GLOMERULAR DISEASE

Primary glomerular disease incidences range from 17 to 60 cases per million population. Any
age group can be affected, though some types are particularly
common in children. GN is an important cause of end-stage renal
Peter Mathiesona
disease (ESRD) and late diagnosis of GN remains a major prob-
lem; non-specialists can have a vital role in improving the
Abstract management of GN by knowing when to suspect it, arranging
This article reviews the clinical features, pathogenesis, investigation and appropriate investigations and making early referral to a
management of glomerulonephritis (GN). This can occur as a primary iso- nephrologist.1 Proteinuria is a cardinal feature of GN and the
lated renal disease, as a manifestation of systemic diseases such as importance of proteinuria to the generalist is emphasized by the
vasculitis or lupus, or secondary to drugs, infections or tumours. It is fact that it is now also recognized as an unequivocal independent
an important cause of morbidity and mortality and a potentially prevent- cardiovascular risk factor.2 Proteinuria may be asymptomatic,
able cause of end-stage renal disease, so early diagnosis is vital to allow especially at low concentration; when severe it may be associ-
timely referral to specialist units where renal biopsy can be performed. ated with nephrotic syndrome, in which the patient’s symptoms
Proteinuria and/or haematuria are typical findings. Pathogenesis involves typically include oedema and lethargy which can be profound.
cells and mediators of the immune system, including the complement The age of the patient influences the frequency of causes of
pathway. Intrinsic glomerular cells, especially podocytes, are important nephrotic syndrome (NS): in children under 10 years of age in
in glomerular injury and the response to it. Schemes for appropriate in- the developed world, about 80% of NS is caused by minimal-
vestigations when GN is suspected, guidelines for referral, and strategies change nephropathy (MCN, see below).
for investigation of proteinuria and haematuria, and for management of Studies from several countries show an increasing incidence
common forms of GN are presented. When nephrotic syndrome is present, of focal segmental glomerulosclerosis (FSGS) over the last
it can lead to major morbidity and potential mortality and should be decade.
managed, irrespective of the cause, with diuretics, antiproteinuric agents,
cholesterol-lowering agents and, sometimes, anticoagulants. Treatment When should glomerulonephritis be suspected?
with corticosteroids, with or without other immunosuppressive agents,
is effective in many forms of GN, but adverse effects are problematic. Primary glomerular disease presents clinically with abnormal-
Improved understanding of the pathogenesis of GN promises more spe- ities of the urine, often with hypertension, oedema and/or
cific forms of treatment in the future. impaired excretory renal function (Table 2). As routine health
screening becomes more widespread and cheap, reliable urine
Keywords complement; glomerulonephritis; haematuria; kidney;
dipstick tests more widely available, asymptomatic abnormalities
nephrotic syndrome; podocyte; proteinuria; treatment
of the urine will be detected more commonly.
Patients presenting with hypertension, ankle oedema, non-
specific ill health or unexplained lethargy should always un-
The term glomerulonephritis (GN) covers a group of conditions
dergo urine testing. Protein dipsticks are semiquantitative; un-
in which there is injury in the glomerulus, the filtering unit of the
derlying renal disease, particularly GN, is very likely when
kidney. This can occur either as a primary glomerular disease, or
proteinuria greater than 1þ is detected. Asymptomatic urinary
secondary to drugs, infections or tumours (see Secondary
tract infection does not cause proteinuria, and sending a mid-
glomerular disease, pp 513e516 of this issue).
stream urine sample (MSU) to be tested for infection is not an
GN can be isolated or a manifestation of renal involvement in
adequate response to the finding of protein in the urine.3
a systemic disease (Table 1). The diagnosis of GN, and particu-
Quantification of the proteinuria and investigation of the
larly its subdivision into various categories, depends on clinical
possible causes are required. Quantification requires simple
features, laboratory data and histological analysis. Renal biopsy,
estimation of albumin:creatinine ratio (ACR) on a random urine
which is undertaken in specialist centres, is a crucial element in
sample; timed urine collections are now rarely used.
the management of glomerular diseases.
Casts can be identified by simple microscopy of fresh urine
after gentle centrifugation: cellular casts are particularly
Epidemiology of GN
Reported incidences of GN vary depending on ascertainment bias
and variations in renal biopsy policies. In the UK, estimated
Systemic diseases in which glomerulonephritis may
feature
C Connective tissue diseases, particularly systemic lupus
Peter Mathieson FRCP PhD FMedSci has been President of The University of erythematosus
Hong Kong since April 2014, Hong Kong. He qualified in Medicine in C Systemic vasculitis
London and started his research career in Cambridge (PhD 1992) before C Infective endocarditis
moving to the University of Bristol as the founding Professor of Renal C Other infections, including meticillin-resistant Staphylococcus
Medicine in 1995, later becoming Professor of Medicine and Dean of the aureus, malaria, hepatitis B and C virus, HIV
Faculty of Medicine & Dentistry. His research interests have been focused C Drug reactions, particularly non-steroidal anti-inflammatory
on human glomerular cell biology and the effects of immunosuppressive drugs; also gold, penicillamine
and anti-inflammatory therapies. Competing interests: none declared. C Carcinoma, lymphoma, myeloma
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 still miss him. Table 1

