Seminar
Primary glomerulonephritides
Lancet 2016; 387: 2036–48
Published Online
February 24, 2016
http://dx.doi.org/10.1016/
S0140-6736(16)00272-5
Department of Nephrology
and Clinical Immunology,
University Hospital, Rheinisch
Westfälische Technische
Hochschule Aachen, Aachen,
Germany (Prof J Floege MD);
and Department of
Nephropathology, Department
of Pathology, University of
Erlangen-Nürnberg, Erlangen,
Germany (Prof K Amann MD)
Correspondence to:
Prof Jürgen Floege, Department
of Nephrology and Clinical
Immunology, Rheinisch
Westfälische Technische
Hochschule University of Aachen,
D-52057 Aachen, Germany
juergen.floege@rwth-aachen.
de
2036
Jürgen Floege, Kerstin Amann
Most glomerulonephritides, even the more common types, are rare diseases. They are nevertheless important since
they frequently affect young people, often cannot be cured, and can lead to chronic kidney disease, including end-
stage renal failure, with associated morbidity and cost. For example, in young adults, IgA nephropathy is the most
common cause of end-stage renal disease. In this Seminar, we summarise existing knowledge of clinical signs,
pathogenesis, prognosis, and treatment of glomerulonephritides, with a particular focus on data published between
2008 and 2015, and the most common European glomerulonephritis types, namely IgA nephropathy, membranous
glomerulonephritis, minimal change disease, focal segmental glomerulosclerosis, membranoproliferative
glomerulonephritis, and the rare complement-associated glomerulonephritides such as dense deposit disease and
C3 glomerulonephritis.
Introduction Laboratory findings
Glomerulonephritides account for about 20% of chronic Clinically manifest glomerulonephritides exhibit
kidney disease cases in most countries and, unlike variable amounts of proteinuria or haematuria. Excretion
major causes of chronic kidney disease such as diabetes of large amounts of albumin but no high-molecular-
and hypertension, they frequently affect young people weight proteins characterises minimal change disease
and many carry a lifelong burden of chronic kidney in children, but this so-called selective proteinuria is
disease. Indeed, in young adults, glomerulonephritides rarely present in adults. Increased urinary excretion of
are the most frequent cause of end-stage renal disease. low-molecular-weight proteins such as alpha-1-
The glomerulonephritides are a heterogeneous group of microglobulin suggests that the primary glomerular
diseases, most of which qualify as orphan diseases. injury has spread to the tubular system, impairing
Consequently, few clinical trials exist. The 2012 the reabsorption of such proteins in the tubule,
guidelines by the Kidney Disease: Improving Global a prognostically adverse sign.2 In particular,
Outcomes (KDIGO) initiative on the treatment of oligosymptomatic glomerulonephritides such as IgA
glomerular diseases1 represent a major advance in nephropathy frequently exhibit some renal failure at
this specialty. first presentation. More specific laboratory tests, such as
the detection of antibodies to phospholipase A2 receptor
Clinical presentation (PLA2R), are strongly suggestive of a membranous
No specific clinical signs of glomerulonephritis exist, glomerulonephritis,3 whereas identification of cir-
which emphasises the need to keep this potential culating immune complexes, total IgA in serum, or anti-
diagnosis in mind. The clinical course of glomerulo- streptolysin O titres is no longer regarded as
nephritis is variable, ranging from chance findings in diagnostically helpful in most cases.
asymptomatic patients (eg, hypertension, proteinuria by
dipstick, haematuria, and raised serum creatinine
concentrations), to massive weight gain and oedema with
Search strategy and selection criteria
nephrotic syndrome, to rapidly progressive glomerulo-
nephritis with uraemia. Some clinical presentations can We searched PubMed, Embase, and the Cochrane Library
be suggestive of a particular diagnosis; in children and between October, 2008, and Oct 31, 2015, for the following
young adults, nephrotic syndrome suggests minimal search terms: “IgA-nephropathy”, “IgA glomerulonephritis”,
change disease or focal segmental glomerulosclerosis, “IgA nephritis”, “membranous nephropathy”, “membranous
whereas in older adults it suggests a membranous glomerulonephritis”, “minimal change disease”, “minimal
glomerulonephritis. Young oligosymptomatic adults with change nephrotic syndrome”, “focal segmental
hypertension or mild oedema might have IgA nephro- glomerulosclerosis”, “FSGS”, “membranoproliferative
pathy. In these cases, the onset of macrohaematuria glomerulonephritis”, “mesangiocapillary glomerulonephritis”,
within 1–2 days after a respiratory tract infection is “dense deposit disease”, “C3 nephropathy”,
suggestive of IgA nephropathy. Additional glomerulo- “C3 glomerulonephritis”, “anti-GBM disease”, “anti-GBM
nephritis signs and symptoms might arise according to nephritis”, “C1q nephropathy”, and “fibrillary
the chronic kidney disease stage, such as renal anaemia glomerulonephritis”. No language restriction was applied.
with fatigue or nausea and vomiting caused by uraemic From about 11 000 articles, we selected original research and
gastroenteritis. The classic signs of acute glomerulo- meta-analyses that provided evidence-based information
nephritis, such as oliguria, oedema, haematuria, about the cause, management, and treatment of various
headache, and flank pain that develop about 2 weeks after types of glomerulonephritis in human beings. Particular focus
a streptococcal pharyngitis, have become rare in most was placed on randomised controlled trials.
developed countries.
