21.8.5 Proliferative glomerulonephritis 4933 Alan

21.8.5 Proliferative glomerulonephritis 4933 Alan D. Salama and Mark A. Little

21.8.5  Proliferative glomerulonephritis 4933 co-​trimoxazole) should be considered in these patients. Routine prophylaxis against gastrointestinal bleeding in patients taking cor- ticosteroids without nonsteroidal anti-​inflammatory drugs is no longer recommended. Adequate measures to prevent corticosteroid-​ induced osteoporosis are advocated. Treatment of secondary membranous nephropathy The therapy of secondary MN consists of removing the offending agent or treating the underlying disease. If this can be done success- fully the clinical manifestations are likely to resolve. Areas of uncertainty, controversy, and future developments The timing of initiation of immunosuppressive therapy in patients with nephrotic syndrome remains a matter of debate. Some advocate a conservative approach, based on the observation that up to 30% of MN patients achieve spontaneous remission of proteinuria, enjoy long-​term renal survival, and, as a consequence, should be spared the risks of immunosuppression. In patients with higher grades of proteinuria at presentation (>10 g/​24 h), however, the chance of spontaneous remission is much lower. One approach has been to start immunosuppression only when progressive loss of kidney func- tion occurs, and studies in this group of patients have been deemed successful because proteinuria and azotaemia decreased. However, careful review of the data shows that reversal of azotaemia is almost always incomplete and often transient, suggesting that the decline in GFR is merely attenuated. In addition, persistence of nephrotic syn- drome may lead to long-​term cardiovascular complications because lipid abnormalities remain uncorrected. Conversely, an early start of treatment has been demonstrated to reduce the risk of loss of renal function, but may expose a number of patients to unnecessary and potentially hazardous treatment. The prognostic value of the anti-​ PLA2R antibody titres may provide a compromise between these diverging approaches. Early treatment should be given to patients with severe nephrotic syndrome (e.g. proteinuria >10 g/​24 h) and high or increasing anti-​PLA2R antibody titres, while conservative therapy is continued in asymptomatic patients, who maintain pro- teinuria at less than 4 g/​24 h and have low or decreasing anti-​PLA2R antibody titres. Patients with severe kidney failure (serum creatinine

265 μmol/​L (3 mg/​dl)) are unlikely to benefit from immunosup- pression therapy, and as such treatment carries a high risk of serious adverse events, they should be managed conservatively. FURTHER READING Beck LH Jr, et al. (2009). M-​type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med, 361, 11–​21. Beck LH Jr, et al. (2011). Rituximab-​induced depletion of anti-​PLA2R autoantibodies predicts response in membranous nephropathy.
J Am Soc Nephrol, 22, 1543–​50. Bobart SA, et al. (2019). Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies. Kidney Int, 95(2), 429–38. Cattran DC, et al. (1997). Validation of a predictive model of idio- pathic membranous nephropathy: its clinical and research implica- tions. Kidney Int, 51, 901–​7. Cattran DC, et al. (2001). Cyclosporine in patients with steroid re- sistant membranous nephropathy: a randomized trial. Kidney Int, 59, 1484–​90. De Vriese AS, et al. (2017). A Proposal for a Serology-Based Approach to Membranous Nephropathy. J Am Soc Nephrol, 28(2), 421–30. Fervenza FC, et al. (2019). Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New Engl J Med, 381, 36–46. Hladunewich MA, et  al. (2009). The natural history of the non-​ nephrotic membranous nephropathy patient. Clin J Am Soc Nephrol, 4, 1417–​22. Howman A, et al. (2013). Immunosuppression for progressive mem- branous nephropathy:  a UK randomised controlled trial. Lancet, 381, 744–​51. Ponticelli C, et al. (1995). A 10-​year follow-​up of a randomized study with methylprednisolone and chlorambucil in membranous neph- ropathy. Kidney Int, 48, 1600–​4. Ruggenenti P, et  al. (2012). Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol, 23, 1416–​25. Sethi S, et al. (2019). Exostosin 1/Exostosin 2-associated Membranous Nephropathy. J Am Soc Nephrol (in press). Tomas NM, et al. (2014). Thrombospondin type-​1 domain-​containing 7A in idiopathic membranous nephropathy. N Engl J Med, 371, 2277–​87. 21.8.5  Proliferative glomerulonephritis Alan D. Salama and Mark A. Little ESSENTIALS Proliferative glomerulonephritis describes the finding of increased cellularity of the glomerulus, which may be due to proliferation of intrinsic glomerular cells, infiltration of leucocytes, or both. This principally occurs in the context of glomerular deposition of im- munoglobulins, immune complexes, or complement components. Different subtypes are described based on histological features: pro- liferation of mesangial cells, endocapillary proliferation, diffuse proliferation, or extracapillary proliferation (also termed crescentic glomerulonephritis). Patients will typically have haematuria, and this may be associated with proteinuria and/​or impairment of excretory renal function and/​or hypertension. The best characterized proliferative glomerulonephritis is post­ streptococcal glomerulonephritis. This most commonly affects children, who present with nephritis about 2 weeks after pharyn- gitis or skin infection caused by streptococci of Lancefield group A. Treatment is directed at eradicating the infection with an appro- priate antimicrobial and providing symptomatic relief. Recovery is the rule, although haematuria and proteinuria may persist. Acknowledgement: the chapter on proliferative glomerulonephritis in the fifth edition of this textbook was written by Professor Peter W. Mathieson. Much of his chapter is retained here.

