- Email: [email protected]
Primary glomerular disease
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Primary glomerular disease
incidences range from 17 to 60 cases per million population. Any age group may be affected, though some types are particularly common in children. GN is an important cause of end-stage renal disease (ESRD), a condition that causes major morbidity and mortality and consumes a disproportionate amount of health expenditure. Late diagnosis of GN remains a major problem; non-specialists can have a vital role in improving the management of GN by knowing when to suspect it, arranging appropriate investigations and making early referral to a nephrologist.2 Proteinuria is a cardinal feature of GN and the importance of proteinuria to the generalist is emphasized by the fact that it is now accepted as an unequivocal independent cardiovascular risk factor.3 Proteinuria may be asymptomatic, especially at low levels; when severe it may be associated with nephrotic syndrome in which the patient’s main symptomatic complaint is typically oedema. The age of the patient influences the frequency of causes of nephrotic syndrome (NS): in children under 10 years of age in the developed world, about 80% of NS is caused by minimalchange nephropathy (MCN, see below). Studies from several countries show an increasing incidence of focal segmental glomerulosclerosis (FSGS) over the last decade.
Peter Mathiesona
Abstract This article reviews the clinical features, pathogenesis, investigation and management of glomerulonephritis (GN). This can occur as a primary isolated renal disease, as a manifestation of systemic diseases such as vasculitis or lupus, or secondary to drugs, infections or tumours. It is an important cause of morbidity and mortality and a potentially preventable cause of end-stage renal disease, so early diagnosis is vital to allow timely referral to specialist units where renal biopsy can be performed. Proteinuria and/or haematuria are typical findings. Pathogenesis involves cells and mediators of the immune system, including the complement pathway. Intrinsic glomerular cells, especially podocytes, are important in glomerular injury and the response to it. I present schemes for appropriate investigations when GN is suspected, guidelines for referral, and strategies for investigation of proteinuria and haematuria, and for management of common forms of GN. Nephrotic syndrome (heavy proteinuria, hypoalbuminaemia and oedema) causes major morbidity and potential mortality and should be managed, irrespective of the cause, with diuretics, antiproteinuric agents, cholesterollowering agents and, sometimes, anticoagulants. Treatment with corticosteroids, with or without other immunosuppressive agents, is effective in many forms of GN, but toxicities are problematic. Improved understanding of pathogenesis of GN promises more specific forms of treatment in the future.
When should glomerulonephritis be suspected? Primary glomerular disease presents clinically with abnormalities of the urine, often with hypertension, oedema and/or impaired excretory renal function (Table 2). As routine health screening becomes more widespread,4 and with the availability of cheap, reliable urine dipstick tests, asymptomatic abnormalities of the urine will be detected more commonly.5 Patients presenting with hypertension, ankle oedema or nonspecific ill health should always undergo urine testing. Protein dipsticks are semiquantitative; underlying renal disease, particularly GN, is very likely when proteinuria greater than 1þ is detected. One important point is that asymptomatic urinary tract infection does not cause proteinuria. One of the most common responses to the finding of proteinuria is to send a mid-stream urine sample (MSU) to be tested for infection. This is not an adequate response.6 Quantification of the proteinuria and investigation of the possible causes are required. Quantification
Keywords complement; glomerulonephritis; haematuria; kidney; nephrotic syndrome; podocyte; proteinuria; treatment
The term glomerulonephritis (GN) covers a group of conditions in which there is injury in the glomerulus, the filtering unit of the kidney. This can occur either as a primary glomerular disease, or secondary to drugs, infections or tumours (see Secondary Glomerular Disease, pp 464e466 of this issue). GN may be isolated or a manifestation of renal involvement in a systemic disease (Table 1). Diagnosis of GN, and particularly its subdivision into various categories, depends on clinical features, laboratory data and histological analysis. Renal biopsy, which is undertaken in specialist centres, is a crucial element in the management of glomerular diseases.1
Epidemiology of GN
Systemic diseases in which glomerulonephritis may feature
Reported incidences of GN vary depending on ascertainment bias and variations in renal biopsy policies. In the UK, estimated
C
Peter Mathieson FRCP PhD FMedSci is Professor of Medicine and Dean of the Faculty of Medicine & Dentistry at the University of Bristol, UK. He qualified in London and started his research career in Cambridge (PhD 1992) before moving to Bristol in 1995. His research interests are focused on human glomerular cell biology and the effects of immunosuppressive and anti-inflammatory therapies. Competing interests: none declared. a I dedicate this article to the late Momir Macanovic who co-authored the original version with me. Momir sadly died in April 2007 and I miss him.
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C C C
C
C
Connective tissue diseases, particularly systemic lupus erythematosus Systemic vasculitis Infective endocarditis Other infections, including methicillin-resistant Staphylococcus aureus, malaria, hepatitis B and C virus, HIV Drug reactions, particularly non-steroidal anti-inflammatory drugs; also gold, penicillamine Carcinoma, lymphoma, myeloma
Table 1
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Presentation of primary glomerular disease (GN) C C
C C
C
C
Non-specific measures in the management of people with nephrotic syndrome
Asymptomatic proteinuria Microscopic haematuria (occasionally macroscopic, particularly with concurrent infections in immunoglobulin A nephropathy) Hypertension Nephritic syndrome (acute GN and rapidly progressive GN) with acute onset of haematuria, proteinuria, ‘active urinary sediment’ with red cells, white cells, cellular casts, oliguria, hypertension, oedema, impaired excretory renal function) Nephrotic syndrome (heavy proteinuria >3.5 g/day, hypoalbuminaemia and oedema) Impaired excretory renal function (assessed by serum creatinine, or by estimated glomerular filtration rate. If severe, there may be symptoms of uraemia: nausea, vomiting, anaemia, pericarditis, hypertension, and coma
C
C
C
C
Table 2
C
can be by timed (usually 24-hour) urine collection or more simply by estimation of albumin:creatinine ratio (ACR) on a random urine sample. Casts can be identified by simple microscopy of fresh urine after gentle centrifugation: cellular casts are particularly significant because they indicate acute inflammation in the kidney, usually from GN. Dysmorphic (irregularly shaped) red blood cells (RBCs) in a fresh urine sample are suggestive of haematuria of glomerular origin. Urine analysis also provides information about the severity of glomerular disease. Heavy proteinuria, marked haematuria and/or RBC casts generally indicate more severe disease than isolated microscopic haematuria or lowgrade proteinuria. When either proteinuria or haematuria is associated with evidence of systemic disease, or there is loss of excretory renal function, referral to a nephrologist may be particularly urgent. Rapidly progressive glomerulonephritis is a medical emergency requiring urgent treatment to prevent irreversible kidney damage.
Table 3
when GN complicates infections or tumours). In many cases, the target is unknown and an autoimmune aetiology is suspected. As in other autoimmune conditions, primary GN is thought to result from the combination of genetic susceptibility and an environmental precipitant.9 The genetic factors are typically genes involved in control of the immune response, particularly the major histocompatibility complex human leucocyte antigen (HLA) genes. The environmental precipitants may be drugs, chemicals or infectious agents. The known predisposing factors are considered in more detail below. The role of immune mechanisms in the pathogenesis of GN is indicated by the presence of circulating autoantibodies and/or abnormalities of serum complement, and glomerular deposition of antibodies, immune complexes, complement and fibrin.
Nephrotic syndrome Nephrotic syndrome (NS) is defined by heavy proteinuria, hypoalbuminaemia and oedema. Primary GN is an important cause of NS, although NS may also result from secondary glomerular disease, diabetic nephropathy or amyloidosis. Urine should be tested in all patients presenting with oedema; if there is no proteinuria, it is unlikely that renal disease is the cause of the oedema. In addition to specific treatment of the underlying condition, non-specific measures remain important in the management of patients with NS (Table 3).7,8
The complement system in glomerulonephritis The association of abnormalities of the complement system with renal disease is well established. Initial observations included alterations in the serum concentration of specific complement components and/or glomerular complement deposits. Recent advances have highlighted new pathogenetic mechanisms.10,11 Hypocomplementaemia is used as a diagnostic marker and for monitoring treatment response in some forms of GN. The complement components most frequently measured in clinical practice are C3 and C4. Chronic bacteraemic states, poststreptococcal GN or lupus nephritis are frequently accompanied by reduction of the classical pathway activation protein C4 along with C3. In lupus nephritis, the extent of hypocomplementaemia can be useful for monitoring disease activity non-invasively. In mesangiocapillary GN (MCGN, see below), the pattern of
Pathogenesis of glomerulonephritis Immune reactions underlie GN, with contributions from cellular immunity (T lymphocytes, macrophages), humoral immunity (antibodies, immune complexes, complement) and other inflammatory mediators (including the coagulation cascade). In some cases, the target of the immune response is known (e.g.