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 Seminar

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Glomerulonephritides

Figure 1: Kidney biopsy diagnoses in 2243 adult patients undergoing native kidney biopsy at the Division of Nephrology, Aachen University Hospital,
Aachen, Germany, between 1990 and 2013
ANCA=anti-neutrophil cytoplasmic antibodies. Data from Schlieper and colleagues (Schlieper G, Aachen University Hospital, Aachen, Germany, personal communication).

Differential diagnosis shown in the appendix. A renal biopsy is deemed a safe

Although nephrotic syndrome and rapidly progressive
renal failure are suggestive of a glomerulonephritis,
most other clinical and laboratory findings carry a broad
range of differential diagnoses, including many non-
renal disorders (eg, cardiac oedema or lower urogenital
sources of haematuria). Phase-contrast microscopy of a
freshly voided urine specimen can help detect
dysmorphic red blood cells, in particular acanthocytes
(ie, red blood cells with one or more blebs of different
size and shape protruding from a ring-shaped body),4 or
urinary red blood cell casts, both of which suggest a
glomerular bleeding source.
Establishment of whether a glomerulonephritis is
primary or secondary is key in the work-up of a suspected
glomerulonephritis, because secondary glomerulo-
nephritis often necessitates treatment of the underlying
disorder rather than treatment for the glomerulonephritis.
Adequate diagnostic assessment should be considered
depending on the clinical situation (appendix).
Diagnostic investigations
A definitive diagnosis of glomerulonephritis requires a
kidney biopsy, which should be read by a nephro-
pathologist. The biopsy core is assessed by light microscopy
and immunohistology, and often also by electron
microscopy. The biopsy will also provide important
information about acute inflammatory versus chronic
scarring changes. Common renal biopsy indications are
procedure if conditions are optimised (ie, experienced
physician, normal coagulation, no antiplatelet drugs for
7 days, normal blood pressure, no urinary tract infection,
and biopsy under ultrasound view with a 16–18 gauge
needle).5 Perirenal haematoma is detected in 50–80% of
patients and arteriovenous fistulas in up to 15% of
patients.6,7 These are usually asymptomatic and do not
need intervention. Macroscopic haematuria occurs in up
to 8% of cases, but rarely results in bladder obstruction.6,7
Bleeding that necessitates transfusion, surgical
intervention, or nephrectomy occurs in less than 0·5% of
cases. In many centres, an overnight hospital stay is a
requirement after a kidney biopsy, particularly if moderate-
to-advanced chronic kidney disease is present, because an
assessment period of 8 h or less will miss about a third of
clinically relevant complications.6
Epidemiology
Figure 1 shows a typical range of diagnoses in a European See Online for appendix
renal biopsy cohort. Annual incidence has been estimated
as 2·5 cases per 100 000 adults for IgA nephropathy,
1·2 per 100 000 for membranous glomerulonephritis,
0·6–0·8 per 100 000 for minimal change disease and focal
segmental glomerulosclerosis, and 0·2 per 100 000 for
membranoproliferative glomerulonephritis.8 However,
these percentages are usually underestimates because
they do not take into account people with asymptomatic
glomerulonephritis variants, those whose glomerulo-

www.thelancet.com Vol 387 May 14, 2016 2037

 Seminar

nephritis remits spontaneously, or, vice versa, those who

For GN Tools see http:/www.
gntools.com
have advanced chronic kidney disease at first presentation
for whom a renal biopsy is no longer warranted.
Important regional differences in glomerulonephritis
distribution exist; the percentage of IgA nephropathy
diagnoses is higher in Asian cohorts, whereas in cohorts
from the USA and Canada, focal segmental glomerulo-
sclerosis is more prevalent. Additionally, within one
region, the distribution of glomerulonephritis types
is associated with socioeconomic factors, with
wealthier countries exhibiting more IgA nephropathy
and less wealthy countries having more cases of
membranoproliferative glomerulonephritis.9
Risk factors
In most glomerulonephritides, only a subgroup of
patients experiences progressive glomerular filtration
rate (GFR) loss; such high-risk patients should be
followed up by a nephrologist. These patients are
usually those with arterial hypertension, clinically
significant proteinuria (ie, >1 g/day in those with
IgA nephropathy or >3·5 g/day in those with
focal segmental glomerulosclerosis, membranous
glomerulonephritis, or membranoproliferative glom-
erulonephritis), and reduced estimated GFR at
glomerulonephritis diagnosis or histological presence
of scars (ie, glomerulosclerosis or tubulointerstitial
fibrosis). In particular, proteinuria maintained over
6–24 months is a potent predictor of outcome in the
common glomerulonephritis types.10 Additional risk
factors for a progressive course include smoking11,12 and
obesity,13 probably via increasing hypertension or
glomerular hyperfiltration, or both. Genetic factors
such as the apolipoprotein L1 gene in African-
Americans can also contribute to progression of
glomerulonephritides.14–16 Finally, coincident disorders
that damage the kidneys (eg, primary hypertension and
diabetes mellitus) can also affect disease progression.
At the opposite end of the spectrum are those patients
who only have mild renal failure, or renal failure that is
adequate for their age (most individuals will lose about
1 mL/min GFR per year after age 40 years), normo-
tension, minor proteinuria (below 1 g/day), or isolated
microhaematuria. These patients should be followed up
only periodically.
