The immune system and kidney disease: Basic concepts and clinical implications

1] Institutes of Molecular Medicine and Experimental Immunology (IMMEI), Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. [2].
Nature Reviews Immunology (Impact Factor: 34.99). 09/2013; 13(10). DOI: 10.1038/nri3523
Source: PubMed


The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.


Available from: Christian Kurts, Jun 12, 2015
Considerable progress has been made both in under-
standing the basic immune mechanisms of kidney
disease and in translating these findings to clinical
therapies. Sophisticated animal studies combined
with the analysis of clinical samples have led to a pre-
cise knowledge of the autoimmune targets and of the
mechanisms responsible for kidney injury. Kidney
diseases are highly prevalent and cost-intensive,
but many discoveries in renal immunology are not
widely known in the immunological community,
although they are often relevant to diseases that affect
In this Review, we discuss recent advances in our
understanding of immune-mediated kidney diseases,
emphasizing those of particular relevance to the wider
immunology community and those that have led to a
better understanding of basic immunological mechan-
isms. We have had to be selective in the topics consid-
ered and so have excluded a discussion of acute kidney
injury, kidney transplantation and alloimmunity, as
well as of systemic diseases with associated kidney
disease, such as type2 diabetes and hypertension,
that are not primarily caused by the immune system,
despite the involvement of innate (and possibly adap-
tive) immune responses in the renal injury they cause.
Here, we discuss the innate immune mechanisms of
kidney injury and introduce novel concepts about the
role of the cellular immune responses that drive renal
disease. Moreover, we summarize recent discoveries
about complement- and antibody-mediated nephritis,
and we discuss kidney pathologies that are mediated
by renal autoantigen-specific antibodies, especially those
that are induced by crossreactive microorganism-specific
antibodies. Finally, we describe how the disruption of
kidney function and kidney pathologies can influence
systemic immune responses.
Kidney-resident immune cells
In the kidneys, toxic waste products of metabolism are
removed from the blood by nephrons. Each nephron
contains one glomerulus, which functions as a size-
selective filter that retains molecules above ~50 kDa
in the blood. Compounds of lower molecular mass
pass through the glomerular filter, enter the tubular
system and are excreted with the urine unless they
are re absorbed by the tubular epithelium (BOX1). The
kidneys produce several hormones that directly or
indirectly affect immune responses, including vita-
minD, which regulates bone homeostasis and phago-
cyte function, erythropoietin, which is induced in
response to hypoxia to regulate erythropoiesis, and
renin, which induces angiotensin and aldosterone to
regulate electrolyte balance, extracellular osmolarity
and blood pressure.
Institutes of Molecular
Medicine and Experimental
Immunology (IMMEI),
Rheinische Friedrich-
Sigmund-Freud-Str. 25,
53105 Bonn, Germany.
III. Medizinische Klinik,
Martinistrasse 52,
20246 Hamburg, Germany.
Medizinische Klinik und
Poliklinik IV, Ludwig-
Maximilians Universität
München, Ziemssenstr. 1,
80336 München, Germany.
Clinical Institute of Pathology,
Medical University of Vienna,
Währinger Gürtel 18–20,
A-1090 Vienna, Austria.
hjanders@med.uni-; andrew.rees@
All authors contributed
equally to this work.
Published online
16 September 2013
The immune system and kidney
disease: basic concepts and clinical
Christian Kurts
, Ulf Panzer
, Hans-Joachim Anders
and Andrew J.Rees
Abstract | The kidneys are frequently targeted by pathogenic immune responses against
renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in
rodent models and humans have uncovered several underlying mechanisms that can be
used to explain the previously enigmatic immunopathology of many kidney diseases. These
mechanisms include kidney-specific damage-associated molecular patterns that cause
sterile inflammation, the crosstalk between renal dendritic cells and Tcells, the development
of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens.
Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction,
systemic inflammation and immunodeficiency that contribute to the morbidity and mortality
of patients with kidney disease. In this Review, we summarize the recent findings regarding
the interactions between the kidneys and the immune system.