section 21  Disorders of the kidney and urinary tract 4934 Introduction The term proliferative glomerulonephritis covers a wide variety of conditions (Box 21.8.5.1) where there is increased cellularity within the glomerulus, either due to the proliferation of resident glomerular cells, or infiltration of leucocytes, or both. The proliferative changes may be focal (only affecting some glomeruli) and/​or segmental (only affecting parts of each glomerulus). Many of these entities are considered in other chapters, and only those not covered elsewhere (Box 21.8.5.1) will be described here. Different forms of prolifera- tive glomerulonephritis may coexist, for example, in IgA nephrop- athy with mesangial, endocapillary, and extracapillary proliferation. Mesangial proliferative glomerulonephritis Patients will typically have haematuria and this may be associated with proteinuria and/​or impairment of excretory renal function and/​or hypertension. Most patients whose renal biopsies show only mesangial prolif- eration will have IgA nephropathy (see Chapter 21.8.1), but a few will have no IgA deposits and their classification is not straightfor- ward; possibilities include IgM nephropathy, ‘idiopathic’ mesangial proliferative glomerulonephritis, and C3 glomerulonephritides (see Chapter 21.8.6). IgM nephropathy There is continuing controversy about this diagnostic entity. In pa- tients with nephrotic syndrome, if the only abnormalities on the renal biopsy are in the mesangial region, with proliferation of mesangial cells and deposition of IgM, many authorities would assign a diag- nosis of minimal-​change nephropathy (see Chapter  21.8.3) and advocate treatment with corticosteroids. Some would consider that these morphological features are markers for a poorer prognosis and a reduced likelihood of a response to corticosteroids, but others would consider the patient to have a completely different disease entity and give a diagnosis of IgM nephropathy. Some of this confusion may be explained by methodological fac- tors: assessment of the degree of mesangial hypercellularity is sub- jective, and reagents to detect IgM are notoriously unreliable since they may give high background staining. Mesangial IgM has been found in up to 60% of ‘normal’ kidneys donated for transplantation, and the diagnostic significance of IgM is also cast into doubt by its presence in over 75% of controls as well as in patients with various other forms of glomerulonephritis. However, the presence of signifi- cant electron-​dense deposits on electron microscopy in some cases suggests that the IgM may not be nonspecifically deposited and may be part of a specific pathological process. The best support for the existence of IgM nephropathy as an entity distinct from minimal-​change nephropathy comes from the occur- rence of a familial form; from the identification of this pattern of glomerular injury in patients who, after lengthy follow-​up, have an appreciable risk of developing impaired excretory kidney function; and from a case report in which there was recurrence of IgM neph- ropathy after renal transplantation. Idiopathic mesangial proliferative glomerulonephritis This term may be applied if there is isolated mesangial proliferation without deposition of IgA or IgG, with no evidence of a systemic disorder such as systemic lupus erythematosus. With this patho- logical appearance it is important to exclude the rare entity of fibril- lary glomerulonephritis with electron microscopy. Again there is overlap with minimal-​change nephropathy; if the patient presents with nephrotic syndrome, most nephrologists would not allow the presence of mesangial proliferation to deflect them from treating the patient with corticosteroids, although there is evidence that the presence of this histological finding is associated with a poorer re- sponse rate. If, however, the patient has haematuria and/​or hyper- tension and/​or impaired kidney function, none of which are typical features of minimal-​change nephropathy, it is difficult to resist the need for another separate diagnostic category. Unfortunately, there are no informative studies to guide treatment or give information on prognosis. Glomerulonephritis with C3 deposition Proliferative glomerulonephritis associated with immune deposits restricted to C3, a key component of the complement cascade, is now termed C3 glomerulonephritis and is described in detail in the chapter on membranoproliferative glomerulonephritis (see Chapter 21.8.6). This lesion is associated with mutations in com- plement regulatory genes factor H and/​or factor I, and so almost certainly shares aetiological similarities with other forms of glom- erulonephritis seen in association with such genetic variants, such as haemolytic uraemic syndrome (see Chapter 21.10.6) and mesangiocapillary glomerulonephritis (see Chapter 21.8.6). Familial C3 glomerulonephritis caused by mutation of the comple- ment factor H-​related protein 5 gene (CFHR5) has been described in kindreds usually of Cypriot descent. Mutations in CFHR1–​4 causing C3 glomerulonephritis have recently been described. Affected indi- viduals invariably have nonvisible haematuria, and recurrent (often Box 21.8.5.1  Proliferative glomerulonephritis 1.  Proliferation of mesangial cells