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Oedema can be reduced by salt restriction and diuretics; water immersion may be effective for intractable oedema Hypertension should be treated using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) as the drugs of first choice. These have additional antiproteinuric effects and delay the progression of renal disease8 Patients usually have hypercholesterolaemia, which should be treated with a statin since dietary measures alone are usually ineffective There is a predisposition to infection, partly because of associated hypogammaglobulinaemia; also, cellulitis is common in oedematous tissues. Consequently, there should be a low threshold for administration of systemic antibiotics and vaccination against encapsulated bacteria A prothrombotic state is present, so disproportionate limb swelling, breathlessness, chest pain or haemoptysis should raise the suspicion of thromboembolism and a need for systemic anticoagulation. Renal vein thrombosis is a particular problem in patients with nephrotic syndrome; it may be silent or may cause flank pain, macroscopic haematuria or deterioration in excretory renal function
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complement depletion differs between the different subtypes and is useful in diagnosis. Glomerular deposits of complement in GN, especially C3, can be visualized by immunohistochemistry. Complement deposits may be dominant (as in MCGN) or associated with immunoglobulin deposits (as in many other forms of GN). Deficiencies of certain complement components are also associated with primary forms of GN and may also be seen in systemic disease with renal involvement, such as lupus nephritis. Deficiency of the regulatory protein, factor H, has been implicated in both haemolytic uraemic syndrome and in MCGN, suggesting shared pathogenetic mechanisms between these two apparently different conditions. Intriguingly, another apparently unrelated disorder, age-related macular degeneration (ARMD), appears to share similar pathogenetic mechanisms.11 Several autoantibodies directed against complement components have been identified. C3 nephritic factor (C3NeF), an autoantibody against the C3 convertase of the alternative pathway (C3bBb), is strongly linked with MCGN. Patients with C3NeF develop MCGN in 50% of cases and virtually all patients with type II MCGN have a high serum concentration of C3NeF. Anti-C1q autoantibodies have been related to nephritis in lupus patients. About one-third of lupus patients have high titres of anti-C1q antibody; these antibodies are strongly associated with hypocomplementaemia and severe lupus nephritis.
nephropathy. The cells lining Bowman’s capsule are called parietal epithelial cells. These may be involved in crescent formation in severe forms of GN. Glomerular endothelial cells are primarily injured in pre-eclampsia and in haemolytic uraemic syndrome. Mesangial cells appear to be secondarily injured in a variety of glomerular diseases. Production of cytokines and other mediators by intrinsic glomerular cells may be responsible for attraction and/or activation of leucocytes and for manifestations of glomerular injury including proteinuria.
Subtypes of glomerulonephritis Different patterns of abnormality within the glomerulus may be used to define subtypes of glomerular disease (Table 4). However, a single morphological pattern may be associated with several aetiologies. In some cases, more specific patterns of glomerular abnormality suggest that the GN is secondary to a well-defined aetiology. Although there is overlap in presentation, treatment and markers of good prognosis, the distinguishing features of the most common forms of primary glomerular disease are discussed below. Minimal-change nephropathy (MCN) (lipoid nephrosis, nil disease, minimal-change disease) typically presents with nephrotic syndrome and occurs in both children and adults, although it is most common in children. More than 80% of children in the developed world below the age of 10 years with primary nephrotic syndrome, and about 20% of adults, have MCN. It is very rarely associated with hypertension, hypocomplementaemia, haematuria, cellular casts in urine or persistent impairment of excretory renal function. MCN is occasionally secondary to drug use (particularly non-steroidal anti-inflammatory drugs (NSAIDs)) or malignancy (particularly Hodgkin’s disease and other lymphomas). The idiopathic form is believed to result from an abnormality of T lymphocytes, but extensive searches for lymphocyte-derived permeability factors have not produced consistent results. Renal biopsy is normal by light microscopy and immunohistology, but electron microscopy shows typical abnormalities. Most patients (>90%) respond to high-dose corticosteroids (prednisolone, 1 mg/kg/day, maximum 80 mg/day; Figure 2). Remission usually occurs between days 7 and 14, though some adult patients may need up to 16 weeks’ therapy to achieve
Intrinsic glomerular cells in glomerular nephritis There has been considerable recent interest in the role of intrinsic glomerular cells in the initiation and/or progression of glomerular injury. Much attention has focused on the podocyte12 (also known as the visceral glomerular epithelial cell, Figure 1). It is now recognized that mutations in podocyte-specific genes cause many congenital or early-onset forms of nephrotic syndrome, although their importance in apparently sporadic cases remains uncertain. Podocytes are terminally differentiated cells with very limited capacity for repair or regeneration, and podocyte loss is thought to be a major factor in progression of glomerular injury, including that occurring in non-GN conditions such as diabetic
Subtypes of glomerulonephritis C
C C C C C
Figure 1 Scanning electron micrograph of normal human glomerulus showing podocytes.
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Minimal-change nephropathy (renal biopsy normal on light microscopy; electron microscopy shows typical features) Focal segmental glomerulosclerosis Membranous nephropathy Immunoglobulin A nephropathy Mesangiocapillary glomerulonephritis Focal necrotizing glomerulonephritis, often with ‘crescents’ (associated with the clinical syndrome of rapidly progressive glomerulonephritis)
Table 4
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a temporary reduction in proteinuria achieved by plasmapheresis in these cases suggests a circulating permeability factor. Diagnosis of FSGS requires kidney biopsy. Histology shows areas of scarring in glomeruli; the sclerotic changes are focal (affecting some glomeruli and not others) and segmental (affecting only parts of individual glomeruli). Similar glomerular changes are seen as a secondary phenomenon when the number of functioning nephrons is reduced for any reason (e.g. nephrectomy, ischaemia, other primary renal disease), leading to the hypothesis that FSGS results from ‘overloading’ (hyperfiltration) of the remaining nephrons. There is evidence to support this theory in experimental animals, but no direct evidence in humans. Similar changes may be seen in association with extreme obesity. In recent years, a variant of FSGS has been recognized in association with HIV infection; this is so-called ‘collapsing’ FSGS, in which the glomerulus collapses as a result of proliferation of the surrounding epithelial cells, filling Bowman’s space. Untreated FSGS carries a high risk of progression to renal insufficiency. In primary FSGS, treatment with a prolonged course of high-dose corticosteroids (prednisolone 1 mg/kg/day up to a maximum 80 mg/day for up to 6 months) is advocated by some authorities (Figure 3). Prednisolone should be continued for 1e2 weeks after remission has been induced and then tapered very slowly. In patients who relapse after repeated courses of corticosteroids, and in corticosteroid-resistant patients, ciclosporin (3e5 mg/kg/day for 4e12 months) may induce remission, but relapse is common when treatment is stopped. An angiotensin-converting enzyme inhibitor (ACEI) to reduce proteinuria and statins for hyperlipidaemia should also be given. The disease often progresses; ESRD develops in about 50% of patients within 10 years. There is no evidence that corticosteroids or other immunosuppressive agents are effective in secondary forms of
Management of minimal-change nephropathy Prednisolone 1 mg/kg/day (maximum 80 mg/day)
Remission in >90% of patients
Failure in <10% of patients
Reduce dose
Second-line agents
Remission
Relapse
Repeat prednisolone treatment or Figure 2
complete remission. After disappearance of proteinuria, or 1 week after remission is induced, the corticosteroid dose is reduced to 0.5 mg/kg/day and then tapered slowly. An attempt to stop treatment should be made after 8 weeks. Longer durations of corticosteroid therapy significantly reduce the risk of relapse. Relapse is common as the dose is reduced. In patients who suffer a relapse, the course of corticosteroids should be repeated. Up to 50% of patients remain corticosteroid-dependent. In these, alkylating agents, such as cyclophosphamide or chlorambucil, are sometimes successful. The cyclophosphamide regimen is 1.5e2 mg/kg/day with concomitant prednisolone 7.5e15 mg/day for 8e12 weeks. The neutrophil count must be checked every 2 weeks and cyclophosphamide stopped if it falls below 2000/mm3. Mycophenolate mofetil (MMF) has been used with good effects in the treatment of corticosteroid-dependent or frequently relapsing MCN in adults. Ciclosporin (3e5 mg/kg/ day) is effective in some corticosteroid-resistant or corticosteroiddependent patients. Blood ciclosporin should be checked and dosage adjusted to achieve trough concentrations of 80e150 ng/ ml. Low-dose prednisolone (7.5e15 mg/day) is given with ciclosporin. Tacrolimus, another calcineurin inhibitor, is an alternative if ciclosporin is ineffective or poorly tolerated. There is considerable overlap in toxicity seen with these two agents, including their unfortunate tendency to cause nephrotoxicity. In corticosteroid-dependent children, levamisole (2.5 mg/kg to a maximum of 150 mg on alternate days) is useful for maintenance of remission, but its mode of action is unexplained.