Nature Reviews Immunology
AOP, published online 16 September 2013; doi:10.1038/nri3523
© 2013 Macmillan Publishers Limited. All rights reserved
Page 1
Anatomically and functionally
independent kidney units that
each consist of one glomerulus
and one tubule. The nephron
delivers urine into collecting
ducts that empty into the renal
pelvis and, through the ureters,
into the urinary bladder.
An anatomical structure that
is located in the kidney cortex
and that filters blood into the
tubular system.
The space between the tubuli
and glomeruli, which contains
capillaries, fibroblasts and
dendritic cells, and thus
is an important site for the
progression of nephritis.
Bacterial pyelonephritis
A bacterial infection of the
kidney, mostly due to
uropathogenic Escherichiacoli
that ascend through the
urethra, bladder and ureter
into the kidneys.
Under homeostatic conditions, the resident
immune cells of the kidneys include dendritic cells
(DCs) and macrophages, as well as a few lympho-
. DCs are restricted to the tubulointerstitium and
are absent from the glomeruli
. In mice, kidney DCs
are CD11c
have a transcriptome that is typical of DCs resident
in various non-lymphoid tissues
. Kidney DCs are
derived from monocytes and from common DC pre-
cursors (CDPs), but in contrast with other organs,
some CDP-derived kidney DCs express CD64 (also
known asFcγRI)
. Kidney DCs function as sentinels
in homeostasis, local injury and infection
. They rap-
idly produce neutrophil-recruiting chemokines dur-
ing bacterial pyelonephritis, which is the most prevalent
kidney infection
. Neutrophils can also be recruited by
tubular epithelial cells, but not as quickly as by DCs.
Mice lacking expression of CX
C-chemokine recep-
tor1 (CX
CR1) have a selective reduction in kidney
DC numbers
. There is also a high renal expression of
its ligand CX
C-chemokine ligand 1 (CX
, which
suggests that the CX
CL1 chemokine pair
are important for DC recruitment to the kidney and
that CX
CR1 might be a specific therapeutic target to
modulate DC numbers in the kidneys. In renal ischae-
mia (which is relevant in kidney transplantation) and
in ureteral obstruction, renal DCs promote tissue
injury by producing pro-inflammatory cytokines
Basic leucine zipper transcriptional factor ATF-like3
(BATF3)-dependent CD103
tissue DCs, which can
cross-present antigens to CD8
Tcells, are rare and
their function in the kidney is unclear
. Macrophages
are preferentially found in the renal medulla and cap-
and have homeostatic and repair functions
There are also mast cells in the kidney tubulointer-
stitium but their function is poorly understood
In addition, the role of innate-like lymphocytes is
currently unclear. Finally, the renal lymph nodes rep-
resent a priming site for nephritogenic Tcells during
renal inflammation
Low-molecular-mass proteins can pass through the
glomerular filter but are reabsorbed and degraded by
tubular epithelial cells. However, some of these proteins
are captured by renal DCs or reach the renal lymph
nodes by lymphatic drainage within seconds after filtra-
. Importantly, filtered proteins are concentrated in
Box 1 | Basic kidney anatomy and physiology
The kidneys purify toxic metabolic waste products from the blood in several hundred thousand functionally
independent units called nephrons. A nephron consists of one glomerulus and one double hairpin-shaped tubule
that drains the filtrate into the renal pelvis. The glomeruli located in the kidney cortex are bordered by the Bowman’s
capsule. They are lined with parietal epithelial cells and contain the mesangium with many capillaries to filter the
blood. The glomerular filtration barrier consists of endothelial cells, the glomerular basement membrane and visceral
epithelial cells (also known as podocytes). All molecules below the molecular size of albumin (that is, 68 kDa) pass
the filter and enter the tubule, which consists of the proximal convoluted tubule, the loop of Henle and the distal
convoluted tubule. An intricate countercurrent system forms a high osmotic gradient in the renal medulla that
concentrates the filtrate. The tubular epithelial cells reabsorb water, small proteins, amino acids, carbohydrates
and electrolytes, thereby regulating plasma osmolality, extracellular volume, blood pressure and acid–base and
electrolyte balance. Non-reabsorbed compounds pass from the tubular system into the collecting ducts to form
urine. The space between the tubules is called the interstitium and contains most
of the intrarenal immune system, which mainly consists of dendritic cells,
but also of macrophages and fibroblasts.
