Autoimmune AEs were detected in MS patients treated with alemtuzumab in clinical trials . The 6-year follow-up data of the CARE-MS studies were presented at ECTRIMS 2016 and showed the following frequencies: 39% of alemtuzumab-treated patients experienced an autoimmune thyroid disorder, 2.6% an immune thrombocytopenic purpura, and 0.2% (two cases) an autoimmune renal disease . In post-marketing use through February 2017, 13,000 patients have been treated worldwide with alemtuzumab for MS and the frequency for anti-GBM disease and membranous nephropathy was estimated at 0.13% . Post-marketing frequencies are not directly comparable to clinical trial incidences because of differences in ascertainment methodology and follow-up duration, and limitations of post-marketing reporting.
Anti-glomerular basement membrane (anti-GBM) disease
Anti-GBM disease is a rare renal disease caused by the presence of antibodies directed against an antigen located in the glomerular basement membrane (noncollagenous domain 1 of the α3 chain of type IV collagen (α3[IV]NC1), resulting in rapidly progressive glomerulonephritis with crescent formation with or without concomitant pulmonary symptoms (hemoptysis, shortness of breath, and cough) [9, 10]. Crescents are defined as two or more layers of proliferating cells in Bowman’s space and are a hallmark of inflammatory glomerulonephritis and a histologic marker of severe glomerular injury. Goodpasture’s disease is defined as the presence of glomerulonephritis and pulmonary hemorrhage in the presence of anti-GBM antibodies.
Anti-GBM disease affects approximately 0.5–1.0 patients per million in the general population. This disease represents around 20% of cases of rapidly progressive glomerulonephritis and is found in less than 3% of all kidney biopsies for any reason [11, 12]. Anti-GBM disease occurs in older children and adults without age preference. Younger patients more often have concurrent pulmonary involvement, than older patients [13, 14]. Although anti-GBM disease is most often idiopathic, several triggering factors have been proposed, e.g., infection, smoking, hydrocarbons, smoked cocaine, urinary tract obstruction, and lithotripsy [9, 15,16,17,18]. A genetic predisposition to anti-GBM disease has been reported: increased risk associated with HLA-DR15 and DR4 and decreased risk associated with HLA-DR1 and DR7 [19,20,21,22]. HLA-DR15 is also associated with an increased risk of MS.
Clinically, patients affected by anti-GBM disease can present with diverse symptoms [general symptoms, edema, hypertension, pulmonary symptoms (dyspnea, hemoptysis)]. General symptoms such as fever, malaise, anorexia, weight loss, and arthralgia may occur but are generally only mild. The outcome of anti-GBM disease is determined by the renal function, the need for dialysis at presentation, and the number of glomeruli affected by crescent formation determined post biopsy. Without immunosuppressive treatment, death or dialysis ensues in more than 90% of patients with anti-GBM disease . A recent report confirmed oligoanuria as the strongest negative predictor of renal and patient survival. Furthermore, the percentage of glomerular crescents was the only pathologic parameter associated with poor renal outcome in anti-GBM disease .
The treatment of anti-GBM disease consists of a combination of plasmapheresis, corticosteroids, and cyclophosphamide. Plasmapheresis will result in a rapid decline of anti-GBM antibodies in the circulation, while prednisone and cyclophosphamide are administered to halt antibody production. Almost half of anti-GBM patients will benefit from this treatment by not progressing to dialysis-dependency and survive [24, 25]. Renal recovery is most likely in patients without oligoanuria at the time of diagnosis. Renal recovery is unlikely in patients with 100% of glomeruli affected on biopsy and with early dialysis-dependency. Early initiation of therapy is most important to optimize renal outcome and long-term prognosis .
Membranous nephropathy (MN)
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. In this disease, immunoglobulins (IgG) and complement factors deposit in the subepithelial area of the glomerular basement membrane (GBM); between the GBM and the visceral epithelial cells (podocytes). Podocytes are highly specialized cells responsible for the protein sieving of the glomerular barrier. Podocytes form interdigitating foot processes covering the GBM. Foot processes are connected through a scale-like protein complex called the “slit-diaphragm”. The presence of antibodies and complement fractions in contact with the podocytes leads to their dedifferentiation with foot process effacement and fusion. Consequently, abnormal amounts of protein pass through the glomerular filter from the vascular compartment into the urine. MN symptoms include edema, hypertension, and lab abnormalities: elevated urinary protein, low serum albumin and protein, and dyslipidemia with or without abnormal glomerular filtration rate.
MN may be primary or secondary in nature. Secondary membranous nephropathy can be seen in the context of autoimmune diseases such as systemic lupus erythematosus (class V according to the ISN/RPS classification) or, more rarely, be associated with infectious diseases (hepatitis B, C, parasites, etc.), drugs and toxins (gold, penicillamine, NSAID), or with malignancies (mainly solid tumors, and more common in patients older than 65 years). In 70% of the cases, MN is primary or idiopathic (pMN). In 2009, the group of David Salant identified the most important antigen involved in the pathogenesis of pMN, the M-type phospholipase A2 receptor (PLA2-R) . This receptor is overexpressed on the membrane of podocytes and may elicit an auto-immunization resulting in the formation of mainly IgG4 anti-PLA2R antibodies and the subsequent development of membranous nephropathy. Anti-PLA2R antibodies can be detected in 70–80% of patients with pMN. In 2014, another podocyte antigen was reported to be involved in the pathogenesis of pMN: Thrombospondin type-1 domain containing 7A (THSD7A). This antibody is found in approximately 10% of pMN . For the remaining 10–20% of patients with pMN, the responsible antigen has not yet been identified.
The outcome for patients with MN is difficult to predict. Three patterns of clinical evolution have been identified in patients with MN. About one-third will experience spontaneous remission, one-third will remain stable with persisting nephrotic syndrome with no progression to renal failure, and one-third will experience progressive kidney function deterioration necessitating renal replacement therapy (dialysis, renal transplant). Factors that predict poor prognosis (high likelihood of progression to end-stage renal disease) are decreased renal function at diagnosis and heavy proteinuria (> 8 g/day) [28,29,30,31,32,33,34]. In addition, the titer of anti-PLA2R antibodies has been reported to be a predictor of outcome [35,36,37].
The diagnosis and treatment of MN are not a nephrological emergency. If MN is considered secondary, the underlying cause should be treated/removed. First line treatment in all MN patients is symptomatic, anti-proteinuric therapy consisting of ACE inhibitors or antagonists of type II angiotensin receptors in combination with salt restriction and, if necessary, diuretics. Immunosuppression is to be considered for patients with persistent nephrotic syndrome and proteinuria above 4 g/day after 6 months of anti-proteinuric therapy and/or disabling or life-threatening symptoms related to nephrotic syndrome (thromboembolic events), and/or patients in whom serum creatinine has risen by 30% or more within 6 months . The recommended immunosuppressive treatment consists of the modified Ponticelli scheme consisting of three 2-monthly cycles of 1 month IV and then oral steroids followed by 1 month oral alkylating agents (cyclophosphamide rather than chlorambucil). Continuous use of oral cyclophosphamide may also be an option. As an alternative, calcineurin inhibitors, cyclosporine + corticosteroid, or tacrolimus monotherapy  can be used. In recent years, several groups have reported promising results using rituximab in the treatment of MN .