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 GLOMERULAR DISEASE

Pathogenesis of glomerulonephritis
Presentation of primary glomerulonephritis (GN)
Immune reactions underlie GN, with contributions from cellular
C Asymptomatic proteinuria immunity (T lymphocytes, macrophages), humoral immunity
C Microscopic haematuria (occasionally macroscopic, particularly (antibodies, immune complexes, complement) and other in-
with concurrent infections in immunoglobulin A nephropathy) flammatory mediators (including the coagulation cascade). In
C Hypertension some cases, the target of the immune response is known (e.g.
C Nephritic syndrome (acute GN and rapidly progressive GN) with when GN complicates infections or tumours). In many cases, the
acute onset of haematuria, proteinuria, ‘active urinary sediment’ target is unknown and an autoimmune aetiology is suspected.
with red cells, white cells, cellular casts, oliguria, hypertension, As in other autoimmune conditions, primary GN is thought to
oedema, impaired excretory renal function) result from the combination of genetic susceptibility and an
C Nephrotic syndrome (heavy proteinuria >3.5 g/day, hypo- environmental precipitant.4 The genetic factors typically include
albuminaemia and oedema) genes involved in control of the immune response, particularly
C Impaired excretory renal function (assessed by serum creatinine, the major histocompatibility complex human leucocyte antigen
or by estimated glomerular filtration rate. If severe, there may be (HLA) genes, although membranous nephropathy (see below) is
symptoms of uraemia: nausea, vomiting, anaemia, pericarditis, a special case in this regard. The environmental precipitants
hypertension, and coma include drugs, chemicals or infectious agents. Known predis-
posing factors are considered in more detail below. The role of
Table 2
immune mechanisms in the pathogenesis of GN is indicated by
the presence of circulating autoantibodies and/or abnormalities
significant because they indicate acute inflammation in the kid-
of serum complement, and glomerular deposition of antibodies,
ney, usually from GN. Dysmorphic (irregularly shaped) red
immune complexes, complement and fibrin.
blood cells (RBCs) in a fresh urine sample are suggestive of
haematuria of glomerular origin. Urine analysis also provides
The complement system in glomerulonephritis
information about the severity of glomerular disease. Heavy
proteinuria, marked haematuria and/or RBC casts generally The association of abnormalities of the complement system with
indicate more severe disease than isolated microscopic haema- renal disease is well established. Initial observations included
turia or low-grade proteinuria. alterations in the serum concentration of specific complement
When either proteinuria or haematuria is associated with components and/or glomerular complement deposits. Recent
evidence of systemic disease, or there is loss of excretory renal advances have highlighted new pathogenetic mechanisms.5
function, referral to a nephrologist may be particularly urgent. Hypocomplementaemia is used as a diagnostic marker and for
Rapidly progressive glomerulonephritis is a medical emergency monitoring treatment response in some forms of GN. The com-
requiring urgent treatment to prevent irreversible kidney plement components most frequently measured in clinical prac-
damage. tice are C3 and C4. Chronic bacteraemic states, post-
streptococcal GN or lupus nephritis are frequently accompanied
Nephrotic syndrome by reduction of the classical pathway activation protein C4 along
with C3. In lupus nephritis, the extent of hypocomplementaemia
NS is defined by heavy proteinuria, hypoalbuminaemia and
can be useful for monitoring disease activity non-invasively. In
oedema. Primary GN is an important cause of NS, although NS
mesangiocapillary GN (MCGN, see below), the pattern of com-
can also result from secondary glomerular disease, diabetic ne-
plement depletion differs between the different subtypes and is
phropathy or amyloidosis.
useful in diagnosis.
Urine should be tested in all patients presenting with oedema;
Glomerular deposits of complement in GN, especially C3, can
if there is no proteinuria, it is unlikely that renal disease is the
be visualized by immunohistochemistry. Complement deposits
cause of the oedema. In addition to specific treatment of the
may be dominant (as in MCGN) or associated with immuno-
underlying condition, non-specific measures remain important in
globulin deposits (as in many other forms of GN).
the management of patients with NS (Table 3).