Management of nephrotic focal segmental glomerulosclerosis Prednisolone 1 mg/kg/day (maximum 80 mg/day) for maximum of 12 weeks
Focal segmental glomerulosclerosis (FSGS) typically presents with asymptomatic proteinuria or nephrotic syndrome. It is more likely than MCN to be associated with hypertension, microscopic haematuria, impaired excretory renal function and/or corticosteroid resistance. Proteinuria is non-selective (the urine contains both albumin and higher molecular weight proteins) and the serum concentration of complement components is normal. Primary FSGS tends to recur after renal transplantation and
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Remission in 20–50% of patients (?maximized by 6 months)
Failure in 50–80% of patients
Reduce dose
Second-line agents
Remission
Relapse
Repeat prednisolone treatment or Figure 3
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FSGS and they are not recommended. Obese patients should be encouraged to lose weight.
anticoagulation if the plasma albumin is below 20 g/litre (2 g/dl). As in other conditions with nephrotic syndrome, patients with MN have hyperlipidaemia and an increased risk of cardiovascular disease. Therefore, statins should be used in patients with highgrade proteinuria and hyperlipidaemia. In patients receiving long-term and/or high-dose corticosteroids, bisphosphonates should be considered, to reduce bone loss. Several other drugs, including ciclosporin plus low-dose prednisolone (10 mg/day) and MMF, have been tried in the treatment of MN.
Membranous nephropathy (MN) typically presents with proteinuria, which may be asymptomatic or sufficiently severe to cause nephrotic syndrome. Microscopic haematuria, hypertension and/or impaired excretory renal function may occur; the latter two are poor prognostic signs. Identical glomerular histology is seen in the primary (‘idiopathic’) form and when MN is secondary to drugs (particularly NSAIDs, gold, penicillamine), solid-organ tumours (particularly carcinoma of the bronchus, colon or breast), infection (particularly hepatitis B and C), SLE (lupus nephritis class V) or hypothyroidism. Secondary MN is associated with malignancy in up to 20% of patients over the age of 60 years, so screening investigations (especially if there are suggestive symptoms or signs) can include chest X-ray, mammography, colonoscopy, faecal occult blood, and prostatespecific antigen. There have been striking recent advances in the understanding of MN. Susceptibility to idiopathic MN and to some forms of secondary MN is closely linked to the major histocompatibility complex (MHC) with a recent study showing tight linkage to HLA-DQA1 and also to a locus on chromosome 2 that coincides with the gene encoding PLA2R, the putative autoantigen.13 Of patients with the idiopathic form of the disease, 70e80% have autoantibodies to the phospholipase A2 receptor (PLA2R).14 Interestingly, these autoantibodies seem to be absent in secondary MN, although this remains to be proven in larger numbers of subjects. Another intriguing recent observation is the transplacental transfer of immunoglobulin G (IgG) antibodies causing MN in the fetus/neonate, arising due to maternal deficiency of a protein that acts as an immunizing neoantigen during pregnancy with a fetus expressing the normal protein.15 The prognosis of secondary MN depends entirely on the prognosis of the underlying condition. In MN secondary to drugs, complete resolution can be expected when the offending drug is withdrawn. Malignancy-associated MN has a poor prognosis unless the associated tumour can be eradicated. The efficacy of immunosuppressive therapy in idiopathic MN remains controversial. At least 25% of patients exhibit spontaneous remission of proteinuria even without treatment, and most nephrologists reserve treatment for those with poor prognostic signs, particularly deteriorating excretory renal function and/or heavy proteinuria (>8 g/day) with severe nephrotic syndrome. A combination of prednisolone and an alkylating agent (either chlorambucil or cyclophosphamide) given in alternating monthly cycles for a total of 6 months appears to be the most efficacious treatment in trials. Many centres use this so-called ‘Ponticelli regimen’ (or slightly modified versions thereof) in the treatment of MN (months 1, 3 and 5 methylprednisolone 1 g/day pulse dose intravenously for three consecutive days followed by oral prednisolone 0.5 mg/kg/day for subsequent 27 days; months 2, 4 and 6 chlorambucil 0.1e0.2 mg/kg/day or cyclophosphamide 2.5 mg/ kg/day for 30 days). ACEIs (and possibly also angiotensin receptor blockers (ARBs)) reduce proteinuria and may slow progression of renal insufficiency. Nephrotic syndrome caused by MN is associated with a particular risk of thrombotic complications in 10e30% of cases, so many nephrologists routinely prescribe anticoagulants to such patients. The risk:benefit ratio favours prophylactic
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IgA nephropathy (IgAN, Berger’s disease) is the most common type of GN worldwide. It typically presents with episodes of haematuria, which may be macroscopic, particularly in those with concurrent infection of the upper respiratory tract. Proteinuria is variable. The prognosis is generally good in patients without associated heavy proteinuria, hypertension or impairment of excretory renal function. The risk of eventual development of ESRD is about 25% in those with proteinuria of more than 1 g/24 hours (or an ACR >100). On renal biopsy, the pathognomonic feature of IgAN is deposition of polymeric IgA in the glomerulus, usually associated with proliferation of intrinsic glomerular cells. The aetiology is unknown, but there is increasing evidence that the primary abnormality is in the IgA system, not in the kidney. Up to 50% of patients exhibit elevated serum IgA concentrations, and there is evidence that the IgA is chemically abnormal, with altered carbohydrate constituents. An identical glomerular lesion is seen €nlein purpura (HSP), in which it is accompanied in HenocheScho by a vasculitic rash, often with arthritis and/or gastrointestinal inflammation. HSP is more common in children and often resolves spontaneously, though tissue injury in the acute phase may be very severe, necessitating corticosteroid therapy. Transplantation is an option for patients with IgAN who reach ESRD. The disease recurs in more than 50% of patients but rarely causes transplant failure, presumably because the immunosuppressive drugs used for the prevention of rejection have a favourable effect on the GN. Immunosuppressive drugs (cyclophosphamide and corticosteroids) are not widely used, though it is suggested that they hasten recovery in some aggressive forms of the disease and in HSP. Current trends include the use of fish oils, which in some trials have been shown to protect renal function in poor-prognosis subgroups. ACEIs are the firstchoice antihypertensive agents; some nephrologists advocate their use (or that of ARBs) even in normotensive patients. ACEI or ARB or both in combination not only control blood pressure (to the target of 125e120 mmHg systolic), but also reduce proteinuria and delay progression to ESRD. Mesangiocapillary GN (MCGN, also known as membranoproliferative GN, MPGN) is uncommon. There are three subtypes, with indistinguishable clinical presentations (proteinuria, haematuria, hypertension, hypocomplementaemia, impaired renal function) and findings on conventional histology. The subtypes are defined according to appearances on electron microscopy and probably have different pathogeneses. MCGN is associated with activation of the complement cascade, involving the classical pathway (low C4 and C3) in type I MCGN, the alternative pathway (low C3, normal C4) in type II, or the terminal pathway (type III).
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Type II MCGN may be associated with partial lipodystrophy, in which selective loss of fat cells in the face and upper trunk gives patients a characteristic cadaveric appearance. Type II MCGN may also be associated with abnormalities in the eye, especially with prominent presence of drusen (deposits within Bruch’s membrane). Recent observations provide a unifying explanation for this, and again involve regulation of the alternative pathway of complement. Recently it has been reported that variations in the gene-encoding factor H, the regulator of the alternative complement pathway mentioned above, predispose to age-related macular degeneration (ARMD). Drusen are the hallmark lesions of ARMD; histologically, these lesions show evidence of local complement activation. It is likely, therefore, that drusen result from dysregulated complement activation in the subretinal pigment epithelial layer in exactly the same way as glomerular injury occurs when the alternative pathway escapes its normal tight regulation. Secondary forms of MCGN are usually of type I pattern and result from chronic infection (visceral abscesses, infective endocarditis, infected prosthetic materials such as ventriculoperitoneal shunt) or cryoglobulinaemia (which may complicate infections, particularly HCV). All types of MCGN tend to have a progressive course. Up to 50% of patients develop end-stage renal failure within 10 years. There is a tendency to histological recurrence in kidney transplants, though this seldom causes graft loss. Treatment of idiopathic MCGN is difficult. It is essential to achieve good blood pressure control and to treat other complications such as hypercholesterolaemia. The only other intervention for which there is some support from clinical trials is high-dose corticosteroids, but these are not universally effective and adverse effects may be limiting. Therapy aimed at blocking complement activation would be useful, and several such treatments are in development.
