Crescentic glomerulonephritis

The term crescentic glomerulonephritis (CrGN) refers to a diverse collection of disorders of widely different etiology and pathogenesis having in common the development of extensive proliferation of cells within Bowman's space (Couser, 1988; Glassock et al., 1995; Nachman et al., 1998; Pusey and Rees, 1998; Morgan et al., 2006; Lionaki, et al., 2007). The resulting accumulation of cells gives rise to a ‘crescent’ enveloping the glomerular tuft itself. Polymerization of fibrinogen in Bowman's space due to passage of fibrinogen through gaps in the capillary wall, the elaboration of procoagulant factors by infiltrating monocytes and impaired fibrinolysis all contribute to the pathogenesis of the crescent (Couser, 1988, Glassock et al., 1995). Usually 〉50% of glomeruli are involved with crescentic lesions. Such patients also frequently manifest rapid and progressive deterioration of renal function leading to the clinical syndrome of rapidly progressive glomerulonephritis. Early and aggressive treatment can often delay or prevent the development of end-stage renal disease (ESRD). See Table 10.1 for an etiologic and pathogenetic classification of CrGN.

Immunoglobulin A nephropathy

The term immunoglobulin A nephropathy (IgA nephropathy or IgA N) refers to a primary glomerular disease characterized by the dominant or co-dominant, diffuse, and generalized mesangial deposition of IgA, often accompanied by deposition of IgG and the C3 component of complement in a similar distribution (Donadio and Grande, 2004; Barratt and Feehally, 2005; Tomino, 2007; Glassock, 2008; Lai, 2008). In the past, it has also been referred to as Berger's disease, to signify the senior author of the original publication describing the disorder that first appeared more than 4 decades ago in September of 1968 (Berger and Hinglais, 1968). IgA N is most likely the commonest primary glomerular disease in the developed world (D’Amico, 1987). The disease is characterized principally by episodic glomerular hematuria often with persistent proteinuria of a variable degree. It usually runs an indolent course, but may lead to end-stage renal disease (ESRD) in about 30–50% of cases after 25 years or more of follow-up.

Membranous nephropathy

Membranous nephropathy (MN) is a glomerular disease which is characterized histologically by uniform thickening of the glomerular capillary due to the presence of immunoglobulin-containing deposits on the outer or subepithelial aspect of the glomerular basement membrane (GBM). It exists in idiopathic (etiology unknown) or secondary (causally associated with another disorder) forms. Differentiation of the idiopathic membranous nephropathy (IMN) from secondary forms of MN may be difficult. It is a frequent cause of the nephrotic syndrome in adults. It is also characterized by a tendency for spontaneous remission in some patients and by persistence of proteinuria and slow progression to end-stage renal disease (ESRD) in others. Those patients with severe and un-remitting nephrotic syndrome may also suffer from disabling and even life-threatening extra-renal complications, such as thromboembolic events.

Minimal change nephropathy

Minimal change nephropathy (MCN), also called ‘minimal change disease’ in the USA, is chiefly characterized by episodes of nephrotic syndrome—presenting with massive proteinuria, hypoalbuminemia, generalized edema, hyperlipidemia—and no lesions or only minimal glomerular abnormalities in the renal biopsy examined by light microscopy.

Evaluation of observational and controlled trials of therapy

The literature on the subject of treatment of glomerular disease is immense (over 15,000 articles in PubMed as of July, 2008). Negotiating this broad and complex panorama can be a difficult task, especially in relationship to the evaluation of the best evidence for a particular treatment strategy for a specific disease entity occurring in an individual patient. Perfection is not attainable in clinical trials of therapy and every report has some pitfall or limitation. Some studies, however, stand out as excellent examples of design and execution. Unfortunately, in the field of treatment of glomerular disease such studies are relatively uncommon. The good news is that well designed and executed studies of treatment of primary glomerular disease are being reported with increasing frequency in recent years. This has occurred in part because of increased collaboration among groups interested in furthering knowledge in this important area of inquiry, but also because of better recognition of the deficiencies of past efforts to study treatment of glomerular disease in clinical trials. Many interinstitutional collaborative studies have been aided by improvements in trial design and by more complete descriptions of the natural history of untreated disease. One of the main weaknesses of clinical studies of therapy in primary glomerular disease is the small numbers of subjects studied in individual reports. This increases the risks of confounding and of both false positive and false negative results. The purpose of this chapter is to provide a concise analysis of the strengths and weakness of the various approaches to the study of therapeutic efficacy and safety of agents used in primary glomerular disease. The focus will be on observational studies, controlled clinical trials, and meta-analyses of published reports. The specific aims are to equip the discerning reader for improved understanding of the evidence-base for therapy of primary glomerular disease. The details of the specific reports and how they can be integrated into an ‘evidence-based’ approach to therapeutic decision-making are dealt with in the chapters devoted to specific disease entities which follow.