Supportive therapy: one approach for all
patients at risk of progressive disease
Supportive measures are not specific for patients with
glomerulonephritis, but apply to all patients with
proteinuric glomerular diseases who are at risk of
progressive disease (panel).17 Key measures include
antihypertensive, antiproteinuric, and dietary approaches
aimed at slowing down non-specific mechanisms that
contribute to progression of renal disease. Such a
comprehensive approach can slow progression of
proteinuric glomerulonephritis substantially.18
Panel: Supportive measures in patients with
glomerulonephritis who are at risk of progressive loss of
renal function
Aim to implement all level A recommendations and as many
level B recommendations as possible.
Level A recommendations
• Target seated systolic blood pressure 120–129 mm Hg
• Start ACE inhibitor or ARB treatment and up-titrate
dosage to reach the target systolic blood pressure and
reduce proteinuria to less than 1 g/day
• Avoid dihydropyridine calcium-channel blockers unless
needed for blood pressure control (and then only after
starting an ACE inhibitor or ARB)
• Control protein intake to about 0·8 g/kg per day
Level B recommendations
• Restrict sodium chloride intake or start diuretic treatment,
or both
• Control fluid intake
• Non-dihydropyridine calcium-channel blocker
treatment
• Control each component of the metabolic syndrome
• Aldosterone antagonist treatment (adapt dose to chronic
kidney disease stage)
• β-blocker treatment
• Smoking cessation
• Allopurinol treatment (controversial)
• Empiric sodium bicarbonate treatment, independent of
whether or not metabolic acidosis is present
(controversial)
Other measures to delay disease progression
• Avoid non-steroidal anti-inflammatory drugs if possible
(if not, use a maximum of once or twice weekly)
• Avoid prolonged severe hypokalaemia
• Correct vitamin D deficiency
• Control hyperphosphataemia and hyperparathyroidism
Modified from Wilmer and colleagues.17 ACE=angiotensin converting enzyme.
ARB=angiotensin receptor blocker.
In patients with nephrotic syndrome, the afore-
mentioned measures should also include thrombosis
prophylaxis. The concentration of serum albumin is
usually used as a surrogate parameter to assess the risk
of thromboembolism. In particular, patients with
membranous glomerulonephritis, especially those with
serum albumin below 20 g/L, are at an increased risk of
thromboembolic events; the hazard ratio for thrombo-
embolism was 10·8 for patients with membranous
glomerulonephritis (95% CI 2·4–49·4) and 5·9 for those
with focal segmental glomerulosclerosis (1·3–27·9)
compared with those with IgA nephropathy.19 Risk:benefit
instruments have been developed to establish who
should receive anticoagulation; for example, GN Tools
for membranous glomerulonephritis.20

2038 www.thelancet.com Vol 387 May 14, 2016


IgA nephropathy
IgA nephropathy (figure 2) is the most common
glomerulonephritis in developed countries. It is usually an
oligosymptomatic glomerulonephritis, often discovered
coincidentally. Spontaneous remissions can occur.21 It is
regarded as an immune-mediated disease with deposition
of under-galactosylated, dimeric, or polymeric IgA in the
glomerular mesangium followed by the onset of
mesangioproliferative glomerulonephritis.22 IgG or IgA
autoantibodies to the under-galactosylated IgA might also
contribute to IgA nephropathy,23,24 and both the circulating
concentrations of under-galactosylated IgA and of
autoantibodies are associated with IgA nephropathy
progression.24,25 Findings from a genome-wide association
study26 showed a pronounced genetic predisposition to IgA
nephropathy, with high prevalence in southeast Asia,
intermediate prevalence in the USA and Europe, and low
prevalence in Africa. Gene polymorphisms associated with
IgA nephropathy include complement factors and related
genes,27 HLA loci, and loci related to mucosal barrier
function and innate immunity.28,29
Major diagnostic advances
Since many patients have a benign disease course or
remit spontaneously,21 identification of those who will
progress to renal failure is crucial. In a French cohort,30 a
three-point score based on proteinuria above 1 g/day,
presence of hypertension, and histological changes in
the biopsy sample sensitively predicted the risk of death
or dialysis after 20 years (ranging from 4% in those with
a score of 0 to 64% with a score of 3).
The Oxford-MEST classification of IgA nephropathy
comprises four histological parameters associated with a
progressive course: glomerular mesangial hyper-
cellularity; endocapillary hypercellularity; glomerular
sclerosis or tuft adhesions; and tubular atrophy and
interstitial renal fibrosis affecting more than 25% of the
section.31,32 Glomerular crescents were not included in
this classification, possibly because patients who had a
rapid decline to end-stage kidney disease were not
included in the original study. Additionally, in IgA
nephropathy, crescents can even occur in patients who
are judged to have benign disease, such as isolated
microhaematuria.33 Such single crescents need to be
differentiated from the rare clinical situation of crescentic
IgA nephropathy with glomerular necroses, crescents
affecting more than 50% of the glomeruli, and a clinical
course of rapidly progressive glomerulonephritis. In a
Chinese study,34 70% of such patients developed end-stage
renal disease after 5 years despite immunosuppressive
treatment. A serum creatinine concentration higher than
600 μmol/L on admission defined a threshold beyond
which immunosuppression might no longer be
indicated. Rapidly progressive glomerulonephritis in IgA
nephropathy must be distinguished from acute kidney
injury induced by macrohaematuria with obstruction
and damage of tubules from glomerular bleeding.