Figure 4 Glomerulus from a patient with anti-neutrophil cytoplasmic antibody-associated focal necrotizing glomerulonephritis showing segmental necrosis (H and E stain).
commonly, there is no immunoglobulin in the glomerulus in cases of RPGN and the condition is termed ‘pauci-immune FNGN’; at least 80% of these patients exhibit circulating ANCA. ANCA are closely associated with systemic vasculitis,
Focal necrotizing GN (FNGN) usually presents with acute nephritic syndrome (acute renal failure (ARF), haematuria, proteinuria, cellular casts in the urine). This is sometimes associated with pulmonary haemorrhage, and this combination is known as pulmonary renal syndrome. Goodpasture’s disease is one cause of this syndrome and is due to anti-glomerular basement membrane antibodies. A more common cause of the syndrome is small-vessel vasculitis (microscopic polyangiitis, Wegener’s granulomatosis) which is usually associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Other causes include SLE, cryoglobulinaemia and HSP. FNGN is the renal lesion typically associated with the clinical syndrome of RPGN and is a medical emergency. Untreated FNGN progresses rapidly to renal insufficiency. Severe acute inflammation occurs in the glomerulus, sometimes with formation of ‘crescents’ when the glomerulus is squashed by cells that fill Bowman’s space; these cells are a mixture of infiltrating inflammatory cells and proliferating resident cells. AKI can occur without crescents if glomerular necrosis is sufficiently severe (Figure 4). Whatever the cause, similar appearances are seen on light microscopy, and immunohistology is required to identify the aetiology. The diagnosis of anti–glomerular basement membrane (anti-GBM) disease can be made by the detection of anti-GBM antibodies in the serum or on renal biopsy. If antibodies to GBM are present (Goodpasture’s disease), the glomerulus shows linear deposition of IgG (Figure 5). More
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Figure 5 Immunofluorescence microscopy of a glomerulus in anti-glomerular basement membrane disease, showing linear deposition of immunoglobulin G.
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and pauci-immune FNGN is probably a form of small-vessel vasculitis confined to the kidney. Rapid, reliable serological tests are available for ANCA and anti-GBM antibodies; if FNGN is suspected, it is possible to confirm the diagnosis with these simple laboratory tests. Tissue destruction may be very rapid, so early diagnosis is vital if the outcome is to be improved by treatment. Environmental factors (such as exposure to hydrocarbons, smoking, viral or other infections) may precipitate anti-GBM GN. Anti-GBM antibodies are known to be directly pathogenic. Anti-GBM disease is the only form of GN in which the pathogenesis is fully understood and the treatment truly rational (plasma exchange to remove circulating antibody, corticosteroids to suppress inflammation from antibody already deposited in the tissues, cyclophosphamide to suppress further antibody synthesis). Four litres of plasma is exchanged daily for 14 days or until antibodies can no longer be detected in the serum. Cyclophosphamide is given orally at a dose of 2e3 mg/kg/day (but this must be reduced in renal impairment and with increasing age) with prednisolone 1 mg/kg/day at the start. Prednisolone is then reduced weekly, reaching 20 mg/day by week 6. If the treatment is effective, cyclophosphamide and prednisolone can be stopped at 3e6 months. Relapses of anti-GBM disease are rare; long-term maintenance treatment with corticosteroids or cytotoxic agents is not needed. In anti-GBM disease, the prognosis is directly related to the extent of glomerular damage (measured by percentage of crescents, serum creatinine concentration or creatinine clearance) at the initiation of treatment. In contrast to ANCA-associated renal vasculitis, patients with anti-GBM antibody disease with serum creatinine >500 mm/ litre at the onset of disease, or patients already on dialysis, rarely recover renal function, which makes an early diagnosis, referral and treatment all the more critical in this disease (see Lupus Nephropathy and Vasculitis, pp 486e491 of this issue). Similar treatments are used in other forms of FNGN and are often effective, though in these cases the mode of action is unclear. Renal transplantation in anti-GBM disease should be performed only after disappearance of antibodies from serum.
blood pressure of 130/80 mm Hg, or 125/75 mm Hg in patients with proteinuria >1 g/day. Progression of renal disease in proteinuric renal diseases can be retarded by use of ACEI or ARB; patients with greater proteinuria, even if normotensive, benefit more from this treatment. Dialysis and transplantation are available for those who progress to ESRD. Some forms of GN tend to recur in transplanted kidneys.
Hope for the future Improved understanding of pathogenetic mechanisms in GN should allow the design of more specific forms of therapy. As more selective forms of immunotherapy become available they are being tested in GN, often with promising results.18 Techniques for gene delivery to the inflamed glomerulus are being developed.19 Stem cell therapy is showing promise in GN as it is in so many areas of human disease.20 There is evidence that current treatments may act on intrinsic glomerular cells as well as on immune/inflammatory mediators.21 The author believes that future therapies should focus on these mechanisms of action in the hope that our reliance on non-specific and potentially toxic forms of therapy in GN may soon be replaced by new approaches. Even if this is true, early diagnosis will remain a major challenge and here the non-specialist will retain a vital role. Detection and assessment of proteinuria and/or haematuria, suspicion of GN, consideration of potentially life-threatening systemic diseases and appropriate timely referral to specialist units can make a major contribution to the health of our patients. A
REFERENCES 1 Salama AD. Renal biopsy. Medicine 2011; 39: 339e42. 2 Mathieson PW. GN: is it worth worrying about? Clin Med 2005; 5: 264e6. 3 Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073e81. 4 Park YH, Choi JY, Chung HS, et al. Hematuria and proteinuria in a mass school urine screening test. Pediatr Nephrol 2005; 20: 1126e30. 5 Barratt J. Interpretation and management of abnormal dipstick urinalysis. Medicine 2011; 39: 312e6. 6 Carter Jl, Tomson CR, Stevens PE, Lamb EJ. Does urinary tract infection cause proteinuria or microalbuminuria? A systematic review. Nephrol Dial Transplant 2006; 21: 3031e7. 7 Bernard D. Extra-renal complications of the nephrotic syndrome. Kidney Int 1988; 33: 1184e202. 8 Ruggenenti P, Perna A, Gherardi G, et al. Renal function and requirement for dialysis in chronic nephropathy patients on longterm ramipril. Lancet 1998; 352: 1252e6. 9 Hurtado A, Johnson RJ. Hygiene hypothesis and prevalence of glomerulonephritis. Kidney Int Suppl 2005; 97: S62e7. 10 Macanovic M, Lachmann P. The complement system in renal diseases. In: Zipfel PF, ed. Complement and kidney disease. Basel: Birkhauser Verlag, 2006.
Prognosis Poor prognostic factors for progression of GN include hypertension, persistent and heavy proteinuria, impaired renal function at the time of diagnosis, glomerulosclerosis and interstitial fibrosis on renal biopsy.
Principles of management In addition to the general measures described above for nephrotic syndrome, if an underlying precipitant can be identified, the management and prognosis of GN depend on whether that precipitant can be eradicated.16 As many types of GN are mediated by immune mechanisms, most attempts at treatment involve corticosteroids, antiinflammatory, cytotoxic or immunosuppressive drugs.17 The more aggressive the disease, the more aggressive should be the therapy. The most important factor in improving renal outcome in these conditions is early diagnosis and treatment. Hypertension associated with GN should be controlled with antihypertensive drugs (preferably ACEI or ARB) to a target
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zsi M, Skerka C. Complement and diseases: 11 Zipfel PF, Heinen S, Jo defective alternative pathway control results in kidney and eye diseases. Mol Immunol 2006; 43: 97e106. 12 Mathieson PW. The cellular basis of albuminuria. Clin Sci 2004; 107: 533e8. 13 Stanescu HC, Arco-Burgos M, Medlar A, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. New Engl J Med 2011; 364: 616e26. 14 Beck Jr LH, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361: 11e21. 15 Debiec H, Guigonis V, Mougenot B, et al. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med 2002; 346: 2053e60. 16 Montseny JJ, Meyrier A, Kleinknecht D, Callard P. The current spectrum of infectious glomerulonephritis. experience with 76 patients and review of the literature. Medicine (Baltimore) 1995; 74: 63e73. 17 Cattran DC. Evidence-based recommendations for the management of glomerulonephritis. Kidney Int 1999; 70: S1e62. 18 Salama AD, Pusey CD. Drug insight: rituximab in renal disease and transplantation. Nat Clin Pract Nephrol 2006; 2: 221e30. 19 Imai E, Isaka Y. Perspectives for gene therapy in renal diseases. Intern Med 2004; 43: 85e96. 20 Rabelink TJ, van Kooten C. Stem cell therapy for glomerular disease. J Am Soc Nephrol 2006; 17: 2086e8. 21 Mathieson PW. Proteinuria and immunity e an overstated relationship? N Engl J Med 2008; 359: 2492e4.