Non-specific measures in the management of people with nephrotic syndrome

C Oedema can be reduced by salt restriction and diuretics; water immersion may be effective for intractable oedema
C Hypertension should be treated using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), which have
additional antiproteinuric effects and delay the progression of renal disease
C Patients usually have hypercholesterolaemia, which should be treated with a statin since dietary measures alone are usually ineffective
C 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
C 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

Table 3

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 GLOMERULAR DISEASE

Deficiencies of certain complement components are also General principles of management

associated with primary forms of GN and may also be seen in
In addition to the general measures described in Table 3 for
systemic disease with renal involvement, such as lupus nephritis.
nephrotic syndrome, if an underlying precipitant can be identi-
Deficiency of the regulatory protein, factor H, has been impli-
fied, the management and prognosis of GN depend on whether
cated in both haemolyticduraemic syndrome (HUS) and in
that precipitant can be eradicated.
MCGN, suggesting shared pathogenetic mechanisms between
As many types of GN are mediated by immune mechanisms,
these two apparently different conditions.5
most attempts at treatment involve corticosteroids, anti-
Several autoantibodies directed against complement compo-
inflammatory, cytotoxic or immunosuppressive drugs.8 The
nents have been identified. C3 nephritic factor (C3NeF), an
more aggressive the disease, the more aggressive should be the
autoantibody against the C3 convertase of the alternative
therapy. The most important factor in improving renal outcome
pathway (C3bBb), is strongly linked with MCGN. Patients with
in these conditions is early diagnosis and treatment.
C3NeF develop MCGN in 50% of cases and virtually all patients
Hypertension associated with GN should be controlled with
with type II MCGN have a high serum concentration of C3NeF.
antihypertensive drugs (preferably angiotensin-converting
Anti-C1q autoantibodies have been related to nephritis in lupus
enzyme inhibitors (ACEI) or angiotensin II receptor blockers
patients. About one-third of lupus patients have high titres of
(ARB) to a target blood pressure of 130/80 mmHg, or 125/75
anti-C1q antibody; these antibodies are strongly associated with
mmHg in patients with proteinuria greater than 1 g/day. Pro-
hypocomplementaemia and severe lupus nephritis.
gression of proteinuric renal diseases can be retarded by use of
ACEI or ARB; patients with greater proteinuria, even if normo-
Intrinsic glomerular cells in glomerulonephritis
tensive, benefit more from this treatment. Dialysis and trans-
Much of the recent interest in the role of intrinsic glomerular cells plantation are available for those who progress to ESRD. Some
in the initiation and/or progression of glomerular injury has forms of GN tend to recur in transplanted kidneys.
focused on the podocyte6 (also known as the visceral glomerular
epithelial cell, Figure 1). Mutations in podocyte-specific genes Prognosis
cause many congenital or early-onset forms of nephrotic syn-
Poor prognostic factors for progression of GN include hyperten-
drome, although their importance in apparently sporadic cases
sion, persistent and heavy proteinuria, impaired renal function at
remains uncertain. Podocytes are terminally differentiated cells
the time of diagnosis, glomerulosclerosis and interstitial fibrosis
with very limited capacity for repair or regeneration, and podo-
on renal biopsy.
cyte loss is thought to be a major factor in the progression of
glomerular injury, including that occurring in non-GN conditions
Subtypes of glomerulonephritis
such as diabetic nephropathy. The cells lining Bowman’s capsule
are called parietal epithelial cells. These may be involved in Different patterns of abnormality within the glomerulus can be
crescent formation in severe forms of GN and may also provide a used to define subtypes of glomerular disease (Table 4). How-
source of progenitors for podocyte replacement.7 Glomerular ever, a single morphological pattern can be associated with
endothelial cells are primarily injured in pre-eclampsia and in several aetiologies. In some cases, more specific patterns of
HUS. Mesangial cells appear to be secondarily injured in a variety glomerular abnormality suggest that the GN is secondary to a
of glomerular diseases. Production of cytokines and other me- well-defined aetiology. Although there is overlap in presentation,
diators by intrinsic glomerular cells may be responsible for treatment and markers of good prognosis, the distinguishing
attraction and/or activation of leucocytes, and for manifestations features of the most common forms of primary glomerular dis-
of glomerular injury including proteinuria. ease 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 with primary nephrotic syndrome in the developed