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Seminar
A B
*
100 µm
C
100 µm 100 µm
Figure 2: IgA nephropathy
(A) In IgA nephropathy, segmental areas (arrows) of mesangial hypercellularity and matrix expansion occur,
characteristic of mesangioproliferative glomerulonephritis. Part of the glomerular tuft adheres to Bowman’s
capsule (white dashed oval), constituting the starting point of a secondary focal segmental glomerulosclerosis
lesion. Tubulointerstitial damage with leucocyte infiltrates, tubular atrophy and fibrosis (arrowhead), and tubular
protein casts (asterix) is also present. PAS stain. (B) Other glomeruli in the same patient exhibit few pathological
abnormalities on light microscopy (PAS stain), but the characteristic mesangial granular IgA deposition (C) can be
found in these glomeruli as well.
Therapeutic advances
Uncertainty exists regarding immunosuppression in
patients with IgA nephropathy who are at risk of
progressive disease.35 There is a consensus no longer to
offer immunosuppression to patients with a GFR below
30 mL/min at presentation unless they also have a rapidly
progressive glomerulonephritis course (see earlier).1
Findings from a recent retrospective study36 suggest that
corticosteroids might be beneficial for patients with a
GFR below 50 mL/min, particularly if proteinuria exceeds
3 g/day. In two randomised controlled trials (RCTs),
angiotensin-converting enzyme (ACE) inhibition was
compared with ACE inhibition plus high-dose oral
prednisone in patients with IgA nephropathy who were at
risk of progression (ie, proteinuria >1 g/day), but who had
a baseline GFR above 50 mL/min.37,38 Findings from both
studies showed that the combination was more effective
than ACE inhibition alone at preserving GFR. However,
in both studies, patients were required to stop any pre-
existing renin-angiotensin system (RAS) blockers at least
4 weeks before entering the trial, raising the concern that
some patients who entered the trial were already well
controlled and in a low-risk proteinuria range (ie, below
1 g/day) with an RAS blocker alone. In a meta-analysis of
the role of corticosteroids in IgA nephropathy, findings
from all studies showed reductions in proteinuria, but
several detected no benefits for GFR.39 In particular, the
question of whether corticosteroids still exert a benefit if
added after optimisation of supportive measures,
2039
 Seminar
A B
100 µm 100 µm
C D
100 µm 100 µm
Figure 3: Membranous glomerulonephritis
The PAS stain (A) shows slightly thickened glomerular basement membranes and prominent podocytes. On
immunohistology, granular deposits of (B) IgG and (C) C3c can be found along the glomerular basement membrane,
and pronounced de-novo expression of (D) PLA2R is present on the podocytes. PLA2R=phospholipase A2 receptor.
including intense RAS blockade, remains unresolved.
The sequence of first optimising supportive measures for
3–6 months before considering corticosteroids in patients
with persistent proteinuria above 1 g/day and GFR greater
than 50 mL/min has been suggested by the guidelines.1
We tested this sequence in the STOP-IgAN RCT,40 in
which only patients who maintained proteinuria above
0·75 g/day after a comprehensive optimisation of
supportive treatment were randomly assigned to receive
additional immunosuppression or to continue on
supportive care only. Although we too noted a transient
reduction of proteinuria with immunosuppression, we
did not identify a benefit in the GFR endpoint at 3 years
and adverse effects increased with immunosuppression
compared with no immunosuppression.41
Other immunosuppressive drugs, or combination
immunosuppressive treatment, are not recommended in
patients with high-risk IgA nephropathy except for those
rare patients with a rapidly progressive glomerulo-
nephritis course (see earlier).1 Even though benefits of
mycophenolate mofetil have been described in a small
RCT in Chinese patients with IgA nephropathy,42 such
benefits have not been noted in similarly small RCTs in
white people.43–45 Additionally, several cases of lethal
pneumocystis pneumonia occurred in patients with IgA
nephropathy with reduced GFR who were receiving
2040
mycophenolate mofetil.46 Findings from an Italian
multicentre RCT showed that the combination of
high-dose corticosteroids with azathioprine for 6 months
was not superior to steroids alone and again only
increased the frequency of adverse effects.47
The finding of intestinal hypersensitivity to many food
antigens in IgA nephropathy led to the suggestion of
enteric corticosteroids as a new treatment for IgA
nephropathy.48 In a pilot trial49 of budesonide given in a
formulation with preferential release in the terminal
ileum, albuminuria was reduced in IgA nephropathy; this
approach is being tested more formally in the multicentre
Nefigan phase 2 RCT (NCT01738035), and findings from
this trial are expected to be published soon. The value of a
tonsillectomy in patients with IgA nephropathy seems
questionable,50 and it is not routinely recommended.1 Fish
oil treatment is recommended by some, but not all,
physicians, if the patient can tolerate the taste.1
Controversies, uncertainties, and remaining research
questions
In view of increasing data suggesting that immuno-
suppression is not particularly effective in IgA nephro-
pathy, better understanding of the pathophysiology of the
disease, in particular the mucosa–kidney axis, is of
imminent importance.51 Perhaps IgA nephropathy
exhibits more similarities to allergic than to autoimmune
diseases; the absence of suitable animal models hampers
testing this theory.22 Clarification of several other aspects,
ranging from the role of complement in IgA nephropathy
to inhibition of growth factors for glomerular cells such
as platelet-derived growth factor, might also lead to new
therapeutic approaches for IgA nephropathy.22
Membranous glomerulonephritis
Membranous glomerulonephritis (figure 3) primarily
affects middle-aged and old adults and can occur secondary
to infections (eg, hepatitis B and C), tumours (see later52),
systemic immune diseases (lupus erythematosus), or
some drugs (eg, gold and penicillamine). The disease
often manifests as nephrotic syndrome with or without
loss of GFR. The risk of thromboembolism in patients
with nephrotic syndrome is high (see earlier).