— IgA nephropathy ± IgA vasculitis (HSP) disease

— IgM nephropathya

— Systemic lupus erythematosus

— Idiopathica 2.  Endocapillary proliferation

— Postinfectious glomerulonephritisa

— Infective endocarditis

— Other infections, including leprosy 3.  Extracapillary proliferation (crescent formation)

— Small vessel vasculitides (granulomatosis with polyangiitis/​micro- scopic polyangiitis)

— Antiglomerular basement membrane disease

— IgA vasculitis (HSP) disease

— Systemic lupus erythematosus

— HIV nephropathy (proliferation of podocytes)

— Idiopathic (rare) 4.  Diffuse proliferative glomerulonephritis (may include elements of 1–​3)

— Systemic lupus erythematosus

— Idiopathica a Conditions discussed in this chapter.

21.8.5  Proliferative glomerulonephritis 4935 synpharyngitic) visible haematuria is present in about 50% of pa- tients. Impaired renal function ensues in most affected males, but is much less common in females. Endocapillary proliferative glomerulonephritis Patients will often have impaired excretory function, haematuria, proteinuria, and hypertension, sometimes presenting acutely as a ‘nephritic syndrome’. On renal biopsy, the glomerular hypercellularity is confined within the glomerular capillary tuft, which is probably due to the combination of a proliferation of intrinsic (endothe- lial and mesangial) cells together with an infiltration of inflam- matory cells. This can occur in systemic lupus erythematosus (see Chapter 21.10.3), IgA disease, and as a complication of a variety of infections (see Chapter  21.10.8). Only postinfectious glomerulo- nephritis (PIGN) will be considered here, with the main focus on poststreptococcal glomerulonephritis. Poststreptococcal glomerulonephritis Most infection-​related glomerulonephritis occurs concurrently with the infection. By contrast, PIGN—​of which poststreptococcal glom- erulonephritis is the most frequent and best characterized—​occurs, as the name implies, after the infection. In poststreptococcal glom- erulonephritis the delay between the inciting infection and the onset of the renal complication may be long enough for the infection to have resolved, and this may contribute to diagnostic confusion. The typical case follows infection with streptococci of Lancefield group A (β-​haemolytic streptococci, Streptococcus pyogenes), either causing pharyngitis or skin infection such as cellulitis or impetigo. Children are most commonly affected, although the disease can occur in all age groups, and males more often than females. Poststreptococcal glomerulonephritis is less common in the developed than in the developing world, possibly influenced by socioeconomic factors. Approximately 2 weeks following the infection, sometimes longer after skin infections, the patient develops nephritis which may be suf- ficiently acute and severe to cause a nephritic syndrome with oliguria, hypertension, and oedema. If a renal biopsy is performed, it will show diffuse proliferative glomerulonephritis, with infiltration by neutro- phil polymorphs often particularly prominent (Figs. 21.8.5.1 and 21.8.5.2). Immunohistochemistry shows deposition of IgG, IgM, and complement in the mesangial and subepithelial areas, and electron microscopy shows large subepithelial deposits (‘humps’). Serological tests There are typical serological features which give clues to the patho- genesis, including IgG antibodies to streptococcal antigens and evidence of activation of the complement cascade. Reactivity with numerous streptococcal antigens has been reported, including streptolysin O, deoxyribonuclease B, hyaluronidase, and strepto- kinase. Antistreptolysin O (the ASO test) is the most useful diag- nostic test after