Subtypes of glomerulonephritis
C Minimal-change nephropathy (renal biopsy normal on light mi-
croscopy; electron microscopy shows typical features)
C Focal segmental glomerulosclerosis
C Membranous nephropathy
C Immunoglobulin A nephropathy
C Mesangiocapillary glomerulonephritis
C Focal necrotizing glomerulonephritis, often with ‘crescents’
(associated with the clinical syndrome of rapidly progressive
glomerulonephritis)
Figure 1 Scanning electron micrograph of normal human glomerulus
showing podocytes. Table 4

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 GLOMERULAR DISEASE

world below the age of 10 years, and about 20% of adults, have dosage adjusted to achieve trough concentrations of 80e150 ng/
MCN. It is very rarely associated with hypertension, hypo- ml. Tacrolimus, another calcineurin inhibitor, is an alternative if
complementaemia, haematuria, cellular casts in urine or persis- cyclosporin is ineffective or poorly tolerated. There is consider-
tent impairment of excretory renal function. MCN is occasionally able overlap in toxicity seen with these two agents, including their
secondary to drug use (particularly non-steroidal anti-inflam- unfortunate tendency to cause nephrotoxicity.
matory drugs (NSAIDs)) or malignancy (particularly Hodgkin’s
disease and other lymphomas). The idiopathic form has been Focal segmental glomerulosclerosis (FSGS) typically presents
said to result from an abnormality of T lymphocytes, but with asymptomatic proteinuria or nephrotic syndrome. It is more
extensive searches for lymphocyte-derived permeability factors likely than MCN to be associated with hypertension, microscopic
have not produced consistent results. Renal biopsy is normal by haematuria, impaired excretory renal function and/or cortico-
light microscopy and immunohistology, but electron microscopy steroid resistance. Proteinuria is non-selective (the urine contains
shows typical abnormalities. both albumin and higher molecular-weight proteins) and the
Most patients (>90%) respond to high-dose corticosteroids serum concentration of complement components is normal.
(prednisolone, 1 mg/kg/day, maximum 80 mg/day; Figure 2). Primary FSGS tends to recur after renal transplantation, and a
Remission usually occurs between days 7 and 14, though some temporary reduction in proteinuria achieved by plasmapheresis
adult patients may need up to 16 weeks’ therapy to achieve in these cases suggests a circulating permeability factor. Diag-
complete remission. After disappearance of proteinuria, or 1 week nosis of FSGS requires kidney biopsy. Histology shows areas of
after remission has been induced, the corticosteroid dose is scarring in glomeruli; the sclerotic changes are focal (affecting
reduced to 0.5 mg/kg/day and then tapered slowly. An attempt to some glomeruli and not others) and segmental (affecting only
stop treatment should be made after 8 weeks. Longer durations of parts of individual glomeruli).
corticosteroid therapy significantly reduce the risk of relapse. Similar glomerular changes are seen as a secondary phe-
Relapse is common as the dose is reduced. In patients who suffer a nomenon when the number of functioning nephrons is reduced
relapse, the course of corticosteroids should be repeated. Up to for any reason (e.g. nephrectomy, ischaemia, other primary
50% of patients remain corticosteroid-dependent. In these, alky- renal disease), leading to the hypothesis that FSGS results from
lating agents, such as cyclophosphamide (1.5e2 mg/kg/day) or ‘overloading’ (hyperfiltration) of the remaining nephrons. There
chlorambucil (dosage as recommended by detailed specialist is evidence to support this theory in experimental animals, but
literature or local chemotherapy protocol) with concomitant no direct evidence in humans. Similar changes may be seen in
prednisolone (7.5e15 mg/day) for 8e12 weeks are sometimes association with extreme obesity. A variant of FSGS is recog-
helpful. The neutrophil count must be checked every 2 weeks and nized in association with HIV infection, so-called ‘collapsing’
cyclophosphamide stopped if this falls below 2000/mm3. Le- FSGS, in which the glomerulus collapses as a result of prolif-
vamisole (1.25 mg/kg/day) is a less toxic alternative that has eration of the surrounding epithelial cells, filling Bowman’s
useful effects in children9 and adults,10 albeit without controlled space.
trials in the latter. Similarly, other agents have not been subjected Untreated, FSGS carries a high risk of progression to renal
to rigorous controlled trials. Mycophenolate mofetil (MMF) has insufficiency. In primary FSGS, some authorities advocate treat-
been used with variable effects; cyclosporin (3e5 mg/kg/day) is ment with a prolonged course of high-dose corticosteroids
effective in some corticosteroid-resistant or corticosteroid- (prednisolone 1 mg/kg/day up to a maximum 80 mg/day for up
dependent patients. Blood cyclosporin should be checked and