Findings from a landmark study in 20093 showed that
70–80% of primary membranous glomerulonephritis
cases in white people represent autoimmune responses
against the M-type PLA2R, which can be detected on
glomerular podocytes and in subepithelial immune
deposits. Subsequently, findings from a genome-wide
association study showed that particular polymorphisms
of the PLA2R gene combined with HLA-DQA1 poly-
morphisms increased the risk for primary membranous
glomerulonephritis by up to 79 times.53 Major pathogenic
epitopes of PLA2R have been identified54,55 and might
facilitate the design of new therapeutic approaches. A less
common autoantigen is thrombospondin type-1 domain-
containing 7A (THSD7A).56 Other autoantigens are likely
www.thelancet.com Vol 387 May 14, 2016

to be discovered, establishing primary membranous
glomerulonephritis as a family of autoimmune disorders.
Autoantigens or exogenous antigens in the rare situation
of neonatal membranous glomerulonephritis include
neutral endopeptidase and bovine serum albumin.57
Major diagnostic advances
Assays for circulating PLA2R antibodies rapidly change
the diagnostic approach to membranous glomerulo-
nephritis. Circulating PLA2R antibodies seem to be
specific for membranous glomerulonephritis;58 however,
they can also occur in secondary membranous
glomerulonephritis. Their titre is associated with disease
activity and predicts prognosis and response to
treatment,59–62 the disease course after treatment,63 and
recurrences after kidney transplantation.64 A decrease in
antibody titres during treatment often precedes
proteinuria response65 and can thus help to differentiate
patients who respond to treatment from those who are
refractory to treatment. The finding of PLA2R on
podocytes on renal biopsy can also aid in the diagnosis
of membranous glomerulonephritis. In particular,
patients who are negative for PLA2R or THSD7A
autoantibodies exhibit a high probability of spontaneous
remission but should be screened for malignancy.66 In a
2014 meta-analysis, the most common malignancies
associated with membranous glomerulonephritis were
lung carcinomas (22 [26%] of 85 cases), followed by
prostate carcinomas (13 cases [15%]), haematological
malignancies (12 cases [14%]), and colorectal tumours
(nine cases [11%]).52
Major therapeutic advances
Spontaneous remission occurs in up to a third of
patients, after a mean of 14 months, even if the initial
presentation includes massive proteinuria.67 This finding
supports the policy of waiting for 6 months and asse-
ssing the pattern in proteinuria before considering
immunosuppression unless a rapid loss of GFR is
present or life-threatening complications of nephrotic
syndrome occur.1 In a Dutch RCT,68 this approach was
tested by randomly assigning 26 patients with nephrotic
syndrome with a normal GFR to early immuno-
suppression or waiting with immunosuppression until
serum creatinine concentration had increased by 25% or
more. The two treatment groups did not differ in
remission rates, the course of GFR loss, or complications.
The same Dutch group retrospectively analysed
the outcome of 254 patients with membranous
glomerulonephritis.69 Immunosuppression was only
given if GFR decreased or serious complications of the
nephrotic syndrome occurred. After 10 years, seven
patients (3%) had developed end-stage kidney disease,
25 (10%) had died, 52 (20%; 95% CI 44–60) had achieved
full remission, and 90 (35%; 85–94) a partial remission of
their nephrotic syndrome. These data support a watchful
waiting approach in most patients.
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A B
100 µm 4 µm
Figure 4: Minimal change disease
(A) By light microscopy (PAS stain), no substantial abnormalities of the glomerular structure are noted.
(B) Electron microscopy shows widespread effacement of podocyte foot processes (arrows) in the absence of
electron-dense or fibrillary deposits.
Immunosuppressive treatment for membranous
glomerulonephritis has so far relied on alkylating agents
plus corticosteroids or calcineurin inhibitors. In British
high-risk patients (ie, those with impaired GFR at
baseline), the combination of prednisolone and
chlorambucil delayed GFR loss significantly better than
ciclosporin or supportive treatment, but at the cost of
more adverse effects.70 By contrast, mycophenolate
mofetil plus RAS blockers did not induce more partial
or full remissions in patients with membranous
glomerulonephritis than RAS blockers alone.71 Findings
from a meta-analysis72 showed that alkylating agents
(mostly cyclophosphamide) plus corticosteroids protect
GFR, that ciclosporin and mycophenolate mofetil are
not superior to this combination, and that long-term
effects of tacrolimus or adrenocorticotropic hormone,
both of which also reduce proteinuria in membranous
glomerulonephritis, are not well established. A newer
therapeutic option is rituximab; about two-thirds
of patients with nephrotic membranous glom-
erulonephritis achieve partial or full remission with
rituximab.73 However, in a large retrospective study,
rituximab was not superior to alkylating agents or
calcineurin inhibitors at inducing proteinuria remission
at 12 months.74
Controversies, uncertainties, and remaining research
questions
The search is on to clarify the pathogenesis of
membranous glomerulonephritis in the 20–30% of
patients who are negative for PLA2R and THSD7A, as
well as the pathogenesis of membranous lupus nephritis.