Nature Reviews | Immunology
Bowman’s capsule
Loop of
© 2013 Macmillan Publishers Limited. All rights reserved
Page 2
Hairpin-like structures that
receive filtered blood. The
tubular epithelium reabsorbs
water, electrolytes, nutrients
and proteins. Each nephron
has a single tubule, which
defines proximal and distal
tubules as parts of the
Chronic kidney disease
(CKD). Chronic (and often
progressive) impairment of
renal functions, such as blood
purification, barrier function
of the glomerular filter, water,
electrolyte and acid–base
homeostasis, endocrine
functions such as vitaminD
processing, erythropoietin
production and blood pressure
End-stage chronic kidney
disease, the treatment of
which requires dialysis or
kidney transplantation.
A heterogeneous group of
immune-mediated kidney
diseases that initiate in the
A visceral epithelial cell
that covers the glomerular
capillaries in the Bowman’s
capsule. Podocytes are a
component of the glomerular
filtration barrier.
Monocyte-derived collagen-
producing cells that have been
suggested to contribute to
kidney fibrosis.
Kidney fibrosis
The end stage of chronic kidney
disease, when functional renal
tissue has been replaced by
fibrotic scar tissue and is usually
accompanied by uraemia.
the kidney proximal tubules, where >85% of the fluid is
reabsorbed. Thus, renal DCs and the renal lymph nodes
receive low-molecular-mass antigens from the circulation
at concentrations that are over tenfold higher than in any
other tissue. BATF3-dependent DCs in the renal lymph
nodes capture and cross-present these proteins to CD8
Tcells, which results in the programmed cell death1
ligand 1 (PDL1)-mediated deletion of these Tcells
Thus, the renal lymph nodes have a special role in the
development of immune tolerance against circulating
innocuous low-molecular-mass proteins, such as food
antigens and hormones.
Immune-mediated kidney disease
The kidneys are a frequent target of systemic immune and
autoimmune disorders, including systemic autoimmunity
and vasculitis, immune complex-related serum sickness
and complement disorders. This is partly related to the
size-selective and charge-dependent filtration process in
the glomeruli that promotes glomerular immune com-
plex deposition. In addition, immune responses against
kidney-derived autoantigens can cause autoimmune
kidney diseases.
In chronic kidney disease (CKD), low-molecular-
mass compounds accumulate in the body, which causes
uraemia. CKD affects approximately 10% of the Western
population and is a serious social and economic burden,
especially for those who progress to kidney failure and
that require dialysis or transplantation. The tissue injury
associated with CKD is commonly directly or indirectly
caused by the immune system (BOX2).
Direct immune-mediated injury often affects the glo-
meruli, at least initially, which causes different forms of
glomerulonephritis. Irreversible kidney damage occurs
when inflammation spreads to the tubulointerstitium
Various mechanisms that cause this spreading have been
proposed: podocyte damage might facilitate leakage of the
glomerular filtrate and detachment of tubular cells from
their basement membrane
; destruction of glomerular
capillaries might restrict the perfusion of their downstream
tubulointerstitial capillaries and cause ischaemia
; pro-
inflammatory cytokines from inflamed glomeruli might
perfuse the tubulointerstitial capillaries and cause inflam-
; reabsorption of abnormal amounts of protein
from the glomerular filtrate might induce stress responses
in tubular epithelial cells
; and glomerular antigens might
reach DCs in the adjacent tubulointerstitium, which in
turn might stimulate infiltrating Tcells to produce pro-
inflammatory cytokines
. Tubulointerstitial mono nuclear
cell infiltrates can contribute to continuing immuno-
pathology and to progressive tissue remodelling, which lead
to tubular atrophy and interstitial scarring, both by main-
taining local chronic inflammation and by recruiting fibro-
. The end state of CKD is kidney fibrosis — a state in
which functional nephrons are replaced by fibrotictissue.