Management of minimal-change nephropathy

Prednisolone 1 mg/kg/day (maximum 80 mg/day)

Remission in Failure in
>90% of patients <10% of patients

Reduce dose Second-line agents

Remission Relapse

Repeat prednisolone treatment or

Figure 2 Figure 3

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 GLOMERULAR DISEASE

to 6 months) (Figure 3). Prednisolone should be continued for 1 patients with impaired excretory renal function because the
e2 weeks after remission has been induced and dosage then parent drug and its metabolites are renally excreted. ACEIs (and
tapered very slowly. In patients who relapse after repeated possibly also ARBs) reduce proteinuria and may slow progres-
courses of corticosteroids, and in corticosteroid-resistant pa- sion of renal insufficiency. Nephrotic syndrome caused by MN is
tients, cyclosporin (3e5 mg/kg/day for 4e12 months) may associated with a particular risk of thrombotic complications in
induce remission, but relapse is common when treatment is 10e30% of cases, so many nephrologists prescribe anticoagu-
stopped. An ACEI should be given to reduce proteinuria, and lants routinely to such patients. The risk:benefit ratio favours
statins to reduce hyperlipidaemia. The disease often progresses; prophylactic anticoagulation if the plasma albumin is below 20
ESRD develops in about 50% of patients within 10 years. There is g/litre (2 g/dl). As in other conditions with nephrotic syndrome,
no evidence that corticosteroids or other immunosuppressive patients with MN have hyperlipidaemia and an increased risk of
agents are effective in secondary forms of FSGS and they are not cardiovascular disease. Therefore, statins should be used in pa-
recommended. Obese patients should be encouraged to lose tients with high-grade proteinuria and hyperlipidaemia. In pa-
weight. tients treated with long-term and/or high-dose corticosteroids,
addition of bisphosphonates should be considered, to reduce
Membranous nephropathy (MN) typically presents with pro- bone loss. Several other drugs, including cyclosporin plus low-
teinuria, which may be asymptomatic or sufficiently severe to dose prednisolone (10 mg/day) and MMF, have been tried in
cause nephrotic syndrome. Microscopic haematuria, hyperten- the treatment of MN.
sion and/or impaired excretory renal function may occur; the
latter two are poor prognostic signs. Identical glomerular his- IgA nephropathy (IgAN, Berger’s disease) is the most common
tology is seen in the primary (‘idiopathic’) form and when MN is type of GN worldwide. It typically presents with episodes of
secondary to drugs (particularly NSAIDs, gold or penicillamine), haematuria, which may be macroscopic particularly in those
solid-organ tumours (particularly carcinoma of the bronchus, with concurrent infection of the upper respiratory tract. Pro-
colon or breast), infection (particularly hepatitis B and C), SLE teinuria is variable. The prognosis is generally good in patients
(lupus nephritis class V) or hypothyroidism. Secondary MN is without associated heavy proteinuria, hypertension or impair-
associated with malignancy in up to 20% of patients over the age ment of excretory renal function. The risk of eventual develop-
of 60 years, so screening investigations (especially if there are ment of ESRD is about 25% in those with proteinuria of more
suggestive symptoms or signs) can include chest X-ray, than 1 g/24 hours (or an ACR >100).
mammography, colonoscopy, faecal occult blood, and prostate- On renal biopsy, the pathognomonic feature of IgAN is
specific antigen. deposition of polymeric IgA in the glomerulus, usually associ-
There have been striking recent advances in the understand- ated with proliferation of intrinsic glomerular cells. The aeti-
ing of MN. Susceptibility to idiopathic MN and to some forms of ology is unknown, but there is increasing evidence that the
secondary MN is closely linked to the major histocompatibility primary abnormality is in the IgA system, not in the kidney. Up
complex (MHC) with a recent study showing tight linkage to to 50% of patients exhibit elevated serum IgA concentrations,
HLA-DQA1 and also to a locus on chromosome 2 that coincides and there is evidence that the IgA is chemically abnormal, with
with the gene encoding PLA2R, the putative autoantigen.11 Of altered carbohydrate constituents. An identical glomerular
patients with the idiopathic form of the disease, 70e80% have lesion is seen in HenocheScho €nlein purpura (HSP), in which it
autoantibodies to the phospholipase A2 receptor (PLA2R).12 is accompanied by a vasculitic rash, often with arthritis and/or
Interestingly, these autoantibodies seem to be absent in sec- gastrointestinal inflammation. HSP is more common in children
ondary MN. Another intriguing recent observation is the trans- and often resolves spontaneously, though tissue injury in the
placental transfer of immunoglobulin G (IgG) antibodies causing acute phase may be very severe, necessitating corticosteroid
MN in the fetus/neonate, arising due to maternal deficiency of a therapy.
protein that acts as an immunizing neo-antigen during pregnancy Transplantation is an option for patients with IgAN who reach
with a fetus expressing the normal protein.13 ESRD. The disease recurs in more than 50% of patients but rarely
The prognosis of secondary MN depends entirely on the causes transplant failure, presumably because the immunosup-
prognosis of the underlying condition. In MN secondary to drugs, pressive drugs used for the prevention of rejection have a
complete resolution can be expected when the offending drug is favourable effect on the GN. Immunosuppressive drugs (cyclo-
withdrawn. Malignancy-associated MN has a poor prognosis phosphamide and corticosteroids) are not widely used, though it
unless the associated tumour can be eradicated. is suggested that they hasten recovery in some aggressive forms
The efficacy of immunosuppressive therapy in idiopathic MN of the disease and in HSP. Current trends include the use of fish
remains controversial. At least 25% of patients exhibit sponta- oils, which in some trials have been shown to protect renal
neous remission of proteinuria even without treatment, and most function in poor-prognosis subgroups. ACEIs are the first-choice
nephrologists reserve treatment for those with poor prognostic antihypertensive agents; some nephrologists advocate their use
signs, particularly deteriorating excretory renal function and/or (or that of ARBs) even in normotensive patients. ACEI or ARB, or
heavy proteinuria (>8 g/day) with severe nephrotic syndrome. A both in combination, not only control blood pressure (to the
combination of prednisolone and an alkylating agent (either target of 125e120 mmHg systolic) but also reduce proteinuria
chlorambucil or cyclophosphamide) given in alternating monthly and delay progression to ESRD.
cycles for a total of 6 months (the ‘Ponticelli regimen’), appears
to be the most efficacious treatment in trials.14 It is important to Mesangiocapillary GN (MCGN, also known as mem-
note that the dosage of chlorambucil should be reduced in branoproliferative GN, MPGN) is uncommon. There are three