Animal models mimicking the human autoimmune
situation are in development and should help in the
design of new therapeutic approaches. Additionally, we
still do not have formal proof that therapeutic decisions
can be made on the basis of autoantibody titres. RCTs
studying the effects of B-cell-targeted treatment are
ongoing (eg, MENTOR, NCT01180036).
2041
 Seminar
A B
100 µm
Figure 5: Focal segmental glomerulosclerosis
(A) Light microscopy (PAS stain) shows a segment of the glomerular tuft, which is collapsed and scarred resulting in adhesion of the glomerular tuft with Bowman‘s
capsule (arrow). (B and C) Parietal epithelial cell markers are sensitive markers for the detection of focal segmental glomerulosclerosis lesions. Serial sections of a
glomerulus with a lesion at the glomerular tip are shown. The PAS section (B) shows a glomerulus with minimal sclerosis. The glomerular tuft protrudes into the
tubular lumen (arrow), but no marked sclerosis or synechiae are visible in this section. Immunostaining (C) of the extracellular matrix produced by parietal epithelial
cells (red staining) and the parietal epithelial cell marker annexin A3 (green) clearly stain the lesion (arrow). (B and C) kindly provided by Bart Smeets, Nijmegen,
Netherlands, and Marcus Moeller, Aachen, Germany.
Minimal change disease and focal segmental
glomerulosclerosis
Minimal change disease (figure 4) is the most common
disease underlying childhood nephrotic syndrome, but
also manifests in adults. Secondary forms occur in
diseases such as atopy or malignancy, particularly in
lymphomas. Minimal change disease is occasionally
accompanied by glomerular IgA deposits, and this
situation should not be confused with IgA nephropathy.75
Whether minimal change disease and focal segmental
glomerulosclerosis represent different manifestations of
one disease (with minimal change disease potentially
progressing to focal segmental glomerulosclerosis) or
two different diseases is unknown. They are both covered
jointly here, since therapeutic studies often do not
differentiate between them.
Focal segmental glomerulosclerosis is a confusing
term because it is used by pathologists both to describe a
glomerular scar (figure 5), which can result from almost
any injury affecting the kidneys, and clinically to denote a
family of glomerular diseases. Central to the pathogenesis
is damage to podocytes, resulting in their loss. A second
central event is activation of parietal epithelial cells on
Bowman’s capsule, which then migrate onto the
glomerular tuft to replace or displace podocytes.76 Once
on the glomerular tuft, parietal cells, unlike podocytes,
are unable to produce sufficient vascular endothelial
growth factor, and this triggers endothelial problems,
with collapse and scarring of the affected capillary.77 The
finding of parietal cell activation markers can help to
distinguish focal segmental glomerulosclerosis from
minimal change disease (figure 5).78
Minimal change disease is assumed to result from
circulating permeability factors (see later).79 Within the
clinical focal segmental glomerulosclerosis family, one
group relates to circulating permeability-inducing factors
or mutations of podocyte proteins, both of which lead to
nephrotic syndrome mostly in children or young adults.
Another group of focal segmental glomeruloscleroses
are secondary, adaptive forms, related to glomerular
2042
C
100 µm 100 µm
hyperfiltration and hypertrophy; for example, in obesity
or situations of reduced nephron mass (eg, premature
birth or surgical removal of significant kidney mass).
Renal risk variants in APOL1 contribute to focal
segmental glomerulosclerosis progression in black
patients, regardless of diabetes status.14–16 Finally, focal
segmental glomerulosclerosis can also result from toxic
effects of drugs (eg, anabolic steroids)80 or viral infections
(eg, HIV), inducing a collapsing variant of focal
segmental glomerulosclerosis.
Major diagnostic advances
Glomerular permeability factors in minimal change
disease include angiopoietin-like-4,81 and in focal
segmental glomerulosclerosis they might include
soluble urokinase plasminogen activator receptor
(suPAR),82 cardiotrophin-like cytokine-1,83 and others.84
Only suPAR has been assessed in several clinical studies.
Raised circulating suPAR concentrations specifically
identified patients with primary focal segmental
glomerulosclerosis in an initial study,82 but subsequent
studies did not confirm this finding experimentally85 or
clinically.86–90 Rather, non-specific increases of suPAR
serum concentrations occur in patients with reduced
GFR or ongoing inflammation, or both. Thus, suPAR
measurements are not recommended in the differential
diagnosis of nephrotic syndrome.
Another potential diagnostic and therapeutic (see
later) target is the co-stimulatory protein B7-1 (CD80).
