Glomerular disease
Primary glomerular disease
Momir Macanovic
Peter Mathieson
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 prevent-
able 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. We present schemes for
appropriate investigations when GN is suspected, guidelines for referral,
strategies for investigation of proteinuria and haematuria, and manage-
ment 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 diuret-
ics, anti-proteinuric agents, cholesterol-lowering agents and sometimes
anticoagulants. Treatment with corticosteroid drugs, 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.
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 pages 49799).
Momir Macanovic PhD FRCP who was a Consultant Nephrologist in Abu
Dhabi, UAE died in April 2007. He qualified from the University of
Sarajevo, Bosnia-Herzegovina, and trained at the Royal Postgraduate
Medical School, London, UK. His research interests included humoral
and cell-mediated allergic responses to the glomerular basement
membrane, complement, complement receptors and regulatory
proteins, immune complexes and experimental systemic lupus
erythematosus. Competing interests: none declared.
Peter Mathieson FRCP PhD FMedSci is Professor of Renal Medicine at
the University of Bristol, UK. He qualified in London and undertook
research in Cambridge. His research interests include human
glomerular cell biology and clinical trials. Competing interests:
none declared.
MEDICINE 35:9
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 fea-
tures, 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
Reported incidences of GN vary depending on ascertainment
bias and variations in renal biopsy policies. In the UK, esti-
mated incidences range from 17/million to 60/million popula-
tion. 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 which 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 improv-
ing the management of GN by knowing when to suspect it,
arranging appropriate investigations and making early referral
to a nephrologist.2
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 minimal
change nephropathy (MCN, see below).
Studies from several countries show an increased incidence of
focal segmental glomerulosclerosis (FSGS) over the last decade.
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,3 and with the availability of cheap,
reliable urine dipstick tests, asymptomatic abnormalities of the
urine will be detected more commonly.4
Patients presenting with hypertension, ankle oedema or non-
specific ill health should always undergo urine testing. Protein
dipsticks are semiquantitative; underlying renal disease, par-
ticularly GN, is very likely when proteinuria greater than + is
detected. One important point is that asymptomatic urinary tract
infection does not cause proteinuria. One of the most common
Systemic diseases in which glomerulonephritis may
feature
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
489 2007 Elsevier Ltd. All rights reserved.
 Glomerular disease
Presentation of primary glomerular disease
Asymptomatic proteinuria
Microscopic haematuria (occasionally macroscopic,
particularly with concurrent infections in IgA 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 plasma/serum
creatinine, or by estimated glomerular filtration rate (eGFR).
If severe, there may be symptoms of uraemia: nausea,
vomiting, anaemia, pericarditis, hypertension, and coma
Table 2
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.5 Quantification of the proteinuria, and inves-
tigation of the possible causes, are required.
Casts can be identified by simple microscopy of fresh urine
after gentle centrifugation: cellular casts are particularly signifi-
cant 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 glomerular-origin
haematuria. Urine analysis also provides information about the
severity of glomerular disease. Heavy proteinuria, marked hae-
maturia and/or RBC casts generally indicate more severe disease
than isolated microscopic haematuria or low-grade proteinuria.
When either proteinuria or haematuria is associated with evi-
dence of systemic disease, or there is loss of excretory renal func-
tion, referral to a nephrologist may be particularly urgent. Rapidly
progressive glomerulonephritis is a medical emergency requiring
urgent treatment to prevent irreversible kidney damage.
Nephrotic syndrome
Nephrotic syndrome (NS) is defined by heavy proteinuria, hypo-
albuminaemia and oedema. Primary GN is an important cause of
NS, although it may also result from secondary glomerular dis-
ease, and diabetic nephropathy and amyloidosis are numerically
important.
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).6
Pathogenesis of glomerulonephritis
Immune reactions underlie GN, with contributions from cel-
lular immunity (T lymphocytes, macrophages), humoral immu-
nity (antibodies, immune complexes, complement) and other
inflammatory mediators (including the coagulation cascade).
In some cases, the target of the immune response is known
MEDICINE 35:9
Nonspecific measures in the management of people
with nephrotic syndrome
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
disease7
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
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
(e.g. 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 consid-
ered to result from the combination of genetic susceptibility and
an environmental precipitant.8 The genetic factors are typically
genes involved in control of the immune response, particularly
the major histocompatibility complex and human leucocyte anti-
gen (HLA) genes. The environmental precipitants may be drugs,
chemicals or infectious agents. The known predisposing fac-
tors are considered in more detail below. The role of immune
mechanisms in the pathogenesis of GN is indicated by the pres-
ence of circulating autoantibodies and/or abnormalities of serum
complement, and glomerular deposition of antibodies, immune
complexes, complement and fibrin.