pharyngitis; anti-​DNase B is best after skin infections. Hypocomplementaemia (low C3 in most cases, also low C4 in some) reflects activation of both the alternative and the classic pathways (the complement system is discussed in more detail in Chapter 21.8.6). In poststreptococcal glomerulonephritis, the alter- native complement pathway may be activated by bacterial antigens and/​or by IgG autoantibodies called nephritic factors, which re- semble those seen in mesangiocapillary glomerulonephritis; the classic pathway may be activated by circulating immune complexes. Pathogenesis It is believed that the pathogenesis of poststreptococcal glomerulo- nephritis can be explained as follows: streptococcal antigens are de- posited in glomeruli by virtue of some aspect of their charge, size, or other physicochemical characteristics, during the early phase of the infection. After the 10 to 14 days necessary for the host to mount an immune response to the bacterial infection, circulating antibody ap- pears and binds to the ‘planted’ glomerular antigens. Complement is activated, leucocytes are attracted (by complement-​activation prod- ucts C3a and C5a among other chemoattractants), and an inflam- matory reaction is provoked, injuring the glomeruli. The precise nature of the streptococcal antigens that act in this nephritogenic manner remains controversial; only certain sero- logical types of streptococci (referred to as M types and serotyped according to cell wall protein antigens) are capable of inciting Fig. 21.8.5.1  Poststreptococcal glomerulonephritis. The glomerulus shows significant hypercellularity with many neutrophils. Fig. 21.8.5.2  Poststreptococcal glomerulonephritis. The electron micrograph shows three large subepithelial ‘humps’, and a single small subendothelial deposit (arrow). Reproduced with permission from Rodríguez-​Iturbe B, and Haas M. Post-​ streptococcal glomerulonephritis. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4936 glomerulonephritis, but the M proteins themselves are not believed to be nephritogenic. In addition to the planted antigen mechanism, streptococci may lead to glomerulonephritis by their other complex effects on the immune response. These include the direct activation of T cells by a superantigen effect, whereby M proteins can bind to particular Vβ regions of the T-​cell receptor and activate families of T cells sharing receptors of this ‘family’. Antigenic cross-​reactivity (‘molecular mimicry’) similar to that thought to be responsible for rheumatic fever may also occur, so that antistreptococcal antibodies cross-​react with, and therefore bind to, renal autoantigens such as laminin and collagen. The immunopathological mechanisms previously outlined may be instructive in understanding other forms of glomerulonephritis where the inciting stimulus is not so evident. Management Treatment of patients with poststreptococcal glomerulonephritis should be directed at eradicating the infection (a 10-​day course of penicillin or erythromycin is advised even if the original infection appears to have resolved) and providing symptomatic relief of the consequences of the acute nephritis, including aggressive treatment of hypertension, which is common but generally transient; salt and water restriction, with or without diuretics, for oedema; and dialysis if necessary (which is uncommon). The prognosis in children is good, but historical series describe early mortality in adults of 25%, mainly due to cardiovascular com- plications. Haematuria, proteinuria, and hypertension may persist. Some authors believe that in the long term there is a risk of chronic renal failure, but this is uncertain: adult communities with a high