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Glomerular nephritis (GN) should be suspected in patients with urine abnormalities, particularly proteinuria Quantification and investigation of the cause of proteinuria is required Many cases of GN are secondary to drugs, infection, malignancy or systemic diseases such as vasculitis or systemic lupus erythematosus; simple laboratory tests exclude associated systemic illnesses and rapidly identify the acute forms of GN for which urgent treatment is essential Small-vessel vasculitis should be suspected if anti-neutrophil cytoplasmic antibody (ANCA) is positive; treatment may be urgent and is usually effective Renal biopsy is usually required to identify the subtype of GN; this is important because treatment and prognosis differ Antihypertensive drugs, especially those that block the angiotensin cascade, may be used to reduce proteinuria and slow the progression of renal insufficiency Anti-inflammatory and/or immunosuppressive drugs are effective in many types of GN, but more selective forms of treatment are needed. These should be based on detailed knowledge of pathogenic mechanisms, but these remain poorly understood in many forms of GN
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incidences range from 17 to 60 cases per million population. Any age group may be affected, though some types are particularly common in children. GN is an important cause of end-stage renal disease (ESRD), a condition that causes major morbidity and mortality and consumes a disproportionate amount of health expenditure. Late diagnosis of GN remains a major problem; non-specialists can have a vital role in improving the management of GN by knowing when to suspect it, arranging appropriate investigations and making early referral to a nephrologist.2 Proteinuria is a cardinal feature of GN and the importance of proteinuria to the generalist is emphasized by the fact that it is now accepted as an unequivocal independent cardiovascular risk factor.3 Proteinuria may be asymptomatic, especially at low levels; when severe it may be associated with nephrotic syndrome in which the patient’s main symptomatic complaint is typically oedema. The age of the patient influences the frequency of causes of nephrotic syndrome (NS): in children under 10 years of age in the developed world, about 80% of NS is caused by minimalchange nephropathy (MCN, see below). Studies from several countries show an increasing incidence of focal segmental glomerulosclerosis (FSGS) over the last decade.
Peter Mathiesona
Abstract This article reviews the clinical features, pathogenesis, investigation and management of glomerulonephritis (GN). This can occur as a primary isolated renal disease, as a manifestation of systemic diseases such as vasculitis or lupus, or secondary to drugs, infections or tumours. It is an important cause of morbidity and mortality and a potentially preventable cause of end-stage renal disease, so early diagnosis is vital to allow timely referral to specialist units where renal biopsy can be performed. Proteinuria and/or haematuria are typical findings. Pathogenesis involves cells and mediators of the immune system, including the complement pathway. Intrinsic glomerular cells, especially podocytes, are important in glomerular injury and the response to it. I present schemes for appropriate investigations when GN is suspected, guidelines for referral, and strategies for investigation of proteinuria and haematuria, and for management of common forms of GN. Nephrotic syndrome (heavy proteinuria, hypoalbuminaemia and oedema) causes major morbidity and potential mortality and should be managed, irrespective of the cause, with diuretics, antiproteinuric agents, cholesterollowering agents and, sometimes, anticoagulants. Treatment with corticosteroids, with or without other immunosuppressive agents, is effective in many forms of GN, but toxicities are problematic. Improved understanding of pathogenesis of GN promises more specific forms of treatment in the future.
When should glomerulonephritis be suspected? Primary glomerular disease presents clinically with abnormalities of the urine, often with hypertension, oedema and/or impaired excretory renal function (Table 2). As routine health screening becomes more widespread,4 and with the availability of cheap, reliable urine dipstick tests, asymptomatic abnormalities of the urine will be detected more commonly.5 Patients presenting with hypertension, ankle oedema or nonspecific ill health should always undergo urine testing. Protein dipsticks are semiquantitative; underlying renal disease, particularly GN, is very likely when proteinuria greater than 1þ is detected. One important point is that asymptomatic urinary tract infection does not cause proteinuria. One of the most common responses to the finding of proteinuria is to send a mid-stream urine sample (MSU) to be tested for infection. This is not an adequate response.6 Quantification of the proteinuria and investigation of the possible causes are required. Quantification
Keywords complement; glomerulonephritis; haematuria; kidney; nephrotic syndrome; podocyte; proteinuria; treatment
The term glomerulonephritis (GN) covers a group of conditions in which there is injury in the glomerulus, the filtering unit of the kidney. This can occur either as a primary glomerular disease, or secondary to drugs, infections or tumours (see Secondary Glomerular Disease, pp 464e466 of this issue). GN may be isolated or a manifestation of renal involvement in a systemic disease (Table 1). Diagnosis of GN, and particularly its subdivision into various categories, depends on clinical features, laboratory data and histological analysis. Renal biopsy, which is undertaken in specialist centres, is a crucial element in the management of glomerular diseases.1
Epidemiology of GN
Systemic diseases in which glomerulonephritis may feature
Reported incidences of GN vary depending on ascertainment bias and variations in renal biopsy policies. In the UK, estimated
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Peter Mathieson FRCP PhD FMedSci is Professor of Medicine and Dean of the Faculty of Medicine & Dentistry at the University of Bristol, UK. He qualified in London and started his research career in Cambridge (PhD 1992) before moving to Bristol in 1995. His research interests are focused on human glomerular cell biology and the effects of immunosuppressive and anti-inflammatory therapies. Competing interests: none declared. a I dedicate this article to the late Momir Macanovic who co-authored the original version with me. Momir sadly died in April 2007 and I miss him.
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Connective tissue diseases, particularly systemic lupus erythematosus Systemic vasculitis Infective endocarditis Other infections, including methicillin-resistant Staphylococcus aureus, malaria, hepatitis B and C virus, HIV Drug reactions, particularly non-steroidal anti-inflammatory drugs; also gold, penicillamine Carcinoma, lymphoma, myeloma
Table 1
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Presentation of primary glomerular disease (GN) C C
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Non-specific measures in the management of people with nephrotic syndrome
Asymptomatic proteinuria Microscopic haematuria (occasionally macroscopic, particularly with concurrent infections in immunoglobulin A nephropathy) Hypertension Nephritic syndrome (acute GN and rapidly progressive GN) with acute onset of haematuria, proteinuria, ‘active urinary sediment’ with red cells, white cells, cellular casts, oliguria, hypertension, oedema, impaired excretory renal function) Nephrotic syndrome (heavy proteinuria >3.5 g/day, hypoalbuminaemia and oedema) Impaired excretory renal function (assessed by serum creatinine, or by estimated glomerular filtration rate. If severe, there may be symptoms of uraemia: nausea, vomiting, anaemia, pericarditis, hypertension, and coma
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Table 2
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can be by timed (usually 24-hour) urine collection or more simply by estimation of albumin:creatinine ratio (ACR) on a random urine sample. Casts can be identified by simple microscopy of fresh urine after gentle centrifugation: cellular casts are particularly significant because they indicate acute inflammation in the kidney, usually from GN. Dysmorphic (irregularly shaped) red blood cells (RBCs) in a fresh urine sample are suggestive of haematuria of glomerular origin. Urine analysis also provides information about the severity of glomerular disease. Heavy proteinuria, marked haematuria and/or RBC casts generally indicate more severe disease than isolated microscopic haematuria or lowgrade proteinuria. When either proteinuria or haematuria is associated with evidence of systemic disease, or there is loss of excretory renal function, referral to a nephrologist may be particularly urgent. Rapidly progressive glomerulonephritis is a medical emergency requiring urgent treatment to prevent irreversible kidney damage.
Table 3
when GN complicates infections or tumours). In many cases, the target is unknown and an autoimmune aetiology is suspected. As in other autoimmune conditions, primary GN is thought to result from the combination of genetic susceptibility and an environmental precipitant.9 The genetic factors are typically genes involved in control of the immune response, particularly the major histocompatibility complex human leucocyte antigen (HLA) genes. The environmental precipitants may be drugs, chemicals or infectious agents. The known predisposing factors are considered in more detail below. The role of immune mechanisms in the pathogenesis of GN is indicated by the presence of circulating autoantibodies and/or abnormalities of serum complement, and glomerular deposition of antibodies, immune complexes, complement and fibrin.
Nephrotic syndrome Nephrotic syndrome (NS) is defined by heavy proteinuria, hypoalbuminaemia and oedema. Primary GN is an important cause of NS, although NS may also result from secondary glomerular disease, diabetic nephropathy or amyloidosis. Urine should be tested in all patients presenting with oedema; if there is no proteinuria, it is unlikely that renal disease is the cause of the oedema. In addition to specific treatment of the underlying condition, non-specific measures remain important in the management of patients with NS (Table 3).7,8
The complement system in glomerulonephritis The association of abnormalities of the complement system with renal disease is well established. Initial observations included alterations in the serum concentration of specific complement components and/or glomerular complement deposits. Recent advances have highlighted new pathogenetic mechanisms.10,11 Hypocomplementaemia is used as a diagnostic marker and for monitoring treatment response in some forms of GN. The complement components most frequently measured in clinical practice are C3 and C4. Chronic bacteraemic states, poststreptococcal GN or lupus nephritis are frequently accompanied by reduction of the classical pathway activation protein C4 along with C3. In lupus nephritis, the extent of hypocomplementaemia can be useful for monitoring disease activity non-invasively. In mesangiocapillary GN (MCGN, see below), the pattern of
Pathogenesis of glomerulonephritis Immune reactions underlie GN, with contributions from cellular immunity (T lymphocytes, macrophages), humoral immunity (antibodies, immune complexes, complement) and other inflammatory mediators (including the coagulation cascade). In some cases, the target of the immune response is known (e.g.
