小球疾患的全新免疫治疗靶点---来自国际权威杂志Biologics-好医生

Glomerulonephritis is a common cause of chronic kidney disease and end stage renal failure. Current therapy relies on variably effective, nonspecific and toxic immunosuppression. Recent insights into underlying biology and disease pathogenesis in human glomerulonephritis combined with advances in the fields of inflammation and autoimmunity promise a cadre of novel targeted interventions. This review highlights the therapeutic potential of two antigens, alpha3 (IV)NC1 collagen and podocyte neutral endopeptidase, and two cell signaling and effector molecules, IgG Fc receptors and complement, judged to be particularly amenable to therapeutic manipulation in man. It is anticipated that continued dissection of pathogenesis in the diverse disorders that comprise the glomerulonephritides will provide the basis for individualized disease-specific therapy.

Keywords: glomerulonephritis, immunotherapy, Goodpasture syndrome, membranous nephropathy

作者从全新的角度探讨了小球疾患免疫治疗治疗的优越性和必要性，不及拓宽了我们对传统的小球疾患的免疫治疗基础的认识，也为小球疾患，尤其是糖尿病状况下的被糖基化修饰的分子激活自身免疫这一全新的理念的推广起到了重要的作用。这提示我们，难治性的糖尿病肾病有可能成为免疫抑制治疗又一个新的适应症。

Glomerulonephritis encompasses a cluster of diseases that have been described as the most common single cause of end stage renal disease (ESRD) in the world (Timoshanko and Tipping, 2005). GN was listed as the cause of ESRD in over 70,000 US patients in 2004 (US Renal Data System 2007). Glomerulonephritis and hypertension together are also the most common causes of chronic kidney diseases (CKD) in developing countries, and GN trails only hypertension and diabetes as a leading cause of CKD in the US, Europe, and Japan. Notably, for every patient with clinical GN, an estimated 5–10 patients have undiagnosed subclinical disease (Couser 1999). It is thus striking that an estimated 26 million Americans, or 13% of the US adult population, and over 50 million individuals worldwide have CKD (Dirks et al 2005; Coresh et al 2007). Chronic GN may underlie pathogenesis of CKD in a significant proportion of this population. CKD not only places patients at risk for the various complications of renal damage, including increased cardiovascular disease and mortality, but it is estimated that each year more than one million CKD patients develop ESRD. Survival with ESRD requires renal replacement therapy with dialysis or transplantation, costly medical interventions not available in many developing countries. Clearly, effective therapy for GN would have significant impact globally on human health and health care financing.

GN is particularly prevalent among renal allograft recipients (Briganti et al 2002; Couser 2005). Glomerular diseases, including diabetes and glomerulonephritis, account for over 70% of patients receiving renal allografts, and in some countries GN alone accounts for up to 50% of patients (Briganti et al 2002). In a recent review of the Australian registry, among 1505 pts with biopsy-proven GN receiving a primary renal transplant between 1988 and 1997, recurrent or de novo GN occurred in 6%–20% of patients. Recurrence was the third most frequent cause of allograft loss at 10 years, after chronic rejection and death with a functioning transplant. Among patients transplanted due to GN, 8.4% lost their allograft to recurrent GN by 10 years (Briganti et al 2002). These patients may particularly benefit from novel targeted therapies, since disease onset can be readily identified and intervention initiated promptly, if not pre-emptively.

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GN is a common cause of renal injury and CKD that continues to rely on non specific immunosuppression for therapeutic intervention. Recent insights into underlying biology and disease pathogenesis in human nephritis combined with advances in the fields of inflammation and autoimmunity bring the promise of new therapies. Notable breakthroughs include the discovery that alloimmunity to a glomerular antigen underlies antenatal membranous nephropathy, that podocytes are key regulators of glomerular filtration, that complement inhibitors are pivotal to pathogenesis in MPGN, and that IgG Fc receptors form a crucial link between antibody deposition and tissue injury. These discoveries provide the basis for novel therapies based on specific antigen or antibody responses or dominant effector cells or molecules engaged in individual nephritides. Future additional insights into cellular immunity, immune tolerance and regulatory networks, effector mechanisms, and genetic and environmental disease susceptibility will extend this armamentarium and provide the foundation for tailored individualized therapy.