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.9,10
Hypocomplementaemia is used as a diagnostic marker for,
and monitoring treatment response in some forms of GN. The
complement components most frequently measured in clini-
cal practice are C3 and C4. Chronic bacteraemic states, post-
streptococcal 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
490 2007 Elsevier Ltd. All rights reserved.
 Glomerular disease
can be useful in non-invasively monitoring disease activity. In
mesangiocapillary GN (MCGN, see below) the pattern of com-
plement 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 immunoglob-
ulin deposits (as in many other forms of GN).
Deficiencies of certain complement components are also asso-
ciated with primary forms of GN and may also be seen in sys-
temic 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.10
Several autoantibodies directed against complement compo-
nents have been identified; characteristic is C3Nef, an autoanti-
body against C3 convertase of the alternative pathway (C3bBb).
Patients with C3Nef develop MCGN in 50% of cases. Virtu-
ally all patients with type II MCGN have high serum concen-
tration of C3NeF. Finally, 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.
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 glomeru-
lar injury. Much attention has focused on the podocyte11 (also
known as the visceral glomerular epithelial cell, Figure 1). Muta-
tions in podocyte-specific genes are now recognized to 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,
Figure 1 Scanning electron micrograph of normal human glomerulus
showing podocytes.
MEDICINE 35:9
including in non-GN conditions such as diabetic nephropathy.
The cells lining the Bowmans capsule are called parietal epi-
thelial 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 media-
tors by intrinsic glomerular cells may be responsible for attrac-
tion 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). How-
ever, a single morphological pattern may be associated with
several aetiologies. In some cases, more specific patterns of glo-
merular abnormality suggest primary or secondary disease 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 dis-
ease, 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, hypocomplementae-
mia, 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 Hodgkins 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
Subtypes of glomerulonephritis
Minimal-change nephropathy (renal biopsy normal on light
microscopy; electron microscopy shows typical features)
Focal segmental glomerulosclerosis
Membranous nephropathy
IgA nephropathy
Mesangiocapillary glomerulonephritis
Focal necrotizing glomerulonephritis, often with crescents
(associated with the clinical syndrome of rapidly progressive
glomerulonephritis)
Table 4
491 2007 Elsevier Ltd. All rights reserved.
 Glomerular disease
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
adult patients may need up to 16 weeks therapy to achieve com-
plete 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 treat-
ment should be made after 8 weeks. Longer durations of cortico-
steroid 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 1.52 mg/kg/day
with concomitant prednisolone 7.515 mg/day for 812 weeks.
The neutrophil count must be checked every 2 weeks and cyclo-
phosphamide stopped if it falls below 2000/mm3. Mycophenolate
mofetil (MMF) has been used with good effects in the treatment
of steroid-dependent or frequently-relapsing MCN in adults.
Ciclosporin (35 mg/kg/day) is effective in some corticosteroid-
resistant or corticosteroid-dependent patients. Blood levels should
be checked and doses adjusted to achieve trough concentrations
of 80150 ng/ml. Low-dose prednisolone (7.515 mg/day) is given
with the ciclosporin. Tacrolimus, another calcineurin inhibitor, is
an alternative if cyclosporine is ineffective or poorly tolerated.
There is considerable overlap in toxicity seen with these two
agents, including their unfortunate tendency to cause nephrotoxic-
ity. In corticosteroid-dependent children, levamisole (2.5 mg/kg to
a maximum of 150 mg on alternate days) is useful in maintenance
of remission, but its mode of action is unexplained.
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 cortico-
steroid resistance. Proteinuria is non-selective (urine contains
albumin and high molecular weight proteins) and serum con-
centration of complement components is normal. Primary
FSGS tends to recur after renal transplantation and a temporary
MEDICINE 35:9
reduction in proteinuria achieved by plasmapheresis suggests a
circulating permeability factor in these cases. Diagnosis of FSGS
requires kidney biopsy. Histology shows areas of scarring in
glomeruli; the sclerotic changes are focal (affecting some glom-
eruli and not others) and segmental (affecting only parts of each
glomerulus).
Similar glomerular changes are seen as a secondary phenom-
enon 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 over-
loading (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 asso-
ciation 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
Bowmans space.
Untreated FSGS carries a high risk of progression to renal insuf-
ficiency. In primary FSGS, treatment with a prolonged course of
high-dose corticosteroids (prednisolone 1 mg/kg/day up to a maxi-
mum 80 mg/day for up to 6 months) is advocated by some author-
ities (Figure 3). Prednisolone should be continued for 12 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 (35 mg/kg/day for
412 months) may induce remission, but relapse is common when
treatment is stopped. An angiotensin-converting enzyme inhibi-
tor (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 FSGS and they are not recommended. Obese
patients should be encouraged to lose weight.