Normally macrophage derived, this molecule is found
on podocytes in proteinuric diseases. Soluble urinary
CD80 increased in patients with nephrotic syndrome
with minimal change disease, but was low in patients
in remission from minimal change disease and in
those with focal segmental glomerulosclerosis.91
In view of the growing list of podocyte molecules that
can be mutated in focal segmental glomerulosclerosis, an
important issue is whether genetic testing should be
done once a patient is diagnosed with primary focal
segmental glomerulosclerosis. Guidelines argue against
www.thelancet.com Vol 387 May 14, 2016

this unless a family history of focal segmental glomerulo-
sclerosis is present.1 This recommendation is supported
by findings from a US study in non-familial focal
segmental glomerulosclerosis, in which mutations in
commonly affected genes (NPHS2, TRPC6, ACTN4,
INF2, and PLCE1) were found in four of 28 children and
none of 37 adults.92 By contrast, in families with steroid-
resistant nephrotic syndrome, a single-gene cause was
detected in 526 (30%) of 1783 patients whose disease
manifested before age 25 years.93 In adults, mutations of
the collagen IV alpha 3–5 genes, which also underlie
Alport syndrome, have been identified in many patients
with focal segmental glomerulosclerosis.94 Additional
genetic causes are emerging.95–100
Major therapeutic advances
Treatment of minimal change disease and focal segmental
glomerulosclerosis relies on corticosteroids, with
prolonged high-dose treatment needed in focal segmental
glomerulosclerosis.1 Corticosteroids, at least in focal
segmental glomerulosclerosis, might exert their effect by
inducing expansion of myeloid-derived suppressor cells.101
Treatment is difficult in steroid-resistant or frequently
relapsing patients. In an RCT, ciclosporin was compared
with a combination of steroid pulses plus mycophenolate
mofetil in 138 patients with steroid-resistant primary focal
segmental glomerulosclerosis.102 All endpoints, in
particular remission, did not differ between the two
approaches. However, even this large RCT is likely to have
been underpowered to detect therapeutic differences in
view of the heterogeneity of focal segmental glomerulo-
sclerosis pathogenesis and thus potential differences in
therapeutic responses.103 In another RCT, 6-monthly
cyclophosphamide boluses was compared with tacrolimus
in adults with steroid-dependent minimal change
disease.104 Both treatments induced complete remission
in over 75% of patients without major differences between
treatment groups. In an Indian RCT,105 ciclosporin was
compared with tacrolimus (both combined with
corticosteroids) in paediatric steroid-resistant nephrotic
syndrome; similar efficacy in inducing remission was
noted, but relapses occurred 4·5 times more often with
ciclosporin and more cosmetic adverse effects occurred
with ciclosporin, an important consideration in children
and young adults. Finally, findings from a Cochrane
review106 on immunosuppression in adults with focal
segmental glomerulosclerosis showed that ciclosporin
combined with low-dose prednisolone can induce at least
partial remission of nephrotic syndrome, but that the
long-term benefits of preserving GFR are not well
established. The review advises against widespread use of
alkylating agents in such patients.
Rituximab is increasingly used in minimal change
disease and focal segmental glomerulosclerosis. In an
RCT107 in children with frequently relapsing or steroid-
dependent nephrotic syndrome, rituximab (four doses of
375 mg/m²) was compared with placebo. All other
www.thelancet.com Vol 387 May 14, 2016
Seminar
immunosuppressive drugs were discontinued shortly
after randomisation. At 1 year, 17 (71%) of 24 patients
who received rituximab had relapsed compared with
23 (96%) of 24 patients receiving placebo. Similar
findings were noted in children receiving a single dose
of rituximab only108 and in adults.109–111 Side-effects were
generally mild to moderate, but occurred more
frequently with rituximab than with placebo.107 One
possible explanation for the efficacy of rituximab in
minimal change disease might be a direct effect of
rituximab on podocytes.112 Rituximab-resistant patients
with nephrotic syndrome responded to ofatumumab,
another CD20 antibody.113
In a case series of five patients with primary or
recurrent focal segmental glomerulosclerosis after
kidney transplantation,114 abatacept, an inhibitor of B7-1
(see earlier), induced remissions of proteinuria, possibly
by reducing podocyte migration. In all cases, B7-1
overexpression was identified in podocytes before
treatment. However, others have not confirmed the
overexpression of B7-1115 or similar effects of abatacept,116
and thus further confirmation should be awaited before
considering abatacept in patients with focal segmental
glomerulosclerosis. In another recent study,117 the value
of galactose or adalimumab treatment in focal segmental
glomerulosclerosis was assessed, but findings were
inconclusive because of recruitment problems.
Controversies, uncertainties, and remaining research
questions
One of the most important research issues in both
minimal change disease and focal segmental glomerulo-
sclerosis is the identification of circulating permeability
factors since this is likely to change our therapeutic
approaches radically. Alternatively, a better understanding
of what mediates the damage to podocytes and activation
of parietal glomerular epithelial cells in focal segmental
glomerulosclerosis is likely to result in new treatments. If
such activation is indeed a common pathway in various
causes of focal segmental glomerulosclerosis, it might be
particularly attractive for future RCTs.
Membranoproliferative glomerulonephritides
Membranoproliferative glomerulonephritis is a morpho-
logical pattern of injury and strictly speaking not a
disease. The term is likely to be phased out over time in
favour of a more cause-specific nomenclature. Indeed,
the existence of a primary, idiopathic membranopro-
liferative glomerulonephritis type I (mesangiocapillary
glomerulonephritis type I) has been questioned.118
Membranoproliferative glomerulonephritis type I has
become a rare disease in most developed countries. About
a quarter of patients have an underlying hepatitis B or C
infection.119 Another quarter exhibit a monoclonal
gammopathy or lymphomas.119
Older electron-microscopy-based classification
systems also included membranoproliferative
2043
 Seminar
glomerulonephritis type II (dense deposit disease) and
type III. A new terminology that distinguishes
immunoglobulin-mediated membranoproliferative
glomerulonephritis (ie, the former type I mentioned
earlier) from complement-mediated membranopro-
liferative glomerulonephritis has been proposed
(appendix).120 The latter group, termed C3
glomerulopathy, is characterised by defects in the
alternative pathway of complement, in particular of
factor H,121 or autoantibodies to complement-regulatory
proteins (so-called C3 nephritic factors) leading to
increased complement activation. The group includes
dense deposit disease and C3 glomerulonephritis
(appendix).122–125 The two entities are distinguished on
the basis of the immunohistological pattern of C3 and
the electron microscopy detection of ribbon-like
electron-dense deposits in the glomerular basement
membrane in dense deposit disease, versus deposits of
usual density in C3 glomerulonephritis. Compared
with patients with C3 glomerulonephritis, those with
dense deposit disease are usually younger and have
lower C3 serum concentrations, more extensive renal
damage, and a higher risk of GFR loss.126 High-
throughput genetic analysis enabled identification of
the defect underlying C3 glomerulonephritis in
13 (43%) of 30 cases.127 Recurrence after kidney
transplantation occurs in about 60–70% of patients
with C3 glomerulonephritis and more than 90% of
those with dense deposit disease.128
Major therapeutic advances
No new RCTs in membranoproliferative glomer-
ulonephritis type I have been published in the past
5 years, and the KDIGO guidelines,1 which recommend
combined treatment with corticosteroids plus either
mycophenolate mofetil or cyclophosphamide in patients
with nephrotic syndrome with progressive GFR loss, are
based on weak evidence.