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Oedema can be reduced by salt restriction and diuretics; water immersion may be effective for intractable oedema Hypertension should be treated using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) as the drugs of first choice. These have additional antiproteinuric effects and delay the progression of renal disease8 Patients usually have hypercholesterolaemia, which should be treated with a statin since dietary measures alone are usually ineffective There is a predisposition to infection, partly because of associated hypogammaglobulinaemia; also, cellulitis is common in oedematous tissues. Consequently, there should be a low threshold for administration of systemic antibiotics and vaccination against encapsulated bacteria A prothrombotic state is present, so disproportionate limb swelling, breathlessness, chest pain or haemoptysis should raise the suspicion of thromboembolism and a need for systemic anticoagulation. Renal vein thrombosis is a particular problem in patients with nephrotic syndrome; it may be silent or may cause flank pain, macroscopic haematuria or deterioration in excretory renal function
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complement depletion differs between the different subtypes and is useful in diagnosis. Glomerular deposits of complement in GN, especially C3, can be visualized by immunohistochemistry. Complement deposits may be dominant (as in MCGN) or associated with immunoglobulin deposits (as in many other forms of GN). Deficiencies of certain complement components are also associated with primary forms of GN and may also be seen in systemic disease with renal involvement, such as lupus nephritis. Deficiency of the regulatory protein, factor H, has been implicated in both haemolytic uraemic syndrome and in MCGN, suggesting shared pathogenetic mechanisms between these two apparently different conditions. Intriguingly, another apparently unrelated disorder, age-related macular degeneration (ARMD), appears to share similar pathogenetic mechanisms.11 Several autoantibodies directed against complement components have been identified. C3 nephritic factor (C3NeF), an autoantibody against the C3 convertase of the alternative pathway (C3bBb), is strongly linked with MCGN. Patients with C3NeF develop MCGN in 50% of cases and virtually all patients with type II MCGN have a high serum concentration of C3NeF. Anti-C1q autoantibodies have been related to nephritis in lupus patients. About one-third of lupus patients have high titres of anti-C1q antibody; these antibodies are strongly associated with hypocomplementaemia and severe lupus nephritis.
nephropathy. The cells lining Bowman’s capsule are called parietal epithelial cells. These may be involved in crescent formation in severe forms of GN. Glomerular endothelial cells are primarily injured in pre-eclampsia and in haemolytic uraemic syndrome. Mesangial cells appear to be secondarily injured in a variety of glomerular diseases. Production of cytokines and other mediators by intrinsic glomerular cells may be responsible for attraction and/or activation of leucocytes and for manifestations of glomerular injury including proteinuria.
Subtypes of glomerulonephritis Different patterns of abnormality within the glomerulus may be used to define subtypes of glomerular disease (Table 4). However, a single morphological pattern may be associated with several aetiologies. In some cases, more specific patterns of glomerular abnormality suggest that the GN is secondary to a well-defined aetiology. Although there is overlap in presentation, treatment and markers of good prognosis, the distinguishing features of the most common forms of primary glomerular disease are discussed below. Minimal-change nephropathy (MCN) (lipoid nephrosis, nil disease, minimal-change disease) typically presents with nephrotic syndrome and occurs in both children and adults, although it is most common in children. More than 80% of children in the developed world below the age of 10 years with primary nephrotic syndrome, and about 20% of adults, have MCN. It is very rarely associated with hypertension, hypocomplementaemia, haematuria, cellular casts in urine or persistent impairment of excretory renal function. MCN is occasionally secondary to drug use (particularly non-steroidal anti-inflammatory drugs (NSAIDs)) or malignancy (particularly Hodgkin’s disease and other lymphomas). The idiopathic form is believed to result from an abnormality of T lymphocytes, but extensive searches for lymphocyte-derived permeability factors have not produced consistent results. Renal biopsy is normal by light microscopy and immunohistology, but electron microscopy shows typical abnormalities. Most patients (>90%) respond to high-dose corticosteroids (prednisolone, 1 mg/kg/day, maximum 80 mg/day; Figure 2). Remission usually occurs between days 7 and 14, though some adult patients may need up to 16 weeks’ therapy to achieve
Intrinsic glomerular cells in glomerular nephritis There has been considerable recent interest in the role of intrinsic glomerular cells in the initiation and/or progression of glomerular injury. Much attention has focused on the podocyte12 (also known as the visceral glomerular epithelial cell, Figure 1). It is now recognized that mutations in podocyte-specific genes cause many congenital or early-onset forms of nephrotic syndrome, although their importance in apparently sporadic cases remains uncertain. Podocytes are terminally differentiated cells with very limited capacity for repair or regeneration, and podocyte loss is thought to be a major factor in progression of glomerular injury, including that occurring in non-GN conditions such as diabetic
Subtypes of glomerulonephritis C
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Figure 1 Scanning electron micrograph of normal human glomerulus showing podocytes.
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Minimal-change nephropathy (renal biopsy normal on light microscopy; electron microscopy shows typical features) Focal segmental glomerulosclerosis Membranous nephropathy Immunoglobulin A nephropathy Mesangiocapillary glomerulonephritis Focal necrotizing glomerulonephritis, often with ‘crescents’ (associated with the clinical syndrome of rapidly progressive glomerulonephritis)
Table 4
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a temporary reduction in proteinuria achieved by plasmapheresis in these cases suggests a circulating permeability factor. Diagnosis of FSGS requires kidney biopsy. Histology shows areas of scarring in glomeruli; the sclerotic changes are focal (affecting some glomeruli and not others) and segmental (affecting only parts of individual glomeruli). Similar glomerular changes are seen as a secondary phenomenon when the number of functioning nephrons is reduced for any reason (e.g. nephrectomy, ischaemia, other primary renal disease), leading to the hypothesis that FSGS results from ‘overloading’ (hyperfiltration) of the remaining nephrons. There is evidence to support this theory in experimental animals, but no direct evidence in humans. Similar changes may be seen in association with extreme obesity. In recent years, a variant of FSGS has been recognized in association with HIV infection; this is so-called ‘collapsing’ FSGS, in which the glomerulus collapses as a result of proliferation of the surrounding epithelial cells, filling Bowman’s space. Untreated FSGS carries a high risk of progression to renal insufficiency. In primary FSGS, treatment with a prolonged course of high-dose corticosteroids (prednisolone 1 mg/kg/day up to a maximum 80 mg/day for up to 6 months) is advocated by some authorities (Figure 3). Prednisolone should be continued for 1e2 weeks after remission has been induced and then tapered very slowly. In patients who relapse after repeated courses of corticosteroids, and in corticosteroid-resistant patients, ciclosporin (3e5 mg/kg/day for 4e12 months) may induce remission, but relapse is common when treatment is stopped. An angiotensin-converting enzyme inhibitor (ACEI) to reduce proteinuria and statins for hyperlipidaemia should also be given. The disease often progresses; ESRD develops in about 50% of patients within 10 years. There is no evidence that corticosteroids or other immunosuppressive agents are effective in secondary forms of
Management of minimal-change nephropathy Prednisolone 1 mg/kg/day (maximum 80 mg/day)
Remission in >90% of patients
Failure in <10% of patients
Reduce dose
Second-line agents
Remission
Relapse
Repeat prednisolone treatment or Figure 2
complete remission. After disappearance of proteinuria, or 1 week after remission is induced, the corticosteroid dose is reduced to 0.5 mg/kg/day and then tapered slowly. An attempt to stop treatment should be made after 8 weeks. Longer durations of corticosteroid therapy significantly reduce the risk of relapse. Relapse is common as the dose is reduced. In patients who suffer a relapse, the course of corticosteroids should be repeated. Up to 50% of patients remain corticosteroid-dependent. In these, alkylating agents, such as cyclophosphamide or chlorambucil, are sometimes successful. The cyclophosphamide regimen is 1.5e2 mg/kg/day with concomitant prednisolone 7.5e15 mg/day for 8e12 weeks. The neutrophil count must be checked every 2 weeks and cyclophosphamide stopped if it falls below 2000/mm3. Mycophenolate mofetil (MMF) has been used with good effects in the treatment of corticosteroid-dependent or frequently relapsing MCN in adults. Ciclosporin (3e5 mg/kg/ day) is effective in some corticosteroid-resistant or corticosteroiddependent patients. Blood ciclosporin should be checked and dosage adjusted to achieve trough concentrations of 80e150 ng/ ml. Low-dose prednisolone (7.5e15 mg/day) is given with ciclosporin. Tacrolimus, another calcineurin inhibitor, is an alternative if ciclosporin is ineffective or poorly tolerated. There is considerable overlap in toxicity seen with these two agents, including their unfortunate tendency to cause nephrotoxicity. In corticosteroid-dependent children, levamisole (2.5 mg/kg to a maximum of 150 mg on alternate days) is useful for maintenance of remission, but its mode of action is unexplained.