Management of nephrotic focal segmental
glomerulosclerosis
Prednisolone 1 mg/kg/day (maximum 80 mg/day)
for maximum of 12 weeks
Remission in 2050% of patients Failure in 5080%
(?maximized by 6 months) of patients
Reduce dose Second-line agents
Remission Relapse
Repeat prednisolone treatment or
Figure 3
492 2007 Elsevier Ltd. All rights reserved.
 Glomerular disease
Membranous nephropathy (MN) typically presents with pro-
teinuria, which may be asymptomatic or sufficiently severe to
cause nephrotic syndrome. Microscopic haematuria, hyperten-
sion and/or impaired excretory renal function may occur; the
latter two are poor prognostic signs. Identical glomerular histol-
ogy 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 HBV, HCV), SLE (lupus
nephritis class V) or hypothyroidism. Secondary MN is associ-
ated with malignancy in up to 20% of patients over the age of
60 years, therefore screening investigations (especially if there
are suggestive symptoms or signs) can include chest X-ray,
mammography, colonoscopy, occult blood in stool, and prostate
specific antigen.
Susceptibility to idiopathic MN and to some forms of secondary
MN is closely linked to the major histocompatibility (MHC) allele
DR3, strongly suggesting that shared immunological mechanisms
are involved. Unlike most forms of human GN, there is a useful
animal model in which the morphological appearances closely
resemble the human condition. This is Heymann nephritis, which
is induced in susceptible rats by immunization with renal auto-
antigens. Studies of this model, and of certain secondary forms
of MN in humans, have led to the hypothesis that idiopathic
MN results from formation of immune complexes, the physical
characteristics of which (possibly including the predominant IgG
subclass they contain) determine their site of localization in the
kidney. The nature of the antigens to which these antibodies are
directed, and whether they are autoantibodies analogous to those
seen in Heymann nephritis, remain unknown. Intriguing recent
observations have been made on the trans-placental transfer of
IgG antibodies causing MN in the fetus/neonate, arising due to
maternal deficiency of a protein, which acts as an immunizing
neoantigen during pregnancy with a fetus expressing the normal
protein.
The prognosis of secondary MN depends entirely on the prog-
nosis 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 spon-
taneous remission of proteinuria even without treatment, and
most nephrologists reserve treatment for those with poor prog-
nostic signs, particularly deteriorating excretory renal function
and/or heavy proteinuria (> 8 g/day) with severe nephrotic
syndrome. A combination of prednisolone and chlorambu-
cil given in alternating monthly cycles for a total of 6 months
appears to be the most efficacious 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 methyl-
prednisolone 1 g/day pulse dose IV for three consecutive days
followed by oral prednisolone 0.5 mg/kg/day for subsequent
27 days; months 2, 4 and 6 chlorambucil 0.10.2 mg/kg/day
or cyclophosphamide 2.5 mg/kg/day for 30 days). ACEIs (and
possibly also angiotensin II receptor blockers [ARBs]) reduce
proteinuria and may slow progression of renal insufficiency.
Nephrotic syndrome caused by MN is associated with a par-
ticular risk of thrombotic complications in 1030% of cases, so
MEDICINE 35:9
many nephrologists routinely prescribe anticoagulants to such
patients. The risk:benefit ratio favours prophylactic anticoagula-
tion if the plasma albumin is below 20 g/l (2 g/dl). As in other
conditions with nephrotic syndrome, patients with MN have
hyperlipidaemia and increased risk of cardiovascular disease.
Therefore, statins should be useful in patients with high-grade
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
cyclosporin plus low-dose prednisolone (10 mg/day) and MMF,
have been tried in the treatment of MN.
IgA nephropathy (IgAN, Bergers disease) is the most common
type of GN worldwide. It typically presents with episodes of hae-
maturia, 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 with-
out 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.
On renal biopsy, the pathognomonic feature of IgAN is depo-
sition 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 moieties. An identical glomerular lesion is seen in
HenochSchnlein purpura (HSP), in which it is accompanied
by a vasculitic rash, often with arthritis and/or gastrointesti-
nal 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 >50% of patients but rarely
causes transplant failure, presumably because the immuno-
suppressive drugs used for the prevention of rejection have a
favourable effect on the GN. Immunosuppressive drugs (cyclo-
phosphamide 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 first-choice
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 125120 mmHg systolic), but also reduce
proteinuria and delay progression to ESRD.