Individual patients with single dense deposit disease
or C3 glomerulonephritis were given eculizumab, a
C5 antibody.129,130 Clinical symptoms and histological
findings improved in some patients. After 1 year of
eculizumab, deposition of eculizumab was noted in
glomeruli in a pattern resembling monoclonal IgG
deposition disease.131 The relevance of this finding is
unknown. Two patients with dense deposit disease with
autoantibodies against C3b or factor H received kidney
transplants successfully without rapid disease recurrence
under a special protocol of immunosuppression before
and after transplantation.132 In another case, expression
of a hybrid protein (CFHR2-CFHR5) stabilised
C3 convertase, and the resulting increased complement
activation could be stopped by soluble complement
receptor 1 only.133 Benefits from more non-specific
immunosuppression with mycophenolate mofetil plus
corticosteroids have been described in patients with
C3 glomerulonephritis.134
2044
Controversies, uncertainties, and remaining research
questions
The identification of specific causes underlying mem-
branoproliferative glomerulonephritis and C3 glomer-
ulopathies should hopefully allow rational treatment in
most cases. Studies of the rare so-called idiopathic
membranoproliferative glomerulonephritis type I cases
should be intensified to identify infectious or
other causes.
Rare glomerulonephritides
Anti-glomerular basement membrane disease is a rare
autoimmune glomerulonephritis affecting all age groups
that develops as a result of conformational changes in
the α3NC1 and α5NC1 subunits of collagen IV in the
glomerular basement membrane followed by inter-
molecular and intra-molecular epitope spreading.135,136
This disease can occur as renal limited disease or with
lung haemorrhage (Goodpasture disease). Symptoms
usually last only a few weeks, and progression within
days can also occur. Older patients usually exhibit milder
disease and, as in younger individuals, outcomes depend
on initial estimated GFR.137 Circulating antibodies to
glomerular basement membrane collagen IV are
characteristic. However, 5% of patients are negative for
circulating antibodies but have linear IgG deposition
along the glomerular basement membrane.138 Anti-
glomerular basement membrane disease can occur
together with membranous glomerulonephritis, in
which case the renal manifestations tend to be milder
than in pure anti-glomerular basement membrane
disease.139 Treatment of anti-glomerular basement
membrane disease should be started rapidly, using
corticosteroids, cyclophosphamide, and plasmapheresis.1
Plasmapheresis seems to be essential, since
corticosteroids plus cyclophosphamide alone did not
improve renal outcomes.140 Rituximab can help in
inducing disease remission.141 If patients present with
end-stage renal disease without pulmonary involvement,
immunosuppression is no longer recommended.1
Although the disease can recur after kidney
transplantation, survival of the allograft is not different
from other diseases.142
C1q nephropathy is a rare glomerulonephritis charac-
terised by dominant or co-dominant mesangial or
glomerular capillary C1q deposits. In a large case
series,143 clinical presentations ranged from minimal
urinary findings to nephrotic syndrome, and histological
findings from those suggestive of minimal change
disease or focal segmental glomerulosclerosis to
immune complex glomerulonephritis. In particular,
patients with pathological abnormalities consistent
with focal segmental glomerulosclerosis progressed
to dialysis.
Fibrillary glomerulonephritis is another rare disease of
unknown cause associated with malignancies, para-
proteinaemias, and other autoimmune diseases.144
www.thelancet.com Vol 387 May 14, 2016

Proteinuria is often nephrotic. Half of patients progress
to end-stage renal disease, with frequent recurrence
after transplantation. Whether immunosuppression, in
particular rituximab, affects the course of this disease
is unknown.145
Conclusions
A former, descriptive glomerulonephritis classification,
based largely on histological patterns, is increasingly
being replaced on the basis of new pathogenic insights.
This change in classification has led to more and
more cause-driven treatments being developed. The
infrequency of most glomerulonephritides and the
increasing knowledge about cause and treatment implies
that such patients should be followed up in specialised
centres, which, in turn, will facilitate RCTs, which are
desperately needed in nephrology.146
Contributors
JF and KA contributed to data collection, data analysis, data
interpretation, and writing of the manuscript.
Declaration of interests
JF has received personal fees from Pharmalink, Amgen, Sanofi,
Vifor/Fresenius, Chugai, and Bristol-Myers Squibb. KA declares no
competing interests.
Acknowledgments
This work was supported by the German Research Foundation
(Deutsche Forschungsgemeinschaft) grant SFB TRR57, project p25.
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