Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis in detail remains unclear. In regard to the heterogeneous course, classical immunosuppressive and specific therapeutic regimens adapted to the loss of renal function will here be discussed in addition to the essential common renal supportive therapy. Renal supportive therapy alleviates secondary, surrogate effects or sequelae on renal function and proteinuria of high intraglomerular pressure and subsequent nephrosclerosis by inhibition of the renin angiotensin system (RAASB). In patients with physiological (ΔGFR < 1·5 ml/min/year) or mild (ΔGFR 1·5-5 ml/min/year) decrease of renal function and proteinuric forms (> 1 g/day after RAASB), corticosteroids have shown a reduction of proteinuria and might protect further loss of renal function. In patients with progressive loss of renal function (ΔGFR > 3 ml/min within 3 months) or a rapidly progressive course with or without crescents in renal biopsy, cyclophosphamide with high-dose corticosteroids as induction therapy and azathioprine maintenance has proved effective in one randomized controlled study of a homogeneous cohort in loss of renal function (ΔGFR). Mycophenolic acid provided further maintenance in non-randomized trials. Differentiated, precise, larger, randomized, placebo-controlled studies focused on the loss of renal function in the heterogeneous forms of IgAN are still lacking. Prospectively, fewer toxic agents will be necessary in the treatment of IgAN.

Keywords: IgA nephropathy; corticosteroids; cyclophosphamide; high dose intravenous immunoglobulines; mycophenolic acid.

Figure 1

Pathophysiology, proven immunosuppressive drugs and new immunotherapies, check‐point inhibitors and other stratified interventions with their modes of action in immunoglobulin A nephropathy (IgAN). The pleiotropic effects of the classical immunosuppressive drugs are depicted in Table 1 and their clinical use in Table 2. Underlined interventions were used in therapy of primary IgAN. References are given in Table 1 and in the text. ACEI = angiotensin converting enzyme inhibitor = ADAM A disintegrin and metalloproteinase; AMG = anti‐interferon (IFN)‐γ IgG1 monoclonal antibody; APC = antigen‐presenting cells; ARB = angiotensin receptor blocker; ASS = acetylsalicylic acid; C = corticosteroids; CD = cluster of differentiation; CKD = chronic kidney disease; CTLA = cytotoxic T lymphocyte‐associated protein; CyC = cyclophosphamide; Fab = fragment antigen‐binding; GALT = gut‐associated lymphoid tissue; GFR = glomerular filtration rate; ICOS = inducible T cell co‐stimulator; IDEC = epidermal cell‐like dendritic cells; IL = interleukine IVIg = intravenous immunoglobulin; JAK‐STAT = Janus kinase–signal transducers and activators of transcription; MALT = mucosa‐associated lymphoid tissue; MAP = mitogen‐activated protein; MCSF = macrophage colony‐stimulating factor, MMF = mycophenolate mofetil = MPA mycophenolic acid; MPS = mononuclear phagocyte system; mTOR = mechanistic target of rapamycin; nuclear factor (NF) kappaB nuclear factor k‐light‐chain‐enhancer of activated B cells; NK = natural killer cell; p = pathological; PDGF = platelet‐derived growth factor; RAASB = renin angiotensin system blocker; RANTES = regulated on activation, normal T cell expressed and secreted; s = soluble; STI‐571 = Imatinib mesylate; TNF = tumour necrosis factor; TLR = Toll‐like receptor.

Figure 2

Risk‐adapted treatment strategy in order of degree of proteinuria and loss of renal function (ΔGFR) based on clinical studies (Table 2). Normal kidney size and morphology in ultrasound has to be evaluated before specific immunosuppressive treatment is initiated. Corticosteroids monotherapy showed proven benefit only in patients with mild to moderate impaired renal function (*, Table 2) and the progressive treatment strategy is recommended in patients with severely impaired renal function. In patients with nephrotic syndrome, the proteinuric course treatment regimen will be recommended.