Mesangiocapillary GN (MCGN, also known as membranopro-
liferative GN, MPGN) is uncommon. There are three subtypes,
with indistinguishable clinical presentations (proteinuria, hae-
maturia, 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 clas-
sical pathway (low C4 and C3) in type I MCGN, the alternative
493 2007 Elsevier Ltd. All rights reserved.
 Glomerular disease

pathway (low C3, normal C4) in type II, or the terminal pathway
(type III).
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
Bruchs membrane). Recent observations provide a unifying
explanation for this, and again involve regulation of the alter-
native 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, predis-
pose 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 endo-
carditis, infected prosthetic materials such as ventriculoperitoneal
shunt) or cryoglobulinaemia (which may complicate infections,
particularly HCV). Figure 4 Glomerulus from a patient with antineutrophil cytoplasm
All types of MCGN tend to have a progressive course. antibody-associated focal necrotizing glomerulonephritis showing
Up to 50% of patients develop chronic renal failure within segmental necrosis (H and E stain).
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 If antibodies to GBM are present (Goodpastures disease), the
pressure control and to treat other complications such as hyper- glomerulus shows linear deposition of IgG (Figure 5). More com-
cholesterolaemia. The only other intervention for which there is monly, there is no immunoglobulin in the glomerulus in cases
some support from clinical trials is high-dose corticosteroids, but of RPGN and the condition is termed pauci immune FNGN; at
these are not universally effective and the adverse effects may be least 80% of these patients exhibit circulating ANCA. ANCA are
limiting. Therapy aimed at blocking complement activation would
be useful, and several such treatments are in development.

Focal necrotizing GN (FNGN) usually presents with acute

nephritic syndrome (acute renal failure (ARF), haematuria, pro-
teinuria, cellular casts in the urine). This is sometimes associated
with pulmonary haemorrhage, and this combination is known as
pulmonary renal syndrome or Goodpastures syndrome. Good-
pastures disease is one cause of this syndrome and is due to
anti-glomerular basement membrane antibodies. A more com-
mon cause of the syndrome is small vessel vasculitis (micro-
scopic polyangiitis, Wegeners granulomatosis) which is usually
associated with the presence of 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 insuf-
ficiency. Severe acute inflammation occurs in the glomerulus,
sometimes with formation of crescents when the glomerulus
is squashed by cells that fill Bowmans space; these cells are a
mixture of infiltrating inflammatory cells and proliferating resi-
dent cells. ARF can occur without crescents if the glomerular
necrosis is sufficiently severe (Figure 4). Whatever the cause,
similar appearances are seen on light microscopy, and immuno-
histology is required to identify the aetiology. Figure 5 Immunofluorescence microscopy of a glomerulus in
The diagnosis of anti-GBM disease can be made by the detec- antiglomerular basement membrane disease, showing linear
tion of anti-GBM antibodies in the serum or on renal biopsy. deposition of IgG.

MEDICINE 35:9 494 2007 Elsevier Ltd. All rights reserved.

 Glomerular disease
closely associated with systemic vasculitis, 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 pos-
sible 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 patho-
genesis 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 liters 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 23 mg/kg/day
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 steroids can be stopped at
36 months. Relapses of anti-GBM disease are rare; so long term
maintenance dose of steroids or cytotoxic agent 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 vas-
culitis, patients with anti-GBM antibody disease with serum cre-
atinine >500 m/l at the onset of disease, or patients already on
dialysis, rarely recover renal function.
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.
Prognosis
Poor prognostic factors for progression of GN include hyperten-
sion, 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 nephritic
syndrome, if an underlying precipitant can be identified, the
management and prognosis of GN depend on whether that pre-
cipitant can be eradicated (see pages 49799).12
As many types of GN are mediated by immune mechanisms,
most attempts at treatment involve corticosteroids, anti-inflam-
matory, cytotoxic or immunosuppressive drugs.13 The more
aggressive the disease, the more aggressive the therapy. The
most important factor in improving renal outcome in these con-
ditions is early diagnosis and treatment.
Hypertension associated with GN should be controlled with
antihypertensive drugs (preferably ACEI or ARB) to a target blood
pressure of 130/80 mm Hg, or 125/75 mm Hg in patients with
proteinuria of more than 1 g/day. Progression of renal disease in
proteinuric renal diseases can be retarded by use of ACEI or ARB;
MEDICINE 35:9
patients with greater proteinuria, even if normotensive, benefit
more from this treatment. Dialysis and transplantation are avail-
able 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.14 Tech-
niques for gene delivery to the inflamed glomerulus are being
developed.15 Stem cell therapy is showing promise in GN as it
is in so many areas of human disease.16 The authors hope and
believe 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.
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 Glomerular disease
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Practice points
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
MEDICINE 35:9
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 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
496 2007 Elsevier Ltd. All rights reserved.