incidence of poststreptococcal glomerulonephritis (e.g. aboriginal populations) have a high prevalence of other conditions that cause chronic renal failure (e.g. diabetes). Nonstreptococcal postinfectious/​infection-​related proliferative glomerulonephritis It is apparent in modern series of patients with infection-​related glomerulonephritis that similar clinical and histopathological fea- tures occur without evidence of prior streptococcal infections. In one series from France describing 76 adult patients from suburban Paris, including a high proportion of alcoholics and intravenous drug abusers, staphylococci and Gram-​negative organisms were more commonly isolated than streptococci, and a poor renal prog- nosis was reported. The importance of knowledge of local variations in prevalent in- fections or other environmental factors is further emphasized by the description of a novel form of eosinophilic glomerulonephritis in a large series of children from rural Uganda (Fig. 21.8.5.3). The cause of this is not known, but it does not seem to be attributable to streptococcal infection, or to HIV or malaria that are also locally prevalent. Symptomatic treatment allows most children to recover. Various infectious agents have been described in association with PIGN, including viral (rotavirus, parvovirus, influenza), parasitic (plasmodium), and bacterial (borrelia, pneumococcus, klebsiella) agents, with many case reports or cohorts describing additional mi- crobes that have rarely been associated with PIGN. However, there is some dispute whether these should be termed postinfectious or infection related, the former being reserved for glomerulonephritis that arises following a resolved infection. A form of IgA-​rich PIGN has been described recently. This was originally reported in diabetics and older patients, often following a coagulase-​positive staphylococcal infection, frequently a methi- cillin resistant form (MRSA). It may be difficult to differentiate this condition from classical IgA nephropathy, with deposited IgA dominant or codominant with IgG, and in association with C3 deposition. There may be associated crescent formation. Again, this may not be a true postinfectious entity, but rather may relate to ongoing immune complex deposition in the presence of active infection. The basic principles of management of infection-​related glomer- ulonephritis apply, including eradication of the infection if possible, supportive care during the acute phase, and moves towards pre- vention whenever possible by detailed investigation of underlying causes. Idiopathic diffuse proliferative glomerulonephritis A few cases will have no preceding history of infection, no evidence of lupus, and/​or atypical features on the renal biopsy. These may be assigned the unsatisfactory ‘idiopathic’ descriptor, with the implica- tion that the prognosis and the appropriate treatment are uncertain. FURTHER READING Gale DP, et  al. (2010). Identification of a mutation in complement factor H-​related protein 5 in patients of Cypriot origin with glomer- ulonephritis. Lancet, 376, 748–​50. Glassock RJ, et al. (2015). Staphylococcus-​related glomerulonephritis and poststreptococcal glomerulonephritis: why defining ‘post’ is im- portant in understanding and treating infection-​related glomerulo- nephritis. Am J Kidney Dis, 65, 826–​32. Ji-​Yun Y, et  al. (1984). No evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome. Kidney Int, 25, 100–​6. Myllymäki J, et al. (2003). IgM nephropathy: clinical picture and long-​ term prognosis. Am J Kidney Dis, 41, 343–​50. Fig. 21.8.5.3  Eosinophilic proliferative glomerulonephritis. Numerous eosinophils (some arrowed) expand the glomerulus.