater than three mesangial cells in areas away from the vascular pole by LM as well as mesangial immune deposits. ISN/RPS Class III is focal LN, defined as focal segmental and/or global endocapillary and/or extra-capillary glomerulonephritis affecting less than 50% of the glomeruli. ISN/RPS Class IV is diffuse LN. It is characterized by segmental and/or global endocapillary and/or extra-capillary glomerulonephritis affecting more than 50% of glomeruli [Table 1]. Both Class III and IV have sub-endothelial immune deposits. LN Class IV is subdivided into diffuse segmental versus diffuse global proliferation, and both Class III and IV may have active A (proliferative), and inactive chronic C (sclerosing) lesions. ISN Class V is membranous LN defined by sub-epithelial immune deposits. SLE patients may have combined lesions noted as Class III plus V or IV plus V. Class VI is defined as advanced sclerosing LN with more than 90% global glomerular sclerosis. In LN, IgG staining on IF is almost always present and C1q is particularly common. “Full house staining” (the presence of IgG, IgA, IgM, and C3 and C1q) is very suggestive of LN as is IF deposition along the tubular basement membranes and the glomerular basement membranes [Table 1].

Table 1. International Society of Nephrology/Renal Pathology Society classification of lupus nephritis^¶

Treatment

Prompt diagnosis after the onset of LN and subsequent initiation of appropriate therapy are associated with improved outcomes regardless of the histologic subclass.[29] Patients with active proliferative LN (Class III and Class IV) should receive intravenous methylprednisolon (MP) 1.0 g/m²/day for 1-3 days then prednisone 0.5-1.0 mg/kg/day tapered to <0.5 mg/kg/day after 8-12 weeks of treatment plus mycophenolate mofetil (MMF) 1.2 g/m²/day for 6 months followed by maintenance lower doses of MMF 0.6 g/m²/day or azathioprine (AZA) 2 mg/kg/day for 3 years.[30, 31]

Kidney disease improving global outcomes (KDIGO) recent guideline for glomerulonephritis recommends cyclophosphamide (CYC) induction therapy for patients with severe proliferative (Class III/IV) LN, with respect to level of proteinuria, and decline in renal function.[32] Furthermore, based on the KDIGO guideline one cannot conclude that induction therapy with MMP is equal or superior to CYC therapy in terms of future renal function and numbers of flares as the long-term follow-up in the randomized clinical trials reported with MMF therapy are shorter than the CYC containing regimen.

Patients with membranous LN (Class V) plus diffuse or local proliferative LN (Class III and Class IV) should receive either the standard 6 monthly pulses of CYC (0.5-1 g/m²/month) followed by infusion every 3^rd month or to a shorter treatment course consisting of 0.5 g/m² IV CYC every 2 weeks for six doses (total dose 3 g) followed by maintenance therapy with daily AZA (2 mg/kg/day) or MMF (0.6 g/m²/day) for 3 years. Both regimens are equally effective, but the shorter regimen is less toxic with fewer severe and total infections.[33, 34] Controlled clinical trials and meta-analyses compared treatment with CYC to MMF found that MMF-treated patients had greater reductions in proteinuria, improved renal histology with fewer adverse effects. With the results of these clinical trials, MMF is considered as a first-line induction agent for severe LN.[34, 35]

Patients with membranous LN (pure Class V) and subnephrotic proteinuria do extremely well regardless the treatment and may be treated with low doses MMF (1.2 g/m²/day) and prednisone 0.5 mg/kg/day. In Class V LN with nephrotic syndrome both MMF and IV CYC proved equivalent in inducing partial or complete remission of the nephrotic syndrome.[26] Patients with Class VI LN generally do not response to immunosuppression and should be prepared for renal replacement therapy. In a large randomized controlled trial of 86 patients with diffuse proliferative LN (Classes III and IV) with or without membranous LN (Class V) showed that treatment with plasmapheresis, prednisone, and short-term oral CYC led to a more rapid decline in circulating autoantibody levels, but no difference in outcome when compared with prednisone and CYC alone.[36]

In patients fail to respond adequately to induction therapy within 6 months, a switch from either CYC to MMF or from MMF to CYC plus pulse MP followed by daily low dose prednisone is probably more effective than no change in their medications. Combination of MMF plus rituximab or MMF plus calcineurin inhibitors may be an effective co-therapy for those refractory to induction or maintenance therapies.[9, 36] [Figure 1]. There are limited data on the use of repeated dosing of rituximab either every 6 months or when the CD19-20 B cell count rises.

[Figure ID: F1] Figure 1. Treatment algorithm for proliferative lupus nephritis (Class III and Class IV). AZA = Azathioprine, CI = Calcineurin inhibitors, CYC = Cyclophosphamide, MP = Methylprednisolone, PD = Prednisone

A number of adjunctive agents have proved helpful in treating LN patients including angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Use of hydroxychloroquine is recommended for all patients with LN regardless of the type or severity of glomerular lesions.[5] The use of hydoxychloroquine may help with extra-renal symptoms, but there are only limited data on their effect in renal involvement.