Management of nephrotic focal segmental glomerulosclerosis Prednisolone 1 mg/kg/day (maximum 80 mg/day) for maximum of 12 weeks
Focal segmental glomerulosclerosis (FSGS) typically presents with asymptomatic proteinuria or nephrotic syndrome. It is more likely than MCN to be associated with hypertension, microscopic haematuria, impaired excretory renal function and/or corticosteroid resistance. Proteinuria is non-selective (the urine contains both albumin and higher molecular weight proteins) and the serum concentration of complement components is normal. Primary FSGS tends to recur after renal transplantation and
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Remission in 20–50% of patients (?maximized by 6 months)
Failure in 50–80% of patients
Reduce dose
Second-line agents
Remission
Relapse
Repeat prednisolone treatment or Figure 3
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FSGS and they are not recommended. Obese patients should be encouraged to lose weight.
anticoagulation if the plasma albumin is below 20 g/litre (2 g/dl). As in other conditions with nephrotic syndrome, patients with MN have hyperlipidaemia and an increased risk of cardiovascular disease. Therefore, statins should be used in patients with highgrade proteinuria and hyperlipidaemia. In patients receiving long-term and/or high-dose corticosteroids, bisphosphonates should be considered, to reduce bone loss. Several other drugs, including ciclosporin plus low-dose prednisolone (10 mg/day) and MMF, have been tried in the treatment of MN.
Membranous nephropathy (MN) typically presents with proteinuria, which may be asymptomatic or sufficiently severe to cause nephrotic syndrome. Microscopic haematuria, hypertension and/or impaired excretory renal function may occur; the latter two are poor prognostic signs. Identical glomerular histology is seen in the primary (‘idiopathic’) form and when MN is secondary to drugs (particularly NSAIDs, gold, penicillamine), solid-organ tumours (particularly carcinoma of the bronchus, colon or breast), infection (particularly hepatitis B and C), SLE (lupus nephritis class V) or hypothyroidism. Secondary MN is associated with malignancy in up to 20% of patients over the age of 60 years, so screening investigations (especially if there are suggestive symptoms or signs) can include chest X-ray, mammography, colonoscopy, faecal occult blood, and prostatespecific antigen. There have been striking recent advances in the understanding of MN. Susceptibility to idiopathic MN and to some forms of secondary MN is closely linked to the major histocompatibility complex (MHC) with a recent study showing tight linkage to HLA-DQA1 and also to a locus on chromosome 2 that coincides with the gene encoding PLA2R, the putative autoantigen.13 Of patients with the idiopathic form of the disease, 70e80% have autoantibodies to the phospholipase A2 receptor (PLA2R).14 Interestingly, these autoantibodies seem to be absent in secondary MN, although this remains to be proven in larger numbers of subjects. Another intriguing recent observation is the transplacental transfer of immunoglobulin G (IgG) antibodies causing MN in the fetus/neonate, arising due to maternal deficiency of a protein that acts as an immunizing neoantigen during pregnancy with a fetus expressing the normal protein.15 The prognosis of secondary MN depends entirely on the prognosis of the underlying condition. In MN secondary to drugs, complete resolution can be expected when the offending drug is withdrawn. Malignancy-associated MN has a poor prognosis unless the associated tumour can be eradicated. The efficacy of immunosuppressive therapy in idiopathic MN remains controversial. At least 25% of patients exhibit spontaneous remission of proteinuria even without treatment, and most nephrologists reserve treatment for those with poor prognostic signs, particularly deteriorating excretory renal function and/or heavy proteinuria (>8 g/day) with severe nephrotic syndrome. A combination of prednisolone and an alkylating agent (either chlorambucil or cyclophosphamide) given in alternating monthly cycles for a total of 6 months appears to be the most efficacious treatment in trials. Many centres use this so-called ‘Ponticelli regimen’ (or slightly modified versions thereof) in the treatment of MN (months 1, 3 and 5 methylprednisolone 1 g/day pulse dose intravenously for three consecutive days followed by oral prednisolone 0.5 mg/kg/day for subsequent 27 days; months 2, 4 and 6 chlorambucil 0.1e0.2 mg/kg/day or cyclophosphamide 2.5 mg/ kg/day for 30 days). ACEIs (and possibly also angiotensin receptor blockers (ARBs)) reduce proteinuria and may slow progression of renal insufficiency. Nephrotic syndrome caused by MN is associated with a particular risk of thrombotic complications in 10e30% of cases, so many nephrologists routinely prescribe anticoagulants to such patients. The risk:benefit ratio favours prophylactic
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IgA nephropathy (IgAN, Berger’s disease) is the most common type of GN worldwide. It typically presents with episodes of haematuria, which may be macroscopic, particularly in those with concurrent infection of the upper respiratory tract. Proteinuria is variable. The prognosis is generally good in patients without associated heavy proteinuria, hypertension or impairment of excretory renal function. The risk of eventual development of ESRD is about 25% in those with proteinuria of more than 1 g/24 hours (or an ACR >100). On renal biopsy, the pathognomonic feature of IgAN is deposition of polymeric IgA in the glomerulus, usually associated with proliferation of intrinsic glomerular cells. The aetiology is unknown, but there is increasing evidence that the primary abnormality is in the IgA system, not in the kidney. Up to 50% of patients exhibit elevated serum IgA concentrations, and there is evidence that the IgA is chemically abnormal, with altered carbohydrate constituents. An identical glomerular lesion is seen €nlein purpura (HSP), in which it is accompanied in HenocheScho by a vasculitic rash, often with arthritis and/or gastrointestinal inflammation. HSP is more common in children and often resolves spontaneously, though tissue injury in the acute phase may be very severe, necessitating corticosteroid therapy. Transplantation is an option for patients with IgAN who reach ESRD. The disease recurs in more than 50% of patients but rarely causes transplant failure, presumably because the immunosuppressive drugs used for the prevention of rejection have a favourable effect on the GN. Immunosuppressive drugs (cyclophosphamide and corticosteroids) are not widely used, though it is suggested that they hasten recovery in some aggressive forms of the disease and in HSP. Current trends include the use of fish oils, which in some trials have been shown to protect renal function in poor-prognosis subgroups. ACEIs are the firstchoice antihypertensive agents; some nephrologists advocate their use (or that of ARBs) even in normotensive patients. ACEI or ARB or both in combination not only control blood pressure (to the target of 125e120 mmHg systolic), but also reduce proteinuria and delay progression to ESRD. Mesangiocapillary GN (MCGN, also known as membranoproliferative GN, MPGN) is uncommon. There are three subtypes, with indistinguishable clinical presentations (proteinuria, haematuria, hypertension, hypocomplementaemia, impaired renal function) and findings on conventional histology. The subtypes are defined according to appearances on electron microscopy and probably have different pathogeneses. MCGN is associated with activation of the complement cascade, involving the classical pathway (low C4 and C3) in type I MCGN, the alternative pathway (low C3, normal C4) in type II, or the terminal pathway (type III).
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Type II MCGN may be associated with partial lipodystrophy, in which selective loss of fat cells in the face and upper trunk gives patients a characteristic cadaveric appearance. Type II MCGN may also be associated with abnormalities in the eye, especially with prominent presence of drusen (deposits within Bruch’s membrane). Recent observations provide a unifying explanation for this, and again involve regulation of the alternative pathway of complement. Recently it has been reported that variations in the gene-encoding factor H, the regulator of the alternative complement pathway mentioned above, predispose to age-related macular degeneration (ARMD). Drusen are the hallmark lesions of ARMD; histologically, these lesions show evidence of local complement activation. It is likely, therefore, that drusen result from dysregulated complement activation in the subretinal pigment epithelial layer in exactly the same way as glomerular injury occurs when the alternative pathway escapes its normal tight regulation. Secondary forms of MCGN are usually of type I pattern and result from chronic infection (visceral abscesses, infective endocarditis, infected prosthetic materials such as ventriculoperitoneal shunt) or cryoglobulinaemia (which may complicate infections, particularly HCV). All types of MCGN tend to have a progressive course. Up to 50% of patients develop end-stage renal failure within 10 years. There is a tendency to histological recurrence in kidney transplants, though this seldom causes graft loss. Treatment of idiopathic MCGN is difficult. It is essential to achieve good blood pressure control and to treat other complications such as hypercholesterolaemia. The only other intervention for which there is some support from clinical trials is high-dose corticosteroids, but these are not universally effective and adverse effects may be limiting. Therapy aimed at blocking complement activation would be useful, and several such treatments are in development.