Immune-mediated CKD can be induced by immune
complex deposition, by innate immunity and by Tcells
that interact with kidney-resident immune cells.
Importantly, these immune mechanisms generally con-
tribute to the progression of CKD, even in non-immune-
initiated forms of the disease, and therefore there are
obvious implications for therapy.
Box 2 | Kidney disorders grouped by their involvement in immunity
Kidney disorders that are initiated and mainly mediated by an immune response
•Renal infections with renotrophic pathogens, including uropathogenic Escherichia coli (UPEC), Hantan virus, BK virus,
Leptospira spp., Mycobacterium tuberculosis and HIV
•Extrarenal infections with renal manifestations, including septic kidney injury, immune complex-mediated nephritis
(for example, post-infectious glomerulonephritis and endocarditis, hepatitis and virus-related immune complex
glomerulonephritis), interstitial nephritis and HIV nephropathy
•Systemic autoimmunity against ubiquitous antigens with renal inflammation, including IgA nephropathy or Henoch–
Schönlein purpura, lupus nephritis, Sjögren’s syndrome, anti-neutrophil cytoplasmic antibody (ANCA)-associated
vasculitis, interstitial nephritis, secondary membranous nephropathy and antibody-mediated forms of atypical
haemolytic uraemic syndrome (aHUS)
•Immune responses against renal antigens, including anti-glomerular basement membrane (anti-GBM) autoimmune
disease, the autoimmune disease primary membranous nephropathy and allograft rejection
•Other systemic disorders that affect the kidneys and that have genetic (including, complement C3 glomerulonephritis
and aHUS) or unclear (including, minimal change disease and renal sarcoidosis) causes
Kidney disorders that involve renal inflammation as a secondary mechanism
•Systemic autoimmunity against ubiquitous antigens with renal manifestations causing renal vascular obstruction
and ischaemia, including scleroderma renal crisis, panarteritis nodosa, giant cell vasculitis or phospholipid antibody
•Other systemic disorders that affect the kidney, including genetic disorders such as hereditary defects of GBM or
podocyte genes leading to focal segmental glomerulosclerosis and hereditary tubulopathies or polycystic disorders;
disorders driven by toxins, including Shiga toxin-producing Escherichia coli-induced HUS, drug- or contrast
media-induced kidney injury; crystal and paraprotein-related nephropathies; and disorders caused by metals or
food-borne toxins and toxic forms of focal segmental glomerulosclerosis
•Disorders that affect haemodynamics and the vascular system can also affect the kidney, including atherosclerosis,
embolism, macro- or microvascular stenosis, shock, hepato-renal syndrome, thrombotic microangiopathy, eclampsia,
hyperfiltration-associated focal segmental glomerulosclerosis, global glomerulosclerosis
•Obstructive nephropathy or renal amyloidosis
© 2013 Macmillan Publishers Limited. All rights reserved
Page 3
Nature Reviews | Immunology
Toxins, ischaemia and trauma
renal cell
Dendritic cell Endothelial cell Tubular epithelial cellPodocyte
Macrophage Mesangial cell
Type I IFNs, CXCL2,
IL-1β and IL-12
Acute kidney injury
and infections
TNF, IL-6, chemokines
and IFNα
IC-GN, diabetes and
TNF, IL-6 and
Most glomerular
TNF, IL-6 and
Acute kidney injury
and late-stage GN
ROS, IL-1β,
TNF, IL-6 and
Most kidney
TNF, IL-6,
and IFNα
diabetes and
An intracellular complex
containing pattern recognition
receptors that activate
caspase1. Caspase 1
activation induces pyroptotic
cell death and interleukin-1β
(IL-1β) and IL-18 secretion.