Membranoproliferative glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN, also known as mesangiocapillary glomerulonephritis) is a designation given to a very heterogeneous collection of disorders that manifest by light microscopy both mesangial hyper-cellularity and proliferation accompanied by broadening of the peripheral capillary loops (Holley and Donadio, 1994; Glassock et al., 1995; Strife and West, 2001; Glassock, 2008) due to reduplication of the glomerular capillary basement membrane (known as ‘double-contour’). In many instances, these broadened capillary loops also display prominent interposition of cells between the layers of the basement membrane and/or subendothelial or intra-membranous electron-dense deposits that may be accompanied by fragmentation or distortion of the basement membrane itself. The disorders encompassed by this definition also frequently display persistent reduction in serum complement levels (West et al., 1965).

Acute post-infectious glomerulonephritis

Acute post-infectious glomerulonephritis (APIGN) is a primary glomerular disease characterized by intra-glomerular inflammation and cellular proliferation resulting from immunological events triggered by a variety of bacterial, viral, and protozoal infections. We use the term ‘primary’ to describe this disease since the kidney is the only organ directly involved in the disease, and extra-renal manifestations are generally the consequence of disturbed kidney function. The prototype of APIGN is post-streptococcal glomerulonephritis (PSGN) which most often occurs in children following a pharyngeal infection caused by a particular strain of streptococci and has a favorable outcome. However in the last few decades the spectrum of APIGN has changed. The incidence of PSGN, particularly in its epidemic form, has progressively declined in industrialized countries. In many cases APIGN is caused today by other Gram-positive bacteria such as staphylococci or by Gram-negative bacteria. Moreover the disease tends to affect more and at a higher frequently adults with an immunocompromised background, due to alcoholism, diabetes, drug addiction, and/or viral hepatitis. Finally, while spontaneous recovery within few weeks is still the rule in children affected by the typical PSGN, the prognosis in immunodeficient adults is often severe and the response to treatment is uncommon. Therefore we will treat separately these two sub-types of acute glomerulonephritis.

Glucocorticoids and immunomodulating agents

Although the rationale for an etiological treatment of primary glomerulonephritis is still lacking, a number of clinical studies have shown that some subtypes of these diseases may benefit from empirical treatment based upon the use of glucocorticoids or immunomodulating agents. In this chapter the clinical pharmacology, the mechanisms of action, and the toxic effects of these drugs will be reviewed.

Other primary glomerular diseases

Fibrillary glomerulonephritis (FGN) and immunotactoid glomerulopathy (ITG) are both glomerular diseases characterized histologically by a diffuse increase in mesangial matrix due to deposits having a fibrillary structure by electron microscopy, which are negative for Congo-red stains but positive for immunoglobulin deposition. Most patients present with proteinuria, often in a nephrotic range, microhematuria, and hypertension. Almost half of patients have a reduced renal function at presentation. Although FGN and ITG have quite similar light microscopical and clinical features the current opinion is that they represent two separate diseases. FGN is an idiopathic (primary) condition characterized by polyclonal immune deposits with restricted gamma isotypes. Most patients present with significant renal insufficiency and have a poor outcome despite immunosuppressive therapy. By contrast, ITG very often contains monoclonal IgG deposits and has a significant association with underlying monoclonal paraproteinemia and hypocomplementemia. ITG is more properly classified as a mono-clonal immunoglobulin deposition disease (MIDD). Differentiation of FGN from the much more rare entity ITG appears justified on immunopathologic, ultrastructural, and clinical grounds (Fogo et al., 1993; Bridoux et al., 2002; Rosenstock et al., 2003). Both will be discussed together, although only FGN should be regarded as a primary glomerular disease, as defined in this monograph.

Focal and segmental glomerular sclerosis

Focal and segmental glomerular sclerosis (FSGS) is a glomerular lesion which is associated with distinctive clinical features. Because it may be pathogenetically heterogeneous, it is not yet appropriate to call it a disease, yet its discovery in a renal biopsy in a patient with the nephrotic syndrome does have important connotations with respect to response to treatment and to long-term outcome. By light microscopy the characteristic finding is segmental areas of sclerosis (and hyalinosis) involving only some glomeruli. Patients with the FSGS lesion typically have proteinuria which is usually in the nephrotic range (〉3.5g/d in an adult), accompanied by the typical constellation of signs and symptoms of the nephrotic syndrome and arterial hypertension. A minority of patients may have only asymptomatic proteinuria and these patients usually do not progress to end-stage renal disease (ESRD) but the natural course of FSGS is ominous in most patients with nephrotic syndrome. However, numerous observational studies have shown that about 50–70% of patients may respond completely or partially to prolonged glucocorticoid therapy or other ‘immunosuppressive’ treatments and thus have a fair outcome in the long term.