Figure 4 Glomerulus from a patient with anti-neutrophil cytoplasmic antibody-associated focal necrotizing glomerulonephritis showing segmental necrosis (H and E stain).
commonly, there is no immunoglobulin in the glomerulus in cases of RPGN and the condition is termed ‘pauci-immune FNGN’; at least 80% of these patients exhibit circulating ANCA. ANCA are closely associated with systemic vasculitis,
Focal necrotizing GN (FNGN) usually presents with acute nephritic syndrome (acute renal failure (ARF), haematuria, proteinuria, cellular casts in the urine). This is sometimes associated with pulmonary haemorrhage, and this combination is known as pulmonary renal syndrome. Goodpasture’s disease is one cause of this syndrome and is due to anti-glomerular basement membrane antibodies. A more common cause of the syndrome is small-vessel vasculitis (microscopic polyangiitis, Wegener’s granulomatosis) which is usually associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Other causes include SLE, cryoglobulinaemia and HSP. FNGN is the renal lesion typically associated with the clinical syndrome of RPGN and is a medical emergency. Untreated FNGN progresses rapidly to renal insufficiency. Severe acute inflammation occurs in the glomerulus, sometimes with formation of ‘crescents’ when the glomerulus is squashed by cells that fill Bowman’s space; these cells are a mixture of infiltrating inflammatory cells and proliferating resident cells. AKI can occur without crescents if glomerular necrosis is sufficiently severe (Figure 4). Whatever the cause, similar appearances are seen on light microscopy, and immunohistology is required to identify the aetiology. The diagnosis of anti–glomerular basement membrane (anti-GBM) disease can be made by the detection of anti-GBM antibodies in the serum or on renal biopsy. If antibodies to GBM are present (Goodpasture’s disease), the glomerulus shows linear deposition of IgG (Figure 5). More
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Figure 5 Immunofluorescence microscopy of a glomerulus in anti-glomerular basement membrane disease, showing linear deposition of immunoglobulin G.
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and pauci-immune FNGN is probably a form of small-vessel vasculitis confined to the kidney. Rapid, reliable serological tests are available for ANCA and anti-GBM antibodies; if FNGN is suspected, it is possible to confirm the diagnosis with these simple laboratory tests. Tissue destruction may be very rapid, so early diagnosis is vital if the outcome is to be improved by treatment. Environmental factors (such as exposure to hydrocarbons, smoking, viral or other infections) may precipitate anti-GBM GN. Anti-GBM antibodies are known to be directly pathogenic. Anti-GBM disease is the only form of GN in which the pathogenesis is fully understood and the treatment truly rational (plasma exchange to remove circulating antibody, corticosteroids to suppress inflammation from antibody already deposited in the tissues, cyclophosphamide to suppress further antibody synthesis). Four litres of plasma is exchanged daily for 14 days or until antibodies can no longer be detected in the serum. Cyclophosphamide is given orally at a dose of 2e3 mg/kg/day (but this must be reduced in renal impairment and with increasing age) with prednisolone 1 mg/kg/day at the start. Prednisolone is then reduced weekly, reaching 20 mg/day by week 6. If the treatment is effective, cyclophosphamide and prednisolone can be stopped at 3e6 months. Relapses of anti-GBM disease are rare; long-term maintenance treatment with corticosteroids or cytotoxic agents is not needed. In anti-GBM disease, the prognosis is directly related to the extent of glomerular damage (measured by percentage of crescents, serum creatinine concentration or creatinine clearance) at the initiation of treatment. In contrast to ANCA-associated renal vasculitis, patients with anti-GBM antibody disease with serum creatinine >500 mm/ litre at the onset of disease, or patients already on dialysis, rarely recover renal function, which makes an early diagnosis, referral and treatment all the more critical in this disease (see Lupus Nephropathy and Vasculitis, pp 486e491 of this issue). Similar treatments are used in other forms of FNGN and are often effective, though in these cases the mode of action is unclear. Renal transplantation in anti-GBM disease should be performed only after disappearance of antibodies from serum.
blood pressure of 130/80 mm Hg, or 125/75 mm Hg in patients with proteinuria >1 g/day. Progression of renal disease in proteinuric renal diseases can be retarded by use of ACEI or ARB; patients with greater proteinuria, even if normotensive, benefit more from this treatment. Dialysis and transplantation are available for those who progress to ESRD. Some forms of GN tend to recur in transplanted kidneys.
Hope for the future Improved understanding of pathogenetic mechanisms in GN should allow the design of more specific forms of therapy. As more selective forms of immunotherapy become available they are being tested in GN, often with promising results.18 Techniques for gene delivery to the inflamed glomerulus are being developed.19 Stem cell therapy is showing promise in GN as it is in so many areas of human disease.20 There is evidence that current treatments may act on intrinsic glomerular cells as well as on immune/inflammatory mediators.21 The author believes that future therapies should focus on these mechanisms of action in the hope that our reliance on non-specific and potentially toxic forms of therapy in GN may soon be replaced by new approaches. Even if this is true, early diagnosis will remain a major challenge and here the non-specialist will retain a vital role. Detection and assessment of proteinuria and/or haematuria, suspicion of GN, consideration of potentially life-threatening systemic diseases and appropriate timely referral to specialist units can make a major contribution to the health of our patients. A
REFERENCES 1 Salama AD. Renal biopsy. Medicine 2011; 39: 339e42. 2 Mathieson PW. GN: is it worth worrying about? Clin Med 2005; 5: 264e6. 3 Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073e81. 4 Park YH, Choi JY, Chung HS, et al. Hematuria and proteinuria in a mass school urine screening test. Pediatr Nephrol 2005; 20: 1126e30. 5 Barratt J. Interpretation and management of abnormal dipstick urinalysis. Medicine 2011; 39: 312e6. 6 Carter Jl, Tomson CR, Stevens PE, Lamb EJ. Does urinary tract infection cause proteinuria or microalbuminuria? A systematic review. Nephrol Dial Transplant 2006; 21: 3031e7. 7 Bernard D. Extra-renal complications of the nephrotic syndrome. Kidney Int 1988; 33: 1184e202. 8 Ruggenenti P, Perna A, Gherardi G, et al. Renal function and requirement for dialysis in chronic nephropathy patients on longterm ramipril. Lancet 1998; 352: 1252e6. 9 Hurtado A, Johnson RJ. Hygiene hypothesis and prevalence of glomerulonephritis. Kidney Int Suppl 2005; 97: S62e7. 10 Macanovic M, Lachmann P. The complement system in renal diseases. In: Zipfel PF, ed. Complement and kidney disease. Basel: Birkhauser Verlag, 2006.
Prognosis Poor prognostic factors for progression of GN include hypertension, persistent and heavy proteinuria, impaired renal function at the time of diagnosis, glomerulosclerosis and interstitial fibrosis on renal biopsy.
Principles of management In addition to the general measures described above for nephrotic syndrome, if an underlying precipitant can be identified, the management and prognosis of GN depend on whether that precipitant can be eradicated.16 As many types of GN are mediated by immune mechanisms, most attempts at treatment involve corticosteroids, antiinflammatory, cytotoxic or immunosuppressive drugs.17 The more aggressive the disease, the more aggressive should be the therapy. The most important factor in improving renal outcome in these conditions is early diagnosis and treatment. Hypertension associated with GN should be controlled with antihypertensive drugs (preferably ACEI or ARB) to a target
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zsi M, Skerka C. Complement and diseases: 11 Zipfel PF, Heinen S, Jo defective alternative pathway control results in kidney and eye diseases. Mol Immunol 2006; 43: 97e106. 12 Mathieson PW. The cellular basis of albuminuria. Clin Sci 2004; 107: 533e8. 13 Stanescu HC, Arco-Burgos M, Medlar A, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. New Engl J Med 2011; 364: 616e26. 14 Beck Jr LH, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361: 11e21. 15 Debiec H, Guigonis V, Mougenot B, et al. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med 2002; 346: 2053e60. 16 Montseny JJ, Meyrier A, Kleinknecht D, Callard P. The current spectrum of infectious glomerulonephritis. experience with 76 patients and review of the literature. Medicine (Baltimore) 1995; 74: 63e73. 17 Cattran DC. Evidence-based recommendations for the management of glomerulonephritis. Kidney Int 1999; 70: S1e62. 18 Salama AD, Pusey CD. Drug insight: rituximab in renal disease and transplantation. Nat Clin Pract Nephrol 2006; 2: 221e30. 19 Imai E, Isaka Y. Perspectives for gene therapy in renal diseases. Intern Med 2004; 43: 85e96. 20 Rabelink TJ, van Kooten C. Stem cell therapy for glomerular disease. J Am Soc Nephrol 2006; 17: 2086e8. 21 Mathieson PW. Proteinuria and immunity e an overstated relationship? N Engl J Med 2008; 359: 2492e4.
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Glomerular nephritis (GN) should be suspected in patients with urine abnormalities, particularly proteinuria Quantification and investigation of the cause of proteinuria is required Many cases of GN are secondary to drugs, infection, malignancy or systemic diseases such as vasculitis or systemic lupus erythematosus; simple laboratory tests exclude associated systemic illnesses and rapidly identify the acute forms of GN for which urgent treatment is essential Small-vessel vasculitis should be suspected if anti-neutrophil cytoplasmic antibody (ANCA) is positive; treatment may be urgent and is usually effective Renal biopsy is usually required to identify the subtype of GN; this is important because treatment and prognosis differ Antihypertensive drugs, especially those that block the angiotensin cascade, may be used to reduce proteinuria and slow the progression of renal insufficiency Anti-inflammatory and/or immunosuppressive drugs are effective in many types of GN, but more selective forms of treatment are needed. These should be based on detailed knowledge of pathogenic mechanisms, but these remain poorly understood in many forms of GN
Ó 2011 Published by Elsevier Ltd.