Innate immune responses in CKD. Clinical entities of kid-
ney disease, such as post-ischemic and toxic acute kidney
injury, as well as nephropathies that are induced by dia-
betes, hypertension and crystal deposition, involve sterile
inflammation. As in other organs, sterile renal inflamma-
tion is induced by intrinsic damage-associated molecular
patterns (DAMPs) that are either released from dying
parenchymal cells or that are generated during extracellu-
lar matrix remodelling
. The kidney hosts a large range
of different parenchymal cell types, including tubular
epithelial cells, and endothelial cells that express a subset
of Toll-like receptors (TLRs; that is, TLR1 to TLR6) and
inflammasome components, which suggests that these cells
can respond to DAMPs and that they can induce innate
immune responses and subsequent renal inflammation
However, NLRP3 (NOD-, LRR- and pyrin domain-con-
taining 3) inflammasome activation is limited to renal
mononuclear phagocytes. The resulting inflammation
depends on the nature of the stimulus (whether it is tran-
sient, repetitive or persistent) and the renal compartment
that is affected (FIG.1); for example, glomerular deposi-
tion of antibodies or immune complexes and the activa-
tion of complement and Fc receptor signalling drives the
several forms of immune complex glomerulonephritis
that have been described (BOX2; see below).
By contrast, ischaemia, toxins, crystals and urinary
outflow obstruction target the tubulointerstitial com-
partment, in which they drive sterile inflammation.
Renal tubular epithelial cells are highly susceptible to
intrinsic oxidative stress because of their high reabsorp-
tive and secretory activity and because their capillary
network is downstream of the glomerular capillaries,
which renders the medullary part of the tubulointer-
stitium susceptible to hypoxia, as occurs during renal
hypoperfusion and shock. During sepsis and ischae-
mia–reperfusion injury, necrotic tubular cells and
neutrophils release high-mobility group box1 protein
(HMGB1), histones, heat-shock proteins, hyaluronan,
fibronectin, biglycan and other DAMPs that activate
TLR2 and TLR4 on renal parenchymal cells and renal
DCs. Renal parenchymal cells and DCs then secrete
chemokines that promote an acute neutrophil-dependent
inflammatory response that mainly contributes to acute
kidney injury
. Another important DAMP is ATP
that triggers sterile inflammation in the kidneys via
the NLRP3 inflammasome
. By contrast, adenosine
receptor A2a signalling inactivates DCs and abrogates
kidney injury
. The DAMP Tcell immunoglobulin
and mucin domain-containing protein1 (TIM1; also
known as kidney injury molecule 1) is induced on the
Figure 1 | Innate immune mechanisms in kidney inflammation. Renal cell necrosis or programmed forms of
inflammatory cell death release damage-associated molecular patterns (DAMPs) into the extracellular space, where
they activate pattern recognition receptors (PRRs). Renal dendritic cells and macrophages express numerous PRRs,
whereas PRR expression is limited on renal non-immune cells. PRR ligation activates the cell, which results in cell
type-specific consequences, such as the secretion of pro-inflammatory mediators that promote renal
immunopathology. In the glomerulus, PRR activation in mesangial cells also stimulates their proliferation, for example,
in mesangioproliferative forms of glomerulonephritis such as lupus nephritis, IgA nephropathy and hepatitis C
virus-associated glomerulonephritis. PRR activation of endothelial and epithelial cells (including podocytes and
tubular epithelial cells) in the glomerulus increases their permeability, which results in proteinuria, a clinically useful
biomarker of glomerular vascular permeability, inflammation and damage. Moreover, the activation of endothelial and
epithelial cells manifests as interstitial oedema and secretory dysfunction, for example, in septic acute kidney injury.
CXCL2, CXC-chemokine ligand 2; GN, glomerulonephritis; HUS, haemolytic uraemic syndrome; IC-GN, immune
complex glomerulonephritis; IFN, interferon; IL, interleukin; ROS, reactive oxygen species; TNF, tumour necrosis factor.