MEDICINE 43:9 511 Ó 2015 Elsevier Ltd. All rights reserved.

 GLOMERULAR DISEASE

subtypes, with indistinguishable clinical presentations (protein- future therapies should focus on these mechanisms of action in
uria, haematuria, hypertension, hypocomplementaemia, the hope that our reliance on non-specific and potentially toxic
impaired renal function) and findings on conventional histology. forms of therapy in GN may soon be replaced by new ap-
The subtypes are defined according to appearances on electron proaches. Even if this is true, early diagnosis will remain a major
microscopy and probably have different pathogeneses. MCGN is challenge and here the non-specialist will retain a vital role.
associated with activation of the complement cascade, involving Detection and assessment of proteinuria and/or haematuria,
the classical pathway (low C4 and C3) in type I MCGN, the suspicion of GN, consideration of potentially life-threatening
alternative pathway (low C3, normal C4) in type II, or the ter- systemic diseases and appropriate timely referral to specialist
minal pathway (type III). units can make a major contribution to the health of our
Type II MCGN may be associated with partial lipodystrophy, patients. A
in which selective loss of fat cells in the face and upper trunk
gives patients a characteristic cadaveric appearance. Type II
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should allow the design of more specific forms of therapy. As glomerulonephritis due to anti-neutral endopeptidase antibodies.
more selective forms of immunotherapy become available they N Engl J Med 2002; 346: 2053e60.
are being tested in GN, often with promising results. Techniques 14 Howman A, Chapman TL, Langdon MM, et al. Immunosuppression for
for gene delivery to the inflamed glomerulus are being devel- progressive membranous nephropathy: a UK randomised controlled
oped. Stem cell therapy is showing promise in GN as it is in so trial. Lancet 2013; 381: 744e51.
many areas of human disease. There is evidence that current 15 Mathieson PW. Proteinuria and immunity e an overstated relation-
treatments may act on intrinsic glomerular cells as well as on ship? N Engl J Med 2008; 359: 2492e4.
immune/inflammatory mediators.15 The author believes that

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