© 2013 Macmillan Publishers Limited. All rights reserved
Page 4
Haemolytic uraemic
(HUS). A group of diseases,
which are induced by infection
with Shiga toxin-producing
bacteria, or by genetic or
acquired defects in
complement regulators,
that are characterized by
microvascular injury and
thrombosis, which results
in haemolytic anaemia,
thrombocytopenia and
organ dysfunction (kidney
and often brain).
thrombocytopenic purpura
(TTP). A rare life-threatening
disease, characterized by the
development of platelet
thrombi and microvascular
injury, which results from either
genetic or acquired defects of
the enzyme a disintegrin and
metalloproteinase with
thrombospondin motifs 13
(ADAMTS13), which has a
unique role in the homeostasis
of the coagulation system.
surface of tubular epithelial cells and binds to CD300b
(also known as CLM7) on myeloid cells, which drives
neutrophil recruitment to the post-ischemic kidney
The initial inflammatory response is amplified by infil-
trating neutrophils and later by LY6C
which results in acute kidney injury. The cellular
pathophysiology of ischemic acute kidney injury has
recently been reviewed by others
Tubular cells are especially sensitive to the freely
filtered low-molecular-mass toxins that they reabsorb
from the tubular fluid. These toxins can accumu-
late and induce tubular cell necrosis and subsequent
TLR4-mediated tubulointerstitial inflammation
. The
high osmolarity and varying pH of urine promotes the
crystallization of small filtered molecules, such as uric
acid, calcium oxalate, calcium phosphate, myoglobin
and free immunoglobulin light chains in the tubules. The
crystals obstruct the tubules and directly injure the epi-
thelial cells that line them, which indirectly causes sterile
inflammation; examples of such crystalline nephropa-
thies include kidney stone disease, oxalate nephropathy,
acute urate nephropathy, adenine nephropathy, cysti-
nosis, rhabdomyolysis-induced acute kidney injury and
myeloma-associated cast nephropathy. A recently dis-
covered pathological mechanism of sterile renal inflam-
mation is that crystals that reach the tubulointerstitial
compartment can directly induce inflammation by
activating the NLRP3 inflammasome in renal DCs
In addition, urinary outflow obstruction causes renal
sterile inflammation through multiple mechanisms. It
remains to be clarified which kidney diseases will ben-
efit most from selective therapeutic blockade of these
aforementioned innate immune pathways. Persistent
renal inflammation is usually associated with epithelial
atrophy and aberrant mesenchymal cell repair, which is
known as glomerulosclerosis or interstitial fibrosis. The
direct contribution of innate immune responses to pro-
gressive fibrosis remains an area of debate
. In addi-
tion, NLRP3 has inflammasome-independent effects
in the tubular epithelium; for example, NLRP3 and
the adaptor molecule ASC are needed for SMAD2 and
SMAD3 phosphorylation in response to transforming
growth factor-β receptor1 (TGFβR1) signalling
. As
TGFβR1 signalling is an essential pathway for epithe-
lial–mesenchymal transition and renal fibrosis, this non-
canonical effect of NLRP3 contributes to renal scarring.
Whether this process also contributes to other forms of
CKD remains to be studied.
Uromodulin (also known as Tamm–Horsfall pro-
tein) is a kidney-specific molecule that is synthesized
by epithelial cells in the distal tubules and that is selec-
tively released into the tubular lumen. Uromodulin is
an adherent polymer that binds to particles, pathogens,
crystals and cytokines in the urine and facilitates their
elimination. Uromodulin deficiency aggravates uri-
nary tract infections, crystal aggregation and cytokine-
mediated luminal inflammation in the kidneys
Uromodulin leaks into the interstitium after tubular
injury and activates intrarenal DCs and blood monocytes
via TLR4 and the NLRP3 inflammasome in a DAMP-
like manner
. This provides another example of
endogenous molecules that function as immunostimula-
tory danger signals when they escape their normal physi-
ological compartment; uromodulin may also contribute
to the systemic inflammation associated withCKD.
Taken together, these findings show that non-infec-
tious triggers induce innate immune responses in the
kidney that can cause inappropriate immunopathol-
ogy. Distinct immune pathways contribute to certain
types of renal sterile inflammation such as the NLRP3
inflammasome in crystalline nephropathies. It remains
necessary to identify the predominant pathways in each
of the many different kidney diseases. Furthermore, the
non-canonical function of NLRP3 during TGFβ1R sig-
nalling that was first described in kidney disease not
only awaits validation in systemic immune regula-
tion but also deserves further study in different renal
epithelial celltypes.
Complement dysregulation and CKD. Recent advances
in complement biology have led to the reclassifica-
tion of glomerular diseases that are characterized by
complement deposition in the absence of concomitant
antibody deposition
. Complement C3 glomerulopa-
thies are caused by spontaneous and uncontrolled acti-
vation of the alternative complement pathway because
of mutations in the components or the molecules that
regulate it, such as factor B, factor H, factor I, mem-
brane cofactor protein and factor H-related proteins
An autoimmune variant of C3 glomerulopathy is medi-
ated by an autoantibody (known as C3 nephritic factor)
that is specific for C3 convertase. C3 nephritic factor
stabilizes the C3 convertase, which leads to unrestrained
complement activation and the subsequent deposition
of C3 in the kidneys, which is accompanied by variable
pathomorphological findings (most often membrano-
proliferative changes). The importance of recognizing
C3 glomerulopathies as a separate clinical entity is
emphasized by initial reports that indicate the effec-
tiveness of treatment with the C5 inhibitor eculizumab
(Soliris; Alexion Pharmaceuticals)
Thrombotic microangiopathy (TMA) is character-
ized by microvascular injury and thrombosis, which
results in haemolytic anaemia with erythrocyte frag-
mentation, thrombocytopenia and organ dysfunc-
tion. The kidney and brain are primarily affected by
this disease and the functional impairment in these
organs mainly determines the outcome of the patients.
The classification, pathogenesis and treatment strate-
gies of TMA remain controversial. Three major types of
TMA are commonly identified: two forms of haemolytic
uraemic syndrome (HUS), including Shiga toxin-
producing Escherichia coli-induced HUS (STEC-HUS)
and atypical HUS (aHUS), as well as thrombotic thrombo-
cytopenic purpura (TTP). Recent studies have improved
our knowledge of all three groups of disease.
Infection with Shiga toxin-producing E.coli, which
cause haemorrhagic enteritis, is the most common cause
of HUS in children. After translocation across the intes-
tinal epithelium, the Shiga toxin is transported in the cir-
culation by poorly defined mechanisms to capillary beds
in target organs. In the kidneys, Shiga toxin binds to the
© 2013 Macmillan Publishers Limited. All rights reserved
Page 5
Anti-neutrophil cytoplasmic
(ANCA). An autoantibody
that is commonly found in
pauci-immune focal necrotizing
A rapidly progressive
form of glomerulonephritis
characterized by the
hyperproliferation of parietal
epithelial cells, which is driven
by Tcell and macrophage
infiltrates and by plasma
components leaking through
the glomerular filter.
(DTH). An inappropriate
Tcell-initiated response to
self or foreign antigens that is
carried out by macrophages,
eosinophils or cytotoxic Tcells.
glycolipid receptor globotriaosylceramide (Gb3), which is
highly expressed on the glomerular endothelium, thereby
initiating the events that are responsible for microvascular
cell injury. Shiga toxin directly induces the expression of
P-selectin on human endothelial cells, and P-selectin then
binds to and activates complement C3 via the alternative
complement pathway, which leads to thrombus forma-
tion in the microvasculature
. This can be prevented
by treatment with a C3a receptor antagonist in a mouse
model of STEC-HUS
. Children with STEC-HUS have
complement hyperactivation
, and early reports docu-
ment marked improvement in small numbers of patients
shortly after treatment with eculizumab
. This is sup-
ported by a clinical study that used eculizumab during
the major STEC-HUS outbreak in northern Germany in
2011 (R.A.K.Stahl, personal communication).
Complement is also central to the pathogenesis of
aHUS, which is a rare group of disorders that includes
sporadic and familial diseases and that is often caused
by uncontrolled complement activation as a result of
innate or acquired defects in the regulatory components
of the complement system. In particular, mutations in
the genes that encode factor H, membrane cofactor pro-
tein, factorI and thrombomodulin have a crucial role
in aHUS
. Interesting